Goldberg Reaction: Development, Mechanistic Insights and Applications

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Mini-Reviews in Organic Chemistry, 2015, 12, 3-23 3

Goldberg Reaction: Development, Mechanistic Insights and Applications

Anns Maria Thomas, Asha Sujatha and Gopinathan Anilkumar*

School of Chemical Sciences, Mahatma Gandhi University, Priyadarsini Hills P.O. 686 560 Kottayam, Kerala, India

Abstract: Cu-catalyzed N-arylation of amides commonly known as Goldberg reaction is an important trans-formation in organic synthesis for the construction of pharmaceuticals and fine chemicals. This is the first review in this area which exclusively deals with recent developments in Goldberg reactions with special fo-cus on mechanistic aspects, catalyst development as well as on the recent applications of this reaction in drug synthesis.

Keywords: amides, arylations, C-N coupling, catalysis, copper, Goldberg reaction.

1. INTRODUCTION

Transition metal catalyzed cross-coupling reactions are important processes in organic chemistry for the synthesis of many valuable chemicals like pharmaceuticals, agrochemi-cals, fine chemicals, etc. The history of Cu catalysis begins a few years after the development of biaryl synthesis by Ullmann in 1901 [1], when he succeeded in extending the C-C coupling protocol for carbon-heteroatom condensation reac-tions which are now known as Ullmann condensation. Cu-cata-lyzed N-arylation of amides using aryl halides is generally known as Goldberg reaction named after Irma Goldberg, who was a student of Ullmann. She tried to extend Ullmann’s pro-tocol to C-N coupling reaction and in 1906, she independently reported the coupling of benzamide with bromobenzene in the presence of K2CO3 and catalytic Cu (Scheme 1) [2].

Goldberg reaction did not attract much attention initially due to the drawbacks such as elevated reaction temperature, limited substrate tolerance, high catalyst loading and low yields. In this context, Pd catalysis gained prominence and many Pd-catalyzed C-N bond forming reactions have been reported. Among them the development of Buchwald’s N-arylation of amines by Pd catalysis is another breakthrough [3]. However, the high price and toxicity of Pd forced the scientific community to search for a new alternative metal which eventually led to revisit the original Goldberg reaction. Modifications in the original reaction protocol in the last few decades triggered the development of newer variations of Goldberg reaction [4] and enabled to develop useful synthetic strategies for the production of many biologically active and industrially important compounds. Meanwhile, Buchwald also succeeded in replacing Pd-catalyst with Cu and he also reported some Goldberg reactions under mild conditions [5]. The major advances in this reaction are the use of catalytic amount of Cu salts, mild reaction temperatures, addition of various ligands, etc. The present review discusses on recent advances in Goldberg reactions with special focus on mechanistic aspects, catalyst development and applications of this reaction in drug

*Address correspondence to this author at the School of Chemical Sciences, Mahatma Gandhi University, Priyadarsini Hills P.O. 686 560 Kottayam, Kerala, India; Tel: +91 481 2731036; Fax: +91 481 2731009; E-mail: [email protected]

synthesis and covers literature from 2000-2013. At present, Goldberg reaction is carried out in a wide variety of catalytic systems and reaction conditions. The important ones are discussed below:

2. DIFFERENT CATALYTIC SYSTEMS

2.1. Cu-Nitrogen Complexes Complexes of Cu with nitrogen ligands are the most

commonly used catalytic system for Goldberg reactions. Among the various nitrogen ligands used, vicinal diamines and their derivatives are found to be the excellent ones.

2.1.1. Cu-Ethylenediamine Complexes Kang et al. used ethylenediamine as a ligand in the N-

arylation of nitrogen heterocycles and benzamides under copper catalysis [6]. Under typical reaction conditions, aryl iodides react with benzamide in the presence of 10 mol% CuI, 10 mol% ethylenediamine and K3PO4 or Cs2CO3 at 110°C under argon affording N-arylated products. Electron rich aryl iodides and 2-iodothiophene react with a number of electron deficient amides such as benzamides, pyrrolidi-nones, and oxazolidinones affording good yields of the N-arylated products (Scheme 2).

A convenient method for the N-arylation of oxazolidinones was developed by Nandakumar [7] by the reaction of 1,4-diiodobenzene with substituted oxazolidi-nones in presence of catalytic CuI, ethylenediamine and K3PO4 in dioxane at 80°C (Scheme 3).

N-arylation of amides, oxazolidinones and pyrroles were also achieved with 2-Iodoselenophene in the presence of CuI, ethylenediamine and K3PO4 in refluxing dioxane [8]. Phenyl amides gave good yields while aliphatic amides gave moderate yields of the product.

2.1.2. Cu-DMEDA Complexes Padwa and Crawford reported that CuI in presence of

N,N’-dimethylethylenediamine (DMEDA) as a ligand and K3PO4 or K2CO3 as the base could be used as an efficient catalytic system for amidations of bromo substituted furans and thiophenes [9]. This synthetic route was utilized for the synthesis of highly substituted amido heteroaromatic substrates.

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4 Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 1 Thomas et al.

OH

O

NH2

+

Br OH O

NHcat.Cu, K2CO3

3h, 210 °C,PhNO2 (56%)

Scheme 1. The classical Goldberg reaction.

HN

O

R1N

O

R1Ar

N

O

S N O

O

S NH

OO2N

N O

OMeO

NH2

NH2

Ar-I +

CuI (10%)

K3PO4/1,4-dioxane

L (10%)

24h, 110 °C

(95%) (59%) (88%)(45%)

L

Scheme 2. Cu-catalyzed N-arylation of amides using ethylenediamine as ligand.

O

HN O

R1 R2

I I

O

N O

R1 R2

O

O N

R2 R1

O

N O

R1 R2

I

A B

CuI (10%)

K3PO4/dioxane

(10%)

3-5h,80 °C

+

+

R1 = Me, R2 = Ph : A/B (43:9), 52%R1 = CH2Ph, R2 = H : A/B (61:17), 78%R1 = CHMe2, R2 = H : A/B (45:0), 45%

Ethylenediamine

Scheme 3. Cu-catalyzed N-arylation of oxazolidinones with diiodobenzene using ethylenediamine as ligand.

The catalyst system used by Buchwald for the N-arylation of N-heterocycles was extended to the N-arylation of amides as well [10]. Thus amidation of aryl halides was achieved in the presence of CuI, DMEDA or trans-N,N’-dimethyl-1,2-cyclohexanediamine and a base (K3PO4, K2CO3 or Cs2CO3) in different solvents usually at 110 °C (Scheme 4). Aryl iodides underwent amidation with both 1° and 2° amides affording the products in > 90% yield. Wide varieties of functional groups on the aryl iodide and amide components were tolerated in the reaction.

In the aryl iodide component, electron donating and electron withdrawing groups at the o-, m- and p- positions, -NH2, -OH, -CN, -OMe groups and α,β-unsaturated ketone are well tolerated. On the amide part, 1° amides, 2° amides, lactams of all sizes and cyclohexyl amide are tolerated. The reactivity was less for aryl bromides and aryl chlorides, and thus they required high temperatures for the reaction. K2CO3 was found to be the choice of base in most cases. Intramolecular amidation on haloarenes leading to an indoline skeleton was also achieved by this method.

