The Castagnoli–Cushman Reaction

Since the first reports of the reaction of imines and cyclic anhydrides by Castagnoli and Cushman, this procedure has been applied to the synthesis of a variety of lactams, some of them with important synthetic or biological interest. The scope of the reaction has been extended to the use of various Schiff bases and anhydrides as well as to different types of precursors for these reagents. In recent years, important advances have been made in understanding the mechanism of the reaction, which has historically been quite controversial. This has helped to develop reaction conditions that lead to pure diastereomers and even homochiral products. In addition, these mechanistic studies have also led to the development of new multicomponent versions of the Castagnoli–Cushman reaction that allow products with more diverse and complex molecular structures to be easily obtained.


Introduction
The reaction of imines with cyclic anhydrides, commonly named the Castagnoli-Cushman reaction (CCR), has been used for the last 50 years for the synthesis of a wide variety of lactams. This reaction has been partially reviewed in the past, [1][2][3][4][5] but the relevant contributions made in the field in the last few years require an up-to-date account. Here, we summarise the developments and applications of the Castagnoli-Cushman reaction from its discovery until now.
It has long been known that anhydrides react with different electrophiles and bifunctional reagents to yield condensation products. For example, Perkin observed 150 years ago that the condensation of anhydrides (1) and aldehydes (2) yielded α,β-unsaturated carboxylic acids (3; Scheme 1) [6,7]. This reaction is still used for the preparation of diverse types of compounds such as coumarins [6,8] or stilbene derivatives (3) [9].
with important synthetic or biological interest. The scope of the use of various Schiff bases and anhydrides as well as to diffe reagents. In recent years, important advances have been made i the reaction, which has historically been quite controversial. T

