Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes

Quinolone and quinoline derivatives are frequently found as substructures in pharmaceutically active compounds. In this paper, we describe a procedure for the synthesis of azuleno[2,1-b]quinolones and quinolines from 2-arylaminoazulene derivatives, which are readily prepared via the aromatic nucleophilic substitution reaction of a 2-chloroazulene derivative with several arylamines. The synthesis of azuleno[2,1-b]quinolones was established by the Brønsted acid-catalyzed intramolecular cyclization of 2-arylaminoazulene derivatives bearing two ester groups at the five-membered ring. The halogenative aromatization of azuleno[2,1-b]quinolones with POCl3 yielded azuleno[2,1-b]quinolines with a chlorine substituent at the pyridine moiety. The aromatic nucleophilic substitution reaction of azuleno[2,1-b]quinolines bearing chlorine substituent with secondary amines was also investigated to afford the aminoquinoline derivatives. These synthetic methodologies reported in this paper should be valuable in the development of new pharmaceuticals based on the azulene skeleton.

Azulene is one of the 10π-electron non-benzenoid aromatic hydrocarbons having a fused structure of five-and seven-membered rings. To elucidate the physicochemical properties, especially optical and electrochemical properties, a variety of synthetic methods have been developed for azulene-fused derivatives [17][18][19][20][21][22][23]. However, despite the fact that azulene derivatives fused by several heterocycles, such as pyridine [24], thiophene [25], pyrrole, and furan [26,27], have been reported, the preparation of quinoloneand quinoline-fused derivatives have not been conducted so far. Since anti-inflammatory and anti-ulcer properties have been revealed in azulene derivatives [28,29], the incorporation of a quinolone and quinoline framework could create compounds with unique chemical, physical, and pharmacological characteristics that are not present in the individual compounds, potentially leading to new pharmaceutical discoveries. In this context, we Azulene is one of the 10π-electron non-benzenoid aromatic hydrocarbons having a fused structure of five-and seven-membered rings. To elucidate the physicochemical properties, especially optical and electrochemical properties, a variety of synthetic methods have been developed for azulene-fused derivatives [17][18][19][20][21][22][23]. However, despite the fact that azulene derivatives fused by several heterocycles, such as pyridine [24], thiophene [25], pyrrole, and furan [26,27], have been reported, the preparation of quinolone-and quinoline-fused derivatives have not been conducted so far. Since anti-inflammatory and anti-ulcer properties have been revealed in azulene derivatives [28,29], the incorporation of a quinolone and quinoline framework could create compounds with unique chemical, physical, and pharmacological characteristics that are not present in the individual compounds, potentially leading to new pharmaceutical discoveries. In this context, we sought to develop a new synthetic method for azulene-fused quinolones and quinolines, i.e., azuleno [2,1-b]quinolones and quinolines.

Results and Discussion
The acid-catalyzed intramolecular cyclization of diarylamine derivatives bearing ester function represents a valuable strategy for the construction of quinolone frameworks via Friedel-Crafts-type reaction [30]. Hence, we decided to adopt this methodology for the synthesis of azuleno [2,1-b]quinolones.
Initially, we investigated the preparation of 2-arylaminoazulenes, which serve as the precursors for azuleno [2,1-b]quinolones. In the synthesis of 2-and 6-aminoazulene derivatives, the aromatic nucleophilic substitution (SNAr) reaction of haloazulenes with aliphatic amines has already been reported by our group [31,32]. In the early years of azulene chemistry, Nozoe et al. reported that the SNAr reaction of diethyl 2-chloroazulene-1,3-dicarboxylate (1) with aniline yields the corresponding substituted product 2a at a 59% yield [33]. However, there have been few reports on the SNAr reaction of haloazulenes with aniline derivatives so far, except for an unsuccessful case [34]. In addition, since the reaction of 1 with aromatic amines with a function on the benzene ring has not been studied, we investigated the synthesis of 2-arylaminoazulene derivatives via SNAr reaction with several aniline derivatives.

