Abstract
Chan–Lam coupling is one of the most popular and easy methods to perform arylation of amines (N-arylations). This cross-coupling is generally performed by reacting aryl boronate derivatives with a variety of substrates involving nitrogen containing functional groups such as amines, amides, ureas, hydrazine, carbamates. This article summarizes the synthetic applications of this reaction and the efforts of scientists to develop novel and efficient methodologies for this reaction.
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Introduction
Compounds with carbon-heteroatom bonds find tremendous importance in organic synthesis and pharmaceutical chemistry. Specially, C–N-containing compounds have great contribution toward synthesis of dyes, agrochemicals and drugs [1]. Until now, several methods have been discovered and applied to generate carbon-heteroatom bonds; however, each method has its own merits and demerits. In 1998, Chan, Evans and Lam independently worked on C–N bond construction [2]. This classical protocol involved the use of aryl boronic acids with amines under mild reaction conditions and offers many advantages over the others such as inexpensive catalyst, normal temperature, good functional group tolerance, use of air and variety of substrates including amines, amides, ureas, hydrazine, carbamates and different heterocycles (imidazole, pyrazole, indole) which are used for the arylation [3].
In the last decade, a lot of effort has been made by the researchers on Chan–Lam coupling and still efforts are ongoing to develop new methodologies as well as its applications such as use of cellulose-supported catalyst [4]. Chan–Lam coupling has found application in the synthesis of N-arylated pyridine-2(1H)-one analogues which paved the path toward formation of an anti-epileptic drug, named Perampanel [5] (Fig. 1).
Structure of Perampanel 1
Structurally modified nucleosides such as inosine (2) and guanosine (3) (responsible for having antiviral and anticancer activities) can also be accessed by N-arylation of purine nucleosides using Chan–Lam coupling [6] (Fig. 2).
Structure of inosine (2) and guanosine (3)
Another important application of Chan–Lam coupling involves its use for functionalization of the surface of silica gel [7] and formation of porous aromatic framework [8]. The obtained material can be modified for further applications and use. Similarly, Chan–Lam coupling can also be used to prepare polymer coated microelectrode array by adding amino acid to it [9] which can be helpful in electrochemical signaling.
Review of the literature
Amine and ether formation via Chan–Lam coupling
The reaction involving the formation of C–N and C–O bonds is of significant importance in organic and medicinal chemistry. This importance is largely due to the occurrence of amine and ether linkages in many molecules of biological importance. Chan–Lam coupling reactions have appeared as an important synthetic tool for the development of such bonds.
Coumarin moiety is the one of the important structure having great contribution in pharmaceutical industry. Keeping in view its biological importance, Medda et al. [10] reported the first Cu-catalyzed coupling of hydroxycoumarins with aryl boronic acid by applying Chan–Lam coupling. The reaction of 3-hydroxycoumarin was performed with aryl boronic acid having electron-donating groups such as –OMe, –Me, t-Bu and electron-withdrawing groups –F, –Br, –Cl. It was observed that electron-donating groups showed higher yield (56–86%) as compared to electron-withdrawing groups (63–73%). The reaction of 3-hydroxycoumarin 4 with 4-methoxyphenyl boronic acid 5 and 4-flourophenyl boronic acid 6 afforded 86% and 73% yield of product 7 and 8, respectively (Scheme 1).
Synthesis of O-arylated 3-hydroxycoumarin 7–8
Reactions of 4-hydroxycoumarin 9 were performed with phenyl boronic acid 10 and 4-chlorophenyl boronic acid 11 to afford 70% and 66% yield of the corresponding products 12–13, respectively (Scheme 2).
Arylation of 4-hydroxy coumarin 9
Similarly, reaction of 7-hydroxy-4-methylcoumarin with different aryl boronic acid gave good yields (54–82%). Reaction of 7-hydroxy-4-methylcoumarin 14 with 4-methoxyphenyl boronic acid 5 resulted in 82% yield of corresponding product 15 (Scheme 3).
Synthesis of ether 15 from 7-hydroxy-4-methylcoumarin 14
O-Arylation of (hydroxyamino)ethylcoumarin resulted in 55–75% yield on reacting with different boronic acid. (Phenoxyimino)ethyl-7-methoxycoumarin 17 was obtained in 75% yield when phenyl boronic acid 10 was allowed to react with (hydroxyamino)ethylcoumarin 16 (Scheme 4).
Synthesis of (phenoxyimino)ethyl-7-methoxycoumarin 17
Sueki and Kuninobu [11] reported the synthesis of alkylated amine and alkyl aryl ethers via Chan–Lam coupling reaction. For example, reaction of benzyl boronic acid pinacol ester 18 with N-methyl-substituted amine 19 and tyrosine derivative 20 resulted in alkylated amine 21 (> 99%) and alkyl aryl ether 22 (91%) (Scheme 5).
Synthesis of alkylated amine 21 and alkyl aryl ether 22 through Chan–Lam coupling
Formation of mono/polychlorinated diphenyl ethers was reported by Cermak and Cirkva [12] using Chan–Lam coupling. Monochlorinated biphenyl ethers were obtained in 86–90% yield, and polychlorinated biphenyl ethers were obtained in 8–84% yield. Chlorinated phenol 23 reacted with phenyl boronic acid 10 to give the chlorinated diaryl ether 24 with 90% yield (Scheme 6).
Synthesis of chlorinated ether 24
El Khatib and Molander [13] discovered the protocol for synthesis of alkyl aryl ethers through Chan–Lam coupling of β-hydroxy-α-amino acid derivatives. In their approach, protected l-serine and l-threonine derivatives 26–27 were allowed to react with aryl boronic acids/trifluoroborates, and corresponding products 28 and 29 were obtained in good-to-excellent yields (14–94%) and (70–84%), respectively (Scheme 7)
O-Arylation of l-serine and l-threonine derivatives 26–27
However, in case of l-serine derivatives, study of substitution pattern revealed that electron-donating groups gave higher yield. For example, protected l-serine derivative 30 was allowed to react with t-butyl-substituted potassium triflouroborate 31 and 3,5-trifluoromethyl-substituted trifluorobortate 32. Results showed that t-butyl-substituted potassium triflouroborate 31 gave higher yield (94%) of the corresponding product 33 (Scheme 8).
Synthesis of O-arylated l-serine derivative 33–34
Under same reaction conditions, O-arylation of l-threonine derivatives was performed. Maximum yield (84%) of the product 36 was obtained as single diastereomer when protected l-threonine derivative 35 was treated with t-butyl-substituted potassium trifluoroborate (Scheme 9).
Synthesis of O-arylated l-threonine derivative 36
The methodology was further applied to the synthesis of O-arylated dipeptide. In this case, dipetide 37 was allowed to react with potassium phenyl triflouroborate 38 and product 39 was formed (22%), showing that the arylation occurred selectively at the l-serine moiety (Scheme 10).
Synthesis of O-arylated dipeptide 39 by Chan–Lam coupling
Same methodology was applied to synthesize tyrosine O-arylated tyrosine 42, by the reaction of (4-isopropyl phenyl)trifluoro borate 40 with Boc-L-Try-OMe 41 and product 42 was obtained in 42% yield (Scheme 11).
Synthesis of O-arylated tyrosine 42
They also investigated the formation of side product and concluded that in absence of amino acid, organoboron reagents with electron-donating group resulted in ether 44 (25%) of corresponding boron reagents. It was postulated that this transformation occurred due to copper promoted oxidation of ArBF3K (Scheme 12).
Formation of ether 44 as side product
A new process for the preparation of dicyclopropylamine hydrochloride by using Chan–Lam coupling was developed by Mudryk et al. [14]. The key step involved the reaction of sulfonamide 45 with cyclopropyl boronic acid 46 to synthesize dicyclopropyl sulfonamide 48 which was subjected to different reactions continuously to give final product dicyclopropylamine hydrochloride 49 (Scheme 13).
Synthesis of dicyclopropylamine hydrochloride 49 by using Chan–Lam coupling
McGarry et al. [15] applied Chan–Lam coupling strategy on boronate esters and aniline. Studies showed that benzylamine moiety enhanced the reactivity of boronate ester. Effect of electron-deficient and electron-rich substituents on both reactants was studied and good functional group tolerance was observed, whereas the major side product was formed via homocoupling of aryl boronate ester. Maximum yield (98%) of corresponding product 52 was obtained when simple aniline 50 was treated with boronate ester having benzylamine moiety 51 (Scheme 14).
N-arylation of aniline 50 using Chan–Lam coupling
Effect of substituents on aryl ring of boronate ester showed that electron-donating groups resulted in higher yield as compared to electron-withdrawing groups. Aniline 50 was allowed to react with methyl-substituted boronate ester 53 and bromine-substituted boronate ester 54. Results proved that methyl-substituted boronate ester gave higher yield (59%) of the product 55 (Scheme 15).
Effect of substituents on N-arylation of aniline 50
Similarly, 2,4,6-methyl aniline 57 was reacted with boronate ester 51 to yield the corresponding product 58 (66%) (Scheme 16).
Synthesis of N-arylated product 58 by using substituted aniline
Chan–Lam coupling has also found application in the synthesis of trifluoroethyl aryl/heteroaryl ethers via copper mediated coupling of trifluoro ethanol and aryl/heteroaryl boronic acids as reported by Wang et al. [16]. For example, 2,2,2-trifluoroethanol 59 was allowed to react with substituted aryl boronic acid 60 and substituted heteroaryl boronic acid 61 to provide trifluoroethyl aryl ether 62 in 79% yield and trifluoro heteroaryl ether 63 in 80% yield (Scheme 17).
Synthesis of trifolouro aryl ether 62 and trifolouro heteroaryl ether 63
Synthesis of biologically important biaryl ethers via Chan–Lam coupling was described by Marcum et al. [17]. Etherification was achieved by the reaction of benzylic amine boronate esters 51 with substituted phenols 64 to afford the biaryl ethers 65 (53–77%) (Scheme 18).
