title: 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. Graphical abstract.
authors.affiliation: Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, 41522 Egypt.
authors.forename: Ahmed T A
authors.initials: AT
authors.lastname: Boraei
authors.affiliation: Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
authors.forename: El Sayed H
authors.initials: el SH
authors.lastname: El Ashry
authors.affiliation: Institute of Analytical Chemistry, Chemo and Biosensors, University of Regensburg, Universitätsstrasse 31, 93053 Regensburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Duerkop
keywords: 1,2,4-Triazoles; Alkylation; Regioselectivity; Single-crystal X-ray diffraction