A rapid access to aliphatic sulfonyl fluorides

The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO2F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.


Synthesis of sultam 48 & 49
The reaction was performed on a 0.2 mmol scale, according to the general procedure, followed by deprotection with TFA. After irradiation for 12 hours, the reaction mixture was 5 concentrate in vacuo and diluted with dichloromethane (0.4 mL). The solution was transferred to a 5 mL glass vial and 0.2 ml of TFA was added slowly via syringe. The reaction mixture was stirred overnight at room temperature to achieve full conversion. The product was purified by flash chromatography (SiO2, PE/EA = 2:1, Rf = 0.48) to obtain the product as a colorless oil in 84% yield.
To a solution of the sulfonyl fluoride (28.1 mg, 0.10 mmol) in dichloromethane (0.2 mL) was added TFA (0.1 mL) slowly via syringe. The reaction mixture was stirred overnight at room temperature to achieve full conversion. The product was purified by flash chromatography (SiO2, PE/EA = 2:1, Rf = 0.28) to obtain the product as a colorless oil in 80% yield.

Isotope-labeling experiment
The deuterated Hantzsch ester was synthesized according to the reported procedure. 13 An oven dried round bottom flask was charged with ethyl acetoacetate (1.6 ml, 12.48 mmol, 4 equiv.), D2-paraformaldehyde (0.1 g, 3.12 mmol, 1 equiv.), ammonium acetate (0.48 g, 6.24 mmol, 2 equiv.) and water (6.5 ml), then the mixture was heated at 86 °C. After 3 hours, the reaction mixture was allowed to cool down to room temperature and filtered. The precipitate was dried in vacuo to afford the desired compound as yellow solid (0.6 g, 76%). 1

Proposed mechanism
Based on the above experiments and our results, as well as the reported eosin Y mediated photocatalysis, 11 a plausible mechanism was proposed as shown below.

Supplementary Figure 5. Proposed reaction mechanism
The low yields with commonly used DIPEA and TEA may be ascribed to the radical species from DIPEA and TEA, which would cause side reactions to consume VSF. And, when the last HAT step with DIPEA is slow, the radical I-a formed through the R radical addition to VSF can also cause side reactions like polymerization to consume VSF. While, a fast hydrogen atom transfer to the radical intermedate I-a from HE would efficiently suppress the side reactions, as confirmed by the isotope-labeling experiments in part 3.4.

Supplementary Note 1 Stability test of aliphatic sulfonyl fluorides in physiological buffer:
The stability of sulfonyl fluoride products in physiological buffers was tested in phosphate-buffered saline (PBS buffer, pH = 7.2) at room temperature. 19 F NMR analysis was employed to monitor the change of the sulfonyl fluoride content, and 2,2,2-trifluroethanol (F3CCH2OH) was used as an internal standard and isopropanol or DMSO was used to dissolve the sulfonyl fluorides, which are not soluble in the aqueous PBS buffer.