FU Xinbo, GAO Wentao, LI Yang, WANG Dongfang, ZHAO Ya’nan

(Institute of Superfine Chemicals, Bohai University, Jinzhou 121000, Liaoning, China)

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One-pot synthesis of novel 6-chloro substituted 2-(phenoxymethyl) quinoline-3-carboxylic acid derivatives

FU Xinbo, GAO Wentao*, LI Yang, WANG Dongfang, ZHAO Ya’nan

(InstituteofSuperfineChemicals,BohaiUniversity,Jinzhou121000,Liaoning,China)

Ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate (1) as a starting compound was subjected to the reaction with various substituted phenols 2a-o by using K2CO3as acid-binding agent and MeCN as solvent by one-pot to obtain corresponding 6-chloro-2-(phenoxymethyl)quinoline-3-carboxylic acid derivatives 3a-o, with containing chlorine atom in quinoline ring. The structure of the synthesized compounds 3a-o was characterized by IR,1H NMR,13C NMR and HRMS.

chlorine atom; phenoxymethyl; quinoline-carboxylic acid; one-pot; synthesis

Article ID： 1008-1011(2016)05-0578-09

Quinoline ring is a back-bone of many natural products and pharmacologically significant compounds displaying a broad range of biological properties[1-2]. Many functionalized quinolines are widely used as antimalarial[3-5], antibacterial[6-9], anti-inflammatory[10-12], anti-tumor[13-15]activities. In addition, quinoline skeleton is also used for the design of many synthetic compounds with diverse pharmacological properties. Indeed, the synthesis of new quinoline derivatives and the development of new synthetic methods would be of considerable importance. In this regard, our research group have reported the synthesis of aryloxymethylquinoline -3-carboxylate derivatives from the reaction between ethyl 2-halomethylquinoline-3-carboxylates and various substituted phenols[16-19].

As well known, halogen substituted quinoline derivatives are important heterocyclic compounds. Because the introduction of halogen atom to quinoline compounds can enhance greatly their biological activity, many synthetic efforts have been made to halogen substituted quinoline derivatives widely applied in the design and discovery of novel bioactive molecules and drugs. 6-Bromoquinoline is widely used in the synthesis of special pharmaceutical intermediates, such as anticancer drugs of reinforcing agent, receptor tyrosine kinase inhibitor and cardiotonic[20]. 3,7-Dichloroquinoline-8-carboxylic acid is a common herbicide, and has good herbicidal effect with long residual period[21]. 4,5,7-Trichloroquinoline is an important pharmaceutical intermediate with antimalarial activity[22]. ZHU et al[23]reported that the response rate of iodoquinoline azo reagent is higher than corresponding bromoquinoline azo reagent as well as unsubstituted quinoline azo reagent. SINGH et al[24]reported 2-chloroquinoline-3-carbonitrile can be used as an interme-diate to obtain more complex quinoline compounds with biological activity.

In order to synthesize structurally novel halogen substituted quinoline compounds with higher biological activities, herein, we report a facile synthesis of halogen substituted phenoxymethylquinoline compounds, i.e., 6-chloro-2-(phenoxymethyl)quinoline-3-carboxylic acid derivatives by the reaction of ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate with phenols.

1　Experimental section

1.1Instruments and reagents

Melting points were determined by using WRS-1B melting points apparatus and were uncorrected. IR spectra of the compounds in KBr pellets were obtained in the range of 400-4 000 cm-1on a Nicolet AVAR 360 FT-IR spectrophotometer.1H (400 MHz) and13C (100 MHz) NMR spectra were recorded on an Agilent1100 using DMSO-d6as the solvent. The reported chemical shifts (δvalues) were given in part per million downfield from tetramethylsilane (TMS) as the internal standard. HRMS spectra was obtained on an Apex Ⅲ (7.0T) FTICR. The progress of reactions was monitored by thin-layer chromatography (TLC) on silica gel GF254 using petroleum ether/ethyl acetate (3:1) as eluent.

All reagents are commercially available for analytical reagent or chemically reagent.

