Acylation and Related Acylation and Related Transformations Transformations Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel-Fattah, Rachel Witek, Chunming Cai University of Florida, Center for Heterocyclic compounds Lecture presented in 2005 Reviews of Benzotriazole Chemistry Early Reviews: • [91T2683] “Benzotriazole: A novel Synthetis Auxiliary” • [94ACA31] “Benzotriazole-Stabilized Carbanions: Generation, Reactivity, and Synthetic Utility • [94Sip] “Benzotriazole as a Synthetic Auxiliary: Benzotriazolylalkylations and Benzotriazole Mediated Heteroalkylation” • [94CSRsub] “Benzotriazole Mediated Arylalkylation and Heteroalkylation” Review Comprehensive through 1996: • [98CR409] “Properties and Synthetic Utility of N-Substituted More Recent Reviews: • [98AA33] “Benzotriazole-Based Reagents for Efficient Organic Synthesis” • [99T8263] “Benzannulations • [98CCCC599] “Michael Additions of Benzotriazole-Stabilized Carbanions” • [98T2647] “ The Generation and Reactions of Non-Stabilized a-Aminocarbanions” • [00PAC1597] “Designing Efficient Routes to Polyfunctionality” • [01SL458] “The preparation of Mono-, 1,1-Di-, trans-1,2-Di- and Tri- Substituted Ethylenes by Benzotriazole Methodology” • [03CEJ4586] “Benzotriazole:An Ideal Synthetic Auxiliary” 1
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Acylation and Related Transformations Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel- Fattah, Rachel Witek, Chunming Cai University of Florida, Center.
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Acylation and Related TransformationsAcylation and Related TransformationsAlan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel-
Fattah, Rachel Witek, Chunming Cai
University of Florida, Center for Heterocyclic compounds
Lecture presented in 2005
Reviews of Benzotriazole Chemistry
Early Reviews:
• [91T2683] “Benzotriazole: A novel Synthetis Auxiliary”
• [94ACA31] “Benzotriazole-Stabilized Carbanions: Generation, Reactivity, and Synthetic Utility
• [94Sip] “Benzotriazole as a Synthetic Auxiliary: Benzotriazolylalkylations and Benzotriazole Mediated Heteroalkylation”
• [94CSRsub] “Benzotriazole Mediated Arylalkylation and Heteroalkylation”
Review Comprehensive through 1996:
• [98CR409] “Properties and Synthetic Utility of N-Substituted Benzotriazoles” (includes 403 references of which 253 are from our group)
More Recent Reviews:
• [98AA33] “Benzotriazole-Based Reagents for Efficient Organic Synthesis”
• [99T8263] “Benzannulations
• [98CCCC599] “Michael Additions of Benzotriazole-Stabilized Carbanions”
• [98T2647] “ The Generation and Reactions of Non-Stabilized a-Aminocarbanions”
• [00PAC1597] “Designing Efficient Routes to Polyfunctionality”
• [01SL458] “The preparation of Mono-, 1,1-Di-, trans-1,2-Di- and Tri-Substituted Ethylenes by Benzotriazole Methodology”
Acylation in Organic SynthesisAcylation in Organic Synthesis
• Scope: on
