# Advances in Enaminomaleimides Chemistry: Synthesis, Chemical Applications, and Perspectives

Adrián López-Francés, Birane Diop, Xingyu Jiang, Jean Rodriguez, Muriel

Amatore, Thierry Constantieux

► To cite this version:

Adrián López-Francés, Birane Diop, Xingyu Jiang, Jean Rodriguez, Muriel Amatore, et al. Advances in Enaminomaleimides Chemistry: Synthesis, Chemical Applications, and Perspectives. ChemistryEurope, 2025, 3 (5), pp.e202500220. 10.1002/ceur.202500220. hal-05452362

HAL Id: hal-05452362

https://hal.science/hal-05452362v1

Submitted on 10 Jan 2026

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
<figure><img src="image_2.png" /></figure>

# Advances in Enaminomaleimides Chemistry: Synthesis, Chemical Applications, and Perspectives

Adrián López-Francés,* Birane Diop, Xingyu Jiang, Jean Rodriguez, Muriel Amatore, and Thierry Constantieux*

Interest in enaminomaleimides has grown significantly over the past decades, as they have proven to be versatile building blocks for the synthesis of functionalized heterocycles. Their unique nucleophilic character, in contrast to the classical electrophilic nature of maleimides, has unlocked new synthetic possibilities, enabling their application across a wide range of chemical transformations. Moreover, their potential extends beyond synthetic

chemistry, with promising results reported in both materials science and medicinal chemistry. This review provides a comprehensive overview of the synthesis and chemical applications of enaminomaleimides over time, while also highlighting emerging trends and future directions in this rapidly evolving field.

## 1. Introduction

Since their initial synthesis in the latter half of the 19th century,[1] maleimides have steadily gained prominence due to their broad range of applications, particularly in materials science[2] and bioconjugation strategies.[3] Their distinctive electrophilic character has made them valuable intermediates in synthetic organic chemistry, where they are widely employed in conjugate additions,[4-6] cycloadditions,[7,8] and C-H functionalization reactions (Figure 1).[9-12] In addition to their synthetic versatility, maleimides hold significant biological relevance, being structural motifs in various bioactive compounds, including kinase inhibitors,[13,14] antimicrobial,[15] or antiparasitic agents,[16] as well as key components in functional polymers.[17] Moreover, maleimide derivatives have also been identified as natural products in microbial extracts from Streptomyces species.[18]

In contrast to the well-established electrophilic character of classic maleimides, enaminomaleimides (also known as α-aminomaleimides) constitute a distinct subclass distinguished by their bis-pro-nucleophilic behavior at both carbon and nitrogen centers (Figure 1). These compounds contain an electron-rich enamine moiety, that significantly alters their reactivity, shifting them from traditional Michael acceptors to versatile C,N-bis-nucleophiles. This unique feature opens new synthetic avenues for constructing valuable functionalized maleimide derivatives

by exploiting the enamino functionality.[19] Beyond their synthetic utility, enaminomaleimides have attracted attention for their diverse properties,[20-22] including promising antimicrobial[23] or anticancer activities.[24,25]

In this review, we provide a comprehensive overview the chemistry of enaminomaleimides, covering their synthesis, reactivity, and synthetic applications. The review is organized into three main sections: Section 2 focuses on synthetic methodologies, Section 3 discusses chemical applications, and Section 4 presents concluding remarks along with future perspectives on the subject.

## 2. Synthesis of Enaminomaleimides

Multiple strategies have been described for the synthesis of enaminomaleimides, involving distinct key intermediates and reactivity patterns that will be presented in this section along two directions involving either (1) acyclic precursors by de novo construction of the maleimide ring (Scheme 1, routes a, b, c) or (2) cyclic precursors by selective functionalization of the preformed maleimide ring (Scheme 1, routes d, e, f), respectively.

### 2.1. From Acyclic Precursors by De Novo Formation of the Maleimide ring (Scheme 1, Routes a, b, c)

As the first example of the synthesis of enaminomaleimides, Surrey and Cutler described the direct construction of two different N-aryl-α-arylaminomaleimides 2 by heating diethyl α-arylaminomaleates 1 at 180-190 °C in acetic acid for seven hours in the presence of aniline or m-chloroaniline (Scheme 2).[26] This approach, reported in 1946, provided the corresponding enaminomaleimides 2a and 2b in 38% and 52% yield, respectively, demonstrating an efficient method for the construction of the enaminomaleimide core.

A. López-Francés, B. Diop, X. Jiang, J. Rodriguez, M. Amatore, T. Constantieux
Centrale Marseille, CNRS
Aix-Marseille Université
iSm2 UMR, 7313, 13397 Marseille, France
E-mail: adrián.lopez-frances@univ-amu.fr
thierry constantieux@univ-amu.fr

<figure><img src="image_3.png" /></figure>

© 2025 The Author(s). ChemistryEurope published by Chemistry Europe and Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 1.** Contrasting the reactivity of maleimides and enaminomaleimides.</figcaption></figure>

<figure><img src="image_6.png" /></figure>

In 1970, an alternative strategy for the direct synthesis of enaminomaleimides was reported by Heindel, involving the reaction of dimethyl acetylenedicarboxylate with aryl amines (Scheme 3).[27] Two different reaction pathways for this methodology were described:

*Method A* (Scheme 3, top) proceeds through an initial aza-Michael addition between dimethyl acetylenedicarboxylate and an excess of the corresponding aryl amine (ArNH₂) leading to anilinofumarates 3. These intermediates undergo pyrolysis in the presence of a fourfold excess of another alkylamine (RNH₂) for ten minutes, yielding the desired enaminomaleimides 4 in moderate to good yields (40%-73%). Notably, this approach was also

successful using ammonia (Scheme 3, *Method A*, R = H) instead of aryl amines, further highlighting its synthetic significance.

*Method B* (Scheme 3, bottom) represents the one-pot version of *Method A*, where dimethyl acetylenedicarboxylate reacts directly with a fivefold excess of the corresponding aniline (ArNH₂). After the initial exothermic reaction, the mixture was heated at reflux (220-245 °C) for 5 min, affording enaminomaleimides 5 in good yields (50%-69%), thus eliminating the need to isolate intermediate adducts 3.

A more recent application of this seminal approach was reported by Alizadeh and collaborators in 2006,[28] with the reactivity of arylsulfonyl isocyanates 6 with dialkyl acetylenedicarboxylates

<figure><img src="image_7.png" /></figure>

Adrián López-Francés was born in Arnedo (Spain) in 1996 and obtained his Ph.D. in 2024 from the University of the Basque Country, working on the synthesis, DFT studies, and biological applications of amino acid derivatives from multicomponent reactions. He then joined Aix-Marseille Université (France) as a postdoctoral research associate with the CNRS, focusing on the synthesis of novel stable atropisomers. His main research interests include stereoselective transformations, multicomponent reactions, and the synthesis of conformationally rigid scaffolds.

<figure><img src="image_8.png" /></figure>

Birane Diop holds a bachelor's degree in physics and chemistry and a master's degree in Organic Chemistry from Cheikh Anta Diop University in Dakar. He is currently pursuing a Ph.D. in Organic Chemistry at the same university. His research is conducted in collaboration with Aix-Marseille University, under the supervision of Thierry Constantieux and Muriel Amatore. His work focuses on developing synthetic methodologies aimed at controlling multiple stereogenic elements.

<figure><img src="image_9.png" /></figure>

Xingyu Jiang studied chemistry for his bachelor's degree and a master's degree in organic chemistry at University of Montpellier. After completing his studies, he worked at Asymchem (Tianjin, China) for six months and then he began his Ph.D. at Aix-Marseille University under the direction of Pr. Thierry Constantieux and Dr. Muriel Amatore. His research focuses on the reactivity of the N-substituted enaminomaleimides and their derivatives or eventually the control of the enantio- or diastereoselectivity of these reactions.

<figure><img src="image_10.png" /></figure>

Jean Rodriguez was born in Cieza (Spain) in 1958, and studied chemistry at the University of Aix-Marseille (France), he completed his Ph.D. in 1987, and his Habilitation in 1992. He is currently Professor and was appointed Director of the UMR-CNRS-7313-iSm2 until December 2023. His research interests include the development of multiple bond-forming transformations and their application in stereoselective organocatalysed synthesis. In 2021, he was awarded the "Grand Prix Emile Jungfleisch from the French Academy of Sciences".

<figure><img src="image_11.png" /></figure>

Muriel Amatore After her Ph.D. (2006, Dr. C. Gosmini), carried out post-doctoral research stays in enantioselective organocatalysis (Prof. D. W. C. MacMillan) and organometallic catalysis (Dr C. Gosmini / Dr. C. Aubert) before achieving a permanent position as assistant professor (UPMC, 2010). In 2018, she moved to Aix-Marseille Université to join the group of Prof. T. Constantieux (iSm2, stereO). Her research focuses on the development of transition metal-catalyzed and organocatalysed processes for their application in stereoselective synthesis.

<figure><img src="image_12.png" /></figure>

Thierry Constantieux studied chemistry at the University Bordeaux I (France), he received a Ph.D. degree in 1994. He completed his Habilitation in 2004, at Aix-Marseille Université (France), where he is currently Professor, and Director of the "Institut des Sciences Moléculaires de Marseille". His main research interest is focused on the development of new eco-compatible synthetic methodologies, especially organocatalytic enantioselective domino and multicomponent reactions from 1,3-dicarbonylcompounds, and their applications in heterocyclic chemistry.
<figure><img src="image_13.png" /></figure>

(1) From acyclic precursors

<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>

(2) From cyclic precursors

<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /><figcaption>Scheme 1. Synthetic approaches to enaminomaleimides.</figcaption></figure>

<figure><img src="image_21.png" /></figure>

Ar = Ph, m-ClPh

<figure><img src="image_22.png" /></figure>

2a : Ar = Ph (38%)

2b Ar = m-ClPh (52%)

<figure><img src="image_23.png" /><figcaption>Scheme 2. First reported example of the synthesis of enaminomaleimides in 1946.</figcaption></figure>

3

<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /></figure>

4

MeO₂C≡CO₂Me

+ ArNH₂

<figure><img src="image_26.png" /></figure>

<figure><img src="image_27.png" /></figure>

5

<caption>Scheme 3. Synthesis of enaminomaleimides via two-step (Method A) and one-pot (Method B) strategies.</caption>

and either diethyl amine or morpholine (Scheme 4). The reaction evolves through an aza-Michael addition providing the nucleophilic enaminofumarate intermediates 7, which add to the electrophilic isocyanates 6 followed by intramolecular amidation and proton transfert to form the N-sulfonyl carbalcoxy-aminomaleimides 8 or 9 in very good yields.

Following this study, Chepyshev and coworkers developed the above described method of Surrey and Cutler[26] from

aminomaleates 1 under milder conditions using methanol at 20 °C, achieving higher yields (56%-75%) for enaminomaleimides 4 formation, at the expense of a significantly longer reaction time of 10 days (Scheme 5).[29] One year later, they adapted Method A from Heindel,[27] omitting the isolation of the formed aminomaleate intermediates 3 and reducing the temperature required for the formation of enaminomaleimides 4 from 220-245 °C to 20 °C.[30] However, this modification significantly increased the
<figure><img src="image_28.png" /></figure>

<figure><img src="image_29.png" /><figcaption>**Scheme 4.** Synthesis of carbalkoxy-substituted *N*-sulfonyl carbalcoxy-enaminomaleimides.</figcaption></figure>

**Chepyshev (2007)**

<figure><img src="image_30.png" /></figure>

4 (56-75%)

3 examples

**Chepyshev (2008)**

<figure><img src="image_31.png" /></figure>

4 (69-73%)

3 examples

**Muthusubramanian and Rajagopal (2013)**

<figure><img src="image_32.png" /></figure>

5 (95-97%)

5 examples

<caption>**Scheme 5.** Synthesis of enaminomaleimides under mild conditions.</caption>

reaction time, with one case requiring 28 days to be completed. Despite the extended reaction duration, the method led to improved yields in some of the examples (69%-73%). More recently, in 2013, Muthusubramanian and Rajagopal reported a procedure using microwave irradiation under neat conditions for the preparation of a series of *N*-aryl enaminomaleimides 5 in high yields after only 10 min.[31]

Similarly, in 2015, Kizaki's group introduced a novel strategy for the synthesis of *N*-alkyl-4 and *N*-aryl-arylaminomaleimide derivatives 5 from dimethyl acetylenedicarboxylate, expanding the scope of the previous described methodologies and enabling the incorporation of both aryl and alkyl substituents at the maleimide nitrogen atom (Scheme 6).[32] Two different methods were

described depending on the nature of the substitution on the maleimide nitrogen atom:

**Method A (Scheme 6, left):** direct reaction between dimethyl acetylenedicarboxylate and aniline derivatives, leading to the preparation of *N*-aryl arylaminomaleimide derivatives 5 under solvent-free conditions at 150 °C. The reaction proceeded with six different examples, but yields varied significantly depending on the aromatic group. While the use of simple aniline provided moderate yield (54%), most substituted aromatic derivatives exhibited significantly lower efficiencies (3%-6%) indicating a strong substituent effect on the reactivity.

**Method B (Scheme 6, right):** a stepwise approach where the corresponding aniline first reacts with dimethyl
<figure><img src="image_33.png" /></figure>

<figure><img src="image_34.png" /><figcaption>**Scheme 6.** Reaction pathways for the synthesis of *N*-alkyl- and *N*-aryl-arylaminomaleimides.</figcaption></figure>

acetylenedicarboxylate, yielding arylaminofumarate intermediates **3** (93%-99%). This intermediate subsequently undergoes aminolysis with an alkyl amine at room temperature, affording *N*-alkyl arylaminomaleimide **4**. However, this final step often resulted in poor yields (2%-28%), highlighting the limitations of this methodology.

More recently, a novel phenol-directed, two-step one-pot ring-closing/ring-opening cascade reaction was developed by the groups of Huang and Liu for the synthesis of enaminomaleimides **12** under mild, catalyst-free conditions (**Scheme 7**).[33] The reaction involves the condensation of acetylenedicarboxylate derivatives with 2-aminophenols **10**, and aliphatic amines (Scheme 7, *n* = 1,2,3) in an ethanol/water mixture (1:10 v/v), which enhances the solubility of the reactants. Reaction times range from 2 to 4 h at room temperature. The proposed mechanism proceeds via the formation of key cyclic intermediates **11** through an aza-Michael addition followed by a 1,3-hydrogen shift and an intramolecular ester exchange. Subsequently, nucleophilic addition of the primary alkylamine to the lactone carbonyl induces lactone aminolysis, ultimately affording to the final hydroxy enaminomaleimide products **12**. This methodology

demonstrated broad scope, with 39 examples reported, delivering good to excellent yields (68%-93%).

Concurrently, the same group reported a complementary strategy involving a one-pot two-step sequence using benzylic aminoalcohols **13** as nucleophiles, enabling the synthesis of pyrroloquinoline-dione derivatives **15** (**Scheme 8**).[34] The reaction begins with an aza-Michael addition followed by a double ester aminolysis in the presence of a catalytic amount of K₂CO₃, affording the corresponding enaminomaleimide intermediate **14**. Although the primary focus of the study was the synthesis of fused quinoline derivatives **15**, this methodology also offers a versatile platform for accessing a broad range of enaminomaleimide intermediates. In this case, however, compound **14** serves merely as a transient intermediate, undergoing a subsequent I₂-mediated oxidative annulation under microwave irradiation. This second step is carried out in DMSO at 90 °C for 10 min, ultimately yielding the final quinoline derivatives **15** in very good yields (70%-87%).

Additionally, He and coworkers reported a catalyst-free multicomponent domino polymerization protocol between dimethyl acetylenedicarboxylate and aliphatic diamines **16** (**Scheme 9**).[35]

<figure><img src="image_35.png" /><figcaption>**Representative examples**</figcaption></figure>

<figure><img src="image_36.png" /><figcaption>**Scheme 7.** Ring-closing/ring-opening cascade reaction for the synthesis of hydroxy enaminomaleimides.</figcaption></figure>
<figure><img src="image_37.png" /></figure>

<figure><img src="image_38.png" /><figcaption>**Scheme 8.** Benzylic alcohols directed one-pot stepwise synthesis of enaminomaleimides.</figcaption></figure>

<figure><img src="image_39.png" /><figcaption>**Scheme 9.** Catalyst-free multicomponent synthesis of poly-aminomaleimides.</figcaption></figure>

(Poly)aminomaleimides **17** were obtained under mild conditions, involving the initial formation of the corresponding monomer after 30 min of reaction, followed by a second amine addition promoting polymerization over 48 h. A series of aliphatic diamine derivatives **16** were successfully employed, affording the corresponding (poly)aminomaleimides **17** in very good to excellent yields (85%–99%).

As an alternative to the use of maleates, fumarates, and acetylenedicarboxylates, a novel approach for the synthesis of N-H-free aminomaleimides **21** was reported by Aksenov's group in 2023, employing 2'-nitrochalcones **18** as key precursors instead of traditional Michael acceptors (Scheme 10).[36] This method involves a one-pot transformation using potassium cyanide and formic acid in DMSO, affording 2-carboxyaniline-substituted maleimides **21** in yields ranging from 35% to 82% across 18 examples. Mechanistically, the reaction proceeds through a domino sequence: initially, compound **18** reacts with KCN at 30 °C for 15 min, leading to the formation of a nitrile intermediate **19**. This intermediate is then treated with acetic acid at 65 °C for an additional 15 min to yield compound **20**. Finally, heating the reaction mixture at 80 °C for two more hours, a final cyclization step occurs, delivering the desired N-H-free aminomaleimides **21**.

In addition, although only two examples were reported by Morris and collaborators, the condensation of a threefold excess of phenylisocyanate with terminal arylalkynes represents a

nonconventional yet effective strategy for the one-pot, pseudo-three-component synthesis of arylated enaminomaleimides **23** (Scheme 11).[37,38] Following deprotonation of the alkyne, sequential C/N additions of two equivalents of phenylisocyanate provided the key intermediate **22**. Subsequently, the addition of a third equivalent of phenylisocyanate initiates a ring forming/ring opening cascade, ultimately yielding the final compounds **23**.