1.2Preparation of ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate

Ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate was prepared according a reference [25], yield 79%, m.p. 126.3-126.6 ℃ (lit[25]: yield 82%, m.p. 122-123 ℃).

1.3Synthesis of 6-chloro-2-(phenoxymethyl)quinoline-3-carboxylic acid derivatives

A mixture of ethyl 6-chloro-2-(chloromethyl) quinoline-3-carboxylate (1) (0.284 g, 1.0 mmol), substituted phenols 2a-o (1.1 mmol) and K2CO3(0.414 g, 3.0 mmol) was stirred in CH3CN (12 mL) under reflux. After completion of the reaction (monitored by TLC), CH3CN was evaporated. Then, a solution of 2.000 g KOH in 80% ethanol (15 mL) was added to the residue, and the mixture was heated under reflux for 4 h, cooled, and acidified with 1 mol/L HCl solution. The resulting crude product was recrystallized from ethanol to afford pure compounds 3a-o.

6-Chloro-2-(phenoxymethyl)quinoline-3-carboxylic acid (3a): light yellow solid, yield: 84.2%，m.p.: 183.3-184.5 ℃; IR (KBr,υ, cm-1): 3 429, 3 079, 2 913, 2 538, 2 360, 1 933, 1 710, 1 494, 1 227, 940, 838, 762, 698;1H NMR (400 MHz, DMSO-d6):δ13.59 (s, 1H), 8.89 (s, 1H), 8.31 (s, 1H), 8.06 (d,J= 9.0 Hz, 1H), 7.88 (d,J= 8.9 Hz, 1H), 7.29 (t,J= 7.7 Hz, 2H), 7.00 (d,J= 8.1 Hz, 2H), 6.94 (t,J= 7.2 Hz, 1H), 5.57 (s, 2H);13C NMR (100 MHz, DMSO-d6):δ167.58, 158.95, 156.13, 146.07, 139.21, 132.67, 132.39, 131.11, 129.88, 127.91, 127.66, 126.28, 121.25, 115.09, 70.68; HRMS: Calcd. For: C17H13ClNO3[M+H]+: 314.058 4, Found: 314.058 6.

6-Chloro-2-((o-tolyloxy)methyl)quinoline-3-carboxylic acid (3b): light yellow solid, yield: 79.9%, m.p.: 194.1-195.1 ℃; IR (KBr,υ, cm-1): 3 437, 3 062, 2 940, 2 724, 2 551, 2 356, 1 931, 1 721, 1 491, 1 245, 1 123, 935, 835, 755;1H NMR (400 MHz, DMSO-d6):δ13.61 (s, 1H), 8.88 (s, 1H), 8.33 (s, 1H), 8.09 (d,J= 9.0 Hz, 1H), 7.91 (d,J= 9.0 Hz, 1H), 7.14 (d,J= 5.3 Hz, 2H), 7.05 (d,J= 8.4 Hz, 1H), 6.85 (t,J= 7.3 Hz, 1H), 5.57 (s, 2H), 2.14 (s, 3H);13C NMR (100 MHz, DMSO-d6):δ167.83, 156.96, 156.28, 145.94, 138.95, 132.61, 132.39, 131.13, 130.81, 127.89, 127.73, 127.32, 126.68, 126.33, 120.86, 111.83, 70.92, 16.38; HRMS: Calcd. For: C18H15ClNO3[M+H]+: 328.074 0, Found: 328.074 4.

2-((2-(tert-Butyl)phenoxy)methyl)-6-chloroquinoline-3-carboxylic acid (3c): brown solid, yield: 76.7%, m.p.: 190.1-191.5 ℃; IR (KBr,υ, cm-1): 3 442, 3 006, 2 659, 2 350, 1 849, 1 718, 1 573, 1 429, 1 298, 1 049, 923, 829, 749, 672;1H NMR (400 MHz, DMSO-d6):δ13.60 (s, 1H), 8.98 (s, 1H), 8.34 (s, 1H), 8.07 (d,J= 8.9 Hz, 1H), 7.91 (d,J= 8.6 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.10 (d,J= 7.9 Hz, 1H), 6.88 (t,J= 7.3 Hz, 1H), 5.64 (s, 2H), 1.28 (s, 9H);13C NMR (100 MHz, DMSO-d6):δ167.28, 157.73, 156.39, 146.33, 139.85, 137.58, 132.83, 132.41, 131.16, 128.01, 127.65, 127.56, 126.66, 125.66, 120.73, 112.69, 70.63, 34.85, 30.08; HRMS: Calcd. For: C21H21ClNO3[M+H]+: 370.121 0, Found: 370.121 6.