– Nitrogen Amides, especially peptides
– Sulfur Thiol esters
– Oxygen Esters
– Carbon Ketones
• Reagents for Acylation — Activated Derivatives of Carboxylic Acid
– Acid chloride or Anhydride
– Activated ester or Amide
– From acid via non-isolated activated derivatives
2
•Disadvantages of Common Acylation Agents– Sensitivity to water — precludes use of aqueous solutions– Problems in handling, storage, weighing– Lack of chiral stability– Incompatibility of other functionality
• Acylazoles or Azolides — Staab ca. 1961
– Especially acylimidazoles
NN
O
RWidely used
Preparation of N-AcylbenzotriazolesPreparation of N-Acylbenzotriazoles direct from Carboxylic Acidsdirect from Carboxylic Acids
N-AcylbenzotriazolesN-AcylbenzotriazolesFrom Unsaturated, Functionalized and Bis-acidsFrom Unsaturated, Functionalized and Bis-acids
RCOBt mp Yield
oil 83
CH3CH=CHCOBt 87-88 86
PhCH=CHCOBt 151-152 96
HC≡ CCOBt 99-100 83
PhC≡ CCOBt 124-125 92
87-88 86
BrCH2COBt 91-92 87
Cl2CHCOBt 87-88 86
CH3OCH2COBt 103-104 96
PhSCH2COBt 103-104 90
PhCOCOBt 72-73 72
174-175 82
BtCO(CH2)4COBt 170-171 75
BtCO(CH2)18COBt 121-122 63
MeO2C(CH2)3COBt 51-52 87
300 77
COBt
COBtCl
BtOC COBt
5
RCOBt mp Yield
223-225 94
247 16
188-189 60
158-160 80
98-100 40
142-144 98
159-160 87
104-105 98
Bt
O
Bt
O
BtS
O
Bt
O
BtO
O
Bt
O
Bt
O
Bt
O
Bt
O
Bt
O
Bt SS
OBt
O
Bt
OBt
O
O
BtO
Bt
RCOBt mp Yield
142-144
169-170
95
98
183-184 96
244-245 90
136-137 98
183 65
196-197 95
118-120 56
91-92
165-167
86
59
O COBt
S COBt
COBtCl
COBtO2N
COBtMeO
MeO
MeO
COBtO
HO
COBtS
SCOBt
OCOBt
COBtCOBtBtOC
6N-Acylbenzotriazole Derivatives from N-Protected Amino Acids (No Extra Functionality)-All solid, m.p.s in range of 50~180 oC.
Amino Acid
N-Protecting Group
Structure of N-Acylbenzotriazole
Yield ee.*
L-Gly Cbz Cbz-Gly-Bt 99 >97
L-Ala Boc Boc-Ala-Bt 61 >97
L-Ala Cbz Cbz-L-Ala-Bt 95 >97
L-Ala Fmoc Fmoc-L-Ala-Bt 79 >97
L-Ala Tfa Tfa-L-Ala-Bt 76 >97
D-Ala Cbz Cbz-D-Ala-Bt 90 >97
DL-Ala Cbz Cbz-DL-Ala-Bt 94 >97
L-Val Boc Boc-L-Val-Bt 83 >97
L-Val Cbz Cbz-L-Val-Bt 91 >97
* e.e. values were estimated in NMR and HPLC analysis by preparing a dipeptide for each N-aminoacylbenzotriazoles.
Amino Acid
N-Protecting Group
Structure of N-Acylbenzotriazole
Yield ee.*
L-Phe Boc Boc-L-Phe-Bt 81 >97
L-Phe Cbz Cbz-L-Phe-Bt 88 >97
L-Phe Fmoc Fmoc-L-Phe-Bt 83 >97
L-Phe Tfa Tfa-L-Phe-Bt 82 >97
L-Leu Boc Cbz-L-Leu-Bt 66 >97
L-Leu Cbz Cbz-L-Leu-Bt 95 >97
L-Ileu Cbz Cbz-L-Ileu-Bt 95 >97
L-Pro Cbz Cbz-L-Pro-Bt 74 >97
(04S2645)(04S1806)(05S397)(In Preparation)
NN-Acylbenzotriazole Derivatives-Acylbenzotriazole Derivatives from from NN-Protected -Protected Amino Acids with FunctionalityAmino Acids with Functionality
(05S397) (In Preparation)
Structure of N-Acylbenzotriazole
Functionality Yield ee.a
Cbz-L-Trp-Bt Indole NH 95 >97
Cbz-L-Tyr-Bt Phenol OH 86 >97
Cbz-L-Gln-Bt Amide NH2 72 >97
Cbz-L-Cys-Bt SH 76 >97
Cbz-L-Asn-Bt Amide NH2 72 >97
Cbz-L-Asp(OMe)-Bt CO2Me 82 >97
