Advances in Carbon–Element Bond Construction under Chan–Lam Cross-Coupling Conditions: A Second Decade

In memory of Siva Reddy

Key words

Chan–Lam coupling - C–O bond formation - C–N bond formation - N-arylation - copper-catalyzed - copper mediated

1

Introduction

Metal-mediated aromatic/heteroaromatic carbon–heteroatom­ bond-forming reactions have been used as an efficient protocol for the construction of (hetero)aryl motifs, which are ubiquitous in many natural products and pharmaceutically important compounds.[1] In addition, the construction of heteroaromatic building blocks for the synthesis of pharmaceuticals, crop protection chemicals, and materials in a site-selective manner is highly recognized by organic chemists. The discovery of novel and optimized catalytic systems for functionalizing reactants with multiple heteroatom sites using Cu-mediated coupling reactions is a great challenge for the synthetic community. The synthesis of complex systems using minimum synthetic operations via the selective N- or O-arylation of heteroaromatic molecules is promising in this regard.

During the past few decades, different groups have developed promising synthetic protocols for the formation of C–N or C–O bonds, which can overcome the drawbacks of the original Ullmann and Goldberg procedures.[2] [3] The exploration of Pd-catalyzed amination reactions by Buchwald[4] and Hartwig[5] marked an era in the construction of a wide variety of aromatic amines, which cannot be accomplished through the reaction conditions previously reported. However, this strategy also has several limitations, such as sensitivity to air and moisture, relatively high temperatures, expensive palladium and ligands, a limited number of substrates, and so on. These drawbacks necessitated the demand for the invention of novel metal catalysts, and the Ullmann[6] and Goldberg[7] coupling reactions are among the more explored strategies.[8] [9] [10] To overcome these limitations, many researchers have tried various more reactive arylating reagents instead of aryl halides to develop milder reaction conditions involving organometalloids such as organobismuth, organolead, organostannane, and organosiloxane derivatives or hypervalent iodonium salts.

In 1998, research groups of Chan,[11] Evans,[12] and Lam[13] reported Cu-mediated heteroatom arylation reaction using arylboronic acids as coupling partners for the construction of C–N and C–O bonds. In addition to N- and O-based nucleophiles, sulfur, selenium, tellurium, and halogen nucleophiles are also suitable partners in these reactions. The use of copper salts and organoboron compounds are beneficial as they have several advantages, such as readily availability, low toxicity, etc. (Scheme [1]). As the oxidation of Cu(II) complexes bearing electron-deficient aryl groups is challenging, arylboronic acids bearing electron-withdrawing substituents are poor substrates for the Chan–Lam reaction. The sensitivity to the electronic properties of the arylboronic acids, which imparts a limited substrate scope, and the use of a large amount of catalyst are areas that still need further improvement in these reactions.

Scheme 1 Chan–Lam cross-coupling reaction

In order to overcome these limitations and their applications for the synthesis of aromatic or heteroaromatic building blocks, various research groups have developed various reaction conditions under modified Chan–Lam coupling conditions. In particular, recent developments of chemo- and regioselective N-arylations or O-arylations and synthesis of medicinally or pharmaceutically important heterocycles have been significant discoveries and are discussed in this review, which includes the construction of complex chemical scaffolds for synthetic methodology development. Proper mechanistic investigations including the choice of copper source, ligands, base, and other additives have benefitted the development of efficient and milder methods. The Chan–Lam coupling reaction is now capable of forming 12 different C–element bonds (C–N, C–O, C–S, C–P, C–F, C–C, C–Cl, C–Br, C–I, C–At, C–Se, and C–Te). This makes the Chan–Lam coupling reaction one of the most diverse mild reactions known in organic chemistry. This review concentrates mostly on publications starting from 2010, where our previous review[1h] ends. However, some historic significant work will also be discussed, in particular those not discussed in our 2011 Synthesis review.[1h] The present review covers all the 12 C–element bonds, including astatine, which is gaining importance for radiotherapy because of its unique properties.[14]

2

Construction of C–N and C–O Bonds

2.1

C–N Bond Formation

2.1.1

Original Discovery via Stoichiometric Copper-Mediated C–N Bond Formation

The N-arylation of a wide variety of NH-containing moieties, such as amines, amides, ureas, imides, sulfonamides and carbamates, with boronic acids 2 using a stoichiometric amount of copper reagent was first reported by Chan and co-workers (Scheme [2]).[11]

Scheme 2 Stoichiometric Cu-mediated C–N bond formation with various nitrogen nucleophiles

Lam and co-workers demonstrated that NH-containing heteroaromatics such as imidazoles, triazoles, tetrazoles, pyrazoles, benzimidazoles, and indazoles could also be used as coupling partners in this reaction; 2.0 equiv of arylboronic acid and 1.0 equiv of heteroarene were treated with 1.5 equiv anhydrous Cu(OAc)₂ and 2 equiv of pyridine as the base in the presence of 4 Å molecular sieves in air at room temperature for 2 days (Scheme [3]).[13] Even though azoles such as triazoles and tetrazoles, which are electron-poor, pyrrole, and indole gave the corresponding products in low yields, pyrazoles and imidazoles gave good yields.

Scheme 3 Cu-mediated C–N bond formation with various azoles

2.1.2

Copper-Catalyzed C–N Bond Formation

In 2001, the Collman group reported the synthesis of a wide range of N-arylimidazoles 7 in good to excellent yields by the reaction of arylboronic acids and imidazoles 6 using a novel binuclear bis-μ-hydroxocopper(II) complex [Cu(OH)·TMEDA]₂Cl₂ (Scheme [4]).[15] This procedure required the use of 10 mol% catalyst and the ratio of imidazole/arylboronic acid was 1:2; the products were obtained in good to excellent yields and the use of stoichiometric amount of copper salts and amines was minimized.

Scheme 4 [Cu(OH)·TMEDA]₂Cl₂-catalyzed N-arylation of azoles with arylboronic acids

A plausible mechanism for the formation of N-arylated products based on Evans’ postulated mechanism via the coupling of arylboronic acids and phenols is shown in Scheme [5]. In the initial step, the arylboronic acid 2 undergoes transmetalation with catalyst 8 to afford 9 which subsequently complexes with the imidazole 6 to form 10. The Cu(II) in complex 10 is oxidized to Cu(III) by oxygen to form 11. This is followed by reductive elimination to generate the products and complex 12 which regenerates the active catalyst. The formation of triarylboroxine and water from boronic acids can arylate H₂O which results in a competitive reaction between phenol and imidazole molecules to give lower yield of desired coupling products.

Scheme 5 Mechanism for the catalytic Cu-catalyzed N-arylation of azoles

Next, in 2001, the Collman group reported the first example of the synthesis of N-arylimidazoles using [Cu(OH)·TMEDA]₂Cl₂ as the catalyst in water as the solvent (Scheme [6]).[16] The yields are lower as compared with the reaction in dichloromethane, nevertheless the use of water as the solvent opens up the future arena of green chemistry and the arylation of the nucleophilic sidechains of peptides, proteins, and carbohydrates.

Scheme 6 [Cu(OH)·TMEDA]₂Cl₂-catalyzed N-arylation of azoles with arylboronic acids in water

In 2004, Yu, Xie, and co-workers developed a useful method using only 5 mol% of simple CuCl with methanol as the solvent that gave the corresponding N-arylimidazoles in almost quantitative yields without the addition of base or ligand (Scheme [7]).[17] Methanol was used for better solubility of CuCl, and it is interesting that methanol did not undergo O-arylation. This coupling reaction was also performed in a mixture of water and protic solvent to give N-arylimidazoles in high yields.

Scheme 7 CuCl-catalyzed N-arylation of imidazoles with arylboronic acids

In 2006, Kantam and co-workers reported coupling of imidazoles and amines with arylboronic acids using copper-exchanged fluorapatite (CuFAP) in methanol at room temperature to give N-arylated imidazoles and amines in good to excellent yields (Scheme [8]).[18] Screening a variety of catalysts found that Cu(OAc)₂, CuI, and copper-exchanged hydroxyapatite (CuHAP) gave poor yields; CuFAP was the best catalyst and it could be reused a number of times with the same activity even after the fourth catalytic cycle. The catalyst CuFAP can be recovered from the reaction using simple filtration, and it was also confirmed using atomic absorption spectroscopy there is no leaching of copper from the reaction mixture.

Scheme 8 CuFAP-catalyzed N-arylation of azoles and amines with arylboronic acids

The Buchwald group, in 2001, reported the reaction of amines with arylboronic acids using Cu(OAc)₂ as the catalyst, 2,6-lutidine as the base, and myristic acid as an additive at room temperature (Scheme [9]).[19] The reaction was general to both aryl- and alkylamines and gave diarylamines and N-alkylanilines in good (58–91%) to moderate (50–64%) yields, respectively.

Scheme 9 Cu(OAc)₂-catalyzed N-arylation of amines with arylamines

The coupling of anilines and both primary and secondary amines with arylboronic acids and aryltrifluoroborates using a catalytic amount of Cu(OAc)₂·H₂O was described by Batey and Quach in 2003 (Scheme [10]).[20] This base- and ligand-free strategy worked with a wide variety of functional groups in the presence of oxygen at slightly elevated temperatures. The reaction was general to different boronic acids­ containing both electron-donating and electron-withdrawing­ substituents.

Scheme 10 Cu(II)-catalyzed N-phenylation of aliphatic amines, ammonium salts, and anilines

As the arylboronic acids are more solubility in dichloromethane than trifluoroborates, slightly greater yields were obtained with the former. Also, the presence of 4 Å molecular sieves was essential, and the N-dealkylated side product was not observed in the reaction. Comparing the conditions of Batey and Quach[20] (Table [1], conditions A; see Scheme [10]) to those of the Buchwald group[19] (conditions B; see Scheme [9]) shows that for aliphatic amines the yield of N-arylamines diminishes using the Buchwald conditions as the high concentration of copper in the reaction favors the formation of N-dealkylated side products (Table [1], entry 1). As the aryltrifluoroborates are insoluble in toluene, they failed to react under Buchwald’s conditions (entries 1 and 2). To date, among the Chan–Lam reactions that use Cu(OAc)₂ catalysts, the conditions developed by Batey and Quach continue to be the best for the arylation of alkylamines in the literature.

Table 1 Comparison of Cu(II)-Catalyzed Methods

Entry	R-NH2	Conditions	Product	Yield (%)
				From 13a	From 2a
1		A B	3a	89 0	92 47
2		A B	3b	30 0	53 91

In 2016, our group reported the selective C–NH₂ arylation of various derivatives of C-amino-NH-azoles and 2-amino­benzimidazoles using Cu(II)-catalyzed coupling with arylboronic acids in the presence of 2,2′-bipyridine (bpy) and Cs₂CO₃ at 60 °C in DMF under air.[21] Many unexplored heteroaromatics with multiple nucleophilic sites such as 1H-pyrazolo[3,4-d]pyrimidin-4-amine and 9H-purin-6-amine underwent the reaction smoothly to furnish the products without the protection of the diazole N–H bonds (Scheme [11]). It is noteworthy that the reaction of PMB-protected 1H-pyrazolo[4,3-c]pyridine-3,4-diamine gave selective N-1 arylation due to steric crowding by the protecting group.

Scheme 11 Selective C–NH₂ arylation of C-amino-NH-azoles and 2-aminobenzimidazoles

We have examined the selective N-arylation of unprotected aminophenols using Cu(OAc)₂/AgOAc in methanol as the solvent at room temperature.[22] This open-flask chemistry was extended to 4-aminophenol derivatives albeit with the use of the Cu(OAc)₂/Cs₂CO₃ system with benzoic acid as an additive. These two novel Cu-mediated catalytic systems provided a robust protocol that tolerates many functional groups for the chemoselective N-arylation of aminophenols (Scheme [12]). By employing density functional theory (DFT) calculations for a better overview of the reaction mechanism, we concluded that the O-arylation process has a higher overall barrier (39.99 kcal mol^–1) compared to the N-arylation process (18.87 kcal mol^–1) making the latter more kinetically and thermodynamically favorable.

Scheme 12 Cu-catalyzed chemoselective N-arylation of aminophenols with phenylboronic acid

In 2017, Zhang, Xu, and co-workers developed the chemoselective N-arylation of unprotected aminobenzamides using Cu-catalyzed coupling with arylboronic acids under open-flask conditions.[23] Reactions between 2-aminobenzamides and arylboronic acids in methanol at room temperature under air for 12 hours using 15 mol% of CuCl as the catalyst and 0.5 equiv of triethylamine gave chemoselectively 2-(arylamino)benzamides (Scheme [13]). The reaction was general with both electron-rich and electron-deficient arylboronic acids and also with a variety of substituted 2-aminobenzamides. The selective arylation of 3- or 4-aminobenzamides using this system was unsuccessful, however the use of copper thiophene-2-carboxylate (CuTC, 20 mol%), 2,6-lutidine (1.0 equiv), and DMF (1.0 mL) as the reaction­ system resulted in a Cu-catalyzed C–N cross-coupling­ reaction to give the corresponding 3-(arylamino)- or 4-(arylamino)benzamides (Scheme [14]).

Scheme 13 Cu-catalyzed N-arylation of 2-aminobenzamides with arylboronic acids

Scheme 14 Cu-catalyzed N-arylation of 3- or 4-aminobenzamides with arylboronic acids

We have developed (2014) an efficient route for the synthesis of methyl carbazole-3-carboxylates via the Cu-catalyzed N-arylation of methyl 4-amino-3-iodobenzoates with boronic acids to give methyl 4-(arylamino)-3-iodobenzoates which underwent Pd-catalyzed intramolecular C–H arylation to give the final product.[24] The synthesis of many naturally occurring carbazole alkaloids, such as clausine, glycozoline, and glycozolidal, and including the first reported total synthesis of 2,6-dioxygenated sansoakamine, were accomplished with this methodology. A variety of methyl 4-(arylamino)-3-iodobenzoates were synthesized using Cu(OAc)₂ and 2,6-lutidine as the catalytic system and n-decanoic acid as an additive in toluene under air (Scheme [15]). These synthesized aryl(2-iodoaryl)amines underwent an intramolecular cyclization reaction to produce carbazole alkaloids using 10 mol% Pd(OAc)₂ as the catalyst and K₂CO₃ as the base in DMSO at 130 °C.

Scheme 15 Cu-catalyzed coupling of methyl 4-amino-3-iodobenzoates with boronic acids and subsequent Pd-catalyzed C–H arylation

In 2018, Zhang and co-workers explored the use of a copper embedded polyimide covalent organic framework (Cu@PI-COF) with a high thermal and chemical stability as an active heterogeneous catalyst for the Chan–Lam coupling reaction of arylboronic acids and amines.[25] The synthesis of Cu@PI-COF included heating a mixture of an equal molar ratio of pyromellitic dianhydride and melamine with to 325 °C for 4 hours followed by impregnating the synthesized PI-COF in a solution of Cu(OAc)₂ in EtOH at room temperature. Exploring the scope of the Cu@PI-COF-catalyzed coupling reaction showed that anilines with electron-donating­ groups gave good yields compared to those bearing electron-withdrawing ones (Schemes 16 and 17). A variety of arylboronic acids bearing electron-neutral, -donating, and -withdrawing groups underwent the reaction and furnished the desired products in good to excellent yields (Scheme [17]). The scope of this reaction was checked with different amines, heteroarylamines and benzamides and arylboronic­ acids which furnished the corresponding cross-coupling products in excellent yields (Scheme [16]). The catalyst is highly stable and can be reused eight times by recycling without any significant loss in its catalytic activity.

Scheme 16 Cu@PI-COF-catalyzed reaction of arylboronic acids and various amines

Also in 2018, Hu and co-workers reported the oxidative Chan–Lam coupling reaction of fluoroalkylamines with arylboronic­ acids to generate useful and interesting fluoroalkylamine-containing compounds (Scheme [18]).[26] The use of inexpensive Cu(OAc)₂ as the catalyst and air as an oxidant effected good functional group tolerance which substantiates the strategy. The reactivity of four different fluoroalkylated amines proceeded as 2,2-difluoroethylamine > 2,2,2-trifluoroethylamine > pentafluoropropylamine ≈ heptafluorobutylamine.

