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Review

Recent Developments in Azomethine Ylide-Initiated Double Cycloadditions

by
Tieli Zhou
1,
Xiaofeng Zhang
2,*,
Yan Jan Sheng
3,
Desheng Zhan
4 and
Wei Zhang
2,*
1
College of Food Science and Engineering, Changchun University, Changchun 130022, China
2
Center for Green Chemistry, Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
3
Department of Biochemistry, Brandeis University, Waltham, MA 02453, USA
4
College of Chemistry, Changchun Normal University, Changchun 130031, China
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(19), 4019; https://doi.org/10.3390/molecules30194019
Submission received: 22 August 2025 / Revised: 5 October 2025 / Accepted: 6 October 2025 / Published: 8 October 2025
(This article belongs to the Special Issue Cyclization Reactions in the Synthesis of Heterocyclic Compounds)
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Versions Notes

Abstract

Azomethine ylides (AMYs) have a nitrogen–carbon double bond and an electron lone pair on the nitrogen atom. They are essential 1,3-dipoles for [3+2] cycloadditions in the synthesis of pyrrolidine-containing heterocycles. Significant progress in 1,3-diplolar cycloadditions has been made in the construction of novel heterocyclic scaffolds, with efforts to broaden substrate scope, enhance stereoselectivity, and integrate green chemistry principles. This article summarizes double cycloadditions of AMYs derived from amino esters and amino acids for the synthesis of novel polyheterocycles. The design of double cycloadditions through the pot, atom, and step economic (PASE) method to increase the reaction efficiency is discussed. The examples presented in this paper may be applied to the synthesis of biologically active molecules.

Graphical Abstract

1. Introduction

Azomethine ylides (AMYs) are 1,3-dipoles that have a unique nitrogen–carbon double bond and a lone pair of electrons on the nitrogen atom [1,2,3]. They are versatile synthons for [3+2] cycloaddition with dipolarophiles in making pyrrolidine-containing heterocycles [4,5,6,7]. Given the widespread occurrence of pyrrolidine-containing natural products and bioactive compounds 1–7, as exemplified in Figure 1, significant effort has been dedicated to the development of new methods for the synthesis of pyrrolidine-based heterocyclic systems with broad substrate scope and high stereo- and regioselectivities [8,9,10,11]. These methods have been applied to the synthesis of some natural products and biologically active polyheterocyclic compounds, such as 8–15, as shown in Figure 2 [12]. Chiral catalyst-promoted asymmetric [3+2] cycloadditions have also been developed to make enantiomerically pure compounds and drug molecules [12,13,14,15,16,17,18,19,20]. Recently, green principles have been applied to increase synthetic efficiency and reduce environmental impact, especially for large-scale synthesis [21,22].
There are a number of reviews on AMYs derived from amino acids/esters [9,11]. They can be generated in situ by various methods, such thermal or photochemical decomposition of iminium salts, condensation of aldehydes with amines, and metal-catalyzed reactions [9]. The resulting AMYs undergo 1,3-dipolar cycloadditions with dipolarophiles, such as electron-deficient alkenes and alkynes. Presented in this paper is AMY-initiated [3+2] cycloaddition, followed by a second cycloaddition of [3+2] or a [4+2] cycloaddition (Scheme 1). Two sequential cycloadditions could be conducted in one pot or as stepwise reactions. These one-pot cycloadditions, without isolation of the intermediates, enhance the atom economy by reducing the number of operational steps, minimizing solvent usage, and reducing the workup and purification steps, increasing time and resource efficiency [23,24,25,26,27,28,29]. This approach has been successfully applied to the synthesis of natural products and bioactive polyheterocyclic systems for medicinal chemistry and agrochemical applications [12].

