Synthesis, transformations and biological activity of chloro enamines and ynamines derived from chloroalkenyl- and alkynyl-N-substituted purine and pyrimidine bases of nucleic acids

Abstract

Reactions of nucleic acid bases and related heterocycles 1–5, 18 and 22 with tetra-, tri- and dichloroethylenes 6–9 in hexamethylphosphoric triamide gave the corresponding N-trichloro-, -dichloro- and -chloro- enamines 11–17, 19, 20, 23 and 24 in high regioselectivity (N9 for purines and N1 for pyrimidines). Bases 1, 5, 18, 22 and trichloroethylene 7 gave the respective E-dichloro enamines 15, 16, 20 and 24. Compounds 16 and 20 were identical with the products obtained by addition of bases 1 and 18 to dichloroacetylene. Thymine 18 and compound 7 gave N1,N3-bisdichloro enamine 21 as the major product. The latter exists at room temperature as a mixture of rotamers 28 and 29(ΔG‡≅ 18 kcal mol–1). The reaction of adenine 1 with (Z)-1,2- or 1,1-dichloroethylene 8 or 9 furnished Z-chloro enamine 17 whereas thymine 18 and tetrachloroethylene 6 in dimethyl sulfoxide afforded a reduction product 20. Benzoylation of N9-(trichlorovinyl)adenine 11 gave N6,N6-dibenzoyl derivative 26. The reaction of N1-(dichlorovinyl)cytosine 24 with N,N-dimethylformamide dimethyl acetal afforded amidine 25. Interaction of (E)-N9-(dichlorovinyl)adenine 16 with sodium methoxide gave exclusively E-enamine 27. Trichloro enamines 11–14, 19, 23 and 26 were transformed to ynamines 30–35. Hydrogenation of compounds 30 and 35 furnished N9-ethyladenine 36 and N1-ethylthymine 37. Alkylation of ynamine 30 with acetone 38 gave only carbinol 41 whereas cyclohexanone 39 gave both compound 42 and cyclic ketal 43. The reaction of ynamines 30 and 35 with ketone 40 afforded only ketals 44 and 45. The reaction of compound 30 with N,N-dimethylformamide dimethyl acetal led to N-dimethylaminomethylene derivative 46. Ynamine 30 is a substrate for adenosine deaminase.