One-Pot Synthesis of Substituted Pyrimidine Derivatives from Acetylenedicarboxylate, Amine and Orthoformate

Abstract

Substituted pyrimidine derivatives with a disubstituted pattern are produced in a novel one-pot reaction from diethyl(methyl)acetylenedicarboxylate, amine, and trimethyl(ethyl)orthoformate under solvent-free conditions using ZnCl₂ catalyst.

Key words

solvent-free conditions - diethyl acetylenedicarboxylate - trimethyl orthoformate - pyrimidine

References and Notes

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14

General Procedure for Pyrimidine
To a stirred mixture of acetylenedicarboxylate 1 (2 mmol), amine 2 (4 mmol), and orthoformate 3 (2 mmol), ZnCl₂ (0.5 mol%) was added successively at r.t. with vigorous stirring for 1-3 h. The precipitated solid was purified with a mixture of EtOAc-hexane (20:80 v/v). The product was further purified by recrystallization from EtOAc and found to be pure as indicated by TLC, ^¹H NMR and ^¹³C NMR data. Compound 4b: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.09 (t, J = 6.9 Hz, 3 H), 3.77 (s, 6 H), 3.95 (s, 3 H), 4.13 (q, J = 7.6 Hz, 2 H), 5.29 (s, 1 H), 6.80-6.81 (m, 5 H), 6.88-6.90 (m, 4 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.2, 55.5, 59.8, 61.1, 62.0, 92.0, 114.3, 121.3, 123.4, 129.8, 133.6, 139.7, 149.5, 157.0, 164.4, 169.9. LCQ-MS (ESI): m/z (%) = 412. Anal. Calcd for C₂₂H₂₄N₂O₆: C, 64.07; H, 5.87; N, 6.79. Found: C, 64.19; H, 5.79; N, 6.91.
Compound 4h: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.15 (t, J = 6.8 Hz, 3 H), 3.73 (s, 3 H), 4.18 (q, J = 6.8 Hz, 2 H), 5.56 (s, 1 H), 6.62 (s, 1 H), 6.64 (s, 1 H), 7.22-7.24 (m, 3 H), 7.49-7.50 (m, 2 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.4, 31.0, 60.4, 62.4, 97.3, 116.2, 122.3, 126.6, 130.1, 130.6, 131.2, 132.3, 136.9, 142.1, 146.2, 163.6, 169.1. LCQ-MS (ESI): m/z = 578. Anal. Calcd for C₂₀H₁₆Br₂Cl₂N₂O₄: C, 41.48; H, 2.79; N, 4.84. Found: C, 41.57; H, 2.93; N, 4.72.
Compound 4i: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.13 (t, J = 6.9 Hz, 3 H), 2.19 (s, 6 H), 3.76 (s, 3 H), 4.11 (q, J = 6.8 Hz, 2 H), 5.61 (s, 1 H), 7.18 (s, 2 H), 7.33 (s, 3 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.4, 20.5, 60.1, 62.0, 92.4, 108.7, 121.9, 129.4, 132.2, 132.7, 135.7, 138.5, 139.6, 148.2, 162.6, 170.0. LCQ-MS (ESI): m/z = 696.1. Anal. Calcd for C₂₂H₂₀Br₄N₂O₄: C, 37.96; H, 2.90; N, 4.02. Found: C, 37.85; H, 3.00; N, 4.13. Compound 4p: ^¹H NMR (500 MHz, CDCl₃): δ = 0.85 (t, J = 7.6 Hz, 6 H), 0.95 (t, J = 7.6 Hz, 3 H), 1.52-1.67 (m, 4 H), 3.10 (t, J = 7 Hz, 2 H), 3.38 (t, J = 6.9 Hz, 2 H), 3.70 (s, 3 H), 4.06 (q, J = 6.8 Hz, 2 H), 5.52 (s, 1 H), 6.86 (s, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 11.3, 11.4, 11.5, 21.9, 22.1, 29.8, 39.2, 61.1, 62.0, 83.7, 129.1, 140.0, 167.7, 172.8. LCQ-MS (ESI): m/z = 284.2. Anal. Calcd for C₁₄H₂₄N₂O₄: C, 59.13; H, 8.51; N, 9.85. Found: C, 59.02; H, 8.48; N, 9.86.