Next Article in Journal
Traditional vs. Energetic and Perchlorate vs. “Green”: A Comparative Study of the Choice of Binders and Oxidising Agents
Next Article in Special Issue
Polyaromatic Bis(indolyl)methane Derivatives with Antiproliferative and Antiparasitic Activity
Previous Article in Journal
Epsom Salt-Based Natural Deep Eutectic Solvent as a Drilling Fluid Additive: A Game-Changer for Shale Swelling Inhibition
Previous Article in Special Issue
Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 15
10.3390/molecules28155785
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Taku Shoji
1,*,
Mutsumi Takeuchi
2,3,
Mayumi Uda
2,
Yukino Ariga
2,
Akari Yamazaki
2,
Ryuta Sekiguchi
4 and
Shunji Ito
4
1
Department of Chemical Biology and Applied Chemistry, College of Engineering, Nihon University, Koriyama 963-8642, Japan
2
Graduate School of Science and Technology, Shinshu University, Matsumoto 390-8621, Japan
3
Department of Chemistry, School of Science, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551, Japan
4
Graduate School of Science and Technology, Hirosaki University, Hirosaki 036-8561, Japan
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(15), 5785; https://doi.org/10.3390/molecules28155785
Submission received: 6 July 2023 / Revised: 26 July 2023 / Accepted: 26 July 2023 / Published: 31 July 2023
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
Browse Figures
Versions Notes

Abstract

:
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.

1. Introduction

Quinolone derivatives are compounds used as a range of antibiotics [1,2]. Thus, a number of antibiotics have been developed based on them, such as levofloxacin [3,4], moxifloxacin [5], gemifloxacin [6,7], ciprofloxacin [8,9], and so on (Figure 1). Quinoline derivatives are also compounds used as antimalarial drugs, and chloroquine [10], quinine [11], and primaquine [12] have traditionally been used. In recent years, quinoline derivatives such as bosutinib [13], lenvatinib [14], and cabozantinib [15] have been employed clinically as anticancer agents (Figure 1). Hence, synthetic methods for a variety of quinolone and quinoline derivatives have been developed to date [16].
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.
Herein, we describe a novel synthetic procedure for the synthesis of azuleno[2,1-b]quinolones via Brønsted acid-catalyzed intramolecular cyclization of 1,3-diethoxycarbonyl-2-arylaminoazulene derivatives. The azuleno[2,1-b]quinolones obtained were converted into azuleno[2,1-b]quinolines via halogenative aromatization with phosphoryl chloride (POCl3). The aromatic nucleophilic substitution reaction with several amines at the chlorine substituent of a quinoline derivative was investigated, allowing the conversion to the corresponding 4-aminoquinolines.

2. 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.
The yields and structures of the 2-arylaminoazulene derivatives obtained via SNAr reaction are summarized in Table 1. The SNAr 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 SNAr 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 SNAr 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).
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 1H 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 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 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 SNAr 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 SNAr reaction was investigated.
Recently, Poole et al. disclosed that the SNAr 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 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 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.
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 11H 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).

