Copper-Catalyzed Coupling Reactions of ... - ACS Publications

Chapter 10

Copper-Catalyzed Coupling Reactions of Organoboron Compounds Downloaded by UNIV OF GEORGIA on December 3, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch010

Astha Verma and Webster L. Santos* Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States *E-mail: [email protected]

Copper-catalyzed coupling reactions provide a unique and inexpensive alternative to noble transition-metal catalyzed cross-couplings for the construction of carbon-carbon and carbon-heteroatom bonds. Significant progress has been made using organoboron reagents as the coupling partners in these copper-catalyzed reactions. Important contributions in the field ranging from seminal work to recent advances in the area of copper-catalyzed coupling reactions using organoboron compounds are discussed.

Introduction Transition metal-catalyzed cross-coupling reactions have emerged as a powerful tool to achieve ubiquitous C-C and C-heteroatom bond formations. The area of cross-coupling reactions is closely associated with palladium catalysis due to the monumental development of palladium-catalyzed cross-coupling reactions in the last half of the 20th century. The rapid development of palladium-catalyzed reactions is attributed to their low catalytic loading, mild reaction conditions, and high product yields. However, a careful search of the literature reveals that copper catalysis is actually several decades older than palladium catalysis (1–6). In 1901, Ullmann reported the homo-coupling of bromo-2-nitrobenzene in the presence of copper powder to give the corresponding biaryl product (7). The work was later extended to carbon-nitrogen (C-N) and carbon-oxygen (C-O) bond formation (1, 2). An important limitation of these copper-mediated couplings was the requirement of stoichiometric amounts of copper and harsh conditions © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Downloaded by UNIV OF GEORGIA on December 3, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch010

(high reaction temperatures ≥ 200 °C) (8). A major breakthrough was achieved in the early 21st century when Buchwald demonstrated that incorporation of chelating ligands such as a diamine allows for the coupling between aryl halides and amides to be performed under milder conditions such as lower temperature, non-polar solvents, and most importantly in the presence of catalytic amounts of copper (9). As a consequence, a resurgence in copper-catalyzed reactions ensued. These developments have been summarized in excellent reviews (10–20); however, none exclusively focused on copper-catalyzed cross-coupling reactions with organoborons for C-C and C-heteroatom bond construction. Organoboron compounds benefit from their air- and moisture stability, non-toxicity, and commercial availability (21). Further, copper is abundant, inexpensive, and can access four oxidation states ranging from 0 to +3, which makes it a versatile catalyst that can undergo one electron or two electron processes (22). This chapter focuses on C-C and C-heteroatom (N, S, O) bond formations utilizing copper in catalytic amounts. Reactions employing stoichiometric amounts of copper are discussed when pertinent to the development of catalytic processes. Furthermore, both traditional cross-coupling reactions and oxidative cross-coupling reactions are reviewed. In traditional coupling reactions, a nucleophile couples to an electrophile in the presence of a catalyst. However, in an oxidative coupling a nucleophile couples to another nucleophile in the presence of a catalyst and an oxidant (23). Reactions involving miscellaneous C-heteroatom bond formations such as C-P, C-Se, C-Te; where P = phosphorus, Se = selenium and Te = tellurium are excluded (20, 22).

Bond Formation Coupling of Aryl Organoborons with Aryl Substrates In 2002, Thathagar et al. first reported copper or copper-based nanocolloid catalyzed C-C cross-coupling of an aryl halide with aryl boronic acids (24). However, the substrate scope of their investigation was limited to phenyl iodide and phenyl boronic acid when copper nanocolloid was used as the catalyst (Equation 1) (24, 25).

Demir and co-workers reported the first example of oxidative self coupling of aryl boronic acids to give symmetrical biaryls in the presence of Cu(OAc)2 and oxygen as the oxidant (Scheme 1) (26). The homocoupled products were obtained in moderate to good yield. The reaction was sensitive to steric effects, and 2,6-disubstituted boronic acid substrates did not undergo coupling. 314 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 1. Copper-Mediated Oxidative Dimerization of Aryl Boronic Acids (26). An improved protocol was developed by Kirai and co-workers (27). Homo-coupling of aryl boronic acids was achieved in the presence of 2-4 mol % of copper(II) bis-μ-hydroxo adduct with 1,10-phenanthroline (Phen) ligand (Scheme 2). Their protocol’s success was attributed to the use of a binuclear (μ-hydroxido)copper(II) complex that facilitated transmetalation. Twenty five different substituted aryl boronic acids were investigated to afford the desired biaryls in 19-92% yields. Low yields were observed in case of ortho-substituted aryl boronic acids due to substantial protodeboration.

Scheme 2. Homocoupling of Aryl Boronic Acids Catalyzed by 1,10-Phenanthroline-Ligated Copper (II) Complex (27). Later, Li and co-workers reported a CuI/DABCO system (DABCO = 1,4diazabicyclo[2.2.2]octane) for efficiently coupling aryl iodides and aryl bromides with aryl boronic acids (Scheme 3) (28). A diverse range of aryl iodides underwent cross-coupling in the presence of CuI (10 mol %), DABCO (20 mol %) using Cs2CO3 in DMF at 125-130 °C. The desired products were obtained in good yields; 315 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


however, aryl bromides were inefficient coupling partners. Hence, the reaction was performed using stoichiometric quantities of CuI and tetra-n-butylammonium bromide (TBAB) as an additive at elevated temperature (150 °C) to achieve the desired products. Aryl chlorides remained unreactive under the given reaction conditions, and only trace amount of product was obtained. It was found that this catalytic system could be extended to include vinyl halides (I, Br) as the coupling partner (29). Subsequently, a copper-catalyzed ligand-free TBAB promoted crosscoupling of aryl halides (I, Br) with aryl boronic acid in DMSO was also developed (30).

Scheme 3. Copper-Catalyzed Cross-Coupling Reaction of Aryl Halides and Aryl Boronic Acids (28). Mao et al. developed a reusable catalytic system consisting of copper powder in polyethylene glycol 400 (PEG 400) for cross-coupling of aryl halides with aryl boronic acids (Scheme 4) (31). PEG is speculated to play the dual role of solvent and ligand for the copper catalyst (31). Coordinating alcohols such as ethanediol and propanediol were also considered as alternatives but gave poor results. Aryl iodides conveniently reacted under the optimized reaction conditions to yield the cross-coupled products in excellent yields. Molecular iodine (KI and CuI gave inferior results) was used as an additive when aryl bromides and aryl chlorides were used as substrates for in-situ formation of aryl iodides.

