Azlactone rings: uniting tradition and innovation in synthesis

Abstract

Azlactones, also known as oxazolones, are a class of heterocyclic compounds with significant relevance in the synthesis of non-natural amino acids and their derivatives. Their reactivity stems from the presence of both pro-nucleophilic and electrophilic sites, making them highly versatile and enabling a diversity of transformations. In recent years, numerous synthetic strategies utilizing azlactones as key substrates have been developed, encompassing photochemical reactions, cycloadditions, conjugate additions, and dynamic kinetic resolutions. Particular emphasis has been placed on transition-metal catalysis and organocatalyzed processes, which offer precise control over stereo- and/or regioselectivity. This review offers a comprehensive perspective on recent advances in azlactone chemistry, highlighting key reaction mechanisms and activation modes through a variety of examples.

---

Marcelo H. R. Carvalho

Marcelo Henrique Reis Carvalho was born in Barbacena, Brazil, in 1998. He got his degree in Chemistry (2021) from the Federal Institute of Southeast Minas Gerais. He is currently working on his PhD in Chemistry (Organic Chemistry) at the Federal University of Juiz de Fora, under the supervision of Prof. Giovanni W. Amarante. His current research interests include experimental and theoretical investigation of multicomponent reactions and catalytic transformations.

Geovana F. Vargas

Geovana Fontes Vargas was born in Valença, Brazil, in 2001. She is a bachelor's student in Chemistry at the Federal University of Juiz de Fora where she is currently working on the synthesis of bioactive molecules under the supervision of Prof. Giovanni W. Amarante.

João P. R. S. Ribeiro

João Paulo Ramalho dos Santos Ribeiro was born in Juiz de Fora, Brazil, in 1997. He has been a bachelor's student in Chemistry at the Federal University of Juiz de Fora since 2019. Currently, he is developing new methodologies with N-heterocycles, including azlactone scaffolds, under the supervision of Prof. Giovanni W. Amarante.

Pedro P. de Castro

Prof. Pedro Pôssa de Castro was born in Belo Horizonte, Brazil. He got his undergraduate degree in Pharmacy (2014), his Master's degree in Pharmaceutical Sciences (2016) and his PhD in Organic Chemistry (2020), at the Federal University of Juiz de Fora UFJF. He spent a year as a post-doc researcher at the UFJF and two years as a post-doc at the Federal University of São Carlos. In 2024, he started his own career at the Department of Pharmacy at the Federal University of Juiz de Fora – Campus Governador Valadares. His research interests are focused on multicomponent reactions and organic electrosynthesis.

Giovanni W. Amarante

Prof. Giovanni W. Amarante finished his PhD in Sciences (Organic Chemistry) at the University of Campinas (UNICAMP), Brazil, 2009. Afterwards, he spent a year as a post-doc researcher at the University of California Berkeley (USA) working on gold catalysis under the supervision of Prof. F. Dean Toste. Beginning in 2011, he started his own career at the Federal University of Juiz de Fora where he is currently associate Professor. His laboratory has focused on the development of catalytic organic transformations and total synthesis of bioactive molecules.

---

Introduction

Azlactones (1), commonly referred to as oxazolones (Fig. 1), are a class of five-membered oxygen- and nitrogen-containing heterocycles that have been widely explored in organic synthesis. Their distinct ring system provides a versatile platform for a variety of chemical transformations, making them valuable intermediates in modern synthetic methodologies. Azlactones exhibit an electrophilic character at the carbonyl and imine positions and possess an activated α-carbonyl group (pro-nucleophile), which allows them to participate in diverse reactions, including nucleophilic additions, ring-opening reactions, pericyclic processes, and transition-metal-catalyzed transformations.^1,2

Fig. 1 General structure of azlactones and Erlenmeyer–Plöchl azlactones.

Among them, Erlenmeyer–Plöchl azlactones (2) stand out as key substrates in the preparation of diverse amino acid derivatives. This classical reaction, which involves the condensation of an acylglycine with an aromatic aldehyde in the presence of a base, remains an important approach for the synthesis of non-natural amino acids and related scaffolds.³

Beyond their traditional use in amino acid chemistry, azlactones have gained increasing attention across multiple fields of chemistry. In medicinal chemistry, they serve as precursors for pharmacologically active compounds,⁴ including bioactive analogues, enzyme inhibitors and active pharmaceutical ingredients (APIs).^5–9 In materials chemistry, azlactone-functionalized scaffolds have been utilized in polymer modifications and advanced material design.^10–14 Moreover, their ability to undergo diverse transformations make them attractive platforms for modern synthetic strategies, including asymmetric catalysis, organocatalysis, and transition-metal-catalyzed functionalizations.¹⁵

Despite being a well-established class of heterocycles, azlactones continue to be a subject of intense research. In recent years, numerous research groups have dedicated efforts to expanding the synthetic utility of these derivatives, uncovering new reactivities and broadening their application scope. This ongoing exploration has led to significant methodological advancements and innovative transformations in this area.

Our research group has actively contributed to the study of azlactone chemistry and has previously published two comprehensive review articles on this topic. The first covered developments up to 2016,¹⁶ while the second focused on advances from 2016 to 2019.¹⁷ Given the rapid progress in this field, the present review aims to provide an updated overview of the most recent synthetic strategies and transformations involving azlactone rings, including Steglich rearrangements, Michael-type additions, Mannich-type reactions, C2 functionalization, dynamic-kinetic resolutions, ring-opening reactions, and cycloaddition reactions, focusing on studies published since 2019.

Steglich rearrangement

The Steglich rearrangement is a traditional reaction involving azlactone rings, in which an acetyl or acetoxy oxazole derivative is converted to its corresponding 4-substituted analogue.^18,19 Notably, in this transformation, a new stereogenic center is generated, highlighting its potential for the development of enantio- and diastereoselective protocols.

For example, in 2019, Xie, Guo, and co-workers reported the asymmetric Steglich rearrangement of O-acylated azlactones (3) using a chiral prolinamide-based DMAP N-oxide (4) as a catalyst, affording azlactones with a tetra-substituted stereogenic center (5) in up to 97% yield and 97% e.e. (Scheme 1).²⁰ Although most of the reactions achieved high efficiency (e.g., 6 and 8), the introduction of bulky substituents at the azlactone C4 position reduced both yield and enantioselectivity (e.g., 7).

Scheme 1 Asymmetric Steglich rearrangement of O-acylated azlactone with a chiral DMAP N-oxides organocatalyst.

Based on control experiments, a reaction mechanism has been proposed by the authors (Scheme 2). Initially, an ion-pair intermediate 9 is formed through the acyl transfer of the O-acylated azlactone 3 to catalyst 4. Next, the interaction between the oxygen atom of the enolate and the amide hydrogen stabilizes the anion, creating a favorable molecular arrangement (10) that enables the azlactone enolate to attack the carbonyl group attached to the catalyst. This reaction ultimately yields the desired product (5) while regenerating the catalyst.

Scheme 2 Proposed mechanism for the Steglich rearrangement using a chiral DMAP N-oxides catalyst.

In the same year, a DMAP–thiourea derivative (12) as a bifunctional catalyst for a similar rearrangement was introduced by Liu, Tian, and co-workers.²¹ Employing this chiral catalyst, the transformation of oxazolyl carbonates (11) into C4-carboxyazlactones (13) was achieved with yields of 60%–90% and enantiomeric excesses ranging from 85 to 97% e.e. (Scheme 3). While modifications at the C4 position maintained enantioselectivity, replacing the benzyl group with other substituents led to lower yields (e.g., 15). Additionally, variations in the ester moiety were only minimally investigated (e.g., 16). A gram-scale reaction of 14 was carried out, revealing a decrease in terms of enantioselectivity (90% e.e. compared with 97% e.e. observed on a small scale) while maintaining a high yield of 93%.

Scheme 3 Steglich rearrangement using a chiral DMAP–thiourea bifunctional catalyst.

A plausible reaction mechanism has been proposed (Scheme 4), in which the reaction between the catalyst 12 and the carbonate 11 produces the ion-pair intermediate 17. Product 13 is generated through an irreversible C-carboxylation, and the catalyst is regenerated. The authors suggest that (S)-products are favored, probably due to both π–π and electrostatic interactions influencing the stereochemical outcome of this transformation.

Scheme 4 Proposed mechanism for the DMAP–thiourea-catalyzed Steglich rearrangement.

In 2020, Zhang, Zhang, and co-workers reported a one-pot protocol for the synthesis of tetrasubstituted α-amino acid derivatives (23) through a Steglich rearrangement.²² The process involves the in situ generation of anhydrides, which undergo intramolecular cyclization to form azlactones, followed by a second acylation step to afford the final products (21). After a ring-opening reaction, the final products were isolated in 65–83% yield with low to excellent enantiomeric excesses (up to 99% e.e.) (Scheme 5). The reaction scope revealed that bulky groups at the C4 position of the core led to reduced yields and enantioselectivity (e.g., 26), whereas sterically demanding nucleophiles adversely affected reaction efficiency (e.g., 25).

Scheme 5 Sequential acylation reactions to obtain tetrasubstituted α-amino acid derivatives.

Based on experimental results, a reaction mechanism has been proposed (Scheme 6). Initially, substrate 27 is formed from the reaction of the catalyst (20) and benzyl chloroformate (19). This substrate is attacked by the N-substituted amino acid (18) to produce the intermediate 28. Subsequently, this substrate reacts with the catalyst (20) to form the intermediate 29, which from an intermolecular reaction produces the anionic azlactone 30. Then, an enantioselective direct acylation occurs to generate 4-carboxyazlactone (21). Chiral catalyst acylation gives the corresponding species 31, followed by the nucleophilic attack of the amino ester, releasing the final product and regenerating the catalyst.

Scheme 6 Proposed mechanism for asymmetric acylation of amino acids.

Michael-type addition

One of the most common transformations involving azlactone rings is the Michael-type addition involving conjugated olefins (e.g., enones). Although numerous studies have explored this type of reactivity, there is still ample room for innovation. For instance, novel protocols involve either designing new catalysts for this asymmetric transformation or performing the Michael-type reaction followed by additional transformations, such as ring-opening reactions, to access new classes of enantioenriched compounds.

In this context, Nakamura and co-workers have recently described the cinchona alkaloid sulfonamide as a catalyst for the asymmetric preparation of β^2,2-amino acids (36), which feature two contiguous tetra-substituted stereogenic centers (Scheme 7).²³ The reaction between azlactone 32 and β-nitroacrylates 33 in the presence of the organocatalyst 34 yielded the desired analogues 35, which, after a one-pot ring-opening, afforded the products (36). These products were isolated in moderate to good yields (55–85%) and exhibited excellent diastereomeric ratios (>20 : 1 in all cases) and enantiomeric excesses (up to 98% e.e.) (Scheme 7). A 20-fold scale-up reaction was performed for compound 37, achieving 84% yield without any loss in terms of enantioselectivity (99% e.e.). However, an important limitation of this approach involves the fact that only azlactones bearing aryl groups as substituents were employed.

Scheme 7 Cinchona sulfonamide-organocatalyzed preparation of β^2,2-amino acid derivatives.

The plausible mechanism begins with the quinuclidine moiety (34), which induces the conversion of azlactone (32) to its enol form (40) (Scheme 8). Next, the β-nitroacrylate (33) is activated through a hydrogen bonding interaction with the sulfonamide moiety, facilitating a Si-face nucleophilic attack from the activated oxazolone (41). Finally, after proton transfer, the catalyst is regenerated and provides the (2R,4′S)-isomer as the major product (35).

Scheme 8 Proposed mechanism for the organocatalyzed reaction between azlactones and β-nitroacrylates.

In 2019, Jiang, Chang and co-workers described the first enantioselective vinylogous conjugate addition between Erlenmeyer–Plöchl azlactones (42) and 4-nitro-5-styrylisoxazoles (43) using a bifunctional phase-transfer catalyst (44) (Scheme 9).²⁴ Notably, in this protocol, the azlactone acts as a Michael donor rather than playing its usual role as a Michael acceptor. The desired chiral cyclohexenones (45), bearing two or three contiguous stereogenic centers, were isolated in yields ranging from low to excellent (35–99%) and moderate to excellent diastereo- (7 : 1 to >19 : 1) and enantioselectivities (84–95%). The use of aryl groups in both substrates, whether with electron-withdrawing or electron-donating substituents, was well tolerated (e.g., 46 and 47). However, when the methyl group of the azlactone was replaced with an ethyl or phenethyl group, the reaction rate decreased (e.g., compounds 47 and 48). A notable limitation of this protocol is that the reaction failed when tri- or tetrasubstituted alkenes were utilized in the 4-nitro-5-styrylisoxazoles.

Scheme 9 Asymmetric synthesis of cyclohexenones between azlactone and 4-nitro-5-styrylisoxazoles catalyzed by bifunctional phase-transfer ammonium salt.

The authors proposed a viable reaction mechanism based on control experiments (Scheme 10). The reaction begins with the counter-anion exchange of the catalyst by its reaction with KF, producing 49. Next, the fluorine acts as a Brønsted base (50) and deprotonates the olefinic azlactone 42, generating the enolate intermediate 51. Subsequently, 4-nitro-5-styrylisoxazoles 43 interact with the catalyst through hydrogen bonding activation, providing an adequate molecular arrangement (52) for the vinylogous conjugate addition, leading to the formation of intermediate 53. This intermediate may follow two distinct paths: direct cyclization to 45 or protonation (54), followed by a deprotonation/cyclization step, ultimately affording the product 45.

Scheme 10 Plausible mechanism for the formation of chiral cyclohexenones.

Recently, Chen and Liang reported a 1,4-addition cascade reaction involving Erlenmeyer–Plöchl azlactones (55) and cyclohexane-1,3-dione-derived enaminones (56), affording quinoline-2,5-diones (57) through a phase-transfer protocol using tetrabutylammonium bromide (TBAB) as catalyst (Scheme 11).²⁵ A diversity of derivatives were synthesized in moderate to excellent yields (53–95%) and diastereomeric ratios (60 : 40 to >99 : 1 d.r.). The reaction tolerated substitutions in both azlactone and enaminone scaffolds, including the use of aryl or heteroaryl groups (e.g., 58 and 59). However, primary enaminones failed to generate the desired product, and the presence of stereogenic centers in the cyclohexanone ring negatively impacted the diastereoselectivity outcome (e.g., 60). Although an enantioselective version was attempted, the yields and enantiomeric ratios obtained were unsatisfactory.

Scheme 11 Quinoline-2,5-diones obtained from azlactone and cyclohexane-1,3-dione-derived enaminones reaction.

Based on the roles of water, TBAB, and KOH in the reaction, a mechanism for the cascade reaction was proposed (Scheme 12). The process starts with TBAB facilitating hydroxide transfer through solid–liquid phase transfer, generating tetrabutylammonium hydroxide (61). Subsequently, hydroxide deprotonates enaminone 56, initiating a nucleophilic attack on arylidene azlactone 55via a Michael-type addition (62), forming the ionic intermediate 63. Protonation then leads to intermediate 64, which undergoes cyclization to afford 65. Finally, proton transfer of the amide group yields the desired product 57 while regenerating the catalyst.

Scheme 12 Proposed mechanism for TBAB-catalyzed synthesis of quinoline-2,5-diones.

In 2019, Terada and co-workers presented a classic asymmetric Markovnikov-type reaction, which involved the activation of styrene derivatives using a strong Brønsted acid.²⁶ The study began with azlactone (66) and a styrene-like cyclic framework (67), in which the nonpolar carbon–carbon double bond was activated by the F₁₀BINOL-derived N-triflyl phosphoramide catalyst (68), leading to the formation of azlactones with vicinal tetrasubstituted stereogenic centers (69) (Scheme 13). The reaction provided the desired products in moderate to excellent yields (47–92%) and stereoselectivities (up to 98 : 2 d.r. and 93% e.e.). Although styrenes bearing both electron-withdrawing (e.g., 72) and electron-donating groups were well tolerated, electron-rich substituents in the aryl groups of azlactones led to a decrease in terms of yield (e.g., 71).

Scheme 13 Brønsted acid-catalyzed reaction among azlactones and styrene derivatives.

An enantioselective and diastereodivergent synthesis of trisubstituted allenes (76 and 78) through asymmetric addition of azlactones (73) to activated 1,3-enynes (74) was described by Peng, Yang, and co-workers in 2020 (Scheme 14a).²⁷ This transformation was catalyzed by chiral phosphoric acids, enabling access to different diastereomers through catalyst modifications (75 and 77). Both stereoisomers were obtained with excellent enantioselectivity and moderate to high diastereoselectivity over a broad substrate scope. While the reaction involving the formation of product 76 allowed various substitutions on the 1,3-enynes, modifications in the azlactone substituents led to a considerable decrease in diastereoselectivity, though yields and enantioselectivities remained largely unaffected (e.g., 81). Conversely, the reaction producing 78 tolerated modifications on both the azlactone and the 1,3-enyne moieties (e.g., 79). Based on detailed mechanistic studies, the authors proposed that both catalysts promote the same (S,R)-syn configuration for the Michael addition step through a Münchnone-type activation mode (Scheme 14b).

Scheme 14 (a) Diastereodivergent synthesis of trisubstituted allenes through asymmetric addition of azlactones to activated 1,3-enynes. (b) Münchnone-type activation mode.

In 2021, Zhu, Zhang, and Yan described an enantioselective conjugate addition of azlactones (82) to ethylene sulfonyl fluorides (83) using cooperative catalysis with (DHQD)₂PHAL (84) and thiourea (85) (Scheme 15a).²⁸ Using the optimized reaction conditions, a diverse substrate scope was prepared, yielding products in moderate to excellent yields (63–97%) and with enantioselectivity ranging from 53% to 99%. Substrate modifications revealed that 4-benzyl azlactones as starting materials (e.g., 87 and 88) exhibited superior enantioselectivity in the outcome product compared with their 4-phenyl-substituted counterparts (e.g., 89). A subsequent acid hydrolysis afforded the sulfonyl fluoride-functionalized amino acid in high yield and enantiomeric excess (89% e.e.). A stereochemical model has been discussed, in which the enol is activated via hydrogen bonding by (DHQD)₂PHAL, while ethylene sulfonyl fluoride is simultaneously activated through dual hydrogen bonding in the presence of thiourea (Scheme 15b). The (S)-configured product is predominantly formed due to Si-face attack, attributed to steric hindrance exerted by (DHQD)₂PHAL.

Scheme 15 (a) Enantioselective conjugate addition of azlactone to ethylene sulfonyl fluoride. (b) Proposed stereochemical models.

In 2019, Khosropour, Beyzavi, and co-workers reported a one-pot process for the synthesis of structurally complex dihydro-5′H-spiro[benzo[c]chromene-8,4′-oxazole]-5′,6(7H)-diones (92).²⁹ Utilizing a base-mediated pseudo-multicomponent approach (Scheme 16), two molecules of azlactone (90) reacted with 4-hydroxycoumarin (91), affording compound 92 with high diastereomeric ratio (>19 : 1 d.r.) and yields of up to 90% (e.g., 93). Notable features of this reaction include the formation of three C–C bonds and four contiguous stereocenters. However, a limitation of the methodology is that only aromatic substituents in azlactones were explored.

Scheme 16 Pseudo-multicomponent reaction between azlactones and 4-hydroxycoumarins.

Mechanistic studies were conducted, and a reaction pathway was proposed (Scheme 17). Initially, the base deprotonates the hydroxyl group of coumarin, triggering a Michael-type addition to the azlactone and forming intermediate 96. This species then tautomerizes to 97, which undergoes a second conjugate addition to another azlactone, yielding intermediate 98. An intramolecular Michael-type addition subsequently leads to 99, followed by lactonization to form 100. A cycloreversion reaction then releases CO₂, generating intermediate 101. Finally, a tautomerization/protonation step furnishes the desired product (92).

Scheme 17 Plausible mechanism for reaction of arylidene-azlactones with 4-hydroxycoumarins.

Waser and co-workers have developed a protocol for the asymmetric β-addition of azlactones (102) to allenoates (103), employing Maruoka's catalyst (104), yielding α-vinyl-substituted azlactone derivatives (105) (Scheme 18).³⁰ Enantioselectivities ranged from low to moderate (34–66% e.e.), with yields of up to 91%. Notably, the ester group of the allenoate moiety exhibited tolerance to both alkyl and aryl substituents, although the sterically demanding tert-butyl group led to lower enantioselectivity (e.g., 107). Additionally, a variety of azlactones was explored, successfully affording the desired products (e.g., 106–108).

Scheme 18 Asymmetric β-addition of azlactones to allenoates using Maruoka's catalyst.

