A Facile Microwave Induced One-Pot Synthesis of Novel Pyrimido[4,5-d]pyrimidines and Pyrido[2,3-d]pyrimidines under Solvent-Free Conditions

Abstract

Electron rich 6-[(dimethylamino)methylene]aminouracil 1, undergoes [4+2] cycloaddition reactions with various electron deficient substrates to give pyrimido[4,5-d]pyrimidines and pyrido[2,3-d]pyrimidines, after elimination of dimethylamine from the (1:1) cycloadducts and oxidative aromatisation. The reaction gives excellent yields when carried out under microwave irradiation under solvent-free conditions.

Key words

N-sulfonylimines - pyrido[2,3-d]pyrimidines - pyrimido[4,5-d]pyrimidines - quinones - coumarins

References

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19

Typical Reaction under Thermal Conditions: To a solution of 6-[(dimethylamino)methylene]amino-1,3-dimethyl uracil (1; 0.210 g, 1 mmol) in dry DMF (15 mL), sulfonylimine 2a (Ar¹ = p-ClC₆H₄, Ar² = p-MeC₆H₄, 0.298 g, 1 mmol) was added and the resulting mixture allowed to reflux for 4 h (monitored by TLC). After completion of the reaction, the DMF was distilled off from the reaction mixture under reduced pressure. The crude product was extracted with EtOAc (2 × 20 mL), washed with H₂O and the combined organic phases were dried over anhyd Na₂SO₄ and subjected to column chromatography to afford the corresponding pyrimido[4,5-d]pyrimidine 3a in 70% yield, mp 199-200 °C, recrystallised from EtOAc-petroleum ether (40-60 °C) (1:3).
Typical Reaction under Microwave Irradiations: Equi-molar quantities of 6[(dimethylamino)methylene]amino-1,3-dimethyl uracil (1; 0.210 g, 1 mmol), and sulfonylimine 2a (0.298 g, 1 mmol) were mixed together in the reaction vessel of the microwave reactor (Synthwave 402 Monomod Reactor from Prolabo) and allowed to react under micro-wave irradiation at 60% power for 4.5 min. The temperature was not allowed to increase above 110 °C. The automatic mode stirrer helps in mixing and uniform heating of the reactants. After completion (monitored by TLC), the reaction vessel was cooled to r.t. and the crude product was extracted with EtOAc (3 × 20 mL) and washed with H₂O. The combined organic phases were dried over anhyd Na₂SO₄ and subjected to column chromatography to afford the corresponding pyrimido[4,5-d]pyrimidine, mp 199-200 °C in 98% yield. Analytical data of 3a (whitish solid): IR (KBr): 1698, 1645 (C=O), 1610 (C=N), 1168 cm^-1 (S=O). ¹H NMR (CDCl₃): δ = 8.82 (s, 1 H, CH=N-), 7.51-7.90 (m, 6 H, ArH), 7.36 (d, 2 H, ArH), 6.23 (s, 1 H, H-5), 3.48 (s, 3 H, NCH₃), 3.20 (s, 3 H, NCH₃), 2.46 (s, 3 H, CH₃). ¹³C NMR: δ = 21.00, 27.02, 29.01, 58.55, 90.86, 121.62, 124.22, 126.32, 128.51, 128.68, 140.96, 147.88, 150.98, 151.96, 161.21. MS: m/z = 458 (M⁺). Anal. Calcd for C₂₁H₁₉N₄O₄S: C, 55.02; H, 4.14; N, 12.22%. Found: C, 55.11; H, 4.22; N, 12.32%. Similarly, pyrimido[4,5-d]pyrimidines 3b-h were prepared and characterised.