3. 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. 1H and 13C NMR spectra were recorded with a JEOL ECA500 spectrometer at 500 MHz and 125 MHz, respectively.
Diethyl 2-(phenylamino)azulene-1,3-dicarboxylate (2a): A solution of 1 (1.59 g, 5.19 mmol) and aniline (1.46 g, 15.7 mmol) in EtOH (16 mL) was refluxed for 15 h. After the reaction mixture was cooled, the generated precipitate was collected via filtration to afford 2a (1.79 g, 95%) as an orange solid. M.p. 138–139 °C (lit. 141–142 °C); IR (ATR): νmax = 1674 (C=O) cm−1; 1H NMR (500 MHz, CDCl3): δH = 10.03 (br.s, 1H, NH), 9.06 (dd, 2H, J = 10.2, 1.6 Hz, H4,8), 7.57–7.51 (m, 3H, H6, m-Ph), 7.32–7.29 (m, 2H, H5,7), 7.23 (dd, 2H, J = 8.6, 1.1 Hz, o-Ph), 7.08 (t, 1H, J = 7.3 Hz, p-Ph), 4.09 (q, 4H, J = 7.2 Hz, CO2Et), 1.17 (t, 6H, J = 7.2 Hz, CO2Et) ppm; 13C NMR (125 MHz, CDCl3): δC = 166.5, 155.3, 144.5, 142.8, 134.1, 132.1, 131.8, 129.3, 123.9, 119.6, 103.8, 60.3, 14.3 ppm; HRMS (ESI-TOF): calcd for C22H21NO4 + Na+ [M + Na]+ 386.1363; found: 386.1373.
Diethyl 2-(p-tolylamino)azulene-1,3-dicarboxylate (2b): A solution of 1 (616 mg, 2.01 mmol) and p-toluidine (648 mg, 6.05 mmol) in EtOH (6 mL) was refluxed for 16 h. After the reaction mixture was cooled, the generated precipitate was collected via filtration to afford 2b (679 mg, 89%) as an orange solid. M.p. 148–149 °C; IR (ATR): νmax = 1690 (C=O), 1645 (s), 1587 (m), 1555 (s), 1513 (s), 1475 (m), 1432 (m), 1385 (m), 1302 (m), 1268 (w), 1230 (m), 1206 (m), 1167 (s), 1111 (m), 1031 (m), 987 (w), 943 (w), 928 (w), 903 (w), 880 (w), 858 (w), 823 (m), 802 (w), 784 (m), 761 (w), 734 (m), 701 (w), 668 (w), cm−1; 1H NMR (500 MHz, CDCl3): δH = 9.97 (br.s, 1H, NH), 9.02–9.00 (m, 2H, H4,8), 7.46–7.55 (m, 3H, H5,6,7), 7.13–7.10 (m, 4H, o,m-Ph), 4.09 (q, 4H, J = 7.1 Hz, CO2Et), 2.32 (s, 3H, Me), 1.18 (t, 6H, J = 7.1 Hz, CO2Et) ppm; 13C NMR (125 MHz, CDCl3): δC = 166.6, 155.7, 144.6, 140.2, 133.8, 133.6, 131.73, 131.71, 129.8, 119.8, 103.6, 60.3, 21.0, 14.3 ppm; HRMS (ESI-TOF): calcd for C23H23NO4 + Na+ [M + Na]+ 400.1519; found: 400.1527.
Diethyl 2-[(p-butylphenyl)amino]azulene-1,3-dicarboxylate (2c): A solution of 1 (617 mg, 2.01 mmol) and p-butylaniline (905 mg, 6.06 mmol) in EtOH (6 mL) was refluxed for 16.5 h. After the reaction mixture was cooled, the generated precipitate was collected via filtration to afford 2c (752 mg, 89%) as an orange solid. M.p. 87–88 °C; IR (ATR): νmax = 1685 (C=O) cm−1; 1H NMR (500 MHz, CDCl3): δH = 9.99 (br.s, 1H, NH), 9.01 (d, 2H, J = 10.0 Hz, H4,8), 7.55–7.48 (m, 3H, H5,6,7), 7.13 (m, 4H, o,m-Ph), 4.08 (q, 4H, J = 7.1 Hz, CO2Et), 2.58 (t, 2H, J = 7.4 Hz, n-Bu), 1.57 (sext., 2H, n-Bu), 1.36 (quint., 2H, J = 7.4 Hz, n-Bu), 1.17 (t, 6H, J = 7.1 Hz, CO2Et), 0.93 (t, 3H, J = 7.4 Hz, n-Bu) ppm; 13C NMR (125 MHz, CDCl3): δC = 166.6, 155.6, 144.6, 140.4, 138.8, 133.8, 131.73, 131.71, 129.2, 119.7, 103.6, 60.3, 35.2, 34.0, 22.3, 14.3, 14.0 ppm; HRMS (ESI-TOF): calcd for C26H29NO4 + Na+ [M + Na]+ 442.1989; found: 442.1995.
Diethyl 2-[(p-methoxyphenyl)amino]azulene-1,3-dicarboxylate (2d): A solution of 1 (616 mg, 2.01 mmol) and p-anisidine (742 mg, 6.02 mmol) in EtOH (6 mL) was refluxed for 21 h. After the reaction mixture was cooled, the generated precipitate was collected via filtration to afford 2d (760 mg, 96%) as an orange solid. M.p. 156–157 °C; IR (ATR): νmax = 1688 (C=O) cm−1; 1H NMR (500 MHz, CDCl3): δH = 9.94 (br.s, 1H, NH), 8.97 (d, 2H, J = 10.0 Hz, H4,8), 7.53–7.46 (m, 3H, H5,6,7), 7.16 (d, 2H, J = 8.9 Hz, m-Ph), 6.85 (d, 2H, J = 8.9 Hz, o-Ph), 4.10 (q, 4H, J = 7.0 Hz, CO2Et), 3.80 (s, 3H, OMe), 1.21 (t, 6H, J = 7.0 Hz, CO2Et) ppm; 13C NMR (125 MHz, CDCl3): δC = 166.6, 156.6, 156.1, 144.6, 136.1, 133.6, 131.7, 131.5, 121.5, 114.5, 103.3, 60.3, 55.7, 14.3 ppm; HRMS (ESI-TOF): calcd for C23H23NO5 + Na+ [M + Na]+ 416.1468; found: 416.1483.
Diethyl 2-[(m-methoxyphenyl)amino]azulene-1,3-dicarboxylate (2e): A solution of 1 (615 mg, 2.00 mmol) and m-anisidine (757 mg, 6.15 mmol) in EtOH (6 mL) was refluxed for 17.5 h. The reaction mixture was extracted with AcOEt/hexane, and the organic layer was washed with aq. HCl and brine, dried over Na2SO4. The solvent was concentrated under reduced pressure, and the residue was purified by recrystallization with ethanol to afford 2e (723 mg, 92%) as an orange solid. M.p. 105–106 °C; IR (ATR): νmax = 1673 (C=O) cm−1; 1H NMR (500 MHz, CDCl3): δH = 10.02 (s, 1H, NH), 9.05 (d, J = 10.3 Hz, 2H, H4,8), 7.57–7.51 (m, 3H, H5,6,7), 7.20 (t, 1H, J = 8.2 Hz, H5 of Ph), 6.80–6.83 (m, 2H, H2,4 of Ph), 6.64 (dd, 1H, J = 8.2, 2.3 Hz, H6 of Ph), 4.12 (q, 4H, J = 7.2 Hz, CO2Et), 3.77 (s, 3H, OMe), 1.20 (t, 6H, J = 7.2 Hz, CO2Et) ppm; 13C NMR (125 MHz, CDCl3): δC = 166.5, 160.7, 155.0, 144.4, 144.0, 134.2, 132.2, 131.7, 130.0, 112.1, 110.4, 104.6, 103.9, 60.3, 55.4, 14.3 ppm; HRMS (ESI-TOF): calcd for C23H23NO5 + Na+ [M + Na]+ 416.1468; found: 416.1483.
