Novel conversion of 4-aminoquinolines to new tricyclic ( R,S )-3-methylazeto[3,2- c ] quinolin-2(2a H )-ones and versatile one step synthesis of N - (quinolin-4-yl) carbamates from 4-aminoquinolines

Reaction of 4-aminoquinolines with 4-nitrophenyl chloroformate have resulted in finding a novel transformation of 4-aminoquinolines to tricyclic ( R,S )-3-methylazeto[3,2- c ]quinolin-2(2a H )-ones. The structure of azeto-quinolinone was determined via spectroscopic and chemical methods. Various alcohols were used as nucleophiles to open the 1-azetinone ring to give the corresponding N - (quinolin-4-yl)carbamates in good yields. We also found a new and versatile one step synthesis of N - (quinolin-4-yl)carbamates by reacting 4-aminoquinolines with alkyl chloroformates in the presence of anhyd K 2 CO 3 in acetonitrile.

During the course of developing new chemical entities, the synthesis of quinoline carbamates (19) was needed. We reasoned that 19a can be easily prepared by a reaction of 4-
As a further examination, we continued to investigate the effect of solvent used in the intramolecular cyclization. The reaction was carried out in THF, acetone or chloroform solution. The results showed that 21a (5 %) together with 1,3-bis(quinolin-4-yl)urea (24a) (23 %) were isolated after column chromatography when the reaction was proceeded in THF International Letters of Chemistry, Physics and Astronomy Vol. 30 (Table 1). No desired product was obtained when acetone or chloroform was used as the reaction medium. However, we obtained compound 24a in 30 and 23 % yield, respectively. The formation of urea derivative 24a may be caused by the interaction of the C4-NH 2 function of the unreacted 18a with 19a. This demonstrated that the intramolecular cyclization of intermediate 19a to 21a was preferable in acetonitrile over THF. To optimize the yield of 21a by using various bases, we found that the reaction did not occur or caused a complex decomposition. However, when DBU or anhyd K 2 CO 3 was used as the base, urea 24a was isolated in 11 and 54 %, respectively with decomposed tar. To prove the formation of urea 24a, an alternative synthetic way was developed. We found that compound 24a can be synthesized in low yield (29 %) from the treatment of 18a with triphosgene in acetonitrile in the presence of triethylamine at room temperature (Scheme 2). This suggests that compound 18a may be converted into N-(quinolin-4-yl)isocyanate (23a), which simultaneously reacts with the unreacted 18a to form 24a. Table 1. Synthesis of (R,S)-3-methylazeto[3,2-c]quinoline-2-(2aH)-one (21a,b) and 1,3-bis(2methylquinolin-4-yl)urea (20a). The structures of 21a and 21b were elucidated by Mass, IR, 1 H NMR, and 13 C NMR spectroscopies. The IR (MeOH/CHCl 3 ) spectrum showed an absorption at 1720 cm -1 for the C=O function. One can anticipate that compound 21a (Fig. 1) might exist as an azetoquinolinone and/or its β-lactam form (21a′). However, the 1 H NMR (DMSO-d 6 ) spectrum showed two singlet (δ 7.78 and 7.94 for 21a) assigned for H-3 in a ratio of 2:1 suggested that compound 21a might be a racemic mixture. The H-3 proton appeared at the aromatic proton region likely due to the highly deshielding effect of the neighboring carbonyl and imine functions. In addition, the long range 1 H-13 C correlations (HMBC, Fig. 2) of H-3/H-4, H-3/H-4a, H-3/C-9, H-3/C-2, H-11/C-3, and H-11/C-9 supported that 1-azetinone ring is incorporated with the quinoline ring in 21a. The NOESY (Fig. 1) analysis also provided evidence that H-3 was vicinal to the methyl protons (H-11). The 13 C NMR spectrum of this compound revealed that only the chemical shifts for C-3 (122.6 and 122.7) and C-5 (123.1

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and 123.2) have noticeable difference between the two isomers. Furthermore, the 1 H NMR spectra of 21a lacked an exchangeable NH proton. From these analytical data, it is clear that compound 21a exists as an azetoquinolinone form (21a) rather than its β-lactam tautomeric form (21a′, Fig. 1). A plausible mechanism for the formation of (R,S)-3-methylazeto[3,2c]quinolin-2(2aH)-ones (21a,b) is shown in Scheme 2. The 4-aminoquinolines (18a,b) reacts with 1 to give the intermediate 19a,b which was then transformed into the tricyclic 21a,b via an intramolecular ring closure reaction, which was followed by elimination of 4-nitrophenol. In the meantime we found an interesting paper by Rao and co-workers, which described that 1-azetinone ring is susceptible to nucleophilic attack. 21 As noted above, the compound 21b was converted into methyl carbamate 25ba′ in the presence of methanol. This transformation prompted us to investigate the reaction of 21a with various alcohols. We treated 21a with methanol, ethanol, n-propanol or benzyl alcohol at reflux temperature and isolated N-(quinolin-4-yl)carbamates (25aa′, 25ab′, 25ac′, and 25ad′) in good yields ( Table  2). The proposed mechanism for the formation of N-(quinolin-4-yl)carbamates from 21a is illustrated in Scheme 2. The nucleophilic attack on 21a lead to ring opening at C3 position to give N-(quinolin-4-yl)carbamates (25aa′, 25ab′, 25ac′, and 25ad′). The opening of the 1azetinone ring was fast in the presence of catalytic amount of acid (i.e., acetic acid or silica gel). For example, the reaction was completed within 24 h when 21a was reacted with methyl alcohol in the presence of acetic acid at reflux temperature to yield 25aa′ (62 %). While in the absence of acid, the reaction could not be completed even after 48 h under reflux.