2. Double 1,3-Dipolar Cycloadditions

Presented in this section are AMYs for double 1,3-dipolar cycloadditions. There are three types of AMYs generated from the condensation of aldehydes with amino acids/esters through dehydration or decarboxylation processes (Scheme 2) [9]. (1) Stabilized AMYs A1 derived from amino esters have high regio- and stereoselectivity in 1,3-dipolar cycloadditions due to the electron-withdrawing group (EWG). But only glycine esters with two α-hydrogens can be used for the second cycloaddition of B1 for making pyrrolizidines C1. (2) Semi-stabilized AMYs A2 generated from the reaction of α-2H/alkyl amino acids with aromatic aldehydes after decarboxylation give rise to products C2 with reduced stereoselectivity. (3) Non-stabilized AMYs A3 generated from the reaction of α-2H/alkyl amino acids with aliphatic aldehydes give rise to products with more stereoisomers, C3. It was found that pyrrolidines B2 and B3 generated in situ from the decarboxylative 1,3-dipolar cycloaddition of semi- or non-stabilized AMYs A2 and A3 would undergo second 1,3-dipolar cycloaddition via α-C-H functionalization [30,31,32,33,34].

2.1. Double [3+2] Cycloadditions with Stabilized AMYs

Stabilized AMYs are in conjugation with electron-withdrawing groups, such as carbonyl or ester groups on the adjacent carbon atom [17,35]. They have high regio- and stereoselectivity in the 1,3-dipolar cycloaddition reactions. But only glycine esters, which have two α-hydrogens, can be used for double [3+2] cycloaddition reactions [9,11]. This limits the scope of using stabilized AMYs for double [3+2] cycloadditions.

2.1.1. Intermolecular Double [3+2] Cycloadditions

The Gan group reported the first intermolecular double [3+2] cycloadditions of three components. AMY I, generated from the condensation of glycine ester 16a and cinnamaldehyde 17a, reacted with N-phenylmaleimide 18a to give pyrrolidine 19a, which then underwent a second [3+2] cycloaddition with the second equivalent of 17a and 18a under microwave irradiation to afford pyrrolizidine 20a (Scheme 3) [36]. The addition of ICl could further convert pyrrolizidine 20a into highly stereoselective cycl[3.2.2]azine 22 via 6-exo-trig cyclization of 21. The stereochemistry of 22 was determined by single-crystal X-ray analysis. In the presence of RuCl3/AgOTf, pyrrolizidines 20 bearing styrenyl substituents at the 3,5-positions underwent 6-exo-trig cyclization followed by an intramolecular Friedel–Crafts reaction to form decahydrocycl[3.2.2]azines 23a–c in 34–82% yields. The stereochemistry of 23 was determined by NOESY analysis. The proposed mechanism suggests that the coordination of a Ru catalyst with a less sterically hindered styrenyl double bond gives intermediates 24 (Scheme 4) [37]. The Ru catalyst is activated by AgOTf to form RuCl2(OTf) and AgCl. The 6-exo-trig cyclization of 24 cis to the ester group gives intermediates 25, in which a benzyl cation is generated for the Friedel–Crafts reaction to afford 26. Finally, rearomatization and hydrolysis of 26 give products 23. When the OMe group was present as R2 and/or R3 on the styrenyl groups, it was found that 20 could be epimerized to 28 at the pyrrolizidine carbons connected to the styrenyl group (Scheme 5) [37].
Zhang’s group developed microwave-assisted one-pot double [3+2] cycloadditions of glycine ester 16a with aromatic aldehydes 29 and maleimides 18 for the first cycloaddition to make intermediates 30, followed by a second cycloaddition with aromatic aldehydes 29′ and maleimides 18′ to afford tetracyclic pyrrolizidines 31 in 10–80% yields. The product structure was determined by single-crystal X-ray analysis (Scheme 6) [38]. Quiroga’s group also accomplished diastereoselective synthesis of pyrazolylpyrrolizines 34 through double cycloadditions of glycine ester 16a with two equivalents each of formylpyrazoles 32 and maleimides 18 under conventional heating (Scheme 7) [39].
The Guiry group employed a series of chiral UCD Imphanol ligands possessing central and planar chirality in Zn-catalyzed asymmetric [3+2] cycloadditions [40]. Among them, compound 35 was made in a 92% yield with excellent diastereo- and enantioselectivities (endo/exo > 99/1 and 99.7% ee) using Zn(OTf)2 and (S,S,RP)-UCD-Imphanol. The second cycloaddition of pyrrolidines 35 gave tetracyclic pyrrolizidine 36 in a 76% yield with endo/exo > 92/8 and 99.2% ee. During the second cycloaddition, no stereochemistry erosion was observed (Scheme 8).
Instead of using maleimides 18 as dipolarophiles, the Miftakhov lab employed methyl acrylate 37 for Ag-catalyzed double [3+2] cycloadditions to afford pyrrolizidine alkaloids 38 in 30–65% yields (Scheme 9) [41]. The structure confirmation was accomplished via NOE and X-ray single-crystal analyses. Zhang’s group employed different aldehydes, 29 and 29′, as well as maleimides 18 and olefinic oxindoles 39 as different dipolarophiles for two [3+2] cycloadditions in the diastereoselective synthesis of spirooxindole pyrrolizidines 40 in 49–69% yields (Scheme 10) [42]. When olefinic oxindole 39a was used for the first cycloaddition, it was found that adducts 41 failed to react with 29c and 18b for the second cycloaddition. The proton in the β-ester group of AMY-X is probably less acidic than that in AMY-X’, which prevents the second cycloaddition from forming product 42 (Scheme 11) [42].

