Recent Progress in Heterocycle Synthesis: Cyclization Reaction with Pyridinium and Quinolinium 1,4-Zwitterions

Heteroarene 1, n-zwitterions are powerful and versatile building blocks in the construction of heterocycles and have received increasing attention in recent years. In particular, pyridinium and quinolinium 1,4-zwitterions have been widely studied and used in a variety of cyclization reactions due to their air stability, ease of use, and high efficiency. Sulfur- and nitrogen-based pyridinium and quinolinium 1,4-zwitterions, types of emerging heteroatom-containing synthons, have attracted much attention from chemists. These 1,4-zwitterions, which contain multiple reaction sites, have been successfully used in the synthesis of three- to eight-membered cyclic compounds over the last decade. In this review, we present the exciting progress made in the field of cyclization reactions of sulfur- and nitrogen-based pyridinium and quinolinium 1,4-zwitterions. Moreover, the mechanistic insights, the transition states, some synthetic applications, and the challenges and opportunities are also discussed. We hope to provide an overview for synthetic chemists who are interested in the heterocycle synthesis from cyclization reaction with pyridinium and quinolinium 1,4-zwitterions pyridinium and quinolinium 1,4-zwitterions.

The aim of this review is to provide a comprehensive overview of the recent advancements in the transformation of pyridinium and quinolinium 1,4-zwitterions in the synthesis of heterocycles. At present, partial reactions of pyridinium and quinolinium 1,4-zwitterions have been selected as particular aspects, appearing in several published reviews and perspectives [20,31]. However, because of the explosive development of multifarious cyclization reactions involving pyridinium and quinolinium 1,4-zwitterions, these summaries cannot cover the latest achievements. In this context, a comprehensive and up-todate overview of the application of pyridinium and quinolinium 1,4-zwitterions in the synthesis of heterocycles is highly desired.
The review is organized based on the categories of negative ions in pyridinium and quinolinium 1,4-zwitterions, which can be divided into sulfur-based and nitrogen-based types (Scheme 1). The annulation process is further classified based on the number of atoms of the final ring present in each fragment, designating the union of an m-atom fragment and an n-atom fragment as an (m + n) cyclization reaction. The purpose of this formalism is to make the skeletal analysis more convenient and it does not imply any mechanistic details.
The aim of this review is to provide a comprehensive overview of the recent advancements in the transformation of pyridinium and quinolinium 1,4-zwitterions in the synthesis of heterocycles. At present, partial reactions of pyridinium and quinolinium 1,4-zwitterions have been selected as particular aspects, appearing in several published reviews and perspectives [20,31]. However, because of the explosive development of multifarious cyclization reactions involving pyridinium and quinolinium 1,4-zwitterions, these summaries cannot cover the latest achievements. In this context, a comprehensive and up-to-date overview of the application of pyridinium and quinolinium 1,4-zwitterions in the synthesis of heterocycles is highly desired.
The review is organized based on the categories of negative ions in pyridinium and quinolinium 1,4-zwitterions, which can be divided into sulfur-based and nitrogen-based types (Scheme 1). The annulation process is further classified based on the number of atoms of the final ring present in each fragment, designating the union of an m-atom fragment and an n-atom fragment as an (m + n) cyclization reaction. The purpose of this formalism is to make the skeletal analysis more convenient and it does not imply any mechanistic details.

Formal (3 + 2) Cyclization
In early 2020, annulations of pyridinium 1,4-zwitterions, and activated allenes were reported by Zhai, Wang, and Cheng et al. [51], who used pyridinium 1,4-zwitterions as three-carbon synthons to construct five-membered heterocyclic compounds. As illustrated in Scheme 4, the type of substituent presented a remarkable effect on the regioselectivity. When the reaction was conducted with γ-aryl-substituted allenoates 9, a low level of regioselectivity was observed and major isomer 10 could be obtained in 19-68% yields. In contrast, when γ-alkyl-substituted allenoates 11 were used as the substrates, a highly regioselective cycloaddition reaction proceeded to yield the fully substituted thiophenes 12 in yields of up to 89%. Using this mechanism, it has been proposed that the S-Michael addition of pyridinium 1 to allenoates 9 results in the formation of intermediates 13 and 13 (Scheme 5). This is followed by the intramolecular C-Michael addition of the carbanion located at the α-position of ester or benzyl position, yielding 14 and 14 . The retro-Michael reaction results in the release of 4-MeO-pyridine, and this reaction is followed by a double bond isomerization reaction that yields two isomers (10 and 10 ).