In 2024, Liu's group presented a direct approach for highly functionalized chiral δ-lactones (112 and 114) (Scheme 19).³¹ In this study, guanidine-amide (111) served as a bifunctional organocatalyst, providing diastereo- and enantioselective control in the coupling between azlactones (109) and α-alkynyl-α,β-enones (110 and 113). When acyclic enones (110) were employed, fully substituted δ-lactones (112) were obtained in moderate to excellent yields (41–98%), while cyclic enones (113) led to the formation of pseudo-three-component derivatives (114). Notably, the reaction proceeded efficiently with a low catalyst loading (only 1 mol%) in most cases, and a diversity of azlactones was well tolerated under the optimized reaction conditions. However, a drop in terms of yield was observed when cyclopentenone was tested (e.g., 116), and cycloheptenone failed to provide the desired product. To elucidate the stereoinduction process, an in-depth mechanistic investigation was conducted. Computational calculations revealed a favored activation model in which the substrates approach through the Si–Si faces during the conjugate addition step.

Scheme 19 Asymmetric synthesis of δ-lactones using guanidine-amide organocatalysis.

Mannich-type reaction

The Mannich-type reaction involving azlactones has emerged as a powerful strategy for the functionalization of these versatile intermediates, enabling the synthesis of diverse non-natural amino acid derivatives and nitrogen-containing heterocycles.³²

In 2019, Li, Zhang, Jiang, and co-workers reported a diastereoselective protocol for synthesizing aminooxindole-oxazolone adducts (120) through the addition of 4-substituted azlactones (118) to isatin-derived ketimines (119) (Scheme 20).³³ By using triphenylphosphine as a catalyst, the reaction provided the final products in up to 98% yield and with high diastereomeric ratio (up to 20 : 1 d.r.). Under the optimized reaction conditions, the effect of N-substitution on the oxindole nitrogen and electronic effects on the isatin core were evaluated, revealing a slight decrease in reaction yields when using 4-bromo-substituted isatin (e.g., 122). Additionally, modifications on the azlactone ring showed that even bulky substituents, such as a phenyl group, did not significantly affect the reaction efficiency (e.g., 123). An enantioselective version of the reaction was also explored for a single example using a chiral phosphoric acid catalyst, affording the desired derivative (121) with 86% yield, >20 : 1 d.r. and 52% e.e.

Scheme 20 Triphenylphosphine-catalyzed addition of azlactones to isatin-derived ketimines.

In 2020, Xu, Ren, and co-workers developed an enantioselective reaction between isatin-derived ketimines (125) and azlactones (124) using a chiral bifunctional squaramide organocatalyst (Scheme 21).³⁴ This protocol provided α,β-diamino acid derivatives (127) in yields ranging from 56 to 95%, with diastereomeric ratios from 3 : 1 to 20 : 1 and enantiomeric excesses between 66 and 97%. A comprehensive substrate scope was explored, revealing key aspects of the reaction. Notably, steric hindrance on the azlactone played a crucial role in stereoselectivity, as the use of a tert-butyl group (e.g., 128 and 130) led to higher efficiency compared with a phenyl substituent (e.g., 129). The reaction also exhibited good tolerance to modifications on the isatin core; however, for halide-substituted substrates, a temperature reduction from 25 °C to 0 °C was necessary to maintain the levels of the stereoselectivity. Additionally, attempts using an N-unprotected ketimine resulted in a complex mixture, preventing product isolation.

Scheme 21 Bifunctional chiral squaramide catalyzed synthesis of enantioenriched aminooxindole-oxazolone derivatives.

A Mannich-type reaction between azlactones (131) and 2-aminoacrylates (132) catalyzed by DABCO was developed by Hou, Xiong, and co-workers in 2022 (Scheme 22).³⁵ The Mannich adducts (133) were accessed in high yields (up to 98%) and with diastereomeric ratios ranging from 5 : 1 to 20 : 1 d.r. However, certain limitations were observed. For instance, the presence of an aryl substituent at the C4 position of the azlactone, such as a phenyl group (e.g., 135), led to lower yields compared with alkyl groups (e.g., 134 and 136). Substitutions at the C2 position were generally well tolerated, except for alkyl groups, which negatively impacted the reaction outcome. The access to α,β-diamino diacid derivatives through the ring-opening of azlactone intermediate 133 with water was also demonstrated. To achieve an enantioselective version, the cinchona alkaloid dimer (DHQD)₂PHAL was used instead of DABCO. Under these conditions, the α,β-diamino diacid derivative was synthesized in 90% yield, with high diastereomeric ratio (94 : 6 d.r.), and an enantiomeric excess of 96%.

Scheme 22 Mannich-type reaction between azlactones and 2-aminoacrylates.

In 2019, Šebesta's group reported protocols using cinchona alkaloid-derived catalysts to obtain Mannich adducts. These were strategically designed for subsequent conversion into either chiral lactones or dihydropyrroles.³⁶ Initially, they described the coupling of azlactones (137) and N-protected imines (138), catalyzed by a thiourea derivative (139) in the presence of an acid co-catalyst (e.g., benzoic acid), affording Mannich products (140) (Scheme 23a). However, the scope was limited, with only four examples reported. While some adducts (e.g., 143) exhibited high enantioselectivity, diastereoselectivity remained a challenge. Interestingly, a gold-catalyzed 6-exo-dig cyclization of compound 143 enabled the synthesis of spirocyclic 2,3-dihydro-1H-pyrrole 144 in 50% yield, preserving the stereochemistry at both contiguous stereogenic centers (Scheme 23b).

Scheme 23 (a) Thiourea-catalyzed coupling between azlactones and N-protected imines. (b) Gold-catalyzed synthesis of spirocyclic 2,3-dihydro-1H-pyrrole.

In the same study, the researchers expanded the scope to include glyoxylate imines (146), necessitating a change in the catalyst to a squaramide (147) and the use of triethylamine as an additive (Scheme 24a). A variety of Mannich adducts (148) were prepared, including the use of both aromatic (e.g., 149 and 151) and aliphatic imines (e.g., 150), although a decrease in yield was noted for the latter. Notably, some analogues exhibited high enantioselectivity and diastereoselectivity (e.g., 151). Additionally, by employing sodium borohydride, the synthesis of lactone 153 was achieved with a high enantiomeric excess (96%) and in 81% yield (Scheme 24b). In this process, the azlactone ring is opened, leading to intermediate 152, which subsequently undergoes intramolecular cyclization.

Scheme 24 (a) Squaramide-catalyzed reaction among azlactones and glyoxylate imines. (b) Preparation of an enantioenriched lactone.

A strategy to prepare diazaspiro[4.4]nonenes (157), key intermediaries to produce functionalized pyrrolidines (158), was published in 2019, by Moshkin's group.³⁷ This methodology involves the in situ generation of N-methylazomethine ylide (156) via the reaction of sarcosine (155) with paraformaldehyde, which subsequently undergoes cycloaddition with (Z)-arylidene azlactone (154) to form the spiro compound 157 (Scheme 25a). Upon treatment of the crude reaction mixture with sodium hydroxide, N-methylpyrrolidines (158) bearing two contiguous stereocenters and an amido acid motif were obtained in yields ranging from 69% to 89%. However, achieving optimal yields required an excess of reagents for azomethine pre-formation. Notably, this approach exhibits tolerance to both alkyl (e.g., 161) and aryl (e.g., 159 and 160) substituents at C2, and the amide group undergoes facile hydrolysis under acidic conditions, enabling the synthesis of curcubitine derivatives (e.g., 162) through a one-pot three-step protocol. Additionally, with minor modifications to the reaction conditions, the methodology allows access to N-benzylpyrrolidines, further expanding their synthetic scope.

Scheme 25 (a) Synthesis of pyrrolidines using azlactone rings. (b) Proposed pathway for diazaspiro[4.4]nonenes isomerization.

Finally, based on the experimental results, a plausible mechanism has been disclosed (Scheme 25b). Upon heating, the spiro compound 163 undergoes pyrrolidine ring opening, generating intermediate 164, which features an enolate form of the azlactone and an iminium ion. This intermediate can also exist as the conformer 165, which, upon ring closure, yields diastereomer 166, ultimately resulting in a loss of diastereoselectivity.

C2 Functionalization

The reactivity at the C4 position of azlactones is widely explored, allowing for multiple functionalization through a diversity of transformations.¹⁶ However, selective modifications at the C2 position have also been highlighted, offering unique synthetic opportunities.¹⁷

In 2019, He's group reported an iridium-catalyzed protocol for accessing enantioenriched allylated 2,4-diaryloxazol-5(2H)-ones (170) via a tandem allylic alkylation/aza-Cope rearrangement.³⁸ The reaction of azlactones (167) with protected alkenes (168), using [Ir(cod)Cl₂] and a chiral ligand (169), afforded the desired adducts with enantiomeric excesses ranging from 78% (e.g., 173) to 94% (e.g., 171) and yields between 36% and 90% (Scheme 26a). Some limitations in the method were noted, such as the requirement for aromatic-substituted oxazolones and the necessity of a high excess of DBU (3.0 equiv.). Given the strong preference of the aza-Cope rearrangement for a chair-like transition state, the authors proposed a mechanistic model based on the observed product configuration (Scheme 26b).³⁹ It was suggested that intermediates 174 (major) and 176 (minor) undergo rearrangement, with the major proceeding through a chair-like transition mode (175), ultimately leading to the (S)-configured product 170.

Scheme 26 (a) Enantioselective preparation of allylated 2,4-diaryloxazol-5(2H)-ones. (b) Proposed rearrangement for the major and minor enantiomers.

In 2021, Nakamura and co-workers developed a stereoselective protocol for synthesizing oxazolones with two contiguous stereocenters, employing cinchona alkaloid sulfonamides as catalysts.⁴⁰ The method begins with α-azideacrylates (178), which are thermally converted into 2H-azirines (179) before reacting with azlactones (180) in the presence of the organocatalyst (181), affording C2-substituted products (183) in up to 99% yield with high diastereo- and enantioselectivity (Scheme 27a). A broad substrate scope was demonstrated, maintaining excellent selectivity across all cases. However, some limitations were noted. For instance, when a C4 benzyl-substituted azlactone (184) was used, an extended reaction time (144 h) was required, and catalyst 182 had to be employed instead of 181. Notably, these adducts can be further transformed into chiral β-ketoesters through a one-pot procedure without compromising enantiopurity (e.g., 190) (Scheme 27b).

Scheme 27 (a) Organocatalyzed reaction between oxazolones and azirines. (b) Enantioselective one-pot synthesis of β-ketoester.

A plausible reaction mechanism, emphasizing dual activation by the organocatalyst, has been disclosed (Scheme 28). First, the electrophilicity of aziridine (179) is enhanced through hydrogen bonding activation with the catalyst, forming intermediate 191. Based on the absolute configuration observed in the product, it is suggested that the enol form of azlactone (180) engages in hydrogen bonding with the quinuclidine moiety, generating intermediate 192. With both species activated, the Re-face of the oxazolone attacks the Si-face of 179, followed by a proton transfer step, ultimately yielding (S,S)-183 as the major product.

Scheme 28 Proposed mechanism for the reaction between azlactones and azirines.

Cinchona alkaloid-bearing squaramides (195) have also been successfully employed as multifunctional catalysts to facilitate the asymmetric C2 addition of azlactones (193) to γ-keto-α,β-unsaturated esters (194), as demonstrated by Lin's group in 2023 (Scheme 29a).⁴¹ This reaction produced a diverse array of γ-keto esters featuring a C2-oxazolone moiety, achieving yields ranging from 52% to 98% and high stereoselectivities across all examples (>20 : 1 d.r., 90–98% e.e.). The representative scope indicated that electron-rich γ-aryl groups (e.g., 197 and 199) promoted higher yields compared with electron-deficient substrates (e.g., 198). This behavior is contrary to what is typically observed with general Michael acceptors and supports the activation model presented in Scheme 29b. The authors propose that the protonated quinuclidine moiety in the catalyst forms an ionic pair with the enolate form of the azlactone, while substrate 194 is activated through hydrogen bonding with the squaramide scaffold (200). Additionally, the aryl moiety in the squaramide may enhance π–π stacking with the γ-aryl group, where electron-rich rings exhibit stronger interactions, thus justifying the higher yields. With both substrates activated, the oxazolone attacks the keto ester, leading to a 1,4-addition and the formation of intermediate 201. Finally, following protonation, the (S,S)-196 product is obtained, and catalyst 195 is released. The reaction using compound 194 with alkyl groups in the γ-position did not proceed, highlighting the importance of π-stacking in the activation of the Michael acceptor.

Scheme 29 (a) Asymmetric 1-4-addition of C2-oxazolone to γ-keto-α,β-unsaturated esters. (b) Proposed reaction pathway.

Dynamic kinetic resolution

Dynamic kinetic resolution is a well-established strategy for accessing enantioenriched amino acid derivatives, particularly through transformations involving azlactone rings. This approach leverages the simultaneous resolution and racemization of reactive intermediates, enabling high enantioselectivity in the synthesis of valuable chiral building blocks.^16,42

In 2020, Xie, Tian, Guo, and co-workers reported an acyl transfer reaction for the dynamic kinetic resolution of azlactones (202), employing DMAP-N-oxides (204) as catalysts and alcohols (203) as nucleophiles.⁴³ Under optimized conditions, a broad substrate scope was achieved with high yields (84–98%) and excellent enantiomeric excesses (87–96% e.e.), by modifying the C4 and C2 positions of azlactones and varying the alcohols (203) (Scheme 30). However, some limitations were observed, such as the presence of bulky groups at the C4 position (e.g., iPr – 207), which slightly reduced reaction yields. Moreover, substrates bearing phenyl groups at the C4 position of the azlactone required higher catalyst loading. Notably, variations in the alcohols had minimal impact on yield and enantioselectivity (e.g., 208). A gram-scale experiment demonstrated the efficiency of the method, affording the final product in 93% overall yield and 93% e.e. using only 1 mol% of the organocatalyst.

Scheme 30 Dynamic kinetic resolution of azlactones using DMAP-N-oxide as catalyst.

Based on mechanistic studies, a reaction mechanism has been disclosed (Scheme 31). Initially, (S)-azlactone (209), catalyst (204), benzoic acid, and alcohol (e.g., methanol) form transition mode 211, leading to the generation of the ring-opened tautomer 212. Due to steric factors, the (S)-azlactone is suggested to be the preferred reactive species. Finally, an isomerization step then converts 212 into the final product 213.

Scheme 31 Proposed mechanism for the dynamic kinetic resolution of azlactones using a DMAP-N-oxide as catalyst.

An asymmetric dynamic kinetic resolution of azlactones (214) through alcoholysis, using bifunctional thioureas, was developed by Hernández-Rodríguez and co-workers in 2022. This study focused on the influence of a chiral stereogenic center bearing a CF₃ group in the catalyst (216) compared with non-fluorinated systems (217).⁴⁴ Under the optimized reaction conditions, modifications at the C4 position of azlactone led to the formation of products (218) with yields ranging from 10 to 98% and a broad variation in terms of enantioselectivity (1–83%) (Scheme 32). Some limitations were noted, such as reduced yields (e.g., 220) and lower enantioselectivities (e.g., 221) when using ortho-substituted benzyl azlactones. In contrast, azlactones with bulky alkyl groups provided improved outcomes (e.g., 219). Notably, tests with different alcohols showed that sterically hindered ones (e.g., isopropanol and tert-butanol) resulted in significantly lower yields and poor stereocontrol.

Scheme 32 Dynamic kinetic resolution of azlactone catalyzed by a bifunctional thiourea catalyst.

In 2024, Zheng, Li, and co-workers reported the desymmetrization of prochiral diamines (223) using achiral azlactones (222) and a chiral phosphoric acid catalyst (224).⁴⁵ This strategy enabled the synthesis of C–O axially chiral diaryl ethers (225) with up to 98% yield and excellent enantiomeric excesses (up to 99% e.e.) (Scheme 33). A representative scope was presented, exploring modifications to the diamine and the C2 position of azlactone. The reaction demonstrated broad tolerance to substituents, as both electron-withdrawing (e.g., 226) and electron-donating groups (e.g., 228) at the 4′-position of the diaryl ether were well accepted. Additionally, polycyclic substrates maintained high enantioselectivity (e.g., 227), and modifications to the phenyl group in azlactone had no detrimental effect on either reaction yields or enantioselectivity (e.g., 228).

Scheme 33 Enantioselective preparation of axially chiral diaryl ethers using azlactones.

Ring-opening reactions

In 2019, Liu, Engle, and co-workers reported an enantioselective α-alkylation of azlactones (229) using non-conjugated alkenes (230) catalyzed by palladium(II), followed by a ring-opening step (Scheme 34).⁴⁶ This method employs chiral phosphoric acids (231) for stereoinduction, which operates through coordination as an X-type ligand to Pd, influencing either the nucleopalladation or protodepalladation steps. Under the optimized reaction conditions, the reaction scope yielded products ranging from 28 to 87% with varying enantioselectivities (64–90%). Modifications at the C2 position of the azlactone indicated that electron-donating groups in the para-position of the aryl group (e.g., 233) produced superior results compared with electron-withdrawing groups. A similar trend was observed for modifications at the C4 position, in which stronger electron-withdrawing groups led to decreased yields (e.g., 234). The authors noted that the 4-phenoxyphenyl group at the C2 position of the azlactone enhanced stereocontrol in the reaction (235) and suggested that this group may participate in π–π stacking interactions with the chiral phosphoric acid.

Scheme 34 Palladium(II)-catalyzed α-alkylation of azlactones.

In 2020, Cheng, Shao, and co-workers presented a three-component cascade reaction involving water, 3H-indoles (237) and azlactones (236), mediated by para-toluenesulfonic acid (PTSA) (Scheme 35a).⁴⁷ This protocol yielded functionalized indoline N,O-aminals (238) in excellent yields (80–94%) and diastereomeric ratios ranging from 9 : 1 to 21 : 1 d.r. A variety of substrates were explored, including mono- and di-substituted indoles, which were generally well tolerated. However, when a bromine substituent was employed, a decrease in diastereoselectivity was observed (e.g., 240). Additionally, modifications at the C3 position of the indole were tolerated, along with alterations to the azlactone core (e.g., 239 and 241). The authors also proposed an enantioselective version of the reaction using a chiral phosphoric acid catalyst, which furnished several analogues with moderate to good enantioselectivity upon modification of the C4 position of the azlactone (Scheme 35b).

Scheme 35 (a) Three-component reaction involving 3H-indoles, azlactones, and water. (b) Enantioselective version by employing a chiral phosphoric acid catalyst.

A plausible reaction mechanism is shown in Scheme 36. Initially, with the assistance of the Brønsted acid, a [2 + 2] cycloaddition occurs between 3H-indoles (237) and the enol form 246 of the azlactone, resulting in the formation of intermediate 247. Next, 247 undergoes ring-opening to generate β-lactam 248, followed by a rearrangement to produce 249. Subsequently, 249 is attacked by a water molecule, leading to the formation of the final product 238 after another ring-opening step.

Scheme 36 Proposed mechanism for the three-component cascade reaction.

In 2020, Liu's group developed an organocatalytic nucleophilic aromatic substitution reaction of azlactone (250) with 1-fluoro-2,4-dinitrobenzene (251) to produce chiral α-amino acid derivatives (253) after a ring-opening step (Scheme 37a).⁴⁸ Under the optimized reaction conditions, a broad scope was described, with yields ranging from 41 to 99% and enantiomeric excesses between 45% and 93% e.e. The synthesis of peptides was also explored using various nucleophiles, and notably, the incorporation of chiral substrates led to products with good diastereoselectivity (e.g., 255). The authors proposed a potential catalyst dual activation mode based on the product's configuration and control experiments (Scheme 37b). It was suggested that enantiocontrol of the reaction arises from steric hindrance imposed by the amide unit, which interacts with the enolate and blocks the azlactone Si-face (257). Consequently, the reaction proceeds through the attack of the Re-face of the azlactone, resulting in the formation of the σ-complex 258, which subsequently generates the tetra-substituted azlactone derivative 259 after fluorine elimination.

Scheme 37 (a) Organocatalyzed nucleophilic aromatic substitution reaction employing azlactones. (b) Proposed dual catalytic mode.

A three-component reaction of azlactones (260), N,O-acetals (261), and alcohols (262), catalyzed by pyrrolidine, was reported by Hu's group in 2023.⁴⁹ In this protocol, the N,O-acetal acts as source of both iminium and methanol, thereby facilitating the synthesis of α,β-diamino esters (263) in yields ranging from 34% to 99% (Scheme 38). A representative scope demonstrated that the reaction exhibited broad tolerance to modifications in both azlactones and N,O-acetals. While the reaction performed well with primary alcohols (e.g., 264 and 266), the use of bulky alcohols (e.g., 65) led to a significant decrease in yield.

Scheme 38 Synthesis of α,β-diamino esters via a three-component reaction catalyzed by pyrrolidine.

Based on control experiments, a reaction pathway was then proposed (Scheme 39). Initially, in the presence of a base, azlactone is converted into its enolate form (267),⁵⁰ which then undergoes a Mannich-type reaction with the N,O-acetal, yielding the α-functionalized azlactone (268) and methanol. The α,β-diamino ester (263) is then generated through the ring-opening reaction of the α-functionalized azlactone via nucleophilic addition of the alcohol.