Diethyl 2-[(p-iodophenyl)amino]azulene-1,3-dicarboxylate (2f): A solution of 1 (615 mg, 2.00 mmol) and p-iodoaniline (1.31 g, 6.00 mmol) in EtOH (6 mL) was refluxed for 45 h. After the reaction mixture was cooled, the generated precipitate was collected via filtration to afford 2f (707 mg, 72%) as an orange solid. M.p. 152–153 °C; IR (ATR): νmax = 1677 (C=O) cm−1; 1H NMR (500 MHz, CDCl3): δH = 10.01 (s, 1H, NH), 9.11–9.08 (m, 2H, H4,8), 7.56–7.60 (m, 5H, H5,6,7 and m-Ph), 6.99 (d, 2H, J = 8.6 Hz, o-Ph), 4.14 (q, 4H, J = 7.1 Hz, CO2Et), 1.20 (t, 6H, J = 7.1 Hz, CO2Et) ppm; 13C NMR (125 MHz, CDCl3): δC = 166.4, 154.7, 144.4, 142.7, 138.1, 134.7, 132.6, 131.9, 121.4, 103.9, 86.1, 60.4, 14.3 ppm; HRMS (ESI-TOF): calcd for C22H20NO4I + Na+ [M + Na]+ 512.0329; found: 512.0345.
Diethyl 2-(naphthalen-1-ylamino)azulene-1,3-dicarboxylate (2g): A solution of 1 (616 mg, 2.01 mmol) and 1-naphthylamine (867 mg, 6.05 mmol) in EtOH (6 mL) was refluxed for 15 h. After the reaction mixture was cooled, the generated precipitate was collected via filtration to afford 2g (507 mg, 61%) as an orange solid. M.p. 164–165 °C; IR (ATR): νmax = 1693 (C=O) cm−1; 1H NMR (500 MHz, CDCl3): δH = 10.31 (s, 1H, NH), 9.03 (dd, 2H, J = 10.0, 1.4 Hz, H4,8), 8.34 (d, 1H, J = 8.2 Hz, H8 of Naph.), 7.89–7.87 (m, 1H, H5 of Naph.), 7.64 (d, J = 8.2 Hz, 1H, H4 of Naph.), 7.59–7.49 (m, 5H, H5,6,7 and H6,7 of Naph.), 7.44 (d, 1H, J = 7.9 Hz, H2 of Naph.), 7.38 (t, 1H, J = 7.9 Hz, H3 of Naph.), 3.92 (d, 4H, J = 6.9 Hz, CO2Et), 0.89 (t, 6H, J = 6.9 Hz, CO2Et) ppm; 13C NMR (125 MHz, CDCl3): δC = 166.6, 156.8, 144.5, 139.3, 134.6, 134.0, 131.9, 131.7, 128.3, 128.2, 126.6, 126.4, 125.9, 124.7, 122.4, 115.4, 103.8, 60.2, 13.9 ppm; HRMS (ESI-TOF): calcd for C26H23NO4 + Na+ [M + Na]+ 436.1519; found: 436.1540.
Diethyl 2-(N-methyl-N-phenylamino)azulene-1,3-dicarboxylate (2h): A solution of 1 (309 mg, 1.01 mmol) and N-methylaniline (324 mg, 3.02 mmol.) was refluxed for 1.5 h. The reaction mixture was poured into 5% HCl and extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with hexane/AcOEt (4:1) to afford 2h (124 mg, 33%) as an orange solid. M.p. 99–100 °C; IR (ATR): νmax = 1676 (C=O) cm−1; 1H NMR (500 MHz, CDCl3): δH = 9.34 (d, 2H, J = 10.0 Hz, H4,8), 7.73 (d, 1H, J = 10.0 Hz, H6), 7.62 (t, 2H, J = 10.0 Hz, H5,7), 7.17 (dd, 2H, J = 8.2, 7.3 Hz, m-Ph), 6.82–6.79 (m, 3H, o,p-Ph), 4.13 (q, 4H, J = 7.2 Hz, CO2Et), 3.45 (s, 3H, Me), 1.18 (t, 6H, J = 7.2 Hz, CO2Et) ppm; 13C NMR (125 MHz, CDCl3): δC = 165.1, 157.9, 148.8, 143.1, 137.9, 136.0, 130.6, 128.9, 119.1, 114.3, 112.9, 60.3, 41.3, 14.3 ppm; HRMS (ESI-TOF): calcd for C23H23NO4 + Na+ [M + Na]+ 400.1519; found: 400.1527.
Azuleno[2,1-b]quinolin-12(5H)-one (3a): To a solution of 2a (614 mg, 1.69 mmol) in polyphosphoric acid (17 mL) was stirred at 140 °C for 6 h. After the reaction mixture was cooled, it was poured into water. The generated precipitate was collected via filtration to afford 3a (396 mg, 96%) as a reddish-brown solid. M.p. 245 °C (decomp.); IR (ATR): νmax = 1698 (C=O) cm−1; 1H NMR (500 MHz, DMSO-d6): δH = 12.30 (s, 1H, NH), 9.56–9.54 (m, 1H, H11), 8.36–8.33 (m, 2H, H2,7), 7.72–7.69 (m, 1H), 7.62–7.58 (m, 3H, H11), 7.46–7.42 (m, 1H), 7.34–7.31 (m, 1H, H8), 7.11 (s, 1H, H6) ppm; 13C NMR (125 MHz, DMSO-d6): δC = 175.5, 151.8, 144.9, 140.4, 140.1, 134.9, 134.5, 132.5, 131.9, 130.4, 129.0, 126.3, 124.1, 122.2, 118.0, 110.3, 104.3 ppm; HRMS (ESI-TOF): calcd for C17H11NO + H+ [M + H]+ 246.0913; found: 246.0927.
2-Methylazuleno[2,1-b]quinolin-12(5H)-one (3b): To a solution of 2b (382 mg, 1.01 mmol) in polyphosphoric acid (10 mL) was stirred at 140 °C for 2.5 h. After the reaction mixture was cooled, it was poured into water. The generated precipitate was collected via filtration to afford 3b (224 mg, 85%) as a reddish-brown solid. M.p. > 300 °C; IR (ATR): νmax = 1629 (C=O) cm−1; 1H NMR (500 MHz, DMSO-d6): δH = 12.21 (s, 1H, NH), 9.53–9.51 (m, 1H, H11), 8.31 (d, 1H, J = 10.3 Hz, H7), 8.15 (s, 1H, H1), 7.51–7.57 (m, 4H, H3,4,9,10), 7.40–7.44 (m, 1H, H8), 7.09 (s, 1H, H6), 2.44 (s, 3H, Me) ppm; 13C NMR (125 MHz, DMSO-d6): δC = 175.4, 151.7, 144.8, 140.2, 138.3, 134.6, 134.3, 133.7, 131.7, 131.3, 130.4, 128.9, 125.7, 124.0, 117.9, 110.2, 104.2, 21.3 ppm; HRMS (ESI-TOF): calcd for C18H13NO + H+ [M + H]+ 260.1070; found: 260.1071.