Finally, Yang and coworkers developed two practical strategies for the synthesis of dibutylenaminomaleimide **24** starting from commercially available L-tartaric acid (Scheme 12).[39] In the first approach (Route I), compound **24** was obtained directly via a one-pot thermal dehydration reaction between *n*-butylamine and L-tartaric acid. In an alternative route (Route II), **24** was synthesized using (+)-diacetyl-L-tartaric anhydride as the starting material. Although the yields were modest, both methodologies provide straightforward, catalyst-free approaches for accessing enaminomaleimides under mild conditions.

## 2.2. From Cyclic Precursors (Scheme 1, Routes d, e, f)

### 2.2.1. Amination of Maleimides

One of the earliest approaches is based on the well-established reactivity of maleimides toward Michael addition with various
<figure><img src="image_40.png" /></figure>

<figure><img src="image_41.png" /><figcaption>**Scheme 10.** Synthesis of 2-carboxyaniline-substituted maleimides from 2'-nitrochalcones.</figcaption></figure>

<figure><img src="image_42.png" /><figcaption>**Scheme 11.** One-pot synthesis of arylated enaminomaleimides from alkynes and isocyanates.</figcaption></figure>

<figure><img src="image_43.png" /><figcaption>**Scheme 12.** Synthesis of enaminomaleimide from L-tartaric acid (Route I) and its anhydride (Route II).</figcaption></figure>

nucleophiles. This strategy was first proposed by Awad and coworkers in 1963, employing alkyl- or arylazides as nucleophiles to generate triazolines 25, which upon thermal decomposition finished the corresponding enaminomaleimides **26** (Scheme 13, left).<sup>[40-43]</sup> A similar approach was later applied by Washburne

and collaborators<sup>[44]</sup> for the synthesis of a unique silylated enaminomaleimide **27**, which, upon hydrolysis, afforded the N-free enaminomaleimide **28** (Scheme 13, bottom). Additionally, Hedaya and Theodoropulos reported the synthesis of compound **2a** (R = Ph) using the stable triphenylphosphine ylide **29**, formed via
<figure><img src="image_44.png" /></figure>

<figure><img src="image_45.png" /><figcaption>**Scheme 13.** Alternative pathways for the synthesis of simple alkyl- and arylmaleimides.</figcaption></figure>

nucleophilic addition of triphenylphosphine to *N*-phenylmaleimide (Scheme 13, right).[45] This ylide reacted efficiently with nitrosobenzene in methanol at 50 °C for 15 min, affording the desired compound **2a** in nearly quantitative yield.

In 2021, Krasavin's group reported a Rh(II)-catalyzed diazo coupling between (E)-3-arylidene-4-diazopyrrolidine-2,5-diones **30** with either 3- or 4-aminobenzenesulfonamide, affording the corresponding exo-arylidene compounds **31** (Scheme 14).[46] Building on this initial approach, the same group expanded the scope of the reaction in 2022, enabling access to a broader range of derivatives **31** in good to excellent yields (45%-88%).[24] Furthermore, selected para-substituted derivatives **31** were thermally converted into their endo-cyclic maleimide counterparts **32** by heating in DMF at 100 °C.

Complementing these relatively limited strategies, the oxidation of succinimide adducts, formed via aza-Michael additions to

maleimides, has proven to be a more effective approach, as demonstrated in the pioneering work of Maulding in 1988 (Scheme 15).[47,48] Two different succinimides **33** were synthesized by reacting maleic anhydride with either two equivalents of aniline (R = Ph) or a combination of aniline and *n*-butylamine (R = *n*-Bu), yielding 74% and 58%, respectively. Subsequent, oxidation of succinimides **33** to the corresponding enaminomaleimides was performed using manganese dioxide in refluxing toluene, affording a moderate yield for 3-anilino-*N*-phenylmaleimide **2a** (41%, R = Ph) and excellent yield in the case of *N*-butylanilinomaleimide **4** (93%, R = *n*-Bu). Additionally, for the synthesis of **2a** (R = Ph), an alternative oxidation using chloranil was explored, resulting in an improved yield to 65%.

In a strategy similar to Maulding's methodology, a novel metal-free approach for the synthesis of alkylaminomaleimides **35** was reported in 2021 by the groups of Wang and Zhang

<figure><img src="image_46.png" /><figcaption>**Scheme 14.** Rh(II)-catalyzed diazo coupling with aminosulfonamides, and thermal rearrangement to enaminomaleimides.</figcaption></figure>

<figure><img src="image_47.png" /><figcaption>**Scheme 15.** Synthesis of enaminomaleimides via succinimides oxidation.</figcaption></figure>
<figure><img src="image_48.png" /></figure>

(Scheme 16).[49] This method involves a Michael addition of amines to maleimides 34, followed by an aerobic oxidation process mediated by molecular oxygen. In the first step, the addition of amine to maleimide 34 is carried out in methanol at room temperature for 12 h, yielding 3-aminosuccinimide intermediates 33 in yield ranging from 52% to 98% across 12 examples. In the second step, these intermediates are oxidized to enaminomaleimides 35 under various conditions. Exposure to air at room temperature resulted in very low conversion (2% after 60 days), while the use of singlet oxygen, generated using a tetraphenylporphyrine photosensitizer under LED irradiation, improved the conversion to 11% within 12 h. The most efficient conditions involved the use of molecular iodine as an initiator and xenon lamp irradiation (500 W) under air atmosphere, affording up to 71% yield in just 2 hours. Additionally, density functional theory (DFT) calculations supported a radical oxidation mechanism in which molecular oxygen plays a central role in the transformation of succinimides 33 into the desired enaminomaleimides 35. This methodology, provides a metal-free alternative to conventional oxidative protocols, demonstrating the potential of molecular oxygen as a sustainable and efficient oxidant for maleimide functionalization.

Complementing these oxidative strategies, Zhao's group reported a more general Cu(II)/Ag(I)-catalyzed oxidative aza-Michael addition of amines to maleimides 34, enabling direct

access to aminomaleimides 35 under aerobic conditions (Scheme 17).[50] The reaction is initiated by Ag₂CO₃, which coordinates with the maleimide, increasing its electrophilicity and promoting a rapid 1,4-nucleophilic addition of the amine to afford the aminosuccinimide intermediate 33. In the presence of a catalytic amount of Cu(OAc)₂, this intermediate is subsequently oxidized to afford the desired aminomaleimides 35. The catalytic cycle is sustained by reoxidation of the Cu(I) species back to Cu(II) by molecular oxygen from air. The reaction is carried out in chlorobenzene at 120 °C under air atmosphere delivering moderate to excellent yields (55%-95%) depending on the nature of the amine substituent. Notably, when Cu(OAc)₂ is replaced with one equivalent of CuCl₂, the process undergoes a selective oxidative chloroamination, yielding 3-amino-4-chloromaleimides 36 as the final products.

Furthermore, the direct oxidative chloroamination of maleimides 34 was developed by Wu's group in 2021, using a 37% HCl solution as the chloride source (Scheme 18).[51] Control experiments demonstrated that under these conditions, the in situ generated amine hydrochloride salts acted as bifunctional reagents, facilitating both the Cu-catalyzed oxidative amination of maleimides to enaminomaleimides 35 via an aza-Michael addition and the subsequent radical chlorination through a Cu(II)-complex intermediate 37. Moreover, this protocol was successfully applied to the late-stage functionalization of various

<figure><img src="image_49.png" /><figcaption>Scheme 16. Synthesis alkylaminomaleimides via metal-free aerobic oxidation.</figcaption></figure>

<figure><img src="image_50.png" /><figcaption>Scheme 17. Cu-catalyzed aerobic oxidative amination of maleimides.</figcaption></figure>
<figure><img src="image_51.png" /></figure>

<figure><img src="image_52.png" /></figure>

Representative examples

<figure><img src="image_53.png" /><figcaption>**Scheme 18.** Cu-catalyzed aerobic oxidative three-component chloroamination of maleimides.</figcaption></figure>

drug molecules, including nortriptyline, maprotiline, atomoxetine, fluoxetine, nortropine, and paroxetine.

Alternatively, a Cu-catalyzed sequential bromoamination of maleimides using N-bromosuccinimide (NBS) as the bromine source was first reported by Zhao's group in 2018 (**Scheme 19**, right).[52] In this approach, the reaction begins with a CuBr₂-catalyzed oxidative halogenation of maleimides **34**, generating a bromomaleimide intermediate **38**. This is followed by amination through addition and elimination of a secondary amine, releasing HBr, and a final oxidative bromination step to afford the bromoenaminomaleimides **39** in

good yields. Three years later, Wu and collaborators[53] extended this methodology to N-chlorosuccinimides (NCS) and, notably, N-iodosuccinimides (NIS) in a three-component one-pot procedure catalyzed by CuCl (**Scheme 19**, left). This aerobic oxidative radical process proceeds via oxidative amination intermediates **35** and **37**, followed by reductive elimination, delivering comparable yields while enabling, for the first time, the synthesis of iodoenaminomaleimides **40** (X = I).

More recently, the same group reported a closely related aerobic oxidative aminohalogenation approach using dihaloethanes

<figure><img src="image_54.png" /><figcaption>**Scheme 19.** Cu-catalyzed aerobic oxidative sequential halogenation of maleimides.</figcaption></figure>
<figure><img src="image_55.png" /></figure>

41 as both the solvent and halide source, catalyzed by CuCN under acidic conditions (Scheme 20).[54] In this transformation, the presence of HI is essential for the in situ generation of I₂, which initiates the formation of the key amino radical 42 involved in the oxidative amination to produce enaminomaleimides 35. Simultaneously, nucleophilic substitution between the dihaloethane and the secondary amine generates the required halide in situ, facilitating the formation of the Cu(III) intermediates 43. Reductive elimination from these intermediates then releases the final haloenaminiomaleimides 39 and 40 in moderate to good yields.

The oxidative C(sp²)—H thioamination of maleimides represents an intriguing multicomponent strategy, first reported by Zhao's group in 2018, for the synthesis of 3,4-biheteroatom-functionalized maleimides 44 using copper iodide as catalyst (20 mol%) (Scheme 21).[55,56] The reaction involves maleimides 34, thiols, and amines in DMA at 120 °C under air atmosphere for 6 h, yielding a variety of derivatives in 27%–84% yield, depending on the substrates. Mechanistically, as described by Wu and coworkers,[51] the process initiates with an aza-Michael addition of amines to maleimides 34, forming 3-aminosuccinimide

<figure><img src="image_56.png" /></figure>

**Representative examples**

<figure><img src="image_57.png" /><figcaption>**Scheme 20.** Cu-catalyzed aerobic oxidative chloro- and bromoamination of maleimides.</figcaption></figure>

<figure><img src="image_58.png" /><figcaption>**Scheme 21.** Cu-catalyzed aerobic oxidative three-component thioamination of maleimides with thiols and amines.</figcaption></figure>
<figure><img src="image_59.png" /></figure>

intermediates **33**. These intermediates then undergo copper-catalyzed aerobic oxidative dehydrogenation to generate 3-aminomaleimides **35**. The final step involves a copper-mediated nucleophilic substitution of the transient enaminomaleimides **35** with the electrophilic copper-disulfide species **45** formed in situ, leading to the formation of thioaminomaleimides **44**.

In addition, Wu's group developed a related Cu-catalyzed oxidative thioamination of maleimides **34** using Bunte's salts as the sulfur source and secondary amines (Scheme 22).[57] Similarly, the reaction proceeds via an initial oxidative amination, followed by C–H activation to form the Cu-complex intermediate **46**. Subsequent release of SO₃ and reductive elimination then furnish the corresponding thioalkyl enaminomaleimides **44** in good to excellent yields (52%–98%).

Furthermore, one year later, Majee and coworkers reported a complementary of thioamination of maleimides using a stoichiometric amount of phenyliodonium(III) diacetate (PIDA) as oxidant in refluxing acetonitrile.[58] Six examples of 3-amino-4-thiomaleimides **47** were obtained in this work, with very good yields after 12 h (72%–82%) (Scheme 23).

A related thioamination of maleimides **34** using diethylphosphorodithioate and amines was reported by Wu and coworkers in 2021.[59] In this study, a catalytic amount of CuCl was employed in toluene at 100 °C under air atmosphere, with FeCl₃ as an additive, to afford the corresponding 3,4-disubstituted aminothiomaleimide derivatives **48** (Scheme 24). The reaction proceeds via an initial oxidative amination of maleimide **34** to generate the enaminomaleimide **35**, followed by a regioselective phosphorothiolation

<figure><img src="image_60.png" /></figure>

**Representative examples**

<figure><img src="image_61.png" /><figcaption>R² = alkyl, benzyl</figcaption></figure>

<figure><img src="image_62.png" /></figure>

<figure><img src="image_63.png" /></figure>

<figure><img src="image_64.png" /><figcaption>from cystisine</figcaption></figure>

<figure><img src="image_65.png" /><figcaption>**Scheme 22.** Cu-catalyzed aerobic oxidative three-component thioamination of maleimides with Bunte's salts.</figcaption></figure>

**Representative examples**

<figure><img src="image_66.png" /></figure>

<figure><img src="image_67.png" /></figure>

<figure><img src="image_68.png" /><figcaption>47 (72-82%)</figcaption></figure>

<caption>6 examples</caption>

<caption>**Scheme 23.** PIDA-promoted thioamination of maleimides.</caption>
<figure><img src="image_69.png" /></figure>

<figure><img src="image_70.png" /><figcaption>**Scheme 24.** Cu-catalyzed aerobic oxidative three-component aminophosphorothiolation of maleimides.</figcaption></figure>

step. Notably, the protocol was successfully applied to the late-stage functionalization of drug molecules, including atomoxetine, troxipide, and a paliperidone fragment.

Building on these results, the same group proposed an alternative three-component Cu-catalyzed radical aminophosphinylation of maleimides **34** with anilines and phosphine oxides one year later (**Scheme 25**).[60] The reaction proceeded efficiently in the presence of an excess of di-tert-butyl peroxide (DTBP) as a radical oxidant. The process begins with a P-Michael addition

to furnish the key radical intermediate **49**. This intermediate is then trapped by the in situ formed amino-Cu complex **50**, followed by reductive elimination to afford the difunctionalized maleimides **51** in moderate to good yields (51%–77%).

In the same vein, Cai and collaborators proposed in 2023 the first Cu-catalyzed three-component aminosulfonylation of maleimides **34**, leading to a new family of sulfonylated enaminomaleimides **55** (**Scheme 26**).[61] This bifunctionalization strategy involves the condensation of secondary amine benzoates **52**

<figure><img src="image_71.png" /></figure>

**Representative examples**

<figure><img src="image_72.png" /><figcaption>R = Me, Ph, OMe, Ac, F, Cl, I, Ph
CO₂Me, SO₂Me, CF₃, SCF₃, COCF₃</figcaption></figure>

<figure><img src="image_73.png" /></figure>

<figure><img src="image_74.png" /></figure>

<figure><img src="image_75.png" /><figcaption>R = Me, OMe, Cl,</figcaption></figure>

<caption>**Scheme 25.** Cu-catalyzed radical oxidative aminophosphinylation of maleimides.</caption>
<figure><img src="image_76.png" /></figure>

<figure><img src="image_77.png" /><figcaption>**Scheme 26.** Cu-catalyzed radical oxidative aminosulfonylation of maleimides.</figcaption></figure>

and sulfonylhyrazines in the presence of Cul as catalyst and tert-butyl hydroperoxide (TBHP) as oxidant, affording the desired aminosulfonylated adducts **55** in moderate to good yields. Based on literature precedents and supporting control experiments, a radical mechanism is proposed, in which the key secondary amino radical **53** and the in situ generated sulfonyl radical **54** add sequentially to the maleimide core, followed by a final oxidation step. The robustness and synthetic utility of this method are demonstrated through the selective late-stage functionalization of

various amine-containing pharmaceuticals including desloratadine, fluoxetine, atomoxetine, and maprotiline.

Complementing the aforementioned bifunctionalization strategies, Wu and collaborators also reported a notable four-component Cu-catalyzed aerobic oxidative aminoarylselenation of maleimides **34** (**Scheme 27**).[62] This unique transformation enables the simultaneous formation of C—Se bond and C—N bonds in the presence of aryliodides and Se powder under an O₂ atmosphere. Using only 10 mol% of Cu(OAc)₂ as the catalyst,

<figure><img src="image_78.png" /><figcaption>**Scheme 27.** Cu-catalyzed four-component aminoarylselenation of maleimides under aerobic conditions.</figcaption></figure>
<figure><img src="image_79.png" /></figure>

the reaction efficiently delivers selenated enaminomaleimides 57 in good yields across a broad substrate scope. Notably, the methodology is applicable to the late-stage functionalization of bioactive molecules, as demonstrated by the successful modification of atomoxetine to afford adduct 58a. Moreover, the protocol can be adapted to thioamination by replacing selenium with elemental sulfur ($S_2$). Mechanistic studies indicate that the Cu catalyst plays multiple roles throughout the transformation. The reaction begins with an aza-Michael addition, followed by Cu-catalyzed aerobic dehydrogenation to form the enaminone intermediate 35. This intermediate then reacts with the in situ generated *bis*-selenocuprate species 56, leading to the formation of the key organocopper-intermediate 57, from which a reductive elimination furnishes the desired selenated enaminomaleimides 58.

