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Reductive Radical Conjugate Addition of Alkyl Electrophiles Catalyzed by a Cobalt/Iridium Photoredox System

Randolph A. Escobar* and Jeffrey W. Johannes*

*Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA 02451, United States, Email: randolph.escobarastrazeneca.com, jeffrey.johannesastrazeneca.com

R. A. Escobar, J. W. Johannes, Org. Lett., 2021, 23, 6046-6051.

DOI: 10.1021/acs.orglett.1c02114 (free Supporting Information)



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Abstract

Formation of alkyl radicals via activation of alkyl bromides through cobalt/iridium catalysis enables a reductive radical conjugate addition under mild and less toxic conditions. The reaction conditions tolerate benzylic halides and halides containing free alcohols, silanes, and chlorides.


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proposed mechanism

[Ir(dF(CF3)ppy)3(dtbpy)PF6



General Procedure for the Cobalt Catalyzed Reductive Radical Conjugate Addition Reaction

To a 1-dram vial equipped with a stir bar was added CoBr2 (22.0 mg, 0.10 mmol, 0.10 equiv), XantPhos (58 mg, 0.10 mmol, 0.10 equiv), [Ir(dF(CF3)ppy)2(dtbpy)]PF6 (20 mg, 0.02 mmol, 0.02 equiv), triethylamine (0.209 mL, 2.0 mmol, 2.0 equiv), alkyl halide (1.0 mmol, 1.0 equiv), olefin (1.0 mmol, 1.0 equiv) and acetonitrile (2.5 mL, 0.4 M). The reaction mixture was then sealed with a plastic screw cap and placed in a HepatoChem reactor on a stir plate and irradiated for 36 hours with 34 W blue LED with an internal fan to regulate the temperature. After the elapsed time, the reaction mixture was  concentrated in vacuo over silica, then it was purified by flash column chromatography on silica gel (9:1, hexanes in ethyl acetate) to afford the desired product.


Key Words

esters, piperidines


ID: J54-Y2021