Introduction
The reaction of imines with cyclic anhydrides, com Cushman reaction (CCR), has been used for the last 50 y variety of lactams. This reaction has been partially revie relevant contributions made in the field in the last few account. Here, we summarise the developments and a Cushman reaction from its discovery until now.
Palamareva and co-workers also support a similar concerted mechanism for the CCR of imines with HPA, arguing its similarity to Tamura's reaction, which has often been described as a [4+2] cycloaddition [46].
More recent computational studies (considering the effect of substituents on the imine and the anhydride) and experimental findings disagree with both the concerted mechanisms and the two-step mechanisms initiated by iminolysis. In contrast, the currently most widely accepted mechanism for the CCR consists of a stepwise process involving a Mannich-type addition of the anhydride enolate to the imine, followed by the Scheme 7. Iminolysis mechanism proposed by Castagnoli and Cushman. This mechanism is also apparently supported by the fact that the CCR is limited to imines derived from non-enolisable aldehydes. Otherwise, enamines can be formed from the imines (24) and then acylated by the anhydrides (25), preventing the formation of the Castagnoli-Cushman adducts. In these cases, the reaction usually yields exclusively N-acyl enamines (26; Scheme 8) [42,43].
that enhance its nucleophilicity. [39,40]. Moreover, succinic anhydrides substitut electron-withdrawing groups react very fast, which is also consistent with further stabilisation on the cyclisation intermediate (23) [41]. Scheme 7. Iminolysis mechanism proposed by Castagnoli and Cushman. This mechanism is also apparently supported by the fact that the CCR is lim imines derived from non-enolisable aldehydes. Otherwise, enamines can be form the imines (24) and then acylated by the anhydrides (25), preventing the formatio Castagnoli-Cushman adducts. In these cases, the reaction usually yields exclus acyl enamines (26; Scheme 8) [42,43]. However, it has been argued that zwitterionic intermediates (22) shown in S are too high in energy, rendering the iminolysis mechanism unworkable [30,44,45 Based on computational studies on small model substrates, Kaneti prop concerted mechanism through the enol form of the cyclic anhydride (16en; Scheme MO and DFT computation reveal the concerted mechanism would preferentially p the cis diastereomer, through a less energetic TS from the imine's Z-isomer, in a contradiction to experimental findings. Kaneti suggests that the exper stereochemical product distribution must then result from a thermodyna controlled process, in which the kinetic cis adduct (17b) would epimerise to yield t stable trans product (17a), likely through an enol intermediate (Scheme 9). Scheme 9. Concerted reaction mechanism proposed by Kaneti. Palamareva and co-workers also support a similar concerted mechanism for t of imines with HPA, arguing its similarity to Tamura's reaction, which has oft described as a [4+2] cycloaddition [46].
More recent computational studies (considering the effect of substituents imine and the anhydride) and experimental findings disagree with both the co mechanisms and the two-step mechanisms initiated by iminolysis. In contr currently most widely accepted mechanism for the CCR consists of a stepwise involving a Mannich-type addition of the anhydride enolate to the imine, followe However, it has been argued that zwitterionic intermediates (22) shown in Scheme 7 are too high in energy, rendering the iminolysis mechanism unworkable [30,44,45].
Based on computational studies on small model substrates, Kaneti proposed a concerted mechanism through the enol form of the cyclic anhydride (16en; Scheme 9) [44]. MO and DFT computation reveal the concerted mechanism would preferentially produce the cis diastereomer, through a less energetic TS from the imine's Z-isomer, in apparent contradiction to experimental findings. Kaneti suggests that the experimental stereochemical product distribution must then result from a thermodynamically controlled process, in which the kinetic cis adduct (17b) would epimerise to yield the more stable trans product (17a), likely through an enol intermediate (Scheme 9). shown to be favoured by the presence of electron-donating substituents on the Schiff base that enhance its nucleophilicity. [39,40]. Moreover, succinic anhydrides substituted with electron-withdrawing groups react very fast, which is also consistent with further enolate stabilisation on the cyclisation intermediate (23) [41]. Scheme 7. Iminolysis mechanism proposed by Castagnoli and Cushman. This mechanism is also apparently supported by the fact that the CCR is limited to imines derived from non-enolisable aldehydes. Otherwise, enamines can be formed from the imines (24) and then acylated by the anhydrides (25), preventing the formation of the Castagnoli-Cushman adducts. In these cases, the reaction usually yields exclusively N acyl enamines (26; Scheme 8) [42,43]. However, it has been argued that zwitterionic intermediates (22) shown in Scheme 7 are too high in energy, rendering the iminolysis mechanism unworkable [30,44,45].
Based on computational studies on small model substrates, Kaneti proposed a concerted mechanism through the enol form of the cyclic anhydride (16en; Scheme 9) [44] MO and DFT computation reveal the concerted mechanism would preferentially produce the cis diastereomer, through a less energetic TS from the imine's Z-isomer, in apparen contradiction to experimental findings. Kaneti suggests that the experimenta stereochemical product distribution must then result from a thermodynamically controlled process, in which the kinetic cis adduct (17b) would epimerise to yield the more stable trans product (17a), likely through an enol intermediate (Scheme 9). Scheme 9. Concerted reaction mechanism proposed by Kaneti. Palamareva and co-workers also support a similar concerted mechanism for the CCR of imines with HPA, arguing its similarity to Tamura's reaction, which has often been described as a [4+2] cycloaddition [46].
More recent computational studies (considering the effect of substituents on the imine and the anhydride) and experimental findings disagree with both the concerted mechanisms and the two-step mechanisms initiated by iminolysis. In contrast, the currently most widely accepted mechanism for the CCR consists of a stepwise process involving a Mannich-type addition of the anhydride enolate to the imine, followed by the Scheme 9. Concerted reaction mechanism proposed by Kaneti. Palamareva and co-workers also support a similar concerted mechanism for the CCR of imines with HPA, arguing its similarity to Tamura's reaction, which has often been described as a [4+2] cycloaddition [46].
More recent computational studies (considering the effect of substituents on the imine and the anhydride) and experimental findings disagree with both the concerted mechanisms and the two-step mechanisms initiated by iminolysis. In contrast, the currently most widely accepted mechanism for the CCR consists of a stepwise process involving a Mannich-type addition of the anhydride enolate to the imine, followed by the opening of the anhydride from the intramolecular attack of the intermediate amine (27;Scheme 10) [30,47]. An experimental fact that supports this mechanism is the formation, under certain conditions, of a Knoevenagel-type alkene product (28), which can be explained by the elimination of an amine from intermediate 27 [48]. The occurrence of Mannich-type intermediates (30) was also confirmed in the reaction of HPA (9) with N-tertbutylbenzalimine (29) by its trapping in basic conditions at low temperatures to yield βlactam products (31), which can be explained by the attack of the amine on the vicinal carbonyl group (Scheme 11) [49]. Scheme 11. Diastereoselective synthesis of β-lactams from imines and HPA.
Further experimental evidence supporting this mechanism is the fact that the CCR is catalysed by N-methylimidazole (32), which has been proposed to favour the amine acylation of the Mannich adduct intermediate (27) through a more reactive intermediate (33;Scheme 12) [45]. An experimental fact that supports this mechanism is the formation, under certain conditions, of a Knoevenagel-type alkene product (28), which can be explained by the elimination of an amine from intermediate 27 [48]. The occurrence of Mannich-type intermediates (30) was also confirmed in the reaction of HPA (9) with N-tert-butylbenzalimine (29) by its trapping in basic conditions at low temperatures to yield β-lactam products (31), which can be explained by the attack of the amine on the vicinal carbonyl group (Scheme 11) [49].
Molecules 2023, 28, x FOR PEER REVIEW 5 of 46 opening of the anhydride from the intramolecular attack of the intermediate amine (27; Scheme 10) [30,47]. An experimental fact that supports this mechanism is the formation, under certain conditions, of a Knoevenagel-type alkene product (28), which can be explained by the elimination of an amine from intermediate 27 [48]. The occurrence of Mannich-type intermediates (30) was also confirmed in the reaction of HPA (9) with N-tertbutylbenzalimine (29) by its trapping in basic conditions at low temperatures to yield βlactam products (31), which can be explained by the attack of the amine on the vicinal carbonyl group (Scheme 11) [49]. Scheme 11. Diastereoselective synthesis of β-lactams from imines and HPA.
Further experimental evidence supporting this mechanism is the fact that the CCR is catalysed by N-methylimidazole (32), which has been proposed to favour the amine acylation of the Mannich adduct intermediate (27) through a more reactive intermediate (33;Scheme 12) [45]. Shaw and Cheong proposed a Mannich reaction between the enolate of cyanosuccinic anhydride and the iminium cation which forms a pseudo-Zimmerman-Traxler transition state (TS) where the instability of zwitterionic intermediates is alleviated by hydrogen Scheme 11. Diastereoselective synthesis of β-lactams from imines and HPA.
Further experimental evidence supporting this mechanism is the fact that the CCR is catalysed by N-methylimidazole (32), which has been proposed to favour the amine acylation of the Mannich adduct intermediate (27) through a more reactive intermediate (33;Scheme 12) [45].
Molecules 2023, 28, x FOR PEER REVIEW 5 of 46 opening of the anhydride from the intramolecular attack of the intermediate amine (27; Scheme 10) [30,47]. An experimental fact that supports this mechanism is the formation, under certain conditions, of a Knoevenagel-type alkene product (28), which can be explained by the elimination of an amine from intermediate 27 [48]. The occurrence of Mannich-type intermediates (30) was also confirmed in the reaction of HPA (9) with N-tertbutylbenzalimine (29) by its trapping in basic conditions at low temperatures to yield βlactam products (31), which can be explained by the attack of the amine on the vicinal carbonyl group (Scheme 11) [49]. Further experimental evidence supporting this mechanism is the fact that the CCR is catalysed by N-methylimidazole (32), which has been proposed to favour the amine acylation of the Mannich adduct intermediate (27)  Shaw and Cheong proposed a Mannich reaction between the enolate of cyanosuccinic anhydride and the iminium cation which forms a pseudo-Zimmerman-Traxler transition state (TS) where the instability of zwitterionic intermediates is alleviated by hydrogen Shaw and Cheong proposed a Mannich reaction between the enolate of cyanosuccinic anhydride and the iminium cation which forms a pseudo-Zimmerman-Traxler transition state (TS) where the instability of zwitterionic intermediates is alleviated by hydrogen bonds. Subsequent transannular acylation would yield the final product, satisfactorily explaining both the reactivity and stereoselectivity reported by different authors for related reactions of HPAs with imines [30].
Knapp outlined different Mannich transition state possibilities for the HPA-imine reaction [49]. A transition state stabilised by the hydrogen bond between the enol and the imine nitrogen can adopt two different geometries. The aryl group can be placed either close to the benzo ring in a "chair" configuration, or away from the benzo ring in a "boat" configuration. Alternatively, an "open" transition state may also be possible, in which the favoured relative orientation of the HPA enolate and the iminium cation will depend on the relative size of the nitrogen substituent R. Knapp's experimental results, in which the ratio of cis versus trans products increases with the increasing size of the N-substituents (Me < n-Bu < i-Bu < t-Bu), lead to the conclusion that the reaction proceeds through an open transition state that leads to a short-lived amino-anhydride intermediate (27).
It has been shown that CCRs can be enantiocontrolled by classical hydrogen bond donor-acceptor catalysts, such as chiral ureas and thioureas, and squaramides, as exemplified by compounds 34a-m ( Figure 1) [50][51][52]. bonds. Subsequent transannular acylation would yield the final product, satisfactorily explaining both the reactivity and stereoselectivity reported by different authors for related reactions of HPAs with imines [30]. Knapp outlined different Mannich transition state possibilities for the HPA-imine reaction [49]. A transition state stabilised by the hydrogen bond between the enol and the imine nitrogen can adopt two different geometries. The aryl group can be placed either close to the benzo ring in a ''chair" configuration, or away from the benzo ring in a ''boat" configuration. Alternatively, an ''open" transition state may also be possible, in which the favoured relative orientation of the HPA enolate and the iminium cation will depend on the relative size of the nitrogen substituent R. Knapp's experimental results, in which the ratio of cis versus trans products increases with the increasing size of the N-substituents (Me < n-Bu < i-Bu < t-Bu), lead to the conclusion that the reaction proceeds through an open transition state that leads to a short-lived amino-anhydride intermediate (27).
It has been shown that CCRs can be enantiocontrolled by classical hydrogen bond donor-acceptor catalysts, such as chiral ureas and thioureas, and squaramides, as exemplified by compounds 34a-m ( Figure 1) [50][51][52]. DFT calculations suggest that in all cases the hydrogen bonding of the catalyst to the anhydride stabilises the formation of an ion-paired iminium-enolate intermediate. Specifically, the enolate forms interactions with the N-H of thiourea or squaramide unit of the catalyst, while the iminium cation forms additional hydrogen-bonds with a carbonyl on the urea or amide groups (Scheme 13) [50]. DFT calculations suggest that in all cases the hydrogen bonding of the catalyst to the anhydride stabilises the formation of an ion-paired iminium-enolate intermediate. Specifically, the enolate forms interactions with the N-H of thiourea or squaramide unit of the catalyst, while the iminium cation forms additional hydrogen-bonds with a carbonyl on the urea or amide groups (Scheme 13) [50]. Interestingly, Cossío et al. reported the reaction between HPA (9) and imines (15) in the presence of TiCl4 and diisopropyl ethyl amine to be trans-selective in contrast with the uncatalysed reaction made in dichloromethane at room temperature (rt), whose stereochemistry depends on the nature of the nitrogen substituent R. DFT calculations reveal that the TiCl4-catalysed reaction takes place through a Perkin-Mannich pathway Scheme 13. Representative mechanism of the enantioselective CCR catalysed by general urea. Interestingly, Cossío et al. reported the reaction between HPA (9) and imines (15) in the presence of TiCl 4 and diisopropyl ethyl amine to be trans-selective in contrast with the uncatalysed reaction made in dichloromethane at room temperature (rt), whose stereochemistry depends on the nature of the nitrogen substituent R. DFT calculations reveal that the TiCl 4 -catalysed reaction takes place through a Perkin-Mannich pathway where both the imine and the anhydride enolate are linked to the titanium in a TS (36) which favours the trans adduct (Scheme 14) [53]. Scheme 13. Representative mechanism of the enantioselective CCR catalysed by general urea.
Interestingly, Cossío et al. reported the reaction between HPA (9) and imines (15) the presence of TiCl4 and diisopropyl ethyl amine to be trans-selective in contrast with th uncatalysed reaction made in dichloromethane at room temperature (rt), who stereochemistry depends on the nature of the nitrogen substituent R. DFT calculatio reveal that the TiCl4-catalysed reaction takes place through a Perkin-Mannich pathwa where both the imine and the anhydride enolate are linked to the titanium in a TS (3 which favours the trans adduct (Scheme 14) [53]. Scheme 14. CCR catalysed by TiCl4.

Anhydride Substrates
The traditional CCR involves an imine and an anhydride (commonly succin glutaric, or homophthalic anhydrides) allowing the synthesis of lactams with differe substitution patterns. Post-condensation transformations can lead to more compl structures or a different substitution pattern. For example, β-carboxyl-γ-butyrolactam have been obtained by decarboxylative fluorination of the CCR adducts of succin anhydrides using Selectfluor ® as a fluorine source [54]. However, in the last decad several efforts have been made to increase the anhydride scope of CCR, which has allowe for the expansion of the product space covered by this reaction.

5-Membered Cyclic Anhydrides
An obvious extension of the CCR is the use of substituted succinic and glutar anhydrides. Castagnoli and Cushman's early reports already include the use substituted anhydrides, such as 3,3-dimethylsuccinic anhydride [40] and phenylsuccin anhydride [39]. Substitution not only introduces structural diversity but sometimes al offers synthetic advantages. Substituents that stabilise the anhydride enolate significant facilitate the reaction. Thus, Shaw reported the smooth reaction of 2-fluoronitrophenylsuccinic anhydride (38) with imines (15) in toluene at room temperatu (Scheme 15). However, as happens with other reactions at low temperatures, th diatereoselectivity is modest [29,41]. The reaction was also performed on the solid pha under microwave irradiation [29]. The resulting carboxylic acids (39) can be transforme into the corresponding methyl esters or amides as a mixture of diasteroisomers easi separated by column chromatography. Post-condensation transformations of Castagnol Cushman adducts have been employed by a number of groups to obtain compl Scheme 14. CCR catalysed by TiCl 4 .

