Recent Advances in the Domino Annulation Reaction of Quinone Imines

Abstract

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.

1. Introduction

With the rapid development of medicinal and natural product chemistry, the diversity and complexity of organic molecules are increasing [1,2,3,4,5,6]. Therefore, developing efficient organic synthesis strategies to cope with this situation is very necessary. By exploring a series of reliable synthetic methods, it is possible to efficiently construct the structurally complex molecular frameworks found in natural products and biologically active compounds, including carbocyclic and heterocyclic structures, thereby facilitating the discovery of potential new drugs and pesticides [7,8,9,10,11,12]. Among the numerous reported synthetic strategies, domino reactions have attracted considerable attention due to their potential to conserve resources, reduce waste generation during the synthesis process, and align with the principles of green chemistry [13,14,15,16]. Most importantly, they enable the rapid assembly of polycyclic structures from simple starting materials [17,18,19,20,21,22]. This strategy has been successfully applied in the synthesis of natural products and bioactive compounds, demonstrating its potential to streamline the construction of complex molecular architectures [23,24,25,26]. By designing new synthons and optimizing domino reaction pathways, researchers can efficiently construct complex organic molecular structures and make breakthroughs in synthesizing natural products and drugs. In addition, domino reactions can provide ample space for developing new catalysts and reaction conditions to drive innovation and progress in organic synthesis. As domino reaction technology continues to be refined, new opportunities are emerging in organic synthesis.

Quinones and their derivatives have attracted increasing attention in organic synthesis because of their wide applications in medicine, pesticides, dyes, energy storage, and various fine chemical products [27,28,29,30,31]. Quinone imines, as highly reactive electrophiles containing multiple active sites, can be used in aromatic functionalization, amination, and cyclization reactions, providing efficient tools and methods for synthetic chemistry [32,33,34,35,36,37,38,39]. In particular, annulation reactions involving quinone imines have been widely used to efficiently construct heterocycles, especially nitrogen- and oxygen-containing fused aromatic rings, providing an efficient method for the synthesis of complex molecules. The disclosed quinone imines mainly include ortho-quinone monoimines, ortho-quinone diimines, para-quinone monoimines, para-quinone diimines, and quinone imine ketals, which are defined by the number and locations of the imine groups attached to the quinone structure (Figure 1). The ortho-quinone monoimines can be used as aza-dienes for [4 + 2] annulation with alkenes or ketene enolates. The ortho-quinone diimines can be selected as imines to participate in [2 + n] cyclization reactions, and as 1,4-diazadienes to undergo [4 + n] cycloaddition reactions. The para-quinone monoimines commonly undergo [3 + 3] and [3 + 2] annulations. The para-quinone diimines are always used as C–C–N units to construct indole derivatives. The [3 + 2], [4 + 2], and [5 + 2] annulations can be achieved using quinone imine ketals as electrophilic species. Although the annulation reaction involving quinone imines has become an efficient platform for obtaining heterocyclic compounds, there is no comprehensive summary of this research area [40]. Therefore, a timely and relevant review on this topic is urgently needed, which is important for the future development of this field. Herein, for the first time, we discuss in detail the recent advances in the construction of cyclic compounds by the annulation reactions of quinone imines. This review is organized into five sections according to the types of quinone imines, including ortho-quinone monoimines, ortho-quinone diimines, para-quinone monoimines, para-quinone diimines, and quinone imine ketals.

2. Domino Reactions of Ortho-Quinone Imines

2.1. Domino Reaction of Ortho-Quinone Monoimines

In 2006, Lectka et al. developed an asymmetric [4 + 2] cycloaddition reaction involving ortho-quinone monoimines 1 and in situ generated ketene enolates (Scheme 1) [41]. In this report, the ketene enolate intermediates in situ generated from the reaction between benzoylquinidine C1 and acid chlorides 6 underwent Michael addition to ortho-quinone monoimines 1, leading to aromatization. Subsequently, intramolecular cyclization led to the formation of a series of 1,4-benzoxazines 7 in moderate yields and excellent enantioselectivities. Notably, the authors also disclosed a one-pot transformation to enable the highly stereoselective synthesis of chiral α-amino acid derivatives [42].