2-((4-(tert-Butyl)phenoxy)methyl)-6-chloroquinoline-3-carboxylic acid (3d): light yellow solid, yield: 84.4%, m.p.: 204.3-205.8 ℃; IR (KBr,υ, cm-1): 3 441, 3 066, 2 958, 2 551, 2 360, 1 901, 1 723, 1 608, 1 507, 1 481, 1 366, 1 297, 1 251, 1 182, 1 029, 933, 825, 749, 660;1H NMR (400 MHz, DMSO-d6):δ13.60 (s, 1H), 8.89 (s, 1H), 8.33 (s, 1H), 8.09 (d,J= 9.2 Hz, 1H), 7.90 (dd,J= 2.0, 8.8 Hz, 1H), 7.30 (d,J= 8.4 Hz, 2H), 6.93 (d,J= 8.4 Hz, 2H), 5.55 (s, 2H), 1.26 (s, 9H);13C NMR (100 MHz, DMSO-d6):δ167.65, 156.71, 156.29, 146.04, 143.40, 139.08, 132.66, 132.38, 131.14, 127.92, 127.69, 126.50, 126.45, 114.54, 70.78, 34.21, 31.76; HRMS: Calcd. For: C21H21ClNO3[M+H]+: 370.121 0, Found: 370.121 4.

6-Chloro-2-((2,4-di-tert-butylphenoxy)methyl)quinoline-3-carboxylic acid (3e): light yellow solid, yield: 70.7%, m.p.: 213.1-214.5 ℃; IR (KBr,υ, cm-1): 3 359, 3 092, 2 933, 2 495, 1 920, 1 714, 1 590, 1 348, 1 022, 912, 832, 750, 689;1H NMR (400 MHz, DMSO-d6):δ13.61 (s, 1H), 8.97 (s, 1H), 8.35 (d,J= 2.2 Hz, 1H), 8.09 (d,J= 9.0 Hz, 1H), 7.91 (dd,J= 9.0, 2.3 Hz, 1H), 7.24 (d,J= 2.2 Hz, 1H), 7.17 (dd,J= 8.5, 2.2 Hz, 1H), 7.02 (d,J= 8.6 Hz, 1H), 5.61 (s, 2H), 1.29 (s, 9H), 1.26 (s, 9H);13C NMR (100 MHz, DMSO-d6):δ167.32, 156.55, 155.49, 146.29, 142.37, 139.76, 136.69, 132.78, 132.38, 131.17, 127.99, 127.65, 125.77, 123.86, 123.42, 112.19, 70.77, 35.00, 34.33, 31.85, 30.16; HRMS: Calcd. For: C25H29ClNO3[M+H]+: 426.183 6, Found: 426.184 1.

6-Chloro-2-((2-methoxyphenoxy)methyl)quinoline-3-carboxylic acid (3f): light yellow solid, yield: 73.7%, m.p.: 186.5-187.8 ℃; IR (KBr,υ, cm-1): 3 501, 3 022, 2 905, 2 548, 2 309, 1 849, 1 702, 1 549, 1 294, 1 044, 975, 829, 723;1H NMR (400 MHz, DMSO-d6):δ13.50 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 8.06 (dd,J= 8.9, 1.1 Hz, 1H), 7.89 (d,J= 8.9 Hz, 1H), 7.05 (dd,J= 7.8, 1.6 Hz, 1H), 6.97 (d,J= 7.3 Hz, 1H), 6.92-6.85 (m, 2H), 5.55 (s, 2H), 3.72 (s, 3H);13C NMR (100 MHz, DMSO-d6):δ167.45, 156.27, 149.61, 148.55, 146.11, 139.38, 132.69, 132.40, 131.12, 127.92, 127.69, 126.24, 121.78, 121.10, 114.40, 112.85, 71.49, 55.96; HRMS: Calcd. For: C18H15ClNO4[M+H]+: 344.068 9, Found: 344.069 2.