Results and Discussion
The acid-catalyzed intramolecular cyclization of diarylamine derivatives bearing ester function represents a valuable strategy for the construction of quinolone frameworks via Friedel-Crafts-type reaction [30]. Hence, we decided to adopt this methodology for the synthesis of azuleno [2,1-b]quinolones.
Initially, we investigated the preparation of 2-arylaminoazulenes, which serve as the precursors for azuleno [2,1-b]quinolones. In the synthesis of 2-and 6-aminoazulene derivatives, the aromatic nucleophilic substitution (S N Ar) reaction of haloazulenes with aliphatic amines has already been reported by our group [31,32]. In the early years of azulene chemistry, Nozoe et al. reported that the S N Ar reaction of diethyl 2-chloroazulene-1,3-dicarboxylate (1) with aniline yields the corresponding substituted product 2a at a 59% yield [33]. However, there have been few reports on the S N Ar reaction of haloazulenes with aniline derivatives so far, except for an unsuccessful case [34]. In addition, since the reaction of 1 with aromatic amines with a function on the benzene ring has not been studied, we investigated the synthesis of 2-arylaminoazulene derivatives via S N Ar reaction with several aniline derivatives.
The yields and structures of the 2-arylaminoazulene derivatives obtained via S N Ar reaction are summarized in Table 1. The S N Ar reaction of 1 with anilines was examined by using EtOH as a solvent. The yield of the product significantly depended on the substituent on the benzene ring of arylamines, as shown in Table 1. The S N Ar reaction of 1 with aniline afforded 2-phenylaminoazulene derivative 2a at a 96% yield (entry 1). The melting point of 2a was consistent with the reported value. Moreover, even though the same reaction condition was employed, the extension of the reaction time (15 h) resulted in higher product yield compared to Nozoe's result. Similar to aniline, arylamines bearing electron-donating group on the benzene ring also reacted with 1 to produce the desired 2-arylaminoazulene derivatives 2a-2e in excellent yields (89-96%, entries 2-5). In these cases, pure products could be obtained via simple filtration protocols because the products were precipitated by cooling the reaction mixture, whereas the reaction with arylamine derivatives substituted with an electron-withdrawing group and sterically bulky 1-naphthylamine resulted in lower product yields (2f: 72% and 2g: 61%; entries 6 and 8). In the S N Ar reaction with p-nitroaniline, no reaction was observed even under the reflux temperature conditions in N-methylpyrolidone (NMP), which was attributed to the strong electron-withdrawing nature of the nitro group (entry 7). The reaction with N-methylaniline afforded the desired product 2h, but with a low yield (33%), which was probably due to the steric hindrance of the methyl group on the amine moiety (entry 9). tion condition was employed, the extension of the reaction time (15 h) resulted in higher product yield compared to Nozoe's result. Similar to aniline, arylamines bearing electrondonating group on the benzene ring also reacted with 1 to produce the desired 2-arylaminoazulene derivatives 2a−2e in excellent yields (89-96%, entries 2-5). In these cases, pure products could be obtained via simple filtration protocols because the products were precipitated by cooling the reaction mixture, whereas the reaction with arylamine derivatives substituted with an electron-withdrawing group and sterically bulky 1-naphthylamine resulted in lower product yields (2f: 72% and 2g: 61%; entries 6 and 8). In the SNAr reaction with p-nitroaniline, no reaction was observed even under the reflux temperature conditions in N-methylpyrolidone (NMP), which was a ributed to the strong electron-withdrawing nature of the nitro group (entry 7). The reaction with N-methylaniline afforded the desired product 2h, but with a low yield (33%), which was probably due to the steric hindrance of the methyl group on the amine moiety (entry 9). product yield compared to Nozoe's result. Similar to aniline, arylamines bearing electrondonating group on the benzene ring also reacted with 1 to produce the desired 2-arylaminoazulene derivatives 2a−2e in excellent yields (89-96%, entries 2-5). In these cases, pure products could be obtained via simple filtration