Anhydride Substrates
The traditional CCR involves an imine and an anhydride (commonly succinic, glutaric, or homophthalic anhydrides) allowing the synthesis of lactams with different substitution patterns. Post-condensation transformations can lead to more complex structures or a different substitution pattern. For example, β-carboxyl-γ-butyrolactams have been obtained by decarboxylative fluorination of the CCR adducts of succinic anhydrides using Selectfluor ® as a fluorine source [54]. However, in the last decade, several efforts have been made to increase the anhydride scope of CCR, which has allowed for the expansion of the product space covered by this reaction.

5-Membered Cyclic Anhydrides
An obvious extension of the CCR is the use of substituted succinic and glutaric anhydrides. Castagnoli and Cushman's early reports already include the use of substituted anhydrides, such as 3,3-dimethylsuccinic anhydride [40] and phenylsuccinic anhydride [39]. Substitution not only introduces structural diversity but sometimes also offers synthetic advantages. Substituents that stabilise the anhydride enolate significantly facilitate the reaction. Thus, Shaw reported the smooth reaction of 2-fluoro-5-nitrophenylsuccinic anhydride (38) with imines (15) in toluene at room temperature (Scheme 15). However, as happens with other reactions at low temperatures, the diatereoselectivity is modest [29,41]. The reaction was also performed on the solid phase under microwave irradiation [29]. The resulting carboxylic acids (39) can be transformed into the corresponding methyl esters or amides as a mixture of diasteroisomers easily separated by column chromatography. Post-condensation transformations of Castagnoli-Cushman adducts have been employed by a number of groups to obtain complex molecules with applications in different fields. Here, biologically relevant cores, such spirooxindoles (40) were readily obtained from 39 in just two steps (Scheme 15) [29,41]. Alternatively, the reaction of bromo-or iodoaryl imines (41) with aryl-substituted succinic anhydrides (42) yielded tricyclic dihydroquinolones (44) by an intramolecular amidation reaction of the corresponding amidolactams (43; Scheme 16) [29]. Scheme 15. Synthesis of γ-lactams and spirobicyclic lactams from imines and succinic anhydrides (HOBt: Hydroxybenzotriazole, EDC: 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide).
Alternatively, the reaction of bromo-or iodoaryl imines (41) with aryl-substituted succinic anhydrides (42) yielded tricyclic dihydroquinolones (44) by an intramolecular amidation reaction of the corresponding amidolactams (43; Scheme 16) [29]. Recently, aryl-substituted succinic anhydrides (42) have proved to be effective in CCR couplings with asymmetric bisurea catalysis (Scheme 17) [52]. The presence of a phenyl ring is essential for the correct orientation of the Mannich-type transition state, which is conducted on products with high diastereo-and enantioselelectivities and very good yields. Scheme 17. Asymmetric CCR with a phenyl-modified succinic anhydride.
Shaw and co-workers performed a highly diastereoselective reaction of imines (15) and arylthio-substituted succinic anhydrides (46; Scheme 18) [55]. The preferred enolisation of the thioaryl substituted α position undoubtedly determines the regio-and stereoselectivity of this reaction [42]. Recently, aryl-substituted succinic anhydrides (42) have proved to be effective in CCR couplings with asymmetric bisurea catalysis (Scheme 17) [52]. The presence of a phenyl ring is essential for the correct orientation of the Mannich-type transition state, which is conducted on products with high diastereo-and enantioselelectivities and very good yields.
Alternatively, the reaction of bromo-or iodoaryl imines (41) with aryl-substituted succinic anhydrides (42) yielded tricyclic dihydroquinolones (44) by an intramolecular amidation reaction of the corresponding amidolactams (43; Scheme 16) [29]. Recently, aryl-substituted succinic anhydrides (42) have proved to be effective in CCR couplings with asymmetric bisurea catalysis (Scheme 17) [52]. The presence of a phenyl ring is essential for the correct orientation of the Mannich-type transition state, which is conducted on products with high diastereo-and enantioselelectivities and very good yields. Scheme 17. Asymmetric CCR with a phenyl-modified succinic anhydride.
Shaw and co-workers performed a highly diastereoselective reaction of imines (15) and arylthio-substituted succinic anhydrides (46; Scheme 18) [55]. The preferred enolisation of the thioaryl substituted α position undoubtedly determines the regio-and stereoselectivity of this reaction [42]. Shaw and co-workers performed a highly diastereoselective reaction of imines (15) and arylthio-substituted succinic anhydrides (46; Scheme 18) [55]. The preferred enolisation of the thioaryl substituted α position undoubtedly determines the regio-and stereoselectivity of this reaction [42]. Reactions with other substituted succinic anhydrides were developed by Shaw's group [41]. Cyanosuccinic anhydrides (48) react smoothly at room temperature to produce highly substituted γ-lactams in high yield and with high diastereoselectivity. The resulting carboxylic acid can be further converted into its methyl ester (49) and reduction of the nitrile can lead to the corresponding amines by hydrogenation with Nickel-Raney catalysis. The use of enantiomerically pure alkyl-substituted cyanosuccinic anhydrides affords enantiomerically pure penta-substituted lactam products (Scheme 19) [30,31]. Reactions with other substituted succinic anhydrides were developed by Shaw's group [41]. Cyanosuccinic anhydrides (48) react smoothly at room temperature to produce highly substituted γ-lactams in high yield and with high diastereoselectivity. The resulting carboxylic acid can be further converted into its methyl ester (49) and reduction of the nitrile can lead to the corresponding amines by hydrogenation with Nickel-Raney catalysis. The use of enantiomerically pure alkyl-substituted cyanosuccinic anhydrides affords enantiomerically pure penta-substituted lactam products (Scheme 19) [30,31].
Reactions with other substituted succinic anhydrides were developed by Shaw's group [41]. Cyanosuccinic anhydrides (48) react smoothly at room temperature to produce highly substituted γ-lactams in high yield and with high diastereoselectivity. The resulting carboxylic acid can be further converted into its methyl ester (49) and reduction of the nitrile can lead to the corresponding amines by hydrogenation with Nickel-Raney catalysis. The use of enantiomerically pure alkyl-substituted cyanosuccinic anhydrides affords enantiomerically pure penta-substituted lactam products (Scheme 19) [30,31]. Likewise, sulfone-substituted succinic anhydrides (50) produce the corresponding sulfone-substituted γ-lactam carboxylic acids that can be trapped as methyl esters (52) or allowed to decarboxylate under mild conditions to yield anti-sulfones (51; Scheme 20). Sulfone-substituted γ-lactam 52 can also be smoothly desulfonylated with magnesium in methanol to produce the corresponding lactam 53 in good yields [56]. This strategy was employed for the preparation of the alkaloid (±)-isoretronecanol (57) from the imine 54a and anhydride 50. The ester (55) was then subjected to a ringclosing metathesis to produce the pyrrolizidine scaffold (56) that yields (±)isoretronecanol (57) through two alternative routes in three or two reaction steps, respectively (Scheme 21) [56]. Likewise, sulfone-substituted succinic anhydrides (50) produce the corresponding sulfone-substituted γ-lactam carboxylic acids that can be trapped as methyl esters (52) or allowed to decarboxylate under mild conditions to yield anti-sulfones (51; Scheme 20). Sulfone-substituted γ-lactam 52 can also be smoothly desulfonylated with magnesium in methanol to produce the corresponding lactam 53 in good yields [56].
group [41]. Cyanosuccinic anhydrides (48) react smoothly at room temperature to produce highly substituted γ-lactams in high yield and with high diastereoselectivity. The resulting carboxylic acid can be further converted into its methyl ester (49) and reduction of the nitrile can lead to the corresponding amines by hydrogenation with Nickel-Raney catalysis. The use of enantiomerically pure alkyl-substituted cyanosuccinic anhydrides affords enantiomerically pure penta-substituted lactam products (Scheme 19) [30,31]. Likewise, sulfone-substituted succinic anhydrides (50) produce the corresponding sulfone-substituted γ-lactam carboxylic acids that can be trapped as methyl esters (52) or allowed to decarboxylate under mild conditions to yield anti-sulfones (51; Scheme 20). Sulfone-substituted γ-lactam 52 can also be smoothly desulfonylated with magnesium in methanol to produce the corresponding lactam 53 in good yields [56]. This strategy was employed for the preparation of the alkaloid (±)-isoretronecanol (57) from the imine 54a and anhydride 50. The ester (55) was then subjected to a ringclosing metathesis to produce the pyrrolizidine scaffold (56) that yields (±)isoretronecanol (57) through two alternative routes in three or two reaction steps, respectively (Scheme 21) [56]. This strategy was employed for the preparation of the alkaloid (±)-isoretronecanol (57) from the imine 54a and anhydride 50. The ester (55) was then subjected to a ring-closing metathesis to produce the pyrrolizidine scaffold (56) that yields (±)-isoretronecanol (57) through two alternative routes in three or two reaction steps, respectively (Scheme 21) [56]. Surprisingly, other heteroatom-substituted succinic anhydrides, such as those containing -OCH3, -OPh, -NHCHO, and 1-pyrrolyl, did not react or yield unidentified products [55].
An anionic version of the Castagnoli-Cushman reaction was developed by Shaw and was used for the synthesis of the phytoalexin bisavenanthramide B-6 (62) [57]. In this reaction, 3-benzylidenedihydrofuran-2,5-dione (58) is treated with sodium hydride at a low temperature to yield the corresponding enolate (59). This reacts with N-sulfonyl protected imine (60) to produce a trans-δ-lactam intermediate (61) which is further transformed into the desired bisavenanthramide B-6 (62) by a double Buchwald Narylation (Scheme 22).
An anionic version of the Castagnoli-Cushman reaction was developed by Shaw and was used for the synthesis of the phytoalexin bisavenanthramide B-6 (62) [57]. In this reaction, 3-benzylidenedihydrofuran-2,5-dione (58) is treated with sodium hydride at a low temperature to yield the corresponding enolate (59). This reacts with N-sulfonyl protected imine (60) to produce a trans-δ-lactam intermediate (61) which is further transformed into the desired bisavenanthramide B-6 (62) by a double Buchwald N-arylation (Scheme 22).
was used for the synthesis of the phytoalexin bisavenanthramide B-6 (62) [57]. In this reaction, 3-benzylidenedihydrofuran-2,5-dione (58) is treated with sodium hydride at a low temperature to yield the corresponding enolate (59). This reacts with N-sulfonyl protected imine (60) to produce a trans-δ-lactam intermediate (61) which is further transformed into the desired bisavenanthramide B-6 (62) by a double Buchwald Narylation (Scheme 22). Likewise, a Mukaiyama-aldol type reaction has been described by Pohmakotr and Reutrakul, where 2,5-bis(trimethysilyloxy)furan (63) reacts with imines (15), employing Sc(OTf)3 as a catalyst, to produce the lactam 17a (Scheme 23) [58]. An interesting attempt to incorporate new anhydrides into the CCR chemical arsenal was made by Shaw and co-workers, who reacted alkyl-substituted maleic anhydrides (64-Scheme 23. Mukaiyama-related CCR. An interesting attempt to incorporate new anhydrides into the CCR chemical arsenal was made by Shaw and co-workers, who reacted alkyl-substituted maleic anhydrides (64)(65) with the imines 66-68, providing valuable information about the behaviour of maleic anhydride analogues in CCR [36]. Allylic stabilisation of the intermediate enolates facilitates the reaction of alkyl-substituted maleic anhydrides (64-65) with cyclic (67-68) or acyclic imines (66, R = H), providing a synthesis of unsaturated lactams 69-72. The kinetic anti-diestereoisomer is usually formed as the major product. Interestingly, diastereoselectivity is reversed when the reaction is performed in the presence of triethylamine and triethylammonium hydrochloride, and regiochemistry seems to be defined by the alkyl region of the anhydride (Scheme 24).
According to the currently accepted mechanism of the CCR [49,59], polycyclic lactams 71 are formed by a first attack of the allylic enolate of anhydride 64 to the imine 67, yielding the intermediate 73. Then, cyclisation by the intramolecular attack of the nitrogen on the distal carbonyl of the anhydride results in the final product (71a; Scheme 25) [36].
Interestingly, Royer and co-workers published an identical synthesis of syn lactam 71b simultaneously and independently from that of Shaw. They also reported the reduction of the amide function by treatment with [Et3O]BF4 followed by NaBH4 to yield antihyperglycemic alkaloid jamtine 82 (Scheme 28) [37].
Succinic anhydride derivatives in which one of the endocyclic carbons has been replaced with a heteroatom have also been successfully used in CCRs. For instance, Sucu and co-workers employed Leuch s anhydride (83), a special succinic-type anhydride that can be obtained from amino acids, to obtain a CCR-type product 84 by condensation with imines (15) in the presence of a base with MeOH as a solvent (Scheme 29) [60]. Interestingly, Royer and co-workers published an identical synthesis of syn lactam 71b simultaneously and independently from that of Shaw. They also reported the reduction of the amide function by treatment with [Et 3 O]BF 4 followed by NaBH 4 to yield antihyperglycemic alkaloid jamtine 82 (Scheme 28) [37]. Similarly, the reaction of disubstituted maleic anhydrides (65) with cyclic ketimines (77) allowed for obtaining new tricyclic unsaturated lactam CCR adducts (81) through an iminolysis/aza-Michael sequence (Scheme 27). Interestingly, Royer and co-workers published an identical synthesis of syn lactam 71b simultaneously and independently from that of Shaw. They also reported the reduction of the amide function by treatment with [Et3O]BF4 followed by NaBH4 to yield antihyperglycemic alkaloid jamtine 82 (Scheme 28) [37].
Succinic anhydride derivatives in which one of the endocyclic carbons has been replaced with a heteroatom have also been successfully used in CCRs. For instance, Sucu and co-workers employed Leuch s anhydride (83), a special succinic-type anhydride that can be obtained from amino acids, to obtain a CCR-type product 84 by condensation with imines (15) in the presence of a base with MeOH as a solvent (Scheme 29) [60].
Succinic anhydride derivatives in which one of the endocyclic carbons has been replaced with a heteroatom have also been successfully used in CCRs. For instance, Sucu and co-workers employed Leuch s anhydride (83), a special succinic-type anhydride that can be obtained from amino acids, to obtain a CCR-type product 84 by condensation with imines (15) in the presence of a base with MeOH as a solvent (Scheme 29) [60].