Scheme 17 Cu@PI-COF-catalyzed reaction of phenylboronic acids and aniline derivatives

Scheme 18 Cu-catalyzed coupling of fluoroalkylamines with arylboronic acids

Scheme 19 Chan–Lam coupling between a haloarylboronic acid pinacol ester and an aryl methanesulfonamide in the synthesis of GSK8175

In 2019, Kowalski, Leitch, and co-workers reported the eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175, which utilized a Chan–Lam coupling between a haloarylboronic acid pinacol ester and an N-arylmethanesulfonamide.[27a] A mixture of CuCl/CuCl₂ in conjunction with KPF₆ was used as the catalyst system for this transformation (Scheme [19]). This route has a better 20% overall yield as compared to the previous route, which has an overall 10% yield involving 13 steps in a completely linear sequence.[27b]

Krasavin and Dar’in reported (2016) the Cu(OAc)₂-promoted N-arylation of 2-imidazolines with arylboronic acids (Scheme [20]).[28] Using a 1:2:1.5 molar ratio of the substrate/boronic acid/Cu(OAc)₂, as reported by Chan–Lam, the reaction was optimized to give the best yield in DMSO. Various 2-imidazolines bearing different substituents on the nitrogen and a number of boronic acids underwent the reaction smoothly to furnish N-aryl-2-imidazolines in moderate to good yields.

Scheme 20 Cu(OAc)₂-promoted N-arylation of 2-imidazolines with arylboronic­ acids

In 2017, Mokhtari, Naimi-Jamal, and co-workers reported the Chan–Lam coupling of arylboronic acids with arylamines using nanoporous Cu₂(BDC)₂(4,4′-bpy)-MOF as the catalyst in the presence of air via a ball-milling strategy (Scheme [21]).[29] The desired MOF was synthesized by solvent-free ball-milling a mixture of 1:1:0.5 ratio of Cu(OAc)₂·H₂O, terephthalic acid, and 4,4′-bipyridine (4,4′-bpy) at room temperature which was analyzed by XRD that indicated mutually interpenetrating structure of a pair of three-dimensional frameworks. The optimized conditions used a 0.5:1 ratio of aniline and phenylboronic acid with Cu₂(BDC)₂(4,4′-bpy) as the catalyst in H₂O/MeOH (1:1) as the solvent. Different arylamines with electron-withdrawing and electron-releasing groups gave the corresponding N-arylanilines in good yields.

Scheme 21 Nanoporous Cu₂(BDC)₂(4,4′-bpy)-MOF-catalyzed coupling of arylboronic acids with arylamines

Leitch, Watson, and co-workers (2018) established the Chan–Lam N-arylation of primary and secondary N-arylsulfonamides at room temperature on a practical and large scale (Scheme [22]).[30] After mechanistic studies, they selected Cu(MeCN)₄PF₆ as the catalyst to reduce the amount of H₂O present and competing ligating anions available (e.g., AcO^–) in the reaction mixture. The utilization of a stronger amine base, such as N-methylpiperidine, was crucial for the transformation of arylboronic acids. However, for aryl­boronic acid pinacol esters (ArBpin) substrates the base used was K₃PO₄ instead of an amine base due to catalyst inhibition by pinacol.

Scheme 22 Cu(MeCN)₄PF₆-catalyzed N-arylation of N-arylsulfonamides with arylboronic acids and arylboronic acid pinacol esters

In 2015, Clark and co-workers investigated the Cu-catalyzed coupling between 2-(aminomethyl)phenylboronate esters and arylamines using Cu(OAc)₂ under oxidative conditions to give N-aryl-2-(aminomethyl)anilines (Scheme [23]).[31a] Homocoupling of the arylboronate ester was reported as a major side product in this reaction. In the absence of base, the N-aryl-2-(aminomethyl)anilines were formed with improved yield and increased selectivity over the homocoupled product. Both the boronate ester substrates and the aniline coupling partners bearing electron-donating and electron-withdrawing substituents were well tolerated under the reaction conditions. The reactivity of the boronate ester was enhanced by the presence of the adjacent benzylamine moiety, which affected the competing rates of transmetalation in the catalytic cycles and thereby influencing the resulting product distribution.

Previous studies on Cu-mediated C–N bond-forming reactions have shown that the pKa of the N–H bond is an important factor in the rate of the coupling reaction, with more acidic substrates exhibiting faster reactivity. Alternatively, alkylamines may also undergo oxidative deamination under the Cu-mediated conditions, thus limiting the formation of the desired product. It was observed that the product distribution is related to the size of the counterion of the base. Alkylamines compared to arylamines generated different product distributions as the acidity and nucleo­philicity of the amines are crucial factors toward the construction­ of desired diamines.[31b]

Scheme 23 Cu(OAc)₂-catalyzed reaction under oxidative conditions of 2-(aminomethyl)phenylboronate esters and arylamines

In 2016, Phukan and co-workers synthesized a novel square pyramidal copper complex, [Cu(DMAP)₄I]I via the disproportionation reaction of CuI and DMAP in DMSO.[32] This catalyst was subsequently used in the Chan–Lam coupling reaction of arylboronic acids with either an amine, amide, azide (Section 2.1.3), or thiol (Section 3). The reaction of arylboronic acids with alkyl- and arylamines required the use of only 2 mol% [Cu(DMAP)₄I]I in methanol at room temperature for a short time to give the N-arylated products in high yields (Scheme [24]). In this rapid reaction the use of arylboronic acids with electron-withdrawing groups increased the reaction rate. This new protocol is important not only because of the excellent yields of amine substrates, but it may provide more information of the configuration of the copper reactive intermediate. More work needs to be done in this area of coordinated copper with known configuration.

Scheme 24 [Cu(DMAP)₄I]I-catalyzed reaction of arylboronic acids with alkyl- and arylamines

The reaction was extended to different benzamides under the same optimized conditions (Scheme [25]). However, the reaction with amides gave the corresponding products in lower yield and with a slower rate compared to that for amines.

Scheme 25 [Cu(DMAP)₄I]I-catalyzed reaction of arylboronic acids with benzamides

Scheme 26 Electrochemical amination of arylboronic acids in aqueous NH₃

The electrosynthesis of arylamines and phenols from arylboronic acids in aqueous ammonia was explored by Huang and co-workers in 2013.[33] By changing the anode potential and the aqueous ammonia concentration, the synthesis of anilines and phenols can be achieved chemoselectively in an undivided cell. Cu foils served as the cathode and anode, whereas a Ag/AgCl electrode was chosen as the reference electrode. A variety of arylboronic acids bearing electron-donating or electron-withdrawing groups underwent the reaction chemoselectively to generate the arylamines in good yields (Scheme [26]). The N-arylation of ammonia to give primary aniline is a very useful reaction.

Arylboronic acid pinacol esters are very useful reagents due to their ease of synthesis and improved stability compared to arylboronic acids, especially heteroarylboronic acids. However, there was only limited success in using arylboronic acid pinacol ester in Chan–Lam coupling reactions. In 2016, Watson and co-workers reported a breakthrough in the Chan–Lam coupling of arylboronic acid pinacol esters with alkyl- and arylamines using a mixed MeCN/EtOH solvent system.[34a] Careful optimization of the solvent ratio of MeCN/EtOH mixture to 20:1 was required as the use of EtOH as solvent in the reaction furnishes the corresponding ether product, and this solvent mix minimizes byproduct formation. Both arylboronic acid pinacol esters and arylamines bearing electron-donating or -withdrawing substituents were tolerated by this solvent mixture, which shows the broad functional group tolerance of this strategy (Scheme [27]). Alkylamines underwent the reaction in MeCN, and EtOH was not necessary for this transformation (Scheme [28]). Further careful mechanistic studies showed that excess amine and B(OH)₃ additives (to remove unproductive pinacol binding to the copper intermediate) are important. At 80 °C, arylboronic acid pinacol ester arylated anilines, amines, phenol, thiophenol sulfonamide, pyrrole, and indazole.[34b]

Scheme 27 Cu(OAc)₂-mediated reaction of arylboronic acid pinacol esters with arylamines

In 2019, Gale-Day and co-workers reported the electrochemical synthesis of a variety of N-arylanilines via the Chan–Lam coupling of anilines and arylboronic acids utilizing a dual copper anode/cathode system in the presence of Et₃N and air or oxygen (Scheme [29]).[35] Anilines with electron-rich substituents or with para-halo groups reacted well, whereas those bearing electron-deficient groups gave moderate yields. A variety of arylboronic acids bearing both electron-withdrawing and -donating groups underwent the reaction smoothly to furnish the products in good to excellent yields.

In 2015, the Kobayashi group developed the Cu(II)-catalyzed aerobic oxidative coupling reaction between aryl­boronic acids and aniline derivatives under visible-light-mediated photoredox catalysis (Scheme [30]).[36] This synthetic protocol was even applied to arylboronic acids with electron-deficient groups. As the oxidation of Cu(II) in complexes with electron-withdrawing group substituted arylboronic acids was difficult, the reaction with these substrates was poor. However, to overcome this drawback and to oxidize Cu(II) to Cu(III), they utilized a combination of photoredox catalysis and copper. This reaction was more efficient in nitrile-based solvents. However, as removing benzonitrile is very difficult, they chose a 1:1 mixture of toluene and MeCN, which furnished N-arylanilines 3 in excellent yields. The presence of visible-light photo redox catalyst, copper catalyst, and blue LED radiation were found to be crucial for this reaction and was illustrated using controlled experiments.

Scheme 28 Cu(OAc)₂-mediated reaction of arylboronic acid pinacol esters with alkylamines

Scheme 29 Cu(OAc)₂-catalyzed electrochemical reaction of boronic acids and anilines

Scheme 30 Visible-light-mediated photoredox catalysis of anilines and arylboronic acids

A plausible mechanism for the reaction of anilines 1 and arylboronic acids 2 is illustrated in Scheme [31]. Ligand exchange followed by transmetalation of the Cu catalyst with aniline 1 and arylboronic acid 2 produces the Cu amide 38. At the same time, the light-induced metal-to-ligand charge transfer of [Ir(ppy)₃] furnishes the complex 40, which on quenching with O₂ produces complex 41. The complex 41 further oxidizes Cu(II) to Cu(III) and generates the Cu(III) intermediate 39. The intermediate 39 undergoes reductive elimination to furnish N-arylaniline 3 and generates the catalyst Cu(I) which is subsequently oxidized to produce Cu(II) and continues the catalytic cycle.

Scheme 31 Mechanism for the visible-light-mediated Chan–Lam coupling reaction

Scheme 32 Formation of 2-amino-1-arylbenzimidazoles by Cu-catalyzed­ reaction of 2-aminobenzimidazoles and aryl halides

Our group have also achieved the chemoselective N-arylation of the azole nitrogen by Cu-catalyzed coupling with aryl halides using catalytic Cu₂O and KOH in DMSO at 120 °C to give 2-amino-1-arylbenzimidazoles (Scheme [32]).[37]

2.1.3

Coupling with Azides, Sulfoximines, and Sulfonediimines as Nitrogen Nucleophiles

Reddy and co-workers first reported the N-arylation of aryl azides by Chan–Lam cross-coupling with arylboronic acids mediated by Cu(OAc)₂ and indium metal for the construction of N-arylanilines in 2011 (Scheme [33]).[38] Optimization of the conditions showed that methanol was the best solvent, and the reaction did not proceed in the absence of Cu(OAc)₂ and indium metal. Examination of the scope of the reaction under the optimized conditions showed that aryl azides bearing substituents such as methoxy, ethyl, and 2,4,6-trimethylphenyl groups underwent the reaction smoothly. This reaction was unsuccessful if the azide is replaced by an aryl halide.

Scheme 33 Cu(OAc)₂/indium metal mediated coupling of arylboronic acids and aryl azides

Scheme 34 Proposed mechanism for the Cu(OAc)₂/indium metal mediated coupling of arylboronic acids and aryl azides

Mechanistically, in the first step, the aryl azides are converted into arylamines with indium metal, and this is followed by N-arylation with the arylboronic acid (Scheme [34]).[38]

The work by Phukan and co-workers (see Sections 2.1.2 and 3) using the novel square pyramidal copper complex [Cu(DMAP)₄I]I also utilized this catalyst for the Chan–Lam coupling of arylboronic acids with tosyl azide to give N-aryl­sulfonamides in moderate yields (Scheme [35]).[32]

Scheme 35 Cu-catalyzed coupling of arylboronic acids with tosyl azide

Cai and co-workers developed a l-proline-functionalized MCM-41-immobilized copper(I) complex [MCM-41-l-proline–CuCl] catalyzed heterogeneous Chan–Lam coupling reaction of sulfonyl azides with arylboronic acids under open-air conditions without the aid of base or additive that gave a variety of N-arylsulfonamides (Scheme [36]).[39] The new heterogeneous MCM-41-l-proline–CuCl utilized readily available and cheap starting materials and can be used up to 8 times with the same catalytic activity by recovering it from the reaction mixture by simple filtration. The optimized conditions used 10 mol% of MCM-41-l-proline–CuCl as the catalyst with methanol as the solvent at room temperature for 4 hours. The reaction of tosyl, arenesulfonyl, or methanesulfonyl azides with various arylboronic acids bearing electron-donating as well as electron-withdrawing substituents gave N-aryl and N-methylsulfonamides in excellent yields (87–97%) in 2–6 hours.

Scheme 36 MCM-41-l-proline–CuCl-catalyzed coupling of arylboronic acids with sulfonyl azides

In 2014, Kim and co-workers developed a novel method using sulfonyl azides 39 as nitrogen nucleophiles with various arylboronic acids using CuCl as the catalyst in the absence of a base or ligand at room temperature, in a mild and efficient coupling reaction that gave a variety of N-aryl­sulfonamides (Scheme [37]).[40]

Scheme 37 Cu(OAc)₂-catalyzed N-arylation of sulfonyl azides with arylboronic­ acids

To examine the generality of the reaction, the reaction of sulfonyl azides with various phenylboronic acid derivatives was performed (Scheme [38]).[40] The reaction of tosyl azide (39b) with potassium trifluoro(phenyl)borate (13a) gave N-tosylaniline (34a) in a maximum yield of 97% after 15 hours and 100% conversion, but the reaction with phenyl­boronic acid pinacol ester (27b) gave 34a in 21% yield with 30% conversion.

Scheme 38 Cu(OAc)₂-catalyzed N-arylation of sulfonyl azides with different aryl donors

Scheme 39 CuCl-catalyzed N-arylation of benzyl azidoformate with arylboronic­ acids

In 2015, Kim and co-workers reported the CuCl-catalyzed reaction of azidoformates and arylboronic acids gave N-arylcarbamates 46 (Scheme [39]).[41] Arylboronic acids with both electron-donating and electron-neutral substituents furnished benzyl N-arylcarbamates in good yields in the absence of a base or ligand at room temperature .

The generality of the reaction was also examined using phenylboronic acid and a variety of azidoformates 46; generally the reactions readily proceeded at room temperature to yield alkyl and phenyl N-phenylcarbamates 47 in moderate to excellent yields (Scheme [40]).[41]

Scheme 40 CuCl-catalyzed N-arylation of various azidoformates with phenylboronic acid

To understand the reaction mechanism better, several control experiments were performed (Scheme [41]). These results highlighted the unique necessity of the azidoformate functionality, and also a 14.5% deuterium incorporation in the final product proved that both the solvent and the boronic acid can act as a proton source.

Scheme 41 Control experiments for the CuCl-catalyzed N-arylation of azidoformates with arylboronic acids

Bolm and co-workers reported a mild and simple N-arylation of sulfoximines (sulfoximides) by the Cu(OAc)₂-catalyzed coupling of NH-sulfoximines with arylboronic acids in the absence of base or heating.[42] Optimization experiments were performed with sulfoximine 48a and phenylboronic acid (2a), and the results of the effect of various copper salts are summarized in Table [2]. Among them, anhydrous Cu(OAc)₂ as catalyst gave the highest yield for the reaction.

Table 2 Effect of Various Copper Salts on the Reaction of a Sulfox­imine and Phenylboronic Acid

Entry	Copper salt	Yield (%) of 49a
1	CuI	85
2	CuCl	55
3	CuSO4	91
4	Cu(OAc)2·H2O	87
5	Cu(OAc)2	93

The reaction was efficient with different commercially available arylboronic acids and various sulfoximines under the optimized conditions (Scheme [42]). Good to excellent results were achieved with para- and ortho-substituted boronic­ acids, irrespective of the electronic nature of the substituent of the boronic acid.

Scheme 42 Cu(OAc)₂-catalyzed N-arylation of sulfoximines with arylboronic acids

In 2013, Bolm and co-workers reported the Cu-catalyzed C–N cross-coupling of sulfonediimines with boronic acids to give a variety of N,N′-disubstituted sulfonediimines, including N-(hetero)aryl and N-alkenyl sulfonediimines in good to excellent yields (Scheme [43], Figure [1]).[43] Optimization of the conditions with a variety of Cu(I) and Cu(II) salts and solvents showed that only anhydrous Cu(OAc)₂ and anhydrous methanol were effective, the remainder furnished the products in poor yields. The presence of a significant amount of oxygen and water was crucial for the transformation. In the presence of argon, the product was obtained in low yield (64%) with incomplete conversion. However, the use of a CaCl₂-drying tube for the removal of moisture increased the yield of the desired product 47 to 85%.