protocols because the products were precipitated by cooling the reaction mixture, whereas the reaction with arylamine derivatives substituted with an electron-withdrawing group and sterically bulky 1-naphthylamine resulted in lower product yields (2f: 72% and 2g: 61%; entries 6 and 8). In the SNAr reaction with p-nitroaniline, no reaction was observed even under the reflux temperature conditions in N-methylpyrolidone (NMP), which was a ributed to the strong electron-withdrawing nature of the nitro group (entry 7). The reaction with N-methylaniline afforded the desired product 2h, but with a low yield (33%), which was probably due to the steric hindrance of the methyl group on the amine moiety (entry 9). product yield compared to Nozoe's result. Similar to aniline, arylamines bearing electrondonating group on the benzene ring also reacted with 1 to produce the desired 2-arylaminoazulene derivatives 2a−2e in excellent yields (89-96%, entries 2-5). In these cases, pure products could be obtained via simple filtration protocols because the products were precipitated by cooling the reaction mixture, whereas the reaction with arylamine derivatives substituted with an electron-withdrawing group and sterically bulky 1-naphthylamine resulted in lower product yields (2f: 72% and 2g: 61%; entries 6 and 8). In the SNAr reaction with p-nitroaniline, no reaction was observed even under the reflux temperature conditions in N-methylpyrolidone (NMP), which was a ributed to the strong electron-withdrawing nature of the nitro group (entry 7). The reaction with N-methylaniline afforded the desired product 2h, but with a low yield (33%), which was probably due to the steric hindrance of the methyl group on the amine moiety (entry 9). product yield compared to Nozoe's result. Similar to aniline, arylamines bearing electrondonating group on the benzene ring also reacted with 1 to produce the desired 2-arylaminoazulene derivatives 2a−2e in excellent yields (89-96%, entries 2-5). In these cases, pure products could be obtained via simple filtration protocols because the products were precipitated by cooling the reaction mixture, whereas the reaction with arylamine derivatives substituted with an electron-withdrawing group and sterically bulky 1-naphthylamine resulted in lower product yields (2f: 72% and 2g: 61%; entries 6 and 8). In the SNAr reaction with p-nitroaniline, no reaction was observed even under the reflux temperature conditions in N-methylpyrolidone (NMP), which was a ributed to the strong electron-withdrawing nature of the nitro group (entry 7). The reaction with N-methylaniline afforded the desired product 2h, but with a low yield (33%), which was probably due to the steric hindrance of the methyl group on the amine moiety (entry 9). donating group on the benzene ring also reacted with 1 to produce the desired 2-arylaminoazulene derivatives 2a−2e in excellent yields (89-96%, entries 2-5). In these cases, pure products could be obtained via simple filtration protocols because the products were precipitated by cooling the reaction mixture, whereas the reaction with arylamine derivatives substituted with an electron-withdrawing group and sterically bulky 1-naphthylamine resulted in lower product yields (2f: 72% and 2g: 61%; entries 6 and 8). In the SNAr reaction with p-nitroaniline, no reaction was observed even under the reflux temperature conditions in N-methylpyrolidone (NMP), which was a ributed to the strong electron-withdrawing nature of the nitro group (entry 7). The reaction with N-methylaniline afforded the desired product 2h, but with a low yield (33%), which was probably due to the steric hindrance of the methyl group on the amine moiety (entry 9). The synthesis of azuleno[2,1-b]quinolone derivatives via intramolecular cyclization of 2-arylaminoazulenes 2a-2g was investigated using several Brønsted acids. No reaction was observed when 2a was treated with trifluoroacetic acid, but the reaction with 100% phosphoric acid led to complete decomposition. We found that the reaction of 2a with polyphosphoric acid (PPA) leads to concomitant decarboxylation of the ester function to produce azulenoquinolone 3a in excellent yield (96%) ( Table 2, entry 1). Thus, the reaction condition utilizing PPA as a Brønsted acid was selected for further investigations. As shown in Table 2, all the