Formal (3 + 2) Cyclization
In early 2020, annulations of pyridinium 1,4-zwitterions, and activated allenes were reported by Zhai, Wang, and Cheng et al. [51], who used pyridinium 1,4-zwitterions a three-carbon synthons to construct five-membered heterocyclic compounds. As illus trated in Scheme 4, the type of substituent presented a remarkable effect on the regiose lectivity. When the reaction was conducted with γ-aryl-substituted allenoates 9, a low level of regioselectivity was observed and major isomer 10 could be obtained in 19-68% yields. In contrast, when γ-alkyl-substituted allenoates 11 were used as the substrates, a highly regioselective cycloaddition reaction proceeded to yield the fully substituted thio phenes 12 in yields of up to 89%. Using this mechanism, it has been proposed that the S Michael addition of pyridinium 1 to allenoates 9 results in the formation of intermediate 13 and 13′ (Scheme 5). This is followed by the intramolecular C-Michael addition of the carbanion located at the α-position of ester or benzyl position, yielding 14 and 14′. The retro-Michael reaction results in the release of 4-MeO-pyridine, and this reaction is fol lowed by a double bond isomerization reaction that yields two isomers (10 and 10′).
In the same year, Zhai et al. used sulfur-based pyridinium 1,4-zwitterion as a versatile building block to synthesize polysubstituted thiophenes [52]. The reactions between pyridinium 1,4-zwitterions 1 and activated alkynes 16 were accomplished in 1, 2-dichloroethane (DCE) at 85 °C via a (3 + 2) process, affording tri-and tetra-substituted thiophenes 17 in 25-99% yields (Scheme 6, top). The limitations in the substrate scope were explored, and it was observed that some modified alkynes were not compatible with the developed protocol. In the following year, an extension of this strategy was reported by Zhai et al. (Scheme 6, bottom) [53]. Various modified and activated alkynes 18 bearing aryl, alkenyl, alkyl, or silyl groups were used to conduct (3 + 2) annulation reactions with pyridinium 1,4-zwitterions 1. The reaction proceeded smoothly to afford tetrasubstituted thiophenes 19 in 40-97% yields under the same reaction conditions. The developed approach has the features of being metal-free and catalyst-free. In 2020, Zhai's group used o-(trimethylsilyl)phenyl triflate 20 and pyridinium 1,4zwitterions 1 as substrates to conduct cyclization reactions. They reported that the reactions could follow two pathways (Scheme 7) [54]. The formal (5 + 2) cyclization reaction produced benzopyridothiazepines 22 as its major products. Although the (3 + 2) cyclization reaction was considered a side reaction, the results revealed that pyridinium 1,4-zwitterions could be used as powerful potential synthons to construct benzothiophenes 21. In the developed protocol, benzothiophenes 21 could be obtained in up to 43% isolated yield. Scheme 5. Proposed mechanism for (3 + 2) cyclization reaction between sulfur-based pyridinium 1,4-zwitterions and activated allenes.
In the same year, Zhai et al. used sulfur-based pyridinium 1,4-zwitterion as a versatile building block to synthesize polysubstituted thiophenes [52]. The reactions between pyridinium 1,4-zwitterions 1 and activated alkynes 16 were accomplished in 1, 2-dichloroethane (DCE) at 85 • C via a (3 + 2) process, affording triand tetra-substituted thiophenes 17 in 25-99% yields (Scheme 6, top). The limitations in the substrate scope were explored, and it was observed that some modified alkynes were not compatible with the developed protocol. In the following year, an extension of this strategy was reported by Zhai et al. (Scheme 6, bottom) [53]. Various modified and activated alkynes 18 bearing aryl, alkenyl, alkyl, or silyl groups were used to conduct (3 + 2) annulation reactions with pyridinium 1,4-zwitterions 1. The reaction proceeded smoothly to afford tetrasubstituted thiophenes 19 in 40-97% yields under the same reaction conditions. The developed approach has the features of being metal-free and catalyst-free.
In the same year, Zhai et al. used sulfur-based pyridinium 1,4-zwitterion as a versatile building block to synthesize polysubstituted thiophenes [52]. The reactions between pyridinium 1,4-zwitterions 1 and activated alkynes 16 were accomplished in 1, 2-dichloroethane (DCE) at 85 °C via a (3 + 2) process, affording tri-and tetra-substituted thiophenes 17 in 25-99% yields (Scheme 6, top). The limitations in the substrate scope were explored, and it was observed that some modified alkynes were not compatible with the developed protocol. In the following year, an extension of this strategy was reported by Zhai et al. (Scheme 6, bottom) [53]. Various modified and activated alkynes 18 bearing aryl, alkenyl, alkyl, or silyl groups were used to conduct (3 + 2) annulation reactions with pyridinium 1,4-zwitterions 1. The reaction proceeded smoothly to afford tetrasubstituted thiophenes 19 in 40-97% yields under the same reaction conditions. The developed approach has the features of being metal-free and catalyst-free. In 2020, Zhai's group used o-(trimethylsilyl)phenyl triflate 20 and pyridinium 1,4zwitterions 1 as substrates to conduct cyclization reactions. They reported that the reactions could follow two pathways (Scheme 7) [54]. The formal (5 + 2) cyclization reaction produced benzopyridothiazepines 22 as its major products. Although the (3 + 2) cyclization reaction was considered a side reaction, the results revealed that pyridinium 1,4-zwitterions could be used as powerful potential synthons to construct benzothiophenes 21. In the developed protocol, benzothiophenes 21 could be obtained in up to 43% isolated yield. In 2020, Zhai's group used o-(trimethylsilyl)phenyl triflate 20 and pyridinium 1,4zwitterions 1 as substrates to conduct cyclization reactions. They reported that the reactions could follow two pathways (Scheme 7) [54]. The formal (5 + 2) cyclization reaction produced benzopyridothiazepines 22 as its major products. Although the (3 + 2) cyclization reaction was considered a side reaction, the results revealed that pyridinium 1,4-zwitterions could be used as powerful potential synthons to construct benzothiophenes 21. In the developed protocol, benzothiophenes 21 could be obtained in up to 43% isolated yield. The reaction mechanism involves the transformation of alkanesulfonyl chloride 25 into sulfene 27 through the promotion of a selected base, which was attacked by sulfur anion of pyridinium 1,4-zwitterion to form sulfur-sulfur bonds. This is followed by a domino Michael/retro-Michael reaction that releases the pyridine group and yields the product 26. In this paper, the authors also found that arylmethanesulfonyl chloride could react with pyridinium 1,4-zwitterions through a stepwise ((5 + 2) − 1) pathway.  