20

Typical Procedure under Thermal Conditions: To a solution of 6-[(dimethylamino)methylene]amino-1,3-dimethyluracil (1; 0.210 g, 1 mmol) in nitrobenzene (10 mL) was added coumarin 7a (0.146 g, 1 mmol) and the mixture was allowed to reflux for 5 h (monitored by TLC). After completion of the reaction, nitrobenzene was distilled off from the reaction mixture under reduced pressure. Then it was extracted with CHCl₃ (2 × 20 mL) and washed with H₂O. The organic layer was dried over anhyd Na₂SO₄ and then subjected to column chromatography to give the pure product 8a in 80% yield. Similarly pyrido[2,3-d]pyrimidines 8b-c and 6a-c were prepared and characterised.
Reactions under Microwave Irradiations: Equimolar quantities of 6[(dimethylamino)methylene]amino-1,3-dimethyl uracil (1; 0.210 g, 1 mmol) and coumarin 7a (0.146 g, 1 mmol) were added in the reaction vessel of the micro-wave reactor (Synthwave 402 Monomode Reactor from Prolabo) and allowed to react under microwave irradiation at 80% power and 130 °C for 6 min. The automatic mode stirrer helps in mixing and uniform heating of the reactants. The reaction vessel was cooled to r.t. and the solid compound obtained was recrystallised from EtOAc-petroleum ether (40-60)(1:4) to give pyrido[2,3-d]pyrimidine 8a in 92% yield. Analytical data of 8a: mp 246-247 °C. IR (KBr): 1744, 1710, 1705, 1675, 1607 1593, 1547 cm^-1. ¹H NMR (CDCl₃): δ = 8.89 (s, 1 H, CH=N-), 7.11-7.63 (m, 4 H, ArH), 3.60 (s, 3 H, NCH₃), 3.32 (s, 3 H, NCH₃). MS: m/z = 309 (M⁺). Anal. Calcd for C₁₆H₁₁N₃O₄: C, 62.13; H, 3.55; N, 13.59%. Found: C, 62.03; H, 3.58; N, 13.73%. Analytical data of 8b (yellow solid): MS: m/z 323 (M⁺). ¹H NMR (CDCl₃): δ = 8.96 (s, 1 H, -CH=N), 7.06-7.68 (m, 3 H, ArH), 3.30 (s, 3 H, NCH₃), 3.82 (s, 3 H, NCH₃). Anal. Calcd for C₁₇H₁₃N₃O₄: C, 63.15; H, 4.02; N, 13.00%. Found: C, 63.05; H, 4.10; N, 12.85%. Analytical data of 8c (yellowish solid): MS: m/z = 354 (M⁺). ¹H NMR (CDCl₃): δ = 8.90 (s, 1 H, -CH=N), 7.10-7.76 (m, 3 H, ArH), 3.32 (s, 3 H, NCH₃), 3.78 (s, 3 H, NCH₃). Anal. Calcd for C₁₆H₁₀N₄O₆: C, 54.23; H, 2.82; N, 15.81%. Found: C, 54.06; H, 2.88; N, 15.94%. Analytical data of 6a (decomposed): IR (KBr): 1717, 1666, 1659, 1595 cm^-1. ¹H NMR (CDCl₃): δ = 9.02 (s, 1 H, -CH=N), 7.34-7.92 (d, 2 H), 3.75 (s, 3 H, NCH₃), 3.35 (s, 3 H, NCH₃). MS: m/z = 271 (M⁺). Anal. Calcd for C₁₃H₉N₃O₄: C, 57.56; H, 3.32; N, 15.49%. Found: C, 57.45; H, 3.27; N, 15.40%. Analytical data of 6b: MS: m/z = 285 (M⁺). ¹H NMR (CDCl₃): δ = 8.98 (s, 1 H, -CH=N), 7.20 (s, 1 H, ArH), 3.80 (s, 3 H, NCH₃), 3.29 (s, 3 H, NCH₃). Anal. Calcd for C₁₄H₁₁N₃O₄: C, 58.94; H, 3.85; N, 14.74%. Found: C, 58.84; H, 3.96; N, 14.62%. Analytical data of 6c: MS: m/z = 321 (M⁺). ¹H NMR (CDCl₃): δ = 8.96 (s, 1 H, -CH=N), 7.22-7.67 (m, 4 H, ArH), 3.76 (s, 3 H, NCH₃), 3.34 (s, 3 H, NCH₃). MS: m/z = 271 (M⁺). Anal. Calcd for C₁₇H₁₁N₃O₄: C, 63.35; H, 3.42; N, 13.12%. Found: C, 63.45; H, 3.35; N, 13.00%.