Synthesis of biaryl ethers 65 by using substituted phenol 64
Further, the effect of various electron-donating groups (–Me, –OMe) and electron-withdrawing groups (–F, –COOEt) on benzylic amine boronate ester was examined, and the best results were achieved in case of electron-withdrawing substituents (Scheme 19).
Formation of biaryl ether 68 by using substituted benzylic boronate amine ester 66
Under same reaction conditions, multi-substituted biaryl ethers were also synthesized in moderate yields (42–55%) (Fig. 3).
General structure of multi-substituted biaryl ethers 69
In order to evaluate the reactivity of phenols and anilines, a competition reaction was carried out with parent boronate ester using two sets of reaction conditions. For aniline 50, Cu(OAc)2 was used in the absence of base while for phenol 67, Cu(CO2CF3)2 was used with KF as base. However, phenols showed higher selectivity to synthesize the desired product (Scheme 20).
Competition experiment between phenol and aniline
Considering the importance of glycobiology, Dimakos et al. [18] applied Chan–Lam coupling for O-arylation of carbohydrates and satisfactory results were obtained. The synthesis afforded the target compounds in 38–77% yield. The highest yield 77% was recorded when α-d-glactopyranoside 71 reacted with phenyl boronic acid 10 (Scheme 21).
Synthesis of sugar-derived aryl ether 72
Further, to evaluate the substrate scope of aryl boronic acids, methyl α-L-rhamnopyranoside 73 was chosen as model substrate. Both electron-withdrawing and electron-donating groups on boronic acid showed good results (35–76%), but the best result was obtained when methyl α-L-rhamnopyranoside was allowed to react with 4-methoxyphenyl boronic acid 5 and 76% yield of product 74 was obtained (Scheme 22).
Synthesis of sugar-derived aryl ether 74
Synthesis of amides and their derivatives
Until 2013, few alkyl Chan–Lam coupling reactions were reported and most of them were limited to the use of methyl or cyclopropyl boronates. Rossi et al. [19] carried out the copper-catalyzed reaction to synthesize secondary amides using alkyl boronic acids, and products were obtained in moderate-to-high yields (40–91%). The best result was obtained when primary amide 75 was allowed to react with isobutyl boronic acid 76 to afford secondary amide 77 in 91% yield (Scheme 23).
Synthesis of secondary amide 77 via copper-catalyzed reaction
Srivastava et al. [20] reported the very first synthesis of copper-catalyzed formanilides. A number of aryl boronic acids having electronically diverse substitution pattern was subjected to Chan–Lam coupling under the optimized reaction conditions. Results revealed that aryl boronic acids having electron-donating groups resulted in higher yields. p-Methoxyphenyl boronic acid 5 was allowed to react with formamide 78, and corresponding formanilide 80 was obtained in 94% yield. In case of electron-withdrawing substituted phenyl boronic acids, boronic acid having aldehyde group 79 gave the best yield (Scheme 24).
Synthesis of formanilide 80 and 81
N-Arylation of unprotected sulfonimidamides in presence of anhydrous Cu(OAc)2 was achieved by Battula et al. [21]. Previously, this reaction was performed in the presence of palladium catalyst. Reaction of 4-(phenylsulfonimidoyl)morpholine was conducted with different substituted heteroaryl systems and alkyl boronic acids, resulting in good yield of products. Maximum yield was reported for 4-SO2Me phenyl boronic acid 83 when it was treated with 4-(phenyl sulfonimidoyl morpholine) 82, and N-arylated product 84 was obtained in 85% yield (Scheme 25).
N-arylation of unprotected sulfonimidamides 84
Similarly, piperidine-based sulfonimidamide 85 underwent N-arylation with phenyl boronic acid 10 under same reaction conditions and resulted in 85% yield of desired product 86 (Scheme 26).
Synthesis of N-arylated sulfonimidamides 86 by using Chan–Lam coupling
Nandi et al. [22] described another route for N-arylation of N-protected and N′-deprotected sulfonimidamides. It was observed that both electron-withdrawing and electron-donating groups on aryl boronic acid gave good-to-excellent yields. Substituted sulfonamide 87 reacted with substituted boronic acids 88 and corresponding products 89 were obtained (Scheme 27).
Synthesis of N-arylated sulfonamides 89
Under same reaction conditions, fused aryl boronic acids were treated with sulfonamides, and products were obtained in excellent yields. Reaction of fused aryl boronic acid 91 with sulfonamide gave 81% yield while methyl-substituted sulfonamide 90 was treated with fused boronic acid 91 and corresponding product 92 was obtained in 84% yield (Scheme 28).
Synthesis of N-arylated sulfonamide 92
Furthermore, morpholine moiety of sulfonamides was replaced by pyrrolidine 93 and treated with substituted aryl boronic acid 88 to give corresponding product in good-to-excellent yield (87–94%) (Scheme 29).
Synthesis of N-arylated sulfonamides 94
Reaction of 2-thienylboronic acid with sulfonamide resulted the product 95 in 38% yield. It was observed that addition of Et3N resulted in complex reaction. Therefore, only Cu(OAc)2 was used to carry out these reactions, and longer reaction time (13 h) for completion was required (Fig. 4).
Structure of N-arylated sulfonamide 95
Their research group also worked on N-arylation of protected sulfonimidamides by applying the same methodology to afford the products in good-to-excellent yields (82–93%) (Scheme 30).
Synthesis of N-arylated protected sulfonamides 97
The reaction between protected sulfonamide 98 and benzofused boronic acid 91 gave rise to the product 99 in 82% yield (Scheme 31).
Synthesis of N-arylated protected sulfonamide 99
Green synthesis of medicinally important N-arylated sulfonamides was presented by Nasrollahzadeh et al. [23]. It was observed that this methodology has wide scope of substrate when a variety of aryl boronic acids with electron-donating (Me, OMe) and electron-withdrawing (CF3) substituents was used. Same methodology was applicable for heteroaryl boronic acid as well (65–89%). The best results were observed when sulfonamide 100 was reacted with phenyl boronic acid 10 and heteroaryl boronic acid 101, corresponding products 102 and 103 were obtained in 95% and 89% yield (Scheme 32).
Synthesis of N-arylated sulfonamide 102 and 103
N-Arylation of benzamides was performed by Alapati et al. [24]. The N-arylation of different benzamides was done with substituted aryl boronic acid and 80–91% yield of desired compounds was obtained. The best result was obtained when 4-nitrobenzamide 104 was treated with phenyl boronic acid 10 and 91% yield was obtained (Scheme 33).
Formation of N-arylated amides 105
Scope of substrates was also evaluated by treating benzamide with different substituted boronic acids. Maximum yield of 89% was obtained when benzamide 106 was treated with 4-nitrophenyl boronic acid 107 (Scheme 34).
Formation of N-arylated amides 108 by using substituted boronic acid
Sahoo et al. [25] described C–N coupling between boronic acid and various amides and 54–93% yield of products was obtained. The best result was obtained when N-(4-bromo-3-methylphenyl)picolinamide 109 was treated with phenyl boronic acid 10 and furnished the required product in 93% yield (Scheme 35).
Synthesis of N-arylated amide 110 through Chan–Lam coupling
Similarly, heterocyclic-substituted amide also underwent this reaction and 70% yield was obtained when N-(2-(1H-indol-3-yl)ethyl)picolinamide 112 was treated with 4-bromophenyl boronic acid 111 (Scheme 36).
Synthesis of N-arylated amide 113
Xu et al. [26] extended the scope of Chan–Lam coupling by applying it on phosphonic/phosphinic amides. The phosphonamides having electron-donating and electron-withdrawing groups demonstrated good results. Maximum yield of 88% of product 116 was obtained when phosphonamide having unsaturated carbon–carbon triple bond containing substituent 114 was treated with p-Tol-B(OH)2115 (Scheme 37).
Synthesis of N-arylated phosphonamide 116
Afterward, scope of substituents on aryl boronic acid was investigated. Encouraging results were obtained showing good yield of products. The best results were seen in case of 4-methoxy phenyl boronic acid 5 when it was treated with P,P-diphenyl phosphinamide 117 and 83% yield of N-arylated P,P-diphenyl phosphinamide 118 was obtained (Scheme 38).
Formation of N-arylated P,P-diphenyl phosphinamide 118
A controlled experiment was conducted in which P,P-phosphinamide 117 was treated with potassium trifluoro p-totyl borate 119 to afford the arylated product 118 in 82% yield. Further, arylation attempts to form diarylated product were tried. It was observed that at 80 °C and 100 °C, no traceable product was formed; however, at 120 °C, diarylated product 120 could be accessed in only 32% yield (Scheme 39).
Controlled experiment to form diarylated product 120
Formation of pyridine and purine derivatives
Chen et al. [27] developed the methodology for O-arylation of C-6-substituted pyridine-2-ones by using a number of arylboronic acids. A study of different groups as C-6 substituents showed that electron-withdrawing groups gave higher yield. For example, phenyl boronic acid 10 was allowed to react with 6-(3-(trifluoromethyl)phenyl)pyridin-2(1H)-one 121 in the presence of Cu(OTf)2, DABCO, Et3N, and K2HPO4 to attain the product 122 in 81% yield (Scheme 40).
Formation of 2-phenoxy-6-(3-(trifluoromethyl)phenyl)pyridin 122
Similarly, effect of different substituents on phenyl boronic acid was investigated. It was observed that electron-donating groups on phenyl boronic acid facilitated the coupling reaction. For example, 6-methyl-pyridine-2-one 123 was allowed to react with 3-methoxyphenyl boronic acid 124 under same reaction conditions and corresponding product 125 was obtained in 56% yield (Scheme 41).
Synthesis of O-arylated pyridine-2-ones 125 using substituted phenyl boronic acid
It was also postulated that steric hindrance of DABCO catalyst system and C-6 substituents contributed to regioselectivity.
