康 · 学术 | Reaction of the Day No. 1512

转自：康龙化成

Alkyl Sulfonylhydrazide-Enabled, Chemoselective Ni-catalyzed Directed C(sp2)–H Alkylation via Low-Temperature, Amine-Assisted Metalation/Deprotonation

Shuanghu Wang,†1 David A. Cagan,†1 Yilin Cao,†1 Benjamin P. Vokits,2 Maximilian D. Palkowitz,3 Yu Kawamata,1Phil S. Baran*1, Keary M. Engle*1

1 Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, United States. 2 Discovery and Development Sciences, Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543 United States. 3 Discovery and Development Sciences, Bristol Myers Squibb, 250 Water Street, Cambridge, MA, 02141, United States. † These authors contributed equally to this work.

—ChemRxiv, 2025, 10.26434/chemrxiv-2025-4sf42

Recommended by Rui Jin _ MC5

KEY WORDS:C–H activation; alkylation; Ni catalysis,chemoselective(反应类型), C(sp2)-C(sp3) (成键类型),alkyl sulfonylhydrazides, (hetero)arenes(原料), C–H alkylated product (产物),DCE (oxidant), radical precursors, 8-aminoquinoline directing group (其他)

ABSTRACT: Disclosed herein is the invention of a method for facile C–H alkylation of a range of (hetero)arenes under Ni-catalysis. This reaction takes place at 50 oC, is scalable, tolerates heterocyclic substrates, and can be applied to both primary and complex secondary alkyl donors. Success hinges on the use of sulfonylhydrazide-based alkyl donors that mildly generate alkyl radicals thereby obviating the need for alkyl halide precursors that require more harsh conditions to activate. The demonstrated substrate scope is broad (>70 examples), and the reaction was also applied to natural product synthesis. Mechanistic studies (both computational and experimental) suggest that an asynchronous, amine-assisted C–H activation pathwayis operative which may have larger implications for the field.

Background and this work

Condition screening

Substrate scope: 1oand 2o alkyl sulfonylhydrazides with a variety of (hetero)arenes

Applications:Scale-up and product derivatization examples

Proposed mechanism

Prof. Phil S. Baran and Prof. Keary M. Engle et aldisclose the invention of a method for facile C–H alkylation of a range of (hetero)arenes under Ni-catalysis using sulfonylhydrazides as simple radical donors. The present protocol features an extremely simple reaction setup, proceeds at 50 ℃, is easily scalable, and the only exogenous redox applied is a single equivalent of an inexpensive solvent (DCE). Mechanistically, the findings reveal an amine-assisted C–H activation pathwaythat is followed by a rapid radical captureand C–C coupling. The study and mechanistic understanding of this reaction delineated in this work has the potential to guide future efforts in first-row transition-metal catalyzed, mild C–H activation across a range of substrate classes.

Scripps研究所Baran课题组和Engle课题组共同报道了一种镍催化导向C–H烷基化方法，利用磺酰肼作为简易自由基供体，实现了多种杂环芳烃的高效官能化。该反应装置简单，条件温和（50℃下进行）且易于放大，仅需1当量廉价溶剂1,2-二氯乙烷（DCE）作为外源氧化剂。机理研究表明，该反应通过胺辅助C–H活化→快速自由基捕获→C–C偶联的三阶段路径进行。该研究为发展更多第一过渡系金属催化的C–H活化反应提供了重要引导，有望推动杂环药物分子、功能材料等领域的发展。