Azomethine Ylides—Versatile Synthons for Pyrrolidinyl-Heterocyclic Compounds

Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new contiguous stereogenic centers. This review article complies the most important [3+2]-cycloaddition reactions of azomethine ylides with various olefinic, unsaturated 2π-electron components (acyclic, alicyclic, heterocyclic, and exocyclic ones) reported over the past two decades.


Introduction
The three-atom component (TAC) is an organic species that is represented by zwitterionic octet structures and undergoes [3+2]-cycloadditions with an unsaturated 2π-electron component in a one-step reaction, often in an asynchronous and symmetry-conducive fashion, via a thermal six-electron Hückel aromatic transition state. The formal charges are lost in the [3+2→5] cycloaddition ( Figure 1) [1]. Recently, studies based on molecular electron density theory (MEDT) have suggested that the compounds involved in these reactions do not have a polar nature but a diradical, pseudoradical, or carbenoid nature. Therefore, the use of the term "1,3-dipole" is unjustified and should be replaced with "three-atom component". It was also recommend that the designation of "dipolarophile" should be replaced with "unsaturated 2π-electron component", and "1,3-dipolar cycloaddition" with "[3+2]-cycloaddition" [2].

Introduction
The three-atom component (TAC) is an organic species that is represented by zwitterionic octet structures and undergoes [3+2]-cycloadditions with an unsaturated 2π-electron component in a one-step reaction, often in an asynchronous and symmetry-conducive fashion, via a thermal six-electron Hückel aromatic transition state. The formal charges are lost in the [3+2→5] cycloaddition ( Figure 1) [1]. Recently, studies based on molecular electron density theory (MEDT) have suggested that the compounds involved in these reactions do not have a polar nature but a diradical, pseudoradical, or carbenoid nature. Therefore, the use of the term "1,3-dipole" is unjustified and should be replaced with "three-atom component". It was also recommend that the designation of "dipolarophile" should be replaced with "unsaturated 2π-electron component", and "1,3-dipolar cycloaddition" with "[3+2]-cycloaddition" [2].  While there is a mechanistic spectrum of this reaction from a synchronous one-step process to a stepwise overall transformation (including radical pathways), to avoid mechanistic digressions that may not have chemical or stereochemical consequences, in this synthetic review article, we will refer to the azomethine ylide reaction as a pericyclic While there is a mechanistic spectrum of this reaction from a synchronous one-step process to a stepwise overall transformation (including radical pathways), to avoid mechanistic digressions that may not have chemical or stereochemical consequences, in this synthetic review article, we will refer to the azomethine ylide reaction as a pericyclic cycloaddition.
This review article deals with the [3+2]-cycloaddition reaction of azomethin with an unsaturated carbon-carbon bond (in either acyclic, alicyclic, heterocyclic cyclic systems) that leads to the formation of pyrrolidinyl-containing analogs rep the last two decades and their biological applications. This review article is intend a critical resource for the researchers involved or interested in azomethine ylid ated heterocyclic synthesis. It is also hoped that this review article will inspire che this area of research.
It was assumed that the reaction proceeds through S-shaped ylide with a cycloaddition via the endo-transition state (pathway B), yielding cycloadducts 38, and not the exotransition state (pathway A). Computational studies (Gaussian 03) of the transition states (Density Functional Theory (DFT), B3LYP, and 6-31G(d,p) basis set) confirmed these assumptions (Scheme 12) [31]. Scheme 12. Proposed mechanism for the cycloaddition of the azomethine ylides with nitrostyrene.
It was assumed that the reaction proceeds through S-shaped ylide with a cycloaddition via the endo-transition state (pathway B), yielding cycloadducts 38, and not the exo-transition state (pathway A). Computational studies (Gaussian 03) of the transition states (Density Functional Theory (DFT), B3LYP, and 6-31G(d,p) basis set) confirmed these assumptions (Scheme 12) [31]. It was assumed that the reaction proceeds through S-shaped ylide with a cycload tion via the endo-transition state (pathway B), yielding cycloadducts 38, and not the ex transition state (pathway A). Computational studies (Gaussian 03) of the transition sta (Density Functional Theory (DFT), B3LYP, and 6-31G(d,p) basis set) confirmed these sumptions (Scheme 12) [31]. Scheme 12. Proposed mechanism for the cycloaddition of the azomethine ylides with nitrostyre A series of spiro[indoline-3,3′-pyrrolizin]-2-ones 40 with potential anti-amyloid genic properties useful against Alzheimer's disease were obtained by the microwavesisted cycloaddition of nitroalkenes 36 and azomethine ylides (generated from isatin and L-proline 27) [32]. Analogously, spirooxindole-pyrrolidines 42 were obtained by t reaction of tyrosine 41 in an ionic liquid [bmim]Br at 100 °C. Promising antiproliferati Scheme 12. Proposed mechanism for the cycloaddition of the azomethine ylides with nitrostyrene.
A series of spiro[indoline-3,3 -pyrrolizin]-2-ones 40 with potential anti-amyloidogenic properties useful against Alzheimer's disease were obtained by the microwave-assisted cycloaddition of nitroalkenes 36 and azomethine ylides (generated from isatin 19 and L-proline 27) [32]. Analogously, spirooxindole-pyrrolidines 42 were obtained by the reaction of tyrosine 41 in an ionic liquid [bmim]Br at 100 • C. Promising antiproliferation properties were observed for some of the synthesized compounds (42) against human A549 (adenocarcinoma basal epithelial) and Jurkat (T-cell lymphoma) cell lines (MTT assay) using Camptothecin as a positive control; the compounds exhibited a safe response against the non-cancer cell lines MCF-10 (normal breast) and PCS-130-010 (lung smooth muscle). Caspase-dependent apoptosis (especially caspase-3) was mentioned as the mode of action for the observed antiproliferative activity (Scheme 13) [33].
Molecules 2023, 28, x FOR PEER REVIEW 8 of 79 properties were observed for some of the synthesized compounds (42) against human A549 (adenocarcinoma basal epithelial) and Jurkat (T-cell lymphoma) cell lines (MTT assay) using Camptothecin as a positive control; the compounds exhibited a safe response against the non-cancer cell lines MCF-10 (normal breast) and PCS-130-010 (lung smooth muscle). Caspase-dependent apoptosis (especially caspase-3) was mentioned as the mode of action for the observed antiproliferative activity (Scheme 13) [33]. Ionic liquid chemistry was utilized to prepare 4′-nitrospiro[indeno [1,2-b]quinoxaline-11,2′-pyrrolidines] 47 by the cycloaddition reaction of nitroalkenes 36 with azomethine ylide (generated from indenoquinoxalinone 45 and L-phenylalanine 46) in an ionic liquid [bmim]Br. Some of the synthesized agents revealed antimycobacterial properties (Mycobacterium tuberculosis H37Rv) with an efficacy comparable to that of ethambutol (reference standard) [34]. Similarly, spiro compounds 49 were obtained by using L-histidine 48 instead of L-phenylalanine 46 in this reaction. Some of the synthesized compounds revealed cholinesterase (acetylcholinesterase and butyrylcholinesterase)-inhibitory properties with considerable efficiencies relative to Galantamine (Scheme 14) [35]. Ionic liquid chemistry was utilized to prepare 4 -nitrospiro[indeno [1,2-b]quinoxaline-11,2 -pyrrolidines] 47 by the cycloaddition reaction of nitroalkenes 36 with azomethine ylide (generated from indenoquinoxalinone 45 and L-phenylalanine 46) in an ionic liquid [bmim]Br. Some of the synthesized agents revealed antimycobacterial properties (Mycobacterium tuberculosis H37Rv) with an efficacy comparable to that of ethambutol (reference standard) [34]. Similarly, spiro compounds 49 were obtained by using L-histidine 48 instead of L-phenylalanine 46 in this reaction. Some of the synthesized compounds revealed cholinesterase (acetylcholinesterase and butyrylcholinesterase)-inhibitory properties with considerable efficiencies relative to Galantamine (Scheme 14) [35].

