Indolizine Derivatives Research Articles

Mechanistic Insights into the Reaction of N‐Propargylated Pyrrole‐ and Indole‐Carbaldehyde with Ammonia, Alkyl Amines, and Branched Amines: A Synthetic and Theoretical Investigation

The reaction of pyrrole‐ and indole‐carbaldehydes having a propargyl group attached to the nitrogen atom with various amines was studied. The reaction with ammonia formed pyrrolo[1,2‐a]pyrazine and pyrazino[1,2‐a]indole while the reaction with alkylamines such as methyl, ethyl, hexyl, and benzylamines formed the corresponding pyrazinone derivatives. Unexpectedly, the reaction with allylamine and propargylamine formed pyrazine derivatives in which the allyl and propargyl groups were removed from the molecule. On the other hand, the reaction of N‐propargylated pyrrole‐carbaldehyde formed indolizine derivatives upon reaction with sterically bulky adamantyl‐ and tert‐butylamines. To understand the main factors causing these differences in reactivity, the reaction mechanisms were studied by means of computational methods. Our calculations showed that bulky amines tend to attack the central carbon of allene formed by the isomerization of N‐propargyl functionality, while the attack on the carbonyl carbon by aliphatic amines is more profound.

TFA-Mediated DMSO-Participant Sequential Oxidation/1,3-Dipolar Cycloaddition Cascade of Pyridinium Ylides for the Assembly of Indolizines.

A trifluoroacetic acid (TFA)-mediated cascade oxidation/1,3-dipolar cycloaddition reaction of stabilized pyridinium salts with dimethyl sulfoxide (DMSO) has been developed in the presence of K2S2O8 and trimethylethylenediamine (TMEDA). In this transition-metal-free reaction, DMSO acts as a one-carbon source, thus providing a convenient method for the efficient and direct synthesis of various indolizine derivatives.

Correction: Indolizine quaternary ammonium salt inhibitors part II: a reinvestigation of an old-fashioned strong acid corrosion inhibitor phenacyl quinolinium bromide and its indolizine derivative

Correction for ‘Indolizine quaternary ammonium salt inhibitors part II: a reinvestigation of an old-fashioned strong acid corrosion inhibitor phenacyl quinolinium bromide and its indolizine derivative’ by Yefei Wang et al., New J. Chem., 2018, 42, 12977–12989.

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles to form indolizine derivatives via an Au-π-allene intermediate.

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles afford indolizine derivatives with a structural rearrangement. The mechanism of these new annulations does not involve α-imino gold carbenes generated from gold π-alkyne intermediates. We postulate alkyne attack on gold π-allenes, yielding vinyl gold carbenes. These newly generated carbenes react with isoxazole derivatives to yield Z-3-imino-2-en-1-als, further enabling sequential cyclizations to deliver indolizine derivatives in two distinct classes.

Synthesis and study of Au(iii)-indolizine derivatives: turn-on luminescence by photo-induced controlled release.

The photo- and structural properties of a series of Au(iii) indolizine complexes were determined. Controlled release of halogenated indolizine derivatives from the corresponding Au(iii) complexes was achieved by photoinduced C-X bond formation, which provided turn-on luminescence with an increase in emission intensity of up to 67 times.

Indolizine quaternary ammonium salt inhibitors, part III: insights into the highly effective low-toxicity acid corrosion inhibitor – synthesis and protection performance

Three indolizine derivatives (Di-BQC, QM-DiBQC, PyM-DiBQC) were prepared facilely in high yield via 1,3-dipolar cycloaddition. These compounds exhibit good inhibition for steel in concentrated acid without the synergism of propargyl alcohol (PA).

Copper(i)-carbenes as key intermediates in the [3 + 2]-cyclization of pyridine derivatives with alkenyldiazoacetates: a computational study.

This work reports a computational study of the copper(i)-catalyzed regioselective synthesis of indolizine derivatives through the [3 + 2]-cyclization reaction of vinyldiazo acetates and pyridine derivatives. This reaction is predicted to proceed via a multi-step process with the initial decomposition of the diazo function and generation of an electrophilic copper(i) carbene intermediate. Subsequent attack of the pyridine derivative at the vinylogous position of the carbene would generate a vinylcuprate intermediate that would evolve to the final products through a sequence involving cyclization, reductive elimination, metal decoordination and final oxidative aromatization. According to our calculations, an alternative pathway involving the initial activation of the pyridine seems unlikely. These theoretical results could pave the way for further developments in vinyldiazo chemistry.