Scheme 4. Copper-Catalyzed Cross-Coupling Reaction of Aryl Halides and Aryl Boronic Acids (31). Fu and co-workers disclosed the copper-catalyzed Suzuki-Miyaura cross-coupling of aryl boronic acids with primary and secondary benzyl halides (Scheme 5) (32). Optimization of the reaction conditions using benzyl chloride (1) and phenyl boronate (2) as the model substrates revealed that CuI (20 mol %), and diketone ligand (L1, 20 mol %) in N-methylcaprolactam (NMCPL) formed the coupling product (3) in high yields. Nickel or palladium contamination in the 316 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


catalyst was ruled out by conducting reactions using Pd(OAc)2 or NiI2 that gave the desired product in low yield. Investigation of primary benzyl halide substrate scope demonstrated that functional groups on the aryl ring such as ethers, esters, trifluoromethyl, olefins, and halogens were tolerated under the reaction conditions (Scheme 5A). Competition experiments established the selectivity for benzyl C-X (X = Cl, Br) over alkyl C-X (X = OTs, Br, I; OTs = tosylate). Notably, sterically hindered and β-hydrogen containing secondary benzyl substrates gave the cross-coupled products in good yields without observable β-hydride elimination (Scheme 5B). Subsequently, they also investigated a copper-catalyzed cross-coupling of alkyl/aryl epoxides and N-sulfonyl aziridines with aryl boronate esters (33). Ring opening of epoxides and aziridines gave the desired secondary alcohols and secondary amines in good yields (33).

Scheme 5. Copper-Catalyzed Cross-Coupling of Primary (A) and Secondary Benzyl Halides (B) with Arylboronates (32).

While Pd- (34–37), Ni- (38–44), and Fe- (45) catalyzed coupling of alkyl halides with organoboron compounds have been widely developed; the analogous reactions using copper catalysts were unprecedented. Liu et al. were the first to report the coupling of primary halides and pseudo halides containing C-X bond (X= I, Br, Cl, OMs, and OTs; Ms = methanesulfonyl, Ts = p-toluenesulfonyl) with organoboron compounds using CuI in the presence of LiOtBu as the base 317 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


in DMF (Scheme 6) (46). Catalysts such as CuBr, CuI, Cu(OTf)2, Pd(OAc)2, NiI2 and bases such as Cs2CO3, K3PO4, CsOAc, NaN(SiMe3)2, KOtBu, NaOtBu, Li2CO3, LiOMe, LiOEt were explored as alternatives. Electron-rich and electron-deficient aryl rings and heterocycles were tolerated on the boronate ester substrate. Different boron-containing derivatives (Scheme 6, compounds 9-11) were also viable coupling partners. Higher temperatures were employed when alkyl chlorides were used as substrates. Furthermore, the reactivity of different leaving groups on the alkyl halides was tested using competition experiments and revealed the following activity trend: I > Br > OTs > OMs > Cl (Table 1). Unlike nickel-catalyzed Suzuki coupling of alkyl halides, the possibility of a radical mechanism was excluded (39).

Scheme 6. Copper-Catalyzed Cross-Coupling of Alkyl Electrophiles with Aryl Boronates (46).

In 2011, Brown and co-workers reported a copper-catalyzed cross-coupling of aryl iodides with aryl boronates (Scheme 7A) and demonstrated its application in carboboration of alkynes and allenes (47). The foundation of the cross-coupling was built on a putative catalytic cycle (Scheme 7B). According to the investigators, CuAr1 intermediate formed by initial transmetalation of aryl boronic acid (Ar1B(OR)2) with Cu catalyst could undergo oxidative addition followed by reductive elimination to form the desired cross-coupled product Ar1-Ar2. It should be noted that in palladium-catalyzed Suzuki-Miyaura cross-coupling, oxidative addition of Ar2-X precedes transmetalation with Ar1-B(OR)2. CuCl with Xantphos as the ligand effectively catalyzed the C-C coupling between a broad range of aryl halides and aryl boronate esters at 80 °C in toluene within 15 h. In the case of sterically hindered aryl boronic esters, Cy3PCuCl was used.

318 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Table 1. Selectivity of Various Alkyl Electrophiles in Competition Experiments (46).

Scheme 7. General Reaction Scheme (A) and Catalytic Cycle (B) for Copper-Catalyzed Cross-Coupling of Cryl Boronates with Aryl Halides (47).


Coupling of Aryl Boronic Acid Derivatives with Alkyne Substrates


In 2008, Mao and co-workers reported the CuBr-catalyzed cross-coupling of aryl boronic acids with terminal alkynes (Scheme 8) (48). Although the desired coupling products were obtained in low yields, it offered an unprecedented protocol for performing Sonogashira reaction using terminal alkynes and aryl boronic acids under phosphine- and palladium-free conditions.

Scheme 8. Copper-Catalyzed Sonogashira Coupling Reactions of Alkynes with Aryl Boronic Acids (48).

Subsequently, a mild, efficient and ligand-free protocol was developed by Pan et al. for Sonogashira coupling of terminal alkynes with aryl boronic acids (Scheme 9A) (49). Notably, electron-deficient terminal alkynes gave the desired cross-coupling product in moderate to good yield in the presence of CuI as the catalyst and silver (I) oxide as the oxidant. Although the reaction showed no sensitivity to electronic effects of the boronic acids, diminished yields were observed with sterically hindered boronic acid substrates. Remarkably, no homocoupling by-products were obtained in the reaction. The proposed mechanism proceeds through the formation of a Cu(I)-alkyne complex followed by oxidation to a Cu(III)-alkyne complex using Ag2O that undergoes transmetalation, and subsequent reductive elimination to give the desired product (Scheme 9B). Rao and co-workers used molecular oxygen as the oxidant for cross-coupling of terminal alkynes with aryl boronic acids at room temperature, thereby limiting the use of metal oxidants (Scheme 10) (50). Depending on the substrate under investigation, either pyridine or a 1:1 ratio of pyridine and methanol as the additive with Cu2O open to air afforded the desired internal alkynes in good to excellent yields. Aryl boronic acids containing halogens, aldehydes, ethers, and nitro functional groups were tolerated and terminal alkynes containing esters, alcohols, and amino groups performed well under the reaction conditions. 320 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 9. Ligand-free Copper-Catalyzed Sonogashira Reactions of Alkynes with Aryl Boronic Acids (A) and the Proposed Catalytic Cycle (B) (49).

Scheme 10. Copper-Catalyzed Aerobic Oxidative Coupling of Terminal Alkynes with Aryl Boronic Acids (50). Similarly, Yasukawa and co-workers reported the cross-coupling of alkynes with aryl boronic acids utilizing molecular oxygen as the oxidant and low catalytic loading of copper catalyst (0.15-3.0 mol % of CuBr) in the presence of 2,6-lutidine as the additive (Equation 2) (51). Notably, the concentration of the reaction and catalyst loading dramatically affected the outcome of the reaction. The high catalyst loading as well as reaction concentration promoted 321 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

the undesired homocoupling of alkyne and aryl boronic acid substrates. Further, amongst the pyridine bases investigated only 2,6-lutidine gave good results.


