Synthesis of New Functionalized Indoles Based on Ethyl Indol-2-carboxylate

Successful alkylations of the nitrogen of ethyl indol-2-carboxylate were carried out using aq. KOH in acetone. The respective N-alkylated acids could be obtained without separating the N-alkylated esters by increasing the amount of KOH and water. The use of NaOMe in methanol led to transesterification instead of the alkylation, while the use of NaOEt led to low yields of the N-alkylated acids. Hydrazinolysis of the ester gave indol-2-carbohydrazide which then was allowed to react with different aromatic aldehydes and ketones in ethanol catalyzed by acetic acid. Indol-2-thiosemicarbazide was used in a heterocyclization reaction to form thiazoles. The new structures were confirmed using NMR, mass spectrometry and X-ray single crystal analysis

Synthesis and Regioselectivity in the Alkylation of 1,3,4-Oxadiazolethiones with Dihaloalkanes and Epichlorohydrin

[GRAPHICS] The regioselectivity in the alkylation of 1,3,4-oxadiazolethiones with dihaloalkanes was found that it depends mainly on the length of the alkyl chain connecting the two halides; moreover, the formation of thiirane ring instead of epoxide ring during the alkylation with epichlorohydrin was surprising

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

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

MOESM2 of Regioselectivity of the alkylation of S-substituted 1,2,4-triazoles with dihaloalkanes

Additional file 2: File S2. Copies of the NMR spectra of new synthesized compounds

MOESM1 of Regioselectivity of the alkylation of S-substituted 1,2,4-triazoles with dihaloalkanes

Additional file 1: File S1. Chemical information files (cif) of compounds 4, 6, 8 and 10

Design, selective alkylation and X-ray crystal structure determination of dihydro-indolyl-1,2,4-triazole-3-thione and its 3-benzylsulfanyl analogue as potent anticancer agents

Three sets of substituted indolyl-triazoles were synthesized by the alkylation of 1,2-dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione with different alkyl halides. The use of pyridine restricted the alkylation to sulfur. Whereas, upon using K2CO3, the alkylation exceeded sulfur to one of the remaining triazole nitrogens. The assignment of which nitrogen is alkylated besides sulfur is made for the first time using X-ray analysis of single crystals and 2D NMR which indicated that S-, 2-N-isomers will be preferably formed over the S-, 1-N-isomers. The antiproliferative activity on HEPG-2 and MCF-7 cancer cell lines was tested. The results showed that compound 2a is the most active with an IC50 3.58 mu g/mL and 4.53 mu g/mL for HEPG-2 and MCF-7 respectively and compound 7 is the least active with an IC50 > 100 mu g/mL compared to the standard drug doxorubicin (IC50 4.0 mu g/mL). The interaction of the synthesized compounds with tyrosine kinases, namely, Akt, PI3, and EGFR was also studied using molecular docking simulation to predict their mode of action which will drive future work directions. (C) 2016 Elsevier Masson SAS. All rights reserved