Rhodium(II)‐Catalyzed Highly Stereoselective C3 Functionalization of Indolizines with N‐Sulfonyl‐1,2,3‐triazoles

AbstractAn efficient and highly stereoselective approach for the C3 functionalization of indolizines through rhodium(II)‐catalyzed insertion of aza‐vinyl carbenes to synthesize N‐sulfonylamine alkenyl derivatives of indolizines is disclosed. Variably functionalized indolizines underwent C3 functionalization to afford moderate to good yields. Under similar reaction conditions pyrrolo[1,2‐a]quinolines resulted in regioselective C1 functionalization to give their N‐sulfonylamine alkenyl derivatives. The reaction methodology was successfully extended for the preparation of 1,3‐bis(N‐sulfonylamine alkenyl)indolizine derivatives and C3‐functionalized indolizines were used for the preparation of new molecular entities.

Novel indolizine derivatives lowers blood glucose levels in streptozotocin-induced diabetic rats: A histopathological approach.

Diabetes mellitus is a deadly disorder in human which induce chronic complications. The streptozotocin (STZ)-induced diabetes in rat is the most common animal model of human diabetes. The present study investigated the effects of novel indolizine derivatives (1-16) on plasma blood glucose concentrations in STZ-diabetic rats. In vitro experiments were performed on 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide free radicals, α-glucosidase enzyme and in vivo studies on normal, oral glucose loaded and STZ-induced diabetic rats. Among all synthetic derivatives, compound 12 showed good inhibitory profile against DPPH, superoxide free radicals and α-glucosidase enzyme with half maximal inhibitory concentration (IC50) values of 56.2, 33.5 and 26.5 μg/mL, respectively. The lethal dosage of indolizine derivatives was found to be above 1000 mg/kg body weight (b.w.). From the in vivo studies, it can be determined that the compound 12 depicted pronounced protective hypoglycemic effects in normal, glucose-loaded and STZ-induced diabetic rats with respect to the standard. Furthermore, 21 days of successive treatment with compound 12 in diabetic rats exhibited better recovery of body weight and considerable variations in biochemical parameters as that of the standard drug. Moreover, the histopathological section of pancreas and testes justifies the rehabilitation and regeneration of islets, acini and Sertoli cells in animals treated with compound 12. Our data suggest that the indolizine derivatives can be a benchmarks for designing potent oral antidiabetic agents.

Drug likeness, targets, molecular docking and ADMET studies for some indolizine derivatives.

The aim of this work was to investigate the biomolecular targets for a library of indolizines, study their molecular properties, drug likeness, target prediction, performing docking studies and exploring their ADMET profile in search for a lead compound. All compounds appeared to comply with Lipinski's rule without any violation, additionally their solubility is viewed good except for compounds 4a-c which are anticipated to be reasonably soluble, their Milog P score was 4.18-4.9, proposing that these compounds are the most lipophilic with least water solubility, however this may be helpful as the cannabinoid receptor-1 is the most probable target for these three compounds. The inclusive target for the selected library was tau protein. Structure based studies demonstrated great fitting of indolizines with tau protein, along these lines they are expected to have pharmacological action in vivo. This urged us to think about the ADMET properties of this library. These investigations suggested the ability of the selected compounds to pass the blood brain barrier (BBB) (aside from them compounds 2c and 3c) and affect tau proteins, which will be valuable for the treatment of Alzheimer's disease, particularly compound 5 which does not require any SAR modifications to attain the BBB.

Base‐Promoted Cycloisomerization for the Synthesis of Indolizines and Related Heterocycles

AbstractThe base‐mediated 5‐exo‐dig type cyclization reaction of homopropargyl pyridines for the construction of indolizines has been reported for the first time. A variety of indolizine derivatives could be obtained in moderate to excellent isolated yields by treatment of homopropargyl pryidines with cesium carbonate in DMSO at 100 °C. This strategy could also be adapted to the synthesis of pyrrolo[1,2‐a]quinolines and pyrrolo[1,2‐a]pyrimidines from the corresponding homopropargylquinolines and homopropargylpyrimidines, respectively. The mechanism involves α C−H deprotonation, 5‐exo‐dig cyclization, and isomerization of the exocyclic double bond to provide the heteroaromatic system. The transformation reported herein does not require the aid of transition metal catalysts or halogens, and is thus environmentally friendly.