In contrast to the previously developed heteroamination, the corresponding carboamination remains less developed. A recent advancement in this area was reported in 2022 by the groups of Ma and Wu, who developed a Cu-catalyzed oxidative C-functionalization of maleimides 34 with $\alpha$-bromo carboxylates 59 and secondary alkylamines (Scheme 28).[63] The reaction proceeds via an initial aza-Michael/dehydrogenation sequence to generate enaminomaleimides 35, which subsequently undergo a Cu-catalyzed radical alkylation involving the in situ generated alkyl radical 60. The resulting key amino radical intermediate 61 is then oxidized and deprotonated to furnish the alkylated enaminomaleimides 62 in generally good yields. This method features a broad substrate scope and enables late-stage functionalization of complex molecules, including bioactive paroxetine, which is converted into the corresponding adduct 62a.

More recently, the same group reported a related oxidative strategy for the aminoalkylation of maleimides 34 using alkyltin fluorides 63 ($R^4 = Me, Bu$). This transformation proceeds via an unexpected in situ alkylation pathway, affording enaminomaleimides 64 through copper-catalyzed radical C-Sn bond cleavage (Scheme 29).[64] Initially, the authors anticipated the formation of the aminostannylation products 65; however, the reaction yielded

exclusively the aminoalkylated maleimides 64. The reaction was performed using CuCl (10 mol%) as a catalyst and $FeCl_2$ (80 mol%) as an additive in benzene at 130 °C under an air atmosphere for 24 h. This methodology proved to be robust, successfully accommodating a broad substrate scope of 35 compounds. Moreover, the approach was extended to the late-stage functionalization of pharmaceutically relevant molecules, including a duloxetine intermediate, D-prolinol, and a ziprasidone intermediate.

To bypass the need for an oxidation step, Kandhasamy and coworkers proposed an aza-Morita-Baylis-Hillman (aza-MBH) reaction, in which maleimides 34 react with azodicarboxylates in the presence of a catalytic amount of 1,4-diazabicyclo [2.2.2] octane (DABCO) (20 mol%) under solvent-free conditions at 70 °C (Scheme 30).[65] The reaction proceeds via Michael addition of DABCO to 34, forming a zwitterionic intermediate 66, which then undergoes intermolecular amination. This is followed by the release of DABCO, yielding the corresponding hydrazine-substituted maleimide derivatives 67 in good to excellent good yields (72%–88%).

Another example of an oxidant-free approach was reported by Baidya and coworkers in 2017, involving a direct ruthenium(II)-catalyzed C-H functionalization of simple maleimides 34 (Scheme 31).[66] This unprecedented amination proved effective with N-methoxybenzamides 68, employing only 2.5 mol% of $[Ru(p-cymene)Cl_2]_2$ at room temperature to afford the corresponding amidated maleimides 69 in moderate yields (54%–57%). A series of control experiments were conducted to rule out a radical mechanism and instead support a pathway involving direct C-H activation through a ruthenium-mediated process. The results suggest that the benzamide moiety acts as a directing group, possibly via nucleophilic ruthenium intermediate 70.

More recently, in 2023, Nanda and coworkers reported a complementary rhodium-catalyzed carboamination of maleimides 34 using phenoxyacetamide derivatives 71 (Scheme 32).[67] The transformation involves a direct *ortho* C-H activation of the phenol ring, which simultaneously introduces the nitrogen fragment

<figure><img src="image_80.png" /><figcaption>Scheme 28. Cu-catalyzed radical carboamination of maleimides.</figcaption></figure>
<figure><img src="image_81.png" /></figure>

<figure><img src="image_82.png" /><figcaption>**Scheme 29.** Cu-catalyzed aminoalkylation of maleimides with alkyltin fluorides.</figcaption></figure>

<figure><img src="image_83.png" /><figcaption>**Scheme 30.** Aza-MBH reaction of maleimides with azodicarboxylates.</figcaption></figure>

<figure><img src="image_84.png" /><figcaption>**Scheme 31.** Ru(II)-catalyzed direct C–H amidation of maleimides.</figcaption></figure>

during the carboamination process. The reaction is catalyzed by $(Cp^*RhCl_2)_2$ in the presence of $CsOAc$ (50 mol%), $K_3PO_4$ (50 mol%), and $Na_2SO_4$ (50 mol%), in trifluoroethanol (TFE) at 60 °C for 12 h. Under these conditions, N-substituted maleimides afford the primary enaminomaleimides **72** in yields up to 68% across 11 examples. Mechanistic investigations, including ¹⁹F nuclear magnetic resonance and high-resolution mass spectrometry analysis,

support a pathway involving *ortho*-metalation of the phenoxyacetamide, followed by olefin insertion to generate the key intermediate **73**. This intermediate then evolves into the arylated maleimide **74** and a Rh(III)nitrenoid species **75**. Subsequent nitrenoid insertion furnishes the aziridine intermediates **76**, which undergo ring fragmentation to deliver the final free-amino maleimides **72**.
<figure><img src="image_85.png" /></figure>

<figure><img src="image_86.png" /><figcaption>**Scheme 32.** Rh(III)-catalyzed carboamination of maleimides with phenoxyacetamides.</figcaption></figure>

By replacing phenoxyacetamide pronucleophiles **71** with glycine methyl ester, Zhang and coworkers developed a stereoselective one-pot pseudo four-component protocol for the synthesis of highly functionalized enaminomaleimides, via a sequential

double dipolar cycloaddition/(5 + 1) annulation sequence (**Scheme 33**).[68] The process begins with an initial (3 + 2) dipolar cycloaddition between *N*-methylmaleimide **34** (*R* = Me), glycine methyl ester, and 2-azidobenzaldehyde in the presence of

<figure><img src="image_87.png" /><figcaption>**Scheme 33.** One-pot stereoselective synthesis of highly functionalized enaminomaleimides by sequential (3 + 2) dipolar cycloaddition (up) and (5 + 1) annulation (down).</figcaption></figure>
<figure><img src="image_88.png" /></figure>

Et<sub>3</sub>N as a base in acetonitrile, under microwave irradiation at 115 °C for 25 min, affording the key intermediate **78** (Scheme 33, top). Without isolation or work-up, a second equivalent of maleimide **34** was directly added to the reaction mixture, which then underwent a second (3 + 2) dipolar cycloaddition under microwave heating at 125 °C for an additional 25 min. This sequence led to the formation of enaminomaleimides **77** in low to good yields (21%–73%) and with excellent diastereoselectivities (up to 40:1), following nitrogen extrusion from the corresponding triazole **79**. Furthermore, the resulting highly functionalized enaminomaleimides **77** were used as substrates in a (5 + 1) annulation reaction with formaldehyde, yielding fused tetrahydroquinazolines **80**. This step was carried out in 1,4-dioxane at 110 °C for 3 h, affording the desired products in excellent yields (88%–95%) (Scheme 33, bottom).

### 2.2.2. Amination of Halogenated Maleimides

Enaminomaleimides can also be accessed through the direct condensation of nucleophilic primary or secondary amines with mono- or dihalogenated maleimides. In this approach, halogenated maleimides serve as electrophilic partners, enabling direct amination via a straightforward addition/elimination sequence under mild conditions.

A pioneering example of this strategy was reported by Heindel and coworkers in 1968, in which monobrominated free-NH-maleimides **81** (R¹ = H) were directly aminated using methyl anthranilate derivatives **82**, yielding NH-aryl enaminomaleimides **83** (Scheme 34, right).<sup>[69]</sup> The nucleophilic substitution of the bromine atom by the amine functionality was carried out in methanol at room temperature over 8 h, providing five different derivatives in moderate to good yields (21%–61%). The reaction tolerated both electron-withdrawing and electron-donating groups at the *para* position of the anthranilate moiety **82**, demonstrating the versatility of this approach. Building on this strategy, Wang's group later showed that the addition of one

equivalent of NaHCO<sub>3</sub> in refluxing ethanol significantly improved the preparation of a broad range of N-phenyl enaminomaleimides **84**, using various primary or secondary aromatic or aliphatic amines (Scheme 34, left).<sup>[70]</sup> Finally, Renault, Finck, and collaborators, developed an efficient two-step synthesis of N-free enaminomaleimide **28**, starting with nucleophilic substitution using sodium azide, followed by catalytic hydrogenation, affording the desired product in 61% overall yield (Scheme 34, bottom).<sup>[71]</sup>

As a complementary strategy, Bowler and coworkers reported an efficient one-pot sequential protocol for accessing NH-free enaminomaleimides **86** (Scheme 35).<sup>[72]</sup> The process begins with the bromination of commercially available maleimide **85** using Br<sub>2</sub> in refluxing chloroform for 2 h, resulting in a mixture of 2-bromomaleimide and 2,3-dibromosuccinimide. Notably, as the authors highlight, no separation of these intermediates was required, as both were ultimately converted into the desired enaminomaleimides upon treatment with the appropriate alkyl or aryl amines. The second step, a nucleophilic amination, was performed in acetonitrile at room temperature overnight, delivering enaminomaleimides **86** in good to excellent yields. Remarkably, when allylamine (R = CH<sub>2</sub>CH=CH<sub>2</sub>) was used as the nucleophile, the overall transformation proceeded with quantitative yield, showcasing the efficiency of the method.

In addition, dibromomaleimides **87** have proven to be versatile precursors for the synthesis of a series of mono- or dienaminomaleimides **89** and **90**, as demonstrated by the groups of

<figure><img src="image_89.png" /><figcaption>Scheme 35. One-pot bromination and amination of maleimides.</figcaption></figure>

<figure><img src="image_90.png" /><figcaption>Scheme 34. Direct amination of bromomaleimides with various primary or secondary amines and sodium azide.</figcaption></figure>
<figure><img src="image_91.png" /></figure>

Mahboobi and Lakatosh in 2000 and 2003, respectively (Scheme 36).[73–76] In the first step, mono-bromo indolyl enaminomaleimides 89 are obtained in two steps: mono-substitution of dibromomaleimides 87 with indoline 88, followed by oxidation with DDQ. Subsequent nucleophilic substitution of the remaining bromine atom with various amines leads to the formation of dienaminomaleimides 90. This second step proceeds through a robust and versatile reaction that tolerates a wide range of nucleophiles, including primary and secondary alkyl amines, ammonia as well as aryl-and heteroaryl-amines. Additionally, both N-H and

N-alkyl-maleimides were shown to be accessible, as further demonstrated by the same group in 2011.[77]

Following these results, Capretta and Awuah in 2011 extended the sequential disubstitution strategy through slight modifications to the protocol (Scheme 37).[78] Treatment of dibromo-N-p-methoxybenzylmaleimide 91 with 1 equiv. of amine at room temperature led to rapid mono-substitution, affording monoaminated maleimides 92 in high yields (Scheme 37). In contrast, the synthesis of nonsymmetric diaminated maleimides 93 required harsher conditions starting from the monobrominated

<figure><img src="image_92.png" /><figcaption>Scheme 36. Synthesis of mono- and dienaminomaleimides from dibromomaleimides.</figcaption></figure>

<figure><img src="image_93.png" /></figure>

<figure><img src="image_94.png" /><figcaption>Scheme 37. Mono- and diamination of dibromomaleimides.</figcaption></figure>
<figure><img src="image_95.png" /></figure>

derivatives **92** under microwave irradiation at 100 °C in the presence of 3 equivalents of a second amine afforded the desired product in excellent yields (Scheme 37). Interestingly, using *N*-p-nitrophenyl dibromomaleimides **94** enabled the preparation of other nonsymmetrical dienaminomaleimides **96**. Subsequent deprotection with ammonia in methanol readily provided the corresponding *NH*-free dienaminomaleimides **97**.

Additionally, a straightforward method for the synthesis aminothiomalimides **102** was described by Li and Chen in 2021 (Scheme 38).[79] The protocol involves the monosubstitution of *N*-benzyl dibromomaleimide **98** with ethanolamine **99** at room temperature in the presence of sodium carbonate. This reaction yields intermediate **100**, which then undergoes a base-promoted addition-elimination reaction with either 1-butanethiol (**101**, *R* = *H*) or mercaptoethanol (**102**, *R* = *OH*) to afford the corresponding aminothiomalimides **102**.

Monochlorinated *N*-aryl maleimides **103** have also served as valuable precursors for aminations, as demonstrated in a comprehensive study by Augustin and Köhler in 1974,[80] with further developments reported later.[81-83] These studies explored the condensation of **103** with a broad range of aromatic and aliphatic amines, as well as phenylhydrazine **104**, to synthesize the corresponding aryl- and alkyl-enaminomaleimides **105** and **106**, and phenylhydrazinomaleimides **107**, respectively (Scheme 39). Related aryl-enaminomaleimides have been efficiently prepared

from their chlorinated precursors by the groups of Smith's and Connell in the pursuit of novel potential therapeutic agents in oncology. Some of these derivatives have shown potent and selective inhibition of glycogen synthase kinase-3 and RAD51 protein inhibitors, respectively (Scheme 39).[84,85]

Dihalomaleimides **108**, prepared from maleic anhydride in two or three steps, also serve as versatile starting materials for the preparation of functionalized enaminomaleimides via monosubstitution of one halogen atom (Scheme 40). This approach was first demonstrated by Ciamician and Silber as early as 1889 with ammonia and aniline ($R^2 = H, Ph$) and later expanded to various primary amines by Oda and collaborators in 1968 (Scheme 40, top).[86-90] Notably, a chloroenaminomaleimide derivative **109a** ($R^1 = Bn, R^2 = m-Ph-OH$) exhibited anticancer activity, displaying low micromolar $GI_{50}$ values against multiple human cancer cell lines.[91] More recently, in 2013, Connell and collaborators, prepared a series of dichloro-, dibromo-, and diiodo-enaminomaleimides **108** enabling the selective synthesis of piperidine- and morpholine-functionalized derivatives **110** (Scheme 40, bottom).[85]

Additionally, Naka's group reported in 2015 the in situ generation of dichloromaleimides **111** via the reaction of dichloromaleic anhydride with two equivalents of *p*-toluidine in refluxing toluene for 24 h. This method enabled the one-pot synthesis of 3-*p*-toluidino-2-chloro-*N*-(*p*-tolylmaleimide **112** in moderate yield (Scheme 41).[92]

<figure><img src="image_96.png" /><figcaption>Scheme 38. Two steps synthesis of aminothiomaleimides.</figcaption></figure>

<figure><img src="image_97.png" /></figure>

<figure><img src="image_98.png" /><figcaption>Scheme 39. Direct amination of chloromaleimides with amines and phenylhydrazine.</figcaption></figure>
<figure><img src="image_99.png" /></figure>

<figure><img src="image_100.png" /><figcaption>**Scheme 40.** Synthesis of halo-enaminomaleimides from maleic anhydride.</figcaption></figure>

<figure><img src="image_101.png" /><figcaption>**Scheme 41.** Synthesis 3-p-toluidino-2-chloro-N-p-tolylmaleimide via direct amination of dichloromaleic anhydride.</figcaption></figure>

More recently, dichloro-N-cyclohexylmaleimide 113 proved to be an effective precursor for the synthesis of related 2-chloro-3-amino-N-cyclohexylmaleimides 114 and 115, incorporating cyclic secondary amines, as reported by Onimura in 2022 (Scheme 42).[93] Two distinct protocols were employed depending on the amine used. When morpholine was utilized, the reaction was carried out under reflux in THF for 12 h, affording 114 in excellent yield (92%). In contrast, reactions with pyrrolidine (n = 1) or piperidine

(n = 2) proceeded efficiently under milder conditions at room temperature over the same reaction time, affording compounds 115.

### 2.2.3. Amination of Hydroxy- and Methylthio-Maleimides

Building on Wiley's pioneering 1958 report on the synthesis of 2-hydroxy-3-carbamylmaleimide 120,[94] Sakamoto and collaborators, two decades later, developed the first practical synthesis

<figure><img src="image_102.png" /><figcaption>**Scheme 42.** Amination of dichloro-N-cyclohexylmaleimide with cyclic secondary amines.</figcaption></figure>
<figure><img src="image_103.png" /></figure>

of 2-acetyl-3-hydroxy-5-phenylmaleimide **118** via the condensation of dioxovalerate ester **116** with phenylhydroxylamine **117** (*Scheme* **43**).[⁹⁵] Interestingly, they also observed the formation of the corresponding enaminomaleimide **119** as a by-product, which could be obtained in quantitative yield by heating intermediate **118** with aniline in ethanol at 50 °C for 5 min.

From these seminal contributions, 3-hydroxymaleimides **124**, easily obtained by condensation of acetamides **121** or monosubstituted acetonitriles **122** with oxalates **123** in the presence of a

strong base (*Scheme* **44**, up),[⁹⁶,⁹⁷] emerged as valuable synthetic scaffolds for the preparation of various enaminomaleimides **125** in the search for new bioactive compounds of broad medicinal relevance. In this context, one of the first detailed study was reported in 2004 by Inaba's group, describing the synthesis of a large series of monoindolyl enaminomaleimides **128** and the biological evaluation of potent and selective protein kinase C inhibitors (*Scheme* **44**, middle).[⁹⁸] Subsequent studies focused on the biological assessment of structurally related enaminomaleimides,

<figure><img src="image_104.png" /><figcaption>**Scheme 43.** First preparations of hydroxymaleimide precursor of enaminomaleimides.</figcaption></figure>

<figure><img src="image_105.png" /></figure>

<figure><img src="image_106.png" /><figcaption>**Scheme 44.** Preparation of enaminomaleimides from 3-hydroxymaleimides and selected examples of bioactive scaffolds.</figcaption></figure>
<figure><img src="image_107.png" /></figure>

including liver receptor agonists,[⁹⁹] orally bioavailable PKCβ-selective inhibitors,[¹⁰⁰] lead series for the treatment of prion disease,[¹⁰¹] and other kinase inhibitors (Scheme 44, bottom).[¹⁴,¹⁰²]

Alternatively, a modified version of Faul's procedure for the synthesis of bis-indolylmaleimides,[¹⁰³] was proposed by Lakatosh and coworkers in 2005.[¹⁰⁴] In this approach, oxalates were replaced with indole-3-glyoxylate **129**, enabling the direct synthesis of indolyl enaminomaleimides **131** via condensation with 2-aminoacetamides **130** under basic conditions (Scheme 45). Similar to Faul's method, the transformation likely begins with an amidation through nucleophilic substitution, followed by a Perkin-type condensation and subsequent dehydration upon acidification.