Cbz-L-Met-Bt CH2SMe 95 >99
Cbz-L-His-Bt Imidazole NH 70b >95c
Structure of N-Acylbenzotriazole
Functionality Yield ee.a
Fmoc-L-Trp-Bt Indole NH 90 >97
Fmoc-L-Met-Bt CH2SMe 87 >97
Fmoc-L-Ser-Bt Alcoholic OH 68 >97
Tfa-L-Asp(OMe)-Bt CO2Me 80 >97
Tfa-L-Glu(OMe)-Bt CO2Me 82 >97
Di-Bt derivatives
Structure of N-Acylbenzotriazole
Functionality Yield ee.a
Z-L-Cystine-Bt S-S dimer 90 >97
Z-L-Asp-diBt Two COBt 87 >97
Z-L-Glu-diBt Two COBt 68 >97
a: e.e. values were estimated in NMR and HPLC analysis by preparing a dipeptide for each N-aminoacylbenzotriazoles. b; Characterized as amides. c; Determined on amides in NMR
7
NN-Acylbenzotriazole Derivatives-Acylbenzotriazole Derivatives from from NN-Protected Dipeptides-Protected Dipeptides
R1
Z
O
NHNHO
HO
R2R1
Z
O
NHNHO
Bt
R2BtH, SOCl2
THF, -10oC
Entry Product Yield (%) Mp (oC) e.e.*
1 Z-L-Ala-L-Phe-Bt 90 148149 95
2 Z-L-Phe-L-Ala-Bt 85 180181 95
3 Z-L-Phe-D-Ala-Bt 90 156157 95
4 Z-L-Trp-L-Ala-Bt 78 176177 95
5 Z-L-Trp-L-Trp-Bt 76 152154 95
6 Z-L-Met-L-Ala-Bt 85 104105 95
7 Z-L-Met-D-Ala-Bt 87 135137 95
*e.e. was estimated in 1H NMR.
8
(04S2645)(04S1806)(05S397)
Virtues of AcylbenzotriazolesVirtues of Acylbenzotriazoles
Preparation: (i) RCOCl + BtH + base RCOBt
(ii) RCO2H + NEt3 + BtSO2Me [RCOOSO2Me + Bt] RCOBt
Scope Prepared from a very wide range of Acids (see previous slides)
9
Advantages: (i) Solids, highly crystalline compounds (ii) Soluble in organic solvents (iii) Non-hydroscopic, stable in air, can be weighed out, and stored indefinitely (iv) Can be used in aqueous media (v) Compatible with wide range of functionality (vi) Chirally stable for long periods (vii) Selectivity (e.g. diketones, not vinyl esters) (viii) Prepared directly from RCO2H in near quantitative yields (ix) Benzotriazole reagent easily recovered and recycled
Utility: (i) Peptide synthesis in aqueous media(ii) Peptide synthesis with diverse unprotected functionality(iii) Efficient S-acylation(iv) O-Acylation(v) Wide range of C-acylation
N-AcylationN-Acylation:Amides from N-acylbenzotriazoles
(00JOC8210)For reactions with Wang resin linked amines see 02BMCL1809
10
11Chiral Integrity of Peptide SynthesisChiral Integrity of Peptide SynthesisPreparation of N-(Boc acylamino)amides
1H NMR of Boc-Valine derivatives (02Arkivoc(viii)134)
Boc NH
O
Bt
R
Me
PhH2N
Boc NH
O
HN
R
Ph
Me
1. The NMR method 2. The chiral column methodHPLC: Performed on Beckman system gold with Chirobiotic T column, detection at 254 nm, flow rate of 1.0 mL/min, and MeOH/H2O (50:50)
L,L R.Time L,D R.Time
Cbz-L-Tyr-L-Phe-OH
10.8 Cbz-L-Tyr-D-Phe-OH
11.7
Cbz-L-Trp-L-Ala-OH
11.0 Cbz-L-Trp-D-Ala-OH
12.9
Fmoc-L-Trp-L-Ala-OH
11.1 Fmoc-L-Trp-D-Ala-OH
13.6
Cbz-L-Cys-L-Phe-OH
11.5 Cbz-L-Cys-D-Phe-OH
24.3
Cbz-L-Met-L-Ala-OH
10.9 Cbz-L-Met-D-Ala-OH
15.9
Cbz-L-Gln-L-Phe-OH
12.9 Cbz-L-Gln-D-Phe-OH
15.9
R.Time = Retention Time
(05S397)
Methods of Peptide PreparationMethods of Peptide Preparation
