New Facile Synthesis of 3,4-Dihydroquinazoline-2(1H)-thiones by a Sequential Ugi-Azide/Staudinger/Aza-Wittig/Cyclization Reaction

Abstract

A new facile synthesis of 3,4-dihydroquinazoline-2(1H)-thiones by an Ugi-azide/Staudinger/aza-Wittig/cyclization sequence has been developed. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced tetrazoles, which, when treated with methyldiphenylphosphane and CS₂, produced 3,4-dihydroquinazoline-2(1H)-thiones in good overall yields via a sequential Staudinger/aza-Wittig/cyclization reaction.

Key words

3,4-dihydroquinazoline-2(1H)-thione - Ugi-azide reaction - methyldiphenylphosphane - aza-Wittig reaction - cyclization reaction

• References and Notes

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• 26 Preparation of Ugi Intermediates 5; General Procedure: A mixture of 2-azidobenzaldehyde 1 (2 mmol), amine 2 (2 mmol), trimethylsilyl azide 3 (2 mmol), and isocyanide 4 (2 mmol) was stirred in methanol (10 mL) at room temperature for 12–24 h. After the reaction was complete, the precipitate was filtered to give 5 (when R² is an aryl group) or the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (ether/petroleum ether = 1:4, v/v) to give 5 (when R² is an alkyl group).
• 27 Compound 5n: Yellow solid (88%); mp 201–203 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 7.45–6.54 (m, 7 H, Ar-H), 6.26 (d, J = 9.6 Hz, 1 H, CH), 4.49 (d, J = 8.4 Hz, 1 H, NH), 2.22 (s, 3 H, CH₃), 1.76 (s, 9 H, 3 CH₃). ¹³C NMR (CDCl₃, 150 MHz): δ = 154.3, 142.6, 138.6, 135.2, 130.0, 129.8, 128.8, 127.8, 125.7, 118.3, 114.1, 62.1, 48.3, 29.9, 20.4. HRMS (ESI): m/z [C₁₉H₂₁ClN₈+H]⁺ calcd: 397.1650; found: 397.1655.
• 28 Preparation of 3,4-Dihydroquinazoline-2(1H)-thiones 8; General Procedure: To the azide 5 (1 mmol) in anhydrous toluene (5 mL) was added dropwise Ph₂PCH₃ (0.20 g, 1 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at r.t. for 0.5 h to form iminophosphorane 6 (TLC monitoring). CS₂ (0.15 g, 2 mmol) was then added and the solution was heated to 110 °C for 4–6 h, After the reaction was complete, the precipitate was filtered to give 3,4-dihydroquinazoline-2(1H)-thione 8.
• 29 Compound 8a: White solid (yield: 86%); mp 257–258 °C. ¹H NMR (DMSO-d ₆, 600 MHz): δ = 11.40 (s, 1 H, NH), 7.33–7.07 (m, 9 H, Ar-H), 6.99 (s, 1 H, CH), 1.34 (s, 9 H, 3 CH₃). ¹³C NMR (DMSO-d ₆, 150 MHz): δ = 175.7, 155.9, 143.7, 134.1, 129.6, 129.4, 128.2, 126.1, 123.2, 118.6, 114.9, 62.6, 56.4, 29.6. HRMS (ESI): m/z [C₁₉H₂₀N₆S+H]⁺ calcd: 365.1543; found: 365.1545.