13.13 Product Class 13: 1,2,3-Triazoles - stuba.skszolcsanyi/education/files/Chemia... · 2012. 11. 6. · 418 Science of Synthesis 13.13 1,2,3-Triazoles A. C. Tom, Section 13.13,

b13.13 Product Class 13:

1,2,3-Triazoles

A. C. Tom�

General Introduction

Previously published information regarding this product class can be found in Houben–Weyl, Vol. E 8d, pp 305–405 (1,2,3-triazoles)[1] and pp 406–478 (benzotriazoles).[2] Other im-portant reviews on the chemistry of 1,2,3-triazoles and their benzo derivatives are alsoavailable.[3–9]

1,2,3-Triazoles and benzotriazoles are important types of heterocyclic compounds.They find numerous applications in industry, namely as dyestuffs, fluorescent whiteners,photostabilizers of polymers, optical brightening agents, corrosion inhibitors and as pho-tographic photoreceptors.[6,7] Also, due to their extensive biological activities, they findsuccessful application in medicine and as agrochemicals.[6,7] Beyond this, these com-pounds are intensively studied by many research groups due to their theoretical interestand synthetic usefulness.

The 1,2,3-triazoles can be divided in three main groups: monocyclic 1,2,3-triazoles,benzotriazoles, and 1,2,3-triazolium salts. As indicated in Scheme 1, for monocyclic1,2,3-triazoles three subclasses can be recognized, depending on the position of the sub-stituents in the ring. While 1H- and 2H-1,2,3-triazoles are aromatic compounds their 4H-isomers are not. This fact is reflected in the abundance of examples of 1H- and 2H-1,2,3-triazoles and the rarity of 4H-1,2,3-triazoles.[3] In the literature, the 1,2,3-triazole system issometimes named as “v-triazole” in order to distinguish it from “s-triazole”, the 1,2,4-tri-azole system.

Scheme 1 Classes of 1,2,3-Triazoles

1H-1,2,3-triazoles

N

NN

R1

R1

1

5

4 3

2

2H-1,2,3-triazoles

N

NNR1

R1

R1

1

5

4 3

2

4H-1,2,3-triazoles

N

NNR1

1

5

4 3

2

R1

R1

R1

1H-benzotriazoles

1

5

4 3

2

NN

N

6

7

2H-benzotriazoles

1

5

4 3

2NNR1

N

6

7R1

1

2

NNR1

N

1,2,3-triazolium salts

N

NNR1

R1

R1

1

2NR1

NN

R1

R1

1

2

benzotriazolium salts

+ ++

1

2

NN

R1

N

+

R1 R1 R1 R1

415

for references see p 587

A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG

FOR PERSONAL USE ONLY

bN-Unsubstituted 1,2,3-triazoles can be regarded either as 1H- or as 2H-derivatives sincethese two tautomeric forms are in equilibrium, both in solution and in the gas phase(Scheme 2). In this article, for simplification, this type of compound will be representedas 1H-triazoles, independently of the predominant tautomer.

Scheme 2 Tautomerism in 1,2,3-Triazoles

1

2

N

NH

N

1

2N

NNH

1H-1,2,3-triazole 2H-1,2,3-triazole

1

2

1H-benzotriazole 2H-benzotriazole

NH

NN

NNH

N

1

2

The two tautomeric forms of 1,2,3-triazole and benzotriazole are in equilibrium, both insolution and in the gas phase (Scheme 2). However there is an extraordinary difference instability between 1,2,3-triazole and benzotriazole tautomers. In the gas phase, the 2H-tau-tomer of 1,2,3-triazole represents more than 99.9% of the equilibrium mixture, whereasin benzotriazole the 1H-tautomer is the predominant one (more than 99.99% at equilibri-um).[10] In solution, the much higher dipole moment of 1H-tautomers favor these struc-tures and, as a consequence, mixtures of 1H- and 2H-1,2,3-triazole are observed in solu-tion whereas the higher stability of 1H-benzotriazole is reinforced.[10] In the solid state,1,2,3-triazole exists as a 1:1 mixture of 1H- and 2H-tautomers, while 4-phenyl-1,2,3-tria-zole and 4-nitro-1,2,3-triazole are, respectively, in the 2H- and 1H- tautomeric forms.[11]

The experimental dipole moment in benzene for the tautomeric mixture of 1H- and 2H-1,2,3-triazole is 1.85 D at 25 8C and 2.08 D at 45 8C. The experimental dipole moments areas follows: 1H-1,2,3-triazole 4.38 D, 2H-1,2,3-triazole 0.22 D, 1H-benzotriazole 4.15 D, and2-methyl-2H-benzotriazole 0.49 D.[7]

1H-1,2,3-Triazole is both a weak base (pKa 1.17) and a weak acid (pKa 9.4) of compara-ble strength to phenol. 1H-1,2,3-Triazole-4,5-dicarbonitrile (pKa 2.53), 4,5-dibromo-1H-1,2,3-triazole (pKa 5.37), and 4-nitro-1H-1,2,3-triazole (pKa 4.80) are much more acidic com-pounds. 1-Methyl-1H-1,2,3-triazole (pKa 1.25) shows a basicity comparable to 1H-1,2,3-tria-zole, but 2-methyl-2H-1,2,3-triazole is a much weaker base.[12–14] The basicity of N-unsub-stituted and N-methyl-1,2,3-triazoles in the gas phase, in solution, and in the solid statehas been determined.[11] The fused benzene ring in benzotriazole (pKa 8.2) is base-weaken-ing and acid-strengthening. Substitution of hydrogen atoms by chlorine in the benzenering results in increased acidity: 5-chlorobenzotriazole, pKa 7.7; 4,5,6,7-tetrachlorobenzo-triazole, pKa 5.5.[15,16]

The application of semi-empirical and ab initio methods in theoretical calculationsfor 1,2,3-triazoles and benzotriazoles and the description of a number of instrumentaltechniques used in the characterization of these systems have been reviewed.[7]

1,2,3-Triazoles with a strong electron-withdrawing group at N1 (e.g., cyano, nitro, orarylsulfonyl groups) undergo ready and reversible ring opening to Æ-diazoimine tauto-mers (Scheme 3). This ring–chain tautomerism, also observed in some benzotriazole de-rivatives, is markedly temperature dependent.[17–20]

416 Science of Synthesis 13.13 1,2,3-Triazoles



bScheme 3 Ring–Chain Tautomerism in 1,2,3-Triazoles and Benzotriazoles

N

NX

NR1

R2

R1 NX

R2 N2

X = CN, SO2Ar1

X = CN, SO2Ar1, NO2

NX

NN N2

NX

This type of tautomerism is also involved, for example, in the interconversion of 1-aryl-1,2,3-triazol-5-amines and 5-anilino-1,2,3-triazoles (R1 = aryl) (Scheme 4). This isomeriza-tion is known as the Dimroth rearrangement. It is also observed in the interconversionof triazoles with other substituents at position 5 (or 4) and in the conversion of 1,2,3-tri-azoles into other ring systems. The equilibrium is established thermally, but its positionis influenced by the basicity of the solvent. In pyridine, for example, the equilibrium po-sition is shifted to the more acidic NH triazoles. It is also observed that electron-withdraw-ing groups and large, rigid groups tend to favor the exocyclic nitrogen while alkyl groupstend to favor the cyclic nitrogen. This subject has been reviewed.[21]

Scheme 4 Dimroth Rearrangement in 1,2,3-Triazoles

R1 = Me

N

NN

R2

H2N

R1 H2N NR1

R2 N2

R1HN NH

R2 N2 N

NH

N

R2

R1HN R1 = aryl

In terms of stability, monocyclic 1,2,3-triazoles and benzotriazoles are remarkably stablecompounds. The triazole ring is not normally cleaved by hydrolysis or oxidation and re-ductive cleavage only occurs under forcing conditions. The presence of substituents thathave a destabilizing effect on the ring system can facilitate the cleavage. When subjectedto pyrolysis or photolysis, 1,2,3-triazoles and benzotriazoles extrude nitrogen and pro-duce very reactive species which react further to form a range of stable compounds: ni-triles, ketenimines, azirines, pyrazines, indoles, etc. The thermal or photochemical extru-sion of nitrogen from 1-arylbenzotriazoles leads to the formation of carbazoles (Scheme5).

General Introduction 417




bScheme 5 Photolysis of 5-Chloro-1-(4-chlorophenyl)-1H-benzotriazole

NN

N

Cl

Cl

Cl

N

Cl

NH

Cl Cl

MeCN, hν

− N2

•

•

Both monocyclic 1,2,3-triazoles and benzotriazoles are readily alkylated on nitrogen byalkyl halides, dimethyl sulfate, diazoalkanes, methyl sulfonates, and other alkylatingagents; generally mixtures of all possible N-alkyl isomers are obtained. With more reac-tive reagents, or under forcing reaction conditions, triazolium salts are obtained. N-Aryla-tion is also possible if activated aryl halides are used. 1,2,3-Triazoles and benzotriazolesalso react with acyl halides and anhydrides to furnish the corresponding N-acyl deriva-tives. These compounds also react with sulfonyl chlorides, isocyanates, chlorotrimethyl-silane, etc. to give the corresponding N-substituted derivatives. Electrophilic substitutionat CH positions is also possible: halogenation and nitration are examples of such transfor-mations. Lithiation of triazoles followed by addition of electrophilic reagents is anotherversatile approach to functionalization of these compounds at CH positions. Triazoles canalso be activated toward electrophiles by introduction of an N-oxide group.

All these types of reactions, and many others that produce new 1,2,3-triazole deriva-tives, are described in this section. Also, the synthetic methods available for the construc-tion of the 1,2,3-triazole ring are reviewed.

13.13.1 Product Subclass 1:Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles

13.13.1.1 Synthesis by Ring-Closure Reactions

13.13.1.1.1 By Formation of One N-N and One N-C Bond

13.13.1.1.1.1 Fragments C-C-N-N and N

13.13.1.1.1.1.1 Method 1:From 2-Diazo-1,3-dicarbonyl Compounds and Amine Derivatives

The cyclocondensation reaction of 2-diazo-1,3-dicarbonyl compounds with amine deriva-tives is an old but versatile, simple, and completely regioselective method for the prepa-ration of 1H-1,2,3-triazoles. This method was developed by Wolff at the beginning of the20th century; he reported the synthesis of triazoles 3 by the reaction of ethyl 2-diazo-3-oxobutanoate (1) with phenylhydrazine, semicarbazide, hydroxylamine, aniline, or am-monia (Scheme 6).[22,23,246] The mechanism of the reaction involves the in situ formationof Æ-diazoimines of type 2 followed by ring closure. Several variations of this method ap-peared since then and a range of 2-diazo-1,3-dicarbonyl compounds can be used: Æ-diazo-�-oxo esters, Æ-diazo-�-formyl esters, Æ-diazo-�-oxoaldehydes, diazomalonaldehyde, anddiazomalonates.




bScheme 6 Reaction of Ethyl 2-Diazo-3-oxobutanoate with Amine Derivatives[22–24,246]

ZNH2 N

NZ

N

EtO2C

3

N2

O

EtO

O

1

N2

O

EtO

NZ

2

Z = H, Ph, NHPh, OH, NHCONH2

The 1H-1,2,3-triazol-1-ol 3 (Z = OH) is obtained in 53% yield by reaction of 1 with an excessof hydroxylamine (EtOH/H2O 1:1, 80 8C, 5 h).[24]

The method described by Wolff can be extended to Æ-diazo-�-oxo esters with bulkysubstituents. For example, the 5-(1-adamantyl)-1H-1,2,3-triazoles 5 are prepared by the re-action of the diazo compound 4 with aniline and methylamine, respectively (Scheme7).[25] In this case titanium(IV) chloride is used as catalyst to promote the formation ofthe intermediate imine and thus facilitate the formation of the triazole.

Scheme 7 Reaction of Ethyl 3-(1-Adamantyl)-2-diazo-3-oxopropanoate with Amines[25]

N

NN

EtO2C

5

N2

O

EtO

O

4

+ R1NH2

TlCl4, ClCl

reflux, 15 h

R1R1 = Ph 74%

R1 = Me 51%

Ethyl 5-(1-Adamantyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylate (5, R1 = Ph);Typical Procedure:[25]

A soln of 4 (28 mg, 0.1 mmol), PhNH2 (13 mg, 0.14 mmol), and TiCl4 (19 mg, 0.1 mmol) indry 1,2-dichloroethane (2 mL) was refluxed for 15 h, and the resulting mixture was basi-fied with 1 M NaOH (1 mL). After adding Et2O/H2O (1:1, 10 mL) and shaking, the organiclayer was separated, washed with H2O and dried (Na2SO4). Evaporation of the solvent lefta residue, which was chromatographed to give 5 (R1 = Ph) as crystals; yield: 26 mg (74%);mp 134–138 8C.

13.13.1.1.1.1.1.1 Variation 1:From 2-Diazo-3-oxopropanoates and Amine Derivatives

Ethyl 2-diazo-3-oxopropanoate (6) reacts with a range of amine derivatives to give the cor-responding triazoles 7 (R1 = H, alkyl, aryl, OH, NHPh, NHCONH2) (Scheme 8).[26–28] Theyields of the reactions are highly dependent on the amine derivative used. The reactionof compound 6 with 2-aminoethanol gives triazole 7 (R1 = CH2CH2OH), which is used asprecursor to several 1,2,3-triazole-containing antibiotics.[29,30]

13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 419




bScheme 8 Reaction of Ethyl 2-Diazo-3-oxopropanoate with Amine Derivatives[26–28]

N

NN

EtO2C

N2

O

EtO

O

6

+ R1NH2

R1H

7

R1 R1NH2 Conditions Yield (%) Ref

H NH3 AcOH, 100 8C, 3–4 h 50 [27]

H NH2OH H2O, rt, 48 h 7 [27]

NHCONH2 H2NNHCONH2 H2O, rt, 48 h 35 [27]

Ph PhNH2 EtOH, AcOH, rt, 30 min 74 [26]

Ph PhNH2 EtOH, AcOH, rt, 16 h 70 [28]

NH

N

But

NH

NH2N

But

EtOH, AcOH, rt, 16 h 81 [28]

Ethyl 1-Phenyl-1H-1,2,3-triazole-4-carboxylate (7, R1 = Ph); Typical Procedure:[28]

Ethyl 2-diazo-3-oxopropanoate (6; 0.426 g, 3 mmol) was dissolved in EtOH (3 mL). A soln ofPhNH2 (0.27 g, 2.9 mmol) in EtOH (1.8 mL) and AcOH (0.6 mL) was added and the mixturewas stirred at rt for 16 h. On removal of the solvent a solid was obtained, and crystalliza-tion (EtOH) gave white needles of the triazole 7 (R1 = Ph); yield: 0.45 g (70%); mp 86–87 8C.

13.13.1.1.1.1.1.2 Variation 2:From 2-Diazo-3-oxoaldehydes and Amine Derivatives

2-Diazo-3-oxoaldehydes 8 react with anilines, hydroxylamine, or semicarbazide yielding4-acyl-1-substituted 1H-1,2,3-triazoles 9 in moderate to good yields (Scheme 9).[26,27] Theyalso react with ammonia to give N-unsubstituted 1,2,3-triazoles in 20–26% yield. In thecondensations with hydroxylamine and semicarbazide the reaction goes further and theketone functions are converted into oximes and semicarbazones, respectively.[27] A newermethod for the preparation of a wide range of the required 2-diazo-3-oxoaldehydes hasbeen published.[31] Diazomalonaldehyde (8, R1 = H) reacts with aniline hydrochloride, inwater and at room temperature to yield 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (9,R1 = H; R2 = Ph) in 96% yield.[32]

Scheme 9 Reaction of 2-Diazo-3-oxoaldehydes with Amine Derivatives[26–28]

N

NNN2

O

H

O

R1

+ R2NH2

R1 = H, alkyl, aryl; R2 = H, aryl, OH, NHCONH2

8 9

R2

O

R1




bCondensation of 2-Diazo-3-oxoaldehydes with Aniline; General Procedure:[27]

A soln of the 2-diazo-3-oxoaldehyde 8 (10 mmol) in EtOH (6 mL) and a mixture of PhNH2

(10.7 mmol) and AcOH (1.25 mL) were mixed. The mixture was stirred at rt for 30 min. Inmost cases during this time the triazoles precipitated and were obtained pure after recrys-tallization (EtOH). The yields were within the range of 26–87%.

13.13.1.1.1.1.1.3 Variation 3:From Dimethyl Diazomalonate and Amines

Dimethyl diazomalonate (10) undergoes reaction with primary alkylamines to generatethe corresponding primary ammonium salts of methyl 1-alkyl-5-hydroxy-1H-1,2,3-tria-zole-4-carboxylates 12 in 66–98% yield (Scheme 10).[33] The probable mechanism of this re-action involves the formation of the intermediate diazoamide 11, which then undergoesbase-catalyzed cyclization to the 1,2,3-triazole salt 12. Acidification of an aqueous solu-tion of 12 and extraction with dichloromethane gives the free triazolols. However, sincetriazol-5-ols undergo facile isomerization to the corresponding diazoamides, care must betaken during their formation and purification. The major limitation of this reaction is thefact that aromatic amines, e.g. aniline, fail to react. This is consistent with the reducednucleophilicity of the nitrogen in aromatic amines.[33]

Scheme 10 Reaction of Dimethyl Diazomalonate with Amines[33]

N

NNN2

O

MeO

O

MeO R1NH2

10 12

R1

MeO2C

N2

O

MeO

NHR1

O

11

R1NH2

−OR1NH3+

R1 Amine Time (d) Yield (%) mp (8C) Ref

Bu BuNH2 3 82 111–113 [33]

(CH2)4Me Me(CH2)4NH2 5 85 110–113 [33]

(CH2)5Me Me(CH2)5NH2 3 70 120–122 [33]

Cy CyNH2 3 66 154–157 [33]

(CH2)2OH HO(CH2)2NH2 3 98 119–124 [33]

Bn BnNH2 3 84 153–156 [33]

2-thienyl 2-thienylamine 3 67 160–161 [33]

3-thienyl 3-thienylamine 6 72 160–162 [33]

1,2,3-Triazole Salts 12; General Procedure:[33]

Dimethyl diazomalonate (10 mmol) was added to a large excess of the amine and the mix-ture was stirred at rt and monitored by IR spectroscopy until the diazo ester was com-pletely consumed (3–6 d). At this point the resultant salt had crystallized from soln andwas isolated by filtration and recrystallized. Alternatively, the reaction could be per-formed in toluene using 2–5 equiv of amine; yield: 66–98%.





b13.13.1.1.1.1.2 Method 2:

From Vinyldiazonium Salts and Amine Derivatives

Vinyldiazonium salts 13 react with ammonia and amine derivatives (primary amines, hy-drazines, hydroxylamine ethers) to give 1-substituted 1,2,3-triazoles 14 (Scheme 11).[34–36]

A probable mechanism for this reaction is represented in Scheme 11.[36] The reaction ofvinyldiazonium salts 13 with ø,ø¢-diaminoalkanes leads to ø,ø¢-bis(1H-1,2,3-triazol-1-yl)alkanes.[37]

Scheme 11 Reaction of Vinyldiazonium Salts with Amine Derivatives[36]

N

NN

R4NH2

13

R4

R1

− HX

N

R1

R3

R2

N

••

X−

+

N

R1••

NHR4

R2R3

N+

R2

R3

N

NN

R4

R1

14

R5

R5 = R2, R3

− R2H or R3H

−

R1 R2 R3 X R4 R5 Yield (%) Ref

H OEt OEt SbCl6 H OEt 65 [36]

H OEt OEt SbCl6 3-morpholinopropyl OEt 54 [36]

H OEt OEt SbCl6 Cy OEt 62 [36]

H OMe 4-MeOC6H4 SbCl6 furfuryl 4-MeOC6H4 63 [36]

4-O2NC6H4 OEt piperidino SbCl6 H piperidino 48 [36]

4-O2NC6H4 OEt piperidino SbCl6 furfuryl piperidino 80 [36]

4-O2NC6H4 OEt piperidino SbCl6 3-morpholinopropyl piperidino 65 [36]

4-O2NC6H4 OEt piperidino BF4 4-MeOC6H4 OEt 51 [36]

4-O2NC6H4 OEt piperidino BF4 NH2 OEt 24 [36]

2-(Benzoyloxy)alk-1-enediazonium trifluoromethanesulfonates 17 [generated in situ fromthe reaction of Æ-diazo ketones 15 and benzoyl trifluoromethanesulfonate (16)] reactwith isopropylamine to give the corresponding 1-isopropyl-1H-1,2,3-triazoles 18 in highyields (Scheme 12).[38]




bScheme 12 Reaction of 2-(Benzoyloxy)alk-1-enediazonium Trifluoromethanesulfonateswith Isopropylamine[38]

• •

+

N

NN

Pri

R1

18

R1

A: R1 = Me 77%

B: R1 = Ph 80%

R1

O

R1

N2

+ BzOTfOBz

R1

N

R1

N

1715 16

OTf−

A: 1. CH2Cl2, −70 to −50 oC, 2 h

2. iPrNH2, −70 oC to rt, 2 h

B: 1. CH2Cl2, −95 oC, 2 h

2. iPrNH2, −95 oC, 0.5 h; −75 oC, 2 h

1-Isopropyl-4,5-dimethyl-1H-1,2,3-triazole (18, R1 = Me); Typical Procedure:[38]

A soln of benzoyl trifluoromethanesulfonate (5.20 g, 20.4 mmol) in CH2Cl2 (50 mL) wascooled to –70 8C and a soln of 15 (R1 = Me; 2.00 g, 20.4 mmol) in CH2Cl2 (50 mL) was addeddropwise. After the addition, the suspension was stirred at –70 8C for 1 h and at –50 8C for3 h. iPrNH2 (6.00 g, 102 mmol) was gradually added after cooling to –70 8C. A homogene-ous soln was formed and after 2 h at rt it was extracted with H2O (4 �). The organic layerwas dried (MgSO4) and the solvent was removed at 15 Torr. Distillation (90 8C/0.05 Torr, Ku-gelrohr apparatus) gave triazole 18 (R1 = Me); yield: 2.19 g (77%).

13.13.1.1.1.1.3 Method 3:From Dichloro- or Trichloroacetaldehyde Sulfonylhydrazones andPrimary Amines

Tosyl and mesyl hydrazones of dichloroacetaldehyde and trichloroacetaldehyde reactwith ammonia and primary amines to produce 1H-1,2,3-triazoles 20 and 22, respectively,in good yields (Scheme 13).[39,40] This is a much more convenient and secure reaction sys-tem, especially for large-scale production of triazoles, than some alternative methodswhere thermally unstable, or explosive, starting materials are used, namely diazo and azi-do derivatives. For example, 1H-1,2,3-triazole itself can be prepared in 75% yield from thereaction of dichloroacetaldehyde tosylhydrazone (19, X = Ts) with ammonia.[40] The samehydrazone can be converted into 1-benzyl-1H-1,2,3-triazole, 1-phenyl-1H-1,2,3-triazole, or1H-1,2,3-triazol-1-amine in similar yields. These triazoles can also be prepared from themesylhydrazone 19 (X = Ms) in almost the same yields (60–85%). When trichloroacetalde-hyde tosylhydrazone (21) is treated with aqueous ammonia only unidentified materialsare obtained, but the reaction with methylamine or benzylamine gives the 1,5-disubsti-tuted triazoles 22.[39]

Scheme 13 Reaction of Dichloro- and TrichloroacetaldehydeSulfonylhydrazones with Ammonia and Primary Amines[39,40]

R1NH2, MeOH

0−40 oC, 4 h

20

X = Ts, Ms; R1 = H, Ph, Bn, NH2

N

NN

R1H N

HCl

Cl

NHX

19

70−83%





bR1 = Me: MeNH2, MeOH, 0 oC to rt, 19 h

R1 = Bn: BnNH2, MeOH, 0 oC, 2.5 h

22

N

NN

R1H N

ClCl

Cl

NHTs

21

R1 = Me 25%

R1 = Bn 30%

R1HN

Æ,Æ-Dichloro ketone tosylhydrazones can also be used as precursors of 1H-1,2,3-triazoles.For example, 1,1-dichloroacetone tosylhydrazone (23) is converted into 1-benzyl- and 1-al-lyl-4-methyl-1H-1,2,3-triazoles 24 in good yields (Scheme 14).[39] Also, an attempted syn-thesis of tosylhydrazone 26 from 2,2-dichloro-1-phenylethanone 25 gives the triazole di-rectly 27.[39]

Scheme 14 Reaction of Æ,Æ-Dichloro Ketone Tosylhydrazones with Primary Amines[39]

24

N

NN

R1O

HCl

Cl

R1 = Bn 84%

R1 =

TsNHNH2

N

HCl

Cl

NHTs

23

R1NH2

CH2CH CH2 83%

27 20%

N

NN

Ph O

HCl

Cl Ph

Ph N

HCl

Cl

NHTs

2625

NHTs

TsNHNH2 TsNHNH2

1H-1,2,3-Triazole (20, R1 = H); Typical Procedure:[40]

To a soln of NH3/H2O (8.9 g, 523 mmol) in MeOH (40 mL) under ice-cooling was added slow-ly dichloroacetaldehyde tosylhydrazone (19, X = Ts; 4.4 g, 15.7 mmol) in MeOH (60 mL).The mixture was stirred at 22 8C for 9 h and then it was filtered to remove NH4Cl. The fil-trate was concentrated and chromatographed (silica gel, EtOAc/hexane 1:1) to give 1H-1,2,3-triazole as a colorless oil; yield: 0.81 g (75%); bp 208–210 8C.

13.13.1.1.1.2 Fragments C-C-N and N-N

13.13.1.1.1.2.1 Method 1:From Enaminones and Diazo Transfer Reagents

Enaminones react with a range of diazo transfer reagents to give 1H-1,2,3-triazoles. 3-Di-azo-1,3-dihydro-2H-indol-2-one derivatives and sulfonyl azides are particularly useful inthese reactions.

13.13.1.1.1.2.1.1 Variation 1:From Enaminones and 3-Diazo-1,3-dihydro-2H-indol-2-one Derivatives

�-Amino-Æ,�-unsaturated ketones (enamino ketones) 28 (R2 = Me) and �-amino-Æ,�-unsat-urated esters (enamino esters) 28 (R2 = OEt) react with 3-diazo-1,3-dihydro-2H-indol-2-onederivatives to give 1H-1,2,3-triazoles of type 30 in good to excellent yields (Scheme15).[41,42] Various 3-diazo-1,3-dihydro-2H-indol-2-ones can be used but the best results areobtained with the nitro derivatives 29 and 31.[41] When cyclic enaminones 33 or 34 areused, carbocyclic fused 1,2,3-triazoles of types 33 and 35 are obtained in good yields (49–




b83%).[42] The 3-diazobenzo[b]thiophen-2-one also reacts with enaminones to give 1,2,3-tri-azoles.[41] In these reactions, compounds 29, 31, and 3-diazobenzo[b]thiophen-2-one act asdiazo transfer reagents; a probable mechanism has been described.[41]

Scheme 15 Reaction of Enaminones with 3-Diazo-1,3-dihydro-2H-indol-2-ones[41,42]

30

N

NN

R1

O

R2

NH

O

N2

O2N

NO2

+

H

R1HN

O

R2

2928

R1 = Me, t-Bu; R2 = Me, OEt

55−81%

30

N

NN

R1

O

R2

NO

N2

O2N

+

H

R1HN

O

R2

3128

R1 = Me, t-Bu; R2 = Me, OEt

Me

55−82%

+

32

NH

O

N2

O2N

NO2

29

O

NHMeR1

R1

NN

N

33

R1

R1 Me

O

R1 = H 49%

R1 = Me 50%

+

34

NH

O

N2

O2N

NO2

29

N NN

35

CO2Et

( )

n = 1, 2, 3

nNH

CO2Et

H

( )n

73−83%

Reaction of Enaminones with 3-Diazo-1,3-dihydro-2H-indol-2-ones; General Procedure:[41]

A mixture of the diazocarbonyl compound (1 mmol) and the enaminone (1 mmol) in drytoluene (30 mL) was refluxed until the disappearance of the N2 absorption band at2100 cm–1 in the IR spectrum. The solvent was evaporated and the residue was submittedto column chromatography (Florisil, hexane/CH2Cl2/MeOH mixtures). The products werefurther purified by preparative TLC (silica gel, CHCl3/MeOH 100:1).





b13.13.1.1.1.2.1.2 Variation 2:

From Enaminones and Sulfonyl Azides

Mesyl and tosyl azides can act as diazo transfer reagents to enaminones yielding triazoles36 in good yields (Scheme 16).[43] For this purpose, mesyl azide is a much better reagentthan tosyl azide (yields of 20–97% and 2–50%, respectively). The reaction works betterwith N-alkyl-substituted enaminones (72–97%) than N-aryl-substituted enaminones (20–37%).

Scheme 16 Reaction of Enaminones with Sulfonyl Azides[43]

TsN3 or MsN3, NaH N

NN

R1

R1 = alkyl, aryl; R2 = Me, OEt

O

R2

H

R1HN

O

R2

36

Reaction of Enaminones with Sulfonyl Azides; General Procedure:[43]

To a stirred mixture of NaH (6.67 mmol; free of oil) in anhyd MeCN (4 mL), under N2 at rt,was added a soln of the enaminone (1.85 mmol) in anhyd MeCN (4 mL). The stirring wascontinued for 30 min, followed by dropwise addition of mesyl azide (5 mmol) in anhydMeCN (1 mL). Stirring was maintained for 24 h and the reaction was quenched withNaOH soln (10%). The separated organic layer was dried (MgSO4) and the solvent was re-moved under reduced pressure to give a residue that was extracted with CH2Cl2

(3 � 10 mL). The crude 1,2,3-triazoles were purified by column chromatography (silicagel, hexane/EtOAc 9:1).

13.13.1.1.2 By Formation of One N-N and One C-C Bond

13.13.1.1.2.1 Fragments C-N-N and C-N

13.13.1.1.2.1.1 Method 1:From Diazoalkanes and Nitriles

Diazoalkanes react with activated nitriles such as cyanogen, cyanogen halides, methyl cy-anoformate, aryl cyanates, sulfonyl cyanides, and others to give 1,2,3-triazoles (Scheme17). These reactions can formally be regarded as 1,3-dipolar cycloadditions.[3] If an excessof diazoalkane is used the triazoles may be N-alkylated; generally mixtures of the threepossible N-alkyl-1,2,3-triazoles are obtained. For example, cyanogen bromide reacts withexcess diazomethane to give a mixture of the 4-bromo-2-methyl-2H-1,2,3-triazole (21%), 5-bromo-1-methyl-1H-1,2,3-triazole (6.4%), and 4-bromo-1-methyl-1H-1,2,3-triazole (5.5%).[44]

Tosyl cyanide reacts with 1 equivalent of diazomethane to afford 4-tosyl-1H-1,2,3-triazole(37, R1 = H; X = Ts) in 68% yield. With excess diazomethane it gives a mixture (95%) of thethree isomeric N-monomethylated triazoles 38 (R1 = H; X = Ts).[45] Similarly, 4-oxo-4H-1-benzopyran-2-carbonitriles react with diazomethane to yield mixtures of three isomericN-methyl-1,2,3-triazoles.[46]




bScheme 17 Reaction of Activated Nitriles with Excess Diazoalkanes[44,45]

37

N

NN

X

R1

N

NN

X

R1

H

38

R1CHN2XCN

R1

R1CHN2

The importance of the nature of electron-withdrawing groups in nitriles with respect totheir reactivity toward diazomethane is demonstrated by the relative yields of N-methyl-triazoles 39–41 given in Table 1.[47] For example, 1-methyl-1H-imidazole-4,5-dicarbonitrilereacts with diazomethane only at the 5-cyano group.

Table 1 Examples of N-Methyltriazoles Obtained by Reaction of Diazomethanewith Activated Nitriles[47]

R1CN + CH2N2

N

NNMe

R1

+N

NN +

N

NN

R1

R1

4039 41

Me Me

R1 Ratio Ref

39 40 41

CCl3 88.6 9.8 1.6 [47]

CO2Et 23.6 74.8 1.6 [47]

Bz 62.2 34.5 3.3 [47]

O

O

91.5 3.1 5.4 [47]

N

NMe

NC

55.7 42.2 2.1 [47]

Diazomethane also undergoes addition to the C”N bond of chloro(fluoroimino)acetoni-trile (42) to yield triazole 43 (Scheme 18). Two equivalents of diazomethane are consumedin this reaction; the insertion of a methylene group is observed in the final product.[48]

Scheme 18 Reaction of Diazomethane withChloro(fluoroimino)acetonitrile[48]

N

NH

N

42

NF

Cl CN

NFCl

43

19.5%

CH2N2 (2 equiv)

Et2O, −78 oC





bReaction of Activated Nitriles with Diazomethane; General Procedure:[47]

CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhala-tion.

A soln of CH2N2 (0.13 mol) in Et2O (600 mL) was added to the nitrile (0.02 mol). The reac-tion was monitored by TLC until the nitrile was completely consumed (several days). Thesolvent was evaporated and the residue was submitted to column chromatography (silicagel). The isomeric N-methyltriazoles were separated using appropriate eluents.

13.13.1.1.2.1.1.1 Variation 1:From Diazoalkanes and Aryl Cyanates

Aryl cyanates 44 react with diazoalkanes in a 2:1 proportion to yield the aryl 4-(aryloxy)-1H-1,2,3-triazole-1-carboximidates 45 (44–83%), which after hydrolysis give the corre-sponding N-unsubstituted triazoles 46 (Scheme 19).[49]

Scheme 19 Reaction of Aryl Cyanates with Diazoalkanes[49]

44

Ar1OCNN

NH

N

Ar1O

R1

N

NN

Ar1O

R1

HN OAr1

45

N

NH

N

Ar1O

R1

46

H2O

Ar1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4; R1 = H, CO2Et

R1CHN2 Ar1OCN

13.13.1.1.2.1.1.2 Variation 2:From Diazoalkanes and Unactivated Nitriles

Unactivated nitriles generally do not react with diazomethane or other diazoalkanes,however, reaction can occur in the presence of a catalyst. Aluminum trichloride, triethyl-aluminum, and other aluminum complexes can be used as catalysts in the reaction of di-azomethane with benzonitrile.[50] Aryldiazomethanes also react with benzonitriles in thepresence of potassium tert-butoxide (molar ratio 1:1:1), in toluene, to give 4,5-diaryl-1H-1,2,3-triazoles, mostly in good to satisfactory yields (26–75%).[51] A plausible mechanismfor this reaction is shown in Scheme 20. The reaction can be carried out at room temper-ature or in refluxing toluene.




bScheme 20 Synthesis of 4,5-Diaryl-1H-1,2,3-triazoles by Reaction of Aryldiazomethaneswith Benzonitriles in the Presence of Potassium tert-Butoxide[51]

Ar1CN + Ar2CHN2

N

NNAr1

t-BuOK

N

NH

N

Ar2

Ar1

47

H3O+N

NN

Ar2

Ar1− K+

Ar2

H

Ar1 Ar2 Conditions Yield (%) Ref

Ph Ph rt, 24 h 69 [51]

Ph Ph 110 8C, 2 h 75 [51]

4-ClC6H4 4-ClC6H4 110 8C, 2 h 70 [51]

4-ClC6H4 Ph 110 8C, 2 h 44 [51]

4-BrC6H4 Ph rt, 24 h 66 [51]

4-Tol Ph 110 8C, 2 h 26 [51]

13.13.1.1.2.1.1.3 Variation 3:From [Diazo(trimethylsilyl)methyl]lithium and Nitriles

[Diazo(trimethylsilyl)methyl]lithium (48) [generated in situ from the reaction of diazo(tri-methylsilyl)methane and butyllithium] reacts smoothly with nitriles to give 4-substituted5-(trimethylsilyl)-1,2,3-triazoles 49 in excellent yields (Scheme 21).[52,53] Various nitriles,including aromatic, heteroaromatic, and aliphatic nitriles, react efficiently with 48 togive 4-(trimethylsilyl)triazoles 49. Since treatment of diazo(trimethylsilyl)methane withbutyllithium followed by protonation gives 4,5-bis(trimethylsilyl)-1H-1,2,3-triazole,[54]

the generation of 48 needs to be carefully controlled.

Scheme 21 Reaction of Nitriles with [Diazo(trimethylsilyl)methyl]lithium[52,53]

R1CNEt2O, 0 oC, 3 h N

NH

N

TMS

R1

48

R1 = Pr, t-Bu, Bn, 3,7-dimethylocta-2,6-dienyl, Ph, 1-naphthyl, 2-pyridyl, 1-isoquinolyl, SEt, OPh, PO(OEt)2, TMS

+44−96%

TMS

N2

Li

49

Triazoles 49; General Procedure:[52]

15% BuLi in hexane (0.76 mL, 1.2 mmol) was added dropwise to a soln of TMSCHN2

(0.55 mL, 1.2 mmol) in Et2O (10 mL) at 0 8C under argon and the mixture was stirred for20 min at 0 8C. To the resulting soln was added dropwise a soln of a nitrile (1 mmol) inEt2O (3 mL) at 0 8C, then the mixture was stirred at 0 8C for 3 h. The mixture was treatedwith sat. aq NH4Cl and extracted with Et2O. The Et2O extracts were washed with H2O anddried (MgSO4). Concentration of the solvent gave a residue, which was purified by prepar-ative layer chromatography to give the triazole.





b13.13.1.1.2.1.2 Method 2:

From Diazoalkanes and Imines, Oximes, or Diarylazines

The 1,3-dipolar cycloaddition of diazoalkanes to C=N bonds is a general method for thesynthesis of 4,5-dihydro-1H-1,2,3-triazoles and 1H-1,2,3-triazoles (Scheme 22).[4] It is an es-pecially useful method for the regioselective preparation of 1H-1,2,3-triazoles with bulkysubstituents in positions 1 and 5. Imines are the most versatile C=N system to be used inthis method, but oximes and diarylazines can also be used.

Scheme 22 Addition of Diazoalkanes to Imines[55,56]

NR3

R2

R1

50

+ R4CHN2

N

NN

R4

R3

R2

R1

51

13.13.1.1.2.1.2.1 Variation 1:From Diazoalkanes and Imines

4,5-Dihydro-1H-1,2,3-triazoles 51 are the expected products from the cycloaddition reac-tion of imines 50 with diazoalkanes but in some cases they spontaneously aromatize tothe corresponding triazoles. When the 4,5-dihydro-1H-1,2,3-triazoles are the isolatedproducts they can be converted into triazoles by a large number of alternative procedures(see Section 13.13.1.3).

The addition of diazoalkanes (especially diazomethane) to imines, to give 4,5-dihy-dro-1H-1,2,3-triazoles 51, is very well studied.[4] In general it is favored by the presence ofelectron-withdrawing substituents in the imine, especially on an N-aryl moiety.[55,56]

Though kinetic investigations of this reaction show that it follows essentially a concertedprocess and is not generally dependent on solvent polarity, a sizable increase in rate isnoticed in the presence of protic solvents such as water or alcohols.[57] For example, whilereaction of diazomethane with N-benzylideneaniline (52, Ar1 = Ar2 = Ph) does not occur indry ether, it does occur in aqueous dioxane giving the 4,5-dihydro-1H-1,2,3-triazole 53(Ar1 = Ar2 = Ph) in 53% after eight days (Scheme 23).[55] This solvent system can be success-fully used for the preparation of 5-hetaryl-substituted 4,5-dihydro-1H-1,2,3-triazoles oftype 53 (Ar1 = 2- or 3-pyridyl, 2-quinolyl).[58,59] Triethylaluminum and other aluminumcomplexes have been used as catalysts in the reaction of diazomethane with imines.[50]

Scheme 23 Addition of Diazomethane to Diarylimines[58]

N

Ar1

52

+ CH2N2

N

NN

53

dioxane, H2O (cat.)

rt, 2−8 d

Ar1

Ar2

Ar2

Diazomethane undergoes addition to hexafluoroacetone imines 54 to give 4,5-dihydro-1H-1,2,3-triazoles 55 as the sole product or to give mixtures of 4,5-dihydro-1H-1,2,3-tria-zoles 55 and 56 (the latter produced as a result of the addition of diazomethane to theC=C bond) (Scheme 24).[60]




bScheme 24 Addition of Diazomethane to Hexafluoroacetone Imines[60]

54

+ CH2N2

N

NNEt2O, rt

R2

R1

N

F3C

F3C

R1

R2

N

NN

N

N

R1

R2

+

55 56

F3C F3C

F3C F3C

R1 R2 Yield (%) Ref

55 56

Me Me 91 – [60]

Ph H 88 – [60]

Me H 30 32 [60]

iPr H 42 51 [60]

Diazomethanes of the types 57, 58, and 59 react with formimidamides 60 to give directlythe corresponding triazoles 61 in 11–62% yields (Scheme 25).[61]

Scheme 25 Addition of Substituted Diazomethanes to Formimidamides[61]

R1 = Me, Et, t-Bu

N

NN

R1O2C N2

N2

(R1O)2P N2

57

58

59

R1 = Me, t-Bu, Ph

R1 = Me, Et

11−62%

, MeCN, 81 oC, 24 hNBut

Me2NX

But

61

60R1

O

O

13.13.1.1.2.1.2.2 Variation 2:From Diazoalkanes and Oximes

Diazomethane undergoes addition to oximes to give 4,5-dihydro-1H-1,2,3-triazoles. The O-methyl oxime 62 reacts with diazomethane to yield the unstable 4,5-dihydro-1H-1,2,3-tri-azole 63 (87%) that on treatment with piperidine gives the triazole 64 in 50% yield(Scheme 26).[62]





bScheme 26 Reaction of Diazomethane with Dimesylmethanone O-Methyloxime[62]

N

Ms

Ms

62

+ CH2N2

N

NN

Ms

Ms

OMe

OMe

63

dioxane, EtOAc

0 oC, 30 min

87%

N

NN

OMe

64

Ms

piperidine, dioxane, EtOAc

−10 to 50 oC, 3 h

50%

13.13.1.1.2.1.2.3 Variation 3:From Diazoalkanes and Diarylazines

Aromatic aldehyde azines 65 react with aryldiazomethanes in the presence of potassiumtert-butoxide to give N-unsubstituted 4,5-diaryl-1H-1,2,3-triazoles 66 (Scheme 27).[51] Thescope of this method has yet to be demonstrated since only two symmetrical triazoles66 are prepared by this way. The mechanism of this reaction seems to involve one 1,3-di-polar cycloaddition followed by base elimination of an aromatic imide anion. However itshould be noted that even in the absence of the aryldiazomethanes, the aromatic alde-hyde azines (DMSO, rt) in the presence of potassium tert-butoxide (1 equiv), give thesame 4,5-diaryl-1H-1,2,3-triazoles, although in much lower yields.[51]

Scheme 27 Reaction of Aromatic Aldehyde Azines with Aryldiazomethanes in the Presenceof Potassium tert-Butoxide[51]

65

+ Ar1CHN2

DMSO, rt, 24 h

N

NNH

N Ar1

Ar1

N

NH

N

Ar1

Ar1

N

N

Ar1CH

CHAr1

t-BuOKAr1

H

N

NN

N Ar1

Ar1

H

Ar1

H

66 Ar1 = Ph 92%

Ar1 = 4-ClC6H4 38%

13.13.1.1.2.1.3 Method 3:From Diazoalkanes and Heterocumulenes

The reaction of diazoalkanes (or their organometallic derivatives) with heterocumulenesis a versatile method for the synthesis of 1H-1,2,3-triazoles. The reactions with keten-imines, carbodiimides, isocyanates, and isothiocyanates are performed under very mildconditions and generally they give the desired triazoles in moderate to excellent yields.




b13.13.1.1.2.1.3.1 Variation 1:

From Diazoalkanes and Ketenimines

Diazomethane reacts with ketenimines 67 (rt, 4 d) to give triazoles of type 68 in moderateyields (Scheme 28).[63,64] Other diazoalkanes fail to react with ketenimines 67 to give thecorresponding 1,2,3-triazoles.[64]

Scheme 28 Reaction of Ketenimines with Diazomethane[63,64]

Et2O

rt, 4 d• NAr1

Ph

Ph

67

N

NN

Ar1

Ph

Ph31−43%

N

NN

Ar1

Ph

Ph

68

Ar1 = Ph, 4-Tol, 4-ClC6H4, 4-BrC6H4

+ CH2N2

Better yields of triazoles are obtained if [diazo(trimethylsilyl)methyl]lithium (48) is used(Scheme 29). For example, alkyl and aryl ketenimines 69, (R1 = R2 = X = alkyl, aryl) reactsmoothly with 48 [prepared from diazo(trimethylsilyl)methane and butyllithium] to give4-(trimethylsilyl)-1,2,3-triazoles 71 in good yields.[65] Since desilylation of 71 is readilyachieved in almost quantitative yields (10% aq KOH/MeOH, reflux, 6 h),[65] reagent 48 canbe used, with better results, as a diazomethane equivalent.

The reaction of 48 with ketenimines bearing electron-withdrawing groups (69,X = EWG) also gives 1,2,3-triazoles but in some cases only pyrazoles are obtained: it cangive either 1H-1,2,3-triazoles 71 or pyrazoles 72 as the sole product or mixtures of thesecompounds (Scheme 29).[66] The nature and the yields of the products change with the sol-vent used in the reaction. The betaines 70 are likely to be intermediates in these reac-tions: the triazoles are formed by the attack of the nitrogen anion on the diazonium nitro-gen.[66]

Scheme 29 Reaction of Ketenimines with [Diazo(trimethylsilyl)methyl]lithium[65,66]

Et2O, 0 oC, 2 h

NZ

N

R2HN

R1

72

N2

TMS

Li

• NR2

R1

X

+

48 69

X

R1 NR2

N2LiTMS

+−

TMS

N

NN

TMS

71

R2

X

R1

X = alkyl, aryl, EWG

X = EWG

Z = X, H

70





bR1 X R2 Solvent Yield (%) Ref

71 72

Ph Ph 4-Tol Et2O 74 [65]

Ph Ph Bu Et2O 67 [65]

Me Me 4-Tol Et2O 82 [65]

Et Bu Bu Et2O 82 [65]

Me PO(OEt)2 Et Et2O 73a [66]

Me PO(OEt)2 Ph Et2O 68 2a [66]

Me Ac Ph Et2O 76 [66]

Me Ac Ph THF 58 [66]

Me Ac Ph hexane 46 14b [66]

Me CN Et Et2O 43 [66]

a Z = PO(OEt)2.b Z = H.

Reaction of Ketenimines with [Diazo(trimethylsilyl)methyl]lithium;General Procedure:[65]

To 1.87 M TMSCHN2 in hexane (0.64 mL, 1.2 mmol) in Et2O (10 mL) was added, dropwise15% BuLi in hexane (0.76 mL, 1.2 mmol) at 0 8C under argon. The mixture was stirred atthis temperature for 20 min. A soln of an alkyl or aryl ketenimine (1 mmol) in Et2O(2 mL) was then added dropwise at 0 8C. The mixture was stirred at 0 8C for 2 h. After addi-tion of cold H2O, the mixture was extracted with benzene (CAUTION: carcinogen). The or-ganic layer was washed with H2O, dried (MgSO4), and concentrated in vacuo. The residuewas purified by column chromatography (silica gel) to give triazoles 71.

13.13.1.1.2.1.3.2 Variation 2:From Diazoalkanes and Carbodiimides

Carbodiimides 73 react with diazoalkanes to give 1H-1,2,3-triazoles 74 (Scheme 30). Forexample, reaction of diazomethane with di(1- or 2-naphthyl)carbodiimides[67] or withbis(4-X-phenyl)carbodiimides (X = H, NMe2, OMe, Me, Cl, Br, Ac) gives triazoles 74 (R1 = H)in low to moderate yields.[63,68,69]

Scheme 30 Reaction of Carbodiimides with Diazoalkanes[63,67–69]

• NAr1Ar1NN

NNAr1N

R1

Ar1

Et2O, rt, 4 d N

NNAr1HN

R1

Ar1

7473

+ R1CHN2

Organometallic diazomethanes also react with carbodiimides to form 1,2,3-triazoles, forexample diazo(trimethylsilyl)methane and diazobis(trimethylstannyl)methane give, re-spectively, compounds 75 (19%) and 76 (96%) by reaction with 73 (Ar1 = 4-Tol) (Scheme31).[68]




bScheme 31 Reaction of Organometallic Diazoalkanes with Carbodiimides[68]

N

NNAr1HN

TMS

75

73

Et2O

35 oC, 2 h

N

NNN

Me3Sn

76

Ar1

Me3Sn

TMSCHN2

(Me3Sn)2CN2

Ar1

Ar1

Ar1N • NAr1

19%

96%

Ar1 = 4-Tol

Reaction of Carbodiimides with Diazomethane; General Procedure:[63]

CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhalation.

A freshly prepared ethereal soln of CH2N2 (12 mmol) was added to the carbodiimide(10 mmol) dissolved in a sufficient quantity of Et2O. The mixture was allowed to stand atrt for 4 d. The separated crystals were collected by filtration and washed with Et2O. Thetriazoles 74 were then recrystallized (MeOH or aq acetone).

13.13.1.1.2.1.3.3 Variation 3:From Diazoalkanes and Isocyanates

Alkyl and aryl isocyanates react with [diazo(trimethylsilyl)methyl]lithium (48) to give 1-substituted 1H-1,2,3-triazol-5-ols 77 in good yields (Scheme 32).[70] Experimental data indi-cate that these reactions proceed by a stepwise process, not by a concerted 1,3-dipolar cy-cloaddition process.[70]

Scheme 32 Reaction of Isocyanates with [Diazo(trimethylsilyl)methyl]lithium[70]

N

NNLiO

TMS

77

48

N2

TMS

Li

+ R1NCOEt2O

R1N

O−

LiN2TMS

+

R1

N

NNHO

R1

H2O

− TMSOH

R1 Conditions Yield (%) mp (8C) Ref

Bu Et2O, –78 8C, 1,5 h; rt, 3.5 h 63 132–133 [70]

t-Bu Et2O, 0 8C, 1 h; reflux, 6h 53 126–131 (dec) [70]

Cy Et2O, 0 8C, 1 h; rt, 1.7 h 71 148 [70]

Ph Et2O, 0 8C, 2 h 79 113–115 (dec) [70]

4-ClC6H4 Et2O, 0 8C, 2 h 83 111 (dec) [70]

1-naphthyl Et2O, 0 8C, 1 h 83 125 (dec) [70]





bBenzoyl isocyanate reacts with ethyl diazoacetate, in refluxing xylene, to give ethyl 1-ben-zoyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylate in 60% yield (Scheme 33).[71]

Scheme 33 Reaction of Benzoyl Isocyanate with Ethyl Diazoacetate[71]

xylene, reflux N

NNHO

BzNCO + EtO2CCHN2

Bz

EtO2C

60%

1-(4-Chlorophenyl)-1H-1,2,3-triazole (77, R1 = 4-ClC6H4); Typical Procedure for the Reac-tion of Isocyanates with [Diazo(trimethylsilyl)methyl]lithium:[70]

To 2 M TMSCHN2 in hexane (0.6 mL, 1.2 mmol) in Et2O (10 mL) was added dropwise, 15%BuLi in hexane (0.76 mL, 1.2 mmol) at 0 8C under argon. The mixture was stirred at thistemperature for 20 min. A soln of 4-chlorophenyl isocyanate (154 mg, 1 mmol) in Et2O(3 mL) was then added dropwise at 0 8C. The mixture was stirred at 0 8C for 2 h and ice wa-ter was then added. The aqueous layer was separated and the organic phase was extractedwith H2O. The combined aqueous layer was acidified with 2 M HCl. The resulting whiteprecipitates were collected by filtration, dried in vacuo, and purified by column chroma-tography (silica gel) to give 77 (R1 = 4-ClC6H4); yield: 162 mg (83%).