Soon after, Chen et al. also developed an organocatalytic enantioselective inverse-electron-demand hetero-Diels–Alder reaction (HDAR) of ortho-quinone monoimines 1 with aldehydes 8 (Scheme 2) [43]. The 1,4-benzoxazinones 10 were smoothly obtained with excellent stereoselectivities (up to 99% ee) after pyridinium chlorochromate (PCC) oxidation.

Another study on the construction of 1,4-benzoxazine derivatives based on ortho-quinone monoimines was reported by Peddinti et al. in 2012 (Scheme 3, top) [44]. In this research, highly reactive ortho-quinone monoimines 1 were in situ generated from ortho-aminophenol 11 by oxidation with diacetoxyiodobenzene (DAIB) as an oxidizing agent. The newly generated ortho-quinone monoimines 1 were then captured by vinylic (thio)ethers 12 to afford the desired 1,4-benzoxazine derivatives 13 in up to 78% yield. In 2020, Zhong et al., also developed an oxidative [4 + 2] cycloaddition of ortho-aminophenols 11 with cyclic enamines 14 (Scheme 3, bottom) [45]. For the mechanism, biomimetic Mn(III) catalyzed the oxidation of ortho-aminophenols 11 to furnish ortho-quinone monoimines 1, which underwent the [4 + 2] cycloaddition with cyclic enamines 14 to give various tricyclic 1,4-benzoxazines 15 in up to 94% yield.

In 2021, Beccalli et al. disclosed a divergent oxidative cyclization of in situ generated ortho-quinone monoimines (Scheme 4) [46]. Selecting hypervalent iodines as the oxidant, Pd(OAc)₂ enabled 6-exo-trig cyclization involving N-allyl-N-tosyl 2-aminophenol 16 to afford functionalized dihydro-1,4-benzoxazines 17 in a generally good yield. In the absence of a palladium catalyst, sequential nucleophilic addition and intramolecular Diels–Alder reactions gave a functionalized tricyclic system 18 in up to 71% yield. The present protocol featured that the oxidant acted as both a nucleophilic donor and an oxidizing agent. The following year, the group of Broggini developed a copper-catalyzed dimerization/cyclization reaction involving aminophenols (Scheme 5) [47]. The authors proposed that the ortho-quinone-type intermediates 24, generated in situ from aminophenols 22 via phenyliodine diacetate (PIDA) oxidation, underwent a cyclization reaction with 2-benzylamino-phenols 22 to form the key intermediates 25. According to the proposed mechanism, the intermediates 25 could also be produced through an alternative pathway (not shown). The intermediates 25 was further oxidized by PIDA to generate the intermediates 26, followed by intramolecular cyclization and oxidation reactions of the intermediates 26, ultimately furnishing the 5H-oxazolo[4,5-b]phenoxazine compounds 18 in up to 82% yield.

2.2. Domino Reaction of Ortho-Quinone Diimines

The ortho-quinone diimines are a class of structurally stable variants that possess structural motifs including diene, imine, and 1,4-diazadiene. Based on these features, they can serve as arylation reagents for 1,4-conjugate addition [48,49], as imines to participate in [2 + n] cyclization reactions, and as 1,4-diazadienes to undergo [4 + n] cycloaddition reactions.

There is only one study using ortho-quinone diimines as imines to participate in a domino reaction. In 2005, Nair et al. developed a three-component [3 + 2] cycloaddition reaction of ortho-quinone diimines, dimethyl acetylenedicarboxylate (DMAD), and isocyanates, which led to the construction of the spiroiminolactam derivatives 30 in moderate yields (up to 64%) (Scheme 6) [50]. In the transformation, the reaction between DMAD 28 and isocyanate 29 smoothly generated a zwitterionic intermediate, which then underwent a 1,3-dipolar cycloaddition reaction with the imine group of the ortho-quinone diimine to furnish spiroiminolactam.