A general and effective method for the preparation of acyclic tertiary amides was developed by Wang et al. under

aerobic conditions in the presence of CuBr2 and DMEDA ligand (Scheme 5) [11]. The tertiary amides obtained are found in numerous biologically active compounds and are also valuable intermediates in total synthesis. Various N-arylbenzamides bearing both electron withdrawing and electron donating groups are arylated smoothly to give N,N-disubstituted benzamides in moderate to excellent yields. Sterically hindered substrates gave low yields of the product. Aryl iodides are found to be the best substrates, and the authors extended this protocol to aryl bromides also.

2.1.3. Cu-cyclohexane Diamine Complexes

Buchwald et al. discovered that selective N- and C-arylation of oxindoles is possible with Cu-catalyzed coupling reactions [12]. Thus, m- and p-substituted aryl iodides underwent Cu-catalyzed exclusive N-arylation smoothly at 80-100°C using 1-5 mol% CuI, 4-10 mol% trans-N,N’-dimethylcyclohexane-1,2-diamine ligand in the presence of K2CO3 in dioxane (Scheme 6). The o-substituted aryl iodides did not give the coupling product even at elevated temperatures possibly due to their inherent difficulty to get activated. Use of 4 A° molecular sieves provided the coupling

Goldberg Reaction: Development, Mechanistic Insights and Applications Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 1 5

H2N

O

R1Ar-X

NH

O

R1Ar

NHMe

NHMe

NH2

NH2

NHMe

NHMe

O

NH

Ph

NO2 O

NH N

O

S

O

N H

Bn

O

NH

PhS N

OiPr O

NH

Ph

+

CuI (1-5%)

Base/Solvent

Ligand (10%) L1

L2

L3

(X = I, 69%)a,b

a: ligand L1 was used. b: dioxane, 110 °C, 23h.

(X = I, 95%)c,d

c: ligand L2 was used.d: DMF, 80 °C, 23h.

X = I, Br, Cl

(X = I, 97%)a,b

e: ligand L3 was used.

(X = I, 99%)a,b

(X = Br, 97%)a,b (X = Br, 94%)e,f

f: toluene, 110 °C, 24h.

(X = Cl, 93%)e,g

g: neat, 110 °C, 23h. Scheme 4. Cu-catalyzed N-arylation of amides using 1,2-diamines as ligand.

R1

O

NH+ Ar'-X R1

O

NAr'

CuBr2 10mol%

DMEDA 20mol%

Toluene,Cs2CO3130 °C

R2

R2

Scheme 5. N-arylation of amides under aerobic conditions in presence of CuBr2.

NH

O

Ar-X

R1

K2CO3

N

O

OMe

N

O

CN

+CuI (1-10%),

1,4-dioxane8-24h, 80-100 °C

(86%)(72%)b

N

O

R1

Ar

Scheme 6. C-N coupling of oxindoles using Cu catalysis.

product for substrates containing hydroxide or water sensitive functional groups.

Methyl, chloride, fluoride and -CF3 substituents on the oxindole are tolerated in the reaction. An isolated example in which a small amount of the N- and C- bis arylated product was observed when 5-bromo-m-xylene was used as the substrate. The reactivity of aryl halides follows the order ArI>ArBr>ArCl and aryl chlorides are almost unreactive.

Buchwald et al. also reported that the combination of CuI and racemic trans- 1,2- cyclohexanediamine in the presence

of K3PO4 as the base could be used as an efficient catalytic system for the N-amidation of aryl and heteroaryl iodides and bromides and the N-arylation of a number of heterocycles [13]. Buchwald and coworkers also used N,N’-dimethylethylenediamine and trans N,N’-dimethyl-1,2-cyclohexyldiamine in the N-arylation of lactams, amides, carbamates and urea (Scheme 7) [14].

The Goldberg-Buchwald protocol has been used by Li et al. for the synthesis of a number of bis aryl urea derivatives using CuI and trans N, N’-dimethylcyclohexane-1,2-diamine and K2CO3 in toluene (Scheme 8) [15].

Along the lines of Buchwald chemistry on N-arylation of amines/amides, Nandakumar achieved bis arylation of urea using CuI and 1,2-diaminocyclohexane (mixture of cis and trans) in presence of K3PO4 in DMF at 80 °C, which afforded 60% of the biphenyl urea (Scheme 9) [16]. When the protocol was extended to other aryl iodides, electron rich compounds gave good yields of the diaryl urea.

Ghosh et al. achieved N-arylation of oxazolidinones with arylbromides/iodides in excellent yields in the presence of CuI-1,2-diaminocyclohexane and K2CO3 under refluxing conditions in dioxane (Scheme 10) [17]. The authors presumed that the bidentate ligand enhances the solubility of the Cu salt and also promotes Cu (I)/(II) disproportionation thus stabilizing the Cu(I) species. The reaction was found to be less sensitive to the electronic nature of the substituent on the aryl halides.

2.1.4. Cu Chxn-Py-Al and Salox Catalysts

Taillefer et al. extended the methodology used for N-arylation of amines using Chxn-Py-Al and Salox catalysts in the N-arylation of amides (Scheme 11) [18]. N-arylation of amides and anilide derivatives were observed to be sluggish using Chxn-Py-Al or Salox and in some cases, the O-arylation product was also obtained along with the N-arylation


NH HNN

N

X

F

N

N

F

N

R2

O

R1

HN

R2

O

R1

NH HNA

B

HN

R2

O

R1

ANH

O

B

PhCONH2 A 99

X

Br

Br

CH3CONH2 I B

I

PhNHCONH2 I ABnNHCHO I A

CuI (10%)

K2CO3/toluene

L (A or B) (10%)

20h, 110 °C

+

Entry Ligand Yield (%)

188

92

X = Br, I

85

5843

2

345

_________________________________________

_________________________________________

_________________________________________ Scheme 7. Cu-catalyzed N-arylation of amides, lactams, carbamates and urea.

NHHN

O

Ar-Br NN

O

ArArNH

NH

NN

O

N N

NN

O

NN

OEtO2C CO2Et

NN

OO2N NO2

NN

ONC CN

+

CuI (10%)

K2CO3/toluene

L (20%)

24h, refluxL

(92%) (73%)

(54%) (84%)

(82%)

Scheme 8. Cu-catalyzed N-arylation of imidazolidinone using trans N,N’-dimethylcyclohexane-1,2-diamine as ligand.

I

R1

O

NH2H2N

O

NH

NH

R1 R1 NH2

NH2

O

NH

NH

O

NH

NH

O

NH

NH

CF3 CF3

+

CuI (10%)

K3PO4/DMF24h, 80 °C

L (10%)

L

(60%) (63%) (29%) Scheme 9. Cu-catalyzed N,N’-bis arylation of urea using 1,2-diaminocyclohexane as ligand.


Ar X

O

HN O

R1 R2

O

N O

R1 R2

ArNH2

NH2

O

N O

F3C

Bn

O

N O

Ph

O

N O

Ph

NC

+

CuI (10%)

K2CO3/dioxane

L (10%)

reflux L

(95%) (85%) (82%)

X = Br,I

Scheme 10. Cu-catalyzed N-arylation of oxazolidinones using 1,2-diaminocyclohexane as ligand.

IR1

R2O

HN R3

Cs2CO3, 50-82 °C

R2O

N R3

R1

PhO

HN PhN

O

Ph N

NH2O

ON

O

Ph

+Salox

Chxn.Py-AlL1

L2

a: Chxn-Py-Al was used.b: Salox was used.