International Letters of Chemistry, Physics and Astronomy Vol. 30
Furthermore, we found that 21a did not react with amino nucleophile, such as anilines or alkylamines, to form urea derivatives under various reaction conditions. Alternatively, compounds 25aa′ and 25ab′ were successfully synthesized in good yield from the reaction of either methyl chloroformate or ethyl chloroformate with 2methylquinolin-4-amine (18a) in acetonitrile in the presence of anhyd K 2 CO 3 (Scheme 2). Comparing spectrophotometric analysis and mixed melting point measurements, 25aa′ and 25ab′ synthesized under these conditions, were identical with the compounds previously synthesized from azetoquinolinone 21a. These results further prove that the structures of 21a,b exist as an azetoquinolinone ring system and the ring opening takes place at C3 position upon nucleophilic attack. To extend the scope of this new procedure for the synthesis of the N-(quinolin-4-yl)carbamates, 4-aminoquinolines (18b-e) were then examined for their reactions with methyl chloroformate of ethyl chloroformate in the presence of anhyd K 2 CO 3 .
Under the optimized reaction conditions, compounds 18b-e gave N-(quinolin-4yl)carbamates (25ba′, ca′, cb′, da′, db′, ea′, and eb′) in fair to good yields ( Table 2). It is of great interest to note that the carbamate formation was affected by the substituent at C6 of the 270 ILCPA Volume 30 quinoline ring. Experiments revealed that the product was formed in low yields when N,Ndimethylamino or methylenedioxy groups (i.e. 25ba′, 25da′ and 25db′) were attached to the quinoline ring at C6 or C6,7 positions, respectively. The higher yields of compound 25ca′ and 25cb′ were obtained when methoxy function substituted at C6 position of the quinoline ring. N-(quinolin-4-yl)carbamate analogues were previously synthesized in low yield starting from quinolin-4-carboxylic acid ester in one-pot reaction via formation of the corresponding hydrazide, azide, curtius rearrangement to isocyanate, followed by reaction with alcohols. 22,23 Our current studies provide an alternative versatile synthetic method to prepare N-(quinolin-4-yl)carbamates.

1. Chemistry: General Methods
All commercial chemicals and solvents were reagent grade and were used without further purification unless otherwise specified. Melting points were determined on a Fargo melting point apparatus and are uncorrected. Column chromatography was carried out on silica gel G60 (70-230 mesh, ASTM; Merck and 230-400 mesh, Silicycle Inc.). Thin-layer chromatography was performed on silica gel G60 F 254 (Merck) with short-wavelength UV light for visualization. All reported yields are isolated yields after chromatography or crystallization. Elemental analyses were done on a Heraeus CHN-O Rapid instrument. 1 H NMR and 13 C NMR spectra were recorded on a 600 MHz, Brucker AVANCE 600 DRX and 400 MHz, Brucker Top-Spin spectrometers in the indicated solvent. The chemical shifts were reported in ppm () relative to TMS.

Synthesis of 4-aminoquinolines (18b-e).
Detailed procedures for the synthesis of compound 18b-e, intermediate 17b-e along with their spectroscopic data are provided in the supplementary information.

Method 1.
A suspension of 21a in appropriate alcohols containing catalytic amount of acetic acid (2-3 drops) was refluxed for 24 h, while the reaction of 21a with benzyl alcohol was heated at 100 °C for 2 h. After all starting material was consumed; the clear reaction mixture was concentrated under reduced pressure to dryness. The residue was diluted with water, extracted with dichloromethane, washed with water and dried over anhyd Na 2 SO 4 . The dichloromethane extract was concentrated in vacuo to dryness. The desired product was purified either by recrystallization (ethyl acetate, for 25aa′, ab′, ac′) or by silica gel column chromatography (solvent: ethyl acetate/hexane, 6:4 v/v, for 25ad′).

Method 2.
General procedure for the synthesis of 25aa′-eb′ by reacting 18a-e with alkyl chloroformates. Compound 25aa′: A mixture of 2-methylquinolin-4-amine (0.79 g, 5 mmol) and anhyd K 2 CO 3 (1.38 g, 10 mmol) in dry acetonitrile (50 mL) was sonicated for 30 min. Methyl chloroformate (1.2 mL, 15 mmol) was added dropwise to this mixture at room temperature within a period of 30 min. The reaction mixture was stirred at room temperature for additional 10 h and then concentrated under reduced pressure. The solid product was purified by column chromatography on a silica gel column using EA/Hexane (3:7 v/v) as the eluent. The fractions containing the main product were combined and evaporated under reduced pressure to give 25aa′, 0.91 g (84 %); mp 177-178 °C; which was identical with the product synthesized from compound 21a. By following the same procedure the following compounds were synthesized. Compound 25ab′. Compound 25ab′ was synthesized from 2methylquinolin-4-amine (1.58 g, 10 mmol) and ethyl chloroformate (2.9 mL, 30 mmol). Yield: 1.85 g (81 %); mp 180-181 °C. The product is identical with the one previously synthesized from 21a.