The main application of ortho-quinone diimines 2 is mainly focused on using them as 1,4-diazadienes to participate in [4 + 2] cycloaddition for constructing dihydroquinoxaline derivatives. In 2006, Lectka et al. successfully developed the asymmetric [4 + 2] cycloaddition reaction between ortho-quinone diimines 2 and acid chlorides 6 (Scheme 7) [51]. In the reaction process, benzoylquinidine C1 and Hünig’s base cooperatively activated the acid chlorides 6 to generate ketene enolates, which then underwent [4 + 2] cycloaddition with Lewis acid-activated ortho-quinone diimines 2, resulting in the formation of biologically active quinoxalinone derivatives 31 with excellent stereoselectivities (all cases >99% ee). It is worth mentioning that the selective removal of nitrogen protecting groups could be achieved by trifluoroacetic acid (TFA) to furnish the compounds 32.

In 2009, Chen et al. reported the asymmetric inverse-electron-demand HDAR between N-benzoyl ortho-quinone diimine 2 and aldehydes 8 (Scheme 8) [39]. Under the catalysis of proline-derived siloxane C2 and benzoic acid, the reaction exhibited excellent enantioselectivities (95–99% ee). Another cyclization reaction of ortho-quinone diimines 2 with aldehydes 39 was disclosed in 2019 (Scheme 9) [52]. In this report, the chiral N-heterocyclic carbene C4 activated α-haloaldehydes 39 to generate enol intermediates, which then underwent [4 + 2] cycloaddition reactions with ortho-quinone diimines 2 to give chiral dihydroquinoxaline products 40 with generally excellent ee values (92–98%).

The cycloaddition reaction of in situ generated ortho-quinone diimines represents a powerful tool for streamlining the synthesis of functionalized tetrahydroquinoxalines and has potential applications in the construction of nitrogen-containing heterocycles. Recently, Zhong et al. employed an in situ oxidative activation strategy to accomplish a [4 + 2] cyclization reaction between ortho-phenylenediamine 41 and alkenes 12 (Scheme 10) [53]. This transformation is compatible with a range of alkene derivatives, such as styrenes, vinylic (thio)ethers, benzofurans, and indoles, affording a series of tetrahydroquinoxaline derivatives 42 in up to 94% isolated yield.

More recently, Mei et al. reported, for the first time, the diversity-oriented catalytic asymmetric dearomatization of indoles 43 through reacting with ortho-quinone diimides 2 (Scheme 11) [54]. When 2,3-dimethylindoles were involved in the asymmetric dearomatization with chiral phosphoric acid C5 as the catalyst, the arylation reaction afforded the products 44 with high reactivity and excellent stereoselectivity (68–93% yields, 92–99% ee). The reaction of tryptophols/tryptamines with ortho-quinone diimides could also be realized via a sequential dearomatization–cyclization process, leading to polycyclic indoline skeletons 45 that are widely present in biologically active compounds. Moreover, the dearomatic [4 + 2] cycloaddition reactions between ortho-quinone diimides and 3-substituted indoles were facilitated by chiral phosphoric acid C6. This transformation proceeded with high yields and excellent stereoselectivities, resulting in the fused indolines 46 in 76–96% yields with 63–98% ee.

3. Domino Reactions of Para-Quinone Imines

3.1. Domino Reaction of Para-Quinone Monoimines

In 2010, Jørgensen et al. presented the [3 + 2] cycloaddition of aldehydes with in situ formed para-quinone monoimines by combining electrocatalysis and asymmetric organic catalysis (Scheme 12) [55]. Anodic oxidation of N-toluenesulfonyl-4-aminophenol 50a proceeded smoothly to give para-quinone monoimine. The in situ generated para-quinone monoimine reacted with aldehydes 8 under the catalysis of proline-derived siloxane C2 to furnish corresponding products 51, which smoothly converted into the final products 52 by treatment with NaBH₄. In addition, the developed transformation could also be achieved via the chemical oxidation process in 70–98% yields with 93–98% ee values.

In 2014, Zhang et al. pioneered the asymmetric domino cyclization reaction involving para-quinone monoimines (Scheme 13) [56]. Under the catalysis of chiral phosphoric acid C5, 3-substituted indoles 43 underwent an asymmetric [3 + 2] cyclization reaction with para-quinone monoimines 3, successfully affording a series of benzofuroindoline derivatives 53 with high stereoselectivities (up to 99% ee). This transformation features that the bifunctional phosphoric acid C5 activated both the 3-methylindoles and the para-quinone monoimines (shown as 54). The 3-substituted indoles attacked the para-quinone monoimines from the Re face to give the intermediates 55, which were promptly aromatized to produce the phenol intermediates 56. Subsequently, an intramolecular cyclization occurred to generate the final products 53.