Cu2O (5%)

L1 or L2 (20%)

DMF or MeCN

(82oC, 48h, 91%)a

(82oC, 40h, 92%)a(82oC, 48h, 82%)a

(82oC, 24h, 86%)b

N

N

N

N

NOH

OH

Chxn-Py-AlSalox

Scheme 11. Cu-catalyzed N-arylation of amides using Chxn-Py-Al and Salox ligands.

HN NHBoc X R1 H

NBocN R1

BocN NHBoc I R1 N

+

+

X = I, Br

a

X = I, R1 = H: 87%X = I, R1 = OMe: 81%X = Br, R1 = CO2Et: 45%

a

a: CuI/1,10-(phen) (10%),Cs2CO3, DMF, 80 °C, 5-48h.

R1 = H: 43%, (99%)b

b: Values in ( ) refer to yield when 1 equiv. of CuI/1,10-(phen) was used.

R1 = NO2: 33%, (99%)b

R1 = OMe: 93%, (99%)b

BocN R1

Boc

Scheme 12. Cu-catalyzed N-arylation of N’-arylhydrazines and bis Boc aryl hydrazines.

product. Addition of 3 A° molecular sieves prevented hydrolysis of amide and improved the yields of the products.

2.1.5. Cu-1,10-Phenanthroline Complexes

Cu-catalyzed N-arylation of N’-arylhydrazines and bis Boc aryl hydrazines were achieved with aryl halides under

Buchwald conditions using 10 mol% CuI/(phen) and Cs2CO3 in DMF at 80°C in moderate yields (Scheme 12) [19].

Buchwald and co-workers demonstrated the CuI-cata-lyzed N-arylation of N-Boc hydrazine with substituted aryl iodides in the presence of Cs2CO3 as the base and 1,10-phen-anthroline as the ligand in DMF at 80°C (Scheme 13) [20].


Almost quantitative yields were obtained in the N-arylation of bis Boc aryl hydrazines when stoichiometric amount of CuI was used. The reaction tolerated both electron donating and electron withdrawing groups on the aryl halide component. The bis Boc diaryl hydrazines were oxidized in good yields to azobenzene derivatives with stoichiometric CuI at 110°C in DMF. Combining the two reactions, a one pot synthesis of azobenzene starting from bis Boc aryl hydrazine and aryl iodide was achieved in good yield with stoichiometric CuI/(phen) in presence of Cs2CO3 in DMF at 110°C. The aryl bromides recorded slightly lower yields compared to the corresponding aryl iodides.

2.1.6. Cu-Bis(7-azaindolyl)Methane Complexes

Perez and co-workers synthesized two new dinuclear copper(I) complexes of bis(7-azaindolyl)methane ligands represented as [(Lsym)CuI]2 [Lsym = bis(7-azaindenyl)methane (symmetric)] and [(Lasym)-CuI]2 [Lasym = bis(7-azaindenyl) methane (asymmetric)] (Fig. 1). They used these complexes as precatalysts for the N-arylation of pyrrolidinones using only a 1:1 metal to ligand ratio [21].

N

N

N

N

L sym

NN

N N

L asym

Fig. (1). Structures of bis(7-azaindolyl)methane ligands.

2.2. Cu-N and O Bidentate Ligand Complexes

2.2.1. Cu-Aminoacid Complexes Aminoacids are found to be suitable ligands for C-N

coupling reaction effecting the reaction under mild conditions. Guo and coworkers reported an interesting N-arylation of amides with aryl iodides using aminoacids as ligands [22]. They utilized a catalyst system consisting of 5

mol% CuI and 20 mol% glycine in the presence of K3PO4 in dioxane at 100°C for N-arylation of amides (Scheme 14). L-arginine and β-alanine showed essentially identical results with that obtained using glycine. A plethora of amides such as aliphatic amides, anilides, lactams, hydrazides and sulfo-namides reacted with aryl iodides affording the products in good to excellent yields. However, acrylamide gave a polymeric material possibly by a 1,4-addition of the amino group of the aminoacid resulting in anomeric polymeri-zation. As expected aryl bromides and aryl chlorides affor-ded moderate and low yields of the products, respectively. On the aryl iodide component, no specific influence of electronic effect of substitution on the aryl ring was observed as electron donating, electron neutral and electron with-drawing groups at the o-and p- positions afforded very good yields of the products.

A mechanism based on a four-coordinated Cu(III) intermediate proposed earlier is suggested for the reaction [23]. A convenient method for coupling aryl bromides which are less expensive than aryl iodides was developed by Deng et al. using readily available N,N-dimethylglycine as the ligand and K3PO4 as the base [24]. Both aromatic and aliphatic amides effectively coupled with a variety of aryl bromides. Ortho substituted aryl bromides were also used in this reaction. Recently, Mitra et al. reported that Goldberg reaction could also be performed in the presence of α-aminoamide ligands for the N-arylation of primary and secondary amides using aryl bromides [25]. Even though α-aminoamide ligands are found to be not much reactive, their use as ligands expands the scope of available ligand motifs.

2.2.2.Cu- N-Methylpyrrolidine-2-Carboxylate Complexes N-Methylpyrrolidine-2-carboxylate (10 mol %) has been

used as a ligand in the CuI (5 mol %) catalyzed N-arylation of cyclic and open chain amides with aryl iodides in DMSO at 110°C (Scheme 15) [26]. The electronic properties of the aryl iodide did not affect the yield of the products.

2.2.3. Cu- 8-Hydroxyquinoline Complexes An efficient method for the N-arylation of pyridazinone

pharmacophores was reported by Pu et al. using a Cu-

R

IHN

NH2

BocR

NBoc

NH2

CuI/ 1,10- phenanthroline

Cs2CO3, DMF, 80 °C

NBoc

NH2

NBoc

NH2

NBoc

NH2N

Boc

NH2

H2NBr

(97%)(87%)

(78%) (71%) Scheme 13. Cu-catalyzed N-arylation of N’-Boc and bis Boc aryl hydrazines.


hydroxyquinoline derived catalytic system (Scheme 16) [27]. The reaction was found to be less sensitive to electronic or steric effects, and many functional groups in the aryl halides were tolerated in this reaction. They were also able to confirm the structure of the Cu-ligand complex by single crystal X-ray analysis.

2.2.4. Cu-DABDO Complexes Recently, Shang et al. reported Cu-catalyzed arylation of

poorly nucleophilic acyclic secondary amides with sterically

hindered substituted 2-halobenzoates in the presence of a new ligand, 1,4-dimethyl-3,4-dihydro-1H-benzo[e][1,4]dia-zepin-5(2H)-one (DMBDO) (Scheme 17) [28]. Various hindered tertiary amides were successfully synthesized by this method. It is also observed that -COOR group has a strong ortho-substituent effect on this coupling reaction.

2.3. Cu-Oxygen Complexes Scant reports are available in Goldberg reaction in the

presence of oxygen ligands. Lv et al. showed that the β-

HN

O

R1N

O

R1ArAr-X

O

OHNH2

N

O

O

O

N

O

O

NH

MeO

O

NH

NO2

O

N

CuI (5%)

K3PO4/1,4-dioxane

L (20%)

24h, 100 °C+

X = I,Br,ClL

(98%)

(84%)

(90%)

(98%)

(95%)

Scheme 14. Cu-catalyzed N-arylation of amides using glycine as ligand.

