A Green Approach to the Synthesis of Fused Uracils: Pyrano[2,3-d]pyrimidines. ‘On-Water’ One-Pot Synthesis by Domino Knoevenagel/Diels-Alder Reactions

Abstract

‘On-water’ Knoevenagel condensations of 2-thiobarbituric acid and N,N-dimethylbarbituric acid with aromatic and heteroaromatic aldehydes were carried out without a catalyst and at room temperature. Condensations in aqueous suspensions occurred rapidly, giving excellent yields. Solvent-free hetero-Diels-Alder reactions of 5-arylidene derivatives of barbituric acids with ethyl vinyl ether were investigated at room temperature and pyrano[2,3-d]pyrimidines of potential pharmacological activity were obtained in excellent yields. Three-component one-pot syntheses of annulated uracils were performed in aqueous suspensions. Reactions of barbituric acids, aldehydes, and ethyl vinyl ether were carried out at ambient temperature, whereas the one-pot synthesis with barbituric acids, aldehydes, and styrene or N-vinyl-2-oxazolidinone required the heating of aqueous suspensions at 60 ˚C. ‘On-water’ cycloadditions were characterized by high diastereoselectivity in contrast to reactions carried out in homogeneous organic media (dichloromethane, toluene). They allowed the cis adducts to be obtained preferentially or exclusively. The presented green methods avoid the use of catalysts, the heating of reaction mixtures for long times at high temperatures, and the use of organic solvents, and make the synthesis of a variety of pyrano[2,3-d]pyrimidines chemically efficient. The results reveal water as the medium of choice for the examined cycloadditions.

Key words

Diels-Alder reactions - drugs - green chemistry - pyrano[2,3-d]pyrimidines - solvent effects

References

• 1a Rideout DS. Breslow R. J. Am. Chem. Soc.  1980,  102:  7816 
• 1b Narayan S. Muldoon JM. Finn GV. Fokin V. Kolb HC. Sharpless KB. Angew. Chem. Int. Ed.  2005,  44:  3275 
• 2 Jovanovic MV. Biel ER. J. Org. Chem.  1987,  24:  191 
• 3 Haldar MK. Scott MD. Sule N. Srivastava DK. Mallik S. Bioorg. Med. Chem. Lett.  2008,  18:  2373 
• 4 Kitamura N, and Onishi A. inventors; EP  163599.  ; Chem. Abstr. 1984, 104, 186439
• 5 Furuja S, and Ohtaki T. inventors; EP Application  608565.  ; Chem. Abstr. 1994, 121, 205395
• 6 Heber D. Heers C. Ravens U. Pharmazie  1993,  48:  537 
• 7 Coates W. inventors; EP  351058.  ; Chem. Abstr. 1990, 113, 40711
• 8 Sakuma Y, Hasegawa M, Kataoka K, Hoshina K, Yamazaki N, Kadota T, and Yamaguchi H. inventors; WO Application  9105785.  ; Chem. Abstr. 1989, 115, 71646
• 9 Anderson GL. Shim JL. Broom AD. J. Org. Chem.  1976,  41:  1095 
• 10a Ahluvalia VK. Sharma HR. Tyagi R. Tetrahedron  1986,  42:  4045 
• 10b Wamhoff H. Muhr J. Synthesis  1988,  919 
• 10c Ahluwalia VK. Kumar R. Khurana K. Batla R. Tetrahedron  1990,  46:  3953 
• 10d Hirota K. Kuki H. Maki Y. Heterocycles  1994,  37:  563 
• 10e Srivastava P. Saxena AS. Ram VJ. Synthesis  2000,  541 
• 11 Devi I. Kumar BSD. Bhuyan PJ. Tetrahedron Lett.  2003,  44:  8307 
• 12 Devi I. Bhuyan PJ. Tetrahedron Lett.  2004,  45:  7727 
• 13 Devi I. Borah HN. Bhuyan PJ. Tetrahedron Lett.  2004,  45:  2405 
• 14 Naya S. Miyagawa M. Nitta M. Tetrahedron  2005,  61:  4919 
• 15a Brufola G. Fringuelli F. Piermatti O. Pizzo F. Heterocycles  1997,  45:  1715 
• 15b Binev IG. Binev YG. Stamboliyska BA. Juchnovski IN. J. Mol. Struct.  1997,  435:  235 
• 15c Ayoubi SA. Texier-Boullet F. Hamelin J. Synthesis  1994,  258 
• 16 Jursic BS. Stevens ED. Tetrahedron Lett.  2003,  44:  2203 
• 17 Deb ML. Bhuyan PJ. Tetrahedron Lett.  2005,  46:  6453 
• 18 Paasz A. Monatsh. Chem.  2008,  139:  1397 
• 19 Bushweller CH. O’Neil JW. Tetrahedron Lett.  1969,  4713 
• 20 Sankararaman S. Pericyclic Reactions - A Textbook   Wiley-VCH; Weinheim: 2005. 
• 21a Tietze LF. Meier H. Nutt H. Chem. Ber.  1989,  122:  643 
• 21b Tietze LF. Stegelmeier H. Harms K. Brumby T. Angew. Chem., Int. Ed. Engl.  1982,  21:  863 
• 21c Tietze LF. Brumby T. Brand S. Bratz M. Chem. Ber.  1988,  121:  499 
• 21d Tietze LF. Bachmann J. Wichmann J. Burkhardt O. Synthesis  1994,  1185 
• 21e Tietze LF. Brand S. Pfeiffer T. Antel JJ. Harms K. Sheldrick GM. J. Am. Chem. Soc.  1987,  109:  921 
• 21f Tietze LF. Chem. Rev.  1996,  96:  115 
• 21g Tietze LF. Brasche G. Gericke KM. Domino Reactions in Organic Synthesis   Wiley-VCH; Weinheim: 2006. 
• 21h Tietze LF. Kettschau G. Top. Curr. Chem.  1997,  189:  1 
• 22 Bogdanowicz-Szwed K. Paasz A. Z. Naturforsch., B  2001,  56:  416 
• 23 Paasz A. Org. Biomol. Chem.  2005,  3:  3207 
• 24a Hu Y. Chen ZC. Le ZG. Zheng QG. Synth. Commun.  2004,  34:  4521 
• 24b Wang C. Ma J. Zhou X. Zang X. Wang Z. Gao Y. Cui P. Synth. Commun.  2005,  35:  2759 
• 24c Medien HAA. Zahran AA. Phosphorus, Sulfur Silicon Relat. Elem.  2003,  178:  1069 
• 24d Shi DQ. Chen J. Zhuang QY. Wang XS. Hu HW. Chin. Chem. Lett.  2003,  14:  1242 
• 24e Moskvin AV. Polkovnikova II. Ivin BA. Russ. J. Gen. Chem.  1998,  68:  801