In 2015, Shi et al. successfully developed a three-component [3 + 3] cycloaddition reaction involving para-quinone monoimines, aldehydes, and amino-esters (Scheme 14, top) [57]. Under the catalysis of GaBr₃, the condensation of aldehydes 8 with amino-esters 57 resulted in the formation of azomethine ylides 60, which completed the Michael addition reaction with para-quinone monoimines to form intermediates 63. After keto-enol tautomerization, the generated intermediates 64 underwent intramolecular cyclization reactions, leading to the formation of dihydrobenzoxazine derivatives 58 in 41–98% yields. The in situ generated azomethine ylides 60 might also undergo a formal [3 + 2] cycloaddition process with the C=C bond of para-quinone monoamines to give compounds 59 but not the major products. Subsequently, Guo and his collaborators also reported the [3 + 3] cycloaddition reaction between para-quinone monoimines 3 and the azomethine ylide precursor 65 using racemic binaphthol-derived phosphoric acid C7 as a catalyst, in which the transformation furnished dihydrobenzoxazine derivatives 58 in up to 96% yield (Scheme 14, bottom) [58].

The Shi group also demonstrated the catalytic asymmetric [3 + 2] cycloaddition of para-quinone monoimine 3 with 3-vinylindoles 69 (Scheme 15) [59]. The cyclization products 70 were obtained in generally high yields with good to excellent stereoselectivities (up to 99% yield, 95:5 dr, 96:4 er), and no formal [4 + 2] cyclization products 71 were observed. In the reaction process, the spiro-chiral phosphoric acid C8 promoted the enantioselective vinylogous Michael addition of 3-vinylindoles 69 to para-quinone monoimines 3 via the transition state 72 and formed the transient intermediate 73, which then underwent intramolecular oxa-Michael addition to give the chiral indole-based 2,3-dihydrobenzofuran derivatives 70. In the same year, Zhang et al. developed the asymmetric [3 + 2] cyclization reaction between para-quinone monoimines 3 and cyclic enamines 14 under the catalysis of chiral phosphoric acid C5 (Scheme 16) [60]. Various polycyclic 2,3-dihydrobenzofurans 74 were obtained in moderated to excellent enantioselectivities (11–99% ee). In their report, the acyclic enamines could also undergo the desired transformation but exhibited very poor diastereoselectivities. Moreover, the para-quinone monoimine or cyclic enamine bearing a methyl group was not suitable for the developed protocol (not shown).

Co-catalysis involves the collaborative action of two or more catalysts to enhance a chemical reaction. These catalysts can carry out distinct functions, such as triggering different substrates, expediting various reaction steps, or boosting the effectiveness. By working in tandem reaction, co-catalysis often results in an increased reaction speed, selectivity, and overall efficacy compared to using a single catalyst [61]. Jiang et al. developed the first example of an Ag/Sc-catalyzed transformation involving para-quinone monoimine (Scheme 17) [62]. The disclosed reaction features an Ag/Sc-catalyzed 6-endo-dig cyclization reaction of aromatic ortho-alkynyl ketones 75 to furnish intermediates 78, which underwent a proton transfer to give 1-naphthols 79 with simultaneous release of the Ag catalyst. The formed 1-naphthols 79 underwent a 1,4-addition reaction with para-quinone monoimines to give intermediates 80, which then aromatized, followed by an intramolecular cyclization and dehydrogenation, finally providing tetracyclic naphtho[1,2-b]benzofurans 76 in moderate yields (46–62%).

Spiroketal moieties are commonly found in natural products and pharmaceutical compounds, and they can impart unique biological characteristics and chemical reactivity to molecules. Xu et al. first developed the synthesis of spirocyclic compounds with a spiroketal skeleton by using para-quinone imines as three-atom building blocks (Scheme 18) [63]. Under the action of a gold catalyst, 2-ethynylbenzyl alcohol 82 underwent intramolecular 5-exo-dig cyclization to form enol ether intermediates 84. The Michael addition of intermediates 84 to para-quinone monoimines 3 afforded intermediates 85, followed by intramolecular cyclization to generate the desired 5,5-benzannulated spiroketals 83 in up to 93% yield.