13.13.1.1.2.1.3.4 Variation 4:From Diazoalkanes and Isothiocyanates

Treatment of isothiocyanates with [diazo(trimethylsilyl)methyl]lithium (48) in tetrahy-drofuran, followed by quenching with alkyl halides, gives 1-substituted 5-(alkylsulfanyl)-4-(trimethylsilyl)-1H-1,2,3-triazoles 78 in excellent yields (Scheme 34).[72] A dramatic sol-vent effect is observed in this reaction: changing tetrahydrofuran for diethyl ether leadsto the exclusive formation of 1,3,4-thiadiazol-2-amines in good yields.[73] This is in con-trast to the results observed with isocyanates (Scheme 32). Removal of the trimethylsilylgroup from 78 is readily carried out with 10% aqueous potassium hydroxide in boilingmethanol to give triazoles 79 in almost quantitative yields.[72]

Scheme 34 Reaction of Isothiocyanates with [Diazo(trimethylsilyl)methyl]lithium[72]

N

NNLi+ −S

TMS

79

48

N2

TMS

Li

+ R1NCSTHF

R1N

S−

LiN2

TMS+

R1

N

NNR2S

R1

OH−

78

N

NNR2S

R1

TMS

R2X




bR1 R2X Yield (%) Ref

78 79

Ph MeI 98 94 [72]

Ph BnBr 99 97 [72]

Me MeI 96 100 [72]

Me BnBr 90 98 [72]

Bu BnBr 97 95 [72]

Cy BnBr 98 96 [72]

Bn BnBr 91 99 [72]

CH2=CHCH2 BnBr 91 83 [72]

Reaction of Isothiocyanates with [Diazo(trimethylsilyl)methyl]lithium;General Procedure:[72]

To a soln of 2 M TMSCHN2 in hexane (0.6 mL, 1.2 mmol) in THF (10 mL) was added drop-wise 15% BuLi in hexane (0.76 mL, 1.2 mmol) at –78 8C under argon. The mixture wasstirred at this temperature for 20 min. A soln of the isothiocyanate (1 mmol) in THF(3 mL) was then added dropwise at –78 8C. After 1 h at –78 8C, the alkyl halide (1.2 mmol)was added and the mixture was stirred at –78 8C for 1 h, then at 0 8C for 2 h. After additionof ice water, the mixture was extracted with benzene (CAUTION: carcinogen). The organiclayer was washed with H2O, dried (MgSO4), and concentrated in vacuo. The residue waspurified by column chromatography (silica gel) to give triazoles 78.

13.13.1.1.2.1.4 Method 4:From N-Alkyl-N-nitrosoamines and Nitriles

Lithium salts of N-alkyl-N-nitrosoamines react with aryl cyanides to form triazoles 80 in40–70% yield (Scheme 35).[74] The main limitation of this method is the fact that enolizablenitriles cannot be used.

Scheme 35 Reaction of Lithium Salts of N-Alkyl-N-nitrosoamines withAryl Cyanides[74]

80

+THF, −78 oC, 10 h N

NNR2

R1

Ar1CN NNO

Li+R1 40−72%

Ar1

Ar1 = Ph, 4-Tol, 2-naphthyl; R1 = Me, iPr, t-Bu; R2 = H; R1,R2 = (CH2)3

R2−

1-Methyl-4-phenyl-1H-1,2,3-triazole (80, R1 = Me; R2 = H; Ar1 = Ph); Typical Procedure:[74]

CAUTION: N-Methyl-N-nitrosomethylamine (N,N-dimethylnitrosamine) is a probable humancarcinogen and an eye and skin irritant. It is hepatotoxic and an exp. carcinogen and teratogen.All operations should be performed in a well-ventilated fume hood using appropriate safety pre-cautions and procedures.

Pure N-methyl-N-nitrosomethylamine (1.62 mL, 22 mmol) was added with stirring to asoln of LDA (23 mmol) in anhyd THF (70 mL) [from iPr2NH (3.22 mL) and 1.6 M BuLi in hex-ane (14.2 mL)] at –78 8C and after 10 min the mixture was treated with PhCN (1.03 mL,10 mmol). The mixture was maintained at the temperature of dry ice for 10 h and the mix-ture was treated with a soln of glacial AcOH (1.32 mL, 23 mmol) in THF (5 mL). Working up





bwith CH2Cl2 afforded a crystalline crude product that was recrystallized (CCl4); yield:1.15 g (72%); mp 122 8C.

13.13.1.1.3 By Formation of Two N-C Bonds

13.13.1.1.3.1 Fragments N-N-N and C-C

The most important and general approach to the synthesis of the 1,2,3-triazole ring sys-tem involves azides. A wide variety of azides (organic or inorganic) can be used: alkyl,aryl, hetaryl, acyl, alkoxycarbonyl and sulfonyl azides, azidotrimethylsilane, hydrazoicacid, sodium azide, etc. All are suitable reagents for triazole synthesis.

Azides react with various types of compounds to yield 1,2,3-triazoles or their imme-diate precursors. The most used are: (i) compounds with C”C bonds (here referred to asalkynes, irrespectively of other functional groups), (ii) compounds with C=C bonds (herereferred to as alkenes, and including allenes, enamines, enol ethers, etc.), and (iii) activat-ed methylene compounds.

In spite of the great usefulness of the azides in the triazole synthesis, if the reactionconditions (especially the temperature) are not well controlled, the products obtainedmay be not the expected triazoles. This is because of the thermal instability of the azidesand of some of the intermediates (dihydrotriazoles) formed during the triazole synthe-sis.[75] It is very important to always consider that most organic azides undergo thermalor photochemical decomposition to nitrenes. The decomposition temperature is depen-dent on the azide type (Table 2) and some azides, especially cyanogen azide and the loweralkyl azides, are unpredictably explosive. When the decomposition is carried out in thepresence of an alkene the corresponding aziridine is usually obtained.[75]

Table 2 Decomposition Temperature of Azides[76]

Azide Type Decomposition Temp (8C) Ref

alkyl azides 180–200 [76]

aryl azides 140–170 [76]

sulfonyl azides 120–150 [76]

alkoxycarbonyl azides 100–130 [76]

acyl azides 25–80 [76]

13.13.1.1.3.1.1 Addition of Azides to Alkynes

The thermal 1,3-dipolar cycloaddition of azides to alkynes is often the method of choicefor the synthesis of 1,2,3-triazoles since it gives directly the desired product. However,when unsymmetrical alkynes are used, mixtures of the two possible regioisomers areusually obtained. In general, addition to unsymmetrical alkynes tends to give mainly theisomers with the electron-withdrawing groups at the 4-position and the electron-releas-ing groups at 5-position.[3] The low regioselectivity of these reactions is the major disad-vantage of this method as a preparative procedure. The accepted mechanism for these re-actions is a concerted 1,3-dipolar cycloaddition. Kinetic data and the regio- and stereose-lectivity of these reactions strongly support this mechanism. However, the reactions in-volving ionic azides (e.g., sodium azide) follow a nonconcerted ionic mechanism. Thesemechanisms have been discussed and documented in reviews.[76,77]

N-Unsubstituted 1,2,3-triazoles are prepared by the direct addition of hydrazoic acidor an azide ion to alkynes but it is often more convenient to obtain these compounds byremoval of a N-substituent from a 1H- or 2H-triazole.




b13.13.1.1.3.1.1.1 Method 1:

Addition of Hydrazoic Acid to Alkynes

Hydrazoic acid reacts with alkynes to give the corresponding N-unsubstituted triazoles 81(Scheme 36). This method was originally performed by Dimroth and Fester who preparedthe parent compound by heating an alcoholic solution of hydrazoic acid with an acetonesolution of acetylene at 100 8C for 70 hours.[78] With alk-1-ynes the reaction is generallycarried out in benzene in a closed vessel at temperatures ranging from 90 to 135 8C for30–48 hours.[79] The triazoles are obtained in low to moderate yields. Reactions involvingalkynes with electron-withdrawing or donating groups are faster and the yields are high-er.

Scheme 36 Addition of Hydrazoic Acid to Alkynes[44,79–83]

81

N

NH

NR1

R2

R2R1 + HN3

R1 R2 Yield (%) mp (8C) bp (8C)/Torr Ref

H Me 14 35–36 108–109/25 [79]

H Bu 56 – 103–105/1 [79]

H (CH2)5Me 63 27 120–122/2 [79]

H (CH2)9Me 29 59 148–149/0.6 [79]

H Ph 48 148 – [79,80]

H CHO 50 141–142 – [81]

H CO2H 71 222–224 – [44]

Ph CHO 90 186–188 – [82]

TMS CHO 83 171–183 – [83]

TMS Ac 88 159–160 – [83]

TMS CO-t-Bu 79 84–85 – [83]

TMS Bz 85 102 – [83]

4-Phenyl-1H-1,2,3-triazole (81, R1 = H; R2 = Ph):[79]

CAUTION: Hydrazoic acid is highly toxic and explosive. Adequate protection and shielding arenecessary during the preparation and handling of this reagent.

A combustion tube containing phenylacetylene (14.7 g, 0.144 mol) and a soln of HN3 inbenzene (50 mL of 14.2% HN3 in benzene, 0.165 mol) (CAUTION: carcinogen) was sealedand heated in a bath at 110–115 8C for 40 h. After cooling to rt almost the entire contentscrystallized. The solid was collected by filtration, washed with benzene, and recrystal-lized twice (benzene). Decolorizing charcoal was used during the first crystallization;yield: 10 g (48%); mp 148 8C.





b13.13.1.1.3.1.1.2 Method 2:

Addition of the Azide Ion to Alkynes

The azide ion undergoes addition to alkynes to give triazoles 82 in low to moderate yields(Scheme 37). Better yields are obtained with alkynes bearing electron-withdrawinggroups. Almost quantitative yields (>98%) of 5-substituted 1H-1,2,3-triazole-4-carbalde-hydes are obtained from the reaction of alk-2-ynals with sodium azide in dimethyl sulfox-ide, at room temperature.[84] Generally the reaction is carried out in dimethyl sulfoxide ordimethylformamide; sodium azide[84–87] is frequently used as the azide ion source but lith-ium azide[88] and aluminum azide[89] have also been used. The mechanism of the reactionprobably involves the nucleophilic addition of the azide ion to the triple bond followed by1,5-dipolar cyclization of the resulting vinyl anion. Addition of sodium azide to 1-aryl-5-phenylpent-4-yne-1,3-diones in refluxing dimethylformamide gives the corresponding 4-(3-aryl-1,3-dioxopropyl)-5-phenyl-1H-1,2,3-triazoles 82 (R1 = Ph; R2 = COCH2Bz, COCH2CO-4-Tol, 4-MeOC6H4COCH2CO) in good yields.[86]

Scheme 37 Addition of Sodium Azide to Alkynes[84–86]

R2R1 + NaN3DMSO N

NNR1

R2

−

+

−

82

N

NH

NR1

R2

−

H3O+

NN

NR2

R1

R1 R2 Yield (%) mp (8C) Ref

H H 11 – [85]

H Ph 40 148 [85]

Ph Ph 16 140 [85]

H CO2Me 49 145 [85]

CO2Me CO2Me 54 132 [85]

Ph CHO >98 – [84]

Bu CHO >98 – [84]

Ph COCH2Bz 72 87 [86]

Ph COCH2CO-4-Tol 72 122 [86]

Ph 4-MeOC6H4COCH2CO 60 79 [86]

The reaction of propynenitrile with aluminum azide (THF, reflux, 24 h) gives a mixture ofthe triazoles 83 (32%) and 84 (47%) (Scheme 38).[89] The formation of the tetrazole ring re-sults from the addition of an azide ion to the cyano group.




bScheme 38 Addition of Aluminum Azide to Propynenitrile[89]

CNH + Al(N3)3

THF, reflux

24 h N

NH

NNC

84 47%

N

NH

N

HNN

N N+

83 32%

Addition of sodium azide to (arylethynyl)triphenylphosphonium halides 85 gives 4-aryl-5-triphenylphosphonio-1,2,3-triazolide ylides 86 in high yields (Scheme 39).[87] These ylidesare readily hydrolyzed in aqueous basic solution to give quantitatively triazoles 87 andtriphenylphosphine oxide.

Scheme 39 Addition of Sodium Azide to (Arylethynyl)triphenylphosphonium Halides[87]

PPh3 X−Ar1

NaN3, DMF

60 oC, 3 h N

NH

N

86

+

NN

N−

Ph3P

Ar1

+

Ar1

87

NaOH

EtOH/H2O (1:2)

reflux, 2 h

85

Ar1 = Ph 93%

Ar1 = 4-ClC6H4 94%

− Ph3PO

100%

Propargyl sulfonates 88 react with lithium azide/copper(I) chloride complex (THF/DMF,–60 8C) to give, after acidification, the 5-(1-azidoalkyl)-1H-1,2,3-triazoles 89 in low yields(4–24%); 50–70% of the starting material is recovered (Scheme 40).[88]

Scheme 40 Addition of Lithium Azide to Propargyl Sulfonates[88]

N

NH

N

R3

89

LiN3, CuCl

THF/DMF (1:1)

−60 oC, 10 h

88

MsO

R3

R1 R2

N3

R2R1

4−24%

R1 = t-Bu, Ph, 3-O2NC6H4; R2 = H, Ph; R3 = t-Bu, Ph

4-(3-Aryl-1,3-dioxopropyl)-5-phenyl-1H-1,2,3-triazoles 82 (R1 = Ph; R2 = COCH2Bz,4-TolCOCH2CO, 4-MeOC6H4COCH2CO); General Procedure:[86]

CAUTION: Sodium azide can explode on heating and is highly toxic.

A soln of 1-aryl-5-phenylpent-4-yne-1,3-dione (4 mmol) in DMF (20 mL) was refluxed withNaN3 (4.6 mmol) for 3 h. The mixture was then poured into cold H2O (200 mL), acidifiedwith dil H2SO4, and the precipitated triazole 82 was collected by filtration, washed withH2O several times, dried, and recrystallized [benzene/petroleum ether (bp 60–80 8C)] asyellow needles.

13.13.1.1.3.1.1.3 Method 3:Addition of Alkyl, Aryl, or Hetaryl Azides to Alkynes

The addition of alkyl, aryl, and hetaryl azides to alkynes is the most popular method forthe synthesis of 1,2,3-triazoles. The number of publications related to this method is soimpressive that, although no substantial differences are found in the experimental proce-dures, for easier systematization of the information available, several variations of themethod will be presented according to the type of alkyne used. Once again, it should beemphasized that azides are dangerous compounds, especially alkyl azides which are





btreacherously explosive and should be treated with extreme caution. Wherever possiblethese compounds should only be handled as solutions.

13.13.1.1.3.1.1.3.1 Variation 1:Addition of Azides to Acetylene and to Symmetrically Substituted Alkynes

Azides undergo addition to acetylene and to symmetrically substituted alkynes 90 to giveonly one 1-substituted 1H-1,2,3-triazole 91, which simplifies the purification step(Scheme 41); this is a general method for the preparation of triazoles 91 and in some casesthe yields are excellent. Addition of phenyl azide,[78] arylmethyl azides[90–92] or other alkylazides[90] to acetylene yields the corresponding 4,5-unsubstituted triazoles 91 (R2 = H). Thismethod has also been used for the preparation of dendrimers containing various 1,2,3-tri-azole rings.[93] The addition of dimethyl acetylenedicarboxylate to per(6-azido-6-deoxy-2,3-di-O-methyl)cyclodextrins yields the corresponding per(4,5-dicarboxy-1,2,3-triazol-1-yl)derivatives.[94] 1,4-Diazidobuta-1,3-dienes react with cyclooctyne at room temperature togive the corresponding bis(triazolyl) derivatives in high yields (86–99%).[95] 1,2-, 1,3-, and1,4-Bis(azidomethyl)benzenes react with dimethyl, diethyl, and di-tert-butyl acetylenedi-carboxylates to afford the corresponding benzobis(triazoles) in good yields.[96] Other inter-esting bis(triazolyl) derivatives have been prepared by reacting dimethyl acetylenedicar-boxylate and bis-azides (produced from the reaction of sodium azide and bis-epoxides).[97]

Scheme 41 Addition of Azides to Symmetrically Substituted Alkynes[92,98–115]

R1N3 +N

NNR2

91

R2R2

R2

R1

90

R1 R2 Conditions Yield (%) Ref

Me Ph benzene, 60 8C, 2 months 30 [98]

CF2CHFCF3 Ph 180 8C, 18 h 88 [99]

(CF2)2CO2Me CO2Me 130 8C, 6 h 94 [99]

Ph CH2OH benzene, 80 8C, 12 h 73 [100]

Ph CH(OEt)2 EtOH, 100 8C, 28 h 82 [101]

Ph CO2Me EtOH, reflux, 20 h 92 [102]

(CH2)5Me CH(OEt)2 EtOH, 100 8C, 43 h 90 [101]

4-MeOC6H4 CO2Me benzene, reflux, 24 h 97 [103]

4-O2NC6H4 CO2Me benzene, reflux, 24 h 87 [103]

4-O2NC6H4 CO2Me benzene, reflux, 24 h 80 [104]

2-AcOC6H4 Bz toluene, reflux, 2–30 h 82 [92]

Bn CO2H acetone, rt to reflux, 1 h 93 [105]

1-naphthyl Bz benzene, reflux, 48 h 70 [106]

1-naphthyl CO2Me benzene, reflux, 5 h 95 [106]

1-naphthyl TMS CHCl3, reflux, 96 h 37 [106]

1-adamantyl CO2Me toluene, reflux, 24 h 77 [107]

1-adamantyl CH2OH toluene, reflux, 90 h 32 [107]

1-adamantyl Ph toluene, reflux, 500 h 17 [107]




bR1 R2 Conditions Yield (%) Ref

(E)-CPH=CHMe CO2Me rt 70 [108]

cyclohepta-2,4,6-trienyl CO2Me CCl4, reflux, 1 h 73 [109]

cyclohepta-2,4,6-trienyl Bz benzene, 100 8C, 2 h 58 [109]

CH2PO(OEt)2 CO2Me toluene, reflux, 30–40 h 92 [110]

CH2PO(OEt)2 Bz toluene, reflux, 30–40 h 85 [110]

OAcOAcO

AcO

OAc

CH2OH toluene/pyridine, reflux, 18 h 38 [111]

S

O

OO

Pri

CO2Me benzene, reflux, 6 h 84 [112]

N−O+

CO2Me toluene, 80 8C, 1.5 h 7 [113]

O O

Ph 80 8C, 120 h 51 [114]

O O

CH2OH 80 8C, 30 h 66 [114]

NH

CO2Et

EtO2CCO2Me benzene, rt, 12 h 95 [115]

13.13.1.1.3.1.1.3.2 Variation 2:Addition of Azides to Alk-1-ynes

Azides undergo addition to alk-1-ynes to give mixtures of 1,4- and 1,5-disubstituted 1H-1,2,3-triazoles (Scheme 42). The ratio of the two products is mainly dependent on thestructure of alkyne: when R2 is an electron-withdrawing group it goes preferentially toposition 4 (triazoles 93), however isomers 94 are predominant when R2 is an electron-re-leasing group. The mechanism and kinetics of the cycloaddition of phenyl azide to vari-ous 4-substituted phenylacetylenes has been reported.[116] Phenyl azide reacts regioselec-tively with trifluoromethyl-substituted alkynyl Æ-amino acids to give the 1,4-disubstitut-ed triazole.[117] It has been shown that cucurbituril substantially accelerates (ca. 105-fold)the reaction of azide-substituted ammonium ions with alkyne-derived ammonium ions.The reaction is regioselective, affording only the 1,4-disubstituted triazole derivatives.[118]

This method has been used for the preparation of oligo-1,2,3-triazoles and [n]rotax-





banes.[119,120] A catalytic effect is also observed for zinc chloride doped natural phosphatefor the cycloaddition of alkyl azides with alk-1-ynes.[121] With this catalyst a significant re-duction in the reaction time is observed but the yields and the 1,4-/1,5-substitution ratioof the triazole are not improved. The enzyme acetylcholinesterase, which plays a key rolein neurotransmitter hydrolysis in the central and peripheral nervous systems, has beenused as a catalyst for the reaction of a tacrine-substituted alkyl azide with a phenanthridi-nium-substituted terminal alkyne. The 1,5-disubstituted triazole is the predominant iso-mer.[122] A high-yielding and simple copper(I)-catalyzed reaction sequence leading exclu-sively to 1,4-disubstituted 1,2,3-triazoles has been described.[123] It involves the reactionof organic azides with alk-1-ynes in the presence of the catalyst (0.25–2 mol%) preparedin situ by reduction of copper sulfate with ascorbic acid and/or sodium ascorbate. The re-action proceeds to completion in 6 to 36 hours at room temperature in a variety of sol-vents, including aqueous tert-butyl alcohol or ethanol and, very importantly, water withno organic cosolvent. The use of microwave-induced 1,3-dipolar cycloaddition of organicazides to alk-1-ynes under solvent-free conditions is also another important develop-ment.[124,125] It allows a substantial decrease in reaction times, reduced pollution, lowcost, and simplicity in processing and handling. The addition of O-propargyl glycosidesand propargyloxy-calixarenes to a calixarene diazide leads to the formation of interesting1,2,3-triazole derivatives having glycosyl and calixarene moieties.[126]

Scheme 42 Addition of Azides to Alk-1-ynes[99,103,104,106–108,112,124,125,127–132]

R1N3 +N

NN

93

H R2

R2

R1

92

N

NNR2

94

R1

+


93 94

Ph Ph toluene, reflux, 17 h 43 52 [127]

Ph (CH2)3OH 100 8C, 15 h 63 31 [128]

Ph CO2Me rt, 12 d; 60 8C, 34 h 88 12 [103]

Bn Ph toluene, reflux, 17 h 39 55 [127]

Bn CONHBn microwave irradiation,55 8C, 30 min

65 22 [125]

(CH2)3Ph piperidino-carbonyl

microwave irradiation,55 8C, 30 min

65 22 [125]

CH2CO2Et Ph toluene, reflux, 48 h 41 36 [129]

1-adamantyl Ph toluene, reflux, 35 h 60 21 [107]

1-adamantyl 1-adamantyl toluene, reflux, 30 h 67 0 [107]

1-adamantyl CO2Me toluene, reflux, 11 h 84 0 [107]

CH2PO(OEt)2 Ph microwave irradiation,120 8C, 30 min

45 54 [124]

CH2PO(OEt)2 CH2OH microwave irradiation,100 8C, 30 min

30 69 [124]

CH2PO(OEt)2 CO2Et microwave irradiation,100 8C, 5 min

61 31 [124]

CF2CFHCF3 Ph steel bomb, 130 8C, 6 h 32 62 [99]

CF2CFHCF3 Bu steel bomb, 120 8C, 6 h 37 58 [99]





93 94

CF2CFHCF3 CO2Me steel bomb, 120 8C, 6 h 70 18 [99]

CF2CFHCF3 TMS steel bomb, 90 8C, 6 h 50 – [99]

CH2C(NO2)2Me CO2H CHCl3, rt, 3 d 89a [130]

CH=CH-t-Bu CO2Me rt 54 13 [108]

4-O2NC6H4 CO2Et benzene, reflux, 48 h 60 25 [104]

CH2CH2CO2Et Bz benzene, reflux, 22 h 48 30 [131]

Cy Bz benzene, reflux, 48 h 26 10 [131]

4-Tol Bz benzene, reflux, 26 h 60 11 [131]

1-naphthyl Bz benzene, reflux, 24 h 44 14 [131]

1-naphthyl CO2Et 100 8C, 8 h 71 12 [106]

S

O

OO

Pri

CO2Me benzene, reflux, 18 h 66 23 [112]

S

O

OO

Pri

TMSbenzene, reflux, 7 d

81 – [112]

S

O

OO

Pri

SO2Ph benzene, reflux, 16 h 72 5 [112]

NN

N

Ph toluene, reflux, 2 h 40 60 [132]

a Combined yield of 93 and 94.

The 1,3-dipolar cycloaddition of aryl azides to (trimethylsilyl)acetylene is regioselectiveand gives, after several days at 25 8C, almost quantitative yields of the 1-aryl-4-(trimethyl-silyl)-1,2,3-triazoles 96 (Scheme 43).[133] A study has shown that the rate of these cyclo-additions increases logarithmically with pressure.[134] For example, the reaction of 4-methoxyphenyl azide with 95 takes 55 days, at atmospheric pressure, to complete con-sumption of the azide. The same reaction is complete in 1.5 hours if it is conducted atroom temperature but under pressure (0.3 GPa). At pressures of about 1 GPa these reac-tions are almost instantaneous and quantitative.[134]





bScheme 43 Addition of Aryl Azides to (Trimethylsilyl)acetylene[133]

Ar1N3 +N

NN

96

TMSH

TMS

Ar1

95

sealed tube

25 oC

Ar1 Time (d) Yield (%) Ref

Ph 35 96 [133]

4-Tol 40 95 [133]

4-MeOC6H4 55 95 [133]

4-ClC6H4 25 95 [133]

4-O2NC6H4 20 95 [133]

4-NCC6H4 26 96 [133]

benzo[b]thien-2-yl 9 93 [133]

benzo[b]thien-3-yl 28 95 [133]

13.13.1.1.3.1.1.3.3 Variation 3:Addition of Azides to Unsymmetrical Disubstituted Alkynes

Azides add to unsymmetrical disubstituted alkynes to give mixtures of isomeric triazoles97 and 98 (Scheme 44). The relative proportions of the two products are strongly depen-dent on the nature of R2 and R3.

Scheme 44 Addition of Azides to Unsymmetrical Disubstituted Alkynes[103,124,135–137]

R1N3 +N

NN

97

R3R2

R2

R1

N

NNR2

98

R3

R1

+R3

R1 R2 R3 Conditions Yield (%) Ref

97 98

Ph CH2OH CO2Me toluene, 55 8C, 14 d 8 49 [135]

4-MeOC6H4 CH2OH CO2Me benzene, rt, 60 d 31 59 [136]

Ph Ph Bz benzene, 80 8C, 19 h 0 86 [103]

1-naphthyl Me CO2Me 100 8C, 8 h 9 72 [106]

CH2CO2-t-Bu CF3 PO(OiPr)2 Et2O, rt, 20 h 68 22 [137]

CH2PO(OEt)2 Me PO(OEt)2 100 8C, 60 h 73 23 [124]

CH2PO(OEt)2 Ph CO2Et 160 8C, 10 min 58 42 [124]

A recognition-mediated reaction between 4-(azidomethyl)benzo-15-crown-5 99 and theasymmetric alkyne 100 shows that the regioselectivity of the cycloaddition can be con-trolled. The mutual recognition between the ammonium cation and the crown etherleads to the formation of triazole 101 and its regioisomer in the ratio of 97:3 (Scheme45).[138]




bScheme 45 Recognition-Mediated Reaction between Azides and UnsymmetricalDisubstituted Alkynes[138]

99

N

NN

101

O

H3N

But

+

+

CF3CO2−

O

O

O

O

O

N3

O

OO

OO

H3N

O

But

+

CF3CO2−

100

Azido sugars have been extensively used to prepare carbohydrate-derived 1,2,3-tria-zoles.[139] For example, the �-D-galactopyranosyl azide 102 reacts with alkyne 103 to yieldmixtures of the nucleoside triazole analogues 104/105 (30%/49%) (Scheme 46).[139] Analo-gously, the 5-azido-5-deoxy-Æ-D-xylofuranose 106 reacts with a range of alkynes to givemixtures of 5-(1H-1,2,3-triazol-1-yl)-Æ-D-xylofuranoses 107/108.[140,141] 2,3,5-Tri-O-benzoyl-�-D-ribofuranosyl azide reacts with methyl 4-hydroxybut-2-ynoate to yield a mixture ofthe two expected isomeric triazoles in 75% yield.[142]

Scheme 46 Addition of Azido Sugars to Alkynes[139–141]

102

N

NNF3C

105 49%

Ph

OAcO

AcOAcO

OAc

O

OAcAcO

AcO

OAc

N3+ Ph CF3

toluene

reflux, 14 h

N

NNPh

104 30%

F3C

OAcO

AcOAcO

OAc

+

103





b108

+ R1 H

toluene

reflux

107

+O

N3

OH

OO

O

N

OH

OO

NN

R1

O

N

OH

OO

NN

R1

R1 = Ph, CH2OH, CO2Et

106

13.13.1.1.3.1.1.3.4 Variation 4:Using Polymer-Supported Methods

The use of polymer-supported methods to prepare carbohydrate-derived 1,2,3-triazoles isalready established. Addition of azidodeoxy carbohydrate derivatives to the monomethylether derivative of polyethylene glycol 109 (a soluble polymer-supported alkyne) yieldsthe polymer-supported triazoles 110/111 in a proportion of approximately 2:1 (Scheme47). Treatment of these polymers with sodium borohydride in hot ethanol gives the cor-responding “free” triazoles 112/113 in greater than 75% yield.[143] In a variation of this pro-cedure a succinate ester linkage (instead of an oxalyl ester) is also successfully used to pre-pare polymer-supported glycosyl triazoles. In this procedure, the “free” glycosyl triazolescan be obtained in high yields (>90%) and high purity by treatment of the polymer with anexcess of ammonia in methanol solution, followed by precipitation of the polymer withether and filtration.[141]

Scheme 47 Addition of Azido Sugars to Soluble Polymer-Supported Alkynes[143]

toluene

reflux, 12 h

O

N3

OH

OO

MeO

O

O

O

On

109

sugar N3+

N

NN

110sugar

O

OO

O

O

Me

n

N

NN

111sugar

nO

O

O

OOMe

N

NN

sugar

HON

NN

sugar

HO

112 113

+

NaBH4, EtOH

heat, 3 h

sugar N3 =

N3O

O

OO

O

N3

AcOAcO

OMeAcO

, ,

+




bThe complementary method, i.e. reaction of a polymer-supported azido sugar with al-kynes, can also be used (Scheme 48). Azide 114 reacts with alkynes to give mixtures ofthe two regioisomers 115/116 in high yields (R1 = Ph; R2 = H, 50%; R1 = CO2Et; R2 = H,>95%; R1 = CH2OH; R2 = H, >95%). Treatment of these compounds with ammonia in meth-anol solution, followed by precipitation of the polymer with diethyl ether and filtrationgives the corresponding “free” triazoles 117/118.[141]

Scheme 48 Addition of Alkynes to Soluble Polymer-Supported Azido Sugars[141]

toluene

reflux, 2 d

114

+

n

NH3, MeOH

rt, 10 h O

N

OH

OO

NN

R2

R1

O

N

OH

OO

NN

R1

R2

+

117 118

O

N

O

OO

NN

R1

R2

O

O

O

OMe

nO

N

O

OO

NN

R2

R1

O

O

O

OMe

n O

N3

O

OO

O

O

O

OMe

R2R1

115 116

+

A solid-phase synthesis of functionalized 1,2,3-triazoles from the reaction of resin-boundazides 119 and terminal alkynes has been reported (Scheme 49).[144] The reaction withmethyl propynoate occurs in dimethylacetamide at 60 8C and, after cleavage in trifluoro-acetic acid, provides the free acids 120 (R2 = CO2Me), as single isomers, in moderate yields(17–27%). The reaction with phenylacetylene requires higher temperatures (120 8C) andprovides 1:1 mixtures (22–25%) of the possible regioisomers 120 (R2 = Ph) and 121(R2 = Ph) after trifluoroacetic acid cleavage.

Scheme 49 Solid-Phase Synthesis of 1H-1,2,3-Triazoles Using Resin-Bound Azides andTerminal Alkynes[144]

N

NN

120

H1. R2

R2

N

NNR2

121

+

R1 CO2H R1 CO2H

DMA, 60 or 120 oC, 3 d

2. TFA, CH2Cl2, rt, 18 h

O

O

N3

R1

R1 = H, Me, Et, (CH2)5Me; R2 = CO2Me, Ph

17−27%

119 1:1





bA solid-phase, regioselective, copper(I)-catalyzed, 1,3-dipolar cycloaddition of terminal al-kynes to azides has been used to prepare peptido-1,2,3-triazoles.[145] Copper(I) salts areused as catalysts in the reaction of resin-bound terminal alkynes to primary, secondary,and tertiary alkyl azides, aryl azides, and an azido sugar at 25 8C, affording selectively 1,4-disubstituted 1H-1,2,3-triazoles with quantitative conversions and purities ranging from75 to 99%.[145]

13.13.1.1.3.1.1.3.5 Variation 5:Intramolecular 1,3-Dipolar Cycloadditions

The intramolecular 1,3-dipolar cycloaddition of an azido group onto a C”C bond givespolycyclic triazoles. Azides 122 and 124, for example, give triazoles 123 (52%) and 125(59%), respectively, when heated in refluxing toluene (Scheme 50).[146]

Scheme 50 Synthesis of 1,2,3-Triazoles via Intramolecular1,3-Dipolar Cycloadditions[146]

123

toluene, reflux, 36 h

N3

OH

N NN

OH

122

52%

125

toluene, reflux, 24 h

N3

OTBDMS

N NN

OTBDMS

124

HO HO

59%

Propargyl azides 127 undergo intramolecular cycloaddition reactions yielding N-unsub-stituted 1H-1,2,3-triazoles 130 (Scheme 51). The reaction must be carried out in nucleo-philic solvents, such as methanol or ethanol, or in the presence of nucleophiles such asazide ion, amines, or thiols, if not, then only polymeric triazole products are obtained.The mechanism of this transformation involves the rearrangement of the propargyl azideto allenyl azide 128 that gives by rapid ring closure the triazafulvene 129. This short-livedintermediate is trapped by nucleophiles to give triazoles 130 in good yields.[147,148] Sincepropargyl azides can be prepared from propargyl halides or propargyl tosylates 126(X = halogen, OTs) and sodium azide, various substituted 1,2,3-triazoles can be synthe-sized in good yields in one-pot procedure from these precursors without the necessity toisolate the potentially hazardous propargyl azides. In the presence of sodium hydroxidethe propargyl azides 127 undergo base-catalyzed (prototropic) rearrangement to allenylazides 131. The immediate cyclization of this intermediate leads to the triazafulvene132, which can be trapped by nucleophiles to give triazoles 133 in good yields (Scheme51).[148]




bScheme 51 Synthesis of 1H-1,2,3-Triazoles from Propargyl Azides or Their Precursors[148]

128

N

NH

N

130

126

R2

X

R1

N3

127

R2

N3

R1

•R2

N3

R1

NuH

R2

Nu

R1

129

131

N

NH

N

133

•R2

R1

NuH

132

20−70 oC

NaOHN3

R1

R2

Nu

N

NN

R2

R1

N

NNR1

R2

R1 R2 X Conditions Nu Yield (%)of 130

Ref

Me H OTs NaN3, MeOH, H2O, 20–40 8C OMe 82 [148]

Ph H Br NaN3, MeOH, H2O, reflux OMe 87 [148]

H H Br 1. NaN3, dioxane, H2O, rt, 1 h S-iPr 31 [148]

2. iPrSH, 70 8C, 3 h

H H OTs 1. NaN3, dioxane, H2O, rt NH2 77 [148]

2. NH3, H2O, 50–60 8C

H MOM OSO2Ph 1. NaN3, MeOH, H2O, rt, 24 h OMe 88 [148]

2. MeOH, reflux, 6 h

H Ph OTs 1. NaN3, MeOH, H2O, 35 8C OMe 73 [148]

2. MeOH, reflux, 45 h

Depending on the reaction conditions, propargyl azides 127 can be selectively convertedinto triazoles 130 or 133. For example, azide 134 can produce triazole 135 or triazole 136depending only on the presence or absence of sodium hydroxide (Scheme 52).[148]





bScheme 52 Selective Synthesis of Isomeric 1H-1,2,3-Triazoles from Propargyl Azides[148]

N

NH

N

135

134

H2N

NH3, NaOH

NH3

62%

MeO

N

NH

N

136

H2N

MeO

75%

N3

MeO

The intramolecular 1,3-dipolar cycloaddition of an azide group with a C”C bond has beenused extensively for the synthesis of nonclassical polycyclic �-lactams.[149–154]

13.13.1.1.3.1.1.3.6 Variation 6:Addition of Azides to Alkoxyalkynes

Nitrophenyl azides 138 undergo cycloaddition reactions with 1-methoxyalk-1-ynes 137 atroom temperature to give 1H-1,2,3-triazoles 139 in low yields (R1 = Et; X = H, 22%) or thecorresponding ring-opened isomeric Æ-diazocarboximidates 140 (R1 = Me, 52%; R1 = Et,75%) (Scheme 53).[155] The reaction of ethoxyacetylene with 4-methxoyphenyl azide and4-nitrophenyl azide also gives the corresponding 1-aryl-5-ethoxy-1H-1,2,3-triazoles.[103]

Scheme 53 Addition of Aryl Azides to 1-Methoxyalk-1-ynes[155]

N

NNMeO

139

R1

OMeR1

N3

O2N

NO2

X

+

CHCl3, rt

3−10 d

NO2

O2N X

N

140

NO2

O2N X

MeO

R1 N2

138137

R1 = Me, Et; X = H, NO2

X = NO2

Similarly, 5-ethoxy-1H-1,2,3-triazoles 143 are obtained from the reaction of ethoxyacety-lene (141) with phenyl azide, substituted phenyl azides[156] and hetaryl azides[114] 142(Scheme 54). The best yield is obtained with phenyl azide (87%). With 2-nitrophenyl azide,and 4-nitrophenyl azide the yields are very low (6–12%).




bScheme 54 Addition of Azides to Ethoxyacetylene[114,156]

N

NNEtO

143

OEtH + R1N36−87%

142141

R1 = aryl,

R1

O O

5-Ethoxy-1-(6-methyl-2-oxo-2H-pyran-4-yl)-1H-1,2,3-triazole (143, R1 = 6-methyl-2-oxo-2H-pyran-4-yl); Typical Procedure:[114]

A mixture of 4-azido-6-methyl-2H-pyran-2-one (0.77 g, 5.09 mmol), ethoxyacetylene(7.13 mmol, from a 50% soln in hexanes) and anhyd THF (18 mL) was left in a closed reac-tor for 7 d. The resulting precipitate of the product was collected by filtration and the fil-trate was left 7 d more at 30 8C to give a second crop. The combined precipitates werewashed with hexane to afford the pure product; yield: 24% (57% with respect to consumedazide 142); mp 159–161 8C.

13.13.1.1.3.1.1.4 Method 4:Addition of Ethyl Azidoformate and Cyanogen Azide to Alkynes

Ethyl azidoformate (144) undergoes addition to phenylacetylene to give 1,2,3-triazoles. Ifthe reaction is carried out at 50 8C (3 weeks) a mixture of the 1,4- and 1,5-disubstituted tri-azoles is obtained in a ratio of about 53:47 and an overall yield of 36% (Scheme 55).[157] Ifthe reaction is performed at 130 8C the two initially formed triazoles 145/146 isomerize toethyl 4-phenyl-2H-1,2,3-triazole-2-carboxylate (147) and this is the isolated triazole prod-uct (16%). Under these reaction conditions, 2-ethoxy-4(or 5)-phenyloxazole 148 (16%) isalso obtained.[157,158] The formation of this compound is due to the addition of (ethoxycar-bonyl)nitrene (generated by thermal decomposition of the azide) to phenylacetylene. Thereaction of ethyl azidoformate with dimethyl acetylenedicarboxylate and methyl propyn-oate also gives the corresponding triazoles (23 and 50% yield, respectively) and 2-ethoxy-oxazoles (3%).[158]

Scheme 55 Addition of Ethyl Azidoformate to Phenylacetylene[157,158]

N

NN

145

144

Ph

130 oC

50 oC

N

NN

147 16%

Ph

CO2Et

N

NN

146

CO2Et

Ph+

CO2Et

N

O

Ph

OEt+

148 or isomer 16%

HPh N3CO2Et+ 53:47

36%





bEthyl azidoformate reacts with N,N-diethylprop-1-yn-1-amine (149, R1 = Me) in carbon tet-rachloride at room temperature to yield only triazole 150 (R1 = Me) (Scheme 56).[159] How-ever, if an excess of the ynamine is used, the initially formed triazole isomerizes to ethyl5-(diethylamino)-4-methyl-2H-1,2,3-triazole-2-carboxylate.[159] Ethyl azidoformate alsoadds to ynamines 149 (R1 = Ac, CO2Me) to give the corresponding triazoles 150 in goodyields.[160] Benzoyl azide also adds readily to ynamines.[159,161] Addition of ethyl azido-formate to ethoxyacetylene (no solvent, rt, 35 d) gives a mixture of three isomeric tri-azoles: ethyl 5-ethoxy-1H-1,2,3-triazole-1-carboxylate, ethyl 4-ethoxy-1H-1,2,3-triazole-1-carboxylate, and ethyl 4-ethoxy-2H-1,2,3-triazole-2-carboxylate in a ratio of 54.5:42:3.5(by NMR). Addition of 1,4-diazabicyclo[2.2.2]octane converts 1-ethoxycarbonyl isomersinto the 2-ethoxycarbonyl derivative.[159]

Scheme 56 Addition of Ethyl Azidoformate to Ynamines[159,160]

N

NN

150144

R1

CO2Et

R1Me2NN3CO2Et +

CCl4, rt, 20 min, or

THF, 65 oC, 3 h

Me2N

149

R1 = Me 100%

R1 = Ac 82%

R1 = CO2Me 70%

Cyanogen azide (N3CN) reacts with acetylene at 45 8C to give 77% of a 1:1 adduct that iscolorless below its melting point (33 8C) but is yellow in the melt or in solution. The ad-duct is a tautomeric mixture of 1H-1,2,3-triazole-1-carbonitrile and N-cyano-Æ-diazoethyl-idenimine (see Scheme 3).[20] The cyanogen azide adducts of prop-1-yne, but-2-yne, andhex-1-yne are also tautomeric mixtures of the corresponding triazoles and N-cyano-Æ-di-azoimines.[20] Cyanogen azide reacts with ethoxyacetylene[20] and N,N-diphenylacetyl-amine[162] to afford only the diazo derivatives, resulting from ring opening of the initiallyformed 1H-1,2,3-triazole-1-carbonitriles.

13.13.1.1.3.1.1.5 Method 5:Addition of Sulfonyl Azides to Alkynes

Sulfonyl azides 151 undergo addition to electron-rich alkynes (ynamines and alkoxyal-kynes 152) to yield 1-sulfonyl-1H-1,2,3-triazoles 153 (Scheme 57).[103,155,163–167] However,these compounds are very labile and, in solution, exist in equilibrium with open-chain di-azo tautomers. In many cases the diazo tautomer is the sole product. As an example, ad-dition of arenesulfonyl azides 151 (R1 = aryl) to ynamine 152 (R2 = Me; Y = NEt2) givesmainly 1,2,3-triazoles 153 while the reaction of this type of azides with ynamine 152(R2 = Ph; Y = NMe2) gives the Æ-diazoamidines 154 (Scheme 57).[166]




bScheme 57 Addition of Sulfonyl Azides to Electron-Rich Alkynes[166]

N

NN

153151

R2

SO2R1

YR2

Y

152

R1SO2N3 +

N

SO2R1

Y

R2 N2

154

R1 R2 Y Yield (%) mp (8C) Ref

153 154

Ph Me NEt2 62 – 84–85 [166]

4-MeOC6H4 Me NEt2 58 – 54–56 [166]

4-Tol Me NEt2 65 – 49–52 [166]

4-AcHNC6H4 Me NEt2 78 – 131–132 [166]

4-O2NC6H4 Me NEt2 – 81 97–98 [166]

2,4-Cl2C6H3 Me NEt2 – 62 87–88 [166]

4-MeOC6H4 Ph NMe2 – 79 95–96 [166]

4-O2NC6H4 Ph NMe2 – 70 106–107 [166]

4-BrC6H4 Ph NMe2 – 65 102–103 [166]

3-O2NC6H4 Ph NMe2 – 78 104–105 [166]

2,5-Cl2C6H3 Ph NMe2 – 83 112–113 [166]

Tosyl azide reacts with 3-aminoprop-2-ynimidamides 155 to yield 1H-1,2,3-triazole-4-carboximidamide 156 in good yields (Scheme 58).[168]

Scheme 58 Addition of Tosyl Azide to 3-Aminoprop-2-ynimidamides[168]

NTs

NN

155

MeNMeNPh

NAr1Ar1HN

+ TsN3

CHCl3rt, 20 d

Ph

Ar1HN

Ar1N

N

NN

NTs

MeNPh

Ar1HN

Ar1

156 65−74%

Ar1 = Ph, 4-Tol

Reaction of Arenesulfonyl Azides 151 with Ynamines 152 (Y = Dialkylamino);General Procedure:[166]

A soln of the sulfonyl azide (0.01 mol) in THF (10 mL) was added to a soln of the ynamine(0.01 mol) in THF (5 mL) at –78 8C (cooled in dry ice/acetone bath) over 1 h. The soln wasthen allowed to warm to rt, filtered through anhyd alumina, and the solvent was removedby evaporation under reduced pressure. The resulting solid (or oil) was crystallized (Et2O/petroleum ether) to afford the appropriate triazole or Æ-diazoamidine.





b13.13.1.1.3.1.1.6 Method 6:

Addition of Azidotrimethylsilane and Azidotributylstannane to Alkynes

Azidotrimethylsilane can be successfully used as a safe synthetic equivalent of the highlyexplosive hydrazoic acid.[169,170] It undergoes addition to alkynes to give the corresponding2-(trimethylsilyl)-2H-1,2,3-triazoles 158 [via the 1-(trimethylsilyl)-1H-isomers 157] in goodyields (Scheme 59). For example, the reaction of azidotrimethylsilane with but-2-yne gives4,5-dimethyl-2-(trimethylsilyl)-2H-1,2,3-triazole (158, R1 = R2 = Me) in 78–87% yield. Sim-ilar results are obtained with other alkynes.[171] The trimethylsilyl group can be subse-quently replaced by a proton under very mild conditions.[171–173] In some cases, the N-un-substituted triazole 159 is the isolated product of the cycloaddition reaction.[174,175] A relat-ed silyl azide, (trimethylsilyl)methyl azide (TMSCH2N3), also reacts with alkynes to givequantitative yields of the corresponding 1-[(trimethylsilyl)methyl]-1H-1,2,3-triazoles.[176]

Scheme 59 Addition of Azidotrimethylsilane to Alkynes

N

NN

R2

TMSN3 +

120−150 oC

10−20 hR2R1

R1

TMS

N

NNTMS

R2

R1

H2O or

EtOH N

NH

N

R2

R1

159158 50−90%

157

100%

Azidotributylstannane (160) is another synthetic equivalent of hydrazoic acid. It gives 2-substituted triazoles 162 by reaction with mono- and disubstituted alkynes by a 1,3-dipo-lar cycloaddition to give initially the 1-substituted triazoles 161 (Scheme 60).[177–179]

Triazoles 162 can be converted into the N-unsubstituted derivatives by treatment with hy-drogen chloride. As an example, phenylacetylene reacts with 160 (neat, 140 8C, 12 h) togive triazole 162 (R1 = H; R2 = Ph) in 61% yield. On treatment with hydrogen chloride thiscompound is converted into triazole 163 (R1 = H; R2 = Ph) in 75% yield.

Scheme 60 Addition of Azidotributylstannane to Alkynes[177–179]

N

NN

R2

Bu3SnN3 +

140−180 oC

12−70 hR2R1

R1

N

NN

R2

R1

N

NH

N

R2

R1

163162

161

SnBu3

SnBu3

HCl, Et2O

160




b13.13.1.1.3.1.1.7 Method 7:

Addition of Azides to Metal Acetylides

Alkyl,[180,427] aryl,[180,181,425,427] and sulfonyl[182–184] azides form triazole derivatives with lith-ium, magnesium, and sodium derivatives of terminal alkynes. The mildness of the condi-tions required for the additions (0 8C or below) suggests that the mechanism of the reac-tion may be different from that of normal azide addition to alkynes. A plausible mecha-nism (Scheme 61) involves nucleophilic attack of the acetylenic anion 164 on the termi-nal nitrogen of the azide, followed by 1,5-anionic cyclization to give the triazolyl anion165.[3] The total regioselectivity of the reaction supports this interpretation. The triazolylanion so formed can be protonated (to give 166), carboxylated (to give 167) or can reactwith more azide to give a linear triazene 168 which, in turn, can be hydrolyzed to the tri-azolamine 169.[182]

Scheme 61 Addition of Azides to Metal Acetylides[182]

N

NN

NN NR2

R1

165

H3O+

164

R1 +− −+

R2

−NN

NR1

R2

N

NNR1

166

R2

CO2N

NNR1

167

R2

HO2C

R2N3N

NNR1

168

R2

NN

R2N− H3O+ N

NNR1

169

R2

H2N

−

Sodium phenylacetylide reacts with tosyl azide (1 equiv) to yield, after acidification, tria-zole 170. If an excess of tosyl azide is used, the 4-azidotriazole 171 is obtained (Scheme62). In both cases the yields are very low.[184] A copper(I)-catalyzed reaction of resin-boundterminal alkynes (probably involving the corresponding copper acetylides) with a rangeof organic azides has been reported.[145]





bScheme 62 Addition of Sodium Phenylacetylide to Tosyl Azide[184]

N

NN

170

Ph

Ph Na+−

1. TsN3 (1 equiv)

2. H3O+

Ts

N

NN

171

Ph

Ts

N31. TsN3 (excess)

2. H3O+

16%

9%

4-Azido-5-phenyl-1-tosyl-1H-1,2,3-triazole (171); Typical Procedure:[184]

A slurry of sodium phenylacetylide [prepared from PhC”CH (0.05 mol) and Na (0.05 mol)]in dry Et2O (25 mL) was added slowly to a stirred soln of tosyl azide (19.7 g, 0.10 mol) in dryEt2O (50 mL) at a rate which maintained the solvent at reflux. As the mixture was stirredfor 24 h a brown solid separated (15.2 g, 58%), which corresponds to a sodium salt of anintermediate compound. Part of this compound (5.0 g) was treated with hot glacial AcOH(10 mL) and a light yellow solid was obtained upon cooling. Two recrystallizations (glacialAcOH) afforded pure triazole 171; yield: 0.52 g (16%); mp 170–171 8C (dec).

13.13.1.1.3.1.2 Addition of Azides to C=C Bonds

The thermal cycloaddition of azides to alkenes is an important route to 1H-1,2,3-triazoles.Azides undergo addition to a wide range of angle strained, unstrained, and unactivateddouble bonds; to electron-rich double bonds such as enamines, enamides, enol ethers,and ketene acetals; and to alkenes bearing one or two electron-withdrawing groups.[7] Inthese reactions, 4,5-dihydro-1H-1,2,3-triazoles (D2-1,2,3-triazolines) are the addition prod-ucts but they can be aromatized to the corresponding triazoles by elimination of suitablegroups or by oxidation. In some cases the dihydrotriazoles aromatize spontaneously. Un-like the case of alkynes, the reaction of azides with alkenes is highly regioselective. Be-cause of this, it may be convenient to prepare a triazole via the dihydrotriazole since atthe end the separation of regioisomers is not needed.

The synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition of azides to alkenes re-quires patience. It may take weeks to months to obtain reasonable yields of the desiredcompound, especially if the C=C bond is not activated by electron-withdrawing or elec-tron-donating substituents. Increasing the reaction temperature is not always a solutionsince it is restricted by the thermal lability of most dihydrotriazoles (they readily extrudeN2).