Considering the importance of antitumor agents, a novel route to synthesize these biologically important compounds was designed by Chen et al. [28] through applying a consecutive Chan–Lam coupling and Suzuki coupling. The target compounds were synthesized in two subseries. In first subseries, N-arylation was performed by treating 6-bromopyridine-2(H)-one 126 with 3,4,5 trimethoxyphenyl boronic acid 127, resulting product 128 was subjected to Suzuki coupling to synthesize the final product (Scheme 42).
Synthesis of 1,6-diaryl pyridine-2(1H)-one analogs 128 by using Chan–Lam coupling
For second subseries, Suzuki coupling was applied on 6-bromopyridine-2(H)-one 126 and resulting product 129 was subjected to Chan–Lam coupling to get target compounds 130 (Scheme 43).
Synthesis of 1,6-diaryl pyridine-2(1H)-one analogs 130 by using Chan–Lam coupling
Anti-proliferative activity of both the subseries of pyridine-2(1H)-one was investigated for human ovarian carcinoma cell line (SKOV-3) and human hepatoma cell line (HepG2). First subseries showed more potent anti-proliferative activity. Compounds 131 and 132 (Fig. 5) were found equally effective for both cell lines with IC50 < 0.01 µM/mL. In vivo antitumor activity of these compounds was also investigated against H22 cell line and moderate activities were observed.
Structure of anti-proliferative compounds
Chen et al. [29] described the synthesis of N-(3,4,5-trimethoxyphenyl)pyridine-2(1H)-one derivatives via consecutive Chan–Lam and Buchwald–Hartwig couplings. 6-Bromopyridine-2(1H)-one 126 was allowed to react with (3,4,5-trimethoxyphenyl)boronic acid 127 and product 128 was obtained (77%), which was further subjected to a Buchwald–Hartwig coupling. Two subseries of compounds were prepared by coupling of 128 with substituted anilines 133 and benzyl amines 134, respectively (Scheme 44).
Synthesis of N-(3,4,5-trimethoxyphenyl)pyridine-2(1H)-one derivatives 135–136 by using Chan–Lam and Buchwald–Hartwig coupling
Antitumor activity of all the synthesized compounds was tested against human colon carcinoma HCT-116. All compounds of the first subseries showed moderate cytotoxic activity. The most potent compounds 137 and 138 of this series showed activity IC50 = 0.96 and 0.40 µg/mL, respectively. However, the second subseries did not show good anti-proliferative activity except a single compound 139 which showed activity 7.53 µg/mL (Fig. 6).
Structure of antitumor compounds 137, 138, and 139
Activity of conformation restricted compound 140 was compared to a flexible compound 141. Results showed that rigidity of conformation contributed positively to the antitumor activity (Fig. 7).
Structure of compounds 140 and 141 showing effect of conformation
Morellato et al. [30] performed a Chan–Lam coupling to synthesize the series of 9-hetero aryl purine derivatives. For example, 6-chloropurine 142 was treated with 3-bromo boronic acid 143 and hetero aryl boronic acid 144, products 145 (90%) and 146 (69%) were obtained. The products were treated with ammonia in the presence of methanol to yield target compounds (Scheme 45).
Synthesis of aryl purine using Chan–Lam coupling
Chen et al. [31] reported the synthesis of N-arylpyridin-2-amines using the Chan–Lam coupling. A variety of phenyl boronic acids with electron-donating (–Me, –OMe) and electron-withdrawing groups (–F, –Cl, –CF3) were used, and good results were obtained. For example, 2-amino pyridine 147 was treated with substituted boronic acid 148 and resulted in product 150 (88%). Similarly, pyridine-3-boronic acid 149 reacted with 2-aminopyridine 147, and product 151 (52%) was obtained at 40 °C (Scheme 46).
Synthesis of N-arylpyridine-2-amines 150 and 151
Formation of arylated thiocyanates
Organic thiocyanates are used as intermediates for the formation of different sulfur-containing compounds such as thioethers, thiocarbamates, disulfides, and heterocycles. It is also observed that aryl thiocyanates are biologically active compounds. Sun et al. [32] reported the first construction scheme for aryl thiocyanates by direct C–S bond formation. The effect of different substitution patterns was observed which reflected the suitability of this protocol for electron-donating and moderate electron-withdrawing groups. However, strong electron-withdrawing groups resulted in lesser yield. This protocol was also applicable to fused aryl boronic acids. The best results were obtained when KSCN 152 was treated with substituted phenyl boronic acid 153 and naphthyl boronic acid 154, desired products 155 (91%) and 156 (80%) were obtained (Scheme 47).
Synthesis of aryl thiocyanates 155 and 156 using Chan–Lam coupling
Arylation of thiophene
Rizwan et al. [33] studied the N-arylation of methyl 2-aminothiophene-3-carboxylate through Chan–Lam coupling. It was observed that longer reaction time (24 h) led to formation of diaryl products. To overcome this problem, reaction concentration was decreased to 0.03 M. The reaction yields were not significantly influenced by the electronic nature of different substituents on boron substrates. Aryl boronic acids having electron-withdrawing groups such as fluoro, cyano, formyl, and acetyl groups resulted in formation of desired compounds. The best results were obtained in case of acetyl group where methyl 2-aminothiophene-3-carboxylate 157 was allowed to react with 4-acetylphenyl boronic acid 158 which resulted in formation of corresponding arylated product 160 in 73% yield. Same reaction was carried out at gram-scale level and 69% yield of desired product was obtained. Different electron-donationg groups were also tried such as 4-isopropyl, 4-tert-butyl, 4-ethyl phenyl boronic acid and 2,4-dimethyl phenyl boronic acid. The best result was obtained when the reaction was done by 4-tert-butyl phenyl boronic acid 159, and N-arylated 2-aminothiophene-3-carboxylate 161 (80%) was obtained (Scheme 48).
Synthesis of N-arylated thiophene 160 and 161
Some modifications were made in reaction conditions by replacing DCM with toluene having few drops of water and conducting the reaction at 60 °C in air made possible the coupling of 2-aminothiophene-3-carboxylate with potassium aryltrifluoroborate. Electron-donating groups on potassium trifluoroborates resulted in good yield (such as 3-methyl, 2-methyl, 4-t-butyl, 4-ethoxy, 3-methoxy). Similarly, electron-withdrawing groups substituted potassium triflouro borates were well tolerated such as 4-chloro potassium triflouroborate 162. However, excellent yield was observed when 3-methoxy-5-trifluoromethyl trifluoroborate 163 was allowed to react with 2-amino-3-thiophene-caroxylate 157 giving product 165 (81%) (Scheme 49).
Synthesis of N-arylated 2-aminothiophene-3-carboxylate 164 and 165
Furthermore, it was observed that the position of substituent strongly effected the yield. For example, good yield of 166 (50%) was obtained which was derived from 3-methyl-substituted potassium trifluoro borate and it was higher as compared to the derivative of 2-methyl-substituted potassium triflouro borate 167 (35%). Same effect was also observed in case of 4-chloro- and 3-chloro-substituted derivatives (Fig. 8).
Structure of compounds 166 and 167 showing effect of position of substituent
Arylation of thiols
C–S bond formation through Chan–Lam coupling was demonstrated by Pulakhandam et al. [34]. The methodology involved the reaction of 1,4-dihydroquinazoline with different aryl/heteroaryl boronic acid and good-to-excellent yield was obtained (72–90%). The best result was obtained when 1,4-dihydroquinazoline-2-thiol 168 reacted with (5-formylthiophen-2-yl)boronic acid 169 to give corresponding product 170 in 92% yield (Scheme 50).
Construction of C–S bond in 170 through Chan–Lam coupling
Preparation of indoles/oxindoles
Until 2014, different methods were being used to prepare the 1,2-disubstituted indoles and most of the methods involved the use of toxic and expensive catalysts. Gao et al. [35] reported the first one-pot method for the formation of 1,2-disubstituted indoles using Chan–Lam coupling. The synthesis was done by using 2-alkenylanilines and boronic acids.
The synthesis of 1,2-disubstituted indoles was carried out by treating 2-phenylethynyl-aniline with a number of aryl/alkyl boronic acid. The best results were seen when 2-(phenylethynyl)-aniline 171 was treated with 4-methylphenyl boronic acid 115 and cyclopropyl boronic acid 46 and corresponding products 172 (91%) and 173 (55%) were formed (Scheme 51).
Synthesis of 1, 2 disubstituted indoles 172 and 173
Scope of this reaction for substituted 2-alkenylanilines was also investigated. Results showed that electron-donating as well as electron-withdrawing groups are well tolerated. However, strong electron-withdrawing groups, such as cyano, led to lower yields. The best results were obtained when methyl-substituted alkenylaniline 174 was treated with 4-methylphenyl boronic acid 115, and corresponding product 175 was obtained in 90% yield (Scheme 52).
Synthesis of 1, 2 disubstituted indoles 175 by using substituted alkenylaniline 174
Effect of various substituents on ethynyl chain of 2-alkenylaniline was also investigated, and results indicated that reaction was equally feasible for the reactants with substituted aryl and alkyl groups and moderate-to-good yields were obtained (48–85%). The best results were obtained for aryl-substituted 2-alkenylanilines 176 when it was treated with phenyl boronic acid 10, and 1,2 disubstituted indole 177 was synthesized in 85% yield (Scheme 53).
Synthesis of indoles 177 by using substituents on alkenyl chain
The synthesized compounds were further allowed to undergo the Pd-catalyzed intramolecular arylation to produce the polycyclic indole derivatives.
Chan–Lam coupling was successfully applied on 3-(hydroxyimino)indoline-2-ones to perform N-vinylation by Chen et al. [36]. Substituted vinyl boronic acid and substituted 3-(hydroxyimino)indolin-2-one were reacted to form products in (5–98%) yield. Best results were obtained when (Z)-3-(hydroxyimino)indolin-2-one 178 was allowed to react with boronic acid 179 and resulted in 98% product 180 (Scheme 54).