2-Butylazuleno[2,1-b]quinolin-12(5H)-one (3c): To a solution of 2c (420 mg, 1.00 mmol) in polyphosphoric acid (10 mL) was stirred at 140 °C for 2 h. After the reaction mixture was cooled, it was poured into water. The generated precipitate was collected via filtration to afford 3c (260 mg, 86%) as a reddish-brown solid. M.p. 239–240 °C; IR (ATR): νmax = 1627 (C=O) cm−1; 1H NMR (500 MHz, DMSO-d6): δH = 12.22 (s, 1H, NH), 9.53–9.51 (m, 1H, H11), 8.31 (d, 1H, J = 10.6 Hz, H7), 8.14 (s, 1H, H1), 7.57–7.52 (m, 4H, H3,4,9,10), 7.44–7.40 (m, 1H, H8), 7.09 (s, 1H, H6), 2.72 (t, 2H, J = 7.4 Hz, n-Bu), 1.57–1.63 (m, 2H, n-Bu), 1.31 (sext., 2H, J = 7.4 Hz, n-Bu), 0.89 (t, 3H, J = 7.4 Hz, n-Bu) ppm; 13C NMR (125 MHz, DMSO-d6): δC = 175.5, 151.7, 144.8, 140.2, 138.5, 136.3, 134.6, 134.3, 133.0, 131.6, 130.4, 128.9, 125.1, 124.0, 118.0, 110.3, 104.3, 35.0, 33.9, 22.2, 14.4 ppm; HRMS (ESI-TOF): calcd for C21H19NO + H+ [M + H]+ 302.1539; found: 302.1522.
2-Methoxyazuleno[2,1-b]quinolin-12(5H)-one (3d): To a solution of 2d (394 mg, 1.00 mmol) in polyphosphoric acid (10 mL) was stirred at 140 °C for 3 h. After the reaction mixture was cooled, it was poured into water. The generated precipitate was collected via filtration to afford 3d (250 mg, 91%) as a reddish-brown solid. M.p. 240 °C (decomp.); IR (ATR): νmax = 1663 (C=O) cm−1; 1H NMR (500 MHz, DMSO-d6): δH = 12.28 (s, 1H, NH), 9.50 (d, 1H, J = 9.5 Hz, H11), 8.28 (d, 1H, J = 10.6 Hz, H7), 7.80 (d, 1H, J = 2.9 Hz, H1), 7.60–7.51 (m, 3H, H4,9,10), 7.41–7.35 (m, 2H, H3,8), 7.08 (s, 1H, H6), 3.86 (s, 3H, OMe) ppm; 13C NMR (125 MHz, DMSO-d6): δC = 174.9, 155.1, 151.3, 144.7, 140.3, 134.7, 134.4, 134.2, 131.4, 130.3, 128.8, 125.0, 122.1, 119.6, 110.0, 106.6, 104.4, 56.0 ppm; HRMS (ESI-TOF): calcd for C18H13NO2 + H+ [M + H]+ 276.1019; found: 276.1018.
Cyclization reaction of 2e: To a solution of 2e (396 mg, 1.01 mmol) in polyphosphoric acid (10 mL) was stirred at 140 °C for 2.5 h. After the reaction mixture was cooled, it was poured into water. The generated precipitate was collected via filtration to afford the mixture of 3e and 3e′ (257 mg, 93%) as a reddish-brown solid. M.p. 171 °C (decomp.); IR (ATR): νmax = 1645 (C=O) cm−1; 1H NMR (500 MHz, DMSO-d6): δH = 12.19 (s), 9.53–9.55 (m), 8.24–8.33 (m), 7.50–7.58 (m), 7.38–7.44 (m), 7.14 (d), 7.09 (s), 7.00–7.03 (m), 6.92 (dd), 6.80 (d), 3.86 (d) 2.47 (t) ppm; 13C NMR (125 MHz, DMSO-d6): δC = 175.7, 175.2, 162.8, 161.2, 151.8, 150.7, 144.8, 144.5, 143.0, 142.3, 139.9, 134.8, 134.5, 134.4, 133.1, 131.9, 131.8, 130.1, 128.7, 128.1, 118.3, 113.8, 111.3, 110.3, 110.1, 104.6, 104.0, 103.4, 99.8, 56.4, 56.0 ppm; HRMS (ESI-TOF): calcd for C18H13NO2 + H+ [M + H]+ 276.1019; found: 276.1018.
2-Iodoazuleno[2,1-b]quinolin-12(5H)-one (3f): To a solution of 2f (490 mg, 1.00 mmol) in polyphosphoric acid (10 mL) was stirred at 140 °C for 4.5 h. After the reaction mixture was cooled, it was poured into water. The generated precipitate was collected via filtration to afford 3f (309 mg, 63%) as a reddish-brown solid. M.p. 240 °C (decomp.); IR (ATR): νmax = 1622 (C=O) cm−1; 1H NMR (500 MHz, DMSO-d6): δH = 12.41 (s, 1H, NH), 9.52–9.50 (m, 1H, H11), 8.59 (d, 1H, J = 2.0 Hz, H1), 8.35 (d, 1H, J = 10.6 Hz, H7), 7.95 (dd, 1H, J = 8.6, 2.0 Hz, H3), 7.61–7.59 (m, 2H, H4,9), 7.48–7.42 (m, 2H, H8,10), 7.10 (s, 1H, H6) ppm; 13C NMR (125 MHz, DMSO-d6): δC = 173.9, 151.5, 145.2, 140.2, 140.0, 139.6, 135.3, 134.9, 134.7, 132.4, 130.7, 129.3, 125.9, 120.5, 110.3, 104.3, 85.8 ppm; HRMS (ESI-TOF): calcd for C17H10NOI + H+ [M + H]+ 371.9880; found: 371.9889.
Azuleno[2,1-b]benzo[h]quinolin-7(14H)-one (3g): To a solution of 2g (416 mg, 1.01 mmol) in polyphosphoric acid (10 mL) was stirred at 140 °C for 2.5 h. After the reaction mixture was cooled, it was poured into water. The generated precipitate was collected via filtration to afford 3g (297 mg, 100%) as a reddish-brown solid. M.p. 208 °C (decomp.); IR (ATR): νmax = 1631 (C=O) cm−1; 1H NMR (500 MHz, DMSO-d6): δH =12.60 (s, 1H, NH), 9.65 (d, 1H, J = 9.7 Hz, H8), 8.93 (d, 1H, J = 8.0 Hz, H6), 8.47 (d, 1H, J = 10.3 Hz, H12), 8.42 (d, 1H, J = 8.6 Hz, H4), 8.08 (d, 1H, J = 7.4 Hz, H1), 7.80–7.74 (m, 3H, H2,3,10), 7.68–7.61 (m, 2H, H5,9), 7.48 (t, 1H, J = 10.0 Hz, H11), 7.39 (s, 1H, H13) ppm; 13C NMR (125 MHz, DMSO-d6): δC = 175.3, 151.1, 144.1, 139.5, 137.3, 135.6, 135.4, 135.2, 132.8, 130.1, 129.2, 128.9, 128.6, 127.0, 123.9, 123.2, 122.9, 122.4, 120.4, 111.4, 105.2 ppm; HRMS (ESI-TOF): calcd for C21H13NO + H+ [M + H]+ 296.1070; found: 296.1084.
