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Science. 2018 Apr 6;360(6384):75-80. doi: 10.1126/science.aar7335. Epub 2018 Feb 18.

Modular radical cross-coupling with sulfones enables access to sp3-rich (fluoro)alkylated scaffolds.

Author information

1
Department of Chemistry, The Scripps Research Institute (TSRI), 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457, China.
3
Department of Chemistry, La Jolla Laboratories, Pfizer, 10770 Science Center Drive, San Diego, CA 92121, USA.
4
Pfizer Medicinal Sciences, Eastern Point Road, Groton, CT 06340, USA.
5
Department of Chemistry, The Scripps Research Institute (TSRI), 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. pbaran@scripps.edu.

Abstract

Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp2)-C(sp3) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.

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