Acyclic Unsaturated 2π-Electron Components Containing Olefinic Linkage and Azirdine
Scheme 47 shows the thermolysis of aziridines 144 that led to the in situ formation of azomethine ylides, which underwent intramolecular cycloaddition, thus affording Nphthalimidopyrrolidine derivatives 145 as a mixture of two diastereoisomers [70].

Acyclic Unsaturated 2π-Electron Components Containing Olefinic Linkage and Azirdine
Scheme 47 shows the thermolysis of aziridines 144 that led to the in situ formation of azomethine ylides, which underwent intramolecular cycloaddition, thus affording Nphthalimidopyrrolidine derivatives 145 as a mixture of two diastereoisomers [70].

Indanones and Indanediones
A series of dispiro compounds of type 167 were regioselectively synthesized by t cycloaddition of 2-(ylidene)-1-indanones 166 with azomethine ylides (formed from isa derivatives 19 with sarcosine 20) in refluxing ethanol. Promising anti-inflammatory pro erties were exhibited by the synthesized compounds (via a rat carrageenan paw edem assay) relative to Indomethacin (standard reference drug) [84]. Antiproliferative prop ties were also revealed by some of the synthesized derivatives against human metasta melanoma cells (GaLa, LuPiCi, and LuCa), with a potency relative to that of Doxorubic (SRB assay) (Scheme 56) [85]. In an analogous reaction, by using L-thioproline 22 inste of sarcosine 20, spiro-pyrrolothiazolyloxindole derivatives of type 168 were obtaine Some of these compounds showed activities against Mycobacterium tuberculosis H37Rv r ative to Ethambutol (standard reference) [

Indanones and Indanediones
A series of dispiro compounds of type 167 were regioselectively synthesized by the cycloaddition of 2-(ylidene)-1-indanones 166 with azomethine ylides (formed from isatin derivatives 19 with sarcosine 20) in refluxing ethanol. Promising anti-inflammatory properties were exhibited by the synthesized compounds (via a rat carrageenan paw edema assay) relative to Indomethacin (standard reference drug) [84]. Antiproliferative properties were also revealed by some of the synthesized derivatives against human metastatic melanoma cells (GaLa, LuPiCi, and LuCa), with a potency relative to that of Doxorubicin (SRB assay) (Scheme 56) [85]. In an analogous reaction, by using L-thioproline 22 instead of sarcosine 20, spiro-pyrrolothiazolyloxindole derivatives of type 168 were obtained. Some of these compounds showed activities against Mycobacterium tuberculosis H37Rv relative to Ethambutol (standard reference) [86].