Synthesis of nitrone 180
The double N-vinylated product was formed by using 2 equivalents of Cu(OAc)2, keeping the other conditions same. (E)-Hex-1-en-1-ylboronic acid 182 was treated with (Z)-7-fluoro-3-(hydroxyimino)indolin-2-one 181, which resulted in 90% yield of double vinylated product 183 (Scheme 55). The resulting compound underwent thermal reaction to form final product spirooxindole.
Synthesis of divinylated indole 183
3-Aryloxy-2-oxindoles are considered pharmaceutically important compounds due to their diverse biological properties. Li et al. [37] described the copper(II) catalyzed formation of 3-aryloxy-2-oxindole. A number of aryl boronic acids were allowed to react with 3-hydroxy-2-oxindoles, but the best yield was observed when 3-hydroxy-2-oxindole 184 was reacted with 3-methylphenyl boronic acid 185 and resulted in 95% yield of desired product 186 (Scheme 56).
Synthesis of O-arylated oxindole 186
In case of substituted 3-hydroxy 2-oxindoles, the best results were obtained when chloro-substituted 3-hydroxy-2-oxindol 187 was reacted with phenyl boronic acid 10 to form the desired product 188 in 91% yield. This reaction was also performed at gram-scale level to check its applicability, and 95% of product was obtained (Scheme 57).
Synthesis of O-arylated substituted oxindole 188
Arylation of benzimidazole and 3-amino pyrazole
One-pot N1,N2-diarylation of 3-amino pyrazole was described by Beyer et al. [38]. The first N-arylation was performed under Ullman conditions and 46–94% yield of resulted compounds, as mixture of regioisomers, was obtained. Monoarylated pyrazole 189 was selected to perform second N-arylation under Chan–Lam conditions. The products were obtained in up to 88% yield, and the results proved the efficiency for electron-rich and electron-neutral substrates, while electron-withdrawing groups resulted in less yield due to lack of reactivity such as para-nitro boronic acid where no product formation (0%) was observed except para-iodo boronic acid. Maximum yield of 88% was obtained in case of 4-methylphenyl boronic acid 115 when it was treated with 189 (Scheme 58).
N-Arylation of substituted pyrazole 189
Rasheed et al. [39] described the preparation of benzimidazole-fused heterocycles by applying Chan–Lam coupling followed by Ullmann-*type reaction. The synthesis involved the one-pot reaction of 2-iodoarylboronic acid and 2-aminoheteroarenes. During the reaction, intermolecular C–N bond formation was done by Chan–Lam coupling and intra molecular cyclization was done by Ullmann type reaction. 2-Aminopyridine 147 was allowed to react with different substituted phenyl boronic acid having electron-donating as well as electron-withdrawing groups and corresponding products were obtained in good yields (75–91%). The best results were obtained when 2-aminopyridine 147 was allowed to react with (2-iodo-5-methoxyphenyl)boronic acid 191 and benzo[d][1,3]dioxo 1-5-yl boronic acid 192 and corresponding products 193 (91%) and 194 (76%) were obtained (Scheme 59).
Synthesis of benzimidazole-fused heterocycles 193 and 194
This methodology was also applied on substituted 2-aminopyridine derivatives (75–89%) and benzimidazo [1,2-a]pyrazine. Maximum yields were obtained when (2-iodo-5-methoxyphenyl)boronic acid 191 was treated with methyl-substituted amino pyridine 195 and 2-amino pyrazine 196 (Scheme 60).
Synthesis of benzimidazole-fused heterocycle 197 and 198
It was also observed that steric hindrance did not play any role, and different products were formed in good yield. For example, 6-methyl-substituted 2-amino pyridine 199 was allowed to react with dimethoxy-substituted phenyl boronic acid 200, and this highly substituted compound furnished the product 201 in 80% yield (Scheme 61).
Synthesis of benzimidazole based heterocycle 201
This methodology also proved helpful for synthesis of fused heterocylces 202–203 (Fig. 9).
Structures of heterocyclic compounds 202 and 203 prepared by Chan–Lam coupling
N-(Hetero)aryl-substituted 2-imidazolines are widely applied as an important motif in medicinal chemistry. Different inhibitors and anti-tubercular agents are based on this important moiety. Previously reported methods involved the use of palladium and copper catalyst at higher temperature (100–150 °C). Darin and Krasavin [40] successfully disclosed the application of Chan–Lam coupling for N-arylation of 2-imidazolines with little modification which was made by replacing pyridine (base) with K2CO3. This research group created a library of N-arylated-2-imidazolines which fall in range of good yields. Maximum yield of 86% of 205 was reported for phenyl boronic acid 10 and heteroaryl-substituted 2-imidazoline 204 (Scheme 62).
Formation of 2-(furan-2-yl)-1-phenyl-4,5-dihydro-1H-imidazole 205
Moreover, the reaction with electron-donating substituent 4-methoxyphenyl 2-imidazoline 206 with 4-chlorophenyl boronic acid 11 resulted in desired product 207 in 84% yield (Scheme 63).
Synthesis of N-arylated 2-imidazoline 207 using substituted substrates
Regioselective N-arylation of 4-methyl-4, 5-dihydro-1H-imidazole 208 was achieved by treating it with phenyl boronic acid 10 which resulted in 3.6:1 ratio of regioisomers 209a and 209b (Scheme 64).
Regioselective N-arylation of 4-methyl-4, 5-dihydro-1H-imidazole 208
Formation of arylated iminochromenes
Mandal et al. [41] reported the synthesis of arylated iminochromenes. The reaction was performed with various substituted aryl boronic acids with 3-phenyl iminochromene, and products were obtained in 42–85% yield. For example, 3-phenyl iminochromene 210 was allowed to react with 4-bromo aryl boroic acid 211 producing arylated iminochrome 212 in 85% yield (Scheme 65).
Synthesis of arylated iminochromenes 212
Similarly, substituted iminochromenes were allowed to react with simple phenyl boronic acid and products were formed in good yield (77–94%). For example, phenyl boronic acid 10 was reacted with 3-(3-(trifluoromethyl)phenyl)-2H-chromen-2-imine 213, 3-cynao iminochromene 214, 7-(diethylamine)-3-(4-nitrophenyl) iminochromene 215, and desired produtcs 216 (94%), 217 (91%), and 218 (84%) were formed (Scheme 66).
Synthesis of arylated iminochromene 216–218
Their research group tried a one-pot synthesis of N-arylated iminochromene by using a Knoevenagel reaction of salicylaldehyde 219 and malononitrile 220 in the presence of piperidine (old method) by replacing it with DABCO due to low yield. Addition of Cu(OAc)2·H2O and phenyl boronic acid into the reaction mixture led to the formation of N-arylated iminochromene 221 in 89% yield (Scheme 67).
One-pot synthesis and arylation of iminochromene 221
Synthesis of arylated aminomethyl acetylene
Jiang and Huang [42] described the formation of aryl aminomethyl acetylenes. The target was achieved by treating substituted phenyl boronic acid with aqueous ammonia and propargyl halide. A variety of aromatic boronic acids having electron-donating groups and electron-withdrawing groups was used. Electron-donating groups such as methyl and methoxy gave better results. The best results were obtained when 4-methylphenyl boronic acid 115 was treated with aqueous ammonia 222 and propargyl chloride 223, and 88% yield of the corresponding product 224 was obtained (Scheme 68).
Synthesis of aryl aminomethyl acetylene 224–225
It was also observed that para-substituted substrates gave higher yields as compared to ortho-substituted substrates (Fig. 10).
Structure of different positional isomer
Preparation of alkaloids
Feng et al. [43] worked on the synthesis of biologically active alkaloids Verruculogen and Fumitremorgin A. A series of steps was involved where Chan–Lam coupling was applied as an intermediate step. The synthesis was started with easily available Boc-L-Trp-OMe 228 which was protected with TIPS-Cl. Afterward, Boc-L-Trp(TIPS)-OMe 229 was borylated at the C6 position and then immediately subjected to Chan–Lam coupling with methanol to generate the corresponding product 230 in 65% yield which further underwent a series of chemical reactions to yield the target compound 231 (Scheme 69).
Synthesis of biologically active alkaloids 231
Kumar et al. [44] described the N-arylation of different tautomerizable heterocycles such as quinoline-2(1H)-one, bicyclic,6,7-dimethoxy isoquinoline-1(2H)-one, bromoquinazoline-4(3H)-one, and 7-bromoqunioxalin-2(1H)-one, and different products were obtained in good yield (60–90%). The best results were observed when pyridine2(1H)-one 232 was treated with phenyl boronic acid 10 and 4-methylphenyl boronic acid 115; both reactant afforded 90% yield in 12 h (Scheme 70).
Synthesis of N-arylated pyridine2(1H)-ones 233 and 234
The same reaction conditions were applied on benzo[d] oxazole-2(3H)-ones 235 to yield N-arylated benzooxazolone. The best results were obtained on treating it with phenyl boronic acid 10 and 4-methoxyphenyl boronic acid 5 (Scheme 71).
Formation of N-arylated benzo[d] oxazole-2(3H)-ones 236–237
N-Arylated benzoxazolone were further subjected to different reactions to synthesize oxygenated carbazole alkaloids.
Formation of sulfondiimines
Bohmann and Bolm [45] described the route to synthesize the N–N′-disubstituted sulfondiimines. Sulfondiimine was treated with variety of boronic acids having electronically diverse substitution pattern. Results demonstrated the fact that this reaction was equally feasible for electron-donating as well as electron-withdrawing groups and corresponding products were formed in good yields (51–85%). The best results were obtained in case of 2-naphthyl-boronic acid 239 and 2-bromo phenyl boronic acid 240 when these reactants were allowed to react with sulfondiimine 238 under optimum conditions, in both cases corresponding products were obtained in 94% yield (Scheme 72).