The reaction mechanism involves the transformation of alkanesulfonyl chloride 25 into sulfene 27 through the promotion of a selected base, which was attacked by sulfur anion of pyridinium 1,4-zwitterion to form sulfur-sulfur bonds. This is followed by a domino Michael/retro-Michael reaction that releases the pyridine group and yields the product 26. In this paper, the authors also found that arylmethanesulfonyl chloride could react with pyridinium 1,4-zwitterions through a stepwise ((5 + 2) − 1) pathway.  The reaction mechanism involves the transformation of alkanesulfonyl chloride 25 into sulfene 27 through the promotion of a selected base, which was attacked by sulfur anion of pyridinium 1,4-zwitterion to form sulfur-sulfur bonds. This is followed by a domino Michael/retro-Michael reaction that releases the pyridine group and yields the product 26. In this paper, the authors also found that arylmethanesulfonyl chloride could react with pyridinium 1,4-zwitterions through a stepwise ((5 + 2) − 1) pathway.
More recently, Wen et al. investigated the (3 + 2) cycloaddition of pyridinium 1,4-zwitterion with trifluoroacetaldehyde O-(aryl)oxime (Scheme 9) [56]. The reaction, performed in N-methylpyrrolidone (NMP) at 95 • C, afforded the 2-trifluoromethyl 4,5disubstituted thiazoles 31 in good-to-perfect yields (30-92% yield). The reaction mechanism was proposed. It was hypothesized that the treatment of oxime 30 with pyridine yielded CF 3 CN 32. This reaction was followed by sequential S-nucleophilic addition and N-Michael reaction cascade that resulted in the formation of intermediate 33. Finally, the retro-Michael reaction led to pyridine extrusion, and simultaneously furnished the desired products.  [56]. The reaction, performed in N-methylpyrrolidone (NMP) at 95 °C, afforded the 2-trifluoromethyl 4,5-disubstituted thiazoles 31 in good-to-perfect yields (30-92% yield). The reaction mechanism was proposed. It was hypothesized that the treatment of oxime 30 with pyridine yielded CF3CN 32. This reaction was followed by sequential S-nucleophilic addition and N-Michael reaction cascade that resulted in the formation of intermediate 33. Finally, the retro-Michael reaction led to pyridine extrusion, and simultaneously furnished the desired products.   [58]. The reaction with both alkyl-and arylsubstituted aziridines provided a wide range of functionalized 3,4-dihydro-2H-1,4-thiazines (42 and 43) in good-to-high yields with excellent levels of regioselectivity. Substrate scope was studied, and it was observed that the type of substituents on aziridines significantly affected the regioselectivity of the reaction. The authors proposed a mechanism to illustrate the origin of regioselectivity (Scheme 12). For 2-arylaziridine, the S-nucleophilic addition to the more sterically hindered site of the aziridine ring via a loose S N 2 ring-opening process [59,60] lead to the formation of intermediate 44. This reaction was followed by an N-Michael/retro-Michael reaction that yielded 1,4-thiazine 42. In contrast, the ringopening reaction of 2-alkylaziridine occurred at the less sterically hindered site via an S N 2 pathway to yield intermediate 46. This resulted in the formation of the corresponding product 43. The protocol's features include being catalyst-and base-free and having high regioselectivity. Another example of the formal (3 + 3) cyclization of pyridinium 1,4-zwitterions 1 was reported by Chen et al. in 2022 (Scheme 11) [58]. The reaction with both alkyl-and arylsubstituted aziridines provided a wide range of functionalized 3,4-dihydro-2H-1,4-thiazines (42 and 43) in good-to-high yields with excellent levels of regioselectivity. Substrate scope was studied, and it was observed that the type of substituents on aziridines significantly affected the regioselectivity of the reaction. The authors proposed a mechanism to illustrate the origin of regioselectivity (Scheme 12). For 2-arylaziridine, the S-nucleophilic addition to the more sterically hindered site of the aziridine ring via a loose SN2 ringopening process [59,60] lead to the formation of intermediate 44. This reaction was followed by an N-Michael/retro-Michael reaction that yielded 1,4-thiazine 42. In contrast, the ring-opening reaction of 2-alkylaziridine occurred at the less sterically hindered site via an SN2 pathway to yield intermediate 46. This resulted in the formation of the corresponding product 43. The protocol's features include being catalyst-and base-free and having high regioselectivity. Scheme 11. Formal (3 + 3) cyclization reaction of sulfur-based pyridinium 1,4-zwitterions and aziridines.
Zhai and Cheng et al. were the first to report a clever strategy for (3 + 4) cycloaddition reactions involving pyridinium 1,4-zwitterions (Scheme 13). Pyridinium 1,4-zwitterions 1 were selected as three-atom synthons to react with α-halo hydrazones 48, leading to the formation of 1,4,5-thiadiazepine derivatives 49 in generally good-to-excellent yields (51-98%) [72]. For the reaction mechanism, azoalkenes 50 were generated in situ from α-halo hydrazones 48 in the presence of a base. The S-Michael addition, N-Michael addition, and retro-Michael addition reactions proceeded sequentially, resulting in the formation of 2,5-dihydro-1,4,5-thiadiazepines 49. It is of note that the selective oxidation of 49 was also successfully established, in which sulfone 53 and sulfoxide 54 analogs could be produced in good, isolated yields (Scheme 13, bottom).