Scheme 39 Proposed pathway for the synthesis of α,β-diamino esters.

Swaroop, Shobith, Sadashiva, and co-workers reported a cyclocondensation reaction between Erlenmeyer–Plöchl azlactones (269) and malonitriles (270) under mild basic conditions, affording the desired Δ²-pyrrolines (271) in up to 89% yield (Scheme 40).⁵¹ The study focused only on modifications to the exocyclic double bond of the azlactone, revealing that electron-withdrawing groups (e.g., 272) slightly accelerated the reaction compared with electron-donating groups (e.g., 273). Additionally, heteroaryl and styryl groups (e.g., 274) were explored, though no alkyl-substituted examples were reported.

Scheme 40 Preparation of Δ²-pyrrolines via cyclocondensation of Erlenmeyer–Plöchl azlactones.

The proposed pathway for the 1,2-addition reaction is illustrated in Scheme 41. The mechanism begins with the deprotonation of malonitrile (270) by the base, generating the carbanionic species 275. This nucleophile then attacks the azlactone (269), leading to the formation of intermediate 276. A subsequent ring-opening step produces species 277, which undergoes a base-mediated intramolecular cyclization to afford pyrroline 278. Finally, a tautomerization step furnishes the desired product (271).

Scheme 41 Mechanism for the cyclocondensation reaction of malonitrile to Erlenmeyer–Plöchl azlactones.

Cycloaddition reactions

Cycloaddition reactions are widely employed in organic synthesis to efficiently construct complex frameworks with high atom economy and stereochemical control.⁵² In this context, cycloadditions involving azlactone rings have gained significant attention, enabling the formation of diverse heterocyclic structures with valuable applications in medicinal and synthetic chemistry.⁵³

In 2019, Du and co-workers developed methods to synthesize two CF₃-branched 3,2′-pyrrolidinyl spirooxindoles (283) and CF₃-containing dispirooxindoles (284). These derivatives were prepared through an asymmetric reaction between arylidene azlactones (279) and N-2,2,2-trifluoroethylisatin ketimines (280), catalyzed by a hydroquinine-derived thiourea catalyst (281) (Scheme 42).⁵⁴ The [3 + 2] cycloaddition initially afforded 3,2′-pyrrolidinyl spirooxindoles (282), which were unstable and had to be converted into 283 or 284 to improve the observed yields of the final products. Electron-withdrawing and electron-donating groups on the aryl ring attached to the oxindole core were well tolerated, as well as various substituents attached to the nitrogen atom, including hydrogen (e.g., 285) and benzyl groups (e.g., 286 and 287). However, when using 4-substituted oxindoles, the reaction did not proceed due to steric hindrance. A gram-scale synthesis was successfully performed for 3,2′-pyrrolidinyl spirooxindoles, while maintaining high diastereo- and enantioselectivities.

Scheme 42 Asymmetric cycloaddition among arylidene azlactones and N-2,2,2-trifluoroethylisatin ketimines.

Wang's group demonstrated a silver-catalyzed [3 + 2] cycloaddition of alkylidene azlactones (288) with trifluoromethyl imines (289) to access pyrrolidines (290) bearing four contiguous stereocenters as products (Scheme 43).⁵⁵ The spiro adducts were furnished in moderate to high yields (60–85%) with an excellent diastereomeric ratio in all cases (e.g., 291–293). It is worth mentioning that an enantioselective version of this reaction was carried out for some analogues, employing an axially chiral phosphine ligand, reaching enantiomeric excesses of up to 97%. The presence of the quinine in the imine scaffolds plays a pivotal role in the mechanism, in which the N atom participates in the formation of a rigid 5-membered ring through coordination with the metal, facilitating both proton transfer and the diastereoselective cycloaddition steps.

Scheme 43 Spiro[pyrrolidine-azlactone] synthesized via cycloaddition between azlactones and trifluoromethylated imines.

Singh's group recently investigated the vinylogous nucleophilicity of alkylidene azlactones (294) in an asymmetric hetero-Diels–Alder reaction, enabling the synthesis of α,β-unsaturated δ-lactones (297) featuring a CF₃-substituted stereogenic center (Scheme 44a).⁵⁶ The reaction employed trifluoromethyl aryl ketones (295) as activated carbonyl dienophiles and a bifunctional urea catalyst (296). The choice of catalyst was crucial, as its relatively weak N–H donor acidity helped stabilize the in situ-generated dienolate form of the azlactone moiety, facilitating its reaction with the ketone. Both aryl-substituted (e.g., 298) and alkyl-substituted methylidene azlactones (e.g., 299) delivered the desired products with high enantiomeric excess (94–98% e.e.). The scope of the ketone substrate was also explored, demonstrating good tolerance for a variety of aryl groups (e.g., 300). However, aliphatic ketones failed to undergo the transformation.

Scheme 44 (a) Asymmetric hetero-Diels–Alder reaction between alkylidene azlactones and trifluoromethyl aryl ketones. (b) Proposed activation mode.

A plausible activation mode (301) in which the catalyst deprotonates the γ′-carbon of the azlactone framework, stabilizing the dienolate through interaction with the N–H group of the urea moiety is disclosed (Scheme 44b). Simultaneously, the ketone is activated via hydrogen bonding with the protonated quinuclidine unit. This activation directs the attack of the alkenyl group of the azlactone to the Si-face of the ketone, leading to the formation of cycloadduct 302, which subsequently undergoes a ring-opening step to afford the final product (297).

In the following year, 2021, Singh and co-workers reported an asymmetric [3 + 2] cycloaddition-lactamization cascade reaction involving Erlenmeyer–Plöchl azlactones (303) and N-protected o-amino aryl aldimines (304) (Scheme 45a).⁵⁷ By using a cinchona-derived bifunctional squaramide catalyst (305), this strategy enabled the synthesis of pyrrolo[3,2-c]quinolines (306) in up to 88% yield, >20 : 1 d.r. and with enantiomeric excesses ranging from 51 to 84%. The substrate scope was relatively limited, with variations only in aryl-substituted azlactones and protected anilines (e.g., 307–309). Based on the stereochemical outcome of this transformation, the authors proposed a viable activation mode for the reaction (310) (Scheme 45b). In this mechanism, the catalyst simultaneously activates the azlactone (303) and the imine (304) through hydrogen bonding interactions. A subsequent [3 + 2] cycloaddition yields the spiro intermediate 311, which undergoes intramolecular lactamization to afford the final product (306).

Scheme 45 (a) Asymmetric [3 + 2] cycloaddition-lactamization cascade reaction between Erlenmeyer–Plöchl azlactones and N-protected o-amino aromatic aldimines. (b) Proposed activation mode.

Recently, Ren's group described an enantioselective synthesis of 1,7-annulated indazoles (315) via a cascade reaction among 7-imine indazoles (313) and alkylidene azlactones (312), employing squaramide (314) as catalyst (Scheme 46a).⁵⁸ High diastereo- (>19 : 1 d.r.) and enantioselectivities (83 to >99% e.e.) were obtained for the desired fused-heterocycles, tolerating diverse substituted azlactones (e.g., 316–318). The substrate scope revealed that benzylidene azlactones ortho-substituted presented a slight drop in the enantiocontrol (e.g., 317). Activation modes were proposed by the authors, evidencing the bifunctional role played by the employed catalyst (Scheme 46b). With both substrates activated, the enolate anion attacks the exocyclic azlactone double bond at the Re-face, as shown in 319. Then, the carbanion attacks the imine Si-face (320), explaining the favored stereoisomer in this transformation.

Scheme 46 (a) Asymmetric synthesis of 1,7-annulated indazoles. (b) Proposed reaction model.

In 2020, Wang and co-workers developed a [2 + 2 + 2] cycloaddition strategy to synthesize spirocycloalkyl oxazolones (323) (Scheme 47).⁵⁹ This base-mediated pseudo-multicomponent reaction employed Erlenmeyer–Plöchl azlactones (321) and two molecules of β-nitrostyrenes (322), affording the desired products in good yields (64–76%) and excellent diastereomeric ratio (>19 : 1 d.r.). The substrate scope demonstrated that β-nitrostyrenes bearing electron-rich aryl rings (e.g., 323–325) were well tolerated, whereas substrates containing halogens, NO₂, or CF₃ substituents were not explored, probably due to electronic polarization effects on the olefin. Additionally, diverse aryl groups, including heteroaryl substituents (e.g., 323), were incorporated into the azlactone framework, further expanding the applicability of this transformation.

Scheme 47 Base-mediated [2 + 2 + 2] cycloaddition between Erlenmeyer–Plöchl azlactones and β-nitrostyrenes.

In 2019, Albrecht and co-workers reported the use of an inverse-electron-demand hetero-Diels–Alder reaction for the construction of tricyclic lactones (328) (Scheme 48).⁶⁰ Under base-mediated conditions, oxazolones (326) and α,β-unsaturated ketones (327) smoothly coupled to furnish the corresponding cycloadducts in good yields (up to 89%) and high diastereomeric ratio (up to >20 : 1 d.r., e.g., 329). Notably, full conversion of the starting materials was achieved within only 5 minutes. However, under the reaction conditions, partial epimerization of the products was observed, leading to an increase in the diastereomeric ratio over time. An enantioselective variant of the transformation was also explored. Using 20 mol% of a cinchona alkaloid-derived organocatalyst, compound 331 was obtained in 68% yield, with excellent diastereomeric ratio (>20 : 1 d.r.) and an enantiomeric excess of 63%.

Scheme 48 Diastereoselective synthesis of δ-lactones derivatives.

In the same year, a cycloaddition/decarboxylation cascade strategy between azlactones (332) and aryldiazonium salts (333) was developed, enabling the synthesis of 1,2,4-trisubstituted triazoles (334), as shown in Scheme 49.⁶¹ The transformation was optimized using tetrabutylammonium chloride (20 mol%) and sodium sulfate as additives, affording the corresponding triazole derivatives in yields of up to 89%. In several cases, a mixture of regioisomers was obtained (e.g., 338 and 339), suggesting that the electronic nature of the aryl substituent plays a key role in governing the regioselectivity. A noted limitation of the protocol is that the use of phenyl or hydrogen at the C4 position of the azlactone failed to afford the desired products. A plausible mechanism was proposed for this transformation, involving tautomerization of azlactone (332) to its enol form (340), which undergoes a [3 + 2] cycloaddition with the diazonium salt to generate intermediate 342 (Scheme 49b). Owing to its inherent instability, this intermediate rapidly undergoes decarboxylation to furnish the major regioisomer 334. Access to the alternative regioisomer 335 is attributed to the cycloaddition of the azlactone isomer 341 with 333.

Scheme 49 (a) Regioselective synthesis of substituted triazoles from azlactones. (b) Proposed mechanism.

In 2020, Zhang, Ma, and co-workers reported a regioselective approach for the synthesis of highly substituted pyrroles (346) using potassium acetate as a catalyst (Scheme 50).⁶² The reaction between oxazolones (344) and isoxazolidinediones (345), using 20 mol% of the catalyst, furnished the corresponding pyrrole derivatives in excellent yields (up to 99%, e.g., 347). Substrate scope analysis revealed that azlactones bearing aryl groups at the C4 position (e.g., 338) led to diminished yields when compared with their alkyl-substituted counterparts (e.g., 347 and 349), suggesting a steric and/or electronic influence on the efficiency of the transformation.

Scheme 50 Synthesis of pyrroles through the reaction between azlactones and isoxazolidinediones.

Mechanistic insights were obtained through a series of investigations, culminating in the proposal illustrated in Scheme 51. The reaction is initiated by deprotonation of azlactone (344) by the catalyst, followed by a 1,4-conjugate addition to isoxazolidinedione (345), generating the endo-intermediate 351. Subsequent ring-opening of the oxazolone moiety affords intermediate 352, which undergoes an intramolecular spirocyclization to yield species 353. Two successive decarboxylation steps then lead to the advanced intermediate 355, which isomerizes to the final pyrrole product (346).

Scheme 51 Plausible mechanism for KOAc-catalyzed pyrrole synthesis.

An inverse-electron-demand [4 + 2] cycloaddition reaction was presented by Lu, Lan, Xiao, and co-workers through a palladium-catalyzed protocol involving azlactones (356) and cyclic vinyl carbamates (357) (Scheme 52).⁶³ This transformation enabled the stereoselective synthesis of dihydroquinol-2-ones (359) using a chiral hybrid P–S ligand (358), affording products with enantiomeric excesses of up to 92%. Notably, substrates bearing a methyl-substituted alkenyl moiety retained both yield and selectivity (e.g., 362). However, other substituents at this position, as well as 4-substituted azlactones, were not examined.

Scheme 52 Pd-catalyzed asymmetric synthesis of dihydroquinol-2-ones.

Access to highly functionalized dihydropyridinones (366) was reported in 2019 by Xu's group via an inverse-electron-demand aza-Diels–Alder reaction (Scheme 53a).⁶⁴ The cycloaddition between saccharin-derived 1-azadienes (364) and azlactones (363) furnished the desired dihydropyridinone derivatives (366) with high stereocontrol, enabled by the use of a bifunctional squaramide catalyst (365). Within the examined substrate scope, the electronic nature of the aryl groups in the alkenyl moiety showed only a slight influence on the enantioselectivity. For instance, para-substituted electron-donating groups (e.g., 367) afforded the products with better enantiomeric excesses than their electron-withdrawing counterparts. In the proposed mechanism, the bifunctional catalyst activates both substrates (363 and 364) through hydrogen bonding interactions, generating the activated complex 370 (Scheme 53b). Subsequent azlactone enolate attack from the Si-face onto the azadiene promotes the [4 + 2] cycloaddition, forming intermediate 371. Final ring-opening and protonation steps afford the desired product 366 while regenerating the catalyst.

Scheme 53 (a) Inverse-electron demand [4 + 2] cycloaddition between 1-azadienes and azlactones. (b) Proposed reaction model.

In 2020, a synthetic strategy for accessing seven-membered lactones (374) through a formal [5 + 2] cycloaddition between vinyloxiranes (373) and azlactones (373) was described by Zhao's group (Scheme 54).⁶⁵ This transformation, enabled by palladium catalysis, afforded the corresponding cycloadducts (374) in yields ranging from 67 to 96%. Despite the overall efficiency and broad applicability of the method, certain electronic features of the substrates presented limitations. For instance, while several para-substituted aryl groups in the vinyloxirane core were well tolerated (e.g., 376 and 377), strongly electron-donating substituents such as para-methoxy failed to deliver the desired product. Additionally, non-substituted azlactones or those bearing a phenyl group at the C4 position did not lead to the product formation. The plausible mechanism involves initial epoxide ring opening to generate a Pd–π–allyl intermediate, which subsequently undergoes nucleophilic attack on the azlactone carbonyl. Proton transfer steps and an intramolecular cyclization event then furnish the final lactone product.

Scheme 54 Palladium-catalyzed formal [5 + 2] cycloaddition of azlactones and vinyloxiranes.

The construction of chiral dihydropyridinones (381 and 383) bearing contiguous stereogenic centers was achieved by He, Yang, and co-workers through the reaction of azlactones (378) with disubstituted 3-amido allylic tertiary alcohols (379) (Scheme 55).⁶⁶ This transformation proceeds via in situ generation of a ketimine intermediate, formed by the elimination of benzoic acid. The selection of an appropriate chiral phosphoric acid catalyst was critical to ensuring high stereocontrol. Using catalyst 380, the reaction delivered products with excellent diastereo- and enantioselectivities for substrates bearing multiple aryl groups (e.g., 384 and 385). In contrast, catalyst 382 was more effective for dialkenyl-containing alcohols, as exemplified by compound 386.

Scheme 55 Asymmetric preparation of dihydropyridinones using azlactones.

To construct chiral pyrrolo[1,2-a]indoles (390), a straightforward method based on copper catalysis employing the PyBox ligand (389) was developed by Deng, Yang, and co-workers (Scheme 56).⁶⁷ This protocol involves a decarboxylative [3 + 2] annulation between an azlactone (387) and an ethynyl indoloxazolidone (388), efficiently applied to a diverse set of examples, affording the desired products with excellent diastereomeric ratio (>20 : 1 d.r.), along with moderate to high yields and enantiomeric excesses (up to 99% e.e.). Within the substrate scope, the use of 3-substituted indoles (e.g., 392) exhibited a drop in terms of enantioselectivity. Additionally, although ethynyl pyrroloxazolidone was also tolerated (e.g., 393), prolonged reaction times of up to 72 hours were required.

Scheme 56 Copper-catalyzed asymmetric annulation between ethynyl indoloxazolidones and azlactones.

The cycloaddition of oxazolones (394) with 2-vinylindoles (395) was demonstrated by Li and co-workers, providing pyrrolo[1,2-a]indoles (397) as products (Scheme 57).⁶⁸ Chiral phosphoric acid 396 was employed as the catalyst in this transformation, affording the cycloadducts with up to 92% e.e. and diastereomeric ratios ranging from 70 : 30 to 95 : 5 d.r. Most examples involved azlactones bearing electron-donating groups on the aryl ring (e.g., 398–400), which led to the best results in terms of stereoselectivities. The indole core tolerated a variety of substituents (e.g., 398), except at the C3-position, in which methyl substitution completely suppressed the reaction. Additionally, ortho-substituted aryl ketones led to decreased stereoselectivity (e.g., 399).

Scheme 57 Preparation of pyrrolo[1,2-a]indoles through the annulation between azlactones and 2-vinylindoles.

A stereoselective [4 + 2] cycloaddition between azlactones (401) and benzothiazolimines (402) was developed by Ni, Song, and co-workers to access chiral benzothiazolopyrimidine derivatives (404) under mild conditions, using a chiral squaramide catalyst (389) (Scheme 58a).⁶⁹ A variety of analogues (e.g., 406–407) with high diastereo- and enantioselectivities were prepared using the optimized reaction conditions. The methodology was also extended to a benzoxazolimine substrate, successfully affording the corresponding adduct (e.g., 405) in good yield and stereoselectivity. According to the proposed activation model (408), the bifunctional catalyst interacts with the benzothiazolimine through hydrogen bonding interactions, directing the Si-face attack by the azlactone enolate onto the Re-face of the benzothiazolimine, thus accounting for the outcome stereochemistry (Scheme 58b).

Scheme 58 (a) Benzothiazolopyrimidines synthesis through the cycloaddition between azlactones and benzothiazolimines. (b) Plausible activation mode.

In 2021, Liu's group presented an asymmetric protocol for the synthesis of indolin-3-one derivatives (412) through the coupling of azlactones (409) with isatogens (410), catalyzed by a chiral guanidine (411) (Scheme 59a).⁷⁰ These compounds were constructed with excellent diastereomeric ratios (>19 : 1 d.r.) and high enantioselectivities in most cases (up to 99% e.e.). Among the positive results observed in the scope (e.g., 413 and 415), some drawbacks remained for aryl isatogens, which exhibited low enantiomeric excesses (e.g., 414). The authors proposed a bifunctional activation mode (416), in which the activated enol tautomer of the azlactone approaches the Si-face of the isatogen from its Re-face. This stereochemical outcome is attributed to the lower steric hindrance associated with this trajectory (Scheme 59b).

Scheme 59 (a) Preparation of indolin-3-ones catalyzed by a chiral guanidine. (b) Proposed activation mode.

Chen's group demonstrated a palladium-catalyzed cycloaddition between azlactones (417) and pyrrolidines (418), enabling the synthesis of azepines (419) in moderate to excellent yields (Scheme 60).⁷¹ The reaction was optimized using 5 mol% of the bidentate ligand DPPBz and boronic acid as an additive, affording the desired products in up to 92% yield. Notably, the use of chiral proline derivatives as substrates proved to be effective, maintaining high yields while delivering reasonable stereoselectivity (e.g., 420). However, the application of substituted alkenes led to a marked decrease in yield, as exemplified by compound 421.

Scheme 60 Palladium-catalyzed synthesis of azepines.

A method for ring expansion of saturated cyclic amines (424) via insertion of azlactones (423) was established by Chen's group (Scheme 61).⁷² The Shvo's catalyst (425) was selected for this transformation, enabling access to diverse azepine derivatives (426) in up to 83% yield. A representative scope of amines was tested, showing the efficiency of the reaction for diverse substituted substrates (e.g., 427–430). Interestingly, for some substrates a mixture of regioisomers was obtained (e.g., 427 and 428), and the regioselectivity was influenced by stereo and electronic effects. To increase the yields of some analogues, an overstoichiometric amount of 2,2,2-trifluoroacetophenone was required (e.g., 429 and 430).

Scheme 61 Shvo's catalyst-enabled ring expansion of saturated cyclic amines by reaction with azlactones.