N-arylation of sulfondiimines 238
It was observed that steric effect strongly influenced the yield of the products. Para- and meta-substituted boronic acids gave higher yields compared to ortho-substituted boronic acids, while 2,4,6-trimethylphenyl-substituted boronic acid led to the failure of reaction.
Moreover, reaction of hetero aromatic boronic acid was also tested, and moderate-to-good results were observed. The best results were given when sulfondiimines 238 was allowed to react with 6-chloro-pyridine-3-yl-boronic acid 243 and resulted in product 245 (84%). Sulfondiimine 238 was also treated with (E)-styryl boronic acid 244. This reaction paved the path for the synthesis of new class of N–N′-disubstituted sulfondiimines (Scheme 73).
Synthesis of arylated sulfoniimides 245 and 246
The reaction was further extended to S-aryl-S-alkyl sulfondiimines to get the phenylated products. Reaction of sulfondiimine 238 with 4-methoxyphenyl boronic acid 5 resulted in 72% yield while same product 248 was formed in higher yield (90%) by phenylation of N-(4-methoxyphenyl)-NH-sulfondiimine 247 (Scheme 74).
Synthesis of arylated sulfoniimides 248
However, sulfondiimines having strong electron-withdrawing groups such as tosyl, benzyl, and tetrahydrothiophene resulted in failure of reaction, and no product was obtained.
Synthesis of functionalized aldehyde/ketone
Konstokosa et al. [46] worked on the synthesis of α-imino aldehydes. The target was achieved by applying Chan–Lam coupling on benzophenone oxime and alkenyl boronic acids to generate the O-alkenyl oximes which underwent [1,3] rearrangement followed by olefination to get the target compound ϒ-imino-α, β-unsaturated esters. A number of trans-alkenyl boronic acids were treated with benzophenone oxime 249. The best results were obtained in case of n-hexane and –(CH2)3CN containing acid 250, and 96% yield of corresponding product 251 was obtained in both cases which underwent [1,3] rearrangement to produce the corresponding aldehyde 252 in 62% and 58% yield, respectively. The synthesized aldehydes were further subjected to olefination to get the desired product (Scheme 75).
Synthesis of α-imino aldehyde 252
Kroc et al. [47] synthesized α-oxygenated ketones and substituted catechols by rearrangement of N-enoxy- and N-aryloxyphthalimides. These precursors were generated by applying Chan–Lam coupling. The synthesis of N-enoxyphthalimides was achieved by reaction of N-hydroxypthalimide with alkenyl boronic acid under typical Chan–Lam conditions. Maximum yield of 98% of product 255 was observed when methyl-substituted alkenyl boronic acid 253 was allowed to react with N-hydroxy phthalimide 254 under optimum conditions (Scheme 76).
Synthesis of N-enoxyphthalimide 255
Carbamate formation through Chan–Lam coupling
Until 2014, no reaction was reported between azido formate/acyclic carbamate with boronic acids at room temperature. Moon et al. [48] got the credit for reporting the first synthesis of N-aryl carbamate at room temperature by applying Chan–Lam coupling. The synthesis was performed by reaction of azido formate/acyclic carbamates with electronically diverse boronic acids. Electronically neutral and electron-donating groups on boronic acids resulted in higher yields (23–95%) as compared to electron-withdrawing groups (13–75%). The best results in both cases were obtained when benzyl azidoformate was allowed to react with 3,5-dimethyl phenyl boronic acid and 4-fluoro aryl boronic acid, desired product 256 (95%) and 257 (75%) was obtained. The reaction was extended to naphthalene and methylene dioxy substituted aryl/non-aryl/heteroaryl boronic acids. The best results were given by bicyclic aryl boronic acid, (E)-styrylboronic acid, 3-thienylboronic acid on reacting with benzyl azidoformate in different time, and corresponding products 258–260 were obtained (Fig. 11).
Synthesis of carbamates 256–260
Moreover, a number of different substituted azido formates were allowed to react with phenyl boronic acid. Maximum yield was obtained when methyl azido formate 261 was allowed to react with phenyl boronic acid 10 to yield methyl-N-arylcarbamate 262 in 92% under same reaction conditions (Scheme 77).
Synthesis of carbamate 262 by methyl azido formate 261
Two-step, one-pot synthesis of urea derivatives was also performed. Addition of aluminum–amine complex, to the N-arylcarbamates prepared through Chan–Lam coupling, resulted in multicomponent products (70–95%). Scope of Chan–Lam coupling was investigated for phenyl boronic acid derivatives such as pinacol phenyl borate, potassium triflouroborate, and dimethyl phenyl borate to react with benzyl azidoformate 264. Maximum product formation was observed in case of dimethyl phenyl boronate 263 (Scheme 78).
Investigation of the reactive boronic acid derivative 263
Arylation of esters
Huang et al. [49] explored the use of Chan–Lam coupling for synthesis of enol esters. The reaction was found to be regioselective and stereospecific to prepare (E) or (Z)-enol esters. A trial experiment was performed by using potassium (E)-triflourohexenyl borate with four different carboxylic acids and maximum yield was obtained when potassium (E)-triflourohexenyl borate 266 was treated with potassium 4-cyclohexylbutanoate 267 (Scheme 79).
Cross-coupling reaction between potassium carboxylate 267 and potassium (E) hexenyl borate 266
A number of substituted carboxylic acids were allowed to react with potassium (E) triflouroborates Studies showed that both electron-deficient and electron-rich benzoic acid/carboxylate salts resulted in cis-selectivty of products. Experiments revealed that different solvent systems could be used for this transformation, for example, one system involved the use of MeCN (Method 1) and other involved the mixture of MeCN/DMSO (4:1) (Method 2). Potassium (E) triflourohexenyl borate 266 was allowed to react with phenyl-substituted carboxylic acid 269 under method 1, and corresponding product 271 was obtained in 94% yield. Application of method 2 gave the highest yield of 97% of product 272 when potassium (E) triflourohexenyl borate 266 was treated with biphenyl-substituted carboxylic acid 280 (Scheme 80).
Synthesis of enol ester 271 and 272 through cross-coupling
Jacobson et al. [50] applied the Chan–Lam coupling for the methylation of carboxylic acids by using methyl boronic acid in the presence of CuCO3·Cu(OH)2, pyridine, DCM at 90 °C. Before this work, only cyclopropylation of indoles was reported. Aromatic carboxylic acids with electron-donating and electron-withdrawing groups were well tolerated. Fused carboxylic acid and heterocyclic carboxylic acids also showed good results. The best example was provided by 4-(tert-butyl)benzoic acid, 2-naphthalene carboxylic acid, 1-methyl-1H-indole-2-carboxylic acid when these substrates were allowed to react with methyl boronic acid and resulted in corresponding products 273–275. The reaction was extended to aliphatic and alkenyl acid which were allowed to react with methyl boronic acid, and products were obtained in 60–80% yield. Hydrocinnamic acid provided the best yield (80%) of the ester 276 (Fig. 12).
Synthesis of ester 273–276 by using Chan–Lam coupling
Methodology development
This section of the paper covers all the developments for the new/novel methodologies reported by different research groups to cater the research needs in this field.
Use of bimetallic catalyst in Chan–Lam coupling
A novel reusable bimetallic catalyst consisting of Cu-Mn was introduced by Sawant et al. [51]. In this heterogeneous and reusable catalyst, Mn stabilizes the copper and avoids the need of expensive catalyst. This catalyst was tested for N-arylation of anilines, and good-to-excellent yields (70–95%) of desired products were obtained. Screening for optimum conditions suggested that use of 2 equivalents of K2CO3 in water with this bimetallic catalyst made the reaction feasible. The N-arylation of aryl/alkyl and heteroaryl amines was done and results showed that aryl amines exhibited higher yields as compared to alkyl and heteroaryl amines. The best result was obtained when phenyl boronic acid 10 was allowed to react with aniline, 2-methylaniline, and 4-methoxyaniline under given conditions, and corresponding products 277–279 were obtained in 95% yield each (Fig. 13).
Synthesis of N-arylated anilines 277–279 by using bimetallic catalyst
In case of heterocyclic compounds and alkyl amines, 3-amino pyridine 280 and cyclo hexanamine 281 gave the maximum yield on reacting with phenyl boronic acid 10 (Scheme 81).
N-Arylation of 3-amino pyridine 280 and cyclohexanamine 281 using bimetallic catalyst
Role of metal complexes in C–N bond formation
Singh et al. [52] succeeded in developing a series of complex catalyst and evaluated their activity for C–N bond construction. The synthesis of complex was achieved by treating bis-(2-acetylthiophene)oxalyldihydrazone with different transition metal ions. Different metals such as Co(II), Ni(II), Cu(II) and Zn(II) were employed. Among synthesized complexes, Ni(II) 284 was the most efficient catalyst giving the products in good yield (Fig. 14).
Structure of Ni(II) complex 284
Use of Ni complex (15 mol%) with 2 equivalents 1,8-Diazabicyclo[5.4.0]undec-7ene (DBU) in acetonitrile at 40 °C gave maximum results. Different electron-deficient and electron-rich anilines were treated with phenyl boronic acid and 4-methylphenyl boronic acid to find the catalytic activity of this complex. Maximum results were obtained when 4-methylaniline 285 was allowed to react with phenyl boronic acid 10 and N-arylated product 286 was formed in 82% yield (Scheme 82).