O
BtNH
R1
Cbz
O
OHH2N
R2Et3N O
HNNH
R1
CbzO
HO
R2+
CH3CN/H2O
r.t. 0.5 h
85~98%
O
BtNH
R1
Cbz
O
HNH2N
R2Et3N O
HNNH
R1
CbzO
HN
R2+
CH3CN/H2O
r.t. 0.5~1.0hO
HO
R3
OHO
R3
85~98%
Stepwise coupling:
O
HNNH
R1
CbzO
Bt
R2
O
OHH2N
R3
O
HNNH
R1
CbzO
HO
R2
O
HNNH
R1
CbzO
HN
R2
OHO
R3
BtH, SOCl2
0 oC
R1 = CH2Ph, R2 = Me, 85%
R1 = Me, R2 = CH2Ph, 90% 92~95%
Fragment coupling:
O
HNNHO
Bt
Cbz
Ph O
HNH2NO
HO
Et3N
O
HNNHCbzO
HN
OHN
O
HO
Ph
+CH3CN/H2O
r.t. 2.0h
86%
12
(04S2645)
Preparation of DipeptidesPreparation of DipeptidesChiral Dipeptides Yield(%) ee.a
Cbz-L-Ala-L-Phe-OH 90 >97
Cbz-L-Ala-L-Ser-OH 85 >97
Cbz-L-Ala-L-Trp-OH 97 >97
Cbz-L-Val-L-Phe-OH 98 >97
Cbz-L-Val-L-Trp-OH 96 >97
Cbz-L-Phe-L-Ala-OH 98 >97
Cbz-L-Phe-L-Val-OH 95 >97
Cbz-L-Phe-L-Phe-OH 98 >97
Cbz-L-Phe-L-Ser-OH 96 >97
Cbz-L-Tyr-L-Phe-OH 86 >97
Cbz-L-Tyr-L-Trp-OH 98 60
Cbz-L-Trp-L-Ala-OH 90 >97
Cbz-L-Trp-L-Cys-OH 86 >97
Cbz-L-Trp-L-Ser-OH 86 >97
Cbz-L-Trp-L-Trp-OH 85 >97
Cbz-L-Cys-L-Ala-OH 98 >97
13
Cbz-L-Met-L-Ala-OH 95 >97
Cbz-L-Met-D-Ala-OH 95 >97
Cbz-L-Met-L-Met-OH 95 >97
Cbz-L-Met-L-Trp-OH 82 >97
Cbz-L-Met-L-Glu-OH 60 >97
Cbz-L-Gln-L-Phe-OH 72 >97
Cbz-L-Gln-L-Gln-OH 47 >97
Cbz-L-Gln-L-Val-OH 95 >97
Fmoc-L-Trp-L-Ala-OH 70 >97
Fmoc-L-Trp-L-Ser-OH 87 >97
Fmoc-L-Met-L-Ser-OH 88 >97
Fmoc-L-Met-L-Glu-OH 93 >97
a:e.e. value was estimated by 1H NMR and HPLC analysis.
(05S397) (In Preparation)
Diastereomeric mixture of Dipeptide
Yield
Cbz-L-Tyr-DL-Phe-OH 86
Cbz-L-Trp-DL-Ala-OH 98
Cbz-L-Cys-DL-Ala-OH 71
Cbz-L-Met-DL-Ala-OH 72
Cbz-L-Gln-DL-Phe-OH 74
Fmoc-L-Trp-DL-Ala-OH 68
Preparation of Tri-, Preparation of Tri-,
Tripeptides Yield (%) ee.a
Cbz-L-Ala-L-Gly-L-Leu-OH 93 >97
Cbz-L-Ala-L-Phe-L-Trp-OH 95 >97
Cbz-L-Val-L-Gly-L-Leu-OH 85 >97
Cbz-L-Phe-L-Gly-L-Gly-OH 98 >97
Cbz-L-Phe-L-Ala-L-Ala-OH 92 >97
Cbz-L-Phe-L-Ala-L-Ser-OH 94 >97
Cbz-L-Trp-L-Ala-L-Cys-OH 86 >97
Cbz-L-Trp-L-Trp-L-Try-OH 87 33
Cbz-L-Met-L-Ala-L-Ala-OH 86 >97
Cbz-L-Met-L-Ala-L-Ser-OH 83 64
Cbz-L-Met-L-Ala-L-Trp-OH 92 60
Cbz-DL-Ala-L-Gly-L-Leu-OH 94 b
Cbz-L-Met-DL-Ala-L-Ala-OH 86 b
Tetrapeptides Yield (%) ee.*
Cbz-L-Phe-L-Ala-L-Gly-L-Leu-OH 86 >97
Cbz-L-Ala-L-Phe-L-Gly-L-Leu-OH 85 >97
a:The ee. value was estimated by 1H NMR and HPLC analysis. b; Diastereomeric mixture
14
(04S2645)(In progress)
and Tetraand Tetra-Peptides-Peptides
Synthesis of Weinreb amides and Hydroxamic acidsSynthesis of Weinreb amides and Hydroxamic acids15a
4a Ph H 76 83 4b 4-ClC6H4 H 84 78 4c 4-MeC6H4 H 85 86 4d 2-Furyl H 70 93 4e 4-Pyridyl H 71 39 4f n-C5H11 H 58 92 4g 4-MeC6H4 Me 76 100 4h n-C5H11 Me 52 93 4i 2-Furyl Me 71 100 4j 2-Thienyl Me 60 100 4k 2-Pyridyl Me 60 100 4l Ph Me 54 100
Drawbacks of Route A:(i) Lawesson’s reagent is expensive, and the large amount of reagent-derived byproducts which accompany its reactions can only be removed by chromatography. (ii) 1,1-thiocarbonyl diimidazole is unstable and decomposes after 28 days of storage at room temperature.