12-Chloroazuleno[2,1-b]quinoline (4a): To a solution of 3a (613 mg, 2.50 mmol) was added POCl3 (20 mL) and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with MeCN, poured into ice-cooled aq. NaOH, and generated precipitate was collected via filtration. The residue was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 4a (590 mg, 89%) as a greenish-brown solid. M.p. 206–207 °C; 1H NMR (500 MHz, CDCl3): δH = 9.00–8.98 (m, 1H, H11), 8.59 (dd, J = 8.6, 0.9 Hz, 1H, H1), 8.28 (d, J = 8.6 Hz, 1H, H4), 7.89–7.85 (m, 1H, H3), 7.75 (d, J = 11.2 Hz, 1H, H7), 7.68–7.65 (m, 1H, H2), 7.27 (s, 1H, H6), 7.04–7.02 (m, 2H, H9,10), 6.85–6.81 (m, 1H, H8) ppm; 13C NMR (125 MHz, CDCl3): δC = 159.9, 148.7, 147.8, 139.5, 137.8, 135.1, 134.8, 131.9, 130.2, 128.7, 128.5, 127.9, 124.9, 124.6, 123.0, 121.2, 117.6 ppm; HRMS (MALDI-TOF): calcd for C17H10NCl + H+ [M + H]+ 264.0575; found: 264.0586.
12-Chloro-2-methylazuleno[2,1-b]quinoline (4b): To a solution of 3b (130 mg, 0.503 mmol) was added POCl3 (5 mL) and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with MeCN, poured into ice-cooled aq. NaOH, and generated precipitate was collected via filtration. The residue was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 4b (132 mg, 94%) as a greenish-brown solid. M.p. 172–174 °C; 1H NMR (500 MHz, CDCl3): δH = 8.93 (m, 1H, H11), 8.31 (s, 1H, H1), 8.16 (d, 1H, J = 8.6 Hz, H4), 7.67–7.72 (m, 2H, H3,7), 7.23 (s, 1H, H6), 6.97–6.99 (m, 2H, H8,10), 6.78 (m, 1H, H9), 2.65 (s, 3H, Me) ppm; 13C NMR (125 MHz, CDCl3): δC = 159.6, 147.7, 147.4, 139.8, 137.2, 135.4, 135.0, 134.9, 132.7, 131.9, 128.7, 128.4, 127.6, 123.4, 123.1, 121.3, 117.8, 22.0 ppm; HRMS (MALDI-TOF): calcd for C18H12NCl + H+ [M + H]+ 278.0731; found: 278.0737.
2-Butyl-12-chloroazuleno[2,1-b]quinoline (4c): To a solution of 3c (200 mg, 0.664 mol) was added POCl3 (7 mL) and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with MeCN, poured into ice-cooled aq. NaOH, and generated precipitate was collected via filtration. The residue was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 4c (197 mg, 93%) as a greenish-brown solid. M.p. 126–128 °C; 1H NMR (500 MHz, CDCl3): δH = 8.94–8.92 (m, 1H, H11), 8.31 (d, 1H, J = 1.1 Hz, H1), 8.18 (d, 1H, J = 8.6 Hz, H4), 7.71 (m, 2H, H3,7), 7.23 (s, 1H, H6), 7.00–6.94 (m, 2H, H8,10), 6.79–6.75 (m, 1H, H9), 2.91 (t, 2H, J = 7.7 Hz, n-Bu), 1.77 (sext., 2H, J = 7.7 Hz, n-Bu), 1.45 (sept., 2H, J = 7.7 Hz, n-Bu), 0.99 (t, 3H, J = 7.7 Hz, n-Bu) ppm; 13C NMR (125 MHz, CDCl3): δC = 159.6, 147.9, 147.4, 139.9, 137.4, 135.3, 134.4, 132.0, 128.8, 128.6, 128.0, 123.1, 122.8, 121.3, 118.3, 117.8, 117.4, 36.1, 33.8, 22.6, 14.1 ppm; HRMS (MALDI-TOF): calcd for C21H18NCl + H+ [M + H]+ 320.1201; found: 320.1190.
12-Chloro-2-methoxyazuleno[2,1-b]quinoline (4d): To a solution of 3d (228 mg, 0.829 mmol) was added POCl3 (8 mL) and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with MeCN, poured into ice-cooled aq. NaOH, and generated precipitate was collected via filtration. The residue was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 4d (202 mg, 83%) as a greenish-brown solid. M.p. 201–203 °C; 1H NMR (500 MHz, CDCl3): δH = 8.90 (d, 1H, J = 8.0 Hz, H11), 8.15 (d, 1H, J = 9.2 Hz, H4), 7.74 (d, 1H, J = 2.9 Hz, H1), 7.70 (d, 1H, J = 11.5 Hz, H7), 7.50 (dd, 1H, J = 9.2, 2.6 Hz, H3), 7.22 (s, 1H, H6), 7.00–6.93 (m, 2H, H8,10), 6.79–6.75 (m, 1H, H9), 4.02 (s, 3H, OMe) ppm; 13C NMR (125 MHz, CDCl3): δC = 158.4, 157.1, 146.4, 145.2, 139.5, 136.2, 135.5, 135.0, 132.1, 130.4, 128.1, 127.2, 124.0, 123.5, 121.3, 117.7, 102.1, 55.8 ppm; HRMS (MALDI-TOF): calcd for C18H12NOCl + H+ [M + H]+ 294.0680; found: 294.0699.
Reaction of 3e and 3e′: To a solution of 3e and 3e′ (201 mg, 0.730 mmol) was added POCl3 (7 mL) and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with MeCN, poured into ice-cooled aq. NaOH, and generated precipitate was collected via filtration. The residue was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford the mixture of 4e and 4e′ (156 mg, 72%) as a greenish-brown solid. M.p. 191–195 °C; 1H NMR (500 MHz, CDCl3): δH = 9.17 (m), 8.97–8.99 (m), 8.45 (d), 7.87 (dd, 7.79 (d), 7.70–7.75 (m), 7.58 (d), 7.29 (dd), 7.21–7.25 (m), 7.01–7.07 (m), 6.97 (d), 6.80–6.89 (m), 4.06 (s), 4.02 (s) ppm; 13C NMR (125 MHz, CDCl3): δC = 161.8, 160.4, 159.7, 157.7, 150.9, 150.7, 148.2, 147.6, 140.4, 139.6, 138.1, 135.2, 135.2, 134.8, 134.7, 132.3, 131.5, 130.2, 128.7, 128.5, 127.9, 127.9, 125.9, 121.9, 121.8, 119.4, 118.4, 118.3, 117.1, 117.0, 115.3, 106.3, 105.1, 56.2, 55.8 ppm; HRMS (MALDI-TOF): calcd for C18H12NOCl + H+ [M + H]+ 294.0680; found: 294.0699.
