A Simple Preparative Synthesis of Isomeric 2-Chloroquinolinecarboxylic Esters

A simple two-stage method for the synthesis of isomeric esters of 2-chloroquinoline-5-, 6, 7-carboxylic acids by successive oxidation and chlorination reactions of methyl quinoline-5-, 6, 7-carboxylates has been developed. The target compounds have been obtained in acceptable yields using readily available reagents, simple transformations, and purification methods. Quinoline-8-carboxylic acid ester is unreactive under these conditions. The ester of 2-chloroquinoline-8-carboxylic acid has been obtained with an overall yield of 55 %, starting from 8-methylquinoline. The multi-stage process is paid off by the fact that several transformations occur in one reaction cycle. All the methods developed can be used for the synthesis of target compounds on a multigram scale. Intermediate 2(1 H )-oxoquinoline carboxylates are promising compounds in the synthesis of functionalized and condensed heterocycles.


■ Introduction
2-Chloroquinolines with a carboxyl/ester substituted ring are attractive compounds with a great potential for transformation of the quinoline core [1].A chlorine atom in position 2 can be easily substituted by N-, O-and S-nucleophiles [2], and this ability is widely used in organic and pharmaceutical chemistry.2-Chloroquinoline derivatives with carboxyl substituents have a wide range of activities, including antimicrobial [3], antiinflammatory [4], antitumor [5] and antiparasitic ones [6,7].There are several methods of introducing halogen into position 2 of the quinoline molecule, but most of them relate to 2-chloroquinoline derivatives with a carboxyl/ester group in the pyridine nucleus [8,9].
Modern synthetic approaches to 2-chloroquinolines with an ester function in the benzene ring use metal complex catalysts based on ruthenium or iridium [11,12], which are not always cost effective.Unfortunately, the reaction of C-2 chlorination of N-oxides for quinoline esters in our hands did not give satisfactory results [13,14].The aim of this work is to develop simple preparative methods for the 2-chloroquinolines synthesis with ester substituents in positions 5, 6, 7, and 8 of quinoline.Amazingly, all 2-chloroquinolinecarboxylic acids have been known for a long time, but their physical and spectral properties are given in fragments.And we provide known data when it is available.

■ Results and discussion
We studied the possibilities of optimization for the known classical reactions.The easiest way to obtain the desired compounds is the oxidation of the quinoline 2-position to quinolone-2 followed by the replacement of an oxygen atom with chlorine according to the Friedlander method [15].Therefore, it seemed attractive to optimize the oxidation reaction of quinolines into quinolone-2 with sodium hypochlorite, an effective low-cost reagent [16].A series of experiments on the oxidation of 5-, 6-, 7-, and 8-quinoline carboxylate esters 1a -d with sodium hypochlorite in a twophase benzene-water system was performed.
In an alkaline solution of hypochlorite (pH ≈ 11), the oxidation of esters 1a -d did not proceed; therefore, the pH of the solution was adjusted by adding an acidifier potassium dihydrogen phosphate (Scheme 1).We obtained the best results with such ratio of NaClO/KH 2 PO 4 reagents as 2:1.07, while the initial solution had a pH value of 11.After the addition of potassium dihydrogen phosphate and esters 1, the solution had a pH of 7.5, at the end of the reaction the pH was 5. A fivefold hypochlorite excess was used for the oxidation.The reaction was monitored by the presence of sodium hypochlorite in the reaction mixture.The reaction was not carried out for complete ether 1 conversion since during a prolonged contact the excess hypochlorite also oxidized the target reaction products 2. The conversion of starting esters 1a -c reached 80 %, and methyl quinoline-8-carboxylate 1d was unreactive under the reaction conditions.
For better yields of products 2a -c, sodium thiosulfate Na 2 S 2 O 3 was added to the reaction mixture immediately after exhausting the oxidizing agent.Quinolones-2 2a,b precipitated from the reaction mixture, then they were filtered, and impurities were removed by the extraction with boiling ethanol.In contrast to compound 1a, upon the oxidation of esters 1b,c together with quinolones 2b,c, minor products were formed -2,4-dihydroxy derivatives 3b,c, which were also poorly soluble.Quinolones 2a -c under short-term heating with POCl 3 [15] were transformed into 2-chloroquinoline esters 4a -c, in the case of esters 4b,cwith an impurity of 2,4-dichloro derivatives 5b,c.Monochlorinated 4b and dechlorinated 5b quinolines were separated by column chromatography and recrystallized from benzene.
The low yield of ester 7 and the presence of minor products forced us to develop an alternative route based on 8-methylquinoline (10).The alkylation of 10 with dimethyl sulfate and the subsequent oxidation by potassium hexacyanoferra-te(III) yielded 1,8-dimethylquinolone-2 (11) in one reaction cycle (Scheme 3).
The chlorination of quinolone 11 with a mixture of PCl 5 /POCl 3 gave 8-methyl-2-chloroquinoline (12) [18], which was converted into the corresponding dibromomethyl derivative 13 with N-bromosuccinimide in CCl 4 .The hydrolysis of the dibromomethyl group with silver acetate into aldehyde 14 and its oxidation with silver oxide yielded 2-oxoquinoline-8-carboxylic acid (15).After the chlorination of acid 15 in POCl 3 and the esterification of 2-chloro-8-carboxyquinoline (8) with diazomethane in ether, the target ester 7 was obtained.Despite the multistep process, the overall yield of the target product was 55 % based on 8-methylquinoline.

