Multicomponent Reaction-Based Heteroannulations: A Direct Access to Fused Tetrazolo Piperazinones and 1,4-Diazepanones

Abstract

By exploiting the chemistry of bifunctional isocyanides, straightforward, rapid, and scalable Ugi-tetrazole-based multicomponent reaction heteroannulations were developed. Our synthetic approach provides a series of diverse fused tetrazolo piperazinones and 1,4-diazepanones in just one step.

Key words

isocyanides - tetrazoles - piperazinones - diazepanones - Ugi reaction - multicomponent reaction

• References and Notes

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• 52 Ugi-Tetrazole Four-Component Synthesis of 10a–k; General Procedure The aldehyde (1.0 mmol) was added to a stirred solution of the amine (1.0 mmol) and Et₃N (1.0 mmol) in MeOH (1.0 mL), and the mixture was stirred for 10 min. The isocyanide 9 (1.0 mmol) and TMSN₃ (1.0 mmol) were then added, and the mixture was stirred vigorously for 48 h at 40 °C. The solvent was removed under reduced pressure, and the residue was purified by column chromatography [silica gel, PE–EtOAc (5:1 to 1:1)].
• 53 Ethyl 3-(4-Cyclopropyl-9-methyl-6-oxo-4H-tetrazolo[1,5-a]thieno[2,3-f][1,4]diazepin-5(6H)-yl)propanoate (10a) Yellow oil; yield: 157 mg (51%). ¹H NMR (500 MHz, CDCl₃): δ = 7.37–7.33 (d, J = 19.5 Hz, 1 H), 4.10–4.06 (m, 1 H), 3.70–3.68 (d, J = 7.5 Hz, 3 H), 3.64–3.61 (d, J = 12.9 Hz, 2 H), 3.15–3.12 (m, 1 H), 2.45–2.43 (m, 1 H), 2.34–2.30 (m, 1 H), 2.00–1.94 (d, J = 16.1 Hz, 3 H), 1.13–0.95 (m, 1 H), 0.63–0.47 (m, 1 H), 0.33–0.31 (m, 1 H), 0.15–0.13 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 173.0, 160.1, 158.6, 157.8, 136.9, 134.1, 127.2, 60.5, 58.1, 52.7, 51.7, 43.0, 34.6, 15.6, 13.3, 4.3, 3.3, 2.9. HRMS (ESI): m/z [M + CH₃OH]⁺ calcd for C₁₇H₂₃N₅O₄S: 394.1514; found: 394.1547. Ethyl [8-(4-Chlorophenyl)-6-oxo-5,6-dihydrotetrazolo[1,5-a]pyrazin-7(8H)-yl]acetate (10i) Yellow oil; yield: 162 mg (57%). ¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.40 (m, 2 H), 7.26–7.25 (m, 2 H), 6.13 (s, 1 H), 5.31–5.26 (m, 2 H), 4.75–4.71 (d, J = 17.5 Hz, 1 H), 4.19–4.17 (m, 2 H), 3.54–3.50 (d, J = 17.5 Hz, 1 H), 1.26–1.24 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 167.6, 161.6, 149.6, 136.1, 132.9, 129.9, 128.9, 61.9, 57.3, 47.8, 45.9, 13.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅ClN₅O₃: 336.0842; found: 336.0856.