Coupling of Aryl Organoborons with Heteroarene Substrates Shen and co-workers developed a one-pot protocol for C-H arylation of pyridine N-oxides with aryl boronate esters to give 2-aryl pyridines (Equation 3) (52). Amongst a variety of copper catalyst and bases screened, Cu(acac)2, t-BuOK, and toluene in air gave the best results. 2-Unsubstituted pyridine N-oxides underwent the cross-coupling with aryl boronic acids smoothly; however, low yields were obtained with electron deficient N-oxides such as 4-cyano pyridine N-oxides. Further, the reaction was found sensitive to steric crowding in aryl boronate ester substrates.

Yang et al. reported the copper-catalyzed oxidative arylation of benzoxazoles, benzothiazoles, oxazoles, and thiazoles with aryl boronate esters using molecular oxygen as the oxidant (Scheme 11) (53). Amongst the catalyst and solvents investigated, CuCl and DMF gave the best yields. Lower yields were obtained when aryl boronate esters were replaced with aryl boronic acids. The reaction of oxazoles and thiazoles with aryl boronate esters required 80 °C and t-BuONa as the base while full conversion was observed at 40 °C when benzoxazole and benzothiazole were used as substrates. A wide range of electron-deficient and electron-rich boronate esters were also investigated under their reaction conditions and the desired products were obtained in good to excellent yields.

Scheme 11. Copper-Catalyzed Oxidative Coupling of Heteroarenes with Aryl Boronate Esters (53). Coupling of Alkyl Organoborons with Alkenyl- and Alkyl Substrates Liwosz and Chemler reported copper-catalyzed C(sp3)-C(sp2) oxidative Heck-type coupling of alkyltrifluoroborates and vinyl arenes (Scheme 12) (54). 322 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Cu(OTf)2/1,10-phenanthroline in the presence of MnO2 as the terminal oxidant effectively promoted the cross-coupling of potassium benzyltrifluoroborate and 1,1-diphenylethylene (DPE) in high yields. Wide substrate scope with respect to vinyl arenes and alkylborates was investigated. Although, alkyltrifluoroborates gave the cross-coupled product in good yields, aryl or vinyltrifluoroborates were unreactive under their reaction conditions.

Scheme 12. Copper-Catalyzed Oxidative Coupling of Alkyltrifluoroborates and Vinyl Arenes (54). Yang and co-workers disclosed the C(sp3)-C(sp3) coupling of alkyl 9-BBN (9-BBN = 9-borabicyclo[3.3.1]nonane) organoboron compounds with primary alkyl halides using a CuI/LiOtBu catalytic system (Scheme 13) (46). Alkyl boronate esters were not suitable coupling partners and limited alkyl 9-BBN substrate scope was explored in their report. Further, 9-BBN organoboron compounds are difficult to handle due to their high reactivity and they have limited commercially availability (36).

Scheme 13. Copper-Catalyzed Cross-Coupling of Alkyl 9-BBN Reagents with Primary Electrophiles (46). To address this problem, Zhang et al. developed a C(sp3)-C(sp3) bond formation utilizing gem-diborylalkanes and alkyl halides in copper-catalyzed/ promoted conditions leading to alkyl boronic esters in moderate to good yields (Scheme 14) (55). In a model study, it was shown that the coupling of n-hexyl bromide and diborylmethane proceeded smoothly in the presence CuI (20 mol %), LiOtBu (3 equiv) as the base and tetra-n-butylammonium iodide (TBAI, 1 equiv) 323 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


as the additive in DMF at 60 °C (Scheme 14A). Tosylates were also efficient. However, in the case of more reactive alkyl iodides, milder conditions employing 10 mol % of CuI and LiOMe (3 equiv) as the base at 40 °C or room temperature provided the desired transformation. Broad substrate scope with respect to the primary alkyl electrophiles bearing functional groups such as acetals, olefins, esters, cyano, heterocylces (thiophene, phthalimide) were tolerated. Stoichiometric amounts of CuI and 4 equivalents of the LiOtBu were sufficient for the coupling of 1,1-diboryl alkanes to give the secondary alkyl boronic esters (Scheme 14B). However, the synthesis of tertiary alkylboronic esters required 3 equivalents of CuI and 8 equivalents of the LiOtBu (Scheme 14C). In 2015, the scope of the reaction was extended to include primary/secondary/tertiary halides with allyl boronate esters (Scheme 15) (56). In the presence of 10 mol % CuI and 2 equivalents of LiOtBu the cross-coupling product was formed in good yield. Primary alkyl iodides and bromides were suitable substrate; however, the corresponding chlorides proved to be unreactive. Low product yield was obtained when substrates containing secondary amines were used due to the presence of an acidic N-H hydrogen. Unactivated alkanes prone to β-hydride elimination were also viable substrates for coupling with allyl boronate esters (57, 58) when a catalytic amount of TMEDA was used as an additive.

Scheme 14. Cross-Coupling of Gem-diborylalkanes with Non-activated Primary Alkyl Halides (55). 324 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 15. Cross-Coupling of Allyl Boronic Esters with Primary Alkyl Halides (56).

Recently, Li et al. developed a copper-catalyzed oxidative coupling of aryl boronic acids with alkyltrifluoroborates (Equation 4) (59). Remarkably, cross-coupling of 4-methoxyphenyl boronic acids with potassium 3-phenylpropyl trifluoroborate using Cu(OAc)2, Ag2O as the oxidant, and sodium methoxide as the base in the presence of water effectively gave the desired product 29 in 86% yield within 10 mins at room temperature. In the absence of water, lower yields were observed. Water was thought to convert the trifluoroborate salt into the more reactive boronic acid derivate. A wide range of substrates were tolerated. Mechanistically, the transformation was proposed to proceed through a single electron transmetalation step. As shown in Scheme 16, transmetalation of the aryl boronic acid with the copper catalyst generates a ArCu(II)X species. A second transmetalation of an alkyl radical generated by the oxidation of an alkyl trifluoroborate salt generates a ArCu(III)RX complex. This hypervalent intermediate undergoes facile reductive elimination to furnish the desired product.

