Synlett 2004(7): 1179-1182  
DOI: 10.1055/s-2004-825601
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Mukut Gohaina, Dipak Prajapati*a, Baikuntha J. Gogoib, Jagir S. Sandhuc
a Department of Medicinal Chemistry, Regional Research Laboratory, JORHAT-785 006, Assam, India
b Defence Research Laboratory, P. Bag. No. 2, Tezpur-784 001, India
c Department of Chemistry, Panjabi University, Patiala-147 002, Punjab, India
Further Information

Publication History

Received 11 January 2004
Publication Date:
10 May 2004 (online)

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.

    References

  • 1 Melik-Ogandzhanyan RG. Khachatryan VE. Gapoyan AS. Russ. Chem. Rev.  1985,  54:  262 
  • 2 Figueroa-Villar JD. Carneiro CL. Cruz ER. Heterocycles  1992,  34:  891 
  • 3 Campaigne E. Ellis RL. Bradford M. Ho J. J. Med. Chem.  1996,  12:  339 
  • 4 Blume F, Arndt F, and Ress R. inventors; Ger. Patent  3712782.  1988 ; Chem. Abstr. 1989, 110, 154312e
  • 5a Lunt E. In Comprehensive Organic Chemistry   Vol 4:  Barton D. Ollis WD. Pergamon Press; Oxford: 1974.  p.493 
  • 5b Brown JD. In Comprehensive Heterocyclic Chemistry   Vol 3:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.57 
  • 5c Clercq ED. Beraaerts R. J. Biol. Chem.  1987,  262:  14905 
  • 6 Coates WJ. inventors; Eur. Pat.  351058.  1990; Chem. Abstr. 1990, 113, 40711
  • 7 Kitamura N, and Onishi A. inventors; Eur. Pat.  163599.  1984; Chem. Abstr. 1984, 104, 186439
  • 8 Raddatz P, and Bergmann R. inventors; Ger. Pat.  360731.  1988; Chem. Abstr. 1988, 109, 54786
  • 9 Delia TJ. Baumann M. Bunker A. Heterocycles  1993,  35:  1397 
  • 10a Hirota K. Kitade Y. Senda S. Halat MJ. Watanabe KA. Fox JJ. J. Org. Chem.  1981,  46:  846 
  • 10b Su TL. Huang JT. Burchanal JH. Watanabe KA. Fox JJ. J. Med. Chem.  1986,  29:  709 
  • 10c Prajapati D. Sandhu JS. Synthesis  1988,  342 
  • 11a Taylor EC. Sawinski F. J. Org. Chem.  1974,  39:  907 
  • 11b Wamhoff H. Winfried S. J. Org. Chem.  1986,  51:  2787 
  • 11c Hirota K. Benno K. Yamada Y. Senda S. J. Chem. Soc., Perkin Trans. 1  1985,  1137 
  • 11d Sasaki T. Minamoto T. Suzuki T. Suguira T. J. Am. Chem. Soc.  1978,  100:  2248 
  • 12 Billings BK. Wagner JA. Cook PD. Castle RN. J. Heterocycl. Chem.  1975,  12:  1221 
  • 13 Wamhoff H. Muhr J. Synthesis  1988,  919 
  • 14 Broom AD. Shim JL. Anderson CL. J. Org. Chem.  1976,  411:  1095 
  • 15a Walsh EB. Wamhoff H. Chem. Ber.  1989,  122:  1673 
  • 15b Walsh EB. Nai-Jue Z. Fang G. Wamhoff H. Tetrahedron Lett.  1988,  29:  4401 
  • 16 Hirota K. Kuki H. Maki Y. Heterocycles  1994,  37:  563 
  • 17a Perreux L. Loupy A. Tetrahedron  2001,  57:  9199 
  • 17b Lidstrom P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 
  • 17c Loupy A. Petit A. Hamelin J. Texier-Boullet F. Jacquault P. Mathe D. Synthesis  1998,  1213 
  • For the preparation of N-sulfonylimines see:
  • 18a Sisko J. Weinreb SM. J. Org. Chem.  1990,  55:  393 
  • 18b Davis FA. ThimmaReddy R. Weismiller MC. J. Am. Chem. Soc.  1989,  111:  5964 
  • 18c McKay WR. Proctor GR. J. Chem. Soc., Perkin Trans. 1  1981,  2435 
  • 21 Prasad AS. Sandhu JS. Baruah JN. J. Heterocycl. Chem.  1984,  21:  1657 
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%.