Synthesis of Functionalized Dihydropyrido[2,3-d]pyrimidines in Aqueous Medium

Dedicated to Prof. Dr. Uli Kazmaier on the occasion of his birthday

Abstract

Synthesis of functionalized 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one from a cascade reaction between 3-formylchromone, malononitrile, diammonium hydrogen phosphate, and aromatic aldehydes in aqueous media is described.

Keywords

2-aminopyridine - dihydropyrido[2,3-d]pyrimidine - aqueous medium

• References and Notes

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• 19 General Procedure for the Synthesis of Functionalized 2-Aminopyridines 4a–c:To a solution of 3-formylchromone (1 mmol, 174 mg) and malononitrile (1 mmol, 66 mg) in water (10 mL) was added diammonium hydrogen phosphate (926 mg, 20% equiv) and the reaction mixture was stirred at room temperature for 30 min. After formation of the desired chromonyl malononitrile (monitoring by TLC, eluent: n-hexane/EtOAc, 3:1). The reaction mixture was stirred at 50 °C for 3 h. The precipitate was filtered and was washed with water and ethanol.2-Amino-5-(2-hydroxybenzoyl)nicotinonitrile (4a)Yield: 222 mg (93%); yellow powder; m.p. 198–200 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 6.90–6.97 (m, 2 H, H-Ar), 7.33 (d, J = 7.5 Hz, 1 H, H-Ar), 7.38–7.43 (m, 1 H, H-Ar), 7.81 (br. s, 2 H, N-H), 8.11 (d, J = 2.4 Hz, 1 H, H-Py), 8.47 (d, J = 2.4 Hz, 1 H, H-Py), 10.25 (br. s, 1 H, -OH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 88.9, 116.1, 116.6, 119.3, 121.8, 124.7, 130.1, 133.0, 143.9, 155.6, 156.0, 161.3, 192.1. HRMS (EI): m/z calcd. for C₁₃H₉N₃O₂ [M]⁺ 239.0675; found: 239.0675.Colorless crystal (lamina); dimensions 0.150 × 0.120 × 0.010 mm³; crystal system triclinic; space group P1; Z=2; a=3.7932(9) Å, b=8.0333(19) Å, c=19.135(5) Å, α = 79.772(6)°, β = 89.384(6)°, γ = 79.103(6)°; V=563.3(2) ų; ρ = 1.410 g/cm³; T = 200(2) K; θ _max= 27.514°; radiation Mo Kα, λ = 0.71073 Å; 0.5° ω-scans with a CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 2.20 and a completeness of 85.6% to a resolution of 0.77 Å, 4556 reflections measured, 2073 unique (R(int)=0.0453), 1868 observed (I > 2σ(I)). Intensities were corrected for Lorentz and polarization effects, an empirical absorption correction was applied using SADABS based on the Laue symmetry of the reciprocal space, μ=0.10mm^–1, T _min=0.55, T _max=0.96. The structure was refined against F² with a full-matrix least-squares algorithm using the SHELXL-2014/7 (Sheldrick, 2014) software, 168 parameters were refined, hydrogen atoms were treated using appropriate riding models, except H12 of the hydroxy group, which was refined isotropically. Goodness of fit 1.12 for observed reflections, final residual values R1(F) = 0.049, wR(F²)=0.130 for observed reflections, residual electron density –0.27 to 0.24 eÅ^–3.²¹ CCDC 1496174 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif²¹
• 20 General Procedure for the Synthesis of Functionalized 2,3-Dihydropyrido[2,3-d]pyrimidin-4(1H)-one 6a–o:A mixture of functionalized 2-amino-pyridine 4a–c (1 mmol), aromatic aldehyde 5a–l (1.2 mmol), and potassium phosphate (1.5 mmol, 340 mg) in water (10 mL) was heated for 7 h at 100 °C. The precipitate was washed with water and ethanol. 2-(4-Chlorophenyl)-6-(2-hydroxybenzoyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (6a):Yellow solid; m.p. 290–293 °C^.IR: 3183, 3075, 1681, 1600 cm^–1; ¹H NMR (300 MHz, DMSO-d ₆): δ = 6.00 (s, CH, 1 H), 6.95 (t, J = 7.2 Hz, 2 H, Ar-H), 7.30–7.45 (m, 6 H, Ar-H), 8.14 (s, 1 H, Py-H), 8.53 (s, 1 H, Py-H), 8.80 (s, 1 H, NH), 8.99 (br. s, 1 H, NH), 10.23 (br. s, 1 H, OH). ¹³C NMR (75 MHz, DMSO-d₆ ): δ = 64.6, 107.6, 116.5, 119.1, 123.6, 125.4, 128.2, 128.6, 129.7, 132.6, 133.2, 137.1, 140.7, 155.4, 155.9, 158.9, 161.7, 193.4. HRMS (ESI): m/z [M–H]^– calcd. for C₂₀H₁₃ ³⁵ClN₃O₃: 378.066563; found: 378.06552.6-(2-Hydroxybenzoyl)-2-(4-nitrophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (6d):Yellow solid; m.p. 265–268 °C. IR: 3419, 3183, 1688 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 6.14 (s, CH, 1 H), 6.94–6.95 (t, J = 7.2 Hz, 1 H, Ar-H), 7.29–7.39 (m, 1 H, Ar-H), 7.69 (d, J = 7.0 Hz, 1 H, Ar-H), 8.08–8.27 (m, 4 H, Ar-H), 8.45–8.46 (d, J = 7.0 Hz, 1 H, Ar-H), 8.54 (s, 1 H, Py-H), 8.96 (s, 1 H, Py-H), 9.13 (s, 1 H, NH), 10.05 (s, 1 H, NH), 10.14 (s, 1 H, OH). ¹³C NMR (75 MHz, DMSO-d₆ ): δ = 64.4, 116.5, 119.3, 123.2, 124.0, 125.4, 127.6, 130.2, 130.5, 136.1, 138.5, 147.5, 148.8, 150.8, 155.7, 161.7, 192.3. HRMS (ESI): m/z [M–H]^– calcd. for C₂₀H₁₃N₄O₅: 389.08906; found: 389.08908
• 21a Program SADABS 2012/1 for absorption correction; Sheldrick, G. M.; Bruker Analytical X-ray-Division, Madison, Wisconsin, 2012.
• 21b Program SHELXL-2014/7; Sheldrick, G. M, 2014; for structure refinement; Acta. Cryst. 2015, C71, 3-8.