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

Jonathan A. Andrews, Jagadeesh Kalepu, Christopher F. Palmer, Darren L. Poole, Kirsten E. Christensen and Michael C. Willis*

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

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.

DOI: 10.1021/jacs.3c07974



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Abstract

Readily available and structurally diverse alkyl carboxylic acids can serve as the starting materials for sulfinamides, sulfonamides, and sulfonimidamides syntheses. The methods harness alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products.


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Divergent Synthesis of Sulfonamides and Sulfonimidamides from Carboxylic Acids



Photochemical Reaction Setup:

395 - 405 nm LEDs, where specified, comprised of 10 W LED strips wrapped inside a crystallising dish. 0.20 mmol scale reactions were carried out in 8 mL sample vials, sealed with a screw cap and Parafilm. 3.5 mmol scale reactions were carried out in a round bottom flask. Fan cooling was used during reactions to give an internal temperature of ~22 °C.

Synthesis of Sulfinamides:

Carboxylic acid (0.2/0.3 mmol), sulfinylamine/N-Sulfinyl-O-(tert-butyl)hydroxylamine (0.2/0.3 mmol), and photocatalyst (10/20 mol%) were weighed into a 10 mL vial, followed by dichloromethane (4/2/1 mL). The headspace was flushed with argon and the vial sealed. The reaction was then stirred under 395 - 405 nm LED irradiation with fan cooling for 18 h. Upon completion (determined by TLC), the reaction mixture was concentrated and purified using silica gel flash column chromatography.

Synthesis of Sulfonamides:

Carboxylic acid (0.3 mmol), N-Sulfinyl-O-(tert-butyl)hydroxylamine (0.2 mmol), and photocatalyst (10/20 mol%) were weighed into a 10 mL vial, followed by dichloromethane (2.0 mL). The headspace was flushed with argon and the vial sealed. The reaction was then stirred under 395 - 405 nm LED irradiation with fan cooling for 18 h. Upon completion (determined by TLC), NaOH (0.4 mmol, 0.4 M solution in i-PrOH) was added and the reaction stirred at room temperature for a further 18 h. After completion (determined by TLC) the reaction mixture was washed with water (10 mL), and extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica gel flash column chromatography.

Synthesis of Sulfonimidamides:

Carboxylic acid (0.3 mmol), N-Sulfinyl-O-(tert-butyl)hydroxylamine (0.2 mmol), and 9-mesitylacridine (10 mol%) were weighed into a 10 mL vial followed by dichloromethane (2.0 mL). The headspace was flushed with argon and the vial sealed. The reaction was then stirred under 395 - 405 nm LED irradiation with fan cooling for 18 h. Upon completion (determined by TLC), the reaction mixture was concentrated in vacuo. The crude material was then dissolved in THF (2.0 mL) was added to it under inert atmosphere and cooled it to 0 °C. NaH (0.26 mmol, 60% dispersion in mineral oil) was added and the reaction was allowed to warm to room temperature and stirred for a further 3 h. After completion (determined by TLC) the reaction mixture was washed with water (10 mL), and extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica gel flash column chromatography.


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

T. Q. Davies, M. J. Tilby, D. Skolc, A. Hall, M. C. Willis, Org. Lett., 2020, 22, 9495-9499.

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

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


Key Words

sulfinamides, sulfonamides, photochemistry, organocatalysis


ID: J48-Y2023