■ Conclusions
Simple methods for the synthesis of isomeric esters of 2-chloroquinoline-5-, 6-and 7-carboxylic acids have been developed with acceptable yields using available reagents, simple transformations, and methods of purifying target compounds.A convenient route for the synthesis of methyl 2-chloroquinoline-8-carboxylate with the total yield of 55 % starting from 8-methylquinoline has been developed.The multi-stage process for obtaining this compound is paid off by the fact that several transformations occurred as a telescopic process.All the methods developed can be used for the synthesis of target compounds on a multigram scale.In addition, this reaction set provides easy access to useful intermediates with a carboxyl group in a functionalized quinolone core.

■ Experimental part
Control over the course of the reactions, purity and identity of the products obtained was carried out by thin-layer chromatography on Merck 60 F254 plates. 1 H and 13 C NMR spectra were measured in DMSO-d 6 solution on a Bruker 170 Avance 500 spectrometer (400 MHz on protons and 100 MHz on carbon atoms, respectively), the internal standard was TMS.Chemical shifts were reported in δ (ppm).Data were presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet), coupling constants (Hz) and integration.The elemental analysis data corresponded to the calculated data.The melting points were determined on a Fisher-Johns apparatus.A commercial aqueous solution of sodium hypochlorite in 0.305 mol L -1 concentration was used.The consumption of the oxidizer was monitored using iodine-starch paper.Melting points of known substances were given if they were found in the literature.Intermediates and nontarget substances 5c, 6, 9, 13, 15 were characterized only by melting points and 1 H NMR spectroscopy.The elemental analysis was performed in the Analytical Laboratory of the Institute of Organic Chemistry of the National Academy of Sciences of Ukraine.
Methyl 2-oxoquinoline-5-carboxylate (2a) Potassium dihydrogen phosphate (15.2 g, 0.112 mol) under vigorous stirring was added to a mixture of the solution of methyl quinoline-5-carboxylate (1a) (10 g, 0.053 mol) in 150 mL of benzene and 850 mL (0.255 mol) of the sodium hypochlorite solution at room temperature, and the resulting mixture was stirred for 5 h.Then sodium thiosulfate (53 g, 0.212 mol) was added and stirred for another 3 h.The resulting precipitate was filtered, washed with benzene, water and air-dried.From the benzene mother liquor, 4.8 g of the starting ester 1a was recovered.
A white powder.Yield -4.5 g (42 %).M. p. ~290 о С. Methyl 2-chloroquinoline-5-carboxylate (4a) Quinolone 2a (6.4 g, 0.0315 mol) and 12 mL (0.128 mol) of phosphoryl chloride were heated on a water bath (100 °C) for 20 min.The reaction mass was cooled to room temperature, 25 mL of acetic acid was added, and the mixture was poured onto 500 g of ice.The mixture was made alkaline with NaOH solution (36 g, 0.8 mol) in 75 mL of water, the precipitate was filtered off, washed with water, and dried.The solution of the reaction product in 100 mL of benzene was passed through a layer of Al 2 O 3 (5 cm), evaporated to 15 ml, and ~60 mL of heptane was then added.The precipitated crystals were filtered yielding methyl 2-chloroquinoline-5-carboxylate (4a).