13.13.1.1.3.1.2.1 Method 1:Addition of Sodium Azide to Activated Alkenes

Sodium azide undergoes addition to alkenes with strongly electron-withdrawing substitu-ents to give N-unsubstituted 1,2,3-triazoles in good yields (Scheme 63). The mechanismseems to involve the conjugate addition of the azide ion to the double bond, cyclizationof the resulting anion, and aromatization. The synthesis of triazoles 173 by the reactionof sodium azide with Æ-nitroacrylic ester 172 (Y = CO2Et) and Æ-nitro ketone 172 (Y = Bz)are examples of this method.[185] Other nitroalkenes are converted into 1,2,3-triazoles inthe same way.[186] Similarly, triazole 175 is obtained, along with two minor dihydrotri-azoles, from the reaction of diethyl (4-nitrobenzylidene)malonate (174) with sodium




bazide.[187] Ethyl 3-(4-nitrophenyl)acrylate reacts with sodium azide, in aprotic solvents, togive triazole 175 in moderate yields.[188] The reaction of �-aryl-Æ-(phenylsulfinyl)acrylates176 with sodium azide gives triazoles 177 in good yields.[189] 5-Tosyl-1H-1,2,3-triazole(179) is prepared in 50% yield from the reaction of 1,2-ditoylacetylene (178) with sodiumazide.[190,191] It has been shown that (E)-2-azidovinyl 4-methylphenyl sulfone is an inter-mediate in this transformation. Another example of synthesis of 1,2,3-triazoles from theaddition of sodium azide to activated alkenes is found in the preparation of (4-oxo-4H-1-benzopyran-2-yl)-1,2,3-triazoles 181 from 2-(2-arylvinyl)-4H-1-benzopyran-4-ones 180.[192]

Using 180 (X = H) as starting compounds, triazoles 181 are the only isolated products;the yields are in the range of 48–59%. When 2-(2-aryl-1-bromovinyl)-4H-1-benzopyran-4-ones 180 (X = Br) are used the triazoles 181 (38–40%) are obtained together with unexpect-ed 1-aryl-5-[(4-oxo-4H-1-benzopyran-2-yl)methyl]tetrazoles (10–12%).

Scheme 63 Addition of Sodium Azide to Activated Alkenes

HN

NO2

Y

172

+ NaN3

DMF, rt, 120 h

173

Y = CO2Et 70%

Y = Bz 54%

HN

NH

N

NY

174

+ NaN3

DMSO, 25 oC, 2 h

N

N

NH

175

41%

4-O2NC6H4 H

EtO2C CO2Et

4-O2NC6H4

EtO2C

176

+ NaN3

DMF, AcOH, rt, 24 h

N

N

NH

177

57−73%

Ar1 H

EtO2C SOPh

Ar1

EtO2C

Ar1 = Ph, 1-naphthyl, 2-furyl

178

+ NaN3DMSO, rt, 24 h

N

N

NH

179

50% TsTs

Ts

180

+ NaN3

DMF, reflux

181

O

O

X

Ar1

O

O

NH

NN

Ar1

X = H 48−59%

X = Br 38−40%





bSodium azide also adds to Æ-chloroenamines 182 (NR2R3 = NMe2, pyrrolidinyl, morpholi-no) to give 1,2,3-triazoles 184 (via the Æ-azidoenamines 183) in good yields (Scheme64).[193,194] However, with less basic Æ-chloroenamines (NR2R3 = NMePh), azirines 185 arethe sole reaction products.

Scheme 64 Addition of Sodium Azide to Æ-Chloroenamines[193,194]

182

+ NaN3

NR2R3

ClR1MeCN, CCl4

NR2R3

N3R1

N

NNR1

R3R2NN

NH

NR1

R3R2N

183

184 58−84%

N

NR2R3R1

185

R1 = Me, t-Bu, Ph

The addition of sodium azide to (1- and 2-acylvinyl)triphenylphosphonium salts 186 and189 gives, respectively, acyl or alkoxycarbonyl-1,2,3-triazoles 188 and 191 (via the ylides187 and 190) (Scheme 65).[195,196]

Scheme 65 Addition of Sodium Azide to (1- and 2-Acylvinyl)triphenylphosphoniumSalts[195,196]

186

NaN3, MeOH

H2O N

NH

N

R2

188 15−50%

R1 = iPr, t-Bu, Cy, cyclopropyl; R2 = H, Et

R1

O

Ph3P

R2

+

Cl−R1

O

Ph3P

R2

+

−

N3

187

− PPh3 R1

O

189

NaN3, H2O

1 h N

NH

N

191 30−95%

R1 = Me, Et, Pr, iPr, Ph, OMe

Ph3P+

X−

Ph3P+

−

N3

190

− PPh3 R1

O

R1

O O

R1

Ethyl 5-(4-Nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (175); Typical Procedure:[187]


Diethyl (4-nitrobenzylidene)malonate (174; 2.0 g, 6.82 mmol) was added in one portion toa soln of NaN3 (443 mg, 6.82 mmol) in dry DMSO (10 mL) at 25 8C. The mixture immediate-ly became deep orange-brown in color and heat was evolved. After stirring for 2 h, themixture was poured onto an ice/water slurry (40 g). The resultant mixture was extracted




bwith Et2O (two minor dihydrotriazoles could be obtained from this fraction), the aqueouslayer was acidified with dil HCl to pH 1 and extracted with Et2O. These ethereal extractswere dried (MgSO4) and evaporated to give a yellow amorphous solid (800 mg) which wasrecrystallized (CH2Cl2) to give pale yellow crystals; yield: 730 mg (41%); mp 174–176 8C.

13.13.1.1.3.1.2.2 Method 2:Addition of Azides to Activated Alkenes

Azides undergo addition to alkenes with strongly electron-withdrawing substituents togive 4,5-dihydro-1H-1,2,3-triazoles. Frequently these 4,5-dihydro-1H-triazoles are unstableand, by elimination of a stable fragment, aromatize to 1,2,3-triazoles[197–199] or are convert-ed into aziridines by elimination of nitrogen.[200] Generally the addition of azides to thesealkenes is regioselective and only one triazole is obtained. However, in some cases mix-tures of triazoles are formed. For example, 1-nitroalk-1-enes 192 react with phenyl ormethyl azide to give mixtures of the triazoles 193, 194, and 195 (Scheme 66).[197] The rel-ative proportions of these compounds are dependent of the experimental conditions.Nitrotriazoles 195 are obtained by air oxidation of the corresponding 4,5-dihydro-1H-tria-zoles. The formation of the two regioisomeric triazoles 193 and 194 is explained by theisomerization of the 1-nitroalk-1-enes to 2-nitroalk-1-enes.[197]

Scheme 66 Reaction of Azides with 1-Nitroalk-1-enes[197]

192

R1 = Me, Ph; R2 = Me, Ph, CO2Me

H

R2

H

NO2

R1N3 +

benzene

30−70 oC

4−15 d N

NNR2

193

R1

N

NN

194

R1

N

NNR2

195

R1

R2 O2N

+ +

Phenyl azide adds to 1-bromoethenesulfonyl chloride (196), in refluxing chloroform, toyield 4-bromo-1-phenyl-1H-1,2,3-triazole (198) in 45% yield (Scheme 67).[198] The unstable4,5-dihydro-1H-triazole 197 aromatizes promptly by losing sulfur dioxide and hydrogenchloride.

Scheme 67 Addition of Phenyl Azide to 1-Bromoethenesulfonyl Chloride[198]

196

H

H

Br

SO2ClPhN3 +

CHCl3reflux, 1 h N

NN

197

Ph

H

H

ClO2SBr

− SO2

− HCl

N

NN

198 45%

Ph

Br

Several perfluoroalkyl-substituted 1,2,3-triazoles linked to C6 of D-galactose and D-altroseare synthesized by this method.[199] For example, addition of the monosaccharide azide199 to the perfluoroalkyl-substituted phenyl vinyl sulfones 200 yields the reversed nu-cleosides 201 in good yields (Scheme 68). Only a single 1,2,3-triazole derivative is formedin each of these reactions.





bScheme 68 Addition of Monosaccharide Azides to Perfluoroalkyl-SubstitutedPhenyl Vinyl Sulfones[199]

199

OO

O

OO

N3

R1

SO2Ph

+

toluene, reflux

17−21 h

72−75%

OO

O

OO

NN

N

R1

200 201

R1 = CF3, (CF2)3CF3, (CF2)5CF3

Other sugar-derived 1,2,3-triazoles are prepared by a one-pot substitution–cyclization–ox-idation procedure starting from D-arabinose and L-fucose. The key step in this process isan intramolecular 1,3-dipolar cycloaddition of an azide to the C=C bond of an Æ,�-unsat-urated carboxylic ester. The resulting 4,5-dihydro-1H-triazole is readily aromatized by airoxidation.[201] Analogous sugar-derived 4,5-dihydro-1H-1,2,3-triazoles (related to D-glucoseand D-galactose) are stable but can be aromatized in good yields to the corresponding tri-azoles by oxidation with bromine.[202]

Maleimides and quinones have also been used as dipolarophiles in reactions witharyl azides,[203–206] silyl azides,[207] (azidoalkyl)indoles,[208] glycosyl azides,[209] (1-azidoalkyl)-phosphonates[210] and Æ-azidocarboxylic esters.[210]

6-Deoxy-1,2:3,4-di-O-isopropylidene-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]-Æ-D-galactopyranose, (201, R1 = CF3); Typical Procedure:[199]

A soln of azide 199 (0.85 g, 3.0 mmol) and sulfone 200 (R1 = CF3; 0.57 g, 2.40 mmol) in tol-uene (15 mL) was refluxed under argon for 17 h (TLC control). Then the solvent was evapo-rated under reduced pressure and the residue was purified by column chromatography(toluene/EtOAc 20:1); yield: 0.64 g (72%); mp 128–130 8C; [Æ]D –49.2 (CHCl3).

13.13.1.1.3.1.2.3 Method 3:Addition of Azides to Strained Alkenes

Azides react with alkenes to yield 4,5-dihydro-1H-1,2,3-triazoles. Whereas unactivated al-kenes are sluggish in their reaction with aryl azides, in contrast strained bicyclic alkenesare particularly reactive.[76] For example, the reaction of 4-bromophenyl azide with hex-1-ene (in excess) affords the corresponding 4,5-dihydro-1H-1,2,3-triazole in 89% yield after5.5 months at room temperature. At elevated temperatures (>80 8C), extensive decompo-sition of the 4,5-dihydro-1H-1,2,3-triazole is observed.[211] No detectable addition productis observed when the same azide and cyclohexene are left for three months at room tem-perature. Conjugated dienes are, however, much more reactive than the correspondingmono-unsaturated alkenes. For example, the adduct from the reaction of cyclohexa-1,3-diene and 4-bromophenyl azide begins to crystallize after three days at room temperatureand, after 18 days, a 77% yield of the corresponding 4,5-dihydro-1H-1,2,3-triazole is ob-tained.[211] On the other hand, phenyl azide and substituted phenyl azides react with nor-bornene, in refluxing petroleum ether (60–90 8C) for three to four hours, to give the cor-responding 1-aryl-4,5-dihydro-1H-1,2,3-triazoles in 51–93% yield.[212,213] Norbornene andother strained alkenes also react with azidotrimethylsilane to give the corresponding 1-(trimethylsilyl)-4,5-dihydro-1H-1,2,3-triazole adducts in high yields.[214] The reaction ofnorbornene and dicyclopentadiene with several heterarylmethyl azides has been stud-ied.[132]




bThe reaction of azides with norbornadiene is particularly interesting since it allows

the synthesis of 4,5-unsubstituted triazoles 204 (Scheme 69). The thermolysis of the inter-mediate 4,5-dihydro-1H-1,2,3-triazole 203 gives the triazole and cyclopentadiene (via aretro-Diels–Alder reaction). For example, the reaction of norbornadiene with diethyl (azi-domethyl)phosphonate [202, X = PO(OEt)2] in tetrahydrofuran at room temperature givesthe 4,5-dihydro-1H-1,2,3-triazole [203, X = PO(OEt)2] in 92% yield. Thermolysis of this com-pound at 60 8C yields the corresponding triazole in 74% yield.[249] Similarly, Æ-alkoxy- andÆ-alkylsulfanyl-substituted azides, on reaction with norbornadiene in refluxing 1,4-diox-ane, also give the corresponding triazoles in high yields.[215] Phenyl azide and substitutedphenyl azides also react with norbornadiene to give the corresponding 4,5-dihydro-1H-1,2,3-triazoles which, by thermolysis, yield the corresponding 1-aryl-1H-1,2,3-tria-zoles.[213,216,217] In the reaction of norbornadiene with azidotrimethylsilane the initiallyformed 4,5-dihydro-1H-1,2,3-triazole is converted, spontaneously, into 2-(trimethylsilyl)-2H-1,2,3-triazole.[214] Addition of a range of hetaroyl azides to the strained 5-methylenebi-cyclo[2.2.1]hept-2-ene, at room temperature, afforded carbonyl aziridines as the majorproduct. These compounds are formed by loss of molecular nitrogen from the 4,5-dihy-dro-1H-1,2,3-triazole adducts.[218]

Scheme 69 Reaction of Azides with Norbornadiene[215,249]

202

THF, rt

203

X = PO(OEt)2, OR1, SR1

X N3+ N

NN

X 60 oC

−

204

N

X

N

N

The oxa and aza analogues of norbornadiene 205 (X = O, NCO2Et) also react with phenylazide to give 1,2,3-triazoles (Scheme 70). While triazole 207 is obtained in quantitativeyield from 205 (X = O), the reaction with 205 (X = NCO2Et) gives two triazoles: 207 (64%)and 1-phenyl-1H-1,2,3-triazole (36%).[219,220]

Scheme 70 Reaction of Phenyl Azide with 7-Oxa- and 7-Azabicyclo[2.2.1]hepta-2,5-dienes[219,220]

205 206

X = O, NCO2Et

X X

NPh

NN

CO2Me

CO2Me

PhN3

CO2Me

MeO2C−

207

NN

N

X PhMeO2C

MeO2C

Methylenecyclopropane is another interesting strained system that reacts readily withphenyl azide to give stable 4,5-dihydro-1H-1,2,3-triazoles.[221] However, the equivalent re-action with alkyl 2-methylenecyclopropane-1-carboxylates 208 yields 1,2,3-triazoles 210(Scheme 71).[128] A probable mechanism for the rearrangement of the intermediate 4,5-di-hydro-1H-1,2,3-triazoles 209 is shown in Scheme 71.





bScheme 71 Reaction of Phenyl Azide with Alkyl 2-Methylenecyclopropane-1-carboxylates[128]

209

+ PhN3

R3

R1O2C

R2

100 oC

12−24 h

208

210 R1 = Me; R2 = H; R3 = CO2Me 91%

R1 = Et; R2 = R3 = H 50%

R1 = Et; R2 = Me; R3 = H

NN

N

Ph

R3R2

R1O2C

N

NN

R3

R2

R1O

O HPh

Dimethyl 2-(1-Phenyl-1H-triazol-4-yl)butanedioate (210, R1 = Me; R2 = H; R3 = CO2Me);Typical Procedure:[128]

A mixture of 208 (R1 = Me; R2 = H; R3 = CO2Me; 2 g) and phenyl azide (10 mL) was heated ona steam bath for 12 h. The mixture was cooled and hexane was added to dissolve the re-maining phenyl azide. The supernatant layer was decanted and the resulting brown solidwas recrystallized (acetone/cyclohexane) to give triazole 210 (R1 = Me; R2 = H; R3 = CO2Me);yield: 3.1 g (91%). A pure sample was obtained by recrystallization (EtOAc); mp 114–115 8C.

13.13.1.1.3.1.2.4 Method 4:Addition of Azides to Allenes

Aryl azides undergo addition to allenes to give 4-alkylidene-4,5-dihydro-1H-1,2,3-triazolesin reasonable yields. 4,5-Dihydro-1H-1,2,3-triazoles 212, for example, are obtained in 29–73% yield from the reaction of 2,4-dimethylpenta-2,3-diene (211) (tetramethylallene) withphenyl azide and nitrophenyl azides (Scheme 72).[222]

Scheme 72 Addition of Aryl Azides to Tetramethylallene[222]

+ Ar1N3

212

Ar1 = Ph 29%

Ar1 = 4-O2NC6H4 73%

Ar1 = 2,4,6-(O2N)3C6H2 72%

•

211

NN

N

Ar1

When it is possible, the 4-alkylidene-4,5-dihydro-1H-1,2,3-triazoles aromatize spontane-ously to 1,2,3-triazoles, as observed in the reaction of propa-1,2-diene with phenyl azide.In this case a mixture of 5-methyl-1-phenyl-1H-1,2,3-triazole (0.6%), 4-methyl-1-phenyl-1H-1,2,3-triazole (1%), and a diamine (18%) is obtained.[223] Similarly, addition of phenyl azideto methyl buta-2,3-dienoate (213) gives a mixture of the triazoles 214 and 215 (9:1) in 67%yield (Scheme 73);[224] the addition occurs exclusively at the Æ,�-double bond.




bScheme 73 Addition of Phenyl Azide to Methyl Buta-2,3-dienoate[224]

+ PhN3

214

67%•

CO2Me

213

74 oC, 24 h

215

+

NN

N

Ph

MeO2C

NN

N

PhMeO2C

9:1

Phenyl azide adds to cyclonona-1,2-diene (216) to give selectively the 4,5-dihydro-1H-1,2,3-triazole 217 (Scheme 74). This stable compound can be isomerized to the corre-sponding triazole 218 by treatment with a strong base.[223] When optically active (+)-(R)-cy-clonona-1,2-diene is used the (+)-(S)-4,5-dihydro-1H-1,2,3-triazole 217 is obtained, suggest-ing a concerted cycloaddition mechanism.

Scheme 74 Addition of Phenyl Azide to Cyclonona-1,2-diene[223]

+ PhN3

217

21%•

216

toluene

reflux, 10 h

NN

N

Ph

70%

NaOEt, EtOH

reflux, 3 d

218

NN

N

Ph

2,4,6-Trinitrophenyl azide (220) (picryl azide) adds to (aryloxy)allenes 219 to give triazoles222 or 223, depending on the substituents R1 and R5 (Scheme 75). The reactions proceedvia the unisolated 4,5-dihydro-1H-1,2,3-triazoles 221, which undergo an exceptionally fac-ile Claisen rearrangement to triazoles 222.[225] These compounds, unless blocked by a sub-stituent at R1, rapidly tautomerize to the isomeric compounds 223. When R1 and R5 arechloro or methyl the cyclohexadienone derivatives 222 are isolated in 66–85% yield.When R1 or R5 is hydrogen, triazoles 223 are isolated in 67–79% yield.

Scheme 75 Addition of 2,4,6-Trinitrophenyl Azide to (Aryloxy)allenes[225]

+ Ar1N3

219

CHCl3, rt

24 h to 3 weeks

O

•R1

R2

R3

R4

R5

221

R2

R3

R4

R5

O

R1

NN

N

220

222 R1 = R5 = Cl, Me 66−85% 223 R1 or R5 = H 67−79%

R2

R3

R4

R5

Ar1 = 2,4,6-(O2N)3C6H2

N

NN

OH

Ar1

Ar1

R2

R3

R4

R5

N

NN

O Ar1

R1





bAn interesting one-pot procedure for the conversion of allenyl derivatives into 4,5-unsub-stituted 1,2,3-triazoles has been described.[226,227] The method involves a sequential andcascade palladium-catalyzed azide formation (from aryl/hetaryl/vinyl iodides, allene, andsodium azide) followed by a 1,3-dipolar cycloaddition to norbornadiene and finally a ret-ro-Diels–Alder reaction.

1-Phenyl-1,4,5,6,7,8,9,10-octahydrocyclonona[d][1,2,3]triazole (218); Typical Procedure:[223]

A soln of cyclonona-1,2-diene (216; 1.22 g, 0.01 mol) and phenyl azide (1.19 g, 0.01 mol) intoluene (15 mL) was refluxed for 10 h. The viscous yellow oil, obtained upon solvent evap-oration, crystallized when stored at rt for several days. Recrystallization [petroleum ether(bp 60–110 8C)] gave 4,5-dihydro-1H-1,2,3-triazole 217; yield: 0.51 g (21%). A soln of the 4,5-dihydro-1H-triazole (1.00 g, 4.14 mmol) in 0.75 M NaOEt in EtOH (40 mL) was refluxed for3 d. After solvent evaporation, the residue was extracted with Et2O and the ether extractwas washed with H2O until the aqueous washes were neutral. The Et2O layer was dried(MgSO4) and evaporated to give 0.81 g of crude product. Crystallization (petroleumether/benzene 3:1) afforded white crystalline triazole 218; yield: 0.70 g (70%); mp 77–78 8C.

13.13.1.1.3.1.2.5 Method 5:Addition of Azides to Æ-Acylphosphorus Ylides

The addition of azides to Æ-acylphosphorus ylides is a versatile method for the synthesisof 1,2,3-triazoles. Combining different Æ-acyl- or Æ-alkoxycarbonyl phosphorus ylides 224with azides of various types gives a range of substituted triazoles 226 (Scheme 76). Thereaction is regioselective, it requires mild conditions (room temperature or refluxing ben-zene) and generally the triazoles are obtained in good to very good yields.

Æ-Acylphosphorus ylides are commonly represented in the three resonance forms224A, 224B, and 224C. However, it has been demonstrated that they exist essentially orexclusively in the cis-enolate configuration 224C. The reaction of these ylides with azidesis accelerated by electron-releasing substituents on the ylide and electron-withdrawingsubstituents on the azide. The polarity of the solvent has only a small effect on the reac-tion rate. Low entropies of activation are obtained for these reactions. All these kineticdata indicate that the mechanism of these reactions involves a concerted 1,3-dipolar cy-cloaddition of the azide to the C=C bond in 224C.[228] The resulting 4,5-dihydro-1H-1,2,3-triazoles 225 are converted into triazoles 226 by spontaneous elimination of triphenyl-phosphine oxide. When acyl or alkoxycarbonyl azides are used, the initially formed 1-sub-stituted triazoles 226 (R1 = COX) isomerize to the corresponding 2-substituted triazoles227.[229,231] This synthetic method is, however, not general; with some phosphorus ylides,especially Æ-ethoxycarbonyl phosphorus ylides (224, R2 = OEt), diazo compounds and oth-er products are obtained rather than triazoles.[230–232] With these compounds, in the caseswhere 1,2,3-triazoles are formed the yields are moderate (when R3 = Me) or very low(when R3 = Ph).




bScheme 76 Addition of Azides to Æ-Acylphosphorus Ylides[228–230,233,234]a

+ R1N3

224A

R1 = COX

R1 = alkyl, aryl, COR4, CO2Et, SO2Ar1

R2 O

R3 PPh3

R2 O

R3 PPh3+−

R2 O−

R3 PPh3+

224B 224C

N

N

N

R3

Ph3P

−O

R2

+

− Ph3PO

R1

225 226 227

NN

N

R1

R3

R2N

NR1

NR3

R2

R1 R2 Conditions Yield (%) Ref226 227

O

OO

O(MeO)3C6H2

Mebenzene, reflux,14–16 h

63 – [233]

O

OO

O(MeO)3C6H2

Phbenzene, reflux,14–16 h

52 – [233]

acridin-9-yl CH2NMe2 benzene, reflux, 2 h 49 – [234]

acridin9-yl N benzene, reflux, 2 h 73 – [234]

Ph Ph benzene, reflux, 48 h 80 – [228]

Ph 4-O2NC6H4 benzene, reflux, 6 d 67 – [228]

4-O2NC6H4 Me benzene, reflux, 0.5 h 73 – [228]

4-O2NC6H4 4-O2NC6H4 benzene, reflux, 48 h 98 – [228]

4-MeOC6H4 Ph benzene, reflux, 72 h 54 – [228]

4-MeOC6H4 4-O2NC6H4 benzene, reflux, 10 d 70 – [228]

Ts Me CH2Cl2, rt, 0.25 h 98 – [230]

Ts Ph CH2Cl2, rt, 1 h 98 – [230]

Ts 4-O2NC6H4 CH2Cl2, rt, 10 h 87 – [230]

Bz Me CH2Cl2, rt, 48 h – 50 [229]

4-O2NC6H4CO Me CH2Cl2, rt, 24 h – 65 [229]

4-O2NC6H4CO Ph CH2Cl2, rt, 24 h – 68 [229]

4-MeOC6H4CO Me CH2Cl2, rt, 7 d – 24 [229]

4-MeOC6H4CO Ph CH2Cl2, rt, 14 d – 75 [229]

3-O2NC6H4CO 4-O2NC6H4 CH2Cl2, rt, 20 d – 43 [229]

CO2Et Ph CH2Cl2, rt, 48 h – 46 [229]

CO2Et 4-O2NC6H4 CH2Cl2, rt, 14 d – 76 [229]

a Note: R3 = H for all examples in the table.





bThe reaction of a quinuclidin-3-yl Æ-acylphosphorus ylide with 3-nitrobenzoyl azide in re-fluxing acetonitrile, followed by column chromatography on basic alumina, affords thecorresponding N-unsubstituted 1,2,3-triazole in 52%.[235] The reaction of vinyl azides withÆ-acylphosphorus ylides is a convenient method for the synthesis of 1-vinyl-1H-1,2,3-tria-zoles.[236] The reaction of Æ-acylphosphorus ylides with azides has been used to prepare arange of 1-[(diethoxyphosphoryl)methyl]-1H-1,2,3-triazoles 230[237] and 1,2,3-triazole nu-cleosides 231[238] and 232[239] (Scheme 77). Addition of acetyl azide to Æ-acyl-Æ-alkylphos-phorus ylides or acetylation of those phosphorus ylides and subsequent treatment withsodium azide gives the same 1,2,3-triazoles.[240]

Scheme 77 Addition of (Diethoxyphosphoryl)methyl Azides and Glycosyl Azides toÆ-Acylphosphorus Ylides[237–239]

R1 = H, Ph; R2 = Me, Ph, CO2Et

R2 O−

PPh3+

229 230

(EtO)2P N3

R1

+

toluene

110 oC, 5−27 h

228

61−83%

O

NN

N

R2

R1 P(OEt)2

O

O−

PPh3+

231

+O

BzON3

OBzBzO

Br

toluene

110 oC, 45 min

38%

O

BzON

OBzBzO

N

NBr

R2 O−

PPh3+

232

+O

N3

OAcAcO

toluene

80 oC, 60 h

59−82%

ON

OAcAcO

N

N R2BzO BzO

R2 = Me, Et, iPr, CO2Et

1-[1-(Diethoxyphosphoryl)alkyl]-1H-1,2,3,-triazoles 230; General Procedure:[237]

A soln of diethyl (azidomethyl)phosphonate 228 (2 mmol) and Æ-acylphosphorus ylide229 (2–2.3 mmol) in dry toluene (15 mL) was refluxed for 5–27 h. The solvent was thenevaporated in vacuo. The product was separated from the Ph3PO by flash chromatographyto give analytically pure triazole 230.

13.13.1.1.3.1.2.6 Method 6:Addition of Azides to Enamines or Enol Ethers

Azides undergo addition to enamines 233 (R1 = amino)[241] and to enol ethers 233 (R1 = alk-oxy)[242,243] under mild conditions, frequently at room temperature, to yield 4,5-dihydro-1H-1,2,3-triazoles 234 (Scheme 78). These reactions are completely regioselective; theamino or alkoxy group in the resulting 4,5-dihydro-1H-1,2,3-triazoles is in the 5-position.In some cases the 4,5-dihydro-1H-1,2,3-triazoles aromatize spontaneously to 1,2,3-tria-zoles 235, in others the aromatization is effected by heating the compound alone (forenol ether adducts) or by treatment with acid or base (Scheme 78).




bScheme 78 Addition of Azides to Enamines or Enol Ethers[241–243]

R3 H

Y

234

H+ or OH−

Y = NR42, OR4

R2

R1N3 +N

NN

R1

Y

R2

− HY

235

N

NN

R1

R3

R2

233

HR3

The thermal elimination of nitrogen from the 4,5-dihydro-1H-1,2,3-triazoles is a possiblecompeting reaction. Some dihydrotriazoles derived from cyclic enol ethers and enaminesfail to give triazoles for this reason.[242,244,245] In general, however, yields are very good. Thereaction is most effective with azides bearing electron-withdrawing groups such as nitro-phenyl, phenylsulfonyl, or ethoxycarbonyl. Sulfonyl azide adducts give N-unsubstitutedtriazoles, the substituent being lost on aromatization.[13]

13.13.1.1.3.1.2.6.1 Variation 1:Addition of Azides to Enamines

There are substantial differences in the products obtained from the reactions of enamineswith aryl azides or sulfonyl azides. Nitroenamine 236 (X = NO2), for example, reacts witharyl azides to yield the expected triazoles 237 while with tosyl azide it gives the N-unsub-stituted triazole 238 (X = NO2) (Scheme 79).[13] With sulfonylenamines 236 (X = SO2Ph, 4-O2NC6H4SO2) the corresponding triazoles 238 are also obtained. Similar results are ob-served in the reaction of methyl (E)-3-pyrrolidin-1-ylprop-2-enoate (239) with hetaroylazides 240 (Scheme 79). In all cases methyl 1H-1,2,3-triazole-4-carboxylate is formed in ap-proximately 90% yield.[218] Dienamines also react with 4-nitrophenyl azide to give 1,2,3-tri-azoles but with tosyl azide only amidines are obtained (formed by decomposition of theintermediate 4,5-dihydro-1H-1,2,3-triazoles).[247]

Scheme 79 Addition of Aryl, Sulfonyl, and Hetaroyl Azides to Enamines[13,218]

X = NO2, SO2Ph, 4-O2NC6H4SO2; Ar1 = Ph, 4-O2NC6H4

237

N

NN

Ar1

O2N

O N

238

N

NH

N

XTsN3, EtOH

reflux, 12−24 h

Ar1N3

X = NO2

O NTs+

236

50−80%

X

R1 = 2-furyl, 2-thienyl, 2-selanylphenyl,

N

NH

N

MeO2CCHCl3rt, 20−25 d

239

90%

MeO2C

N

+R1 N3

O

R1 N

O

240

S

S

+





bAn interesting difference in chemical behavior is observed with the two isomeric cyano-enamines 241 and 244 (Scheme 80). Both react with aryl azides to give 4,5-dihydro-1H-1,2,3-triazoles (242 and 245, respectively), which spontaneously aromatize to 1,2,3-tria-zoles 243 and 246.[248] However, under identical experimental conditions, in one casethe elimination of hydrogen cyanide is the favorable process while in the other onlyamine is eliminated. Both reactions are completely regioselective. The elimination of hy-drogen cyanide or amine is independent of the structure of the amine; the process de-pends only on the relative positions of the amino and cyano groups. These reactions canbe done without solvent, at 62–65 8C, and the yields, in both cases, are very good (75–95%).

Scheme 80 Addition of Aryl Azides to Cyanoenamines[248]

NC

R1R2N

H

H+ Ar1N3

242

N

NN

Ar1

− HCN

N

NNR1R2N

Ar1

243241

NC

R1R2N

H

R1R2N

CN

H+ Ar1N3

245

N

NN

Ar1

R1R2N

H− HNR1R2

N

NN

Ar1

246244

NCHNC

The synthetic versatility of this method is exemplified in Scheme 81: a range of 1,2,3-tri-azoles 249 are obtained in good yields from the reaction of (azidomethyl)phosphonates247 with enamines 248.[124,249,250]

Scheme 81 Reaction of (Azidomethyl)phosphonates with Enamines

R4

R3R2N

R5

H

56−77%

N

NN

249248

R5

(EtO)2P N3

R1

+

toluene, reflux

48 h R4

R1 P(OEt)2

247

R1 = H, Me, Ph; NR2R3 = piperidino, morpholino; R4,R5 = (CH2)4; R4 = H, Me; R5 = CO2Me, CO2Et, POPh2, PO(OEt)2

O

O

The synthesis of 4-(aminomethyl)-1H-1,2,3-triazoles (Scheme 82) is another interesting ap-plication of this method. Enamines 250 (resulting from the reaction of propenal with 2equivalents of secondary amines) react with aryl azides to give 4,5-dihydro-1H-1,2,3-tria-zoles 251[251,252] which, upon treatment with base,[251] are converted into triazoles 252. In asimilar process, reaction of propenal with benzenethiol, followed by the addition of a sec-ondary amine and an aryl azide gives 4-[(phenylsulfanyl)methyl]-4,5-dihydro-1H-1,2,3-tri-azoles which, after treatment with base, give mixtures of three triazoles, resulting fromthe elimination of the amine or the phenylsulfanyl group.[253] Thiopyrano[3,4-d]-1,2,3-tria-zoles can also be prepared in moderate yields from the reaction of enamines, derivedfrom tetrahydrothiopyran-4-one, and aryl azides.[254]




bScheme 82 Synthesis of 4-(Aminomethyl)-1H-1,2,3-triazoles[251,252]

250

R12NH

NR12 = NMe2, morpholino, piperidino, pyrrolidin-1-yl; X = H, Cl, CN, NO2

H

O

R12N NR1

2

X N3

251

N

NNR1

2N

H

H

X

R12N NaOH or

NaOMe

252

N

NN

X

R12N

The reactions of azides with enamines in which tautomerism is possible give mixtures oftriazoles (Scheme 83).[255]

Scheme 83 Addition of Azides to Enamines in Which Tautomerism Is Possible[255]

− R12NH

N

NN

H

H

R12N

R2

R12N

R2

H

+ R3N3

+ R3N3− R1

2NH

R2

R3

N

NN

R3

R2

Imines with an Æ-methylene group can also react with azides via their enamine tauto-mers.[256] This method has been extended to the solid-phase synthesis of 1,2,3-triazoles.The resin-bound 3-oxobutanamide 253 reacts with primary aliphatic amines yielding 3-aminobut-2-enamides which react with tosyl azide to give the polymer supported tria-zoles 254 (Scheme 84). Upon treatment with trifluoroacetic acid, the “free” triazoles (astrifluoroacetates) 255 are obtained in purities of up to 82% (1H NMR, HPLC).[257]





bScheme 84 Solid-Phase Synthesis of Triazoles via Enamines[257]

O N

O

N

O O

R1NH2, DMF

HC(OEt)3 O N

O

N

O NHR1

TsN3, DMF

iPr2NEt O N

O

N

O

NN

NR1TFA H2N

N

O

NN

NR1+

253

254 255CF3CO2

−

Enamides 256, despite being less reactive than enamines, also react with aryl azides atroom temperature (3 days to 10 months) to give 4,5-dihydro-1H-1,2,3-triazoles 257 as sta-ble crystalline products (Scheme 85). In refluxing ethanol, however, the reaction yieldsthe corresponding triazoles as the major product. The reaction of the 4,5-dihydro-1H-1,2,3-triazoles 257 with potassium hydroxide in refluxing methanol yields triazoles258.[258]

Scheme 85 Reaction of Aryl Azides with Enamides[258]

Y = 2-oxopyrrolidin-1-yl, NMeAc

257

N

NN

X

Y

258

N

NN

X

KOH, MeOH

reflux, 30 min

EtOH, reflux

24−90 h

17−66%

rt, 3 d to 10 months

44−91%

N3

+

X

Y

70−84%256

1-[1-(Diethoxyphosphoryl)alkyl]-1H-1,2,3-triazoles 249; General Procedure:[249]

To the (azidomethyl)phosphonate 247 (5 mmol) dissolved in toluene (20 mL) was addedthe enamine 248 (5 mmol). The resulting mixture was refluxed for 48 h, with stirring.The soln was concentrated and the residue was then purified by flash chromatography(silica gel, hexane/Et2O 1:1).




b13.13.1.1.3.1.2.6.2 Variation 2:

Addition of Azides to Enol Ethers

As indicated in Section 13.13.1.1.3.1.2.6, azides react very readily with enol ethers to af-ford 4,5-dihydro-1H-1,2,3-triazoles in good yields;[242,243] these reactions are completelyregioselective. As an example, 2-ethoxypropene reacts with 4-nitrophenyl azide to givethe 4,5-dihydro-1H-1,2,3-triazole 259 in 99% yield; when heated at 150 8C it eliminates eth-anol and the corresponding 1,2,3-triazole 260 is formed in quantitative yield (Scheme86).[242] Cyclic enol ethers, like 2,3-dihydrofuran or 3,4-dihydro-2H-pyran, also react withazides to give the corresponding 4,5-dihydro-1H-1,2,3-triazoles 261. However, when thesecompounds are heated, nitrogen is evolved and the imino ethers 262 are formed.[242,259]

The reaction of enol ethers with heterocyclic azides gives similar results.[114]

Scheme 86 Reaction of Aryl Azides with Enol Ethers[242]

259

N

NN

50 oC, 90 h

99%

N3

NO2

OEt+

NO2

EtO

150 oC

100%

260

N

NN

NO2

261

20 oC

72−98%Ar1N3 +

O( )n

NN

N

O

( )n 100−130 oC

O NAr1

Ar1

262

( )n

n = 1, 2

Aryl azides containing no electron-withdrawing groups add to the enolate ion of acetalde-hyde (formed by cycloreversion of tetrahydrofuran in the presence of butyllithium) togive 1-aryl-4,5-dihydro-1H-1,2,3-triazol-5-ols 263 in very good yields (Scheme 87).[260] Thesecompounds are converted into the corresponding 1-aryl-1H-1,2,3-triazoles 264 in good tonearly quantitative yields by treatment with sodium methoxide in methanol or withpotassium tert-butoxide in tert-butyl alcohol.[260] In a similar process, benzyl azide andphenyl azide react with the enolate ions of methyl ketones to give mixtures of triazolederivatives.[261,262] For example, benzyl azide reacts with acetone, in the presence of potas-sium tert-butoxide, to give a mixture (ca. 1:1) of 1-benzyl-5-methyl-1H-1,2,3-triazole (265)and 1-benzyl-4-isopropenyl-5-methyl-1H-1,2,3-triazole (266) (Scheme 87). When phenylazide is used, triazole 267 is the main product.[262] Under similar reaction conditions,phenylacetone reacts with organic azides to give triazoles 268 in high yields.[263]





bScheme 87 Reaction of Azides with Enolates[260]

X = H, 2-SMe, 2-SEt, 4-Me, 2-OMe, 3-OMe, 4-OMe

263

N

NN

X

HO

264

N

NN

X

NaOR1, R1OH

rt, 0.5−60 h

THF

rt, 1−24 h

70−99%

N3

+

X

O−

65−100%

265

N

NN

t-BuOK, t-BuOH

rt, 3.5 h

77%BnN3 +

O

Bn

+

266

N

NN

Bn

t-BuOK, t-BuOH

rt, 40 min

74%PhN3 +

O

267

N

NN

Ph

NHNO

t-BuOK, t-BuOH

rt, 0.5−4 h

79−92%R1N3 +

O

268

N

NN

R1

Ph

Ph

R1 = Me, Bn, Ph

1-Benzyl-5-methyl-4-phenyl-1H-1,2,3-triazole (268, R1 = Bn); Typical Procedure:[263]

Benzyl azide (2.48 mL, 0.02 mol) and phenylacetone (2.67 mL, 0.02 mol) were added to t-BuOK stock soln (20 mL). The mixture turned red and heat evolution was observed aftera few min. After 2 h, the mixture was poured into ice water (150 mL). The crystalline prod-uct was washed with H2O and pentane; crude product yield: 4.22 g (85%). Recrystallization(EtOAc/pentane) gave the pure product; mp 93–94 8C.

13.13.1.1.3.1.2.7 Method 7:Addition of Azides to Vinyl Acetate

Azides undergo addition to vinyl esters of lower (C1–C4) carboxylic acids to yield 1-substi-tuted 1,2,3-triazoles 269 in good yields (Scheme 88). Vinyl acetate is the most readily avail-able and is the preferred vinyl ester substrate. Generally vinyl acetate is also used as sol-vent and the reaction takes place at 50–150 8C. This method has been frequently used forthe preparation of 1-aryl- and 1-benzyl-1H-1,2,3-triazoles with biological activities.[264–268]

Heteraryl azides also add to vinyl acetate to give the corresponding triazoles.[114] Similarreaction with isopropenyl acetate yields the 5-methyl-1-substituted 1H-1,2,3-triazoles.[114]




bScheme 88 Reaction of Azides with Vinyl Acetate[114,264–268]

50−150 oCR1N3 +

269

N

NN

R1

AcO

1-(4-Acetylphenyl)-1H-1,2,3-triazole (269, R1 = 4-AcC6H4); Typical Procedure:[267]

A soln of 4-azidoacetophenone (4.0 g, 24.8 mmol) and vinyl acetate (6 mL) in a closed tubewas heated at 80 8C for 24 h. After evaporation of the solvent, the residue was dissolved inCHCl3 and the soln was washed with 2 M NaOH and 2 M HCl. The CHCl3 layer was evapo-rated in vacuo and the crude residue was recrystallized [benzene (CAUTION: carcinogen)];yield: 2.86 g (61%); mp 169–171 8C.

13.13.1.1.3.1.2.8 Method 8:Addition of Azides to Ketene Acetals

Ketene N,N-, S,S-, S,N-, O,O-, and O,N-acetals react with organic azides or sodium azide toyield 1,2,3-triazoles. These reactions are completely regioselective but the yields arestrongly dependent on the structure of the ketene acetal.

Aryl azides undergo 1,3-dipolar cycloaddition to 1,1-dimorpholinoethenes 270 togive 4,5-dihydro-1H-1,2,3-triazoles 271 (Scheme 89). When R1 = Me the 4,5-dihydro-1H-1,2,3-triazoles 271 are stable and can be isolated.[253] These compounds are deaminatedin almost quantitative yields (95–98%) to the corresponding triazoles 272 by treatmentwith acetic acid (60 8C, 30 min).[253] When R1 is an electron-withdrawing group (COR2,CO2R

2, SO2R2, NO2) the 4,5-dihydro-1H-1,2,3-triazoles 271 cannot be isolated or detected;

the deamination process to 272 proceeds so rapidly that NMR monitoring of the reactionmixture does not allow detection of signals unequivocally associated with the structure271.[269]

Scheme 89 Reaction of Aryl Azides with 1,1-Dimorpholinoethenes[253]

Ar1N3, toluene

rt or reflux, 4−50 h

271

N

NN

Ar1N N

R1 H

O O

N

N

O

O

O NH−

N

NN

Ar1

R1

NO

272

270

16−73%

R1

Cyclic ethene-1,1-diamines 273 react readily with 4-nitrophenyl azide to yield exclusively1,2,3-triazoles 274 in excellent yields (Scheme 90). However, when phenyl azide or othersubstituted phenyl azides are used the reaction proceeds much more slowly and mixturesof triazoles 274 and 275 are obtained.[270] The formation of triazoles 274 can be explainedby a mechanism where the ethene-1,1-diamines act as nucleophiles and attack the termi-nal nitrogen of the azide. Cyclization and elimination of one molecule of water yields the





btriazoles. The formation of triazoles 275 can be explained by a 1,3-dipolar cycloadditionof the azide to the ethene-1,1-diamine, followed by Dimroth rearrangement of the inter-mediate dihydrotriazole and finally aromatization by deamination.[270]

Scheme 90 Reaction of Aryl Azides with Cyclic Ethene-1,1-diamines[270]

n = 1, 2; Y = H, Cl, Me, OMe, NO2

274

N

NN

1,4-dioxane

rt to 80 oC, 5 h to 5 d

N3

+

Y

X

NH

N

( )n

Y

HN NH

O

X

( )n

NN

N

NH

O

X

( )n

+

275

273

2-Nitroethene-1,1-diamines of types 276 or 280, with at least one free NH group, reactwith 4-chlorobenzenesulfonyl azide to give 4-nitro-1,2,3-triazoles 279 and 281, respec-tively, in low to moderate yields (Scheme 91). The mechanism of formation of these com-pounds is likely to involve Dimroth rearrangement of the 4,5-dihydro-1H-triazoles 277,resulting from 1,3-dipolar cycloaddition, to 278 followed by elimination of the arylsulfo-namide as show in Scheme 91.[271]

Scheme 91 Reaction of 4-Chlorobenzenesulfonyl Azide with2-Nitroethene-1,1-diamines[271]

4-ClC6H4SO2N3

MeCN, rt, 7 dHN NH

H

( )n

NN

N

NH

( )n

+

277

NO2

N

NN

SO2Ar1

HN

NH NHAr1O2S

NN

N

NH

NO2

( )n

279

278276

( )n

35−65%

NO2

NO2

n = 1, 2

4-ClC6H4SO2N3

dioxane, 80 oC, 15 h

281

N

NHMe

NO2

H

12%N

N

NN

O2N

Me

280




bAroylketene dithioacetals 282 react with sodium azide via intermediates 283 to afford N-unsubstituted 1,2,3-triazoles 284 in good yields (Scheme 92).[272] Under similar conditions,the reaction with 4,4-bis(methylsulfanyl)but-3-en-2-one does not yield the correspondingtriazole.

Scheme 92 Reaction of Aroylketene Dithioacetals with Sodium Azide[272]

NaN3, DMSO

110 oC, 12−25 h

65−75%

O

Ar1

H

MeS SMe

N

NN

−

Na+− NaSMe

N

NH

N

MeS

Ar1

O

282 283 284

Ar1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4, 3,4-Cl2C6H3

O

Ar1

MeS

MeS

Tosyl azide reacts smoothly with acylketene S,N-acetals 285 in ethanolic sodium hydrox-ide solutions to give 1,2,3-triazoles 286 in good yields (Scheme 93).[273] Under similar con-ditions, the reaction of tosyl azide with cyclic ketene S,N-acetals 288 results in intractabletar, however, in dioxane, at higher temperature, the fused thiazolo[3,2-c][1,2,3]triazole de-rivatives 289 are obtained in good yields.[273] Detosylation of compounds 286 with concen-trated sulfuric acid leads to the corresponding 4-acyl-1,2,3-triazol-5-amines 287.

Scheme 93 Reaction of Acylketene S,N-Acetals with Tosyl Azide[273]

NaOH, EtOH

0 oC to rt, 10 h

44−75%

O

R1H

MeS NHR2

N

NN

285

287

R1 = Me, Ph, 4-ClC6H4, 4-Tol; R2 = Me, Et, Pr, iPr, Bu, Cy, CH2CH(OEt)2, Bn, Ph

+ TsN3TsHN

O

R1

R2

concd H2SO4

rt, 25 min

75−95%

N

NNH2N

O

R1

R2

286

dioxane

95−100 oC, 15 h

60−69%

O

R1H

288

R1 = Ph, 4-ClC6H4, 4-MeOC6H4

+ TsN3N N

NS

R1

O

S NH

289

Ketene O,O-acetals (1,1-bis-enol ethers) 290 react with aryl azides to give triazoles 291 invarying yields (Scheme 94).[6,156,274] With temperature control and in the presence of an ex-cess of the ketene acetal, the intermediate 4,5-dihydro-1H-1,2,3-triazole is obtained.[275,276]

The intermediate 4,5-dihydro-1H-1,2,3-triazole obtained from the reaction of ethyl azido-formate and ketene acetals decomposes readily at room temperature, the reaction path-





bway depending on the presence of the substituents on the 4-position.[276] With benzoylazide the main products are oxazole derivatives.[275]

Scheme 94 Reaction of Ketene O,O-Acetals with Azides[156,274]

290

+ Ar1N3

EtO OEt

R1 HN

NN

Ar1

− EtOH

N

NN

Ar1

R1

EtO

291

R1

EtO

EtO

4-Acyl-5-(tosylamino)-1H-1,2,3-triazoles 286; General Procedure for Reaction ofAcylketene S,N-Acetals with Tosyl Azide:[273]

A soln of NaOH (4.80 g, 0.12 mol) in EtOH (10 mL) was added slowly (5 min) to an ice-cooledand stirred suspension of the ketene S,N-acetal 285 (0.01 mol) and tosyl azide (2.36 g,0.012 mol) in EtOH (10 mL), and the mixture was further stirred at rt for 10 h. It was thenpoured over crushed ice (150 g), acidified with 20% AcOH (30 mL), and extracted withCHCl3 (3 � 50 mL). The organic extract was washed with H2O (3 � 50 mL), dried (Na2SO4),and evaporated to give crude triazoles 286, which were further purified by recrystalliza-tion (EtOH).

13.13.1.1.3.1.3 Reaction of Azides with Active Methylene Compounds

The base-catalyzed condensation of azides with active methylene compounds (the Dim-roth reaction) is a versatile method for the preparation of 1H-1,2,3-triazoles. It was firstdescribed by Dimroth in 1902.[277,426] Depending on the functional groups present in theactive methylene compound used, the substituent in the 5-position of the triazole can bean alkyl or aryl group, a hydroxy group, an alkoxycarbonyl group, or an amino group. Al-though the reactions are stepwise,[278] they are completely regioselective. The mechanismof the Dimroth reaction can be envisaged as a nucleophilic attack by the carbanion on theterminal nitrogen of the azide, followed by cyclization to a dihydrotriazole and aromati-zation. In accord with this mechanism, the reaction goes least readily with azides bearingelectron-releasing groups. The reactions are generally carried out with alkoxides in alco-hols at room temperature or under reflux. However, in some cases better results are ob-tained using potassium tert-butoxide in tetrahydrofuran,[279] sodium amide in diisopropylether,[280] or potassium carbonate in dimethyl sulfoxide.[281]

13.13.1.1.3.1.3.1 Method 1:Reaction of Azides with 1,3-Diketones, 3-Oxo Esters, or 3-Oxoamides

Organic azides react with 1,3-diketones, 3-oxo esters, or 3-oxoamides to yield, generally ingood yields, 1H-1,2,3-triazoles with a carbonyl group in position 4 (Scheme 95). The reac-tion with aryl or hetaryl azides gives better yields. With simple vinyl azides[282] and 2-azi-dovinyl ketones[283] the expected 1-vinyl-1,2,3-triazoles are obtained. However, when 1-azidovinyl ketones are reacted with 3-oxo esters in the presence of triethylamine the ini-tially formed 1-vinyl-1,2,3-triazoles undergo further reaction with another molecule ofthe oxo ester.[284] In hexamethylphosphoric triamide, 4-nitrophenyl azide reacts smoothlywith acyclic 1,3-diketones and 3-oxo esters to afford the corresponding triazoles 293 inalmost quantitative yields.[285] However, with five- and six-membered cyclic 1,3-diones itgives mainly the corresponding diazo derivatives. 1,3-Dicarbonyl compounds react withtosyl azide in hexamethylphosphoric triamide to give only the corresponding diazo com-pounds, usually in high yields.[285]




bScheme 95 Reaction of Azides with 1,3-Diketones, 3-Oxo Esters, or 3-Oxo-amides[135,267,281,286–295]

R1N3 +N

NN

R1

base

N

NNR2

293

R2 R3

O ON

−NN

R1

R1

R2 = alkyl, aryl; R3 = alkyl, aryl, OR4, NR4R5

−O

R2

O

R2

O

R3

O

R3

O

R3

R1 R2 R3 Conditions Yielda (%) Ref

4-O2NC6H4 Me Me NaOEt, EtOH, rt, 5 h 83 [267]

3-HO-4-MeO2CC6H3 Ph Ph Et3N, MeOH, reflux, 15 h 60 [286]

2-O2NC6H4 Me OEt NaOEt, EtOH, 0 8C, 2 h 56 [287]

Ph Me OMe Et3N, MeOH, 70 8C, 10 d 68 [135]

3,5-Cl2C6H3CH2 Me OEt K2CO3, DMSO, 35 8C, 18 h 89 [281]

2-O2N-4-ClC6H3 Me NHPh NaOEt, EtOH, rt, 18 h 80 [287]

4-(HO2CCH2O)C6H4 Me NEt2 NaOEt, EtOH, reflux, 16 h 65 [288]

4-pyridyl 4-O2NC6H4 OEt NaOEt, EtOH, rt, 24 h 86 [289]

N N

Me Me NaOEt, EtOH, rt, 4 h 90 [290]

N N Ph

Ph OEt NaOEt, EtOH, rt, 4 h 71 [291]

N

MeO4-O2NC6H4 OEt NaOEt, EtOH, 0–3 8C, 6 h n.r. [292]

NCl

Me NHPh NaOEt, EtOH, 0 8C to rt, 6 h n.r. [293]

acridin-9-yl Me Me NaOMe, MeOH, rt, 24 h 62 [294]

acridin-9-yl Me OMe KOH, MeOH, rt, 12 h 75 [294]





bR1 R2 R3 Conditions Yielda (%) Ref

S

HO

MeO2CMe Me MeOH, Et3N, rt, 2 d 67 [295]

S

HO

MeO2CMe OEt MeOH, Et3N, rt, 2 d 62 [295]

a n.r. = not reported.

