Synthesis of 2-Sulfonylthiazoles via Heteroaryl C–H Sulfonylation of Thiazole N-Oxides

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 (SO₂ ^2–) strategy, provides direct access to sulfonylated thiazole scaffolds without recourse to the use of 2-halothiazoles.

Key words

silyloxymethanesulfinate - C–H functionalization - modular synthesis - azole N-oxides - sulfonylazoles

Publication History

Received: 12 January 2023

Accepted after revision: 21 March 2023

Accepted Manuscript online:
21 March 2023

Article published online:
24 April 2023

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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:
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• 19 2-[({[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%); R_f = 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.