12-Chloro-2-iodoazuleno[2,1-b]quinoline (4f): To a solution of 3f (259 mg, 0.698 mmol) was added POCl3 (7 mL) and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with MeCN, poured into ice-cooled aq. NaOH, and generated precipitate was collected via filtration. The residue was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 4f (165 mg, 61%) as a greenish-brown solid. M.p. 201–203 °C; 1H NMR (500 MHz, CDCl3): δH = 8.92 (dd, 1H, J = 9.2, 1.1 Hz, H11), 8.88 (d, 1H, J = 1.7 Hz, H1), 8.04 (dd, 1H, J = 8.9, 2.0 Hz, H4), 7.96 (d, 1H, J = 8.9 Hz, H3), 7.73 (d, 1H, J = 11.5 Hz, H7), 7.20 (s, 1H, H6), 7.07–7.00 (m, 2H, H8,10), 6.86–6.82 (m, 1H, H9) ppm; 13C NMR (125 MHz, CDCl3): δC = 158.1, 149.1, 148.0, 140.3, 137.8, 136.4, 135.1, 130.6, 129.8, 129.6, 129.5, 125.6, 124.6, 123.9, 120.6, 84.4 ppm, one signal is overlapped with other signal; HRMS (ESI-TOF): calcd for C17H9NICl + H+ [M + H]+ 389.9541; found: 389.9540.
7-Chloroazuleno[2,1-b]benzo[h]quinoline (4g): To a solution of 3g (246 mg, 0.823 mmol) was added POCl3 (8 mL) and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with MeCN, poured into ice-cooled aq. NaOH, and generated precipitate was collected via filtration. The residue was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 4g (206 mg, 80%) as a greenish-brown solid. M.p. 209–210 °C; 1H NMR (500 MHz, CDCl3): δH = 9.55 (d, 1H, J = 7.7 Hz, H1), 9.12 (dd, 1H, J = 8.3, 1.1 Hz, H8), 8.39 (d, 1H, J = 9.2 Hz, H6), 7.94–7.90 (m, 2H, H3,12), 7.83 (d, 1H, J = 9.2 Hz, H5), 7.79–7.72 (m, 2H, H2,4), 7.48 (s, 1H, H13), 7.16–7.06 (m, 2H, H9,11), 6.90 (m, 1H, H10) ppm; 13C NMR (125 MHz, CDCl3): δC = 147.8, 146.1, 139.0, 137.8, 135.9, 135.5, 133.8, 132.9, 131.2, 128.9, 128.0, 127.8, 127.1, 127.1, 126.3, 125.8, 121.7, 120.6, 120.5, 117.6 ppm, one signal is overlapped with other signal; HRMS (ESI-TOF): calcd for C21H12NCl + H+ [M + H]+ 314.0731; found: 314.0749.
12-(Pyrrolidin-1-yl)azuleno[2,1-b]quinoline (5a): A solution of 4a (136 mg, 0.516 mmol) in pyrrolidine (3 mL) was stirred at room temperature for 1 h. The amine was removed under reduced pressure. The crude product was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 5a (131 mg, 85%) as a brown oil. 1H NMR (500 MHz, CDCl3): δH = 8.24 (d, J = 8.7 Hz, 1H, H11), 8.19–8.15 (m, 2H, H2,4), 7.72–7.65 (m, 2H, H1,7), 7.43–7.39 (m, 1H, H3), 7.21 (s, 1H, H6), 6.92–6.88 (m, 2H, H8,10), 6.74 (dd, J = 11.1, 7.2 Hz, 1H, H9), 3.66–3.62 (m, 4H, pyrrolidine), 2.21–2.18 (m, 4H, pyrrolidine)ppm; 13C NMR (125 MHz, CDCl3): δC = 161.3, 150.8, 150.5, 146.5, 140.5, 134.4, 132.9, 129.4, 129.3, 129.1, 128.6, 127.2, 124.5, 123.0, 122.4, 120.0, 117.7, 52.8, 26.7 ppm; HRMS (ESI-TOF): calcd for C21H18N2 + H+ [M + H]+ 299.1543; found: 299.1545.
12-(Piperidin-1-yl)azuleno[2,1-b]quinoline (5b): A solution of 4a (132 mg, 0.501 mmol) in piperidine (3 mL) was stirred at 50 °C for 4 h. The amine was removed under reduced pressure. The crude product was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 5b (122 mg, 78%) as a brown oil. 1H NMR (500 MHz, CDCl3): δH = 9.03 (d, 1H, J = 8.0 Hz, H11), 8.44 (dd, 1H, J = 8.6, 0.9 Hz, H4), 8.29 (dd, 1H, J = 8.4, 0.7 Hz, H2), 7.76–7.69 (m, 2H, H1,7), 7.49–7.46 (m, 1H, H3), 7.25 (s, 1H, H6), 6.99–6.91 (m, 2H, H8,10), 6.76 (m, 1H, H9), 3.54 (t, 4H, J = 5.2 Hz, piperidine), 1.92–1.84 (m, 6H, piperidine) ppm; 13C NMR (125 MHz, CDCl3): δC = 161.5, 154.2, 150.5, 147.2, 140.7, 134.9, 133.8, 130.7, 129.6, 129.2, 128.6, 127.4, 125.6, 125.1, 122.8, 120.7, 118.1, 52.7, 27.0, 24.6 ppm; HRMS (ESI-TOF): calcd for C22H20N2 + H+ [M + H]+ 313.1699; found: 313.1690.
12-(Morpholin-4-yl)azuleno[2,1-b]quinoline (5c): A solution of 4a (135 mg, 0.512 mmol) in morpholine (3 mL) was stirred at 50 °C for 4 h. The amine was removed under reduced pressure. The crude product was purified by silica gel column chromatography with CHCl3/AcOEt (5:1) as the eluent to afford 5c (118 mg, 74%) as a brown solid. M.p. 130–132 °C; 1H NMR (500 MHz, CDCl3): δH = 9.21–9.19 (m, 1H, H11), 8.49 (d, 1H, J = 8.6 Hz, H4), 8.32–8.30 (m, 1H, H2), 7.80–7.77 (m, 1H, H1), 7.73 (d, 1H, J = 11.2 Hz, H7), 7.55–7.52 (m, 1H, H3), 7.27 (s, 1H, H6), 7.02–6.97 (m, 2H, H8,10), 6.82–6.78 (m, 1H, H9), 4.09 (t, 4H, J = 4.4 Hz, morpholine), 3.65 (t, 4H, J = 4.4 Hz, morpholine) ppm; 13C NMR (125 MHz, CDCl3): δC = 161.5, 152.0, 150.7, 147.4, 140.6, 135.1, 134.3, 130.9, 129.9, 129.4, 128.6, 127.6, 125.1, 124.6, 123.3, 121.3, 118.4, 68.0, 51.0 ppm, one signal is overlapped with other signal; HRMS (ESI-TOF): calcd for C21H18N2O + H+ [M + H]+ 315.1492; found: 315.1490.