6-Chloro-2-((3-methoxyphenoxy)methyl)quinoline-3-carboxylic acid (3g): light yellow solid, yield: 76.4%, m.p. 201.1-202.7 ℃; IR (KBr,υ, cm-1): 3 429, 1 004, 2 890, 1 439, 1 904, 1 722, 1 581, 1 366, 1 120, 984, 859, 744, 674;1H NMR (400 MHz, DMSO-d6):δ13.60 (s, 1H), 8.89 (s, 1H), 8.31 (s, 1H), 8.07 (d,J= 9.0 Hz, 1H), 7.89 (d,J= 8.9 Hz, 1H), 7.18 (t,J= 8.1 Hz, 1H), 6.59 (d,J= 8.4 Hz, 2H), 6.53 (d,J= 8.4 Hz, 1H), 5.56 (s, 2H), 3.72 (s, 3H);13C NMR (100 MHz, DMSO-d6):δ167.58, 160.82, 160.19, 156.05, 146.06, 139.21, 132.68, 132.40, 131.11, 130.36, 127.92, 127.66, 126.31, 107.28, 106.94, 101.39, 70.80, 55.47; HRMS: Calcd. For: C18H15ClNO4[M+H]+: 344.068 9, Found: 344.069 6.

6-Chloro-2-((4-methoxyphenoxy)methyl)quinoline-3-carboxylic acid (3h): light yellow solid, yield: 80.1%, m.p.: 198.3-198.4 ℃; IR (KBr,υ, cm-1): 3 437, 3 062, 2 831, 2 558, 2 371, 1 851, 1 700, 1 570, 1 519, 1 376, 1 224, 1 043, 943, 885, 828, 755;1H NMR (400 MHz, DMSO-d6):δ13.60 (s, 1H), 8.89 (s, 1H), 8.32 (s, 1H), 8.08 (d,J= 9.0 Hz, 1H), 7.90 (d,J= 8.9 Hz, 1H), 6.95 (d,J= 9.0 Hz, 2H), 6.86 (d,J= 8.9 Hz, 2H), 5.52 (s, 2H), 3.70 (s, 3H);13C NMR (100 MHz, DMSO-d6):δ167.68, 156.34, 153.98, 152.96, 146.03, 139.04, 132.61, 132.35, 131.11, 127.89, 127.64, 126.41, 116.13, 114.92, 71.40, 55.72; HRMS: Calcd. For: C18H15ClNO4[M+H]+: 344.068 9, Found: 344.069 5.

6-Chloro-2-((2-fluorophenoxy)methyl)quinoline-3-carboxylic acid (3i): light yellow solid, yield: 82.0%, m.p.: 192.2-193.3 ℃; IR (KBr,υ, cm-1): 3 436, 2 044, 2 984, 2 601, 2 293, 1 890, 1 710, 1 576, 1 384, 1 046, 933, 846, 732, 669;1H NMR (400 MHz, DMSO-d6):δ13.63 (s, 1H), 8.95 (s, 1H), 8.35 (d,J= 2.2 Hz, 1H), 8.07 (d,J= 9.0 Hz, 1H), 7.91 (dd,J= 9.0, 2.3 Hz, 1H), 7.27 (d,J= 8.3 Hz, 1H), 7.22 (d,J= 11.9 Hz, 1H), 7.11 (t,J= 7.8 Hz, 1H), 6.98 - 6.93 (m, 1H), 5.68 (s, 2H);13C NMR (100 MHz, DMSO-d6):δ167.37, 155.73, 153.34, 150.92, 146.86, 146.11, 139.60, 132.80, 132.47, 131.14, 127.98, 125.92, 125.15, 121.71, 116.50, 115.79, 71.52; HRMS: Calcd. For: C17H12ClFNO3[M+H]+: 332.048 9, Found: 332.049 2.

