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. 2020 Dec 18;22(24):9495-9499.
doi: 10.1021/acs.orglett.0c03505. Epub 2020 Nov 25.

Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent N-Sulfinyl- O-(tert-butyl)hydroxylamine, t-BuONSO

Thomas Q Davies  1 , Michael J Tilby  1 , David Skolc  2 , Adrian Hall  2 , Michael C Willis  1
Affiliations

Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent N-Sulfinyl- O-(tert-butyl)hydroxylamine, t-BuONSO

Thomas Q Davies et al. Org Lett. .

Abstract

Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. In particular, primary sulfonamides are common in marketed drugs. Here we describe the direct synthesis of these valuable compounds from organometallic reagents and a novel sulfinylamine reagent, t-BuONSO. A variety of (hetero)aryl and alkyl Grignard and organolithium reagents perform well in the reaction, providing primary sulfonamides in good to excellent yields in a convenient one-step process.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Primary sulfonamide-containing drugs.
Scheme 1
Scheme 1. Common Methods to Prepare Primary Sulfonamides: (a) Reaction of Sulfonyl Chlorides with Ammonia or Ammonia Surrogates; (b) Noël’s Electrochemical Approach; (c) Reaction of Sulfinates with NH2+ Sources; (d) Chemical Oxidation–Amination of Thiols; (e) Our Alkyl/Aryl Halide Based Approach
Scheme 2
Scheme 2. Synthesis of t-BuONSO, 1, and Initial Reaction with Amine Leading to Reaction Discovery and Optimization
Yield determined by 19F NMR spectroscopy. 0.3 mmol of t-BuONSO. Isolated yields.
Scheme 3
Scheme 3. Scope of the Direct Primary Sulfonamide Synthesis
Commercial solution of Grignard reagent used. Organolithium reagent formed from aryl bromide and n-butyllithium. Turbo Grignard reagent formed by coupling of aryl halide and i-PrMgCl.LiCl. Organolithium reagent formed by deprotonation with n-butyllithium.
Scheme 4
Scheme 4. Proposed Mechanism for Sulfonamide Formation
See this image and copyright information in PMC

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