4. 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 SNAr 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 [2,1-b]quinolones with POCl3 afforded azuleno [2,1-b]quinolines with a chlorine substituent. Additionally, the SNAr 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.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28155785/s1, Figures: 1H and 13C NMR spectra of new compounds.

Author Contributions

Methodology, T.S.; analysis, T.S., M.T., M.U., Y.A., A.Y., R.S. and S.I.; investigation, T.S., M.T., M.U., Y.A., A.Y., R.S. and S.I.; writing, original draft preparation, T.S.; writing, review and editing, T.S., M.T., M.U., Y.A., A.Y., R.S. and S.I. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by JSPS KAKENHI Grant Number 21K05037.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are available from the corresponding author.

Acknowledgments

We thank Ikumi Uchiyama (Hirosaki University) for her technical assistance.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not available.

References

  1. Jones, J.A.; Virga, K.G.; Gumina, G.; Hevener, K.E. Recent Advances in the Rational Design and Optimization of Antibacterial Agents. Med. Chem. Commun. 2016, 7, 1694–1715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Pham, T.D.M.; Ziora, Z.M.; Blaskovich, M.A.T. Quinolone Antibiotics. Med. Chem. Commun. 2019, 10, 1719–1739. [Google Scholar] [CrossRef] [PubMed]
  3. Derbali, R.M.; Aoun, V.; Moussa, G.; Frei, G.; Tehrani, S.F.; Del’Orto, J.C.; Hildgen, P.; Roullin, V.G.; Chain, J.L. Tailored Nanocarriers for the Pulmonary Delivery of Levofloxacin against Pseudomonas Aeruginosa: A Comparative Study. Mol. Pharm. 2019, 16, 1906–1916. [Google Scholar] [CrossRef] [Green Version]
  4. Berry, L.; Domalaon, R.; Brizuela, M.; Zhanel, G.G.; Schweizer, F. Polybasic Peptide–Levofloxacin Conjugates Potentiate Fluoroquinolones and Other Classes of Antibiotics against Multidrug-Resistant Gram-Negative Bacteria. Med. Chem. Commun. 2019, 10, 517–527. [Google Scholar] [CrossRef] [PubMed]
  5. Clemens, D.L.; Lee, B.-Y.; Plamthottam, S.; Tullius, M.V.; Wang, R.; Yu, C.-J.; Li, Z.; Dillon, B.J.; Zink, J.I.; Horwitz, M.A. Nanoparticle Formulation of Moxifloxacin and Intramuscular Route of Delivery Improve Antibiotic Pharmacokinetics and Treatment of Pneumonic Tularemia in a Mouse Model. ACS Infect. Dis. 2018, 5, 281–291. [Google Scholar] [CrossRef]
  6. Taha, M.O.; Bustanji, Y.; Al-Ghussein, M.A.S.; Mohammad, M.; Zalloum, H.; Al-Masri, I.M.; Atallah, N. Pharmacophore Modeling, Quantitative Structure–Activity Relationship Analysis, and in Silico Screening Reveal Potent Glycogen Synthase Kinase-3β Inhibitory Activities for Cimetidine, Hydroxychloroquine, and Gemifloxacin. J. Med. Chem. 2008, 51, 2062–2077. [Google Scholar] [CrossRef]
  7. Soltani, S.; Akhbari, K. Embedding an Extraordinary Amount of Gemifloxacin Antibiotic in ZIF-8 Framework with One-Step Synthesis and Measurement of Its H2O2-Sensitive Release and Potency against Infectious Bacteria. New J. Chem. 2022, 46, 19432–19441. [Google Scholar] [CrossRef]
  8. Dahiya, S.; Chuttani, K.; Khar, R.K.; Saluja, D.; Mishra, A.K.; Chopra, M. Synthesis and Evaluation of Ciprofloxacin Derivatives as Diagnostic Tools for Bacterial Infection by Staphylococcus Aureus. Metallomics 2009, 1, 409–417. [Google Scholar] [CrossRef]
  9. Ji, C.; Miller, P.A.; Miller, M.J. Syntheses and Antibacterial Activity of N-Acylated Ciprofloxacin Derivatives Based on the Trimethyl Lock. ACS Med. Chem. Lett. 2015, 6, 707–710. [Google Scholar] [CrossRef] [Green Version]
  10. Tremblay, T.; Bergeron, C.; Gagnon, D.; Bérubé, C.; Voyer, N.; Richard, D.; Giguère, D. Squaramide Tethered Clindamycin, Chloroquine, and Mortiamide Hybrids: Design, Synthesis, and Antimalarial Activity. ACS Med. Chem. Lett. 2023, 14, 217–222. [Google Scholar] [CrossRef]
  11. Chen, Y.-J.; Ma, K.-Y.; Du, S.-S.; Zhang, Z.-J.; Wu, T.-L.; Sun, Y.; Liu, Y.-Q.; Yin, X.-D.; Zhou, R.; Yan, Y.-F.; et al. Antifungal Exploration of Quinoline Derivatives against Phytopathogenic Fungi Inspired by Quinine Alkaloids. J. Agric. Food Chem. 2021, 69, 12156–12170. [Google Scholar] [CrossRef] [PubMed]
  12. Araújo, M.J.; Bom, J.; Capela, R.; Casimiro, C.; Chambel, P.; Gomes, P.; Iley, J.; Lopes, F.; Morais, J.; Moreira, R.; et al. Imidazolidin-4-One Derivatives of Primaquine as Novel Transmission-Blocking Antimalarials. J. Med. Chem. 2005, 48, 888–892. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Bowles, P.; Busch, F.R.; Leeman, K.R.; Palm, A.S.; Sutherland, K. Confirmation of Bosutinib Structure; Demonstration of Controls to Ensure Product Quality. Org. Process Res. Dev. 2015, 19, 1997–2005. [Google Scholar] [CrossRef]
  14. Okamoto, K.; Ikemori-Kawada, M.; Jestel, A.; von König, K.; Funahashi, Y.; Matsushima, T.; Tsuruoka, A.; Inoue, A.; Matsui, J. Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealed by Biochemical Characterization. ACS Med. Chem. Lett. 2014, 6, 89–94. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Veliks, J.; Videja, M.; Kinens, A.; Bobrovs, R.; Priede, M.; Kuka, J. Trans-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs. ACS Med. Chem. Lett. 2020, 11, 2146–2150. [Google Scholar] [CrossRef]
  16. Mitscher, L.A. Bacterial Topoisomerase Inhibitors:  Quinolone and Pyridone Antibacterial Agents. Chem. Rev. 2005, 105, 559–592. [Google Scholar] [CrossRef]
  17. Shoji, T.; Ito, S. The Preparation and Properties of Heteroarylazulenes and Hetero-Fused Azulenes. Adv. Heterocyclic Chem. 2018, 126, 1–54. [Google Scholar]
  18. Shoji, T.; Sugiyama, S.; Kobayashi, Y.; Yamazaki, A.; Ariga, Y.; Katoh, R.; Wakui, H.; Yasunami, M.; Ito, S. Direct Synthesis of 2-Arylazulenes by [8+2] Cycloaddition of 2H-Cyclohepta[b]Furan-2-Ones with Silyl Enol Ethers. Chem. Commun. 2020, 56, 1485–1488. [Google Scholar] [CrossRef]
  19. Shoji, T.; Okujima, T.; Ito, S. Development of Heterocycle-Substituted and Fused Azulenes in the Last Decade (2010–2020). Int. J. Mol. Sci. 2020, 21, 7087. [Google Scholar] [CrossRef]
  20. Shoji, T.; Ito, S.; Yasunami, M. Synthesis of Azulene Derivatives from 2H-Cyclohepta[b]Furan-2-Ones as Starting Materials: Their Reactivity and Properties. Int. J. Mol. Sci. 2021, 22, 10686. [Google Scholar] [CrossRef]
  21. Xin, H.; Hou, B.; Gao, X. Azulene-Based π-Functional Materials: Design, Synthesis, and Applications. Acc. Chem. Res. 2021, 54, 1737–1753. [Google Scholar] [CrossRef] [PubMed]
  22. Wang, S.R. Direct Access to Functionalized Azulenes and Pseudoazulenes via Unconventional Alkyne Cyclization Reactions. Chem Asian J. 2023, 18, e202300244. [Google Scholar] [CrossRef] [PubMed]
  23. Shoji, T.; Sakata, N.; Ariga, Y.; Yamazaki, A.; Katoh, R.; Okujima, T.; Sekiguchi, R.; Ito, S. Construction of a 2,2′-Biazulene Framework via Brønsted Acid-Promoted Annulation of 2,3-Di(1-Azulenyl)Benzofurans. Chem. Commun. 2023, 59, 3447–3450. [Google Scholar] [CrossRef] [PubMed]
  24. Nozoe, T.; Kikuchi, K. The Synthesis of Azuleno[2,1-b]Pyridine Derivatives. Bull. Chem. Soc. Jpn. 1963, 36, 633–637. [Google Scholar] [CrossRef]
  25. Yamane, K.; Fujimori, K.; Takeuchi, T. A Convenient Synthesis of Azuleno[2,1-b]Thiophene. Bull. Chem. Soc. Jpn. 1981, 54, 2537–2538. [Google Scholar] [CrossRef] [Green Version]
