Support for this research was provided by the National Research Foundation (NRF) funded by the Ministry of Science and ICT of Korea (2020R1A2B5B03002271, 2021R1A5A6002803 and RS-2023-00208586).
This paper is dedicated to Professor Masahiro Murakami for his inspiring contributions to chemical science.
Abstract
Described here is an efficient method for the modular synthesis of 2-sulfonylthiazole derivatives via heteroaryl C–H sulfonylation. The protocol is composed of two stages involving O-activation of thiazole N-oxides and nucleophilic addition of a sulfinate, which induces N(3)-deoxygenation and C(2)-sulfonylation. The vicarious substitution is performed most effectively by using 4-methoxybenzoyl chloride for O-acylation while employing sodium [tert-butyl(dimethyl)silyloxy]methanesulfinate (TBSOMS-Na) as the nucleophile. The sulfones thus obtained can be converted to an array of thiazolyl sulfones, sulfonamides, and sulfonyl fluorides by displacing the silyloxymethyl moiety with alkyl, aryl, amino, and fluoro groups. The C–H sulfonylation approach, in combination with a sulfoxylate (SO22–) strategy, provides direct access to sulfonylated thiazole scaffolds without recourse to the use of 2-halothiazoles.
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Fujiwara Y,
Baran PS.
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Campeau L.-C,
Stuart DR,
Leclerc J.-P,
Bertrand-Laperle M,
Villemure E,
Sun H.-Y,
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Guimond N,
Lecavallier M,
Fagnou K.
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The attempted C–H sulfonylation via N-activation of benzothiazole using triflic anhydride led to extensive decomposition (see the Supporting Information for details). For reports on the direct N-activation approach to the C–H sulfonylation of azine-type N-heteroaromatics, see:
15a
Friedrich M,
Schulz L,
Hofman K,
Zangl R,
Morgner N,
Shaaban S,
Manolikakes G.
Tetrahedron Chem 2022; 1: 100003
18 As with 3f, facile protodesulfonylation was observed in the attempted copper-catalyzed S-arylation of a ketosulfone substrate (Scheme 3, unpublished results from ref. 8b). Also examined were the reaction of 3f with iodobenzene under metallaphotoredox conditions and the SNAr reaction employing an iodonium salt, both of which resulted in the formation of the protodesulfonylation product 4f (see the Supporting Information for details).
192-[({[tert-Butyl(dimethyl)silyl]oxy}methyl)sulfonyl]-1,3-thiazole; Typical Procedure
4-methoxybenzoyl chloride (1.1 equiv, 0.44 mmol, 60 μL) was added dropwise to a solution of 1,3-thiazole N-oxide (2a; 0.4 mmol) and TBSOMS-Na (1; 1.5 equiv, 0.6 mmol, 0.1394 g) in anhyd DCM (2 mL), and the mixture was stirred at 30 ℃ for 2 h under atmospheric conditions. Organic fractions were gathered with DCM, washed with aq NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) to afford the desired sulfone product 3f as a colorless liquid, yield: 85.7 mg (73%); Rf = 0.48 (hexane–EtOAc, 5:1).
1H NMR (500 MHz, CDCl3): δ = 8.10 (s, 1 H), 7.78 (s, 1 H), 4.95 (s, 2 H), 0.80 (s, 9 H), 0.06 (s, 6 H). 13C NMR (126 MHz, CDCl3): δ = 163.5, 145.4, 127.0, 79.5, 25.5, 18.3, –5.4. IR (neat): 3116, 2931, 2889, 2858, 1471, 1432, 1362, 1340, 1312, 1258, 1172, 1128, 1067, 1007, 939, 833, 784, 764, 728, 668, 544, 527, 463, 404 cm–1. HRMS (ESI): m/z [M + Na]+ calcd for C10H19NNaO3S2Si: 316.0468; found: 316.0468.
