Reactions of 5-diazoimidazoles with steroid hydrazones

Abstract

The reaction of 5-diazoimidazoles with steroid hydrazones was studied. The structure of the steroid derivative was found to have a significant effect on the direction of the nitrogen transfer in the unstable intermediate tetrazene. The presence of a labile proton in the reaction mixture permits stabilization of one of the tetrazene forms such that only direction was found for the nitrogen transfer in all the reactions studied, leading to imidazole azides and iminosteroid derivatives.Keywords: 5-azidoimidazoles, 3-hydrazono-5α-hydrazono-5α-androstan-17β-ol, 17-hydrazonoestra-1,3,5(10)-trien-3-ol, 5-diazoimidazoles, 3-imino-5α-androstan-17β-ol, 17-iminoestra-1,3,5(10)-trien-3-ol, tetrazenes.Nitrogen-transfer reactions between aromatic diazo compounds and aliphatic hydrazine have been studied by Tishler [1,2]. Depending on the nature of the reagents, the reaction product may lead either to a stable tetrazene, which can be isolated as a solid, or products of tetrazene decomposition. In the latter case, nitrogen transfer occurs, leading to the formation either of an aromatic azide and aliphatic amine or of an aromatic amine and aliphatic azide.In the present work, we studied the reaction of 5-diazoimidazoles 1a-d possessing antitumor and antibacterial activity [3][4][5] with steroid hydrazones 2 and 3, which also display antitumor activity [6]. The products, tetrazenes 4 and 5, may hold interest since they display selective penetration into tumors both as diazoimidazoles and steroid hormones.We might have expected the formation of a mixture of multiple products, which would be difficult to separate into individual components, since nitrogen transfer upon decomposition of the tetrazene could occur concurrently in two directions. Furthermore, 5-diazoimidazole-4-carboxamide (1a) and 5-diazoimidazole-4-(Nmethylcarboxamide) (1b) may undergo intramolecular cyclization leading to imidazotriazines 6a and 6b [5,7,8].The reaction course and composition of the reaction mixture were monitored by thin-layer chromatography with reference to known standards. Thus, azidoimidazoles 7a-c were obtained according to our previous procedure [9,10]. The ethyl ester of 5-azidoimidazole-4-carboxylic acid (7d) was obtained for the first time from the reaction of the ethyl ester of 5-diazoimidazole-4-carboxylic acid (1d) with sodium azide in aqueous ethanol. Unfortunately, we were unable to obtain the corresponding steroid references either by reduction with NaBH 4 , LiAlH 4 , Na 2 S 2 O 4 , Ni/Ra, or Pd/C or by diazotization of steroid hydrazones due to the instability of the corresponding amine and azide products.