A Convenient One-pot Synthesis of 2,3-Disubstituted Thieno[2,3-d]pyrimidin-4(3H)-ones from 2H-Thieno[2,3-d][1,3]oxazine-2,4(1H)-diones, Aromatic Aldehydes and Amines

Abstract

An efficient, simple protocol has been established for convenient synthesis of novel 2,3-disubstituted thieno[2,3-d]pyrimidin-4(3H)-one derivatives in good to high yields through a one-pot, two-step and three-component reaction from 2H-thieno[2,3-d][1,3]oxazine-2,4(1H)-diones, aromatic aldehydes, and amines.

Key words

thieno[2,3-d]pyrimidin-4(3H)-one - one-pot synthesis - intramolecular cyclization - pyrimidinone - quinazolinone

• References and Notes

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• 20 Synthesis of 4a–ag; General ProcedureA mixture of 2H-benzo[4,5]thieno[2,3-d][1,3]oxazine-2,4(1H)-dione (0.366 mmol, 1.5 equiv), amine (0.366 mmol, 1.5 equiv) and aldehyde (0.244 mmol, 1.0 equiv) in EtOH was heated to reflux for 10–14 h. After TLC indicated that the aldehyde had been completely consumed, KOH (0.488 mmol, 2.0 equiv) was added and the mixture was heated to reflux for a further 6–10 h. Upon completion of the reaction (verified by TLC), the mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with petroleum ether/ethyl acetate (10:1–2:1) to obtain the pure product.3-Benzyl-2-(4-chlorophenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (4a): Yield: 62%; white solid; m.p. 157–159 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (d, J = 8.1 Hz, 2 H), 7.30–7.19 (m, 4 H), 6.94 (t, J = 2.4 Hz, 2 H), 5.23 (s, 2 H), 3.08 (t, J = 5.1 Hz, 2 H), 2.81 (t, J = 5.6 Hz, 2 H), 2.02–1.82 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃): δ = 161.37 (CON), 158.81, 154.72, 136.68, 136.38, 134.74, 133.46, 132.01, 129.74 (2×CH), 128.92 (2×CH), 128.82 (2×CH), 127.65, 126.80 (2×CH),121.52, 48.49 (CH₂Ph), 25 .78 (CH₂), 25.48 (CH₂), 23.09 (CH₂₎, 22.42 (CH₂). HRMS: m/z [M+H]⁺ calcd for C₂₃H₂₀ClN₂OS: 407.09849; found: 407.09697.2-(4-Fluorophenyl)-3-(4-hydroxyphenethyl)-3,5,6,8-tetrahydro-4H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one (4w): Yield: 62%; white solid; m.p.247–249 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.23 (s, 1 H), 7.62–7.50 (m, 2 H), 7.42–7.30 (m, 2 H), 6.71–6.55 (m, 4 H), 4.78 (s, 2 H), 4.02–3.88 (m, 4 H), 3.03 (t, J = 4.5 Hz, 2 H), 2.69 (t, J = 7.6 Hz, 2 H); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.80 (CF), 161.34, 161.28, 157.59 (NCO), 155.99 (CPhOH), 155.11, 131.40, 130.83, 130.63/ 130.54, 129.27 (2×CH), 128.47, 127.76, 120.17, 115.48/115.27, 115.29 (2×CH), 64.36 (CH₂), 63.94 (CH₂), 46.99 (CH₂N), 32.92 (CH₂Ph), 26.02 (CH₂); HRMS: m/z [M+H]⁺ calcd for C₂₃H₂₀FN₂O₃S: 423.11787; found: 423.11631.
• 21 CCDC 1813089 contains the supplementary crystallographic data for compound 4w. The data can be obtained free of charge from www.ccdc.cam.ac.uk/getstructures