The mechanism pathway was proposed by the authors (Scheme 62). Initially, the Shvo's catalyst (425) releases the monomer (431), which coordinates with the amine (424), generating the intermediate 432. The ruthenium hydride species 433 is formed via proton abstraction, leading to the iminium species (437 and 438). Then, azlactone (423) undergoes a deprotonation by 11, forming the enolate 434 and the intermediate 435. The catalyst is regenerated by proton transfer to the ketone, irreversibly converted to the alcohol 436. With the ionic species 434 and 437 pre-formed, the coupling among them affords the adduct 439, which undergoes a retro-aza-Michael reaction, and the intermolecular annulation of 440 furnishes the desired product (426).

Scheme 62 Proposed mechanism for ring expansion of saturated cyclic amines.

Jiang, Zhang, Shi, and co-workers have recently described the synthesis of dihydroquinolinones (443) via a [4 + 2] cycloaddition between azlactones (441) and aza-o-quinone methides (442) (Scheme 63).⁷³ The reaction was promoted by a base, either Cs₂CO₃ or DBU, and further improved by the addition of a catalytic amount of TBAB as a phase-transfer agent when using the inorganic base. Under these reaction conditions, a diversity of protected dihydroquinolinones was obtained in yields ranging from 40 to 98%. Among the examples, it was noted that the reaction between C4-alkyl substituted azlactones and sulfonamides (e.g., 445) exhibited lower efficiency compared with other substrates (e.g., 444 and 446), indicating some sensitivity to steric or electronic factors in this transformation.

Scheme 63 Synthesis of dihydroquinolinones via [4 + 2] cyclization of azlactones with aza-o-quinone methides.

A decarboxylative [3 + 2] annulation between azlactones (447) and ethynylethylene carbonates or carbamates (448) was developed by You, Yuan, and co-workers (Scheme 64a).⁷⁴ Using catalytic copper(II) triflate and DMAP as a base, this protocol enabled the diastereoselective synthesis of γ-lactones and γ-lactams. While structural variations on the carbonate/carbamate component 448 were well tolerated (e.g., 450 and 451), modifications in the azlactone scaffold led to decreased yields or diastereomeric ratios in some cases (e.g., 452). An enantioselective version of the reaction was achieved using a chiral PyBox ligand (455) in combination with copper(II) acetate monohydrate and a catalytic amount of DABCO (Scheme 64b), affording the corresponding lactones (456) with moderate enantiomeric excesses (58–71%). A subsequent study enabled an enantiocontrolled version of the γ-lactam synthesis, furnishing the target products in excellent enantiomeric excesses (up to 99%).⁷⁵

Scheme 64 (a) Copper-catalyzed diastereoselective synthesis of γ-butyrolactones and γ-butyrolactams. (b) Enantioselective version by employing a PyBox ligand.

In 2022, Ouyang and co-workers reported the silver-catalyzed synthesis of benzothiazolo[3,2-a]pyridines (459) via a [4 + 2] annulation between azlactones (457) and 2-vinylbenzothiazoles (458) (Scheme 65).⁷⁶ This strategy enabled the formation of a series of fused heterocycles with excellent diastereomeric ratio (>20 : 1 d.r.) and high yields for most analogues. A decrease in terms of yield was observed for azlactones bearing bulky alkyl substituents (e.g., 461). As a limitation, only aryl substituents were explored at the alkene moiety of 458. Notably, in the same study, an enantioselective version of the reaction using the chiral phosphoric acid R-TRIP instead of the silver catalyst was also described, affording the products with enantiomeric excesses ranging from 52 to 94%.

Scheme 65 Synthesis of benzothiazolo[3,2-a]pyridines through a [3 + 2] annulation reaction.

Su and Liu's group have described an asymmetric protocol for the construction of bicyclic lactams and lactones (467) through an [8 + 2] annulation between azlactones (463) and tropones or azaheptafulvenes (464), catalyzed by chiral guanidines (465 and 466) (Scheme 66).⁷⁷ This strategy afforded the desired adducts in yields of up to 95%. The formation of lactones (e.g., 468 and 469) proceeded with excellent stereocontrol (85–96% e.e., >19 : 1 d.r.). In contrast, the synthesis of lactams exhibited a significant drop in terms of stereoselectivities (e.g., 470), which could not be overcome even with variation of the catalyst. In this reaction, it was proposed that the guanidine-based catalysts play a key role in stereocontrol by engaging in multiple hydrogen bonding interactions.

Scheme 66 Chiral guanidine-catalyzed [8 + 2] cycloaddition between azlactones and tropones or azaheptafulvenes.

In 2023, Huang, Mei, and co-workers developed an enantioselective synthesis of fully substituted 4-pyrrolin-2-ones (473) via a [3 + 2] cycloaddition between azlactones (471) and azoalkenes (472), catalyzed by the chiral phosphoric acid S-TRIP (Scheme 67).⁷⁸ This protocol provided the desired products in high yields (72–95%) and excellent enantiomeric excesses (87–99%). Some limitations include the prolonged reaction time (up to 3 days) and the restriction to azlactones bearing ester substituents. Additionally, when alkenes bearing alkyl chains of varying lengths were employed, both the yields and enantiomeric excesses were drastically reduced.

Scheme 67 Enantioselective synthesis of 4-pyrrolin-2-ones catalyzed by a chiral phosphoric acid.

The same group has reported a domino strategy for the construction of highly substituted bicyclic furofurans (480) (Scheme 68).⁷⁹ The reaction involved azlactones (477) and triketone enones (478), catalyzed by the chiral phosphoric acid 479, affording the products in moderate to excellent yields (66–92%) with high stereoselectivity (>20 : 1 d.r., 70–90% e.e.). Recrystallization of the crude products allowed further enhancement of enantiomeric purity, reaching >99% e.e. in some cases (e.g., 481), albeit with significant loss in yield (e.g., 60% for 483). A catalyst-free variant of the reaction was also demonstrated, maintaining high levels of diastereomeric ratios. Notably, the reaction selectivity was attributed to the occurrence of π–π interactions between the aryl groups of both substrates.

Scheme 68 Access of bicyclic furofurans via domino coupling of triketone enones and azlactones.

Kim's group has developed a diastereoselective annulation between δ-hydroxy or δ-sulfonamido-α,β-unsaturated ketones (485) and azlactones (484), affording 3-amino-δ-lactones or δ-lactams (486) using DBU as base (Scheme 69).⁸⁰ The protocol exhibited good to excellent diastereomeric ratios (7 : 1 to > 20 : 1 d.r.), and tolerated both aliphatic (e.g., 487) and aromatic substituents (e.g., 488 and 489) at the azlactone C2 position. However, attempts using 4-aryl-substituted oxazolones led only to trace product formation. An enantioselective variant employing a bifunctional squaramide catalyst was also explored, delivering the target compound in 70% e.e., though with limited efficiency (20% yield, 3 : 1 d.r.).

Scheme 69 Synthesis of 3-amino-δ-lactones and 3-amino-δ-lactams via [4 + 2] annulation.

Yang, Huang, and co-workers have recently described the preparation of tetrahydro-β-carbolin-1,3-diketones (492) through a [4 + 2] annulation of azlactones (490) with indole-2-ylamides (491) under mild reaction conditions (Scheme 70).⁸¹ Using two equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the β-carboline derivatives were obtained in yields ranging from 37 to 97%. Lower reactivity was observed in the absence of an aryl group at the C4 position of the azlactone scaffold (e.g., 494). Enantioselective attempts employing a chiral phosphoric acid (20 mol%) for selected analogues were also conducted, affording compound 495 with an enantiomeric excess of 45%.

Scheme 70 DDQ-mediated synthesis of tetrahydro-β-carbolin 1,3-diketones derivatives.

Liu and co-workers have demonstrated a [3 + 2] cycloaddition between azlactones (496) and α-amido acids (497) to construct 3,4-diaminopyrrolidine-2,5-diones (499) with good stereoselectivity (up to > 95 : 5 d.r. and 86% e.e.) (Scheme 71).⁸² The reaction was catalyzed by the chiral guanidine 498, affording the adducts in yields ranging from 15 to 90%. When non-benzylic azlactones were employed, the formation of by-products led to diminished yields of the desired products (e.g., 501). As an application, the treatment of the products (499) with TFA and LiAlH₄ enabled the synthesis of pyrrolidine derivatives while retaining both diastereomeric ratios and enantiomeric excesses.

Scheme 71 Chiral guanidine-catalyzed access of 3,4-diaminopyrrolidine-2,5-diones.

Huang, Yang, Lan, and co-workers have developed an enantioselective [4 + 2] cyclization between azlactones (503) and azadienes (504), enabled by a chiral phosphoric acid catalyst (505), affording 3-amino-δ-lactam derivatives (506 and 507) with high stereoselectivity (Scheme 72).⁸³ When terminally substituted azadienes were employed, products 506 were obtained in moderate to high yields (47–97%) and enantiomeric excesses (56–90% e.e.). A broad substrate scope was tolerated (e.g., 508 and 509); however, azlactones bearing 3-methyl indole at the C4 position or 2-alkyl substituents did not furnish the desired products. The use of chalcone-derived azadienes enabled access to the corresponding δ-lactams 507 with low to excellent diastereomeric ratios (2 : 1 to >20 : 1 d.r.) and high enantiomeric excesses (up to 96% e.e.). The stereochemical outcome was rationalized by a Si-face attack of the enol form of the azlactone, directed by the chiral environment of the phosphoric acid catalyst.

Scheme 72 Annulation reaction between azlactones and azadienes to access chiral δ-lactams.

In 2024, Wang and Ren reported an enantioselective [4 + 2] cyclization between azlactones (511) and hydroxyphenyl indolinones (512), enabling the synthesis of spirooxindole δ-lactones (514) with excellent stereoselectivity (up to >20 : 1 d.r. and 99% e.e.) (Scheme 73a).⁸⁴ The transformation was promoted by a bifunctional squaramide catalyst (513) in the presence of an overstoichiometric loading of Ag₂O as oxidant. A diversity of substituents was tolerated on both coupling partners (e.g., 515–517), with little impact on either yields or stereoselectivities. The stereochemical outcome was rationalized by a dual activation model, in which the catalyst (518) orients the substrates through hydrogen bonding interactions to promote a highly selective [4 + 2] cycloaddition (Scheme 73b).

Scheme 73 (a) Stereoselective construction of spirooxindole δ-lactones. (b) Suggested catalyst dual activation model.

In a related study, Kim and co-workers have also developed an enantioselective protocol for the construction of 3,4-dihydrocoumarins using a structurally distinct squaramide catalyst and Ag₂O as oxidant.⁸⁵ This approach also delivered the target products with excellent enantiomeric excesses (87–96% e.e.), further highlighting the utility of squaramide-based catalysis in oxidative annulation processes.

A series of 4,5-dihydropyridazin-3(2H)-ones (522) was synthesized through the reaction of α-halohydrazones (519) with 4-aryl-substituted azlactones (520) under mild conditions (Scheme 74).⁸⁶ Upon base-mediated generation of azoalkenes from the hydrazone precursors, the annulation proceeded efficiently, tolerating a diversity of substrates and delivering the desired products in yields of up to 99%. A one-pot variant of the protocol was also demonstrated, in which azlactones were generated in situ from amino acid derivatives (521), leading to improved outcomes in certain cases (e.g., 523 and 524). Notably, 4-alkyl-substituted azlactones failed to afford the corresponding products, whereas 2-alkyl-substituted analogues were well tolerated, providing the desired heterocycles in good yields (e.g., 525).

Scheme 74 Reaction between azlactones and azoalkenes to construct 4,5-dihydropyridazin-3(2H)-ones.

A mild asymmetric [4 + 2] cycloaddition strategy to access piperidine-2-one-fused tryptanthrins (529) was developed through the reaction of azlactones (526) with tryptanthrin-derived aza-dienes (527), catalyzed by a chiral phosphoric acid (528) (Scheme 75a).⁸⁷ The reaction exhibited a broad functional group tolerance for both coupling partners, affording the desired products in moderate to excellent yields 62–97%, diastereomeric ratios (> 19 : 1 d.r. in all cases), and enantiomeric excesses (up to 98% e.e.) across a diversity of substrates (e.g., 530–532). However, the substrate scope did not include 4-aryl-substituted azlactones, which limits the generality of the methodology. A transition state model (533) was proposed to rationalize the observed stereochemical outcome of the products, in which both substrates are simultaneously activated through hydrogen bonding interactions with the catalyst (Scheme 75b). In this model, the enol form of the azlactone preferentially undergoes Re-face attack on the aza-diene, leading to the formation of product 529.

Scheme 75 (a) Asymmetric synthesis of piperidine-2-one-fused tryptanthrins. (b) Proposed transition state.

Kim and co-workers have developed a stereoselective [4 + 2] cyclization between azlactones (534) and 2-amino-β-nitrostyrenes (535), catalyzed by a bifunctional squaramide (536), to access 3,4-dihydroquinolin-2-ones (537) (Scheme 76a).⁸⁸ The desired products were isolated with variable diastereomeric ratios (1.2 : 1 to 19 : 1 d.r.) and low to excellent enantiomeric excesses (52–97% e.e.). A diversity of azlactone substrates, including both 4-alkyl (e.g., 540) and 4-aryl derivatives (e.g., 538 and 539) were well tolerated under the optimized reaction conditions. Notably, fine-tuning of the squaramide catalyst, such as incorporation of a methoxy-substituted quinolinyl group, was required to enhance the stereochemical outcome when using 4-alkyl azlactones. A transition state model (541) was proposed to rationalize the observed stereoselectivity, in which the nitrostyrene is activated through dual hydrogen bonding interactions with the squaramide moiety, while the azlactone enol tautomer is simultaneously oriented by the quinuclidinium group (Scheme 76b). This cooperative activation mode facilitates both the conjugate addition and the subsequent intramolecular ring-opening step, leading to the (S,S)-product as the major stereoisomer.

Scheme 76 (a) Asymmetric synthesis of 3,4-dihydroquinolin-2-ones. (b) Proposed activation mode.

In 2021, Fisyuk and co-workers reported a protocol for the synthesis of 3-aminopyrido[2,1-a]isoquinolin-4-ones (544) via the reaction of Erlenmeyer–Plöchl azlactones (542) with 1-alkyl-3,4-dihydroisoquinolines (543) (Scheme 77).⁸⁹ The transformation proceeded under DMF or solvent-free conditions, delivering the target products in yields ranging from 15 to 89%. Although a diversity of analogues was prepared, a limitation of the method lies in the exclusive use of dihydroisoquinolines bearing electron-donating substituents (e.g., 545–547), which may restrict its broader applicability.

Scheme 77 Synthesis of 3-aminopyrido[2,1-a]isoquinolin-4-ones using azlactones and 1-alkyl-3,4-dihydroisoquinolines as starting materials.

Based on experimental findings, a plausible mechanistic pathway to rationalize the product formation has been disclosed (Scheme 78). Initially, substrate 548 undergoes tautomerization to its enamine form 549. Under refluxing DMF, a direct coupling between 549 and the azlactone affords product 551. In contrast, when acetonitrile or other solvents were used, 549 reacts with 550 to generate intermediate 552, which eliminates ethanol to form species 553. This intermediate then is converted into the conjugated diastereomers E,E-554 and E,Z-554. Upon heating in DMF, the E,Z-554 undergoes intramolecular cyclization to form 555, which, after ring-opening, furnishes the final product 551.

Scheme 78 Plausible mechanistic pathways to access 3-aminopyrido[2,1-a]isoquinolin-4-ones.

In 2022, the same research group reported a related protocol for the synthesis of 3-amino-6,7-dihydroferroceno[a]quinolizin-4-one derivatives (Scheme 79).⁹⁰ The transformation involved the reaction of azlactones (557) with 3,4-dihydroferroceno[c]pyridines (556), affording the target compounds of 561 in low to good yields (34–76%). Although the substrate scope was limited to only six examples, the study provided valuable mechanistic insights. For example, the use of azlactone (557) resulted in a two-step process, initially forming a mixture of diastereomeric intermediates (558), which were readily oxidized with DDQ to furnish the final product (e.g., 564). In contrast, azlactones featuring O-substituted alkene moieties (e.g., 559 and 560) underwent a single-step transformation, leading directly to the corresponding products (e.g., 562 and 563).

Scheme 79 Synthesis of 3-amino-6,7-dihydroferroceno[a]quinolizin-4-ones.

Fisyuk's group continued to expand the chemistry of azlactones and enamines in the years that followed (Scheme 80).⁹¹ In 2023, they reported a one-pot protocol for the synthesis of 4-arylpyrazolo[3,4-b]pyridin-6-ones (568) via the coupling of 5-aminopyrazoles (566) and Erlenmeyer–Plöchl azlactones (565).⁹² Although the substrate scope was limited to aryl groups at both the azlactone and the N1 position of the pyrazole, the study laid the groundwork for further functionalization of intermediate 567. In a follow-up publication,⁹³ treatment of 567 with POCl₃ under reflux conditions afforded oxazolo[5,4-b]pyrazolo[4,3-e]pyridines (569) in yields of up to 77%. These polycyclic systems served as versatile intermediates for subsequent transformations, such as the conversion to 5-aminopyrazolo[3,4-b]pyridin-6-ones (570) using hydrazine and potassium hydroxide, or to 3,4-dihydro-5H-pyrazolo[4,3-f][1,7]naphthyridin-5-ones (571) via AlCl₃-mediated cyclization.

Scheme 80 Fused-heterocycles preparation from the reaction between Erlenmeyer–Plöchl azlactones and 5-aminopyrazoles.

In 2019, Urriolabeitia and co-workers reported the synthesis of dinuclear cyclobutane derivatives (576) via a [2 + 2] photocycloaddition of orthopalladated azlactones⁹⁴ (575) (Scheme 81).⁹⁵ The transformation gave the cyclobutane adducts in yields of up to 98% and with complete selectivity, isolating a single isomer (ε). Despite the success (e.g, 580–582), the methodology presented a notable limitation: azlactones bearing heteroaryl substituents at the C2 position failed to furnish the desired products. Further functionalization of compound 576 was explored through its reaction with PhICl₂ or Br₂, enabling access to 1,3-diaminotruxillic derivatives (577 and 578). However, these halogenation steps resulted in modest yields, with 578 being obtained in only 24% and 577 being found only in solution (not isolated). Moreover, attempts to react 576 with I₂ led only to traces of the retro [2 + 2] product 579.

Scheme 81 Photocycloaddition of orthopalladated azlactones to access 1,3-diaminotruxillic derivatives.

In a follow-up study, Urriolabeitia and co-workers have described a stereoselective [2 + 2] photocycloaddition protocol involving Erlenmeyer–Plöchl azlactones bearing a styryl group at the C2 position (Scheme 82).⁹⁶ The desired derivatives (584) were isolated in up to 96% yield and as a single isomer (ε). Notably, the presence of the styryl group at C2 did not alter the regioselectivity of the C–H activation during the preparation of the orthopalladated azlactone 583, which consistently occurred at the C4 aryl ring. Further treatment of the photocycloadducts (584) with CO in MeOH/MeCN enabled the carbonylation and release of ortho-functionalized 1,3-diaminotruxillic bis-amino esters (585) in up to 91% yield (e.g., 587).

Scheme 82 Photocycloaddition of orthopalladated azlactones.

In 2022, Urriolabeitia's group presented an alternative to access cyclobutane-containing bis(oxazolones) (589) through the ruthenium-photocatalyzed [2 + 2] cycloaddition of Erlenmeyer–Plöchl azlactones (Scheme 83).⁹⁷ Notably, a regio- and stereoselective dimerization of the exocyclic C=C bonds was achieved, furnishing exclusively the μ-isomer (589) through an anti-head-to-head coupling. Due to difficulties in the isolation of these adducts, a subsequent base-induced ring-opening of 589 was carried out and afforded 1,2-diaminotruxinic bis-amino esters (590) in yields ranging from 30 to 87%. The methodology was carried out in both batch and continuous-flow regime systems (e.g., 591–593), with the latter significantly reducing reaction time from 24–48 hours to only 1 hour. Mechanistic studies confirmed that the reactive excited state corresponds to a triplet diradical (Scheme 85600 and 601), generated via energy transfer from the ruthenium complex.

Scheme 83 Synthetic protocol to access the μ-isomer of 1,2-diaminotruxinic methyl ester derivatives.

In 2023, the same group presented a modified version of their previous methodology, employing similar irradiation conditions in the presence of a Ru-based photocatalyst but now adding BF₃·OEt₂ as a Lewis acid (Scheme 84).⁹⁸ Under these conditions, the [2 + 2] photocycloaddition of Erlenmeyer–Plöchl azlactones (594) led to the selective formation of the δ-isomer of 1,2-diaminotruxinic bis-amino esters (595) in low to moderate yields (up to 50%). This stereochemical outcome contrasts with the μ-isomer obtained in the absence of Lewis acid, highlighting the key influence of BF₃. Interestingly, in the case of compound 598, a small proportion of the corresponding cyclobutane 599 containing the intact oxazolone rings (without ring opening) was also isolated, providing indirect support for the proposed mechanistic pathway. Moreover, the δ-cyclobutanes could be transformed, upon heating with NaOMe in methanol, into densely substituted pyrrolidine-2,5-dicarboxylates.