Trifluoromethylation and Carboxylation of Aryl- and Alkenyl Organoborons Xu et al. reported a copper-catalyzed trifluoromethylation of aryl boronic acids using an electrophilic trifluoromethyl cation source (Scheme 17) (60). Earlier strategies for trifluoromethylation of aryl boronic acids required stoichiometric transition metal catalyst and trifluoromethylating agent (61–64). The reaction of the model substrate diphenylboronic acid with (trifluoromethyl)dibenzothiophenium triflate as the trifluoromethylating reagent in the presence of CuI, 2,4,6-trimethylpyridine, and sodium acetate gave the desired product in only 4% yield. The low yield was attributed to the formation of 325 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


by-products such as protodeborated starting material, homo-coupled product and diphenyl acetate. After an extensive screen of copper catalyst and nitrogen ligands, CuOAc and 2,4,6-trimethylpyridine in dimethylacetamide gave the desired product in 80% yield. 2,4,6-Trimethylpyridine acted as ligand and a base, thereby dramatically decreasing the formation of diphenyl acetate by-product. 1.0:1.6 ratio of the diphenyl boronic acid to trifluoromethylating reagent was essential to obtain high yields. Further, no reaction was observed in the absence of copper catalyst. Electron donating and electron withdrawing groups on aryl boronic acids were tolerated under the reaction conditions. Un-protected functional groups such as OH and NH, carbonyl, chloro, ortho-substituted or heteroaryl boronic acids gave the desired product in good yield. Trifluoromethylation of phenyl vinyl boronic acids demonstrated their utility as substrates. Furthermore, the reaction proved insensitive to moisture. Later, Li et al. demonstrated the copper-catalyzed trifluoromethylation of aryl- and vinyl boronic acids using CF3 radical (Scheme 18) (65). In situ generation of CF3 radical was achieved through reaction of Langlois reagent (CF3SO2Na) and TBHP (t-BuOOH). The reaction of aryl boronic acids with CF3 radical in the presence of Cu(OAc)2, 2,4,6-collidine as the ligand, imidazole as the additive in DCM and water mixture at room temperature gave the desired product in good yield. Further, improved chemoselectivity and yield was observed in the presence of slightly acidic conditions and higher TBHP to NaSO2CF3 ratio. Aryl boronic acids with electron-donating functional groups gave the desired products in good yields; however, lower yields were observed with aryl boronic acids with ortho-substitution and electron-withdrawing substituents. Higher catalyst loading was necessary with halide substituted aryl boronic acids. Although heteroaryl boronic acids yielded the trifluoromethylated product in moderate yield; no reaction was observed when alkyl boronic acids were used as substrates. Further, vinyl boronic acids were viable substrates for trifluoromethylation and demonstrated exclusive (E) stereoselectivity when (E)-vinyl boronic acids were employed. On the contrary, (Z)-vinyl boronic acids gave mixture of (Z) and (E) product owing to higher stability of (E)-isomer. Takaya et al. reported a Cu(I)-catalyzed carboxylation of aryl- and alkenyl boronic esters (Scheme 19) (66). Amongst the catalyst and ligands screened, 5 mol % of CuI and 6 mol % of bisoxazoline in the presence of 3 equiv of CsF in DMF at 90 °C gave the desired aryl carboxylic acids in good yields. In the case of heteroaryl boronic esters, 1 mol % of CuI at 60 °C was sufficient to obtain the corresponding products in high yields. When alkenyl boronic esters were used as substrates, ligandless conditions in the presence of 3 mol % of CuI efficiently promoted the reaction to give the corresponding α,β-unsaturated carboxylic acids in good yields. Both β-alkyl and aryl substituents were tolerated on alkenyl boronic acids. Moreover, under their optimized conditions, a number of substituted aryl and alkenyl boronic esters that resulted in no carboxylated products under their complimentary Rh(I)-catalyzed conditions, gave the desired products in good yields.



Scheme 16. Catalytic Cycle for Oxidative Copper-Catalyzed Cross-Coupling of Aryl Boronic Acids with Alkyltrifluoroborates (59).

Scheme 17. Copper-Catalyzed Trifluoromethylation of Aryl Boronic Acids (60).

Scheme 18. Copper-Catalyzed Trifluoromethylation of Aryl and Vinyl Boronic Acids (65).



Scheme 19. Copper-Catalyzed Carboxylation of Aryl and Alkenyl Boronic Esters (66).

Later, Ohishi and co-workers also developed carboxylation of aryl- and alkenyl boronic esters catalyzed by N-heterocyclic carbene (NHC) copper complex (Scheme 20) (67). The carboxylation of 4-methoxylphenyl boronic ester with CO2 using 5 mol % of CuCl with 5 mol % of IPr·HCl in the presence of 2 mmol of KOt-Bu at 70 °C in THF yielded the desired product in quantitative yield. The catalyst loading was reduced to 1 mol % when isolated [(IPr)-CuCl] complex was used as the catalyst with 1.05 mmol of KOt-Bu. Further, no reaction was observed in the absence of Cu catalyst, or NHC ligand or KOt-Bu. The reaction showed insensitivity to substituent effect on the aryl ring of boronic ester substrate. A wide range of substituents were tolerated under the reaction conditions such as epoxy, carbonyl, vinyl, propargyl ether, and halides. Additionally, boronic esters including heteroaryl derivatives, alkenyl, and sterically hindered aryl groups were viable substrates for carboxylation. Later, they also reported NHC copper-catalyzed carboxylation of alkyboranes with CO2 (68). Alkyl boranes synthesized from insitu hydroboration of terminal alkynes with 9-BBN-H underwent carboxylation to give the corresponding carboxylic acids in good yields.

Scheme 20. Copper-Catalyzed Carboxylation of Organoboronic Esters (67). 328 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Around the same time, Ohmiya and co-workers reported a similar protocol for synthesis of alkynoic acids from carboxylation of in-situ generated alkylboranes (alkyl-9-BBN) using Cu(OAc), 1,10 phenanthroline and KOt-Bu at 100 °C for 12 h (Scheme 21) (69). Copper catalysts such as Cu(OAc)2, CuCl(IPr) lead to lower product yield; although CuCl showed efficacy similar to Cu(OAc). No reaction was observed in the absence of KOt-Bu. Further, temperature control was crucial to avoid deborylation of the alkylborane starting material. Extensive substrate scope with respect to the terminal alkenes bearing functional groups such as siloxy ester, acetal, methoxy, bromo, phthalimide and benzyloxy groups was tolerated. β-Branched terminal alkenes such as 1,1-diphenylethylene were viable substrates for the reductive carboxylation protocol; however, secondary alkyl boranes synthesized from internal alkenes were unreactive under the reaction conditions.

Scheme 21. Copper-Catalyzed Carboxylation of Alkylboranes (69).

Carbon-Heteroatom (N, O, S) Cross-Coupling In 1903, Ullmann reported the condensation of aryl halides with phenols, and anilines for the construction of C-O, and C-N bonds (Scheme 22) (1, 2, 10, 11, 70). Although pioneering, the major drawback of this protocol was the harsh reaction conditions involving elevated temperature, strong base, and the need for a stoichiometric amount of copper to achieve the required transformations. In 1998, the introduction of boronic acids as coupling partners for N- and O- nucleophiles revolutionized copper-mediated heteroatom arylation chemistry (10). In a series of independent publications, Chan (71), Lam (72), and Evans (73) reported copper-promoted, simple and mild routes for achieving N- and O- arylation using aryl boronic acids as the electrophilic partner. These groundbreaking reports marked the renaissance of copper-mediated heteroatom-carbon coupling (10). Copper-promoted, carbon-heteroatom cross-coupling (where copper is used stoichiometrically) has recently been reviewed and is beyond the scope of this chapter (74). However, a few reactions will be discussed in detail when pertinent to the discussion. 329 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 22. Ullmann Carbon-Heteroatom Cross-Coupling (1, 2).