A complementary approach to the synthesis of enaminomaleimides involves the straightforward chlorination of 3-hydroxymaleimides **132** to yield the 3-chlorinated **133** or carbonated **134** derivatives, a strategy first reported by Wiley in 1958[⁹⁴] (Scheme 46). In this pioneering work, 2-hydroxy-3-carbamylmaleimide **132** (R¹ = H, R² = NH₂, R³ = H) was chlorinated and dehydrated using POCl₃ to afford the corresponding chloronitriles **133** (Scheme 46, equation 1). Later, in 1987, Augustin and Jeschke[⁸²] described the selective chlorination of the hydroxyester **134** with PCl₅ (Scheme 46, equation 2). Both chlorinated derivatives readily undergo substitution with various primary or secondary amines to produce functionalized enaminomaleimides **135** and **136**, respectively. Likewise, the

corresponding carbonate **132** can be aminated with aniline to generate expected enaminomaleimide **137** (Scheme 46, equation 3). This strategy has since been widely adopted by numerous research groups, including in recent years, for the synthesis of diverse biologically active compounds or molecular sensors (Scheme 46, bottom).[⁸⁴,¹⁰⁵⁻¹⁰⁷]

Finally, in 1996, Tominaga and coworkers explored the unique reactivity of functionalized methylthiomaleimides **138** toward primary aryl and heteroaryl amines (Scheme 47).[¹⁰⁸⁻¹¹⁰] They found that the substitution of the methylthio group proceeded efficiently through the reaction with anilines or aminopyrazoles in refluxing methanol, affording the corresponding enaminomaleimides **139** and **140**, respectively, in good yields.

### 3. Chemical Applications

Beyond their synthesis, enaminomaleimides exhibit remarkable chemical versatility, enabling a wide range of transformations with significant synthetic and functional implications. In this section, we examine their reactivity across various contexts, categorized into five key areas: (1) *Miscellaneous Synthetic Applications*, (2) *Photophysical Applications*, (3) *Multicomponent Reactions (MRCs)*, (4) *Annulations and Cycloadditions*, and (5) *Enantioselective Transformations*. These

<figure><img src="image_108.png" /><figcaption>**Scheme 45.** Preparation of indolyl enaminomaleimides from indole-3-glyoxylate and 2-aminoacetamides.</figcaption></figure>
<figure><img src="image_109.png" /></figure>

<figure><img src="image_110.png" /><figcaption>**Scheme 46.** Preparation of enaminomaleimides from 3-hydroxymaleimides and selected examples of active derivatives.</figcaption></figure>

<figure><img src="image_111.png" /><figcaption>**Scheme 47.** Synthesis of enaminomaleimides from thiomethymaleimides.</figcaption></figure>

classifications underscore growing importance of enaminomaleimide derivatives in both organic synthesis and materials science.

### 3.1. Miscellaneous Synthetic Applications

One of the earliest synthetic applications for enaminomaleimides was reported in 1984 by Augustin and coworkers.[111] In this study, enaminomaleimides **141** were used for the chemoselective synthesis of thioenaminomaleimides **142** via treatment with Lawesson's (**Scheme 48**). This transformation efficiently converts a carbonyl group into a thiocarbonyl moiety, yielding the corresponding thioenaminomaleimides **142**. Nine examples were

reported, featuring various substituents at the three key positions of the enaminomaleimide core, with isolated yields ranging from 13% to 70%. The reaction proceeds with high chemoselectively, preferentially modifying the carbonyl group adjacent to the enamine moiety. Moreover, further treatment of selected derivatives **142** under the same conditions enabled substitution of the second carbonyl group, affording dithioenaminomaleimides **143**. This extended methodology was applied to two thioenaminomaleimides **142** bearing a *p*-tolyl group at the ring nitrogen (R³ = *p*-tolyl) and a proton (R² = H). Yields of the corresponding dithio derivatives reached 50% when the enamine substituent was *p*-tolyl (R¹ = *p*-Tolyl) and 41% when it was *n*-butyl (R¹ = *n*-Bu).

<figure><img src="image_112.png" /></figure>

<figure><img src="image_113.png" /><figcaption>**Scheme 48.** Thiocarbonylation of enaminomaleimides using Lawesson's reagent.</figcaption></figure>
<figure><img src="image_114.png" /></figure>

In addition to carbonyl functionalization strategies, Chepyshev and coworkers reported an efficient mono-transamination of various N,N-dialkyl enaminomaleimides **144**, enabling the selectively N-aryl enaminomaleimides **4**.[29,30] In this process, treatment of compounds **144** with arylamine hydrochlorides **145** resulted in a vinylic nucleophilic substitution ($SN_{vin}$), where the alkylamino group was replaced by an arylamino moiety, to afford 1-alkyl-3-arylaminopyrrole-2,5-diones **4** (Scheme 49). The authors proposed that the driving forces behind the $SN_{vin}$ reaction is the generation of both a weaker conjugate acid (the alkylammonium cation **146**) and a weaker base (the resulting 1-alkyl-3-arylaminopyrrole-2,5-dione **4**). This hypothesis was supported by experimental pKa values, which indicated that the nucleophiles used were significantly less basic than the corresponding leaving groups, rendering the substitution thermodynamically favorable. The methodology was further extended, to a broad and structurally diverse range of 26 examples, with yields ranging from moderate to excellent (from 41% to 93%). However, when morpholine was employed, the yield dropped markedly to 12%, resulting in a 1:1 mixture of the target maleimide and 1-methyl-3-morpholinopyrrole-2,5-dione (Scheme 49).

Alternatively, direct C-functionalization based on the nucleophilic character of the enamine moiety was first proposed in 1987 by Augustine and coworkers, who investigated the unique reactivity of enaminomaleimides with arylidene-pyrrolidinetriones **148** as electrophilic partners under acidic conditions

(Scheme 50, right).[83] When N-alkylenaminomaleimides **106** ($R$ = alkyl) were used, the expected Michael adducts **149** were obtained in good yields. In contrast, reactions involving N-morpholinoenaminomaleimides **147** led to the formation of the corresponding hydrolyzed derivatives **150** in moderate to good yields. More recently, Patil and coworkers reported the direct formylation of N-arylenaminomaleimides **106** for the synthesis of hydroxyphosphonate derivatives **151**, which exhibited moderate to good microbial activity (Scheme 50, left).[112]

Enaminomaleimides can also serve as efficient starting materials for the synthesis of N1-substituted orotic acid derivatives **153** (Scheme 51). In this context, Bowler and coworkers reported the use of previously obtained aminosubstituted maleimides **86** for the preparation of such derivatives.[72] The reaction begins with the treatment of compounds **86** with ethyl chloroformate in anhydrous acetone in the presence of triethylamine. Both reagents were added dropwise simultaneously, and the reaction was stirred at room temperature for 45 min, followed by refluxing for an additional 45 min. This yielded the intermediate **152**, which was used in the next step without purification. Subsequently, intermediate **152** was suspended in 1 M aqueous NaOH and heated at 65 °C for 2 h. After acidification the reaction mixture with 6 N HCl, the corresponding N1-substituted orotic acids **153** were obtained in good to excellent yields (51%–90%) following recrystallization from water or a water/ethanol mixture.

<figure><img src="image_115.png" /><figcaption>Scheme 49. Transamidation of 1-alkyl-3-alkylaminopyrrole-2,5-diones.</figcaption></figure>

<figure><img src="image_116.png" /><figcaption>Scheme 50. C-functionalization of enaminomaleimides.</figcaption></figure>
<figure><img src="image_117.png" /><figcaption>**Scheme 51.** Synthesis of N1-substituted orotic acid derivatives from enaminomaleimides.</figcaption></figure>

In addition, the use of α-aminomaleimides in transition metal-free thiolation, selenation, and arylation was reported by Khurana and collaborators in 2019 (Scheme 52).[113] In this work, thioarylation reactions were performed between methyl, phenyl, and benzyl enaminomaleimides 154 and various thiophenol derivatives 155 in the presence of an excess of K₂CO₃ in DMSO under aerobic conditions at room temperature, affording the corresponding 3-thioarylated-2-aminomaleimide derivatives 156 in very good to excellent yields (80%–91%) (Scheme 52, left). Similarly, two seneloar-ylation examples were carried out under identical conditions using diphenyl diselenide (157a, R³ = H) and di-(4-tolyl) diselenide (157b, R³ = Me), yielding the corresponding 3-selenoarylated-2-aminometh-ylmaleimides 158 in high yields (81%–83%) (Scheme 52, right). Both transformations are proposed to proceed via the nucleophilic substitution of the enamine moiety in 154 by the disulfide or diselenide species, followed by deprotonation and selective formation of the C—S or C—Se bond. Moreover, direct arylation was explored (Scheme 52, bottom) through the reaction of N-methyl

enaminomaleimide 154a with arylhydrazine hydrochlorides 159 under the same conditions (excess of K₂CO₃ in DMSO at room temperature), yielding 3-arylated 2-aminomethylmaleimide derivatives 160 in very good yields (76%–86%). In this case, the proposed mechanism involves in situ generation of aryl radicals from hydrazines 159 in the presence of K₂CO₃, followed by air oxidation to furnish the final arylated products. Notably, the use of DMSO as green solvent in all these transformations, adds further value to the methodology from sustainability standpoint.

Regarding metal-catalyzed arylations of enaminomaleimides, although Suzuki couplings with brominated derivatives 92 have proven efficient (Scheme 53, left),[78] a more recent advancement was reported by Taheri and Jafarpour, who developed a direct, regioselective C—H arylation of enaminomaleimides 92 via palladium-catalyzed Heck reaction with various aryl iodides (Scheme 53, right).[114] This ligand-free cross-coupling proceeds with 10 mol% of Pd(OAc)₂ in DMF at 120 °C over 24 h, furnishing a wide range of corresponding 3-aryl-4-aminomaleimides 161

<figure><img src="image_118.png" /><figcaption>**Scheme 52.** Transition metal free thiolation, selenation, and arylation reactions of enaminomaleimides.</figcaption></figure>
<figure><img src="image_119.png" /></figure>

Suzuki couplings

<figure><img src="image_120.png" /></figure>

161

<figure><img src="image_121.png" /></figure>

<figure><img src="image_122.png" /></figure>

<figure><img src="image_123.png" /></figure>

92

Heck couplings

<figure><img src="image_124.png" /></figure>

<figure><img src="image_125.png" /></figure>

<figure><img src="image_126.png" /></figure>

162 (45-95%)
21 examples

<caption>**Scheme 53.** Pd-catalyzed direct arylation of enaminomaleimides.</caption>

and **162** in moderate to excellent yields (Scheme 53). In a complementary approach, additional palladium-catalyzed selective functionalizations of chloroenaminomaleimide **40**, including alkynylation **163**, ethoxylation **164**, and phosphonylation **165**, were reported by Wu and collaborators in 2023 (Scheme 54).[54]

An alternative metal-free arylation of enaminomaleimides was reported in 2024 by Wang and coworkers, based on a cesium fluoride (CsF)-promoted trapping of arynes generated in situ from o-silylaryl triflates **167** (Scheme 55).[115] The reaction was carried out in acetonitrile at room temperature for 6 h under fluoride

activation, leading to the formation of 3-aryl-4-aminomaleimides **166** via a practical and transition-metal-free selective C-arylation.

In addition to these regioselective functionalizations, Han and Oriyama reported in 2021 the first use of α-aminomaleimides **169** in a Mannich reaction with aldimines **170** (Scheme 56).[116] The reaction was carried out in DMSO at room temperature using 4 Å molecular sieves as dehydrating agent, as control experiments confirmed that the presence of water had a detrimental effect on the reaction. A broad substrate scope was explored, resulting in 24 successfully synthesized derivatives **171** with

<figure><img src="image_127.png" /><figcaption>**Scheme 54.** Pd-catalyzed functionalizations of enaminomaleimides.</figcaption></figure>

<figure><img src="image_128.png" /></figure>

166

+

<figure><img src="image_129.png" /></figure>

167

<figure><img src="image_130.png" /></figure>

<figure><img src="image_131.png" /></figure>

168 (60-83%)
25 examples

<caption>**Scheme 55.** CsF-promoted C-arylation of α-aminomaleimides with o-silylaryl triflates.</caption>
<figure><img src="image_132.png" /></figure>

<figure><img src="image_133.png" /><figcaption>**Scheme 56.** Mannich reaction between α-aminomaleimides and imines.</figcaption></figure>

yields ranging from low to quantitative (25%–100%). Clear trends were observed based on electronic effects and steric effects. In general, N-tosylaldimines bearing halogen or electron-donating substituents on the phenyl ring (R³) afforded high yields (81%–100%), with the notable exception of the *ortho*-chloro-substituted analog **170a** (R³ = *o*-ClPh), which yielded only trace amounts after 48 h. Electron-withdrawing groups, such as CN, NO₂, or CO₂Me, at the *para*-position led to excellent yields (93%–97%) within just 3 h. Naphthyl-derived imines **170b,c** (R³ = 1-naphthyl, 2-naphthyl) were also well tolerated, providing products in 85%–91% yield. In contrast, aliphatic and heteroaromatic imines **170d,e** (R³ = 2-furyl, Cy) resulted in significantly lower yield (25%–36%). The reaction was also influenced by the nature of the imine protecting group. N-nosylimine **171f** (R⁴ = Ns) afforded a moderate yield (69%), while N-phenylsulfonylimine **170g** (R⁴ = PhSO₂) gave a quantitative yield (100%) with aryl enaminomaleimides. Aliphatic enaminomaleimides also performed well, and the introduction of a benzyl group at the maleimide nitrogen (R¹ = Ph, R² = Bn) resulted in a quantitative yield after just 7 h. To demonstrate the scalability of the method, a gram-scale reaction was performed using 1-methyl-3-(phenylamino) maleimide **169a** (R¹ = Ph, R² = Me) and *p*-bromophenyl N-tosylimine **170h** (R³ = *p*-BrPh, R⁴ = H, R⁵ = Ts), affording 1.12 g of product **171a** in 90% yield.

In 2013, the research groups of Zhu and Tang reported a base-promoted deiminative coupling of gramines **172** with

aminomalaimides **174** under redox-neutral conditions (**Scheme 57**).[25] This operationally simple transformation enabled the efficient synthesis of a series of indolmethyl-substituted amino-maleimides **178** in good to excellent yields (45%–97%). The proposed reaction mechanism involves base-induced elimination of dimethylamine from gramine **172**, generating the highly reactive 3-methyleneindolenine intermediate **173**. Concurrently, deprotonation of enaminomaleimide **174** forms nucleophilic intermediate **175**, which undergoes conjugate addition to electrophilic methyleneindolenine **173**. Subsequent protonation and enamine-imine tautomerization afford derivatives **177**. Notably, biological evaluation of selected derivatives revealed antiproliferative activity against human cancer cell lines, underscoring the medicinal potential of these scaffolds.

Additionally, in 2022, Onimura and coworkers utilized chloroaminomaleimides **114** and **115**, bearing morpholine, pyrrolidine (*n* = 1), and piperidine (*n* = 2) substituents, respectively (**Scheme 58**), as starting materials for the synthesis of aminobiphenyl-N-cyclohexylmaleimides **179** and **180** via a Suzuki-Miyaura coupling with 4-biphenylboronic acid **178**.[93] The coupling reaction was catalyzed by 20 mol% palladium acetate in the presence of triphenylphosphine and a base. For the morpholine derivative **114**, the reaction was conducted in a toluene/ethanol mixture using a saturated aqueous solution of sodium bicarbonate as the base, under reflux for 5 h (**Scheme 58**). In contrast, for the pyrrolidine and piperidine derivatives **115**, the same palladium catalytic system

<figure><img src="image_134.png" /><figcaption>**Scheme 57.** Base-promoted deiminative coupling between gramine and aminomaleimides.</figcaption></figure>
<figure><img src="image_135.png" /></figure>

<figure><img src="image_136.png" /><figcaption>**Scheme 58.** Pd-catalyzed Suzuki–Miyaura coupling between chloro-aminomaleimides and 4-biphenylboronic acid.</figcaption></figure>

was employed; however, saturated aqueous potassium carbonate replaced sodium bicarbonate, and the reaction was performed in refluxing THF for 14 h (Scheme 58).

Also, in 2023 by Aksenov's group reported several late-stage derivatizations of 2-carboxyaniline-substituted maleimides **21** (Scheme 59).[36] In one transformation, an amidation reaction using methylamine hydrochloride **181** in the presence of carbonylimidazole (CDI) afforded the corresponding amide in excellent yield (96%) after just 15 min (Scheme 59, A). Similarly, Fisher esterification with refluxing methanol yielded ester **183**

in 85% yield (Scheme 59, B). Moreover, treatment with dimethyl sulfate and sodium hydride in DMSO at room temperature led to compound **184** via double methylation of both the maleimide nitrogen and the carboxylic acid oxygen atoms (Scheme 59, C). Finally, decarboxylation was achieved under harsh conditions using imidazole hydrochloride **185** at 300 °C for 3 h, affording the desired product in a modest yield of 33% (Scheme 59, D).

Finally, in 2025, Wang and coworkers reported a direct C(sp²)-H alkylation of 3-iminophosphorane maleimide derivatives **187** via an Fe(III)-catalyzed hydrogen atom transfer (HAT) strategy

<figure><img src="image_137.png" /><figcaption>**Scheme 59.** Synthetic applications of 2-carboxyaniline-substituted maleimides.</figcaption></figure>

<figure><img src="image_138.png" /><figcaption>**Scheme 60.** Direct C(sp²)-H bond alkylation of 3-iminophosphorane maleimides via Fe(III)-catalyzed HAT strategy.</figcaption></figure>
<figure><img src="image_139.png" /></figure>

(Scheme 60). This method enables the efficient formation of C(sp²)—C(sp³) bonds under mild reaction conditions.[115] The transformation exhibits broad substrate scope, accomodating both allyl alcohols 188 and unactivated olefins 190, and proceeds using catalytic amounts of iron(III) acetylacetonate with diphenylsilane as a reductant (Scheme 60). Mechanistic investigations, supported by complementary experiments and theoretical calculations, suggest a reaction pathway involving key steps such as HAT, radical conjugate addition, and single-electron transfer. This work provides a valuable strategy for constructing C(sp²)—C(sp³) bonds via direct C(sp²)—H functionalization.