6-Chloro-2-((4-chlorophenoxy)methyl)quinoline-3-carboxylic acid (3j): light yellow solid, yield: 86.3%, m.p.: 206.6-207.4 ℃; IR (KBr,υ, cm-1): 3 398, 3 028, 2 605, 2 323, 1 855, 1 719, 1 569, 1 330, 1 219, 1 054, 945, 836, 775, 639;1H NMR (400 MHz, DMSO-d6):δ13.64 (s, 1H), 8.93 (s, 1H), 8.34 (d,J= 2.2 Hz, 1H), 8.06 (d,J= 9.0 Hz, 1H), 7.90 (dd,J= 9.0, 2.3 Hz, 1H), 7.34 (d,J= 8.9 Hz, 2H), 7.04 (d,J= 8.9 Hz, 2H), 5.60 (s, 2H);13C NMR (100 MHz, DMSO-d6):δ167.47, 157.85, 155.84, 146.08, 139.41, 132.75, 132.42, 131.12, 129.61, 127.96, 127.66, 126.01, 124.89, 116.90, 70.99; HRMS: Calcd. For: C17H12Cl2NO3[M+H]+: 348.019 4, Found: 348.019 8.

6-Chloro-2-((2-bromophenoxy)methyl)quinoline-3-carboxylic acid (3k): light yellow solid, yield: 79.7%, m.p.: 207.7-209.3 ℃; IR (KBr,υ, cm-1): 3 441, 3 079, 2 907, 2 545, 2 366, 1 939, 1 710, 1 589, 1 386, 1 309, 1 227, 1 137, 1 074, 1 048, 933, 877, 749, 685;1H NMR (400 MHz, DMSO-d6):δ13.62 (s, 1H), 8.97 (s, 1H), 8.36 (d,J= 2.0 Hz, 1H), 8.07 (d,J= 8.8 Hz, 1H), 7.92 (dd,J= 8.8, 2.4 Hz, 1H), 7.59 (dd,J= 8.0, 1.2 Hz, 1H), 7.34 (t,J= 8.0 Hz, 1H), 7.24 (d,J= 7.6 Hz, 1H), 6.91 (t,J= 7.2 Hz, 1H), 5.69 (s, 2H);13C NMR (100 MHz, DMSO-d6):δ167.26, 155.71, 155.29, 146.09, 139.71, 133.35, 132.81, 132.48, 131.15, 129.32, 128.01, 127.78, 125.96, 122.60, 114.45, 111.42, 71.73; HRMS: Calcd. For: C17H12BrClNO3[M+H]+: 391.968 9, Found: 391.969 0.

6-Chloro-2-((4-bromophenoxy)methyl)quinoline-3-carboxylic acid (3l): light yellow solid, yield: 82.4%, m.p.: 211.6-212.5 ℃; IR (KBr,υ, cm-1): 3 439, 3 065, 2 900, 2 602, 2 411, 1 893, 1 720, 1 577, 1 255, 1 167, 1 056, 963, 862, 768, 687;1H NMR (400 MHz, DMSO-d6):δ13.62 (s, 1H), 8.92 (s, 1H), 8.33 (s, 1H), 8.05 (d,J= 8.8 Hz, 1H), 7.89 (d,J= 8.7 Hz, 1H), 7.45 (d,J= 8.5 Hz, 2H), 6.98 (d,J= 8.6 Hz, 2H), 5.59 (s, 2H);13C NMR (100 MHz, DMSO-d6):δ167.45, 158.29, 155.82, 146.07, 139.43, 132.75, 132.50, 132.41, 131.11, 127.96, 127.65, 125.98, 117.43, 112.63, 70.89; HRMS: Calcd. For: C17H12BrClNO3[M+H]+: 391.968 9, Found: 391.969 3.