2.1.2. Intramolecular Double [3+2] Cycloadditions

The first intramolecular double [3+2] cycloaddition of glycine ester was reported by Zhang’s group in 2005. In this case, the one-pot reaction of glycine esters 16 with an excess amount of O-allyl salicylaldehydes 43 afforded a novel hexacyclic ring system 45, which had four new rings and seven stereocenters (Scheme 12) [43]. The first cycloaddition generated tricyclic proline intermediates 44, which then underwent a second cycloaddition to afford compounds 45 diastereoselectively. The major stereoisomers were isolated in 30–40% yields, and the stereochemistry of the product was confirmed by X-ray crystal structure analysis. If the major diastereomers have perfluoro C8F17(CH2)3 as the R group, they can simply be purified by fluorous solid-phase extraction (F-SPE) [44,45].

2.1.3. Intermolecular and Intramolecular [3+2] Cycloadditions

The combination of inter- and intramolecular [3+2] cycloadditions could lead to the formation of novel and complex scaffolds. Zhang’s group utilized benzaldehydes 29, glycine ester 16a, and N-ethylmaleimides 18 for intermolecular cycloaddition to make intermediate 30 under microwave heating. Without isolation, the reaction mixture was reacted with dipolarophiles 46 or 48 under TFA catalysis for the intramolecular [3+2] cycloaddition (Scheme 13) [46]. The reaction of alkynes 46 generated 47 with three new rings, six new bonds, and five stereocenters in 29–77% yields with 8:1 to 13:1 dr. The reaction of terminal alkenes 48a,b afforded products 49a,b with six stereocenters in up to a 57% yield and > 5:1 dr. The reactions of alkenes 48c–j with an R4 group gave products 49c–j, bearing seven stereocenters in 46–79% yields with 5:1 to 8:1 dr.

2.2. Decarboxylative Double [3+2] Cycloadditions

Stabilized AMYs derived from amino esters have been well utilized in [3+2] cycloadditions. AMYs derived from amino acids were first reported in 1980s, but they have not been well explored in [3+2] cycloadditions because the reactions are more complicated [47,48,49,50,51,52]. In 2019, Zhang’s group reported the double [3+2] cycloadditions of amino acids involving the key intermediate of oxazolidin-5-ones (Scheme 14) [9]. Compared to using glycine esters to generate AMYs for double cycloadditions, a range of α-amino acids could be used in cycloadditions since the CO2 is released to generate a reactive site for the second cycloaddition. However, if R2 is not an EWG, AMYs derived from α-amino acids may be semi-stabilized or non-stabilized, producing less stereoselective cycloaddition products. It is important to understand the mechanism of amino acid-based double cycloadditions.