## 3.2. Photophysical Applications

Over the past decade, several photophysical applications of aminomaleimides have been reported, highlighting their potential in fluorescence-based technologies and materials science due to their unique optical properties.

In 2012, Kato and Naka investigated the aggregation-induced emission (AIE) behaviour of arylaminomaleimides 5a (Scheme 61), observing intense green (λ<sub>max</sub> = 505 nm) and yellow (λ<sub>max</sub> = 521 nm) luminescence in the solid state.[117] In contrast, no emission was detected in solution using solvents such as CHCl<sub>3</sub> or THF. Luminescence was significantly enhanced upon aggregation and in thin films, with fluorescence observed in solution only at high water content (>58% H<sub>2</sub>O in THF). Additionally, the authors reported that the fluorescence was pH-responsive: luminescence was switched “on” at high pH and “off” at low pH, attributed to ionization and deionization under basic and acidic conditions, respectively, which disrupted aggregation. DFT calculations revealed that the highest occupied molecular orbitals exhibited significant orbital density on both the maleimide core and the arylamine substituents, suggesting strong π-conjugation throughout the molecule. Alternatively, Muthusubramanian and Rajagopal[31] demonstrated that the AIE properties of enaminomaleimide 5b

(R = H) could be readily tuned by addition water to a THF solution, resulting in a substantial increase in luminescence intensity accompanied by a red shift of up to 80 nm (from 424 to 500 nm). This corresponds to a 240-fold enhancement in emission intensity compared to its fluorescence in pure THF. This AIE was also associated with a significant increase in quantum yield from 2.4% in THF up to 45% in a THF:H<sub>2</sub>O mixture (1:9 v/v), which was attributed to the formation of J-aggregates.

Following their initial study, Naka's group further investigated the photophysical properties of a series of N-alkyl arylaminomaleimides 4, bearing various substituents on both the aryl and maleimide moieties (Scheme 61, R¹ ≠ R²), to investigate the influence of electronic effects on their optical behaviour.[32] Consistent with their early findings, these derivatives (192) exhibited intense fluorescence in the solid state, but no emission in solution, confirming their AIE characteristics. UV-vis absorption and photoluminescence measurements under aggregation conditions supported this behaviour. Among the series, the highest quantum yields (Φ) were observed for derivatives with alkyl substituents (R² = alkyl), with propyl-substituted compounds showing the best performance (Φ = 0.51). Furthermore, these compounds demonstrated potential as emitting dyes in the polymer matrices, making them promising candidates for luminescent film applications. Building on these findings, the same group conducted a complementary study in which they systematically evaluated the impact of N-alkyl substituents on the emission properties of AIE-active aminomaleimide dyes (Scheme 61).[118] The results observed in UV-vis absorption and circular dichroism spectra suggested that the N-alkyl moieties did not directly participate in the π-conjugated system. However, factors such as chain length, presence of hydroxyl groups, and branching structure significantly affected solid-state emission by modulating molecular packing and intermolecular interactions in the aggregated state. Additionally, the group reported that the bis-met trifluoro enaminomaleimide 193 displayed reversible, stimulus- responsive mechanochromic luminescence (Scheme 61).[119]

<figure><img src="image_140.png" /><figcaption>**Scheme 61.** Substrates evaluated in the different reported photophysical studies.</figcaption></figure>
<figure><img src="image_141.png" /></figure>

Specifically, the compound exhibited green emission upon mechanical grinding, which was quenched upon heating. This reversible crystalline-to-amorphous phase transition was confirmed by DFT calculations in conjunction with X-ray diffraction analyses. Contemporaneously, O-Reilly and collaborators,[120] investigated a series of N-alkyl enaminobromomaleimides **194** (Scheme 61), which showed notable fluorescence properties in 1,4-dioxane, with absorption maxima ranging from 230 to 363 nm and emission maxima centered around 467 nm. Among them, fluorophore **194a** (X = Br, R¹ = H, R² = Bu, or Bn) was virtually nonemissive (Φ = 0.05%) due to extended π-conjugation with the phenyl ring, which facilitates nonradiative decay pathways. Subsequently, the same group explored the photodynamics of N,N-dimethyl enaminomaleimide[121] and synthesized a diverse library of maleimide-based luorophores with tunable emissions ranging from blue to yellow, high quantum yields (up to 64%) and pronounced solvafluorochromism, highlighting their utility in advanced fluorescence applications.[122]

Building on the growing interest in the photophysical properties of aminomaleimides, and inspired by earlier work from the Zhu and Tang groups,[123] which investigated mono- and disubstituted alkyl enaminomaleimides **195**, Zhang and coworkers reported a comprehensive evaluation of various derivatives bearing alkyl substituents at the maleimide nitrogen atom, and for the first time, alkyl chains and cyclic groups at the enamine nitrogen atom.[49] In contrast to previous studies, their work revealed that alkylamine-substituted maleimides can function as donor-acceptor system exhibiting twisted intramolecular charge transfer (TICT) characteristics. Through a combination of experimental and computational approaches, the authors established a clear structure-property relationship, enabling the rational prediction and tuning of the luminescent behaviour of these compounds. Notably, they found that decreasing the electron-donating strength of the amine substituent and introducing intermolecular hydrogen bonding effectively suppress the TICT formation, resulting in enhanced fluorescence. In a complementary study, O'Reilly and collaborators reported a novel N-trityl substituted maleimide **198** (R¹ = trityl) that displays rigidochromic behavior, characterized by strong fluorescence when immobilized within a solid matrix.[124]

Finally, in 2022, the amino-biphenyl-N-cyclohexylmaleimides **199** (Scheme 61), previously synthesized by Onimura's group,

were further evaluated for their photophysical properties.[93] Notably, these compounds are the only derivatives discussed in this section that bear substituents on the carbon atom of the enamine double bond (Scheme 61). This specific structural modification had a significant impact on their optical behaviour, leading to the development of new class of AIE enhancement fluorophores. Unlike the previously reported AIE-active enaminomaleimides, which were nonemissive in solution, these derivatives exhibited fluorescence in both, solution and the solid state. The authors attributed this dual-phase emission to restricted intramolecular rotation, which suppresses nonradiative decay pathways and enhances fluorescence efficiency.

### 3.3. MRCs

Over the last decades, MRCs have attracted considerable attention in modern organic synthesis due to their numerous advantages over traditional stepwise methods, including high atom economy, simplified purification procedures, and reduced reagent consumption. Within this framework, MCRs involving maleimides have emerged as powerful strategies for broadening synthetic utility of these versatile scaffolds, enabling the efficient construction of a wide variety of functionalized heterocycles, such as disubstituted enaminomaleimides and fused heterocyclic systems.

In 2014, Zhu, Xie, and Liu reported a novel L-proline-catalyzed multicomponent approach for the synthesis of fused pyrrolo[3,4-d]tetrahydropyrimidine derivatives **201** and **202** under mild conditions (Scheme 62).[125] Two complementary strategies were developed: a three-component reaction involving enaminomaleimides **200**, amines, and an excess of formaldehyde (4.0 equiv.) in the presence of L-proline (2.0 equiv.) in methanol at room temperature, affording 28 examples in good to excellent yields (74%-91%). Additionally, a four-component approach was described using the same conditions, but substituting formaldehyde with benzaldehyde (4.0 equiv.). This modification yielded eight additional products, albeit with significantly reduced yields (18%-51%). The proposed mechanism involves the in situ generation of reactive methylene iminium ions intermediates **203** and **204** from the condensation of amines and aldehydes, a process promoted by L-proline. These electrophilic intermediates are

<figure><img src="image_142.png" /><figcaption>**Scheme 62.** L-Proline-promoted three- and four-component reactions for the synthesis of fused pyrrolo[3,4-d]tetrahydropyrimidines.</figcaption></figure>
<figure><img src="image_143.png" /></figure>

trapped by the nucleophilic centers enaminomaleimides 200, through both C- and N-addition, leading to the formation of the desired pyrrolo[3,4-d]tetrahydropyrimidine scaffolds.

More recently, Huang and Liu reported a closely related regio- and chemoselective synthesis of pyrrolo[3,4-d]tetrahydropyrimidines 205 via a Brønsted-acid-catalyzed aldehyde insertion, employing a [3 + 1 + 1 + 1] annulation strategy (Scheme 63).[126] This pseudo four-component annulation proceeds efficiently using only 10 mol% of racemic CPA, in the presence of one equivalent of a primary amine and two equivalents of formaldehyde. The reaction is carried out in ethanol under microwave irradiation at 50 °C and completes within just 10 min, delivering the desired products in good yields (74%-91%).

The use of malonic pronucleophiles was pioneered by Yan's group in 2014, who developed an efficient protocol for the synthesis of spirooxindole derivatives 210.[127] This involves a three-component reaction between enaminomaleimides 207, isatin derivatives 208, and ethyl cyanoacetate 209 as the pronucleophile, using a stoichiometric amount of triethylamine in refluxing ethanol (Scheme 64). The reaction proceeds smoothly within just one hour, affording the desired products in excellent yields ranging from 82% to 94% across the 26 reported examples. The proposed mechanism begins with a triethylamine-catalyzed Knoevenagel

condensation between isatins 208 and ethyl cyanoacetate 209, generating the reactive electrophilic intermediates 211. This is followed by a regioselective Michael addition of the enaminomaleimides 207 to the adducts 211, and a final nucleophilic ring-closing step onto the nitrile group, ultimately furnishing the corresponding spirooxindoles 210.

In a complementary study, the same group extended this three-component reaction to other cyclic diketones, including ninhydrin 214, acenaphthylene-1,2-dione 216, and phenenathrene-9,10-dione 218 (Scheme 65).[128] While the first two substrates exhibited reactivity similar to that of isatins, affording the corresponding spirocyclic derivatives 215 and 217 with comparable efficiency, the reaction with phenenathrene-9,10-dione 218 led unexpectedly to the formation of a more complex spirofused polyheterocyclic system 219 in high yields. In this case, the regioselectivity of the Michael addition to the Knoevenagel intermediate 220 appears to be altered by the presence of a six-membered ring, as opposed to a five-membered ring in isatin and ninhydrin derivatives, resulting in the formation of adduct 221. This intermediate then undergoes nucleophilic addition to the nitrile, followed by an intramolecular oxa-Michael addition, ultimately generating the final polycyclic system 222.

<figure><img src="image_144.png" /><figcaption>Scheme 63. Brønsted acid-catalyzed pseudo four-component aldehyde insertion via [3 + 1 + 1 + 1] annulation.</figcaption></figure>

<figure><img src="image_145.png" /><figcaption>Scheme 64. Three-component reaction for the synthesis of spirooxindole derivatives.</figcaption></figure>
<figure><img src="image_146.png" /></figure>

<figure><img src="image_147.png" /><figcaption>**Scheme 65.** Three-component reactions with cyclic diketones and malononitrile.</figcaption></figure>

<figure><img src="image_148.png" /><figcaption>**Scheme 66.** Three-component protocol for the synthesis of pyrrolo[3,4-b]pyridines and pyrrolo[3,4-b]quinolines.</figcaption></figure>

Finally, they also reported two additional multicomponent protocols for the synthesis of pyrrolo[3,4-b]pyridines **224** and pyrrolo[3,4-b]quinolines **226**, **228**, and **229** (**Scheme 66**).[129] The pyrrolypyridines **224** were synthesized in good to excellent yields (52%–92%) after 5 h of reaction, using the same protocol previously described for the preparation of spirooxindole derivatives **210**, but replacing the isatin derivatives **208** for the aromatic aldehydes **223** (Scheme 66, left). On the contrary, pyrroloquinolines **226** were obtained via a three-component reaction involving enaminomaleimides **207**, aromatic aldehydes **223**, and cyclic

1,3-diketones **225** as pronucleophiles, using acetic acid as both catalyst and solvent (Scheme 66, top right). In a related study, Kushnir and coworkers[130] proposed a variation of this protocol employing trifluoracetic acid under ultrasound irradiation at room temperature, using dimedone (225a, R = Me) or barbituric acid **227** as pronucleophiles. This method afforded the related fused heterocycles **228** and **229**, respectively, in good yields (Scheme 66, bottom right). A similar mechanism was proposed for this second protocol, involving the initial formation of Knoevenagel adducts **230a,b** from the condensation of
<figure><img src="image_149.png" /></figure>

1,3-dicarbonyls and aromatic aldehydes, followed by a Michael addition of the enaminomaleimide and a subsequent nucleophilic cyclization to furnish the final fused heterocycles.

Closely related to the aforementioned developments in multi-component methodologies for the synthesis of pyrrolo[3,4-b]pyridines **234**, the groups of Khan and Oriyama independently reported two catalytic variants of this transformation. These reactions involved enaminomaleimides **231**, aromatic aldehydes **232**, and cyano derivatives **233**, and were catalyzed by either 10 mol% of 4-dimethylaminopyridine (DMAP)[131] or 10 mol% of diazabicycloundecene (DBU),[132] replacing the previously used stoichiometric amount of Et₃N, thus offering more efficient and sustainable alternatives (Scheme 67).[23] Notably, the reaction catalyzed by DMAP demonstrated good recyclability. It was repeated over five consecutive cycles without a significant decrease in catalytic activity, showing only a minor drop in yield from 92% in the first cycle to 84% in the fifth.

Another noteworthy multicomponent reaction was reported in 2019 by the group of Song for the synthesis of trifluoromethylated pyrazolones **237** from methylaminomaleimides **207**, aromatic aldehydes **235**, and 1-phenyl-3-trifluoromethyl-5-pyrazolone **236**

as the pronucleophilic partner, using acetic acid as both catalyst and solvent at 90 °C (Scheme 68).[133] Mechanistic investigations, supported by experimental evidence, indicated that the transformation proceeds via an initial dehydrative condensation between the enaminomaleimide **207** and aldehyde **235**, generating the azadiene intermediate **238**. This is followed by a Michael addition of the pyrazolone derivative **239** to the diene. The acidic medium plays a dual role as catalyst and solvent facilitating both the condensation and the addition steps (Scheme 68). Interestingly, single-crystal X-ray analysis of one of the products revealed the presence of a strong intramolecular hydrogen bond between the hydroxyl group of the pyrazolone and the carbonyl of the pyrrole ring, providing additional insight into the stability and confirmation of the final structure.

A unique three-component functionalization of enaminomaleimides **240** was reported in 2018 by the groups of Han and Yan, involving triphenylphosphine and acetylenedicarboxylates **241** (Scheme 69).[134] When stoichiometric amounts of the three reagents were combined in dichloromethane, a smooth condensation occurred, affording new stable functionalized enaminomaleimide ylides **242** in excellent yields. The proposed mechanistic

<figure><img src="image_150.png" /><figcaption>**Scheme 67.** DMAP- and DBU-catalyzed multicomponent reaction for the synthesis of pyrrolo[3,4-b]pyridines.</figcaption></figure>

<figure><img src="image_151.png" /><figcaption>**Scheme 68.** One-pot multicomponent synthesis of trifluoromethylated pyrazolones.</figcaption></figure>
<figure><img src="image_152.png" /></figure>

<figure><img src="image_153.png" /><figcaption>**Scheme 69.** PPh<sub>3</sub>-promoted three-component reaction to ylides.</figcaption></figure>

pathway begins with the nucleophilic addition of PPh<sub>3</sub> to acetylenedicarboxylate **241**, generating a zwitterionic intermediate **243**. Subsequent transprotonation is followed by a Michael addition of the enaminomaleimides **240**, ultimately leading to the formation of the ylide products **242**.

### 3.4. Annulations and Cycloadditions

Annulation and cycloaddition reactions are well-established as powerful strategies for constructing complex fused carbocyclic and heterocyclic systems, enabling the rapid formation of multiple bonds, often with high levels of regio- and diastereoselectivity. Within this context, enaminomaleimides have emerged as versatile building blocks for such transformations, granting access to a wide array of complex and valuable nitrogen-containing heterocycles.

One of the earliest examples in this area was reported in 1988 by Maulding, who employed 3-anilino-N-phenylmaleimide **2a** (R = Ph) and N-butylanilinomaleimide **4** (R = n-Bu)[47] as starting materials for the synthesis of acridinimide derivatives **245**. In the case of **2a** (R = Ph), heating in the presence of dimethyl formamide acetal resulted in the formation of iminosuccinimide derivative **244a** in 77% yield. Subsequent ring-closure of **244a** in polyphosphoric acid (PPA) afforded N-phenylacridinimide **245a** in excellent yield (90%) after stirring for 20 min at 140–145 °C (**Scheme 70**). In contrast, when the same protocol was applied to N-butylanilinomaleimide **4** (R = n-Bu), the corresponding acridinimide **245b** was obtained in a one-pot process. This involved

initial reaction with dimethyl formamide acetal in refluxing toluene for 3 h, followed by brief heating in PPA, yielding the final compound **245b** in 47% (**Scheme 70**).

Following these seminal studies, Tominaga's group proposed an intramolecular Friedel-Crafts acylation from enaminomaleimides **139** and **140** as a straightforward method for the synthesis of fuzsed heterocycles (**Scheme 71**).[108–110] Under simple thermal conditions, the reaction afforded quinolines **246** and pyridazines **247** in good yields.