Bolm and co-workers also reported the palladium-catalyzed coupling of NH-sulfonediimines using aryl bromides to give the N-arylated products in high yields.[44] However, the construction of N,N′-disubstituted moieties using this method has various drawbacks, such as the use of costly palladium, poor substrate scope, glove box usage, use of harsh conditions such as high temperature, and so on.

To check the substrate scope of the optimized Cu(OAc)₂-catalyzed reaction,[43] the reaction of S-methyl N,S-diphenyl sulfonedimine (50; R¹ = H) was performed with different boronic acids to give N,N′-disubstituted products 51 in good to excellent yields (Scheme [43]).

Scheme 43 Cu(OAc)₂-catalyzed N-arylation of sulfonediimines with arylboronic acids

The optimized reaction conditions were applicable to alternatively substituted sulfonediimines (Figure [1]).[43] In general, good yields of N-phenylated products were synthesized when S-alkyl S-aryl sulfonediimines were reacted with phenylboronic acid derivatives.

Figure 1 Cu(OAc)₂-catalyzed N-arylation of different sulfonediimines with arylboronic acids

In 2014, the Battula[45] and Arvidsson[46] groups independently reported efficient and low-cost Cu-catalyzed systems for the N-arylation of sulfonimidamides. The Battula group used 10 mol% Cu(OAc)₂ in methanol in the absence of base at room temperature to successfully introduce various aryl, heteroaryl, and cyclopropyl groups, while the Arvidsson group used 100 mol% Cu(OAc)₂ with Et₃N as the base in acetonitrile­ at room temperature to successfully introduce various aryl and heteroaryl groups in both cases in good to excellent yields.

2.1.4

Coupling with N,N-Dialkylhydroxylamines

In 2012, Miura, Hirano, and co-workers reported the Cu-catalyzed N-arylation of hydroxylamines with aryl­boronic acids to give N-arylamines (Scheme [44]).[47] The hydroxylamines were generally secondary acyclic amines and the arylboronic acid pinacol or neopentylglycol esters (neop) were substituted with I, Cl, Br, CO₂Me, COPh, and CHO. Arylboronates bearing electron-donating groups and electron-withdrawing groups underwent the amination smoothly. The strategy was even extended toward the preparation of heteroarylamines like 2- and 3-thienylamines. Attempts to use alkylboronates such as butyl­boronic acid neopentylglycol ester were unsuccessful. Acyclic amines bearing N,N-diethyl, N,N-diallyl, N-benzyl-N-methyl substituents were compatible under standard reaction conditions.

Scheme 44 Cu-catalyzed amination of arylboronates with various hydroxylamines­

Scheme 45 Plausible reaction mechanism for the Cu-catalyzed amination of arylboronates with various hydroxylamines

The mechanism proposed for the amination is shown in Scheme [45]. Initially, the Cu(II) catalyst is reduced to Cu(I) forming CuO ^t Bu, which reacts with the neopentylglycol boronate 52 to form the monoarylcopper. This is followed by the generation of diarylcuprate 54 by the reaction of monoarylcopper with boronate using LiO ^t Bu; 54 reacts with the hydroxylamine 53 to generate the product 3 and the monoarylcopper to continue the reaction.

Also in 2012, Lalic and co-workers reported the synthesis of sterically hindered anilines in high yields via the Chan–Lam cross-coupling reaction of O-benzylhydroxylamines with (hetero)arylboronic acid neopentylglycol esters using XantphosCu-O ^t Bu, formed in situ from (CuO ^t Bu)₄ and Xantphos in toluene (Scheme [46]), in the presence of LiO ^t Bu in concentrated isooctane solution.[48] Various aryl- and heteroarylboronic esters underwent the reaction smoothly with a variety of electrophiles, such as N-(benzyloxy)morpholine, -pyrrole, and -piperazine. For the reaction of ortho-substituted boronic esters with less hindered electrophiles, replacing LiO ^t Bu with CsF was beneficial in improving the yield.

Scheme 46 Cu-catalyzed reaction of O-benzylhydroxylamines with aryl- and heteroarylboronic acid neopentylglycol esters

2.1.5

Enolate Coupling with sp³-Carbon Nucleophiles

In 2016, Lundgren and co-workers reported the arylation of active methylene species via oxidative methods. Functionalized arylboronic acid esters were coupled with a variety of stabilized sp³-nucleophiles mediated by Cu(OTf)₂ under mild reaction conditions (rt to 40 °C).[49a] Quaternary centers were generated by using substrates like tertiary malonates and amido esters (Scheme [47]). This mild enolate Chan–Lam reaction is chemoselective in the presence of halogen electrophiles, such as haloarylboron reagents, and thus complements traditional cross-coupling and SNAr protocols. Furthermore, the generality extends to activated methylene substrates such as phosphonyls, amides, and sulfonyls, which have not been reported to undergo Hurtley-type reaction conditions (Schemes 48 and 49).[49b] This method could overcome the drawbacks of the oxidative arylation strategies employing organoboron reagents and activated methylenes that require the use of Pb(OAc)₄ and Hg additives in stoichiometric amounts.[49c]

Scheme 47 Chan–Lam coupling of arylboron reagents with enolates

Other reactions such as homocoupling, protodeborylation, and acetoxylation were also observed, which furnished the minor side products in the coupling reaction. The reaction of diethyl malonate with 3-bromophenylboronic acid and 3-bromophenylboronic acid pinacol ester was poor and gave diethyl 2-(3-bromophenyl)malonate (42) in 2% and 7% yield, respectively whereas 3-bromophenylboronic acid neopentylglycol ester gave 42 in 68% yield and, surprisingly, arylboroxine gave 42 in 86% yield (Scheme [48]).[49]

Scheme 48 Enolate Chan–Lam coupling: effect of arylboronic acid

Scheme 49 Cu-mediated oxidative arylation of arylboroxines with sp³-nucleophiles

2.1.6

Nickel-Catalyzed Chan–Lam Coupling

In 2012, nickel was used as a catalyst for the first time in the Chan–Lam couple by Singh and co-workers. They developed a Ni-catalyzed N-arylation using the reaction of arylboronic acids with amines, amides, and N-heterocycles with 20 mol% NiCl₂·6H₂O and 20 mol% bpy as the catalyst and DBU as the base in acetonitrile at room temperature under atmospheric conditions (Scheme [50]).[50] This method was successful with various boronic acids irrespective of their nature. The reaction was also performed on a larger scale (20 mmol, gram) giving the product in 70% yield, showing that it is suitable for industrial applications.

Scheme 50 Ni-catalyzed N-arylation of phenylboronic acids with nitrogen nucleophiles

Scheme 51 Formation of 2-(arylamino)benzimidazoles by Ni-catalyzed reaction of 2-aminobenzimidazoles and arylboronic acids

We have developed a facile one-pot Ni-catalyzed coupling reaction strategy for the selective N-arylation of the primary amine (C–NH₂) group of 2-aminobenzimidazoles using boronic acids under ligand-free conditions (Scheme [51]).[37] The reaction of diverse 2-aminobenzimidazoles and phenylboronic acids was examined under the optimized conditions for the Ni-catalyzed coupling reaction, which used 20 mol% Ni(OAc)₂ and 2.0 equiv DBU as the base in DMSO at 50 °C. This was the first report of a Ni-catalyzed selective C–NH₂-arylation in such substrates with multiple reactive nucleophilic sites.

In 2019, Ball and co-workers reported the nickel-promoted pyrrolidone N–H arylation of pyroglutamate-histidine sequences using 2-nitroarylboronic acids under mild aqueous conditions (Scheme [52]).[51a] The synthetic procedures utilizing copper catalysts cause serious selectivity concerns as they furnish histidine-directed products at both internal and pyroglutamate sites.[51b] The presence of ortho π-conjugated electron-deficient groups, such as the nitro group, was required in the arylboronic acids to generate the N-arylation product in good yields.

Scheme 52 Ni(II)-promoted pyrrolidone N–H arylation of pyroglutamate-histidine sequences using arylboronic acids

2.1.7

Coupling with Amino Acids

In 2010, the Campagne group utilized Chan–Lam cross-coupling reaction conditions for the N-arylation of Cbz-protected histidine (Scheme [53]).[52] Protected histidines were directly functionalized with arylboronic acids to give the corresponding N(τ)-arylhistidines in moderate to good yields under mild conditions. They first examined various methods for the metal-catalyzed transformation of protected histidines to synthesize N(τ)-(hetero)arylhistidine derivatives including recent variants of the Buchwald–Hartwig and Ullmann coupling and Cu-catalyzed cross-coupling from aryllead triacetates but none proved successful. Moving to the Chan–Lam–Evans cross-coupling reaction had a dramatic influence on the reaction outcome. The optimized conditions used Cu(OAc)₂·H₂O as the catalyst in methanol under open-air conditions in the presence of 3 equiv of NaOAc as the base (Table [3]). No improvement in the product yield was observed without the use of a base.

Table 3 Optimization of Reaction Conditions

Catalyst (10 mol%)	Conditions (50 °C, 24 h)	Additive	Isolated yield (%)
Cu(OTf)2	CH2Cl2, air	–	n.r.
CuBr	CH2Cl2, air	–	26
Cu(OAc)2·H2O	MeOH, air	–	31
Cu(OAc)2·H2O	MeOH, air	–	44
Cu(OAc)2·H2O	MeOH, air	NaOAc (3 equiv)	62
Cu(OAc)2·H2O	MeOH, air	KF (3 equiv)	40
Cu(OAc)2·H2O	MeOH, air	4 Å MS	27
Cu(OAc)2·H2O	MeOH, N2	NaOAc (3 equiv)	n.r.

Scheme 53 Cu(OAc)₂·H₂O-catalyzed coupling of Cbz-protected histidine with various boronic acids

The optimized conditions were used in the reaction of Cbz-protected histidine with various arylboronic acids to give N(τ)-arylhistidines in moderate to good yields (Scheme [53]). This reaction was successful with arylboronic acids containing either electron-donating or withdrawing groups.

2.1.8

Coupling with Alkylboron Reagents

Even though it is challenging to introduce a cyclopropyl group into indoles, pyrroles, and amides, Gagnon and co-workers successfully achieved the cyclopropylation of cyclic amides and azoles in 2007.[53] This pioneering work utilized a triscyclopropylbismuth reagent with Cu(OAc)₂, and the reaction proceeded in good yields with broad substrate scope. A few issues with this reaction are reagent availability and atom efficiency: the triscyclopropylbismuth reagent is not commercially available and cannot be stored for a long time, and two cyclopropyl substituents on bismuth remain unaffected in the transformation.

In 2008, Tsuritani and co-workers developed the Cu-mediated coupling reaction of cyclopropylboronic acid with indoles, pyrroles, and carbazoles and cyclic amides using catalytic or stoichiometric Cu(OAc)₂, DMAP, and NaHMDS at 95 °C under an oxygenated atmosphere (Scheme [54]).[54] Various functional groups were tolerated.

Scheme 54 Cu(OAc)₂-mediated reaction of cyclopropylboronic acid with indoles and pyrroles

Table 4 Optimization of the Reaction Conditions for the N-Methylation of 4-Methylaniline

Entry	Base	Solvent	Yield (%)
1	pyridine	CH2Cl2	9
2	pyridine	DCE	23
3	pyridine	THF	29
4	pyridine	xylenes	33
5	pyridine	DMF	24
6	pyridine	MeCN	37
7	pyridine	dioxane	53
8	DIPEA	dioxane	21
9	Et3N	dioxane	42

In 2009, Cruces and co-workers reported a new method for the selective monomethylation of anilines by the Cu(II)-promoted coupling of anilines and methylboronic acid to give N-methylanilines in high yields (Scheme [55]).[55] This is the first reported example of the use of methylboronic acid in a Chan–Lam coupling reaction and is a new approach to the selective monomethylation of anilines. It is necessary to incubate the substrate with the copper reagent before the addition of methylboronic acid. Screening a variety of Cu(I) and Cu(II) salts showed Cu(OAc)₂ to be the best catalyst for this transformation; the Pd-catalyzed reaction, as well as the use of other copper salts, were unsuccessful. The use of a variety of solvents at different temperatures was examined (Table [4]).

Use of excess base was not a crucial factor for the transformation as conversions with 3 and 5 equiv of pyridine were similar. However, the reaction mainly depended on the ratio of boronic acid and copper salt. Maximum yields were obtained when a mixture of the aniline, 2.5 equiv of Cu(OAc)₂, and pyridine in dioxane was incubated for 10–15 minutes, and then 2.5 equiv of methylboronic acid were added. This order of addition was crucial as it lowered the yield of dimethylated amine.

Both electron-deficient and -rich anilines underwent the reaction smoothly, showing good functional group tolerance (Scheme [55]). Anilines bearing ortho substituents also produced monomethylated products but required a longer reaction time due to steric hindrance. Anilines with a ketone or ester group, which are problematic in reductive amination reactions, also gave the corresponding products. The reaction was shown to be general to other substituted anilines.

Scheme 55 Cu(OAc)₂-mediated monomethylation of anilines with methylboronic acid

In 2010, Zhu, Neuville, and Benard reported the reaction of anilines and primary and secondary aliphatic amines with cyclopropylboronic acid in dichloroethane in the presence of Cu(OAc)₂ (1 equiv), 2,2′-bipyridine (1 equiv), and Na₂CO₃ or NaHCO₃ (2 equiv) under air atmosphere to give the corresponding N-cyclopropyl derivatives in good to excellent yields (Scheme [56]).[56] Anilines having electron-donating and -withdrawing groups participate in this reaction to afford N-cyclopropylanilines in good to excellent yields. The N-cyclopropylation of various cyclic secondary amines such as N-monoacylated/arylated piperazines, isoindoline, piperidine, and N-Boc-1,4-diazepine was also achieved using this protocol. It is interesting to note that 1-(2,5-dimethylphenyl)piperazine was successfully converted into 1-cyclopropyl-4-(2,5-dimethylphenyl)piperazine in 75% yield. Chemoselective cyclopropylation of amines was also developed by using these optimized reaction conditions (Scheme [57]).

Scheme 56 Cu-mediated cyclopropylation of anilines and aliphatic amines with cyclopropylboronic acid

Scheme 57 Chemoselective Cu-mediated cyclopropylation of amide-substituted amines with cyclopropylboronic acid

Scheme 58 Cu(OAc)₂-promoted N-cyclopropylation of various secondary amides with cyclopropylboronic acid pinacol ester

In 2013, Taillefer and co-workers explored the N-cyclopropylation of poor nucleophiles, such as aromatic and aliphatic secondary acyclic amides, using a simple and cheap copper system.[57] Treatment of acyclic N-alkyl- and N-arylamides with cyclopropylboronic acid pinacol ester under the optimized reaction conditions of 1 equiv of Cu(OAc)₂, 3 equiv of pyridine, 0.5 equiv of Cs₂CO₃ in toluene at 100 °C in dry air gave tertiary N-alkyl- and N-aryl-N-cyclopropylamides in good to excellent yields (Scheme [58]); these compounds constitute a wide family of biologically active compounds. In devising the optimal conditions the use of several oxidants other than the dioxygen from dry air such as pyridine N-oxide (PINO) or 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO) was examined but no improvement in the yield was observed. On the other hand, performing the reaction under an inert atmosphere of N₂ led to a dramatic decrease in the yield.

In 2013, Watson and co-workers reported the first Chan–Lam coupling of alkylboronic acids with primary amides (Scheme [59]).[58] The Cu-catalyzed coupling of amides with alkylboronic acids used NaOSiMe₃ as a mild base and di-tert-butyl peroxide (DTBP) as the oxidant and gave N-monoalkylamides in good to very good yields. This transformation was possible even with amides containing β-hydrogen atoms using the alkylboronic acid only in slight excess. This alkyl C–N cross-coupling has been shown to be the best facile and simple strategy for the synthesis of secondary amides.

Scheme 59 Cu-catalyzed coupling of amides with alkylboronic acids

As the alkylboronic acids were difficult to prepare and the functional group tolerance of the reaction limited, in 2016 Watson and co-workers reported the oxidative Cu-catalyzed cross-coupling of both primary and secondary alkylboronic esters with a variety of primary amides using appropriate diketimine ligands.[59] Copper catalysts were developed based on two new diketimine (NacNac) ligands (Figure [2]) that easily coupled both primary and secondary alkylboronic acid pinacol esters. Optimization studies revealed that the primary boronic esters underwent coupling using ligand L3 whereas the anisidine-derived ligand L2 furnished the products with secondary boronic esters containing minimal rearranged products. The scope and generality of various substituted primary alkylboronic esters with primary amides is shown in Scheme [60], while those of different secondary alkylboronic esters with primary amides are shown in Scheme [61].