Pterocarpen derivatives exhibit a wide range of biological activities, including anti-HCV and antiestrogen properties [64,65,66]. Therefore, the efficient construction of these compounds has increasingly attracted the attention of synthetic chemists. In 2019, Zhang et al. presented the efficient synthesis of a novel class of pterocarpen analogs 87 through a [3 + 2] cyclization–elimination reaction between para-quinone monoimines 3 and α,α-dicyanoolefins 86 (Scheme 19) [67]. Using triethylamine (TEA) as a catalyst, the α,α-dicyanoolefins 86 underwent a Michael addition reaction with para-quinone imines 3, followed by aromatization to generate intermediates 89. Subsequently, the intramolecular cyclization reaction occurred to form the intermediates 90, which then eliminated malononitrile to produce the final products 87 in up to 75% yield. It should be noted that a benzo-five-membered ring, benzo-seven-membered ring, and 2-cyclohexylidenemalononitrile did not react with the para-quinone imine under standard conditions.

The first example of an asymmetric cycloaddition reaction between para-quinone monoimines generated by in situ oxidation and substituted indoles 43 was demonstrated by Zhong et al. (Scheme 20) [68]. In this report, the (salen)Mn(III) complex C3 was used as a biomimetic surrogate of the metallocofactor to accomplish the in situ oxidation of 4-hydroxyanilines 50 for generating transient para-quinone monoimines 3. Subsequent catalysis by chiral phosphoric acid C9 induced the annulation of para-quinone monoamine 3 with substituted indoles 43, resulting in the formation of chiral benzofuroindoline derivatives 91 in moderate to excellent yields with excellent stereoselectivities.

The asymmetric dearomatization reaction, one of the efficient approaches for the synthesis of chiral heterocycles, has received wide attention from chemists [69,70,71]. Over the past 10 years, a variety of aromatic compounds, including naphthol, indole, benzofuran, and benzothiophene, have been used in asymmetric dearomative reactions. In contrast, the asymmetric dearomative cyclization of isoxazoles has only recently been achieved. In 2020, the Zhang group first reported the chiral phosphoric acid-catalyzed asymmetric dearomative cyclization reaction of 5-amino-isoxazoles 93 (Scheme 21) [72]. Chiral phosphoric acid C10 catalyzed the enantioselective dearomative [3 + 2] annulations between 5-amino-isoxazoles 93 and para-quinone monoimines 3 in 1,2-dimethoxyethane (DME) at 0 °C to give the corresponding polycyclic compounds 94. Furthermore, the reactions involving ethyl 4-acetate-isoxazol-5-amines and para-quinone monoimines afforded the bridged polycyclic scaffolds 95 in moderate yields with high ee values. Recently, the Zhang group also disclosed the dearomative cyclization reaction of 4-amino-isoxazoles 99 (Scheme 22) [73]. Similar to their previous report, highly enantioselective [3 + 2] annulation of 4-amino-isoxazoles 99 with para-quinone monoimines 3 was achieved under the catalysis of chiral phosphoric acid C11, providing access to structurally diverse isoxazoline-fused dihydrobenzofurans 100 with generally excellent enantioselectivities.

In 2021, Zhang et al. also demonstrated an enantioselective [3 + 2] annulation involving para-quinone monoimines 3 and 3-hydroxymaleimides 104 (Scheme 23) [74]. The chiral phosphoric acid C5 catalyzed the transformation to produce fused succinimide and dihydrobenzofuran 105 with generally excellent results (up to 99% yield, 99% ee).

The [3 + 3] cyclization reaction involving para-quinone monoimines was reported by Zhen et al. in 2021 (Scheme 24) [75]. In their report, 2-indolylmethanols 108 acted as nucleophiles at the C3-position attacking para-quinone monoimines 3 to form the intermediates 110, which underwent proton transfer and loss of water to form the intermediates 111. A final intramolecular nucleophilic attack led to the formation of the desired cyclization products 109 in good to excellent yields.