Drawbacks of Route B:(i) Necessity of synthesizing thiocarbamic acid thioanhydride.(ii) Instability of alkyl isothiocyanates.(iii) Use of expensive metal catalyst and lack of commercially available thiocarbamoyl chlorides with substituents other than N,N-dimethyl.
Reagents for the Preparation of AmidinesReagents for the Preparation of Amidines
• Conventional methods • Preparation of Imidoylbenzotriazoles
O
NH
N
Cl
N
EtO
H
N
TfO
H
N
N
NH
R2
R2
R1
R2
R1
+
BF4
_
R2
R1
+
OTf_
1
2
3
R2
R1R3
R4
R3 R4
R1
• Imidoyl chlorides are generally prepared in situ, but they are extremely labile toward hydrolysis and side reactions have been reported at elevated temperatures.
• Iminium triflates and imidate fluoroborates require handling under inert atmosphere and cannot be isolated or purified.
N
Bt
NH
O
R1R2
NH
O
R1R2
NOH
R1 R2
O
BtR1
NH
O
R1R2
R2
R1
Bt2SO
PPh3/BtCl
BtTs
R2NCO
BtR1
R2NC/BF3
BtHPOCl3, NEt3
95H231, 10 examples Yield: 15-75%
90CB1545, 8 examples
Yield: 38-96%
04JOC5108, 9 examples
Yield: 40-90%
01JOC2865
11 examples
Yield: 87-99%
01JOC1043
6 examples
Yield: 71-99%
99OL577, 12 examples
Yield: 20-87%
27
Imidoylbenzotriazoles are good substitutesfor imidoyl chlorides.
A Facile Preparation Method for Imidoylbenzotriazoles
Preparation of Polysubstituted AmidinesPreparation of Polysubstituted Amidines
•Reaction took place under microwave irradiation, and just needed 10 minutes to finish.
• Acetic acid acts as a solvent, catalyst, and reactant.
• 15 amidines are listed here with good to excellent yields.
• Most amidines were isolated as acetic acid salts.
• The examples obtained showed the versatility of the method.
29
ArHN
S
NHAr
R
N PPh3
BocHN
NHBoc
S
BocHN
NBoc
SMe
H2N
NHBoc
S
H2N
NR1
SMe
HgCl2 , TEA,
DMF, 60oC
N Me
Cl
I
N
NH
N NR2
R1
HN
R
N
N
Cl
O
Cl
NH2R
H2N
NR1
SO3H
R1HN
NH
SMe
R1HN
NR1
N N
R1HN
NTf
NHR1
R1N
O
NR1
2a-j
+aR1 = Alkyl
Et2O, 0oC
bR1 = Boc, Cbz
DCM, 20oC
cR1 = Boc, Cbz
THF, 20oC
dR1 = Ph, Pr
MeCN, 20oC
eR1 = Mtr, Pmc
Hg(ClO4)2 , TEA
f
g
hEDCl, TEA,
DCM, 20oC
iR1 = Ar
t-BuOH, heat
j
R = Ar, 4
R1= Ar, Alk;
R2 = H
THF, reflux
1 3 5
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
H2N
NH2+
Bt Bt
NR
Cl
TsO
6 7
• Reagents 6–7 both guanylate primary and secondary amines under mild conditions in high yields.