2-((4-tert-Butyl)-2-fluorophenoxy)methyl)-6-chloroquinoline-3-carboxylic acid (3m): light yellow solid, yield: 82.6%, m.p.: 231.9-233.7 ℃; IR (KBr,υ, cm-1): 3 435, 3 072, 2 971, 2 767, 2 551, 2 360, 1 876, 1 716, 1 571, 1 525, 1 424, 1 233, 1 131, 1 061, 927, 838, 762, 634;1H NMR (400 MHz, DMSO-d6):δ13.63 (s, 1H), 8.92 (s, 1H), 8.33 (s, 1H), 8.07 (d,J= 9.0 Hz, 1H), 7.90 (d,J= 8.9 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.15 (t,J= 8.8 Hz, 1H), 7.08 (d,J= 8.6 Hz, 1H), 5.63 (s, 2H), 1.24 (s, 9H);13C NMR (100 MHz, DMSO-d6):δ167.40, 155.86, 150.53, 146.09, 144.88, 144.48, 139.48, 132.76, 132.47, 131.15, 127.96, 127.72, 126.07, 121.30, 121.26, 115.26, 71.69, 34.42, 31.50; HRMS: Calcd. For: C21H20ClFNO3[M+H]+: 388.111 5, Found: 388.111 9.

2-((4-tert-Butyl)-2-chlorophenoxy)methyl)-6-chloroquinoline-3-carboxylic acid (3n): light yellow solid, yield: 80.7%, m.p.: 216.3-217.6 ℃; IR (KBr,υ, cm-1): 3 435, 3 063, 2 953, 2 557, 2 401, 1 855, 1 719, 1 570, 1 524, 1 254, 1 135, 1 035, 944, 843, 775, 666;1H NMR (400 MHz, DMSO-d6):δ13.59 (s, 1H), 8.94 (s, 1H), 8.34 (s, 1H), 8.08 (d,J= 8.9 Hz, 1H), 7.90 (d,J= 8.9 Hz, 1H), 7.39 (s, 1H), 7.28 (d,J= 8.6 Hz, 1H), 7.17 (d,J= 8.6 Hz, 1H), 5.65 (s, 2H), 1.25 (s, 9H);13C NMR (100 MHz, DMSO-d6):δ167.35, 155.82, 152.14, 146.06, 144.74, 139.56, 132.75, 132.48, 131.15, 127.97, 127.76, 127.19, 126.09, 125.21, 121.34, 114.10, 71.70, 34.36, 31.50; HRMS: Calcd. For: C21H20Cl2NO3[M+H]+: 404.082 0, Found: 404.082 4.

2-((4-tert-Butyl)-2-bromophenoxy)methyl)-6-chloroquinoline-3-carboxylic acid (3o): white solid, yield: 77.8%, m.p.: 217.5-218.9 ℃; IR (KBr,υ, cm-1): 3 394, 3 044, 2 604, 2 386, 1 901, 1 704, 1 581, 1 422, 1 211, 1 034, 954, 835, 769, 660;1H NMR (400 MHz, DMSO-d6):δ13.56 (s, 1H), 8.94 (s, 1H), 8.34 (s, 1H), 8.07 (d,J= 8.8 Hz, 1H), 7.90 (d,J= 8.6 Hz, 1H), 7.52 (s, 1H), 7.32 (d,J= 8.3 Hz, 1H), 7.14 (d,J= 8.6 Hz, 1H), 5.64 (s, 2H), 1.25 (s, 9H);13C NMR (100 MHz, DMSO-d6):δ167.29, 155.82, 153.07, 146.06, 145.18, 139.61, 132.77, 132.48, 131.16, 130.11, 127.98, 127.79, 126.08, 125.96, 113.92, 111.08, 71.81, 34.33, 31.53; HRMS: Calcd. For: C21H20BrClNO3[M+H]+: 448.031 5, Found: 448.031 8.

2　Results and discussion

Our synthetic equation was shown in Fig. 1. 2-Chloromethyl group of ethyl 6-chloro-2-(chloromethyl) quinoline-3-carboxylate (1) underwent the Williamson reaction with various phenols 2a-o followed by its ethyl ester hydrolysis reaction at the 3-position to afford the target products 3a-o.

Ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate (1) underwent Williamson reaction with phenols bearing various substituents in the presence of potassium carbonate in acetonitrile under reflux. In this reaction, we chose acetonitrile as a solvent because of its low boiling point for much convenience to the workup procedure. After fuu completion of the Williamson reaction as observed on TLC, acetonitrile was evaporated to dryness, then 80% ethanolic potassium hydroxide solution (15 mL) was directly added to the residue, and the resulting reaction mixture was stirred under reflux. After the reactions were completed (monitored by TLC, usually within four hours) the target products were obtained after recrystallization from ethanol.

The beauty of this reaction is that Williamson ether synthesis and subsequent ester hydrolysis take place in one-pot, with operational and experimental simplicity, providing the acids in good yields of 70.7%-86.3% The scope and generality of the synthesized compounds 3a-o are listed in Table 1 together with yields and melting points.

Table 1　Yields and melting points of compounds 3a-o

As shown in Table 1, ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate (1) reacted with phenols 2a-o to give the corresponding 6-chloro-2-(phenoxymethyl)quinoline-3-carboxylic acid derivatives 3a-o in 70.7%-86.3% yields. It seemed that the electronic nature of the substituent has no significant effect on the reaction, all the phenols with electron-donating (entries 2-8), electron-withdrawing (entries 9-12), or the halo- andtert-butyl disubstituted groups (entries 13-15) worked well and give the corresponding target products in good yields. The relatively lower yield of compound 3e may be ascribed to the sterically hindered nature of the two bulkytert-butyl groups at theo-position andp-position of aryl.

The structure of compounds 3a-o was confirmed by their spectroscopic data with the results being in full agreement with the proposed structure. For example, the IR spectrum of compound 3a exhibited the presence of carbonyl group at 1 710 cm-1. The main feature of1H NMR spectrum of compound 3a was the appearance of the carboxyl proton at 13.59, quinoline protons at 8.89-7.88, the benzene ring protons at 7.29-6.94, and the methylene proton at 5.57, respectively. Its13C NMR spectrum was also in good agreement with the assigned structures, which revealed the presence of the carboxyl and methylene carbons at 167.58 and 70.68, respectively. Further the molecular formula of compound 3a was deduced to be C17H12ClNO3from its HR-MS, which shows a pseudo-molecular-ion peak atm/z314.058 6 ([M+H]+; calc. for C17H13ClNO3+: 314.058 4), indicating the presence of 12° of unsaturation.

3　Conclusions

In conclusion, we have described synthesis of a series of new quinoline-3-carboxylic acid with quinoline ring containing chlorine atom, i.e., 6-chloro-2-(phenoxymethyl)quinoline-3-carboxylic acid derivatives. The advantages of the current protocol as a useful method include the ready availability of starting materials, simple experimental operation, and good yields. These compounds could be potentially applied for the development of biologically and pharmaceutically important compounds. Access to such biologically intriguing structures should allow us to study their biological activities, and we will explore this possibility in near future.

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[責(zé)任編輯:劉紅玲]

“一鍋法”合成6-氯取代的2-苯氧甲基-3-喹啉甲酸衍生物

符鑫博,高文濤,李陽(yáng),王東方,趙雅楠

(渤海大學(xué) 超精細(xì)化學(xué)品研究所,遼寧 錦州 121000)

設(shè)計(jì)了以6-氯-2-氯甲基-3-喹啉甲酸乙酯(1)為起始化合物，在溶劑乙腈、縛酸劑無(wú)水碳酸鉀的條件下，通過(guò)“一鍋法”與苯酚及取代苯酚2a-o反應(yīng)，合成了喹啉環(huán)上含有氯原子的 6-氯-2-苯氧甲基-3-喹啉甲酸衍生物3a-o. 所合成的化合物3a-o的結(jié)構(gòu)經(jīng)紅外光譜、核磁共振氫譜、核磁共振碳譜和高分辨質(zhì)譜得以證實(shí).

氯原子；苯氧甲基；喹啉甲酸；一鍋法；合成

date： 2016-01-03.

國(guó)家自然科學(xué)基金(21476028, 21402011).

, E-mail: isfc@bhu.edu.cn.

O626 Document code： A

Biography： 符鑫博(1991-), 男, 碩士生,研究方向?yàn)橛袡C(jī)合成.*