Oxidative cyclization of D-fructose thiosemicarbazones to 2-amino-5-(D-arabino-1,2,3,4-tetrahydroxybut-1-yl)-1,3,4-thiadiazoles through carbon-carbon bond cleavage of the sugar chain.

Condensation of D-fructose (1) with thiosemicarbazide or 4-phenylthiosemicarbazide gave the corresponding D-fructose thiosemicarbazones (3a and 3b). The latter compounds underwent oxidative cyclization with 10% ethanolic ferric chloride to give mixtures of 2-amino-5-(D-arabino-1,2,3,4-tetrahydroxybut-1-yl)-1,3,4-thiadiazole (6a) and 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (5a) from 3a and the corresponding 2-phenylamino compounds 6b and 5b from 3b. These products were formed as a result of cyclization of the thiosemicarbazone entity accompanied by C-1-C-2 or C-2-C-3 bond cleavage of the sugar chain. Structures of the 1,3,4-thiadiazole acyclo C-nucleosides 6a and 5b were confirmed by comparison with the unequivocally prepared compounds obtained by the dehydrogenative cyclization of D-arabinose thiosemicarbazones 11a and 11b with ethanolic ferric chloride. Structures of the 5-hydroxymethyl-1,3,4-thiadiazoles 5a and 5b were also confirmed by comparison with 5a and 5b unequivocally prepared by periodate cleavage of the alditolyl chain of 6a and 6b followed by reduction of the resulting aldehydes 8a and 8b with sodium borohydride. Compounds 6a and 6b were further characterized as their acetates 7a and 7b and were found to exist in the extended planar zizag conformation 13. Condensative cyclization of the D-arabinose thiosemicarbazones 11a and 11b by boiling with acetic anhydride afforded the 1,3,4-thiadiazoline acyclo C-nucleoside acetates 9a and 9b which exist in the sickle (bent) conformation 14. De-N- and de-O-acetylation with concomitant aromatization of 9a and 9b with 10% ethanolic FeCl3 gave the 1,3,4-thiadiazole acyclo C-nucleosides 6a and 6b. The assigned structures were corroborated by 2D 1H-1H HOMCOR and 2D 1H-13C HETCOR NMR spectroscopy.

Reexamination of some reactions of 3-(D-galactosylidenehydrazino)-1,2,4-triazino[5,6-b]indole.

Incorrect structures described in the literature for the products of reactions of the title compound 6 were reexamined and corrected. Thus, the product of acetylation of 6 with acetic anhydride in the presence of pyridine was found to be the mono-N-penta-O-acetyl derivative 10 and not the previously described di-N-penta-O-acetyl derivative 7. Assignment of structure 10 was based on 1H NMR data as well as its ability to undergo oxidative cyclization with Br2/AcOH to give 12. The previously assigned structure 7 would be incapable of undergoing such cyclization. The linear structure 12 rather than the angular regioisomer 3c was assigned on the basis of its UV absorption pattern and 1H NMR NOE spectra. Attempted preparation of 7 by increasing the duration of the reaction gave only compound 10. A di-N-acetyl-penta-O-acetyl derivative, however, was obtained with acetyl bromide in the presence of pyridine to which structure 8 rather than structure 7 or 9 was assigned on the basis of 1H NMR NOE studies. Acetylation of the triazolo-triazino-indole 11 gave a product identical to 12; structure 15 previously assigned to this product is, therefore, in error. Finally, the angular annelated structure 3e previously ascribed to the oxidative cyclization product of the 5-methylhydrazone congener of 6 (13) is now rectified to the linear annelated structure 14; the latter was found to be identical to the product obtained by N-methylation of the unequivocally linear 1,2,4-triazolo[4,3-b]1,2,4-triazino[5,6-b]indole 11. Compound 8 was found to exist in the preponderantly populated sickle (bent) conformation 18 in contrast to compounds 10 and 12 which were found to adopt the extended planar zigzag conformations 19 and 20 respectively.

Reinvestigation of the regiospecific outcome of heterocyclization of 3-hydrazino-1,2,4-triazino[5,6-b]indoles: angular versus linear annelated 1,2,4-triazolo-1,2,4-triazino[5,6-b]indole structures.

Divergences of the structural assignments reported in the literature for the products of cyclization of 3-hydrazino-1,2,4-triazino[5,6-b]indoles 1 with one-carbon cyclizing reagents have been reinvestigated. The linear annelated 1,2,4-triazolo[4,3-b]1,2,4-triazino[5,6-b]indoles 3 were found to be the products regiospecifically formed, rather than the angular annelated 1,2,4-triazolo[3,4-c]1,2,4-triazino[5,6-b]indoles 2. Our findings were based on comparison of the UV spectral data of the cyclization products with those of unequivocally as well as inevitably linear annelated compounds. Calculations of optimized geometries and electronic structures accord with the results obtained. Divergences reported in the literature were, therefore, attributed to erroneous structural assignments rather than to cyclization by different regiochemical pathways.