A Novel Microwave-assisted One-pot Synthesis of Pyrano[2,3-d]pyrimidines and Pyrido[2,3-d]pyrimidines via a Three Component Reaction in Solvent-Free Condition

Abstract

Three-component cyclocondensation of barbituric acids 1, triethylorthoformate 2 and alkyl nitriles 3 in presence of acetic anhydride proceeds under microwave-assisted conditions to give pyrano[2,3-d]pyrimidines 4 in excellent yields. 6-Aminouracils 5 or 6-hydroxy-aminouracils 7 react with 2 and 3 under identical conditions to yield pyrido[2,3-d]pyrimidines 6 or pyrido[2,3-d]pyrimidine oxides 8 in high yields.

solvent-free reaction - multicomponent reaction - ­microwave-assisted reaction - pyrano[2,3-d]pyrimidines - pyrido[2,3-d]pyrimidines

References

1 Tanaka T. Toda F. Chem. Rev.  2000,  100:  1025 

2a Weber L. Illegen K. Almstetter M. Synlett  1999,  366 

2b Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Rev.  1996,  29:  123 

3 Strecker A. Liebigs. Ann. Chem.  1850,  75:  27 

4 Robinson R. J. Chem. Soc.  1917,  111:  876 

5 Hantzsch A. Justus. Liebig. Ann. Chem.  1882,  215:  1 

6a Dossin R. Marcos CF. Marcaccini S. Pepino R. Tetrahedron Lett.  1997,  38:  2519 

6b Kobayashi K. Matoba T. Susuima I. Takabi M. Morikawa O. Konishi H. Chem. Lett.  1998,  551 ; and references cited therein

7a Yamada T. Omote Y. Yammaka Y. Miyazawa T. Kuwata S. Synthesis  1998,  991 

7b Ross GF. Handtweek E. Ugi I. Tetrahedron  2002,  58:  6127 ; and references cited therein

8 Arend M. Westermann B. Risch N. Angew. Chem. Int. Ed.  1998,  37:  1045 

9a Shestopalov AM. Emeliyanova YM. Shestiopolov AA. Rodinovskaya LA. Niazimbetova ZI. Evans DH. Org. Lett.  2002,  423 

9b List B. Castello C. Synlett  2001,  1687 

9c Nair V. Vinod AU. Rajesh C. J. Org. Chem.  2001,  66:  4427 

9d Bagley MC. Cale JW. Bower J. Chem. Commun.  2002,  1682 

9e Cheng JF. Chen M. Arthenius T. Nadzen A. Tetrahedron Lett.  2002,  43:  6293 

9f Huma HZS. Halder R. Kalra SS. Das J. Iqbal J. Tetrahedron Lett.  2002,  43:  6485 

9g Bertozzi F. Gustafsson M. Olsson R. Org. Lett.  2002,  4:  3147 

9h Yuan Y. Li X. Ding K. Org. Lett.  2002,  4:  3309 

9i Bora U. Saikia A. Boruah RC. Org. Lett.  2003,  5:  435 

9j Dallinger D. Gorobets NY. Kappe CO. Org. Lett.  2003,  5:  1205 

10a Pourashraf M. Delair P. Rasmaissen MO. Greene AE. J. Org. Chem.  2000,  65:  6966 

10b Cossy J. Willis C. Bellosta V. Jalmes LS. Synthesis  2002,  951 

11a Gavrilov MY. Novoseleva GN. Vakhrin MI. Konshin ME. Khim.-Farm. Zh.  1996,  30:  39 

11b Ghorab MM. Hassan AY. Phosphorus, Sulfur Silicon Relat. Elem.  1998,  141:  257 

12a Anderson GL. Shim JL. Broom AD. J. Org. Chem.  1976,  41:  1095 

12b Grivaky EM. Lee S. Siyal CW. Duch DS. Nichol CA. J. Med. Chem.  1980,  23:  327 

13a Furuya S, and Ohtaki T. inventors; Eur. Pat. Appl., EP.  608565.  ; Chem. Abstr., 1994, 121, 205395

13b Heber D. Heers C. Ravens U. Pharmazie  1993,  48:  537 

14 Sakuma Y, Hasegawa M, Kataoka K, Hoshina K, Yamazaki N, Kadota T, and Yamaguchi H. inventors; PCT Int. Appl., WO  9105785.  ; Chem. Abstr., 1991, 115, 71646

15 Bennett LR. Blankely CJ. Fleming RW. Smith RD. Tessonam DK. J. Med. Chem.  1981,  24:  382 

16 Davoll J. Clarke J. Eislager EF. J. Med. Chem.  1972,  15:  837 

17a Kretzschmer E. Pharmazie  1980,  35:  253 

17b Shigo S. Hiroshi I. Yakugaku Zasshi  1969,  89:  266 

18 Ahluwalia VK. Batla R. Khurana A. Kumar R. Indian J. Chem., Sect. B  1990,  29:  1141 

19a Cheng T. Wang Y. Cai M. Youji. Huaxue.  1988,  8:  250 

19b Spada MR. Klein RS. Otter BA. J. Heterocycl. Chem.  1989,  26:  1851 

19c Ahluwalia VK. Kumar R. Khurana K. Bhatla R. Tetrahedron  1990,  46:  3963 

19d Ahluwalia VK. Bhatla R. Khurana A. Kumar R. Indian J. Chem., Sect B  1990,  29:  1141 