Synthesis of N-arylated product by appling newly generated Ni(II) complex 284
Application of Chan–Lam coupling on a new substrate
Until 2013, Chan–Lam coupling was applied on a number of substrates such as phenols, amines, sulfonamides. In 2013, Zhou et al. [53] extended the scope of Chan–Lam coupling by application of aminal reactants for the first time. Use of Cu(acac)2 as catalyst with phCO2H, CH3CN at 50 °C was the best set of conditions for this new substrate. A variety of aryl boronic acids was allowed to react with aminal. Aryl boronic acids having electron-donating groups such as CH3, CH3O, F3CO at para and meta position furnished the products in moderate yields. Maximum yield was obtained when 3,5-methyl-substituted aryl boronic acid 288 was allowed to react with aminal 287 and afforded the corresponding product 290 in 57% yield. It was also observed that ortho-substituted aryl boronic acid lead to significant decrease in yield. This transformation was also done with meta and para F and CF3 groups. The best results were observed when meta-flouro boronic acid 289 was treated with aminal. Further, the reaction was extended to 1-naphthalene boronic acid and 2-naphthalene boronic acid, but reaction was more feasible with 2-naphthalene boronic acid 239 (Scheme 83).
Use of aminal 287 as substrate in Chan–Lam coupling
Reactivity of different aminals toward this cross-coupling reaction was investigated. Results showed that piperidine-derived aminal gave the maximum yield of product (45%), on reacting with phenyl boronic acid as compared to the other substrates such as pyrroline-derived aminal and unsymmetrical aminal.
Use of copper-based heterogeneous catalyst in Chan–Lam coupling
A new heterogeneous catalyst was developed by Debreczeni et al. [54] which was prepared by impregnating Cu(II)chloride in the presence of deionized water. The catalyst proved to be sensitive to atmospheric oxygen. The reaction conditions were screened and results showed the replacing the Cu+2/4A with Cu°/4 A leads to higher yields. A number of reactions were performed using different amines such as N,N-dibutyl amine, morpholine, and N-methyl piperazine and different substituted aryl boronic acids, and corresponding products were obtained in good yield (43–77%). The best yields of products 293–295 were observed when phenyl boronic acid 10 was treated with morpholine, N-methyl piperazine, 4-nitrophenol in the presence of Cu catalyst, dichloromethane and pyridine (Fig. 15).
Effect of new catalyst in Chan–Lam coupling of phenyl boronic acid 10 with different substrates
Copper–salen complex for arylation
Gogoi et al. [55] explored the effect of newly prepared copper–salen complex 296 as catalyst on arylation of anilines and imidazole. Three types of complexes were generated, and their activity was determined in water. Results showed that Cu complex 296 (Fig. 16) was the most effective among the synthesized complexes.
Structure of newly prepared copper–salen complex 296
After finding the most efficient catalyst, other conditions were screened and optimum conditions were established which involved the use of Cu complex 296, K2CO3, H2O at room temperature in the presence of air. Previously reported catalysts were not selective due to OH-containing substrate resulting in competitive C–O coupling. But this catalytic system was selective and resulted in only C–N coupling. Maximum yields were observed when phenyl boronic acid 10 was allowed to react with 4-methylaniline, imidazole, benzimidazole and gave the corresponding products 286, 297, and 298. However, solvent was replaced with 1:1 aqueous iso-propanol in case of imidazole (Fig. 17).
Use of copper–salen complex 296 in Chan–Lam coupling
Coupling reaction by polymer-anchored copper catalyst
Islam et al. [56] reported the use of new polymer-anchored Cu-catalyst for coupling reaction which was prepared by furfural functionalization followed by grafting with copper (Fig. 18). Characterization of this newly generated catalyst was done by UV–Vis spectroscopy, scanning electron microscope and Fourier transform infrared spectroscopy. It was also observed that developed catalyst can be reused five times without any lose in catalytic activity.
Structure of new polymer-anchored copper catalyst 299
N-Arylation was carried out by treating imidazole with a number of aryl boronic acids using this catalyst in presence of MeOH, without using any base. It was observed that aryl boronic acid having electron-donating groups such as o/p Me and OMe gave higher yields as compared to aryl boronic acid containing electron-withdrawing groups such as F, Cl, NO, COMe. It was stated that o/p position did not affect the yield. However, the best results were obtained in case of electronically neutral phenyl boronic acid 10 with imidazole which resulted in product 297 (99%) (Fig. 19).
N-Arylation of imidazole using polymer-anchored copper catalyst 297
Use of Cu(II) Schiff base complex catalyst
N-Arylation of different heterocyles was described by Islam et al. [57] by using copper(II) Schiff base complex catalyst. The copper(II) Schiff base complex [Cu(amp)(OAc)] 300 and heterogeneous polymer-anchored Cu(II) Schiff base catalyst PS-Cu-amp-OAc 301 were employed for the N-arylation of different heterocycles (Fig. 20).
Structure of homogenous and heterogeneous Schiff base catalyst 300 and 301
N-Arylation of imidazole, benzimidazole, phthalimide, succinamide, and sulfonamide was done in presence of new catalyst and methanol at 40 °C for 6 h. Phenyl boronic acid 10, 4-methoxy boronic acid 5, and 4-chloroboronic acid 11 gave the best yields with imidazole when a number of substituted aryl bornic acid were tried in presence of Cu(amp)-OAc. Results showed that homogeneous catalyst (96%) gave slightly higher yield as compared to heterogeneous catalyst (92%) in case of phenyl boronic acid (Fig. 21).
Formation of N-arylated imidazole using homogenous Schiff base catalyst 300
Use of simplified conditions for Chan–Lam coupling
A simple set of conditions was suggested by Liu et al. [58] for N-arylation of H-tetrazoles. The synthesis of N-arylated tetrazole was carried out in the presence of Cu2O (5 mol%), O2 (1 atm), DMSO at 100 °C. The positive aspect of this method was the prevention of metalated tetrazoles. Moreover, additives, ligands, and other external bases were not required as in classical Chan–Lam coupling. A variety of substituted aryl-H-tetrazoles and aryl boronic acids having diverse substitution pattern were allowed to react, and a library of compounds was synthesized in low-to-excellent yields (14–97%). Maximum yield of 97% was observed when 3-chlorophenyl boronic acid 305 and tetrazole 304 were allowed to react under optimum conditions (Scheme 84).
N-arylation of tetrazole 304 under simple conditions
Ligand/base/additive method for arylation
Moon et al. [59] discovered base, ligand, and additive-free Chan–Lam coupling reaction conditions. Positive aspect was that this reaction proceeded at room temperature while no reaction at room temperature between sulfonyl azides and borocnic acid had been reported earlier. Reaction proceeded well at room temperature in open air, using CuCl as catalyst and MeOH as solvent. A variety of aryl boronic acids was treated with tosyl azide to furnish the desired product under optimum conditions. It was demonstrated that electron-donating and electron-withdrawing groups on aryl boronic acid were well tolerated. Excellent yield of N-arylated tosyl azide 309 (99%) was obtained when 4-methylphenyl boronic acid 115 was treated with tosyl azide. Pinacol phenyl boronate and potassium phenyl trifluoro boronate were also treated with tosyl azide 307 to evaluate their efficiencies and the best result was observed in case of potassium phenyl triflouro boronate 38 in 15 h when it was treated with tosyl azide (Scheme 85).
Formation of N-arylated tosyl azide 308–309 at room temperature
Furthermore, substituted aryl boronic acids and hetero aryl boronic acid were allowed to react with mesyl azide under same reaction conditions. Maximum yield of 99% and 94% of products 312 and 313 was obtained when 3-methoxyphenyl boronic acid 124 and thiophen-3-ylboronic acid 311 was allowed to react with mesyl azide 310 (Scheme 86).
N-arylation of mesyl azide under base-free conditions
In case of aryl boronic acids, excellent yield (92–98%) was obtained. For example, phenyl boronic acid 10 was treated with 2,4,6-methylphenyl sulfonyl azide 314 to get the product 315 in 98% yield (Scheme 87).
Formation of N-arylated sufonyl azide 315
Use of triazine based mesoporous material
Synthesis of biologically important N-aryl flavones was reported by Puthiaraj and Pitchumani [60] by using triazine-based mesoporous material as support in the reaction (Fig. 22).
Structure of triazine based mesoporous material 316
N-Arylation of 7-aminoflavone, 6-aminoflavone, and 8-aminoquinoline was done with a variety of substituted aryl boronic acid. Synthesis of N-arylated 7-aminoflavone with substituted aryl boronic acids resulted in corresponding products in good-to-excellent yield (78–93%). Maximum yield (93%) was observed when 7-aminoflavone 317 was treated with 4-ethylphenyl boronic acid 318 (Scheme 88).
Synthesis of N-arylated 7-aminoflavone 319
Under same reaction conditions, N-arylation of 6-aminoflavone 320 and 8-aminoquinoline 321 was done with phenyl boronic acid 10 which resulted in formation of desired products 322 (93%) and 323 (94%), respectively (Scheme 89).
Synthesis of N-arylated flavone and quinoline 322–323
C–N bond formation by using Ni(II) thiolates
Shi et al. [61] reported the synthesis of Ni(II) thiolates and tested their effect on coupling reactions involving the C–N bond construction. These complexes were prepared through transmetallation of Ni(II) ions with [Zn(Tab)4](PF)6 using different ligands. Three complexes were generated and catalytic activity was investigated for Chan–Lam protocol, which involved the reaction of aryl boronic acid with amines to synthesize the N-arylated products in good yield. The complex 324 showed the most amazing and promising results for this reaction (Fig. 23).
Structure of Ni(II) thiolate complex 324
A number of substituted anilines and substituted phenyl boronic acids were used to find the scope of this catalyst and reaction as well. Maximum yield was obtained in case of benzyl amine 325 when it was reacted with phenyl boronic acid 10 to yield the desired product 326 in 80% (Scheme 90).
Formation of N-arylated aniline using Ni(II) thiolate complex 324
It was observed that electron-withdrawing groups on phenyl boronic acids led to the formation of products in lower yields as compared to electron-rich aryl boronic acids. For example, when aniline 50 underwent the reaction with 4-methylphenyl boronic acid 115, it resulted in 71% of product 286, while on reaction with 4-nitroboronic acid 107 gave 59% of product 327 (Scheme 91).
