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. 2020 Nov 20;22(22):8802-8807.
doi: 10.1021/acs.orglett.0c03160. Epub 2020 Oct 13.

Chemoselective α-Sulfidation of Amides Using Sulfoxide Reagents

Mario Leypold  1 , Kyan A D'Angelo  1 , Mohammad Movassaghi  1
Affiliations

Chemoselective α-Sulfidation of Amides Using Sulfoxide Reagents

Mario Leypold et al. Org Lett. .

Abstract

The direct α-sulfidation of tertiary amides using sulfoxide reagents under electrophilic amide activation conditions is described. Employing convenient and readily available reagents, selective functionalization takes place to generate isolable sulfonium ions en route to α-sulfide amides. Mechanistic studies identified activated sulfoxides as promoters of the desired transformation and enabled the extension of the methodology from benzylic to aliphatic amide substrates.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Methods for the α-Sulfidation of Amides
Scheme 2
Scheme 2. α-Sulfidation of Benzylic Amide 1a
Scheme 3
Scheme 3. α-Sulfidation of Benzylic Amides
Reagents and conditions: Method A (methyl sulfoxides): Tf2O (1.05 equiv), 2-ClPy (3.00 equiv), CH2Cl2, −78 → 0 °C, 15 min; methyl sulfoxide (2a, 2f, 1.20 equiv), CH2Cl2, −78 → 22 °C, 45 min; Et3N (10 equiv), MeCN, 60 °C, 15 h. Method B (tert-butyl sulfoxides): Tf2O (1.05 equiv), 2-ClPy (3.00 equiv), CH2Cl2, −78 → 0 °C, 15 min; tert-butyl sulfoxide (2b–2e, 1.20 equiv), CH2Cl2, −78 → 22 °C, 45 min. Yields are reported: Method A, Method B.
Scheme 4
Scheme 4. Proposed Intermolecular Sulfidation Pathway
Scheme 5
Scheme 5. α-Sulfidation of Aliphatic Amides
Reagents and conditions, Method C: Tf2O (1.10 equiv), 2-ClPy (3.00 equiv), CH2Cl2, −78 → 0 °C, 15 min; DMSO (2a, 2.50 equiv), TFAA (1.00 equiv), CH2Cl2, −78 → 22 °C, 45 min; Et3N (10 equiv), MeCN, 60 °C, 15 h. Sulfoxide 2f (2.50 equiv).
See this image and copyright information in PMC

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