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Pyrrole versus quinoline formation in the palladium catalyzed reaction of 2-alkynyl-3-bromothiophenes and 2-alkynyl-3-bromofurans with anilines. A combined experimental and computational study

Benzofuroquinolines were prepared by a new type of Pd catalyzed annulation reaction. In the first step, 2-alkynyl-3-bromobenzofurans were prepared by Sonogashira reactions of 2,3-dibromobenzofuran. Their Pd catalyzed reaction with electron-rich anilines afforded benzofuroquinolines by a domino C-N coupling/annulation process. This reaction proceeds as a C,N-cyclization via the nitrogen atom and the ortho-carbon of the aniline. Similarly, furoquinolines were prepared from 2,3-dibromofuran. In contrast, benzofuropyrroles and furopyrroles were formed by N,N-cyclization when electron-poor anilines were used. Earlier, we reported results related to the thiophene and benzothiophene series. Quinolines were formed from 2,3-dibromobenzothiophene when electron rich anilines were used. In contrast, pyrroles were obtained in the case of electron-poor anilines. On the other hand, pyrroles were generally obtained, not depending on the type of aniline, when 2,3-dibromothiophene was employed as the starting material. In the present article, a detailed DFT study related to the mechanism (quinoline versus pyrrole formation) is reported which provides a rationalization of the selectivities observed for the furan, benzofuran, thiophene and benzothiophene series and for the different selectivities observed for electron-rich and -poor anilines.

Mechanistic insight of TiCl4 catalyzed formal [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 1,3-dielectrophiles

The mechanism of TiCl4 mediated formal [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 1,3-dielectrophiles is studied at the B3LYP level of density functional theory (DFT) to rationalize the experimental regioselectivity. Methyl and trifluoromethyl substituted 1,3 dielectrophiles are studied theoretically since they show different regioselectivities. Two different mechanisms involving 1,2 and 1,4 addition of 1,3-bis(silyl enol ethers) on 1,3-dielectrophiles are studied for each dienophile. The intramolecular transition metal catalyzed and non-catalyzed dynamic shift of the silyl moiety is also studied. The structure of the 1,3 dienophile and the associated Mulliken charges are the driving forces for different regioselectivities in methyl and trifluoromethyl dienophiles.

Synthesis, in vitro potential and computational studies on 2-amino-1,4-dihydropyrimidines as multitarget antibacterial ligands

In this study, we have investigated small multitargeted molecules containing 2-aminopyrimidine scaffold that may further act as precursor for developing more potent antibacterials. An efficient route to 2-amino-1,4-dihydropyrimidines by using ultrasound irradiation as the energy source was developed. In silico density functional theory calculations illustrated that tin chloride-mediated Biginelli reaction to produce 2-amino-1,4-dihydropyrimidines has energetics quite accessible under the reaction conditions. Calculated minimum inhibitory concentrations against the various bacterial strains showed that compounds 3 and 11 displayed comparable in vitro activity to ciprofloxacin in Staphylococcus aureus strains and reduced potency in Escherichia coli strains. Further, we investigated in silico ADMET profiling of synthesized compounds in order to understand the mechanism of action that help in explaining in vitro results. Lead compounds 3, 6, and 11 are predicted to have acceptable pharmacokinetic/drug-like properties. Data mining and computational analysis were employed to derive compound promiscuity phenomenon. All the compounds were found nonsubstrate towards various aminergic G-protein coupled receptors, ion-channels, kinase inhibitor, nuclear receptor ligand, protease inhibitor, and enzyme inhibitor. Compound 3 was further investigated by in silico binding to different antibacterial targets. Binding energy data revealed that that these compounds have the ability to bind with other bacterial targets. Hence, combined in silico and in vitro studies shed insights into the mechanism of synthesis and antibacterial activity of 2-amino-1,4-dihydropyrimidines. Results of this study are promising and can be used for further investigation by medicinal chemists to explore their chemical functionalization and in vivo studies.

