Synthesis of Fused Purine Heterocycles via a One-pot Cascade Reaction of a Trisubstituted Pyrimidine

^‡ These authors contributed equally.

Abstract

A rapid and expedient one-pot procedure for the synthesis of fused purine derivatives from a trisubstituted pyrimidine and various amines has been developed. The tandem substitution reaction and copper(I)-catalyzed annulation exhibited high efficiency. The fused heterocyclic products contain the purine scaffold and may be useful in medicinal chemistry and bioscience.

Key words

one-pot procedure - cascade reaction - fused purine heterocycles - copper(I) catalysis - trisubstituted pyrimidines

• References and Notes

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• 13 General Procedure for the Synthesis of 4a–q: K₂CO₃ (221.1 mg, 1.6 mmol) was added to a solution of 2-(((5-bromo-2-­chloropyrimidin-4-yl)amino)methyl)benzonitrile (1; 257.6 mg, 0.8 mmol) and the amine (2a–n, 0.88 mmol) in DMSO (20 mL) in a 50 mL round-bottom flask at 120 °C. The mixture was stirred for 6–8 h under an argon atmosphere. The complete consumption of benzonitrile 1 was determined by TLC. CuI (30.5 mg, 0.16 mmol) and l-proline (L3, 36.8 mg, 0.32 mmol) were added and the reaction mixture was stirred for another 8 h at 80 °C. After the reaction was complete, the mixture was diluted with saturated ammonium chloride solution (40 mL) and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layer was washed with saturated NaCl, the organic solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc/n-hexanes) to afford the corresponding product.
• 14 Characterization Data of representative compounds: Compound 4a: Yield: 86%; yellow amorphous solid; mp 198–200 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.62 (s, 1 H), 8.04 (m, 1 H), 7.57–7.59 (m, 3 H), 7.30–7.42 (m, 5 H), 6.35 (br. s, 1 H), 5.07 (s, 2 H), 4.75 (d, J = 5.7 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 159.44, 157.23, 153.37, 144.46, 143.76, 138.49, 132.41, 131.11, 129.26, 128.68, 127.74, 127.55, 127.43, 124.35, 122.71, 77.37, 77.05, 76.74, 46.61, 29.73. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₉H₁₆N₅: 314.1397; found: 314.1398. Compound 4d: Yield: 91%; yellow amorphous solid; mp 191–193 °C; ¹H NMR (400 MHz, CDCl₃): δ = 8.70 (m, 1 H), 8.01 (m, 1 H), 7.51–7.70 (3 H), 5.02 (s, 2 H), 3.63 (m, 4 H), 1.65 (m, 4 H), 1.25–1.42 (12 H), 0.90 (m, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 158.50, 152.42, 143.67, 131.07, 130.98, 130.26, 128.94, 128.87, 128.83, 124.15, 122.15, 48.33, 46.29, 31.77, 27.71, 26.74, 22.69, 14.14. HRMS (ESI): m/z [M+H]⁺ calcd for C₂₄H₃₄N₅: 392.1836; found: 392.1839. Compound 4p: Yield: 78%; yellow amorphous solid; mp 202–204 °C; ¹H NMR (400 MHz, CDCl₃): δ = 8.90 (s, 1 H), 8.12–8.14 (m, 1 H), 7.61–7.68 (m, 3 H), 5.18 (s, 2 H), 4.14 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 159.61, 155.05, 148.98, 143.83, 142.10, 130.93, 129.17, 124.34, 122.63, 55.34, 46.74. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₁₁N₄O: 239.0921; found: 239.0922.