Aryl azides react with 2-substituted 1H-indane-1,3(2H)-diones to give fairly stable tricyclic4-acyl-4,5-dihydro-1H-triazol-5-ols in good yields.[296] With tosyl azide the isolated prod-ucts are isoquinolinediones.[296] Ethyl 2-oxocyclododecanecarboxylate (294) reacts withphenyl azide, in the presence of 1 equivalent of sodium ethoxide, to give the 1H-1,2,3-tri-azol-5-ol 295 in 48% yield (Scheme 96).[297]

Scheme 96 Reaction of Ethyl 2-Oxocyclododecanecarboxylate with Phenyl Azides[297]

+ PhN3N

NNHO

295

EtO2C

Ph

NaOEt, EtOH, THF

rt, 3 d

CO2Et

O

294

48%

( )10

3-Oxoamides react with sulfonyl azides in a different way than with alkyl or aryl azides. Inthis case, the sulfonyl azide acts as a diazo transfer agent and the nitrogen of the amidefunction is involved in the formation of the 1,2,3-triazole ring. As indicated in Scheme 97,in the presence of sodium ethoxide, tosyl azide reacts with 3-oxoamides 296 to give thesodium salts of 4-acyl-1H-1,2,3-triazol-5-ols in almost quantitative yields. However, at-tempts to convert salts 297 into the corresponding hydroxy derivatives leads to the for-mation of diazoamides 298.[298]

Scheme 97 Reaction of Tosyl Azide with 3-Oxoamides[298]

+ TsN3

NaOEt

EtOH

N

NN

R1OC

−O

297

R1 NHPh

O O

R1 = Me, Ph

97−100%

Na+

296

NaOEt

H+

R1 NHPh

O O

298

N2Ph

Dimethyl 3-oxopentanedioate (299) reacts with aryl[299] and glycosyl azides[300] to yield se-lectively triazoles 300 (Scheme 98).




bScheme 98 Reaction of Dimethyl 3-Oxopentanedioate with Azides

+ R1N3base N

NNMeO2C

300

MeO

O O

299

OMe

O

R1

MeO2C

R1 Conditions Yield (%) Ref

Ph Et3N, MeOH, reflux, 4 d 62 [299]

4-ClC6H4 Et3N, MeOH, reflux, 1 d 76 [299]

4-O2NC6H4 Et3N, MeOH, reflux, 1 d 94 [299]

4-AcC6H4 Et3N, MeOH, reflux, 1 d 82 [299]

O

BzO OBz

BzO

K2CO3, DMSO, rt, 15 h 95 [300]

O

OBz

BzOOBz

K2CO3, DMSO, rt, 24 h 93 [300]

O

BnOOBn

OBn

K2CO3, DMSO, 45 8C, 24 h 80 [300]

Diethyl 2-oxobutanedioate, ethyl 2,4-dioxo-4-phenylbutanoate, and ethyl 4-(2-furyl)-2,4-dioxobutanoate, all as sodium salts 301, react with aryl azides to afford triazoles 302 inlow yields (Scheme 99).[301]

Scheme 99 Reaction of 2-Oxobutanedioate and 2,4-Dioxobutanoate Derivativeswith Azides[301]

N

NN

Ar1

EtO2CAr1N3+

THF, 50 oC, 7 h

302

O

X

X = OEt, Ph, 2-furyl

O O

XOEt

O

−

301

Na+17−26%

13.13.1.1.3.1.3.2 Method 2:Reaction of Azides with Malonic Esters, Malonamides, or Acetamides

The base-catalyzed reaction of organic azides with malonic acid derivatives is one of thebest methods for the synthesis of 1H-1,2,3-triazol-5-ols 303 with an alkyloxy (or aryloxy)carbonyl or carbamoyl functions in the 4-position (Scheme 100). As observed with otheractive methylene compounds, these reactions are stepwise and completely regioselective.





bScheme 100 Reaction of Azides with Diethyl Malonate[281,302–304]

N

NN

R1

EtO2C

HO

R1N3 EtO2C CO2Et+base

N

O OEt

NNR1

EtO2C

H

303

−


Bn K2CO3, DMSO, 35 8C, 44 h 77 [281]

Bn NaOMe, MeOH, reflux, 15 h 88 [302]

3,5-Cl2C6H3CH2 K2CO3, DMSO, 40 8C, 72 h 96 [281]

4-MeOC6H4CH2 K2CO3, DMSO, 35 8C, 72 h 92 [281]

4-MeOC6H4CH2 NaOEt, EtOH, reflux, 18 h 67 [303]

4-pyridyl NaOMe, MeOH, rt, 24 h 75 [304]

Malonamides 304 (X = CONHR1) give an unusual reaction with phenyl azide from which1H-1,2,3-triazol-5-ols 306 are isolated; aniline is also formed (Scheme 101).[305] A mecha-nism has been suggested involving cyclization of the triazene intermediate 305 with dis-placement of aniline. Similar behavior is observed in the reaction of N-methylphenylacet-amide (304, X = Ph; R1 = Me) with phenyl azide.[305] However, with phenylacetamide (304,X = Ph; R1 = H) a mixture of two triazoles is obtained: the corresponding triazole 306(R1 = H; X = Ph) and 1,4-diphenyl-1H-1,2,3-triazol-5-ol. With malonic esters and amides sub-stituted at the central carbon, triazole formation is accompanied by decarboxylation and4-alkyl- or 4-aryl-1H-1,2,3-triazol-5-ols are obtained.[305,306]

Scheme 101 Reaction of Phenyl Azide with Malonamides and Phenylacetamide[305]

N

NN

R1

X

305

HO

R1 = H, Me; X = CONHR1, Ph

− PhNH2PhN3 X+

NaOEtN

O NHR1

NNHPhX

306

NHR1

O

304

N-Arylsulfonylmalonamide derivatives 307 and malonohydrazides 309 react with tosylazide to give selectively 1-(arylsulfonyl)- and 1-(arylmethyleneamino)-1H-1,2,3-triazol-5-ols 308 and 310, respectively, in moderate to good yields (Scheme 102).[307] The mecha-nism of the reaction involves a diazo group transfer followed by subsequent cyclizationof the intermediate diazomalonate derivative.




bScheme 102 Reaction of Tosyl Azide with Malonohydrazides and N-Tosylmalonamides[307]

N

NNNa+ −O

R1 = H, Me; R2 = Ts, 4-O2NC6H4; Ar1 = 4-Tol, Ph

62−68%

TsN3, NaOEt, EtOHO

R1R2N NH

O

SO2Ar1

308

SO2Ar1

O

R1R2N

307

N

NNNa+ −OAr1 = 4-MeOC6H4 52%

Ar1 = 4-FC6H4 82%

O

BnHN NH

O

N

310

N

O

BnHN

309

Ar1

TsN3, NaOEt, EtOH

0−5 oC to rt, 2 h

Ar1

The reaction of phosphonyl and phosphinyl acetamides 311 with tosyl azide, in the pres-ence of potassium tert-butoxide, yields 1H-1,2,3-triazolols 313, presumably via diazo de-rivatives 312 (Scheme 103).[308,309]

Scheme 103 Reaction of Tosyl Azide with Phosphonyl and Phosphinyl Acetamides[308,309]

N

NH

N

HO

R12P

R1 = OEt 56%

R1 = Ph 70%

313311

R12P CONH2

OTsN3, t-BuOK

R12P CONH2

O

N2 O

312

1-(Arylmethyleneamino)-1H-1,2,3-triazol-5-ol Sodium Salts 310; General Procedure:[307]

The malonohydrazide 309 (2 mmol) was suspended in a soln of NaOEt (0.136 g, 2 mmol) inEtOH (12 mL) and tosyl azide (0.40 g, 2 mmol) was added dropwise at 0–5 8C. The mixturewas stirred for 2 h after which the precipitate 310 was collected by filtration and dried.

13.13.1.1.3.1.3.3 Method 3:Reaction of Azides with Acetonitrile Derivatives

Organic azides react with acetonitrile derivatives 314 to give 1-substituted 1H-1,2,3-tri-azol-5-amines 315 in good yields (Scheme 104). However, to avoid Dimroth rearrange-ment of the products, the reactions must be carried out at low temperatures (0–20 8C).[304]

In the reactions of acetonitrile derivatives with 2-substituted aryl azides (e.g., 2-nitrophen-yl azide, 2-azidobenzoic acid, or 2-azidobenzonitrile), the 1H-1,2,3-triazol-5-amine can re-act further by condensation of the amino group with the ortho substituent on the 1-phenylgroup, resulting in the formation of fused 1,2,3-triazoles.[310–313,317] Best yields are obtainedwith aryl, hetaryl, and benzyl azides but some good results have also been obtained withalkyl azides.[279,314]





bScheme 104 Reaction of Azides with Acetonitrile Derivatives[279–282,291,294,304,315–324]

N

NN

R2

H2N

R2 = aryl, CN, CO2R3, CONR3R4, PO(OEt)2

315

314

R2 CNbase

R1N3 +

R1

N

NN

R1

HN

R2H

N

NN

NR1−R2

H


(CH2)5Me Ph t-BuOK, THF, rt, 12 h 98 [279]

Me t-Bu LDA, Et2O, –78 to 08 C, 1 d 35 [315]

Bn Bn NaNH2, iPr2O, reflux, 7 d 24 [280]

CH2SPh 2-FC6H4 K2CO3, DMSO, rt, 16 h 29 [316]

Ph Ph NaOMe, MeOH, 0 8C to rt, 24 h 99 [317,318]

4-pyridyl Ph NaOMe, MeOH, rt, 24 h 82 [304]

4-O2NC6H4 CO2Me NaOMe, MeOH, rt, 24 h 89 [304]

Bn Ph K2CO3, DMSO, rt to 40 8C, 24 h 84 [281]

Bn Ph t-BuOK, THF, rt, 12 h 78 [279]

Bn CN K2CO3, DMSO, rt to 40 8C, 18 h 48 [281]

Bn CONH2 K2CO3, DMSO, rt to 40 8C, 5 h 84 [281]

Bn CONH2 NaOEt, EtOH, reflux, 1 h 81 [319]

Bn CO2Et NaOEt, EtOH, reflux, 3 h 25 [319]

Bn CO2H NaOEt, EtOH, reflux, 4 h 20 [319]

Ph CONH2 NaOMe, MeOH, rt, 24 h 88 [320]

Ph CONMe2 Et2O, NaOMe, MeOH, 0 8C, 24 h 74 [321]

4-HO2CC6H4 CONH2 NaOMe, MeOH, rt, 7 d 61 [320]

2-O2NC6H4 CONH2 NaOEt, EtOH, 0 8C to rt, 23 h 55 [322]

3,3-dimethylbut-1-enyl CONH2 NaOMe, MeOH, reflux, 30 min 62 [282]

1-naphthyl CO2Et NaOEt, EtOH, 0 8C to rt, 6 h 94 [323]

4-pyridyl CO2Et NaOEt, EtOH, 0 8C to rt, 16 h 86 [323]

4-quinolyl CONH2 NaOEt, EtOH, 0 8C to rt, 21 h 91 [323]

4-quinolyl CO2Et NaOEt, EtOH, 0 8C to rt, 21 h 79 [323]

N N Ph

CN NaOEt, EtOH, rt, 4 h 69 [291]





N N Ph

Ph NaOEt, EtOH, rt, 4 h 81 [291]

acridin-9-yl 2-pyridyl NaOMe, MeOH, rt, 24 h 70 [294]

acridin-9-yl piperidino-carbonyl

NaOMe, MeOH, rt, 24 h 26 [294]

acridin-9-yl 4-ClC6H4NHCO NaOMe, MeOH, rt, 24 h 15 [294]

Ph PO(OEt)2 NaOEt, EtOH, rt, 3 h 76 [324]

The reaction of cyanoacetamide with glycosyl azides, in aqueous dimethylformamidewith potassium hydroxide and at room temperature gives 5-amino-1-glycosyl-1H-1,2,3-tri-azole-4-carboxamide shows that this type of cycloaddition has a two-step mechanism.[278]

Also using cyanoacetamide and gycosyl azides, a study of the influence of the reactionconditions (the nature of the solvent and base) on the retention or inversion of the config-uration of the anomeric carbon has been described.[325] A range of 1-(substituted benzyl)-5-amino-1H-1,2,3-triazole-4-carboxamides has been prepared from the reaction of cyano-acetamide with benzyl azides.[326]

Treatment of 2-oxocyclododecanecarbonitrile (316) with phenyl azide in the pres-ence of a catalytic amount of sodium ethoxide for four days at room temperature leadsto the formation of 1H-1,2,3-triazol-5-amine 317 and lactam 318 in 60 and 10% yield, re-spectively (Scheme 105).[297] A mechanism for the formation of these two compounds hasbeen proposed.

Scheme 105 Reaction of 2-Oxocyclododecanecarbonitrile with Phenyl Azide[297]

N

NNH2N

316

+

O

CN

NaOEt

EtOH, THF

rt, 4 d

Ph

EtO2C ( )10

317 60%

HN

O

NN

N

Ph+

318 10%

PhN3

Sulfonyl azides do not generally give triazoles with activated methylene compounds.However, in aqueous alkaline solutions, sulfonyl azides, and also azidoformates andN,N-dimethylcarbamoyl azide, react with malononitrile to yield N-unsubstituted 1,2,3-tri-azoles 319, 320, and 321, respectively, in good to excellent yields, as indicated in Scheme106.[327]





bScheme 106 Reaction of Malononitrile with Sulfonyl and Carbonyl Azides[327]

CN

CN

OH−, H2O

5 oC, 1 hCN

CN

−N

NH

N

NC

H2N

320

N

NH

N

NC

NH

319

SR1OO

N

NH

N

NC

NH

321

Me2N

OO

Me2N N3

O

R2O N3

R1SO2N3

71−96%

58−60%

63%

R1 = Me, Ph, 4-Tol, 4-MeOC6H4, 4-O2NC6H4; R2 = Et, t-Bu

13.13.1.1.3.1.3.4 Method 4:Reaction of Aryl Azides with Alkoxides

Aryl azides react with sodium ethoxide or propoxide to afford 1-aryl-1H-1,2,3-triazoles322 in moderate yields (Scheme 107).[328] Two equivalents of azide are required, the sec-ond being reduced to aniline. The mechanism[3] of this reaction probably involves the for-mation of an aldehyde by hydride transfer from the alkoxide to one mole of aryl azide.The attack of the carbanion of the aldehyde so produced on a second mole of the azideleads to the triazole. The reaction of tosyl azide with sodium butoxide yields only butyltoluenesulfonate.[184]

Scheme 107 Reaction of Aryl Azides with Alkoxides[328]

N

NN

322

R1

R1 = H, Me; X = H, Cl, Br, Me, NO2

reflux, 1−5 d2 X N3 NaO

R1+

X

− 4-XC6H4NH2

30−70%

1-Aryl-4-methyl-1H-1,2,3-triazoles 322 (R1 = H); Typical Procedure for Condensation ofAryl Azides with Sodium Propoxide:[328]

The appropriate aryl azide (0.03 mol) was added to a cold soln of NaOPr (0.04 mol) and themixture was refluxed on a water bath for 24 h. The brownish product was acidified withconcd HCl, steam-distilled, made alkaline, and steam-distilled again. The residual solnwas extracted with Et2O; when the extract was evaporated, the 1-aryl-4-methyl-1H-1,2,3-triazole 322 (R1 = Me) separated and was crystallized (petroleum ether or EtOH/H2O).




b13.13.1.1.4 By Formation of One N-N Bond

13.13.1.1.4.1 Fragment N-N-C-C-N

13.13.1.1.4.1.1 Method 1:Cyclization of Æ-Diazoamides

Æ-Diazoamides can be cyclized to 1H-1,2,3-triazoles by treatment with base[298,308,309,329] orby other methods. Some reactive Æ-diazoamides cyclize spontaneously to the correspond-ing triazoles; one example is indicated in Scheme 108. The intermediate Æ-diazoamides324, generated in situ from the reaction of ethyl N-(diazoacetyl)glycinate (323) with ben-zoyl bromides, cyclize spontaneously to triazoles 325.[330]

Scheme 108 Cyclization of Ethyl N-(3-Aryl-2-diazo-3-oxopropanoyl)glycinates[330]

325

CH2Cl2rt, 76−91 h

R1 = H 50%

R1 = Br 15%

NH

O

H

N2

CO2Et

R1

Br

O

+

R1

O

NH

O

N2

CO2Et

O

N

NN

HO

324

323

R1

CO2Et

Reaction of Æ-diazoamide 326 with phosphorus pentachloride gives methyl 1-benzyl-5-chloro-1H-1,2,3-triazole-4-carboxylate (328) through the intermediate imidoyl chloride327 (Scheme 109).[331] N-Unsubstituted 5-halo-1H-1,2,3-triazoles are also obtained in goodto excellent yields by treatment of diazomalononitrile derivatives with hydrogen ha-lides.[1]

Scheme 109 Cyclization of a Diazomalonamide[331]

N

NN

326

MeO2CPCl5

80 oC, 3 hMeO2C N2

O NHBn

MeO2C N2

Cl NBn

327 328

BnCl

13.13.1.1.4.1.2 Method 2:Thermolysis of Æ-Azidoacetophenone (Phenylsulfonyl)hydrazones

Æ-Azidoacetophenone (phenylsulfonyl)hydrazones 330, prepared by the reaction of thecorresponding Æ-bromoacetophenone (phenylsulfonyl)hydrazones with sodium azide,are converted into 4-aryl-1H-1,2,3-triazoles 332, in good yields on heating in refluxingbenzene (Scheme 110). The reaction proceeds probably via the elimination of benzene-sulfinic acid from the intermediate 2-(phenylsulfonyl)-2,5-dihydro-1H-1,2,3-triazoles331.[332] The Æ-bromoacetophenone (phenylsulfonyl)hydrazones 329 react with benzyl-





bideneaniline to yield 4-aryl-1-phenyl-1H-1,2,3-triazoles (19–25%) and substituted 2,3,4,5-tetrahydro-1,2,4-triazines (20–45%).[333]

Scheme 110 Thermolysis of Æ-Azidoacetophenone (Phenylsulfonyl)hydrazones[332,333]

N

NH

N

329

332

Ar1− PhSO2H

71−96%

NH

NNAr1 SO2PhAr1 N

HN

N

••

Ar1 N

HN

BrNaN3, DMF

82−94%

330

Ar1 N

HN

N3

− N2

benzene

reflux, 2 h

331

SO2Ph SO2Ph

SO2Ph

Ar1 = 4-XC6H4; X = H, Br, Cl, NO2, Me, Ph, N NPh

13.13.1.1.4.1.3 Method 3:Cyclization of Æ-Hydroxyimino Hydrazones

Cyclic Æ-hydroxyimino hydrazones 334 and 337 (prepared from Æ-hydroxyimino ketones333 and 336, respectively) on heating at 170–190 8C for three hours in diethylene glycolcontaining potassium hydroxide yield the N-unsubstituted 1,2,3-triazoles 335 and 338(Scheme 111). The yield of triazole significantly decreases as the size of the ketone ringincreases from five- to six- to seven-membered, that is as the rings become more flexibleand the hydrazone and oxime groups less coplanar.[334,335] Under the same conditions, acy-clic Æ-hydroxyimino hydrazones do not give triazoles; in this case, the normal Wolff–Kish-ner reduction products are obtained.

Scheme 111 Cyclization of Æ-Hydroxyimino Hydrazones[334,335]

O

N

( )n

333

H2NNH2

N

N( )n

334

15−52%

KOH

diethylene glycol

170−190 oC, 3 h( )n

335

NH

N

N

n = 1−3

OH OH

NH2

336

H2NNH2

32%

KOH

diethylene glycol

170−190 oC, 3 h

338

O

N

337

N

N

NN

NHOH OH

NH2

Glyoxal O-benzyloxime hydrazone 340, generated in situ by addition of glyoxal O-benzyl-oxime 339 to a 10-fold excess of hydrazine, gives 1-(benzyloxy)-1H-1,2,3-triazole 341 byoxidative cyclization (Scheme 112). Copper(II) sulfate is the best oxidant but manganesedioxide and nickel peroxide can also be used.[336]




bScheme 112 Cyclization of Æ-Hydroxyimino Hydrazone Derivatives[336]

N

NN

H2NNH2, MeOH

0 oC, 45 min

341

OBn

N

O

OBn

N

N

OBn

340339

CuSO4•5H2O, py

100 oC, 30 min

52−63%

NH2

3,8-Dihydroindeno[1,2-d][1,2,3]triazole (335, n = 1); Typical Procedure:[335]

1H-Indene-1,2(3H)-dione 1-hydrazone 2-oxime (334, n = 1; 930 mg, 5.3 mmol) and KOH(1.23 g, 22 mmol) in purified diethylene glycol (50 mL) was heated, with a stream of N2

bubbling through it, until the temperature reached 170–190 8C (ca. 30 min). Heating wasmaintained at this temperature for 3 h and N2 was bubbled through the soln for the entiretime. The mixture was then cooled, diluted with 1 M aq KOH (400 mL), and extracted withCH2Cl2 (4 � 200 mL). The alkaline soln was acidified with HCl and the pH was adjusted to 7with NaHCO3. The soln was again extracted with CH2Cl2 (4 � 200 mL). Each extract wasback-washed with sat. aq NaCl (2 � 100 mL). These organic extracts were combined, dried(Na2SO4), filtered, and evaporated in vacuo to yield a weakly acidic fraction (584 mg)which was sublimed (100 8C/0.2 Torr) to yield triazole 335 (n = 1); yield: 432 mg (52%); mp144 8C.

13.13.1.1.4.1.4 Method 4:Cyclization of Æ-Hydroxyimino Aroyl- or Arylsulfonylhydrazones

Oxidation of Æ-hydroxyimino aroylhydrazones 342 with lead(IV) acetate in acetic acidgives 1-(aroyloxy)-4,5-dimethyl-1H-1,2,3-triazoles 344 in moderate yields (Scheme 113).This transformation probably involves an intramolecular [1,3]-aroyl migration in the in-termediate 343.[337]

Scheme 113 Oxidation of Æ-Hydroxyimino Aroylhydrazones with Lead(IV) Acetate[337]

N

NN

Pb(OAc)4, AcOH

CH2Cl20 oC, 30 min

344

O

N

N

342

NH

Ar1

O

35−48%

N

NN

O−

Ar1

O

O

Ar1+

343

Ar1 = 4-XC6H4; X = H, Me, OMe, Cl, NO2

OH

Æ-Hydroxyimino tosylhydrazones 345 are converted into 4-aryl-5-methyl-1H-1,2,3-triazol-1-ols 347 in good yields by thermal cyclization of salts 346 (Scheme 114).[24] The Æ-diazooximes 348 are probable intermediates in this transformation. Attempts to prepare 4,5-dimethyl-1H-1,2,3-triazol-1-ol by this method failed.[24]





bScheme 114 Cyclization of Æ-Hydroxyimino Tosylhydrazones[24]

N

NN

NaOEt, EtOH

DME

rt, 30 min

347

OH

N

N

345

Ar1

NHTs

75−77%

Ar1

Ar1 = Ph, 4-MeOC6H4

N

N

346

Ar1

NHTs

O− Na+

diglyme

reflux, 45−90 min

N

NAr1

NTs

− Na+

NOH

NAr1

N−+

OH

OH

348

1-(Aryloxy)-4,5-dimethyl-1H-1,2,3-triazole 344 by Oxidation of Æ-Hydroxyimino Aroyl-hydrazones; General Procedure:[337]

A soln of 342 (1 mmol) in AcOH/CH2Cl2 (1:5, 30 mL) was added over 20 min to a stirred solnof Pb(OAc)4 (4 mmol) in dry CH2Cl2 (30 mL). The soln was stirred at 0 8C for 30 min and then10% aq Na2S2O3 was added. The organic layer was separated, washed with brine, dried, andevaporated. The resulting residue was either chromatographed or recrystallized from theappropriate solvent.

13.13.1.1.4.1.5 Method 5:Cyclization of 1,2-Diketone Bis(hydrazone) Derivatives

1,2-Diketone bis(hydrazones) and some of their derivatives such as bis(semicarbazones),bis(arylsulfonylhydrazones), and bis(acylhydrazones) are converted into 1H-1,2,3-triazol-1-amines. The cyclization of these compounds is carried out by oxidation or by treatmentwith acids or bases.

13.13.1.1.4.1.5.1 Variation 1:Cyclization of 1,2-Diketone Bis(hydrazones)

Oxidation of bis(hydrazones) 349 with manganese dioxide or mercury(II) oxide gives 1H-1,2,3-triazol-1-amines 350 (Scheme 115). Although two isomeric triazoles would be ex-pected from unsymmetrical bis(hydrazones), compounds 349 give only the 4-aryl-1,2,3-triazol-1-amines.[338] Other vicinal bis(hydrazones) have been converted into 1H-1,2,3-tri-azol-1-amines.[339–342] The major disadvantage of this method is that unless the conditionsare carefully controlled, complete oxidation of the bis(hydrazones) occurs and the isolat-ed products are alkynes. Pyrolysis of cyclooctane-1,2-dione bis(hydrazone) yields the cor-responding N-unsubstituted 1H-1,2,3-triazole.[342]




bScheme 115 Cyclization of 1,2-Diketone Bis(hydrazones)[338]

MnO2 or HgO

N

N

349

Ar1

H

Ar1 = Ph, 4-ClC6H4, 4-BrC6H4, 4-MeOC6H4, 2-naphthyl

N

NN

NH2

H

Ar1

350

NH2

NH2

13.13.1.1.4.1.5.2 Variation 2:Cyclization of 1,2-Diketone Bis(arylsulfonylhydrazones)

Vicinal bis(arylsulfonylhydrazones) 351 can be cyclized using either acid or base to give 1-(arylsulfonylamino)-1H-1,2,3-triazoles.[343,344] When unsymmetrical 1,2-diketones areused, the two possible triazoles 352 and 353 are obtained (Scheme 116).[345,346] Benzil bis-(tosylhydrazone) cyclizes to 4,5-diphenyl-1-(tosylamino)-1H-1,2,3-triazole by oxidationwith either mercury(II) or lead(IV) acetates in acetic acid.[347] This type of triazole is alsoobtained by thermal[348] or photochemical[349] decomposition of the dianions of thebis(tosylhydrazones) of 1,2-diketones. The 1-(arylsulfonylamino)-1H-1,2,3-triazoles areconverted into 1H-1,2,3-triazol-1-amines by treatment with sulfuric acid.

Scheme 116 Cyclization of 1,2-Diketone Bis(arylsulfonylhydrazones)[345,346]

H+ or OH−

heat

351

N

NN

HN

R2

R1

352

N

NN

HN

R1

R2

353

+

NHN

NH

NSO2Ar1

SO2Ar1

R1

R2

SO2Ar1 SO2Ar1

4,5-Diphenyl-1-(tosylamino)-1H-1,2,3-triazole (352, R1 = R2 = Ph; Ar1 = 4-Tol);Typical Procedure:[345]

Benzil bis(tosylhydrazone) (74 g, 0.14 mol) was added rapidly to a stirred soln of KOH (9 g,0.16 mol) in ethylene glycol (400 mL) at 120 8C. After 10 min the soln was cooled to 40 8Cand H2O was added slowly, with rapid stirring, until a precipitate began to appear. Themixture was then acidified with 2 M HCl and more H2O was added until the total volumewas 1 L. The precipitate was then collected by filtration, dried, and washed well withpetroleum ether to leave the triazole; yield: 43 g (81%); mp 232–233 8C (EtOH).

13.13.1.1.4.1.5.3 Variation 3:Cyclization of 1,2-Diketone Bis(semicarbazones)

The 1,2-diketone bis(semicarbazones) 354 undergo cyclization on treatment with lead(IV)acetate to give 1-ureido-1H-1,2,3-triazoles 355 (Scheme 117). These compounds are hy-drolyzed with concentrated hydrochloric acid to give the corresponding 1H-1,2,3-triazol-1-amines 356.[350]





bScheme 117 Cyclization of 1,2-Diketone Bis(semicarbazones)[350]

Pb(OAc)4

CH2Cl2rt, 3 h

354

N

NN

HN

R2

R1

355

N

NN

NH2

R2

R1

356

30−40%

HCl, reflux, 2 h

50−65%

NHN

NH

NCONH2

CONH2

R1

R2

CONH2

R1 R2 1-Ureido-1H-1,2,3-triazole 355 1H-1,2,3-Triazol-1-amine 356 Ref

Yield (%) mp (8C) Yield (%) mp (8C) [350]

Me Me 30 225–226 65 89–91 [350]

Ph Ph 40 209–211 55 126–128 [350]

Ph Me 34 207–208 55 142–144 [350]

4-Tol Me 40 203–204 58 164–165 [350]

4-BrC6H4 Me 38 204–205 50 169–171 [350]

4-Tol H 32 224–226 52 123–124 [350]

1-Ureido-1H-1,2,3-triazoles 355; General Procedure:[350]

Pb(OAc)4 (0.021 mol) was added to a suspension of bis(semicarbazone) 354 (0.02 mol) inCH2Cl2 (100 mL) and the mixture was stirred at rt for 3 h. The mixture was filtered andthe precipitate was treated with MeOH. The methanolic soln upon evaporation gave the1-ureido-triazole which was recrystallized (MeOH or EtOH).

13.13.1.1.4.1.5.4 Variation 4:Cyclization of 1,2-Diketone Bis(acylhydrazones)

1,2-Diketone Bis(acylhydrazones) undergo oxidative cyclization to 1H-1,2,3-triazol-1-amine derivatives 360–362 (via intermediate 358/359) (Scheme 118). Lead(IV) acetate isthe oxidant most used for this transformation. With bis(aroylhydrazones) 357 (R2 = aryl)the principal products are imides 360 and amides 361.[351–355] On the other hand, oxida-tion of bis(arylacetylhydrazones) 357 (R2 = arylmethyl) yields mainly 1-(arylacetylamino)-1,2,3-triazoles 362 (R2 = arylmethyl) in moderate yields.[356] Oxidation of bis(acetylhydra-zones) 357 (R2 = Me) with lead(IV) acetate gives amides 361 (R2 = Me) as the primary prod-ucts but partial hydrolysis to monoacetylamino derivatives 362 may occur in some casesduring the workup.[357] Lead(IV) acetate oxidation of mixed aroylhydrazones of biacetyl af-fords pairs of isomeric triazoles (of the imide 360 type) in different proportions.[358]




bScheme 118 Cyclization of 1,2-Diketone Bis(acylhydrazones)[357]

Pb(OAc)4

CH2Cl2rt, 1−2 h

357

N

NN

−N

R1

R1

358

N

NN

HN

R1

R1

COR2

COR2

+N

NN

N

R1

R1

359

COR2+

N

NN

N

R1

R1

360

OCOR2

R2

N

NN

N

R1

R1

+ +

361 362

R2

O−N

HN

NH

NCOR2

COR2

R1

R1

R2OC COR2 COR2

Lead(IV) Acetate Oxidation of Bis(acylhydrazones) 357; General Procedure:[357]

To a stirred suspension of the bis(acylhydrazone) (2 mmol) in CH2Cl2 (20 mL) was addedPb(OAc)4 (2.4 mmol) dissolved in CH2Cl2 (20 mL). The slight excess of the oxidant waschecked throughout the experiment by the use of KI/starch paper and maintained, if nec-essary, by the addition of extra amounts of Pb(OAc)4. When all the starting material wasconsumed the mixture was filtered and the filtrate was extracted successively with aqNa2S2O3 and Na2CO3. The dried soln was evaporated under reduced pressure and the resi-due was chromatographed (medium pressure, silica gel, petroleum ether/EtOAc, gradientelution). The isolated products were further purified by recrystallization.

13.13.1.1.4.1.6 Method 6:Cyclization of (1,2-Diphenylethene-1,2-diyl)bis(trityldiazene)

(1,2-Diphenylethene-1,2-diyl)bis(trityldiazene) (363) cyclizes readily to the 1H-1,2,3-tri-azol-1-amine derivative 365 when treated with acetic acid or left in suspension in ordina-ry unpurified chloroform for several days (Scheme 119).[359] The dipolar compound 364 isa probable intermediate in this transformation. Treatment of compound 365 with benzo-yl chloride yields 1-benzoylamino)-4,5-diphenyl-1H-1,2,3-triazole. The synthetic useful-ness of this method is still to be demonstrated. See also Section 13.13.2.1.3.1.2 for the cy-clization of 1,2-diketone bis(arylhydrazones) to 2H-triazoles.

Scheme 119 Cyclization of (1,2-Diphenylethene-1,2-diyl)bis(trityldiazene)[359]

N

N

363

Ph

Ph

N

NN

−N

Ph

Ph

NTr

NTr

364

N

NN

NHTr

Ph

Ph

Tr

Tr

+AcOH

365

90%

4,5-Diphenyl-N-trityl-1H-1,2,3-triazol-1-amine (365):[359]

A suspension of (1,2-diphenylethene-1,2-diyl)bis(trityldiazene) (363; 0.5 g, 0.69 mmol) in90% AcOH (10 mL) was evaporated to one half of the original volume on a hot plate. Thesolid dissolved with disappearance of the red color in a few minutes. Upon cooling, the





bwhite crystalline triazolamine 365 was separated; yield: 0.30 g (90%). Recrystallization(petroleum ether/benzene) gave crystals; mp 265–267 8C.

13.13.1.1.5 By Formation of One N-C Bond

13.13.1.1.5.1 Fragment N-N-N-C-C

13.13.1.1.5.1.1 Method 1:Cyclization of Linear Triazenes and Tetrazenes

Triazenes are a recognized intermediate in the synthesis of 1,2,3-triazoles starting froman azide and an activated methylene compound (see Section 13.13.1.1.3.1.3, Scheme 95).Stable triazene compounds can also be cyclized to 1,2,3-triazoles.[360–364] For example, 1-aryl-3-(cyanomethyl)triazenes 366 cyclize in aprotic media with Lewis base catalysis togive 1-aryl-1H-1,2,3-triazol-5-amines 367 (Scheme 120). If the reaction is carried out inprotic media the cyclization is followed by Dimroth rearrangement and the isolated prod-ucts are the isomeric N-aryl-1H-1,2,3-triazol-5-amines 368.[363] Treatment of chloroform so-lutions of triazenes 366 with suspended basic alumina for several days yields the 1H-1,2,3-triazol-5-amines 367 essentially free from isomers 368. However, refluxing the triazenes(X = 4-NO2 or 4-CN) in absolute ethanol for 1–2 hours gives triazoles 368 with no trace ofthe isomeric triazoles 367. In a similar process, 1-aryl-1H-1,2,3-triazol-5-ols are preparedby cyclization of 1-aryl-3-(ethoxycarbonylmethyl)triazenes.[364]

Scheme 120 Cyclization of Linear Triazenes[363]

367N

NH

NHN

N

N NH

CN

X

alumina, CHCl3rt, 7 d

N

NNH2N

X

X

Dimroth

rearrangement

366

368

X = NO2, CN, CO2Me, CONH2

36−92%

The 1,2,3-triazole system can also be formed by the isomerization of 1-(arylazo)aziridines369 (Scheme 121). This isomerization is catalyzed by iodide ions and the product is a 1-aryl-4,5-dihydro-1H-1,2,3-triazole 371.[365] The isomerizations probably occur by a nucleo-philic attack of iodide ion on the aziridinyl carbon to yield the ion 370, which subse-quently displaces an iodide ion by the negatively charged nitrogen. Although the 4,5-dihy-dro-1H-1,2,3-triazoles 371 are obtained in high yields, this is a dangerous method sincesome 1-(arylazo)aziridines 369 explode violently on standing at room temperature for20–30 minutes.[365]




bScheme 121 Isomerization of 1-(Arylazo)aziridines[365]

N

NN

NaI, acetone

rt, 30 min

or reflux, 1 h

369

371

64−98%

Ar1

N

NAr1N

−N

NAr1N

I

N

NAr1N

I

370

−

Anodic oxidation of 1-aryl-3,3-dimethyltriazenes in acetonitrile gives 2-aryl-5-methyl-2H-1,2,3-triazole-4-carbonitriles in low yields.[366] Methyl 1-benzyl-1H-1,2,3-triazole-4-carbox-ylate is obtained in 2% yield, together with several other products, by photolysis of a tet-raz-2-ene;[367] this method has very limited synthetic interest.

1-Aryl-1H-1,2,3-triazol-5-amines 367 by Cyclization of 1-Aryl-3-(cyanomethyl)triazenes;General Procedure:[363]

The triazene 366 (250 mg) was dissolved in the minimum volume of CHCl3 (25–50 mL) andbasic alumina (2.5 g) was added. The suspension was stirred at rt for 7 d. The mixture wasfiltered to remove alumina and the filtrate evaporated to dryness in vacuo. The residuewas the 1H-1,2,3-triazol-5-amine 367.

13.13.1.1.5.1.2 Method 2:Cyclization of Vinyl Azides

In the presence of a base, vinyl azides (e.g., 372) cyclize to 1H-1,2,3-triazoles, such as 374(Scheme 122).[85,190] A probable mechanism for such transformation involves the forma-tion of the anion of the vinyl azide, which then cyclizes to the aromatic triazole anion(e.g., 373). Protonation affords the final product.

Scheme 122 Cyclization of 2-Tosylvinyl Azides[85,190]

N

NH

N

NaTs, DMSO

>24 h

372

374

TsH2O

H N3

Ts H Ts

NN

N

+−

−−

N

NN

Ts

373

Methyl 3,3-diazido-2-cyanoacrylate (375) reacts with amines to give vinyl azides 376,which undergo 1,5-cyclization to form triazoles 378 (via 4H-1,2,3-triazoles 377) in goodyields (Scheme 123).[368] Under controlled reaction conditions (catalytic amount of theamine and absence of moisture) vinyl azides 376 are converted into methyl 1,2,3-tri-azole-2-carboxylates 379.[369]





bScheme 123 Reaction of Methyl 3,3-Diazido-2-cyanoacrylate with Amines[368,369]

N

NH

N

R1R2NH, CH2Cl20 oC to rt, 12 h

375

378

R1R2N

NC CO2Me

N3 N3

− HN3

376

NC CO2Me

R1R2N N3

N

NN

R1R2N

NC

MeO2C

377

NC

N

NN

379

R1R2N

NC CO2Me

61−84%

NR1R2 = pyrrolidin-1-yl 90%

NR1R2 = piperidino 68%

NR1R2 = NEt2, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 4-benzylpiperazin-1-yl

13.13.1.1.5.1.3 Method 3:Cyclization of 2-(Formyloxy)vinyl Azides

(Z)-2-(Formyloxy)vinyl azides are converted into 1H-1,2,3-triazoles by using triethyl phos-phite (Scheme 124).[370] Addition of triethyl phosphite to formate 380 immediately initi-ates an exothermic reaction producing a deep orange solution. Evaporation of the solventand purification by silica gel chromatography gives triazole 382. It has been shown byNMR that N-formyltriazole 381 (which can be isolated) is the initial product of cyclization.4-Phenyl-1H-1,2,3-triazole is prepared by cyclization of formate 383 following the samemethodology.[370]

Scheme 124 Cyclization of (Z)-2-(Formyloxy)vinyl Azides[370]

P(OEt)3

CHCl3rt, 24 h silica gel

380

O

OH

N3

381

NN

NCHO

382 46%

NH

NN

H N3

Ph O O

H

1. P(OEt)3, CHCl3, 10 min

2. silica gel

62%

N

NH

N

Ph

383




b13.13.1.2 Synthesis by Ring Transformation

There are several heterocyclic compounds that, by chemical modification or just by isom-erization, are converted into 1H-1,2,3-triazoles or 2H-1,2,3-triazoles (see also Section13.13.2.2). Despite some synthetically interesting exceptions, in most cases the startingheterocycles are not readily available and the routes are unlikely to be general. Thefollowing are examples of transformations of this type that lead to 1H-1,2,3-triazole deriv-atives: (a) diazotization of isoxazol-4-amines to give triazol-1-ols,[371,372] (b) diazotization of5-aminothiazol-2-ols to give triazol-4-ols,[373] (c) diazotization of 3-aminopyridinium saltsto give 4-(3-oxoprop-1-enyl)-1,2,3-triazole derivatives,[374,375] (d) base-induced rearrange-ment of sydnoneimines to give triazol-4-ols,[376] (e) reaction of ethyl 2-amino-4,5-dihydro-furan-3-carboxylates with phenyl azide to give 1H-1,2,3-triazol-5-amines,[377] (f ) thermoly-sis of 5-diazo-6-methoxyuracils results in the formation of 4-acyl-1,2,3-triazole deriva-tives,[378–380] (g) reaction of 1,2,4-triazin-3-ones with N-chlorinating agents,[381] (h) treat-ment of 1,2,4-triazin-3-one 2-oxides with acetic anhydride,[382] (i) reduction or oxidationof triazolotriazoles,[383,384] (j) diazotization of 7�-amino cephalosporin sulfones,[385] (k)thermolysis of mesoionic oxatriazolones in the presence of alkynes,[386] (l) reaction of1,3,3-trimethyl-2-methylene-2,3-dihydro-1H-indole with aryl azides,[387] (m) reaction ofisothiazole dioxides with sodium azide,[388] (n) reaction of triazolo[1,5-a]pyridines withaniline,[389] (o) permanganate oxidation of substituted benzotriazoles,[390–392] (p) hydrolyticcleavage of 1,2,3-triazolo[4,5-d]pyrimidines,[393–395] and (q) reaction of 4-oxo-4H-pyridi-no[1,2-a]pyrimidine-3-diazonium salts with primary alcohols.[396]

The chemical transformation of 1,2,3-thiadiazoles into 1H-1,2,3-triazoles is a synthet-ically useful method. For example, base-catalyzed isomerization of 1,2,3-thiadiazol-5-amine derivatives affords 1H-1,2,3-triazole-5-thiols in high yields.[397–401] Also, thermolysisof 5-[alkyl- or 5-[allyl(alkoxycarbonyl)amino]-1,2,3-thiadiazoles 384 in a sealed glass tubein the absence of solvent gives 5-(alkylsulfanyl)-1H-1,2,3-triazoles 385 (Scheme 125).[402]

Scheme 125 Thermolysis of 5-(Alkoxycarbonylamino)-1,2,3-thiadiazoles[402]

− CO2

43−92%

N

NNR2S

R1

220 oC, 15 minN

SNN

R2O2C

R1

384 385

R1 = Me, Et, CH2CH CH2; R2 = Me, Et

Another example of this approach is the conversion of 5-chloro-1,2,3-thiadiazole-4-carbal-dehyde 386 into 1H-1,2,3-triazole-4-carbothioamides 390 (Scheme 126).[403] A wide varietyof amine derivatives can be used in this method. A probable mechanism for this transfor-mation involves intermediates 387–389 and is indicated in Scheme 126. Other examplesof conversion of 5-chloro-1,2,3-thiadiazole derivatives into 1H-1,2,3-triazoles are report-ed.[404,405]





bScheme 126 Reaction of 5-Chloro-1,2,3-thiadiazole-4-carbaldehyde with Amines[403]

50−93%

N

SNCl

386

OHC

R1 = Me, Et, Bn, Ph, 4-MeOC6H4, 4-ClC6H4, NH2, NHPh, morpholino, OH

R1NH2, MeOH

rt, 30 min to 8 h

N

SNCl

387

H

R1NN2

NR1

Cl

S

N

NN

R1

S

R1HN

390

R1NH2

N

NN

R1

S

Cl

389388

The reaction of diazoalkanes with 3,5-dichloro-2H-1,4-oxazin-2-ones 391 and 3-chloro-2H-1,4-benzoxazin-2-ones 395 is another interesting method for the synthesis of 1H-1,2,3-tri-azole derivatives (Schemes 127 and 128).[406,407] The intermediate bicyclic or tricyclic tri-azolo-fused compounds 393 and 396 are converted into the monocyclic 1H-1,2,3-triazoles394 or 397 by reaction with nucleophiles (amines, methanol, water). The first step of thisprocedure involves the selective attack of the diazoalkane to the imidoyl chloride func-tion (e.g., giving 392) followed by ring closure. Reactions with diazomethane give higheryields (68–91%) of the fused triazoles than reactions with diazoethane or diazopropane(41–52%). The reaction conditions required for the ring cleavage of the lactone functionin compounds 393 are dependent on the nucleophile: with propylamine or diethylamineit takes one hour at room temperature, with aniline it requires three hours at reflux andwith methanol or water it takes 12 hours at reflux. The triazoles 394 obtained from thistwo-step procedure have the interesting Æ-chloro ketone substituent at N1, which may beused for the elaboration of other heterocycles.




bScheme 127 Reaction of Diazoalkanes with 3,5-Dichloro-2H-1,4-oxazin-2-ones[406,407]

Et2O

0 oC, 3 d

N

NNNuH

N

O O

ClCl

R1

R2

Nu

OCl

R1

O

394

+ R2CHN2

N

O O

Cl

R1

392

N

R2

N

−

+

391

393

O

N NN

Cl

R1

O R2

Compound R1 R2 Nu Yielda,b (%) Ref

393 Me H – 91 [407]

393 Ph H – 81 [407]

393 2,6-Cl2C6H3 H – 72 [407]

393 2,6-Cl2C6H3 Me – n.r. [407]

393 Me Et – n.r. [407]

394 Me H OMe 95 [407]

394 Ph H OMe 80 [407]

394 Me H NEt2 87 [407]

394 Me Et OMe 28c [407]

394 2,6-Cl2C6H3 Me OMe 25c [407]

394 2,6-Cl2C6H3 H NHPh 84 [407]

394 Me H OH 55 [407]

a n.r. = not reported.b Yield of 394 from 393 or 393 from 391 unless otherwise stated.c Yield of 394 from 391.

Scheme 128 Reaction of Diazoalkanes with 3-Chloro-2H-1,4-benzoxazin-2-ones[406,407]

Et2O

0 oC, 3 d

N

NN

N

O O

Cl

R2

Nu

O

397

+ R2CHN2

395 396

OH

R1

R1

O

N NN

O R2

R1

NuH





bCompound R1 R2 Nu Yielda (%) Ref

396 H H – 75 [407]

396 Me H – 71 [407]

396 Cl H – 68 [407]

396 H Me – 52 [407]

396 Cl Et – 41 [407]

397 Cl H OMe 75 [407]

397 Cl Et OMe 60 [407]

397 Cl Et NHPr 76 [407]

397 Me H NHPh 59 [407]

397 H H NEt2 60 [407]

397 H H OH 58 [407]

a Yield of 397 from 396 or 396 from 395.

Methyl 1H-1,2,3-Triazole-5-carboxylates 394 and 397 (Nu = OMe); General Procedure:[407]

CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhala-tion.

Compound 391 or 395 (10 mmol) was slowly added to a Et2O soln of CH2N2 (40 mmol) at0 8C. In the cases of MeCHN2 and EtCHN2, iPr2O was used as solvent and, to avoid violentreactions, the initial temperature was –78 8C. Afterwards the temperature was brought to4 8C and, after stirring for 3 d, the excess of diazo compound and the solvent was evapo-rated. Then the residue was recrystallized (CHCl3/hexane) yielding 393 or 395. This com-pound (10 mmol) was dissolved in MeOH (50 mL), the soln was brought to reflux temper-ature, and the solvent was evaporated after 15 min (for 393) or 12 h (for 396). The residuewas recrystallized (CHCl3/hexane) yielding 394 or 397.

13.13.1.3 Aromatization

4,5-Dihydro-1H-1,2,3-triazoles (triazolines) are intermediates of 1,2,3-triazoles in manysynthetic methods, especially those involving the addition of azides to C=C bonds. Inmost cases 4,5-dihydro-1H-1,2,3-triazoles aromatize spontaneously to the correspondingtriazoles but when they are stable compounds they can be aromatized by oxidation, elim-ination, or isomerization reactions. This subject is discussed in a review.[4] Some illustra-tive examples are described below.

13.13.1.3.1 Method 1:By Oxidation Reactions

The oxidative dehydrogenation of 4,5-dihydro-1H-1,2,3-triazoles 398 to triazoles 399 iscarried out mainly with potassium permanganate or nickel peroxide (Scheme 129). Verygood results are obtained when the reaction is carried out with potassium permanganatein a two-phase system (benzene/water) using tetrabutylammonium chloride as a phase-transfer catalyst.[59,408,409] If the reaction is run in a single phase in anhydrous benzenealone, the products are not triazoles but imines.[410] The oxidation of 4,5-dihydro-1H-1,2,3-triazoles bearing sterically crowded ortho-substituted phenyl groups in the 5-posi-tion with potassium permanganate gives low yields of the corresponding triazoles. Inthese cases much better results are obtained with nickel peroxide.[58,411]




bScheme 129 Oxidative Dehydrogenation of 4,5-Dihydro-1H-1,2,3-triazoles[58,408]

N

NN

399

R2

R1

N

NN

398

R2

R1

A: KMnO4, TBACl, benzene, H2O, reflux, 2−8 h

B: NiO2, benzene, reflux, 3−4 h

R1 R2 Method Time (h) Yield (%) Ref

4-pyridyl Ph A 2 65 [408]

4-pyridyl 4-Tol A 2 73 [408]

4-pyridyl 4-ClC6H4 A 3 72 [408]

3-pyridyl 3-O2NC6H4 A 8 58 [408]

2-quinolyl Ph A 7 40 [408]

2-quinolyl 4-ClC6H4 A 5.5 57 [408]

4-O2NC6H4 4-O2NC6H4 A 8 38 [408]

2-ClC6H4 4-MeOC6H4 B 4 63 [58]

2-ClC6H4 3,4-Cl2C6H3 B 3 63 [58]

2,4-Cl2C6H3 Ph B 4 65 [58]

2,4-Cl2C6H3 4-F3CC6H4 B 4 70 [58]

2,6-Cl2C6H3 Ph B 4 50 [58]

2,6-Cl2C6H3 3-ClC6H4 B 3 52 [58]

2,6-Cl2C6H3 4-BrC6H4 B 3 74 [58]

The oxidation of 1-aryl-4-methylene-5-morpholino-4,5-dihydro-1H-1,2,3-triazoles 400with 3-chloroperoxybenzoic acid affords 1-aryl-1H-1,2,3-triazole-4-carbaldehydes 401(Scheme 130). The corresponding carboxylic acids are also produced as byproducts.[412]

4,5-Dihydro-1H-1,2,3-triazoles 400 also react with halomethyl radicals to yield 1,2,3-tria-zole derivatives.[413] Oxidation of 4,5-dihydro-1H-triazole 402 with bromine gives triazole403 in 83% yield (Scheme 130).[202]

Scheme 130 Oxidation of 4,5-Dihydro-1H-1,2,3-triazoles with3-Chloroperoxybenzoic Acid[412] or Bromine[202]

N

NN

401

MCPBA, CHCl3rt, 30 min

OHC

R1

R2

38−70%

N

NN

400

R1

R2

NO

R1 = CO2Et, Me, NO2, Cl, H; R2 = H, CF3

Br2, NaOAc

MeCCl3rt, 8 h

83%N

NNMeO2C

TBDMSO

OHTBDMSO

OTBDMS

402

N

NNMeO2C

TBDMSO

OHTBDMSO

OTBDMS

403





b1,5-Disubstituted 1H-1,2,3-Triazoles 399 by Nickel Peroxide Oxidation;General Procedure:[58]

To a soln of the 4,5-dihydro-1H-1,2,3-triazole 398 (5 mmol) in benzene (100 mL) (CAU-TION: carcinogen) was added dried, finely powdered NiO2 (0.06 mol) and the mixture wasrefluxed with vigorous magnetic stirring for 3–4 h. The mixture was then allowed to coolto rt and filtered under gravity. The residual NiO2 was washed with hot CHCl3, and thecombined filtrates were subjected to rotary evaporation. The resulting oily residue wascooled and triturated with petroleum ether, or an Et2O/petroleum ether mixture, whenit solidified to a clean, crystalline mass, and the colored impurities remained in soln.Many of the triazoles at this point were quite pure, giving reasonably sharp meltingpoints. Recrystallization (acetone/petroleum ether) gave analytically pure samples.