Scheme 84 Preparation of the δ-isomer of 1,2-diaminotruxinic methyl ester derivatives.

Mechanistically, the presence of BF₃ alters the reaction pathway by coordinating to the carbonyl oxygen of the oxazolone core, leading to 603 (prior to the formation of the diradical) or 604 (after the formation of the diradical) (Scheme 85). The steric hindrance provided by this group prevents the free rotation of the triplet diradical intermediate 605 and locks the system in a conformation that favors the formation of the δ-isomer, in contrast to the free rotation observed in intermediate 601, which leads to the μ-isomer. The selective formation of the δ-isomer in the presence of BF₃ and the isolation of intermediate 599 (in which the oxazolone ring remains intact) support this mechanistic proposal.

Scheme 85 Proposed pathways for Ru-catalyzed photocycloaddition of azlactones, and the role played by BF₃ in the mechanism.

Urriolabeitia and co-workers have also explored the [2 + 2] photocycloaddition of allylidene azlactones (607) under blue light irradiation (456 nm) in the presence of a ruthenium photocatalyst (5 mol%) (Scheme 86).⁹⁹ The [2 + 2] cycloaddition between the exocyclic C=C bond of one oxazolone and the styryl group of another, afforded predominantly a single cyclobutane isomer (608) in up to 43% yield. However, due to the instability of these intermediates (e.g., 610 and 611), which undergo retro-[2 + 2] reactions in solution, the in situ ring opening of the oxazolone moiety was carried out, affording 609 in 77–80% yield.

Scheme 86 Synthesis of cyclobutanes via [2 + 2] photocycloaddition of allylidene azlactones.

In 2024, Amarante and co-workers reported the stereoselective synthesis of substituted cyclobutanes (614) from Erlenmeyer–Plöchl azlactones (613) via a visible-light-driven dual catalysis approach combining an iridium-based photocatalyst with Ni(OTf)₂ as a Lewis acid (Scheme 87).¹⁰⁰ This strategy enabled the direct and single-step access to non-natural amino acid dimers bearing a cyclobutane core, affording exclusively the zeta (ζ) isomer in moderate to good yields (46–67%) and with excellent diastereomeric ratios (>19 : 1 d.r.). An energy transfer from the excited photocatalyst to the nickel-azlactone dimer 618 was found to be the most probable mechanism for this transformation, providing an adequate molecular arrangement that favors the exclusive formation of the ζ-isomer.

Scheme 87 (a) Synthesis of diaminotruxinic acids via [2 + 2] photocycloaddition. (b) Plausible transition state for the experimentally outcome major isomer.

Miscellaneous

In addition to all the transformations discussed so far, several other reactions involving azlactones have been described in the literature. This section highlights representative examples that do not fall under the previously covered categories.

A regio- and stereoselective C–H allylic alkylation of azlactones (620) using palladium catalysis was developed by Wang, Hong, Gong, and co-workers (Scheme 88).¹⁰¹ In this protocol, 1,4-pentadienes (621) were employed to furnish the corresponding allylic adducts (623) with excellent stereoselectivity (up to 99% e.e., >20 : 1 d.r., and >20 : 1 Z/E). Bulky substituents on the azlactone core (e.g., 625) led to lower yields but did not compromise the stereoselectivities. Based on data from this and previous studies, the group concluded that the Z/E selectivity and regioselectivity are primarily driven by the nature of the nucleophile.

Scheme 88 Palladium-catalyzed asymmetric allylic C–H alkylation of 1,4-pentadienes.

In 2019, Serra, Colombo, and co-workers reported an enantioselective decarboxylative allylation of azlactone enol carbonates (629), affording the corresponding products (631) in high both yields and enantiomeric excesses (83–98% yield, 62–85% e.e.) (Scheme 89).¹⁰² Starting from amino acids (627), the oxazolones are prepared and reacted with allyl chloroformates (628) to give enol carbonates (629), which, under catalysis by allylpalladium(II) chloride dimer and chiral ligand 630, are converted to allylated azlactones. This protocol is applicable to both 4-alkyl (e.g., 632 and 634) and 4-aryl azlactones (e.g., 633), enabling access to a diverse scope of α-allyl amino acids.

Scheme 89 Enantioselective decarboxylative allylation of azlactone enol carbonates.

In 2020, Dong, Wang, and co-workers described an asymmetric hydroalkylation of 1,3-dienes (636) with azlactones (635), catalyzed by palladium–phosphinoxazoline complexes, leading to product 638 bearing two contiguous stereogenic centers (Scheme 90).¹⁰³ A broad scope of aryl and alkyl substituents was evaluated, affording the desired compounds in moderate to excellent yields (50–92%), variable diastereomeric ratios (1.2 : 1 to >20 : 1 d.r.) and excellent enantiomeric excesses (86 to >99% e.e.). However, the presence of a methyl group at C2 or a phenyl group at C4 in the azlactone moiety negatively impacted the diastereomeric ratio (e.g., 639), while various alkyl groups were generally well tolerated (e.g., 640). In addition, a diversity of 1,3-dienes bearing aryl, heteroaryl, cyclohexyl, or methoxycarbonyl substituents (e.g., 641) was successfully applied in this transformation.

Scheme 90 Asymmetric hydroalkylation of 1,3-dienes catalyzed by Pd-phosphinoxazoline.

In 2022, Dong, Wang, and co-workers developed an iridium(I)-catalyzed method to access azlactones bearing two allylic groups (645) with high stereocontrol (Scheme 91).¹⁰⁴ This double allylic alkylation, performed by reacting glycine-based azlactone 642 with cinnamyl-derived carbonates 643, enabled the construction of three contiguous stereocenters. A variety of aryl-substituted carbonates was evaluated, affording the corresponding azlactones in yields of up to 96% and excellent diastereomeric ratios (>20 : 1 d.r. in all cases) and enantiomeric excesses (ranging from 98 to >99% e.e.). When a methyl-substituted carbonate was employed, the resulting product 648 was directly subjected to MeOH/K₂CO₃ treatment, providing the corresponding ring-opening methyl ester with 12 : 1 d.r. while maintaining excellent enantiomeric excess (>99% e.e.).

Scheme 91 Stereoselective synthesis of bis-allylic azlactones.

Catalyzed by neodymium(III) triflate, enantioenriched azlactones bearing hydrazide moieties (652) were synthesized through the reaction of azlactones (649) with N-aryl-N-aroyldiazenes (650) (Scheme 92).¹⁰⁵ The method provided products in moderate to high yields (45–93%) and with excellent enantiomeric excesses (80–95% e.e.). The presence of an ortho-alkoxy benzoyl group in the diazene was crucial for the enantioselectivity of this transformation. Owing to the hard Lewis acid character of Nd(III), the authors proposed a coordination of both the carbonyl and alkoxy groups to the metal center, forming a six-membered chelate. This coordination likely blocks the Re-face of the azlactone enol tautomer, disfavoring its attack and leading to the preferential formation of the (S)-configured product.

Scheme 92 Enantioselective synthesis of 4-hydrazide azlactones.

A palladium catalyst combined with the chiral phosphine ligand 658 enabled the construction of 4-allyl azlactones (659) with excellent enantiomeric excesses (89–97% e.e.) and yields ranging from 62 to 97% (Scheme 93).¹⁰⁶ The transformation involved the use of 5-vinyloxazolidine-2,4-diones (657) as substrates, undergoing a decarboxylative process to efficiently afford the allylated azlactones. As a limitation, substrates bearing less sterically demanding groups (e.g., 661) resulted in a slight decrease in yield, while maintaining high enantioselectivity.

Scheme 93 Decarboxylative allylation of azlactones with 5-vinyloxazolidine-2,4-diones.

In this protocol, the desired compounds were obtained via a palladium(0)-catalyzed decarboxylative ring-opening of oxazolidinedione 657, generating the cyclopalladated intermediate 664 (Scheme 94). This complex subsequently deprotonates azlactone 656, and the resulting enolate attacks the palladium–allyl complex, forming the final product 659 while simultaneously regenerating the catalyst (665).

Scheme 94 Proposed catalytic cycle for the palladium-catalyzed allylation of azlactones.

A similar decarboxylative allylation of azlactones (666) was reported by Yuan and co-workers, using vinyl methylene cyclic carbonates (667) as allyl precursors and palladium as the catalyst (Scheme 95).¹⁰⁷ This protocol enabled the selective formation of (Z)-allylic azlactones (669) in low to good yields (up to 89%). Notably, substrates bearing cyclohexyl groups were compatible with the reaction, albeit affording the desired products in lower yields (e.g., 671). The observed (Z)-selectivity was attributed to the formation of an oxapalladacycle intermediate, which is then attacked by the azlactone nucleophile, preferentially leading to the Z-configured product.

Scheme 95 Decarboxylative allylation of azlactones using vinyl methylene cyclic carbonates.

Wang, Qi, Wang, and co-workers have reported a palladium-catalyzed allylic alkylation of azlactones (673) using Morita–Baylis–Hillman (MBH) carbonates (674), affording the corresponding products (676) with high yields and enantiomeric excesses (up to 95% yield and 95% e.e.) (Scheme 96).¹⁰⁸ The choice of ligand proved to be crucial for achieving high enantioselectivity, with ligand 675 enabling the synthesis of over 30 examples, including both aryl-substituted (e.g., 677 and 678) and non-substituted MBH carbonates (e.g., 679), while alkyl-substituted derivatives were not explored.

Scheme 96 Palladium-catalyzed enantioselective allylic alkylation of azlactones.

A regioselective functionalization of azlactones (680) with indoles (681) was achieved through an aerobic iron-catalyzed cross-dehydrogenative coupling in the presence of a PyBox ligand (682) (Scheme 97).¹⁰⁹ The reaction furnished the desired adducts (683) in 25–85% yield, with a strong preference for C4 substitution on the azlactone (10 : 1 to > 30 : 1 regioisomeric ratios, r.r.). Both 4-aryl and 4-alkyl azlactones were compatible with the protocol, requiring only minor adjustments to the oxidant. Notably, when 3-methylindole was employed (e.g., 684), functionalization occurred selectively at the C2 position of the indole, without compromising the regioselectivity at the azlactone core.

Scheme 97 Iron-catalyzed aerobic cross-dehydrogenative coupling of azlactones and indoles.

In 2020, Xing's group demonstrated a palladium-catalyzed allylic alkylation of azlactones using substituted 1,3-dienes (689) and azlactones (687) (Scheme 98).¹¹⁰ This protocol provided the 1,2-addition adducts (691) in low to good yields (up to 83% yield) and stereoselectivities (up to 13 : 1 d.r., and 90% e.e.). Dienes bearing aryl substituents (e.g., 695) generally delivered higher enantiomeric excesses compared with their alkyl-substituted counterparts (e.g., 694). Interestingly, when 1,3-butadiene (688) was employed under the same reaction conditions, the 1,4-addition product (692) predominated, with regioisomeric ratios ranging from 7 : 1 to 14 : 1 r.r.

Scheme 98 Stereo- and regioselective allylic alkylation of azlactones using 1,3-dienes.

A regiodivergent palladium-catalyzed coupling of isoprene (698) with azlactones (697) was investigated by Zhao, Chen, and co-workers, revealing a ligand-dependent regiocontrol (Scheme 99).¹¹¹ When 4-alkyl azlactones and a dicyclohexylphenyl phosphine was employed, prenylation at the C4 position of isoprene was achieved, affording the 2,1-adduct (699) in high yields (e.g., 702), which corresponds to the kinetic product. In contrast, for 4-aryl azlactones, this adduct (699) underwent an aza-Cope rearrangement, delivering C2-prenylated azlactones as the final products. Alternatively, use of the bisphosphine ligand dppe favored formation of the thermodynamic product, leading to C4-prenylated azlactones (700) via 1,4-addition with high regioselectivity (up to >20 : 1 r.r.) and yields ranging from 60 to 99% (e.g., 703 and 704).

Scheme 99 Regiodivergent allylation of azlactones with isoprenes.

In 2023, Wu, Lu, and co-workers reported a light-induced protocol for the construction of alkylated azlactones (707) via the reaction of 705 with redox-active esters bearing alkyl groups (706), or with other alkylated substrates (709) in the presence of a redox-active ester (708) (Scheme 100).¹¹² The method employed 1 mol% of an Ir-based photocatalyst, enabling the formation of 4-disubstituted azlactones as major products, with regioisomeric ratios ranging from 4 : 1 to >25 : 1 r.r. The synthetic scope was exemplified by the incorporation of diverse alkyl groups onto the azlactone core (e.g., 710–712). Notably, in cases involving diastereomeric products (e.g., 710 and 711), low or no diastereoselectivity was observed. In the following year, a related metal-free approach was reported by Zhang and Zhan, employing 2,7-Br-4CzIPN as the photocatalyst.¹¹³

Scheme 100 Photocatalyzed alkylation of azlactones using iridium photocatalysis.

Sala, Alemán, and co-workers have reported the trifluoromethylthiolation of azlactones (713) under quinidinium-based phase-transfer catalysis (715) (Scheme 101).¹¹⁴ Under the optimized reaction conditions, the target products were obtained in 49–98% yields and with moderate to excellent enantiomeric excesses (44–98% e.e.). A diversity of alkyl-substituted azlactones was well tolerated (e.g., 717–719). As a limitation, the method proved to be ineffective for substrates bearing methyl, phenyl, or tert-butyl groups, as well as those lacking substitution at the azlactone C4 position. Notably, modifications at the C2 position of the azlactone revealed a correlation between the electronic nature of the enolate and its reactivity: electron-rich substrates (e.g., 717) reacted within 1 hour, while their electron-deficient counterparts (e.g., 718) required up to 96 hours.

Scheme 101 Enantioselective trifluoromethylthiolation of azlactones under quinidinium phase transfer catalysis.

A enantioselective phenylthiolation of azlactones (720) using 1-(phenylthio)pyrrolidine-2,5-diones (721) was described by Liu and co-workers using guanidine organocatalysis (722) (Scheme 102).¹¹⁵ The resulting sulfenylated azlactones (723) were obtained in good yields (70–95%) and enantioselectivities (74–82% e.e.). Although electronic effects on the substrate were examined (e.g., 724–726), the azlactone scope was limited to only five examples.

Scheme 102 Guanidine-catalyzed enantioselective sulfenylation of azlactones.

Recently, Kanemoto's group described a mild protocol to functionalize azlactones (727) with disulfide groups, employing N-dithiophtalimides (728) as sulfide source, catalyzed by DABCO (Scheme 103).¹¹⁶ This transformation allows easy access to α-disulfide-linked amino acids and peptides, through ring opening of the product. The desired disulfurated azlactones (729) were accessed in high yields for most of the cases demonstrated, tolerating disulfides bearing diverse substituents (e.g., 730–732). In some cases, adjusting in the method was necessary to improve reaction yields. For example, for compound 731, 1 equivalent of DABCO was required.

Scheme 103 DABCO-catalyzed disulfuration of azlactones.

Waser and co-workers have developed an enantioselective synthesis of 4-selenated azlactones (736) using dihydroquinine (735) as the chiral catalyst and a phthalimide-based aryl selenium reagent (734) as the selenium source (Scheme 104).¹¹⁷ A broad substrate scope was demonstrated, revealing variable enantioselectivities (6–88% e.e.). For instance, azlactones bearing alkyl groups at the C2 position (e.g., 738) or selenium reagents containing benzyl substituents (e.g., 739) showed a marked decrease in enantiomeric excesses. Attempts to obtain α-selenated amino acid derivatives through ring-opening reactions were unsuccessful, yielding only the racemic deselenated products.

Scheme 104 Enantioselective α-selenation of azlactones catalyzed by dihydroquinine.

Yavari and co-workers have reported a straightforward method for the synthesis of 1,2,4-oxadiazoles (742) from Erlenmeyer–Plöchl azlactones (740) via reaction with amidoximes (741) (Scheme 105).¹¹⁸ The target oxadiazoles were obtained in moderate to good yields (65–86%), and the protocol tolerated a diversity of aryl substituents with both electron-donating (e.g., 745) and electron-withdrawing groups (e.g., 743 and 744), without notable differences in efficiency. However, the use of alkyl-substituted substrates remains as a limitation of the method.

Scheme 105 Preparation of 1,2,4-oxadiazoles.

A plausible reaction mechanism for this transformation is illustrated in Scheme 106. Initially, the amidoxime (741) attacks the carbonyl group of the azlactone (740), generating resonance-stabilized intermediates 746 and 747. A subsequent proton transfer yields intermediate 748, which undergoes intramolecular cyclization to form 749. Consecutive intramolecular proton transfers (750 and 751), followed by a dehydration step, ultimately afford the desired product (742).

Scheme 106 Proposed mechanism for the reaction between azlactones and amidoximes.

Wu and co-workers have demonstrated the use of a chiral thiourea–phosphonium salt catalyst (716) to promote the enantioselective alkynylation of azlactones (752) with alkynylbenziodoxoles (753) as electrophilic alkyne sources (Scheme 107a).¹¹⁹ The reaction provided alkyne-functionalized azlactones (755) in yields ranging from 55 to 80%, with low to moderate enantiomeric excesses. The substrate scope revealed good reactivity for various 4-alkyl-substituted azlactones, whereas phenyl or methoxycarbonyl-substituted analogues failed to afford the desired products. Additionally, the electronic nature of the aryl group on the alkynyl moiety was investigated, showing similar outcomes for both electron-donating and electron-withdrawing substituents (e.g., 758). A transition state model was proposed for this transformation (759 – Scheme 107b). After in situ generation of the azlactone enolate, a nucleophilic attack on the alkynylbenziodoxole occurs, followed by the release of iodobenzoic acid and formation of a vinylidene intermediate (760). A subsequent [1,2]-aryl migration furnishes the final alkynylated product.

Scheme 107 (a) Thiourea phosphonium salt-catalyzed enantioselective alkynylation of azlactones. (b) Proposed transition state model.

Zhao's group has developed a method for vinyl and allylic C–H functionalization of azlactones (761) via cross-dehydrogenative coupling using p-methoxyphenyl selenoxide (764) as the activator (Scheme 108).¹²⁰ The reaction requires N-fluorobenzenesulfonimide (NFSI) as the oxidant and triflic anhydride as an additive to proceed efficiently. In the case of vinyl C–H functionalization, a variety of alkenes affords the corresponding adducts (765) in good to excellent yields (70–98%). Regarding modifications to the azlactone C4 position, the presence of methyl groups was not tolerated. For allylic C–H-functionalized products (766), moderate to excellent yields (67–96%) were achieved, with varying diastereomeric ratios (up to >20 : 1 d.r.) (e.g., 769).

Scheme 108 C–H functionalization of alkenes using azlactone rings.

In the same year, Zhu, Hao, Jiang, and co-workers reported a diastereoselective nucleophilic addition/oxo-cyclization cascade reaction between terminal propargyl alcohols (771) and azlactones (770), promoted by a BINOL-derived chiral phosphoric acid (BiNPO₄H) (Scheme 109).¹²¹ This protocol enabled the synthesis of 2-substituted azlactone-containing 2H-chromenes (772) with moderate to good yields (57–74%) and low to high diastereomeric ratios (up to >19 : 1 d.r., e.g., 773 and 775). Structural modifications on both the azlactone and alkyne scaffolds were explored, revealing important reactivity trends. Notably, substrates lacking an ortho-hydroxy substituent on one of the aryl rings of the alkyne (e.g., 774) resulted in significantly diminished diastereomeric ratios. Furthermore, non-terminal propargyl alcohols and 4-methyl-substituted azlactones failed to deliver the desired products, highlighting the critical influence of these substituents on the reaction outcome.

Scheme 109 Phosphoric acid-catalyzed diastereoselective synthesis of 2-substituted azlactone 2H-chromenes.

According to the authors, the mechanism begins with the dehydration of propargyl alcohol (771), generating the cationic intermediate 776, which undergoes a 1,6-addition by azlactone (770) to form the allene species 777 (Scheme 110). From this point, two mechanistic pathways are proposed. In Path I, when the alkyne bears an additional phenol group, the catalyst promotes tautomerization to the o-quinone methide 778, which undergoes intramolecular cyclization to furnish the final product 772. In this scenario, a hydrogen bonding interaction between the o-hydroxyl group of the alkyne and the carbonyl group of the azlactone is suggested to enhance the diastereomeric ratio of this transformation. In Path II, the mechanism proceeds via protonation of the allene intermediate (779), followed by intramolecular oxo-cyclization to yield compound 772.

Scheme 110 Proposed mechanistic pathways for the synthesis of 2H-chromene derivatives.