NH

O

R1+

R2

CuI (5mol%) L(10 mol%)

N COOCH3

K3PO4(1eqv) DMSO (1M)

(S)-N-methylpyrrolidine-2-carboxylate (L)

Ar-IN

O

R1

R2

Ar

Scheme 15. Cu-catalyzed N-arylation of amides using N-Methylpyrrolidine-2-carboxylate as ligand.

X

R1 +N

NH

O

R2 N

N

O

R2

R1

CuCl, 7-n-propyl-8-hydroxyquinoline

K2CO3,DMF, 140 °C

O

N

H3C(H2C)2

CuN

O

(CH2)2CH3

Cu-ligand complex Scheme 16. Goldberg reaction using 8-hydroxyquinoline derived catalytic system.


ketoester used for N-arylation of amines could also be used in the arylation of amides [29]. The optimum condition for this reaction was found to be 10 mol% CuBr, 20 mol% ligand and 2 equivalents of Cs2CO3 in DMSO at temperature varying from RT-80°C (Scheme 18). Amides and lactams afforded C-N coupling products with aryl iodides in good yields at 60-75°C. Some reactive aryl halides gave the coupling products at RT. Electron rich aryl halides (Br, I) required higher temperature to get good yields.

Inspired by the results obtained by Buchwald et al. [5a],

in the N-arylation of amines by using ethyleneglycol, Chen and Chen investigated the commercially available tripod ligand 1,1,1-tris(hydroxymethyl)ethane in N-arylation of amides and observed that the catalyst is suitable for C-N, C-O and C-S bond formations [30]. In the optimized reaction condition, amides reacted with aryl iodides in presence of CuI, tripod ligand and K3PO4 or Cs2CO3 in a mixture of

DMF and dioxane (1:9) at 110°C under N2 affording excellent yields of the N-arylated products (Scheme 19). No significant electronic effects were observed for p-substituted aryl iodides. Steric factors adversely affected the rate of the reaction as observed in the lower yield obtained for o-methoxyiodobenzene. In most of the cases, Cs2CO3 was found to be superior to K3PO4 as the base. Oxazolidinones were also N-arylated by this method.

Taillefer et al. reported a versatile and efficient method for the preparation of tertiary amides via Goldberg reaction using the ligand 2,2,6,6-tetramethyl-3,5-heptadione (TMHD) (Scheme 20) [31]. They found that aryl iodides substituted with electron withdrawing groups gave excellent yields while aryl iodides substituted with electron donating groups afforded moderate yields of the product on reaction with various alkyl and aryl iodides.

R1

O

NR2

H+

X

R3 NR2

OR1

R3

K2CO3(3 equiv)CuI(10 mol%)DMBDO(20 mol%)

xylene, 130 °C

N

N

Me

MeO

DMBDO

R1=R2=aryl,alkylR3=ester, X=Br,I

Scheme 17. Synthesis of tertiary amides using DMBDO as the ligand.

Ar-X

O O

OEt

O

NHR1

R2

O

NR1

R2

Ar

N

OBr

N

OOMe

N

NH

O

Ph

CuBr (10%)

RT-80 °C

L (20%)

X = I, Br

+

L

Cs2CO3/DMSO

(RT, 22h, 85%) (75oC, 25h, 85%) (60oC, 24h, 83%) Scheme 18. Cu-catalyzed N-arylation of amides using ethyl 2-oxocyclohexanecarboxylate as ligand.

HN

O

N

O

ArAr-IOH

OHOH

N

OMeO

N

O

OMe

N

O

O

CuI (10%)L (10%),Cs2CO3

24h, 110 °C

+

L

DMF:dioxane (1:9)

(96%) (91%) (92%) Scheme 19. Cu-catalyzed N-arylation of amides using tripod ligand.


3. REACTIONS UNDER MICROWAVE IRRADIATION

Microwave assisted reactions gained attention of researchers since the end of the last century because of short reaction time, milder reaction conditions and enhanced selectivity. Lange et al. in 2002 reported an unprecedented microwave enhanced Goldberg reaction for the N-arylation of piperazinediones, piperazinones and 3,4-dihydroquino-linones (Scheme 21) [32]. They found that the reaction rate is tremendously accelerated on microwave irradiation saving energy and time.

4. LIGAND FREE REACTIONS

Reactions under ligand free conditions are not only favourable from economic point of view, but also they provide unusual selectivity which is not observed in the presence of ligand. Tao and coworkers discovered CuI-catalyzed ligand-less cross-coupling of aryl iodides with nucleophiles like lactams, amides and azoles in the presence of K3PO4 in DMF in good yields [33]. For example, caprolactam on reaction with aryl iodide in the presence of 5 mol% CuI, 3 mol% K3PO4 in DMF at 110°C afforded

quantitative amount (GC yield) of the product. The reaction tolerated a number of N-nucleophiles such as anilides, aliphatic amides, pyrroles, indole, imidazole and benzimi-dazole. A number of substituted aryl iodides were also tolerated in the reaction. Aryl bromides did not respond to the reaction with lactams; however, they gave good yields of the N-arylated products with indole and benzimidazole. The authors presumed that the K3PO4 used in the reaction not only acts as a base but also chelate with the copper catalyst facilitating oxidative addition, an assumption based on a litera-ture precedent on a similar phosphonic acid derivative [34].

A ligand free N-arylation of N nucleophiles including amides in the presence of Cu catalyst was developed by Correa et al. and they found that Cu2O salt was the best Cu source for this reaction [35]. Another convenient eco-friendly strategy for N-arylation with aryl iodides using water as the solvent and Tetra propyl ammonium bromide (TPAB) as the phase transfer catalyst under ligand free conditions was developed by Teo et al. (Scheme 22) [36]. Lactam like pyrrolidinone was found to be excellent substrate for this reaction and the authors also succeeded in coupling aromatic amides giving moderate yields of the product.

R1

N

O

R2

H+

I

R3

N

O

R2R1

t-Bu

O

t-Bu

OCuI 5%

K3PO4,Toluene130 °C,24h

10%

R3 Scheme 20. CuI-TMHD catalyzed Goldberg reaction.

Ar-I + R

O

NH R

O

N

Ar

CuI,K2CO3,2 eq NMP

microwave irradiation

N O

(77%)

N N

O

O

(51%)

N N

O

OCH3

(66%)

N N

O

(75%)

Scheme 21. Microwave assisted N-arylation of amides.

+

Cu2O (10mol%)K3PO4 (2 equiv)

TPAB (10mol%)H2O,130 °C,24h

R1

O

NH

R2

R1

O

N

R2

I

R3

R3

Scheme 22. Ligand free arylation of amides using Cu2O.


Recently, copper thiophenecarboxylate (CuTC) has been developed for Goldberg reactions under ligand-less and mild reaction conditions without the use of any additives (Scheme 23) [37]. This methodology has been used successfully for the N-arylation of various aliphatic and aromatic amides in the presence of CuTC catalyst and t-BuONa as the base in DMSO. Additionally, this protocol was found to be suitable for the synthesis of some unique secondary amides such as N-arylacrylamides, 4-amido-N-phenylbenzamides, and 4-amino(N-phenyl)antipyrenes which are difficult to obtain by classical methods.