A few years later, in 2000, Mahboobi and collaborators reported an intriguing annulation reaction of indolyl substituted amino-enaminomaleimides **90**, leading to the formation of fused pyrrolazepinoindoles **248** via an intramolecular Pictet-Spengler-type cyclization (**Scheme 72**).[73] The proposed mechanism involves the in situ generation of a reactive iminium ion **249**, which facilitates the formation of spiroindolenine intermediate **250**. This intermediate subsequently undergoes a rearrangement through an unusual Wagner-Meerwein-type shift, a process favored by the strong electron-withdrawing character of the maléimide moiety.

Three years later, Lakatosh's group initiated a series of studies on the reactivity of related dienaminomaleimides **90** under acidic conditions, aiming at the synthesis of complex fused-polycyclic piperazine or diazepine derivatives **251** and **252** (**Scheme 73**).[74,75,77] Control experiments supported a mechanistic pathway involving the following key steps: 1) protonation of the indole nucleus to generate the iminium ion **254**; 2) a hydride shift; 3) ring closure via nucleophilic addition; and 4) aromatization. However in the case

<figure><img src="image_154.png" /><figcaption>**Scheme 70.** Synthesis of acridinimides from enaminomaleimides.</figcaption></figure>
<figure><img src="image_155.png" /></figure>

<figure><img src="image_156.png" /><figcaption>Scheme 71. Synthesis of quinoline and pyridazines derivatives.</figcaption></figure>

<figure><img src="image_157.png" /><figcaption>Scheme 72. Synthesis of fused-pyrrolazepinoindoles by intramolecular Pictet-type cylization.</figcaption></figure>

of piperazine 251 formation, the presence of the pyrrole ring inhibits the hydride shift, and the indole iminium intermediate 254 is directly intercepted by the pyrrole nucleus through intramolecular trapping. Interestingly, the resulting dihydrodiazepines 252 could be readily oxidized by DDQ to furnish the corresponding fused indole derivatives 253 in good yields.

In 2013, Lu and Wang, described one of the first regioselective Lewis acid-promoted (3 + 3) annulations of enaminomaleimides 255 with propargylic alcohols 256, leading to the formation of

fused pyrrolopyridine derivatives 257 (Scheme 74).[135] The reaction was carried out in dichloromethane at 0 °C for 1 h, using a stoichiometric amount of BF₃-Et₂O as the Lewis acid and 4 Å molecular sieves as a drying agent, affording the desired compounds 257 in good yields (51%–74%). However, when 2-methyl-4-phenylbut-3-yn-2-ol (Scheme 72, R¹ = R² = Me, R³ = Ph) was used as the propargylic alcohol, a significant drop in yield was observed, with only 37% of product obtained. From a mechanistic perspective, the observed regioselectivity arises from an initial C-alkylation
<figure><img src="image_158.png" /></figure>

<figure><img src="image_159.png" /><figcaption>Scheme 73. Complex fused-polycyclic piperazine and diazepine derivatives.</figcaption></figure>

<figure><img src="image_160.png" /><figcaption>Scheme 74. Lewis acid-promoted (3 + 3) annulation with propargylic alcohols.</figcaption></figure>

involving the allenyl iminium intermediate **258**, formed in situ via a Lewis acid-promoted Meyer–Schuster rearrangement. This cation is intercepted by the enaminomaleimide, forming the allenyl iminium intermediate **259**, which subsequently undergoes tautomerization to enamine **260**. Finally, an intramolecular *N*-alkylation closes the ring, delivering the fused heterocyclic product.

In a complementary study, Han and Yan's group reported in 2018 a related (3 + 3)-type annulation involving dialkyl acetylenedicarboxylates **262** as 1,3-dielectrophiles, promoted by the addition of tri(*n*-butylyl)phosphine (Scheme 75).[134] The reaction proceeds via the formation of a key zwitterionic intermediate **264**, which, following a proton shift, undergoes intramolecular nucleophilic substitution, ultimately furnishing fused-bicyclic 2-pyridones **263** in moderate to good yields.

More recently, the group of Chen and Huang, proposed an alternation (3 + 3)-type annulation for the efficient preparation of fused-bicyclic 4-pyridones **268** (Scheme 76).[136] The reaction between enaminomaleimides **266** and alkynyl esters **267** is promoted by and excess of DABCO under microwave irradiation, affording the desired products in moderate yields. Importantly, the method also proved effective for the synthesis of trifluomethylated derivatives **268** (R² = CF₃) with comparable efficiency. Mechanistic investigations, supported by control experiments, suggest a sequential C-acylation/N-alkylation pathway, proceeding through the formation of a key DABCO-adduct intermediate **269**.

Building on these findings, the use of α-arylaminomaleimides **270** in reactions with activated cyano olefins **271** as bis-electrophiles in a related (3 + 3) annulation was independently reported by the groups of Mashaly[137] and Oriyama[132]
<figure><img src="image_161.png" /></figure>

<figure><img src="image_162.png" /><figcaption>**Scheme 75.** PBu₃-promoted three-component (3 + 3) annulation to bicyclic 2-pyridones.</figcaption></figure>

<figure><img src="image_163.png" /><figcaption>**Scheme 76.** DABCO-promoted (3 + 3) annulation to fused-bicyclic trifluoromethylated 4-pyridones.</figcaption></figure>

<figure><img src="image_164.png" /><figcaption>**Scheme 77.** Synthesis of 1,4-dihydropyridines via (3 + 3) annulation with activated cyanoolefins.</figcaption></figure>

(Scheme 77). The reaction proceeds smoothly in the presence of either piperidine or DBU as catalysts, affording 1,4-dihydroaminopyridine derivatives 274 in excellent yields across all reported cases (54%–100%). The proposed mechanism involves an initial C-Michael addition of the enaminomaleimide 270 to the β-carbon of the dicyano olefin 271, forming an acyclic intermediate 272. This intermediate then undergoes an intramolecular nucleophilic addition of the amino nitrogen onto the nitrile group, yielding the cyclic imine intermediate

273, which subsequently tautomerizes to furnish the final dihydropyridine product 274 (Scheme 77).

Similarly, in 2016, Yan's group reported a regioselective (3 + 3) annulation protocol between α-arylaminomaleimides 275 and α-substituted cinnamaldehydes 276 as *bis*-electrophiles, affording 1,2-diarylpyrrolo[3,4-b]pyridines 277, in excellent yields across a broad scope of 24 examples (Scheme 78).[138] The authors demonstrated that the observed regioselectivity arises from the presence of the α-substituent (R), which directs the
<figure><img src="image_165.png" /><figcaption>**Scheme 78.** (3 + 3) Annulation with α-substituted cinnamaldehydes.</figcaption></figure>

<figure><img src="image_166.png" /></figure>

reaction toward an initial 1,2-addition rather than the typical 1,4-addition seen with simple β-monosubstituted aldehydes. Indeed, when α-unsubstituted cinnamaldehydes **276** (Scheme 78, R = H) were used, the reaction produced a roughly 1:1 mixture of two regioisomeric diarylpyrrolo[3,4-*b*]pyridines, **278** and **279**, resulting from the 1,2- and the 1,4-addition, respectively (Scheme 78).

More recently, Sun, Yan and coworkers developed an efficient method for the synthesis of spiropyridines derivatives **284** and **287** via a (3 + 3) cycloaddition between MBH carbonates derived from isatins **283** and **285** as *bis*-electrophiles and *N*-methylaryl-enaminomaleimides **282** (Scheme 79).[139] In the presence of diazabicyclooctane (DABCO, 0.5 equiv.) in acetonitrile at room temperature, the reaction gave spiro[indoline-3,4'-pyrrolo[3,4-*b*] pyridines] **284a,b**, albeit in low yield and with poor diastereoselectivity (Scheme 79, left). The authors further extended the methodology to MBH maleimides derived from isatin **285**, enabling the synthesis of pentacyclic heterocycles **286a,b** with comparable

efficiency (Scheme 79, right). Mechanistically, the transformation begins with a nucleophilic $S_{N2}'$ reaction of DABCO on the MBH carbonate, generating a reactive ammonium intermediate **287**. This species undergoes a regioselective C-Michael addition with enaminomaleimide **282**, displacing DABCO through a second $S_{N2}'$ process. A final intramolecular *N*-Michael addition from intermediate **288** closes the dehydropiperidine ring, completing the formation of the fused spiro system.

Following this study, Alizadeh and Rostampoor introduced functionalized coumarins as *bis*-electrophiles in a new base-promoted cascade heterocyclization to access fused dihydropyridine derivatives (Scheme 80).[140] Starting from 4-chloro-3-vinyl coumarins **290**, the transformation afforded tetracyclic dihydrochromeno[4,3-*d*]pyrrolo[3,4-*b*]pyridine derivatives **291** in moderate to good yields. Alternatively, when 2 equivalents of 4-chloro-3-formyl coumarin **292** were employed, a pseudo-three-component condensation occurred, delivering the corresponding

<figure><img src="image_167.png" /><figcaption>**Scheme 79.** (3 + 3) Cycloaddition of MBH adducts and α-arylaminomaleimides.</figcaption></figure>
<figure><img src="image_168.png" /></figure>

<figure><img src="image_169.png" /><figcaption>**Scheme 80.** Synthesis of fused tetracyclic dihydrochromeno[4,3-d]pyrrolo[3,4-b]pyridine derivatives.</figcaption></figure>

fused tetracyclic heterocycles **293** with comparable efficiency. Mechanistically, the authors proposed a selective C-alkylation initiated by an addition-elimination of HCl to generate the common intermediate **294**. This intermediate can then undergo divergent cyclization pathways: either an aza-Michael addition leading to product **291** or intramolecular dehydration forming a pyridinium ion intermediate **296**, ultimately resulting in compound **293**.

Vinylogous fluoro-oxindole derivatives **298** have emerged as highly effective 1,3-dielectrophiles in reactions with enaminomaleimides **297**, as shown by Liu and collaborators in 2024 through the synthesis of trifluoromethylated aza-bicyclic maleimide derivatives **300** with remarkable diastereoselectivity (ranging from 86% up to 90%) (**Scheme 81**).[141] The reaction was carried out under basic conditions using 20 mol% of sodium *tert*-butoxide (*t*-BuONa) in acetonitrile at room temperature over 72 h. Mechanistically, the transformation begins with a *t*-BuONa-promoted Michael addition of enaminomaleimide **297** to fluoro-oxindole **298**, followed by a nucleophilic addition of the enamine nitrogen on the oxindole carbonyl, generating intermediate **299**. This species then undergoes a ring-opening via intramolecular aminolysis, ultimately furnishing the desired aza-bicyclic products **300** (Scheme 81).

Contemporaneously, Wang and coworkers, explored the use of tetrabutylammonium difluorotriphenylsilicate (TBAT) as organic fluoride source for the diastereoselective synthesis of

pyrrolo[3,4-b]indoles **302** (**Scheme 82**).[116] The reaction between enaminomaleimide **166** and *ortho*-silylaryl triflates **301** proceeds via a fluorine-triggered *N*-arylation, involving in situ generation of arynes, which are selectively trapped to form the *N*-arylated anionic intermediate **303**. This species undergoes an intramolecular C-Michael addition, leading to the formation of *cis*-fused pyrrolindoles **302** through an overall (3 + 2)-type cyclization pathway. The reaction takes place under mild conditions in acetonitrile at room temperature, affording the desired products in good to excellent yields (75%-98%). Notably, the method displays a broad substrate scope, with 19 examples successfully synthesized.

Recently, functionalized enaminomaleimides have emerged as valuable substrates for intramolecular reactions, enabling access to novel families of fused heterocyclic maleimide derivatives. In this context, Chen and Huang reported an NBS-promoted synthesis of thiocyanated enaminomaleimides **307**, followed by a one-pot (6 + 1) annulation to construct benzothiazepine derivatives **306** (**Scheme 83**).[142] The process begins with a regioselective thiocyanation of substrate **304** using NBS (2.0 equiv.) and KSCN **305** in ethanol at room temperature, delivering the corresponding thiocyanated aminomaleimides **307** in excellent yields (80%-94%). These intermediates, can be used in situ for a site-selective intramolecular annulation. Under oxidative conditions with TEMPO at 100 °C, the desired (6 + 1) cyclization proceeds smoothly, affording

<figure><img src="image_170.png" /><figcaption>**Scheme 81.** Diastereoselective ring-closing/ring-opening cascade with fluoro-oxindole derivatives.</figcaption></figure>
<figure><img src="image_171.png" /></figure>

<figure><img src="image_172.png" /><figcaption>**Scheme 82.** TBAT-promoted synthesis of pyrrolo[3,4-b]indoles.</figcaption></figure>

<figure><img src="image_173.png" /><figcaption>**Scheme 83.** NBS-promoted synthesis of thiocyanated aminomaleimides and oxidative synthesis of benzothiazepines.</figcaption></figure>

benzothiazepine derivatives **306** in moderate to good yields (60%-80%). Mechanistically, the transformation is proposed to involve TEMPO-mediated cleavage of the S–CN bond, generating a thylal radical intermediate **308** that initiates cyclization to furnish the final compounds **306** (Scheme 83).

Concurrently, Huang's group reported an alternative strategy for the synthesis of benzo[1,4]oxazepanes **311** and dihydrobenzo[1,5] oxazocines **312**, via (6 + 1) and (7 + 1) cascade cyclizations of functionalized enaminomaleimides **309** with N-alkyl amines **310** (Scheme 84).[143] This approach is based on the oxidative cleavage of the C(sp³)–N bond in N-alkylamines **310**, via in situ formation of their N-oxide intermediates **313**, leading to the generation of a highly reactive methylene iminium ion **314**. Subsequently, a [n + 1] C–O cascade cyclization takes place, enabling the efficient construction of seven- and eight-membered heterocycles **311** and **312** heterocycles, respectively. Notably, the transformation proceeds under mild, metal-free and solvent-free conditions at room temperature, offering a sustainable and atom-economical route to these medium-sized heterocyclic scaffolds.

More recently, in 2025, Huang and Liu reported an additional method for the regio- and chemoselective synthesis of dihydrobenzo[1,5]oxazocines **316** via a Brønsted-acid catalyzed aldehyde insertion reaction, proceeding through a [6/7 + 1] cycloaddition.[126] Excellent yields (76%-91%) were achieved by reacting functionalized N-aryl enaminomaleimides **205** with aryl and alkyl aldehydes **315** (Scheme 85, R³ = Alk, Ar) in the presence of a catalytic amount of racemic BINOL-derived phosphoric acid [±-CPA] (10 mol%). The reaction was conducted under microwave irradiation at 50 °C in DMSO for just 5 min.

The same group subsequently reported a base-catalyzed chalcogenative annulation of hydroxy-functionalized N-aryl and N-alkyl enaminomaleimides **317** with elemental sulfur and selenium, providing access to 1,4-sulfa- and selena-fused heterocycles **319**, **320**, and **321**, respectively via [5/6 + 1] annulation pathways (Scheme 86).[144] The reactions proceed through an initial dehydration of the corresponding enaminomaleimide **317** generating the key 1-azadiene intermediate **318** in situ. This intermediate then undergoes regioselective annulation in the
<figure><img src="image_174.png" /></figure>

<figure><img src="image_175.png" /><figcaption>Scheme 84. (6 + 1) and (7 + 1) cascade cyclizations for the synthesis of oxazepanes and oxazocines.</figcaption></figure>

<figure><img src="image_176.png" /><figcaption>Scheme 85. Brønsted acid-catalyzed aldehyde insertions via a (6/7 + 1) annulation.</figcaption></figure>

<figure><img src="image_177.png" /><figcaption>Scheme 86. Base-catalyzed chalcogenative annulation of enaminomaleimides with elemental sulfur and selenium.</figcaption></figure>

presence of two equivalents of the corresponding base ($K_2CO_3$ for sulfur or t-BuOK for selenium) in DMF at room temperature under an air atmosphere (Scheme 86). The reaction conditions are chalcogen-dependant, requiring 2 h for sulfur annulations and 4 h for selenium incorporation, ultimately affording the desired fused six- or seven-membered ring heterocycles.

Furthermore, Luo and coworkers developed an intermolecular cascade annulation for the synthesis of dihydrobenzo[b][1,8] naphthyridine-ylidene-pyrrolidinetriones **324** under transition metal-free conditions (Scheme 87).[145] The reaction employs enaminomaleimides **322** and *ortho*-halogenated quinolonechalcones **323** in the presence of excess of $Cs_2CO_3$ (1.5 equiv.) in

DMF at 80 °C for 12 h under an air atmosphere. Mechanistic studies revealed that the reaction is unproductive under anhydrous conditions, highlighting the crucial role of water. The process begins with a Michael addition to iminium **325**, followed by addition of residual water to the resulting tautomeric imine intermediate **326**. This triggers a ring-closing/ring-opening sequence leading to the corresponding enamine **328**. Subsequently, an intramolecular $S_NAr$ displacement and aerobic oxidation afford the final product **324**.

Finally, building on independent earlier observations by the groups of Augustin[146] and Chepyshev[147] regarding the dimerization of enaminomaleimides, Wang, Wang and collaborators have
<figure><img src="image_178.png" /></figure>

<figure><img src="image_179.png" /><figcaption>**Scheme 87.** Cs₂CO₃-mediated cascade annulation of enaminomaleimides and *ortho*-halogenated quinolonechalcones.</figcaption></figure>

<figure><img src="image_180.png" /><figcaption>**Scheme 88.** Preparation of benzene triimides by trimerization of enaminomaleimides.</figcaption></figure>

extended this chemistry to the trimerization of a series of enaminomaleimides **329** (**Scheme 88**).[148] This one-pot cyclocondensation proceeds in refluxing aqueous acetic acid, with the concomitant release of three molecules of amine (HNR₂R₃) to afford the corresponding benzene triimide derivatives **330** (BTIs). The planar structure and unique electron-deficient character of the BTIs enable their self-assembly into various nanostructured motifs, including nanorods, nanotubes, nanobricks, and cross-linked, networks depending on the nature of R¹ substituents.