Formal (4 + n) Cyclization
Due to the existence of the unique sulfur atom extrusion process, the exploitation of sulfur-based pyridinium and quinolinium 1,4-zwitterions goes well beyond the conventional pyridinium ylide and 1,5-dipole concept. It was found that they can be regarded as four atom synthons participating in formal [4 + n] cyclization, allowing the facile synthesis of five-and six-membered rings. Building upon the reaction mechanism, the dearomatization of the heteroarenium ring and the desulfuration reaction always could have been observed in disclosed reports.

Formal (4 + 2) Cyclization
There is only one example of using pyridinium 1,4-zwitterions as four-atom synthons in formal (4 + 2) cyclization for the synthesis of six-membered ring compounds. In 2021, Li et al. achieved a (4 + 2) cyclization between 1-sulfonyl-1,2,3-triazoles 87 and pyridinium 1,4-zwitterions 1 through an addition/elimination process, accessing pyrido[1,2-a]pyrazine derivatives 88. The products were formed in yields of up to 70% (Scheme 19) [57]. The authors proposed a mechanism to explain the observed results. Under thermal conditions, a key intermediate 89 was generated from the 1,2,3-triazole 87 with the release of nitrogen. Following this, a sequential S-nucleophilic addition/N-Michael reaction proceeded to yield a thiazole intermediate 91. A retro-S-Michael reaction resulted in the formation of intermediates 92 and 93, which underwent an intramolecular nucleophilic attack from the carbon atom to access the final product, 88. The key features of the developed procedure are that it is catalyst-free and easy to operate.

Formal (5 + n) Cyclization
Formal (5 + n) cyclization of sulfur-based pyridinium and quinolinium 1,4-zwitterions has been proven to be a straightforward and powerful tactic for the construction of N/Scontaining polyheterocyclic skeletons, but this has not been studied in detail. In this section, the newly reported (5 + 1) and (5 + 2) cyclization processes will be presented and discussed in detail.  [78]. To overcome the difficulties in separation and purification, they explored the process of selective oxidation of product 104 and found that a one-pot stepwise reaction smoothly produced sulfone analogs 105 in excellent isolated yields with perfect diastereoselectivities. The scope of the reaction was investigated, but the protocol was not applied to quinolinium 1,4-zwitterions 1′ that bear the electron-deficient groups at the fifth or sixth position of the quinolinium ring (Scheme 22, bottom). The authors proposed the mechanism with sulfur ylide salt 102 as an example. They hypothesized that the  [78]. To overcome the difficulties in separation and purification, they explored the process of selective oxidation of product 104 and found that a one-pot step-wise reaction smoothly produced sulfone analogs 105 in excellent isolated yields with perfect diastereoselectivities. The scope of the reaction was investigated, but the protocol was not applied to quinolinium 1,4-zwitterions 1 that bear the electron-deficient groups at the fifth or sixth position of the quinolinium ring (Scheme 22, bottom). The authors proposed the mechanism with sulfur ylide salt 102 as an example. They hypothesized that the reaction involved the in-situ formation of sulfoxonium ylide 106, which underwent nucleophilic attack on the quinolinium zwitterion to form intermediate 107. This was followed by an intramolecular nucleophilic substitution reaction that yielded 108. The (5 + 1) cyclization reaction between intermediate 108 and another sulfoxonium ylide 106 gave rise to the final product 104. DMSO was released during the process (Scheme 23). Visible-light photocatalysis is an environmentally friendly strategy that has been used for the synthesis of various organic compounds over the past decade [79][80][81][82][83][84]. In 2022, Xu et al. made a significant breakthrough by introducing the first blue-light-induced annulation of pyridinium 1,4-zwitterions (Scheme 24) [85]. In their developed methodology, the phosphoryl diazo compound 110 was selected as the precursor of an electron-deficient carbene, and the compound was excited under conditions of blue-light irradiation to produce carbene intermediate 112, which then reacted with pyridinium 1,4-zwitterion 1 through a (5 + 1) cyclization reaction. The reactions resulted in the production of phosphoryl-1,9a-dihydropyrido[2,1-c] [1,4]thiazine derivatives 111 in generally good yields (15-99%) and diastereomeric ratios (60:40->99:1 dr). It is worth noting that steric hindrance and electronic effects significantly impacted the reactivity of the molecules, and the developed method could not be applied to some substrates.
Visible-light photocatalysis is an environmentally friendly strategy that has been used for the synthesis of various organic compounds over the past decade [79][80][81][82][83][84]. In 2022, Xu et al. made a significant breakthrough by introducing the first blue-light-induced annulation of pyridinium 1,4-zwitterions (Scheme 24) [85]. In their developed methodology, the phosphoryl diazo compound 110 was selected as the precursor of an electron-deficient carbene, and the compound was excited under conditions of blue-light irradiation to produce carbene intermediate 112, which then reacted with pyridinium 1,4-zwitterion 1 through a (5 + 1) cyclization reaction. The reactions resulted in the production of phosphoryl-1,9a-dihydropyrido[2,1c] [1,4]thiazine derivatives 111 in generally good yields (15-99%) and diastereomeric ratios (60:40->99:1 dr). It is worth noting that steric hindrance and electronic effects significantly impacted the reactivity of the molecules, and the developed method could not be applied to some substrates.

Formal (5 + 2) Cyclization
In 2020, Zhai et al. reported one of the only two instances of (5 + 2) cyclization of pyridinium 1,4-zwitterions to construct seven-membered sulfur-containing heterocyclic rings (Scheme 25) [54]. In this example, the in situ-generated benzyne 23 underwent 1,5dipolar cycloaddition with pyridinium 1,4-zwitterions 1, resulting in the formation of benzopyridothiazepines 22 as the major product. However, due to regioselectivity, a (3 + 2) cascade cyclization reaction also produced benzo[b]thiophenes 21 as a side product.  Another example of a (5 + 2) cyclization is the synthesis of pyridothiazepines 115 via the reaction between pyridinium 1,4-zwitterions 1 and activated allenes 114 (Scheme 26) [86]. The corresponding pyridothiazepine derivatives 115 were obtained in good yields with acceptable Z/E configuration when the reaction was conducted at 65 • C in DCM. A ring-contraction reaction of 115a could also be achieved in an air atmosphere, furnishing indolizine 116a as the final product. The authors proposed a possible mechanism for the (5 + 2) cyclization and subsequent ring-contraction reaction. First, a highly regioselective (5 + 2) cyclization resulted in the formation of pyridothiazepine 115. Due to its instability, the aerobic oxidation of pyridothiazepine 115 yielded a conjugated double bond, and this was followed by an intramolecular nucleophilic addition that yielded intermediate 118.
An extrusion reaction of intermediate 118 produced 119, which underwent an efficient isomerization process to synthesize indolizine 116. The authors noted that the electronic nature of the R 1 group could dictate the pathway of the reaction.
(5 + 2) cyclization resulted in the formation of pyridothiazepine 115. Due to its instability, the aerobic oxidation of pyridothiazepine 115 yielded a conjugated double bond, and this was followed by an intramolecular nucleophilic addition that yielded intermediate 118.
An extrusion reaction of intermediate 118 produced 119, which underwent an efficient isomerization process to synthesize indolizine 116. The authors noted that the electronic nature of the R 1 group could dictate the pathway of the reaction. Scheme 26. The (5 + 2) cyclization reaction of sulfur-based pyridinium 1,4-zwitterions with activated allenes.