• Benzotriazole-1-carboxamidinium tosylate 6 afforded guanidines under mild conditions, in moderate to good yields (55-86%).
• Benzotriazolylcarboximidoyl chlorides 7 are stable, odorless, and convenient to handle. They afforded guanidines in moderate yields (68-69%).
Literature reagents
Disadvantages:• These reagents must be synthetically prepared, most of them in a multi-step sequence.• Harsh reaction conditions are required in some cases to deprotect the protecting groups• A large excess of starting amines is in need at times to reach completion of the reaction.• Low reactivity at times
Early Bt derivatives
95SC1173 01JOC2854
30Guanidylating Agents and First Bt- Literature
Second Generation Bt-Mediated Preparation of GuanidinesSecond Generation Bt-Mediated Preparation of Guanidines
Preparation of symmetrical and cyclic trisubstituted guanidines
5 examples, 79-91%
5 examples, 77-96%
R1HN
BtN
R R1HN
NN
R
R3
R2
R1HN
HNN
R
R2
R2NH2
R3NHR2
13
Toluene, reflux 12h
Toluene, reflux 1h
17a-f
18a-h
NN
N= Bt
6 examples, 67-96 %
8 examples, 71-99%
• Starting materials 11 and 13 were prepared through a novel method with good yields
Preparation of substituted unsymmetrical guanidines
32
Imidolylation at SulfurImidolylation at Sulfur
N
Bt
N
R1
R2
R3
R4
N
N
S
R1
R2
R3
R4 R5R5SHNaOMe
THF, Reflux16-18h
R1 R2 R3 R4 R5 Yield (%)
a H -(CH2)2O(CH2)2- 2,5-Cl2C6H3 4-MeC6H4 44
b H -(CH2)2O(CH2)2- 2,5-Cl2C6H3 C6H5CH2 53
c H Me Ph 2,5-Cl2C6H3 Ph 92
d H -(CH2)2O(CH2)2- 4-NO2C6H4 4-MeC6H4 44
e H -(CH2)2O(CH2)2- C6H5CH2 4-MeC6H4 46
f H -(CH2)2O(CH2)2- C6H5CH2 4-tBu-2-MeC6H3 75
g iBu -(CH2)2O(CH2)2- 3-NO2C6H4 4-Me C6H4 59
(01JOC2865)
R1 R2 R3 Yield (%)
a 4-MeC6H4 Ph iPr 90
b Me Ph iPr 77
c 4-MeC6H4 4 Ph PhCH2 91
d Me Ph PhCH2 94
N
Bt
N
SR3SHNaOMe
THF, Reflux16-18hR1
R2
R1
R2 R3
(95H231)
33
Imidoylation at Carbon (Ketones)Imidoylation at Carbon (Ketones)
N
BtN N
X
N
X
R1
R2
R1
R2
+
LDATHF, -78 oC
Overnight
12a: X=O2b: X=S
3
01JOC4041
entry R1 R2 X Yield (%)
3a Ph Ph O 85
3b Ph Ph S 79
3c Ph 4-ClC6H4 O 87
3d Ph 4-ClC6H4 S 88
3e Ph 4-BrC6H4 O 89
3f Ph 4-BrC6H4 S 98
3g 4-MeC6H4 Ph O 82
3h 4-MeC6H4 Ph S 91
3i 4-MeC6H4 4-BrC6H4 O 96
3j 4-MeC6H4 4-BrC6H4 S 89
3k Ph 4-MeOC6H4 O 84
3l Ph 4-MeOC6H4 S 85
3m 4-MeC6H4 4-MeOC6H4 O 85
3n 4-MeC6H4 4-MeOC6H4 S 84
34
1-Cyanobenzotriazole1-CyanobenzotriazoleA Safe and Convenient Source of +CNA Safe and Convenient Source of +CN
N
NMe2
NBr
N+
NMe2
N
Br-
BtHN
NN
N
NBrN-
NN
Na+
Preparation of 1-Cyanobenzotriazole1-Cyanobenzotriazole
76% 90%
1-Cyanobenzotriazole as a 1-Cyanobenzotriazole as a NN-Cyanating Reagent-Cyanating Reagent
1-Cyanobenzotriazole as a 1-Cyanobenzotriazole as a CC-Cyanating Reagent-Cyanating Reagent
Hughes et al. (98JOC401) 5 examples: 30-66 %
Bt CN2.