cyclization with PPA afforded the target products 3b-3g in excellent yields (85-100%), but the cyclization reaction of 2e having a m-methoxy group on the arylamine moiety afforded regioisomers 3e and 3e′ (3e:3e′ = 3:2 ratio from 1 H NMR spectrum) in 93% yield as an inseparable mixture (entry 5 and Figure 2). The resulting quinolones 3a-3g were stable enough to be stored for several months under ambient conditions but had rather poor solubility in common organic solvents. The synthesis of azuleno[2,1-b]quinolone derivatives via intramolecular cyclization of 2-arylaminoazulenes 2a-2g was investigated using several Brønsted acids. No reaction was observed when 2a was treated with trifluoroacetic acid, but the reaction with 100% phosphoric acid led to complete decomposition. We found that the reaction of 2a with polyphosphoric acid (PPA) leads to concomitant decarboxylation of the ester function to produce azulenoquinolone 3a in excellent yield (96%) ( Table 2, entry 1). Thus, the reaction condition utilizing PPA as a Brønsted acid was selected for further investigations. As shown in Table 2, all the cyclization with PPA afforded the target products 3b-3g in excellent yields (85-100%), but the cyclization reaction of 2e having a m-methoxy group on the arylamine moiety afforded regioisomers 3e and 3e′ (3e:3e′ = 3:2 ratio from 1 H NMR spectrum) in 93% yield as an inseparable mixture (entry 5 and Figure 2). The resulting quinolones 3a-3g were stable enough to be stored for several months under ambient conditions but had rather poor solubility in common organic solvents. The synthesis of azuleno[2,1-b]quinolone derivatives via intramolecular cyclization of 2-arylaminoazulenes 2a-2g was investigated using several Brønsted acids. No reaction was observed when 2a was treated with trifluoroacetic acid, but the reaction with 100% phosphoric acid led to complete decomposition. We found that the reaction of 2a with polyphosphoric acid (PPA) leads to concomitant decarboxylation of the ester function to produce azulenoquinolone 3a in excellent yield (96%) ( Table 2, entry 1). Thus, the reaction condition utilizing PPA as a Brønsted acid was selected for further investigations. As shown in Table 2, all the cyclization with PPA afforded the target products 3b-3g in excellent yields (85-100%), but the cyclization reaction of 2e having a m-methoxy group on the arylamine moiety afforded regioisomers 3e and 3e (3e:3e = 3:2 ratio from 1 H NMR spectrum) in 93% yield as an inseparable mixture (entry 5 and Figure 2). The resulting quinolones 3a-3g were stable enough to be stored for several months under ambient conditions but had rather poor solubility in common organic solvents. The synthesis of azuleno[2,1-b]quinolone derivatives via intramolecular cyclization of 2-arylaminoazulenes 2a-2g was investigated using several Brønsted acids. No reaction was observed when 2a was treated with trifluoroacetic acid, but the reaction with 100% phosphoric acid led to complete decomposition. We found that the reaction of 2a with polyphosphoric acid (PPA) leads to concomitant decarboxylation of the ester function to produce azulenoquinolone 3a in excellent yield (96%) ( Table 2, entry 1). Thus, the reaction condition utilizing PPA as a Brønsted acid was selected for further investigations. As shown in Table 2, all the cyclization with PPA afforded the target products 3b-3g in excellent yields (85-100%), but the cyclization reaction of 2e having a m-methoxy group on the arylamine moiety afforded regioisomers 3e and 3e′ (3e:3e′ = 3:2 ratio from 1 H NMR spectrum) in 93% yield as an inseparable mixture (entry 5 and Figure 2). The resulting quinolones 3a-3g were stable enough to be stored for several months under ambient conditions but had rather poor solubility in common organic solvents. The synthesis of azuleno[2,1-b]quinolone derivatives via intramolecular cyclization of 2-arylaminoazulenes 2a-2g was investigated using several Brønsted acids. No reaction was observed when 2a was treated with trifluoroacetic acid, but the reaction with 100% phosphoric acid led to complete decomposition. We found that the reaction of 2a with polyphosphoric acid (PPA) leads to concomitant decarboxylation of the ester function to produce azulenoquinolone 3a in excellent yield (96%) ( Table 2, entry 1). Thus, the reaction condition utilizing PPA as a Brønsted acid was selected for further investigations. As shown in Table 2, all the cyclization with PPA afforded the target products 3b-3g in excellent yields (85-100%), but the cyclization reaction of 2e having a m-methoxy group on the arylamine moiety afforded regioisomers 3e and 3e′ (3e:3e′ = 3:2 ratio from 1 H NMR spectrum) in 93% yield as an inseparable mixture (entry 5 and Figure 2). The resulting quinolones 3a-3g were stable enough to be stored for several months under ambient conditions but had rather poor solubility in common organic solvents.   