Zhang et al. also developed a divergent reaction between para-quinone monoimines 3 and α-cyano-α-arylacetates 112. In 2019, they found that tandem conjugate addition and C–O ester migration occurred in refluxing acetonitrile to give various 2,2-diarylacetonitriles in generally good yields (not shown) [76]. In 2021, they found that an organic base could also promote the [3 + 2] cycloaddition reaction of para-quinone monoimines 3 with α-cyano-α-arylacetates 112 but resulted in the formation of 2-aminobenzofuran 113, which was protected with di-tert-butyl dicarbonate to give 114 in moderate to good yields (Scheme 25) [77]. For the reaction mechanism, 1,4-diazabicyclo[2.2.2]octane (DABCO) promoted the deprotonation of phenyl α-cyano arylacetates 112 to give enolates 115. Nucleophilic addition of the enolates 115 to para-quinone monoimines followed by aromatic rearrangement and protonation led to the formation of intermediates 117. Then, the nucleophilic addition of DABCO to intermediates 117 gave zwitterions 119, and subsequent C−C cleavage and intramolecular proton transfer generated intermediates 121. Finally, the intramolecular nucleophilic addition of the phenoxy anion to the nitrile group led to the cyclization process to form intermediates 123, which then isomerized to form the final products 113.

In 2022, Xu et al. reported the successful construction of spiro-fused 2,3-dihydrobenzofurans 126 via a one-pot three-component cyclization reaction of para-quinone monoimines, 2-aminoacetophenones, and isocyanates (Scheme 26) [78]. Under Lewis acid catalysis, the [4 + 2] cyclization reaction of 2-aminoacetophenones 124 and isocyanates 125 smoothly generated an intermediate 129, which subsequently underwent a domino [3 + 2] cyclization reaction with para-quinone monoimines 3, affording the spiro-fused 2,3-dihydrobenzofurans 126 in a maximum yield of 92%.

3.2. Domino Reaction of Para-Quinone Diimines

Cyclization reactions involving para-quinone diimines are commonly used to construct nitrogen-containing heterocycles. Currently, the cyclization reactions of para-quinone diimines are mainly categorized into two types: one involving their use as the C–N unit in [3 + 2] cycloaddition reactions to construct spirocyclic compounds, and the other involving their participation as the C–C–N unit in [3 + 2] cycloaddition reactions to construct polycyclic compounds.

There is only one reported case of using para-quinone diimines as a C–N unit to construct the spirocyclic framework. Nair et al. investigated a three-component [3 + 2] cycloaddition reaction involving para-quinone diamines 4, dimethyl acetylenedicarboxylates (DMADs) 28, and isocyanides 131 (Scheme 27) [50]. The reaction mechanism involved the nucleophilic attack of isocyanides 131 on DMADs 28, resulting in the in situ formation of zwitterionic species 133, and finally a 1,3-dipolar cycloaddition with the imine group of the para-quinone diimines to furnish γ-iminolactams 132 in up to 72% yield.

In 2018, Chandra et al. developed the first asymmetric [3 + 2] cycloaddition reaction involving para-quinone diimides (Scheme 28) [79]. In the presence of quinine-derived bifunctional thiourea C12, the α-cyanoacetates 112 first underwent nucleophilic attack to para-quinone diimides 4, followed by aromatization, proton transfer, and intramolecular cyclization processes to afford chiral fused cyclic imidines 136 with up to a 91% ee value. Through DFT calculations, the authors suggested that multiple hydrogen bonds and tertiary amine in the chiral catalyst activated the quinone diimides and α-cyanoacetates, respectively, facilitating the interaction between the substrates and leading to the formation of the key chiral intermediates.

Masson et al. described the synthesis of chiral 2,3-disubstituted indolines with the [3 + 2] cycloaddition of enamides and para-quinone diimides under the catalysis of chiral phosphoric acid (Scheme 29) [80]. For acyclic enamides 137, chiral phosphoric acid C5-catalyzed [3 + 2] cycloaddition reactions provided indoline derivatives 138 in good to excellent yields with moderate diastereoselectivities and generally excellent enantioselectivities. In the presence of chiral phosphoric acid C13, the [3 + 2] cycloaddition reactions between cyclic enamides 14 and para-quinone diimides 4 showed better stereoselectivities, allowing for the formation of polycyclic compounds 139 with the highest enantiomeric excess (up to >99% ee).