C-N Bond Formation Nitrogen-containing heterocycles and aromatic amines are important structures in agrochemical and pharmaceutical industries (75). Several methods have been reported for the construction of these compounds. For a long time, synthetic chemists relied on the palladium-catalyzed amination protocol developed by Buchwald and Hartwig; however, the high cost and moisture sensitivity associated with palladium catalysis is a major road block in the scalability of these reactions (76, 77). Therefore, more economical alternatives such as copper have attracted the attention of chemists (11). Chan et al. (71) developed a mild, Cu(OAc)2-promoted, room temperature protocol for the cross-coupling of N-nucleophiles with aryl boronic acids. The substrate scope for this novel methodology ranged from amines, anilines, amides, imides, ureas, carbamates to sulfonamides. The nature of the substrate and the substituent on aryl boronic acid played a crucial role in determining the yield of the reaction. Further, the reaction was highly dependent on the choice of the amine base such as triethylamine and pyridine. However, the optimal base is difficult to determine since no clear substrate-based trend emerged from their study and no reaction optimization was conducted. In a concurrent publication, Lam et al. reported the cross-coupling of aryl boronic acids with a wide range of N-heterocycles such as imidazoles, pyrazoles, triazoles, tetrazoles, benzamides, and indoles using stoichiometric quantities of Cu(OAc)2 and pyridine (Scheme 23) (72). While the reaction has a wide substrate scope, less nucleophilic heteroarenes such as triazoles 32 and tetrazoles 33 were problematic. Symmetrical diaryl ether 38 was observed as by-product due to the oxidation of p-tolyl boronic acid 36 to p-cresol 37 and the subsequent reaction of p-cresol 37 with p-tolyl boronic acid 36 (Scheme 24). The by-product formation was alleviated by introducing 4Å molecular sieves to the reaction. 330 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 23. N-Arylation of Aryl/Heteroaryl Rings (72).

Scheme 24. Formation of Biphenyl Ether (38)

Following these pioneering discoveries, numerous reports emerged during the last 17 years for N-arylation or N-alkylation of sulfonamides (78, 79), Oacetyl hydroxamic acids (80), amines (81–85), α-amino esters (86), anilines (82, 83, 87–90), heterocylces (79, 91, 92), and sulfonimidamides (93) with aryl/alkyl 331 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


boronic acids using stoichiometric or more quantities of copper catalyst. These reports are beyond the scope of this chapter. Although the use of aryl boronic acids was a substantial improvement over previously reported methods, N-arylation of imidazoles reported by the Chan and Lam group at Dupont required more than equivalent amounts of Cu(II) salts, long reaction times, and large excess of the amine base and aryl boronic acid (71, 72). Collman et al. were the first to report N-arylation of imidazoles using a catalytic amount of Cu(OH)Cl•TMEDA (TMEDA = N,N,N′,N′-tetramethylethylenediamine), providing an excellent substitute for the Cu(II) salt and amine base (Scheme 25) (94). Oxygen was crucial for the regeneration of the catalyst in the catalytic cycle. Molecular oxygen has been speculated to aid in the oxidation of Cu(II) to Cu(III). The higher oxidation state of Cu(III) facilitates the reductive elimination to give the cross-coupled product (95, 96). Addition of pure oxygen gave a high yield of the N-arylated imidazole product while slightly lower yields were obtained when pure O2 was replaced by air. No product formation occurred under a N2 atmosphere. Further, a 2:1 ratio of aryl boronic acid and imidazole with 10 mol % of the catalyst in anhydrous dichloromethane proved optimal for the C-N coupling reaction.

Scheme 25. Copper-Catalyzed N-Arylation of Imidazole Using [(Cu(OH)•TMEDA)]2Cl2 (94). 332 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


As shown in Scheme 25, a range of aryl boronic acid substrates with varying electronic and steric properties were efficient for this catalytic C-N coupling, which afforded products in good to excellent yields. To further improve the above reaction, Collman and co-workers studied the effect of different bidentate nitrogen ligands (sp2-N, sp3-N) and tested Cu(I) salts with various counter anions (Cl−, Br−, CI−, −OTf) for N-arylation of imidazoles. From their study, it was evident that TMEDA was the most efficient ligand for the coupling reaction (97). In search of greener alternatives they also investigated the same reaction with the same substrates in water (98); however, slightly lower product yields were observed. Furthermore, neutral pH proved optimal for the reaction as acidic and basic pH resulted in diminished yields. Following these studies, Wang and Gogoi et al. demonstrated the cross-coupling of aryl boronic acids with imidazole and anilines, respectively, in water using Cu(II)-salen type complexes (99, 100). In addition, there are few reports where the N-arylation of imidazoles with aryl boronic acids was carried out in protic solvents (101–103). Rossi et al. successfully performed the cross-coupling of primary amides with primary alkyl boronic acids in t-butanol (Equation 5) (104). Due to their lack of reactivity towards transmetalation, they were not widely explored in Chan-Lam coupling (105). As a consequence, the substrate scope with respect to alkyl boronic acids in these couplings were limited to methyl or cyclopropylboronates to alleviate β-hydride elimination (79, 87, 88, 106). Remarkably, use of the mild base NaOSiMe3 and di-tert-butyl peroxide (DTBP) as the oxidant in the presence of CuBr efficiently gave the desired secondary amides in moderate to good yield. In a separate report, Won-suk Kim’s group reported an open-to-air, room temperature Chan-Lam coupling of sulfonyl azides with aryl/heteroaryl boronic acids in methanol that proceeded to completion within 2 h (71, 72, 107). As an extension of their work, N-aryl carbamates were synthesized by reacting azidoformates and boronic acids under similar conditions (108). The application of N-aryl carbamates was demonstrated in the synthesis of N-aryl N′-ureas via a two-step, one-pot reaction by reacting N-aryl carbamates with aluminum−amine complexes.

Lam et al. studied the effect of stoichiometric oxidants such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), pyridine N-oxide (PNO), and O2 on the catalytic cross-coupling of amines and N-heterocycles with aryl and vinyl boronic acids (109). However, the ideal oxidant varied with the choice of amine substrate (109). Subsequently, Buchwald et al. reported the coupling of aryl boronic acids with amines using Cu(OAc)2, 2,6 lutidine, and myristic acid (n-C13H27COOH) as the additive at room temperature (Scheme 26) (75). According to the authors, myristic acid increased the solubility of the copper catalyst, thereby increasing the reaction rate. Further, vigorous stirring of the reaction mixture presumably resulted in improved oxygen uptake for oxidation 333 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


of in-situ generated Cu(I) catalyst to Cu(II) and larger volume (100 mL vs 2 mL) of solvent was essential for complete conversion. Substrates such as substituted anilines provided the diarylamine products in good to excellent yields; however, the coupling of alkyl amines gave the coupled N-alkyl anilines in only moderate yields (75).