Formal (3 + 2) Cyclization
Studies on ( [92]. The developed (3 + 2) cyclization reaction worked well in moderate-to-good yields (42-89%). Of note, the stable valence tautomer 145 was also formed under special conditions, and this could be attributed to the dynamic equilibrium between 143, 144, and 145. The silver, salt-mediated HCN gas release process functioned as a driving force to facilitate the formation of the final product 139.

Formal (3 + 2) Cyclization
Studies on (3 + 2) cyclization reactions involving nitrogen-based pyridinium or quinolinium 1,4-zwitterions have been almost completely absent since 2014. The sole example was reported by Yoo et al. in 2021. As shown in Scheme 29, Cu(I) was selected as the catalyst to react with terminal alkyne 138 to generate copper acetylide 140. Copper acetylide 140 regioselectively attacked the 2-position of quinolinium to achieve 1,2-dearomatization and yield intermediate 141. Intermediate 141 could convert to 1,4-diazepine intermediate 142 via the process of 7-endo-dig cyclization. This was followed by detosylation to yield 143. The unstable 8π-electron of 143 participated in the reaction and allowed the sequential 4π-electro-cyclization reaction to proceed smoothly, affording intermediate 144.
The retro-(2 + 2) cycloaddition reaction resulted in the release of HCN gas, delivering the desired pyrrolo[1,2-a]quinoline 139 in the presence of Ag 2 CO 3 [92]. The developed (3 + 2) cyclization reaction worked well in moderate-to-good yields (42-89%). Of note, the stable valence tautomer 145 was also formed under special conditions, and this could be attributed to the dynamic equilibrium between 143, 144, and 145. The silver, salt-mediated HCN gas release process functioned as a driving force to facilitate the formation of the final product 139.

(5 + 2) Cyclization
In 2014, Yoo et al. conducted the first (5 + 2) cyclization reaction for nitrogen-based pyridinium 1,4-zwitterions. As shown in Table 4, dimethyl acetylenedicarboxylates (DMADs) were used as reactants in the (5 + 2) cyclization process under thermal conditions. The 1,4-diazepine compounds 158 could be isolated in excellent yields (following Path a) [49]. Furthermore, a two-step, one-pot (5 + 2) cyclization reaction could also be performed at 120 °C to yield a wide range of desired products 158 in good yields (following Path b). Additionally, a four-component annulation reaction was also investigated and carried out successfully, producing 1,4-diazepines in acceptable yields (following Path c). The broad substrate scope, good tolerance of functional groups, and unique reaction pathways demonstrated the versatility of the developed methodology.

(5 + 3) Cyclization
(5 + 3) cyclization is one of the most effective methods to construct eight-membered heterocycles [102][103][104][105][106][107]. However, it is challenging to conduct the asymmetric version of the reaction, and this problem needs to be addressed. Nitrogen-based pyridinium and quinolinium 1,4-zwitterions, as the most representative 1,5-dipoles, can be used to readily synthesize chiral eight-membered heterocycles. In 2015, Yoo et al. developed the Rh(II)catalyzed (5 + 3) cyclization of pyridinium 1,4-zwitterions 2 and enol diazoacetates 169a (Scheme 36) [108]. Modest yields of products 170 were observed (maximum yield: 71%). The mechanism consisted of three steps, as outlined in the middle of Scheme 36. The first step involved the reaction between enol diazoacetate and Rh(II), and this reaction yielded the Rh(II)-enolcarbene 171. Next, Rh(II)-enolcarbene interacted with pyridinium 1,4-zwitterions to form intermediate 172. Finally, intramolecular cyclization yielded the corresponding compound 170 while regenerating the active Rh(II) catalyst for the next cycle. Additionally, a chiral Rh(II) catalyst was used to promote the stereoselective (5 + 3) cyclization of pyridinium 1,4-zwitterion 2a with TBS-protected enol diazoacetate 169a. The stereoselective synthesis of chiral 170a was achieved in a 60% yield with 90% ee when chiral Rh(II) catalyst C4 was used to conduct the reaction ( Yoo et al. also described a stereoselective (5 + 3) cyclization between quinolinium 1,4zwitterions 2′ and enol diazoacetates 169, catalyzed by Cu(I), as shown in Scheme 37 [109]. The desired diazocine derivatives (S)-173 could be synthesized in excellent yields (up to 97%) with perfect ee values (up to 97%) using a Cu(I)/bisoxazoline ligand L2 complex as a catalyst and a catalytic amount of NaBArF as an additive. The authors proposed that the non-coordinating anion of NaBArF enhanced the electrophilicity of the carbenoid intermediate during the reaction process. A transition state 174 was proposed, where the bisoxazoline ligand L2 binds with the central Cu(I) to guide intramolecular 1,2-dearomative cyclization, thereby ensuring the observed enantioselectivities. It is worth noting that the reactions failed when either the enol diazoamide derivative or the pyridinium 1,4-zwitterion was used as a partner under the specified reaction conditions.