In 2023, Wan et al. also used enamide derivatives as the C–C unit to achieve a formal [3 + 2] cycloaddition reaction with para-quinone diimides (Scheme 30) [81]. Under Zn(OTf)₂ catalysis, the isomers 143 of enamide ketones underwent a 1,4-nucleophilic addition reaction with para-quinone diimides 4 to give intermediates 144. The aromatization and intramolecular cyclization reaction of intermediates 144 led to the formation of the intermediate 146. Finally, the elimination of HNMe₂ resulted in the formation of indoles 141 in moderate to good yields. Of note, this protocol has potential applications in the derivatization of certain natural products.

4. Domino Reactions of Quinone Imine Ketals

Quinone imine ketals (QIKs) have been widely used as aryl group surrogates in organic chemistry. Although Swenton et al. prepared and reported the first stable and separable QIK in 1986 [82], the low reaction selectivity caused by multiple reactive sites severely limits their application. However, with recent advances in catalytic selectivity, the use of QIKs in organic synthesis has gradually expanded. Currently, chemical transformations involving QIKs include carbon functionalization and annulation. Research on the cycloaddition reactions involving QIKs mainly includes [2 + n] annulation, formal [4 + 2] cycloaddition, [3 + 2] cycloaddition, and [5 + 3] annulation.

The [2 + n] annulation reactions involving QIKs include their participation as C–N units in [2 + 4] and [2 + 2] cycloaddition reactions, as 4C units in a formal [4 + 2] cycloadditions reaction, and as dienophiles in Diels–Alder reactions. Swenton and Chou first illustrated the application of QIKs as C–N units in the synthesis of natural products [83]. In 2011, Reisman et al. used the chiral N-tert-butanesulfinyl QIK 5 as a C–N unit to react with an organometallic reagent and realized the [2 + 4] annulation in 2011. With the obtained chiral product 148 as a key intermediate, they also performed the six-step enantioselective total synthesis (−)-3-demethoxyerythratidinone 149 (Scheme 31) [84]. In 2020, Cheng et al. also developed DABCO-catalyzed [2 + 2] cycloaddition reactions between QIKs 5 and allenoates 150 to generate functionalized azaspirocycles 151 in moderate to excellent yields (Scheme 32) [85].

In 2016, Fan et al. used 2-alkynyl QIKs as the 4C building block to successfully developed a metal-free three-component domino reaction that resulted in a series of functionalized quinoline derivatives with yields up to 90% (Scheme 33) [86]. During the reaction process, a secondary amine 153 reacted with QIKs 5 to form intermediates 156, which subsequently underwent transamination and aromatization to give intermediates 158. The secondary amines 153 acted as nucleophiles on the triple bond in intermediates 158 to direct the intramolecular nucleophilic cyclization, giving intermediates 159, followed by the retro-Strecker reaction to generate the desired products 155.

The only reported case of Diels–Alder reaction involving QIKs was reported by Maruoka in 2015 (Scheme 34) [87]. In their study, the selection of axially chiral dicarboxylic acids as the catalyst enabled the high-yield construction of chiral cycloadducts. More importantly, when asymmetric QIKs were used in the developed transformation, changing the type of catalyst led to the selective reaction of the C=C bond. When the chiral dicarboxylic acid C14 was used as the catalyst, the cyclization reaction took place at the unsubstituted C=C bond of QIKs, giving the corresponding products 161 in up to 85% yield and a 96% ee value. The chiral dicarboxylic acid C15 promoted the reaction to occur at the more sterically hindered C=C bond, providing the cycloadducts 163 bearing a chiral all-carbon quaternary center with generally good stereoselectivities.

In the study of the [3 + 2] cycloaddition reaction involving QIKs, Zhang et al. conducted extensive research and successfully constructed a series of indoline derivatives. In 2014, they first developed the formal [3 + 2] reaction between QIKs 5 and 3-methylindoles 43 (Scheme 35, top) [88]. Under the Zn(OTf)₂ catalysis, the elimination of the methoxy group in QIK produced the quinone imine oxonium 165, which was then subjected to nucleophilic addition by 3-methylindole to form the intermediate 166. Subsequently, the aromatization and intramolecular cyclization led to the final product 164 in up to 86% yield. Subsequently, they also developed a Cu(OTf)₂-catalyzed [3 + 2] annulation cyclization reaction involving acyclic QIKs 5 and enamides 137, successfully constructing 2-carbamate-indolines compounds 168 with a maximum yield of 86% (Scheme 35, bottom) [89].

