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

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.


Notes:
1. t-BuONSO 1 is stored in the freezer at -20 °C in a vial wrapped in parafilm and can be taken out and used regularly without loss of performance for at least a year. Storage in a fridge at 2 -8 °C or on the bench at room temperature may also be possible.
2. CAUTION: Hydrolysis of sulfinylamines can result in the formation of toxic sulfur dioxide gas. Evolution of SO2 from t-BuONSO has not been noted by the authors in the normal course of use as it is not moisture-sensitive, but avoidance of contact with water is advised.
3. The moderate yield (57%) is likely due to loss of the volatile product when evaporating solvent on the rotary evaporator. To minimise these losses, we recommend to carry out solvent evaporation under distillation conditions with a Vigreux column.

S4
4. Anhydrous dichloromethane was used as the reaction solvent.

General Procedure A for Primary Sulfonamide Synthesis
O-(tert-Butyl)-N-sulfinylhydroxylamine t-BuONSO 1 (40.5 mg, 0.30 mmol, 1.0 equiv.) was dissolved in THF (1.2 mL) and cooled to -78 °C. The corresponding organometallic reagent was added. The reaction was then taken out of the dry-ice-acetone bath and allowed to warm to room temperature and stirred for 18 h. The reaction mixture was purified directly by flash chromatography to afford the desired primary sulfonamide 2.
Note: the reaction can be quenched by the addition of isopropanol, or SiO2 for base-sensitive products. When carried out on a small scale, the reaction could be added directly to the top of a silica gel column. For reactions with larger quantities of solvent, quenching with SiO2 and evaporation on a rotary evaporator is recommended before addition to the column.
Note: when the reaction was run on gram scale, a pressure build-up was observed. Use of an outlet is therefore recommended when running the reaction on large scale.
The data was consistent with the literature. [
The data was consistent with the literature.
The data was consistent with the literature. [4]
The data was consistent with the literature.
Purification by flash chromatography (SiO2, petrol/ethyl acetate, gradient 9:1 to 1:9) afforded sulfonamide 2h as a white solid (24.5 mg, 56% yield). The data was consistent with the literature.  1.2 equiv.) was added dropwise and the reaction stirred at -78 °C for 15 min. t-BuONSO (31 mg, 0.23 mmol, 1.2 equiv.) was added and the reaction was taken out of the dry-ice acetone bath and allowed to warm to room temperature and stirred for 16 hours. Purification by flash chromatography (SiO2, petrol/ethyl acetate, gradient 9:1 to 1:9) afforded sulfonamide 2i as a white solid (37.5 mg, 85% yield). The data was consistent with the literature. [6]
Reaction (c) was performed in the same manner as reaction (b) but with an additional period of stirring at 50 °C for 48 hours. 25% 18-Oxygen incorporation was detected by LCMS.
Overall, these results indicate that neither oxygen atom of sulfonamide 2a arise from quenching of the reaction, as no incorporation is observed from the addition of H2 18 O at either -78 °C or room temperature. Although 18 O incorporation can be observed to some extent after prolonged heating at 50 °C, this likely occurs via an exchange process. From these results we speculate that both oxygen atoms in sulfonamide 2a arise from t-BuONSO 1.