A yellowish solid.Yield - The mixture was obtained according to the method described for compound 4a.6.6 g of a mixture of quinolones 2b and 3b was obtained from 9.5 g (0.051 mol) of ester 1b, and 1.4 g of the original ester 1b was recovered.After the reaction of mixture 2b and 3b with POCl 3 , 5.33 g of mixture 4b and 5b was obtained, and the components were separated in a column (45×2.5 cm) with silica gel, benzene as an eluent.Methyl 2,4-dichloro-6-carboxylate (5b) was eluted first and recrystallized from a mixture of benzene/ heptane (1:3).Next, methyl 2-chloro-6-carboxylate (4b) was eluted and recrystallized from a mixture of benzene/heptane (1:3).
Methyl The mixture was synthesized according to the method for compound 4b from 9.0 g (0.048 mol) of ester 1c.5.2 g of a mixture of substances 4c and 5c were obtained.2.1 g of the starting ester was isolated from the benzene mother liquor.5.15 g of a mixture of 4c and 5c was dissolved in 400 mL of hot benzene, filtered through a silica gel layer (5 cm) and evaporated to 30 mL. 2,4-Dichloro-7-carboxylate (5c), which precipitated after cooling, was filtered off.The mother solution was evaporated to 10 mL, 20 mL of heptane was added, and the precipitate was filtered off giving 4c.
Methyl Methyl 2-chloroquinoline-8-carboxylate (7).Method 1 Step 1. Methyl 1-methyl-2(1H)-oxoquinoline-8-carboxylate (6) Ester 1d (15.15 g, 0.081 mol) and 26 mL (0.278 mol) of freshly distilled dimethyl sulfate were stirred at 180 -185 o C for 2.5 h.After cooling, 50 mL of water was added to the reaction mixture and then poured into the solution of 75 g (0.2278 mol) of potassium hexacyanoferrate(III) in 220 mL of water at 60 °C.Then the solution of NaOH (32 g, 0.8 mol) in 64 mL of water was added to the mixture while stirring for 2-3 min.After cooling, it was extracted with benzene (2×200 mL).The benzene extract was evaporated to 20 mL, and 60 mL of heptane was added.The precipitate was filtered, dried, and compound 6 was thus obtained.

2(1H)-Oxoquinoline-8-carboxylic acid (15)
A mixture of 21.8 g (0.065 mol) of dibromide 13 and 53.93 g (0.325 mol) of silver acetate in 150 ml of ethanol was heated to 55 °C and, with stirring, 50 mL of hot (50 °C) water was added.Then the solution of 18.2 g (0.455 mol) of NaOH in 50 mL of water was added dropwise over 20 min.Next, 50 mL portion of hot water was added and stirred for 10 min.The reaction mixture was heated to 60 -65 o С, and the stirring was continued for another 40 min, and the heating was removed.After 30 min, the solution was filtered from silver compounds, and the residue on the filter was washed with 200 mL of hot water (60 -65 o С).
The solution obtained was extracted with benzene (2×200 mL) and neutralized with the solution of 35 mL (0.132 mol) of 10 % hydrochloric acid.The precipitate of acid 15 was filtered off and dried.
Step 4. Methyl 2-chloroquinoline-8-carboxylate (7) Acid 8 (14.7 g, 0.0705 mol) was heated to boiling in 650 mL of chloroform and 50 mL of methanol and cooled to 25 o C. The solution of diazomethane (5.6 g, 0.133 mol) in 200 mL of a mixture of benzene/diethyl ether (1:1) was poured into the solution for 10 min.After the release of nitrogen, the excess of diazomethane was decomposed by glacial acetic acid.The resulting solution was washed with water, 300 mL of 3 % sodium bicarbonate solution was passed through the aluminum oxide layer (10 cm), the solvent was evaporated in vacuum.
Yield of ester 7 -15 g (95.6 %) as a yellow oil. 1 H and 13 C NMR spectra were consistent with those for compound 7 obtained by Method 1 and the literature data [20].