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Metal-Free S-Arylation of Phosphorothioate Diesters and Related Compounds with Diaryliodonium Salts

Sudeep Sarkar and Marcin Kalek*

*Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland, Email: m.kalekcent.uw.edu.pl

S. Sarkar, M. Kalek, Org. Lett., 2023, 25, 671-675.

DOI: 10.1021/acs.orglett.2c04310


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Abstract

The use of diaryliodonium salts enables a direct metal-free S-arylation of phosphorothioate diesters. The method allows for the preparation of a broad range of S-aryl phosphorothioates as well as other related organophosphorus compounds under simple conditions. The reaction proceeds with a full retention of the stereogenic center at the phosphorus atom.

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Preparation of Phosphorothioate diesters and related P-S/Se starting materials

An oven dried round bottom flask was charged with H-phosphonate diester/Hphosphinate/phosphine oxide (1.00 equiv.) and sulfur/selenium (1.05 equiv.). The flask was capped with a rubber septum and evacuated/back-filled with nitrogen. A 1:1 mixture of ethyl acetate:diethyl ether (8 mL/mmol substrate; limiting substrate conc. 0.125 M) was added via syringe and the reaction mixture was cooled down to 0 C. Anhydrous triethylamine (3 equiv.) was added dropwise, the reaction mixture was allowed to warm up to room temperature, and it was stirred overnight. The solvents were evaporated under reduced pressure and the product was purified by column chromatography or by washing with diethyl ether.

Arylation of Phosphorothioate Diesters and Related Compounds with Diaryliodonium Salts

A 20 mL vial was charged with phosphorothioate diester/related P-S/Se compound (0.40 mmol) and diaryliodonium tetrafluoroborate (1.2 equiv., 0.48 mmol). The vial was capped and evacuated/back-filled with nitrogen three times. Anhydrous 1,4-dioxane (8 mL; limiting substrate conc. 0.05 M) was added via syringe and the reaction mixture was stirred in an aluminum heating block at 100 C for 18 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. Dichloromethane (2 mL) was added to the residue, followed by a small amount of silica. The solvent was evaporated under reduced pressure, the solid residue was applied on the top of silica column, and the product was purified by column chromatography.

The procedure can also performed in a larger scale. In this case, the 20 mL vial is replaced by a round-bottom flask equipped with a reflux condenser, which is closed with a rubber septum and connected via needle to a positive pressure of nitrogen (from balloon or manifold) throughout the reaction.


Key Words

Phosphorothioates


ID: J54-Y2023