Ultrasound-Mediated One-Pot Synthesis of 7-Methyl-Substituted Pyrido[4,3-d]pyrimidine Scaffolds by a Catalyst-Free Protocol

Abstract

A one-pot and catalyst-free protocol for the construction of 7-methyl-substituted pyrido[4,3-d]pyrimidine derivatives from ethanolic solution of 6-[2-(dimethylamino)prop-1-enyl]-1,3-dimethyluracil, ­aromatic aldehyde, and ammonium acetate is described under both ultrasound and thermal conditions. The ultrasound methodology is clean and the desired products are obtained with good yields in short time.

Key words

multicomponent reactions - aza-Diels–Alder - one-pot - pyrido[4,3-d]pyrimidine - ultrasound-assisted organic synthesis - green chemistry

• References and Notes

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• 6 Typical ProcedureA mixture of 6-[2-(dimethylamino)prop-1-enyl]-1,3-dimethyl­uracil (1b; 1 mmol), 4-fluorobenzaldehyde (2a; 1 mmol), and NH₄OAc (3a; 2 mmol) in EtOH (5 mL) was ultrasonicated for 30 min in a Cole-Parmer 130 watt ultrasonic processor (Model 04714-51) at 70% amplitude. After reaction, the solvent was removed under reduced pressure, the crude product dissolved in EtOAc and directly purified by column chromatography eluting with 2:1 EtOAc–hexane to obtain pure 5-(4-fluorophenyl)-1,3,7-trimethylpyrido[4,3-d]pyrimidine-2,4-dione (4a) as an off-white solid; mp 217–219 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.37–7.04 (m, 4 H, H_arom), 6.92 (s, 1 H, CH=CCH₃), 3.57 (s, 3 H, NCH₃), 3.30 (s, 3 H, NCH₃), 2.66 (s, 3 H, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 164.6, 162.2, 161.6, 160.1, 150.9, 148.0, 136.4, 130.4 (2 C), 114.9 (2 C), 106.9, 106.2, 31.1, 28.6, 25.2. MS (GC–MS): m/z = 299 [M]⁺. Anal. Calcd for C₁₆H₁₄FN₃O₂: C, 64.21; H, 4.71; N, 14.04; O, 10.69. Found: C, 64.20; H, 4.68; N, 14.00; O, 10.61.
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