  26. Shoji, T.; Miura, K.; Ohta, A.; Sekiguchi, R.; Ito, S.; Endo, Y.; Nagahata, T.; Mori, S.; Okujima, T. Synthesis of Azuleno[2,1-b]Thiophenes by Cycloaddition of Azulenylalkynes with Elemental Sulfur and Their Structural, Optical and Electrochemical Properties. Org. Chem. Front. 2019, 6, 2801–2811. [Google Scholar] [CrossRef]
  27. Fujimori, K.; Fukazawa, H.; Nezu, Y.; Yamane, K.; Yasunami, M.; Takase, K. Synthesis of azuleno[1,2-b]pyrrole and azuleno[1,2-b]furan. Chem. Lett. 1986, 15, 1021–1024. [Google Scholar] [CrossRef]
  28. Bakun, P.; Czarczynska-Goslinska, B.; Goslinski, T.; Lijewski, S. In Vitro and in Vivo Biological Activities of Azulene Derivatives with Potential Applications in Medicine. Med. Chem. Res. 2021, 30, 834–846. [Google Scholar] [CrossRef]
  29. Leino, T.O.; Sieger, P.; Yli-Kauhaluoma, J.; Wallén, E.A.A.; Kley, J.T. The Azulene Scaffold from a Medicinal Chemist’s Perspective: Physicochemical and in Vitro Parameters Relevant for Drug Discovery. Eur. J. Med. Chem. 2022, 237, 114374. [Google Scholar] [CrossRef]
  30. Gao, H.; Zhang, G. Synthesis, Structure and Properties of Fused π-Extended Acridone Derivatives. Eur. J. Org. Chem. 2020, 2020, 5455–5463. [Google Scholar] [CrossRef]
  31. Shoji, T.; Sugiyama, S.; Araki, T.; Ohta, A.; Sekiguchi, R.; Ito, S.; Mori, S.; Okujima, T.; Yasunami, M. Synthesis of 2-Amino- and 2-Arylazoazulenes via Nucleophilic Aromatic Substitution of 2-Chloroazulenes with Amines and Arylhydrazines. Org. Biomol. Chem. 2017, 15, 3917–3923. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Shoji, T.; Sugiyama, S.; Takeuchi, M.; Ohta, A.; Sekiguchi, R.; Ito, S.; Yatsu, T.; Okujima, T.; Yasunami, M. Synthesis of 6-Amino- and 6-Arylazoazulenes via Nucleophilic Aromatic Substitution and Their Reactivity and Properties. J. Org. Chem. 2019, 84, 1257–1275. [Google Scholar] [CrossRef] [PubMed]
  33. Nozoe, T.; Seto, S.; Matsumura, S. Synthesis of 2-Substituted Azulenes by Nucleophilic Substitution Reactions of 2-Haloazulene Derivatives. Bull. Chem. Soc. Jpn. 1962, 35, 1990–1998. [Google Scholar] [CrossRef]
  34. Ito, S.; Kubo, T.; Morita, N.; Ikoma, T.; Tero-Kubota, S.; Kawakami, J.; Tajiri, A. Azulene-Substituted Aromatic Amines. Synthesis and Amphoteric Redox Behavior of N, N-Di (6-azulenyl)-p-toluidine and N, N, N ‘, N ‘-Tetra (6-azulenyl)-p-phenylenediamine and Their Derivatives. J. Org. Chem. 2005, 70, 2285–2293. [Google Scholar] [CrossRef]
  35. Littke, A.F.; Fu, G.C. Palladium-Catalyzed Coupling Reactions of Aryl Chlorides. Angew. Chem. Int. Ed. 2002, 41, 4176–4211. [Google Scholar] [CrossRef]
  36. Corbet, J.-P.; Mignani, G. Selected Patented Cross-Coupling Reaction Technologies. Chem. Rev. 2006, 106, 2651–2710. [Google Scholar] [CrossRef]
  37. Johansson Seechurn, C.C.C.; Kitching, M.O.; Colacot, T.J.; Snieckus, V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angew. Chem. Int. Ed. 2012, 51, 5062–5085. [Google Scholar] [CrossRef]
  38. Anderson, J.M.; Measom, N.D.; Murphy, J.A.; Poole, D.L. Bridge Heteroarylation of Bicyclo[1.1.1]Pentane Derivatives. Org. Lett. 2023, 25, 2053–2057. [Google Scholar] [CrossRef]
  39. Cirujano, F.G.; López-Maya, E.; Almora-Barrios, N.; Rubio-Gaspar, A.; Martín, N.; Navarro, J.A.R.; Martí-Gastaldo, C. Diffusion Control in Single-Site Zinc Reticular Amination Catalysts. Inorg. Chem. 2020, 59, 18168–18173. [Google Scholar] [CrossRef]
  40. Kanzian, T.; Nigst, T.A.; Maier, A.; Pichl, S.; Mayr, H. Nucleophilic Reactivities of Primary and Secondary Amines in Acetonitrile. Eur. J. Org. Chem. 2009, 2009, 6379–6385. [Google Scholar] [CrossRef]
Molecules 28 05785 g001 550
Figure 1. Quinolone and quinoline derivatives in clinical use.
Figure 1. Quinolone and quinoline derivatives in clinical use.
Molecules 28 05785 g001
Molecules 28 05785 g002 550
Figure 2. Structure of azuleno[2,1-b]quinolones 3e and 3e′.
Figure 2. Structure of azuleno[2,1-b]quinolones 3e and 3e′.
Molecules 28 05785 g002
Molecules 28 05785 sch001 550
Scheme 1. Plausible reaction mechanism for the formation of azuleno[2,1-b]quinolone 3.
Scheme 1. Plausible reaction mechanism for the formation of azuleno[2,1-b]quinolone 3.
Molecules 28 05785 sch001
Molecules 28 05785 g003 550
Figure 3. Structure of azuleno[2,1-b]quinolines 4e and 4e′.
Figure 3. Structure of azuleno[2,1-b]quinolines 4e and 4e′.
Molecules 28 05785 g003
Molecules 28 05785 sch002 550
Scheme 2. SNAr reactions of 4a with secondary amines.
Scheme 2. SNAr reactions of 4a with secondary amines.
Molecules 28 05785 sch002
Table
Table 1. Synthesis of 2-Arylaminoazulenes 2a–2i via SNAr reaction of 2-Chloroazulene derivative 1 with anilines.
Table 1. Synthesis of 2-Arylaminoazulenes 2a–2i via SNAr reaction of 2-Chloroazulene derivative 1 with anilines.
Molecules 28 05785 i001
EntryAniline DerivativeSolventProductYield a
1anilineEtOHMolecules 28 05785 i0022a, 96%
2p-toluidineEtOHMolecules 28 05785 i0032b, 89%
3p-n-butylanilineEtOHMolecules 28 05785 i0042c, 89%
4p-methoxyanilineEtOHMolecules 28 05785 i0052d, 96%
5m-methoxyanilineEtOHMolecules 28 05785 i0062e, 92%
6p-iodoanilineEtOHMolecules 28 05785 i0072f, 72%
7p-nitroanilineNMPNo reaction
8α-naphthylamineEtOHMolecules 28 05785 i0082g, 61%
9N-methylanilinewithout
solvent		Molecules 28 05785 i0092h, 33%
a Isolated yield.
Table
Table 2. Intramolecular Cyclization of 2a–2g into Azuleno[2,1-b]quinolones 3a–3g.
Table 2. Intramolecular Cyclization of 2a–2g into Azuleno[2,1-b]quinolones 3a–3g.
Molecules 28 05785 i010
EntrySubstrateProductYield a
12aMolecules 28 05785 i0113a, 96%
22bMolecules 28 05785 i0123b, 85%
32cMolecules 28 05785 i0133c, 86%
42dMolecules 28 05785 i0143d, 85%
52eMolecules 28 05785 i0153e + 3e′, 93% b
62fMolecules 28 05785 i0163f, 89%
72gMolecules 28 05785 i0173g, 100%
a Isolated yield. b inseparable mixture.
Table
Table 3. Synthesis of Azuleno[2,1-b]quinolines 4a–4h via halogenative aromatization with POCl3.
Table 3. Synthesis of Azuleno[2,1-b]quinolines 4a–4h via halogenative aromatization with POCl3.
Molecules 28 05785 i018
EntrySubstrateProductYield a
13aMolecules 28 05785 i0194a, 89%
23bMolecules 28 05785 i0204b, 94%
33cMolecules 28 05785 i0214c, 93%
43dMolecules 28 05785 i0224d, 83%
53e + 3e′Molecules 28 05785 i0234e + 4e′, 72% b
63fMolecules 28 05785 i0244f, 61%
73gMolecules 28 05785 i0254g, 80%
a Isolated yield. b inseparable mixture.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Shoji, T.; Takeuchi, M.; Uda, M.; Ariga, Y.; Yamazaki, A.; Sekiguchi, R.; Ito, S. Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes. Molecules 2023, 28, 5785. https://doi.org/10.3390/molecules28155785

AMA Style

Shoji T, Takeuchi M, Uda M, Ariga Y, Yamazaki A, Sekiguchi R, Ito S. Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes. Molecules. 2023; 28(15):5785. https://doi.org/10.3390/molecules28155785

Chicago/Turabian Style

Shoji, Taku, Mutsumi Takeuchi, Mayumi Uda, Yukino Ariga, Akari Yamazaki, Ryuta Sekiguchi, and Shunji Ito. 2023. "Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes" Molecules 28, no. 15: 5785. https://doi.org/10.3390/molecules28155785

APA Style

Shoji, T., Takeuchi, M., Uda, M., Ariga, Y., Yamazaki, A., Sekiguchi, R., & Ito, S. (2023). Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes. Molecules, 28(15), 5785. https://doi.org/10.3390/molecules28155785

Article Metrics

Back to TopTop