Last year, Fisyuk's group reported another contribution to azlactone transformations.¹²² In this study, starting from (Z)-4-[3-chloroallylidene]-2-phenyloxazol-5(4H)-ones (780), the authors described a three-step synthesis of 4,5-disubstituted methyl 1H-pyrrole-2-carboxylates (783) (Scheme 111). The sequence begins with alcoholysis of the azlactone ring to afford intermediate 781, which then undergoes intramolecular cyclization catalyzed by copper(II) acetate to furnish the pyrrole 782. Finally, the benzoyl group is removed via treatment with ethylenediamine (EDA), yielding the target compounds in 38–66% overall yields. The methodology was effective for substrates bearing either alkyl (e.g., 784 and 785) or aryl substituents (e.g., 786), with the reactions proceeding smoothly across the series.

Scheme 111 Synthesis of 4,5-disubstituted methyl 1H-pyrrole-2-carboxylates.

In 2022, Thasana's group described a copper-mediated transformation of (Z)-4-(2-bromobenzylidene)-oxazol-5(4H)-ones (787) into 3-amidocoumarin derivatives (788) under microwave irradiation (Scheme 112).¹²³ Notably, azlactones bearing aryl substituents (e.g., 789 and 790) and a methyl group at the C2 position (e.g., 791) were well tolerated. The absence of aromatic rings bearing electron-withdrawing groups among the successful examples suggests a limitation of the method. It is also worth mentioning that the use of the ring-opened azlactones as substrates was also investigated, resulting in the formation of 3-amidoazacoumarins or 3-benzoylindol-2-carboxamides as alternative products.

Scheme 112 Copper-catalyzed synthesis of 3-amidocoumarins derivatives.

In the following year, 2023, the same group developed protocols for the construction of hydroxynaphthalenamides (793) and phosphorylated dihydronaphthylamides (795), using Erlenmeyer–Plöchl azlactones (792) as common starting materials (Scheme 113).¹²⁴ The synthesis of compound 793 was achieved using in situ-generated sodium methoxide, affording the desired products in yields of up to 73%. In contrast, compounds 795 were obtained through a silver-catalyzed (5 mol%) radical process employing diphenylphosphine oxide (794). Notably, electron-rich arylidene groups were favored in both transformations (e.g., 796–798). Additionally, while azlactones bearing a methyl group at the C2 position showed reduced yields in the synthesis of the phosphorylated product 797, the corresponding hydroxynaphthalenamide 798 was obtained smoothly under the basic conditions.

Scheme 113 Synthetic protocol to access hydroxynaphthalenamides and phosphorylated dihydronaphthylamides.

Last year, the construction of indeno[2,1-c]pyran-3-ones (801) and 1-oxazolonylisobenzofurans (803) was reported by Thasana's group using in situ-generated Erlenmeyer–Plöchl azlactones as key intermediates (Scheme 114).¹²⁵ Through a cascade cyclization involving o-(2-acyl-1-ethynyl)benzaldehydes (799) and N-acylglycines (800), in the presence of acetic anhydride and sodium acetate, the desired products 801 were obtained in low to moderate yields (15–56%). A slight modification of the reaction conditions, employing amino acids (802) instead of N-acylglycines, enabled access to isobenzofurans (803) in yields ranging from 12 to 77%, with Z/E ratios ranging from 59 : 41 to >99 : 1. It was observed that substrates 799 bearing methyl ketones led to high stereoselectivities (e.g., 805), whereas phenyl ketone derivatives generally afforded mixtures of Z/E-isomers (e.g., 806).

Scheme 114 Cascade cyclization reactions to produce indeno[2,1-c]pyran-3-ones and 1-oxazolonylisobenzofurans.

With a better understanding of the reaction features, a plausible mechanism has been disclosed (Scheme 115). The reaction between aldehydes (799) and N-acylglycines (800) initially leads to intermediate 807via a Dakin–West-type reaction. Subsequent dehydration furnishes the arylidene azlactone 808, which upon acetate attack undergoes a 1,4-addition at the alkynyl moiety, generating species 809. An intramolecular 1,4-addition then promotes the first cyclization and azlactone ring opening, affording the ketene intermediate 810. This species undergoes a second intramolecular cyclization/lactonization to give 811, which, after an aromatization step (812), yields the final product 801. In contrast, access to compound 803 begins with the formation of azlactone 813 from amino acid 802, followed by base-mediated deprotonation to form carbanion species 814. Nucleophilic attack on the aldehyde moiety of 799 gives alcohol 815, which then undergoes a 5-exo-dig oxo-cyclization and final protonation to furnish the isobenzofuran core.

Scheme 115 Proposed pathways for the synthesis of indeno[2,1-c]pyran-3-ones and 1-oxazolonylisobenzofurans.

In 2022, Kim, Kim, and co-workers reported the iridium-catalyzed C–H amidation of 2-aryl and 2-alkenyl azlactones (816) (Scheme 116).¹²⁶ The amide-containing azlactones (818) were obtained via reaction of 816 with acyl azides (817) in the presence of [IrCp*Cl₂]₂, affording the desired products in low to high yields (up to 92%). Among the reported examples, both aryl (e.g., 819 and 821) and alkyl acyl azides (e.g., 820) were successfully employed.

Scheme 116 Ir-catalyzed synthesis of amide-containing azlactones.

A plausible catalytic cycle for this transformation was proposed (Scheme 117), beginning with the C–H activation of azlactone 816 to generate the five-membered iridacycle intermediate 822. Coordination of the azide 817 then occurs, forming the nitrene species 823 with concomitant release of N₂. Subsequent nitrene insertion affords intermediate 824, which, upon protonation, delivers the ortho-amidated product 818 and regenerates the catalyst.

Scheme 117 Catalytic cycle for the iridium-catalyzed C − H amidation of azlactones.

The transformation of azlactones (827) into 2,4-disubstituted thiazoles (828) was reported in 2022 by Peng, Wang, and co-workers (Scheme 118).¹²⁷ Utilizing Lawesson's reagent (825), its reactive form (826) reacts with azlactone 827 to afford the desired thiazole products in yields ranging from 26 to 92%. The methodology proved to be effective for both alkyl- and aryl-substituted azlactones (e.g., 829–831). However, substrates bearing alkyl groups at the C4 position, as well as sterically hindered aryl groups, exhibited a significant decrease in reaction efficiency (e.g., 830).

Scheme 118 Synthesis of 2,4-disubstituted thiazoles starting from azlactones.

A plausible mechanism for the transformation was proposed by the authors (Scheme 119). Initially, azlactone 827 undergoes thiolation by the active form of Lawesson's reagent (826), generating intermediate 833. Upon heating, this species rearranges to form 834, which can subsequently isomerize to 835. Both intermediates (834 and 835) then react with an additional equivalent of 826, leading to the formation of tautomers 836, 837, and 838. In the final step, Lawesson's reagent facilitates the conversion of 838 into the desired thiazole product 828.

Scheme 119 Mechanistic pathway for the formation of thiazoles using Lawesson's reagent and azlactones.

In 2023, a copper-catalyzed protocol was developed for the construction of chiral propargyl azlactones (842), which could be readily converted into their corresponding amino acid derivatives (843) (Scheme 120).¹²⁸ Using 10 mol% of Cu(OTf)₂ in combination with a chiral ligand (841), the reaction between N-acyl α-amino acid N-hydroxyphtalimide esters (839) and racemic propargyl carbonates (840) afforded azlactones 842 bearing two contiguous stereogenic centers. Subsequent alcoholysis furnished the desired propargylated amino acid derivatives 843 with varying yields (up to 99%), diastereomeric ratios (up to >19 : 1 d.r.) and enantiomeric excesses (ranging from 50 to 96%). Although some analogues exhibited reduced diastereomeric ratios and yields (e.g., 845), the methodology proved to be effective for both alkyl- and aryl-substituted amino acid derivatives (e.g., 844–846), enabling the generation of a diverse library of chiral products for further applications.

Scheme 120 Copper-catalyzed stereoselective propargylation of azlactones.

A plausible mechanistic pathway was then proposed (Scheme 121), beginning with the deprotonation of substrate 839 to form 847. This species undergoes an intramolecular cyclization to afford intermediate 848, which is subsequently converted into azlactone 849, releasing anion 852. The azlactone is then deprotonated to generate enolate 850, which reacts with the activated copper-allenylidene complex 851, furnishing the chiral propargylated azlactone 842. Finally, alcoholysis of 842 leads to the desired product 843. The authors also suggest that a dicopper-allenylidene complex may serve as a key intermediate responsible for the observed stereoselectivity.

Scheme 121 Plausible reaction pathway for asymmetric synthesis of propargylated amino acid derivatives.

A synthetic method for the preparation of amido piperidones (856) via palladium catalysis was reported by Zhao, Yuan, and co-workers (Scheme 122).¹²⁹ The reaction of azlactones (853) with sulfonamido-substituted allylic carbonates (854) gave the desired protected piperidones in yields of up to 99%. Notably, both alkyl (e.g., 857) and aryl sulfonamides (e.g., 858 and 859) were well tolerated, although electron-deficient aryl rings led to moderate yields (e.g., 858). As a limitation, structural variation on the azlactone core was only explored on the aryl C2 moiety.

Scheme 122 Palladium-catalyzed synthesis of protected piperidones.

The proposed mechanism begins with the decarboxylation of the sulfonamide-containing allylic carbonate (854), generating the zwitterionic aza-π-allylpalladium intermediate 860 (Scheme 123). Subsequent nucleophilic attack by the enol tautomer of the azlactone onto intermediate 860 (as depicted in 861) affords the α-allylated species 862, which undergoes an intramolecular aminolysis to render the final product 856.

Scheme 123 Proposed mechanism for Pd-catalyzed synthesis of piperidones.

A base-mediated cascade reaction for the synthesis of hydantoins (865 and 866) was presented by Chen's group in 2024 (Scheme 124).¹³⁰ The reaction between azlactones (863) and ureidomalonates (864), catalyzed by DBU, afforded the hydantoins bearing α-amino acid ester motifs (865) in short reaction times (only 10–35 min). Alternatively, by replacing DBU with Cs₂CO₃ and TBAB under sunlight irradiation and an aerobic atmosphere, imide-functionalized hydantoins (866) were obtained in moderate to good yields (up to 80%). Most products were isolated as a single diastereomer (e.g., 867 and 870); however, a notable decrease in diastereoselectivity was observed for ortho-substituted N-aryl hydantoins (e.g., 868 and 869).

Scheme 124 Synthesis of hydantoins via the reaction of ureidomalonates with azlactones.

Through mechanistic studies, a plausible mechanism for cascade reactions was proposed (Scheme 125). Upon base-mediated deprotonation, ureidomalonate 871 undergoes conjugate addition to the azlactone, yielding intermediate 873. This species undergoes a base-mediated intramolecular cyclization to form intermediate 874. Interestingly, 874 can also be generated directly via intramolecular ammonolysis (875) of the tautomer 872, followed by conjugate addition to the arylidene azlactone (863). Subsequently, the ring opening of 874via alcoholysis gives product 865. Under sunlight and in the presence of air, the reaction proceeds through a radical mechanism. The anionic azlactone moiety 876, via single-electron transfer, forms the radical species 877 along with the molecular oxygen radical anion. A radical–radical coupling between 877 and the superoxide leads to the formation of anionic intermediate 878. This intermediate undergoes intramolecular cyclization (879), followed by ring-opening, resulting in the imido-functionalized hydantoin product (866).

Scheme 125 Proposed pathways for the base-mediated synthesis of hydantoins.

Veselý and co-workers have developed a method for the preparation of chiral spiroazlactones (882 and 883) via a dual-catalytic system comprising Pd₂(dba)₃ and (S)-TMS-DPP (Scheme 126).¹³¹ The transformation proceeds through a [3 + 2] cycloaddition between vinylcyclopropane azlactones (880) and enals (881), affording the target products with reasonable diastereomeric ratios (1 : 4 to 5 : 1 d.r.) and moderate to excellent enantiomeric excesses (60–90% e.e.). The protocol showed good performance for substrates bearing both alkyl and aryl substituents (e.g., 884–886). Notably, enals with ortho-substituted aryl groups furnished the opposite diastereomer as the major product (e.g., 885). A key limitation of the method is the long reaction times required for certain analogues, reaching up to five days.

Scheme 126 Dual-catalytic asymmetric synthesis of spiroazlactones.

The proposed catalytic cycle illustrates the role played by both catalysts in the reaction (Scheme 127). Initially, palladium coordinates to the vinyl moiety of the azlactone (880), forming intermediate 887, and promotes cyclopropane ring opening via oxidative addition to generate the π-allylpalladium species 888. Simultaneously, condensation between (S)-TMS-DPP and the aldehyde (881) affords the iminium ion 889, which undergoes conjugate addition with 888, forming intermediate 890. A subsequent 5-exo-trig cyclization furnishes 891. The conformation of 890 is crucial for the high level of stereoselectivity observed in this transformation. Finally, hydrolysis of the iminium regenerates the organocatalyst and leads to intermediate 892, which releases the palladium catalyst back into the cycle and delivers the final product 844.

Scheme 127 Proposed catalytic cycle for the preparation of spiroazlactones.

In 2024, Veselý's group reported a stereoselective protocol for the construction of cyclopentene-fused amino acid derivatives (895).¹³² The catalytic system, consisting of Pd₂(dba)₃ (1 mol%) and the chiral secondary amine (S)-TMS-DPP (15 mol%), enabled the reaction between Erlenmeyer–Plöchl azlactones (893) and α,β-unsaturated aldehydes (894) with up to 70% yield, 15. d.r. and 97% e.e. (Scheme 128a). Alkenyl aldehydes bearing alkyl substituents (e.g., 896) generally performed better than their aryl counterparts (e.g., 897 and 898). However, the reaction was unsuccessful with para-dimethylamino and ortho-bromo-substituted cinnamaldehydes. Likewise, azlactones bearing either electron-rich aryl groups or non-terminal alkynes did not afford the desired products. The proposed mechanism involves the formation of a key Michael-type adduct (899) through the coupling of the iminium species (formed from the reaction between 894 and (S)-TMS-DPP) with the azlactone (Scheme 128b). A subsequent 5-exo-dig cyclization affords the spirocyclic intermediate 900. Catalyst release then yields compound 901, which undergoes exocyclic double bond isomerization and azlactone alcoholysis to deliver the final product 895.

Scheme 128 (a) Asymmetric preparation of functionalized cyclopentenes. (b) Proposed reaction pathway.

A regioselective, transition metal-free transformation of α-amino acid-derived esters (902) and Morita–Baylis–Hillman carbonates (903) into allyl-substituted azlactones (904, 905, and 906) was described by Wang, Tan, and co-workers (Scheme 129).¹³³ Exclusive formation of β-C4-azlactones (904) was achieved by using DBU as base in DMSO, with yields ranging from 41 to 88%. When the solvent was switched to toluene and DABCO was used instead of DBU, a mixture of γ-C2-azlactones (905) and γ-C4-azlactones (906) was obtained, with low to excellent diastereomeric ratios (e.g., 909 and 910).

Scheme 129 Base-mediated construction of allyl-substituted azlactones.

The mechanism leading to each regioisomer was proposed by the authors (Scheme 130). Initially, nucleophilic attack of the base on carbonate 903 releases CO₂ and tert-butoxide, generating the cationic intermediate 912. Simultaneously, under basic reaction conditions, the amino acid derivative (902) can isomerize to form the enol 911, which, upon deprotonation by tert-butoxide, reacts with 912via three distinct pathways. When DBU is used (Path I), an S_N2 reaction occurs with C4-selectivity, forming intermediate 914, which undergoes cyclization to furnish product 904. Alternatively, nucleophilic attack of 911 can take place at the γ-position of 912 (Paths II and III), generating intermediates 916 and 918, which lead to the corresponding azlactones (905 and 906) after intramolecular cyclization.

Scheme 130 Proposed mechanism for the regioselective preparation of allyl-substituted azlactones.

The copper-mediated transformation of Erlenmeyer–Plöchl azlactones has also been explored by Xiao, Xu, and co-workers for the synthesis of 3-aryl-substituted isoxazolines and isoxazoles (921).¹³⁴ In this protocol, azlactones (919) were reacted with conjugated unsaturated compounds (920) and copper nitrate, serving as the nitrogen source, to afford a diversity of derivatives in variable yields (21–82%) (Scheme 131). Interestingly, the best performances were observed when maleimides and naphthoquinones were employed as reaction partners (e.g., 922). In contrast, the use of either isothiazol-3(2H)-one derivatives (e.g., 923) or non-cyclic substrates (e.g., 924) resulted in lower yields; the reactions proceeded with good regioselectivity, though. Notably, alkyl-substituted azlactones were tested but failed to afford the desired products, highlighting a limitation of the method.

Scheme 131 Preparation of isoxazolines and isoxazoles using azlactone rings.

The plausible mechanism proposed by the authors is depicted in Scheme 132. Initially, copper nitrate coordinates to the exocyclic double bond of the azlactone, forming intermediate 925. This is followed by a cis-insertion step (926), in which copper binds to the less hindered carbon and coordinates with the azlactone carbonyl group. A subsequent C–C bond cleavage releases 2-phenyloxazole-4,5-dione (931) and generates intermediate 927. An intramolecular rearrangement then leads to species 928, which, upon eliminating the copper salt, affords the nitrile oxide 929. Finally, a [3 + 2] cycloaddition between the 1,3-dipolar compound 929 and the unsaturated substrate (e.g., N-phenylmaleimide) delivers the final product (930).

Scheme 132 Plausible mechanism for the copper-mediated synthesis of isoxazolines and isoxazoles.

In 2022, Zheng's group developed an efficient strategy for the direct functionalization of azlactones (932) using redox-active esters (933) under visible-light irradiation, affording alkyl-functionalized azlactones (934) (Scheme 133).¹³⁵ A three-component protocol involving the use of these substrates and 1,3-enynes (935) or alkenes (936 or 937), to access the corresponding derivatives (938, 939, or 940) was also described in the same study. Across these protocols, more than 100 examples were synthesized, showcasing the broad applicability of this method for incorporating different functional groups onto the azlactone scaffold, thereby facilitating the synthesis of diverse unnatural amino acid derivatives. Notably, primary (e.g., 944), secondary (e.g., 942), and tertiary alkyl groups (e.g., 941 and 943) were generally well tolerated. Moreover, compound 942 was successfully synthesized under continuous flow regime, affording the product in 63% yield and with a productivity of 0.31 mmol h⁻¹.

Scheme 133 Visible-light-enabled functionalization of azlactones.

The proposed mechanism begins with the tautomerization of azlactone 932 to form intermediate 945, which, upon visible-light irradiation, is excited to species 946 (Scheme 134). A subsequent single-electron transfer (SET) between 946 and the ester 933 generates a radical pair 947. Radical coupling between the azlactone-derived radical and the resulting alkyl radical (948) furnishes the alkylated azlactone 934. In the presence of either an olefin (936 or 937) or a 1,3-enyne (935), the alkyl radical undergoes an initial addition to the unsaturated substrate, forming new radical intermediates 949–951. These intermediates then couple with the azlactone radical, affording the corresponding products 938, 939, or 940.

Scheme 134 Proposed radical mechanism for the functionalization of azlactones under visible-light irradiation.

Zheng's group has recently reported the visible-light-mediated addition of conjugated olefins (953) to azlactones (952), enabling the synthesis of deuterium-labeled functionalized azlactones (954) without the need for a photocatalyst (Scheme 135).¹³⁶ The method exhibited high regioselectivity in most cases (e.g., 956 and 957). However, when benzofurans or benzoxazoles were employed (e.g., 955), a notable decrease in the regioselectivity was observed. Interestingly, the reaction with 1,3-butadiene yielded a mixture of regioisomers (957 and 958).

Scheme 135 Photoinduced alkylation of azlactones.

Based on data in the literature,¹³⁵ the reaction is suggested to proceed via the formation of a photoexcited enolized azlactone intermediate (960) under light irradiation (Scheme 136). A subsequent single-electron transfer with the alkene (953) generates the radical species 961 and 962. The diene-derived radical is then deuterated by D₂O to give intermediate 963, which undergoes a radical–radical coupling with 961, affording a mixture of C2 (964) and C4 (954) regioisomers. Under continuous light irradiation, the C2-isomer gradually converts into the thermodynamically more stable C4-isomer via C–C bond cleavage and re-coupling.

Scheme 136 Proposed azlactone alkylation mechanism under photochemical conditions.

Conclusions

In summary, interest in the azlactone core has grown significantly in recent years, as evidenced by the diversity of studies dedicated to this scaffold. The ease of constructing oxazolones from readily available amino acids facilitates research involving this heterocycle, while its dual role as an electrophile and pro-nucleophile enables diverse synthetic applications. While classic transformations such as cycloadditions, Mannich-type reactions, conjugate additions, and dynamic kinetic resolutions remain widely explored, more advanced strategies incorporating transition-metal catalysis, organocatalysis, and photocatalysis have emerged, enhancing regio- and stereoselectivity.