Figure 2 Diketimine (NacNac) ligands

Scheme 60 Cu-catalyzed reaction of primary alkylboronic esters with primary alkylamides

Scheme 61 Cu-catalyzed reaction of primary alkylboronic esters with secondary alkylamides

In 2013, Kuninobu and Sueki reacted amines with alkylboronic acid pinacol esters in the presence of a catalytic amount of Cu(OAc)₂ and di-tert-butyl peroxide to give alkylated amines in good to excellent yields (Scheme [62]).[60] This reaction used stable boronates as substrates, and the addition of a strong base is not necessary. This reaction is a rare example of the catalytic alkylation of amines and has potential applicable to the synthesis of useful compounds such as tyrosine kinase antagonist lavendustin and folic acid antagonist methotrexate.

An examination of the suitability of alkylborane reagents showed that benzylboronic acid pinacol ester, even when containing electron-withdrawing or -donating groups, was more reactive than B-benzyl-9-borabicyclo-[3.3.1]nonane and borate. The reaction was extended to both primary and secondary alkylboronic acid pinacol esters also to alkyl groups containing base-sensitive groups such as cyano and ethoxycarbonyl. The Cu(OAc)₂ and di-tert-butyl peroxide system was also used for the alkylation of phenols with alkylboronic acid pinacol esters to give alkyl aryl ethers (see Section 2.2.2).

Scheme 62 Cu(OAc)₂-catalyzed reaction of amines with alkylboronic acid pinacol esters

In 2018, McAlpine, Engle, and co-workers reported the N-cyclopropylation of nitrogen-containing heterocycles using potassium cyclopropyltrifluoroborate and catalyzed by Cu(OAc)₂ and 1,10-phenanthroline and employing 1 atm of O₂ as the terminal oxidant (Scheme [63]).[61] The use of more stable potassium cyclopropyltrifluoroborate, 1 atm O₂ as the terminal oxidant, bidentate ligands such as 1,10-phenanthroline and a 3:1 ratio of toluene/H₂O dramatically improved the efficiency of the reaction and improved reproducibility. These reaction conditions are not generally effective in promoting N-cyclopropylation of nitrogen nucleophiles such as unprotected, N-Boc, and N-Ac anilines. Nevertheless, three classes of aza-heterocycles such as 2-pyridones, 2-aminopyridines, and 2-hydroxybenzimidazoles were reactive substrates using this method (Scheme [63]).

Scheme 63 Cu(OAc)₂/phen catalyzed N-cyclopropylation

In 2017, Harris and co-workers reported the Chan–Lam coupling of tertiary potassium 3-Boc-3-azabicyclo-[3.1.0]hexan-1-yltrifluoroborate with various 1,2-diazoles mediated by Cu(OAc)₂, phenanthroline monohydrate ligand­, and K₃PO₄ to give 1-heteroaryl-3-azabicyclo-[3.1.0]hexanes containing a C-tertiary heteroarylamine (Scheme [64]).[62] The reaction of a range of substituted pyrazoles proceeded in moderate to good yields while 1H-indazole gave the N-1 substituted product in high yield, but other nitrogen heterocycles, amides, sulfonamides, and phenol gave very poor yields.

Scheme 64 Cu(OAc)₂/phenanthroline monohydrate -mediated coupling of potassium 3-Boc-3-azabicyclo[3.1.0]hexan-1-yltrifluoroborate with various 1,2-diazoles

2.1.9

Coupling with Electron-Deficient Heteroarylamines

In 2013, Das and co-workers reported the ligand- and base-free Cu-catalyzed N-arylation of electron-deficient 2-amino-N-heterocycles with arylboronic acids at ambient temperature in air to give a wide range of 2-(arylamino)-N-heterocycles with potential bioactivity (Scheme [65]).[63]

In the Chan–Lam coupling, electron-rich N-nucleophiles tends to give better results, but the presence of a chelating nitrogen atom in can also significantly influence the product yield. The reaction of 2-amino-substituted heterocycles, such as 2-amino-substituted pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, thiazole, and benzothiazole, with electronically diverse boronic acids using 10 mol% Cu(OAc)₂ in DCE with air as the oxidant gave the corresponding products in good to excellent yields, and the only noticeable difference was observed in the reaction times. The generality of the reaction was shown by the reaction of 5-bromo-2-aminopyridine, which is otherwise difficult to react under palladium-catalyzed amination reactions. The reaction was further extended to pharmaceutically important heterocyclic pyrazolopyridines such as 1-alkyl-substituted 1H-pyrazolo[3,4-b]pyridin-3-amine.

Scheme 65 Cu-catalyzed N-arylation of 2-amino-N-heterocycles with arylboronic acids

In 2015, Wu and co-workers also developed a similar method for the N-arylation of 2-amino-N-heterocycles by using arylboronic acids with Cu(OAc)₂·H₂O as the active catalyst.[64]

In 2014, Pochet and co-workers reported the Cu(OAc)₂-mediated synthesis of 9-(hetero)aryl purine derivatives using 6-chloropurine and arylboronic acids (Scheme [66]).[65] The coupling reaction of sterically demanding (hetero)arylboronic acids was successfully performed by optimizing the reaction conditions in terms of base and solvent. Target adenine derivatives were then obtained from the coupling products.

Scheme 66 Cu-catalyzed N-arylation of 6-chloropurine with aryl­boronic acids

They developed three different conditions: Conditions A: Cu(OAc)₂ (1 equiv), (hetero)arylboronic acid (3 equiv), and 1,10-phenanthroline (2 equiv) in 4 Å MS in CH₂Cl₂ as solvent at room temperature. Conditions B: Cu(OAc)₂ (1 equiv), (hetero)arylboronic acid (3 equiv), 1,10-phenanthroline (2 equiv), and Et₃N (2 equiv) in DMF as solvent at 50 °C . Conditions C: Cu(OAc)₂ (1 equiv) and (hetero)arylboronic acid (3 equiv), 1,10-phenanthroline (2 equiv), and pyridine ( 2 equiv) in CH₂Cl₂ as solvent at room temperature. The described two-step procedure provides simple and rapid access to original adenine fragments, which are valuable starting points for fragment-based screening applications, as well as for further chemical diversification into potential therapeutic agents.

Mo and co-workers reported the N-vinylation or N-arylation of N-hydroxybenzotriazoles by Cu-mediated coupling with alk-1-enyl- or arylboronic acids to give 1-alk-1-enyl- or 1-arylbenzotriazole 3-oxides, respectively (Scheme [67]).[66] Treating HOBt derivatives and various substituted boronic acids with 1.0 equiv Cu(OAc)₂, 6 equiv of Na₂SO₄, and 10.0 equiv pyridine in dioxane at 40 °C provided 1-alk-1-enylbenzotriazole 3-oxides in good to excellent yields. This Cu-mediated coupling reaction was also generalized to N-arylation using arylboronic acids bearing various electron-rich and electron-deficient groups in the ortho-, meta-, and para-positions to give 1-arylbenzotriazole-3-oxides in excellent yields.

Scheme 67 Cu-mediated coupling of N-hydroxybenzotriazoles with alk-1-enyl- or arylboronic acids

Baidya and co-workers explored the chelation-assisted Cu-catalyzed cross-coupling of bidentate amides with arylboronic acids to give unsymmetrical amides in high yields (Scheme [68]).[67] The catalyst system used Cu(OAc)₂·H₂O with DMAP as the base and KI as an additive in DME under open-air conditions at room temperature. This reaction was adapted for the reaction of bidentate amides with phenyl(trimethoxy)silanes using Cu(OAc)₂, Ag₂O, and AgF in DMSO at 80 °C for 24 hours (Scheme [69]). The generality of this reaction was further extended with 1-(2-aminophenyl)pyrazole and aminophenyloxazoline bidentate auxiliaries. It is interesting to note that arylboronic acids containing both electron-rich as well as electron-deficient groups generated the N-arylated products, and ortho C–H arylation was not seen under these conditions.

Scheme 68 Chelation-assisted Cu-catalyzed cross-coupling of bidentate amides with arylboronic acids

Scheme 69 Chelation-assisted Cu-catalyzed cross-coupling of bidentate amides with phenyl(trimethoxy)silane

In 2017, Mo and co-workers reported that 3-(hydroxyimino)indolin-2-ones underwent Cu-catalyzed selective cross-coupling reaction with alk-1-enylboronic acids to furnish (E)-N-(alk-1-enyl)oxindole nitrones under mild conditions (Scheme [70]).[68] They demonstrated that mono-N-vinylation could be achieved using catalytic copper salt whereas 2.0 equiv of copper salt generated double N-vinylation products. The synthesized nitrones were cyclized to spirooxindoles under thermal conditions in toluene at 120–140 °C (Scheme [71]).

Scheme 70 Cu-catalyzed N-vinylation of 3-(hydroxyimino)indolin-2-ones with alk-1-enylboronic acids

Scheme 71 Thermal reaction of (E)-N-(alk-1-enyl)oxindole nitrones to form spirooxindoles

2.1.10

Selective C–N Bond Formation for the Synthesis of Heterocycle-Containing Compounds

In 2014, Das and co-workers reported the Cu(II)-catalyzed sequential N-arylation of C-amino-NH-azoles with (hetero)arylboronic acids (Figure [3]).[69]

Figure 3 (Hetero)arene-fused C-amino-NH-azoles

The N-arylation of cyclic amidines, such as 2-aminobenzimidazole, 3-aminoindazoles, and 3-aminopyrazolopyridine, using transition-metal catalysts is very difficult as they coordinate to the active metal centers. Das and co-workers developed an efficient strategy to first give N-aryl-C-aminoazoles and then N-aryl-C-(arylamino)azole derivatives using various (hetero)arylboronic acids in a one-pot or two steps (Schemes 72 and 73). Using this method, for the first time, even substrates with two different nucleophilic sites, such as pyrazolopyridine and pyridoimidazole, were successfully transformed (Scheme [73]).

Scheme 72 Cu-catalyzed N-arylation of C-amino-NH-azoles with (hetero)arylboronic acids

Scheme 73 Cu-catalyzed C–NH₂-arylation of N-aryl-C-[(hetero)arylamino]azoles with (hetero)arylboronic acids

Mechanistic studies showed that the [Ar–Cu(II)–Nu] complex is oxidized to [Ar–Cu(III)–Nu] in the presence of O₂ (air), which further undergoes reductive elimination to form the product [Ar-azole(Nu)]. Oxygen also helps in the regeneration of the catalyst.

In 2013, Neuville and Li used a three-component system with arylboronic acids, amines, and cyanamides for the Cu-catalyzed formation of N,N′,N′′-trisubstituted aryl guanidines (Scheme [74]).[70] The catalyst system used CuCl₂·2H₂O as the catalyst and K₂CO₃ as the base in the presence of 2,2′-bipyridine and oxygen (1 atm). These structures are prevalent in many pharmaceuticals such as Relenza (antiviral), famotidine (antiulcer), and clonidine (anesthetic R₂ adrenoceptor agonist). This strategy can also be extended toward the synthesis of heterocyclics, such as benzimidazoles or quinazolines.

Scheme 74 Cu-catalyzed reaction of the three-component system of arylboronic acids, amines, and cyanamides

A plausible mechanism for this transformation is illustrated in Scheme [75]. In the initial step, the Cu(II) complex undergoes transmetalation with boronic acid, which coordinates to the deprotonated cyanamide to form complex 103, which then tautomerizes to generate diimide complex 104 that is oxidized to Cu(III) complex 105 by either O₂ or Cu(II). Even though the reductive elimination of this complex 105 can generate the carbodiimide, this was not observed in the reaction. Thus, it is proposed that complex 105 undergoes nucleophilic addition by the amine 1 followed by reductive elimination to generate the product 102 and regenerate the Cu(I) catalyst. The Cu(I) species is oxidized to Cu(II) to continue the catalytic cycle.

Scheme 75 Mechanism of the Cu-catalyzed reaction of the three-component system of arylboronic acids, amines, and cyanamides

In 2014, Onaka, Maegawa, and co-workers developed a mild and regioselective 2-arylation of 5-substituted tetrazoles with various arylboronic acids using [Cu(OH)(TMEDA)]₂Cl₂ to generate 2,5-disubstituted tetrazoles (Scheme [76]). This is the first report of a highly regioselective arylation of 5-alkyltetrazoles.[71]

Scheme 76 [Cu(OH)(TMEDA)]₂Cl₂-catalyzed 2-arylation of 5-substituted tetrazoles with various arylboronic acids

A similar mechanism to that of the Collman group (Scheme [5])[15] [16] was proposed for this transformation (Scheme [77]). In the initial step, the transmetalation of Cu(II) with arylboronic acid followed by the coordination of tetrazole results in the formation of a Cu(III) complex in the presence of oxygen. Even though the reaction of imidazoles using the same catalyst was performed by the Collman group, the reaction with tetrazole was unsuccessful. As the nucleophilicity of tetrazoles is different from imidazoles, the addition of K₂CO₃ was found to be crucial to carry out the reaction. Due to steric repulsion of the aryl group with the substituent on the 5-position, coordination of tetrazole at N-2 is more favored than at N-1. This complex undergoes reductive elimination to furnish the product and regenerates the Cu(II) catalyst.

Scheme 77 Mechanism for the [Cu(OH)(TMEDA)]₂Cl₂-catalyzed 2-arylation of 5-substituted tetrazoles

In 2014, Han and co-workers reported the Chan–Lam reaction by simply stirring 5-aryl-H-tetrazoles with arylboronic acids using 5 mol% of either Cu(I) or Cu(II) catalyst in the presence of O₂ in DMSO as solvent at 100 °C to give 2,5-disubstituted tetrazoles easily and regioselectively in high to excellent yields (Scheme [78]).[72] Tetrazole and DMSO play a significant role in the regeneration of the active catalyst in addition to serving as reactant and solvent, respectively. The Cu(II) complex formed via the oxidation of Cu(I) species by oxygen undergoes oxidative amination to form [CuT₂D] complex [T = tetrazole; D = DMSO]. This is the active complex that generates arylCu(III) and Cu(I) species from which the product is formed by Cu(III) species.

Scheme 78 Cu-catalyzed coupling of various tetrazoles with boronic acids

The steric repulsion in the [Cu(III)T₂(Ar)] intermediate plays a crucial role in the regioselective synthesis of 2,5-disubstituted tetrazoles. Among the three isomers IN1, IN2, and IN3 (Scheme [79]), the least steric hindrance is observed in IN1, in which the Cu–N bond is generated at the N-2 position. Large steric repulsion in the isomers IN2 and IN3 due to the bond formation at N-1 position restricts the formation of these intermediates in the reaction. Thus the 1,5-disubstituted product is not observed in the reaction.

Scheme 79 Proposed reaction mechanism of Cu(I)- and Cu(II)-catalyzed direct coupling of tetrazole and boronic acid

The Cu(OAc)₂-catalyzed mono-N-arylation reaction of amidines 109 using arylboronic acids 2 in the presence of NaOPiv to give N ²-arylamidines was reported by Zhu and co-workers in 2012 (Scheme [80]). Slight modification of the reaction conditions by increasing the temperature to 120 °C in the presence of O₂, resulted in an intramolecular C–H functionalization of the N ²-arylamidines to generate benzimidazoles (Scheme [81]).[73]

Scheme 80 Mono-N-arylation reaction of amidines and intramolecular C–H functionalization of the resulting N ²-arylamidines

Scheme 81 Cu-catalyzed synthesis of benzimidazoles from primary amidines

In 2016, Das and co-workers reported a base-free, open-flask, mild strategy for the N-arylation of tautomerizable N-heterocycles with various arylboronic acids using CuOTf as the catalyst and 1,10-phenanthroline as the ligand (Scheme [82]).[74] The reaction was found to be controlled both kinetically and thermodynamically as determined by the density functional methods. The N-arylation of 1,3-benzoxazol-2(3H)-one gave 3-aryl-1,3-benzoxazol-2(3H)-ones (15 examples) that were further transformed to various naturally occurring oxygenated carbazole alkaloids (e.g., clausenine, clauraila A, clausenal).

Scheme 82 CuOTf/1,10-phen-catalyzed N-arylation of tautomerizable N-heterocycles with arylboronic acids

The selectivity in the N-arylation of pyridin-2(1H)-one was explained both thermodynamically and kinetically by energy calculations (Scheme [83]). The overall energy barrier required for N-arylation is 10.50 kcal/mol, which is 5.10 kcal/mol less than that for O-arylation (15.60 kcal/mol).