In 2022, Zhang et al. also reported a Sc(OTf)₃-catalyzed dearomative [3 + 2] annulation reaction involving QIK 5 and 5-amino-isoxazolines 169, which led to the synthesis of a series of indoline-fused isoxazolines 170 in moderate to high yields with excellent diastereoselectivities (Scheme 36) [90]. The reported reaction mechanism is similar to their previous findings.

The Yan group successfully utilized QIKs 5 as 1,4-nucleophilic addition acceptors to participate in the Michael/aza-Michael addition reaction with acyclic enamines 137, achieving the synthesis of molecularly diverse bridged ring compounds 174 in excellent yields (Scheme 37) [91]. Recently, Sun et al. performed a detailed study on the divergent transformation of QIKs (Scheme 38) [92]. By varying the type of Lewis acid and additives, they were able to achieve carbon functionalization (not shown) and annulation. Using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the catalyst, cascade Michael/oxa-Michael addition reactions were successfully performed, yielding oxygen-bridged compounds 176 in excellent yields. In the presence of trifluoromethanesulfonic acid (TfOH), hydrolysis of the QIKs produced the para-quinone monoimines 3, followed by the preferential attack from the β-ketoesters 175. Subsequent aromatization led to the formation of the intermediate 182. TfOH promoted the dehydration of intermediates 182 to give the benzofuran derivative 177. In the absence of water, iron bromide and TfOH jointly catalyzed the reaction between β-ketoesters 175 and QIKs 5 to achieve C2-site alkylation and to give intermediates 180. Subsequent aromatization and dehydration led to the formation of the indole derivatives 178.

Chen et al. further explored the possibilities of using QIKs to construct chiral polycyclic compounds. In 2016, they reported a sequential asymmetric multi-step cyclization of QIKs 5 and 2,4-dienals 183 under the catalysis of proline-derived siloxane C2, and salicylic acid (Scheme 39) [93]. Via a domino Diels–Alder–aromatization–hemiaminal formation sequence, chiral benzo[d,e]quinolone derivatives 184 were obtained in good yields with excellent enantiocontrol. Further transformations of the products were also investigated, providing additional chiral polycyclic compounds.

5. Summary and Outlook

As described in this review, the widespread application of quinone imines in the efficient construction of cyclic compounds, especially nitrogen-containing heterocycles, has gained considerable attention from numerous research groups. Several quinone imines, including preformed and in situ generated quinone imines, have been designed, synthesized, and used in cyclization reactions. The use of quinone imines is widespread in the construction of polycyclic, spirocyclic, and bridged ring compounds. However, further research is required to overcome some of the remaining challenges. These challenges include, but are not limited to, the following issues. For ortho-quinone monoimines, their transformation only covers [4 + 2] cyclization reactions, which restricts the application of this class of compounds. Exploring other types of cyclizations to construct structurally diverse heterocyclic compounds is necessary. The cyclizations of ortho-quinone diimines are only used to construct five- and six-membered heterocyclic rings through [3 + 2] and [4 + 2] cyclization reactions, so it is desirable to synthesize medium-sized rings. The para-quinone imines are mainly selected as C–C–O(N) building blocks to participate in the [3 + n] cycloaddition reactions for the construction of oxygen- or nitrogen-containing heterocycles, but there are no reports of their involvement as C–C building blocks in annulation reactions. The QIKs exhibit versatile and flexible applications in domino reactions, including participation as a C–N unit in [2 + n] annulation reactions, serving as a C–C–N moiety for [3 + 2] cycloadditions, acting as a dual receptor for the construction of bridged ring compounds, functioning as a dienophile in Diels–Alder reactions, and enabling multi-site reactions for the construction of polycyclic compounds. However, research on asymmetric transformations involving QIKs is still quite limited. Despite the many challenges, we are confident that this area of research will reach a higher level in the coming years through the persistent efforts of chemists. We hope that this analysis will be a valuable reference for synthetic chemists interested in this field of study. The authors would also like to apologize in advance for the unintentional omission of any relevant literature report.