Copper(I)-Catalyst-Free Approach for the Synthesis of Chromene-Fused Pyrido[3,2-d]pyrimidines by Lewis Acid Catalyzed Aza-Diels-Alder Reaction

Abstract

Pyrido[3,2-d]pyrimidine derivatives have been synthesized by the hetero-Diels-Alder reaction of 5-amino-1,3-dimethyl uracil and O-propargylated salicylaldehyde. The reaction requires only a single-step operation and provides potentially bioactive polycyclic heterocycles in high yields (71-82%) from easily available starting materials.

aza-hetero-Diels-Alder reaction - Lewis acid catalysis - Schiff base - Pyrido[3,2-d)]pyrimidine - 5-amino-1,3-dimethyl uracil

References and Notes

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27

Compound 4a A mixture of 5-amino-1,3-dimethyl uracil (3, 50 mg, 0.322 mmol) and O-propargyl salicylaldehyde (2a, 70 mg, 0.322 mmol) was stirred in toluene at r.t. for 10 min. After addition of 10 mol% BF₃˙OEt₂ (mol% calcd relative to the amine) the reaction mixture was refluxed for 4 h. After completion of the reaction as monitored by TLC the reaction mixture was cooled and diluted with sat. NaHCO₃ solution (50 mL). This was extracted with EtOAc (3 × 25 mL). The combined organic extract was washed with brine and dried over Na₂SO₄. The solvent was distilled off. The resulting crude product was purified by column chromatography over silica gel (60-120 mesh) using hexane-EtOAc mixture (1:4) as eluent to give the compound 4a. Yield 82%; colorless solid; mp above 290 ˚C. IR (KBr): ν_max = 1705, 1657, 1502, 1478 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.38 (s, 9 H), 3.55 (s, 3 H), 3.60 (s, 3 H), 5.27 (s, 2 H), 6.91 (d, J = 8.4 Hz, 1 H), 7.30 (s, 1 H), 7.39 (dd, J = 2.4, 8.4 Hz, 1 H), 8.38 (d, J = 2.4 Hz, 1 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): 29.0, 30.7, 31.4 (3 C), 67.7, 116.6, 116.7, 117.8, 121.0, 121.7, 129.2, 131.5, 132.7, 136.9, 145.4, 145.9, 150.1, 153.9 ppm. HRMS: m/z calcd for C₂₀H₂₁N₃O₃ [M + H]⁺: 352.1656; found: 352.1641;
Compound 4c
Yield 75%; colorless solid; mp above 290 ˚C. IR (KBr): ν_max = 1707, 1663, 1504, 1481 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.56 (s, 3 H), 3.63 (s, 3 H), 3.90 (s, 3 H), 5.26 (s, 2 H), 6.92 (d, J = 1.6 Hz, 2 H), 7.33 (s, 1 H), 7.89 (s, 1 H) ppm. MS: m/z = 325 [M⁺]. Anal. Calcd. for C₁₇H₁₅N₃O₄: C, 62.76; H, 4.65; N, 12.92. Found: C, 62.95; H, 4.61; N, 12.85.

28 Ramesh S. Gaddam V. Nagarajan R. Synlett  2010,  757