13.13.1.3.2 Method 2:By Elimination Reactions

Several methods for the synthesis of 1,2,3-triazoles involve spontaneous or induced elim-ination reactions. Typical examples are the reactions of azides with enamines, enolethers, or enolates, and the thermal elimination of stable molecules from 4,5-dihydro-1H-1,2,3-triazoles via retro-Diels–Alder reactions (see, for example, Schemes 69 and70).[213,214,217,220,414] The elimination of morpholine from compound 404 on heating in for-mic acid (Scheme 131) is another example. In this process the piperidine ring is cleavedreductively, with carbon dioxide evolution, and the triazole 405 is obtained.[415] In somecases the elimination reaction corresponds to an isomerization, as exemplified in theconversion of 4,5-dihydro-1H-triazole 406 into triazole 407 (Scheme 131).[387] The base-cat-alyzed dehydration of 4,5-dihydro-1H-1,2,3-triazol-5-ols (by treatment with hot methano-lic potassium hydroxide) also gives high yields of the corresponding triazoles.[263] In arelated method, 1-benzyl-4,5-difluoro-4,5-bis(trifluoromethyl)-4,5-dihydro-1H-1,2,3-tria-zole is converted into 1-benzyl-4,5-bis(trifluoromethyl)-1H-1,2,3-triazole in 69% yield bydefluorination with tetrakis(dimethylamino)ethene.[416]

Scheme 131 Aromatization of 4,5-Dihydro-1H-1,2,3-triazoles byElimination Reactions[387,415]

− CO2

404

HCO2HMeN NN

NN

O

Ph

N

NNMe2N

Ph

+

O

HN

405

67%

KOH, EtOH

406

N N

NN

O2N

Me

407

N

NN

NO2

NHMe




b13.13.1.4 Synthesis by Substituent Modification

13.13.1.4.1 Substitution of Existing Substituents

13.13.1.4.1.1 Of Hydrogen

13.13.1.4.1.1.1 Method 1:Lithiation

1-Substituted 1,2,3-triazoles undergo lithiation with butyllithium or lithium diisopropyl-amide preferentially at the 5-position at –20 to –78 8C. The resulting lithiated species reactwith carbon, silicon, halogen, and sulfur electrophiles to yield a range of 1,5-disubstituted1,2,3-triazoles. This subject has been reviewed comprehensively.[417] At room tempera-ture, the lithiated species rapidly undergo fragmentation to nitrogen and lithium keten-imines.[418,424]

The lithiation of 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,2,3-triazole (408, R1 = SEM)followed by addition of an electrophile, gives moderate yields of 1,5-disubstituted 1,2,3-triazoles 410 (R1 = SEM) (Scheme 132).[419] The 2-(trimethylsilyl)ethoxymethyl (SEM) groupis a particularly interesting N1 protecting group for lithiation: it is readily attached to thetriazole, it helps the stabilization of the intermediate triazol-5-yllithium species by intra-molecular coordination, and it is removed under very mild conditions (by heating withdilute hydrochloric acid or by treatment with tetrabutylammonium fluoride in refluxingtetrahydrofuran). In a similar way, 5-substituted 1-benzyloxy-1H-1,2,3-triazoles 410(R1 = OBn) are obtained in excellent yields from lithiation of 1-(benzyloxy)-1H-1,2,3-tria-zole (408, R1 = OBn), followed by reaction with an electrophile.[336] Removal of the benzylgroup by catalytic hydrogenation affords the corresponding 1H-1,2,3-triazol-1-ols in 98–100% yield. Compound 408 (R1 = OBn) is also converted into 5-acyl- and 5-aryl-1,2,3-tria-zoles through a lithiation–transmetalation strategy.[420] Lithiation of 1-methyl-1H-1,2,3-tri-azole with butyllithium or lithium 2,2,6,6-tetramethylpiperidide, followed by addition ofan electrophile gives moderate yields of 5-alkyl- or 5-acyl-1-methyl-1,2,3-triazoles.[421] Lith-iation of 1-methyl-5-(phenylsulfanyl)-1H-1,2,3-triazole with lithium 2,2,6,6-tetra-methylpiperidide occurs at the 4-position and after quenching with aldehydes and car-boxylic amides the corresponding 4-(1-hydroxyalkyl) and 4-acyl derivatives are obtainedin good yields (71–86%).[421]

Scheme 132 Lithiation of 1H-1,2,3-Triazoles and Quenching with Electrophiles[336,419]

N

NN

R1

BuLi, THF

−78 oC, 5−30 min

408

N

NN

R1

409

Li

electrophile, THF

−78 oC to rt, 1−4 h N

NN

R1

410

R2

R1 R2 Electrophile Yield (%) Ref

SEM CH(OH)Ph PhCHO 45 [419]

SEM Bz EtOBz 21 [419]

SEM Me MeI 30 [419]

SEM SPh PhSSPh 80 [419]

SEM Cl Cl3CCCl3 50 [419]

SEM TMS TMSCl 37 [419]

OBn D D2O 90 [336]

OBn Me MeI 93 [336]





bR1 R2 Electrophile Yield (%) Ref

OBn CHO DMF 87 [336]

OBn CO2Me ClCO2Me 76 [336]

OBn CONMe2 ClCONMe2 97 [336]

OBn Cl Cl3CCCl3 88 [336]

OBn Br Br2 86 [336]

OBn I I2 96 [336]

OBn SMe MeSSMe 67 [336]

OBn TMS TMSCl 93 [336]

OBn SnBu3 Bu3SnCl 91 [336]

The lithiation of 1,2,3-triazoles is also carried out with 4,5-dibromotriazoles (both 1H- and2H-) via a bromine–lithium exchange reaction.[462] For example, 4,5-dibromo-1-(methoxy-methyl)-1H-1,2,3-triazole (411) reacts with butyllithium, in diethyl ether or tetrahydrofu-ran at –80 to –70 8C, at position 5 and the resulting lithiated derivative 412 is quenchedwith aqueous ammonium chloride, carbon dioxide, methyl chloroformate, benzophe-none, or dimethyl or diphenyl disulfide to give high yields of the corresponding 5-substi-tuted 1,2,3-triazoles 413 (Scheme 133).

Scheme 133 Lithiation of 4,5-Dibromo-1-(methoxymethyl)-1H-1,2,3-triazole[462]

N

NN

BuLi, Et2O

−80 oC, 20 min

411

electrophile

−80 to −70 oC

20−60 min

OMe

Br

BrN

NN

412

OMe

Li

BrN

NN

413

OMe

R1

Br

R1 Electrophile Yield (%) Ref

H NH4Cl 84 [462]

CO2H CO2 72 [462]

C(OH)Ph2 Ph2CO 93 [462]

SMe MeSSMe 87 [462]

SPh PhSSPh 71 [462]

5-Substituted 1-Benzyloxy-1H-1,2,3-triazoles 410 (R1 = OBn) by Lithiation Followed byReaction with an Electrophile; General Procedure:[336]

Under N2 at –78 8C, a 0.1 M soln of 408 (R1 = OBn) in dry THF was treated dropwise with1.6 M BuLi in hexane (1.2 equiv). After 5 min the electrophile was added (neat or dissolvedin THF) and stirring was continued at –78 8C for 1 h and at rt 1 h. The mixture was thenquenched with sat. NH4Cl and the product was extracted with CH2Cl2. The organic phasewas washed with H2O, dried (MgSO4), concentrated, and purified by flash chromatogra-phy (EtOAc/heptane 1:2).




b13.13.1.4.1.1.2 Method 2:

N-Trimethylsilylation

1H-1,2,3-Triazole (414, R1 = H)[421,430] and 4-methyl-1H-1,2,3-triazole (414, R1 = Me)[430] reactwith chlorotrimethylsilane to give selectively 2-trimethylsilyl derivatives 415 (Scheme134). Refluxing a mixture of 1H-1,2,3-triazole and hexamethyldisilazane for six hoursgives an 81% yield of 1-(trimethylsilyl)-1H-1,2,3-triazole (416) and 2-(trimethylsilyl)-2H-1,2,3-triazole (417) in a 1:5 ratio.[422] 1,2,3-Triazole N-oxides are C-silylated at ring and exo-cyclic Æ-positions in high yields in a one-pot procedure involving treatment with trimeth-ylsilyl trifluoromethanesulfonate, iodotrimethylsilane, or tert-butyldimethylsilyl trifluo-romethanesulfonate in the presence of 1,2,2,6,6-pentamethylpiperidine, diisopropyleth-ylamine, or lithium tetramethylpiperidide.[423]

Scheme 134 N-Trimethylsilylation of 1H-1,2,3-Triazoles[421,430]

N

NH

N

TMSCl, benzene, Et3N

0 oC, 30 min, then reflux, 2 h

414

R1

N

NNTMS

415 R1 = H, Me

R1

N

NN

416

TMS

N

NNTMS

417

+(TMS)2NH, reflux, 6 h

81−96%

R1 = H 81%

1:5

2-(Trimethylsilyl)-2H-1,2,3-triazole (415, R1 = H):[421]

TMSCl (10.7 mL, 84 mmol) was added to a soln of 1H-1,2,3-triazole (4.7 mL, 80 mmol) andEt3N (12.1 mL, 87 mmol) in benzene (80 mL) (CAUTION: carcinogen) under N2 with ice cool-ing, and the mixture was stirred for 30 min and then refluxed at 80 8C for 2 h. After filtra-tion, the filtrate was evaporated to afford a residue, which was distilled under atmospher-ic pressure to give a colorless oil; yield: 9.72 g (86%); bp 148 8C; 1H NMR (CDCl3, �): 7.73 (s,2H, hetaryl), 0.51 (s, 9H, TMS).

13.13.1.4.1.1.3 Method 3:Carboxylation

Carboxylation of C-lithio[424,425] or Grignard[180,181] derivatives of triazoles gives the corre-sponding carboxylic acids (Scheme 135). The lithiated species 412 (Scheme 133) isquenched with carbon dioxide to give 4-bromo-1-(methoxymethyl)-1H-1,2,3-triazole-5-car-boxylic acid in 72% yield.[462] The 2-methoxymethyl analogue of 412 yields methyl 4-bro-mo-2-(methoxymethyl)-2H-1,2,3-triazole-3-carboxylate in 71% when quenched with meth-yl chloroformate.[462] Similarly, lithiation of 1-benzyloxy-1H-1,2,3-triazole and quenchingthe resulting 5-lithiated species with methyl chloroformate or dimethylcarbamoyl chlo-ride yields the corresponding 5-carboxylate (76%) or N,N-dimethyl carboxamide (97%)(see Scheme 132).[336]

5-Amino-1H-1,2,3-triazole-4-carboxylic acid is obtained in low yield (14%) by heating1H-1,2,3-triazol-4-amine with aqueous potassium hydrogen carbonate for 16 hours at100 8C.[428]





bScheme 135 Carboxylation of 1,4-Diphenyl-1H-1,2,3-triazole[424]

N

NN

1. BuLi

2. CO2

418

Ph

62%

Ph

N

NN

419

Ph

PhHO2C

1,4-Diphenyl-1H-1,2,3-triazole-5-carboxylic Acid (419); Typical Procedure:[424]

To a stirred soln of 1,4-diphenyl-1H-1,2,3-triazole (418; 0.04 mol) in anhyd THF (80 mL) wasadded dropwise over 15 min, 1.6 M BuLi in hexane (26 mL) at –20 to –60 8C under N2. Whenthe addition was completed the mixture was stirred and cooled for an additional 0.5–1 hand then the mixture was poured onto solid CO2. Acidification of an aqueous soln of thesalt yielded the carboxylic acid 419; yield: 62%; mp 169–170 8C (dec).

13.13.1.4.1.1.4 Method 4:Acylation

N-Unsubstituted 1,2,3-triazoles can be N-acylated by acyl halides and anhydrides with drybenzene or pyridine as the solvent. Substitution takes place at the 1-position but the acylgroup may migrate to the 2-position on heating or on treatment with base.[173,429,430] Thus,acetylation with acetyl chloride gives 1-acetyl derivatives that rearrange to the 2-isomersabove 120 8C; acetylation by heating the triazoles with acetic anhydride gives the 2-acetylderivatives directly. An alternative route to 1-acetyl-1H-1,2,3-triazoles is the reaction of 2-trimethylsilyl derivatives (e.g., 420) with acetyl chloride, giving products such as 421(R1 = Me) (Scheme 136).[173,430] This method can be used to prepare a range of 1-acyl-1H-1,2,3-triazoles, intermediates in the synthesis of oxazoles.[431]

Scheme 136 Acylation of 2-(Trimethylsilyl)-2H-1,2,3-triazole[173,430]

benzene, rt

R1 = Me, aryl

N

NNTMS

420

+ R1COClN

NN

421

O R1

+ TMSCl

Reaction of 4,5-diphenyl-1H-1,2,3-triazole with benzoyl chloride in pyridine gives the cor-responding 1-benzoyl derivative.[432] The 1H-1,2,3-triazol-4-ols 422 react with benzoylchloride in pyridine to yield the dibenzoyl derivatives 423 in high yields (Scheme 137).[433]

Scheme 137 Benzoylation of 1H-1,2,3-Triazol-4-ols[433]

BzCl, py, 5 oC, 1 d

R1 = H 80%

R1 = Ph 92%

N

NH

N

422

N

NNBz

423

BzO

R1

HO

R1

The reaction of 1,2,3-triazole with thiobenzoyl chloride (CCl4, Et3N, rt) yields a mixture of1- and 2-thiobenzoyl-1,2,3-triazoles (22:78).[434] Similar results are obtained if the sodiumsalt of 1,2,3-triazole is used. However, only 1-(thiobenzoyl)-1,2,3-triazole is formed in 40%yield in the reaction of thiobenzoyl chloride with 2-(trimethylsilyl)-2H-1,2,3-triazole (CCl4,




b08C).[434] Reaction of 1,2,3-triazole with isocyanates affords the corresponding urea deriva-tives.[435]

1,2,3-Triazoles are also C-acylated. In this case, the corresponding lithiated speciesare reacted with appropriate electrophiles (acyl halides, esters, amides) (see Section13.13.1.4.1.1.1).

13.13.1.4.1.1.5 Method 5:Formylation

As shown in Scheme 132, C-lithiated 1,2,3-triazole species are quenched with dimethyl-formamide to afford the corresponding formyl derivatives in excellent yields;[336] howeverother attempts to quench 1,2,3-triazolyllithium compounds with dimethylformamidehave failed.[419,462] The Vilsmeier–Haack formylation of 1H-1,2,3-triazol-5-amines 424 givesthe corresponding 1H-1,2,3-triazole-4-carbaldehydes 425 in good yields (Scheme 138).These compounds are hydrolyzed by dilute hydrochloric acid to the corresponding 5-ami-no derivatives 426.[436] The Vilsmeier–Haack formylation of 1-benzyl-1,2,3-triazol-5-ols af-fords the corresponding 5-chloro-1H-1,2,3-triazole-4-carbaldehydes in 60–94% yields.[302]

1H-1,2,3-Triazole-4-carbaldehydes are also prepared from the corresponding carbonitrilesby catalytic hydrogenation (10% Pd/C, aq 0.1 M HCl)[437] or by Raney nickel/formic acid re-duction.[438]

Scheme 138 Vilsmeier–Haack Formylation of 1H-1,2,3-Triazol-5-amines[436]

R1 = Me, Bn

N

NN

424

H2N

R1

DMF, POCl385 oC, 1 h

75−85%

N

NN

425

N

R1

1 M HCl

reflux, 20 min

65%

OHC

Me2N

N

NN

426

H2N

R1

OHC

5-Amino-1-methyl-1H-1,2,3-triazole-4-carbaldehyde (426, R1 = Me); Typical Procedure:[436]

POCl3 (0.16 g, 1 mmol) was added to 1-methyl-1H-1,2,3-triazol-5-amine (424, R1 = Me;0.05 g, 0.5 mmol) in DMF (1 mL) at 0 8C. The mixture was then heated at 85 8C for 1 h,cooled, and poured onto ice (15 g). The mixture was adjusted to pH 7 and extracted withCHCl3 (3 � 20 mL). The extract was dried (K2CO3) and the solvent was removed in vacuo.The residue was recrystallized (benzene/cyclohexane 1:4) (CAUTION: carcinogen) to give5-{[(dimethylamino)methylene]amino}-1-methyl-1H-1,2,3-triazole-4-carbaldehyde (425,R1 = Me); yield: 75%; mp 136 8C. This compound was refluxed for 20 min with 1 M HCl (16equiv). The soln was neutralized and extracted with CHCl3. Evaporation of the dried(K2CO3) extract gave 426 (R1 = Me); yield: 65%.

13.13.1.4.1.1.6 Method 6:Arylation

1,2,3-Triazoles can be N-arylated by reaction with activated aryl halides. Reaction of 1H-1,2,3-triazole with 1-fluoro-2-nitrobenzene[439] or 1-fluoro-4-nitrobenzene[440] gives mix-tures of the corresponding 1- and 2-nitrophenyl-1,2,3-triazoles. However, with 1-fluoro-2,4-dinitrobenzene and 2-chloro-1,3,5-trinitrobenzene only the 1-substituted derivativesare obtained (Scheme 139).[440] Reaction of 1H-1,2,3-triazole with 2-chloro-1,3,5-trinitro-benzene (427, X = Cl), 2-fluoro-1,3,5-trinitrobenzene (427, X = F) or 1,2,3,5-tetranitroben-zene (427, X = NO2) in dioxane, dimethylformamide, or dimethyl sulfoxide for two daysat room temperature gives 1-(2,4,6-trinitrophenyl)-1H-1,2,3-triazole (428) exclusively, ex-cept in one case.[471] When the reaction is carried out with 2-fluoro-1,3,5-trinitrobenzene





b(427, X = F) in dimethyl sulfoxide, the 2-(2,4,6-trinitrophenyl)-2H-1,2,3-triazole is alsoformed; the final product composition depends on the way in which the reagents aremixed.

Scheme 139 Arylation of 1H-1,2,3-Triazole with 2,4,6-Trinitrophenyl Derivatives[440]

X = Cl, F, NO2

N

NH

N

dioxane

DMF or DMSO

rt, 2 d

58−96%+ X NO2

O2N

O2N

N

NN

NO2O2N

NO2

428427

1-(4-Tolyl)-1H-1,2,3-triazole is obtained in 11% yield from the reaction of 1H-1,2,3-triazoleand 4-tolylboronic acid in the presence of anhydrous copper(II) acetate and pyridine.[441] Amixture of 9-(1H-1,2,3-triazol-1-yl)acridine (429) (49%) and 9-(2H-1,2,3-triazol-2-yl)acridine(430) (26%) is obtained from the reaction of the anion of 1H-1,2,3-triazole, generated usingsodium hydride in dry dimethylformamide, with 9-chloroacridine (Scheme 140).[442] De-protonation of triazole 431 with potassium hexamethyldisilazanide followed by the addi-tion of pentafluoropyridine gives the 2-(4-pyridyl)-substituted triazole 432 in 49% yield(Scheme 140).[174]

Scheme 140 Arylation of 1H-1,2,3-Triazoles with 9-Chloroacridine[442] andPentafluoropyridine[174]

N

NH

N

NaH, DMF

9-chloroacridine

60 oC, 2 h

N

NN

N

N

NNN

+

429 49% 430 26%

N

NH

N

KHDMS

pentafluoropyridine, THF

0 oC to rt, 20 min

N

N

NN

N N

F

F

F

F

432431

F F

49%

1,2,3-Triazoles are also C-arylated. The palladium-catalyzed reaction of the 1,2,3-triazol-5-ylzinc iodide species 433 with appropriate aryl and hetaryl iodides gives the 5-aryl-1- or 5-hetaryl-1H-1,2,3-triazoles 434 (Scheme 141).[420]




bScheme 141 Arylation of 1-Benzyloxy-1H-1,2,3-triazol-5-ylzinc Iodide[420]

N

NN

BuLi, THF

−78 oC, 5 min

433

OBn

N

NN

ZnI2−78 oC, 30 min

OBn

Li

N

NN

OBn

IZn

Ar1I, DMF

Pd(PPh3)4

−78 oC to rt

then 80 oC, 1 hN

NN

OBn

Ar1

434 Ar1 = aryl 30−87%

Ar1 = 2-pyridyl 80%

Ar1 = 2-thienyl 63%

Ar1 = 49%NN

OBn

1-(2,4,6-Trinitrophenyl)-1H-1,2,3-triazole (428):[471]

A soln of 1H-1,2,3-triazole (4.20 g, 60 mmol), 2-fluoro-1,3,5-trinitrobenzene (427, X = F;13.40 g, 60 mmol) and dry DMF (100 mL), protected from atmospheric moisture, wasstirred at rt for 3 d. This soln was then poured with stirring into H2O (2 L). The precipitatedproduct was collected by filtration, washed with H2O, and dried. The product was thendissolved in a minimal amount of acetone (~400 mL), and to this stirred soln was addedH2O (1.5 L), dropwise at first, until crystallization was induced, at which time the flowwas increased to a slow, steady stream. The precipitated product was again collected byfiltration, washed with H2O, and dried to give white crystals; yield: 14.6 g (90%); mp214 8C (dec).

13.13.1.4.1.1.7 Method 7:Alkylation

1,2,3-Triazoles can be N- and C-alkylated. N-alkylation is readily achieved by one of thefollowing methods: (i) reaction with alkyl halides,[443] dimethyl sulfate,[50,444–446,460] diazo-methane,[44,46,47,50,447] methyl tosylate,[448,449] or methyl fluorosulfonate[450] (ii) by reactionwith alcohols in acidic media,[451] (iii) by addition to aziridines,[90] (iv) by conjugate addi-tion to activated alkenes[90,198,445,452] and alkynes,[87,443] and (v) by the Mannich reaction.[453]

Alkylation with alkyl halides requires the use of a base; generally a sodium alkoxide, so-dium hydride, or sodium hydroxide are employed.

Alkylation of N-unsubstituted 1,2,3-triazoles under basic, neutral or weakly acidicconditions generally affords mixtures of the N-alkyl derivatives. The 1,2,3-triazole itselfand the symmetrical 4,5-disubstituted triazoles give mixtures of 1- and 2-alkyl isomerswhile unsymmetrical 4,5-substituted triazoles frequently give all the three possiblemonoalkyl derivatives. Some selectivity for 1-alkylation is observed when silver or thalli-um salts of the triazoles are reacted with iodoalkanes.[454] Selective alkylation at N1 is ob-tained by reaction of a 2-(trimethylsilyl)-2H-1,2,3-triazole with primary alkyl halides inthe presence of tetrabutylammonium fluoride.[421]

It has been shown that 1H-1,2,3-triazole reacts with propan-2-ol in concentrated sul-furic acid to yield 1-isopropyl-1H-1,2,3-triazole (80%) as the sole reaction product.[451] Thescope of this method is still to be demonstrated.





bAlkylation of 1-methyl- and 1-benzyl-1H-1,2,3-triazole gives only the 1,3-disubstituted

triazolium salts.[455] The 2-alkyl-2H-1,2,3-triazole 1-oxides are quantitatively methylated atthe N-oxygen by trimethyloxonium tetrafluoroborate to yield the corresponding 1-meth-oxytriazolium tetrafluoroborates.[456] 1-Alkyl-1H-1,2,3-triazol-5-ols on reaction with diazo-methane or iodomethane are alkylated at the alcohol oxygen, N2, and N3.[306,331] 1H-1,2,3-Triazole-4-thiol is converted selectively into the 4-(methylsulfanyl) derivative by reactionwith a small excess iodomethane, in the presence of an equimolar amount of ethanolicpotassium hydroxide (1.8 M).[447] Addition of diazomethane to the 4-(methylsulfanyl)tri-azole gives a mixture of the three possible N-methylated 4-(methylsulfanyl)triazoles.[447]

The alkylation of ethyl 4-(4-hydroxyphenoxy)-1H-1,2,3-triazole-5-carboxylate (435)under alkaline conditions exclusively yields the N2 and N3 alkylation products (Scheme142). Alkylation at N1 or at the hydroxy group is not observed.[457] While alkylation of 435with benzyl or 4-methoxybenzyl chlorides gives a 1:1 mixture of the two isomers, with 4-bromophenacyl bromide preferential substitution at N2 is observed (14% and 65% respec-tively to 436 and 437). Alkylation with trityl chloride shows a marked steric preferencefor the less hindered N2 position, with isomer 437 (R1 = Tr) being formed almost exclu-sively.

Scheme 142 Alkylation of Ethyl 4-(4-Hydroxyphenoxy)-1H-1,2,3-triazole-5-carboxylate[457]

1. K2CO3, DMF

2. R1X, 20−40 oC

N

NNR1

EtO2C

OHO

N

NH

NEtO2C

OHO

435

N

NNEtO2C

OHO

436

R1

437

+

R1 = CH2Ar1, CH2COAr1, Tr; X = Cl, Br

N-Unsubstituted triazoles also react with compounds of other types to yield N-substitutedderivatives. For example, they react with nitrilimines (gererated in situ) to yield a mixtureof 1- and 2-(benzohydrazonoyl)-1,2,3-triazoles, as illustrated in Scheme 143,[458] and reactwith 1-O-acetyl ribofuranose derivatives (by an acid-catalyzed fusion procedure) to affordmixtures of triazole nucleosides 438 and 439 (Scheme 144).[459]

Scheme 143 Reaction of Triazoles with Nitrilimines[458]

benzene

reflux, 10 hN

NN

N

NH

NN

N

NN

Ph NPh

41% 33%

+N NPhPhC++ −

NHPh

NHPh




bScheme 144 Reaction of Triazoles with 1-O-Acetyl Ribofuranose Derivatives[459]

heatN

NH

N

X

N

NN

X

+O

OR1OR1

OAcR1O

O

OR1OR1

R1ON

NN

X

O

OR1OR1

R1O

+

438 439

R1 = Bz, Ac; X = H, CO2Me, CN, NO2

C-Alkylation of triazoles is achieved by lithiation followed by addition of an alkyl halide.For example, reaction of 1-phenyl-1H-1,2,3-triazole with butyllithium and addition ofiodomethane gives 5-methyl-1-phenyl-1H-1,2,3-triazole (440, R1 = H) in 94% yield (Scheme145).[424] It is interesting to note that under similar reaction conditions, 4-methyl-1-phenyl-1H-1,2,3-triazole yields 4,5-dimethyl-1-phenyl-1H-1,2,3-triazole (440, R1 = Me), while itsisomer 5-methyl-1-phenyl-1H-1,2,3-triazole gives only the 5-ethyl derivative 441. Lithia-tion of 1,4-diphenyl- and 1,5-diphenyl-1H-1,2,3-triazole, followed by iodomethanequench, gives the corresponding derivatives 440 (R1 = Ph) and 442 in 78 and 99% yield, re-spectively, reflecting the higher steric hindrance in the 1,4-diphenyl isomer. For other ex-amples of C-alkylation of triazoles see Section 13.13.1.4.1.1.1.

Scheme 145 C-Methylation of 1-Phenyl-1H-1,2,3-triazoles[424]

BuLi, THF, MeΙ−60 to −20 oCN

NN

R1

440

R1 = H, Me, Ph

Ph

78−94%

N

NN

R1

Ph

BuLi, THF, MeΙ−20 to −60 oCN

NN

441

R1 = Me, Ph

Ph

N

NN

PhEtR1 = Me 42%

442

N

NN

PhPhR1 = Ph 99%

R1

13.13.1.4.1.1.8 Method 8:Halogenation

The reaction of 1,2,3-triazole, 1-methyl-, 2-methyl-, 4-methyl-, and 4,5-dimethyl-1,2,3-tri-azole with chlorine, bromine, iodine, hypochlorite, hypobromite, and hypoiodite hasbeen studied.[460] 1H-1,2,3-Triazole reacts with bromine to afford 4,5-dibromo-1H-1,2,3-tri-azole (443) in almost quantitative yield (Scheme 146).[461,462] The intermediate monobro-





bmotriazole cannot be trapped; apparently it is brominated faster than the starting mate-rial. The 4,5-dibromo-1H-1,2,3-triazole is also obtained in 90–95% yield by bromodecar-boxylation of 1,2,3-triazole-4-carboxylic acid.[462]

Scheme 146 Bromination of 1H-1,2,3-Triazole[461,462]

N

NH

N

443

97%+ Br2

H2O, 40−45 oC, 1 h N

NH

NBr

Br

1-Methyl- and 4-methyl-1H-1,2,3-triazole react with bromine to give, respectively, the 4-bromo-1-methyl- and 5-bromo-4-methyl-1H-1,2,3-triazole in good yields. The isomeric 2-methyl-2H-1,2,3-triazole, less reactive toward halogenation, reacts with bromine only inthe presence of a catalyst (iron filings) and yields 4,5-dibromo-2-methyl-2H-1,2,3-triazole;the monobrominated product is not obtained.[460] 4-Bromo- and 5-bromo-1H-1,2,3-tria-zoles are obtained indirectly by bromination of a triazole with a removable group at N1,as shown in Scheme 147.[463]

Scheme 147 Bromination of 1H-1,2,3-Triazoles with a Removable Substituent at N1[463]

N

NN

OMe

Br2, Na2CO3

20 oC

N

NN

OMe

Br

Br

NMe

NN

OMe

Br

Br

+

X−N

NN

Me

concd H2SO4

120 oC, 1 h

N

NH

N

Brconcd H2SO4

120 oC, 1 h

MeX

Br

2- and 3-Substituted 1,2,3-triazole 1-oxides 444 and 447 are halogenated selectively in po-sition 5 in excellent yields (Scheme 148).[456,464,465] Since compounds 445 and 448 are deox-ygenated almost quantitatively (see Section 13.13.1.4.1.4.4), this is a useful route for thesynthesis of 1- and 2-substituted 4-halo-1,2,3-triazoles. The chlorination/deoxygenation of2-(4-tolyl)-2H-1,2,3-triazole 1-oxides to give 446 is carried out in one step by reaction withgaseous hydrogen chloride.[466]




bScheme 148 Halogenation of 1,2,3-Triazole 1-Oxides[456,464–466]

NaOCl, Cl2, or Br2

rt

72−100%

444 445

R1 = Me, Bn, Ph; R2 = H, Me; X = Cl, Br

N+

O−

NR1

NR2

N+

O−

NR1

NR2

X

HCl, dioxane

68%

446

R1 = Ph, OMe

N+

O−

N

NR1

4-Tol NN

NR1

4-TolCl

NaOCl or Br2

rt

78−100%

R1 = Me, Bn, Ph; X = Cl, Br

447

N+

O−

N

NR1

448

N+

O−

N

NR1

X

1-Methoxy-2-phenyl-2H-1,2,3-triazol-1-ium tetrafluoroborates 449 react with potassiumhydrogen fluoride to yield 4-fluoro-2-phenyl-2H-1,2,3-triazoles 450 (Scheme 149).[465]

Scheme 149 Fluorination of 1-Methoxy-2-phenyl-2H-1,2,3-triazol-1-ium Tetrafluoroborates[465]

KHF2, MeCN, rt, 3 d

61−64%

R1 = H, Me

BF4−

449

N+

OMe

NPh

NR1

450

NNPh

NR1

F

Mesoionic compound 451 reacts with bromine in acetic acid to give the 5-bromo deriva-tive 452 (Scheme 150).[362]

Scheme 150 Bromination of Mesoionic Triazole Compounds[362]

Br2, AcOH, rt, 2 h

68%

451

NMe

N

N

−O 4 -Tol

+

452

NMe

N

N

−O 4 -Tol

+Br

C-Lithiated 1,2,3-triazole species are quenched with bromine or iodine to afford the corre-sponding halogenated derivatives in excellent yields.[336] Using hexachloroethane as theelectrophile, the chlorinated derivatives are obtained.[336,419]





bReaction of 1H-1,2,3-triazole with iodine monochloride yields 1-iodo-1H-1,2,3-tria-

zole (453). Melting a mixture of this compound with 3,5-dimethyl-2H-1,2,4-triazole for5–10 minutes gives 4,5-diiodo-1H-1,2,3-triazole (454) (Scheme 151).[467] 1H-1,2,3-Triazolegives 1,4,5-tribromo-1H-1,2,3-triazole when treated with an excess of sodium hypobro-mite.[460]

Scheme 151 Iodination of 1H-1,2,3-Triazole[467]

N

NH

N

ICl, NaOEt

EtOH, rt

60−80%

453

N

NN

I

110 oC, 5−10 min

75%

454

N

NH

NI

I

N

NH

N

2-Phenyl-2H-1,2,3-triazol-4-ol reacts with bromine to give the corresponding 5-bromo de-rivative in high yield.[474] A method for the selective conversion of 2,4,5-triphenyl-2H-1,2,3-triazole into 2-(2-chlorophenyl)-4,5-diphenyl-2H-1,2,3-triazole has been reported.[468]

4,5-Dibromo-1H-1,2,3-triazole (443); Typical Procedure:[462]

Br2 (15 mL, an excess) was added dropwise to a stirred soln of 1H-1,2,3-triazole (15.0 g,217 mmol) in H2O (100 mL) warmed to 40–45 8C and the resulting soln was stirred for afurther 1 h. The precipitate was collected by filtration and further Br2 (10 mL) was addedto the filtrate, then it was kept at rt overnight, after which a second crop of product hadprecipitated. The combined amounts of product were washed with H2O (3 � 50 mL), dried,and recrystallized (aq MeOH) to give the product; yield: 47.8 g (97%); mp 192–194 8C.

13.13.1.4.1.1.9 Method 9:N-Amination

4,5-Diphenyl-1H-1,2,3-triazole is aminated by reaction with hydroxylamine-O-sulfonicacid yielding the corresponding triazol-1-amines and triazol-2-amines in approximatelyequal amounts (Scheme 152).[3]

Scheme 152 N-Amination of 4,5-Diphenyl-1H-1,2,3-triazole[3]

N

NH

N

N

NN

Ph

Ph

Ph

Ph

NH2

H2NOSO3H N

NN

Ph

Ph+

NH2

13.13.1.4.1.1.10 Method 10:N-Hydroxylation

1H-1,2,3-Triazole is oxidized by peracids to 1H-1,2,3-triazol-1-ol (Scheme 153). Best yieldsare obtained with 3-chloroperoxybenzoic acid or hydrogen peroxide plus formicacid.[336,469] Yields of 65% are obtained by adding the oxidant (hydrogen peroxide/formicacid) portionwise over 30 days followed by continuous extraction of the triazolol with di-ethyl ether over three weeks.[336] The autoxidation of an N-unsubstituted 1,2,3-triazole tothe corresponding triazol-2-ol has been reported.[342]




bScheme 153 N-Hydroxylation of 1H-1,2,3-Triazole[336,469]

N

NH

N

N

NN

OH

A: HCO2H, H2O2, 20 oC, 30 d

B: MCPBA, EtOAc, rt, 7 d

A: 65%

13.13.1.4.1.1.11 Method 11:Nitration

Direct nitration of 1H-1,2,3-triazole to give 4-nitro-1H-1,2,3-triazole is not possible.[470]

However, this compound is obtained in moderate yield from the reaction of 1-morpholi-no-2-nitroethene and tosyl azide.[471] Attempts to introduce a nitro group in the triazolering of 1-phenyl- and 4-phenyl-1H-1,2,3-triazole are unsuccessful since nitration occursonly in the phenyl ring. For example, the reaction of 4-phenyl-1H-1,2,3-triazole with amixture of nitric acid and sulfuric acid at 0 8C gives the 4-(4-nitrophenyl) derivative in50% yield; at 90 8C the 4-(2,4-dinitrophenyl) derivative is obtained in 35% yield.[471] Similar-ly, the 3-phenyl-1,2,3-triazole 1-oxide is nitrated with fuming nitric acid, at room temper-ature, at the para phenyl position.[464]

The nitration of 2-phenyl-2H-1,2,3-triazole with a mixture of fuming nitric acid andconcentrated sulfuric acid at 20 8C gives a mixture of 2-(4-nitrophenyl)-2H-1,2,3-triazole(454) and 4-nitro-2-(4-nitrophenyl)-2H-1,2,3-triazole (455) (Scheme 154).[472,473] However,if the nitration is carried out with nitric acid in acetic anhydride at 15 8C, only triazole454 is obtained.[473]

Scheme 154 Nitration of 2-Phenyl-2H-1,2,3-triazole[472,473]

N

NN

A: HNO3, H2SO4

20 oC, 1 h

B: HNO3, Ac2O

15 oC N

NN

NO2

N

NN

NO2

O2N

+

454 455

A: 69%; (454/455) 20:3

B: 81% (454 only)

While 2-(2,4,6-trinitrophenyl)-2H-1,2,3-triazole is nitrated at C4 of the triazole ring, theisomeric 1-(2,4,6-trinitrophenyl)-1H-1,2,3-triazole is resistant to nitration, even underforcing conditions.[471] Nitration of 2-phenyl-2H-1,2,3-triazol-4-ol with nitric acid in glacialacetic acid affords 5-nitro-2-phenyl-2H-1,2,3-triazol-4-ol in 60% yield.[474] Under similarconditions, 2-phenyl-2H-1,2,3-triazol-4-ol 1-oxide also gives the corresponding 5-nitro de-rivative.[474] Nitration of 4-(2,4,6-trinitroanilino)-1H-1,2,3-triazole with a mixture of nitricacid and sulfuric acid, at 20–25 8C, affords the corresponding 5-nitro derivative in 30%yield.[475]

Nitration of 2-methyl-2H-1,2,3-triazole with a mixture of fuming nitric acid and con-centrated sulfuric acid, at room temperature, affords 2-methyl-4-nitro-2H-1,2,3-triazole(456) in 98% yield (Scheme 155). Under more vigorous conditions (10 h at 100 8C) this com-pound is further nitrated to 2-methyl-4,5-dinitro-2H-1,2,3-triazole (457) (97%).[456] Nitra-tion of 2-methyl-2H-1,2,3-triazole 1-oxide at room temperature gives a mixture of the 4-and 5-nitro derivatives. At 100 8C both compounds are further nitrated to 2-methyl-4,5-di-nitro-2H-1,2,3-triazole 1-oxide.[456] Nitration of 2-phenyl-2H-1,2,3-triazole 1-oxide at roomtemperature gives initially (detectable after 1 min of reaction time) a mixture of 2-(4-nitro-phenyl)-2H-1,2,3-triazole 1-oxide, 5-nitro-2-phenyl-2H-1,2,3-triazole 1-oxide, and 5-nitro-2-





b(4-nitrophenyl)-2H-1,2,3-triazole 1-oxide. The final product, 2-(2,4-dinitrophenyl)-5-nitro-2H-1,2,3-triazole 1-oxide, is formed after approximately two hours.[465]

Scheme 155 Nitration of 2-Methyl-2H-1,2,3-triazole[456]

N

NNMe

HNO3, H2SO4

rt, 3 h

456

N

NNMe

O2N HNO3, H2SO4

100 oC, 10 h

457

N

NNMe

O2N

O2N98% 97%

2-Methyl-4-nitro-2H-1,2,3-triazole (456); Typical Procedure:[456]

2-Methyl-2H-1,2,3-triazole (1 mmol), concd H2SO4 (1.02 mL), and fuming HNO3 (d 1.55;0.51 mL) were stirred at rt for 3 h. H2O (5 mL) was added. Extraction with CH2Cl2 (5 mL,2 � 3 mL), drying (K2CO3), and removal of the solvent gave the crude product (98%). Recrys-tallization (ligroin) gave crystals; mp 99–101 8C.

13.13.1.4.1.2 Of Metals

13.13.1.4.1.2.1 Method 1:Desilylation

N-Trimethylsilyl substituents are readily removed under very mild conditions: treatmentwith aqueous methanol, ethanol, or aqueous acid.[172,173,476] Triazole derivatives contain-ing both N- and C-trimethylsilyl substituents, such as 458, are selectively desilylated:methanol cleaves N-Si bonds (e.g., to give 459), while methanol/hydrochloric acidcleaves Si-C bonds as well, both with protonation (Scheme 156).[172]

Scheme 156 Selective Desilylation of 4-Phenyl-2,5-bis(trimethylsilyl)-2H-1,2,3-triazole[172]

458

N

NN

Ph

459

N

NH

N

Ph

TMSTMS TMS

MeOH N

NH

N

Ph

MeOH, HCl

Removal of the trimethylsilyl group from 460 is readily carried out with 10% aqueous po-tassium hydroxide in boiling methanol to give triazoles 461 in almost quantitative yields(Scheme 157).[72] Heating 4-substituted 5-(trimethylsilyl)-1H-1,2,3-triazoles with potassiumfluoride and concentrated hydrochloric acid (2 drops) in refluxing ethanol gives the 4-sub-stituted 1H-1,2,3-triazoles in high yields.[52]

Scheme 157 Desilylation of 5-(Alkylsulfanyl)-5-(trimethylsilyl)-1,2,3-triazoles[72]

460

N

NN

TMS

R2S

KOH, H2O, MeOH, reflux

R1

461

N

NNR2S

R1

R1 = Me, Bu, Cy, CH2CH CH2, Bn, Ph; R2 = Me, Bn

~100%




b13.13.1.4.1.3 Of Carbon Functionalities

13.13.1.4.1.3.1 Method 1:Decarboxylation

Most 1,2,3-triazolecarboxylic acids lose carbon dioxide when heated above their meltingpoint. This reaction has been known since the 19th century.[477–479] A reasonable numberof examples of this transformation are found in the literature.[23,105,282,331,430,480] 1H-1,2,3-Triazole (464, R1 = H) is obtained in 93% by heating 1H-1,2,3-triazole-4-carboxylic acid(462, R1 = H) in an oil bath at 220 8C for a few minutes (Scheme 158).[44] 1,5-Disubstituted1,2,3-triazole-4-carboxylic acids decarboxylate slowly in boiling benzene[481] or toluene.[482]

5-Amino-1-benzyl-1H-1,2,3-triazole-4-carboxylic acid is decarboxylated to the correspond-ing triazolamine, in 60–84% yield, by refluxing in N,N-dimethylaniline for 15 min-utes.[319,428] 5-Amino-1-methyl-1H-1,2,3-triazole-4-carboxylic acid decarboxylates in reflux-ing butan-1-ol (3 h, 65% yield)[393] while 5-amino-1H-1,2,3-triazole-4-carboxylic acid and 5-amino-1-cyclohexyl-1H-1,2,3-triazole-4-carboxylic acid are decarboxylated to the corre-sponding triazolamines, in 57 and 63% yield, respectively, by heating in 1 M hydrochloricacid for one hour.[428] 1H-1,2,3-Triazole-4,5-dicarboxylic acids 463 generally lose two molesof carbon dioxide on heating above their melting point (Scheme 158).[105,478] For example,1-benzyl-1H-1,2,3-triazole is obtained in essentially quantitative yield by thermal decar-boxylation of 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylic acid.[105] However 1-phenyl-1H-1,2,3-triazole-4,5-dicarboxylic acid preferentially decarboxylates at the 5-position, givingthe corresponding 4-carboxylic acid.[479] 1-(1-Naphthyl)-1H-1,2,3-triazole-4,5-dicarboxylicacid decarboxylates in refluxing toluene (24 h) to give 1-(1-naphthyl)-1H-1,2,3-triazole in90% yield.[106]

Scheme 158 Decarboxylation of 1H-Triazolecarboxylic Acids[44,105,478]

462

N

NNHO2C

210−240 oC

R1

464

N

NN

R1

R1 = H, alkyl, aryl

463

N

NNHO2C

R1

HO2C

− CO2

200 oC

− 2CO2

1H-1,2,3-Triazole (464, R1 = H); Typical Procedure:[44]

1H-1,2,3-Triazole-4-carboxylic acid (462, R1 = H; 40 g, 0.35 mol) was heated in an oil bath.At a bath temperature of 220 8C a vigorous evolution of CO2 took place. The reaction wasover in a few min and the 1,2,3-triazole was distilled; yield: 22.8 g (93%); bp 205–206 8C/760 Torr.

13.13.1.4.1.3.2 Method 2:Deformylation

1,4-Diphenyl-1H-1,2,3-triazole-5-carbaldehyde (465) is deformylated in almost quantita-tive yield by treatment with sodium methoxide in refluxing methanol (Scheme 159). Un-der the same conditions, the isomer 1,5-diphenyl-1H-1,2,3-triazole-4-carbaldehyde is re-





bcovered quantitatively.[438] Alternatively, quantitative deformylation of 465 is accom-plished, on treatment with a large excess of hydrazine (100-fold) in refluxing ethanol togive 1,4-diphenyl-1H-1,2,3-triazole (466) via hydrazone 467 (Scheme 159).[438]

Scheme 159 Deformylation of 1,4-Diphenyl-1H-1,2,3-triazole-4-carbaldehyde[438]

465

N

NNOHC 93%

Ph

Ph

NaOMe, MeOH, reflux, 12 h

466

N

NN

Ph

Ph

467

N

NN

Ph

Ph

H2NN100%

H2NNH2, EtOH

reflux, 4 h H2NNH2

1,4-Diphenyl-1H-1,2,3-triazole (466); Typical Procedure:[438]

A soln of freshly cut Na (0.23 g, 10 mmol) and 1,4-diphenyl-1H-1,2,3-triazole-5-carbalde-hyde (465; 1.00 g, 4 mmol) in anhyd MeOH (50 mL) was refluxed for 12 h in a vessel provid-ed with a dry ice condenser, after which time 25–30 mL of liquid was distilled. On coolingthe soln remaining in the reaction vessel the product was obtained; yield: 0.83 g (93%).

13.13.1.4.1.3.3 Method 3:Deacylation

1- and 2-Acyltriazoles are readily hydrolyzed in water or dilute acid; the rate constants forhydrolysis and aminolysis of several N-acetyl-1,2,3-triazoles have been measured.[429] 2-Benzoyl-4-(benzoyloxy)-2H-1,2,3-triazoles 468 are hydrolyzed selectively to the corre-sponding 4-benzoyloxy derivatives 469 (Scheme 160).[433]

Scheme 160 Selective Hydrolysis of 2-Benzoyl-4-(benzoyloxy)-2H-1,2,3-triazoles[433]

468

N

NNBzR1

BzOH2O, acetone

reflux, 4−11 h

469

N

NH

N

BzO

R1R1 = H 89%

R1 = Ph 89%

O-Aryl-1H-1,2,3-triazole-1-carboximidates 470 are hydrolyzed to the corresponding N-un-substituted derivatives 471 by reaction with concentrated hydrochloric acid at room tem-perature (Scheme 161);[49] they are also hydrolyzed in aqueous sodium hydroxide (100 8C,15 min).




bScheme 161 Hydrolysis of O-Aryl-1H-1,2,3-triazole-1-carboximidates[49]

HCl, 20 oC, 5 h

471

N

NH

N

Ar1O

R143−91%

470

N

NN

Ar1O

R1

HN OAr1

R1 = H, CO2Et; Ar1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4

13.13.1.4.1.3.4 Method 4:Dearylation

N-Aryl substituents that are activated by nitro groups are removed by nucleophilic dis-placement by hydrazine[483] or by potassium hydroxide.[484] Oxidative removal of a 4-ami-nophenyl substituent at N1 by potassium permanganate has also been reported.[485] Oxi-dation of 2,4-bis(2,4-diaminophenyl)-2H-1,2,3-triazole (472) gives 1H-1,2,3-triazole-4-car-boxylic acid (Scheme 162).[486]

Scheme 162 Oxidative Dearylation of 2,4-Bis(2,4-diaminophenyl)-2H-1,2,3-triazole[486]

KMnO4, NaOH

100 oC N

NH

N

HO2C

80%

472

N

NN

H2NNH2

NH2

H2N

13.13.1.4.1.3.5 Method 5:Dealkylation

N-Benzyl-1,2,3-triazoles are frequently used as precursors of N-unsubstituted triazoles.The benzyl group is removed by reduction with sodium in liquid ammonia,[105,319,432,487]

catalytic hydrogenation,[90,105,457,488] or chromic acid oxidation.[280] The 4-methoxybenzylgroup is readily removed by solvolysis in trifluoroacetic acid[303] at 65 8C or with 47% hy-drobromic acid[336] at 120 8C (Scheme 163). The related 3-bromo-4-methoxybenzyl groupis removed by treatment with concentrated sulfuric acid at 120 8C.[463] Triazoles having a2-acetoxybenzyl group in N1 are dealkylated, in low yield, simply by refluxing in piperi-dine or in diethanolamine.[92] 2-Benzyl-2H-1,2,3-triazole and 1-benzyl-1H-1,2,3-triazole 3-oxides are N-debenzylated by treatment with iodotrimethylsilane, concentrated hydro-bromic acid, or concentrated sulfuric acid.[489]





bScheme 163 Removal of a 4-Methoxybenzyl Group from1-(4-Methoxybenzyl)-1H-1,2,3-triazoles[303,336]

TFA, 60−65 oC, 1−7 h

or 47% HBr, 120 oC, 3 h N

NH

N

R2

52−100%

473

R1

N

NN

R2

R1

OMe

R1 = H, CO2Et; R2 = H, OH, Cl, CN, Ph, OPh, 4-MeOC6H4

Triazoles having a 2-(trimethylsilyl)ethoxymethyl group at N1 (e.g., 474) are dealkylatedin good yields under mild conditions, namely by action of dilute aqueous hydrochloricacid or by treatment with tetrabutylammonium fluoride in tetrahydrofuran (Scheme164).[419] The cleavage of 1-cycloheptatrienyltriazoles 475 is carried out by passing hydro-gen chloride through a solution of the triazole in diethyl ether (Scheme 165).[109] Thecleavage is probably facilitated by the stability of the tropylium ion.

Scheme 164 N-Dealkylation of 1-{[(2-Trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazoles[419]

2 M HCl, EtOH, reflux, 2 h

or 1 M TBAF/THF, reflux, 4 h N

NH

N71−89%

474

R1

N

NNR1

R1 = H, Bz, SPh

OTMS

Scheme 165 Cleavage of 1-Cycloheptatrienyl-1H-1,2,3-triazoles[109]

HCl, EtOH

rt, 30 min to 1 h

475

N

NNR1

R1 = CO2Me 34%

R1 = Bz 100%

R1

NH

NNR1

R1

+

N

NH

NR1

R1

Cl+

1-Benzyloxy-1H-1,2,3-triazoles (e.g., 476) are debenzylated in almost quantitative yields tothe corresponding 1,2,3-triazol-1-ols by catalytic hydrogenation (Scheme 166).[490]




bScheme 166 Catalytic Hydrogenation of 1-Benzyloxy-1,2,3-triazoles[490]

H2, Pd/C, 0 oC, 30 minN

NNR1

R1 = MOM, Ac

OBn

93−99%

N

NNR1

OH476

1H-1,2,3-Triazoles by Removal of the 4-Methoxybenzyl Group from Triazoles 473;General Procedure:[303]

A soln of the N-protected triazole (ca. 1 g) in TFA (15–30 mL) was stirred at 60–65 8C for 1–7 h; the course of the reaction was monitored by RP–HPLC. The TFA was removed in vacuoand H2O was added to the residue. The product was isolated from the water-insoluble ma-terial by column chromatography (CHCl3). In the case of compounds 473 (R1 = CO2Et;R2 = OH, CN) the product was obtained by evaporation of the filtered aqueous phase.

