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

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.

Figure 1

Primary sulfonamide-containing drugs.

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. 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. 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. Proposed Mechanism for Sulfonamide Formation