Open AccessHighly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis
Author(s) -
Yuxuan Ye,
Ilia Kevlishvili,
Sheng Feng,
Peng Liu,
Stephen L. Buchwald
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.0c04286
Subject(s) - chemistry , indazole , steric effects , stereocenter , reactivity (psychology) , enantioselective synthesis , nucleophile , indole test , electrophile , catalysis , substituent , combinatorial chemistry , transition state , stereochemistry , medicinal chemistry , organic chemistry , medicine , alternative medicine , pathology
C3-substituted 1 H -indazoles are useful and important substructures in many pharmaceuticals. Methods for direct C3-functionalization of indazoles are relatively rare, compared to reactions developed for the more nucleophilic N1 and N2 positions. Herein, we report a highly C3-selective allylation reaction of 1 H - N -(benzoyloxy)indazoles using CuH catalysis. A variety of C3-allyl 1 H -indazoles with quaternary stereocenters were efficiently prepared with high levels of enantioselectivity. Density functional theory (DFT) calculations were performed to explain the reactivity differences between indazole and indole electrophiles, the latter of which was used in our previously reported method. The calculations suggest that the indazole allylation reaction proceeds through an enantioselectivity-determining six-membered Zimmerman-Traxler-type transition state, rather than an oxidative addition/reductive elimination sequence, as we proposed in the case of indole alkylation. The enantioselectivity of the reaction is governed by both ligand-substrate steric interactions and steric repulsions involving the pseudoaxial substituent in the six-membered allylation transition state.