(5 + 3) Cyclization
(5 + 3) cyclization is one of the most effective methods to construct eight-membered heterocycles [102][103][104][105][106][107]. However, it is challenging to conduct the asymmetric version of the reaction, and this problem needs to be addressed. Nitrogen-based pyridinium and quinolinium 1,4-zwitterions, as the most representative 1,5-dipoles, can be used to readily synthesize chiral eight-membered heterocycles. In 2015, Yoo et al. developed the Rh(II)catalyzed (5 + 3) cyclization of pyridinium 1,4-zwitterions 2 and enol diazoacetates 169a (Scheme 36) [108]. Modest yields of products 170 were observed (maximum yield: 71%). The mechanism consisted of three steps, as outlined in the middle of Scheme 36. The first step involved the reaction between enol diazoacetate and Rh(II), and this reaction yielded the Rh(II)-enolcarbene 171. Next, Rh(II)-enolcarbene interacted with pyridinium 1,4-zwitterions to form intermediate 172. Finally, intramolecular cyclization yielded the corresponding compound 170 while regenerating the active Rh(II) catalyst for the next cycle. Additionally, a chiral Rh(II) catalyst was used to promote the stereoselective (5 + 3) cyclization of pyridinium 1,4-zwitterion 2a with TBS-protected enol diazoacetate 169a. The stereoselective synthesis of chiral 170a was achieved in a 60% yield with 90% ee when chiral Rh(II) catalyst C4 was used to conduct the reaction (Table 5, entry 3). C4/R = 1-adamantyl 63 90 Yoo et al. also described a stereoselective (5 + 3) cyclization between quinolinium 1,4zwitterions 2 and enol diazoacetates 169, catalyzed by Cu(I), as shown in Scheme 37 [109]. The desired diazocine derivatives (S)-173 could be synthesized in excellent yields (up to 97%) with perfect ee values (up to 97%) using a Cu(I)/bisoxazoline ligand L2 complex as a catalyst and a catalytic amount of NaBArF as an additive. The authors proposed that the non-coordinating anion of NaBArF enhanced the electrophilicity of the carbenoid intermediate during the reaction process. A transition state 174 was proposed, where the bisoxazoline ligand L2 binds with the central Cu(I) to guide intramolecular 1,2-dearomative cyclization, thereby ensuring the observed enantioselectivities. It is worth noting that the reactions failed when either the enol diazoamide derivative or the pyridinium 1,4-zwitterion was used as a partner under the specified reaction conditions. Molecules 2023, 28, x FOR PEER REVIEW 33 of 45 Scheme 37. Cu(I)-catalyzed (5 + 3) cyclization between nitrogen-based quinolinium 1,4-zwitterions and enol diazoacetates.

Cascade 1,4-Dearomative (2 + n) Cycloaddition/Intramolecular Cyclization
One remarkable feature of nitrogen-based pyridinium and quinolinium 1,4-zwitterions is their stability, which can be attributed to the aromaticity of the heteroarenium core. The selective dearomatization of the heteroarenium core intrigues many chemists. In 2018, Yoo et al. discovered that the charge delocalization property of the pyridinium zwitterion could be exploited for the selective 1,2-or 1,4-dearomatization of pyridinium [110]. Based on this discovery, various cascade 1,4-dearomative (2 + n) cycloaddition/intramolecular cyclization reactions have been developed in recent years.

Cascade 1,4-Dearomative (2 + 1) Cycloaddition/Intramolecular Cyclization
The sole example of a cascade dearomative (2 + 1) cycloaddition/intramolecular cyclization was reported by Yoo in 2020 (Scheme 38) [93]. In this study, NaOMe (2.0 equiv. in DMF at 40 °C) was used as a base. Trimethylsulfoxonium iodide 102 or sulfonium ylide salt 103 was used to synthesize the corresponding product 175 in good-to-excellent yields (up to 98%). The mechanism (using 102 as an example) involved the nucleophilic addition of the in situ-generated sulfoxonium ylide 106 to the 4-position of quinolinium, resulting in 1,4-dearomatization and the formation of intermediate 176. This was followed by cyclopropanation to form a cyclopropane ring and the smooth intramolecular cyclization of intermediate 177 to yield the tetrahydroimidazo[1,2-a]quinoline 178. The rearomatization of 178 was achieved by extracting TolSO2H to give the final desired product 175. Chiral benzyl sulfonium salts 179 could also be effectively used to conduct the reactions. Good, isolated yields, variable levels of diastereoselectivity, and excellent enantioselectivity were achieved when the reactions were conducted in the presence of NaH in acetonitrile at 40 °C (Table 6).

Cascade 1,4-Dearomative (2 + n) Cycloaddition/Intramolecular Cyclization
One remarkable feature of nitrogen-based pyridinium and quinolinium 1,4-zwitterions is their stability, which can be attributed to the aromaticity of the heteroarenium core. The selective dearomatization of the heteroarenium core intrigues many chemists. In 2018, Yoo et al. discovered that the charge delocalization property of the pyridinium zwitterion could be exploited for the selective 1,2-or 1,4-dearomatization of pyridinium [110]. Based on this discovery, various cascade 1,4-dearomative (2 + n) cycloaddition/intramolecular cyclization reactions have been developed in recent years.