13.13.1.4.1.4 Of Heteroatoms

13.13.1.4.1.4.1 Method 1:Substitution of Halogens by Nucleophiles

Heating 5-bromo-1-methyl-1H-1,2,3-triazole with ethanolic ammonia for 10 hours at100 8C in a sealed tube affords the corresponding 5-amino derivative in low yield (22% ofthe hydrochloride). The 4-bromo-1-methyl-1H- and 4-bromo-2-methyl-2H-1,2,3-triazolesdo not react with ammonia under the same conditions.[44] 5-Bromo-1-methyl-1H-1,2,3-tri-azole also reacts with aniline to yield the corresponding 5-anilino derivative in 54%.[44] Thedisplacement of the chloro group in triazoles 477 (R1 = Bn)[457,491,756] and 477 (R1 = 4-MeOC6H4CH2)

[303,491,756] by nucleophiles, such as cyanide, aryloxide, and arenethiolate,gives good yields of the corresponding derivatives 478 (Scheme 167). Similarly, 1,4-di-phenyl-1H-1,2,3-triazole-5-carbonitrile is prepared in 75% yield from the reaction of thecorresponding 5-chloro derivative with sodium cyanide in dimethyl sulfoxide (140 8C,4 h).[438]

Scheme 167 Displacement of a Chlorine by Nucleophiles[303,457,491,756]

Nu−, DMF, 70−80 oC, 18−24 hN

NNCl

R1 = Bn, 4-MeOC6H4CH2; Nu = CN, OPh, 4-MeOC6H4S, 2-thienylsulfanyl

66−82%

EtO2C

R1

477

N

NNNu

EtO2C

R1

478

Heating 1-aryl-5-chloro-1H-1,2,3-triazoles 479 with hydrazine gives directly 5-(substitutedamino) 1H-1,2,3-triazol-1,5-diamines 481 (Scheme 168). The 5-hydrazinotriazoles 480 arepresumably formed first but rearrange spontaneously under the reaction conditions.[492]

Heating 5-chloro-1-phenyl-1H-1,2,3-triazole with an aqueous solution of sodium hydrosul-fide at 100 8C in a sealed tube produces a bis(1-phenyl-1H-1,2,3-triazol-5-yl) sulfide.[404] Cu-riously, when the same reaction is carried out at room temperature the product is N-phen-yl-1,2,3-thiadiazol-5-amine.[404]





bScheme 168 Reaction of 1-Aryl-5-chloro-1H-1,2,3-triazoles with Hydrazine[492]

H2NNH2

60−130 oC, 2−24 hN

NNCl

R1 = H, Ph; Ar1 = Ph, 4-ClC6H4, 4-BrC6H4, 4-pyridyl

R1

479

Ar1

47−80%

N

NNH2NHN

R1

480

Ar1

N

NNAr1HN

R1

481

NH2

Attempted displacement of bromine from 4,5-dibromo-1H-1,2,3-triazole by dimethyl-amine under vigorous conditions (sealed tube, 260 8C, 140 h) yields only the dimethyl-amine salt of the dibromotriazole.[445] The halo group in 4-chloro- and 4-bromo-3-substi-tuted 1H-1,2,3-triazole 1-oxides is readily displaced by methoxide ions at 20 8C while the 5-chloro analogues require heating at 140 8C.[464] The displacement of bromine from bromo-and dibromo-1,3-disubstituted 1,2,3-triazolium salts by methoxide, hydroxide, and sul-fide has been studied extensively.[449,493–495] The 5-bromo-1,2-disubstituted 1,2,3-triazo-lium fluorosulfonates react with hydroxide or methoxide ions to form 1,2-disubstituted1,2,3-triazol-5-ones.[450] Intramolecular displacement of chlorine in 4-acyl-5-chloro-1H-1,2,3-triazoles gives access to interesting polycyclic triazole derivatives.[496,497]

13.13.1.4.1.4.2 Method 2:Substitution of Hydroxy Groups by Halogens

Reaction of the 1H-1,2,3-triazol-5-ol 482 with phosphorus pentachloride in toluene at40 8C gives the 5-chloro derivative 483 in 65% yield (Scheme 169).[303]

Scheme 169 Reaction of a 1H-1,2,3-Triazol-5-ol with Phosphorus Pentachloride[303]

PCl5, toluene

40 oC, 90 minN

NNHO

EtO2C

482

OMe

65%

N

NNCl

EtO2C

483

OMe

13.13.1.4.1.4.3 Method 3:Substitution of Diazonium Groups by Nucleophiles

Displacement of nitrogen from diazonium salts derived from 1,2,3-triazol-4-amines and1,2,3-triazol-5-amines is achieved in the same manner as for other aromatic diazoniumsalts. For example, a range of 4-substituted 5-azido-1-phenyl-1H-1,2,3-triazoles 486 is pre-pared in high yield by diazotization of the corresponding 5-amino derivatives 484 fol-lowed by addition of excess sodium azide to the diazonium ions 485 (Scheme 170).[498,499]

In a similar process, 5-amino-1H-1,2,3-triazole-4-carboxamide is converted into the 5-iododerivative in 33%.[500] Diazotization of 1-methyl-1H-1,2,3-triazol-4-amine with sodium ni-trite/hydrobromic acid gives directly the 4-bromo derivative in 41% yield.[44]




bScheme 170 Substitution of Diazonium Groups by Nucleophiles[498,499]

NaNO2, H2O, HCl

−5 to 0 oCN

NNH2N

R1

R1 = Ph, XC6H4, CHO, CONH2, CN, PO(OEt)2, SO2Ph

Ph

484

NaN3, H2O

−30 or 0 oCN

NN+N2

R1

Ph

485

N

NNN3

R1

Ph

486

5-Azido-1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (486, R1 = CHO); Typical Procedure:[499]


An aqueous soln of NaNO2 (0.76 g, 11 mmol) was added slowly to a well stirred soln of 5-amino-1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (484, R1 = CHO; 1.88 g, 10 mmol) inconcd HCl (120 mL) at –5 to 0 8C. Then, a 10-fold excess of NaN3 in H2O was added dropwiseat about –30 8C. After dilution with H2O, the mixture was extracted with Et2O and thecombined extracts were dried (MgSO4). The solvent was evaporated and the residue waschromatographed (silica gel, CH2Cl2). Crystallization (CHCl3/Et2O) gave pure compound;yield: 62%; mp 97 8C (dec).

13.13.1.4.1.4.4 Method 4:Deoxygenation

Triazole N-oxides, such as 487, 489, and 491, are deoxygenated to triazoles (e.g., 488, 490,and 492) in almost quantitative yield by refluxing in phosphorus trichloride (Scheme171)[456,464,465] or by reduction with zinc in acidic media (Scheme 172).[466,501] 2-Aryl-2H-1,2,3-triazole 1-oxides are converted directly into 2-aryl-4-chloro-2H-1,2,3-triazoles by re-action with gaseous hydrogen chloride[466] or by heating with concentrated hydrochloricacid in a sealed tube.[465]

Scheme 171 Deoxygenation of Triazole N-Oxideswith Phosphorus Trichloride[456,464,465]

X = Cl, Br

N

NNR1

487

X

PCl3reflux, 1 h

83−99%

488

O−+

N

NNR1

X

X = Cl, Br

NR1

NN

489

X

PCl3reflux, 1 h

90−97%

490

O−+

NR1

NNX





bScheme 172 Reductive Deoxygenation of 2H-1,2,3-Triazole 1-Oxides[466,501]

Ar1 = Ph, 3-ClC6H4, 4-ClC6H4, 4-EtO2CC6H4

N

NNAr1

491

Zn, AcOH

0 oC to rt, 12 h

80−95%

492

O−+

N

NNAr1

HO HO

13.13.1.4.1.4.5 Method 5:Dehalogenation

1-Substituted 5-bromo-1H-1,2,3-triazole 3-oxides 493 are debrominated in virtually quan-titative yield when heated at 100 8C for 1 hour with sodium sulfite (Scheme 173).[464]

Scheme 173 Debromination of 5-Bromo-1H-1,2,3-triazole 3-Oxides[464]

R1 = Me, Ph, Bn

Na2SO3, H2O

reflux, 1 h

97−100%

493

N+

O−

N

NR1

494

N+

O−

N

NR1

Br

1-Methyl-1H-1,2,3-triazole 3-Oxide (494, R1 = Me); Typical Procedure:[464]

5-Bromo-1-methyl-1H-1,2,3-triazole 3-oxide (493, R1 = Me; 0.56 g, 3.1 mmol), Na2SO3

(1.19 g, 9.4 mmol), and H2O (5.6 mL) were refluxed for 1 h. The H2O was removed and theresidue was extracted with boiling MeCN (3 � 10 mL). Removal of the MeCN afforded 494(R1 = Me); yield: ~100%; mp 123–124 8C.

13.13.1.4.2 Addition Reactions

13.13.1.4.2.1 Method 1:Conversion into N-Oxides

1-Substituted 1,2,3-triazole 3-oxides 496 are prepared by oxidation of 1-substituted tria-zoles 495 with 3-chloroperoxybenzoic acid (Scheme 174). The yields are good but de-crease when electron-withdrawing substituents are present, particularly if situated adja-cent to the nitrogen to be oxidized. Phenyl groups at this position also lead to decreasedyields. The low yield in these cases is not a serious drawback since unchanged startingmaterial is readily recovered.[464,489] Oxidation of 1-(arylmethyl)-1H-1,2,3-triazoles withperacetic acid does not give the expected N-oxides but 1-arylmethyloxy derivatives.[91] At-tempts to obtain 2-phenyl-2H-1,2,3-triazole 1-oxide by oxidation of 2-phenyl-2H-1,2,3-tria-zole with a range of oxygen donators are unsuccessful.[465]




bScheme 174 Preparation of 1-Substituted 1H-1,2,3-Triazole 3-Oxides[464,489]

R1 = Me, Ph, Bn, 4-MeOC6H4CH2; R2 = H, Me, Cl; R3 = H, Me, Ph, Cl, Br, OMe

MCPBA, EtOAc

rt, 5 d

6−85%

495

NN

NR1R2

R3

496

N+

O−

N

NR1R2

R3

1-Substituted 1H-1,2,3-Triazole 3-Oxides 496; General Procedure:[464]

The 1-substituted triazole 495 (1.0 g) was dissolved with heating in EtOAc (1 mL). Aftercooling to 20 8C, MCPBA (1.2 molar equiv) was added. The mixture was stirred for 120 h,diluted with CH2Cl2 (10 mL) and washed with aq 1 M NaOH (8 mL). The aqueous soln wasextracted with CH2Cl2 (2 � 8 mL). The combined organic phase was dried, the CH2Cl2 wasremoved, EtOAc (10 mL) was added, and the suspension was filtered through silica gel(2 g). Washing with further EtOAc (2 � 10 mL) and removal of the solvent gave unchangedstarting material. Subsequent extraction of the silica gel (EtOAc/MeOH 1:1; 5 � 10 mL) andremoval of the solvents gave the crude product.

13.13.1.4.3 Rearrangement of Substituents

Appropriately substituted 1,2,3-triazoles may undergo thermal, photochemical, acid-cat-alyzed, or base-catalyzed isomerizations. As shown in many of the previous methods, fre-quently these isomerizations occur spontaneously during the synthesis of the triazolering. Isomerizations are also observed during reactions involving substitution or modifi-cation of substituents on a 1,2,3-triazole (see, for example, Scheme 168). The most impor-tant isomerization reaction in 1,2,3-triazoles is the Dimroth rearrangement, illustrated inScheme 175 for 1H-1,2,3-triazol-5-amines. This type of isomerization is also observed inother heterocyclic systems. The interconversion of compounds 497 and 498 is mainlycontrolled by the nature of R1, but it is also influenced by the basicity of the solventused. Isomers 498 are favored when R1 is an aryl group, a large rigid group, or an elec-tron-withdrawing group. Isomers 497 are favored when R1 is an alkyl group.[21]

Scheme 175 Dimroth Rearrangement in 1H-1,2,3-Triazol-5-amines

N

NN

497 498

N

NH

NH2NR1

R2

R1HN

R2

R2 N2

H2N NR1

R2 N2

R1HN NH

This type of isomerization is also observed in 1-substituted 4-(iminomethyl)-1H-1,2,3-tria-zoles (Scheme 176). For example, imines 500 and 501 (R1 = H) are interconvertible whenheated in dimethyl sulfoxide at 80 8C. The equilibrium position depends on the electronicproperties of the R2 substituent, favoring 501 when R2 is alkyl, benzyl, and 4-methoxy-phenyl, and 500 when R2 is 4-chlorophenyl and 4-nitrophenyl.[502] An interesting applica-tion of this isomerization is the synthesis of 1-alkyl-1H-1,2,3-triazole-4-carbaldehydes 502from 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (499, R1 = H).[502] This type of isomeriza-tion is also applied to the conversion of 1-phenyl-1H-1,2,3-triazole-4-carbaldehydes 499(R1 = Me, Ph) into 4-oxo-substituted 1-alkyl-1H-1,2,3-triazoles 502 (R1 = Me, Ph).[503]





bScheme 176 Isomerization of 1-Substituted 4-(Iminomethyl)-1H-1,2,3-triazoles[502,503]

N

NN

500 501

N

NNR1

N2

R1 NPhPh

H

R2N

80−130 oC R2N

H

R2

R1

PhN

R2NH2

H2O

HCO2H or silica gel

502

N

NN

R2

R1

ON

NN

499

R1

Ph

H

O

R1 = H, Me, Ph; R2 = Me, Et, iPr, t-Bu, Bn, 4-MeOC6H4, 4-ClC6H4, 4-O2NC6H4

Despite the failure of hydrazone and oxime derivatives 500 (R1 = H; R2 = NH2, NHPh, OH)to isomerize to 501,[502] phenylhydrazone 504 (prepared from aldehyde 503) are convert-ed into derivative 505 (Scheme 177). Similarly, phenylhydrazone 507 (R1 = NHPh) and ox-ime 507 (R1 = OH) are converted into amides 508.[504] Triazole 506 [and 1-benzyl, 1-(4-chlo-robenzyl), and 1-(4-methoxybenzyl) analogues] are converted into carboxamides of type508 (R1 = Me, Et) by reaction with methylamine or ethylamine followed by rearrangementof the resulting imines on heating above their melting points.[302]

Scheme 177 Isomerization of 1-Phenyl-1H-1,2,3-triazoles Bearing a Hydrazone orOxime Function at the 4-Position[504]

N

NN

503 505

N

NNH2N

Ph

H

OPhNHNH2

EtOH

NH2

PhN

86%

N

NN

504

H2NPh

H

NPhHN

CHCl3reflux, 2 d

52%

NHPh

N

NN

506 508

N

NNCl

Ph

H

O

R1NH2

NHPh

O

R1 = NHPh 53%

R1 = OH 56%

N

NN

507

ClPh

H

R1NDMSO

70 oC, 2−3 d

R1 = NHPh 69%

R1 = OH 59% R1

Another interesting type of isomerization in 1,2,3-triazoles corresponds to the migrationof alkyl groups between nitrogens. This is not a very common transformation, but someexamples have been reported.[505,506,757] Triazole 509, for example, isomerizes to 510 whentreated with boron trifluoride (Scheme 178).[506,757]




bScheme 178 Isomerization of 1-Alkyl-1H-1,2,3-triazoles to2-Alkyl-2H-1,2,3-triazoles[506,757]

N

NN

509

MeO2C

MeO2CBF3•OEt2, Et2O

20 oC, 36 h

82%

N

NN

510

MeO2C

MeO2C

BOM

BOM

Migration of alkyl groups is also observed in 1,3-disubstituted 1,2,3-triazolium-4-thiolates511. Heating these compounds in an organic solvent at 180 8C results in transfer of alkylgroups with the formation of (alkylsulfanyl)-1,2,3-triazoles (Scheme 179).[495,507] When R1

and R2 are different alkyl groups, four compounds 512–515 are obtained. The formationof compounds 514 and 515 clearly indicates that this is an intermolecular reaction. If 511has only one alkyl group, only one product is formed. For example, 1-methyl-3-phenyl-1,2,3-triazolium-4-thiolate (511, R1 = Me; R2 = Ph) is quantitatively converted into 5-(meth-ylsulfanyl)-1-phenyl-1H-1,2,3-triazole (513, R1 = Me; R2 = Ph).[495]

Scheme 179 Migration of Alkyl Groups in 1,3-Disubstituted 1,2,3-Triazolium-4-thiolates[495,507]

NR2

NN

511

−S

180 oC

R1

+N

NN

512

R2S

R1

+NR2

NN

513

R1S

+N

NN

514

R1S

R1

+NR2

NN

515

R2S

1-Ethyl-1H-1,2,3-triazole-4-carbaldehyde (502, R1 = H; R2 = Et); Typical Procedure:[502]

To a soln of 499 (R1 = H; 1 g, 5.8 mmol) in MeOH (20 mL), was added 70% aq EtNH2 (0.57 mL,1.5 equiv), and the whole was stirred overnight at rt. The soln was concentrated and theresulting precipitate 500 (R1 = H; R2 = Et) was collected by filtration and dried; yield: 0.6 g(52%); mp 35 8C. This compound (0.6 g, 3 mmol) was heated overnight in DMSO (2 mL) at80 8C. The soln was poured into ice water and the precipitate 501 (R1 = H; R2 = Et) was col-lected; yield: 0.5 g (83%); mp 83 8C. Compound 501 (0.5 g, 2.5 mmol) was dissolved in amixture of H2O/MeOH (1:1; 20 mL) containing 10% of HCO2H and the soln was heated over-night at 80 8C. After addition of H2O (20 mL), the soln was extracted with CHCl3, and theextracts were washed with H2O and dried (MgSO4). The solvent was removed and the re-sulting oil (0.3 g) was chromatographed (silica gel, CH2Cl2/Et2O 9:1) to give 502 (R1 = H;R2 = Et); yield: 0.15 g (48%).





b13.13.2 Product Subclass 2:

Monocyclic 2-Substituted 1,2,3-Triazoles



13.13.2.1.1.1 Fragments C-C-N-N and N

13.13.2.1.1.1.1 Method 1:From N-Aminophthalimide and Conjugated Azoalkenes

2-(Phenylazo)propene (517, R1 = Me; R2 = H) and 1-(phenylazo)cyclopentene [517,R1,R2 = (CH2)3] react with N-aminophthalimide (516), in the presence of lead(IV) acetate,to give 2-phenyl-2H-1,2,3-triazoles 520 in moderate yields (Scheme 180).[508] A probablemechanism for this reaction involves the initial formation of the azimine intermediate518, 1,5-electrocyclization to the 2,5-dihydro-1H-triazole 519, and, finally, 1,2-elimina-tion of phthalimide.

Scheme 180 2H-1,2,3-Triazoles from N-Aminophthalimide and Conjugated Azoalkenes[508]

N

NNPh

520

R1

+N

O

O

NH2

R1

N

R2

HN

PhPb(OAc)4

K2CO3, CH2Cl2−10 oC, 40 min

R2NH

O

O

+

R1 = Me; R2 = H 41%

R1,R2 = (CH2)3 70%516 517

NN

N

518

N

NNPhR1

N

O

O

Ph

N

O

O+

−

519

R2R2

H

R1



13.13.2.1.2.1.1 Method 1:Addition of Azidotrimethylsilane and Azidotributylstannane to Alkynes

Azidotrimethylsilane and azidotributylstannane undergo addition to alkynes to give 2-(trimethylsilyl)- or 2-(tributylstannyl)-2H-1,2,3-triazoles, resulting from the isomerizationof the initially formed 1-substituted derivatives These reactions are discussed in Section13.13.1.1.3.1.1.6 (Schemes 59 and 60). A palladium-catalyzed three-component couplingreaction of azidotrimethylsilane, alkynes, and allyl methyl carbonate has been de-scribed.[509] It affords selectively 2-allyl-2H-1,2,3-triazoles 521 in low to moderate yields(Scheme 181). A �-allylpalladium azide complex, which undergoes the 1,3-dipolar cyclo-addition with the alkyne, has been proposed as a key intermediate in this reaction.




bScheme 181 2-Allyl-2H-1,2,3-triazoles from Azidotrimethylsilane, Alkynes, andAllyl Methyl Carbonate[509]

N

NN

R12.5 mol% Pd2(dba)3, CHCl310 mol% dppp, EtOAc

100 oC, 2−24 h

R2+

521

TMSN3 +

R2

R1

OCO2Me

R1 = H, Et, t-Bu, cyclohex-1-enyl; R2 = Ac

R1 = H, (CH2)5Me, CO2Me; R2 = CO2Me

R1 = (CH2)4Me; R2 = CHO

R1 = Ph; R2 = CN, CHO, Ac, CO2Me, PO(OEt)2, SO2Ph, NEt2

15−66%

13.13.2.1.2.1.2 Method 2:Addition of Acyl or Alkoxycarbonyl Azides to Æ-Acylphosphorus Ylides

Acyl and alkoxycarbonyl azides undergo addition to Æ-acylphosphorus ylides 522 to yield2-substituted 2H-1,2,3-triazoles, which result from the spontaneous isomerization of theinitially formed 1-substituted triazoles (Scheme 182). For the discussion of this type of re-action and examples see Section 13.13.1.1.3.1.2.5 (Scheme 76).

Scheme 182 2H-1,2,3-Triazoles from Acyl or Alkoxycarbonyl Azides andÆ-Acylphosphorus Ylides[229,231]

N

NN

R3

R2

522

R1N3 +

R1 = acyl, CO2Et

− Ph3POR2 O−

R3 PPh3

+

R1

N

NNR1

R3

R2

13.13.2.1.3 By Formation of One N-N Bond


13.13.2.1.3.1.1 Method 1:Cyclization of Æ-Hydroxyimino Hydrazones

The intramolecular elimination of water from Æ-hydroxyimino hydrazones is a generalmethod for the synthesis of 2H-1,2,3-triazoles (Scheme 183). Generally acetic anhy-dride[510–514] is the reagent of choice, but other reagents are also used, namely phosphoruspentachloride,[515] urea,[516] or bromine.[513] As an example, 2H-1,2,3-triazole 524(R1 = R2 = Ph; R3 = 4-O2NC6H4) is obtained in 57% yield by refluxing the corresponding hy-droxyimino hydrazone 523 with acetic anhydride for 40 minutes.[289]

Scheme 183 Cyclization of Æ-Hydroxyimino Hydrazones[289]

523

Ac2O, heat or PCl5, heat

or urea, heat or Br2, heat

R1 NOH

R2 NN

NNR3

R2

R1

NHR3

524

This method has been applied to the synthesis of a range of 2,2¢-diaryl-5,5¢-dimethyl-4,4¢-bi-2H-1,2,3-triazoles 526 from Æ-hydroxyimino hydrazones 525 (Scheme 184).[517]

13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 529




bScheme 184 Synthesis of 4,4¢-Bi-2H-1,2,3-triazoles[517]

525

NN

N

NPhN

N

X

PCl5, CHCl3rt, 1 h

526

X = H, 2-Cl, 3-Cl, 4-Cl, 4-NO2, 2-Br, 3-Br, 4-Br

55−68%NOH

NN

PhN

N

NH

X

Another interesting example of the application of this method is the synthesis of 2-aryl-2H-1,2,3-triazoles starting from dehydro-ascorbic acid 527 (Scheme 185). On boiling withacetic anhydride, the dehydro-ascorbic acid 3-(hydroxyimino)-2-arylhydrazones 528 areconverted into the acetylated triazole derivatives 529, whereas the unacetylated triazolederivatives 530 are obtained upon reaction with bromine in water.[512] Treatment of tria-zole 529 (Ar1 = Ph) with ammonia gives the 2H-1,2,3-triazole-4-carboxamide 531 in quan-titative yield.[512] Compound 529 (Ar1 = 3-BrC6H4) is obtained in 85% yield by treating thecorresponding 3-(hydroxyimino)-2-arylhydrazone 528 with acetic anhydride in pyridineovernight at room temperature.[514]

Scheme 185 Cyclization of Dehydro-ascorbic Acid 3-(Hydroxyimino)-2-arylhydrazones[512,514]

527

Ac2O

reflux, 1 h

Ar1 = Ph, 4-ClC6H4, 3-BrC6H4, 4-Tol, 4-MeOC6H4

O O

OO

HO

HO

2 steps

528

O O

NHON

HO

HO

Ar1HN

NN

N

O OAcO

AcO

Ar1

530

NN

N

O OHO

HO

Ar1

Br2, H2O

rt, 3 h

NH3, MeOH

rt, overnight

NN

N

CONH2HO

OHHO

Ph

529 531

Ar1 = Ph

100%

If the Æ-hydroxyimino hydrazone is N-unsubstituted, dehydration with acetic anhydridegives a 2-acetyl-2H-1,2,3-triazole, which is readily hydrolyzed to the corresponding N-un-substituted triazole (Scheme 186) (see also Section 13.13.1.1.4.1.3).[510]




bScheme 186 Cyclization of N-Unsubstituted Æ-Hydroxyimino Hydrazones[510]

R2 NOH

R1 NN

NNAc

R1

R2

NH2 Ac2O N

NH

N

R1

R2

H2O

Dehydration of amide derivatives 532 in refluxing thionyl chloride gives 2-phenyl-2H-1,2,3-triazole-4-carboxamides 533 in good yields (Scheme 187).[518]

Scheme 187 Cyclization of Æ-Hydroxyimino Hydrazones with Thionyl Chloride[518]

NOH

Ar2 N

N

NNPh

Ar2NHPh

SOCl2

reflux, 3 h

Ar1HN

O

532

Ar1HN

O

533

Ar1 = Ph, 4-Tol, 2-MeOC6H4, 2-ClC6H4, 4-ClC6H4, 2,4-Me2C6H3; Ar2 = Ph, 4-ClC6H4, 4-O2NC6H4

60−80%

In acetic acid, the nitro(arylhydrazono)acetaldehyde oximes 534 are converted into the 2-aryl-2H-1,2,3-triazol-4-ol 1-oxides 536, probably via the intermediate 535 (Scheme188).[466,501]

Scheme 188 Cyclization of Nitro(arylhydrazono)acetaldehyde Oximes[466,501]

NOH

O2N NN

NNAr1

NHAr1AcOH

rt, 12 h

534 536

Ar1 = Ph, 4-Tol, 4-MeOC6H4, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 4-EtO2CC6H4

50−62%

O−+

HOO N

NAr1

NO• •

535

Oxidation of (arylhydrazono)acetaldehyde oximes 537 with copper(II) sulfate[465,466,519] inaqueous pyridine, with mercury(II) oxide,[520] or with N-iodosuccinimide[521] leads to theformation of 2-aryl-2H-1,2,3-triazole 1-oxides 538 (Scheme 189).

Scheme 189 Oxidation of (Arylhydrazono)acetaldehyde Oximes with Copper(II) Sulfate[519]

NOH

R1 NN

NNAr1

NHAr1CuSO4, py, H2O

reflux, 30 min or rt, overnight

537 538

O−+

R1

R1 = H; Ar1 = Ph 80%

R1 = Me; Ar1 = Ph 90%

R1 = Me; Ar1 = 2,6-Cl2-4-F3CC6H2 90%

Cyclization of the oxomalonaldehyde derivatives 540 and 541 [produced from bis(oxyimi-no) hydrazone 539] with cesium carbonate in tetrahydrofuran affords 2-aryl-2H-1,2,3-tria-zoles 542 and 543 in moderate to excellent yields (Scheme 190).[519,522,523] These triazolesare hydrolyzed to the 4-formyl derivative or converted into a range of other interesting 4-substituted 2-aryltriazoles.





bScheme 190 Oxidation of Æ-Acetyloxyimino Arylhydrazones withCesium Carbonate[519,522,523]

N

NNAr1

Ac2O, rt

30 min

539

540H

NOH

NNHAr1

NOHH

H

NOAc

NNHAr1

NOHH

Ac2O, heat

5−10 min H

NOAc

NNHAr1

NOAcH

541

HON

N

NNAr1AcON

Cs2CO3

THF, rt

542

543

Ar1 = Ph, 2-FC6H4, 2-ClC6H4, 4-ClC6H4, 2-BrC6H4, 2,6-Cl2C6H3, 3,4-Cl2C6H3, 2,4,6-Cl3C6H2, 2,6-Cl2-4-F3CC6H2

26−82%

72−95%

Cs2CO3

THF

rt, 1 h

Oxidation of both hydroxyimino arylhydrazones 544 and 545 with lead(IV) acetate yields2-aryl-2H-1,2,3-triazole 1-oxides 546 in moderate to excellent yields (Scheme 191).[524]

Scheme 191 Oxidation of Æ-Hydroxyimino Arylhydrazones with Lead(IV) Acetate[524]

Ar1NHNH2, MeOH, H2O

AcOH (cat.), 0 oC, 20−30 min

544

R2

N

NOH

OR1

N

NNAr1

546

R1 = R2 = Me, Ph; Ar1 = Ph, 4-Tol, 4-ClC6H4, 4-O2NC6H4

NHAr1

R2

N

NOH

NR1

NHAr1

NHAr1

545

23−98%

45−72%

O−+

R2

Pb(OAc)4

CH2Cl2, rt

Pb(OAc)4

CH2Cl2, rtR1

O

13.13.2.1.3.1.2 Method 2:Cyclization of 1,2-Diketone Bis(arylhydrazones)

The oxidation of 1,2-diketone bis(arylhydrazones) to 2-aryl-2H-1,2,3-triazoles (Scheme192) is a very general reaction and it has been used extensively for the preparation of sug-ar “osotriazoles” from osazones. This subject has been reviewed.[525] The nitrogen elimi-nated is that attached to the 1-position for sugar osazones; a possible mechanism for thereaction is shown in Scheme 192.[3] Many oxidizing agents have been used, especially cop-per sulfate and other copper(II) salts,[526–529] and nitrous acid.[530,531] As an example, oxida-tion of the phenyl-D-glucosazone [547, R1 = H; R2 = (CHOH)3CH2OH] with copper(II) sulfategives the corresponding triazole 550 in 59% yield.[526–528] In a similar way, glyoxal is con-verted into 2-phenyl-2H-1,2,3-triazole in 59% overall yield via osazone 547 (R1 = R2 = H).[472]

Oxidation of the tetra-O-acetylphenylosazones from D-glucose, D-galactose, and L-sorbose




bwith nitrous acid gives the corresponding 2-phenyl-2H-1,2,3-triazole tetraacetates in ap-proximately 80% yield.[530]

Scheme 192 Oxidation of 1,2-Diketone Bis(phenylhydrazones)[525]

N

R2 NN

NNPh

NHPh oxidant

547 549

R1 = R2 = H, alkyl, aryl

NPh+

R2

R2 NNPh

NNPh

548

R1NHPh

R1 R1

−

N

NNPh

550

R2

R1

This type of reaction can be extended to 1,2-diketone bis(phenylhydrazones) 547(R1 = R2 = alkyl or aryl). Oxidation of these compounds with potassium dichromate in ace-tic acid,[532] nickel peroxide,[533] manganese(IV) oxide,[534] or with other oxidants yields avariety of products; the products formed depend upon the reaction conditions. In somecases, 2-substituted 2H-1,2,3-triazoles are obtained in low to moderate yields. As indicatedin Scheme 192, a probable mechanism for the formation of triazoles involves the oxida-tion of the bis(phenylhydrazones) to bis(phenylazo)ethene derivatives 548, which can ex-ist in the mesoionic form 549.[535,536] Loss of phenylnitrene from this species yields tria-zoles 550. The bis(phenylazo)ethene derivatives 548 are isolated in high yields,[533] andcan be converted into 2-phenyl-2H-1,2,3-triazoles by acid treatment[537] or by irradiationwith UV light.[538] Mesoionic species 549 have been trapped by dipolarophiles in 1,3-dipo-lar cycloadditions to yield new interesting 1,2,3-triazole derivatives.[535,539,540] N-Benzoylanalogues of mesoionic species 549 are isolated in good yields as stable crystalline com-pounds.[541] 1,2-Bis(arylazo)cycloalkenes (548, R1,R2 = ring with six or more carbons) whenheated or treated with acid undergo intramolecular rearrangements, via 1,2,3-triazoliumimide 1,3-dipoles of type 549, to yield 2-aryl-2H-1,2,3-triazoles bearing a 2-aminoarylgroup in the cycloalkene ring.[542]

1,2-Diketone bis(hydrazones) also cyclize to 1,2,3-triazoles solely by thermolysis:heating biacetyl bis(hydrazone) at 170 8C gives 4,5-dimethyl-1H-1,2,3-triazole (25%) andheating biacetyl bis(phenylhydrazone) at 300 8C yields 2-phenyl-4,5-dimethyl-2H-1,2,3-tri-azole in 51% yield.[543]

Oxidation of phenylhydrazones of aromatic aldehydes 551 with manganese(IV) ox-ide in refluxing benzene also affords triazoles 553 and other isolated products (Scheme193).[534] The dimerization of the phenylhydrazones to 552 appears to be the key step inthis transformation. Triazoles 553 are obtained in low to moderate yields. The oxidationof arylhydrazones derived from 2-acetylpyridine and 2-benzoylpyridine with lead(IV) ace-tate leads to the formation of fused 1,2,3-triazolium systems.[544]





bScheme 193 Oxidation of Phenylhydrazones of Aromatic Aldehydes[534]

551

N

NNPh

553 Ar1 = Ph 44%

Ar1 = 4-Tol 15%

Ar1 = 4-MeOC6H4 7%

Ar1

Ar1

Ar1

H

N NHPh MnO2, benzene

reflux, 4−6 hAr1

H

N NPh•

Ar1

H

N NPh•

Ar1

N

N

Ar1

NPh

NPh

Ar1

N

N

Ar1

NHPh

NHPh

7−44%

552

13.13.2.1.3.1.3 Method 3:Cyclization of Æ-Imino Hydrazones

The oxidative cyclization of 1,2-diketone imine hydrazones 554 with ammoniacal coppersulfate yields 2H-1,2,3-triazoles 555.[545] N-Substituted imines 556 give 1,2-disubstitutedtriazolium salts 557 when N-bromosuccinimide is used as the oxidant (Scheme 194).[546]

Scheme 194 Oxidative Cyclization of Æ-Imino Hydrazones[545,546]

R1 = R3 = alkyl, aryl; R2 = Ac, aroyl, CO2Et, CN

N

NNR3

555

R2

R1

R2

NH

N

R1

554

NHR3 CuSO4, NH3

R1 = alkyl, aryl; R2 = alkyl, CN

N

NNAr1

557

R2

R1

R2

NPh

N

R1

556

NHAr1NBS

Ph+

Br−

A related reaction is the oxidative cyclization of (carbamimidoyl)(phenylazo)acetamide558 (X = O) and (phenylazo)malonimidamide 558 (X = NH) to triazoles 559 (Scheme195).[547]

Scheme 195 Oxidative Cyclization of (Carbamimidoyl)(phenylazo)acetamide and(Phenylazo)malonimidamide[547]

H2N

X

N

HN NH2

NPh

CuSO4, NH4OH, rt, 24 h, then 100 oC, 3 h

or CuSO4, py, 100 oC, 18 h N

NNPh

559

H2N

X

H2N

X = O 64%

X = NH 24%

558




b13.13.2.1.3.1.4 Method 4:

Cyclization of 1,2-Bis(N-alkoxy-N-nitrosoamines)

1,2-Bis(N-alkoxy-N-nitrosoamines) 560 are smoothly converted into 1-alkoxy-4,5-dihydro-1H-1,2,3-triazole 2-oxides 561, in high yields, under reflux in methanol. Reaction of thesecompounds with sodium methoxide affords 4H-1,2,3-triazole 2-oxides 562 or 2H-1,2,3-tri-azol-2-ols 563 (Scheme 196).[548,549]

Scheme 196 Cyclization of 1,2-Bis(N-alkoxy-N-nitrosoamines)[548,549]

MeOH, reflux

0.5−5.5 h

NNO

NON

OR5

OR5

R1

R2

R3

R4

N

NN

561

O−+

OR5

R1

R2

R3

R4

560

NaOMe

MeOH

rt, 48 h N

NN

562

O−+

R2

N

NNOH

563

R2

R3

NaOMe

MeOH

rt, 3 h

78−98%

R1 = H

13−35%

R1 = R4 = H

65−86%

R3

R4

13.13.2.2 Synthesis by Ring Transformation

Thermal or basic treatment of arylhydrazones 565 of 3-acylisoxazoles 564 affords 4-acyl-2-aryl-2H-1,2,3-triazoles 566 (Scheme 197). For example, hydrazone 565 (R1 = R2 = Me;Ar1 = 2-ClC6H4) is converted into the corresponding triazole 566 by warming it to fusionin a test tube plunged in a silicone oil bath at ca. 240 8C.[517] Hydrazone 565 (R1 = R2 = Ph;Ar1 = 4-O2NC6H4) is converted quantitatively into the corresponding triazole 566 when itis melted in the presence of copper powder or by treatment with ammonia.[550] Copper(II)acetate can also be used as catalyst for this transformation.[551] The kinetics of the trans-formation of hydrazones 565 into triazoles 566 catalyzed by amines[552] or in the presenceof borate buffers,[553] has been studied.

Scheme 197 Synthesis of 2-Aryl-2H-1,2,3-triazoles from Arylhydrazones of3-Acylisoxazoles[517,550]

564

N

NNAr1

566

R2

ON

O

R2

R1

Ar1NHNH2

ON

R2

N

R1

NHAr1

565

R1

O

4-(Arylazo)isoxazol-5-ones 568 (produced from 4-arylisoxazol-5-ones 567) are convertedinto 2-aryl-2H-1,2,3-triazoles 569 when refluxed in propan-2-ol, in the presence of a tertia-ry amine, or in 1-(dimethylamino)propan-2-ol (Scheme 198).[554]





bScheme 198 Synthesis of 2-Aryl-2H-1,2,3-triazoles from 4-(Arylazo)isoxazol-5(4H)-ones[554]

567

N

NNAr1

569

R2

R1NO

Ar1N2 Cl−

568

R1 R2

O NO

R1

O

NR2

NAr1

Et3N, iPrOH

reflux, 3 h

R1 = Me, Ph, XC6H4; R2 = Me, Bn; Ar1 = XC6H4, naphthyl, heteroaryl

+

Arylhydrazones of 3-acyl-1,2,4-oxadiazoles yield 4-(acylamino)-2-aryl-2H-1,2,3-triazoles571 by thermal or basic rearrangement (Scheme 199). For example, hydrazone 570(R1 = 3-O2NC6H4; Ar1 = 4-O2NC6H4) is converted into the corresponding triazole in 60% yieldwhen it is melted in the presence of copper powder.[550] The same triazole is obtained in90% yield by treatment of hydrazone 570 (R1 = 3-O2NC6H4; Ar1 = 4-O2NC6H4) with ammo-nia.[550] Phenylhydrazone 570 (R1 = Ar1 = Ph) gives the corresponding triazole 571 in almostquantitative yield when treated with either equimolar or catalytic amounts of copper(II)acetate monohydrate in methanol at room temperature for two hours.[551] A kinetic studyof the rearrangement of arylhydrazones 570 (R1 = Ph; Ar1 = XC6H4) into triazoles 571 hasbeen reported.[555] The effect of �-cyclodextrin on the mononuclear rearrangement of 570(R1 = Ar1 = Ph) into 571 (R1 = Ar1 = Ph), in aqueous borate buffer at pH = 9.6, at temperaturesranging from 293.15 to 313.15 K, has also been reported.[556] The 2,4-dinitrophenylhydra-zone of 3-benzoyl-1,2,4-oxadiazol-5-amine 570 [R1 = NH2; Ar1 = 2,4-(O2N)2C6H3] is convertedrapidly into the 4-ureido-2H-1,2,3-triazole 571 [R1 = NH2; Ar1 = 2,4-(O2N)2C6H3], in dimethylsulfoxide at room temperature or by heating above its melting point.[557]

Scheme 199 Synthesis of 4-(Acylamino)-2-aryl-1,2,3-triazoles fromArylhydrazones of 3-Acyl-1,2,4-oxadiazoles[550,551]

N

NNAr1

571

Ph

NH

N

ON

R1 = NH2, Ph, 3-O2NC6H4; Ar1 = Ph, 4-O2NC6H4, 2,4-(O2N)2C6H3

R1

Ph

N

NHAr1

R1

O

570

When refluxed in ethanol, in the presence of sodium ethoxide, the 1,2,5-oxadiazole phen-ylhydrazone 572 rearranges to triazoles 573 and 574 (Scheme 200). The two isomeric ox-imes 573 (E, 80%) and 574 (Z, 10%) can be separated by column chromatography.[551]

Scheme 200 Synthesis of 2H-1,2,3-Triazoles from the Phenylhydrazone of3-Benzoyl-4-methyl-1,2,5-oxadiazole[551]

N

NNPh

573 80%

Ph

572

NaOEt, EtOH

reflux, 6 h

N

N

NNPh

574 10%

Ph

NHOOH

+

NO

N

Ph

N

NHPh

4-(Alkylamino)-3-nitro-1,2,5-oxadiazole 2-oxides 575 react with primary aliphatic aminesto afford 2-alkyl-4-(alkylamino)-5-nitro-2H-1,2,3-triazole 1-oxides 577, via intermediates576, in low to moderate yields (Scheme 201). Compounds 577 are also prepared in aone-pot procedure from 3,4-dinitro-1,2,5-oxadiazole 2-oxide.[558–560]




bScheme 201 Synthesis of 2-Alkyl-5-nitro-2H-1,2,3-triazole 1-Oxides from 4-(Alkylamino)-3-nitro-1,2,5-oxadiazole 2-Oxides[558–560]

576

N

NOO2N

575

R1HN R2NH2

CH2Cl2, rt N

NNR2

577 30−40%

R1HN

O2N

O−+

R1HN NOH

O2N NNHR2

O−+

− H2O

O−+

Oxidation of 4-(arylhydrazono)-4H-pyrazole-3,5-diamines 578 with lead(IV) acetate (2equiv) provides 2-aryl-2H-1,2,3-triazole-4-carbonitriles 579 in moderate yields (Scheme202). Plausible mechanisms for this transformation have been proposed.[561]

Scheme 202 Synthesis of 2-Aryl-2H-1,2,3-Triazoles from4-(Arylhydrazono)-4H-pyrazole-3,5-diamines[561]

578

N

NNAr1

NC

N

N NNHAr1

NH2

NH2 Pb(OAc)4, DMF, MeCN

0−5 oC, 1.5−2 h

41−58%

579

Ar1 = Ph, 4-Tol, 4-BrC6H4, 4-O2NC6H4, 4-MeOC6H4, 3-O2NC6H4, 3-MeOC6H4

2-Methyl-4-nitro-1-phenyl-1H-imidazole (580) reacts with hydroxylamine, in the presenceof potassium hydroxide, to yield 4-(acetylamino)-2-phenyl-2H-1,2,3-triazole 1-oxide (581)(Scheme 203). A mechanism for this transformation was suggested.[562]

Scheme 203 Synthesis of 2H-1,2,3-Triazole 1-Oxides from2-Methyl-4-nitro-1-phenyl-1H-imidazole[562]

KOH, MeOH

−5 oC, 3 h

57%

581

N

N

O2N

Ph

+ NH2OHN

NNPh

AcHN

O−+

580

Photolysis of 2-methyl-5-phenyl-2H-tetrazole (582) produces, among other minor prod-ucts, 2-methyl-4,5-diphenyl-2H-1,2,3-triazole (583) in low yield (Scheme 204).[563]

Scheme 204 Synthesis of 2H-1,2,3-Triazoles from 2-Methyl-5-phenyl-2H-tetrazole[563]

benzene, hν, 3 h

583 27%

NN

NNMe

N

NNMe

Ph

582

Ph+ other products

Ph

4,6-Disubstituted 2-methyl-2,5-dihydro-1,2,3-triazines 584 are oxidized by 3-chloroper-oxybenzoic acid (2 equiv) to give 4-substituted 2-methyl-2H-1,2,3-triazoles 585 in goodyields if at least one of the substituents is a phenyl group (Scheme 205).[564,565]





bScheme 205 Synthesis of 2H-1,2,3-Triazoles from2-Methyl-2,5-dihydro-1,2,3-triazines[564,565]

MCPBA (2 equiv)

CH2Cl2, 0 oC, 12 h

585

N

NNMe

R1

584

+ R2CO2H

N

N

NMe

R1

R2

R1 = R2 = Me trace

R1 = R2 = Ph 69%

R1 = Ph; R2 = Me 68%

The 1,2,3,4-tetrazine 587, generated from the reaction of an (alkylazo)alkene 586 and di-methyl azodicarboxylate, is unstable and on workup yields 2,5-dihydro-1H-1,2,3-triazole588 (Scheme 206). This isomerization is probably acid catalyzed since by addition of tri-fluoroacetic acid 587 is converted in near quantitative yield into triazole 589.[566] Thesame triazole is also obtained cleanly when 588 alone is treated with trifluoroacetic acidunder the same conditions.

Scheme 206 Synthesis of 2H-1,2,3-Triazoles from 1,2,3,4-Tetrazines[566]

benzene

rt, 12 h

588

N

NNMe

586

O

NHPh

NNMe N

N CO2Me

CO2Me+

NN

NMeN

CO2Me

CO2Me

PhHN

O

75%

CO2MeNHMeO2C

PhHN

O

587

589

N

NNMe

PhHN

O

TFA

TFA, CH2Cl2rt, 6 h

80%

[1,2,3]Triazolo[1,5-b]pyridazinium salts 590, when treated with morpholine, undergoopening of the pyridazine ring to yield mixtures of the triazoles 591 and 592 (Scheme207).[567] The ratio of these products varies significantly depending on whether R1 is analkyl or an aryl group. Reaction of triazolopyridazinium salts 590 with alkoxides or thio-lates affords the 4-vinyl-2H-1,2,3-triazoles 593 and 594, respectively, as the sole prod-ucts.[567]




bScheme 207 Synthesis of 2H-1,2,3-Triazoles from Triazolopyridazinium Salts[567]

morpholine

MeCN, rt

591

N

NNAr1

R1

NN N

N

R1

+Ar1

BF4−

CN

N

O592

N

NNAr1

R1

N

O

+

590

84%

R1 = Me (591/592) 3:2

R1 = 4-ClC6H4 (591/592) 1:10

R1 = Me, 4-ClC6H4; Ar1= 4-BrC6H4

NaOMe, MeOH, rt

593

N

NNAr1

R1

NN N

N

R1

+Ar1

BF4− MeO

590

R1 = Me 72%

R1 = 4-ClC6H4 82%

BnSH, KOH, EtOH, 5−10 oC

594

N

NNAr1

R1

NN N

N

R1

+Ar1

BF4− BnS

590

R1 = Me 95%

R1 = 4-ClC6H4 90%

Irradiation of 2-aryl-2H-benzotriazoles 595 with UV light, in an aerated solvent, results inthe oxidation of the benzo ring and formation of 2-aryl-2H-1,2,3-triazole-4,5-dicarboxylicacids 597 (Scheme 208).[568] The 2-aryl-2H-benzotriazole-4,7-diones 596 are plausible inter-mediates since photooxidation of compound 596 (R1 = R2 = H), obtained by oxidation of595 (R1 = R2 = H) with potassium dichromate, also leads to 597 (R1 = R2 = H). Oxidation of2-phenyl-2H-benzotriazole (595, R1 = R2 = H) with potassium permanganate also gives thedicarboxylic acid 597 (R1 = R2 = H) (in 50% yield) but oxidation of 595 (R1 = OMe; R2 = Me)under similar conditions, results in the formation of a tricarboxylic acid 597 (R1 = OMe;R2 = CO2H) in 48% yield.[568]





bScheme 208 Photooxidation of 2-Aryl-2H-benzotriazoles[568]

O2, EtOH

hν, rt, 12.5 d

597 R1 = R2 = H 93%

N

NN

HO2C

NN

N

HO2C

595

R1

R2

NN

N

596

R1

R2

O

O

R1

R2

oxidation

R1 = H, OMe; R2 = H, Me

13.13.2.3 Synthesis by Substituent Modification

Since substituent modification reactions in 1H- and 2H-1,2,3-triazoles are, in many cases,very similar, the synthesis of new 2H-1,2,3-triazoles by substituent modification of mono-cyclic 2-substituted 2H-1,2,3-triazoles is covered in Section 13.13.1.4.

13.13.3 Product Subclass 3:N-Unsubstituted and 1-Substituted Benzotriazoles


13.13.3.1.1 By Formation of Two N-N Bonds

13.13.3.1.1.1 Fragments N-C-C-N and N

13.13.3.1.1.1.1 Method 1:From Benzene-1,2-diamines and Nitrous Acid

The diazotization of benzene-1,2-diamine derivatives is the most common synthetic routeto benzotriazoles. This is a very general method, which can also be applied to the cycliza-tion of other 1,2-diaminocarbocycles[569] and 1,2-diaminoheterocycles.[570–574] In almost allthe cases the diazotization is carried out with nitrous acid (generated in situ from sodiumnitrite and a mineral acid) but other reagents can also be used. Esters of nitrous acid withprimary or secondary alcohols, preferentially methyl nitrite[575] or diphenylnitros-amine,[576] also react with benzene-1,2-diamine derivatives to afford benzotriazoles inhigh yields. Molecules consisting of a benzene-1,2-diamine group linked to a fluorophoremoiety are used as probes for nitric oxide (NO) detection; fluorescent benzotriazoles areformed in this reaction.[577–579]

The structure of the products obtained from the action of nitrous acid on an aromatic1,2-diamine, or on one of its alkyl, aryl, or acyl derivatives, was the subject of a very inter-esting scientific dispute, which occurred between the 1870s and 1910. The symmetricalstructure 598 (Scheme 209), proposed by Griess,[580,581] was shown to be incorrect andstructure 599, suggested by Kekul�, was confirmed as the correct one.[582,583]




bScheme 209 Proposed Structures for the Product ofthe Reaction of Nitrous Acid on Benzene-1,2-diamine

NN

N

599

R1

598

N

NNR1

A range of diversely substituted benzotriazole derivatives 601 is prepared by diazo-tization of the corresponding benzene-1,2-diamine derivatives 600, a few examples areshown in Scheme 210.

