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. 2022 Dec 14;144(49):22426-22432.
doi: 10.1021/jacs.2c10552. Epub 2022 Dec 1.

Rhodium(III)-Catalyzed Anti-Markovnikov Hydroamidation of Unactivated Alkenes Using Dioxazolones as Amidating Reagents

Noah Wagner-Carlberg  1 , Tomislav Rovis  1
Affiliations

Rhodium(III)-Catalyzed Anti-Markovnikov Hydroamidation of Unactivated Alkenes Using Dioxazolones as Amidating Reagents

Noah Wagner-Carlberg et al. J Am Chem Soc. .

Abstract

The amide is one of the most prevalent functional groups in all of pharmaceuticals, and for this reason, reactions that introduce the amide moiety are of particular value. Intermolecular hydroamidation of alkenes remains an underexplored method for the synthesis of amide-containing compounds. The majority of hydroamidation procedures exhibit Markovnikov regioselectivity, while current methods for anti-Markovnikov hydroamidation are somewhat limited to activated alkene substrates or radical processes. Herein, we report a general method for the intermolecular anti-Markovnikov hydroamidation of unactivated alkenes under mild conditions, utilizing Rh(III) catalysis in conjunction with dioxazolone amidating reagents and isopropanol as an environmentally friendly hydride source. The reaction tolerates a wide range of functional groups and efficiently converts electron-deficient alkenes, styrenes, and 1,1-disubstituted alkenes, in addition to unactivated alkenes, to their corresponding linear amides. Mechanistic studies reveal a reversible rhodium hydride migratory insertion step, leading to exquisite selectivity for the anti-Markovnikov product.

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Figures

Scheme 1.
Scheme 1.. Previous work on hydroamidation of alkenes
Scheme 2.
Scheme 2.. Hydroamidation scope
Unless otherwise noted, we report isolated yields of reactions run on 0.1 mmol scale using five equivalents of dioxazolone. a The NMR yield is reported. b The free alcohol was TMS-protected in the starting material. c With 2.5 equivalents of dioxazolone. d 0.05 mmol scale. Ac = acetyl, Bn = benzyl, Phth = phthaloyl, Ms = methanesulfonyl, TBDPS = tert-butyldiphenylsilyl, Ts = para-toluenesulfonyl.
Scheme 3.
Scheme 3.. Mechanistic studies
Scheme 4.
Scheme 4.. Proposed mechanism
See this image and copyright information in PMC

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