One-pot synthesis of tetrazole-1,2,5,6-tetrahydronicotinonitriles and cholinesterase inhibition: Probing the plausible reaction mechanism via computational studies

In the present study, one-pot synthesis of 1H-tetrazole linked 1,2,5,6-tetrahydronicotinonitriles under solvent-free conditions have been carried out in the presence of tetra-n-butyl ammonium fluoride trihydrated (TBAF) as catalyst and solvent. Computational studies have been conducted to elaborate two plausible mechanistic pathways of this one-pot reaction. Moreover, the synthesized compounds were screened for cholinesterases (acetylcholinesterase and butyrylcholinesterase) inhibition which are consider to be major malefactors of Alzheimers disease (AD) to find lead compounds for further research in AD therapy.

Mechanism of Zn(OTf)2 catalyzed hydroamination-hydrogenation of alkynes with amines: insight from theory

The mechanism of Zn(OTf)2 catalyzed hydroamination–hydrogenation of alkynes with amines is investigated through density functional theory methods, and compared with the mechanism of hydroamination–hydrogenation reactions catalyzed by other late transition metals. Both the inner sphere and outer sphere mechanisms for the nucleophilic attack of nitrogen on the electrophilic alkyne centre to deliver imine have been investigated for a hydroamination reaction. Four different possibilities of hydrogen activation for the hydrogenation of imine to deliver amine have also been studied. These competitive reactions differ regarding the fate of the proton and hydride generated from the heterolytic cleavage of H2. The inner sphere mechanism is kinetically more demanding and not believed to contribute significantly to the progress of the reaction under the experimental conditions. The outer sphere route for the nucleophilic attack of the non-coordinated amine on the coordinated alkyne was found to be most plausible. The overall energy barrier for the outer sphere mechanism in the amine adduct can also be surpassed under the reaction conditions; therefore, this mechanism cannot be excluded safely. For the hydrogenation reaction, the heterolytic hydrogen cleavage involving proton shift on the triflate ligand and hydride to metal was found to be most plausible over the competitive H2 cleavage reactions involving hydrogenation through the dihydride route, and heterolytic H2 cleavage in which the proton shifts towards the ligand and the hydride shifts towards the electrophilic centre. However, the heterolytic hydrogen cleavage involving proton shift to the nitrogen and the hydride towards the metal also cannot be excluded safely. The kinetic barriers associated with the outer sphere mechanism of hydroamination (0.82 kcal mol−1) followed by the heterolytic hydrogen cleavage (33.84 kcal mol−1) mechanism are consistent with the experimental conditions (at 120 °C), suggesting that the mechanism is more plausible under experimental reaction conditions.

Theoretical mechanistic investigation of zinc(II) catalyzed oxidation of alcohols to aldehydes and esters

The mechanism of the Zn(II) catalyzed oxidation of benzylic alcohol to benzaldehyde and ester by H2O2 oxidant was investigated through density functional theory methods and compared with the similar oxidation mechanisms of other late transition metals. Both inner sphere and intermediate sphere mechanisms have been analyzed in the presence and absence of pyridine-2-carboxylic acid (ligand). An intermediate sphere mechanism involving the transfer of hydrogen from alcohol to H2O2 was found to be preferred over the competitive inner sphere mechanism involving β-hydride elimination. Kinetic barriers associated with the intermediate sphere mechanism are consistent with the experimental observations, suggesting that the intermediate sphere mechanism is a plausible mechanism under these reaction conditions. The oxidation of alcohols to aldehydes (first step) is kinetically more demanding than the oxidation of hemiacetals to esters (second step). Changing the oxidant to tert-butyl hydrogen peroxide (TBHP) increases the activation barrier for the oxidation of alcohol to aldehyde by 0.4 kcal mol−1, but decreases the activation barrier by 3.24 kcal mol−1 for oxidation of hemiacetal to ester. Replacement of zinc bromide with zinc iodide causes the second step to be more demanding than the first step. Pyridine-2-carboxylic acid ligand remarkably decreases the activation barriers for the intermediate sphere pathway, whereas a less pronounced inverse effect is estimated for the inner sphere mechanism.