Six-Membered Cyclic Anhydrides
As part of a work on the development of solvent-free CCRs, Krasavin and colleagues made use of alkyl-substituted glutaric anhydrides, which showed the same behaviour as unsubstituted reagents, to produce the corresponding lactams without significant modifications in yield or diastereoselectivity [35].

Six-Membered Cyclic Anhydrides
As part of a work on the development of solvent-free CCRs, Krasavin and colleagues made use of alkyl-substituted glutaric anhydrides, which showed the same behaviour as unsubstituted reagents, to produce the corresponding lactams without significant modifications in yield or diastereoselectivity [35].
2-Cyano-glutaric anhydrides 85 and 87 have been found to readily react with different N-arylarylmethanimines (15) to produce 2-piperidinones 86 and 88, respectively, in high yields. Notably, this process involves the generation of three new stereogenic centres with good diastereoselectivities (Scheme 30) [61]. made use of alkyl-substituted glutaric anhydrides, which showed the same behaviour as unsubstituted reagents, to produce the corresponding lactams without significant modifications in yield or diastereoselectivity [35].
unsubstituted reagents, to produce the corresponding lactams without significant modifications in yield or diastereoselectivity [35].
Further, the Vilsmeier-Haack functionalisation of morpholinonates and thiomorpholinonates (92a,b) produced persubstituted N,O-and N,S-heterocyclic vinyl chlorides that were readily coupled with terminal acetylenes and styrenes or subjected to Scheme 32. CCR with glutaric anhydride analogues containing endocyclic heteroatoms.
Further, the Vilsmeier-Haack functionalisation of morpholinonates and thiomorpholinonates (92a,b) produced persubstituted N,Oand N,S-heterocyclic vinyl chlorides that were readily coupled with terminal acetylenes and styrenes or subjected to a Wittig/Diels-Alder sequence to generate a variety of heterocyclic scaffolds [66].
Further, the Vilsmeier-Haack functionalisation of morpholinonates and thiomorpholinonates (92a,b) produced persubstituted N,O-and N,S-heterocyclic vinyl chlorides that were readily coupled with terminal acetylenes and styrenes or subjected to a Wittig/Diels-Alder sequence to generate a variety of heterocyclic scaffolds [66].
These hetero-substituted anhydrides (25a-c) are more prone to enolisation than the parent glutaric anhydride (19) and, thus, can react in milder conditions. Aryl substituents in the α position also favour enolisation in this position. The combination of both structural features in 3-phenyl-1,4-oxathiane-2,6-dione (96) makes it possible for this anhydride to react at room temperature, yielding a diastereomeric mixture of products (97) in an approximate 1:1 ratio (Scheme 33) [67].
Noticeably, the reaction of anhydride 96 with imines containing bulky motifs leads, in addition to the desired syn/anti mixture of CCR adducts, to the products of the CCR at the less hindered α-position (98), which include three stereogenic centres.
Noticeably, the reaction of anhydride 96 with imines containing bulky motifs leads, in addition to the desired syn/anti mixture of CCR adducts, to the products of the CCR at the less hindered α-position (98), which include three stereogenic centres.

