Development, Application, and Mechanistic Interrogation of a Dual Ni Catalysis Approach to Photoredox-Based C(sp3)–C(sp3) Cross-Coupling

Bucci, Erin M.; Perea, Melecio A.; Lalisse, Remy F.; Mukherjee, Poulami; Raab, T. Judah; Valloli, Lakshmy Kannadi; Min, Daniel S.; Bird, Matthew J.; Gutierrez, Osvaldo; Doyle, Abigail G.

doi:10.1021/jacs.5c10906

Development, Application, and Mechanistic Interrogation of a Dual Ni Catalysis Approach to Photoredox-Based C(sp³)–C(sp³) Cross-Coupling

Journal Article · Tue Nov 04 19:00:00 EST 2025 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.5c10906· OSTI ID:3003147

^[1]; Perea, Melecio A. ^[1]; Lalisse, Remy F. ^[1]; ^[1]; ^[1]; ^[2]; Min, Daniel S. ^[1]; ^[2]; ^[1]; ^[1]

University of California, Los Angeles, CA (United States)
Brookhaven National Laboratory (BNL), Upton, NY (United States)

The installation of alkyl substituents such as methyl groups is a crucial tactic for the synthesis and diversification of medicinal compounds with improved pharmacological profiles. However, strategies that leverage methyl radical for C(sp³) methylation remain underdeveloped due to the challenge of obtaining cross-selectivity between fleeting aliphatic radicals and alkyl electrophiles. Here, we report the development, application, and interrogation of a conceptually novel mechanistic framework for C(sp³)–Me bond formation using two distinct Ni catalysts capable of cross-coupling sterically and electronically diverse alkyl halides (chlorides and bromides) with methyl radical generated photocatalytically from benzaldehyde dimethyl acetal. Furthermore, by modifying the alkyl substituents on the acetal coupling partner, we demonstrate cross-couplings beyond methylation to access an array of 1°–1° and 1°–2° alkyl–alkyl bonds. Experimental and computational mechanistic studies provide support for cooperativity between an in situ-generated (bpy)Ni^I(X) catalyst that facilitates XAT and inner-sphere C–C bond formation and a (Tp*)Ni^II(acac) cocatalyst that captures methyl radical and engages in concurrent outer-sphere S_H2 coupling.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States); Univ. of California, Los Angeles, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division (CSGB); National Science Foundation (NSF); National Institutes of Health (NIH)

Grant/Contract Number:: SC0019370; SC0012704

OSTI ID:: 3003147

Alternate ID(s):: OSTI ID: 3009084

Report Number(s):: BNL--229229-2025-JAAM

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 46 Vol. 147; ISSN 0002-7863; ISSN 1520-5126

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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