Exploration of Biaryl Carboxylic Acids as Proton Shuttles for the Selective Functionalization of Indole C–H Bonds

Abstract

A survey of diversely substituted 2-arylbenzoic acids were synthesized and tested for use as proton shuttle in the direct arylation of indoles with bromobenzenes. It was found that 3-ethoxy-2-phenylbenzoic acid gives superior yield and selectivity for this class of substrates.

Catalyst-Controlled Regioselectivity in Pd-Catalyzed Aerobic Oxidative Arylation of Indoles

“…Aryl transmetalation from boron to Pd II under aerobic conditions similar to those used here is facile, often proceeding efficiently at room temperature. − The L n Pd­(Ar)­X species generated in this step could then react with indole to afford the desired coupling product. At least two different pathways could be considered for this C–C coupling step: (a) a Heck-type pathway initiated by insertion of the indole C2–C3 double bond into a Pd–Ar bond, or (b) indole C–H activation by Pd II , followed by C–C reductive elimination . Studies of thiophene arylation with aryl halides suggest that both Heck and C–H activation pathways are possible, − and we postulated that our observed switch in regioselectivity could arise from a change in the preferred mechanism under different conditions.…”

“…At least two different pathways could be considered for this C−C coupling step: (a) a Heck-type pathway initiated by insertion of the indole C2−C3 double bond into a Pd−Ar bond, 28 or (b) indole C−H activation by Pd II , followed by C−C reductive elimination. 47 Studies of thiophene arylation with aryl halides suggest that both Heck and C−H activation pathways are possible, 48−50 and we postulated that our observed switch in regioselectivity could arise from a change in the preferred mechanism under different conditions.…”

Pd‐Catalyzed Direct Arylations of Heteroarenes with Polyfluoroalkoxy‐Substituted Bromobenzenes

“…Therefore, the direct use of (polyfluoroalkoxy)bromobenzene derivatives for the synthesis of heteroarenes bearing (polyfluoroalkoxy)benzene units has potential for pharmaceutical chemistry. To the best of our knowledge, the Pd‐catalyzed direct arylations of heteroarenes by (difluoromethoxy)bromobenzenes, 2‐ and 3‐(trifluoromethoxy)bromobenzenes or (polyfluoroethoxy)benzenes has not been reported yet; whereas only one example using 1‐bromo‐4‐(trifluoromethoxy)benzene has been described (Scheme , top) . This coupling reaction was performed using 5 mol‐% Pd(OAc) 2 and 10 mol‐% PCy 3 as catalyst system in the presence of a 2‐arylbenzoic acid (30 mol‐%) as proton shuttle.…”

Scalable Multicomponent Synthesis of (Hetero)aryl‐Substituted Phenyls: Focus on Metal‐Free Halogenated Biaryls, 3‐Arylindoles, and Isourolithine A Synthesis

“…In particular, great attention has been given to the development of metal‐free approaches to biaryls, and heterobiaryls, considering the importance of these scaffolds in several fields, ranging from their use as ligands in organic synthesis to their predominance in pharmacologically active natural and synthetic compounds . Moreover, thanks to their electronic properties, (hetero)biaryls play a key role in current research on electronic materials, and liquid crystals (Figure ).…”