An Aluminum(III)-Catalyzed Thioamide–Aldehyde–Styrene Condensation: Direct Synthesis of Allylic Thioamide Derivatives

Abstract

An aluminum(III) triflate catalyzed three-component synthesis of allylic thioamide derivatives by condensation of a thioamide, paraformaldehyde and a styrene is reported.

Key words

thioamides - paraformaldehyde - styrenes - allyl thioamides - multicomponent reactions - condensation

• References and Notes

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• 32 1-[(2E)-3-Phenylprop-2-en-1-yl]azepane-2-thione (4a); Typical Procedure An oven-dried tube was charged with a mixture of cyclic thioamide 1a (1 mmol, 0.129 g), paraformaldehyde (2a; 4 mmol, 0.120 g), styrene (3a; 1.2 mmol, 0.125 g), and Al(OTf)₃ (20 mol%, 0.191 g). Anhydrous xylene (3 mL) was added from a straw, and the mixture was stirred at 110 °C for 24 h while the reaction was monitored by TLC. The mixture was cooled to r.t., and the reaction was quenched with sat. aq NH₄Cl (3 mL). The mixture was extracted with EtOAc (3 × 15 mL) and the organic layers were combined, washed with brine, and dried (MgSO₄). The crude product was purified by column chromatography [silica gel, PE–EtOAc (1:6)] to give a yellow oil; yield: 211 mg (0.86 mmol, 86%). ¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.23 (m, 5 H), 6.49 (d, J = 15.6 Hz, 1 H), 6.18–6.11 (m, 1 H), 4.16 (d, J = 5.2 Hz, 2 H), 3.34 (s, 2 H), 2.57 (d, J = 5.2 Hz, 2 H), 1.66 (d, J = 38.4 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.6, 136.6, 132.5, 128.5, 127.5, 126.3, 125.1, 49.8, 48.6, 37.1, 29.9, 28.4, 23.4. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₅H₂₀NS: 246.1311; found: 246.1316.
• 33 N-Benzyl-N-[(2E)-3-Phenylprop-2-en-1-yl]ethanethioamide (5a); Typical Procedure An oven-dried tube was charged with a mixture of acyclic thioamide 1b (1 mmol, 0.165 g), paraformaldehyde (2a; 4 mmol, 0.120 g), styrene (3a; 1.2 mmol, 0.125 g), and Al(OTf)₃ (20 mol%, 0.191 g). Anhydrous xylene (3 mL) was added from a straw, and the mixture was stirred at 110 °C for 24 h while the reaction was monitored by TLC. The mixture was cooled to r.t., and the reaction was quenched with sat. aq NH₄Cl (3 mL). The mixture was extracted with EtOAc (3 × 15 mL) and the organic layers were combined, washed with brine, and dried (MgSO₄). The crude product was purified by column chromatography [silica gel, PE–EtOAc (1:6)] to give a yellow oil; yield: 202 mg (0.72 mmol, 72%). ¹H NMR (600 MHz, CDCl₃): δ = 7.36–7.22 (m, 10 H), 6.43 (t, J = 16.2 Hz, 1 H), 6.19–6.05 (m, 1 H), 4.65 (s, 1 H), 4.54 (s, 1 H), 4.16 (d, J = 6.6 Hz, 1 H), 3.99 (d, J = 5.4 Hz, 1 H), 2.20 (d, J = 27.0 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 170.9, 133.1, 131.9, 128.9, 128.7, 128.6, 128.5, 128.2, 127.9, 127.7, 127.6, 127.4, 126.4, 124.5, 123.8, 50.9, 49.5, 48.1, 47.3, 21.7, 21.6. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₈H₂₀NS: 282.1311; found: 282.1314.