5. MECHANISM

Although many proposals for the mechanism of Cu-catalyzed arylation of nucleophiles are available, there has not been much experimental support. Based on different Goldberg reactions reported, it was found that Cu salts in various oxidation states can be used for the reaction and in the reaction pathway they may get converted into the same active catalytic species [38]. It is observed that, in the first step a Cu(I)amidate complex is formed which subsequently undergoes reaction with aryl halide. Different mechanisms involving both radical and ionic intermediates are proposed for this step. 1) Oxidative addition/reductive elimination of aryl halide

on copper (I). 2) ∏-complexation of aryl halide on copper (I). 3) Lewis type complexation of aryl halide on copper (I).

4) Aryl radical mechanism.

Kinetic studies on the copper-catalyzed amidation of aryl iodides conducted by Buchwald et al. draw insight in to the role of chelating diamines in the Goldberg reaction [39]. Calorimetric experiments on the reaction between 3,5-dimethyliodobenzene 1 and 2-pyrrolidinone 2 in the presence of N,N’-dimethyl-1,2-cyclohexanediamine L revealed a non-linear relationship between [L] and the rate of the reaction (Scheme 24).

A mechanism is proposed based on the observation in which the intermediate copper(I)amidate (B) is formed either via amide coordination to A followed by deprotonation or through diamine association and subsequent amide disso-ciation from C (Scheme 25). Intermediate B upon formation reacts with aryl iodide affording the N-arylated amide.

The authors suggest that the resting state of the catalyst is the multiply amide-ligated species C. Increasing concen-tration of the diamine L drive the reaction back to inter-mediate B which is in equilibrium with A. Experimental proof for the intermediacy of B was obtained when Cu(I) amidate 4 was synthesized by mixing pyrrolidinone with mesityl copper (Scheme 26). The 1H NMR of 4 in solution showed broadened peak indicating that 4 exists as a multiple oligomer which is consistent with the nature of most of copper (I) complexes. Sharp peaks were observed for 4 when diamine L was added indicating its existence as a single species. When aryl iodide was added to this species the N-arylated amide was formed.

The key points from this study are 1) At low concen-tration of diamine, the catalyst resides as a multiply ligated species, which results from multiple coordination of the amide and is less active towards ArI and, therefore, requires generation of an active Cu(I) intermediate that has been demonstrated to be both chemically and kinetically com-petent for the N-arylation. At high concentration of the dia-mine activation of the aryl iodide becomes the rate limiting step.

Osako and coworkers studied the mechanism of copper(I) complex mediated C-X bond activation on p-substituted benzyl halides in presence of (2-pyridyl)alkylamine ligands [40]. Kinetic studies showed that the reaction obeys a second order kinetics both on copper complex and on the substrate. Based on this, the authors proposed a dinuclear copper (III)-halide organometallic intermediate for the reaction.

Zhang et al. conducted a theoretical study on the mechanism of Cu(I)-catalyzed aryl amidation based on DFT augmented by CPCM salvation model [41]. They suggested four different modes of oxidative addition for the arbitrary

Ar-I + R

O

NH2 R

O

NH

Ar

CuTC,t-BuONa,DMSO

100 °C,6h,N2

HN

O

79%

Ph NH

O

HN

O

Ph

69%O

NN

NH

83% Scheme 23. Ligand free arylation using CuTC.

I

O

N

O

HN+

N,N-dimethyl-1,2-cyclohexanediamine(10%)

K3PO4/toluene, 90 °C

CuI (5%)

1 2 3 Scheme 24. Cu-catalyzed N-arylation of 2-pyrrolidinone using trans N,N’-dimethyl-1,2-cyclohexanediamine ligand. Reprinted with permis-sion from Blackmond, D.G.; Buchwald, S.L. J.Am. Chem. Soc., 2005, 127, 4120.


NNR1

O

R2Cu

R2

OR1

R1O

NH, BR2

R1

N

O

R2Cu

N

N

CuN

NX

R1O

NH, BR2

IR3

NR2

OR1

R3

C

A

B

k2

k-2

k1 k-1

kactMajor species at lowdiamine conc.

Major species at highdiamine conc.

Ar-Xactivation

Multiple ligationof amide

Scheme 25. Mechanism proposed by Buchwald for the Cu-catalyzed N-arylation of amides. Reprinted with permission from Streiter, E.R.; Blackmond, D.G.; Buchwald, S.L. J. Am. Chem. Soc., 2005, 127, 4120.

I

O

NCu

O

NNHMe

NHMe

1

4 3

1) L, toluene

2)

0 °C L

Scheme 26. Formation of N-aryl pyrrolidinone from copper (I) amidate. Reprinted with permission from Streiter, E.R.; Blackmond, D.G.; Buchwald, S.L. J. Am. Chem. Soc., 2005, 127, 4120.

reaction between acetamide and bromobenzene in the presence of catalytic Cu(I) and ethylenediamine as shown in (Fig. 2).

Among the four modes, the first and fourth start with bis coordinated Cu(I) while the 2nd and 3rd start with tricoordinated Cu(I). The tricoordinated Cu species are sterically more crowded and thus may not be favored in the oxidative addition. The calculated free energies for the conversion show that the transformation A B and A D are energetically unfavorable and that from A C is slightly favourable in free energy. The relative concentration of different copper complexes from theoretical calculations shows that C is the major copper species in the reaction mixture.

By calculating the free energy barriers for all the four species A-D, it is observed that the overall free energy barrier decreases in the order D>A>C>B suggesting that the dicoordinated Cu (B) is energetically the most favorable for the oxidative addition (Fig. 3). Since the overall free energy barrier does not reflect the observed reactivity, the relative reactivity was calculated using the equation:

Relative reactivity = Relative conc x Exp (-overall barrier)/RT ------(1)

It was found that the calculated relative reactivity decreases in the order C>A>B>D.

At low concentration of diamine, the complexes A, B and C cannot be formed since they all need the diamine ligand. Therefore, complex D should be the only copper species present at low ligand concentration. But no oxidative addition takes place at low ligand concentration since the reactivity of D is very low. This explains the zero arylation reactivity at zero ligand concentration observed experi-mentally by Buchwald. Thus, complex C is the most reactive and abundant species in the oxidative addition step in which the aryl halide is added.

To achieve reductive elimination, the pentacoordinated Cu(III) species C has to undergo a pseudorotation so that the phenyl and amidyl groups align cis to each other. From theo-retical calculations the authors found that only two Cu(III) intermediates can be formed through this pseudorotation viz. the trigonal bipyramidal and the square pyramidal. From the free energy barriers of these two structures and their corres-ponding transition states in reductive elimination, the authors


NH2

Cu

H2N

NH2

Cu

H2N Br

PhNH2

Cu

H2N Br

Ph

NH2

Cu

H2N

BrNH2

Cu

H2N

Br

Ph

Br

NH2

Cu

H2N

BrPh

Br

NH2

Cu

H2N

NHAcNH2

Cu

H2N

Br

Ph

NHAc

NH2

Cu

H2N

NHAcPh

Br

AcHNCu

AcHN Br

PhAcHN

CuAcHN Br

PhAcHN

CuAcHN

B

A

C

D

++

++

++

++

Fig. (2). Possible oxidative additions to different copper complexes as proposed by Zhang et al. Reprinted with permission from Zhang. S.L,; Liu, L.; Fu, Y.; Guo, Q.X. Organometallics, 2007, 26, 4546.

