Regiospecific synthesis, structure and electron ionization mass spectra of 1,3‐thiazolidin‐4‐ones containing the acridine skeleton

Abstract

The synthesis of regioisomeric 3-alkyl(aryl)-2-(acridin-9'-yl)imino-1,3-thiazolidin-4-ones (8b-i) and 2-alkyl(aryl)imino-3-(acridin-9'-yl)-1,3-thiazolidin-4-ones (11a-i) was performed by the reaction of 3-(acridin-9-yl)-1-alkyl(aryl)thioureas 5a-i with methyl bromoacetate and bromoacetyl bromide, respectively, via the corresponding isothiourea hydrobromides with excellent regioselectivity. The structure, NMR spectra and mass spectrometric behavior of the resulting compounds are discussed.J. Heterocyclic Chem., 42, 907 (2005).Introduction.

Unexpected regiospecific formation and DNA binding of new 3-(acridin-9-yl)methyl-2-iminothiazolidin-4-ones

“…Reaction with BAB followed a strikingly different path: acylation of the sulfur atom occurred first, followed by acyl migration to imine nitrogen to produce reversed 2-(acridin-9-yl)imino-3-R-thiazolidin-4-ones analogous to 6a−d (again with antracen-9-yl/acridin-9-yl instead of the shown (acridin-9-yl)methyl substituent). [16][17][18] In the system under study here (scheme 2), as the acyl transfer is slow, the S-acylated isothiourea 9, which results from the reaction with BAB, has time to adopt − if it hasn't already done so − the spirocyclic form 10, a strongly-favored structure given the above results. 22 The adoption of the spirocyclic form results in CH 2 N= being the imine-type nitrogen and as such it is favored to receive the acyl group when it migrates.…”

“…An apparent enigma of a sole product being produced by two reagents, MBA and BAB, which previously yielded regioisomeric products, though, is easily rationalized and, furthermore, is entirely consistent with the reaction mechanisms previously proposed for these reagents and for the substrates under study. [16][17][18] In these previous works, in the case of MBA and anthracen-9-yl/acridin-9-yl thioureas, the reaction first occurred by alkylation of the sulfur atom to give corresponding isothioureas analogous to 8, possessing antracen-9-yl/ acridin-9-yl substituent instead of the (acridin-9-yl) methyl substituent shown in scheme 2. Displacement of a methoxide ion by amine nitrogen followed then to form the 2-R-imino-3-(anthracen-9-yl/acridin-9-yl)-1,3-thiazolidin-4-ones analogous to 5a−d.…”

“…Novel products 5 and 6 were hoped to possess a better biological activity than the previous ones. [16][17][18] To suppress undesirable spirocyclization of 3a−d to 4a-d, intermediate thioureas 3a−d were set into reactions with MBA or BAB 30 min after mixing of the amine 2 with the isothiocyanates R-NCS, when sufficient amount of thioureas had already been formed (proven by NMR in ref. 22 , scheme 1).…”

“…In our previous studies [16][17][18] we succeeded to isolate intermediate isothiourea hydrobromides analogous to 8 (with MBA) or 9 (with BAB) (scheme 2). In this work, however, due to the complexity of the reaction mixtures, the intermediate isothioureas 8 and 9 (scheme 2) could not be isolated but readily cyclized to target 3-(acridin-9-yl)methyl-2-(R-imino)-1,3-thiazolidin-4-ones 5a−d in 22-42% yields after chromatography and crystallization, based on the starting amine 1.…”

“…[12][13][14] A drawback of this method was a limited control of * For correspondence regioselectivity, particularly when starting compounds were 1,3-diaryl or 1,3-dialkyl thioureas. 15 In our previous studies of 1-alkyl-3-anthracenyl/acridinyl thioureas [16][17][18][19][20] we have shown that regioselectivity could be successfully controlled by using two bifunctional electrophilic reagents, methyl bromoacetate (MBA) and bromoacetyl bromide (BAB) that afforded, sometimes even regiospecifically, two different 2-imino-1,3-thiazolidin-4-one regiomers with anthracene/acridine in the position 3 and 2 of the heterocycle, respectively, depending on the reagent used. Improved regioselectivity resulted from a different reaction mechanism with each of these reagents.…”