19e Ahluwalia VK. Sharma HR. Tyagi R. Tetrahedron  1986,  42:  4045 

19f Ahluwalia VK. Aggarwal R. Alauddin M. Gill G. Khanduri CH. Heterocycle  1990,  31:  129 

19g Broom AD. Shim JL. Anderson CL. J. Org. Chem.  1976,  411:  1095 

19h Wamhoff H. Muhr J. Synthesis  1988,  919 

19i Hirota K. Kuki H. Maki Y. Heterocycles  1994,  37:  563 

19j Srivastava P. Saxena AS. Ram VJ. Synthesis  2000,  541 

20a Bhuyan PJ. Lekhok KC. Sandhu JS. Tetrahedron Lett.  1999,  40:  1793 

20b Bhuyan PJ. Borah HN. Lekhok KC. Sandhu JS. J. Heterocycl. Chem.  2001,  38:  491 

20c Bhuyan PJ. Borah HN. Sandhu JS. Tetrahedron Lett.  2002,  43:  895 

21

In a typical experimental procedure equimolar amounts of 1a (0.312 g, 2 mmol), triethylorthoformate 2 (0.296 g, 2 mmol), malononitrile 3a (0.132 g, 2 mmol) and acetic anhydride (0.648 g, 6 mmol) were added to the reaction vessel of the microwave reactor (Synthewave 402 Monomode Reactor from Prolabo) and allowed to react under microwave irradiation at 360 W and 75 °C for 5 min. The mixture was cooled to r.t. and the solid compound obtained was recrystallised from EtOH (0.392 g, 85%). The compound was confirmed as 4a from the spectroscopic data and elemental analysis. Mp 215 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.00 (s, 3 H), 3.15 (s, 3 H), 8.10 (s, 1 H), 8.85 (s, 1 H). ¹³C NMR (300 MHz, CDCl₃): δ = 28.3 (3-Me), 36.6 (1-Me), 106.4 (C-4a), 118.8 (CN), 142.6 (C-7), 145.02 (C-6), 147.75 (C-5), 151.2 (C-2), 154.12 (C-8a), 158.0 (C-4). IR: 2217, 1695, 1650 cm^-1. MS: 232 [M⁺]. Anal. Calcd for C₁₀H₈N₄O₃: C, 51.72; H, 3.44; N, 24.13. Found: C, 51.75; H, 3.40; N, 24.15. Similarly compounds 4b-d, were synthesised (Table [1] ) and characterised.

22

In a simple experimental procedure equimolar amounts of 5a (0.340 g, 2 mmol), triethylorthoformate 2 (0.296 g, 2 mmol), malononitrile 3a (0.132 g, 2 mmol) and acetic anhydride (0.648 g, 6 mmol) were allowed to react under microwave irradiation at 360 W and 75 °C for 2 min in a monomode microwave reactor. The mixture was cooled to r.t. and the solid compound obtained was recrystallised from EtOH (0.438g, 95%). The compound was confirmed as 6a from the spectroscopic data and elemental analysis. Mp 350-352 °C (lit. 352-353 °C). ¹H NMR (300 MHz, CDCl₃): δ = 3.00 (s, 3 H), 3.15 (s, 3 H), 7.75 (br s, 2 H), 8.40 (s, 1 H). IR: 3250, 2213, 1690, 1655 cm^-1 _. MS: 231 [M⁺]. Anal. Calcd for C₁₀H₉N₅O₂: C, 51.94; H, 3.89; N, 30.30. Found: C, 52.00; H, 3.95; N, 30.25. Similarly compounds 6b-d were synthesised (Table [1] ) and characterised.

23 Hirota K. Kitade Y. Senda S. J. Heterocycl. Chem.  1985,  22:  345 

24

In a typical experimental procedure equimolar amounts of 7a (0.342 g, 2 mmol), triethylorthoformate 2 (0.296 g, 2 mmol), malononitrile 3a (0.132 g, 2 mmol) and acetic anhydride (0.648 g, 6 mmol) were allowed to react under microwave irradiation at 360 W and 75 °C for 8 min in a monomode microwave reactor. The mixture was cooled to r.t. and the solid compound obtained was recrystallised from EtOH (0.321 g, 65%). The compound was confirmed as 8a from the spectroscopic data and elemental analysis. Mp 218 °C (lit. 218 °C). ¹H NMR (300 MHz, CDCl₃): δ = 3.00 (s, 3 H), 3.15 (s, 3 H), 7.85 (br s, 2 H), 8.15 (s, 1 H). ^{1 3}C NMR (300 MHz, CDCl₃): δ = 28.5 (3-Me), 36.8 (1-Me), 107.25 (C-4a), 118.75 (CN), 143.5 (C-7), 145.5 (C-6), 146.55 (C-5), 151.25 (C-2), 154.25 (C-8a), 158.0 (C-4). IR: 3255, 2216, 1715, 1642, 1625 cm^-1. MS: 247 [M⁺]. Anal. Calcd for C₁₀H₉N₅O₃: C, 48.58, H, 3.64, N, 28.34. Found: C, 48.50, H, 3.70, N, 28.40. Similarly compounds 8b-d were synthesised (Table [1] ) and characterised.

25 Bhuyan PJ. Borah HN. Boruah RC. Tetrahedron Lett.  2003,  44:  1847