Scheme 39. Synthesis of BACE1 inhibitors by the Castagnoli-Cushman reaction.
Homophthalic anhydride (HPA, 9) is easily enolisable, and it is one of the most used anhydrides in the CCR. The reaction of different imines 15 with HPA (9) affords the racemic trans isoquinolones (21a) that can be transformed into carboxamide derivatives (123) by amide coupling reactions (Scheme 40) [74]. The introduction of different substituents on the N-2, C-3, and C-4 of the tetrahydro-1-isoquinolone-4-carboxanilides (124) allows for modulating their physiochemical and pharmacological properties. After investigation of the in vivo antimalarial activity of this series, derivatives 124-126 showed high potency, and compound 126 was selected for further study as a preclinical candidate Scheme 38. Tricyclic lactone core from CCR couplings.

Scheme 39. Synthesis of BACE1 inhibitors by the Castagnoli-Cushman reaction.
Homophthalic anhydride (HPA, 9) is easily enolisable, and it is one of the most used anhydrides in the CCR. The reaction of different imines 15 with HPA (9) affords the racemic trans isoquinolones (21a) that can be transformed into carboxamide derivatives (123) by amide coupling reactions (Scheme 40) [74]. The introduction of different substituents on the N-2, C-3, and C-4 of the tetrahydro-1-isoquinolone-4-carboxanilides (124) allows for modulating their physiochemical and pharmacological properties. After investigation of the in vivo antimalarial activity of this series, derivatives 124-126 showed high potency, and compound 126 was selected for further study as a preclinical candidate ( Figure 2) [75]. Homophthalic anhydride (HPA, 9) is easily enolisable, and it is one of the most used anhydrides in the CCR. The reaction of different imines 15 with HPA (9) affords the racemic trans isoquinolones (21a) that can be transformed into carboxamide derivatives (123) by amide coupling reactions (Scheme 40) [74]. The introduction of different substituents on the N-2, C-3, and C-4 of the tetrahydro-1-isoquinolone-4-carboxanilides (124) allows for modulating their physiochemical and pharmacological properties. After investigation of the in vivo antimalarial activity of this series, derivatives 124-126 showed high potency, and compound 126 was selected for further study as a preclinical candidate ( Figure 2) [75].
Homophthalic anhydride (HPA, 9) is easily enolisable, and it is one of the most used anhydrides in the CCR. The reaction of different imines 15 with HPA (9) affords the racemic trans isoquinolones (21a) that can be transformed into carboxamide derivatives (123) by amide coupling reactions (Scheme 40) [74]. The introduction of different substituents on the N-2, C-3, and C-4 of the tetrahydro-1-isoquinolone-4-carboxanilides (124) allows for modulating their physiochemical and pharmacological properties. After investigation of the in vivo antimalarial activity of this series, derivatives 124-126 showed high potency, and compound 126 was selected for further study as a preclinical candidate ( Figure 2) [75]. In a recent application of the CCR, the condensation of DNA-conjugated imines with HPA enabled the synthesis of an isoquinolone core-focused DNA-encoded library [76,77].
Molecules 2023, 28, x FOR PEER REVIEW 19 Indolophenanthridines (138) were analogously obtained from homophth anhydrides (133)  Other topoisomerase I inhibitors were prepared using the Castagnoli-Cushm reaction as starting point. For example, the reaction of aniline-derived imine (139) w 4,5-dimethoxyhomophthalic anhydride (129) in chloroform at room temperature affo lactam 140, which can be further transformed to obtain topoisomerase I inhibitor chloro-8,9-dimethoxy-5-methyldibenzo[c,h][1,6]naphthyridin-6(5H)-one (141; Scheme [84,85]. The CCR of HPA (9) with imines derived from aryl glyoxals and monoprotect diamines (154) affords tetrahydroisoquinolines (155) that were readily transformed pyrazino-and diazepino-fused isoquinolones (156)(157)  The CCR of HPA (9) with imines derived from aryl glyoxals and monoprotected diamines (154) affords tetrahydroisoquinolines (155) that were readily transformed to pyrazino-and diazepino-fused isoquinolones (156)(157) in two chemical operations with moderate or good yields (Scheme 49) [89] Scheme 49. Synthesis of pyrazino-and diazepinoisoquinolones (TFA: trifluoroacetic acid). The CCR of HPA (9) with imines derived from aryl glyoxals and monoprotected diamines (154) affords tetrahydroisoquinolines (155) that were readily transformed to pyrazino-and diazepino-fused isoquinolones (156)(157) in two chemical operations with moderate or good yields (Scheme 49) [89]. The CCR of HPA (9) with imines derived from aryl glyoxals and monoprotected diamines (154) affords tetrahydroisoquinolines (155) that were readily transformed to pyrazino-and diazepino-fused isoquinolones (156)(157)  Additionally, the reaction of HPA (9) with cyclic imine indolenines (158) yields natural product-like benzene-fused hexahydropyrrolo [ As mentioned above, the reaction of imines (15) and HPA (9) in the presence of chiral thiourea organocatalysts (34) was reported to produce the anticipated cis-isoquinolonic acids with high diastereo and enantioselectivities (Scheme 13) [50], similarly to what happens with α-aryl succinic anhydrides (Scheme 17) [52]. Seidel and co-workers used alkoxyisocoumarins (160) as preformed enolether anhydrides in the presence of boron trifluoride diethyl etherate to yield the corresponding δ-lactams. Treatment with sodium methoxide provoke the epimerisation of the initial cis/trans mixtures of products leads to the thermodynamically more stable trans isomers (161; Scheme 51) [91]. The use of a chiral sulfonamide-thiourea catalyst (34h) affords the corresponding lactams (161) moderate to good enantioselectivities. Azole-fused bicyclic anhydride derivatives were introduced in cycloaddition reactions by Tamura in 1985 [92], but they have also been exploited in the last decade as promising reagents in the CCR (Scheme 53). Krasavin's group has made a great effort in this direction. They used (for the first time) a pyrazole-fused cyclic anhydride (165)[93] to lead to the corresponding trans-CCR adducts (166) (Scheme 53A). Moderate 22-70% yields were obtained, possibly due to the formation of several minor by-products. Indole-and As mentioned above, the reaction of imines (15) and HPA (9) in the presence of chiral thiourea organocatalysts (34) was reported to produce the anticipated cis-isoquinolonic acids with high diastereo and enantioselectivities (Scheme 13) [50], similarly to what happens with α-aryl succinic anhydrides (Scheme 17) [52]. Seidel and co-workers used alkoxyisocoumarins (160) as preformed enolether anhydrides in the presence of boron trifluoride diethyl etherate to yield the corresponding δ-lactams. Treatment with sodium methoxide provoke the epimerisation of the initial cis/trans mixtures of products leads to the thermodynamically more stable trans isomers (161; Scheme 51) [91]. The use of a chiral sulfonamide-thiourea catalyst (34h) affords the corresponding lactams (161) moderate to good enantioselectivities. Additionally, the reaction of HPA (9) with cyclic imine indolenines (158) yields natural product-like benzene-fused hexahydropyrrolo [ As mentioned above, the reaction of imines (15) and HPA (9) in the presence of chiral thiourea organocatalysts (34) was reported to produce the anticipated cis-isoquinolonic acids with high diastereo and enantioselectivities (Scheme 13) [50], similarly to what happens with α-aryl succinic anhydrides (Scheme 17) [52]. Seidel and co-workers used alkoxyisocoumarins (160) as preformed enolether anhydrides in the presence of boron trifluoride diethyl etherate to yield the corresponding δ-lactams. Treatment with sodium methoxide provoke the epimerisation of the initial cis/trans mixtures of products leads to the thermodynamically more stable trans isomers (161; Scheme 51) [91]. The use of a chiral sulfonamide-thiourea catalyst (34h) affords the corresponding lactams (161) moderate to good enantioselectivities. Azole-fused bicyclic anhydride derivatives were introduced in cycloaddition reactions by Tamura in 1985 [92], but they have also been exploited in the last decade as promising reagents in the CCR (Scheme 53). Krasavin's group has made a great effort in this direction. They used (for the first time) a pyrazole-fused cyclic anhydride (165)[93] to lead to the corresponding trans-CCR adducts (166) (Scheme 53A). Moderate 22-70% yields were obtained, possibly due to the formation of several minor by-products. Indole-and As mentioned above, the reaction of imines (15) and HPA (9) in the presence of chiral thiourea organocatalysts (34) was reported to produce the anticipated cis-isoquinolonic acids with high diastereo and enantioselectivities (Scheme 13) [50], similarly to what happens with α-aryl succinic anhydrides (Scheme 17) [52]. Seidel and co-workers used alkoxyisocoumarins (160) as preformed enolether anhydrides in the presence of boron trifluoride diethyl etherate to yield the corresponding δ-lactams. Treatment with sodium methoxide provoke the epimerisation of the initial cis/trans mixtures of products leads to the thermodynamically more stable trans isomers (161; Scheme 51) [91]. The use of a chiral sulfonamide-thiourea catalyst (34h) affords the corresponding lactams (161) moderate to good enantioselectivities. Azole-fused bicyclic anhydride derivatives were introduced in cycloaddition reactions by Tamura in 1985 [92], but they have also been exploited in the last decade as promising reagents in the CCR (Scheme 53). Krasavin's group has made a great effort in this direction. They used (for the first time) a pyrazole-fused cyclic anhydride (165)[93] to lead to the corresponding trans-CCR adducts (166) (Scheme 53A). Moderate 22-70% yields were obtained, possibly due to the formation of several minor by-products. Indole-and Azole-fused bicyclic anhydride derivatives were introduced in cycloaddition reactions by Tamura in 1985 [92], but they have also been exploited in the last decade as promising reagents in the CCR (Scheme 53). Krasavin's group has made a great effort in this direction. They used (for the first time) a pyrazole-fused cyclic anhydride (165) [93] to lead to the corresponding trans-CCR adducts (166) (Scheme 53A). Moderate 22-70% yields were obtained, possibly due to the formation of several minor by-products. Indole-and benzimidazole-fused anhydrides do not react in the usual CCR conditions; however, the pyrrole bicyclic anhydride 167 [94] showed exceptional features with the CCR (Scheme 53B). This anhydride (167) reacts at room temperature with N-alkyl- (168) and N-aryl-imines (170) and, remarkably, with "enolisable" α-C-H imines, which is not usual in CCR processes. Remarkably, tetrahydropyrrolopyrazine (171) is mostly obtained in its cis configuration, except when Ar is a thiophenyl group. Moreover, anhydride 167 readily reacts in the presence of triethylamine with aromatic aldehydes. Krasavin and co-workers argued that this outstanding reactivity can be justified by the efficient resonance stabilisation of its enol form involved in the Mannich-type mechanism. This hypothesis was recently confirmed [95] in a study where some pyrrole bicyclic anhydrides with electron-withdrawing groups (EWG) (172) reacted with several imines (168), presenting worse results compared to the non-substituted pyrrole-fused bicyclic anhydride (Scheme 53C). benzimidazole-fused anhydrides do not react in the usual CCR conditions; however, the pyrrole bicyclic anhydride 167 [94] showed exceptional features with the CCR (Scheme 53B). This anhydride (167) reacts at room temperature with N-alkyl- (168) and N-arylimines (170) and, remarkably, with "enolisable" α-C-H imines, which is not usual in CCR processes. Remarkably, tetrahydropyrrolopyrazine (171) is mostly obtained in its cis configuration, except when Ar is a thiophenyl group. Moreover, anhydride 167 readily reacts in the presence of triethylamine with aromatic aldehydes. Krasavin and co-workers argued that this outstanding reactivity can be justified by the efficient resonance stabilisation of its enol form involved in the Mannich-type mechanism (Scheme 53C). This hypothesis was recently confirmed [95] in a study where some pyrrole bicyclic anhydrides with electron-withdrawing groups (EWG) (172) reacted with several imines (168), presenting worse results compared to the non-substituted pyrrole-fused bicyclic anhydride (Scheme 53).