Docking of Indolizine Derivatives on Cube Rhombellane Functionalized Homeomorphs

Docking of Indolizine Derivatives on Cube Rhombellane Functionalized Homeomorphs

Diastereoselective Synthesis of Polycyclic Indolizines with 2-(2-Enynyl)pyridines and Enamines.

A diastereoselective metal-catalyzed reaction of 2-(2-enynyl)pyridines and cyclic enamines is reported. The method provides access to a variety of substituted indolizine derivatives by variation of the enyne component and the reaction conditions. Performing the reaction using a preformed enamine led to the formation of polycyclic indolizines. With in situ generated enamines, ketone-containing indolizine derivatives were obtained. An asymmetric reaction of 2-(2-enynyl)pyridines and enamines generated from an aldehyde and a catalytic amount of amine is presented.

Steady state and time resolved fluorescence studies of new indolizine derivatives with phenanthroline skeleton

Some indolizines with phenanthroline skeleton derivatives have been investigated using steady state absorption, emission and time resolved fluorescence techniques. The effects of the substituents on the electronic absorption spectra and fluorescence emission have been demonstrated. The fluorescence decay curves exhibit one or two decay times. The emission lifetime measurements revealed values of 3–5 ns under the excitation with 370 nm. The quantum yield was also determined. The quenching process of emission using picric acid as quencher was characterized by Stern-Volmer plots. The phenanthroline derivatives 2 and 5 possess high efficiency for the detection of picric acid.

(Aza)indolizines and ethyl propiolate: [8+2] and [1,10] cyclizations

(Aza)indolizines reacted with ethyl propiolate regioselectively forming (aza)[2.2.3]cyclazines. The Sonogashira reaction of 5-iodo(aza)-indolizines and acetylenes led to 5-ethynyl(aza)indolizines. In the case of indolizine derivative the by-product was ethynylcyclazine. The structures of [2.2.3]cyclazines were proved by X-ray structural analysis.

Indolizine quaternary ammonium salt inhibitors part II: a reinvestigation of an old-fashioned strong acid corrosion inhibitor phenacyl quinolinium bromide and its indolizine derivative

Anti-corrosion inhibition was dramatically improved by transforming heterocyclic ammonium inhibitors into their dimer indolizine derivatives.

Regiospecific Synthesis of 1-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)indolizine Derivatives Through a Three-step Sequence from 2-Arylindolizine

Regiospecific Synthesis of 1-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)indolizine Derivatives Through a Three-step Sequence from 2-Arylindolizine

Synthesis of indolizine derivatives containing eight-membered rings via a gold-catalyzed two-fold hydroarylation of diynes.

A gold-catalyzed method for the construction of indolizines with eight-membered rings has been developed. The reaction proceeded through a two-fold hydroarylation with indole or pyrrole derivatives containing a 1,6-diyne using a tri(1-adamantyl)phosphine gold complex as the catalyst, affording 1,8-disubstituted indolizines in moderate to good yields in DCE at 80 °C. The potential usefulness of these indolizines as blue or green OLEDs has been also disclosed.

One-Pot Synthesis of Indolizines via Sequential Rhodium-Catalyzed [2 + 1]-Cyclopropanation, Palladium-Catalyzed Ring Expansion, and Oxidation Reactions from Pyridotriazoles and 1,3-Dienes.

An efficient, one-pot synthetic method for producing functionalized indolizine derivatives was developed via a Rh-catalyzed [2 + 1]-cyclopropanation, Pd-catalyzed ring expansion, and subsequent oxidation using manganese dioxide from pyridotriazoles and 1,3-dienes.

In Situ Generation of Quinolinium Ylides from Diazo Compounds: Copper-Catalyzed Synthesis of Indolizine.

The Cu-catalyzed three-component reaction between quinolines, diazo compounds, and alkenes has been established for direct construction of indolizine derivatives via quinolinium ylides. This methodology is distinguished by the use of a commercially inexpensive catalyst and readily available starting materials, wide substrate scope, and operational simplicity.