Facile Synthesis of Fluorinated Purines and Thiapurines

Abstract

The reaction of 2-(dialkylamino)-1,3-thiazol-4-amines and 1,2-dimethyl-1H-imidazol-5-amine with aryl isocyanates, achloroalkyl isocyanates, N-(alkoxycarbonyl)imidoyl chlorides and 2,4,6-tris(trifluoromethyl)-1,3,5-triazine leads to thiapurines and purines containing trifluoromethyl groups in the 2-and 6-positions of the pyrimidine ring.When biomolecules are modified with fluorine-containing functional groups, new physiologically active compounds are often the result. 1 In particular, fluoro analogues of nucleosides have remarkable antitumor, 2 antiviral 3 and antineoplastic 4 in vivo activities. Simpler (polyfluoroalkyl)purines 5-7 and their derivatives exhibit pronounced antiviral 5e,f,7a and phosphodiesterase inhibitory effects, 5c,8 while high antitumor activities have been discovered for 2-(trifluoromethyl)adenosine. 9Biological activities of 6-(fluoroalkyl)purines and their derivatives have not been studied in detail, primarily due to the lack of easy preparative procedures. 10 The recently discovered high cytostatic activity of some 6-(trifluoromethyl)purine ribosides 11a and the studies on adenosine A3 receptor antagonists 11b indicate that the trifluoromethyl group facilitates hydration at the 6-position of the purine ring, which might mimic the transition state for hydrolytic deamination of adenosine. 11c On the other hand, 6-(trifluoromethyl)purine-substituted RNAs are valuable mimetics for structural studies of RNA and binding studies of RNA-modifying enzymes, 11d such as RNA-editing adenosine deaminases.Thiazolo [4,5-d]pyrimidines, which are thia analogues of the purine ring system, have been widely utilised as starting materials for the synthesis of thiaadenosine analogues. 12 Various derivatives of 3-b-D-ribofuranosyl[1,3]thiazolo[4,5-d]pyrimidine are clinically used as immunomodulators, 13 inhibitors of HCV replication, 14 and antiviral 15 and antitumor agents. 16 Reactions of 1,3-CCN-bis-nucleophiles such as anilines and amino-substituted heterocycles with various 1,3-CNC-bis-electrophiles (functionalised isocyanates 17 and isothiocyanates, 18 N-acylated imidoyl chlorides, 19 imidates 20 and imines 21 ) have been recently employed in the synthesis of annulated pyrimidines.Retrosynthetic analysis revealed that purines and their thia analogues could be obtained by the reaction of 1,3-CNC-bis-electrophiles with 4(5)-aminoimidazoles and 4(5)-aminothiazoles, respectively. Herein we report a new method for the assembly of fluorine-containing purines and thiazolo[4,5-d]pyrimidines (7-thiapurines) using the reaction of 5-amino-1H-imidazoles 22 and 4-amino-1,3-thiazoles 23 with fluorine-containing 1,3-CNC-bis-electrophiles.It has been shown previously that the deprotonation of salts 1·HCl with bases gives bi-1,3-thiazoles 2 (Scheme 1). 23 In order to carry out acylation reactions, amines 1 were generated in the presence of isocyanates. The outcome of these acylations appeared to depend on the reaction conditions.In the presence of an excess of an aryl isocyanate in boiling pyridine, thiazolo[4,5-d]pyrimid...