The plausible reaction mechanism for the formation of 3 is shown in Scheme 1. Initially, the protonation of carbonyl group of 2 by PPA forms intermediate A. Subsequently, the intramolecular Friedel-Craft reaction of the substituted arylamine moiety to the activated carbonyl group affords the hemiacetal intermediate C through the cationic intermediate B. Hemiacetal C is further protonated to form intermediates D or D', which upon the elimination of water or ethanol provide the ester product E. Finally, the ester group on the azulene ring should be decarboxylated to afford azuleno[2,1-b]quinolone 3.         Halogen substituents hold significant importance as functional groups in modern organic synthesis because they can be transformed into a diverse range of substituents through cross-coupling and nucleophilic substitution reactions [35][36][37]. Regarding the halogenation of aromatic compounds, electrophilic substitution reactions with halogens in the presence of Lewis or Brønsted acids can be utilized, or N-halosuccinimide (NXS) is also frequently employed for electron-rich aromatic rings. However, the introduction of halogen substituents through the electrophilic substitution reactions in electron-deficient nitrogencontaining aromatic compounds, such as pyridine and quinoline derivatives, is often difficult due to their inherently low reactivity. Therefore, we undertook an investigation into the conversion of quinolone derivatives into azulene-fused quinolines with a halogen substituent via halogenated aromatization. Halogen substituents hold significant importance as functional groups in modern organic synthesis because they can be transformed into a diverse range of substituents through cross-coupling and nucleophilic substitution reactions [35][36][37]. Regarding the halogenation of aromatic compounds, electrophilic substitution reactions with halogens in the presence of Lewis or Brønsted acids can be utilized, or N-halosuccinimide (NXS) is also frequently employed for electron-rich aromatic rings. However, the introduction of halogen substituents through the electrophilic substitution reactions in electron-deficient nitrogen-containing aromatic compounds, such as pyridine and quinoline derivatives, is often difficult due to their inherently low reactivity. Therefore, we undertook an investigation into the conversion of quinolone derivatives into azulene-fused quinolines with a halogen substituent via halogenated aromatization.
The conversion of quinolone derivatives into azulene-fused quinolines was effectively accomplished through the reaction with phosphoryl chloride (POCl3). The structures and yields of the resultant products are represented in Table 3. Since the solubility of the quinolone derivatives was relatively high, POCl3 was employed as both solvent and reagent in this reaction. The reaction of 3a with POCl3, conducted at reflux temperature, yielded the desired compound 4a as the sole product with a 89% yield (entry 1). The quinolone derivatives 3b-3d with an electron-donating group also underwent a similar reaction, leading to the formation of the corresponding quinolines 4b-4d in excellent yields (4b: 94%, 4c: 93%, and 4d: 83%, entries 2-4). The mixture of 3e and 3e′ was subjected to the reaction to yield 4e and 4e′ at a 72% yield (entry 5, Figure 3). However, the separation of the resulting mixture proved difficult via chromatography or recrystallization. Quinolone 3f, possessing an iodine substituent, produced 4f along with trace amounts of 4a; thus, the product yield of 4f was only 61% due to the competing decomposition reaction (entry 6). Furthermore, quinolone 3g with an extended conjugated system exhibited reactivity with POCl3 to afford 4g at an 80% yield (entry 7).