2.2.1. Double [3+2] Cycloadditions with Maleimides

Zhang’s group reported the first case of amino acid-based decarboxylative double [3+2] cycloaddition. It was a A+2B+2C-type five-component reaction (5-CR), which uses one equivalent of α-amino acids 50 and two equivalents each of aromatic aldehydes 29 and maleimides 18 for making tetracyclic pyrrolizidines 51. Under optimized conditions, the reaction of glycine produced 51a in a 91% yield with >9:1. In addition to glycine, other amino acids such as alanine, butyrine, norvaline, serine, leucine and aspartic acid could be used for the 5-CRs (Table 1) [53,54]. AcOH was added as a catalyst to overcome the hindrance effects of R1 to make 51b-f in up to an 88% yield with dr > 8:1 [53]. The reaction of aspartic acid (R1 = CH2CO2H) afforded compound 51g in a 66% yield with ~4:1 dr [54]. However, some α-amino acids, such as valine and phenylglycine, did not give rise to double cycloaddition products 51 but only the first [3+2] adducts 52. The double cycloaddition reactions were also conducted as one-pot and two-step processes through a reaction of one equivalent each of 18, 29a, and 50 for the first cycloaddition, followed by the addition of another equivalent of 29a and 50 for the second cycloaddition. As shown in the last column of Table 1, the two-step process was only successful for the synthesis of 51a.
Control reactions were conducted to understand the mechanism of 5-CRs. In addition, 3-CRs of amino acids 50 (glutamic acid or cysteine) with equal amounts of molar aldehydes 29 and maleimides 18 gave tetrahydropyrrolizinones 53 in 49–71% yields. A four-component reaction (4-CR) with two equivalents of aldehydes gave tetrahydropyrrolothiazoles 54 in 63–79% yields, while 5-CRs failed in the synthesis of tetracyclic pyrrolizidines 51 (Scheme 15) [54,55].
Stepwise double cycloadditions of glycine 50a with two different sets of aldehydes (29 and 29′) and two different sets of dipolarophiles (18 and 18′) were conducted by Zhang’s group. In the reaction process, the first cycloaddition products 55 generated from the reaction of 50a, 29, and 18 were isolated and used for the second cycloaddition with 29′ and 18′ (Table 1) [53]. Compounds 56 were isolated in 22–60% yields with 3:1 dr (Scheme 16), which is lower than that of the 5-CR for 51a (91%, >9:1 dr) shown in Table 1. Other than glycine, other α-amino acids could not afford double cycloaddition products [53].
The proposed mechanisms for one-step and two-step double cycloadditions are shown in Scheme 17. In the single-step reactions, the reaction of acid 50 with 2 equiv. of aldehydes 29 generates stabilized AMY-I with Ar and lactone as conjugate groups to facilitate decarboxylative cycloaddition with 18 to form semi-stabilized AMY-II for a second cycloaddition with another equivalent of 18 to give pyrrolizidines 51. In the two-step reaction process, pyrrolidines 55 generated from the first cycloaddition of semi-stabilized AMY-III were isolated and used for the formation of another semi-stabilized AMY-IV for a second cycloaddition to give 56 in low yields and with low stereoselectivity (Scheme 16) [53,54]. Only the production of an amino acid with R1 = H is possible due to there being less steric hindrance for α-C-H activation [30,31,32,33,34]. Mechanism analysis indicates that two-step double cycloadditions of two semi-stabilized AMYs limits the reaction scope and gives products with low yields and stereoselectivity.

2.2.2. Double [3+2] Cycloadditions with Olefinic Oxindoles

As part of their effort to develop A+2B+2C-type decarboxylative double [3+2] cycloadditions of amino acids 50, Zhang and coworkers employed olefinic oxindoles as dipolarophiles in the synthesis of dispirooxindole-pyrrolizidines 58 and 59, which have a butterfly-shaped skeleton (Scheme 18). In the reaction of glycine 50a, aldehydes 29, and olefinic oxindoles 57 under heterogeneous catalysis of zeolite HY, compounds 58 were obtained as the major diastereomers in 41–73% yields. Zeolite HY has a three-dimensional pore structure to regulate stereoselectivity via an endo-transition state to produce products that have a symmetric butterfly shape [56]. Using BzOH as a catalyst and heating at 150 °C, the cycloadditions occurred via an exo-transition state to afford 59 as the major diastereomers in 46–71% yields [57]. Compared to reactions using maleimides 18 as dipolarophiles to form 51a–e, the reactions of olefinic oxindoles 57 only reacted with glycine to afford compound 59a. The reactions of R1-substituted amino acids were unsuccessful in the attempted synthesis of compounds 60–62 due to steric hindrance for the second cycloaddition (Scheme 19).

2.2.3. Double [3+2] Cycloadditions with Meta-Dinitrobenzene Derivatives

The Starosotnikov group utilized meta-dinitrobenzene derivatives, such as compound 65, in combination with dual dipolarophiles in double cycloaddition reactions of non-stabilized N-methyl AMY derived from the reaction of sarcosine 63 and paraformaldehyde 64. The reaction process afforded compounds 66–70 in 24–69% yields (Scheme 20) [58]. The AMY has favorable symmetry, which contributes to the stereoselective formation of compounds 66–70. This is a noteworthy case in the parallel cycloaddition of meta-dinitrobenzene derivatives.