NH2

Cu

H2N

Br

A

NH2

Cu

H2N

B

NH2

Cu

H2N

NHAc

C

AcHNCu

AcHN

D

2.7 x 10-2 2.6 x 10-23 1 2.6 x 10-10

Fig. (3). Calculated relative free energies of different copper species as reported by Zhang et al. Reprinted with permission from Zhang, S.L.; Liu, L.; Fu, Y.; Guo, Q.X. Organometallics, 2007, 26, 4546.

conclude that the favored geometry for reductive elimi-nation is the square pyramidal conformation. The free energy barrier between the oxidative addition transition state and the immediate product of transition state is calculated to be +6.1 kcal/mol, which clearly indicates that the rate limiting step in Cu-catalyzed aryl amidation reaction is the oxidative addition of aryl halide to Cu(I)amidate.

The reductive elimination step has a negative reduction free energy due to the formation of a new C-N bond (Fig. 4). The immediate product of the reductive elimination is a 2η Cu(I) complex with N-phenyl acetamide. Dissociation of this 2η Cu(I) complex leads to CuBr ligated by the diamine (complex A) and free N-phenyl acetamide, thus ending a full catalytic cycle. Complex A can interact with acetamide to initiate a new catalytic cycle. In conclusion the Cu(I)amidate is the reactive intermediate in this reaction mechanism and its oxidative addition to phenyl halide is the rate limiting step.

The reactivities of different diamine ligands calculated by the authors are shown in (Table 1).

It is clear that the stability of the Cu(I)amidate is very much affected by the diamine ligand. N,N’-dimethyldiamine furnishes the most stable Cu(I)amidate whereas the tetra-methyldiamine produces the most unstable Cu(I)amidate. These observations are explained by the electronic and steric effects of the methyl groups. Due to the electron donating inductive effect of methyl groups, the methyl group substitu-tion favors the formation of Cu(I)amidate. On the other hand, excessive methyl substitution will give rise to a very crowded copper complex which is energetically unfavour-able. These theoretical calculations indicate that trans N,N’-dimethylcyclohexane-1,2-diamine is an excellent ligand for Cu-catalyzed aryl amidation and fully support the Cu(I) amidate pathway suggested by Buchwald.

Buchwald et al. investigated the C-and N-arylation of oxindole by Pd and Cu based catalysts [10]. The copper-


Cu BrNHAc

Ph

NN

Cu BrNHAc

Ph

NN

CuNHAc

PhBrNN

CuPh

Br

NHAcNN

Cu PhBr

NHAcNN

Cu BrNN

Cu NHAcNN

Cu NHAcNN

_____________

_____________

__________________________

_____________

_____________

__________________________Cu(I) amidate

2! complex

oxidativeaddition TS

pseudorotation

reductiveelimination TS

Cu(I) amidate Fig. (4). General mechanism for Cu-catalyzed aryl amidation proposed by Zhang et al. Reprinted with permission from Zhang, S.L.; Liu, L.; Fu, Y.; Guo, Q.X. Organometallics, 2007, 26, 4546.

Table 1. Relative reactivities of different diamine ligands calculated by Zhang et al. Reprinted with permission from (Organometal-lics 2007, 26, 4546, S-L. Zhang, L. Liu, Y. Fu, Q-X Guo, copyright 2007, American Chemical Society).

S. No. Diamine Overall Free Energy Barrier (kcal/mol) Relative Reactivity

1 H2N NH2 26.6 1.0

2 NH HN 25.0 8.8

3 N N

34.8 1.1 x 10-5

4

H2N NH2

27.7 0.22

5

NH HN

24.0 36

catalyzed N-arylation of oxindole with aryl iodides pro-ceeded in the presence of 1-5 mol% catalyst, 4-10 mol% trans N,N’-dimethylcyclohexane-1,2-diamine (CyDMEDA) as the ligand and K2CO3 as base in dioxane at 80-100°C. The Cu-catalyzed arylation of oxindole regioselectively produced the N-arylated product exclusively while the Pd-catalyzed reaction gave the C-arylated product.

Although the mechanism of the Cu-catalyzed N-arylation of oxindole is not fully understood, available data from cal-culated geometries and free energies of CyDMEDA-Cu-oxindole complex and on the basis of the general transition metal catalyzed reaction pathways, the following mechanism is invoked (Scheme 27).

Theoretical calculations showed that both Pd and Cu based catalysts have strong preference towards the formation of the N-bound amidate as against a C-bound enolate. For Pd catalyst system the energy difference between the Pd-amidate and Pd-enolate was calculated to be ~5kcal/mol; but

the selectivity is decided by the rapid C-C reductive elimina-tion compared to the C-N reductive elimination. But in the case of Cu-catalyzed reaction the preference for Cu to bind at the N was calculated as ~14kcal/mol which clearly ex-plains the exclusive N-arylation when Cu catalysts are used.

Mansour and coworkers investigated the activation of aryl halides by Cu0/1,10-(phen) [42]. The cyclic voltammet-ric experiments conducted on Cu1(CH3CN)4

+PF3- in acetoni-

trile containing n-Bu4NBF4 revealed that in cross coupling reaction between aryl halides and nucleophiles using Cu0 precursor, the Cu0 will be transformed in situ into a Cu(I) species by its reaction with aryl halide at the beginning of the catalytic reaction. Cu0/1,10-(phen) in acetonitrile pro-duces Cu1(phen)(CH3CN)2

+ which is assumed to be the cata-lyst for cross coupling reaction.

Tye et al. investigated in detail on the mechanism of amidation/imidation of aryl iodides [43]. To understand the relationship between ligand structure and its reactivity,


Hartwig synthesized and characterized the Copper(I)amidate and imidate complexes of chelating N,N-donor ligands, which are proposed intermediates in copper-catalyzed ami-dation of aryl halides. A number of copper amidate and imi-date complexes ligated by phenanthroline, bipyridine, dia-mine and diphosphine ligands were prepared by reaction of the amide/imide with CuOtBu and ligand (L) as shown in (Scheme 28).

In some cases, the complexes adopt neutral three coordi-nate trigonal planar structures in the solid state while in other cases they adopt an ionic form consisting of L2Cu+ cations and CuX2

- anions. In solution all the complexes exist pre-dominantly in the ionic form in DMSO and DMF. One com-plex which was soluble enough to measure conductivity in less polar solvent showed some degree of ionic nature in THF and predominantly in neutral form in benzene. The copper complexes were then allowed to react with aryl io-dide yielding the N-aryl amidate and imidate as shown in (Scheme 28). But the ammonium salt of [Cu(Phth)2]- did not form the C-N coupled product.

The relative reactivities of the two iodoarenes (o- and p- iodotoluenes) were studied by reacting an equimolar mixture of the iodotoluenes with (i) CuI, K3PO4 and DMSO at 80°C (ii) [(phen)2Cu][Cu(pyrr)2], DMSO at 80°C giving a 58:42 and 84:16 ratio of the products respectively. All the results are indicative of the fact that the complexes [LCu(Phth)] or [LCu(pyrr)] are intermediates in the Cu-catalyzed reaction of imides and amides with haloarenes (Scheme 29). As per Hartwig the possible mechanistic pathway for the C-N bond formation involves coordination of the aryl halide to the copper amidate/imidate followed by oxidative addition to form Cu(III) intermediate.

