Regioselective Syntheses of 2,7-(Het)Arylpyrido[2,3-d]pyrimidines by an Orthogonal Cross-Coupling Strategy

Abstract

An efficient and easy access to 2,7-disubstituted pyrido[2,3-d]pyrimidine derivatives is reported. These derivatives were obtained using two orthogonal palladium-catalyzed cross-coupling reactions via successive C-7 chlorine and C-2 methylsulfur releases.

Key words

cross-coupling - palladium - copper - alkylsulfur - regio­selectivity - pyridopyrimidine

• References and Notes

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• 7 General Procedure for the Preparation of Compounds 3a–j. 7-Chloro-2-methylsulfanylpyrido[2,3-d]pyrimidine⁵ (1, 0.5 mmol), boronic acid (1.1 equiv), and Na₂CO₃ (2.0 equiv) were dissolved in a mixture of toluene–EtOH (6:3 mL). After argon bubbled, Pd(PPh₃)₄ (0.05 equiv) was added, and the reaction mixture was refluxed for 18 h. The reaction mixture was then cooled to r.t., and the solvent was removed under reduced pressure. Desired compounds 3 were directly obtained after purification by flash silica gel chromatography (eluent PE–EtOAc, 8:2 to 1:1).7-(4-Methoxyphenyl)-2-methylsulfanylpyrido[2,3-d]pyrimidine (3a)Yield 73%; yellow solid; mp 163–165 °C. IR (ATR): 3051, 2929, 1584, 1512, 1462 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.73 (s, 3 H), 3.86 (s, 3 H), 6.99 (d, J = 8.0 Hz, 2 H), 7.84 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 8.0 Hz, 2 H), 9.06 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.7 (CH₃), 55.6 (CH₃), 114.4 (2 CH), 115.5 (Cq), 119.1 (CH), 130.1 (2 CH), 130.4 (Cq), 137.1 (CH), 158.9 (Cq), 160.4 (CH), 162.3 (Cq), 164.6 (Cq), 173.9 (Cq). HRMS (EI-MS): m/z calcd for C₁₅H₁₃N₃OS: 284.08558 [M + H⁺]; found: 284.08521.
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• 10 General Procedure for the Preparation of Compounds 4a–mIn a sealed tube and under argon, 7-aryl-2-methylsulfanylpyrido[2,3-d]pyrimidine 3 (0.3 mmol), boronic acid (2.2 equiv), and CuTC (2.2 equiv) were dissolved in dry DME (3 mL). Pd(PPh₃)₄ (0.05 equiv) was added, and the reaction mixture was stirred under microwave irradiation at 200 °C for 1 h. After cooling to r.t., the reaction mixture was poured into a sat. aq NaHCO₃ solution (20 mL) and the aqueous layer extracted with CH₂Cl₂ (3 × 20 mL). The combined organic phases were dried over MgSO₄, and the solvent was removed under reduced pressure. Desired compounds 4 were purified by flash silica gel chromatography (CH₂Cl₂–MeOH, 100:0 to 98:2).7-(4-Methoxyphenyl)-2-phenylpyrido[2,3-d]pyrimidine (4a)Yield 79%; white solid; mp 313–314 °C. IR (ATR): 3061, 2990, 2834, 1517, 1435 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.89 (s, 3 H), 7.03 (d, J = 8.8 Hz, 2 H), 7.50–7.54 (m, 3 H), 7.97 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 8.28 (d, J = 8.8 Hz, 2 H), 8.70–8.73 (m, 2 H), 9.42 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 55.6 (CH₃), 114.5 (2 CH), 117.0 (Cq), 120.2 (CH), 128.7 (2 CH), 129.4 (2 CH), 130.2 (2 CH), 130.6 (Cq), 131.4 (CH), 136.7 (CH), 137.6 (Cq), 159.3 (Cq), 161.2 (CH), 162.4 (Cq), 164.8 (Cq), 165.1 (Cq). HRMS (EI-MS): m/z calcd for C₂₀H₁₅N₃O: 314.1288 [M + H⁺]; found: 314.1292.
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