2.3. [3+2] Cycloaddition Followed by a Click Reaction

The combination of two different kinds of cycloaddition reactions is an efficient way to synthesize complex molecular scaffolds [23,24,25,26,27]. It has been applied to the synthesis of biologically relevant molecules [9,12]. Zhang’s group employed [3+2] cycloaddition intermediates for subsequential annulation reactions to generate diverse heterocyclic systems. Among these, notable examples using 2-azidobenzaldehyde-based [3+2] cycloadditions paired with cyclization and cycloadditions for synthesizing polyheterocycles 73–79 are shown in Scheme 21. In this section, we only discuss [3+2] cycloaddition followed by a click reaction in the synthesis of 78 and 79 [59,60].

2.3.1. Stabilized AMY-Based [3+2] Cycloadditions

Cycloaddition of amino esters 16, maleimides 18, and 2-azidobenzaldehydes 71 via the formation of stabilized AMYs leads to the formation of intermediates 72a in good stereoselectivity. Zhang’s group conducted N-propargylation of 72a to form 80, which were readily converted to triazolobenzodiazepines 78 after the intramolecular click reaction. By optimizing the reaction conditions, the [3+2] cycloaddition, N-propargylation, and click chemistry were achieved through a one-pot reaction process which eliminated the steps of intermediate purification and metal catalysts for the click reaction. A total of 13 analogs of 78 were obtained in 33–69% yields as single diastereomers. The stereochemistry of the products was confirmed by X-ray crystal analysis (Scheme 22) [59].

2.3.2. Semi-Stabilized AMY-Initiated [3+2] Cycloaddition

The NH pyrrolidines 81 generated by the decarboxylative [3+2] cycloaddition of α-amino acids could be combined through the click reaction in the synthesis of triazolobenzodiazepines 79. As opposed to the cycloadditions shown in Scheme 22, which involve stabilized AMYs, the reaction of α-amino acids involves semi-stabilized AMYs. Ma and coworkers developed a one-pot processes by combining decarboxylative [3+2] cycloaddition, N-propargylation, and the click reaction. Among the amino acids, the reaction of valine, phenylglycine, and aminoisobutyric acid afforded compounds 79a–f in 35–65% yields, but the diastereoselectivity was reduced from 7:1 to 2:1 due to the semi-stabilized AMYs (Scheme 23) [60].

3. [3+2] Cycloaddition and [4+2] Cycloaddition

The [4+2] cycloaddition (Diels–Alder reaction) is the most popular cycloaddition reaction for making six-membered compounds [61,62,63]. The [3+2] adducts could be used for [4+2] cycloaddition in the synthesis of complex structures with diverse functional groups [26,27,64,65,66,67]. Zhang’s group developed sequential [3+2] and [4+2] cycloaddition reactions in the synthesis of highly condensed heterocyclic compounds 86. The stereoselective adducts 84 generated from the [3+2] cycloaddition of 2-furanylaldehydes 83, amino esters 16, and maleimides 18 were N-acylated to give intermediates 85, which readily underwent intramolecular [4+2] cycloaddition to afford polyheterocyclic products 86 in 75–90% yields (Scheme 24) [68].

4. Conclusions

Presented in this paper are double cycloadditions of AMYs derived from amino esters or amino acids for the synthesis of complex polyheterocycles. The pyrrolidine intermediates generated from the initial [3+2] cycloaddition were employed in the subsequent [3+2], click, or [4+2] cycloaddition reactions to demonstrate the versatility of this strategy. Different synthetic designs including multicomponent, one-pot stepwise, and multistep reactions afforded a diverse array of novel heterocyclic architectures, such as tetracyclic, pentacyclic, hexacyclic, and heptacyclic compounds. Notably, the methodology enabled the efficient construction of biologically interesting scaffolds, including pyrrolizidines, spirooxindole- and dispirooxindole-pyrrolizidines, tetrahydropyrrolizinones, tetrahydropyrrolothiazoles, and triazolobenzodiazepines. We believe this synthetic platform is valuable in the generation of structurally complex and diverse polyheterocycles for applications in organic synthesis and medicinal chemistry.