Scheme 26. Copper-Catalyzed Cross-Coupling of Amines with Aryl Boronic Acid (75).

Sasaki et al. employed the above developed protocol for the synthesis of N-aryl aziridines by cross-coupling N-H aziridines with aryl boronic acids (110). With the resurgence of interest in visible light photocatalysis, Kobayashi modified Buchwald’s conditions (75) and reported a visible-light mediated photoredox cross-coupling of anilines with aryl boronic acids that is catalyzed by a copper (II) and an iridium-based photocatalyst (Equation 6) (111). Optimization of the previously reported reaction conditions revealed that fac-[Ir(ppy)3] as a co-catalyst with Cu(OAc)2 in a 1:1 mixture of toluene and acetonitrile (MeCN) under blue LED irradiation was optimal. Substrates such as electron-deficient boronic acids that were unsuccessful under traditional Chan-Lam conditions were viable substrates for visible-light-mediated reactions. A range of primary aryl amines with electron-donating and electron-deficient functional groups were coupled with electron-deficient aryl boronic acids and in each case the desired N,N-diaryl amines were obtained in moderate to excellent yields. However, 2-chlorophenyl boronic acid was a poor substrate under their reaction conditions. No reaction was observed in the absence of the iridium photocatalyst and blue LED.

Owing to the low yield of aliphatic amines under previously reported copper promoted cross-coupling reactions, Quach and Batey devised a ligand- and base free Cu(II)-catalyzed C-N cross-coupling of aliphatic amines and anilines with aryl boronic acids and potassium aryltrifluoroborate salts in the presence of 4Å molecular sieves and oxygen (Scheme 27A) (112). Trifluoroborate salts offer 334 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


several advantages such as air and moisture stability. Many are commercially available and can be stored for extended periods of time under atmospheric conditions. Further, they can be conveniently prepared from the corresponding boronic acids using KHF2 (113). The investigators attributed the low yields of C-N cross-coupling of aliphatic amines under standard Chan-Lam’s and Buchwald’s coupling conditions to the formation of diphenylamine side product 53. Presumably, alkyl arylamine formed after the first cross-coupling reaction undergoes copper-promoted C(alkyl)-N bond scission, and the intermediate 52 undergoes another cross-coupling with aryl boronic acid forming the diarylamine 53 as the by-product (Scheme 27B). This assumption was supported by previous studies conducted by Tolman and co-workers, who observed increased dealkylation of aliphatic amines in the presence of bis(μ-oxo)dicopper complexes (95, 114). Therefore, the reaction was carried out using catalytic amounts of copper and reduced concentrations to prevent the formation of 53. The reaction conditions used by Quach and Batey were adapted from their previously reported copper-catalyzed O-arylation protocol of phenols with aryl boronic acids (115). Nonetheless, the coupling reaction of primary and secondary amines with aryl boronic acids and aryl trifluoroborate salts gave moderate to excellent yields of the product, although yields were lower with anilines. Diverse functional groups on amines (alkenes, esters, ketones, ketals) were tolerated under the optimized reaction conditions; however, chelating substituents on the aliphatic chain gave incomplete conversion at room temperature. Notably, α-amino acid derivatives showed no epimerization upon subjection to coupling conditions. Aryl boronic acids containing both electron-donating and electron-withdrawing substituents reacted well; however, substitution at the ortho-position resulted in reduced yields. The same authors recently developed an efficient base-free synthesis of enamides using Cu(OAc)2-catalyzed cross-coupling of alkenyl trifluoroborate salts with amides under an O2 atmosphere at 40 °C (116). While the oxidative amination developed by Chan and Lam has been widely used for the synthesis of anilines derivatives as describe above, it is highly sensitive to steric properties of the nucleophilic amine partner, resulting in lower yields when hindered amines are used. Electrophilic amination offers a complementary approach for the construction of C-N bonds (17). Contrary to oxidative cross-coupling, electrophilic amination involves C-N bond formation using an electrophilic nitrogen source and a carbon nucleophile. In 2012, Lalic reported a CuOtBu-catalyzed electrophilic amination for the synthesis of hindered anilines from O-benzoyl hydroxylamines and aryl/heteroaryl boronic acids (Equation 7) (117). Notably, the steric properties of the electrophiles had no effect on the reaction outcome, as can be seen in Equation 7.



Scheme 27. (A) Ligand- and Base-Free Copper-Catalyzed Cross-Coupling Reactions of Aliphatic Amines and Anilines with Organoboron Compounds. (B) Copper-Promoted Diaryl Amine by-Product Formation (112).

The Liebeskind group developed a copper-catalyzed N-imination of aryl, heteroaryl, and alkenyl boronic acids with oxime O-carboxylates (Scheme 28) (118). Oximes derived from aldehydes were not suitable substrates for the coupling and underwent β-hydride elimination to yield the corresponding nitriles. A similar protocol employing stoichiometric quantities of CuTC catalyst was developed by their group for N-amidation of boronic acids using O-acetyl hydroxamic acids (80). Additionally, they developed a simple and modular synthesis for the construction of highly substituted pyridines (119). Utilizing N-chloroamides as the electrophilic partner, another group reported electrophilic amination of aryl boronic acids (120). The transformation gave high yields of diaryl amides, and functional groups such as iodo, bromo, and chloro that are generally problematic in palladium-catalyzed reactions were tolerated under the reaction conditions. 336 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 28. Copper-Catalyzed N-Imination of Boronic Acids with O-Acyl Ketoximes (118).