Scheme 210 Diazotization of Benzene-1,2-diamine Derivatives[322,579,584–594]

NN

N

601

R1

600

NHR1

NH2

R2NaNO2, H3O+

R2

R1 = H, alkyl, aryl, acyl, sulfonyl


H H NaNO2, AcOH, H2O, 5–80 8C, 1 h 75–81 [584]

H 5,6-Cl2 NaNO2, HCl, H2O, 0 8C 50 [585]

H 5,6-(NO2)2 NaNO2, HCl, H2O, 5–25 8C, 1 h 83 [586]

Me 6-Cl NaNO2, HCl, H2O, 10 8C 29 [585]

2,4,6-(O2N)3C6H2 4,6-(NO2)2 NaNO2, H2SO4, H2O, 5–25 8C, 1 h 63 [586]

Ac 5,6-Me2 NaNO2, AcOH, H2O, 10–50 8C 63 [587]

Ac 5-NHAc-6-OMe NaNO2, HCl, H2O, 5 8C, 2 h 97 [588]

CSCHMeNHBoc 6-NO2 NaNO2, AcOH, H2O, 0 8C, 30 min 79 [589]

S

H NaNO2, AcOH, H2O >90 [590]

CO2Et 7-Cl-4-OEt-5-CO2Me NaNO2, H2SO4, H2O, 5 8C, 15 min 68 [591]

SO2Ph 5-Me NaNO2, HCl, H2O, rt 100 [592]

NN

HNNH2

O

H NaNO2, HCl, H2O, 0 8C to rt, 2 h 96 [322]

benzotriazol-2-yl H NaNO2, HCl, H2O, 0 8C 63 [593]

6-methyl-3-pyridyl H NaNO2, HCl, H2O, 0 8C, 1 h 84 [594]

acridin-9-yl 5,6-Me2 NaNO2, HCl, H2O, 0 8C, 1 h 85 [579]

Benzo[1,2-d:4,5-d¢]bistriazoles are synthesized, in one step, by diazotization of benzene-1,2,4,5-tetraamine derivatives (Scheme 211). 1,7-Bis(2,4,6-trinitrophenyl)benzobistriazole603 is obtained in 60% yield from the bis(acetylamino) derivative 602,[595] while the 1,7-di-acetyl analogue 605 is prepared in 93% from 1,5-bis(acetylamino)-2,4-dinitrobenzene(604).[596,597]

13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 541




bScheme 211 Diazotization of Benzene-1,2,4,5-tetraamine Derivatives[595–597]

603 60%

602

H2SO4, H2O

100 oC, 20 min

Ar1 = 2,4,6-(O2N)3C6H2

Ar1HN

AcHN NHAc

NHAr1 Ar1HN

H2N NH2

NHAr1

NaNO2

5−10 oC

NN

NNN

NAr1 Ar1

605 93%

604

H2, Pd/C, EtOH

rt, 3100 Torr, 3 h

NaNO2, HCl

0 oC, 30 min

AcHN

O2N NO2

NHAc AcHN

H2N NH2

NHAc

NN

NNN

NAc Ac

An alternative method for the conversion of benzene-1,2-diamine derivatives into benzo-triazoles consists of their reaction with benzonitrile oxide, followed by diazotization ofthe resulting N-substituted benzamide oximes 607 to 1-benzohydroximoyl-1H-benzotri-azoles 608 (Scheme 212). These compounds are hydrolyzed in refluxing concentrated hy-drochloric acid to afford benzotriazoles 609 in quantitative yields.[598,758] There is no obvi-ous advantage of this method over direct diazotization of diamines 606, except the factthat compounds 607 can also be converted into benzimidazoles by treatment with hydro-chloric acid.

Scheme 212 Synthesis of Benzotriazoles via N-Substituted Benzamide Oximes[598,758]

606

benzene

reflux, 1 h

R1

R2 NH2

NH2

NaNO2, H2O, HCl

0 oC to rt, 1 h

NN

N

NPh O−++

607

R1

R2 NH2

NH

NOHPh

100%R1

R2

PhNOH

concd HCl

reflux, 2 h

NH

NN

100%R1

R2

609608

CH)2; R2 = H, Me, ClR1 = H, Me, CO2Me; R1,R2 = (CH

70−82%




b5,6-Dinitro-1H-benzotriazole [601, R1 = H; R2 = 5,6-(NO2)2]; Typical Procedure:[586]

A slurry of 4,5-dinitrobenzene-1,2-diamine (7.0 g, 35 mmol) in concd HCl (300 mL) wastreated dropwise with a 10% aq NaNO2 (90 mL) at 5–10 8C. After the resulting mixturehad stirred at 25 8C for 1 h it was chilled to 0 8C and the product was collected by filtration,washed with H2O, and air-dried to provide analytically pure crystals of the monohydrateof 5,6-dinitrobenzotriazole; yield: 6.6 g (83%); mp 144 8C. Anhyd product was obtainedwhen the monohydrate was dried in an oven at 80 8C overnight.


13.13.3.1.2.1 Fragments C-C-N and N-N

13.13.3.1.2.1.1 Method 1:From Arylamines and 2-Azido-3-ethyl-1,3-benzothiazoliumTetrafluoroborate

The benzothiazolium tetrafluoroborate 610 reacts with 2-naphthylamine to afford naph-tho[1,2-d]triazole 612 in 70% yield (Scheme 213).[599] Since salt 610 is a good diazo-transferreagent,[600] diazoamino derivative 611 is a probable intermediate in this reaction. Com-pound 610 also reacts with amino-heterocycles to yield heterocycle-fused 1,2,3-triazolesin good yields.[599]

Scheme 213 Synthesis of 1H-Naphtho[1,2-d][1,2,3]triazole from 2-Naphthylamine[599]

N

S+

0.4 M HCl, EtOH

rt, 1 h

NH

NN

612 70%

610

N3

Et+

BF4−

NH2 NH2

N2+

611

1H-Naphtho[1,2-d][1,2,3]triazole (612); Typical Procedure:[599]

To a soln of 2-naphthylamine (0.615 g, 5 mmol) in 0.4 M HCl in EtOH (40 mL) at rt wasadded 2-azido-3-ethyl-1,3-benzothiazolium tetrafluoroborate (610; 1.5 g, 5.1 mmol) inone portion and the mixture was stirred for 1 h. The solvent was evaporated and aq 2 MNH3 (20 mL) was added to the residue. The mixture was stirred, filtered, and extractedwith CHCl3 (2 � 5 mL). The organic phase was discharged. The aqueous phase was neutral-ized and the resulting solid was filtered, washed with H2O, and dried; yield: 0.60 g (70%);mp 175–180 8C.





b13.13.3.1.2.2 Fragments C-C-N-N and N

13.13.3.1.2.2.1 Method 1:From Æ-Diazo Ketones and Amines

Benzoyl trifluoromethanesulfonate (614) smoothly transforms 10-diazophenanthren-9(10H)-one (613) into diazonium salt 615, which reacts with isopropylamine to give thephenanthrotriazole 616 in 86% overall yield (Scheme 214).[38]

Scheme 214 Synthesis of Phenanthro[9,10-d][1,2,3]triazole froma Æ-Diazo Phenanthrenone[38]

+

616 86%

613

O

N2Ph OTf

OCH2Cl2−70 to −40 oC, 3 h

OBz

N2 OTf−

+

615614

NN

NiPrNH2, CH2Cl2−70 oC, 5 h

Pri



13.13.3.1.3.1.1 Method 1:From Azides and Dehydrobenzene

Dehydrobenzene (benzyne) reacts with alkyl, aryl, glycosyl, acyl, or sulfonyl azides toyield 1-substituted benzotriazoles 617 (Scheme 215). The benzyne is generated in situ byslow addition of 2-aminobenzoic acid to a solution of the azide and an alkyl nitrite (gen-erally butyl, pentyl, or isopentyl nitrite).[601]




bScheme 215 Synthesis of Benzotriazoles from Azides and Dehydrobenzene[601–604]

617 50−78%

CO2H

NH2

BuONO R1N3

NN

N

R1

R1 = alkyl, aryl, glycosyl, acyl, sulfonyl


(CH2)5Me CH2Cl2, acetone, reflux, 2 h 70 [601]

Ph CH2Cl2, acetone, reflux, 2 h 52 [601]

4-OHCC6H4 CH2Cl2, acetone, reflux, 2 h 50 [601]

4-AcC6H4 CH2Cl2, acetone, reflux, 2 h 50 [601]

4-O2NC6H4 CH2Cl2, reflux, 1.5 h 62 [602]

1-napthyla CH2Cl2, acetone, reflux, 3 h 75 [603]

acridin-9-yl CH2Cl2, acetone, reflux, 2 h 47 [601]

OH

HAcOH

AcO

H

AcO

H

OAc

CH2Cl2, acetone, reflux, 2.5 h 73 [604]

Bz CH2Cl2, reflux, 1.5 h 63 [602]

4-MeOC6H4CO CH2Cl2, reflux, 1.5 h 60 [602]

SO2Ph CH2Cl2, reflux, 1.5 h 52 [602]

4-ClC6H4SO2 CH2Cl2, reflux, 1.5 h 78 [602]

a Isopentyl nitrite was used.

The synthesis of 1-(2-methyl-1-naphthyl)-1H-naphtho[2,3-d][1,2,3]triazole (620) from thereaction of a naphthyl azide with 2,3-dehydronaphthalene (619), produced from 3-ami-no-2-naphthoic acid (618), is an interesting extension of this method (Scheme 216).[603]

Scheme 216 Synthesis of Naphthotriazoles from Azides and 2,3-Dehydronaphthalene[603]

620 21%

Me(CH2)4ONO

DME, reflux, 1.5 h R1N3

NN

N

R1

CO2H

NH2

618 619

R1 =





b1-(1-Naphthyl)-1H-benzotriazole (617, R1 = 1-naphthyl); Typical Procedure:[603]

A stirred soln of 1-naphthylazide (8.45 g, 50 mmol) and isopentyl nitrite (13.5 mL,100 mmol) in CH2Cl2 (400 mL) was refluxed and treated with a soln of 2-aminobenzoicacid (13.7 g, 100 mmol) in acetone (100 mL) over 2 h. Heating was continued for a further1 h, after which the mixture was cooled and evaporated under reduced pressure to leave abrown oil. Chromatography (silica gel) afforded the benzotriazole as a white crystallinesolid; yield: 9.15 g (75%); mp 114–115 8C.

13.13.3.1.3.1.2 Method 2:From Azides and Quinones

As described in Section 13.13.1.1.3.1.2.3, organic azides undergo addition to alkenes withelectron-withdrawing groups to yield dihydrotriazoles or triazoles. When benzoquinonesor naphthoquinones are used, benzotriazole derivatives are obtained. From the reactionof benzo-1,4-quinone and phenyl azide, mono- or bis-addition products 621, and 622 and623, respectively, are formed, depending on the number of equivalents of azide used(Scheme 217).[203,605,759] Phenyl azide adds to 2-methylbenzo-1,4-quinone to give only onemonoadduct.[204]

Scheme 217 Reaction of Benzo-1,4-quinone with Phenyl Azide[203,605,759]

621

PhN3 (1 equiv)

NN

N

O

O

O

OPh

622

PhN3 (2 equiv)

NN

N

O

O

O

OPh

NN

NPh

623

NN

N

O

OPh

NN

N

Ph

+

Naphtho-1,4-quinone reacts with methyl azide (sealed tube, 105 8C, 20 h) to afford triazole624 (R1 = Me) in 48% yield.[205,605,759] Similar reactions of naphtho-1,2-quinone and 6-bro-monaphtho-1,2-quinone with methyl azide or phenyl azide do not give any triazole deriv-atives.[205] Naphtho-1,4-quinone reacts with (azidoalkyl)phosphonates and with ethyl azi-doacetate to afford triazole derivatives 624 in good yields (Scheme 218).[210]

Scheme 218 Reaction of Naphtho-1,4-quinone with Alkyl Azides[210]

624

NN

N

O

O

O

OR1

R1N3, THF

reflux, 20 h

R1 = CH2PO(OEt)2 75%

R1 = CHMePO(OEt)2 70%

R1 = CHPhPO(OEt)2 76%

R1 = CH2CO2Et 80%

1-Substituted 1H-Naphtho[2,3-d][1,2,3]triazole-4,9-diones 624; General Procedure:[210]

A soln of naphtho-1,4-quinone (0.47 g, 3 mmol) in THF was added dropwise, with stirring,to a soln of diethyl (1-azidoalkyl)phosphonate or ethyl azidoacetate (3 mmol) in THF




b(15 mL) and the mixture was refluxed for 20 h. The solvent was evaporated and the resi-due was purified by flash chromatography (silica gel, Et2O/hexane) to give the triazole.

13.13.3.1.4 By Formation of One N-N Bond


13.13.3.1.4.1.1 Method 1:Cyclization of 2-Nitrophenylhydrazines

When treated with a base, 2-nitrophenylhydrazines cyclize to benzotriazol-1-ols (Scheme219).[606–610] Benzotriazol-1-ol exists in tautomeric equilibrium with 1H-benzotriazole 3-ox-ide. The position of the equilibrium depends on the solvent; e.g. in water the N-oxide formpredominates.[611–613] In some circumstances, the use of 2,4-dinitrophenylhydrazine toprepare 2,4-dinitrophenylhydrazones may lead to the formation of 6-nitrobenzotriazol-1-ol.[614] The cyclization of 2-nitrophenylhydrazines can also be carried out with polyphos-phoric acid (e.g., conversion of 625 into 626, Scheme 220).[615] Benzotriazol-1-ols are pow-erful explosives[617] and decompose violently at 200–210 8C to carbonaceous material.[619]

A large variety of benzotriazol-1-ol derivatives are used extensively as coupling re-agents.[616,621]

Scheme 219 Cyclization of 2-Nitrophenylhydrazines in Alkaline Media

NO2

NHNH2

R1NaOH

− H2OR1

NN

N

OH

R1

HN

NN+

O−

Scheme 220 Cyclization of 2-Nitrophenylhydrazines with Polyphosphoric Acid[615]

NO2

NHNH2PPA, 10 min N

NN+

O−

NO2 Me

− H2O

41%

NO2Me

625 626

1-Methyl-7-nitro-1H-benzotriazole 3-Oxide (626); Typical Procedure:[615]

A mixture of 1-(2,6-dinitrophenyl)-1-methylhydrazine (0.4 g, 1.9 mmol) and PPA (15 g) wasgently warmed and stirred for 10 min. The resulting brown soln was cooled and pouredinto H2O (100 mL). The soln was extracted with CHCl3 (3 � 30 mL) and the yellow organicextract was chromatographed (basic alumina, 100–200 mesh, 100 g). The unchanged hy-drazine was eluted with CHCl3. A second fraction was collected, concentrated under re-duced pressure, and recrystallized (EtOH) to give 626 as yellow plates; yield: 0.15 g (41%);mp 242–243 8C.

13.13.3.1.4.1.1.1 Variation 1:Reaction of 1-Chloro-2-nitrobenzenes or1,2-Dinitrobenzenes with Hydrazine

1,2-Dinitrobenzenes 627 (X = NO2)[609,617] and 1-chloro-2-nitrobenzenes 627 (X = Cl)[618–621]

react with hydrazine to yield benzotriazol-1-ols 629 via the 2-nitrophenylhydrazines 628(Scheme 221). The yields of the reactions are highly dependent on the substituents on the





bstarting material. In some cases the substitution of the nitro group is the most favorableprocess, the corresponding arylhydrazines are then the main products.[619] The synthesisof benzotriazol-1-ols from 1-methoxy-2-nitrobenzenes (627, X = OMe) has also been de-scribed.[609,617]

Scheme 221 Benzotriazol-1-ols from 1,2-Dinitrobenzenes or 1-Chloro-2-nitrobenzenesand Aqueous Hydrazine[617,619–621]

NO2

X

R1 R1 R1N

NN

OH

aq H2NNH2

EtOH

reflux, 3−5 h

NO2

NHNH2

− H2O

627 628 629

X R1 Yield (%) Ref

NO2 4,6-Cl2 60 [617]

NO2 4,6-Br2 –a [617]

Cl H 90 [619]

Cl 4,5-Cl2 85 [619]

Cl 4,5,6-Cl3 67 [619]

Cl 4,5,6,7-Cl4 40 [619]

Cl 6-CF3 90 [620]

Cl 6-OMe 6 [620]

Cl 6-CONH2 39 [620]

Cl 6-SO2NHMe 79 [620]

Cl 6-SO2NHBn 96 [621]

a Yield not reported.

Polymer-supported benzotriazol-1-ol derivatives 633[621] and 637[622] are prepared, respec-tively, from the reaction of polymer-supported 1-chloro-2-nitrobenzenes 632 and 636 andhydrazine (Scheme 222). Precursor 632 is obtained from the reaction of the aminometh-ylated polystyrene 630 and the benzenesulfonyl chloride 631 while 636 is prepared byFriedel–Crafts alkylation of polystyrene 634, using 4-chloro-3-nitrobenzyl alcohol (635).The polymeric reagent 633 is highly efficient for the synthesis of amides.[621,623]

Scheme 222 Polymer-Supported Benzotriazol-1-ol Derivatives[621,622]

100%

Et3N, CH2Cl2rt, 5 h

630

NH2 + ClO2S

NO2

Cl

70−80%

1. aq H2NNH2, EtOH, reflux, 5 h

2. HCl, dioxane

S

NO2

Cl

NH

OO

632631

S

HN

O O

633

NN

N

OH




bAlCl3, PhNO2

70 oC, 3 d

634

+

NO2

Cl

2. concd HCl, dioxane, reflux, 20 h

636635

637

NN

N

OH

H

HO

NO2

Cl

MeOOH1. H2NNH2, , reflux, 20 h

Benzotriazol-1-ols 629; General Procedure:[619]

The appropriate 1-chloro-2-nitrobenzene (5 g) was dissolved in hot EtOH (15–20 mL) and85% aq hydrazine (5 g) was added. The mixture was refluxed for 3 h and cooled. The pre-cipitate was collected by filtration, dissolved in hot H2O, and the benzotriazol-1-ol deriva-tive was precipitated with aq HCl. The crude product was decolorized with charcoal andrecrystallized (EtOH/MeOH 1:1).

13.13.3.1.4.1.2 Method 2:Cyclization of (2-Aminophenyl)hydrazine Derivatives

Oxidative cyclization of 1-(acetylamino)-2-hydrazino-3-nitrobenzene with chlorine af-fords 4-nitro-1H-benzotriazole in 80% yield (Scheme 223).[624]

Scheme 223 Cyclization of 1-(Acetylamino)-2-hydrazino-3-nitrobenzene[624]

NO2

NHNH2

NHAc80%

Cl2, EtOH

NH

NN

NO2

13.13.3.1.4.1.3 Method 3:Cyclization of (2-Aminophenyl)triazene Derivatives

Polymer-bound 1-(2-aminophenyl)triazenes 638 are cleaved smoothly with trifluoroaceticacid in dichloromethane at room temperature within minutes to give 1-substituted ben-zotriazoles 639 in excellent yields (Scheme 224).[625]

Scheme 224 Benzotriazoles from Polymer-Bound 1-(2-Aminophenyl)triazenes[625]

up to 95%

TFA, CH2Cl2, rtO2N

NN

N

639638

R1

N

NHR1

O2NN

NBn

CH2, cyclopropyl, cyclopentyl, 4-MeOC6H4CH2R1 = CH2CH





b13.13.3.2 Synthesis by RIng Transformation

13.13.3.2.1 Method 1:From 4,5-Dimethylene-4,5-dihydro-1H-triazoles

4,5-Dimethyl-4,5-dihydro-1H-triazoles 641, generated from 640 by 1,4-elimination of bro-mine, are trapped in low to moderate yields by dienophiles in Diels–Alder reactions(Scheme 225).[626] Benzotriazole 642 is obtained when 641 is generated in the presenceof dimethyl acetylenedicarboxylate; adduct 643 is formed when N-methylmaleimide isused as the dienophile. This adduct is converted into the benzotriazole derivative 644 bytreatment with N-bromosuccinimide.

Scheme 225 Benzotriazoles from 4,5-Dimethyl-4,5-dihydro-1H-triazoles[626]

N

NN

Br

Br

Ph

NaI, DMF

115 oC N

NN

Ph

DMAD

− 2H

27%N

NNMeO2C

MeO2C

641640

642Ph

NMM

38%N

NN

MeN

O

OPh

643

50%N

NN

MeN

O

OPh

644

NBS, CCl4heat

13.13.3.2.2 Method 2:Transformation of 1,3-Dihydro-2H-benzimidazol-2-ones

The reaction of 1,3-dihydro-2H-benzimidazol-2-one (645) with sodium nitrite and water,in a autoclave at high temperature, gives the sodium salt of benzotriazole, which, by acid-ification gives 1H-benzotriazole in high yield (Scheme 226).[627] This reaction can be ex-tended to 1,3-dihydro-2H-benzimidazol-2-ones with substituents on positions 4–7.

Scheme 226 Benzotriazoles from 1,3-Dihydro-2H-benzimidazol-2-ones[627]

61−93%

NN

N

NaNO2, H2O

190−300 oC

pressure

15−75 min

NH

HN

645

O− Na+ N

H

NNH3O+




b13.13.3.2.3 Method 3:

Transformation of 1,2,4-Benzotriazin-3(2H)-ones

1,2,4-Benzotriazin-3(2H)-one (646) and phenanthrotriazin-3-one 647 are converted into1H-benzotriazole and phenanthrotriazole 648, respectively, on treatment with etherealchloramine at room temperature (Scheme 227).[381] Treatment of benzotriazin-3-one 646with lead(IV) acetate in refluxing benzene affords 1-acetyl-1H-benzotriazole in goodyield.[381]

Scheme 227 Benzotriazoles from 1,2,4-Benzotriazin-3(2H)-ones[381]

65%

NH2Cl, CH2Cl2, DMF

rt, 14 h

646

NH

NN

NNH

N O

86%

Pb(OAc)4, benzene

reflux, 2 h

NN

N

Ac

92%

NH2Cl, Et2O, DMF

rt, 48 h

647

NH

NN

NNH

N O

648

13.13.3.2.4 Method 4:Transformation of 1,2,3,4-Benzotetrazine 1,3-Dioxides

The reduction of 1,2,3,4-benzotetrazine 1,3-dioxides 649 with sodium hydrosulfite ortin(II) chloride affords benzotriazoles 651 in almost quantitative yields (Scheme 228).[628]

It has been suggested that this transformation proceeds via the intermediate N-nitroso-benzotriazoles 650.

Scheme 228 Benzotriazoles from 1,2,3,4-Benzotetrazine 1,3-Dioxides[628]

NN

NN

R1

R2

O−

O−

+

+

649

Na2S2O4 (4 equiv) or

SnCl2•2H2O (4 equiv)

EtOAc, H2O

rt, 3 min

R1

R2

650

NN

N

N O

R1

R2

651 95−98%

NH

NN

− HNO2

R1 = H, Br; R2 = H, Br, NO2

H2O





b13.13.3.3 Synthesis by Substituent Modification

13.13.3.3.1 Substitution of Existing Substituents

13.13.3.3.1.1 Of Hydrogen

13.13.3.3.1.1.1 Method 1:N-Trimethylsilylation

Benzotriazole reacts with hexamethyldisilazane to give 1-(trimethylsilyl)-1H-benzotria-zole (652) in 95% yield (Scheme 229).[169,434,629,630]

Scheme 229 N-Trimethylsilylation of 1H-Benzotriazole[169]

652

NN

N

95%

heat

TMS

NH

NN

+ (TMS)2NH

13.13.3.3.1.1.2 Method 2:Carboxylation

Heating an intimate mixture of 1H-benzotriazol-5-ol with a large excess of anhydrous po-tassium carbonate in a nickel-lined steel autoclave, with carbon dioxide under pressure,affords 5-hydroxy-1H-1,2,3-benzotriazole-4-carboxylic acid (653) in 49% yield (Scheme230).[631,632]

Scheme 230 Carboxylation of 1H-Benzotriazol-5-ol[631,632]

653

NH

NN

49%

K2CO3, CO2

180−190 oC, 16 h

NH

NNHO HO

CO2H

Benzotriazole reacts with chloroformates 654, in alkaline solutions, to afford selectivelythe corresponding alkyl 1H-benzotriazole-1-carboxylates 655 (Scheme 231).[633–635]

Scheme 231 N-Alkoxycarbonylation of 1H-Benzotriazole[633–635]

655

NN

N

58−100%

aq NaOH

NH

NN

+ ClCO2R1

654

CO2R1

R1 = Me, Et, Ph, Bn

Ethyl 1H-1,2,3-Benzotriazole-1-carboxylate (655, R1 = Et); Typical Procedure:[634]

Ethyl chloroformate (6.0 g, 0.056 mol) was slowly added to a stirred and cooled aqueoussoln of 1H-benzotriazole (6.0 g, 0.05 mol) and NaOH (2.0 g, 0.05 mol). After completion ofthe addition, the mixture was stirred for an additional 15 min, and the precipitated whitesolid was then collected by filtration, washed with H2O, dried, and recrystallized (Et2O);yield: 9.1 g (95%); mp 70–71 8C.




b13.13.3.3.1.1.3 Method 3:

Acylation

Benzotriazoles react with acyl chlorides and anhydrides to afford the 1-acyl derivatives656 (Scheme 232).[587]

Scheme 232 Acylation of 1H-Benzotriazole[587]

656

NN

NR1COCl or (R1CO)2O

NH

NN

COR1

1-Acyl-1H-benzotriazoles 656 (R1 = aryl, 2-arylvinyl) are prepared in moderate to goodyields from the reaction of 1H-benzotriazole and acyl chlorides in pyridine or in aqueoussodium hydroxide.[634] Other benzotriazole derivatives 656 (R1 = alkyl, aryl) are obtainedin high yields (87–99%) from the reaction of 1H-benzotriazole and acyl chlorides in anhy-drous dichloromethane and triethylamine at 0 8C.[636,637] 1-Acyl-1H-benzotriazoles 656(R1 = Me, Et, Bu, Ph) are prepared in good yields by fusion of 1H-benzotriazole and acylchlorides at 80–100 8C.[630] When the acyl chlorides are not available, 1-acyl-1H-benzotria-zoles are also conveniently prepared from 1-mesyl-1H-benzotriazole and the respectivecarboxylic acids in yields of 80–95%.[630] 1-Acyl-1H-benzotriazoles are also prepared in ex-cellent yields (94–95%) from the reaction of 1-(trimethylsilyl)-1H-benzotriazole and acylchlorides.[629]

5,6-Dimethyl-1H-benzotriazole reacts with acetic anhydride (reflux for 30 min) togive the 1-acetyl derivative in 93% yield.[587] The same compound also reacts with benzoylchloride and 4-nitrobenzoyl chloride, in the presence of aqueous sodium hydroxide, toyield the 1-acyl derivatives in 82 and 50% yield, respectively.[587]

1H-Benzotriazole reacts with trifluoroacetic anhydride in tetrahydrofuran, at roomtemperature, to give 1-(trifluoroacetyl)-1H-benzotriazole (656, R1 = CF3) in almost quanti-tative yield.[638] This compound is a convenient trifluoroacetylating reagent for aminesand alcohols. 1H-Benzotriazol-5-amine reacts with trifluoroacetic anhydride in dimethyl-formamide, at room temperature, to give selectively 5-[(trifluoroacetyl)amino]benzotri-azole in 85% yield.[639]

Thiobenzoyl chloride reacts with benzotriazole or 1-(trimethylsilyl)-1H-benzotri-azole to yield 1-(thiobenzoyl)-1H-benzotriazole in 64 and 44% yield, respectively.[434]

1H-Benzotriazole reacts with aryl isocyanates to yield 1-(arylaminocarbonyl)-1H-ben-zotriazoles.[640]

13.13.3.3.1.1.4 Method 4:N-Formylation

1H-1,2,3-Benzotriazole-1-carbaldehyde (657) is conveniently prepared from 1H-benzotri-azole and formic acid in the presence of dicyclohexylcarbodiimide (Scheme 233).[641] Thiscompound is a stable N- and O-formylating agent for a variety of amines and alcohols. Thediethyl acetal of compound 657 is prepared directly in 90% yield from the reaction of 1H-benzotriazole and triethyl orthoformate.[642]





bScheme 233 N-Formylation of 1H-Benzotriazole[641]

657

NN

NDCC, CH2Cl2, rt, 15 h

NH

NN

CHO

+ HCO2H71%

1H-1,2,3-Benzotriazole-1-carbaldehyde (657); Typical Procedure:[641]

To a mixture of 1H-benzotriazole (14.85 g, 0.125 mol) and HCO2H (6.9 g, 0.15 mol) in anhydCH2Cl2 (250 mL) was added DCC (36.05 g, 0.175 mol). The mixture was stirred at rt for 15 h,the precipitate filtered and the solvent removed in vacuo. Recrystallization of the residuegave pure 657 as white needles; yield: 13 g (71%); mp 94–96 8C.

13.13.3.3.1.1.5 Method 5:Arylation

1H-Benzotriazole reacts with activated aryl halides and hetaryl halides to yield the 1-aryl-or 1-hetaryl-1H-benzotriazole derivatives as the main (or sole) products. With 1-chloro-2-nitrobenzene (658, R1 = R2 = H) it gives a mixture of 659 (R1 = R2 = H; 39%) and 660(R1 = R2 = H; 16%), which can be separated by column chromatography (Scheme 234).[643]

The reaction with 1-chloro-2,4-dinitrobenzene (658, R1 = NO2; R2 = H) in refluxing toluene,in the absence of any added base, affords exclusively the 1H-isomer 659 (R1 = NO2; R2 = H)in 96% yield[644] but if it is carried out in refluxing ethanol, in the presence of anhydroussodium acetate, it gives a mixture of 659 (R1 = NO2; R2 = H) and 660 (R1 = NO2; R2 = H) in theratio of approximately 23:10.[645] With 2-chloro-1,3,5-trinitrobenzene (658, R1 = R2 = NO2)or 2-fluoro-1,3,5-trinitrobenzene the 1H-isomer 659 (R1 = R2 = NO2) is the sole product.[586]

2-Fluoro-1,3,5-trinitrobenzene reacts with mono- and dinitrobenzotriazoles[586] to affordthe corresponding 1-(2,4,6-trinitrophenyl) derivatives; with benzo[1,2-d:4,5-d¢]bistriazoleit gives a mixture of 1,5- and 1,7-bis(2,4,6-trinitrophenyl)benzo[1,2-d:4,5-d¢]bistria-zoles.[595]

Scheme 234 N-Arylation of 1H-Benzotriazole[643,644]

NH

NN

+ Cl

O2N

R2

R1N

NN

O2N

R1

R2

659

NN

N

R2

O2N

R1

660

+

R1 = R2 = H, NO2

658

1H-Benzotriazole reacts with 2-bromopyridine and 2-bromopyrimidine, in the absence ofadded base, to give the corresponding 1-substituted benzotriazole derivatives in highyields.[642,644] The reaction of 1H-benzotriazole with 2-chloro-3-nitropyridine and 4-chlo-




bro-3-nitropyridine in dimethyl sulfoxide at 80 8C, in the presence of sodium carbonate,also affords the corresponding 1-substituted benzotriazole derivatives.[646] Under micro-wave irradiation, benzo- and naphthotriazoles 661 react with 4-chloropyridine and 4-chloroquinoline derivatives 662 to give the 1-substituted derivatives 663 in good yields(Scheme 235).[647]

Scheme 235 N-Arylation of Benzotriazoles under Microwave Irradiation[647]

NH

NN

+

R3

R3

661

N

R2

R2

Cl

R1

microwave irradiation

no solvent, 7−10 min NN

NR3

R3

663

N

R2

R2

R1

662

R1 = R3 = H, Me; R2 = H; R2,R2 = R3,R3 = (CH CH)2

A palladium(0)-catalyzed N-arylation of benzotriazole with aryl iodides with both elec-tron-donating and electron-withdrawing groups and hetaryl halides has been report-ed.[648] The reaction is carried out in dimethylformamide at 150 8C, under phase-transferconditions, in the presence of potassium carbonate and copper salts. The 1-aryl-1H-benzo-triazole derivatives are obtained in excellent yields (75–98%). 1H-Benzotriazole is also N-arylated in water by diaryliodonium salts (Ar1

2IBF4) yielding the 1-aryl derivatives in al-most quantitative yields.[649] This is also a palladium- and copper-catalyzed reaction.

The benzotriazole anion reacts with triacetoxy(4-tolyl)lead [4-TolPb(OAc)3] in thepresence of copper(II) acetate to afford a mixture of 1-(4-tolyl)- and 2-(4-tolyl)benzotri-azoles in 23 and 6% yield, respectively.[650]

The polymer-supported benzotriazole 664 reacts with 4-tolylboronic acid in the pres-ence of copper(II) acetate and pyridine, under microwave irradiation, to yield the corre-sponding N-tolyl derivatives. Cleavage of these products with trifluoroacetic acid givesthe two regioisomeric benzotriazoles 665 and 666 (1:1) in 55% yield (Scheme 236).[651]

Scheme 236 N-Arylation of a Polymer-Supported Benzotriazole[651]

NH

NN

+ 4-TolB(OH)2

664

1. Cu(OAc)2, py

2. TFAHN

O

55%

NN

N

665

H2N

O 4-Tol

NN

N

666

4-Tol

H2N

O

+

1:1

1-(2,4-Dinitrophenyl)-1H-benzotriazole (659, R1 = NO2; R2 = H); Typical Procedure:[644]

A mixture of 1-chloro-2,4-dinitrobenzene (658, R1 = NO2; R2 = H; 6.08 g, 30 mmol), 1H-ben-zotriazole (21.44 g, 180 mmol), and toluene (30 mL) was refluxed for 9 d. The mixture wastreated with 20% KOH (200 mL), extracted with CHCl3 (5 � 500 mL), dried (MgSO4), andevaporated to afford a yellow solid; yield: 8.20 g (96%); mp 182–184 8C.





b13.13.3.3.1.1.6 Method 6:

Alkynylation

Potassium benzotriazol-1-ide, prepared from 1H-benzotriazole and potassium tert-butox-ide, reacts with alkynyl(phenyl)iodonium tosylates 667 to give 1-(2-arylethynyl)-1H-ben-zotriazoles 668 in good yields (Scheme 237).[652,653] The reaction with oct-1-ynyl(phenyl)-iodonium tosylate [667, R1 = (CH2)5Me] affords a mixture of two 1-(alk-1-enyl)-1H-benzotri-azole derivatives. An alternative one-pot synthesis of 1-(substituted ethynyl)-1H-benzotri-azoles 668 (R1 = alkyl or aryl) has been published.[654,655]

Scheme 237 N-Alkynylation of Potassium Benzotriazol-1-ide with Alkynyl(phenyl)-iodonium Tosylates[652,653]

NN

N

+

THF, t-BuOH, CH2Cl2rt, 24 h

45−62%−

K+ OTs−

667

NN

N

R1

668

R1 = Ph, 4-ClC6H4, 4-Tol, 4-MeOC6H4

I+

Ph

R1

13.13.3.3.1.1.7 Method 7:Alkenylation

A simple and convenient method for the stereoselective synthesis of 1-(alk-1-enyl)-1H-ben-zotriazole derivatives, directly from benzotriazole, has been reported.[656] It involves thereaction of alkenyl(phenyl)iodonium salts with 1H-benzotriazole in the presence of abase (Scheme 238). In the reaction with alkenyl(phenyl)iodonium salts 669 (R1 = Ph) and671, retention of configuration is observed in the products 670 and 672, but with 669(R1 = Bu) complete inversion of configuration occurs. This method is particularly efficientfor the preparation of 1-(alk-1-enyl)-1H-benzotriazoles with amino-, acyl-, and alkoxycar-bonyl substituents, which are difficult to prepare by other methods. Other nonselectiveor less convenient methods for the synthesis of 1-(alk-1-enyl)-1H-benzotriazoles are alsoknown.[656]

Scheme 238 N-Alkenylation of 1H-Benzotriazole with Alkenyl(phenyl)iodonium Salts[656]

NH

NN

++

669

NN

N

670

R1 = Ph 64% (E-isomer)

R1 = Bu 59% (Z-isomer)H

R1

I

H

PhBF4

−

R1

t-BuOK, t-BuOH, DMF, rt

NH

NN

+

K2CO3, DMF, H2O

rt, 6 h

+

671

NN

N

672

R1 = Me, Bn, 4-ClC6H4; R2 = Me, Ph, OEt

NHR1

I

R2OC

PhOTs−

NHR1

67−94%

R2OC




b13.13.3.3.1.1.8 Method 8:

Alkylation

1H-Benzotriazole reacts with dimethyl sulfate,[657,658] diazomethane,[657] and iodometh-ane[658] to give mixtures of 1- and 2-methylbenzotriazole. The 1-methyl isomer is alwaysthe main product, except in the reaction with diazomethane where the 1-methyl/2-meth-yl ratio is 5:17.[657] Methylation of 4-nitrobenzotriazole and 5-methylbenzotriazole with di-azomethane leads to the formation of the 2-methyl derivatives.[585] Methylation of 5,6- and4,7-dichlorobenzotriazole with dimethyl sulfate gives the 1-methyl isomer as the mainproduct.[585]

The alkylation of 1H-benzotriazole is frequently carried out with alkyl halides in thepresence of a base; the 1-alkyl isomer 673 is generally the main product and, in somecases, 1,3-dialkyl-1H-benzotriazolium salts 675 are also formed (Scheme 239). Sodium hy-dride[659] and sodium alkoxides[660,661] are frequently used as the base but higher yields maybe obtained using sodium hydroxide in dimethylformamide.[662] Alkylations with alkyl ha-lides using phase-transfer catalysis with 18-crown-6,[663] polyethylene glycols or their dial-kyl ethers,[664] or quaternary ammonium salts[665–667] also give excellent yields. Many otherreaction conditions have also been used, namely aqueous sodium hydroxide,[668] triethyl-amine in toluene,[669] potassium carbonate in tetrahydrofuran,[670] potassium fluoride andalumina in acetonitrile,[661] or just by refluxing the benzotriazole and the alkyl halide inbenzene or toluene in the absence of any added base.[644,671] 1H-Benzotriazole can also bealkylated with alkyl halides in the absence of solvent, either in basic media under solvent-free phase-transfer catalysis conditions or in the absence of base by conventional or mi-crowave heating.[672]

Scheme 239 Alkylation of 1H-Benzotriazole with Alkyl Halides[659–662]

NH

NN

R1X, base

NN

N

673

X = halo

R1N

NR1N

674

NN

N

675

R1

+ +

R1

X−+

The alkylation of 1H-benzotriazole with ethyl bromoacetate, in the presence of sodiumhydride, gives different ratios of the 1-alkyl/2-alkylbenzotriazole depending on the sol-vent used: 85:15 in acetonitrile and 95:5 in toluene.[659] Mixtures of the two isomers arealso obtained by alkylation of the sodium salt of 1H-benzotriazole with other Æ-halo-genated esters or ketones.[644,671] However, in refluxing benzene or toluene, and in the ab-sence of any added base, 1H-benzotriazole reacts with these Æ-halogenated carbonyl com-pounds to yield only the 1-alkyl isomer in good yield.[644,671]

Addition of bromocyclopentane and bromocycloheptane to the anion of benzotria-zole (generated with sodium ethoxide in ethanol) yields the expected mixtures of 1- and2-cycloalkylbenzotriazoles. However, under the same conditions, bromocyclohexanegives only cyclohexene and benzotriazole, cyclohexyl tosylate affords only the 2-cyclo-hexyl-2H-benzotriazole 674 (R1 = Cy), while with tricyclohexyl phosphate the 1-cyclohex-yl-1H-benzotriazole is formed with the complete absence of the N2 isomer.[673]

A high-yielding route to produce selectively 1-ethyl-1H-benzotriazole involves thecarbonylation of 1H-benzotriazole with ethyl chloroformate (see Section 13.13.3.3.1.1.2)followed by alkylation or the resulting compound with triethyloxonium tetrafluoro-borate and then methanolysis (Scheme 240).[634] This gives pure 1-ethyl-1H-benzotriazolein 89% overall yield from 1H-benzotriazole. Another method for the selective synthesis of





b1-alkyl-1H-benzotriazoles involves the reaction of 1-(trimethylsilyl)-1H-benzotriazole withalkyl halides.[629]

Scheme 240 A Selective Route to 1-Ethyl-1H-benzotriazole[634]

NH

NN

EtOCOCl

aq NaOH

NN

N +

CO2Et

95%

Et3O+ BF4−

CH2Cl2

NN

N

CO2Et

Et

BF4−

NN

N

94%

Et

MeOH

The reaction of 1H-benzotriazole with dibromoalkanes may give the two monosubstitut-ed derivatives or the three possible disubstituted isomers, depending on the molar ratioof the dibromoalkane to 1H-benzotriazole.[661,668] 1H-Benzotriazole reacts with 1 equiva-lent of bis(bromomethyl)benzene (1,2-, 1,3-, or 1,4-), 4,4¢-bis(bromomethyl)biphenyl and4¢,4¢¢-bis(bromomethyl)-1,3-terphenyl,[674] and 2,6-bis(bromomethyl)pyridine[675] to yield,in each case, only the bis(benzotriazol-1-yl) isomer. Addition of another equivalent ofthe bis(bromomethyl) derivative affords, in each case, only one dicationic benzotriazo-lophane (see schemes in Section 13.13.5.2.2). 1H-Benzotriazole also reacts with dichloro-methane and chloroform, in the presence of a phase-transfer catalyst, to yield mixtures ofall possible isomers of di- and tri(benzotriazol-1-yl and -2-yl)methane.[676,677]

1H-Benzotriazole reacts with diarylmethanols, in the presence of a catalytic amountof 4-toluenesulfonic acid and azeotropic removal of water, to give mixtures of the corre-sponding 1- and 2-diarylmethylbenzotriazole derivatives (Scheme 241).[669,678]

Scheme 241 Alkylation of 1H-Benzotriazole with Diarylmethanols[669,678]

NH

NN TsOH, benzene

reflux

NN

N

− H2O

66−90%

+ HO

Ar2

Ar1

Ar1Ar2

+N

NN

Ar1

Ar2

Ar1 = Ar2 = Ph, 4-Me2NC6H4, 4-MeOC6H4, 4-ClC6H4, 4-Tol

1H-Benzotriazole reacts with 2-(chloromethyl)oxirane (epichlorohydrin) in benzene toyield the two compounds resulting from oxirane ring opening.[679] Using 2 equivalents ofbenzotriazole (and triethylamine) or sodium benzotriazolide the reaction gives a complexmixture of products resulting from the oxirane ring opening and simultaneous substitu-tion of chlorine by a benzotriazolyl group (Scheme 242).[680]




bScheme 242 Alkylation of 1H-Benzotriazole with 2-(Chloromethyl)oxirane[680]

NH

NN

Et3N, toluene

reflux, 7 h

NN

N

+

Bt1 =

O

Cl

NN

N; Bt2 =

OH

Cl +O

Bt2

+

Bt2

OH

Bt1 + +Bt1OH

Bt1 Bt2OH

Bt2 Bt2

1H-Benzotriazole gives conjugate addition reactions with Æ,�-unsaturated carbonyl com-pounds to yield only 1-alkyl derivatives (reactions carried out without solvent and in thepresence of a few drops of pyridine or benzyltrimethylammonium hydroxide solu-tion).[452] Under similar conditions, and in striking contrast, 4,5,6,7-tetrahalogenated ben-zotriazoles afford only the 2-alkyl derivatives.[16,585] This difference is due mainly to thesteric effect of the 4,7-substituents, which direct this type of addition to the 2-position.This was confirmed by using 4,7-dichloro-1H-benzotriazole and 5,6-dichloro-1H-benzotri-azole, which give only 2- and 1-substituted derivatives, respectively.[585] Heating a mixtureof 1H-benzotriazole and N,2-dimethylpropenamide at 150 8C for six days gives only the N1Michael addition product in 45% yield.[681] 1H-Benzotriazole reacts with acrylamide in ba-sic medium (pyridine–sodium methoxide) to afford only the N1 Michael addition productin 96% yield.[682] However, it was shown by NMR analysis that the crude product of thisreaction is a 35:65 mixture of the N1 and N2 addition products, but after 24 hours onlythe signals of the N1 isomer are observed.[682] This means that the Michael addition yieldsa kinetic mixture which slowly equilibrates to the most stable isomer (the thermodynam-ic product). In an aqueous micellar medium, mixtures of N1 and N2 addition products areobtained from the reaction of benzotriazole with 1,3-diphenylprop-2-en-1-one (chalcone)(Scheme 243), acrylonitrile, and diethyl maleate.[667]

Scheme 243 Reaction of 1H-Benzotriazole with 1,3-Diphenylprop-2-en-1-one[667]

NH

NN

NaOH, H2O, CTAB

rt, 1 d+ Ph

NN

N

Ph

+N

NN Ph

CTAB = cetyltrimethylammonium bromide

79%Ph

O

Ph

O

Ph

O

1H-Benzotriazole reacts with aliphatic aldehydes to yield isolable crystalline 1-hydroxy-alkyl benzotriazole derivatives (Scheme 244).[683] In solution these condensation productsdissociate into their components and equilibrate between the 1- and 2-positions of thebenzotriazole ring.[8] The reaction with aromatic aldehydes or ketones does not affordthe corresponding condensation products.





bScheme 244 Hydroxymethylation of 1H-Benzotriazole[683]

NH

NN

+O

HR1N

NN

OHH

R1

1H-Benzotriazole reacts with an aldehyde or ketone and an amine to yield the condensa-tion products 676 generally in very high yields (Scheme 245).[684] The aminomethylationof 1H-benzotriazole by the Mannich reaction[453,685] is an example of this very general re-action: both aliphatic and aromatic aldehydes can be used, ketones (particularly cyclicones), ammonia, and primary and secondary amines (aliphatic, aromatic, and heteroaro-matic) all give the expected products.[8]

Scheme 245 Aminomethylation of 1H-Benzotriazole[684]

NH

NN

+O

R2R1N

NN

NR3R4

R2R1

+R3

HN

R4

676

1-Chloro- and 1-bromo-1H-benzotriazoles 677 (X = Cl, Br) undergo electrophilic additionto alkenes to afford 1- and 2-(2-haloalkyl)benzotriazoles, with trans configuration, ingood yields.[686,687] 1-Bromo-1H-benzotriazole is much more reactive than the chloro deriv-ative. For example, the addition of 677 (X = Br) to cyclohexene (giving products 678 and679) is essentially instantaneous in dichloromethane at room temperature comparedwith a reaction time of approximately 4 hours for 677 (X = Cl), despite the low solubilityof 677 (X = Br) (Scheme 246). N,4,5,6,7-Pentachlorobenzotriazole, although extremely in-soluble in organic solvents, also undergoes rapid addition to alkenes.[687] 1-Chloro-1H-ben-zotriazole also gives addition products with enamines and enol ethers.[642]

Scheme 246 Addition of 1-Halo-1H-benzotriazoles to Alkenes[686,687]

NX

NN

+CH2Cl2, rt

NN

N

678677

NN

N+

679

X = Cl, Br

X

X

The reaction of 1H-benzotriazol-1-ol derivatives with alkyl halides in the presence of abase affords mainly the 1-alkoxy derivatives 680, but the N-alkyl derivatives 681 can alsobe formed (Scheme 247). For example, methylation of 1H-benzotriazol-1-ol with iodo-methane, in methanol/sodium methoxide, affords a mixture of the O- and N-methyl deriv-atives.[609,615,688] However, using the same conditions, 4-nitro-1H-benzotriazol-1-ol and 6-ni-tro-1H-benzotriazol-1-ol give only the 1-methoxy compounds.[615,689] Reaction of 1H-benzo-triazol-1-ol with 1-acetoxy-4-iodobutane in acetonitrile, with potassium carbonate asbase, gives only the O-alkyl derivative in 95% yield.[670] A range of 1-alkoxy-4,5-dichloro-1H-benzotriazole derivatives is prepared by reaction of the sodium salt of 4,5-dichloro-1H-benzotriazol-1-ol with the appropriate alkyl halides.[690] Several 1-alkoxy-4-nitro-




b1H-benzotriazole derivatives are prepared by alkylation of the 1-hydroxy derivative withalkyl halides under phase-transfer conditions.[691]

Scheme 247 Alkylation of 1H-Benzotriazol-1-ols with Alkyl Halides[688–691]

NN

NR2X, base

680

R1

OH

NN

N

R1

OR2

+

681

NN

R2

N

R1

O−+

Alkylation of 1H-Benzotriazole with Alkyl Halides; General Procedure:[662]

To a flask provided with a CaCl2 guard tube and magnetic stirrer was introduced finelyground NaOH (40 mmol), DMF (8–10 mL), 1H-benzotriazole (10 mmol), and the alkyl ha-lide (10 mmol). After stirring for 15–60 min, the mixture was poured into H2O (50–70 mL)to give a solid or oily product. Solids were collected by filtration, washed with H2O(25 mL), and dried, while the oily products were extracted with CHCl3 (3 � 10 mL), washedwith H2O (5 � 10 mL), dried (MgSO4), and the solvent evaporated under reduced pressure.1-Alkyl- and 2-alkylbenzotriazole isomers were separated by column chromatography(hexane/CHCl3 2:1).

13.13.3.3.1.1.9 Method 9:Halogenation

Benzotriazole is rapidly converted into crystalline 1-chloro-1H-1,2,3-benzotriazole (682,X = Cl) by treatment with sodium hypochlorite in aqueous acetic acid (Scheme 248).[692]

Similar reaction with sodium hypoiodite in aqueous sodium hydroxide gives 1-iodo-1H-benzotriazole in 43% yield.[687] Alternatively 1-iodo-1H-benzotriazole is obtained in94% yield by treatment of 1-chloro-1H-benzotriazole in dichloromethane with 1 equiva-lent of iodine.[687] Similarly, 1-bromo-1H-benzotriazole is prepared in 80% yield by the ad-dition of 1-chloro-1H-benzotriazole to a solution of bromine in dichloromethane.[687] Addi-tion of sodium hypochlorite to a solution of 4,5,6,7-tetrachloro-1H-benzotriazole in gla-cial acetic acid, at room temperature, rapidly affords N,4,5,6,7-pentachloro-1H-benzotri-azole (because of the extreme insolubility of this compound, the position of the fifth chlo-rine at N1 or N2 was not assigned unambiguously).[687]

Scheme 248 Synthesis of 1-Chloro- and 1-Iodo-1H-benzotriazole[687,692]

NH

NN AcOH, H2O, rt

+ NaOXX = Cl 100%

X = I 43%NX

NN

682

1H-Benzotriazole is chlorinated to 4,5,6,7-tetrachloro-1H-benzotriazole (683, X = Cl) in87% yield by refluxing with aqua regia (a mixture of concentrated hydrochloric acid andconcentrated nitric acid) for three hours (Scheme 249).[16] Under similar conditions, 2-methyl-2H-benzotriazole gives 4,5,6,7-tetrachloro-2-methyl-2H-benzotriazole in 50%yield[16] but chlorination of 1-methyl-1H-benzotriazole with aqua regia requires threedays to give 4,5,6,7-tetrachloro-1-methyl-1H-benzotriazole in 57% yield.[585] Refluxing 4-ni-tro-1H-benzotriazole with aqua regia for three days affords 4,5,6,7-tetrachloro-1H-benzo-triazole (62%), and 2,5-dimethyl-2H-benzotriazole gives 4,5,6,7-tetrachloro-2-methyl-2H-benzotriazole (yield not reported); in these systems the substituents on the benzenicring are replaced by chlorine.[585]





bScheme 249 Synthesis of 4,5,6,7-Tetrachloro- and4,5,6,7-Tetrabromo-1H-benzotriazole[16,585]

NH

NN

A: X = Cl 87%

B: X = Br 54%NH

NN

683

A: HCl, HNO3, reflux, 3 h

B: Br2, HNO3, reflux, 30 h

X

X

X

X

Reaction of 1H-benzotriazole with bromine in concentrated nitric acid under reflux af-fords 4,5,6,7-tetrabromo-1H-benzotriazole in 54% yield (Scheme 249).[585] 1-Methyl- and 2-methyl-1H-benzotriazoles are brominated in the same way affording, respectively,4,5,6,7-tetrabromo-1-methyl-1H-benzotriazole (48% yield) and 4,5,6,7-tetrabromo-2-meth-yl-2H-benzotriazole (67% yield).[585]

1-Chloro-1H-benzotriazole (682, X = Cl); Typical Procedure:[692]

CAUTION: 1-Chloro-1H-benzotriazole reacts violently with DMSO.

2 M NaOCl (50 mL, 0.1 mol) was added dropwise at rt to a stirred soln of 1H-benzotriazole(10 g, 0.08 mol) in aq AcOH (1:1). After dilution with H2O the resulting solid was collectedand recrystallized once (CH2Cl2/petroleum ether) to give pure (682, X = Cl) as colorlessneedles; yield: 13 g (~100%); mp 104–108 8C.

