Synthesis of 2-thio derivatives of 4-phenyl-9H-pyrimido[4,5-b]indole

Abstract

The reaction of 3 benzylidene 2 ethoxyindolenine tetrafluoroborate with thiourea gives a mixture of 4 phenylpyrimido [4,5 b]indole 2(1H ) thione, its 3,4 dihydro derivative, and the corresponding disulfide, the product ratio depending on the reaction conditions. A number of transformations of the resulting compounds, in particular, those giving 2 alkylthio pyrimido indole derivatives are described. Key words: 4 phenyl 9H pyrimido[4,5 b]indole 2(1H ) thione, 2 alkylthio derivatives of 4 phenyl 9H pyrimido[4,5 b]indole, alkylation, oxidation, nucleophilic substitution, desulfu rization.The functional derivatives of pyrimido[4,5 b]indole, in particular, synthetically most available 2 and 4 amino substituted derivatives, possess a broad spectrum of bio logical activities and present interest as a base for the development of new medicines. 1-3 The corresponding thio derivatives may also attract attention as biologically active substances, since compounds possessing antioxi dant, antihypoxic, and hepatoprotector activities have been found in the series of related heterocyclic systems, 1,2,4 triazino[5,6 b] and [6,5 b]indoles. 4-6 In order to extend the range of functional derivatives of 4 phenyl pyrimido[4,5 b]indole and to study their properties, we attempted to synthesize its 2 thio derivatives.Previously, we carried out the reaction of 3 ben zylidene 2 ethoxyindolenine tetrafluoroborate (1) with thiourea, which yielded a product identified as 4 phenyl pyrimido[4,5 b]indole 2,4(1H ) thione (2) 7 (Scheme 1). A repeated detailed study of the reaction showed that this product is actually a mixture of thione 2, its 3,4 dihydro derivative 3, and disulfide 4. Similar analytical and spec troscopic characteristics of compounds 2-4, their poor solubility in most organic solvents, similar chromato graphic behaviors of thiones 2 and 3, and easy transfor mation into disulfide 4 make separation and identifica tion of these compounds a difficult task. The presence of both thiones in the mixture can be detected by mass spec trometry, whereas disulfide 4 is not detected due to its very low volatility. All three components of the mixture can be observed by HPLC with mass selective detection (HPLC MSD). In addition, the presence of disulfide 4 can be determined by TLC.