Thiazolo purin-3 -ones

Of all the possible ways of fusing a purine ring onto a thiazole ring, only the syntheses of two, namely, thiazolo[2,3-y]purin-3(2//)-one (304) or thia-zolo[2,3- ]purin-3(2//)-one (305) and thiazolo[2,3-fe]purin-3(2H)-one (307, 311) have been reported. 

The third access was based on the reaction of 1,2-dibromoethane with 2-mercapto-purin-9-one or 2-mercaptoadenine and their derivatives. Preparation of compound 83 from potassium or sodium 2-mercaptoinosine (84) with an excess of 1,2-dibromoethane in water exemplified the first reaction according to Scheme 22. The annulation site of thiazole to purine moieties was proven by desulfuration with Raney-nickel (after previous cleavage of the saccharide grouping) by the appearance of 1-ethylhypoxanthine (74CPB342). An example for the second reaction was the cyclization of 2-mercaptoadenine with an excess of dibromoethane giving a mixture of 3,6,7,9-tetrahydro-9-iminothiazolo[3,2-u]purine (85) and isomeric 4-amino-7,8-dihydro-thiazolo[2,3-7>]purine (86). Both isomers were separated by their much different insolubility in chloroform (80JHC583) (Scheme 23). 

The fourth method employed alkylation of 2-mercaptohypoxanthine derivatives (87) with aroylmethyl halides to 2-(aroylmethylthio)-7-alkyl-hypoxathines (88) and their cyclization to 7-aryl-l-alkyl-thiazolo-[3,2-<2]purin-9( 1 //[-ones (89) with cone, sulfuric acid (89UKZ1076) (Scheme 24). 

In addition to cyclization of 2-mercaptoadenines with dibromoethane to a mixture of [2,3-Z>] and [3,2-a] isomers (86, 85) shown in Scheme 23, the method starting from 2-aminothiazole also produced this heterocycle. This compound—a cyclic isothiourea—was condensed with ethyl nitrosocyanoacetate to 5-amino-6-nitroso-thia/o 1 o[3,2-nitroso group with sodium dithionite to 6-amino derivative 91 followed by acylation with acyl chloride yielded 5-amino-6-acylaminothiazolo[3,2-u]pyrimidin-7-one (92). Heating 92 with polypho-sphoric acid produced 2-aryl- or 2-heteroaryl-thiazolo[2,3-/)]purin-4(3//)-ones 93. 

Known are two of its reactions Phosphorus oxychloride first chlorinated the molecule to a 4-chloro derivative and methanolic ammonia gave 4-amino-2-aryl- or 2-heteroaryl-thiazolo[2,3-6]purines 94. Alkylation of the sodium salt of 93 with methyl tosylate afforded 3-methyl-2-aryl- or 2-heteroaryl-thiazolo[2,3-Z>]purin-4(3//)-ones 95 (95JHC1725) (Scheme 25). 

Three methods were reported to obtain the title compounds. The first was based on a reaction sequence starting from 5,6-diamino-4-thiouracil-sodium salt, alkylation with 1,2-dibromoethane to 7,8-diamino-2,3-dihydro-5//-thiazolo-[3,2-c]pyrimidine (135) and fusion with urea or thiourea under formation of a third ring to the respective 7,8-dihydrothiazolo[2,3-/]purine-2,5(l//,3//)-dione (136) and 2,3,7,8-tetrahydro-2-thioxothiazolo[2,3- ]purin-5(l//)-one (137) (92FES1315) (Scheme 37). 

Other successful uses of triethyl orthoformate include formation of pteri-din-4-ones from 2-aminopyrazine-3-carboxamide (see 9) and its derivatives127,229 233 234 cis- and trans-4a,5,6,7,8,8a-hexahydroquinazolin-4-ones from the related 2-aminocyclohexanecarboxamides61,65 pyrido[2,3-d]pyri-midin-4-ones (see 3) from 2-aminopyridine-3-carboxamide235 thiazolo[5,4-d]pyrimidin-4-one (see 148) from 5-aminothiazole-4-carboxamide236 and purin-6-ones (see 19) from 4-aminoimidazole-5-carboxamide.232,237 Any partial acetylation of 7c-excessive products can be reversed by a final alkaline treatment.238... 

Chloro-3,4-dihydronaphthalene-2-yl)methylene]amino -1 -phenyl-2-thioxo-1,6- dihydro[l,3]thiazolo[5,4-d]pyrimidin-7(2H)-one, which considered as a 7-thia analogue of the natural purine bases, adenine and guanine, was prepared in an excellent yield by condensing 189 with cyanoacetic acid hydrazide followed by Gewald reaction, by reaction of 190 with suhar and phenyl isothiocyanate in the presence of triethylamine as a basic catalyst to give 191(Scheme 84). Thiazolo[5,4-d]pyrimidinone derivative 192 was prepared by heating 191 with a mixture of triethylorthoformate and acetic anhydride (1 1) [117],... 

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