Indanones and Indanediones
A series of dispiro compounds of type 167 were regioselectively synthesized by the cycloaddition of 2-(ylidene)-1-indanones 166 with azomethine ylides (formed from isatin derivatives 19 with sarcosine 20) in refluxing ethanol. Promising anti-inflammatory properties were exhibited by the synthesized compounds (via a rat carrageenan paw edema assay) relative to Indomethacin (standard reference drug) [84]. Antiproliferative properties were also revealed by some of the synthesized derivatives against human metastatic melanoma cells (GaLa, LuPiCi, and LuCa), with a potency relative to that of Doxorubicin (SRB assay) (Scheme 56) [85]. In an analogous reaction, by using L-thioproline 22 instead of sarcosine 20, spiro-pyrrolothiazolyloxindole derivatives of type 168 were obtained. Some of these compounds showed activities against Mycobacterium tuberculosis H37Rv relative to Ethambutol (standard reference) [ Other dispiropyrrolidines of type 169 were synthesized by the cycloaddition of azomethine ylide (formed from ninhydrin 44 and sarcosine 20) with 2-(arylidene)-1-  [89]. Analogously, pyrrolothiazol doles of type 173 were obtained when isatin 19 was used instead of ninhydri acenaphthenequinone 25 in this reaction. Some of the isatin-derived compounds 173 exhibited inhibitory properties toward acetylcholinesterase that could be us Alzheimer's disease therapy (Scheme 58) [90].

Pyrrolidine-2,5-diones
Dispiropyrrolidines of type 200 were prepared regioselectively by the cycloaddition of 3-(ylidene)pyrrolidine-2,5-diones 199 with azomethine ylide (formed from condensation of sarcosine 20 and isatin 19) in refluxing alcohol. Promising cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibitory properties were observed for some of the synthesized compounds (relative to Donepezil, used as the standard reference) that are of potential importance for fighting Alzheimer's disease (Scheme 68) [99]. Some of the

Pyrrolidine-2,5-diones
Dispiropyrrolidines of type 200 were prepared regioselectively by the cycloaddition of 3-(ylidene)pyrrolidine-2,5-diones 199 with azomethine ylide (formed from condensation of sarcosine 20 and isatin 19) in refluxing alcohol. Promising cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibitory properties were observed for some of the synthesized compounds (relative to Donepezil, used as the standard reference) that are of potential importance for fighting Alzheimer's disease (Scheme 68) [99]. Some of the

Thiophenones
The

Thiophenones
The

Coumarins
A cycloaddition strategy for the synthesis of

Conclusions and Outlook
Among various methods, the [3+2]-cycloaddition reaction of azomethine ylides is one of the most adopted protocols for the formation of pyrrolidine and pyrrole systems. The chemistry of azomethine ylides has progressed significantly in the last two decades. Azomethine ylides have been used for the synthesis of many stereoselective natural products, core ring systems of natural products, and several bioactive molecules containing multiple Scheme 140. Synthesis of 1,3-benzodiazepin-5-one 433.

Conclusions and Outlook
Among various methods, the [3+2]-cycloaddition reaction of azomethine ylides is one of the most adopted protocols for the formation of pyrrolidine and pyrrole systems. The chemistry of azomethine ylides has progressed significantly in the last two decades. Azomethine ylides have been used for the synthesis of many stereoselective natural products, core ring systems of natural products, and several bioactive molecules containing multiple chiral centers. The cycloaddition of a three-atom component to an appropriate unsaturated substrate, namely, the unsaturated 2π-electron component, is the most embraced approach to the synthesis of five-membered heterocyclic compounds. By using various unsaturated 2π-electron components in reaction with in situ-generated azomethine ylides, a plethora of pyrrolidinyl-containing heterocycles can be obtained in a highly regio-and stereoselective manner. As a result of intermolecular cycloadditions, one new ring with a defined stereochemistry is formed; however, when the three-atom component and the substrate are part of the same molecule, the cycloaddition is intramolecular and leads to a more complex molecular architecture that is difficult to access by other routes, namely, through the use of new bicyclic systems.
This review summarizes the synthesis of some of the most important compounds resulting from the [3+2]-cycloaddition reactions of azomethine ylides with various olefinic (acyclic, alicyclic/heterocyclic, and exocyclic) unsaturated 2π-electron components and highlights their potential therapeutic significance. We believe the compiled subject will develop interest within this field among the research community and encourage them to develop a wider variety of asymmetric [3+2]-cycloaddition reaction strategies for the synthesis of complex molecules.