Carbon Quaternization of Redox Active Esters and Olefins via Decarboxylative Coupling

Abstract

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of relying exclusively on conventional polar-bond based retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. In fact, the presence of a quaternary center even in seemingly trivial structures can dominate the practitioner's entire retrosynthetic plan (referred to by Corey as a “keying element”). Here we report a simple catalyst and minimal reagents that convert two types of feedstock chemicals—carboxylic acids and olefins—into tetrasubstituted carbons via quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer then combines the fragments by an SH2 reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon-containing materials from simple chemical feedstocks.

Alkene Dialkylation via Triple Radical Sorting

“…The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling logic by enabling the selective merger of any primary radical with any secondary or tertiary radical via a radical sorting mechanism [1][2][3][4][5][6][7][8] . SH2 catalysis can be used to merge common feedstock chemicalssuch as alcohols, acids, and halides-in any permutation for the construction of a single C(sp 3 )-C(sp 3 ) bond.…”

“…Traditional crosscoupling paradigms rely on oxidative addition, transmetallation, and reductive elimination mechanistic steps that limit the pool of potential coupling partners. By contrast, bimolecular homolytic substitution (SH2) catalysis couples primary radicals with secondary or tertiary radicals through a radical sorting mechanism based on carbon-metal bond strength [1][2][3][4][5][6][7][8]15 . As this unique radical sorting mechanism is functional group-agnostic, abundant radical precursors, such as alcohols, acids, and halides, can be coupled in any desired combination to generate complex products from simple feedstock chemicals [1][2][3][4][5][6][7][8].…”

“…By contrast, bimolecular homolytic substitution (SH2) catalysis couples primary radicals with secondary or tertiary radicals through a radical sorting mechanism based on carbon-metal bond strength [1][2][3][4][5][6][7][8]15 . As this unique radical sorting mechanism is functional group-agnostic, abundant radical precursors, such as alcohols, acids, and halides, can be coupled in any desired combination to generate complex products from simple feedstock chemicals [1][2][3][4][5][6][7][8]. This novel approach greatly expands access to C(sp 3 )-rich chemical space and enables formation of otherwise elusive all-C(sp 3 ) quaternary centers 16 .…”