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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 α-glucosidase.

Project description:PurposeOne of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through α-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 β-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 α-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 α-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. α-Glucosidase inhibitory activity of the oxadiazole derivatives 6a-k was evaluated against Saccharomyces cerevisiae α-glucosidase.ResultsMost of the synthesized compounds demonstrated α-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 μM respectively. A kinetic study performed for compound 6c revealed that the compound is a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 μM. 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 α-glucosidase inhibitors to manage the postprandial hyperglycemia incidence. Graphical abstract.

| S-EPMC7214590 | biostudies-literature

Nickel-catalyzed enantioselective vinylation of aryl 2-azaallyl anions.

Project description:A unique enantioselective nickel-catalyzed vinylation of 2-azaallyl anions is advanced for the first time. This method affords diverse vinyl aryl methyl amines with high enantioselectivities, which are frequently occurring scaffolds in natural products and medications. This C-H functionalization method can also be extended to the synthesis of enantioenriched 1,3-diamine derivatives by employing suitably elaborated vinyl bromides. Key to the success of this process is the identification of a Ni/chiraphos catalyst system and a less reducing 2-azaallyl anion, all of which favor an anionic vinylation route over a background radical reaction. A telescoped gram scale synthesis and a product derivatization study confirmed the scalability and synthetic potential of this method.

| S-EPMC8115067 | biostudies-literature

Synthesis of an elusive, stable 2-azaallyl radical guided by electrochemical and reactivity studies of 2-azaallyl anions.

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.

| S-EPMC8179533 | biostudies-literature

A One-Pot Synthesis-Functionalization Strategy for Streamlined Access to 2,5-Disubstituted 1,3,4-Oxadiazoles from Carboxylic Acids.

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| S-EPMC9486941 | biostudies-literature

2-(3-Chloro-5,6-diphenyl-2,5-dihydro-1,2,4-triazin-5-yl)-2-methyl-propane-nitrile.

Project description:The title compound, C(19)H(17)ClN(4), was obtained from the reaction of 3-chloro-5,6-diphenyl-1,2,4-triazine with isobutyronitrile in the presence of lithium diisopropyl-amide as an unexpected product of covalent addition of isobutyronitrile carbanion to the C-5 atom of the 1,2,4-triazine ring. The 2,5-dihydro-1,2,4-triazine ring is essentially planar (r.m.s. deviation = 0.0059?Å) and the 5- and 6-phenyl substituents are inclined to its mean plane with dihedral angles of 89.97?(4) and 55.52?(5)°, respectively. Intra-molecular C-H?N inter-actions occur. In the crystal, mol-ecules related by a c-glide plane are linked into zigzag chains along [001] by N-H?N hydrogen bonds.

| S-EPMC3379491 | biostudies-literature

Copper(I)-Catalyzed 1,3-Dipolar Cycloaddition of Ketonitrones to Dialkylcyanamides: A Step toward Sustainable Generation of 2,3-Dihydro-1,2,4-oxadiazoles.

Project description:CuI-catalyzed cycloaddition (CA) of the ketonitrones, Ph2C=N+(R')O- (R' = Me, CH2Ph), to the disubstituted cyanamides, NCNR2 (R = Me2, Et2, (CH2)4, (CH2)5, (CH2)4O, C9H10, (CH2Ph)2, Ph(Me)), gives the corresponding 5-amino-substituted 2,3-dihydro-1,2,4-oxadiazoles (15 examples) in good to moderate yields. The reaction proceeds under mild conditions (CH2Cl2, RT or 45 °C) and requires 10 mol % of [Cu(NCMe)4](BF4) as the catalyst. The somewhat reduced yields are due to the individual properties of 2,3-dihydro-1,2,4-oxadiazoles, which easily undergo ring opening via N-O bond splitting. Results of density functional theory calculations reveal that the CA of ketonitrones to CuI-bound cyanamides is a concerted process, and the copper-catalyzed reaction is controlled by the predominant contribution of the HOMOdipole-LUMOdipolarophile interaction (group I by Sustmann's classification). The metal-involving process is much more asynchronous and profitable from both kinetic and thermodynamic viewpoints than the hypothetical metal-free reaction.

| S-EPMC6641119 | biostudies-literature

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

Project description:A regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides is described. The palladium-NIXANTPHOS-based catalyst affords diarylmethylamine derivatives in good yield and without product isomerization. A gram scale sequential one-pot ketimine synthesis/arylation protocol was also developed.

| S-EPMC4136662 | biostudies-literature

Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions.

Project description:Diarylmethylamines are of great interest due to their prevalence in pharmaceutical chemistry. As a result, new methods for their synthesis are in demand. Herein, we report a versatile protocol for the synthesis of diarylmethylamine derivatives involving palladium-catalyzed arylation of in situ generated 2-azaallyl anion intermediates. The 2-azaallyl anions are generated by reversible deprotonation of readily available aldimine and ketimine precursors. Importantly, the arylated aldimine and ketimine products do not undergo isomerization under the reaction conditions. Scale-up of the arylation and hydrolysis of the resulting products to furnish diarylmethylamines were also successfully performed.

| S-EPMC4225812 | biostudies-literature

α-Branched amines through radical coupling with 2-azaallyl anions, redox active esters and alkenes.

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| S-EPMC8966660 | biostudies-literature

Rapid, Microwave Accelerated Synthesis of [1,2,4]Triazolo[3,4-b][1,3,4]oxadiazoles from 4-Acylamino-1,2,4-Triazoles.

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| S-EPMC5271595 | biostudies-literature

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