Base-Induced Cyclization of Active Methylene Isocyanides with Xanthate Esters: An Efficient Method for the Synthesis of 5-Alkoxy-4-(tosyl/ethoxycarbonyl)-1,3-thiazoles

Abstract

Sodium hydride-induced cyclization of 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene or ethyl isocyanoacetate with various xanthate esters gave 5-alkoxy-4-tosylthiazoles or ethyl 5-alkoxythiazol-4-ylcarboxylates, respectively, in good to excellent yields. The xanthate ester S-methyl O-phenyl dithiocarbonate gave 5-(methylsulfanyl)-4-tosyl-1,3-thiazole when treated with 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene under similar conditions.

Key words

thiazoles - isocyanides - xanthate esters - cyclization

• References and Notes

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• 30 O-Benzyl S-Methyl Dithiocarbonates 2a–g: General Procedure The appropriate benzylic alcohol 1a–g (10 mmol) was added to a solution of NaOH (20 mmol) in THF (10 mL), and the mixture was stirred at r.t. for 10 mins. The mixture was then cooled to 0 °C, CS₂ (10 mmol) was added, and the mixture was stirred for 10 min. MeI (10 mmol) was then added at 0 °C, and the mixture was stirred at r.t. for a further 2–3 h until the reaction was complete (TLC). Ice-cold H₂O (25 mL) was added, and the mixture was extracted with EtOAc (2 × 25 mL). The organic layers were combined, washed with H₂O (25 mL) and brine (25 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give the crude product that was purified by column chromatography [silica gel, EtOAc–hexane, (1:9)]. O-Benzyl S-Methyl Dithiocarbonate (2a) Yellow viscous liquid; yield: 1.861 g (94%). IR (KBr): 622, 1051, 1185, 1203, 1609, 2920 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.57 (s, 3 H, SMe), 5.63 (s, 2 H, CH₂), 7.24–7.40 (m, 5 H, Ar-H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.0, 75.1, 128.5, 128.6, 130.0, 134.7, 215.7. HRMS: m/z [M + H]⁺ calcd for C₉H₁₁OS₂: 199.0000; found: 199.0173.
• 31 5-Alkoxy-4-(tosyl/ethoxycarbonyl)-1,3-thiazoles (4a–i) and 4-(Methylsulfanyl)-4-tosyl-1,3-thiazole (4j); General Procedure A mixture of the appropriate xanthate ester 2 (2 mmol) and active methylene isocyanide 3 (2 mmol) in DMF (1.5 mL) was added dropwise to NaH (60% suspension in paraffin; 4 mmol) in DMF (1.5 mL) at 0 °C. The mixture was stirred at r.t. for 10–20 min until the reaction was complete (TLC) then poured into sat. aq NH₄Cl (20 mL). The mixture was extracted with EtOAc (2 × 20 mL), and the EtOAc layers were combined, washed with H₂O (20 mL) and brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give the crude product, which was purified by column chromatography [silica gel, EtOA–hexane (2:8)]. 5-(Benzyloxy)-4-tosyl-1,3-thiazole (4a) White solid; yield: 0.635 g (92%); mp 130–132 °C; IR (KBr): 626, 983, 1040, 1318, 1593, 2920 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.39 (s, 3 H, Ar-Me), 5.24 (s, 2 H, CH₂), 7.26 (d, J = 8.0 Hz, 2 H, Ar-H), 7.37–7.41 (m, 5 H, Ar-H), 7.92 (dd, J = 6.8, 2.0 Hz, 2 H, Ar-H), 8.14 (s, 1 H, Ar-H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.6, 80.0, 127.9, 128.1, 128.8, 129.2, 129.6, 133.6, 135.0, 138.2, 140.3, 144.3, 163.7. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₆NO₃S₂: 346.0000; found: 346.0493.