Synthesis of N-arylated anilines 286 and 327 by using Ni complex 324
Similar trend was seen for anilines where p-methyl aniline 285 gave out 75% of arylated product 286 on reacting with phenyl boronic acid 10 while p-nitro aniline 328 resulted in 35% yield of the product 327 (Scheme 92).
Synthesis of N-arylated anilines 286 and 327 by using substituted anilines
Use of chitosan-anchored copper complex
Anuradha et al. [62] worked on the preparation of new chitosan-anchored copper complex having Schiff base ligands and employed it for the N-arylation of amines. Chitosan provided support for this catalyst, and these easily separable heterogeneous catalysts were generated (Fig. 24). Studies showed that copper complex having nitro group was the most efficient as compared to other two catalysts. It was postulated that electron-withdrawing effect of nitro group was the reason of good performance of catalyst because it increased the Lewis acidity of the complex, and it was found effective for five cycles.
Structure of chitosan-based copper complex 329
Aromatic as well as aliphatic amines were used for Chan–Lam coupling; however, aromatic amines easily undergo the transformation in lesser time as compared to aliphatic amines. Aromatic amines having electron-withdrawing groups were more reactive than electron-donating substituted amines. For example, 82% yield of N-arylated product 331 was obtained on reacting the 3-nitro aniline 330 with phenyl boronic acid 10 (Scheme 93).
N-arylation of substituted anilines by using new copper complex 329 as catalyst
Meta- and para-substituted amines gave slightly higher yields as compared to ortho-substituted amines. For example, o-Cl-substituted anilines gave product 332 in 72% yield, whereas p-Cl aniline produced the product 333 in 74% yield (Fig. 25).
Structure of different isomers of N-arylated aniline 332–333
Here, electron-donating groups increased the activity of boronic acid and resulted in higher yield of desired products. 4-Methylphenyl boronic acid 115 was the best example which gave 81% of desired product 286 on reacting with aniline 50 (Scheme 94).
Synthesis of N-arylated aniline 286 using Cu complex 329
Novel nickel-catalyzed Chan–Lam coupling
Keesara [63] described the novel nickel-catalyzed Chan–Lam coupling in which N-(pyridine-2-yl)benzamide ligand 334 was used with Ni(OAc)2·4H2O in the presence of 1,1,3,3-tetramethyl guanidine (TMG base). Substituted anilines were allowed to react with substituted aryl boronic acids and good-to-excellent yields (68–84%) were obtained. Similarly, N-phenyl piperazine 335 was allowed to react with substituted boronic acids. The best yield was observed for the phenyl boronic acid 10 on treating with N-phenyl piperazine 335 and aniline 50 (Scheme 95).
Nickel-catalyzed Chan–Lam coupling of anilines 50 and piperazine 335
Under same reaction conditions, naphthyl boronic acid was allowed to react with piperidine, morpholine, and pyrrolidine derivatives. Maximum yield was obtained in case of piperidine 337 when it was allowed to react with 2-naphthyl boronic acid 239 and product 338 was obtained in 66% yield. Reaction between 2-naphthyl boronic acid 239 and cyclohexyl amine 281 was also performed which resulted in 70% yield of 339 (Scheme 96).
Synthesis of N-arylated piperadine 338 and N-arylated cyclohexyl amine 339
S-Arylation under ligand/base-free conditions
S-Arylation of α-enolic thioesters was performed under ligand and base-free conditions by Koley et al. [64]. A library of compounds under mild reaction conditions were synthesized in excellent yields (71–92%) by the reaction of substituted α-enolic dithioester aryl boronic acid 340. Maximum yield was obtained when 4-acetyl-substituted phenyl boronic acid 158 was reacted with α-enolic thioesters 340 under standard conditions and 92% yield of S-arylated product 342 was recorded. Similar results were observed for pyridine-based dithioester. The methodology could also be applied to heterocyclic dithioethers such as furan-based dithioesters 341 (Scheme 97).
S-arylation of α-enolic thioesters 340 and furan-based dithioester 341
Similarly, naphthalene-based dithioester 344 was treated with phenyl boronic acid 10 and 4-fluorophenyl boronic acid 6, separately; however, phenyl boronic acid resulted in higher yield (90%) of the product 345 (Scheme 98).
S-arylation of naphthalene-based α-enolic thioesters 344
Use of metal organic frame work for Chan–Lam coupling
Wang et al. [65] reported the use of a metal–organic frame work {[Cu(4-tba)](solvent)}n in Chan–Lam coupling. The aforementioned catalyst was synthesized by the reaction of 4-(1H-1,2,4-triazole-1-yl)benzoic acid (Htba) and Cu(II) nodes and was employed for different C–N bond forming reaction. Maximum yield (98%) of the product 297 was obtained when phenyl boronic acid was treated with imidazole in the presence of this metal–organic framework and methanol at 40 °C. It was observed that this catalyst retains its activity till six cycles (Fig. 26).
Formation of N-arylated imidazole 297 using metal–organic framework
Chan–Lam coupling under visible light
Modification in Chan–Lam coupling was made by Yoo et al. [66] by conducting it in the presence of visible light. Cu(OAc)2 was used with iridium-based photocatalyst irradiated with blue light-emitting diode while other parameters included 2,6-lutidine, toluene/MeCN (1:1), myristic acid at 35 °C in open air for 20 h. A number of compounds were synthesized by treating substituted aryl amines with substituted aryl boronic acids. Maximum yield of respective products 346–348 (100%) was obtained when 4-chlorophenyl boronic acid 11 was allowed to react with 2-methylaniline, 4-methylaniline, and 4-chloroaniline (Fig. 27).
Synthesis of N-arylated substituted anilines 346–348
Results showed that electron-withdrawing and electron-donating groups are well tolerated. Similarly, reaction of aniline 50 with phenyl boronic acid 10 resulted in 100% yield of the product 277 (Scheme 99).
N-arylation of aniline 50 with phenyl boronic acid
Use of solid copper reactor as catalyst
Bao and Tranmer [67] developed a novel method for generating C–N bond by using simple alkyl and aryl boronic acids. Use of solid copper reactor was the novelty in the history of catalyst. Optimum conditions included the catalyst, H: TEMPO (1:1.5) in MeCN and 2 equivalents of CH3CO2H. Applying this catalyst, a number of compounds were synthesized by using phenyl boronic acid 10 and 4-methoxyphenyl boronic acid with morpholine and substituted aniline. 79% yield of N-arylated product 277 was obtained on treating the phenyl boronic acid 10 with aniline 50. In case of morpholine, simple phenyl boronic acid 10 gave higher yield (57%) of the product 293 as compared to when 4-chlorophenyl boronic acid was used (25%) (Fig. 28).
Formation of N-arylated aniline 277 and N-arylated norpholine 293 using Cu-column
Heterogeneous copper catalyst for arylation of C–S bond
A novel heterogeneous copper catalyst was developed by Lin et al. [68] to prepare diaryl sulfides. Other previously reported Chan–Lam coupling transformation involved the use of homogenous catalyst which led to the contamination of products by copper and limited their use in biomedicine and electronics. To overcome this problem, heterogeneous catalyst was suggested. For this purpose, mesoporous MCM-41 material was used as support to the copper catalyst. The synthesis of catalyst involved the reaction of immobile material MCM-41 with 1-(1,10-phenanthroline) and complex formation was done by treating it with CuSO4 (Fig. 29).
Structure of mesoporous heterogeneous copper catalyst 349
A number of bases and solvent were tried, and results demonstrated that n-Bu4NOH as base and EtOH as solvent were the best choice to make this transformation effective. After establishing the reaction conditions, this protocol was applied for S-arylation. For this purpose, phenyl boronic acid was allowed to react with substituted thiols. Maximum yield of 89% was obtained when phenyl boronic acid 10 was allowed to react with 4-iso propyl-substituted thiols 350 (Scheme 100).
Synthesis of S-arylated thiol 351 using Cu complex 349
Same reaction conditions were applied on substituted aryl boronic acids and substituted benzene thiol. Both the reactants were substituted with electron-donating and electron-withdrawing groups and resulted in good-to-excellent yield. Reaction of 4-chlorophenyl boronic acid 11 with 4-fluorobenzenethiol 352 was performed and 92% yield of the product 353 was obtained (Scheme 101).
Crosscoupling of substituted thiol 352 and 4-chloroboronic acid 11
New catalyst system based on diketimine ligands
Mori-Quiroz et al. [69] developed the new catalyst system which was based on diketimine (NacNac) ligands 354 and 355. These catalysts were tested for their catalytic activity to form amide through Chan–Lam coupling (Fig. 30).
Structure of diketimine ligands 354–355
A variety of amides and boronic esters were used to synthesize the corresponding products in moderate-to-good yields (36–86%). Maximum yield was obtained when 2-ethoxybenzamide 356 was allowed to react with alkyl boronic ester 357 and resulted in desired product 358 (86%) (Scheme 102).
Synthesis of N-arylated amide 358 by using alkyl ester
Under same reaction conditions, scope of acetamide and trifluoroacetamide was evaluated for different esters and result demonstrated that acetamide resulted in higher yield as compared to trifluoro acetamide (Scheme 103).
Synthesis of N-arylated amide 361
Scope of secondary boronic acid for N-alkylation of amides was also investigated by using ligand 355. Different substrates with different substituents were tried and moderate-to-good yields were obtained. Maximum yield (82%) was obtained when 4-flourobenzamide 362 was allowed to react with alkyl boronic ester 363 under optimum conditions (Scheme 104).