### 3.5. Enantioselective Transformations

Despite the well-established use of maleimides in enantioselective processes, the application of enaminomaleimides as nucleophilic partners in such transformations remains comparatively underexplored. As highlighted in our recent focused review on this subject,[19] only a few pioneering studies in recent years have begun to address this gap. In these examples,

enaminomaleimides have been successfully utilized in various enantioselective reactions, including Michael and Mannich additions, as well as atroposelective annulations, enabling the construction of complex chiral architectures.

In 2021, Oriyama, Mori and coworkers reported the first enantioselective organocatalyzed Michael addition of enaminomaleimides **331** to *trans*-nitrostyrenes **332** (**Scheme 89**, left).[20] The corresponding chiral maleimides **333** were obtained in excellent yields (up to 94%) and enantioselectivities (88%-92% ee) under mild conditions (48 h at 10 °C) using only 1 mol% of a quinidine-derived urea catalyst (**Cat. Ia**). Furthermore, DFT calculations were conducted to elucidate the reaction mechanism. In the key transition state (**Cat. Ia**—**TS**), the nitroolefin is activated via hydrogen bonding by the urea moiety of the organocatalyst, while the donor is oriented by the tertiary amine function, rationalizing the selective formation of the major (*R*)-enantiomer. The following year, Wang and Jin reported the use of Takemoto's catalyst (**Cat. II**) as an alternative, achieving comparable efficiency (yields
<figure><img src="image_181.png" /></figure>

Oriyama and Mori (2021)

<figure><img src="image_182.png" /></figure>

<figure><img src="image_183.png" /></figure>

Oriyama (2024)

<figure><img src="image_184.png" /></figure>

Wang and Jin (2022)

<figure><img src="image_185.png" /><figcaption>**Scheme 89.** Enantioselective Mannich and Michael reactions with enaminomaleimides.</figcaption></figure>

up to 86% and *ee* between 81% and 94%) and substantially expanding the substrate scope.[149] Building on these pioneering results, in 2024 Oriyama's group adapted this organocatalytic activation using catalyst **lb** to develop an enantioselective variant of their previously reported Mannich reaction with *N*-Boc arylimines,[150] affording the corresponding arylamine derivatives **335** in excellent yields (up to 99%) and enantioselectivities (up to 98%) in nearly all of the cases (Scheme 89, right).[151]

One year later, Wang and collaborators introduced a novel cinchona thiourea-pyridoxazoline scaffold **Cat. III** serving both as an organocatalyst and a chiral ligand for a related Cu-catalyzed Mannich reaction between *α*-aminomaleimides **337** and benzothiazolamines **336** (Scheme 90).[152] The purely organocatalytic activity of **Cat. III** was demonstrated by obtaining product **338a** in good yield and moderate enantioselectivity (up to 75% *ee*) using a 20 mol% catalyst loading, outperforming previously reported organocatalytic systems. Notably, the pyridoxazoline moiety also acted as a chiral ligand, synergistically facilitating the Cu(OTf)₂-catalyzed condensation to afford a broad range of adducts **338** in good yields and excellent enantioselectivities (up to 96% *ee*), including on a preparative scale. The proposed transition state **Cat. III–TS** responsible for stereocontrol involves cooperative activation of the benzothiazolimine **336** by the in situ-formed chiral pyridoxazoline–Cu complex, alongside hydrogen bonding between the thiourea NH groups and enaminomaleimide **337**, with potential *π*-stacking interactions further stabilizing the assembly.

Complementing these direct functionalizations, two independent reports on the use of *α*-aminomaleimides **340** for (3 + 3) atroposelective annulations appeared within just a few months. In May 2022, Hui's group published an efficient annulation of *N*-aryl *α*-aminomaleimides **340** with enal derivatives **339** under *N*-heterocyclic carbene (NHC) catalysis (**Cat. IV**), affording pyrrolo[3,4-*b*]pyridines **341** (Scheme 91, Conditions A).[153] Similarly, in October of the same year, Qi and Duan reported a comparable reaction using **Cat. V** along with additives (4 Å molecular sieves and thiourea) to facilitate the activation of the enaminomaleimide **340** and its deprotonation by DBU (Scheme 91, Conditions B).[154] In both cases, excellent yields and enantioselectivities were obtained when *tert*-butyl group was installed at the *ortho* position of the enamino moiety (R³ = *t*-Bu); however, when other *ortho* substituents such as isopropyl, methoxy, bromine, or iodine (R³ = *iPr*, *OMe*, *Br*, *I*) were employed, enantioselectivities dropped significantly (9%–34% *ee*). Additional experiments and DFT calculations revealed that the barrier to rotation of these compounds **341** is around 209 kJ mol⁻¹, which is higher than most C–N atropisomers.

Following a similar (3 + 3) annulation strategy, Biju's group also reported in 2022 a kinetic resolution (KR) approach utilizing racemic axially chiral enaminomaleimides **343** and in situ-generated *α*,*β*-unsaturated acylazolium intermediates derived from 2-bromoenals **342** under NHC catalysis (**Cat. IV**) (Scheme 92).[155] This method enables access to C–N axially chiral fused dihydropyridinones **344** in yields up to 62%, with diastereomeric ratios
<figure><img src="image_186.png" /></figure>

<figure><img src="image_187.png" /><figcaption>**Scheme 90.** Enantioselective Mannich reaction with cinchona thiourea-pyridoxazolines.</figcaption></figure>

<figure><img src="image_188.png" /></figure>

**Hui (2022):** Conditions A
**Cat. IV** (15 mol%)
DBU (1.5 equiv.)
DQ (2 equiv.), THF, 25 °C, 24 h
41 examples, up to 99% yield, 96-99% ee

**Qi and Duan (2022):** Conditions B
**Cat. V** (20 mol%)
DBU (1.0 equiv.), DQ (1.5 equiv.)
thiourea (20 mol%), 4Å MS, DME, rt, 12 h
33 examples, up to 89% yield, 85-98% ee

<caption>**Scheme 91.** NHC-catalyzed atroposelective (3 + 3) annulations.</caption>

ranging from 3:1 to 6:1 and excellent enantioselectivities (82%-98% ee). Meanwhile, the unreacted enantioenriched maleimides **345** were recovered in yield up to 51%, maintaining comparable enantiomeric excesses. The observed remote axial chirality control

was primarily dictated by steric interactions between the bulky *ortho* tert-butyl substituent on the aryl ring and the aminodindol framework of the NHC catalyst. According to the proposed transition state models, this steric hindrance favors *re*-face addition while
<figure><img src="image_189.png" /><figcaption>**Scheme 92.** NHC-catalyzed KR of racemic *N*-aryl enaminomaleimides.</figcaption></figure>

disfavoring *si*-face addition, resulting in high enantioselectivities but only moderate diastereoselectivities.

Building upon the previously reported protocol by Yan's group for the synthesis of spirooxindole derivatives **210** (see Scheme 64),[127] an enantioselective version of this transformation was developed in 2024 by Wang and Jin.[156] This method utilizes enaminomaleimides **207**, isatin derivatives **208**, and cyanoacetate **209** as starting materials. The reaction proceeds through a Knoevenagel/Michael/cyclization cascade catalyzed by a chiral squaramide catalyst **Cat. VI**, affording the desired spirooxindoles

in high yields (78%-91%) and excellent enantiomeric excesses (up to 99%) across 23 examples (**Scheme 93**). The proposed transition state model involves dual hydrogen-bonding interactions: the squaramide moiety activates the electrophilic isatylidene cyanoacetate, while the tertiary amine unit engages with the amino-maleimide **207**. A *si*-face-selective Michael addition, ultimately affording the highly enantioenriched spirooxindoles **210**. Subsequently, in 2025, Liming and Ying reported a related enantioselective approach using thiourea-based catalyst **Cat.VII**. Although this method delivered slightly lower yields (75%-86%)

<figure><img src="image_190.png" /><figcaption>**Scheme 93.** Enantioselective synthesis of spirooxindole derivatives using squaramide and thiourea catalysts.</figcaption></figure>
<figure><img src="image_191.png" /></figure>

and more variable enantioselectivities (16%-92% ee) across 18 examples, a similar transition state model was proposed, featuring analogous hydrogen-bonding interactions to those observed with the squaramide system.[157]

## 4. Summary and Outlook

Over the past decades, enaminomaleimides have emerged as versatile and valuable building blocks in organic synthesis, enabling access to a broad array of functionalized heterocyclic scaffolds. The development of innovative synthetic methodologies, including C–H activation, MRCs, annulations, or cycloadditions, has greatly expanded their synthetic utility. By leveraging the nucleophilic character of the enamine moiety, these strategies allow the construction of increasingly complex enaminomaleimide-based architectures, with promising potential applications in fields such as medicinal chemistry or materials science.

Despite of the significant advances in their synthesis and functionalization, we believe that the full potential of enaminomaleimides remains largely untapped, particularly with respect to stereochemical control through enantioselective catalysis. While recent progress has showcased its versatility, further exploration is essential to unlock new dimensions of reactivity and selectivity.

In particular, the exploration of axial chirality enaminomaleimide scaffolds, along with the development of enantioselective strategies for their construction, represents a promising frontier in this interesting and underexplored area. These efforts are expected to offer exciting opportunities and challenges for the synthesis of architecturally and stereochemically complex molecules.

## Acknowledgements

The authors gratefully acknowledge financial support from Aix-Marseille Université, the Centre National de la Recherche Scientifique (CNRS), and Centrale Méditerranée; A.L.-F. acknowledges ANR for the financial support for DINATROP project (ANR-23-CE07-0044), which funded his postdoctoral stage; B.D. acknowledges Erasmus + program for International Mobility (MIC program 2022-1-FR01-KA171-HED-000072859).

## Conflict of Interest

The authors declare no conflict of interest.

**Keywords:** axial chirality · enaminomaleimide · enantioselective synthesis · heterocycles · organic synthesis

[1] J. A. Berson, R. Swidler, *J. Am. Chem. Soc.* **1954**, *76*, 2835.

[2] B. E. Kirkpatrick, K. S. Anseth, T. S. Hebner, *Polym. Int.* **2024**, *74*, 296.

[3] J. M. J. M. Ravasco, H. Faustino, A. Trindade, P. M. P. Gois, *Chem. Eur. J.* **2019**, *25*, 43.

[4] P. Chauhan, J. Kaur, S. S. Chimni, *Chem. Asian J.* **2013**, *8*, 328.

[5] G. Szőllősi, V. Kozma, *ChemCatChem* **2018**, *10*, 4362.

[6] B. Jana, M. Mondal, S. Halder, A. Mahata, S. Saurav, S. Paladhi, *Asian J. Org. Chem.* **2023**, *12*, e202300387.

[7] E. Arceo, P. Melchiorre, *Angew. Chem. Int. Ed.* **2012**, *51*, 5290.

[8] E. Skolia, C. G. Kokotos, *ACS Org. Inorg. Au* **2023**, *3*, 96.

[9] R. Manoharan, M. Jeganmohan, *Asian J. Org. Chem.* **2019**, *8*, 1949.

[10] S.-L. Liu, Y. Shi, C. Xue, L. Zhang, M.-P. Song, *Eur. J. Org. Chem.* **2021**, *2021*, 5862.

[11] S.-L. Liu, C. Ye, X. Wang, *Org. Biomol. Chem.* **2022**, *20*, 4837.

[12] V. Kumari, S. S. Acharya, N. Mondal, L. H. Choudhury, *J. Org. Chem.* **2024**, *89*, 18003.

[13] M. Gassel, C. B. Breitenlechner, N. König, R. Huber, R. A. Engh, D. Bossemeyer, *J. Biol. Chem.* **2004**, *279*, 23679.

[14] R. A. M. Serafim, F. J. Sorrell, B.-T. Berger, R. J. Collins, S. N. S. Vasconcelos, K. B. Massirer, S. Knapp, J. Bennett, O. Fedorov, H. Patel, W. J. Zuercher, J. M. Elkins, *J. Med. Chem.* **2021**, *64*, 13259.

[15] Z. Ma, S. Qiua, H.-C. Chen, D. Zhang, Y.-L. Lu, X.-L. Chen, *J. Asian Nat. Prod. Res.* **2021**, *24*, 1.

[16] Y. Fan, Y. Lu, X. Chen, B. Tekwani, X.-C. Li, Y. Shen, *Molecules* **2018**, *23*, 2878.

[17] E. Dolci, V. Froidevaux, C. Joly-Duhamel, R. Auvergne, B. Boutevin, S. Caillol, *Polym. Rev.* **2016**, *56*, 512.

[18] J. Chervin, M. Stierhof, M. H. Tong, D. Peace, K.Ø. Hansen, D. S. Urgast, J. H. Andersen, Y. Yu, R. Ebel, K. Kyeremeh, V. Paget, G. Cimpan, A. Van Wyk, H. Deng, M. Jaspars, J. N. Tabudravu, *J. Nat. Prod.* **2017**, *80*, 1370.

[19] M. Amatore, D. Bonne, T. Constantieux, J. Rodriguez, *Chin. J. Chem.* **2024**, *42*, 3605.

[20] N. Sakai, K. Kawashima, M. Kajitani, S. Mori, T. Oriyama, *Org. Lett.* **2021**, *23*, 5714.

[21] A. A. Panov, A. Y. Simonov, S. N. Lavrenov, S. A. Lakatosh, A. S. Trenin, *Chem. Heterocycl. Compd.* **2018**, *54*, 103.

[22] J. E. Barker, J. D. Tibbets, C. T. J. Ferguson, Y. Xie, R. K. O'Reilly, *Angew. Chem. Int. Ed.* **2024**, *63*, e202410550.

[23] Y. S. A. G. Saigal, A. Uddin, S. Khan, M. Abid, M. Khan, *ChemistrySelect* **2021**, *6*, 2323.

[24] P. Paramonova, T. Sharonova, S. Kalinin, E. Chupakhin, A. Bunev, M. Krasavin, *Mendeleev Commun.* **2022**, *32*, 176.

[25] Q. Gao, L. Luo, C. Chen, K. Wen, Z. Zhu, X. Tang, *J. Org. Chem.* **2023**, *88*, 13303.

[26] A. R. Surrey, R. A. Cutler, *J. Am. Chem. Soc.* **1946**, *68*, 514.

[27] N. D. Heindel, *J. Org. Chem.* **1970**, *35*, 3138.

[28] A. Alizadeh, F. Mavahedi, A. A. Esmaili, *Tetrahedron Lett.* **2006**, *47*, 4469.

[29] S. V. Chepyshev, Y. N. Mazurkevich, O. S. Lebed, A. V. Prosyanik, *Chem. Heterocycl. Compd.* **2007**, *43*, 844.

[30] S. V. Chepyshev, Y. N. Chepysheva, A. B. Ryabitskii, A. V. Prosyanik, *Chem. Heterocycl. Compd.* **2008**, *44*, 523.

[31] M. Boominathan, V. Sathish, M. Nagaraj, N. Bhuvanesh, S. Muthusubramanian, S. Rajagopal, *RSC adv.* **2013**, *3*, 22246.

[32] K. Kizaki, H. Imoto, T. Kato, K. Naka, *Tetrahedron* **2015**, *71*, 643.

[33] S. Huang, T. Liu, J. Li, Q. Yang, S. Zhan, C. Huang, *Synthesis* **2023**, *55*, 1441.

[34] S. Huang, Q. Yang, J. Wan, Z. Wang, Z. Zhang, T. Liu, C. Huang, *Adv. Synth. Catal.* **2023**, *365*, 2588.

[35] B. He, J. Zhang, H. Zhang, Z. Liu, H. Zou, R. Hu, A. Qin, R. T. K. Kwok, J. W. Y. Lam, B. Z. Tang, *Macromolecules* **2020**, *53*, 3756.

[36] N. A. Aksenov, D. A. Aksenov, D. D. Ganusenko, I. A. Kurenkov, A. V. Leontiev, A. V. Aksenov, *Org. Biomol. Chem.* **2023**, *21*, 3156.

[37] H. Adams, M. Baker, H. Hodson, M. J. Morris, *Tetrahedron Lett.* **2017**, *58*, 1695.

[38] J. Guild, M. J. Morris, C. C. Robertson, A. W. H. Speed, *Tetrahedron Lett.* **2019**, *60*, 151079.

[39] Z. Yang, Y. Guo, S.-L. Ai, S.-X. Wang, J.-Z. Zhang, Y.-X. Zhang, Q.-C. Zou, H.-X. Wang, *Mater. Chem. Front.* **2019**, *3*, 571.

[40] W. I. Awad, S. M. A. R. Omran, F. Nagieb, *Tetrahedron* **1963**, *19*, 1591.

[41] W. L. Mosby, M. L. Silva, *J. Chem. Soc.* **1965**, 1965, 1003.

[42] Y. Mao, I. Maley, W. H. Watson, *J. Chem. Crystallogr.* **2005**, *35*, 385.

[43] D. de Loera, M. A. Garcia-Garibay, *Org. Lett.* **2012**, *14*, 3874.

[44] S. S. Washburne, W. R. Peterson, D. A. Berman, *J. Org. Chem.* **1972**, *37*, 1738.

[45] E. Hedaya, S. Theodoropulos, *Tetrahedron* **1968**, *24*, 2241.

[46] T. Sharonova, P. Paramonova, S. Kalinin, A. Bunev, R.E. Gasanov, A. Nocentini, V. Sharoyko, T. B. Tennikova, D. Dar'in, C. T. Supuran, M. Krasavin, *Eur. J. Med. Chem.* **2021**, *218*, 113352.

[47] D. R. Maulding, *J. Heterocycl. Chem.* **1988**, *15*, 1777.

[48] X. Zhang, G. Dhawan, A. Muthengi, S. Liu, W. Wang, M. Legris, W. Zhang, *Green Chem.* **2017**, *19*, 3851.
<figure><img src="image_192.png" /></figure>

[49] Y. Guo, L. Yao, L. Luo, H.-X. Wang, Z. Yang, Z. Wang, S.-L. Ai, Y. Zhang, Q.-C. Zoua, H.-L. Zhang, *Org. Chem. Front.* **2021**, *8*, 239.