Cascade 1,4-Dearomative (2 + 1) Cycloaddition/Intramolecular Cyclization
The sole example of a cascade dearomative (2 + 1) cycloaddition/intramolecular cyclization was reported by Yoo in 2020 (Scheme 38) [93]. In this study, NaOMe (2.0 equiv. in DMF at 40 • C) was used as a base. Trimethylsulfoxonium iodide 102 or sulfonium ylide salt 103 was used to synthesize the corresponding product 175 in good-to-excellent yields (up to 98%). The mechanism (using 102 as an example) involved the nucleophilic addition of the in situ-generated sulfoxonium ylide 106 to the 4-position of quinolinium, resulting in 1,4-dearomatization and the formation of intermediate 176. This was followed by cyclopropanation to form a cyclopropane ring and the smooth intramolecular cyclization of intermediate 177 to yield the tetrahydroimidazo[1,2-a]quinoline 178. The rearomatization of 178 was achieved by extracting TolSO 2 H to give the final desired product 175. Chiral benzyl sulfonium salts 179 could also be effectively used to conduct the reactions. Good, isolated yields, variable levels of diastereoselectivity, and excellent enantioselectivity were achieved when the reactions were conducted in the presence of NaH in acetonitrile at 40 • C ( Table 6).   [111]. Pd(PPh3)4 was used to catalyze the dearomative (2 + 3) cycloaddition between trimethylenemethane (TMM) and pyridinium 1,4-zwitterion 2a, resulting in the production of the unstable cycloadduct 182a. Fortunately, the use of acidic additives promoted the elimination of sulfinic acid and the isomerization of the compound to furnish 183a as the major product (Scheme 39). Evaluation of the substrate scope indicated that the efficiency and selectivity of the cycloadditions depended upon the nature of the substituent at the C3-position of pyridinium (Table  7). In the absence of substituents (R = H), compounds 183 were obtained in generally good yields. In contrast, C3-substituted pyridinium zwitterions were compatible with the developed strategy, but a totally different regioselectivity was observed. Compound 184 was smoothly generated in the absence of acetic acid. The authors hypothesized that the Pd(II)-TMM species 185 was initially generated when Pd(PPh3)4 reacted with TMM (Scheme 40, top). Following this, the Pd(II)-TMM species attracted pyridinium zwitterions to yield the Scheme 38. Cascade 1,4-dearomative (2 + 1) cycloaddition/intramolecular cyclization of nitrogenbased quinolinium 1,4-zwitterions and sulfur-based ylides.   [111]. Pd(PPh3)4 was used to catalyze the dearomative (2 + 3) cycloaddition between trimethylenemethane (TMM) and pyridinium 1,4-zwitterion 2a, resulting in the production of the unstable cycloadduct 182a. Fortunately, the use of acidic additives promoted the elimination of sulfinic acid and the isomerization of the compound to furnish 183a as the major product (Scheme 39). Evaluation of the substrate scope indicated that the efficiency and selectivity of the cycloadditions depended upon the nature of the substituent at the C3-position of pyridinium (Table  7). In the absence of substituents (R = H), compounds 183 were obtained in generally good yields. In contrast, C3-substituted pyridinium zwitterions were compatible with the developed strategy, but a totally different regioselectivity was observed. Compound 184 was smoothly generated in the absence of acetic acid. The authors hypothesized that the Pd(II)-TMM species 185 was initially generated when Pd(PPh3)4 reacted with TMM (Scheme 40, top). Following this, the Pd(II)-TMM species attracted pyridinium zwitterions to yield the

Cascade 1,4-Dearomative (2 + 3) Cycloaddition/Intramolecular Cyclization
The 1,4-Dearomative (2 + 3) cycloaddition-triggered intramolecular cyclization of pyridinium 1,4-zwitterions was first disclosed in 2019 [111]. Pd(PPh 3 ) 4 was used to catalyze the dearomative (2 + 3) cycloaddition between trimethylenemethane (TMM) and pyridinium 1,4-zwitterion 2a, resulting in the production of the unstable cycloadduct 182a. Fortunately, the use of acidic additives promoted the elimination of sulfinic acid and the isomerization of the compound to furnish 183a as the major product (Scheme 39). Evaluation of the substrate scope indicated that the efficiency and selectivity of the cycloadditions depended upon the nature of the substituent at the C3-position of pyridinium (Table 7). In the absence of substituents (R = H), compounds 183 were obtained in generally good yields. In contrast, C3-substituted pyridinium zwitterions were compatible with the developed strategy, but a totally different regioselectivity was observed. Compound 184 was smoothly generated in the absence of acetic acid. The authors hypothesized that the Pd(II)-TMM species 185 was initially generated when Pd(PPh 3 ) 4 reacted with TMM (Scheme 40, top). Following this, the Pd(II)-TMM species attracted pyridinium zwitterions to yield the key intermediate 186. Next, the steric hindrance at the C3-position of pyridinium led to two pathways (Paths a and b) that could be followed to obtain the corresponding products. Furthermore, DFT calculations were conducted, and the computational results demonstrated that pyridinium 1,4-zwitterions were more likely to undergo C−C bond formation reactions, resulting in 1, 4-dearomation     A strategy for multicomponent dipolar cycloaddition that involves the participation of in situ-formed azomethine ylides has been widely applied in the generation of nitrogen heterocyclic structures with a high level of functionality [112][113][114][115][116]. Yoo et al. have reported a catalyst-free multicomponent 1,3-dipolar cycloaddition/intramolecular cyclization reaction involving N-heteroarenium 1,4-zwitterions, aldehydes 194 and amino acids 195 (Scheme 41) [117]. The reaction was carried out in CH 3 CN at 80 • C and involved the decarboxylation of the aldehydes with amino acids to generate azomethine ylide 197, which underwent a (2 + 3) cycloaddition reaction with pyridinium to give intermediate 199. Intermediate 200 was then produced via intramolecular cyclization, and this was followed by the elimination of sulfinic acid, resulting in the formation of the desired product 196. It is important to note that a strong electron-withdrawing group should be present at the para-position of the phenyl ring in aromatic aldehydes to achieve a high level of regioselectivity. A strategy for multicomponent dipolar cycloaddition that involves the participation of in situ-formed azomethine ylides has been widely applied in the generation of nitrogen heterocyclic structures with a high level of functionality [112][113][114][115][116]. Yoo et al. have reported a catalyst-free multicomponent 1,3-dipolar cycloaddition/intramolecular cyclization reaction involving N-heteroarenium 1,4-zwitterions, aldehydes 194 and amino acids 195 (Scheme 41) [117]. The reaction was carried out in CH3CN at 80 °C and involved the decarboxylation of the aldehydes with amino acids to generate azomethine ylide 197, which underwent a (2 + 3) cycloaddition reaction with pyridinium to give intermediate 199. Intermediate 200 was then produced via intramolecular cyclization, and this was followed by the elimination of sulfinic acid, resulting in the formation of the desired product 196. It is important to note that a strong electron-withdrawing group should be present at the para-position of the phenyl ring in aromatic aldehydes to achieve a high level of regioselectivity. were catalyzed by Pd(PPh 3 ) 4 (2 mol%) and PBu 3 (20 mol%) in tetrahydrofuran, producing various tetrahydroimidazo[1,2-a]pyridine derivatives 202 in excellent yields with perfect diastereoselectivities. The nucleophilic attack of the carbanion of Pd(II)-zwitterion species 203 on the C4 position of the pyridinium produced species 204, which underwent intramolecular cyclization to form a six-membered ring. Finally, an intramolecular nucleophilic addition within intermediate 205 resulted in cyclization and produced the target compounds 202 (Scheme 43, top). DFT-based calculations indicated that the 1,4-dearomatization of the pyridinium moiety was thermodynamically favored (Scheme 43, bottom). The frontier molecular orbital (FMO) energy difference between the HOMO of the Pd(II)-zwitterion species 203 and the LUMO of the pyridinium zwitterion 2 was only 0.36 eV. This promoted efficient electronic coupling with a remarkably low barrier (not shown).