C-O Bond Formation The Chan (71) and Evans (73) groups simultaneously reported novel protocols for the cross-coupling of aryl boronic acids with oxygen nucleophiles. Their simple and mild methods offered a complementary approach for transition-metal promoted C-O bond formation reactions (121). The strikingly similar methodologies employed phenol (1 equiv), aryl boronic acid (3 equiv), anhydrous Cu(OAc)2 (1-2 equiv), Et3N (2-5 equiv), and the reaction mixtures were stirred for 1-2 days open to air at room temperature (Scheme 29A). Subsequently, the unsymmetrical diaryl ethers 54 were isolated in good to excellent yields. Inert atmosphere led to lower yield of the desired products while dry, pure oxygen atmosphere gave identical results to ambient atmosphere. The crude reaction mixtures were analyzed using GC-MS; significant phenol and diphenyl ether side products were observed (see Scheme 24 for details). It was speculated that water was being generated during the triphenyl boroxine formation from phenyl boronic acid. This was indeed the case since substituting phenyl boronic acid with 0.33 equivalents of triphenyl boroxine gave the desired coupling product in a similar yield. Hence, 4Å molecular sieves were added to the reaction with aryl boronic acids. Higher equivalents of the base did not impede the reaction suggesting that the base could also be acting as a ligand for copper. Both electron-rich and electron-poor phenols were tolerated under their protocols. O-alkyl and ortho-heteroatom substituted phenols were viable substrates, although o-heteroatom substituted boronic acids gave lower yields of the desired product. When the substrate scope was extended to racemization-prone substituted amino acids derivatives, Et3N was necessary to afford the desired diaryl ethers in good yield without racemization of the substrates. Further, the above protocol was utilized for the synthesis of thyroxine derivatives 55a and 55b (Scheme 29B). For these particular substrates, a 1:1 mixture of pyridine and Et3N (5 equiv) was used. The choice of bases was highly substrate dependent. The usefulness of this protocol was demonstrated in the total synthesis of the antibiotic teicoplanin agylcon (122).



Scheme 29. O-Arylation of Phenols (A) and its Application in the Synthesis of Thyroxine Derivatives (B) (73).

The Sharpless group modified Evans’s C-O cross-coupling conditions for the synthesis of N-aryl hydroxylamines using N-hydroxyphthalimide and phenyl boronic acid. Stoichiometric amount of CuCl, pyridine, and 4Å molecular sieves gave the desired products in moderate to good yields (123). Although Evans et al. attempted a catalytic variant of their methodology for the synthesis of 56 (73), the use of substoichiometric quantities of Cu(OAc)2 (10 mol %) gave the desired product in low yield (Equation 8).

Lam et al. further developed the catalytic version by incorporating a co-oxidant in the coupling of 3,5-di-tert-butylphenol with p-tolyl boronic acid (Equation 9) (109). While Cu(OAc)2 with O2 gave the best results (79%, Equation 9), oxidants such as TEMPO and PNO achieved the desired cross-coupling albeit in low yields. In all these cases, a major limitation was the unreactive nature of the aliphatic alcohols even in the presence of stoichiometric amounts of the catalyst (73, 109, 123). Thus, the substrate scope for the nucleophilic counterpart was limited to phenol derivatives.



A solution was proposed by the Batey group, which developed a Cu(II)-catalyzed cross-coupling of alkenyl and aryl trifluoroborate salts with primary and secondary alkyl alcohols under neutral conditions at room temperature (Scheme 30A) (115). Preliminary studies were performed with cinnamyl alcohol and phenyl trifluoroborate salts (Scheme 30B). Optimization of the catalyst and nitrogen ligand revealed that Cu(OAc)2•H2O and 4-dimethylaminopyridine (DMAP) in the presence of 4Å molecular sieves and O2 were optimal, respectively. Other screened bases such as N,N′-Dimethylethylenediamine (DMEDA), N,N-diisopropylethylamine (DIPEA), TMEDA, Et3N, 1,10-phenanthroline, pyridine, and imidazole were inefficient. After establishing the optimized conditions, the substrate scope was examined. Phenols, alkenes, allylic, and internal propargylic alcohols were suitable substrates. Functionalities such as aryl halides, which do not participate in cross-couplings, performed well. No alkene isomerization or epimerization of an α-stereocenter in an enantiomerically pure ester was noticed. Notably, the reaction is highly sensitive to steric effects. Although secondary alcohols underwent cross-coupling, tertiary alcohols were unreactive. Further, aryl boronic acids are good substitutes for trifluoroborate salts; however, lower yields were observed with the former (Scheme 30B). The oxidation product of the phenyl trifluoroborate salt and phenol as well as homocoupled by-product (diphenyl ether) were observed; nevertheless, they were more pronounced when phenyl boronic acid was used (see Scheme 24 for details). Furthermore, terminal alkynes and N-H amine substrates were incompatible with the reaction conditions and oxidative homocoupling (Egliston reaction) (124, 125) occurred and N-arylation byproducts were formed. Wang et al. used a similar catalytic system, Cu(OAc)2/DMAP/O2 to achieve trifluoroethoxylation of aryl and heteroaryl boronic acids using 2,2,2-trifluoroethanol as the solvent. Although the reaction times were shorter, higher temperatures were required to achieve the desired transformation (126).



Scheme 30. Copper-Catalyzed Cross-Coupling of Potassium Organotrifluoroborate Salts with Aliphatic Alcohols (115). Oxygen nucleophiles such as phenol and alkyl/aryl alcohols have been extensively used in Chen-Evans-Lam coupling. On the contrary, carboxylic acids are rarely employed because of competitive decarboxylation occurring under an array of conditions (127–129). As a result, they are mainly used in C-C bond formation reactions as a nucleophilic partner (130). Jacobsen et al. therefore investigated Chan-Lam methylation of carboxylic acids using methylboronic acid (Scheme 31) (131). This method offers a safer alternative to current toxic methylating agents such as such as methyl iodide, dimethyl sulfate, and diazomethane or its substitute (trimethylsilyl) diazomethane (132–136). Upon treating a carboxylic acid with methyl boronic acid in the presence of CuCO3.Cu(OH)2 and pyridine in dimethyl carbonate (DMC) gave the desired methyl ester carboxylic acid in 76% yield (Scheme 31). Keeping the reaction open to air ensured catalytic turnover by utilizing oxygen in air as an oxidant. Similar yields were obtained under inert atmosphere by employing t-BuOOt-Bu as the terminal oxidant. Thus, offering a parallel route to previous reported copper-catalyzed alkylation conditions (104, 137). The reaction tolerated a broad range of structurally and electronically diverse substrates with functionalities such as aryl bromides and chlorides (iodides were unreactive), ketones, nitriles, and esters. The reaction was insensitive to steric effects; o-methyl, o-methoxy-substituted phenyl carboxylic acids gave the desired product in 68% and 78%, respectively. Although, no product was observed with N-H indoles, the N-derivatized indoles produced the desired product in 67% yield. The scope of methylation was extended to aliphatic and alkenyl carboxylic acids. Isotopic labeling studies were conducted to rule out the possible oxidation of methyl 340 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


boronic acid to methanol and the subsequent reaction of methanol with carboxylic acid leading to the product (Scheme 32). The Batey group also developed a CuBr-catalyzed nondecarboxylative cross-coupling of alkenyl trifluoroborates with carboxylate salts or carboxylic acids utilizing DMAP as the nitrogen ligand and 4Å molecular sieves in the presence of O2 atmosphere at 60 °C (138). The regioselective and stereoselective protocol gave the desired enol esters in good yields.

Scheme 31. Copper-Catalyzed Methylation of Carboxylic Acid Derivatives with Methylboronic Acid (131).