[50] Y.-L. An, H.-H. Zhang, Z.-H. Yang, L. Lin, S.-Y. Zhao, *Eur. J. Org. Chem.* **2016**, *2016*, 5405.

[51] W. Zhang, Y. Yao, Y. Xu, X. Zhou, G. Wu, *Org. Chem. Front.* **2021**, *8*, 5766.

[52] D.-H. Kong, Y.-L. an, Z.-Y. Shao, S.-Y. Zhao, *J. Chem. Res.* **2018**, *42*, 476.

[53] X. Zhou, Y. Yao, C. Wang, Y. Xu, W. Zhang, Y. Ma, G. Wu, *Org. Lett.* **2021**, *23*, 3669.

[54] J. Wang, Y. Xu, L. Chen, Y. Ma, G. Wu, *Appl. Organomet. Chem.* **2023**, *37*, e7046.

[55] Z.-H. Yang, H.-R. Tan, Y.-L. An, Y.-W. Zhao, H.-P. Lin, S.-Y. Zhao, *Adv. Synth. Catal.* **2018**, *360*, 173.

[56] Z.-H. Yang, J.-N. Zhu, Z.-H. Jin, J. Zheng, S.-Y. Zhao, *Synthesis* **2018**, *50*, 4627.

[57] S. Shi, Y. Ma, J. Zhou, J. Li, L. Chen, G. Wu, *Org. Lett.* **2020**, *22*, 1863.

[58] S. Pal, R. Chatterjee, S. Santra, G. V. Zyryanov, A. Majee, *Adv. Synth. Catal.* **2021**, *363*, 5300.

[59] Y. Xu, J. Gao, C. Wang, Y. Ma, J. Zhou, G. Wu, *Org. Chem. Front.* **2021**, *8*, 3457.

[60] Y. Xu, X. Zhou, L. Chen, Y. Ma, G. Wu, *Org. Chem. Front.* **2022**, *9*, 2471.

[61] K. Cen, Z. Zeng, W. Shen, Y. Feng, P. Yan, J. Wei, Q. Hou, J. Fu, X. Xia, J. Cai, *Adv. Synth. Catal.* **2023**, *365*, 2530.

[62] X. Gao, L. Tang, L. Huang, Z.-S. Huang, Y. Ma, G. Wu, *Org. Lett.* **2019**, *21*, 745.

[63] X. Zhou, S. Shi, L. Chen, G. Wu, Y. Ma, *Adv Synth. Catal.* **2022**, *364*, 3522.

[64] J. Wang, L. Zhao, Y. Zhang, P. Zheng, P. Zou, G. Wu, *Org. Biomol. Chem.* **2023**, *21*, 5643.

[65] S. Kandhasamy, K. Karthikeyan, K. Ramachandiran, D. Muralidharan, P. T. Perumal, *J. Chem. Sci.* **2013**, *125*, 967.

[66] S. Dana, A. Mandal, H. Sahoo, M. Baidya, *Org. Lett.* **2017**, *19*, 1902.

[67] T. Nanda, S. K. Dhal, G. K. D. Adhikari, N. Prusty, P. C. Ravikumar, *Chem. Commun.* **2023**, *59*, 8818.

[68] X. Zhang, K. Pham, S. Liu, M. Legris, A. Muthengi, J. P. Jasinski, W. Zhang, *Beilstein J. Org. Chem.* **2016**, *12*, 2204.

[69] D. Heindel, V. B. Fish, T. F. Lemke, *J. Org. Chem.* **1968**, *33*, 3997.

[70] Y. Yang, L. Peng, L. Wang, *J. of Henan Univ. of Sci. Technol.* **2017**, *38*, 91.

[71] A. Tourteau, E. Merlet, A. Bontemps, M. Leland, P. Helissey, S. Giorgi-Renault, S. Desbène-Finck, *Eur. J. Org. Chem.* **2015**, *2015*, 7028.

[72] J. T. Bowler, C. R. Clausen, D. J. Blackburn, W. Wu, *Tetrahedron Lett.* **2014**, *55*, 6465.

[73] S. Mahboobi, S. Eluwa, M. Koller, A. Popp, D. Schollmeyer, *J. Heterocycl. Chem.* **2000**, *37*, 1177.

[74] A. Lakatosh, E. E. Bykov, M. N. Preobrazhenskaya, *Org. Biomol. Chem.* **2003**, *1*, 826.

[75] A. Lakatosh, Y. N. Luzikov, M. N. Preobrazhenskaya, *Tetrahedron Lett.* **2005**, *61*, 2017.

[76] S. Y. Zhao, S. W. Mou, Z. L. Chen, Y. Yue, Y. Sun, *J. Chem. Res.* **2009**, *33*, 198.

[77] S. A. Lakatosh, E. E. Bykov, M. N. Preobrazhenskaya, *Chem. Heterocycl. Compd.* **2011**, *10*, 1224.

[78] E. Awuah, A. Capretta, *J. Org. Chem.* **2011**, *76*, 3122.

[79] M. Tan, Z. Hu, Y. Dai, Y. Peng, Y. Zhou, Y. Shi, Y. Li, Y. Chen, *ACS Macro Lett.* **2021**, *10*, 1423.

[80] M. Augustin, M. Köhler, *J. Prakt. Chem.* **1974**, *316*, 113.

[81] M. Augustin, J. Faust, M. Köhler, *J. Prakt. Chem.* **1983**, *325*, 293.

[82] M. Augustin, P. Jeschke, *J. Prakt. Chem.* **1987**, *329*, 599.

[83] M. Augustin, P. Jeschke, *J. Prakt. Chem.* **1987**, *329*, 985.

[84] D. G. Smith, M. Buffet, A. E. Fenwick, D. Haigh, R. J. Ife, M. Saunders, B. P. Slingsby, R. Stacey, R. W. Ward, *Bioorg. Med. Chem. Lett.* **2001**, *11*, 635.

[85] J. H. K. Budke, M. Pawlowski, A. S. Zelivianskaia, M. Wu, A. P. Kozikowski, P. P. Connell, *J. Med. Chem.* **2013**, *56*, 254.

[86] G. Ciamician, P. Silber, *Chem. Ber.* **1889**, *22*, 2490.

[87] H. leismann, G. Marzolph, H.-D. Scharf, M. Behruzi, *Chem. Ber.* **1983**, *116*, 2591.

[88] H. Ley, W. Fischer, *Chem. Ber.* **1913**, *46*, 327.

[89] R. Oda, Y. Hayashi, T. Takai, *Tetrahedron* **1968**, *24*, 4051.

[90] For addition of pyridine, see: M. J. Karten, S. L. Shapiro, E. S. Isaaics, L. Freedman, *J. Org. Chem.* **1965**, *30*, 2657.

[91] S. S. Tarnavskiy, G. G. Dubinina, S. M. Golovach, S. M. Yarmoluk, *Biopolym. Cell.* **2003**, *19*, 287.

[92] H. Imoto, K. Kizaki, S. Watase, K. Matsukawa, K. Naka, *Chem. Eur. J.* **2015**, *21*, 12105.

[93] X. Yang, K. Yamabukia, K. Onimura, *New J. Chem.* **2022**, *46*, 1232.

[94] R. H. Wiley, S. C. Slaymaker, *J. Am. Chem. Soc.* **1958**, *80*, 1385.

[95] T. Kurihara, H. Shin, Y. Sakamoto, *Chem. Pharm. Bull.* **1979**, *27*, 1792.

[96] C. S. Rooney, W. C. Randall, K. B. Streeter, C. Ziegler, H. S. E. J. Cragoe Jr., S. R. Michelson, H. W. R. Williams, E. Eichler, D. E. Duggan, E. H. Ulm, R. M. Noll, *J. Med. Chem.* **1983**, *26*, 700.

[97] D. A. Neel, M. R. Jirousek, J. H. McDonald III, *Bioorg. Med. Chem. Lett.* **1998**, *8*, 47.

[98] M. Tanaka, S. Sagawa, J.-I. Hoshi, F. Shimoma, I. Matsuda, K. Sakoda, T. Sasase, M. Shindo, T. Inaba, *Bioorg. Med. Chem. Lett.* **2004**, *14*, 5171.

[99] C. M., et al. Jaye, *J. Med. Chem.* **2005**, *48*, 5419.

[100] M. Tanaka, S. Sagawa, J.-I. Hoshi, F. Shimoma, K. Yasue, M. Ubukata, T. Ikemoto, Y. hace, M. Takahashi, T. Sasase, N. Ueda, M. Matsushita, T. Inaba, *Bioorg. Med. Chem.* **2006**, *14*, 5781.

[101] M. J. Thompson, J. C. Louth, S. Ferrara, F. J. Sorrell, B. J. Irving, E. J. Cochrane, A. J. M. Meijer, B. Chen, *MedChemMed* **2011**, *6*, 115.

[102] M. E. McDonnell, H. Bian, J. Wrobel, G. R. Smith, S. Liang, H. Ma, A. B. Reitz, *Bioorg. Med. Chem. Lett.* **2014**, *24*, 1116.

[103] M. M. Faul, L. L. Winneroski, C. A. Krumrich, *J. Org. Chem.* **1998**, *63*, 6053.

[104] S. A. Lakatosh, Y. N. Luzikov, M. N. Preobrazhenskaya, *Tetrahedron* **2005**, *61*, 8241.

[105] K. Ostrowska, A. Kaźmierska, M. Rąpała-Kozik, J. Kalinowska-Tłuścić, *New. J. Chem.* **2014**, *38*, 213.

[106] M. A. Tantray, I. Khan, H. Hamid, M. S. Alam, A. Dhulap, A. Kalam, *New. J. Chem.* **2016**, *40*, 6109.

[107] P. Li, B. Wang, G. Li, L. Fu, D. Zhang, Z. Lin, H. Haung, Y. Lu, *Eur. J. Med. Chem.* **2020**, *26*, 112538.

[108] Y. Tominaga, N. Yoshioka, S. Kataoka, *Heterocycles* **1996**, *43*, 1597.

[109] Y. Tominaga, N. Yoshioka, H. Minematsu, S. Kataoka, *Heterocycles* **1997**, *44*, 85.

[110] Y. Tominaga, N. Yoshioka, H. Minematsu, S. Kataoka, *Heterocycles* **1999**, *50*, 43.

[111] M. Augustin, M. Köhler, S. Kazandji, *Tetrahedron* **1984**, *40*, 3499.

[112] N. S. Patil, G. B. Desmukh, S. V. Patil, A. D. Bholay, N. D. Gaikwad, *Eur. J. Med. Chem.* **2014**, *83*, 490.

[113] M. Saroha, G. Bartwal, J. M. Khurana, *Tetrahedron* **2019**, *75*, 130486.

[114] E. Taheri, F. Jafarpour, *Org. Biomol. Chem.* **2024**, *22*, 169.

[115] B. Wang, D.-W. Huang, Y. Xiao, J. Liao, H.-J. Lu, Y.-J. Hu, Q.-H. Zhang, Y.-L. Li, Y.-S. Yang, J.-Y. Wang, *Chin. J. Chem.* **2025**, *43*, 2505.

[116] Z. Wang, S. Huang, L. Yin, J. Wan, C. Liu, T. Liu, C. Huang, *J. Org. Chem.* **2024**, *89*, 5498.

[117] T. Kato, K. Naka, *Chem. Lett.* **2012**, *41*, 1445.

[118] H. Imoto, K. Nohmi, K. Kizaki, S. Watase, K. Matsukawa, S. Yamamoto, M. Mitsuishi, K. Naka, *RSC Adv.* **2015**, *5*, 9434.

[119] H. Imoto, K. Kizaki, K. Naka, *Chem. Asian J.* **2015**, *10*, 1698.

[120] A. B. Mabire, M. P. Robin, W.-D. Quan, H. Willcock, V. G. Stavros, R. K. O'Reilly, *Chem. Commun.* **2015**, *51*, 9733.

[121] M. Staniforth, W.-D. Quan, T. N. V. Karsili, L. A. Baker, R. K. O'Reilly, V. G. Stavros, *J. Phys. Chem. A* **2017**, *121*, 6357.

[122] Y. Xie, J. T. Husband, M. Torrent-Sucarrat, H. Yang, W. Liu, R. K. O'Reilly, *Chem. Commun.* **2018**, *54*, 3339.

[123] Q. Zhu, Z. Ye, W. Yang, X. Cai, B. Z. Tang, *J. Org. Chem.* **2017**, *82*, 1096.

[124] J. T. Husband, Y. Xie, T. R. Wilks, L. Male, M. Torrent-Sucarrat, V. G. Stavros, R. K. O'Reilly, *Chem. Sci.* **2021**, *12*, 10550.

[125] Z.-P. Chen, H.-B. Wang, Y.-Q. Wang, Q.-H. Zhu, Y. Xie, S.-W. Liu, *Tetrahedron* **2014**, *70*, 4379.

[126] Y.-M. Wen, T. Liu, G.-Y. Zeng, J.-J. Li, Z.-H. Yao, C.-X. He, C. Huang, *Eur. J. Org. Chem.* **2025**, *28*, e202401287.

[127] C. Wang, Y.-H. Jiang, C.-G. Yan, *Mol. Divers.* **2014**, *18*, 809.

[128] M. Xiao, C. Yan, *Chin. J. Chem.* **2017**, *33*, 1422.

[129] Y.-H. Jiang, M. Xiao, C.-G. Yan, *RSC Adv.* **2016**, *6*, 35609.

[130] R. I. Eften'eva, O. V. Kushnir, O. S. Lyavinets, I. I. Mangalagiu, M. V. Vovk, *Monatsh. Chem.* **2017**, *148*, 1745.

[131] M. Khan, S. Shareef, S. Khan, S. C. S. Saigal, *Synth. Commun.* **2019**, *49*, 2884.

[132] W. Han, K. Nakajima, M. Kajitani, T. Oriyama, *Heterocycles* **2021**, *102*, 481.

[133] F. Yuana, W. Duana, Z. Lia, X. Luo, M. Zhang, H. Dengb, L. Song, *Synthesis* **2019**, *51*, 3345.

[134] C.-Z. Liu, Y. Han, Y.-Y. Zhang, J. Sun, C.-G. Yan, *Synthesis* **2018**, *50*, 3715.

[135] G. Yin, Y. Zhu, N. Wang, P. Lu, Y. Wang, *Tetrahedron* **2013**, *69*, 8353.

[136] Q. Yang, S. Huang, L. Yin, Z. Wang, X. Chen, C. Huang, *Org. Biomol. Chem.* **2023**, *21*, 6039.

[137] M. M. Mashaly, S. R. El-Gogary, T. R. Kosbar, *J. Heterocycl. Chem.* **2014**, *51*, 1078.

[138] Y. Jiang, C. Yan, *Chin. J. Chem.* **2016**, *34*, 1255.

[139] L.-N. Pan, J. Sun, X.-Y. Liu, C.-G. Yan, *Org. Biomol. Chem.* **2022**, *20*, 7099.
<figure><img src="image_193.png" /></figure>

[140] A. Alizadeh, A. Rostampoor, *Org. Biomol. Chem.* **2023**, *21*, 6160.

[141] Q. Liao, Y. Zhang, J.-Y. Liu, Q.-S. Li, Y.-M. Huang, *Eur. J. Org. Chem.* **2024**, *27*, e202400195.

[142] Q. Yang, S. Huang, L. Yin, Z. Wang, X. Chen, C. Huang, *J. Org. Chem.* **2024**, *89*, 5266.

[143] L. Yin, Z. Zhang, S. Huang, Z. Wang, C. Huang, *J. Org. Chem.* **2024**, *89*, 13629.

[144] Y. Wen, T. Liu, S. Huang, G. Zeng, Z. Zhang, Y. Ye, C. Huang, *Org. Lett.* **2025**, *27*, 1935.

[145] W. Luo, X. Zheng, H. Lin, L. Fu, L. Long, D. Yu, Z. Chen, M. Yang, Z.-X. Wang, *Chem. Sci.* **2025**, *16*, 4119.

[146] M. Augustin, P. Jeschke, *Z. Chem.* **1987**, *27*, 257.

[147] S. V. Chepyshev, Y. N. Chepysheva, A. B. Ryabitsky, A. V. Prosyanik, *Chem. Heterocycl. Comp.* **2009**, *45*, 823.

[148] D.-H. Tuo, Q. He, Q.-Q. Wang, Y.-F. Ao, D.-X. Wang, *Chin. J. Chem.* **2019**, *37*, 684.

[149] H. Mu, Y. Jin, R. Zhao, L. Wang, Y. Jin, *Molecules* **2022**, *27*, 7787.

[150] W. Han, F. Liu, K. Fujisawa, T. Oriyama, *Chem. Lett.* **2021**, *50*, 1607.

[151] S. Suzuki, K. Kimura, W. Han, T. Oriyama, *Bull. Chem. Soc. Japan* **2024**, *97*, u0ae051.

[152] Q. Zhang, J. Yu, G. Cheng, C. Tang, Z. Yang, F. Tian, L. Wang, *J. Org. Chem.* **2025**, *90*, 4829.

[153] Y. Chu, M. Wu, F. Hu, P. Zhou, Z. Cao, X.-P. Hui, *Org. Lett.* **2022**, *24*, 3884.

[154] Y. Li, X.-Y. Duan, Y. Wei, J. Li, X. Ren, J. Qi, *Asian J. Org. Chem.* **2022**, *11*, e202200383.

[155] S. Barik, R. C. Das, K. Balanna, A. T. Biju, *Org. Lett.* **2022**, *24*, 5456.

[156] Y. Sun, Y. Jin, Y. Gu, J. Liu, L. Wang, Y. Jin, *Chem. Eur. J.* **2024**, *30*, e202403349.

[157] J. Yan, M. Hongwen, S. Yuhong, W. Liming, J. Ying, *Chin. J. Org. Chem.* **2025**, *45*, 1569.

Manuscript received: June 16, 2025

Revised manuscript received: July 21, 2025

Version of record online: August 8, 2025