Nickel‐Catalyzed Enantioconvergent Carboxylation Enabled by a Chiral 2,2′‐Bipyridine Ligand

Abstract

In contrast to previous approaches to chiral α‐aryl carboxylic acids that based on reactions using hazardous gases, pressurized setup and mostly noble metal catalysts, in this work, a nickel‐catalyzed general, efficient and highly enantioselective carboxylation reaction of racemic benzylic (pseudo)halides under mild conditions using atmospheric CO2 has been developed. A unique chiral 2,2′‐bipyridine ligand named Me‐SBpy featuring compact polycyclic skeleton enabled both high reactivity and stereoselectivity. The utility of this method has been demonstrated by synthesis of various chiral α‐aryl carboxylic acids (30 examples, up to 95 % yield and 99 : 1 er), including profen family anti‐inflammatory drugs and transformations using the acids as key intermediates. Based on mechanistic experimental results, a plausible catalytic cycle involving Ni‐complex/radical equilibrium and Lewis acid‐assisted CO2 activation has been proposed.

Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic Esters with Arylmethyl Trimethylammonium Triflates

“…Unless otherwise stated, 1 H NMR and 13 C NMR spectra were recorded on Bruker Advance 400 or 500 M NMR spectrometers at ambient temperature in CDCl 3 or DMSO-d 6 at 400 and 101 MHz, or 500 and 126 MHz. The chemical shifts are given in ppm relative to tetramethylsilane [ 1 H, (SiMe 4 ) = 0.00 ppm] as an internal standard or relative to the resonance of the solvent [ 1 H, δ(CDCl 3 ) = 7.26; 13 C, δ(CDCl 3 ) = 77.16 ppm; 1 H, δ(DMSO-d 6 ) = 2.50; 13 C, δ(DMSO-d 6 ) = 39.52 ppm]. Multiplicities were given as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), m (multiplets), etc.…”

“…1 H NMR (400 MHz, Chloroform-d) δ: 12.20 (s, 1H), 8.36−8.31 (m, 1H), 7.96 (dd, J = 8.0, 1.7 Hz, 1H), 7.80−7.65 (m, 1H), 7.55−7.42 (m, 3H), 7.27−7.18 (m, 1H), 7.00 (dd, J = 8.4, 1.2 Hz, 1H), 6.97−6.87 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.65 (d, J = 0.5 Hz, 2H), 3.98 (s, 3H) ppm. 13…”

“…In this case, the homocoupling of activated alkyl halides was found to be predominant due to their extremely high reactivity. Based on this observation, we wondered whether the standing challenge could be addressed by the use of relatively inert quaternary ammonium salts as the polycyclic aryl-activated alkyl source (Scheme B), which have been successfully employed in nickel-catalyzed XEC reactions with vinyl triflates and carbon dioxide. , …”

“…13 C{1 H} NMR (101 MHz, Chloroform-d) δ: 203.9, 162.8, 156.7, 136.8, 136.7, 135.2, 130.6, 130.2, 128.7 (2C), 128.1, 127.8, 127.6 (2C), 127.2, 126.2, 126.1, 125.4, 119.5, 119.2, 119.1, 118.8, 108.3, 70.1, 42.7 ppm. HRMS (ESI) m/z: [M + H] + calcd for C 25 H 21 O 3 369.1485; found: 369.1485.…”

“…Based on this observation, we wondered whether the standing challenge could be addressed by the use of relatively inert quaternary ammonium salts as the polycyclic aryl-activated alkyl source (Scheme 1B), 10 which have been successfully employed in nickel-catalyzed XEC reactions with vinyl triflates 11 and carbon dioxide. 12,13 We began our investigation by using phenyl salicylic acid ester (1a) and 1-naphtylmethyl trimethylammonium triflate (2a) as the model reaction substrates for optimization of the reaction conditions (Table 1). The systematic screening of various reaction parameters revealed that the reductive crosscoupling reaction between 1a and 2a proceeded with the best performance when the reaction was conducted in the presence of NiBr 2 (dme) (15 mol %) as a precatalyst, bathocuproine (L1) (15 mol %) as a ligand, and Zn (4 equiv) as a reductant in NMP (0.4 M) at 80 °C for 12 h under a nitrogen atmosphere, providing the desired product 3aa in an 86% isolated yield (entry 1).…”