Regioselectivity of the alkylation of S-substituted 1,2,4-triazoles with dihaloalkanes

Abstract

Background: 1,2,4-Triazole3-thiones are good scaffolds for preparation of new lead compounds. Their derivatives attracted the attention of chemists due to their wide spectrum of biological activities. Alkylsulfanyl-1,2,4-triazoles have three nucleophilic sites (nitrogens) ready for reaction with electrophiles. Herein, new regioselective isomers were synthesized by the reaction of benzylsulfanyl-1,2,4-triazole with various dihaloalkanes. Regioselectivity was determined by X-ray crystallography and NMR. Results: Coupling of 3-benzylsufanyl-5-(1H-indolyl)-1,2,4-triazole with dibromomethane, 1,2-dichloroethane, 1,3-dibromopropane and di(bromomethyl)quinoxaline was investigated in the presence of potassium carbonate in acetone. In the case of dibromomethane three different bis(triazolyl)methane isomers (-N 1-CH2-N 1-4, -N 1-CH2-N 2-5, -N 2-CH2-N 2-6) were formed in which the two bromide atoms were replaced by two triazole moieties. Among these isomers the reaction was regioselective towards the -N 1-CH2-N 2-5 isomer due to the steric effect. In the case of 1,3-dibromopropane two compounds were obtained due to the alkylation at N(2) to give 2-(3-bromopropyl)-triazole 8 and alkylation at N(1) was followed by cyclization at the indole nitrogen to form a condensed indolo-triazolo-diazepine 10. Upon alkylation of 3-benzylsufanyl-5-(1H-indolyl)-1,2,4-triazole with di(bromomethyl)quinoxaline, two bis(triazolyl-methyl)quinoxaline isomers were separated and characterized as (-N 1-CH2-N 1-) 11 and (-N 2-CH2-N 2-) 12. Single-crystal X-ray diffraction assisted the elucidation and confirmation of the structures of the isomers. An AM1 theoretical study explained the regioselectivity of the alkylation. Conclusions: On reacting S-protected 1,2,4-triazoles with various alkylating agents, only N(1) and N(2) attack the electrophilic carbons. N(2) alkylated isomers are preferentially formed.