Furthermore, azlactones serve as versatile building blocks for the formation of C–C, C–N, C–O, and C–P bonds, granting access to structurally diverse and complex molecules. Nevertheless, challenges persist, particularly regarding substrate scope limitations and the low selectivity observed in certain protocols. Continued advancements and the development of novel methodologies targeting this core are crucial for further expanding the synthetic potential of azlactone-based transformations.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors are grateful for the financial support from FAPEMIG (APQ-00849-22, and APQ-01259-24), CAPES (Finance code 001), and CNPq (308200/2021-7).

References

1. K. Naveen, V. S. Rawat, R. Verma and E. Gnanamani, Catalyst-free ring opening of azlactones in water microdroplets, Chem. Commun., 2024, 60, 13263–13266.
2. A. R. Alba and R. Rios, Oxazolones in Organocatalysis, New Tricks for an Old Reagent, Chem. – Asian J., 2011, 6, 720–734.
3. J. J. Li, in Name Reactions, Springer International Publishing, Cham, 2014, pp. 229–230.
4. D. S. A. Haneen, W. S. I. Abou-Elmagd and A. S. A. Youssef, 5(4H)-oxazolones: Synthesis and biological activities, Synth. Commun., 2021, 51, 215–233.
5. N. Kushwaha and S. Kushwaha, Synthetic approaches and biological significance of oxazolone moieties: A review, Biointerface Res. Appl. Chem., 2022, 12, 6460–6486.
6. L. Kumar, K. Lal, A. Kumar and A. Kumar, Synthesis, antimicrobial evaluation and docking studies of oxazolone-1,2,3-triazole-amide hybrids, Res. Chem. Intermed., 2021, 47, 5079–5097.
7. L. Saadi and S. Adnan, Synthesis, Antibacterial and Antioxidant Evaluation of 2-Substituted-4-arylidene-5(4H)-oxazolone Derivatives, Indones. J. Chem., 2023, 23, 1463–1471.
8. R. F. Algera, C. Allais, A. F. Baldwin, H. Becirovic, P. Bowles, A. R. Brown, J. M. Buske, H. J. Clarke, N. M. Do, K. Doyle, J. Fifer, K. Gray, A. Happe, M. Hardink, A. K. Hubbell, C. James, H. P. Khadamkar, J. Magano, E. L. McInturff, J. Mustakis, G. Ozbuyukkaya, J. L. Piper, D. W. Place, J. A. Ragan, B. Rauschenberger, G. Reyes, R. Shehadeh, C. Stanchina, M. Stanley, R. M. Weekly, E. Weinstein, G. A. Weisenburger, E. Wood, H. G. Yayla and S. Yu, Synthesis of Nirmatrelvir: Development of an Efficient, Scalable Process to Generate the Western Fragment, Org. Process Res. Dev., 2023, 27, 2240–2249.
9. S. Kishimoto, Non-enzymatic reactions in biogenesis of fungal natural products, J. Nat. Med., 2024, 78, 467–473.
10. L. Jia, S. M. Kilbey and X. Wang, Tailoring Azlactone-Based Block Copolymers for Stimuli-Responsive Disassembly of Nanocarriers, Langmuir, 2020, 36, 10200–10209.
11. J. Liebscher, J. Teßmar and J. Groll, In Situ Polymer Analogue Generation of Azlactone Functions at Poly(oxazoline)s for Peptide Conjugation, Macromol. Chem. Phys., 2020, 221, 1–7.
12. X. Yu, A. Herberg and D. Kuckling, Azlactone-functionalized smart block copolymers for organocatalyst immobilization, Eur. Polym. J., 2019, 120, 109207.
13. F. François, G. Gody, J. Wilson, L. Fontaine and S. Pascual, Azlactone-based copolymers by redox-initiated MADIX polymerization at room temperature in ethanol, Polym. Chem., 2024, 15, 1453–1459.
14. M. E. Buck and D. M. Lynn, Azlactone-functionalized polymers as reactive platforms for the design of advanced materials: Progress in the last ten years, Polym. Chem., 2012, 3, 66–80.
15. J.-B. Lin, D.-S. Ji and P.-F. Xu, Catalytically generated noncovalent ammonium dienolate: a versatile platform for the development of organocatalytic asymmetric cascade reactions, Sci. China: Chem., 2024, 67, 2524–2546.
16. P. P. de Castro, A. G. Carpanez and G. W. Amarante, Azlactone Reaction Developments, Chem. – Eur. J., 2016, 22, 10294–10318.
17. I. F. S. Marra, P. P. de Castro and G. W. Amarante, Recent Advances in Azlactone Transformations, Eur. J. Org. Chem., 2019, 5830–5855.
18. P. P. De Castro, J. A. Dos Santos, M. M. De Siqueira, G. M. F. Batista, H. F. Dos Santos and G. W. Amarante, Quantum Chemical-Guided Steglich Rearrangement of Azlactones and Isoxazolones, J. Org. Chem., 2019, 84, 12573–12582.
19. J. C. Ruble and G. C. Fu, Enantioselective Construction of Quaternary Stereocenters: Rearrangements of O -Acylated Azlactones Catalyzed by a Planar-Chiral Derivative of 4-(Pyrrolidino)pyridine, J. Am. Chem. Soc., 1998, 120, 11532–11533.
20. M.-S. Xie, Y.-F. Zhang, M. Shan, X.-X. Wu, G.-R. Qu and H.-M. Guo, Chiral DMAP- N -oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement, Angew. Chem., Int. Ed., 2019, 58, 2839–2843.
21. Q. H. Li, G. S. Zhang, Y. H. Wang, M. S. Mei, X. Wang, Q. Liu, X. Di Yang, P. Tian and G. Q. Lin, A novel chiral DMAP-Thiourea bifunctional catalyst catalyzed enantioselective Steglich and Black rearrangement reactions, Org. Chem. Front., 2019, 6, 2624–2629.
22. M. Wang, M. Zhou, L. Zhang, Z. Zhang and W. Zhang, A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives: Via a bicyclic imidazole-catalyzed direct enantioselective C -acylation, Chem. Sci., 2020, 11, 4801–4807.
23. K. Fujita, M. Hattori, T. Takehara, T. Suzuki and S. Nakamura, Enantioselective Construction of Consecutive Tetrasubstituted Stereogenic Centers by Reaction of α-Substituted β-Nitroacrylates with Oxazol-5-(4H)-ones Catalyzed by Cinchona Alkaloid Sulfonamide Catalysts, Org. Lett., 2023, 25, 2835–2839.
24. B. Zhu, B. Lu, H. Zhang, X. Xu, Z. Jiang and J. Chang, Phase-Transfer-Catalyzed, Enantioselective Vinylogous Conjugate Addition-Cyclization of Olefinic Azlactones to Access Multifunctionalized Chiral Cyclohexenones, Org. Lett., 2019, 21, 3271–3275.
25. L. Chen and W. Liang, Phase-transfer catalyzed Michael/ammonolysis cascade reactions of enaminones and olefinic azlactones: a new approach to structurally diverse quinoline-2,5-diones, Org. Biomol. Chem., 2022, 20, 3201–3210.
26. J. Kikuchi and M. Terada, Enantioselective Addition Reaction of Azlactones with Styrene Derivatives Catalyzed by Strong Chiral Brønsted Acids, Angew. Chem., Int. Ed., 2019, 58, 8458–8462.
27. J. Wang, S. Zheng, S. Rajkumar, J. Xie, N. Yu, Q. Peng and X. Yang, Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies, Nat. Commun., 2020, 11, 1–12.
28. D. Y. Zhu, X. J. Zhang and M. Yan, Enantioselective Addition of Azlactones to Ethylene Sulfonyl Fluoride via Dual Catalysis, Org. Lett., 2021, 23, 4228–4232.
29. B. Shafiee, J. Duffield, R. Timm, R. Liyanage, J. O. Lay, A. R. Khosropour, H. Amiri Rudbari and M. H. Beyzavi, Metal-free and benign approach for the synthesis of dihydro-5′: H-spiro[benzo [c] chromene-8,4′-oxazole]-5′,6(7 H)-dione scaffolds as masked amino acids, Green Chem., 2019, 21, 2656–2661.
30. B. Nasiri, G. Pasdar, P. Zebrowski, K. Röser, D. Naderer and M. Waser, Towards an asymmetric β-selective addition of azlactones to allenoates, Beilstein J. Org. Chem., 2024, 20, 1504–1509.
31. Y. Zhang, L. Ning, T. Zhu, Z. Xie, S. Dong, X. Feng and X. Liu, Chiral guanidine catalyzed cyclization reactions of 1,3-enynes for lactone synthesis: switchable H-bond catalysis, Org. Chem. Front., 2024, 11, 2897–2904.
32. E. P. Ávila, R. M. S. Justo, V. P. Gonçalves, A. A. Pereira, R. Diniz and G. W. Amarante, Chiral Brønsted Acid-Catalyzed Stereoselective Mannich-Type Reaction of Azlactones with Aldimines, J. Org. Chem., 2015, 80, 590–594.
33. P. Tong, Y. Li, Y. Zhang and X. Jiang, Triphenylphosphine-Catalyzed Diastereoselective Addition of Oxazolones to Isatin-Derived Ketimines: Construction of Vicinal N-Substituted Quaternary Stereocenters, Asian J. Org. Chem., 2019, 8, 492–495.
34. Z. Li, J. Peng, C. He, J. Xu and H. Ren, Squaramide-Catalyzed Asymmetric Mannich Reactions of Azlactones with Isatin-Derived Ketimines: Access to α,β-Diamino Acid Derivatives Bearing Vicinal Quaternary Stereocenters, J. Org. Chem., 2020, 85, 3894–3901.
35. F. Zhou, Q. L. Hu, K. Q. Hou, A. S. C. Chan and X. F. Xiong, Construction of α,β-Diamino Diacid Derivatives with Adjacent Acyclic Tetrasubstituted Stereocenters, J. Org. Chem., 2022, 87, 8709–8718.
36. M. Žabka, A. Kocian, S. Bilka, S. Andrejčák and R. Šebesta, Transformation of Racemic Azlactones into Enantioenriched Dihydropyrroles and Lactones Enabled by Hydrogen-Bond Organocatalysis, Eur. J. Org. Chem., 2019, 6077–6087.
37. E. M. Buev, A. A. Smorodina, V. S. Moshkin and V. Y. Sosnovskikh, Nonstabilized azomethine ylides in the synthesis of aryl cucurbitine derivatives, Tetrahedron Lett., 2019, 60, 649–652.
38. X. D. Bai, Q. F. Zhang and Y. He, Enantioselective iridium catalyzed α-alkylation of azlactones by a tandem asymmetric allylic alkylation/aza-Cope rearrangement, Chem. Commun., 2019, 55, 5547–5550.
39. X. D. Bai, Q. F. Zhang and Y. He, Erratum: Enantioselective iridium catalyzed α-alkylation of azlactones by a tandem asymmetric allylic alkylation/aza-Cope rearrangement, Chem. Commun., 2019, 56, 5547–5550 ( Chem. Commun. , 2020 , 56 , 663 ).
40. K. Fujita, M. Miura, Y. Funahashi, T. Hatanaka and S. Nakamura, Enantioselective Reaction of 2 H-Azirines with Oxazol-5-(4 H)-ones Catalyzed by Cinchona Alkaloid Sulfonamide Catalysts, Org. Lett., 2021, 23, 2104–2108.
41. L. Lin, M. Wang, J. Zhou, F. Li and H. Liu, Highly diastereo- and enantioselective C2 addition of 5H-oxazol-4-ones to γ-keto-α,β-unsaturated esters, Chem. Commun., 2023, 59, 3606–3609.
42. P. P. De Castro, G. M. F. Batista, G. W. Amarante and H. F. Dos Santos, Origin of Enantioselectivity in Chiral Phosphoric-Acid-Catalyzed Azlactone Dynamic Kinetic Resolution, J. Org. Chem., 2021, 86, 13169–13174.
43. M. S. Xie, B. Huang, N. Li, Y. Tian, X. X. Wu, Y. Deng, G. R. Qu and H. M. Guo, Rational design of 2-substituted DMAP- N-oxides as acyl transfer catalysts: Dynamic kinetic resolution of azlactones, J. Am. Chem. Soc., 2020, 142, 19226–19238.
44. E. I. Jiménez, M. Cantú-Reyes, M. Flores-Ramos, C. A. Román-Chavarría, H. Díaz-Salazar and M. Hernández-Rodríguez, Dynamic Kinetic Resolution of Azlactones by Bifunctional Thioureas with α-Trifluoromethyl or Methyl Groups, Synlett, 2022, 33, 1751–1755.
45. J. Xu, W. Lin, H. Zheng and X. Li, Enantioselective Synthesis of Axially Chiral Diaryl Ethers through Chiral Phosphoric Acid-Catalyzed Desymmetric Acylation with Azlactones, ACS Catal., 2024, 14, 6667–6673.
46. S. K. Nimmagadda, M. Liu, M. K. Karunananda, D. W. Gao, O. Apolinar, J. S. Chen, P. Liu and K. M. Engle, Catalytic, Enantioselective α-Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation, Angew. Chem., Int. Ed., 2019, 58, 3923–3927.
47. D. J. Cheng, R. Q. Li, X. S. Zhang, L. Zhao, T. Wang and Y. D. Shao, Diastereoselective Synthesis of Functionalized Indoline N,O-Aminals: Unexpected Water-Involved Cascade Reaction of 3H-Indoles and Oxazol-5-(4H)ones, Eur. J. Org. Chem., 2020, 496–500.
48. Y. Li, H. Pan, W. Y. Li, X. Feng and X. Liu, Enantioselective Nucleophilic Aromatic Substitution Reaction of Azlactones to Synthesize Quaternary α-Amino Acid Derivatives, Synlett, 2021, 32, 587–592.
49. H. Hu, X. Wu, B. Wang, L. Zhao, J. Wang and Z. Jiang, The Pyrrolidine-Catalyzed Three-Component Reactions of Azlactones, N,O-Acetals and Alcohols: One-Pot Synthesis of α,β-Diamino Esters, Adv. Synth. Catal., 2023, 365, 2622–2627.
50. P. P. de Castro, G. M. F. Batista, H. F. dos Santos and G. W. Amarante, Theoretical Study on the Epimerization of Azlactone Rings: Keto–Enol Tautomerism or Base-Mediated Racemization?, ACS Omega, 2018, 3, 3507–3512.
51. S. M. Anil, M. S. Sudhanva, T. R. Swaroop, A. C. Vinayaka, N. Rajeev, K. R. Kiran, R. Shobith and M. P. Sadashiva, Base Induced Condensation of Malononitrile with Erlenmeyer Azlactones: An Unexpected Synthesis of Multi–Substituted Δ 2 –Pyrrolines and Their Cytotoxicity, Chem. Biodivers., 2020, 17, e2000014.
52. B. Zhang and J. Wang, Recent advances in metal-free catalytic enantioselective higher-order cycloadditions, Org. Chem. Front., 2024, 11, 1824–1842.
53. I. F. S. Marra, A. M. de Almeida, L. P. Silva, P. P. de Castro, C. C. Corrêa and G. W. Amarante, Stereoselective Intermolecular [2 + 2] Cycloadditions of Erlenmeyer–Plöchl Azlactones Using Visible Light Photoredox Catalysis, J. Org. Chem., 2018, 83, 15144–15154.
54. Y. Lin, Y. X. Song and D. M. Du, Enantioselective Synthesis of CF 3 -Containing 3,2′-Pyrrolidinyl Spirooxindoles and Dispirooxindoles via Thiourea-Catalyzed Domino Michael/Mannich [3 + 2] Cycloaddition Reactions, Adv. Synth. Catal., 2019, 361, 1064–1070.
55. L. Li, X. Wang and Y. Wang, Construction of Spiro[pyrrolidine-azlactone] via [2 + 3] Cycloaddition of Alkylidene Azlactone with Trifluoromethylated Imine, J. Org. Chem., 2024, 89, 17824–17833.
56. H. Joshi, A. Yadav, A. Das and V. K. Singh, Organocatalytic Asymmetric Hetero-Diels-Alder Reaction of in Situ Generated Dienes: Access to α,β-Unsaturated δ-Lactones Featuring CF3-Substituted Quaternary Stereocenter, J. Org. Chem., 2020, 85, 3202–3212.
57. P. Mahto, K. Shukla, A. Das and V. K. Singh, Organocatalytic asymmetric synthesis of pyrrolo[3,2-c]quinolines via a formal [3 + 2] cycloaddition-lactamization cascade reaction using a bifunctional squaramide catalyst, Tetrahedron, 2021, 87, 132115.
58. P. Shao and W. Ren, Synthesis of 1,7−Annulated Indazole Derivatives via Bifunctional Brønsted Base Catalyzed Cascade Reaction, Chin. J. Chem., 2025, 43, 1373–1378.
59. C. Dai, Z. Xie, M. Li and C. Wang, Cs2CO3-Promoted [2 + 2 + 2] Cycloaddition Reaction of 4-Aryliden-5(4H)-Oxazolones and β-Nitrostyrenes: Access to Spirocycloalkyloxazolones, Asian J. Org. Chem., 2020, 9, 61–67.
60. M. Saktura, B. Joachim, P. Grzelak and Ł. Albrecht, Aromatizative Inverse-Electron-Demand Hetero-Diels-Alder Reaction in the Synthesis of Benzothiophene Derivatives, Eur. J. Org. Chem., 2019, 6592–6596.
61. X. Y. Yu, W. J. Xiao and J. R. Chen, Synthesis of Trisubstituted 1,2,4-Triazoles from Azlactones and Aryldiazonium Salts by a Cycloaddition/Decarboxylation Cascade, Eur. J. Org. Chem., 2019, 6994–6998.
62. J. K. Li, B. Zhou, Y. C. Tian, C. Jia, X. S. Xue, F. G. Zhang and J. A. Ma, Potassium Acetate-Catalyzed Double Decarboxylative Transannulation to Access Highly Functionalized Pyrroles, Org. Lett., 2020, 22, 9585–9590.
63. Y. N. Wang, Q. Xiong, L. Q. Lu, Q. L. Zhang, Y. Wang, Y. Lan and W. J. Xiao, Inverse-Electron-Demand Palladium-Catalyzed Asymmetric [4 + 2] Cycloadditions Enabled by Chiral P,S-Ligand and Hydrogen Bonding, Angew. Chem., Int. Ed., 2019, 58, 11013–11017.
64. X. R. Ren, J. B. Lin, X. Q. Hu and P. F. Xu, Bifunctional Brønsted base catalyzed inverse-electron-demand aza-Diels-Alder reactions of saccharin-derived 1-azadienes with azlactones, Org. Chem. Front., 2019, 6, 2280–2283.
65. H. W. Zhao, W. Q. Ding, L. R. Wang, J. M. Guo, X. Q. Song, H. H. Wu, Z. Tang, X. Z. Fan and X. F. Bi, Formal [5 + 2] Cycloaddition of Vinyloxiranes with Oxazol-5-(4H)-ones: A Facile Approach for Construction of Seven-Membered Lactones, Eur. J. Org. Chem., 2020, 5557–5562.
66. S. He, H. Gu, Y. P. He and X. Yang, Asymmetric Aza-Diels-Alder Reactions of in Situ Generated β,β-Disubstituted α,β-Unsaturated N-H Ketimines Catalyzed by Chiral Phosphoric Acids, Org. Lett., 2020, 22, 5633–5639.
67. J. Zhang, T. Ni, W. L. Yang, W. P. Deng and W. P. Deng, Catalytic Asymmetric [3 + 2] Annulation via Indolyl Copper-Allenylidene Intermediates: Diastereo- And Enantioselective Assembly of Pyrrolo[1,2- a]indoles, Org. Lett., 2020, 22, 4547–4552.
68. W. Yang, H. Wang, Z. Pan, Z. Li and W. Deng, Asymmetric synthesis of pyrrolo[1,2-a]indoles via organocatalytic [3 + 2] annulation of substituted 2-vinylindoles with azlactones, Chin. Chem. Lett., 2020, 31, 721–724.
69. Q. Ni, X. Wang, F. Xu, X. Chen and X. Song, Organocatalytic asymmetric [4 + 2] cyclization of 2-benzothiazolimines with azlactones: Access to chiral benzothiazolopyrimidine derivatives, Chem. Commun., 2020, 56, 3155–3158.