Higher Order Cyclic Anhydrides
Higher order anhydrides play a key role in the construction of novel derivatives of CCR. For example, seven-membered cyclic anhydride benzo[d]-oxepine-2,4(1H,5H)-dione (174) was found to react with imines (15)  benzimidazole-fused anhydrides do not react in the usual CCR conditions; however, the pyrrole bicyclic anhydride 167 [94] showed exceptional features with the CCR (Scheme 53B). This anhydride (167) reacts at room temperature with N-alkyl- (168) and N-arylimines (170) and, remarkably, with "enolisable" α-C-H imines, which is not usual in CCR processes. Remarkably, tetrahydropyrrolopyrazine (171) is mostly obtained in its cis configuration, except when Ar is a thiophenyl group. Moreover, anhydride 167 readily reacts in the presence of triethylamine with aromatic aldehydes. Krasavin and co-workers argued that this outstanding reactivity can be justified by the efficient resonance stabilisation of its enol form involved in the Mannich-type mechanism (Scheme 53C). This hypothesis was recently confirmed [95] in a study where some pyrrole bicyclic anhydrides with electron-withdrawing groups (EWG) (172) reacted with several imines (168), presenting worse results compared to the non-substituted pyrrole-fused bicyclic anhydride (Scheme 53).

Higher Order Cyclic Anhydrides
Higher order anhydrides play a key role in the construction of novel derivatives of CCR. For example, seven-membered cyclic anhydride benzo[d]-oxepine-2,4(1H,5H)-dione (174) was found to react with imines (15)  Encouraged by these results, Beng and co-workers used a set of cyclic anhydrides of different sizes, up to 12 members, and containing different heteroatoms ( Figure 3) in a reaction where the imine is generated in situ by deformylation of cyclic α-chloro eneformamides (185; Scheme 55) [98]. This work demonstrates that the Castagnoli-Cushman reaction is not limited to "classic" 5 and 6-membered anhydrides and can provide novel scaffolds in an outstanding way.
Encouraged by these results, Beng and co-workers used a set of cyclic anhydrides of different sizes, up to 12 members, and containing different heteroatoms ( Figure 3) in a reaction where the imine is generated in situ by deformylation of cyclic α-chloro eneformamides (185; Scheme 55) [98]. This work demonstrates that the Castagnoli-Cushman reaction is not limited to "classic" 5 and 6-membered anhydrides and can provide novel scaffolds in an outstanding way.

Diacid Anhydride Precursors
Imine-anhydride coupling using diacids as anhydride precursors is a valuable strategy for generating CCR adducts that cannot be obtained under conventional conditions [93]. The anhydrides are generated in situ from suitable diacids in the presence of a dehydrating agent and then undergo cycloaddition with the imines. For example, indole diacid 191 was found to react with imines and acetic anhydride to mostly produce the trans-isomer of tricyclic piperazines (192) in moderate yields (Scheme 57) [100]. In the case of azaindole dicarboxylic acid starting reagents (191, Y= N), the reaction was found to be significantly accelerated by microwave irradiation [38]. Encouraged by these results, Beng and co-workers used a set of cyclic anhydrides of different sizes, up to 12 members, and containing different heteroatoms (Figure 3) in a reaction where the imine is generated in situ by deformylation of cyclic α-chloro eneformamides (185; Scheme 55) [98]. This work demonstrates that the Castagnoli-Cushman reaction is not limited to "classic" 5 and 6-membered anhydrides and can provide novel scaffolds in an outstanding way.

Diacid Anhydride Precursors
Imine-anhydride coupling using diacids as anhydride precursors is a valuable strategy for generating CCR adducts that cannot be obtained under conventional conditions [93]. The anhydrides are generated in situ from suitable diacids in the presence of a dehydrating agent and then undergo cycloaddition with the imines. For example, indole diacid 191 was found to react with imines and acetic anhydride to mostly produce the trans-isomer of tricyclic piperazines (192) in moderate yields (Scheme 57) [100]. In the case of azaindole dicarboxylic acid starting reagents (191, Y= N), the reaction was found to be significantly accelerated by microwave irradiation [38]. Encouraged by these results, Beng and co-workers used a set of cyclic anhydrides of different sizes, up to 12 members, and containing different heteroatoms (Figure 3) in a reaction where the imine is generated in situ by deformylation of cyclic α-chloro eneformamides (185; Scheme 55) [98]. This work demonstrates that the Castagnoli-Cushman reaction is not limited to "classic" 5 and 6-membered anhydrides and can provide novel scaffolds in an outstanding way.

Diacid Anhydride Precursors
Imine-anhydride coupling using diacids as anhydride precursors is a valuable strategy for generating CCR adducts that cannot be obtained under conventional conditions [93]. The anhydrides are generated in situ from suitable diacids in the presence of a dehydrating agent and then undergo cycloaddition with the imines. For example, indole diacid 191 was found to react with imines and acetic anhydride to mostly produce the trans-isomer of tricyclic piperazines (192) in moderate yields (Scheme 57) [100]. In the case of azaindole dicarboxylic acid starting reagents (191, Y= N), the reaction was found to be significantly accelerated by microwave irradiation [38].

Diacid Anhydride Precursors
Imine-anhydride coupling using diacids as anhydride precursors is a valuable strategy for generating CCR adducts that cannot be obtained under conventional conditions [93]. The anhydrides are generated in situ from suitable diacids in the presence of a dehydrating agent and then undergo cycloaddition with the imines. For example, indole diacid 191 was found to react with imines and acetic anhydride to mostly produce the trans-isomer of tricyclic piperazines (192) in moderate yields (Scheme 57) [100]. In the case of azaindole dicarboxylic acid starting reagents (191, Y = N), the reaction was found to be significantly accelerated by microwave irradiation [38]. Diacid precursors of heteroatom-substituted arene-fused seven-membered cyclic anhydrides (203) reacted with imines (15) in a similar way to yield the corresponding εlactams (204), in contrast to their poor performance in the anhydride-imine "classic" CCR (Scheme 62) [105].  Diacid precursors of heteroatom-substituted arene-fused seven-membered cyclic anhydrides (203) reacted with imines (15) in a similar way to yield the corresponding εlactams (204), in contrast to their poor performance in the anhydride-imine "classic" CCR (Scheme 62) [105]. Scheme 62. Synthesis of arene-fused seven-membered nitrogen heterocycles.
Transformation of the diacid precursors into the corresponding anhydrides can also be facilitated by other dehydrating agents, such as 1,1′-carbonyldiimidazole (206) [106]. This allows for using substrates prone to acylation or sensitive to acidic conditions, such as hydroxyphenyl-substituted imines, that in these conditions afford hydroxyaryl-derived lactams, such as 208 (Scheme 63). Scheme 63. CCR using diacid starting materials in the presence of 1,1′-carbonyldiimidazole.