Synthesis of N-alkylated amide 362 using diketiimine 355
Use of MeCN/EtOH as solvent system
Vantourout et al. [70] elaborated the set of reaction conditions for Chan–Lam coupling of aryl BPin with aryl and alkyl amines. The reaction conditions were modified by switching to MeCN (in case of alkyl amines) and MeCN/EtOH (in case of aryl amines) from typical solvent system, keeping other conditions same such as Cu(OAc)2, Et3N at 80 °C for 24 h. Application of these reaction conditions on aryl amine and variety of substituted aryl BPin, resulted in good-to-high yields. It was observed that electron-donating groups such as MeO and MeO2C and electron-withdrawing groups such as Br, Cl, NC, CF3, F were well tolerated. Maximum yield of 84% product 367 was obtained in case of 3-CN substituted aryl BPin 365 when it was allowed to react with aniline 50. Application of this protocol on fused ring system was also evaluated; for example, naphthalene-based BPin 366 gave 77% yield of product 368 upon treatment with aniline 50 (Scheme 105).
Chan–Lam coupling of aniline 50 with aryl boronate ester
Same reaction conditions were applied on different aryl amine substrates and moderate-to-good yields were obtained. The best results were obtained when phenyl BPin 369 was allowed to react with 4-methoxyphenyl amine 370 and product 279 was obtained in 87% yield. Similarly, a number of substituted alkyl amine were tried for this transformation. The reaction was conducted by the reaction of alkyl amines with Ph-BPin demonstrating good yields. Optimum yield was formed when (1,3,5-trimethyl-1H-pyrazol-4-yl)methanamine 371 allowed to react with phenyl-BPin 369 and afforded the product 372 in 91% yield (Scheme 106).
Chan–Lam coupling of substituted aniline 370 and methanamine 371 with boronate ester 369
Results encouraged their research group to apply these conditions on alkyl amines. Little modification was done by replacing EtOH/MeCN with MeCN. Firstly, this experiment was tried with different substituted Ar-BPin. Different electron-donating (OMe, Me) and electron-withdrawing (Br, Cl, CF3O, NC) groups were employed and resulted in good-to-excellent yields. The best results were observed when 4-bromophenyl BPin 373 was allowed to react with 337, and corresponding product 374 was formed in 85% yield (Scheme 107).
Cross-coupling reaction of boronate ester 373
New copper complexes catalyzed Chan–Lam coupling
Xue et al. [71] described the effect of newly synthesized copper complexes 375 on Chan–Lam strategy. Ligands were synthesized according to already reported method and further treated with CuI to generate the respective complex (Fig. 31). Studies proved that complex was found compatible with H2O/MeCN (2:1) system at 60 °C to perform the reaction between 1H-imidazole and phenyl boronic acid.
Structure of Cu complex 375
Electron-rich p-substituted aryl boronic acids proved to be more reactive and resulted in higher yields as compared to electron-deficient phenyl boronic acid. 4-Methoxyphenyl boronic acid 5 was reacted with 1H-imidazole 376 and afforded the corresponding N-arylated product 303 in 95% yield (Scheme 108).
N-Arylation of imidazole 376 by substituted boronic acid
Scope of this reaction was also investigated by treating phenyl boronic acid 10 with pyrazole, aniline, benzamide. Maximum yield (90%) was obtained when phenyl boronic acid 10 was treated with pyrazole 377 (Scheme 109).
Cross-coupling of pyrazole 377 and boronic acid 10 through Chan–Lam coupling
Use of copper–salen complex in Chan–Lam coupling
Azam et al. [72] studied the catalytic activity of different Cu(II)–salen complexes in Chan–Lam coupling. The Cu(II) complex 379 was found the most effective to perform this coupling (Fig. 32).
Structure of copper(II)–salen complex 379
DNA-binding study and antimicrobial, anticancer activities of Cu(II)–salen complexes were also studied. The Cu(II)–Salen complex 379 (40 mol%) was used along with Et3N in the presence of DCM at room temperature and 83% yield of O-arylated product 380 of phenol 67 with phenyl boronic acid 10 was observed (Scheme 110).
Synthesis of biaryl ether 380 using Cu(II)–Salen complex 379
Chan–Lam coupling through sulfonate diketimine copper(II) complex
Duprac and Schaper [73] prepared the sulfonate diketimine copper(II) complex 381 and applied it on the Chan–Lam coupling of amines and anilines (Fig. 33). This system was used without adding any base, ligand, and molecular sieves.
Structure of copper(II) complex 381
Using this system, relative reactivity of different amines and anilines was determined by treating them with phenyl boronic acid 10, and it was observed that some substituted anilines showed good reactivity up to 100% among the tested compounds.
Use of diaryl boronic acid for N-arylation of (benz)imidazole
Use of diaryl boronic acid 382 for N-arylation of (benz)imidazole was reported by Guan et al. [74]. This protocol involved the use of Cu(OAc)2·H2O, MeOH, tetramethylethylenediamine (TMEDA) at room temperature. Reaction of diaryl boric acid with (benz)imidazole resulted in corresponding product in low-to-good yields (10–99%). Maximum yield (99%) was observed with 1H-imidazole 376 when it was allowed to react with 4-methyl diphenyl boronic acid 382 (Scheme 111).
Synthesis of N-arylated imidazole 383
Similarly, in case of benzimidazole 384, the best yield (99%) of N-arylated benzimidazole 386 was obtained when it was allowed to react with 4-OMe diphenyl boronic acid 385 (Scheme 112).
Synthesis of N-arylated benzimidazole 386
Use of tertiary trifluoroborates
Harris et al. [75] presented the Chan–Lam coupling of tertiary trifluoroborates. This conversion was done in the presence of 1.2 equivalent of Cu(OAc)2, 2 equivalents of phenanthroline monohydrate ligand and three equivalents of K3PO4 (1 M H2O, 3 eq) in presence of DCE at 80 °C for 18 h. The reaction resulted in successful formation of corresponding products in good range (37–76%). Maximum yield was observed when tert-butyl bicyclo[3.1.0] 387 was treated with indazole 388 under these reaction conditions and resulted in 76% yield (Scheme 113).
N-Arylation of 1H-indazole 388
Use of pyridine-based polydentate Cu(11) complex
A novel pyridine-based polydentate Cu(II) complex 390 (Fig. 34) was found helpful in cross-coupling reactions by Sharghi et al. [76]. This new catalyst was economical, efficient with the ability to catalyze a variety of reactions.
Structure of pyridine-based catalyst 390
Its applications in Chan–Lam coupling was proved very effective by observing that the desired products were formed in good yields (65–95%). The reaction of phenyl boronic acid 10 with 1H-imidazole, 1H-pyrrole and 9H-carbazole resulted in 95% yield of corresponding products 297, 391, and 392 (Fig. 35).
Synthesis of N-arylated heterocycles using Cu complex 390
Role of boric acid in Chan–Lam coupling
During the spectroscopic studies of Chan–Lam coupling amination, Vantourout et al. [77] identified the synergistic promotive role of boric acid. The investigation proved the success of the non basic conditions for Chan–Lam coupling. Aryl boronic esters on reacting with different groups of substrates gave good-to-high yields, i.e., alkyl amines (36–94%), aryl amine (52–90%), sulphonamide and azole nucleophile (53–74%) and O-and S-nucelophile (53–74%). Classical conditions were modified by replacing the organic base Et3N with B(OH)3. Maximum yield of 94% of aryl amine was observed when (1,3,5-trimethyl-1H-pyrazol-4-yl)methanamine 371 was treated with phenyl boronate ester 369 (Scheme 114).
N-arylation of heterocyclic compound 371
In case of aryl boronic acid, maximum yield of 90% was recorded when Chan–Lam coupling was performed by treating aniline 50 with substituted aryl boronic ester 393 (Scheme 115).
N-arylation of aniline through substituted boronic ester 393
Same result was also observed on N-arylation of N-methylaniline 395 with phenyl boronic ester 369 under same reaction conditions (Scheme 116).
N-arylation of N-substituted aniline through boronic ester 369
Triflouoromethylation with trifluoroethanol
Zhang et al. [78] described the triflouoromethylation of aryl boronic acid by using only 2 equilvalents of 2,2,2-trifluoroethanol. Reactions were conducted in presence of Cu(OAc)2, pyridine, Na2CO3, Cl(CH2)2Cl and these condition were found suitable for this transformation. A variety of aryl and heteroaryl boronic acid having different functional groups such as ether, amide, vinyl, ester, thioester, nitro, cyano, bromo, iodo, chloro, ketones and aldehyde were well tolerated in this coupling reaction giving moderate-to-good yields (35–82%). Maximum yield was observed when phenyl boronic acid having carbazole group 397 was allowed to undergo the Chan–Lam coupling reaction with 2 equivalents of 2,2,2-trifluoroethanol 59 in the optimum conditions and corresponding product 398 was obtained in 82% yield (Scheme 117).
Chan–Lam coupling by using carbazole based boronic acid
Their research group also attempted to prepare the medicinally important cinacalcet (calcimimetic drug) analogues by trifluoromethylation of substituted phenyl boronic acid 399 which resulted in 67% yield of desired product 400 (Scheme 118).
Synthesis of cinacalcet analogue 400 through Chan–Lam coupling
Conclusion
In this study, a range of strategies have been discussed so as to provide a comprehensive insight into the methodological routes to synthesize the new and biologically important compounds using Chan–Lam coupling. During recent years, a lot of work in organic synthesis has been carried out leading to synthesis of novel and more active drugs to achieve the targets with regard to pharmaceutical needs. In this connection, a number of substrates were employed to meet these requirements of synthesizing different moieties, having great contributions in the activity of compounds. Furthermore, new developments regarding methodologies have also been described to show the pathways for researchers’ fraternity to prepare the desired compounds in more efficient and economical ways. The plethora of research substantiated in this review will provide a detailed outlook on synthetic applications of this coupling and will open new horizons to extend the methodology development.
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Munir, I., Zahoor, A.F., Rasool, N. et al. Synthetic applications and methodology development of Chan–Lam coupling: a review. Mol Divers 23, 215–259 (2019). https://doi.org/10.1007/s11030-018-9870-z
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DOI: https://doi.org/10.1007/s11030-018-9870-z