Scheme 83 Possible catalytic pathway for the selective N-arylation of pyridin-2(1H)-one

In 2015, Das and co-workers reported the synthesis of various benzimidazole-fused heterocycles via a Cu(II)-catalyzed, inter/intramolecular C–N bond-forming reaction.[75] The one-pot reaction of 2-aminoheteroarenes and 2-iodoarylboronic acids furnished a wide range of benzimidazole-fused N-heteroarenes, such as benzimidazo[1,2-a]quinolines, benzo[4,5]imidazo[2,1-b]thiazoles, pyrido[1,2-a]benzimidazole, benzimidazo[1,2-a]pyrazine, etc. (Schemes 84 and 85). The Chan–Lam type coupling was subsequently followed by an Ullmann-type reaction in this novel cascade protocol for C–N bond formation.

Scheme 84 Synthesis of pyrido[1,2-a]benzimidazoles and derivatives

Scheme 85 Synthesis of benzo[d]thiazolo[3,2-a]imidazole and benzo­[4,5]imidazo[2,1-b]thiazoles

In the first step (Scheme [86]), Cu(II) coordinates to 2-aminopyridine and undergoes transmetalation with PhB(OH)₂ to form 116. Then 116 is oxidized to 117, a Cu(III) complex, by O₂ and it undergoes reductive elimination to form an N-arylated product (Intermediate I). Intermediate I can coordinate with Cu(I) to generate 118, which undergoes oxidative addition with aryl halide to form 119. Complex 120 is formed from 119, which further undergoes reductive elimination to form benzo[4,5]imidazo[1,2-a]pyridine, the cyclized product, and regenerates the Cu(I) species. This Cu(I) species is oxidized by O₂ to Cu(III), which continues the catalytic cycle.

Scheme 86 Mechanism for the formation of pyridobenzimidazoles

Scheme 87 Cu-catalyzed arylation of 5- and 6-aminoindazoles with arylboronic­ acids

Also in 2015, Das and co-workers reported the Cu(II)-catalyzed reaction of 5- and 6-aminoindazoles with arylboronic acids to give 5- and 6-(arylamino)-substituted indazoles (Scheme [87]).[76] These (arylamino)indazoles were converted into pyrazole-fused carbazoles by Pd(II)-catalyzed cross-dehydrogenative coupling (CDC). Various polyheterocycles such as 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles were synthesized using this combined N-arylation/C–H arylation strategy (Scheme [88]). Quantum chemical analysis was performed to better understand the regioselectivity and to trace the potential energy surface of the entire reaction upon 5-(arylamino)indazole conversion into the corresponding carbazole.

Scheme 88 Cu-catalyzed N-arylation and Pd-catalyzed C–H arylation to give pyrazolo-carbazoles

Scheme 89 Cu(II)-catalyzed domino coupling/cyclization of 2-alkynylanilines and alkyl- and arylboronic acids

Scheme 90 One-pot Cu(II)-catalyzed domino coupling/cyclization to give 1,2-disubstituted indoles

In 2014, Wang, Lv, and co-workers developed a method for the direct assembly of 1,2-disubstituted indoles via Cu(II)-catalyzed domino coupling/cyclization process (Scheme [89]).[77] The reaction of 2-alkynylanilines and alkyl-and arylboronic acids catalyzed by Cu(OAc)₂ with 2,6-lutidine as a base and decanoic acid as an additive under aerobic conditions gave 1,2-disubstituted indoles (Scheme [90]). The reaction of 2-(2-bromophenylethynyl)anilines with arylboronic­ acids under these conditions gave 1-aryl-2-(2-bromophenyl)-1H-indoles that underwent intermolecular Pd-catalyzed C(sp²)–H arylation by addition of Pd(OAc)₂, (p-Tol)₃P, and Cs₂CO₃ under nitrogen without isolation of the indole intermediate to give indolo[1,2-f]phenanthridines in a one-pot synthesis (Scheme [91]). Polycyclic indole derivatives were also synthesized using this method.

Scheme 91 One-pot Cu(II)-catalyzed domino coupling/cyclization followed by intramolecular Pd-catalyzed C(sp²)–H arylation to give indolo[1,2-f]phenanthridines

A possible mechanism for the coupling/annulation under­ aerobic conditions was proposed (Scheme [92]). The L_nCu^II ₂(OH)₂(OAc)₂ complex undergoes transmetalation with boronic acid promoted by base (such as 2,6-lutidine) to afford R–Cu(II) species 128. This is followed by the generation of Cu(II) complex 129 via the coordination of the complex 128 to aniline 124, which is subsequently oxidized by oxygen to Cu(III) complex 130. Final reductive elimination generates the product 131 and the Cu(I) complex. This Cu(I) complex is oxidized to Cu(II) and this activates the alkyne by coordinating with the C≡C bond giving 132. Finally, the intramolecular cyclization of 132 followed by protonolysis gives the product 125 and regenerates the active catalyst.

Scheme 92 Mechanism for the Cu(II)-catalyzed domino coupling/ cyclization­ to give 1,2-disubstituted indoles

In 2013, Alami, Messaoudi, and co-workers reported an efficient stereoselective Cu(OAc)₂ and pyridine catalyzed method for the N-arylation of glycosylamines with substituted arylboronic acids at room temperature under air to furnish aryl N-glycosides with exclusive β-selectivity (Scheme [93]).[78] One of the most important subfamilies of N-glycosides is (hetero)aryl N-glycosides, whose derivatives show promising biological activities, including antiviral and anticancer properties.

2.1.11

Using Sulfonato-imino Copper(II) Complexes

Scheme 93 Cu-catalyzed N-arylation of glycosylamines with substituted arylboronic acids

In 2017, Schaper and Hardouin Duparc reported the efficient Chan–Lam coupling of various amines or anilines, including sterically hindered examples, with phenylboronic acid using sulfonato-imino copper(II) complexes under mild conditions without the need of an external base or ligand to give N-alkyl- or N-arylanilines (Scheme [94]).[79] The imino-sulfonate copper complex with chloride as the counteranion was prepared in a one-step reaction using commercially available starting materials; this complex underwent anion-exchange with AgOTf furnishing complex 136 with triflate as the counteranion (Scheme [95]). As complex 136 remains active under aqueous conditions, it was used in the synthesis of N-methylaniline using aqueous methylamine and phenylboronic acid. In this reaction, it was only necessary to optimize temperature and time, and typical side reactions, such as deboronation and homocoupling, were absent.

Scheme 94 Imino-sulfonate copper complex catalyzed reaction of amines and anilines with phenylboronic acid

Scheme 95 Formation of imino-sulfonate copper complexes

2.2

C–O Bond Formation

2.2.1

Coupling with (Hetero)arylboron Reagents

In 2013, Luo, Hu, and co-workers used the Cu-catalyzed reaction of 6-substituted pyridin-2(1H)-ones and aryl­boronic acids in the synthesis of O-arylated pyridin-2(1H)-ones (Scheme [96]).[80] Using the optimum conditions with 20 mol% of Cu(OTf)₂ as the catalyst, DABCO as the ligand, Et₃N as the base, and K₂HPO₄ as an additive for 5 hours at 50 °C gave O-arylated pyridin-2(1H)-ones in up to 81% yield.

Scheme 96 Cu(OTf)₂/DABCO-catalyzed reaction of 6-substituted pyridin-2(1H)-ones and arylboronic acids

On the basis of the mechanism of the Chan–Lam coupling reaction and further experiments, they identified two crucial factors for the regioselectivity (Figure [4]): 1. the steric hindrance of DABCO catalyst system, which restricts the generation of the N–Cu(II) intermediate, and 2. steric hindrance by the 6-substituent, such as methyl.

Figure 4 Plausible intermediates for the explanation of regioselectivity of C–O bond formation

Although the Cu-mediated arylation of N-hydroxyphthalimide with arylboronic acids has been previously reported,[81a], the corresponding process for vinylation was unknown. In 2012, Anderson and co-workers reported the of N-hydroxyphthalimide with 2 equiv of alk-1-enylboronic acid under the optimized conditions using Cu(OAc)₂ as the catalyst, 3 equiv of pyridine as the base, and 4 equiv of Na₂SO­₄ in DCE and O₂ (Scheme [97]).[81b] The use of 2 equiv of alk-1-enylboronic acid, air, and halogenated solvents all played a significant role in the reaction.

Scheme 97 Cu(OAc)₂-catalyzed reaction of N-hydroxyphthalimide with alk-1-enylboronic acids

In 2012 in a more efficient alternative to existing protocols, Bora and co-workers used Chan–Lam coupling of aryloximes and arylboronic acids for the synthesis of aryloxime ethers (Scheme [98]).[82] The optimized reaction conditions utilized Cu(OAc)₂ as the catalyst and Cs₂CO₃ as the base in DMSO at room temperature for 5 hours. The use of Cs₂CO₃ has several advantages, such as increased product yields with shorter reaction times, smaller amounts of reagents, easy workup, and clean and mild reaction conditions.

Scheme 98 Cu(OAc)₂-catalyzed coupling of acetophenone oximes with arylboronic acids

The mechanism for the Cu(OAc)₂-mediated construction of O-aryloxime ether from oximes in the presence of inorganic bases has not yet been reported. Lam and co-workers have investigated the formation of a deep blue copper complex from an insoluble mixture of Cu(OAc)₂ and CH₂Cl₂ on the addition of amine-based substrates.[83] Using DMSO as solvent increased the yield as Cu(OAc)₂ is soluble in DMSO.

Bora and co-workers proposed a mechanism that includes the coordination of Cu(OAc)₂ to oxime followed by transmetalation with PhB(OH)₂ (Scheme [99]).[82] The product oxime ether is produced by the reductive elimination of this complex.

Scheme 99 Mechanism for the Cu(OAc)₂-catalyzed coupling of acetophenone­ oximes with phenylboronic acid

The reaction between 141a and Cu(OAc)₂ was carried out to check the involvement of the Cu(II) complex; IR spectroscopic studies of the resulting complex showed that it contains the OH group and this indicates that it is the nitrogen atom of the oxime group that coordinates to the metal and this was also confirmed by IR data. All other evidence, such as mass spectroscopic analysis, the formation of the product using a preformed Cu(II) complex, and formation of the deep blue solution on stirring 141a, 2, Cu(OAc)₂, and Cs₂CO₃ all support the formation of the copper complex. The formation of the Cu(II) complex was not affected by the presence or absence of the base.

In 2014, Gagnon and co-workers reported Cu(OAc)₂-mediated O-arylation reaction of phenols and trivalent organobismuthanes to give highly functionalized diaryl ethers (Scheme [100]).[84] Various phenols bearing different functional groups and a variety of organobismuth reagents reacted under these simple reaction conditions. By using an oxygen atmosphere, the amount of catalyst used in the reaction can be significantly minimized (conditions B). The N-arylation of pyridin-2(1H)-ones was also reported using conditions A.

Scheme 100 Cu(OAc)₂-mediated O-arylation reaction of phenols and trivalent organobismuthanes

2,2,2-Trifluoroethyl ethers have gathered attention as pharmaceuticals and polymer materials; the trifluoro­methoxy group confers metabolic stability and lipophilicity, hence their synthesis is of interest.[85a] Methods for the synthesis of trifluoroethyl ethers have frequently included harsh reaction conditions, such as elevated temperatures, activated substrates, limited applicability, and use of DMSO or the toxic solvent HMPA. For example, in 1985 Suzuki and co-workers reported the construction of aryl 2,2,2-trifluoroethyl ethers using the CuI-assisted reaction of aryl iodides and sodium 2,2,2-trifluoroethoxide in HMPA at 90–100 °C.[85b] In 2015, Zou, Wu, and co-workers developed a Cu-catalyzed­ coupling of 2,2,2-trifluoroethanol with various (hetero)arylboronic acids under mild conditions to give (hetero)aryl 2,2,2-trifluoroethyl ethers in moderate to good yields (Scheme [101]).[86] The optimal conditions used Cu(OAc)₂·H₂O as catalyst and DMAP as base and ligand in 2,2,2-trifluoroethanol as solvent at 40 °C for 1 hour in the presence of O₂.

Scheme 101 Cu(OAc)₂-catalyzed cross-coupling of trifluoroethanol with (hetero)arylboronic acids

Scheme 102 Cu(OTf)₂/urea-catalyzed coupling of carboxylic acids with phenylboronic acids

In 2010, Cheng and co-workers reported the first example utilizing carboxylic acids as an O-donor in the Chan–Lam coupling. The Cu(OTf)₂-mediated coupling of carboxylic acids, such as benzoic, cinnamic, phenylacetic, furan-2-carboxylic, and naphthoic acid, and phenylboronic acids gave esters (Scheme [102]).[87] Substitution on both the benzoic acids (Me, OMe, CN, halo, NO₂, and OH) and phenyl­boronic acids (Me, OMe, Cl, vinyl, Ac, CF₃, CO₂Me) gave the ester products in moderate to good yields. The optimized catalyst system used 40 mol% of Cu(OTf)₂ with 1 equiv of urea as the ligand in EtOAc solvent at 60 °C in the presence of air.

An alternative synthesis of esters using Cu(OTf)₂ as the catalyst with Ag₂CO₃ as a promoter in DMSO at 120 °C for 2 hours was reported in 2011, by Liu and co-workers (Scheme [103]).[88] The scope of carboxylic acid extended to 2,6-disubstituted benzoic acids, heteroarenecarboxylic acids, cinnamic acids, and electron-rich and electron-poor substituted benzoic acids, while both electron-rich and electron-poor boronic acids were tolerated. Yields were generally in the range 60–95%.

Scheme 103 Cu(OTf)₂/Ag₂CO₃-catalyzed coupling of carboxylic acids with phenylboronic acids

In 2016, Clark and co-workers used the Cu-catalyzed etherification of ortho-[(dimethylamino)methyl]phenylboronic acid pinacol esters with phenols to give aryl 2-[(dimethylamino)methyl]phenyl ethers (Scheme [104]).[89] This is similar to their amination work described in Section 2.1.2 (Scheme [23]).[31a] Various substituted arylboronate esters and phenols underwent the reaction smoothly to furnish the product in moderate to high yields. It was observed that during a competition reaction between phenol and aniline, phenol was highly favored over aniline. A simple boronate ester, 2-(pinacolboryl)toluene lacking the pendant (dimethylamino)methyl group gave only 5% conversion to the corresponding ether; thus the pendant (dimethyl­amino)methyl group activates the boronate ester toward coupling.

Scheme 104 Cu-catalyzed etherification of ortho-[(dimethylamino)-methyl]phenylboronic acid pinacol esters with phenols

In 2013, Huang and co-workers synthesized phenols from arylboronic acids using electrochemical techniques by modulating potential and ammonia concentration (Scheme [105]).[33] By keeping the concentration of aqueous ammonia at 0.13 M, various boronic acids chemoselectively gave the corresponding phenols in good yields (see also Scheme [26] in Section 2.1.2).

Scheme 105 Electrochemical hydroxylation of arylboronic acids in aqueous NH₃

2.2.2

Coupling with Alkyl- and Alkenylboron Reagents

Scheme 106 Cu(OAc)₂-mediated coupling of vinylboronic acid esters with aliphatic alcohols

Vinyl ethers are ubiquitous structural moieties which are difficult to synthesize using direct O-alkylation methods of enolates. Some indirect methods developed include the carbonyl alkenylation using Tebbe reagent, etherification using selenium, vinyl ether exchange catalyzed by acid or metal, alcohol addition to alkynes, etc.[90`] [b] [c] [d] However, these methods have different drawbacks, such as the use of strong acid or base, less functional group tolerance, uncontrolled stereochemistry, etc. In this regard, in 2010 Merlic and co-workers developed the Cu(OAc)₂-mediated synthesis of vinyl ethers using the coupling of vinylboronic acid esters with aliphatic alcohols (Scheme [106]).[90e] Vinylboronic acid pinacol esters such as 150 gave the highest yields, whereas other boronate esters, boronic acids, boroxines, and boranes provided lower yields.

Various aliphatic and allylic alcohols were employed in this coupling reaction (Scheme [107]).[90e] Even groups sensitive to acidic, basic, oxidative, nucleophilic, and radical conditions are compatible with this reaction.

Scheme 107 Cu-catalyzed coupling of vinylboronic acid pinacol esters and alcohols

It is proposed that the reaction takes place by a modified Chan–Lam mechanism (Scheme [108]).[90e] The mechanism involves transmetalation, ligand exchange from Cu(OAc)₂, disproportionation, which also explains the need for excess Cu(OAc)₂ and the absence of copper metal formation, and reductive elimination. As alkoxy(vinyl)copper is easily oxidized compared to acetoxy(vinyl)copper, the former undergoes disproportionation, and vinyl acetate side products are not formed in the reaction.

Scheme 108 Mechanism of the Cu-catalyzed coupling of vinylboronic acid pinacol esters and alcohols

In 2013, Kuninobu and Sueki developed a method for the benzylation of aromatic and aliphatic alcohols by the reaction of phenols with benzylboronic acid pinacol ester (Scheme [109]).[60] This cross-coupling reaction used Cu(OAc)₂ as the catalyst in the presence of di-tert-butyl peroxide and gave alkyl and aryl benzyl ethers in good to excellent yields. In this reaction di-tert-butyl peroxide played a crucial role. See also Section 2.1.8 for the amines with alkylboronic acid pinacol esters using this catalyst system.