Author Contributions

Writing—original draft preparation, T.Z.; investigation, T.Z. and D.Z.; formal analysis, Y.J.S. and D.Z.; data curation, X.Z. and Y.J.S.; writing—review and editing, X.Z.; supervision and revision, W.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by a horizontal project to T.Z. (Grant No. 2023JBH26L80, 2024JBH26L23).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AMYAzomethine ylide
BzOHBenzoic acid
EWGElectron-withdrawing group
NOESYNuclear Overhauser effect spectroscopy
PASEPot, atom, and step economic
TEATriethylamine
TFATrifluoroacetic acid
THFTetrahydrofuran
UCD-ImphanolImidazolinyl-[2.2]paracyclophanol

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Molecules 30 04019 g001
Figure 1. Representative pyrrolidine-containing natural products.
Figure 1. Representative pyrrolidine-containing natural products.
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Molecules 30 04019 g002
Figure 2. AMY-based synthesis of natural products.
Figure 2. AMY-based synthesis of natural products.
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Molecules 30 04019 sch001
Scheme 1. Examples of three kinds of [3+2]-initiated double cycloadditions.
Scheme 1. Examples of three kinds of [3+2]-initiated double cycloadditions.
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Molecules 30 04019 sch002
Scheme 2. Three AMYs for double [3+2] cycloadditions.
Scheme 2. Three AMYs for double [3+2] cycloadditions.
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Molecules 30 04019 sch003
Scheme 3. Stereoselective synthesis of pentacyclic pyrrolizidines 22.
Scheme 3. Stereoselective synthesis of pentacyclic pyrrolizidines 22.
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Molecules 30 04019 sch004
Scheme 4. Ru-catalyzed synthesis of heptacyclic pyrrolizidines 23.
Scheme 4. Ru-catalyzed synthesis of heptacyclic pyrrolizidines 23.
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Molecules 30 04019 sch005
Scheme 5. Epimerization of tetracyclic pyrrolizidines 20.
Scheme 5. Epimerization of tetracyclic pyrrolizidines 20.
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Molecules 30 04019 sch006
Scheme 6. One-pot synthesis of tetracyclic pyrrolizidines 31.
Scheme 6. One-pot synthesis of tetracyclic pyrrolizidines 31.
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Molecules 30 04019 sch007
Scheme 7. Cascade synthesis of pyrazolylpyrrolizines 34.
Scheme 7. Cascade synthesis of pyrazolylpyrrolizines 34.
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Molecules 30 04019 sch008
Scheme 8. Enantioselective synthesis of pyrrolizidines 36.
Scheme 8. Enantioselective synthesis of pyrrolizidines 36.
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Molecules 30 04019 sch009
Scheme 9. Intermolecular double [3+2] cycloadditions with methyl acrylate.
Scheme 9. Intermolecular double [3+2] cycloadditions with methyl acrylate.
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Molecules 30 04019 sch010
Scheme 10. Diastereoselective synthesis of spirooxindole pyrrolizidines 40.
Scheme 10. Diastereoselective synthesis of spirooxindole pyrrolizidines 40.
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Molecules 30 04019 sch011
Scheme 11. Attempted reactions for making compound 42.
Scheme 11. Attempted reactions for making compound 42.
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Molecules 30 04019 sch012
Scheme 12. One-pot synthesis of hexacyclic pyrrolizidines 45.
Scheme 12. One-pot synthesis of hexacyclic pyrrolizidines 45.
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Molecules 30 04019 sch013
Scheme 13. One-pot synthesis of pentacyclic pyrrolizidines 47 and 49.
Scheme 13. One-pot synthesis of pentacyclic pyrrolizidines 47 and 49.
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Molecules 30 04019 sch014
Scheme 14. Formation of AMYs via decarboxylation of oxazolidin-5-ones.
Scheme 14. Formation of AMYs via decarboxylation of oxazolidin-5-ones.
