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A Silyl Sulfinylamine Reagent Enables the Modular Synthesis of Sulfonimidamides via Primary Sulfinamides

Mingyan Ding, Ze-Xin Zhang, Thomas Q. Davies and Michael C. Willis*

*Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K., Email: michael.willischem.ox.ac.uk

M. Ding, Z.-X. Zhang, T. Q. Davies, M. C. Willis, Org. Lett., 2022, 24, 1711-1715.

DOI: 10.1021/acs.orglett.2c00347


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Abstract

The reaction of a N-silyl sulfinylamine reagent with Grignard, organolithium, or organozinc reagents provides a broad range of (hetero)aryl, alkenyl, and alkyl primary sulfinamides. Treatment of these primary sulfinamides with an amine in the presence of a hypervalent iodine reagent leads directly to sulfonimidamides.


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Synthesis of triisopropylsilyl amine (TIPS-NH2)

To an oven-dried 1 litre round-bottom flask was dissolved triisopropylsilyl chloride (32.85 g, 170.38 mmol, 1.0 equiv.) in anhydrous diethyl ether (340 mL). The reaction mixture was cooled to -78 °C. Anhydrous ammonia was bubbled through this solution for 2 hours, resulting in the immediate formation of a white precipitate. The reaction was then warmed to 0 °C and stirred for another 3 hours open to air to remove excess ammonia. When bubbling stopped, the reaction slurry was filtered through a pad of anhydrous Na2SO4 (3-4 cm), washed with Et2O (20 mL) and concentrated in vacuo to afford triisopropylsilyl amine as a colourless oil (29.14 g, 168.23 mmol, 99%).

Synthesis of N-sulfinyltriisopropylsilylamine (TIPS-NSO)

To an oven-dried 1 litre round-bottom flask was added triisopropylsilyl amine (5.23 g, 30.20 mmol, 1.00 equiv.). The vessel was sealed and subjected to three N2 evacuation/refill cycles before anhydrous diethyl ether (600 mL) was added. The solution was cooled to 0 °C and anhydrous triethylamine (8.67 mL, 62.21 mmol, 2.06 equiv.) was added. Freshly distilled thionyl chloride (2.27 mL, 31.11 mmol, 1.03 equiv.) was then added dropwise. The reaction slurry was then stirred vigorously at 0 °C for 2 hours. Filtration through a pad of anhydrous Na2SO4 (3-4 cm) and removal of solvent in vacuo afforded TIPS-NSO as a light-yellow oil (6.59 g, 30.03 mmol, 99%).

Synthesis of primary sulfinamides

An oven-dried round-bottom flask containing TIPS-NSO 1 (1.0 equiv.) was sealed and subjected to three N2 evacuation/refill cycles before pre-sparged anhydrous THF (TIPS-NSO conc. 0.1 M) was added. The solution was cooled to 0 °C and then the corresponding Grignard, organolithium, or organozinc reagent (1.2 equiv.) was added dropwise. The reaction was stirred at 0 °C for 5 minutes prior to the addition of tetrabutylammonium fluoride (TBAF) solution (1.0 M in THF, 2.0 equiv.) at the same temperature. The reaction was warmed to room temperature and stirred for another 10 minutes before being diluted with EtOAc (10 mL) and quenched with saturated aqueous solution of EDTA tetrasodium salt (10 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were then washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Primary sulfinamide was then purified by flash column chromatography with the appropriate solvent system.

Reaction between primary sulfinamide and secondary amine

An oven-dried round-bottom flask containing primary sulfinamide 2 (1.0 equiv.) and PhI(OAc)2 (1.5 equiv.) was sealed and subjected to three N2 evacuation/refill cycles before pre-sparged anhydrous toluene (sulfinamide conc. 0.1 M) was added. Anhydrous triethylamine (3.0 equiv.) was added to the solution, followed immediately by the addition of secondary amine (1.5 equiv.). The reaction mixture was then stirred at room temperature for the specified time. Once judged complete by TLC, the reaction was diluted with EtOAc (10 mL) and quenched with saturated aqueous solution of NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Sulfonimidamide was purified by flash column chromatography with the appropriate solvent system.


Sulfinamide Synthesis Using Organometallic Reagents, DABSO, and Amines

P. K. T. Lo, G. A. Oliver, M. C. Willis, J. Org. Chem., 2020, 85, 5753-5760.

DABCO-Bis(sulfur dioxide), DABSO, as a Convenient Source of Sulfur Dioxide for Organic Synthesis: Utility in Sulfonamide and Sulfamide Preparation

H. Woolven, C. Gonzáles-Rodríguez, I. Marco, A. L. Thompson, M. C. Willis, Org. Lett., 2011, 13, 4876-4878.

Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides

J. A. Andrews, J. Kalepu, C. F. Palmer, D. L. Poole, K. E. Christensen, M. C. Willis, J. Am. Chem. Soc., 2023, 145, 21623-21629.


Key Words

sulfinamides, sulfonimidamides, phenyliodonium diacetate


ID: J54-Y2022