4,5,6,7-Tetrachloro-1H-benzotriazole (683, X = Cl); Typical Procedure:[16]

A soln of 1H-benzotriazole (4.76 g, 0.040 mol) in a mixture of concd HCl (525 mL) andconcd HNO3 (175 mL) was refluxed for 3 h, cooled, and diluted to precipitate the product;yield: 9.0 g, (87%). Recrystallization (MeNO2) gave a white crystalline solid; mp 256–260 8C.

13.13.3.3.1.1.10 Method 10:Sulfonylation

1H-Benzotriazole reacts with trifluoromethanesulfonic anhydride, in dry dichlorometh-ane and dry pyridine at –78 8C, to afford 1-(trifluoromethylsulfanyl)-1H-benzotriazole in87% yield.[642]

5,6-Dimethyl-1H-benzotriazole reacts with benzenesulfonyl chloride, in the presenceof 10% aqueous sodium hydroxide solution, to yield the 1-phenylsulfonyl derivative in72% yield;[587] naphthotriazoles also give only the 1-phenylsulfonyl derivatives.[582]

1H-Benzotriazol-4-amine reacts with an equimolar amount of 4-toluenesulfonyl chlo-ride in pyridine at room temperature to give 4-(tosylamino)-1H-benzotriazole (684, Ar1 = 4-Tol) (Scheme 250).[699] Under similar experimental conditions, 5-methyl-1H-benzotriazol-4-amine gives the 1-tosyl-1H-benzotriazole derivative 685 as the only isolated product. Withan excess of arenesulfonyl chloride both starting benzotriazol-4-amines afford the bis-sul-fonylated derivatives 686.[699] The reaction of benzotriazol-5-amines with arenesulfonylchlorides has also been reported.[639] 1-Mesyl- and 1-(phenylsulfonyl)-1H-benzotriazole areprepared in good yields from the reaction of the corresponding sulfonyl chlorides and 1-(trimethylsilyl)-1H-benzotriazole[630] or 1-(tributylstannyl)-1H-benzotriazole.[693]




bScheme 250 Sulfonylation of Benzotriazol-4-amines[699]

NH

NN

R1 = H, Me; Ar1 = Ph, 4-Tol

TsCl (1 equiv)

py, rt

NH2

R1

NH

NN

NHTs

684

NN

N

NH2

685Ts

R1 = H

R1 = Me

Ar1SO2Cl (4 equiv)

py, rt

NN

N

NHSO2Ar1

R1

SO2Ar1

686

13.13.3.3.1.1.11 Method 11:N-Amination

1H-Benzotriazol-1-amines are valuable precursors to didehydrobenzenes under notablymild conditions, using either lead(IV) acetate[694] or N-bromosuccinimide.[695] Treatmentof 1H-benzotriazole with hydroxylamine-O-sulfonic acid in hot (70–75 8C) aqueous potas-sium hydroxide solution gives a mixture of 1H-benzotriazol-1-amine (687) and 2H-benzo-triazol-2-amine in an approximately 3:1 ratio (Scheme 251).[694] The formation of the 2-amino isomer is avoided by changing the reaction conditions (temperature and solvent).The 1-amino isomer is obtained selectively in 62% yield when the reaction is carried out indioxane containing 5% water and the reaction mixture is maintained below 50 8C. Betteryields (69%) of the 1-isomer, uncontaminated by the 2-isomer, are obtained in dimethyl-formamide containing 5% water.[696] In ethanol the conversion is nearly quantitative, but a2:1 mixture of the two isomers is formed, the 2-amino derivative being the main prod-uct.[696]

Scheme 251 N-Amination of 1H-Benzotriazole[694,696]

NH

NN

H2NOSO3H, aq KOH, DMF

<50 oC, 1 h

NN

N

NH2

NN

N+

687

NH2

N-Amination of 1H-naphtho[2,3-d][1,2,3]triazole and 1H-naphtho[1,2-d][1,2,3]triazole inaqueous potassium hydroxide with hydroxylamine-O-sulfonic acid gives mainly the 1-amino derivatives (27 and 18% yields, respectively).[697] N-Amination of benzo[1,2-d:4,5-d¢]-bistriazole (688) under similar conditions gives a mixture of five products: the two mono-amino derivatives and the three possible diamino derivatives (Scheme 252).[596] The com-bined yields of diamino and monoamino products are 45 and 48%, respectively. N-Amina-





btion of a 1,2,3-triazolo[4,5-d][1,2,3]triazole with O-(mesitylsulfonyl)hydroxylamine affordsthe 1-amino and 2-amino derivatives in 22 and 46% yield, respectively.[698] N-Amination of4-cyanoazuleno[1,2-d]-1,2,3-triazole with 1-(aminooxy)-2,4-dinitrobenzene gives a 3:2 mix-ture of two isomeric N-amino derivatives in 54% yield.[569]

Scheme 252 N-Amination of Benzo[1,2-d:4,5-d¢]bistriazole[596]

NN

NH

1. 10% KOH, 60 oC

2. H2NOSO3H

66−68 oC, 2 h

NN

HN

688

NN

NNN

HN

NH2

NN

NNN

N

NH2

NN

NNN

NH

+

+

H2N

NN

NNN

N

NH2

+

NN

NNN

N

+

NH2

H2N

H2N NH2

1H-Benzotriazol-1-amine (687):[696]

Hydroxylamine-O-sulfonic acid (94.9 g, 0.84 mol) was added portionwise to a stirred solnof 1H-benzotriazole (50.0 g, 0.42 mol) and KOH (117.6 g, 2.1 mol) in DMF (250 mL) and H2O(12 mL) such that the temperature of the mixture remained below 50 8C (ca. 1.0 g •min–1).After the addition was complete, the mixture was cooled to rt and stirring continued for afurther 1 h. The resulting precipitate was removed by vacuum filtration and washed thor-oughly with Et2O. The filtrate was evaporated to dryness using a rotary evaporator at-tached to a rotary pump. The temperature of the water bath was kept below 50 8C; abovethis, rearrangement to the corresponding 2-amino isomer became significant. The resi-due was dissolved in a minimum of 2 M HCl and the resulting soln kept at –2 8C overnightduring which time 1H-benzotriazol-1-amine hydrochloride crystallized and was removedby filtration. The solid was dried under vacuum and showed mp 131–134 8C and was >95%pure according to 1H NMR data. The free amine was obtained by direct basification of thesolid salt using aq 2 M NaOH followed by extraction with Et2O (3 � 100 mL). The combinedextracts were dried and evaporated to leave 687 as a colorless solid; yield: 38.8 g (69%); mp84 8C.

13.13.3.3.1.1.12 Method 12:Nitration

Nitration of 1H-benzotriazole with a mixture of concentrated nitric and sulfuric acids, atroom temperature, gives 4-nitro-1H-benzotriazole in 50% yield while 5-methyl-1H-benzo-triazole gives the 4-nitro derivative 689 (R1 = Me) in 90% yield under similar experimentalconditions (Scheme 253).[699] Nitration of 5-chloro-1H-benzotriazole (at 60 8C) affords de-rivative 689 (R1 = Cl) in 83% yield.[700] Nitration of 1H-benzotriazole-5-carboxylic acid at90 8C gives derivative 690 (R1 = CO2H) while 5-nitro-1H-benzotriazole at 115 8C affords amixture of 690 (R1 = NO2, 30%) and 691 (67%).[700]




bScheme 253 Nitration of 1H-Benzotriazoles[699,700]

NN

NH

A: HNO3, H2SO4, rt, overnight

B: HNO3, H2SO4, 0−60 oC, 2 h

689R1

A: R1 = H 50%

A: R1 = Me 90%

B: R1 = Cl 83%

NN

NH

R1

NO2

A: HNO3, H2SO4, 0−90 oC, 2.5 h

B: HNO3, H2SO4, 0−115 oC, 12.5 h

690

A: R1 = CO2H 48% (690 only)

B: R1 = NO2 97%; (690/691) 30:67

NN

NH

R1

NO2

691

NN

NH

O2N

O2N

+

Nitration of 1-methyl-1H-benzotriazole affords 1-methyl-7-nitro-1H-benzotriazole[701]

while 2-methyl-2H-benzotriazole gives 2-methyl-5-nitro-2H-benzotriazole.[585] Nitration of1-(1,2,3-triazolyl)-1H-benzotriazole derivatives with potassium nitrate in concentratedsulfuric acid at 60 8C affords the corresponding 5-nitro derivatives in high yields (ca.80%). If the 5-position is occupied, nitration occurs at the 4-position.[322] 1-Phenyl- and 2-phenylbenzotriazoles give the corresponding 4-nitrophenyl derivatives by nitration withpotassium nitrate in concentrated sulfuric acid at 60 8C.[702,703] Nitration of 1-(2,4,6-trini-trophenyl)-1H-benzotriazole with a mixture of concentrated nitric and sulfuric acids, atreflux for 2 hours, gives the 5,7-dinitro derivative in 73% yield.[586] Nitration of 2-(2-hy-droxy-5-methylphenyl)-2H-benzotriazole with a mixture of concentrated nitric and aceticacids, at 70 8C for 10 minutes, gives the 2-(2-hydroxy-5-methyl-3-nitrophenyl) derivative in84% yield.[704] Nitration of 1,5-bis(2,4,6-trinitrophenyl)benzo[1,2-d:4,5-d¢]bistriazole with amixture of nitric acid and sulfuric acid gives the 4-nitro derivative in 21% yield.[595]

5-Methyl-4-nitro-1H-benzotriazole (689, R1 = Me); Typical Procedure:[699]

To 5-methyl-1H-benzotriazole (5 g, 37.5 mmol) in concd H2SO4 (20 mL) was added a mix-ture of HNO3 (70%, 5 mL) and concd H2SO4 (5 mL) at below 20 8C, and the resulting mixturewas allowed to stand overnight. The soln was poured onto ice, and the resulting precipi-tate was collected by filtration, washed with H2O, and recrystallized (EtOH) to give micro-crystals; yield: 6.0 g (90%); mp 254–255 8C.

13.13.3.3.1.1.13 Method 13:Azo Coupling

N-Unsubstituted, 1- and 2-substituted activated benzotriazoles (with a hydroxy or aminogroup) all react with arenediazonium salts to yield (arylazo)benzotriazoles.[631,701,705] Arange of benzo[1,2-d:3,4-d¢]bistriazoles 695 are prepared by oxidation of the 4-(arylazo)-benzotriazol-5-amines 694 (see Section 13.13.4.1.2.1.1) obtained from the reaction of 2-aryl-2H-benzotriazol-5-amines 692 with diazonium salt 693 (Scheme 254).[706]





bScheme 254 Azo Coupling to 2-Aryl-2H-benzotriazol-5-amines[706]

NNAr1

N

Ar2N2 Cl−

692

R1

R1 = H, Me, Et, OMe, Cl, Br, CO2H, SO3H; Ar1 = Ph, aryl, naphthyl

H2N

+

693N

NAr1

N

694

R1

H2N

NAr2N

695

CuSO4, NH4OH

Ar2 =

SO3H

HO3S

NO2

N

NAr1N

R1

N

Ar2NN

Both 1H-benzotriazol-5-ol and 5-hydroxy-1H-benzotriazole-4-carboxylic acid afford thesame azo dye 696 when reacted with diazonium salts (Scheme 255).[631] The complemen-tary synthetic route to (arylazo)benzotriazoles, i.e. diazotization of benzotriazol-5-aminefollowed by reaction with an activated aromatic compound can also be used successful-ly.[707]

Scheme 255 Azo Coupling with Activated Benzotriazoles[631]

NN

NH

696

HO

NN

NH

HO

NNAr1

85%

− CO2

93%

NN

NH

HO

CO2H

Ar1 = 4-ClC6H4

Ar1N2 Cl−+

693

Ar1N2 Cl−+

693

4-(4-Chlorophenylazo)-1H-benzotriazol-5-ol (696); Typical Procedure:[631]

4-Chloroaniline (6.38 g, 0.05 mol) was dissolved in 2.5 M HCl (100 mL) and diazotized bythe addition of 5 M NaNO2 (10 mL) at 10 8C. This soln was filtered and diluted to 200 mLto make a 0.25 M soln. Part of this soln (8 mL, 2 mmol) was added with stirring to a solnof 1H-benzotriazol-5-ol (0.286 g, 2.12 mmol) dissolved in a mixture of H2O (40 mL), 1 MNaOH (4 mL) and 1 M Na2CO3 (2 mL). A deep orange soln was formed immediately. After15 min stirring, the soln was acidified by the addition of 5 M HCl (1 mL). The reddish-or-ange precipitate formed was collected by filtration, washed, and dried at 100 8C; yield:0.47 g (85%); mp 247–249 8C.




b13.13.3.3.2 Of Carbon Functionalities

13.13.3.3.2.1 Method 1:Decarboxylation

When refluxed in water, 5-hydroxy-1H-benzotriazole-4-carboxylic acid decarboxylates toafford 1H-benzotriazol-5-ol in 76% yield (Scheme 256).[631] Its isomer, 5-hydroxy-1H-benzo-triazole-6-carboxylic acid does not decarboxylate under the same conditions.[631]

Scheme 256 Decarboxylation of Benzotriazoles[631]

H2O

reflux, 20 h

76%

NN

NH

HO

CO2H

NN

NH

HO NN

NH

HO

HO2C

H2O

reflux

13.13.3.3.2.2 Method 2:Deacylation

1-Acetyl-5-methyl-1H-benzotriazole and 1-acetyl-6-methyl-1H-benzotriazole are deacety-lated in boiling acetic acid/water (1:1) for eight to nine hours.[583] 1-Acetyl-6-(acetylamino)-5-methyl-1H-1,2,3-benzotriazole is selectively hydrolyzed to 6-(acetylamino)-5-methyl-1H-1,2,3-benzotriazole which then is hydrolyzed to 5-methyl-1H-benzotriazol-6-amine.[708]

1-Substituted benzotriazol-5-amines are obtained in 85% yield by deacylation of the corre-sponding 5-[(trifluoroacetyl)amino]-1H-benzotriazoles in methanol/potassium carbon-ate.[639] 1-Acetyl-5,6-dimethyl-1H-benzotriazole (697) is slowly deacetylated when dis-solved in ethanol/water (3:1) at room temperature (Scheme 257).[587] Compound 698 ishydrolyzed in 6 M hydrochloric acid to the propanoic acid derivative 699.[709]

Scheme 257 Deacetylation of 1-Acetyl-1H-benzotriazoles[587,709]

EtOH, H2O, rtNN

NAc

697

NN

NH

HCl, H2O, rt, 17 hNN

N

AcO

Ac

698

EtO2C90%

NN

NH

HO

699

HO2C

1,7-Diacetylbenzobistriazole 700, dissolved in ethanol/water (1:1), is deacetylated in al-most quantitative yield by acid treatment (Scheme 258).[596]

Scheme 258 Deacetylation of 1,7-Diacetyl-1,7-dihydrobenzo[1,2-d:4,5-d¢]bistriazole[596]

NN

NAc

700

96%N

N

HN

688

NN

NAc

H2SO4, H2O, EtOH

reflux, 1 h

NH

NN





b1,5-Dihydrobenzo[1,2-d:4,5-d¢]bistriazole (688); Typical Procedure:[596]

A mixture of 1,7-diacetyl-1,7-dihydrobenzo[1,2-d:4,5-d¢]bistriazole (700; 0.73 g, 3 mmol),50% aq EtOH (100 mL), and concd H2SO4 (1 mL) was refluxed for 1 h, then the reflux con-denser was removed and most of the EtOH was allowed to evaporate. The resultant mix-ture was chilled and filtered to remove the product, which was washed with H2O anddried at 100 8C to give pure 688; yield: 0.46 g (96%); explosion temperature 370 8C whenheated at 20 8C •min–1.

13.13.3.3.3 Of Heteroatoms

13.13.3.3.3.1 Method 1:Deoxygenation

2H-Benzotriazole 1-oxides of type 701 are readily deoxygenated to 2H-benzotriazoles 702or 703 by reduction with zinc dust in alkaline ethanolic solutions,[710] zinc powder andsulfuric acid,[711] hydrazine hydrate in a high-boiling ether,[712] or by using baker�s yeastin sodium hydroxide solution[713] (Scheme 259). If the reduction with zinc is carried outwith heating, the 5-chloro-2H-benzotriazole 1-oxides 701 (R1 = Cl) are simultaneously de-oxygenated and dechlorinated (see Section 13.13.3.3.3.2).[710]

Scheme 259 Deoxygenation of 2-Aryl-2H-benzotriazole 1-Oxides[710,713]

NN

N

701

68−88%

Zn, NaOH, EtOH

rt, 1 h

R1

O− HO R2

R3

NN

N

702

R1

HO But

R3

NN

N

703

R1

HO R2

R3

86−90%

baker's yeast

NaOH

85 oC, 24−30 h

R1 = H, Cl; R2 = H, t-Bu, CH2t-Bu; R3 = Me, t-Bu, CH2t-Bu

+

2-Alkyl-2H-benzotriazole 704 is deoxygenated to 705 by reduction with tin(II) chloride(Scheme 260).[714]

Scheme 260 Deoxygenation of 2-Alkyl-2H-benzotriazole 1-Oxides[714]

NN

N

704

O−

72%OHC

SnCl2, HCl

NN

N

705

OHC+

Refluxing 1-nonyl-1H-benzotriazole 3-oxide (706) in neat acetic anhydride gives the deox-ygenated 1-nonyl-1H-benzotriazole (707; yield not reported) (Scheme 261).[715]




bScheme 261 Deoxygenation of 1-Alkyl-1H-benzotriazole 3-Oxides[715]

NN

N

706

+

O−

Ac2O, reflux, 48 h

( )8

NN

N

707

( )8

Polymer-supported 1H-benzotriazol-1-ol 708 is readily converted into the correspondingNH derivative 709 by reductive cleavage of the 1-hydroxy moiety with either phosphorustrichloride or samarium(II) iodide (Scheme 262).[622]

Scheme 262 Reductive Cleavage of the 1-Hydroxy Moiety in a Polymer-Supported1H-Benzotriazol-1-ol[622]

NN

N

708

OH

PCl3, CHCl3, reflux, 20 h

or SmI2, THF, reflux, overnight NN

NH

709

13.13.3.3.3.2 Method 2:Dehalogenation

A simultaneous deoxygenation and dehalogenation, to give products 711, is observedduring the reduction of 5-chloro-2H-benzotriazole 1-oxides 710 with zinc dust in alkalineethanolic solution and heating on a steam bath for five hours (Scheme 263).[710]

Scheme 263 Dehalogenation of 5-Chloro-2H-benzotriazole 1-Oxides[710]

NN

N

710

Zn, NaOH, EtOH, H2O

100 oC, 5 h

Cl

+

O HO But

R1

−

NN

N

711

HO But

R1

R1 = Me 73%

R1 = t-Bu 80%

13.13.3.3.4 Addition Reactions

13.13.3.3.4.1 Method 1:Conversion into N-Oxides or Epoxides

1-Alkyl-1H-benzotriazoles react with dimethyldioxirane to give the corresponding 1-alkyl-1H-benzotriazole 3-oxides 712. In contrast, under similar conditions, 2-alkyl-2H-benzotri-azoles 713 are converted into the corresponding trans-4,5,6,7-diepoxy-4,5,6,7-tetrahydro-2H-benzotriazoles 714 (Scheme 264).[715]





bScheme 264 Oxidation of Benzotriazoles with Dimethyldioxirane[715]

NN

N

712

35−92%

CH2Cl2, rt, 24−36 h

(2−3 equiv)O

ON

NN

O−+

R1 = Me, Et, Pr, (CH2)5Me, (CH2)8Me, Bn, CH2CH2Ph, CHPhMe, CH2CO2Et, CH2OPh, CH2C CH, CH2CN

R1 R1

NN

N

713

CH2Cl2, rt, 3 d

(4 equiv)O

O

Ar1 = Ph 50%

Ar1 = 4-O2NC6H4 77%Ar1

NN

N

714

Ar1

O

O

2-Methyl-2H-benzotriazole is converted into its 1-oxide derivative, in very low yield, by ox-idation with 3-chloroperoxybenzoic acid (Scheme 265).[615] Most of the starting benzotria-zole is recovered unchanged.

Scheme 265 Oxidation of Benzotriazoles with 3-Chloroperoxybenzoic Acid[615]

NNMe

N0.8%

MCPBA (4 equiv)

CH2Cl2, 0 oC to rt, 12 d NNMe

N

O−

+

13.13.4 Product Subclass 4:2-Substituted Benzotriazoles


13.13.4.1.1 By Formation of Two N-N Bonds

13.13.4.1.1.1 Fragments N-C-C-N and N

13.13.4.1.1.1.1 Method 1:From Benzene-1,2-diamine and Nitrobenzenes

Benzene-1,2-diamine reacts with nitrobenzenes to yield 2-aryl-2H-benzotriazoles and 2-aminoazobenzenes (Scheme 266).[716] The latter compounds can be converted into 2-aryl-2H-benzotriazoles (see Scheme 267).

Scheme 266 2-Aryl-2H-benzotriazoles from Benzene-1,2-diamine and Nitrobenzenes[716]

NH2

NH2

+ Ar1NO2

NNAr1

N

NH2

NNAr1

+

Ar1 = Ph, 3-Tol




b13.13.4.1.2 By Formation of One N-N Bond


13.13.4.1.2.1.1 Method 1:Cyclization of 2-Aminoazobenzenes

2-Aminoazobenzenes are converted into 2-aryl-2H-benzotriazoles by oxidation with cop-per sulfate in ammonia or pyridine solution (Scheme 267). Using ammoniacal copper sul-fate, 2,4-diaminoazobenzene (715, R1 = 4-NH2; R2 = H) is converted quantitatively into 2-phenyl-2H-benzotriazole-5-amine,[717] and 2,2¢-diaminoazobenzene (715, R1 = H; R2 = 2-NH2) is oxidized to 2-(2-aminophenyl)-2H-benzotriazole (716; R1 = H, R2 = 2-NH2) with cop-per sulfate in pyridine in 65% yield.[643]

Scheme 267 Oxidative Cyclization of 2-Aminoazobenzenes[643,717]

NN

N

NH2

NN

R1

715

CuSO4, H2O

NH3 or py

rt to reflux, 2 hR1

R2

716

R2

Similarly, 1-(2-nitrophenylazo)-2-naphthylamine 717 is converted into the naphthotria-zole 718 by oxidative cyclization with copper sulfate in pyridine (Scheme 268).[643] Thesame naphthotriazole is obtained in 70% yield by refluxing the azo compound in thionylchloride.[643]

Scheme 268 Oxidative Cyclization of 1-(2-Nitrophenylazo)-2-naphthylamine[643]

NN

N

NH2

NN

717

A: CuSO4, py, reflux, 4 h

B: SOCl2, benzene, reflux, 18 h

718

O2N

A: 83%

B: 70%

O2N

2-(Arylazo)anilines 719 and 1-(arylazo)-2-naphthylamines 721 are converted into the cor-responding 2H-benzotriazoles 720 and 2H-naphthotriazoles 722, respectively, by reflux-ing in dimethylformamide, with a current of bubbling air, in the presence of copper(II)acetate (Scheme 269).[718] This procedure[718,719] and the one using copper sulfate as oxi-dant,[547,720,721] can also be applied to the synthesis of heterocycle-fused 1,2,3-triazoles.

13.13.4 2-Substituted Benzotriazoles 571




bScheme 269 Air Oxidation of 2-(2-Thienylazo)aniline and 1-(2-Thienylazo)-2-naphthylamine Derivatives[718]

NN

N

NH2

NN

719

Cu(OAc)2, air

DMF, reflux, 4 h

720

61−69%

S

S

R2

R1

R1 = Me, OMe; R2 = CN, CO2Et

R1

R2

NN

N

NH2

NN

721

Cu(OAc)2, air

DMF, reflux, 4 h

722

71−74%

S

S

R1

R1

R1 = CN, CO2Et

A range of benzo[1,2-d:3,4-d¢]bistriazoles is prepared by oxidation of 4-(arylazo)benzotri-azol-5-amines (see Scheme 254 in Section 13.13.3.3.1.1.13).[706]

2-(2-Aminophenyl)-2H-benzotriazole (716, R1 = H; R2 = 2-NH2); Typical Procedure:[643]

2,2¢-Diaminoazobenzene (4.4 g, 0.02 mol) was dissolved in pyridine (50 mL) and treatedwith anhyd CuSO4 (12.8 g, 0.08 mol) added in portions with stirring. After 30 min at rt,the mixture was refluxed for 2 h, cooled, and poured into cold H2O (200–250 mL) with stir-ring. The dark solid which separated was collected by filtration and washed with H2O.Three recrystallizations (2 � EtOH and 1 � hexane), with concomitant treatment withactivated carbon, yielded well-defined, yellow crystals; yield: 65%; mp 97–98 8C.

13.13.4.1.2.1.2 Method 2:Cyclization of 2-Azidoazobenzenes

The synthesis of 2H-benzotriazoles by thermal extrusion of nitrogen from 2-azidoazoben-zenes has been known since the 19th century.[722,723] This is a very convenient methodsince a range of 2-azidoazobenzenes can be prepared from simple precursors (Scheme270).[724,725] The kinetics of the thermal decomposition of 2-azidoazobenzenes 723 to 2-aryl-2H-benzotriazoles 724 has been investigated.[726] The reaction of 723 with boron tri-chloride or trifluoride in benzene at room temperature also gives benzotriazoles 724 inhigh yields (90–94%).[727]




bScheme 270 Synthesis of 2-Azidoazobenzenes and Their Conversion into2-Aryl-2H-benzotriazoles[724,725]

NNAr1

N

N3

NNAr1

723

heat

724

− N2

NH2

N3

N2

N3

+ Ar1NO

+ Ar1X

NaNO2, H+

+

− H2O

X = NR1R2, OH

The benzotriazolo[2,1-a]benzotriazole 727 is prepared in good yield by the thermal orphotochemical decomposition of 2,2¢-diazidoazobenzene (725). This transformation re-quires the elimination of 2 equivalents of nitrogen and this can be performed at 175 8C(Scheme 271). However, since the nitrogen is liberated in two distinct stages, 1 equivalentat approximately 60 8C and the second equivalent at approximately 170 8C, it is possible toconvert 725 into 2-(2-azidophenyl)-2H-benzotriazole (726) in good yield.[643,728] Benzotria-zole 726 is also formed when a benzene solution of 725 is exposed to sunlight for threedays. Similarly, 726 is converted into 727 when exposed to sunlight for ten days.[643]

Scheme 271 Thermolysis of 2,2¢-Diazidoazobenzene[643,728]

NN

NN3

NN

725

acetone or benzene

reflux, 2 h

726

N3

− N2

70%N3

Decalin

175 oC, 2−3 hDecalin

175−185 oC, 2−3 h

− N2

95%

− 2N2

93%

N

N

N

N

+ −

727

2,4-Bis(arylazo)-1-azido- and 1-(arylazo)-2-azidonaphthalene derivatives 728 and 730 areconverted into 2H-naphtho[1,2-d][1,2,3]triazoles 729 by thermal decomposition (Scheme272).[729]





bScheme 272 Thermolysis of (Arylazo)azidonaphthalenes[729]

NNAr1

N

N3

NNAr1

R1

R1

heat

N

N3R1

heat

728

730

729NAr1

− N2

R1 = N2Ar1 78−81%

− N2

R1 = H 60−85%

1-(2-Azidophenyl)-3-methyl-3-phenyltriazene (731) is converted into 2-[methyl(phenyl)-amino]-2H-benzotriazole (732) when refluxed in m-xylene (Scheme 273).[725]

Scheme 273 Thermolysis of a (2-Azidophenyl)triazene Derivative[725]

NN

N

N3

NN

m-xylene, reflux, 1 h

− N2

63%

731 732

N

N

Ph

MePh

Me

2-Azidoazobenzenes 734 are intermediates in the conversion of 2-nitro-, 2-chloro-, and 2-bromoazobenzenes 733 into 2-aryl-2H-benzotriazoles 735 (Scheme 274). This transforma-tion is accelerated by the addition of a suitable metal catalyst (e.g., CuBr).[730]

Scheme 274 Synthesis of 2-Aryl-2H-benzotriazoles from 2-Nitro-, or 2-Haloazobenzenesand Sodium Azide[730]

NNAr1

N

N3

NNAr1

734

735

− N2

X = NO2, Cl, Br

R1

R1

X

NNAr1

733

R1

NaN3, DMSO

or DMF

125 oC, 4−10 h

2-(2-Azidophenyl)-2H-benzotriazole (726); Typical Procedure:[643]

A soln of 725 (5 g, 18.9 mmol) in acetone or benzene (CAUTION: carcinogen) was refluxedfor 2 h. N2 was evolved, and the orange color was discharged. The solvent was removed bydistillation, and the crystalline residue was recrystallized (petroleum ether or aq acetone)to afford light yellow needles; yield: 70%; mp 78–79 8C.




b13.13.4.1.2.1.3 Method 3:

Cyclization of 2-Nitroazobenzenes

2-Nitroazobenzenes 736 give reductive cyclization reactions to afford 2-aryl-2H-benzotri-azole 1-oxides 737 or 2-aryl-2H-benzotriazoles 738, depending on the reducing agent andthe reaction conditions (Scheme 275). For example, reduction of azo compounds 736 withglucose[710] or with hydroxylamine[731] in ethanolic sodium hydroxide solution, at reflux,affords 2H-benzotriazole 1-oxides 737 in good yields. 2-Nitroazobenzenes react with thio-urea S,S-dioxide in ethanolic sodium hydroxide to give, depending on the reaction condi-tions, either the corresponding 2-aryl-2H-benzotriazoles 738 or their 1-oxides 737.[732] Sev-eral other reducing agents can be used for the conversion of 2-nitroazobenzenes into 2-aryl-2H-benzotriazoles or their 1-oxides, namely sodium sulfide, sodium hydrosulfide,[733]

ammonium sulfide,[734] sodium dithionite,[735] hydrazine hydrate,[711,712] zinc dust with so-dium hydroxide,[710] molybdenum-promoted Raney nickel,[736] hydrogen in the presenceof a catalyst,[737,738] and carbon monoxide in an alkaline medium in the presence of a cop-per–amine complex catalyst.[739]

Scheme 275 Reductive Cyclization of 2-Nitroazobenzenes[710]

NNAr1

N

738

R1

NO2

NNAr1

736

R1 reduction

NNAr1

N

737

R1

O−+

reduction

2-Nitroazobenzenes 739 cyclize selectively to give 2-aryl-2H-benzotriazole 1-oxides 740by reduction with baker�s yeast (Saccharomyces cerevisiae) in sodium hydroxide solution(Scheme 276). Using twice the amount of baker�s yeast, a larger amount of sodium hy-droxide, and a longer reaction time, gives 2-aryl-2H-benzotriazoles 741 as the sole prod-uct in good yields.[713]





bScheme 276 Reductive Cyclization of 2-Nitroazobenzenes Using Baker�s Yeast[713]

NO2

NN

739

baker's yeast

NaOH, H2O

85 oC, 3.5−4 h

NN

N

740

+

R1

R2

R3

R1

OH

R3

R2

NN

N

741

R1

HO

R3

R2

baker's yeast

NaOH, H2O

85 oC, 24−30 h86−90%

baker's yeast

NaOH, H2O

85 oC, 36−40 h

84−87%

80−87%

R1 = H, Cl; R2 = H, t-Bu, CMe2Et; R3 = Me, t-Bu, CMe2Et

HO

O−

13.13.4.1.2.1.4 Method 4:Cyclization of 1-Substituted 2-(2-Nitroaryl)hydrazines

Under reductive conditions, 1-aryl-2-(2-nitroaryl)hydrazines 743 cyclize to 2-aryl-2H-ben-zotriazoles 744 (Scheme 277).[740] Frequently benzotriazoles 744 are prepared directlyfrom the reaction of 1-halo-2-nitrobenzene derivative 742 (X = Cl, Br), or a 1,2-dinitroben-zene derivative 743 (X = NO2), and an excess of an arylhydrazine.[609,645] Under acidic con-ditions, hydrazines 743 are dehydrated to 2-aryl-2H-benzotriazole 1-oxides 745 (Scheme277).[741] Most 1-aryl-2-(2,4,6-trinitrophenyl)hydrazines 743 [R1 = 4,6-(NO2)2; Ar1 = Ph, 4-Tol,C6F5] are readily cyclized by refluxing in anhydrous ethanolic hydrogen chloride.[742] How-ever, cyclization of 1,2-bis(2,4,6-trinitrophenyl)hydrazine to 4,6-dinitro-2-(2,4,6-trinitro-phenyl)-2H-benzotriazole 1-oxide requires more vigorous conditions. Cyclization pro-ceeds smoothly and nearly quantitatively by gentle heating a suspension of that hydra-zine derivative in concentrated sulfuric acid for 30–60 minutes.[742]

Scheme 277 Cyclization of 1-Aryl-2-(2-nitroaryl)hydrazines[609,445,741]

NNAr1

N

744

R1

X

NO2

742

R1Ar1NHNH2

NNAr1

N

745

R1

O−+

HN

NO2

743

R1 NHAr1

KI, AcOH, heat

or Ar1NHNH2, heat

H+

− H2O

X = Cl, Br, NO2




b2-Methyl-6-nitro-2H-benzotriazole 1-oxide (747) is prepared by acid-catalyzed dehydrationof 1-methyl-2-(2,4-dinitrophenyl)hydrazine (746) or by addition of iodomethane to a solu-tion of 2,4-dinitrophenylhydrazine (Scheme 278).[743]

Scheme 278 Acid-Catalyzed Dehydration of 1-Methyl-2-(2,4-dinitrophenyl)hydrazine[743]

HN

NO2

746

NNMe

N

747

O−+

HCl, MeOH

rt, 7 h

O2N

O2N

NHMe

MeΙ, DMSO

rt, 42 h

HN

NO2O2N

NH2

86%

60%

The 2-nitrophenylhydrazine derivative 748 gives the 2-alkyl-2H-benzotriazole 1-oxide 749when treated with pyridine (Scheme 279).[714]

Scheme 279 Base-Catalyzed Conversion of a 2-NitrophenylhydrazineDerivative into a 2-Alkyl-2H-benzotriazole 1-Oxide[714]

HN

NO2

748

NN

N

749

O−+

pyN+

Br−

OHC

13.13.4.1.2.1.5 Method 5:Cyclization of Vicinal Diazides

2,3-Diazidonaphtho-1,4-quinone (750) reacts with triphenylphosphine to form almostquantitatively the phosphorane 751 (Scheme 280). This compound undergoes an aza-Wit-tig reaction with aldehydes (e.g., to give 753) and is readily hydrolyzed to the triazol-2-amine 752, which is a stable and high-melting compound.[744]





bScheme 280 Synthesis of Naphthotriazol-2-amine Derivatives from Vicinal Diazides[744]

750

Ph3P, MeOH

rt, 3 h

O

O

N3

N3

751

O

O

NN

NN

PPh3 752

O

O

NN

NNH2

753

O

O

NN

NN

1 M HCl

reflux, 4 h

PhCHO, CH2Cl2rt, overnight

43%

36%

− N2

96%

Ph

13.13.4.2 Synthesis by Ring Transformation

13.13.4.2.1 Method 1:Isomerization of 4-(Arylazo)-2,1,3-benzoxadiazoles

Addition of a diazonium salt to 5-(dimethylamino)-2,1,3-benzoxadiazole 1-oxide (754)gives the 4-arylazo derivative 755, which isomerizes to the 2-aryl-2H-benzotriazole 756(Scheme 281).[745]

Scheme 281 2-Aryl-2H-benzotriazoles from 4-(Arylazo)-2,1,3-benzoxadiazoles[745]

NO

N

754

O−+

Ar1N2

Me2N

NO

N

755

O−+

Me2N

NNAr1

NNAr1

N

756

NO2

NMe2

Ar1 = 2,4-(O2N)2C6H3

+

13.13.4.2.2 Method 2:Transformation of 1,3,3-Trialkyl-2-(2,4-dinitrophenyl)diaziridines

1-(2,4-Dinitrophenyl)diaziridines bearing an NH group 757 (R1 = H), upon heating in tolu-ene for ca. 3 hours, rearrange to the corresponding 2,4-dinitrophenylhydrazones. Howev-er, heating 1,3,3-trialkyl-2-(2,4-dinitrophenyl)diaziridines or 1,3-dialkyl-2-(2,4-dinitro-phenyl)diaziridines 757 (R3 = H) does not give hydrazones but affords instead 2-alkyl-6-ni-tro-2H-benzotriazole 1-oxides 759 (via intermediates 758) in almost quantitative yields(Scheme 282).[743]




bScheme 282 Transformation of 1,3,3-Dialkyl-2-(2,4-dinitrophenyl)diaziridines[743]

NNR1

N

759 97−100%

O−+

R1 = Me, iPr, Cy; R2,R3 = (CH2)5; R2 = Me, Et; R3 = H, Me

O2N

758

N

NNR1

O

O2N

toluene, reflux

3−14 h

NO2

N

O2N

NR2

R3

R1

− R2COR3

757

13.13.4.2.3 Method 3:Transformation of 1-(2-Nitrophenyl)-1H-tetrazoles

5-Aryl-1-(2-nitrophenyl)-1H-tetrazoles[746,747] and 1-aryl-5-(2-nitrophenyl)-1H-tetrazoles[748]

decompose when heated to give nitrogen, carbon dioxide, and 2-aryl-2H-benzotriazoles;the former react much faster than the latter. For example, decomposition of 1-(2-nitro-phenyl)-5-phenyl-1H-tetrazole (760) in refluxing nitrobenzene is complete after one hourwhile decomposition of 5-(2-nitrophenyl)-1-phenyl-1H-tetrazole (763) requires 19 hours(Scheme 283).[748] It has been shown that the thermal decomposition of these tetrazolesto 2-aryl-2H-benzotriazoles (e.g., 762) proceeds via 2-nitrophenyl(phenyl)carbodiimides(e.g., 761; Ph may be replaced by a substituted-phenyl ring). A sequence of electrocyclicring closing and opening reactions is proposed as the mechanism of the conversion ofcarbodiimides 761 to 2-aryl-2H-benzotriazoles.[746,747] There are several other precursors(both cyclic and acyclic) of diarylcarbodiimides with an ortho nitro group and, conse-quently, they can be used in the synthesis of 2-aryl-2H-benzotriazoles.[746,747]

Scheme 283 Transformation of 1(5)-(2-Nitrophenyl-5(1)-phenyltetrazoles into2-Phenyl-2H-benzotriazole[748]

NNPh

N

761

NO2

N

PhNO2, reflux

1 h

NO2

N

− N2

70%

760

N

NN

Ph

NO2

763

NN

NN

Ph

PhNO2, reflux

19 h

− N2

60%

− CO2

762

• NPh

The carbodiimides 765 are suggested as probable intermediates in the reaction of thephosphoramidate 764 with aryl isocyanates to yield the 2-aryl-2,4-dihydroimidazo[4,5-d][1,2,3]triazoles 766 (Scheme 284).[749]





bScheme 284 Synthesis of 2-Aryl-2,4-dihydroimidazo[4,5-d][1,2,3]triazoles viaCarbodiimides[749]

764

Ar1NCO

MeCN, 60 oCEtN

N

N

NO2

P(OEt)3

765

EtN

N

N

NO2

NNAr1

NN

N

Et

766 57−79%

• NAr1

13.13.4.3 Synthesis by Substituent Modification

Since substituent modification reactions in 1H- and 2H-benzotriazoles are, in many cases,very similar, the synthesis of new 2H-benzotriazoles by substituent modification is cov-ered in Section 13.13.3.3.

13.13.5 Product Subclass 5:1,2,3-Triazolium Salts



13.13.5.1.1.1 Fragments C-N-N and C-N

13.13.5.1.1.1.1 Method 1:From Diarylnitrilimines and Alkyl Isocyanides

Diarylnitrilimines 768 (generated in situ from 767 and triethylamine) react with alkyl iso-cyanides to form the triazolium salts 769 (Scheme 285).[444,750] Depending on the reactionconditions, other heterocyclic compounds are obtained, namely 1,2,4-triazolium salts,pyrazole derivatives, and quinoxaline derivatives. Experiments with tert-butyl isocyanideand phenyl isocyanide failed to give the respective triazolium salts 769.

Scheme 285 Reaction of Diarylnitrilimines with Alkyl Isocyanides[444,750]

767

Et3N

MeCN, rtAr1

Cl

N

NHAr2

NAr1 NAr2+ −

N

NNAr2

Ar1

R1+

ClO4−

768

769 57−73%

1. R1NC, MeCN, rt, 24 h

2. HClO4, H2O

R1 = Me, iPr, Cy; Ar1 = Ph, 4-Tol; Ar2 = Ph, 4-Tol




bSynthesis of 2H-Triazol-1-ium Salts 769; General Procedure:[444]

CAUTION: Perchlorate salts are potential explosives.

Et3N (2 mmol) was added at rt to a soln of the N-arylbenzohydrazonoyl chloride 767(2 mmol) and the alkyl isocyanide (2 mmol) in dry MeCN (50 mL); the mixture was allowedto stand for 24 h. Removal of the solvent gave a crystalline residue which was washedwith Et2O and dissolved in the minimum amount of H2O (some insoluble material was fil-tered off ). Then 10% aq HClO4 was added to cause precipitation of crude 769 as a greenish-white solid. Chromatography (acidic alumina, acetone), followed by addition of Et2O tothe concentrated eluate, afforded colorless plates.

13.13.5.1.2 By Formation of One N-C Bond

13.13.5.1.2.1 Fragment N-N-N-C-C

13.13.5.1.2.1.1 Method 1:Cyclization of Æ-Imino Hydrazones

The oxidation of substituted Æ-imino hydrazones 770 with N-bromosuccinimide affords1,2-disubstituted 2H-triazol-1-ium salts 771 (Scheme 286).[751]

Scheme 286 Oxidative Ring Closure of Substituted Æ-Imino Hydrazones[751]

N

NN

R2

+

771

R1 NPh

R2 NNH

R3

NBS

Ph

R1

R3

770

R1 = alkyl, aryl; R2 = alkyl, CN; R3 = H, halo, alkyl

13.13.5.1.2.1.2 Method 2:Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives

Cyclization of ethyl (1-methyl-3-phenyltriaz-2-enyl)acetate 772 (Ar1 = Ph; X = OEt) withthionyl chloride/pyridine gives the mesoionic compound 773 (Ar1 = Ph) together with asmall amount of the sulfide 774 (Scheme 287).[362] Under similar reaction conditions, cy-clization of amide 772 (Ar1 = Ph; X = NH2) gives only sulfide 774. Similar results are ob-tained when Ar1 = 4-tolyl. Treatment of acetonitrile derivatives 775 with dry hydrogenchloride affords 4-amino-3-aryl-1-methyl-3H-1,2,3-triazol-1-ium chlorides 776. Cyclizationof 775 with acetyl chloride gives the acetamido derivatives 777. The yields from all thesetransformations are low.

Scheme 287 Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives[362]

NAr1

NN

−O

+

773

Me

Ar1 = Ph, 4-Tol; X = OEt, NH2

X

Ar1N

N

NMeO

SOCl2, py NAr1

NN

−O

+

774

Me

S

2

+

772

13.13.5 1,2,3-Triazolium Salts 581




bNAr1

NN

H2N

+

776

Me

Ar1 = Ph, 4-Tol

HCl

Cl− NC NMe

NAr1N

775

AcCl NAr1

NN

AcHN

+

777

Me

Cl−

This type of chemistry has been applied to the synthesis of the mesoionic 1,3-diaryl-1,2,3-triazoles 778 (Scheme 288).[752]

Scheme 288 Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives[752]

R1 = CO2Me, NHAc, NHCOEt

Ar1N2

NAr1

NN

−O

+

778 20−55%

OH

O

HN

R1

+HO

ON

R1

NAr1N

Ac2O, py, rt

R1

13.13.5.2 Synthesis by Introduction of Substituents

13.13.5.2.1 Method 1:Alkylation of N-Alkyl-1,2,3-triazoles

Alkylation of 1-alkyl-1H-1,2,3-triazoles 779 gives 1,3-disubstituted 3H-1,2,3-triazol-1-iumsalts 780[455] while alkylation of 2-substituted 2H-1,2,3-triazoles 781 affords 1,2-disubsti-tuted 2H-1,2,3-triazol-1-ium salts 782 (Scheme 289).[450] 2-Substituted 2H-triazoles aremuch more difficult to alkylate than the isomeric 1-substituted 1H-triazoles; this differ-ence in reactivity agrees with the fact that 1-substituted triazoles are much more basicthan the isomeric 2-substituted compounds.[450] While 1-substituted 1,2,3-triazoles reactreadily with methyl 4-toluenesulfonate,[448,449] producing 1,3-disubstituted 1,2,3-triazo-lium 4-toluenesulfonates in high yields, 2-substituted 1,2,3-triazoles, when treated withmethyl 4-toluenesulfonate, iodomethane, or dimethyl sulfate do not react, or they givethe triazolium salts in low yield only.[450] 2,4-Diphenyl-2H-1,2,3-triazole is, however, con-verted into the triazolium salt, in 80% yield, by methylation with dimethyl sulfate.[444] M-ethyl fluorosulfonate is a successful methylating reagent for 2-substituted 1,2,3-triazoles(Scheme 289).[450] The reaction is carried out in the absence of a solvent and the requiredtemperature is dependent on the substituents R1 and R2 in triazole 781. For example, 2-methyl-2H-1,2,3-triazole reacts with methyl fluorosulfonate at 0 8C, 2-phenyl-2H-1,2,3-tri-azole reacts at room temperature, and the reaction with 4,5-dibromo-2-methyl-2H-1,2,3-triazole only occurs at 60 8C.[450]




bScheme 289 Alkylation of 1- and 2-Substituted 1,2,3-Triazoles[450,455]

NR2

NN

+

780

R1

I−N

NN

779

R1

+ R2I

acetone, Et2O

rt, 5−8 d

R1 = Me; R2 = Bn 83%

R1 = Bn; R2 = Me 74%

N

NNR2

+

FSO3−

N

NNR2

781

0 oC, rt, or 60 oC

R1 = H; R2 = Me 79%

R1 = H; R2 = Ph 99%

R1 = Br; R2 = Me 99%

R1

R1 FS

OMe

O O+

R1

R1

Me

782

1-Phenyl-1H-1,2,3-triazole adds fairly rapidly to vinylsulfonyl chloride, in the absence of abase, to yield quantitatively the sulfonate 783 (Scheme 290).[198]

Scheme 290 Addition of 1-Phenyl-1H-1,2,3-triazole to Vinylsulfonyl Chloride[198]

N

NN

Ph

benzene

reflux, 6 h N

NN

Ph

SO2Cl

−

+

H2O N

NN

Ph

SO3−

+

783 99%

SO2Cl

1-Ethyl-1H-1,2,3-triazole reacts with tetracyanoethene oxide, at 0 8C, to yield 3-ethyl-3H-1,2,3-triazol-1-ium-1-dicyanomethanide (784) in 73% yield (Scheme 291).[753]

Scheme 291 Reaction of 1-Ethyl-1H-1,2,3-triazole with Tetracyanoethene Oxide[753]

N

NN

Et

EtOAc

0 oC, 2−5 min

73%

784

ONC CN

CNNC

+N

NN

Et

NC

CN−

++ O

CN

CN

13.13.5.2.2 Method 2:Alkylation of N-Alkylbenzotriazoles

As discussed in Section 13.13.3.3.1.1.8, during the alkylation of benzotriazole with alkylhalides, in some cases,[672] the 1,3-dialkylbenzotriazolium salts are also formed (Scheme239). 1-Substituted 3-methyl-3H-benzotriazol-1-ium iodides 785 are prepared in low togood yields by the reaction of 1-substituted 1H-benzotriazoles with iodomethane (Scheme292).[754]





bScheme 292 Methylation of 1-Substituted 1H-Benzotriazoles[754]

785

NN

N

R1

MeI, toluene, sealed tube

80 oC, 16−72 h

R1 = CH2SPh 65%

R1 = CH2SOPh 82%

R1 = CH2SO2Ph 35%

NN

N

R1

Me

I−

+

Alkylation of 1-[(dialkylamino)methyl]-1H-benzotriazoles 786 leads to the formation of(1H-benzotriazol-1-ylmethyl)ammonium salts 787 (Scheme 293).[755] This reaction is limit-ed to iodomethane, iodoethane, and 1-(chloromethyl)-1H-benzotriazole. Methyl 4-tolu-enesulfonate can also be used but reacts only with 1-(pyrrolidin-1-ylmethyl)-1H-benzotri-azole [786, R1,R2 = (CH2)4]. In some cases, the 1,3-dialkylbenzotriazolium salts 790 are ob-tained. Indeed, when 1-(pyrrolidin-1-ylmethyl)-1H-benzotriazole [786, R1,R2 = (CH2)4] isheated with benzyl bromide in a sealed tube at 60–80 8C, 1,3-dibenzyl-3H-benzotriazol-1-ium bromide (790, R3 = Bn; X = Br) is obtained in 65% yield.[755] The explanation for the for-mation of salts 790 depends on the fact that compounds 786, in solution, are in equilibri-um with the ion pair 788, which reacts with the alkylating agent to form successively 1-alkyl-1H-benzotriazole 789 and then 790.

Scheme 293 Alkylation of 1-[(Dialkylamino)methyl]-1H-benzotriazoles[755]

786

NN

NR3X

40−60%X−

+NR1R2

NN

N

N

787

R1,R2 = (CH2)4

NN

N

−

NH2C

R1

R2

R3X

788

+

NN

N

R3

R3X

NN

N

R3

R3

X−

+

789 790 R3 = Bn; X = Br 65%

R1

R3

R2

Ethyl 1H-benzotriazole-1-carboxylate reacts with triethyloxonium tetrafluoroborate toyield the corresponding 3-(ethoxycarbonyl)-1-ethyl-3H-benzotriazol-1-ium salt (seeScheme 240).[634]

Alkylation of benzotriazole with bis(bromomethyl)benzenes (1,2-, 1,3- or 1,4-) in twosteps affords the benzotriazolophanes 791 (Scheme 294).[674] The symmetrical benzotri-azolophanes 792, 793, and 794 are prepared in a similar manner.[674,675]




bScheme 294 Synthesis of Symmetrical Benzotriazolophanes[674]

NH

NN

2Br−

+

791

Br

BrNaOH, MeCN, rt, 2 d

1,2-xylenyl 65%

1,3-xylenyl 60%

1,4-xylenyl 71%

NN

N

NN

N

NN

N

Br

BrMeCN, reflux, 5 d

1,2-xylenyl 42%

1,3-xylenyl 40%

1,4-xylenyl 55%

+

N

NN

2Br−

792

+NN

N

NN

N

+

N

N

+NN

N

+NN

N2Br−

793

+NN

N

+NN

N2Br−

794

The unsymmetrical benzotriazolophanes 796 and 797 are obtained by alkylation of theprecyclophane 795 with the corresponding bis(bromomethyl)benzene derivatives(Scheme 295).[675]





bScheme 295 Synthesis of Unsymmetrical Benzotriazolophanes[675]

N

+NN

N

+NN

N2Br−

796

OMe

N

NN

N

NN

N

795

BrBr

OMe

MeCN, reflux, 5 d

59%

N

+NN

N

+NN

N2Br−

797

NO2

N

NN

N

NN

N

795

52%

OHBrBr

NO2

MeCN, reflux, 5 d

OH

1-Ethyl-1H-benzotriazole reacts with tetracyanoethene oxide, at room temperature, toyield 3-ethyl-3H-benzotriazol-1-ium-1-dicyanomethanide 798 (Scheme 296).[753]

Scheme 296 Reaction of 1-Ethyl-1H-benzotriazole with Tetracyanoethene Oxide[753]

Et

Et2O

rt, 24 h

798 21%

ONC CN

CNNC

+

−

+

+ O

CN

CN

NN

N

EtN

NN

NCCN




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