Dicarboxylic Acid Monoesters
Krasavin and co-workers recently reported the use of o-(alkoxycarbonyl)methyl benzoic acids (209) in place of homophthalic anhydride. Activation of the acid with 1,1′carbonyldiimidazole (CDI) allows for obtaining tetrahydroisoquinolonic esters (213) directly, according to the mechanism shown in Scheme 64 [107]. Transformation of the diacid precursors into the corresponding anhydrides can also be facilitated by other dehydrating agents, such as 1,1 -carbonyldiimidazole (206) [106]. This allows for using substrates prone to acylation or sensitive to acidic conditions, such as hydroxyphenyl-substituted imines, that in these conditions afford hydroxyaryl-derived lactams, such as 208 (Scheme 63). Scheme 61. CCR with 3-aryl glutaric acids.

Dicarboxylic Acid Monoesters
Krasavin and co-workers recently reported the use of o-(alkoxycarbonyl)methyl benzoic acids (209) in place of homophthalic anhydride. Activation of the acid with 1,1carbonyldiimidazole (CDI) allows for obtaining tetrahydroisoquinolonic esters (213) directly, according to the mechanism shown in Scheme 64 [107]. The scope of this variant of the CCR has been extended to other o-methyl benzoic acids α-substituted with electron-withdrawing groups other than an ester. In this way, cyano-, amido-, and sulfonyl-substituted tetrahydroisoquinolones could be readily obtained by activation of the substrate acid with CDI or acetic anhydride [108].
On the other hand, the reaction of N-(2-methoxy-2-oxoethyl)-N-(phenylsulfonyl)glycine monomethyl esters (214) with imines (15) promoted by acetic anhydride led to β-lactams (217), instead of the initially expected Castagnoli-Cushmantype δ-lactams (Scheme 65) [109]. The products were obtained by a cyclisation involving a methylene group adjacent to the acid moiety. The scope of this variant of the CCR has been extended to other o-methyl benzoic acids α-substituted with electron-withdrawing groups other than an ester. In this way, cyano-, amido-, and sulfonyl-substituted tetrahydroisoquinolones could be readily obtained by activation of the substrate acid with CDI or acetic anhydride [108].
The scope of this variant of the CCR has been extended to other o-methyl benzoic acids α-substituted with electron-withdrawing groups other than an ester. In this way, cyano-, amido-, and sulfonyl-substituted tetrahydroisoquinolones could be readily obtained by activation of the substrate acid with CDI or acetic anhydride [108].

Scope of the Imine Substrates
Continuing the exploration of incorporating new reagents in the CCR, the imine component has also received recent attention. Thus, some research groups have introduced new functionalities, such as sulphur-containing groups. For instance, Cronin and co-workers reacted N-mesyl imines (218) and HPA (9) in the presence of asymmetric catalyst 34i in Methyl tert-butyl ether (MTBE) to afford the corresponding lactams (219). These were obtained in good yields with a preponderance of the trans-isomer (219b) in most of the cases (Scheme 66) [51]. Shaw also reported that N-sulfonyl imines (220), or the corresponding precursor aminosulfones (221), produced the desired CCR adducts (223) in high yields and good diastereoselectivity in a base-catalysed process with different anhydrides (222; Scheme 67) [110]. A similar strategy was also followed by Beng [98]. Notably, as already mentioned, a reaction with N-sulfonylimines was the key step in the synthesis of bisavenanthramide B-6 (62), one of the most successful applications of the CCR to total synthesis (Scheme 22) [57]. Scheme 65. Synthesis of β-lactams from dicarboxylic acid monoesters.
Later work by Shaw and co-workers demonstrated that conjugated ketoimines containing a tosyl group on the nitrogen (237) can react with enolisable anhydrides, such as HPA (9), in the presence of a base through the C-C double bond via a Tamura reaction (Scheme 71) [118].

Limitations
Although only an imine (15) and an anhydride (9) participate in the classical Castagnoli-Cushman reaction, this has usually been considered a multicomponent reaction, since the imine (15) can be obtained from the corresponding amine (275) and aldehyde (2). However, until recently it was assumed that anhydrides (9) cannot participate in real three-component reactions with aldehydes (2) and amines (275). It was commonly believed that the amine (275) rapidly reacts with the less hindered anhydride carbonyl to irreversibly yield a monoamide (276a) that can no longer incorporate the aldehyde component (Scheme 82). However, there is recent evidence that the reaction of the amine (275) with the anhydride (9) is reversible under certain conditions, making the coexistence of anhydride (9) and imine (15) in the reaction medium possible to some extent. Scheme 80. Cyclic imino ethers in the CCR (from [130]

Limitations
Although only an imine (15) and an anhydride (9) participate in the classical Castagnoli-Cushman reaction, this has usually been considered a multicomponent reaction, since the imine (15) can be obtained from the corresponding amine (275) and aldehyde (2). However, until recently it was assumed that anhydrides (9) cannot participate in real three-component reactions with aldehydes (2) and amines (275). It was commonly believed that the amine (275) rapidly reacts with the less hindered anhydride carbonyl to irreversibly yield a monoamide (276a) that can no longer incorporate the aldehyde component (Scheme 82). However, there is recent evidence that the reaction of the amine (275) with the anhydride (9) is reversible under certain conditions, making the coexistence of anhydride (9) and imine (15) in the reaction medium possible to some extent. Scheme 81. Imidoyl chlorides in the CCR (from [131,133]).

Limitations
Although only an imine (15) and an anhydride (9) participate in the classical Castagnoli-Cushman reaction, this has usually been considered a multicomponent reaction, since the imine (15) can be obtained from the corresponding amine (275) and aldehyde (2). However, until recently it was assumed that anhydrides (9) cannot participate in real three-component reactions with aldehydes (2) and amines (275). It was commonly believed that the amine (275) rapidly reacts with the less hindered anhydride carbonyl to irreversibly yield a monoamide (276a) that can no longer incorporate the aldehyde component (Scheme 82). However, there is recent evidence that the reaction of the amine (275) with the anhydride (9) is reversible under certain conditions, making the coexistence of anhydride (9) and imine (15) in the reaction medium possible to some extent. participate in real three-component reactions with aldehydes (2) and amines (275). It was commonly believed that the amine (275) rapidly reacts with the less hindered anhydride carbonyl to irreversibly yield a monoamide (276a) that can no longer incorporate the aldehyde component (Scheme 82). However, there is recent evidence that the reaction of the amine (275) with the anhydride (9) is reversible under certain conditions, making the coexistence of anhydride (9) and imine (15) in the reaction medium possible to some extent. Scheme 82. Chemical transformations when mixing an anhydride, an amine, and an aldehyde, which supposedly hinder the success of a 3C-CCR.
In the last two decades, different solutions have been adopted to perform the CCR in a multicomponent manner. These are discussed in the following sections.

Sequential Reactions
The reaction of an aldehyde and an amine to yield a corresponding imine can be combined sequentially with the subsequent reaction with an anhydride. Ryabukhin and co-workers have used this simple strategy to combinatorially synthesise a library of 132 1,2disubstituted 5-oxopyrrolidine-and 6-oxopiperidine-3-carboxylic acids [134].
Analogously, a diacid and a dehydrating agent, such as acetic anhydride can be added to the recently formed imine with a similar result [135].

