Cascade Thiol-Michael–Aldol Reaction Promoted by Tetramethyl Guanidine: Synthesis of 2H-Thiochromene-3-carboxylate Libraries

Abstract

Tetramethylguanidine (TMG) promotes a cascade thiol-­Michael–aldol–dehydration reaction between 2-mercaptobenzaldehyde and cinnamate esters to synthesize 2H-thiochromene-3-carboxylate derivatives. The target thiochromene compounds with a variety of substituents were obtained in high yields.

Key words

thiochromene - cascade thiol-Michael–aldol - 2-mercaptobenzaldehyde - methyl cinnamate - tetramethylguanidine

• References and Notes

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Thiochromene-ester synthesis:
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• 16 General Procedure A mixture of 2-mercaptobenzaldehyde (1, 55 mg, 0.4 mmol), methyl cinnamate (2, 32 mg, 0.2 mmol), and TMG (25 μL, 0.2 mmol) dissolved in dry toluene (1 mL) was stirred at r.t. for 24 h. After completion of the reaction, the solvent was evaporated under vacuum, and the crude product was purified by chromatography (n-hexane–EtOAc, 80:20) to give a mixture of diastereoisomers 3 as a pale yellow liquid (57 mg, 95 %). This product was then dissolved in toluene (1 mL) with PTSA (36 mg, 0.19 mmol). The mixture was heated at 90 °C for 1 h. After completion of the reaction, the solvent was evaporated under vacuum, and the crude product was purified by chromatography (n-hexane–EtOAc, 95:5) to give compound 4 as a yellow solid (40 mg, 75% after 2 steps). Methyl 2-Phenyl-2H-thiochromene-3-carboxylate (4a) ¹H NMR (500 MHz, CDCl₃): δ = 7.84 (s, 1 H), 7.25–7.15 (m, 5 H), 7.08 (t, J = 7.9 Hz, 1 H), 7.01 (dd, J = 7.6, 0.8 Hz, 1 H), 6.81 (dd, J = 8.1, 0.9 Hz, 1 H), 5.23 (s, 1 H), 4.10–3.91 (m, 2 H), 3.78 (s, 3 H), 1.38 (t, J = 7.0 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 165.38, 153.84, 141.53, 136.03, 129.92, 127.51, 126.51, 125.70, 124.18, 123.72, 122.14, 120.57, 112.61, 63.50, 51.23, 38.56, 13.64. HRMS: m/z calcd for [M + Na]⁺ C₁₇H₁₄NaO₂S: 305.0612; found: 305.0615.