Scheme 109 Cu(OAc)₂-catalyzed reaction between benzylboronic acid pinacol esters and aromatic and aliphatic alcohols

Enol esters are diverse and prevalent structural moieties in a number of natural products, pharmaceuticals, and polymers. In 2013, Batey and co-workers reported a mild non-decarboxylative CuBr and DMAP-catalyzed cross-coupling reaction of potassium alk-1-enyltrifluoroborates with carboxylic acids at 60 °C in the presence of oxygen and 4Å MS for the regioselective and stereospecific preparation of (E)- or (Z)-enol esters (Scheme [110]).[91a] Various potassium (E)- and (Z)-alkenyltrifluoroborates, such as hex-1-enyl, oct-1-enyl, 3-(benzyloxy)prop-1-enyl, styryl, and prop-1-enyl, were used with benzoic, heteroarenecarboxylic and alkanoic acids. The reactions of carboxylic acids with alk-1-enyl or aryl halides and organometalloid derivatives for the generation of C–O bonds often suffer from various drawbacks, such as poor yields, the use of excess metal or catalysts, and elevated temperatures, but Batey and co-workers developed a mild protocol without the use of stoichiometric metal additives.

Scheme 110 CuBr/DMAP-catalyzed cross-coupling of carboxylic acids with potassium (E)-trifluoro(hex-1-enyl)borate

The stereospecificity of this transformation was examined by performing the reaction of potassium (Z)-trifluoro-(prop-1-enyl)borate (Z/E ratio 18:1) with benzoic acid or its salts bearing both electron-withdrawing and -donating groups. ¹H NMR of the products showed that all the prop-1-enyl benzoates were generated with high Z-selectivity. Thus, a mechanism similar to earlier reports[91b] was also proposed for this transformation, including transmetalation and reductive elimination of the copper catalyst (Scheme [111]).

Scheme 111 Mechanistic overview of enol acetate formation

In 2013, Anderson and co-workers reported the Cu-mediated thermal [1,3]-rearrangement of benzophenone O-alk-1-enyloximes to give α-imino aldehydes.[92] The benzophenone O-alk-1-enyloximes were synthesized by C–O bond coupling between alk-1-enylboronic acids and benzophenone oximes (Scheme [112]). The α-imino aldehydes were used in the Horner–Wadsworth–Emmons olefination to give γ-imino-α,β-unsaturated esters.

The reaction of benzophenone oxime with various substituted alk-1-enylboronic acids took place under the optimum conditions using 1 equiv of CuTC, 0.5 equiv of AgClO₄, and 3 equiv of DABCO as the base; the addition of a silver salt played a significant role in the yield of the products and its counterion also influenced the transformation.

Scheme 112 CuTC/AgClO₄-mediated reaction of benzophenone oxime with alk-1-enylboronic acids

In order to replace toxic electrophilic alkylating reagents, in 2015 Gorin and co-workers reported the oxidative coupling of alkylboronic acids with oxygen nucleophiles. O-Alkylation with boronic acid is still rare, though Chan–Lam coupling is widely used in the arylation of heteroatom nucleophiles. The Cu-catalyzed non-decarboxylative methylation of carboxylic acids with methylboronic acid under aerobic conditions with no additional oxidant gave methyl esters in good yields (Scheme [113]).[93] Isotope-labeling studies revealed an oxidative cross-coupling mechanism, similar to that proposed for the Chan–Lam arylation, where the methyl group is transferred to the substrate from the boronic acid. Optimization of the solvent found both chlorobenzene and dimethyl carbonate (DMC) to be effective; dimethyl carbonate was selected for use as a nontoxic, green solvent. The optimum catalyst was CuCO₃·Cu(OH)₂.

Two possible reaction mechanisms emerged; there was only one previous report of the aerobic Cu-catalyzed Chan–Lam alkylation with methylboronic acid, see Section 2.1.8.[55] In the first, O-methylation may proceed similarly to Chan–Lam O-arylation (Scheme [114], path A). According to Stahl and co-workers,[94] the carboxylic acid undergoes ligand exchange with the copper complex followed by the transmetalation with methylboronic acid. Reductive elimination followed by oxidation generates the product and active Cu(II) catalyst. In the second mechanism, methanol is formed by the oxidation of methylboronic acid, and it reacts with the carboxylic acid to give the methyl ester (Scheme [114], path B).

Scheme 113 Cu-catalyzed esterification of carboxylic acids with methylboronic­ acid

Scheme 114 Two possible reaction mechanisms for the Cu-catalyzed esterification carboxylic acids with methylboronic acid

The O-arylation of l-serines is usually performed by nucleophilic aromatic substitution, which uses strong bases (NaH and KHMDS) and 1-fluoro-2-nitrobenzene substrates.[95a] Other methods include the Mitsunobu reaction, which furnishes product, albeit in poor yields, and also uses triphenylphosphine as the reagent.[95b] In 2014, Molander and Khatib reported the Cu(II)-catalyzed O-arylation of β-hydroxy-α-amino acid substrates serine and threonine (Scheme [115]).[95c] A wide variety of protected [Boc, Cbz (Z), Tr, and Fmoc] serine and threonine derivatives underwent the reaction smoothly with various (hetero)arylboronic acids and potassium (hetero)aryltrifluoroborates under open flask conditions.

Scheme 115 Cu(II)-catalyzed O-arylation of l-serine derivatives with potassium (hetero)aryltrifluoroborates

The reaction of potassium trifluoro(phenyl)borate (13) with Z-l-Ser-l-Thr-OMe (163) gave a single mono O-arylated product 164 in 22% yield (Scheme [116]). This was also supported by mass spectrometric analysis, which confirmed the selective arylation at the l-serine site.

Scheme 116 Selective O-arylation of Z-l-Ser-l-Thr-OMe with potassium trifluoro(phenyl)borate

In 2018, McAlpine, Engle, and co-workers reported the O-cyclopropylation of phenols using potassium cyclopropyltrifluoroborate and catalyzed by Cu(OAc)₂ and 1,10-phenanthroline and employing 1 atm of O₂ as the terminal oxidant (Scheme [117]).[61] Phenols with diverse functional groups, differing electronic properties, and varied substitution patterns reacted smoothly to furnish the desired product in moderate to high yields.

Scheme 117 Cu(OAc)₂/phen-catalyzed O-cyclopropylation of phenols with potassium cyclopropyltrifluoroborate

In 2019 Van Maarseveen and Steemers developed the Cu(II)-mediated enol esterification of peptide carboxylic acids with triisopropenylboroxine·pyridine complex using Cu(OTf)₂ as the catalyst, with triethylamine as the base, and 1,3-diethylurea as an additive for the synthesis of C-terminal dipeptide isopropenyl esters (Scheme [118]).[96] A variety of amino acid and dipeptide nucleophiles were coupled stereoselectively with these peptide esters in the presence of pyrazole/DBU as the catalyst in high yield and purity.

Scheme 118 Cu(II)-mediated enol esterification of peptide carboxylic acids with triisopropenylboroxine·pyridine complex

3

C–Element (Element = S, P, C, F, Cl, Br, I, Se, Te, At) Bond Formation under Modified Chan–Lam Conditions

The first report on the coupling of alkanethiols with arylboronic acids was in 2000 by Guy and co-workers, they used Cu(OAc)₂ as the catalyst with pyridine as the base in DMF,[97] then in 2002 Liebeskind and co-workers reported the coupling of N-alkyl or N-arylthiosuccinimides with boronic­ acids catalyzed by copper(I) 3-methylsalicylate (CuMeSal) to give sulfides under mild conditions.[98]

Scheme 119 CuSO₄-catalyzed S-arylation of thiols using (hetero)arylboronic acids

In 2012, Feng and co-workers developed the CuSO₄-catalyzed S-arylation of thiols using (hetero)arylboronic acids with 1,10-phen·H₂O as the ligand, EtOH as solvent, and oxygen as the oxidant to give aryl (heteroaryl) sulfides (Scheme [119]).[99]

In 2016, Muthusubramanian and co-workers reported the Cu(II)-catalyzed C–S cross-coupling of thiazolidine-2-thiones with boronic acids using Cu(acac)₂ in DCE to give azole sulfides under base-, ligand-, and additive-free conditions and requiring shorter reactions times (Scheme [120]); one example of the corresponding reaction of an oxazolidine-2-thione was reported.[100] Azole sulfides find applications in the biological, pharmaceutical, and materials fields.

Scheme 120 Cu(II)-catalyzed C–S cross-coupling of thiazolidine-2-thiones with boronic acids

Mechanistically, it is proposed that the thioamide system is readily oxidized to give disulfide 169 stimulated by the Cu(II) reagent in the presence of air. The arylboronic acid then reacts with Cu(acac)₂ in a transmetalation step to form Cu(II) intermediate 170, which reacts with disulfide 169 to give 168 (Scheme [121], path A). As an alternative possible mechanism, disulfide 169 and intermediate 170 may undergo transmetalation with the arylboronic acid to generate intermediate 171, which ultimately delivers aryl sulfide 168 (Scheme [121], path B).

Scheme 121 Mechanism of the Cu(II)-catalyzed C–S cross-coupling of thiazolidine-2-thiones with boronic acids

The first multicomponent reaction (MCR) was explored by Zhao and co-workers in 2016, which involved arylboronic acids, elemental sulfur, and P(O)H compounds. This method provided an efficient protocol for the one-pot synthesis of S-aryl phosphorothioates and S-aryl phosphorodithioates in excellent yields, which can be easily adapted to a large-scale preparation (Scheme [122]).[101]

Scheme 122 Cu(OAc)₂-catalyzed multicomponent reaction phosphorothiolation of arylboronic acids

In addition to the phosphorothiolation of arylboronic acids, this strategy was used to synthesize phosphorothiolated phenylalanine, estrone, and nucleotide analogues, which have tremendous potential to be used for various biological activities (Figure [5]).

Figure 5 Cu(OAc)₂-catalyzed multicomponent reaction phosphoro­thiolation to give highly functionalized targets

The role of sulfur in this synthetic protocol was examined. A complicated reaction mixture was generated by the reaction of sulfur with PhB(OH)₂ for 20 hours, and adding diethyl H-phosphonate to this mixture afforded only a trace amount of the product 172, implying that diaryl disulfide and benzenethiol intermediates are not responsible for the reaction. ³¹P NMR experiments showed that the active phosphorothiolating reagent is S-hydrogen phosphorothioate and that Et₃N is critical to its formation. ³¹P NMR experiments also indicated the formation of the C(aryl)–S–P bond and that the reaction was complete after 24 hours. Based on this information the proposed mechanism is shown in Scheme [123]. The reaction of elemental sulfur with H-phosphonate gives S-hydrogen phosphorothioate, which undergoes Cu(OTf)₂-catalyzed reaction with phenylboronic acid to generate the phosphorothioated product 172.

Scheme 123 Mechanistic pathway for the Cu(OAc)₂-catalyzed multicomponent reaction phosphorothiolation

In 2015, Singh and co-workers developed a Cu(II)-mediated regioselective method for the S-arylation of α-enolic dithioesters with arylboronic acids to give α-oxoketene S,S-acetals (Scheme [124]).[102] The reaction was performed in the absence of a base or a ligand at room temperature in the presence of O₂ and under neutral conditions. The striking features of this novel one-pot strategy include short reaction times (5 min), good to excellent yields, and highly selective C=S functionalization. The α-oxoketene S,S-acetals furnished in this reaction can be utilized for the generation of a number of carbocycles and heterocycles, which can find various applications in pharmaceutical and polymer industries.

Scheme 124 Cu(OAc)₂-mediated S-arylation of α-enolic dithioesters with arylboronic acids

The proposed mechanism is outlined in Scheme [125]. The thioenol form of the dithioester 173 dimerizes to the disulfide species 175 in the presence of Cu(OAc)₂, with the reduction of Cu(II) to Cu(I). Disulfide species 175 undergoes Chan–Lam coupling in the presence of arylboronic acid and Cu(I) and Cu(II) to generate the Cu(I) S,S-acetal complex 176 and Cu(II) S,S-acetal complex 178. The dithioacetal–Cu(I) complex 176 is oxidized to dithioacetal–Cu(II) complex 177, which undergoes transmetalation with arylboronic acid to produce 178. Finally, intermediate 178 undergoes reductive elimination to give α-oxoketene S,S-acetals 174.

Phukan and co-workers also utilized the novel square pyramidal copper complex [Cu(DMAP)₄I]I that they had used for the formation of N-arylamines (Section 2.1.2) and N-arylsulfonamides (from azides, Section 2.1.3) for the formation of the Chan–Lam coupling of arylboronic acids with thiols to give diaryl sulfides (Scheme [126]).[32] This complex successfully catalyzed the C–S cross-coupling reaction and the rate and yield of the reaction increased when thiols bearing electron-withdrawing groups were used. Only 2 mol% of the copper catalyst was required for the reaction in methanol at room temperature within a short time. However, the time required for the S-arylation of thiols (35–65 minutes for 9 examples) was longer than that required for N-arylation of amines (5–20 minutes for 26 examples, 40–75 minutes for 3 examples).

Scheme 125 Mechanism for the Cu(OAc)₂-mediated S-arylation of α-enolic dithioesters with arylboronic acids

Scheme 126 [Cu(DMAP)₄I]I-catalyzed S-arylation of thiols with boronic acids

In 2018–2019, Dong and co-workers explored several new ways of C–S bond formation via Chan–Lam coupling.[103] [104] Thioureas were efficiently S-arylated at room temperature using arylboronic acids catalyzed by Cu(OAc)₂ with 2,2′-bipyridine as the ligand to form S-arylisothioureas in very good yields (Scheme [127]).[104a] A variety of functional groups on the N-aryl-N′,N′-dimethylthiourea and arylboronic acid reagents were tolerated, in particular 2-bromophenylboronic acid gave the corresponding S-(2-bromophenyl)isothiourea in 87% yield. Styrylboronic acids were also used as the boronic acid.

Scheme 127 Cu(OAc)₂/bpy-catalyzed S-arylation of thioureas with aryl- and styrylboronic acids

This chemistry was further applied to cyclic 1,3-dihydro-2H-benzimidazole-2-thiones to provide chemoselectively the useful 2-(arylthio)benzimidazoles (Scheme [128]).[104b] It is interesting to note that the chemoselectivity was achieved by the addition of water, this provides a heterogeneous medium that slows down the reaction to achieve the selectivity, but it was necessary to increase the reaction temperature to 80 °C.

Scheme 128 Cu(OAc)₂/bpy-catalyzed chemoselective S-arylation of 1,3-dihydro-2H-benzimidazole-2-thiones with arylboronic acids

In 2015, Hu and co-workers reported the efficient CuCl-catalyzed oxidative cross-coupling reaction of substituted arylboronic acids with trimethylsilyl isothiocyanate under oxygen atmosphere to give aryl thiocyanates (Scheme [129]).[105]

Scheme 129 CuCl-catalyzed aerobic oxidative thiocyanation of aryl­boronic acids with TMSNCS

The proposed mechanism is given in Scheme [130]. In the initial step, LCu(I)Cl 187 undergoes exchange with the NCS^– anion to give LCu(I)SCN 188, which is oxidized to the bis(μ-oxo)dicopper(III) complex 189 by oxygen; coordination of the diamine ligand TMEDA (L) is crucial as electron density on the Cu is increased by its presence. Bis(μ-oxo)di­copper(III) complex 189 reacts with two molecules of arylboronic acid, and an aryl group is further transferred to the Cu atom to form 190, which generates two molecules of unstable Cu(III) complex 191. Subsequent reductive elimination of 191 generates the product aryl thiocyanate and LCu(I)–OB(OH)₂ 192. The formed 192 undergoes further exchange with the NCS^– anion to form LCu(I)SCN 188 to complete the catalytic cycle.

Scheme 130 Mechanism for thiocyanation of arylboronic acids with TMSNCS

In 2011, Fang, Zhao and co-workers reported the Chan–Lam coupling between H-phosphonate diesters and boronic acids catalyzed by Cu₂O and 1,10-phenanthroline for the construction of arylphosphonates (Scheme [131]).[106]

Scheme 131 Cu₂O/1,10-phen-catalyzed cross-coupling of arylboronic acids with H-phosphonate diester

In 2013, Gao and co-workers reported the Ni-catalyzed cross-coupling of a variety of functionalized arylboronic acids with H-phosphites, H-phosphine oxides, and H-phosphinate esters to give various arylphosphorus compounds; good to excellent yield of triarylphosphine oxides were formed (Scheme [132]).[107] This strategy provided a generalized and substantial tool for the synthesis of arylphosphorus compounds and is the first example of a Ni-catalyzed C–P bond-forming reaction utilizing P(O)H substrates and arylboronic acids. The optimized conditions used NiBr₂ as the catalyst, pyridine as an additive, and K₂CO₃ as the base and gave triarylphosphine oxides in up to 99% yield.