In contrast to the rather low solubility of quinolones 3a-3g in common organic solvents, quinolines 4a-4g showed high solubility. These differences are probably due to intermolecular hydrogen bonds between the NH protons and the carbonyl groups, which causes 3a-3g to exist as multimers in the solid state, resulting in low solubility, whereas the high solubility of 4a-4g is a ributable to the absence of such interactions. The conversion of quinolone derivatives into azulene-fused quinolines was effectively accomplished through the reaction with phosphoryl chloride (POCl 3 ). The structures and yields of the resultant products are represented in Table 3. Since the solubility of the quinolone derivatives was relatively high, POCl 3 was employed as both solvent and reagent in this reaction. The reaction of 3a with POCl 3 , conducted at reflux temperature, yielded the desired compound 4a as the sole product with a 89% yield (entry 1). The quinolone derivatives 3b-3d with an electron-donating group also underwent a similar reaction, leading to the formation of the corresponding quinolines 4b-4d in excellent yields (4b: 94%, 4c: 93%, and 4d: 83%, entries 2-4). The mixture of 3e and 3e was subjected to the reaction to yield 4e and 4e at a 72% yield (entry 5, Figure 3). However, the separation of the resulting mixture proved difficult via chromatography or recrystallization. Quinolone 3f, possessing an iodine substituent, produced 4f along with trace amounts of 4a; thus, the product yield of 4f was only 61% due to the competing decomposition reaction (entry 6). Furthermore, quinolone 3g with an extended conjugated system exhibited reactivity with POCl 3 to afford 4g at an 80% yield (entry 7).
In contrast to the rather low solubility of quinolones 3a-3g in common organic solvents, quinolines 4a-4g showed high solubility. These differences are probably due to intermolecular hydrogen bonds between the NH protons and the carbonyl groups, which causes 3a-3g to exist as multimers in the solid state, resulting in low solubility, whereas the high solubility of 4a-4g is attributable to the absence of such interactions.
As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the S N Ar reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range of nucleophiles, thereby facilitating the conversion into an array of substituents. Therefore, the amination of 5a by the S N Ar reaction was investigated.   As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range   As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range 4a, 89% 2 3b Molecules 2023, 28, x FOR PEER REVIEW 7 of 16  As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range 4b, 94% 3 3c Molecules 2023, 28, x FOR PEER REVIEW 7 of 16  As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range Molecules 2023, 28, x FOR PEER REVIEW 7 of 16  As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range Molecules 2023, 28, x FOR PEER REVIEW 7 of 16  As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range Molecules 2023, 28, x FOR PEER REVIEW 7 of 16  As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range 4f, 61% 7 3g Molecules 2023, 28, x FOR PEER REVIEW 7 of 16  As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range 4g, 80% a Isolated yield. b inseparable mixture.   As discussed in the Introduction section, multiply functionalized quinolines are included in a significant cohort of relevant moieties related to biologically and pharmaceutically active compounds. Considering the proficiency of the chlorine function within the aromatic ring as an efficacious leaving group in the SNAr reaction, it is anticipated that the chlorine substituent of quinoline shall undergo substitution reactions with a diverse range Recently, Poole et al. disclosed that the S N Ar reaction of 4-chloroquinoline with pyrrolidine occurs at 150 • C with microwave irradiation, forming 4-pyrrolidinylquinoline in 89% yield [38]. Furthermore, Cirujano, Martí-Gastaldo, and their collaborators demonstrated that the reaction of 4-chloroquinoline with morpholine in the presence of a zinc catalyst yields 4-morpholylquinoline. However, this transformation resulted in a low product yield (25%) and required a prolonged reaction time of 24 h [39].
It was noted that the S N Ar reaction of 4a with pyrrolidine was completed at ambient temperature to give 4-pyrrolidinylquinoline 5a in excellent yield (85%, Scheme 2). Furthermore, the utilization of piperidine and morpholine in the reaction with 4a yielded the corresponding substituted products 5b (78%) and 5c (74%) with satisfactory yields, although slight heating conditions (50 • C) were required. These findings contrast with the requirements of higher temperature and prolonged reaction time for the reaction involving 4-chloroquinoline. These results might probably be attributed to the extension of the conjugated system by the fused azulene ring, which reduces the HOMO-LUMO energy gap, thereby lowering the LUMO energy level and facilitating the substitution with nucleophilic reagents. Meanwhile, the reaction with diethylamine, which is less nucleophilic than cyclic amines [40], did not proceed, and 4a was recovered.
