Tautomerism, regioisomerism, and cyclization reactions of acridinyl thiosemicarbazides

Abstract

The regioselectivities of methyl-and phenylhydrazine with acridin-9-yl isothiocyanate (thus yielding thiosemicarbazides with acridine substituted on the urea-type side) were examined. Methylhydrazine regioselectivity was high with the -nitrogen atom overwhelmingly more nucleophilic than the -nitrogen atom; phenylhydrazine regioselectivity was poor but varied with the solvent and only in the case of ethanol was nucleophilic predominance of the -nitrogen atom pronounced. Of note, whilst both phenyl thiosemicarbazides were present in solution only as spiro forms, the methyl product was present as an equilibrium mixture of open-chain and spiro thiosemicarbazides. Reactions on the NH 2 blocked analogue of methyl acridin-9-ylthiosemicarbazide (1-isopropylidene-2-methylthiosemicarbazide) were also examined. Interestingly, present in the starting material itself was a structural motif of novelty wherein a triazolethione represented the major species of an equilibrium between cyclic and open-chain forms.

Regioselectivity and Tautomerism of Novel Five-Membered Ring Nitrogen Heterocycles Formed via Cyclocondensation of Acylthiosemicarbazides

“…However, for the exchangeable NH protons, divergence from the correlation line was noticeable; in concert with our previous findings the N-10' atom of the acridinyl moiety present in 3e – h is well known [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] to have a strong propensity to retain a proton, i.e. the HN-10' tautomer (a 9',10'-dihydroacridine structure, see Figure 1 ) is expected to dominate the tautomeric equilibrium in the subseries.…”

“…This observation is presumably a result of rapid proton exchange, for whilst the labile proton signals are usually NMR observable in DMSO solution for these types of compounds [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ], uncharacteristically, with one exception (one proton in the spectrum of 3g ), they were not observed at all in this subseries. This is in contrast to all the other compounds reported herein, where all the exchangeable protons were observed including, of note, all three exchangeable protons of a positional isomer of 3f ( vide infra ).…”

“…the HN-10' tautomer (a 9',10'-dihydroacridine structure, see Figure 1 ) is expected to dominate the tautomeric equilibrium in the subseries. This case is no exception as borne out by the diagnostically [ 17 , 18 ] shielded signals of C-4' and C-5' (ca. 119 ppm).…”

“…The lower than usual value for the chemical shift of the C=S carbon (168 ppm, cf. 175–183 ppm for the C=S carbon in thiosemicarbazides [ 17 , 18 ]) suggests, however, that there might be some contribution of tautomeric structure F through fast exchange. The other carbon of the ring, C-5, resonates at 150 ppm, thereby discounting any contribution of the HC-5 tautomer.…”

Synthesis and antimicrobial activity of some new 1,3-thiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and 1,3-thiazines incorporating acridine and 1,2,3,4-tetrahydroacridine moieties

“…The first step may afford either of the two possible tautomeric intermediates, 5A or 5B (Scheme 2), which are then able to undergo differing reaction routes to form either of the cyclic products 6 or 7. (A third tautomeric intermediate 5C, in which the HN-10' tautomer is also plausible and indeed likely, but it must transpose into either 5A or 5B for the final step of the cyclization reaction to occur) [33,34]. Several recent articles reported [34][35][36] that when acridin-9-yl moiety was comprised of phenyl and pyridinyl moieties, the tautomer 5B was thermodynamically more favorable while the tautomer 5A was kinetically more disfavored, i.e.…”