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Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO4,5H2O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC50 values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC50 value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.

A series of C(2)‐N(4)‐disubstituted 1,3,4‐thiadiazoles bearing dichlorocyclopropane, have been prepared from (R)‐carvone 1 in a three‐step procedure. First, (R)‐carvone was treated with dichlorocarbene, generated in‐situ from chloroform using PTC technique. The resulting dichlorocyclopropane 2 was then converted into thiosemicarbazone derivatives 3 a–c before being transformed peri‐selectively and efficiently (up to 80 % yield) into their corresponding 1,3,4‐thiadiazoles (6 a–d and 7 a–c) via 1,3‐dipolar cycloaddition reaction with diarylnitrilimines 4 a–d and N‐aryl‐C‐ethoxycarbonyl‐nitrilimines 5 a–c. The structures of all the newly synthesized cyclopropanic 1,3,4‐thiadiazoles 6 a–d and 7 a–c were fully identified on the basis of their HRMS and NMR (1D & 2D) spectral data. The evaluation of compounds 2, 3 a–c, 6 a–d and 7 a–c, against HT‐1080 fibrosarcoma, breast adenocarcinoma (MCF‐7 and MDA‐MB‐231), and lung carcinoma A‐549 cells, using viability testing (MTT) showed promising antitumor activity, especially for compounds 3 a, 6 b and 6 c for which the IC50 values, against HT‐1080 fibrosarcoma, were respectively 18.92, 16.12 and 15.37 (μM).