89% yield [38]. Furthermore, Cirujano, Martí-Gastaldo, and their collaborators demonstrated that the reaction of 4-chloroquinoline with morpholine in the presence of a zinc catalyst yields 4-morpholylquinoline. However, this transformation resulted in a low product yield (25%) and required a prolonged reaction time of 24 h [39].
It was noted that the SNAr reaction of 4a with pyrrolidine was completed at ambient temperature to give 4-pyrrolidinylquinoline 5a in excellent yield (85%, Scheme 2). Furthermore, the utilization of piperidine and morpholine in the reaction with 4a yielded the corresponding substituted products 5b (78%) and 5c (74%) with satisfactory yields, although slight heating conditions (50 °C) were required. These findings contrast with the requirements of higher temperature and prolonged reaction time for the reaction involving 4-chloroquinoline. These results might probably be a ributed to the extension of the conjugated system by the fused azulene ring, which reduces the HOMO-LUMO energy gap, thereby lowering the LUMO energy level and facilitating the substitution with nucleophilic reagents. Meanwhile, the reaction with diethylamine, which is less nucleophilic than cyclic amines [40], did not proceed, and 4a was recovered. These new compounds 2a−2i, 3a−3g, 4a−4h, and 5a−5d were fully characterized based on their spectroscopic data, as summarized in the Experimental Section and Supplementary Materials. The 1 H NMR spectroscopic assignments of the reported compounds were confirmed by COSY. The HRMS spectra of the new compounds ionized by ESI showed the expected molecular ion peaks. These results are consistent with the given structures of these products (Firgures S1-S50).

Materials and Methods
General: Melting points were determined with a Yanagimoto MPS3 micromelting apparatus. The HRMS data were obtained with a Waters Xevo G2-XS QTof spectrometer. IR spectrum was recorded with JASCO FTIR-4100 spectrophotometer. 1 H and 13 C NMR spectra were recorded with a JEOL ECA500 spectrometer at 500 MHz and 125 MHz, respectively. These new compounds 2a-2i, 3a-3g, 4a-4h, and 5a-5d were fully characterized based on their spectroscopic data, as summarized in the Experimental Section and Supplementary Materials. The 1 1H NMR spectroscopic assignments of the reported compounds were confirmed by COSY. The HRMS spectra of the new compounds ionized by ESI showed the expected molecular ion peaks. These results are consistent with the given structures of these products (Figures S1-S50).

Conclusions
In conclusion, we have demonstrated herein a procedure for the synthesis of azuleno [2,1-b]quinolones and quinolines from 2-arylaminoazulene derivatives, which are prepared via the S N Ar reaction of 2-chloroazulenes with arylamines. The synthesis of azuleno [2,1-b]quinolones was successfully accomplished through the intramolecular cyclization of 2-arylaminoazulene derivatives bearing ester groups, employing PPA as a Brønsted acid catalyst. Furthermore, halogenative aromatization of the corresponding azuleno [2,1b]quinolones with POCl 3 afforded azuleno [2,1-b]quinolines with a chlorine substituent. Additionally, the S N Ar reaction of azuleno [2,1-b]quinolines with several secondary amines was also investigated. Consequently, the reactions proceeded expeditiously under the low-temperature conditions, yielding the respective aminoquinoline derivatives, except for the reaction with diethylamine.
As discussed in the Introduction section, quinolones and quinolines possess considerable potential in the fields of pharmaceuticals and medicinal chemistry. Therefore, the exploration of additional avenues to functionalize these derivatives may lead to practical pharmaceutical agents. The development of an additional synthetic methodology for azuleno [2,1-d]quinolones and quinolines is currently underway in our laboratory.