Scheme 132 Ni-catalyzed coupling of arylboronic acids with P-nucleophiles

In 2010, Qing and Chu reported the Cu-catalyzed coupling of trimethyl(trifluoromethyl)silane (Me₃SiCF₃) with aryl- and alkenylboronic acids to give (trifluoromethyl)-substituted arenes and alkenes (Scheme [133]).[108a] The optimized conditions used [Cu(OTf)₂]·C₆H₆ (0.6 equiv), 1,10-phen (1.2 equiv), CF₃SiMe₃ (5.0 equiv), KF (5.0 equiv), K₃PO₄ (3.0 equiv), and Ag₂CO₃ (1.0 equiv) in DMF at 45 °C. A wide range of functional groups were tolerated on the arene and alkene component. This oxidative trifluoromethylation resulted in the incorporation of the trifluoromethyl group into highly functionalized organic molecules. However, the [Cu(OTf)]₂·C₆H₆ used in this reaction is highly air-sensitive, and a nitrogen-filled glovebox is required. Also, stoichiometric amounts of trimethyl(trifluoromethyl)silane (TMSCF­₃; 5 equiv) and Ag₂CO₃(1 equiv) were required.

Scheme 133 Cu-catalyzed coupling of Me₃SiCF₃ with aryl- and alkenylboronic acids

Scheme 134 Mechanism for the Cu-catalyzed coupling of Me₃SiCF₃ with aryl- and alkenylboronic acids

The proposed mechanism is shown in Scheme [134] based on an earlier report on the trifluoromethylation of terminal alkynes.[108b] Complex 198 undergoes transmetalation with the arylboronic acid to form aryl(trifluoromethyl)copper 199. The diamine ligand increases the electron density on the Cu atom and stabilizes the intermediate 199, which undergoes reductive elimination to generate the product.

In 2011, Buchwald and co-workers also reported the Cu-mediated trifluoromethylation of (hetero)arylboronic acids at room temperature for short reaction times (1–4 h) to give a wide range of (trifluoromethyl)arenes containing a variety of functional groups (Scheme [135]).[109]

Scheme 135 Cu-catalyzed coupling of Me₃SiCF₃ with (hetero)arylboronic acids

Scheme 136 [(bpy)CuF₂(H₂O)]·2H₂O-catalyzed oxidative trifluoromethylation of phenylboronic acid with TMSCF₃

In 2014, Grushin and co-workers reported an efficient oxidative trifluoromethylation of phenylboronic acid with trimethyl(trifluoromethyl)silane catalyzed by [(bpy)CuF₂(H₂O)]·2H₂O in DMF at room temperature for 15 minutes to give (trifluoromethyl)benzene in >95% yield method.[110] This reaction only occurs under aerobic conditions. A well-defined mechanism justifies this transformation, as shown in Scheme [136]. In the first step, TMSCF₃ undergoes trifluoromethylation with [(bpy)CuF₂(H₂O)]·2H₂O to form [(bpy)Cu(CF₃)₂], which spontaneously disproportionates into two Cu(III) ([Cu(CF₃)₄]⁻ and [(bpy)Cu(CF₃)₃]) and two Cu(I) ([(bpy)Cu(CF₃)] and [Cu(CF₃)₂]⁻) complexes. The Cu(III) complexes generated in the reaction are stable and unreactive throughout the coupling. [Cu(CF₃)₂]^– is in equilibrium with [(bpy)Cu(CF₃)] and serves as the active catalyst for Ph–CF₃ bond formation. Thus, the role of oxygen was found to be crucial for the reaction as trifluoromethylation of PhB(OH)₂ will not happen with [(bpy)Cu(CF₃)₂]. Details are shown in Scheme [137].

Scheme 137 Air oxidation of [(bpy)Cu(CF₃)] in the presence of TMSCF₃ leading to [(bpy)Cu(CF₃)₂(OTMS)]

In 2013, Sanford and co-workers developed the Cu(OTf)₂-mediated fluorination of (hetero)aryltrifluoroborates with KF to give aryl fluorides.[111] Evaluation of 4-fluoro­phenylboron substrates by reaction with 4 equiv KF, 4 equiv of Cu(OTf)₂ in MeCN at 60 °C for 20 hours found that potassium trifluoro(phenyl)boronate gave the best yield (70%) (Scheme [138]). This method tolerates potassium (hetero)aryltrifluoroborates with a wide range of functional groups under mild reaction conditions (Scheme [139]). In this transformation, Cu is used as a mediator for aryl–F coupling and also as an oxidant to generate the Cu(III)(aryl)(F) intermediate.

Scheme 138 Cu(OTf)₂-mediated fluorination of 4-fluorophenylboron substrates with KF

Scheme 139 Cu(OTf)₂-mediated fluorination of (hetero)aryltrifluoro­borates with KF

The proposed mechanism is given in Scheme [140]. As the reaction was performed at 60 °C for 24 hours, this indicates the low activation barrier required for C–F coupling. The disproportion reaction involving the oxidation of the aryl(fluoro)Cu(II) intermediate (1 equiv) using Cu(OTf)₂ (1 equiv) generates the corresponding Cu(III) species leading to the final fluoroarene product 200. As Cu(OTf)₂ is a strongly oxidizing Cu source, it is more effective in this transformation, and the reduction in the number of equivalents from 2 to 1 decreased the yield of the reaction to 15% illustrating the dual role played by copper in this reaction.

Scheme 140 Mechanism for the Cu(OTf)₂-mediated fluorination of (hetero)aryltrifluoroborates with KF

Scheme 141 Cu-mediated ¹⁸F fluorination of (hetero)arylboronic acid pinacol esters with [¹⁸F]fluoride; n = number of repeats

In 2014, Gouverneur and co-workers reported the unprecedented nucleophilic ¹⁸F fluorination of a broad range of (hetero)arylboronic acid pinacol esters with [¹⁸F]KF/K₂₂₂ in the presence of the commercially available copper complex [Cu(OTf)₂(py)₄] (Scheme [141]).[112] This strategy was applied to arenes with both electron-donating and electron-withdrawing groups with a variety of functional groups, and can be used in the synthesis of translocator protein (TSPO­) PET ligand [¹⁸F]DAA1106 and 6-[¹⁸F]fluoro-l-DOPA, 6-[¹⁸F]fluoro-m-tyrosine (Scheme [142]).[112]

Scheme 142 Radiosynthesis of 6-[¹⁸F] fluoro-l-DOPA from [¹⁸F]fluoride; n = number of repeats

In 2015, Sanford and co-workers developed a protocol to synthesize [¹⁸F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors by the copper-mediated radiofluorination of vinyl- and arylboronic acids with K¹⁸F (Scheme [143]).[113] This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, electron-neutral, and electron-rich aryl-, heteroaryl-, and vinylboronic acids.

Scheme 143 Cu-mediated radiofluorination of vinyl- and arylboronic acids with K¹⁸F; n = number of repeats

Scheme 144 CuCl-catalyzed boron–chloride exchange of arylboronic acids

Hynes and co-workers reported the conversion of arylboronic acids into aryl chlorides via a mild and efficient Cu(I)-catalyzed boron–chloride exchange (chlorodeboronation) reaction (Scheme [144]).[114] The optimal conditions of this low-metal-loading method used 0.1 equiv of CuCl and 1 equiv of NCS in MeCN; it was effective for both electron-rich and electron-deficient substituted arylboronic acids. Mechanistically, it is proposed that a Cu(III) complex is generated via the oxidative addition of the Cu(I) halide with the corresponding N-halosuccinimide (Scheme [145]). Subsequent transmetalation with boron generates an Ar–Cu(X)₂ species followed by reductive elimination to afford the aryl chloride product.

Scheme 145 Mechanism of the CuCl-catalyzed boron–chloride exchange of arylboronic acids

In 2016, Sanford and co-workers developed a facile strategy to construct C–O, C–N, and C–halogen bonds by the Cu-mediated functionalization of potassium (hetero)aryltrifluoroborates with tetrabutylammonium or alkali metal salts (Scheme [146]).[115] This versatile reaction requires mild conditions and proceeds well with carboxylate, halide, and azide salts. The corresponding esters were synthesized using alkanoate and arenecarboxylate salts, such as trifluoroacetate, acetate, propanoate, pivalate, and benzoate salts. The optimized conditions for tetraalkylammonium halide salts required 4 equiv of both Cu(OTf)₂ and the nucleophile at room temperature in acetonitrile for 16 hours and gave the corresponding chloro, bromo-, and iodoarenes, whereas fluorination was performed with KF at 60 °C (Scheme [139]).[111] Employing potassium azide as an efficient nucleo­phile in this transformation generated valuable aryl azides in moderate yields.

Scheme 146 Copper-mediated functionalization of potassium (hetero­)aryltrifluoroborates

In 2019, Finko and co-workers reported the selective Se-arylation of 2-selenohydantoins using arylboronic acids under base-free mild conditions (Scheme [147]).[116] The strategy was used in the synthesis of novel 3-substituted 5-arylidene-2-(arylseleno)imidazolin-4-ones in high yields. The starting 2-selenohydantoins were synthesized by converting selenoureas into the corresponding 3-substituted 2-selenohydantoins which then underwent Knoevenagel reaction with the aldehyde present in the reaction mixture. The optimum conditions used 1.1 equiv Cu(OAc)₂·H₂O as catalyst and 2.2 equiv of 1,10-phenanthroline as a ligand in DCE at room temperature in an open flask for 2–6 hours. A wide range of arylboronic acids underwent the arylation reaction to furnish the products in moderate to excellent yields.

Scheme 147 Cu(OAc)₂·H₂O/1,10-phen-catalyzed Se-arylation of 2-selenohydantoins using arylboronic acids

In 2019, Ball and co-workers reported an operationally simple S-arylation reaction of cysteine residues using 2-nitro-substituted arylboronic acids promoted by a simple nickel(II) salt (Scheme [148]).[117] Fast reaction rates were achieved in purely aqueous media with excellent selectivity toward cysteine residue. Investigating the reaction of IL-8 inhibitor containing a single cysteine residue as a model peptide with 2-nitrophenylboronic acid in the presence of a variety of metal salts, such as Ni(II), Cu(II), and Co(II), identified Ni(II) as the best catalyst because of its superior reaction kinetics that helped in avoiding cysteine oxidation and histidine-directed amide N–H modification which is known for copper. A variety of cysteine-containing peptides reacted rapidly with phenylboronic acids bearing electron-deficient­ substituents in the 2-position.

Scheme 148 Ni(II)-promoted S-arylation reaction of cysteine residues using 2-nitro-substituted arylboronic acids

In 2018, Makvandi, Mach, and co-workers reported the first approach to the synthesis of astatinated (²¹¹At) and iodinated (¹²⁵I) compounds under modified Chan–Lam cross-coupling conditions using arylboronic acid pinacol esters with Cu(pyridine)₄(OTf)₂ as a catalyst in just 10 minutes at room temperature (Scheme [149]);[118] this is an efficient and nontoxic protocol that eliminates the traditional need for toxic organotin reagents. The reaction conditions are applicable to a broad range of (hetero)arylboronic reagents with varying steric and electronic properties.

Scheme 149 Cu(II)-promoted ¹²⁵I and ²¹¹At radiolabeling of boronic esters

This protocol was successfully applied to the late-stage installation of radioactive astatine (²¹¹At) and iodine (¹²⁵I) in drug molecules for the development of α-emitting radiotherapeutics. As an example, the late-stage astatination and iodination of anticancer PARP-1 inhibitors provides a practical and environmentally friendly approach to developing α-emitting radiotherapeutics (Scheme [150]).

Scheme 150 Cu(II)-promoted ¹²⁵I and ²¹¹At radiolabeling of PARP-1 inhibitors

4

Conclusions

Copper-promoted Chan–Lam cross-coupling chemistry has come a long way since its invention in 1998. In this review, the recent developments in Cu-catalyzed carbon–heteroatom­ bond formation by using modified Chan–Lam coupling conditions are described. The limitations, scope, and applications of this method are greatly improved for various substrates and with optimization of the Cu catalyst, ligand, base, and solvent, these methods were successfully applied to the formation of various C–X bonds. Optimized reaction conditions are also discussed in terms of their substrate scope and mechanisms.[119] The Chan–Lam coupling reaction is now capable of forming twelve C–element bonds (C–N, C–O, C–C, C–S, C–P, C–F, C–Cl, C–Br, C–I, C–At, C–Se, and C–Te,). This makes the Chan–Lam coupling reaction the most diverse mild reaction known in organic chemistry.

• References


For selected general reviews, see:
• 1a Nakamura I, Yamamoto Y. Chem. Rev. 2004; 104: 2127
• 1b Kim H, Chang S. ACS Catal. 2016; 6: 2341
• 1c Beletskaya IP, Cheprakov AV. Organometallics 2012; 31: 7753
• 1d Zeng Q, Zhang L, Zhou Y. Chem Rec. 2018; 18: 1278
• 1e Bariwal J, Eycken EV. Chem. Soc. Rev. 2013; 42: 9283
• 1f Sadig JE. R, Willis MC. Synthesis 2011; 1
• 1g Rauws TR. M, Maes BU. W. Chem. Soc. Rev. 2012; 41: 2463

For reviews on the Chan–Lam coupling, see:
• 1h For Part I see: Qiao JX, Lam PY. S. Synthesis 2011; 829
• 1i Rao KS, Wu T.-S. Tetrahedron 2012; 68: 7735
• 1j Ma X, Liu F, Mo D. Chin. J. Org. Chem. 2017; 37: 1069