1. LDAAr
CN
CNAr
CN
NC Bt CN
CN
CCH CHN
nBuLi
Drechsler et al. (01JCSPT(2)581) 70% yield
Bt CN NCN
R1R+ NHR
R1 R = H
chlorobenzene
(91RRC573) 7 examples: 84-96 % yields
Whitten et al. (88S470)(91RRC573)
35
Classical Preparation of Sulfonamides:
RS
Cl
O
OR NH2 R
SNH
R
O
O
base+
Disadvanges of Using Sulfonyl Chlorides:
• Highly reactive and hygroscopic Problematic to store• Requires a base for reactions• Many are difficult to access.
Synthetic Equivalents to sulfonyl chlorides:
N N+
S
O
O
CH3
-OTfClS
O
ONH N
TfOCH3
+
Preparation of SulfonylbenzotriazolesPreparation of Sulfonylbenzotriazoles (04JOC1849)
MgBr
S Li
Li
N
Li
MgCl
R M
93
82
65
20
71
Mp(0C)
133-134
143-144
117-119
oil
131-132
of RSO2BtYield (%)
MgCl
N
N
Li
N Li
N
Li
O Li
R M Yield (%)
75
80
71
41
83
Mp(0C)
107-109
147-150
oil
132-135
128-129
of RSO2Bt
R M SO2R S
OMgBr
O
BtClR S
O
O
BtNEt3
+
Sulfonylbenzotriazoles: Preparation
O’Connell, J. F. and Rapoport, H. (92JOC4775)
36
Advantages over existing methods:
• no need for added base • reaction proceeds at ambient temperatures • Less reactive and more selective than sulfonyl chlorides• Selectively sulfonylate a 10 amine over the 20 • Selectively sulfonylate aliphatic amines over aromatic amines
S
O
O
NN N
Ph
NH2R
ArOH
SR
O
O
NH
R
SR
O
O
N R
R
SR
O
O
O Ar
NH
R R1
1
1
1
22
THF/RT
Benzotriazole-Assisted SulfonylationBenzotriazole-Assisted Sulfonylation ([94SC205] and [04JOC1849])
Generation of Sulfonamides from Sulfonylbenzotriazoles
SO
O NH
SO
O N
S SO
O N
NS
O
O
N
S
O
ON
89
72
85
Cyclohexylamine,THF/25 0C/18 h
N-Methylbenzyl-amine,
THF/25 0C/15 h
Piperidine,THF/25 0C/42 h
YieldAmine/Conditions Sulfonamide
99Piperidine,THF/25 0C/20 h
(%)
Piperidine,DMF/80 0C/48 h 99
R S
O
OBt
NH
R2R1
RS
O
ON
R1
R2
S SO
O NH
NO
N
N
S
O
O
N
N
SN
O
OH
O SO
O NH
91
64
80
Morpholine,DMF/80 0C/24 h
1, 5- dimethyl-hexylamine,
DMF/80 0C/24 h
Phenethylamine,DMF/80 0C/48 h
992-Aminopentane,DMF/80 0C/24 h
Yield (%) Amine/Conditions Sulfonamide
3 examples: 87-93% yields
4 examples: 64-99% yields
10 examples: 51-99% yields
37
38Coworkers in Benzotriazole Chemistry 1987-2005Argentina
Laura Moyano
Australia
Darren CundyScott HendersonRichard MusgraveNassem PeerzadaPaul SavageAdam WellsStuart Barrow
Austria
Isolde Puschmann
Azerbaijan
Novruz AkhmedovRena Akhmedova
Belgium
Annie MayenceChris StevensJ.-J. Vanden Eynde
Brazil
Alessandro Soares
China
Weilang BaoChunming CaiXiaohong CaiHe-Xi ChangJie ChenJun ChenKe ChenYaxing ChenDai ChengXilin CuiWeihong DuWei-Qiang FanYunfeng FangDaming FengHai Ying HeQing-Mei HongXiang HongTan Bao HuangZhizhen HuangFu Bao Ji