Regioselective synthesis of enantiopure 1,2- and 1,3-dispirooxindoles along with a DFT study.

In the present study, a library of important enantiopure dispirooxindole [indolizidine, pyrrolizidine, and pyrrolidine] derivatives with three or four contiguous and two quaternary stereogenic centers using different amino acids (pipecolic acid, sarcosine, proline and hydroxyproline) were synthesized in high yields (up to 96%) through a regio- and diastereoselective (up to 99 : 1) multicomponent 1,3-dipolar cycloaddition strategy. Based on the results, the alteration of amino acids led to a change in the regioselectivity and unusual regioisomers (pyrrolizidine versus indolizidine/pyrrolidine) were obtained to construct a novel enantiopure 1,3-dispirooxindole skeleton. The stereochemical outcome of the cycloaddition was determined by single crystal X-ray diffraction analysis and the self-disproportionation of enantiomers (SDE) test confirmed the enantiomeric purity of the desired products. The mechanism and differences in the regioselectivity of the 1,3-dipolar cycloaddition reactions between the stable azomethane ylides obtained from ninhydrin, pipecolinic acid, and proline with (E)-2-oxoindolin-3-ylideneacetyl sultam were theoretically studied through DFT calculations at the M06-2X/6-31G(d,p) level in methanol.

An experimental and mechanism study on the regioselective click reaction toward the synthesis of thiazolidinone-triazole.

An efficient procedure for the synthesis of novel thiazolidinone triazoles through 32 cycloaddition reactions in the presence of copper(I) species was described, and the molecular mechanism of this 32CA was investigated computationally. Different possible pathways for CA process have been studied to achieve this goal, including one-step pathways for both regioisomers 1,4- and 1,5-triazoles (uncatalyzed, mono-copper, di-copper) and also mono- and di-copper stepwise pathways for 1,4-disubstituted triazole. It was exhibited that the most convenient route in terms of energy barriers includes two copper ions. Based on the calculation, the reaction follows a di-copper stepwise mechanism involving the formation of a six-membered ring and then undergoes a ring contraction to a five-membered ring. The regiochemistry of the reaction was investigated based on local and global reactivity indices of reactants, the transition state stabilities calculation. The electron reorganization along the uncatalyzed one-step mechanism has been investigated by the ELF topological analysis of the bonding changes along with the CA reaction.

1,2,3-Triazole-linked 5-benzylidene (thio)barbiturates as novel tyrosinase inhibitors and free-radical scavengers.

In this study, benzyl-1,2,3-triazole-linked 5-benzylidene (thio)barbiturate derivatives 7a-d and 8a-h were designed as potential tyrosinase inhibitors and free-radical scavengers. The twelve derivatives were synthesized via the [3+2] cycloaddition reaction of the corresponding benzyl azide as a dipole and the corresponding alkyne as a dipolarophile in the presence of copper(I) species, generated in situ from copper(II)/ascorbate. The thiobarbiturate derivative 8h and the barbiturate derivative 8b bearing 4-fluoro and 4-bromo groups on the benzyl-triazole moiety were found to be the most potent tyrosinase inhibitors with IC50 values of 24.6 ± 0.9 and 26.8 ± 0.8 µM, respectively. Almost all the compounds showed a good radical scavenging activity with EC50 values in the range of 29.9-324.9 µM. Derivatives 7a, 8f, and 8h were the most potent free-radical scavengers with EC50 values of 29.9 ± 0.8, 36.8 ± 0.9, and 39.2 ± 1.1 µM, respectively. The kinetic analysis revealed that compound 8h was a mixed-type tyrosinase inhibitor. The molecular docking analysis indicated that 8b and 8h were well accommodated in the active site of the tyrosinase enzyme and possessed the most negative binding energy values of -8.55 and -8.81 kcal/mol, respectively. Moreover, it was found that the two residues, Asn81 and Glu322, played a significant role in forming stable enzyme-inhibitor complexes.

A theoretical study on the metal-free triazole formation through tandem [3+2] cycloaddition/retro-Diels-Alder reaction of benzyl azide and oxanorbornadienedicarboxylate.

A density functional theory study was performed on the mechanism and site selectivity of a domino [3 + 2] cycloaddition/retro-Diels-Alder reaction between benzyl azide and 7-oxabicyclo [2.2.1]hepta-2,5-diene-2,3-dicarboxylate (oxanorbornadienedicarboxylate) which provide a stable 1,2,3-triazole and the results were compared with the click reaction between benzyl azide and dimethyl acetylenedicarboxylate (DMAD) with similar triazole product. Parr functions analysis, hard and soft acids and bases (HSAB) principle and potential energy surface analysis were utilized for studying the site selectivity of this reaction, and the results are consistent with the experimental observations. The molecular mechanisms of these reactions were established by electron localization function (ELF) and noncovalent interactions (NCI) topological analysis. ELF topological patterns indicated a two-stage one-step mechanism for the 32CA reaction and NCI analysis displayed the noncovalent interactions which are responsible for the preferred path.

Preparation and application of magnetic chitosan/graphene oxide composite supported copper as a recyclable heterogeneous nanocatalyst in the synthesis of triazoles.

A magnetic chitosan-based biocomposite, MnFe2O4@GO@Chitosan/Cu, was prepared and used as an efficient heterogeneous catalyst for the synthesis of triazoles. The structure, thermal stability and magnetic properties of the composite were investigated by FT-IR, XRD, SEM, TEM, TGA, and VSM methods. The easy separation, recovery, reusability, and high yields of the products make this protocol environmentally friendly and economically attractive.

Mechanism and origins of the regioselectivity in the [3+2] cycloaddition reaction of an azomethine ylide with benzoimidazole-2-yl-3-phenylacrilonitrile: A DFT approach.

The molecular mechanism of the [3+2] cycloaddition (32CA) reaction of an azomethine ylide, generated in situ from isatin and sarcosine, with benzo-imidazol-2-yl-3-phenylacrylonitrile have been theoretically studied by using DFT at the B3LYP and M06-2X levels of theory. This reaction takes place through an asynchronous one-step mechanism. Analysis of the global electron density transfer (GEDT) indicates that this 32CA has a polar character. The regiochemistry of this reaction was investigated using Parr functions analysis, as well as HSAB principle and potential energy surface analysis, where the results are in agreement with the experimental observations. The ELF analysis revealed that this 32CA reaction takes place through a two-stage one-step mechanism.