Scheme 32. A) Alternate Mechanism for Copper-Catalyzed Aerobic O‐Methylation of Carboxylic Acid Derivatives with Methylboronic Acid. B) Isotope Labeling Studies for Copper-Catalyzed O‐Methylation of Phenyl Carboxylic Acid (131). C-S Bond Formation Guy et al. reported the cross-coupling of alkyl thiols with aryl boronic acids using stoichiometric amounts of copper catalyst (139). The investigation was motivated by a need for a milder synthesis of cysteine derivative 62, an intermediate in the synthesis of the HIV protease inhibitor nelfinavir (63) (Scheme 33). Using previously developed conditions for O-arylation of phenols (73), 341 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


the observed rate of S-arylation was slow due to competing disulfide formation from the oxidation of thiol. However, when the reaction was performed under an inert atmosphere in the presence of pyridine, Cu(OAc)2, and DMF at 155 °C, a significant rate enhancement led to the desired product in good yield (Scheme 34). The reaction was insensitive to electronic effects; however, it was moderately affected by steric hindrance. Prolonged reaction times and low yields were observed with sterically hindered substrates such as o-toluene boronic acid (64b, Scheme 34). Tertiary thiols gave trace amount of the product, whereas thio acids and α-carboxy thiols were unreactive. Further, the desired S-aryl cysteine derivative (62) was obtained in good yield with no observed racemization.

Scheme 33. Synthesis of Cysteine Derivative 62 (139).

Scheme 34. Copper-Mediated Cross-Coupling of Alkyl Thiols with Aryl Boronic Acids (139). Subsequently, the Liebeskind group developed a copper(I)-catalyzed reaction of boronic acids with thiols under non-basic, mild conditions (140). Their investigation was based on the premise that Guy’s protocol proceeds through a Cu(I) catalysis instead of Cu(II) as implied by the authors. The harsh conditions 342 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


and Cu(II) catalyst in Guy’s conditions can easily convert thiols into disulfides and Cu(I) as previously proposed by Smith et al. (141). The speculations were confirmed when the reaction of phenyl boronic acid (70) reacted with diphenyl disulfide (71) and Cu(I)-3-methylsalicylate [CuMeSaI] in DMA at 100 °C for 18 h afforded the product diphenyl sulfide (67) in 74% yield (Equation 10). The requirement for stoichiometric Cu(I) for the S-arylation was due to the partial inactivation of the catalyst from the formation of inactive Cu(I) thiolate 72. This led the investigators to employ N-thioimides as an alternative electrophilic sulfide surrogate. A diverse set of boronic acid substrates underwent cross-couplings with N-thioimides in the presence of CuMeSal (20-30 mol %) in THF at 45 °C to form the desired thioethers in moderate to good yield (Scheme 35). These results were remarkable since the transformations were achieved under non-basic and mild conditions. Later, Taniguchi (142, 143), Li (144), and Yu (145) demonstrated copper-catalyzed C-S cross-coupling of aryl boronic acids with diaryldisulfane in DMSO/H2O at 100 °C.

Scheme 35. Copper-Catalyzed Cross-Coupling of Boronic Acids with N-Thioimides (140).



Scheme 36. Copper-Catalyzed Cross-Coupling of Thiols with Boronic Acids at Room Temperature (146).

Scheme 37. Proposed Reaction Pathway for Copper(I)-Catalyzed Trifluoromethylthiolation of Aryl Boronic Acid with TMSCF3 Using Elemental Sulfur (S8) (148).

Succeeding this work, Hua-Jian Xu et al. established a room temperature S- arylation of thiols with aryl/heteroaryl boronic acids (Scheme 36) (146). An extensive optimization of the reaction conditions was conducted. Various metal salts (CuSO4, CuI, CuCl2, FeCl3), bases (Na2CO3, C2CO3, KOt-Bu, n-Bu4NOH) and solvents (MeOH, EtOH, DMSO, THF, DMF) were examined. The optimized reaction condition (phenyl boronic acid, phenyl thiophenol, CuSO4, 1,10-phenanthroline:H2O in a 1:1 mixture of n-Bu4NOH and ethanol under O2 atmosphere) generated the product diphenyl sulfide in excellent yield (Scheme 36). The generality of the transformation was demonstrated with a range of substituted boronic acids and aryl/heteroaryl boronic acids. No reaction occurred with aliphatic thiols and alkyl boronic acids. C-S bond formation using aryl boronic acids and aryl thiols have also been reported in the presence of [Cu(DMAP)4I]I catalyst at room temperature (147). 344 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 38. Copper-Catalyzed Trifluoromethylthiolation of Aryl Boronic Acids with (Trifluoromethyl)trimethylsilane (TMSCF3) Using Elemental Sulfur (S8) (148). The utility of elemental sulfur in cross-coupling reactions was shown by Chen et al. They demonstrated the trifluoromethylthiolation of aryl boronic acids with (trifluoromethyl)trimethylsilane (TMSCF3, Ruppert-Prakash reagent) using elemental sulfur (S8) and Cu(I) catalyst (148). The investigators speculated the formation of a stable copper disulfide complex from the reaction of Cu(I) complex with elemental sulfur (149). The transmetalation of the disulfide complex with boronic acid, followed by reductive elimination of the complex was speculated to give the desired product (Scheme 37). Added oxidant regenerated the catalyst. In the presence of CuSCN, 1,10-phenanthroline, K3PO4 as the base, and Ag2CO3, the trifluoromethylthiolation of phenyl boronic acid yielded the desired product in 95% yield. No product was observed in the absence of catalyst, ligand, or oxidant. A diverse range of aryl boronic acids containing esters, amides, vinylic, halides, nitriles, ketones and sulfonyl groups were tolerated (Scheme 38). The importance of this cross-coupling is highlighted in its high efficiency, commercial 345 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

availability inexpensive starting materials, and mild reaction conditions. In 2014, Yu and co-workers demonstrated a one-pot S-arylation of aryl boronic acids using elemental sulfur and CuF2 as a catalyst (150). Further, Shen and co-workers also achieved a copper-catalyzed trifluoromethylation of primary and secondary alkyl boronic acids using an electrophilic trifluoromethylating source (151).


Conclusion In the last decade tremendous growth has been made in copper-catalyzed cross-coupling reactions using organoborons as the coupling partners. The low cost of copper, mild reactions conditions, and commercial availability of organoborons renders these reactions especially attractive from a synthetic perspective. In spite of these advances, limitations still exists that demand attention. Low atom economy is often an issue due to competing protodeboration and oxidation of organoboron compounds. Further, additives such as base and oxidant, and sometimes higher copper catalyst loading is necessary. These limit the application of cross-coupling reactions on industrial scale. Notably, a better understanding of the mechanistic detail such as the active copper species involved, effect of copper-ligand-nucleophile interactions, clarity of different steps in the catalytic cycle is required to expand the application of copper-catalyzed cross-coupling reactions with organoborons.

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