Recent Advances in the Domino Annulation Reaction of Quinone Imines

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.


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 oxygencontaining fused aromatic rings, providing an efficient method for the synthesis of complex molecules.The disclosed quinone imines mainly include ortho-quinone monoimines, orthoquinone 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.
Molecules 2024, 29, x FOR PEER REVIEW 2 of 29 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.

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

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].
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 orthoquinone-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.
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-benzylaminophenols 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.Scheme 3. The oxidative [4 + 2] cycloaddition reaction between newly generated ortho-quinone monoimines and electron-rich olefins.
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-benzylaminophenols 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.
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.Scheme 5.The oxidative dimerization/cyclization of 2-benzylaminophenols.
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.Scheme 10.The [4 + 2] cyclization reaction between in situ formed ortho-quinone diimines and electron-rich olefins.

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 NaBH 4 .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 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 paraquinone 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 GaBr 3 , 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].
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).+ 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 2,3dihydrobenzofurans 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 paraquinone 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%).+ 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 2,3dihydrobenzofurans 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 paraquinone 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%).
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] 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,αdicyanoolefins 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 Scheme 17. Silver/scandium-catalyzed transformation involving para-quinone monoimines and β-alkynyl ketones.
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.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,αdicyanoolefins 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 Scheme 18. Gold-catalyzed cycloisomerization-spiroketalization of 2-ethynylbenzyl alcohol with para-quinone monoimines.
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,αdicyanoolefins 86 (Scheme 19) [67].Using triethylamine (TEA) as a catalyst, the α,αdicyanoolefins 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 benzofive-membered ring, benzo-seven-membered ring, and 2-cyclohexylidenemalononitrile did not react with the para-quinone imine under standard conditions.
Molecules 2024, 29, x FOR PEER REVIEW 13 of 29 to produce the final products 87 in up to 75% yield.It should be noted that a benzo-fivemembered ring, benzo-seven-membered ring, and 2-cyclohexylidenemalononitrile did not react with the para-quinone imine under standard conditions. .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.

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.
struct 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.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.Scheme 28.Organocatalyzed asymmetric [3 + 2] cycloaddition reaction between para-quinone diimides and α-cyanoacetates.
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 HNMe 2 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.
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).

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.

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]  ganic 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]  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.
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.
alized 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 (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-carbamateindolines compounds 168 with a maximum yield of 86% (Scheme 35, bottom) [89].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].
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-carbamateindolines 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 and 5-amino-isoxazolines which led to the synthesis of a series of indoline-fused isoxazolines in moderate to high yields with excellent (Scheme 36) [90].reported reaction mechanism is similar to their previous findings.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 1,8diazabicyclo[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.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 with excellent enantiocontrol.Further transformations of the were also providing additional chiral polycyclic compounds.

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 paraquinone 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.

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 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.

Funding:
We sincerely thank all leading chemists and co-workers involved in the development of the cyclization reaction of quinone imines.We thank the Natural Science Foundation of China

Molecules 2024 ,
29, x FOR PEER REVIEW 11 of 29 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

Scheme 19 .
Scheme 19.TEA-catalyzed[3 + 2]  cyclization-elimination cascade of α,α-dicyanoolefins with paraquinone monoimines.The first example of an asymmetric cycloaddition reaction between para-quinone monoimines generated by in situ oxidation and substituted indoles 43 was demonstrated byZhong 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.Scheme 19.TEA-catalyzed [3 + 2] cyclization-elimination cascade of α,α-dicyanoolefins with paraquinone monoimines.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.

Scheme 38 .
Scheme 38.Acid-regulated divergent catalytic reaction between QIKs and 1,3-dicarbonyl compounds.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.

Author
Contributions: Z.-H.W.-literature search and initial manuscript writing.X.-H.F.-preliminary drawing of the scheme and figure.Q.L. Y.Y., J.-Q.Z., L.Y. and Y.-P.Z.-revision of the text, schemes, and tables.W.-C.Y.-guidance, revision, and supervision.All authors have read and agreed to the published version of theFunding:We sincerely thank all leading chemists and co-workers involved in the development of the cyclization reaction of quinone imines.We thank the Natural Science Foundation of China (Nos.

Author
Contributions: Z.-H.W.-literature search and initial manuscript writing.X.-H.F.-preliminary drawing of the scheme and figure.Q.L., Y.Y., J.-Q.Z., L.Y. and Y.-P.Z.-revision of the text, schemes, and tables.W.-C.Y.-guidance, revision, and supervision.All authors have read and agreed to the published version of the manuscript.
The Michael/aza-Michael addition reaction between QIKs and acyclic enamines.