Sulfones: A New Functional Group for Modular Radical Cross-Coupling
Rohan R. Merchant,1 Jacob T. Edwards,1 Tian Qin,1 Monika M. Kruszyk,1 Cheng Bi,1 Guanda Che,2 Deng-Hui Bao,2 Wenhua Qiao,2 Lijie Sun,2 Michael R. Collins,3 Gary M. Gallego,3 James J. Mousseau,4 Philippe Nuhant,4 Phil S. Baran.1
1Department of Chemistry, The Scripps Research Institute (TSRI), 10550 North Torrey Pines Road, La Jolla, California, 92037, USA.
2Asymchem Life Science (Tianjin), Tianjin Economic-technological Development Zone, Tianjin 300457, China
3Department of Chemistry, La Jolla Laboratories, Pfizer Inc., 10770 Science Center Drive, San Diego, CA 92121, USA.
4Pfizer Medicinal Sciences, Eastern Point Road, Groton, CT 06340, USA.
—ChemRxiv 2017, DOI: 10.26434/chemrxiv.5715106.v1
Recommended by Hanchu Kong_SC
KEYWORDS: cross-coupling, PT sulfones
ABSTRACT: A cross-coupling chemistry comprises the vast majority of reactions employed in the synthesis of medicines, agrochemicals, and other functional materials. The interest in single-electron-induced coupling chemistry stems from the unique ability of these methods to facilitate the formation of challenging C(sp2)–C(sp3) linkages. This work introduces a new functional group, PT sulfones, for radical cross-coupling, enabling the simplified modular assembly of complex structures in an ordered, practical fashion. The scope of this method is extensively explored, and its strategic application is exemplified through the streamlined preparation of medicinally-oriented fluorine-containing scaffolds that previously required multiple steps, toxic reagents, and non-modular retrosynthetic blueprints. This work has also resulted in the development of five reagents for the rapid assembly of a vast set of structures, many of which contain challenging fluorination patterns.
Summary and Comment：
本文是Phil.S.Baran課題組最近在ChemRxiv預發表的工作：
與脫羧偶聯反應相似，碸類活化基團（SO2PT）可以在Ni催化體系中與芳基金屬試劑發生反應得到相應的偶聯產物，底物範圍廣泛，包括一級、二級碸與各類取代芳環、芳雜環，並適合放大生產；同時，課題組利用該反應開發出一系列的芳基氟化試劑（百克-公斤級），可通過一步反應直接引入氟甲基、二氟甲基、二氟乙基等重要生物活性基團；通過一些天然產物及藥物中間體的合成發現，該方法可以大大簡化合成步驟，提高收率；另外，（氟代）乙烯基碸衍生物可以通過連續偶聯反應，以烷基羧酸為原料合成脫羧芳香（氟代）乙基衍生產物，非常巧妙（下圖所示）。
但由於該活化基團並不是常規官能團，需要由硫醇通過三步反應得到，較羧酸的脫羧偶聯來說更加繁瑣。