70. L. Xie, Y. Li, S. Dong, X. Feng and X. Liu, Catalytic asymmetric formal [3 + 2] cycloaddition of isatogens with azlactones to construct indolin-3-one derivatives, Chem. Commun., 2021, 57, 239–242.
71. L. Wu, T. Wang, C. Gao, W. Huang, J. Qu and Y. Chen, Skeletal Reconstruction of 3-Alkylidenepyrrolidines to Azepines Enabled by Pd-Catalyzed C-N Bond Cleavage, ACS Catal., 2021, 11, 1774–1779.
72. L. Wu, H. Xia, J. Bai, Y. Xi, X. Wu, L. Gao, J. Qu and Y. Chen, Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion, Nat. Chem., 2024, 16, 1951–1959.
73. H. Q. Wang, W. Ma, A. Sun, X. Y. Sun, C. Jiang, Y. C. Zhang and F. Shi, (4 + 2) Cyclization of Aza-O-Quinone Methides With Azlactones: Construction of Biologically Important Dihydroquinolinone Frameworks, Org. Biomol. Chem., 2021, 19, 1334–1343.
74. W. Y. Lu, Y. Wang, Y. You, Z. H. Wang, J. Q. Zhao, M. Q. Zhou and W. C. Yuan, Copper-Catalyzed Decarboxylative [3 + 2] Annulation of Ethynylethylene Carbonates with Azlactones: Access to γ-Butyrolactones Bearing Two Vicinal Quaternary Carbon Centers, J. Org. Chem., 2021, 86, 1779–1788.
75. T. Wang, Y. You, Z. H. Wang, J. Q. Zhao, Y. P. Zhang, J. Q. Yin, M. Q. Zhou, B. D. Cui and W. C. Yuan, Copper-Catalyzed Diastereo- and Enantioselective Decarboxylative [3 + 2] Cyclization of Alkyne-Substituted Cyclic Carbamates with Azlactones: Access to γ-Butyrolactams Bearing Two Vicinal Tetrasubstituted Carbon Stereocenters, Org. Lett., 2023, 25, 1274–1279.
76. B. Pan, A. Li, D. Liu, Q. S. Ni, W. Liang, F. Du, J. Gu and Q. Ouyang, Highly diastereoselective synthesis of benzothiazolo[3,2-a]pyridines via [4 + 2] annulation reaction of 2-vinylbenzothiazoles and azlactones, Org. Biomol. Chem., 2022, 20, 4512–4517.
77. J. Li, Y. Mo, L. Yan, X. Feng, Z. Su and X. Liu, Organocatalytic Stereoselective [8 + 2] Cycloaddition of Tropones with Azlactones, CCS Chem., 2022, 4, 650–659.
78. N. N. Mo, Y. H. Miao, X. Xiao, Y. Z. Hua, M. C. Wang, L. Huang and G. J. Mei, Catalytic asymmetric de novo construction of 4-pyrrolin-2-ones via intermolecular formal [3 + 2] cycloaddition of azoalkenes with azlactones, Chem. Commun., 2023, 59, 5902–5905.
79. Y. D. Fu, X. Gao, S. K. Jia, X. Xiao, M. C. Wang, L. Huang and G. J. Mei, Catalyst-free racemic and H₂O/CPA-catalyzed asymmetric regio-reversed domino processes of triketone enones with azlactones, Green Chem., 2023, 25, 5692–5697.
80. H. Kim and S. G. Kim, [4 + 2] Annulation of δ-Hydroxy/δ-Sulfonamido-α,β-Unsaturated Ketones with Azlactones for Diastereoselective Synthesis of Highly Substituted 3-Amino-δ-Lactones and 3-Amino-δ-Lactams, J. Org. Chem., 2023, 88, 3830–3844.
81. M. Wang, Z. H. Zheng, M. Q. Chen, G. Zhan, J. Wang, Q. Q. Yang and W. Huang, An umpolung strategy for chemoselective metal-free [4 + 2] annulation of azlactones: access to tetrahydro-β-carbolin 1,3-diketone frameworks, Org. Chem. Front., 2023, 11, 822–829.
82. P. Ruan, C. Zhang, J. Wu, F. Xiao, Y. Zhang, Q. Tan, Z. Su, X. Feng and X. Liu, Asymmetric [3 + 2]-cyclization of α-imino amide surrogates to construct 3,4-diaminopyrrolidine-2,5-diones, Chem. Commun., 2023, 59, 8250–8253.
83. W. J. Zhou, X. Yu, C. Chen, W. Lan, G. Zhan, J. Zhou, Q. Liu, W. Huang and Q. Q. Yang, Organocatalytic Asymmetric [4 + 2] Cyclization of Azadienes with Azlactones: Access to Chiral 3-Amino-δ-Lactams Derivatives, J. Org. Chem., 2023, 88, 13427–13439.
84. X. Wang and W. Ren, Catalytic Asymmetric [4 + 2] Cyclization of Hydroxyphenyl Indolinone with Azlactone to Construct Spirooxindole δ-Lactone, Chin. J. Chem., 2024, 42, 3362–3366.
85. K. S. Kim and D. Y. Kim, Organocatalytic Enantioselective One-pot Synthesis of Dihydrocoumarins via C–H Oxidation and Cyclization Cascade, Asian J. Org. Chem., 2023, 12, 10–13.
86. W. C. Yuan, B. X. Quan, J. Q. Zhao, Y. You, Z. H. Wang and M. Q. Zhou, Annulation Reaction of in Situ Generated Azoalkenes with Azlactones: Access to 4,5-Dihydropyridazin-3(2H)-Ones, J. Org. Chem., 2020, 85, 11812–11821.
87. R. Zeng, X. Zhang, Y. Y. Lei, Z. Z. Zhang, M. Jiang, Q. Z. Li, J. L. Li and B. Han, Stereoselective skeletal modification of tryptanthrins to install chiral piperidine-2-ones enabled by Brønsted acid catalysis, Org. Chem. Front., 2024, 11, 2171–2177.
88. H. Kim, Y. Kim and S. G. Kim, Asymmetric Synthesis of 3,4-Dihydroquinolin-2-ones via Organocatalytic [4 + 2]-Cyclization of 2-Amino-β-nitrostyrenes with Azlactones, Adv. Synth. Catal., 2024, 366, 1756–1762.
89. V. Y. Shuvalov, A. L. Samsonenko, Y. S. Rozhkova, V. V. Morozov, Y. V. Shklyaev and A. S. Fisyuk, Synthesis of 3−Aminopyrido[2,1− a ]isoquinolin–4−one Derivatives via Condensation of Azlactones with 1−Alkyl–3,4−dihydroisoquinolines, ChemistrySelect, 2021, 6, 11265–11269.
90. V. Y. Shuvalov, Y. S. Rozhkova, I. V. Plekhanova, A. S. Kostyuchenko, Y. V. Shklyaev and A. S. Fisyuk, Synthesis of 3-Amino-6,7-Dihydroferroceno[a]Quinolizin-4-One Derivatives via the Reaction of 3,4-Dihydroferroceno[c]Pyridines with Azlactones, Chem. Heterocycl. Compd., 2022, 58, 7–14.
91. V. Y. Shuvalov and A. S. Fisyuk, Easy Route to New Fused Dihydroisoquinoline-Naphthyridinone Frameworks, Synthesis, 2022, 55, 1267–1273.
92. V. Y. Shuvalov, E. Y. Vlasova, T. Y. Zheleznova and A. S. Fisyuk, New one-pot synthesis of 4-arylpyrazolo[3,4-b]pyridin-6-ones based on 5-aminopyrazoles and azlactones, Beilstein J. Org. Chem., 2023, 19, 1155–1160.
93. V. Y. Shuvalov, A. L. Shatsauskas, T. Y. Zheleznova, A. S. Kostyuchenko and A. S. Fisyuk, New Synthesis of Pyrazolo[3,4-b]pyridine Derivatives Based on 5-Aminopyrazole and Azlactones, Synthesis, 2023, 56, 1324–1334.
94. G.-D. Roiban, E. Serrano, T. Soler, G. Aullón, I. Grosu, C. Cativiela, M. Martínez and E. P. Urriolabeitia, Regioselective Orthopalladation of (Z)-2-Aryl-4-Arylidene-5(4H)-Oxazolones: Scope, Kinetico-Mechanistic, and Density Functional Theory Studies of the C–H Bond Activation, Inorg. Chem., 2011, 50, 8132–8143.
95. C. Carrera, A. Denisi, C. Cativiela and E. P. Urriolabeitia, Functionalized 1,3-Diaminotruxillic Acids by Pd-Mediated C–H Activation and [2 + 2]-Photocycloaddition of 5(4H)-Oxazolones, Eur. J. Inorg. Chem., 2019, 3481–3489.
96. E. P. Urriolabeitia, P. Sánchez, A. Pop, C. Silvestru, E. Laga, A. I. Jiménez and C. Cativiela, Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore, Beilstein J. Org. Chem., 2020, 16, 1111–1123.
97. S. Sierra, M. V. Gomez, A. I. Jiménez, A. Pop, C. Silvestru, M. L. Marín, F. Boscá, G. Sastre, E. Gómez-Bengoa and E. P. Urriolabeitia, Stereoselective, Ruthenium-Photocatalyzed Synthesis of 1,2-Diaminotruxinic Bis-amino Acids from 4-Arylidene-5(4 H)-oxazolones, J. Org. Chem., 2022, 87, 3529–3545.
98. S. Sierra, R. López, E. Gómez-Bengoa, L. R. Falvello and E. P. Urriolabeitia, Synthesis of 1,2-diaminotruxinic δ-cyclobutanes by BF3-controlled [2 + 2]-photocycloaddition of 5(4H)-oxazolones and stereoselective expansion of δ-cyclobutanes to give highly substituted pyrrolidine-2,5-dicarboxylates, Org. Biomol. Chem., 2023, 21, 3203–3213.
99. S. Sierra, D. Dalmau, J. V. Alegre-Requena, A. Pop, C. Silvestru, M. L. Marín, F. Boscá and E. P. Urriolabeitia, Synthesis of Bis(amino acids) Containing the Styryl-cyclobutane Core by Photosensitized [2 + 2]-Cross-cycloaddition of Allylidene-5(4H)-oxazolones, Int. J. Mol. Sci., 2023, 24, 7583.
100. I. F. S. Marra, L. P. Silva, P. P. De Castro, L. S. Flores, K. T. De Oliveira, P. E. N. De Souza, B. A. D. Neto, H. F. Dos Santos and G. W. Amarante, Visible–Light–Enabled Dual–Catalysis Approach to Stereoselective [2 + 2] Cycloaddition of Erlenmeyer–Plöchl Azlactones, Asian J. Org. Chem., 2024, 13, e202400271.
101. H. C. Lin, P. P. Xie, Z. Y. Dai, S. Q. Zhang, P. S. Wang, Y. G. Chen, T. C. Wang, X. Hong and L. Z. Gong, Nucleophile-Dependent Z/E- and Regioselectivity in the Palladium-Catalyzed Asymmetric Allylic C-H Alkylation of 1,4-Dienes, J. Am. Chem. Soc., 2019, 141, 5824–5834.
102. M. Serra, E. Bernardi, G. Marrubini, E. De Lorenzi and L. Colombo, Palladium-Catalyzed Asymmetric Decarboxylative Allylation of Azlactone Enol Carbonates: Fast Access to Enantioenriched α-Allyl Quaternary Amino Acids, Eur. J. Org. Chem., 2019, 732–741.
103. Z. Zhang, F. Xiao, H. M. Wu, X. Q. Dong and C. J. Wang, Pd-Catalyzed Asymmetric Hydroalkylation of 1,3-Dienes: Access to Unnatural α-Amino Acid Derivatives Containing Vicinal Quaternary and Tertiary Stereogenic Centers, Org. Lett., 2020, 22, 569–574.
104. X. Cheng, C. Shen, X.-Q. Dong and C.-J. Wang, Iridium-catalyzed asymmetric double allylic alkylation of azlactone: efficient access to chiral α-amino acid derivatives, Chem. Commun., 2022, 58, 3142–3145.
105. C. Ke, Q. Cao, Y. Luo, X. Liu and X. Feng, Catalytic asymmetric amination of azlactones with azobenzenes, Chem. Commun., 2022, 5881–5884.
106. K. Li, L. Wang, S. Zhen, L. Zhu, S. Yu, Y. Wu and H. Guo, Palladium-catalyzed regio- and stereoselective allylic alkylation of 5-vinyloxazolidine-2,4-diones with azlactones: synthesis of chiral (Z)-trisubstituted allylic amino acid derivatives, Org. Chem. Front., 2023, 10, 5463–5469.
107. J. Q. Zhao, H. W. Rao, H. L. Qian, X. M. Zhang, S. Zhou, Y. P. Zhang, Y. You, Z. H. Wang and W. C. Yuan, Palladium-catalyzed stereoselective decarboxylative allylation of azlactones: access to (Z)-trisubstituted allylic amino acid derivatives, Org. Chem. Front., 2022, 9, 6172–6178.
108. S. S. Zhou, X. Y. Sun, W. K. Liu, J. Y. Song, Z. Wang, Z. H. Qi and X. W. Wang, COAP-Pd Catalyzed Asymmetric Allylic Alkylation of Azlactones with MBH Carbonates: Access to Unnatural α-Quaternary Stereogenic Glutamic Acid Derivatives, J. Org. Chem., 2023, 88, 11867–11873.
109. T. Tsuji, T. Tanaka, T. Tanaka, R. Yazaki and T. Ohshima, Catalytic Aerobic Cross-Dehydrogenative Coupling of Azlactones en Route to α,α-Disubstituted α-Amino Acids, Org. Lett., 2020, 22, 4164–4170.
110. H. Yang and D. Xing, Palladium-catalyzed diastereo- And enantioselective allylic alkylation of oxazolones with 1,3-dienes under base-free conditions, Chem. Commun., 2020, 56, 3721–3724.
111. W. N. Zhang, Y. C. Hu, Y. Liu, X. Y. Wang, Y. Y. Zhao and Q. A. Chen, Ligand-controlled regiodivergence in Pd-catalyzed coupling of azlactones with isoprene, Cell Rep. Phys. Sci., 2024, 5, 101908.
112. K. Zhu, Y. Ma, Z. Wu, J. Wu and Y. Lu, Energy-Transfer-Enabled Regioconvergent Alkylation of Azlactones via Photocatalytic Radical–Radical Coupling, ACS Catal., 2023, 13, 4894–4902.
113. C. Gao, Y. Z. Liu, Y. N. Wang, Z. Q. Zhang and Z. P. Zhan, Regioselective Synthesis of α-Quaternary Amino Acid Derivatives Enabled by Photoinduced Energy Transfer, J. Org. Chem., 2024, 89, 10393–10402.
114. M. Sicignano, R. I. Rodríguez, V. Capaccio, F. Borello, R. Cano, F. De Riccardis, L. Bernardi, S. Díaz-Tendero, G. Della Sala and J. Alemán, Asymmetric trifluoromethylthiolation of azlactones under chiral phase transfer catalysis, Org. Biomol. Chem., 2020, 18, 2914–2920.
115. Q. Tan, Q. Chen, Z. Zhu and X. Liu, Asymmetric organocatalytic sulfenylation for the construction of a diheteroatom-bearing tetrasubstituted carbon centre, Chem. Commun., 2022, 58, 9686–9689.
116. M. Iwata, Y. Takami, H. Asanuma, K. Hosono, H. Ohno, N. Yoshikai and K. Kanemoto, A versatile entry to unnatural, disulfide-linked amino acids and peptides through the disulfuration of azlactones, Chem. Sci., 2025, 16, 2777–2784.
117. V. Haider, P. Zebrowski, J. Michalke, U. Monkowius and M. Waser, Enantioselective organocatalytic syntheses of α-selenated α- And β-amino acid derivatives, Org. Biomol. Chem., 2022, 20, 824–830.
118. I. Yavari, A. Amirahmadi and M. R. Halvagar, Formation of 1,2,4-oxadiazole derivatives from Erlenmeyer azlactones and amidoximes, Monatsh. Chem., 2019, 150, 1857–1862.
119. B. Meng, Q. Shi, Y. Meng, J. Chen, W. Cao and X. Wu, Asymmetric catalytic alkynylation of thiazolones and azlactones for synthesis of quaternary α-amino acid precursors, Org. Biomol. Chem., 2021, 19, 5087–5092.
120. W. Wei and X. Zhao, Organoselenium-Catalyzed Cross-Dehydrogenative Coupling of Alkenes and Azlactones, Org. Lett., 2022, 24, 1780–1785.
121. M. Y. Hao, M. H. Huang, X. Y. Gu, T. S. Zhang, X. T. Zhu, W. J. Hao and B. Jiang, Diastereoselective Generation of C2-Azlactonized 2H-Chromenes via Brønsted Acid-Catalyzed Oxo-Cyclization of Propargyl Alcohols, J. Org. Chem., 2022, 87, 1518–1525.
122. A. Samsonenko, A. S. Kostyuchenko, T. Y. Zheleznova, V. Shuvalov, E. B. Ulyankin, A. L. Shatsauskas and A. S. Fisyuk, Synthesis of 4,5-substituted methyl 1H-pyrrole-2-carboxylates from 3-chloroacrylaldehydes and hippuric acid, Synthesis, 2024, 2423–2431.
123. R. Worayuthakarn, N. Suddee, P. Nealmongkol, S. Ruchirawat and N. Thasana, Copper-Mediated C-O/C-N Bond Formation: A Facile Synthesis of 3-Amidocoumarin, 3-Amidoazacoumarin, and N -Aroylindole -Derivatives, Synlett, 2022, 33, 1431–1437.
124. R. Worayuthakarn, K. Boontan, K. Chainok, S. Ruchirawat and N. Thasana, Base-Mediated and Silver-Catalyzed Divergent Synthesis of Hydroxynaphthalenamides and Phosphorylated Dihydronaphthylamides from Enone-Oxazolones, J. Org. Chem., 2023, 88, 16520–16538.
125. R. Worayuthakarn, N. Suddee, C. Theppitak, K. Chainok, S. Ruchirawat and N. Thasana, Cascade Cyclization of o-(2-Acyl-1-ethynyl)benzaldehydes with Amino Acid Derivatives: Synthesis of Indeno[2,1-c]pyran-3-ones and 1-Oxazolonylisobenzofurans via the Erlenmeyer–Plöchl Azlactone Reaction, ACS Omega, 2024, 9, 37814–37842.
126. M. S. Park, E. Chung, N. K. Mishra, S. H. Han, S. Han, S. Kim and I. S. Kim, C-H amidation of 2-aryl azlactones under iridium(III) catalysis: access to chiral amino acids, Chem. Commun., 2022, 58, 13365–13368.
127. G. Yin, X. Wang, Y. Wang, T. Shi, Y. Zeng, Y. Wang, X. Peng and Z. Wang, Lawesson's reagent promoted deoxygenation of azlactones for the syntheses of 2,4-disubstituted thiazoles, Org. Biomol. Chem., 2022, 20, 9589–9592.
128. C. Gui, Y. Peng, Y. Zhou, Y. Zheng, H. Wang, Q. Yan, H. Zhou, W. Wang and F. E. Chen, Cu-Catalyzed Intermolecular Asymmetric Propargylic Substitution of N-Hydroxyphthalimide Esters with Propargyl Carbonates, ACS Catal., 2023, 13, 13735–13742.
129. H. W. Rao, T. L. Zhao, L. Wang, H. D. Deng, Y. P. Zhang, Y. You, Z. H. Wang, J. Q. Zhao and W. C. Yuan, Palladium-catalyzed decarboxylative α-allylation of thiazolidinones and azlactones with sulfonamido-substituted acyclic allylic carbonates, Org. Biomol. Chem., 2023, 21, 8593–8602.
130. L. Chen and D. Wang, A Tunable Cascade Reaction of Ureidomalonates and Alkenyl Azlactones for the Divergent Synthesis of Hydantoins with Distinct Functional Groups, J. Org. Chem., 2024, 89, 3365–3382.
131. M. Kamlar, M. Franc, I. Císařová, R. Gyepes and J. Veselý, Formal [3 + 2] cycloaddition of vinylcyclopropane azlactones to enals using synergistic catalysis, Chem. Commun., 2019, 55, 3829–3832.
132. M. Franc, P. Měrka, I. Císařová and J. Veselý, Enantioselective Preparation of Cyclopentene-Based Amino Acids with a Quaternary Carbon Center, J. Org. Chem., 2024, 89, 16522–16530.
133. S. Wang, S. Peng, H. Zhao, Z. Liang, X. Lu, Q. Du, Y. Wang, B. Wei, Q. Huang and H. Tan, Regioselectivity Switch of α-Amino Acid-Derived Esters and MBH Carbonates for the Synthesis of Allyl-Substituted Azlactones, J. Org. Chem., 2024, 89, 3800–3808.
134. Y. Lin, K. Zhang, M. Gao, Z. Jiang, J. Liu, Y. Ma, H. Wang, Q. Tan, J. Xiao and B. Xu, Copper nitrate-mediated synthesis of 3-aryl isoxazolines and isoxazoles from olefinic azlactones, Org. Biomol. Chem., 2019, 17, 5509–5513.
135. Y. Li, J. Yang, X. Geng, P. Tao, Y. Shen, Z. Su and K. Zheng, Modular Construction of Unnatural α–Tertiary Amino Acid Derivatives by Multicomponent Radical Cross–Couplings, Angew. Chem., Int. Ed., 2022, 61, e202210755.
136. R. Chen, C. Lu, Y. Li and K. Zheng, Visible-light-induced Markovnikov addition of olefin for construction of deuterated α-tertiary amino acid derivatives, Org. Chem. Front., 2024, 11, 3427–3435.

---

Footnote

† These authors contributed equally to this work.

---