According to Tye et al. this oxidative addition occurs in several ways, by direct expulsion of the halide to generate a four-coordinated cationic species, by inner sphere electron transfer followed by rupture of the resulting intermediate to form a neutral five-coordinate Cu(III) species or by con-certed insertion of Cu into the C-X bond (Scheme 30). Buchwald recently suggested two possible mechanisms for the Cu-catalyzed N-arylation of amides (Scheme 31) [44]. In

X

L2Cu(I)

Nu-H

L2Cu(I)

Nu

X

R1

Nu

R1

L2Cu(I)XNu-H

Base

Base-HX

Ar-X activation

Scheme 27. Mechanism of Cu-catalyzed nucleophilic substitution of aryl halides proposed by Buchwald et al.

[CuOtBu]4 + L + Phth-H

[CuOtBu]4 + L + Pyrr-H

1/2[L2Cu][Cu(Phth)2] [LCu(Phth)]

where L = 1,10(phen), 4,4'-di-tert-butylbipyridine, dmeda and Xantphos

and Phth-H = Phthalimide.

1/2[L2Cu][Cu(Pyrr)2] [LCu(Pyrr)]

where L = 1,10(phen), and dmeda and Pyrr-H = 2-pyrrolidinone. Scheme 28. Synthesis of copper imidate and amidate complexes.

I N

O

O

I N

O

+

1/2[(phen)2Cu][Cu(Phth)2]

[(phen)Cu(Phth)]

DMSO

120 °C

+

1/2[(phen)2Cu][Cu(Pyrr)2]

[(phen)Cu(Pyrr)]

DMSO

85 °C

t1/2 = 35 min.

t1/2 = 19 min. Scheme 29. Reaction between copper imidate and amidate complexes with aryl iodide.


N

CuN

N

N

N Cu NR

RR

RCu N

R

RN

NCu

N

R

R

N

N

X

Cu

N

R

R

N

N

X

CuN

R

RN

N

X Ar

Cu XN

NAr N

R

R

ArX

N

O

O

N

ON

N

+

1/2

!

Cu(0)/Cu(II)

products

NR2 = = bidentate ligand

Scheme 30. Reaction pathway suggested by Tye et al. for the Cu-catalyzed C-N bond formation between amides/imides and aryl halides.

NCuII

N N

O

Me H

Me H I

NCuI

NN

OMe H

Me H

IR1

R1

NCuI

N N

O

Me H

Me H I

R1

NCuIII

N N

O

MeH

Me H

I

R1

N

O

R1

+

_.

Radical anion Cu(II)complex !2 complex

______________________________

Slow stepSlow step

Fast stepFast

oxidative addn.

Fastreductive

elimination

Scheme 31. Reaction mechanism suggested by Buchwald et al. for the Cu-catalyzed C-N bond formation between amides and aryl halides. Reprinted with permission from Streiter, E.R.; Bhayana, B.; Buchwald, S.L. J. Am. Chem. Soc., 2009, 131, 78.


I

O

N

O

O O

[(phen)2Cu][Cu(pyrr)2]

+DMSO

110 °C31h

+

(95.5%) (1.9%) Scheme 32. Reaction between Cu-pyrrolidinone complex and o-(allyloxy)iodobenzene. Reprinted with permission from Tye, J.W.; Weng, Z.; Johns, A.M.; Incarvito, C.D.; Hartwig, J.F. J. Am. Chem. Soc., 2008, 130, 9971.

F

F

F NH

O

N

Br

NH2+

F

F

F N

O NH2N

F

F

F N

NN

NH2

NHR NHRCuI(Me2NCH2)2

Scheme 33. Synthesis of potent peptidase IV inhibitor.

the first route the aryl iodide coordinates with the Cu(I)amidate followed by a SET from Cu(I) to the aryl io-dide producing a transient Cu(II) species along with an inti-mate radical anion. While electron donating groups on the p-position of aryl iodides facilitate the aryl iodide coordination to Cu(I) amidate, the SET process is facilitated by electron withdrawing groups on the p-position. From the radical an-ion-Cu(II) complex, fast product formation occurs through halide atom transfer to Cu(II) intermediate.

The second pathway suggested originally by Zhang et al. [41] involves the formation of a η2 complex between Cu(I)amidate and the aryl iodide. The η2 complex then un-dergoes a fast oxidative addition in which Cu(I) changes to Cu(III) which is followed by a reductive elimination process leading to the product.

Recently Ding’s group further confirmed the interme-diacy of Cu(I)amidate complex by synthesising and charac-terising the Cu(I)amidate complex [45]. They used ancillary ligand bis(diphenylphosphino)ferrocene (dppf) to stabilize the complex due to their strong chelating ability and weak intermolecular interactions. These complexes were then used as substrates in high temperature Goldberg reactions giving good yields of the product.

Among other alternative mechanisms suggested for Cu-catalyzed Goldberg reaction, one suggests that the reaction resembles classical nucleophilic aromatic substitution by

electronic activation of the aryl group by Cu(I) via a Cu-∏ interaction [46].

In the literature both radical and ionic mechanisms are proposed for the Cu-catalyzed C-N bond formation 31, 47].

The proposed radical mechanism is initiated by electron transfer from copper to the aryl halide forming a haloarene radical anion, which then eliminates the halide to form a neutral aryl radical which subsequently combines with the amidate. In order to find out whether the coupling reaction is going via radical pathway, Hartwig et al. conducted reac-tions on an aryl halide linked to an olefin that serves as a radical clock [33]. It is known that aryl radical generated from o-(allyloxy)iodobenzene undergoes cyclization to yield 2,3-dihydrobenzofuranylmethyl radical, which can either abstract an H from the solvent or can dimerise or combine with the amidate/imidate to form the C-N bond [48].

When [(phen)2Cu][Cu(pyrr)2] was treated with o-(allyloxy)iodobenzene in DMSO-d6, only the C-N coupling product (95.5%) and hydrodehalogenated product (1.9%) were formed, unambiguously disproving the radical pathway in C-N coupling reaction (Scheme 32).

6. APPLICATIONS

Carbon-nitrogen bond forming reactions using transition metal catalysis are indispensible tools in organic chemistry for the synthesis of important structural motifs that has con-


siderable synthetic importance. The Goldberg reaction has been known for more than a century, however its applica-tions are limited due to harsh reaction conditions it needed. But the modifications achieved in the reaction conditions in recent years made it suitable for various synthetic applica-tions. Nowadays Goldberg reaction is frequently used for the synthesis of many important pharmaceuticals and fine chemicals.

N-arylation of amides using aryl bromide in presence of CuI (10 mol %) and DMEDA (100 mol %) has been utilized in the asymmetric synthesis of a potent peptidase IV inhibitor and is found suitable for large scale preparation (Scheme 33) [49].

Sequential Pd-catalyzed Suzuki-Miyaura coupling and CuI/DMEDA (10:20 mol%) catalyzed N-arylation of amides has been utilized in the total synthesis of Canthin-6-one alkaloids (Scheme 34) [50]. This non-classical strategy produced Canthin-6-one and its nine analogues including the naturally occurring 9-methoxy-canthin-6-one and amarori-dine in high yields.

Cl B(OH)2

N

HNO

Br+

N

N

O

R R

then CuIDMEDA, reflux

one pot Pd(dppf)Cl2.CH2Cl2,K2CO3,dioxane/H2Oreflux

R=HCanthin-6-one

Scheme 34. Total synthesis of Canthin-6-one using Goldberg reaction.