Catalysed and Thermal 3C-CCRs
Remarkably, the use of catalysts not only performs the reaction more efficiently and in milder conditions, but also permits, in certain cases, carrying out the three-component reaction with HPA (9), aldehydes (2), and amines (275). Azizian and co-workers reported that KAl(SO 4 ) 2 ·12 H 2 O (alum) effectively catalyses this reaction to yield cis-isoquinolonic acids (21b) with complete stereoselectivity (Scheme 83) [136]. The authors reported the isolation of a supposed intermediate amido acid (276b) that they argue would be transformed into the desired product (21b) when the reaction time was further extended. According to these results, they proposed a reaction mechanism via the initial attack of the amine (275) to HPA (9)  However, recent evidence found by Krasavin [137] and Shaw [59] indicate that the reaction of HPA (9) with amines (275) actually yields the amido acid isomer 276a and not 276b. Based on solid mechanistic investigations, Shaw proposed a mechanism for 3C-CCR in which cyclic anhydride (9) and amido acid (276a) are in equilibrium. In this scenario, the amine (275) and aldehyde (2) would form an imine (15) that would further react with the anhydride (9) in a similar way to what occurs in the 2C-CCRs (Scheme 84) [59]. intramolecular nucleophilic attack of the amide nitrogen with HO-Alum elimination would yield the final product (21b). An alternative mechanism for the transformation of intermediate 276b into the final product (path b) would involve the reaction of the amide nitrogen with the aldehyde to form an intermediate N-acyliminium cation (278) and a subsequent cyclisation with the acid enolate. According to the authors, the catalyst is necessary to allow the transformation of intermediate 276b, which in its absence would remain stable, hampering the three-component reaction. However, recent evidence found by Krasavin [137] and Shaw [59] indicate that the reaction of HPA (9) with amines (275) actually yields the amido acid isomer 276a and not 276b. Based on solid mechanistic investigations, Shaw proposed a mechanism for 3C-CCR in which cyclic anhydride (9) and amido acid (276a) are in equilibrium. In this scenario, Other heterogeneous Lewis acid catalysts, such as silica/sulfuric acid [138], ZnCl2, AlCl3 -SiO2 [139], and sulfonic acid functionalised silica [140] were found to analogously catalyse the reaction of amines (275), aldehydes (2), and HPA (9) to diastereoselectively afford the corresponding cis-isoquinolonic acids (21b). Similarly, the three-component reaction takes place smoothly in ionic liquids to also yield the cis isomers [141]. Other Lewis acids, such as ytterbium(III) triflate [142] and iodine [143] have also been shown to be very convenient catalysts, allowing the reaction to take place in CH2Cl2 at room temperatures to afford again the corresponding kinetic cis-isoquinolonic acid derivatives (21b) with high diastereoselectivity. Importantly, the reaction catalysed by ytterbium(III) triflate [142] has been successfully performed also with enolisable aliphatic imines, suggesting that it might take place through a mechanism different from the uncatalysed reactions. Yu and co-workers have also described the 3C-CCR of HPA (9), amines (275), and aliphatic aldehydes in the presence of excess trimethyl orthoformate [144].
In contrast with other catalysed CCRs, the two-component reaction of imines (15) with HPA (9) catalysed by excess BF3-Et2O leads to trans-isoquinolonic acids (21a) with a high stereoselectivity [146]. In addition, the three-component combination of HPA (9), aldehydes (2), and ammonium acetate in the presence of 50% molar aspartic acid as an organocatalyst affords trans-isoquinolonic acids (21a) [147]. Remarkably, a catalyst-free reaction of HPA (9), ammonium acetate, and carbonyl compounds (279) was recently reported by Krasavin [148]. It is worth noting that these reactions are performed in refluxing CH3CN, which could explain the formation of the thermodynamically more stable trans isomers (280). This protocol applies to cyclic ketones, leading to spirocyclic lactams [148,149], and has also been used for the preparation of poly(ADP-ribose) Scheme 84. The mechanism for the 3C-CCR proposed by Shaw.
Other heterogeneous Lewis acid catalysts, such as silica/sulfuric acid [138], ZnCl 2 , AlCl 3 -SiO 2 [139], and sulfonic acid functionalised silica [140] were found to analogously catalyse the reaction of amines (275), aldehydes (2), and HPA (9) to diastereoselectively afford the corresponding cis-isoquinolonic acids (21b). Similarly, the three-component reaction takes place smoothly in ionic liquids to also yield the cis isomers [141]. Other Lewis acids, such as ytterbium(III) triflate [142] and iodine [143] have also been shown to be very convenient catalysts, allowing the reaction to take place in CH 2 Cl 2 at room temperatures to afford again the corresponding kinetic cis-isoquinolonic acid derivatives (21b) with high diastereoselectivity. Importantly, the reaction catalysed by ytterbium(III) triflate [142] has been successfully performed also with enolisable aliphatic imines, suggesting that it might take place through a mechanism different from the uncatalysed reactions. Yu and co-workers have also described the 3C-CCR of HPA (9), amines (275), and aliphatic aldehydes in the presence of excess trimethyl orthoformate [144].
In contrast with other catalysed CCRs, the two-component reaction of imines (15) with HPA (9) catalysed by excess BF 3 -Et 2 O leads to trans-isoquinolonic acids (21a) with a high stereoselectivity [146]. In addition, the three-component combination of HPA (9), aldehydes (2), and ammonium acetate in the presence of 50% molar aspartic acid as an organocatalyst affords trans-isoquinolonic acids (21a) [147]. Remarkably, a catalyst-free reaction of HPA (9), ammonium acetate, and carbonyl compounds (279) was recently reported by Krasavin [148]. It is worth noting that these reactions are performed in refluxing CH 3 CN, which could explain the formation of the thermodynamically more stable trans isomers (280). This protocol applies to cyclic ketones, leading to spirocyclic lactams [148,149], and has also been used for the preparation of poly(ADP-ribose) polymerase (PARP) inhibitors [150] (282; Scheme 85). In agreement with this, Shaw has also demonstrated the feasibility of the 3C-CCR of HPA (9), aldehydes (2), and both aliphatic and aromatic amines (275) without the necessity of a catalyst [59]. This supports his mechanistic proposal (Scheme 84) and situates the Castagnoli-Cushman reaction as a real multicomponent reaction.

3C-CCR with Diacids
To avoid the formerly assumed irreversible attack of the amine on the anhydride in three-component uncatalysed CCRs, it has been proposed that this can be generated in situ from the corresponding diacids. Unfortunately, the use of dehydrating agents, such as acetic anhydride [135] or 1,1′-carbonyldiimidazole [106], is not compatible with the presence of amines. However, Krasavin showed that the three-component reaction of homophthalic acid (283), amines (275), and aldehydes (2) proceeds satisfactorily with the simultaneous azeotropic removal of water. Under these reaction conditions, rapid formation of the imine (15) occurs before HPA (9) can be generated from the acid (283; Scheme 86) [137].

3C-CCR with Diacids
To avoid the formerly assumed irreversible attack of the amine on the anhydride in three-component uncatalysed CCRs, it has been proposed that this can be generated in situ from the corresponding diacids. Unfortunately, the use of dehydrating agents, such as acetic anhydride [135] or 1,1 -carbonyldiimidazole [106], is not compatible with the presence of amines. However, Krasavin showed that the three-component reaction of homophthalic acid (283), amines (275), and aldehydes (2) proceeds satisfactorily with the simultaneous azeotropic removal of water. Under these reaction conditions, rapid formation of the imine (15) occurs before HPA (9) can be generated from the acid (283; Scheme 86) [137].

3C-CCR with Diacids
To avoid the formerly assumed irreversible attack of the amine on the anhydride in three-component uncatalysed CCRs, it has been proposed that this can be generated in situ from the corresponding diacids. Unfortunately, the use of dehydrating agents, such as acetic anhydride [135] or 1,1′-carbonyldiimidazole [106], is not compatible with the presence of amines. However, Krasavin showed that the three-component reaction of homophthalic acid (283), amines (275), and aldehydes (2) proceeds satisfactorily with the simultaneous azeotropic removal of water. Under these reaction conditions, rapid formation of the imine (15) occurs before HPA (9) can be generated from the acid (283; Scheme 86) [137].

Four-Component Castagnoli-Cushman Reactions (4C-CCRs)
A four-component version of the CCR, starting from amines (275), non-enolis aldehydes (2), maleic anhydrides (291), and thiols (290), affords, in a single step, γ-lact (292) with up to three new stereogenic centres with high diastereoselectivity (Scheme [42]. This approach is also useful for the preparation of N-unsubstituted γ-lactams, w can be further functionalised through acylation and arylation. For this purpose, diffe sources and synthetic equivalents of ammonia have been used [153]. The desulfurisation of γ-lactams (292, 47) leads to the otherwise difficult to ob corresponding cis-4,5-disubstituted-2-pyrrolidinones (293; Scheme 90) [42]. Further transformation of the thioether group in sulfur-substituted γ-lact increases the attainable molecular diversity and has been applied to the synthes several natural product analogues. For example, 4C-CCR followed by reduc desulfurisation, amidation, and aldol condensation leads to the natural pro heliotropamide (300; Scheme 91) [154]. This approach is also useful for the preparation of N-unsubstituted γ-lactams, which can be further functionalised through acylation and arylation. For this purpose, different sources and synthetic equivalents of ammonia have been used [153].

Four-Component Castagnoli-Cushman Reactions (4C-CCRs)
A four-component version of the CCR, starting from amines (275), n aldehydes (2), maleic anhydrides (291), and thiols (290), affords, in a single s (292) with up to three new stereogenic centres with high diastereoselectivit [42]. This approach is also useful for the preparation of N-unsubstituted γ-l can be further functionalised through acylation and arylation. For this pur sources and synthetic equivalents of ammonia have been used [153].
has improved, and new versions of the original reaction have been developed. The limits of the synthetic potential of this reaction are still unknown, and new applications are published every year. Particularly interesting are the three-and four-component CCRs, which allow for the combinatorial synthesis of complex molecules from simple starting materials. In addition, stereochemical control and the use of chiral catalysts allow access to new biologically relevant molecules, which makes CCR a very useful tool in medicinal chemistry.