1,4-Dearomative Ring Expansion/Intramolecular Cyclization
Diazoacetate-and diazomethane-derived Grignard can achieve the 1,2-dearomative ring expansion of quinolinium to produce azepine derivatives [118]. In contrast, Yoo and Kim documented the 1,4-dearomative ring expansion of quinolinium using silver as a catalyst in 2021 (Scheme 44) [119]. They found that a broad range of functional groups were tolerated, and a high degree of regioselectivity, leading to the formation of multifused azepine derivatives 210 in good yields, could be achieved. Under optimized conditions, the in situ-generated diazoacetate anion 211 selectively attacked the C4 position of the quinolinium to effect 1,4dearomatization and form intermediate 212. The silver-carbenoid 213 was generated smoothly when a silver catalyst reacted with intermediate 212 via the release of nitrogen gas. The intramolecular cyclization of 213 resulted in the formation of cyclopropane intermediate 214, followed by ring expansion to produce compound 215. Finally, compound 215 converted into the desired azepine 210 following the process of intramolecular hydroamination. It is worth noting that a separable byproduct 216 was formed during the process, which might have been generated from intermediates 212 or 213. Finally, compound 215 converted into the desired azepine 210 following the process of intramolecular hydroamination. It is worth noting that a separable byproduct 216 was formed during the process, which might have been generated from intermediates 212 or 213.

Summary and Outlook
In this review, we have summarized recent progress in the application of pyridinium and quinolinium 1,4-zwitterions for the efficient synthesis of heterocycles. The reported pyridinium and quinolinium 1,4-zwitterions can be classified into sulfur-based and nitrogen-based 1,4-zwitterions according to the types of anions. As to the study of sulfur-based 1,4-zwitterions, the known cyclization reactions include (2 + 3), (3 + n), (4 + n), (5 + n), and multistep cascade cyclization. With respect to nitrogen-based 1,4-zwitterions, different types of cyclization, such as (3 + 2) cyclization, (5 + n) cyclization, cascade 1,4-dearomative cycloaddition/intramolecular cyclization, and 1,4-dearomative ring expansion/intramolecular cyclization have been reported. The disclosed strategies have allowed the synthesis of a wide range of structurally diverse cyclic compounds, ranging from three-to eightmembered rings. However, there is still much room for improvement in this field. For

Summary and Outlook
In this review, we have summarized recent progress in the application of pyridinium and quinolinium 1,4-zwitterions for the efficient synthesis of heterocycles. The reported pyridinium and quinolinium 1,4-zwitterions can be classified into sulfur-based and nitrogenbased 1,4-zwitterions according to the types of anions. As to the study of sulfur-based 1,4-zwitterions, the known cyclization reactions include (2 + 3), (3 + n), (4 + n), (5 + n), and multistep cascade cyclization. With respect to nitrogen-based 1,4-zwitterions, dif-ferent types of cyclization, such as (3 + 2) cyclization, (5 + n) cyclization, cascade 1,4dearomative cycloaddition/intramolecular cyclization, and 1,4-dearomative ring expansion/intramolecular cyclization have been reported. The disclosed strategies have allowed the synthesis of a wide range of structurally diverse cyclic compounds, ranging from three-to eight-membered rings. However, there is still much room for improvement in this field. For example, the 1,4-dearomatization of sulfur-based, 1,4-zwitterion-triggered cyclization is limited, and only one report has been reported to date. Additionally, the use of nitrogen-based 1,4-zwitterions as pyridinium ylide-type synthons for the construction of nitrogen-containing heterocyclic compounds has not been reported to date. Some progress on the stereoselective reaction involving 1,4-zwitterions has also been made. However, the authors firmly believe that the exploration of asymmetric transformation is always worth pursuing. Additionally, photochemical catalysis is worth exploring in the field of transformations involving pyridinium and quinolinium 1,4-zwitterions.
We believe that this review will provide a useful reference for synthetic chemists who are interested in this area of work. The authors expect to see more progress and advances in the applications and scope of pyridinium and quinolinium 1,4-zwitterions in the near future. The authors also would like to apologize in advance for any unintentional omission of any literature report.