Intramolecular Goldberg reaction has been applied in the synthesis of benzimidazo[1,2-a]quinoxalin-6-(5H)-ones by Meng et al. using CuI/N,N-dimethylglycine in DMF at 150°C (Scheme 35) [51]. These structural subunits show potent anticancer, antiviral and antimicrobial properties.

Diketopiperazine derivatives are important pharma-cophores showing promising biological activities which are helpful in treating human diseases [52]. Lim et al. developed an interesting method for the preparation of N-arylated piperazines via Goldberg reaction from easily assembled dipeptides or functionalized Schollkopf reagents using CuI and CsOAc in DMSO solvent (Scheme 36) [53].

Medium ring heterocycles of ring size 7-10 were prepared by a tandem Cu-catalyzed coupling of β-lactams with aryl bromide/iodide followed by intramolecular ring expansion with a pendant amino group [54]. Thus 2-azetidinone and 2-bromobenzylamine on reaction with 5 mol% CuI, 2 equivalents of K2CO3 in toluene at 110 °C afforded the eight-membered amide in quantitative yield (Scheme 37). In the case of halo benzylamines, no ligand was required for the C-N coupling. This is presumably due to binding of the Cu (I) precatalyst with the amino group of the benzylamine and thus activating the aryl halide towards oxidative addition. The addition of a diamine ligand such as N,N’-dimethylethylenediamine was found to be beneficiary in many cases, especially for N-substituted benzylamines. The reaction tolerates electron donating groups and aliphatic -OH group on the aryl halide, and phenyl as well as isopropyl groups on the β-lactam part.

In the case of 9- and 10- membered ring formation, undesired indoline or tetrahydroquinoline side products

N

N

Br

O

NH

R2

R1

N

N

N

O

R2

R1

CuI,N,N- dimethylglycine

K3PO4, DMF, 150 °C

Scheme 35. Synthesis of benzimidazo[1,2-a]quinoxalin-6-(5H)-ones by Goldberg reaction.

NR'

NH

O

HN

Br

Br

CuI,CsOAc

DMSO

NH

N

Br

N O

O

OOMe

NH

HNO

O

X

CuI,CsOAc

DMSONH

NO

O

Scheme 36. Synthesis of diketopiperazine derivatives by intramolecular Goldberg reaction.


XHN

O

R3 N

O

R1 R1

HN

N O

R2

R1

R3

Cu

NH2

Br NH

NH O

I

NH2

NH

HN

O

NH2

Br NH

HN

O

HN

O

HN

O

HN

O

R3

NHR2

+

NHR2

catalysisRing

expansion

Entry Aryl halide Lactam Product Yielda

1

2

3

96

92

68b

a: reaction condition: CuI (5%),K2CO3, toluene, 24h,110 oC.b: indoline side product was formed in 18%.

_________________________________________________________

_________________________________________________________(%)

_________________________________________________________

_________________________________________________________

Scheme 37. Cu-catalyzed medium ring formation via tandem C-N coupling-ring expansion.

NH2

NH2

O

HN O

THPO

BrF

N

O

F

N

O

O

N O

THPO

F

N

O

O

N O

H3COCHN

O

HN O

THPO

O

N O

OTHP

Br

O

N O

OH

+

CuI (5%)

K2CO3/dioxane

L (10%)

15h,110 °C

L

(85%)

Linezolid

+

CuI (5%)

K2CO3/dioxane

L (10%)

15h,110°C (50%)

(80%)

PPTS, EtOH

refluxToloxatone

Scheme 38. Synthesis of the oxazolidinone antibiotics Linezolid and Toloxatone.


O

NH

O

Ph

Br

NH

O

O

N

O

Ph NH

O

O

NH

NNHO

+

CuI (10%)

K2CO3/dioxane

H2N-(CH2)2NH2(10%)

reflux

(97%)CJ-15161

Scheme 39. Synthesis of the κ-opioid receptor agonist CJ-15161 using Cu-catalyzed N-arylation of oxazolidinones.

N

NO

O

O

H

R1

+

I

R2

N

NO

O

O

R1

R2CuI, Cs2CO3, DMF

MW,180 °C,40 min

R1=H,Me Scheme 40. N3-Arylation of DHPMs by Cu(I) catalysis.

I

NH2

NH

O+ N O

NH2

Cu2O 5%,Chxn-Py-Al 10%

Cs2CO3 2eqv,MS 3A°MeCN, 82 °C,48 h

Amphenidone1.5 eqv.

Scheme 41. Synthesis of the sedative Amphenidone via Goldberg coupling.

respectively competed with the medium ring formation. The N,N’-dimethylethylenediamine ligand increased the yield of the undesired indoline side product in the case of 9-membered ring formation while decreased the amount of undesired tetrahydroquinoline side product in 10-membered ring formation.

Oxazolidinone antibiotics show potent activity against a variety of Gram-positive bacterial pathogens including methicillin resistant Staphylococus aureas (MRSA) and vancomycin resistant Enterococci (VRE) [55]. The Buchwald amidation protocol of aryl halides was applied on oxazolidinones for use in the synthesis of the oxazolidinone antibiotics Linezolid and anti depressant toloxatone (Scheme 38) [56].

Li et al. also used the same strategy in the preparation of Linezolid [57].

Cu-catalyzed N-arylation of oxazolidinones developed by Ghosh et al. has been used for the synthesis of the κ-opioid receptor agonist CJ-15161 (Scheme 39) [14].

Dihydropyrimidones (DHPMs) are important groups of drug like scaffolds [58], Wannberg et al. introduced a new tool for the rapid generation of N3-arylated DHPM derivatives via Goldberg reaction which cannot be obtained

by classical Biginelli condensation strategies (Scheme 40) [59]. They also found that electron poor aryl iodides are better substrate than electron rich aryl iodides.

Taillefer et al. used Goldberg reaction for the synthesis of a sedative Amphenidone from pyridin-2-one and 3-iodoaniline using mild reaction conditions (Scheme 41) [15].

7. CONCLUSION N-arylation of amides via Goldberg reaction is

extensively used in recent times for the synthesis of many important scaffolds in organic chemistry. Even though the Goldberg reaction was reported in 1906 it did not gain much attention due to harsh reaction conditions. But in the last decades many modifications in the reaction conditions have come out. Now scientists have succeeded in doing the reaction under mild conditions in presence of suitable ligands which attracted large attention and widened the applications. Goldberg reaction can be used as a reliable synthetic tool in many natural product syntheses. The most widely used catalytic system for this reaction is the one involving Cu-Nitrogen complexes. It is interesting to note that no Cu-Phosphorus catalytic system, which is common in transition metal catalyzed reactions like Suzuki and Heck, is reported yet for Goldberg reaction. Requirement of high


temperature, high catalyst-loading etc, are some of the challenging problems in this area. Many mechanisms are proposed for this reaction, but sufficient experimental proof is still lacking. Better understanding of the mechanism will be crucial in opening new windows for this reaction. Further efforts to reveal the mechanism and to extent the scope of the reaction are still going on.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

The authors are thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi for the award of research fellowships (AMT and AS) and Kerala State Council for Science, Technology and Environment (KSCSTE), Trivandrum (Order No. 341/2013/KSCSTE dated 15.3.2013) for a research grant (GA).

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Received: December 13, 2013 Revised: June 01, 2014 Accepted: June 02, 2014

Goldberg Reaction: Development, Mechanistic Insights and Applications

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