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SET activation of nitroarenes by 2-azaallyl anions as a straightforward access to 2,5-dihydro-1,2,4-oxadiazoles.

ABSTRACT: The use of nitroarenes as amino sources in synthesis is challenging. Herein is reported an unusual, straightforward, and transition metal-free method for the net [3 + 2]-cycloaddition reaction of 2-azaallyl anions with nitroarenes. The products of this reaction are diverse 2,5-dihydro-1,2,4-oxadiazoles (>40 examples, up to 95% yield). This method does not require an external reductant to reduce nitroarenes, nor does it employ nitrosoarenes, which are often used in N-O cycloadditions. Instead, it is proposed that the 2-azaallyl anions, which behave as super electron donors (SEDs), deliver an electron to the nitroarene to generate a nitroarene radical anion. A downstream 2-azaallyl radical coupling with a newly formed nitrosoarene is followed by ring closure to afford the observed products. This proposed reaction pathway is supported by computational studies and experimental evidence. Overall, this method uses readily available materials, is green, and exhibits a broad scope.

SUBMITTER: Zou D

PROVIDER: S-EPMC8642414 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Study on the interaction of triaryl-dihydro-1,2,4-oxadiazoles with ?-glucosidase.

Project description:PurposeOne of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through ?-glucosidase enzymes inhibition, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense due to inducing oxidative stress induced pancreatic ?-cell destruction through uncontrolled free radicals generation such as ROS, which in turn, leads to various macrovascular and microvascular complications. This study aimed to synthesize 2-aryl-4,6-diarylpyrimidine derivatives, screen their ?-glucosidase inhibitory activity, perform kinetic and molecular docking studies.MethodsA series of 3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole derivatives were synthesized and their ?-glucosidase inhibitory activity was screened in vitro. Compounds 6a-k were synthesized via a two-step reaction with a yield between 65 and 88%. The structural elucidation of the synthesized derivatives was performed by different spectroscopic techniques. ?-Glucosidase inhibitory activity of the oxadiazole derivatives 6a-k was evaluated against Saccharomyces cerevisiae ?-glucosidase.ResultsMost of the synthesized compounds demonstrated ?-glucosidase inhibitory action. Particularly compounds 6c, 6d and 6 k were the most active compounds with IC50 values 215?±?3, 256?±?3, and 295?±?4 ?M respectively. A kinetic study performed for compound 6c revealed that the compound is a competitive inhibitor of Saccharomyces cerevisiae ?-glucosidase with Ki of 122 ?M. The docking study also revealed that the two compounds, 6c and 6 k, have important binding interactions with the enzyme active site.ConclusionThe overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel ?-glucosidase inhibitors to manage the postprandial hyperglycemia incidence. Graphical abstract.

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Project description:The super electron donor (SED) ability of 2-azaallyl anions has recently been discovered and applied to diverse reactivity, including transition metal-free cross-coupling and dehydrogenative cross-coupling processes. Surprisingly, the redox properties of 2-azaallyl anions and radicals have been rarely studied. Understanding the chemistry of elusive species is the key to further development. Electrochemical analysis of phenyl substituted 2-azaallyl anions revealed an oxidation wave at E 1/2 or E pa = -1.6 V versus Fc/Fc+, which is ∼800 mV less than the reduction potential predicted (E pa = -2.4 V vs. Fc/Fc+) based on reactivity studies. Investigation of the kinetics of electron transfer revealed reorganization energies an order of magnitude lower than commonly employed SEDs. The electrochemical study enabled the synthetic design of the first stable, acyclic 2-azaallyl radical. These results indicate that the reorganization energy should be an important design consideration for the development of more potent organic reductants.

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Palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides.

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