Two reviews (1k and 1l) were published during the final stage of our manuscript preparation, see:
• 1k West JW, Fyfe JW. B, Vantourout JC, Watson AJ. B. Chem. Rev. 2019; 119: 12491
• 1l Chen J.-Q, Li J.-H, Dong Z.-B. Adv. Synth. Catal. 2020; 362: 3311
• 2 Kienle M, Dubbaka SR, Brade K, Knochel P. Eur. J. Org. Chem. 2007; 4166
• 3 Taster S, Mies J, Lang M. Adv. Synth. Catal. 2007; 349: 2256
• 4a Guram AS, Buchwald SL. J. Am. Chem. Soc. 1994; 116: 7901
• 4b Ruiz-Castillo P, Buchwald SL. Chem. Rev. 2016; 116: 12564
• 5a Paul F, Patt J, Hartwig JF. J. Am. Chem. Soc. 1994; 116: 5969
• 5b Hartwig JF. Acc. Chem. Res. 2008; 41: 1534
• 6a Ullmann F, Sponagel P. Ber. Dtsch. Chem. Ges. 1905; 38: 2211
• 6b Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 6954
• 7a Goldberg I. Ber. Dtsch. Chem. Ges. 1906; 39: 1619
• 7b Sambiago C, Marsden SP, Blacker AJ, McGowan PC. Chem. Soc. Rev. 2014; 43: 3525
• 8 Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 42: 5400
• 9 Elliott GI, Konopelski JP. Tetrahedron 2001; 57: 5683
• 10 Finet JP, Fedorov AY, Combes S, Boyer G. Curr. Org. Chem. 2002; 6: 597
• 11 Chan DM. T, Monaco KL, Wang R.-P, Winters MP. Tetrahedron Lett. 1998; 39: 2933
• 12 Evans DA, Katz JL, West TR. Tetrahedron Lett. 1998; 39: 2937 The Evans group found out about the discovery of Cu-promoted N/O-arylation by DuPont from the 1997 National Organic Symposium poster presented by Chan
• 13a Lam PY. S, Clark CG, Saubern S, Adams J, Winters MP, Chan DM. T, Combs A. Tetrahedron Lett. 1998; 39: 2941
• 13b Li JJ. Name Reactions: A Collection of Detailed Reaction Mechanisms, 4th ed. Springer; Berlin: 2009: 102
• 14 Meyer GJ. J. Labelled Compd. Radiopharm. 2018; 61: 154
• 15 Collman JP, Zhong M. Org. Lett. 2000; 2: 1233
• 16 Collman JP, Zhong M, Zeng L, Costanzo S. J. Org. Chem. 2001; 66: 1528
• 17 Lan JB, Chen L, Yu X.-Q, You J.-S, Xie R.-G. Chem. Commun. 2004; 188
• 18 Kantam ML, Venkanna GT, Sridhar C, Sreedhar B, Choudary BM. J. Org. Chem. 2006; 71: 9522
• 19 Antilla JC, Buchwald SL. Org. Lett. 2001; 3: 2077
• 20 Quach TD, Batey KA. Org. Lett. 2003; 5: 4397
• 21 Rao DN, Rasheed S, Kumar KA, Reddy AS, Das P. Adv. Synth. Catal. 2016; 358: 2126
• 22 Reddy AS, Reddy KR, Rao DN, Jaladanki CK, Bharatam PV, Lam PY. S, Das P. Org. Biomol. Chem. 2017; 15: 801
• 23 Liu S, Zu W, Zhang J, Xu L. Org. Biomol. Chem. 2017; 15: 9288
• 24 Rasheed S, Rao DN, Reddy KR, Aravinda S, Vishwakarma RA, Das P. RSC Adv. 2014; 4: 4960
• 25 Han Y, Zhang M, Zhang Y.-Q, Zhang Z.-H. Green Chem. 2018; 20: 4891
• 26 Wang H, Tu Y.-H, Liu D.-Y, Hu X.-G. Org. Biomol. Chem. 2018; 16: 6634
• 27a Arrington K, Barcan GA, Calandra NA, Erickson GA, Li L, Liu L, Nilson MG, Strambeanu II, VanGelder KF, Woodard JL, Xie S, Allen CL, Kowalski JA, Leitch DC. J. Org. Chem. 2019; 84: 4680
• 27b Bowman RK, Bullock KM, Copley RC. B, Deschamps NM, McClure MS, Powers JD, Wolters AM, Wu L, Xie S. J. Org. Chem. 2015; 80: 9610
• 28 Dar’in D, Krasavin M. J. Org. Chem. 2016; 81: 12514
• 29 Khosravi A, Mokhtari J, Naimi-Jamal MR, Tahmasebi S, Panahi L. RSC Adv. 2017; 7: 46022
• 30 Vantourout JC, Li L, Bendito-Moll E, Chabbra S, Arrington K, Bode BE, Isidro-Llobet A, Kowalski JA, Nilson MG, Wheelhouse KM. P, Woodard JL, Xie S, Leitch DC, Watson AJ. B. ACS Catal. 2018; 8: 9560
• 31a McGarry KA, Duenas AA, Clark TB. J. Org. Chem. 2015; 80: 7193
• 31b Huffman LM, Stahl SS. J. Am. Chem. Soc. 2008; 130: 9196
• 32 Roy S, Sarma MJ, Kashyap B, Phukan P. Chem. Commun. 2016; 52: 1170
• 33 Qi HL, Chen DS, Ye JS, Huang JM. J. Org. Chem. 2013; 78: 7482
• 34a Vantourout JC, Law RP, Isidro-Llobet A, Atkinson SJ, Watson AJ. B. J. Org. Chem. 2016; 81: 3942
• 34b Vantourout JC, Miras HN, Isidro-Llobet A, Sproules S, Watson AJ. B. J. Am. Chem. Soc. 2017; 139: 4769
• 35 Wexler RP, Nuhant P, Senter TJ, Gale-Day ZJ. Org. Lett. 2019; 21: 4540
• 36 Yoo W.-J, Tsukamoto T, Kobayashi S. Angew. Chem. Int. Ed. 2015; 54: 6587
• 37 Kumar KA, Kannaboina P, Rao DN, Das P. Org. Biomol. Chem. 2016; 14: 8989
• 38 Reddy BV. S, Reddy NS, Reddy YJ, Reddy YV. Tetrahedron Lett. 2011; 52: 2547
• 39 You C, Yao F, Yan T, Cai M. RSC Adv. 2016; 6: 43605
• 40 Moon S.-Y, Nam J, Rathwell K, Kim W.-S. Org. Lett. 2014; 16: 338
• 41 Moon S.-Y, Kim UB, Sung D.-B, Kim W.-S. J. Org. Chem. 2015; 80: 1856
• 42 Moessner C, Bolm C. Org. Lett. 2005; 7: 2667
• 43 Bohmann RA, Bolm C. Org. Lett. 2013; 15: 4277
• 44 Candy M, Bohmann RA, Bolm C. Adv. Synth. Catal. 2012; 354: 2928
• 45 Battula SR. K, Subbareddy GV, Chakravarthy IE. Tetrahedron Lett. 2014; 55: 517
• 46 Nandi GC, Kota SR, Goverder T, Kruger HG, Arridsson PI. Tetrahedron 2014; 70: 5428
• 47 Matsuda N, Hirano K, Satoh T, Miura M. Angew. Chem. Int. Ed. 2012; 51: 3642
• 48 Rucker RP, Whittaker AM, Dang H, Lalic G. Angew. Chem. Int. Ed. 2012; 51: 3953
• 49a Moon PJ, Halperin HM, Lundgren RJ. Angew. Chem. Int. Ed. 2016; 55: 1894
• 49b Jiang Y, Ma D. Copper-Catalyzed Ligand Promoted Ullmann-Type Coupling Reactions. In Catalysis without Precious Metals. Bullock RM. Wiley–VCH; Weinheim: 2010: 213-233
• 49c Morgan J, Pinhey JT. J. Chem. Soc., Perkin Trans. 1 1990; 715
• 50 Raghuvanshi DS, Gupta AK, Singh KN. Org. Lett. 2012; 14: 4326
• 51a Hanaya K, Miller MK, Ball ZT. Org. Lett. 2019; 21: 2445
• 51b Ohata J, Zeng Y, Segatori L, Ball ZT. Angew. Chem. Int. Ed. 2018; 57: 4015
• 52 DalZotto C, Michaux J, Martinand-Lurin E, Campagne JM. Eur. J. Org. Chem. 2010; 3811
• 53 Gagnon A, St-Onge M, Little K, Duplessis M, Barabé F. J. Am. Chem. Soc. 2007; 129: 44
• 54 Tsuritani T, Strotman NA, Yamamoto Y, Kawasaki M, Yasuda N, Mase T. Org. Lett. 2008; 10: 1653
• 55 González I, Mosquera J, Guerrero C, Rodríguez R, Cruces J. Org. Lett. 2009; 11: 1677
• 56 Benard S, Neuville L, Zhu J. Chem. Commun. 2010; 46: 3393
• 57 Racine E, Monnier F, Vors J.-P, Taillefer M. Chem. Commun. 2013; 49: 7412
• 58 Rossi SA, Shimkin KW, Xu Q, Mori-Quiroz LM, Watson DA. Org. Lett. 2013; 15: 2314
• 59 Mori-Quiroz LM, Shimkin KW, Rezazadeh S, Kozlowski RA, Watson DA. Chem. Eur. J. 2016; 22: 15654
• 60 Sueki S, Kuninobe Y. Org. Lett. 2013; 15: 1544
• 61 Derosa J, O’Duill ML, Holcomb M, Boulous MN, Patman RL, Wang F, Tran-Dubé M, McAlpine I, Engle KM. J. Org. Chem. 2018; 83: 3417
• 62 Harris MR, Li Q, Lian Y, Xiao J, Londregan AT. Org. Lett. 2017; 19: 2450
• 63 Rao DN, Rasheed S, Aravinda S, Vishwakarma RA, Das P. RSC Adv. 2013; 3: 11472
• 64 Chen J, Natte K, Man NY. T, Stewart SG, Wu X.-F. Tetrahedron Lett. 2015; 56: 4843
• 65 Morellato L, Huteau V, Pochet S. Tetrahedron Lett. 2014; 55: 1625
• 66 Shi W.-M, Liu F.-P, Wang Z.-X, Bi H.-Y, Liang C, Xu L.-P, Su G.-F, Mo D.-L. Adv. Synth. Catal. 2017; 359: 2741
• 67 Sahoo H, Mukherjee S, Grandhi GS, Selvakumar J, Baidya M. J. Org. Chem. 2017; 82: 2764
• 68 Chen C.-H, Liu Q.-Q, Ma X.-P, Feng Y, Liang C, Pan C.-X, Su GF, Mo D.-L. J. Org. Chem. 2017; 82: 6417
• 69 Rao DN, Rasheed S, Vishwakarma RA, Das P. Chem. Commun. 2014; 50: 12911
• 70 Li J, Neuville L. Org. Lett. 2013; 15: 6124
• 71 Onaka T, Umemoto H, Miki Y, Nakamura A, Maegawa T. J. Org. Chem. 2014; 79: 6703
• 72 Liu C.-Y, Li Y, Ding J.-Y, Dong D.-W, Han F.-S. Chem. Eur. J. 2014; 20: 2373
• 73 Li J, Benard S, Neuville L, Zhu J. Org. Lett. 2012; 14: 5980
• 74 Kumar KA, Kannaboina P, Jaladanki CK, Bharatam PV, Das P. ChemistrySelect 2016; 3: 601
• 75 Rasheed S, Rao DN, Das P. J. Org. Chem. 2015; 80: 9321
• 76 Kumar KA, Kannaboina P, Dhaked DK, Vishwakarma RA, Bharatam PV, Das P. Org. Biomol. Chem. 2015; 13: 1481
• 77 Gao J, Shao Y, Zhu J, Zhu J, Mao H, Wang X, Lv X. J. Org. Chem. 2014; 79: 9000
• 78 Bruneau A, Brion J.-D, Alami M, Messaoudi S. Chem. Commun. 2013; 49: 8359
• 79 Hardouin Duparc V, Schaper F. Dalton Trans. 2017; 46: 12766
• 80 Chen T, Huang Q, Luo Y, Hu Y, Lu W. Tetrahedron Lett. 2013; 54: 1401
• 81a Petrassi HM, Sharpless KB, Kelly JW. Org. Lett. 2001; 3: 139
• 81b Patil AS, Mo D.-L, Wang H.-Y, Mueller DS, Anderson LL. Angew. Chem. Int. Ed. 2012; 51: 7799
• 82 Mondal M, Sarmah G, Gogoi K, Bora U. Tetrahedron Lett. 2012; 53: 6219
• 83a Lam PY. S, Clark CG, Saubern S, Adams J, Averill KM, Chan DM. T. Synlett 2000; 674
• 83b Lam PY. S, Bonne D, Vincent G, Clark CG, Combs AP. Tetrahedron Lett. 2003; 44: 1691
• 84 Crifar C, Petiot P, Ahmad T, Gagnon A. Chem. Eur. J. 2014; 20: 2755
• 85a Makhaeva GF, Aksinenko AY, Sokolov VB, Serebryakova OG, Richardson RJ. Bioorg. Med. Chem. Lett. 2009; 19: 5528
• 85b Suzuki H, Matuoka T, Ohtsuka I, Osuka A. Synthesis 1985; 499
• 86 Wang R, Wang L, Zhang K, Li J, Zou D, Wu Y, Wu Y. Tetrahedron Lett. 2015; 56: 4815
• 87 Zhang L, Zhang G, Zhang M, Cheng J. J. Org. Chem. 2010; 75: 7472
• 88 Dai J.-J, Liu J.-H, Luo D.-F, Liu L. Chem. Commun. 2011; 47: 677
• 89 Marcum JS, McGarry KA, Ferber CJ, Clark TB. J. Org. Chem. 2016; 81: 7963
• 90a Pine SH. Org. React. 1993; 43: 1
• 90b Petrzilka M. Helv. Chim. Acta 1978; 61: 2286
• 90c Bosch M, Schlaf M. J. Org. Chem. 2003; 68: 5225
• 90d Ramana CV, Mallik R, Gonnade RG, Gurjar MK. Tetrahedron Lett. 2006; 47: 3649
• 90e Shade RE, Hyde AM, Olsen J.-C, Merlic CA. J. Am. Chem. Soc. 2010; 132: 1202
• 91a Huang F, Quach TD, Batey RA. Org. Lett. 2013; 15: 3150
• 91b Chan DM. T, Lam PY. S. In Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine . Hall DG. Wiley-VCH; Weinheim: 2005: 205-240
• 92 Kontokosta D, Mueller DS, Wang H.-Y, Anderson LL. Org. Lett. 2013; 15: 4830
• 93 Jacobson CE, Martinez-Muñoz N, Gorin DJ. J. Org. Chem. 2015; 80: 7305
• 94 King AE, Ryland BL, Brunold TC, Stahl SS. Organometallics 2012; 31: 7948
• 95a Flohr A, Jakob-Roetne R, Wostl W. (Hoffmann–La Roche Inc.) US WO2006061136, 2006
• 95b Donnell AF, Michoud C, Rupert KC, Han X, Aguilar D, Frank KB, Fretland AJ, Gao L, Goggin B, Hogg JH, Hong K, Janson CA, Kester RF, Kong N, Le K, Li S, Liang W, Lombardo LJ, Lou Y, Lukacs CM, Mischke S, Moliterni JA, Polonskaia A, Schutt AD, Solis DS, Specian A, Taylor RT, Weisel M, Remiszewski SW. J. Med. Chem. 2013; 56: 7772
• 95c Khatib ME, Molander GA. Org. Lett. 2014; 16: 4944
• 96 Steemers L, Van Maarseveen JH. Org. Biomol. Chem. 2019; 17: 2103
• 97 Herradura PS, Pendola KA, Guy RK. Org. Lett. 2000; 2: 2019
• 98 Savarin C, Srogl J, Liebeskind LS. Org. Lett. 2002; 4: 4309
• 99 Xu H.-J, Zhao Y.-Q, Feng T, Feng Y.-S. J. Org. Chem. 2012; 77: 2878
• 100 Shanmugapriya J, Rajaguru K, Muthusubramanian S, Bhuvanesh N. Eur. J. Org. Chem. 2016; 1963
• 101 Xu J, Zhang L, Li X, Gao Y, Tang G, Zhao Y. Org. Lett. 2016; 18: 1266
• 102 Koley S, Chowdhury S, Chanda T, Ramulu BJ, Anand N, Singh MS. Eur. J. Org. Chem. 2015; 409
• 103a Gao M.-Y, Xu W, Zhang S.-B, Li Y.-S, Dong Z.-B. Eur. J. Org. Chem. 2018; 6693
• 103b Cheng Y, Liu X, Dong Z.-B. Eur. J. Org. Chem. 2018; 815
• 104a Liu X, Zhang S.-B, Zhu H, Cheng Y, Peng H.-Y, Dong Z.-B. Eur. J. Org. Chem. 2018; 4483
• 104b Liu X, Dong Z.-B. J. Org. Chem. 2019; 84: 11524
• 105 Sun N, Che L, Mo W, Hu B, Shen Z, Hu X. Org. Biomol. Chem. 2015; 13: 691
• 106 Zhuang R, Xu J, Cai Z, Tang G, Fang M, Zhao Y. Org. Lett. 2011; 13: 2110
• 107 Hu G, Chen W, Fu T, Peng Z, Qiao H, Gao Y, Zhao Y. Org. Lett. 2013; 15: 5362
• 108a Chu L, Qing F.-L. Org. Lett. 2010; 12: 5060
• 108b King AE, Huffman LM, Casitas A, Costas M, Ribas X, Stahl SS. J. Am. Chem. Soc. 2010; 132: 12068
• 109 Senecal TD, Parsons AT, Buchwald SL. J. Org. Chem. 2011; 76: 1174
• 110a Nebra N, Grushin VV. J. Am. Chem. Soc. 2014; 136: 16998
• 110b Novak P, Lishchynskyi A, Grushin VV. Angew. Chem. Int. Ed. 2012; 51: 7767
• 111 Ye Y, Schimler SD, Hanley DS, Sanford MS. J. Am. Chem. Soc. 2013; 135: 16292
• 112 Tredwell M, Preshlock SM, Taylor NJ, Gruber S, Huiban M, Passchier J, Mercier J, Genicot C, Gouverneur V. Angew. Chem. Int. Ed. 2014; 53: 7751
• 113 Mossine AV, Brooks AF, Makaravage KJ, Miller JM, Ichiishi N, Sanford MS, Scott PJ. H. Org. Lett. 2015; 17: 5780
• 114 Wu H, Hynes J. Org. Lett. 2010; 12: 1192
• 115 Schimler SD, Sanford MS. Synlett 2016; 27: 2279
• 116 Vyhivskyi O, Dlin EA, Finko AV, Stepanova SP, Ivanenkov YA, Skvortsov D, Mironov AV, Zyk NV, Majouga AG, Beloglazkina EK. ACS Comb. Sci. 2019; 21: 456
• 117 Hanaya K, Ohata J, Miller MK, Mangubat-Medina AE, Swierczynski MJ, Yang DC, Rosenthal RM, Popp BV, Ball ZT. Chem. Commun. 2019; 55: 2841
• 118 Reilly SW, Makvandi M, Xu K, Mach RH. Org. Lett. 2018; 20: 1752

For recent mechanistic studies on the Chan–Lam coupling, see:
• 119a ref 34b.
• 119b Duparc VH, Bano GL, Schaper F. ACS Catal. 2018; 8: 7308