Molecules 30 04019 sch014
Molecules 30 04019 sch015
Scheme 15. 3-CR and 4-CR for tetrahydropyrrolizinones 53 and tetrahydropyrrolothiazoles 54.
Scheme 15. 3-CR and 4-CR for tetrahydropyrrolizinones 53 and tetrahydropyrrolothiazoles 54.
Molecules 30 04019 sch015
Molecules 30 04019 sch016
Scheme 16. Two-step synthesis of tetracyclic pyrrolizidines 56.
Scheme 16. Two-step synthesis of tetracyclic pyrrolizidines 56.
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Molecules 30 04019 sch017
Scheme 17. Proposed pathways for single-step vs. two-step double [3+2] cycloadditions.
Scheme 17. Proposed pathways for single-step vs. two-step double [3+2] cycloadditions.
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Molecules 30 04019 sch018
Scheme 18. 5-CR to make dispirooxindole-pyrrolizidines 58 and 59.
Scheme 18. 5-CR to make dispirooxindole-pyrrolizidines 58 and 59.
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Molecules 30 04019 sch019
Scheme 19. Double cycloadditions with maleimide 18c vs. olefinic oxindole 57a.
Scheme 19. Double cycloadditions with maleimide 18c vs. olefinic oxindole 57a.
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Molecules 30 04019 sch020
Scheme 20. Parallel double decarboxylative [3+2] cycloadditions.
Scheme 20. Parallel double decarboxylative [3+2] cycloadditions.
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Molecules 30 04019 sch021
Scheme 21. 2-Azidobenzaldehyde-based [3+2] cycloadditions for heterocyclic systems.
Scheme 21. 2-Azidobenzaldehyde-based [3+2] cycloadditions for heterocyclic systems.
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Molecules 30 04019 sch022
Scheme 22. Stabilized AMY-initiated [3+2] cycloaddition and click chemistry.
Scheme 22. Stabilized AMY-initiated [3+2] cycloaddition and click chemistry.
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Molecules 30 04019 sch023
Scheme 23. [3+2] Cycloaddition of semi-stabilized AMYs and click reaction.
Scheme 23. [3+2] Cycloaddition of semi-stabilized AMYs and click reaction.
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Molecules 30 04019 sch024
Scheme 24. [3+2] Cycloaddition of semi-stabilized AMYs and click reaction.
Scheme 24. [3+2] Cycloaddition of semi-stabilized AMYs and click reaction.
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Table 1. 5-CR for making tetracyclic pyrrolizidines 51.
Table 1. 5-CR for making tetracyclic pyrrolizidines 51.
Molecules 30 04019 i001
Amino Acids 50R1R2ProductOne-Pot Yield (dr) 3Two-Step Yield (dr) 4
glycine 1HEt51a91% (>9:1)48.5% (3:1)
alanineMeEt51b88% (>8:1)--
butyrineEtEt51c88% (>8:1)--
norvalinePrEt51d75% (>8:1)--
serineCH2OHMe51e83% (>8:1)--
leucineiBuMe51f53% (>8:1)--
aspartic acid 2CH2CO2HEt51g66% (~4:1)--
valineiPrEt51h----
phenylglycinePhEt51i----
glutamic acidCH2CH2CO2HEt51j----
cysteineCH2SHEt51k----
1 a EtOH, 90 °C, 3 h; 2 EtOH, AcOH, 110 °C, 12 h; 3 one-pot 5-CR process; 4 two-step process.
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Zhou, T.; Zhang, X.; Sheng, Y.J.; Zhan, D.; Zhang, W. Recent Developments in Azomethine Ylide-Initiated Double Cycloadditions. Molecules 2025, 30, 4019. https://doi.org/10.3390/molecules30194019

AMA Style

Zhou T, Zhang X, Sheng YJ, Zhan D, Zhang W. Recent Developments in Azomethine Ylide-Initiated Double Cycloadditions. Molecules. 2025; 30(19):4019. https://doi.org/10.3390/molecules30194019

Chicago/Turabian Style

Zhou, Tieli, Xiaofeng Zhang, Yan Jan Sheng, Desheng Zhan, and Wei Zhang. 2025. "Recent Developments in Azomethine Ylide-Initiated Double Cycloadditions" Molecules 30, no. 19: 4019. https://doi.org/10.3390/molecules30194019

APA Style

Zhou, T., Zhang, X., Sheng, Y. J., Zhan, D., & Zhang, W. (2025). Recent Developments in Azomethine Ylide-Initiated Double Cycloadditions. Molecules, 30(19), 4019. https://doi.org/10.3390/molecules30194019

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