HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 7, 2011, pp. 1649-1658
Received, 9th April, 2011, Accepted, 25th April, 2011, Published online, 26th April, 2011.
DOI: 10.3987/COM-11-12232

■ Synthesis of Fluorescence Pyriproxyfen Analogues as Juvenile Hormone Agonists

Hideki Abe, Akimi Sato, Shin-ichi Tokishita, Toshihiro Ohta, and Hisanaka Ito*

Laboratory of Bioorganic Chemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Four fluorescence analogues of juvenile hormone agonist pyriproxyfen were designed and synthesized. The synthetic analogue having a dimethylamino group exhibited fluorescence, and therefore can be used for investigation of the mode of action of pyriproxyfen as a juvenile hormone analogue.

Pyriproxyfen (1),1 2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine, is a widely used insecticide2 developed by Sumitomo Chemical Co., Ltd. in the 1990s. It is a broad-spectrum insect growth regulator against public health insects such as whiteflies,3-5 aphids,6,7 mosquitoes,8,9 and cockroaches.10 It has been known that pyriproxyfen mimics the action of juvenile hormone in target insects and is an insecticide with relatively low mammalian toxicity. However, its exact mode of action in target insects is not well understood. Additionally, pyriproxyfen, a potent hormone agonist, is classified as an endocrine disruptor11 that alters function of the endocrine system and causes adverse health effects such as birth defects,12 sexual abnormalities,13,14 and reproductive failures15,16 in both wildlife and humans. For that reason, concerns about the latent toxicity of pyriproxyfen to non-target organisms have recently been raised. It is therefore necessary to determine the detailed molecular mechanism of action of pyriproxyfen.
The ultimate goal of our investigation is the elucidation of the mechanism and action of pyriproxyfen against arthropods. As a first step, the design and synthesis of fluorescence analogues, an important and useful tool in biological studies, were undertaken. Fluorescence analogue 2a having a quinoline ring as a fluorescent group instead of the pyridine ring of pyriproxyfen (1) was designed (Figure 1). Analogue 2b having a dimethylamino group as an electron-donating group at the C6 position of the quinoline ring, and analogues 2c and 2d involving a methyl ester group and a carboxyl group, respectively, as electron-withdrawing groups at C6, were also designed. In this report, we describe the synthesis of our designed analogues and their fluorescence properties.

Our synthetic plan for pyriproxyfen analogues 2a–2c was based on the nucleophilic aromatic substitution of 2-chloroquinoline derivatives 4a–4c with a known alcohol, 1-(4-phenoxyphenoxy)propan-2-ol 3,17 as outlined in Scheme 1. Analogue 2d having a carboxyl group would be easily derived by hydrolysis of the methyl ester moiety from analogue 2c.

The syntheses of 2-chloroquinoline analogues 4b and 4c are shown in Scheme 2. Synthesis of 2-chloro-6-dimethylaminoquinoline (4b) was carried out according to Janiak’s synthetic route,18 which began with acylation of 4-dimethylaminoaniline (5) with 3-ethoxyacryloyl chloride19 prepared from ethyl vinyl ether and oxalyl chloride to give the acylated aniline derivative 6 in 57% yield. Heating 6 in conc. sulfuric acid gave the cyclized product 7. Chlorination of the resulting hydroxyl group in 7 with phosphorus oxychloride produced 2-chloro-6-dimethylaminoquinoline (4b) in 58% yield.
Synthesis of 2-chloro-6-methoxycarbonylquinoline (4c) started from commercially available 6-methylquinoline (8) as the starting material. Oxidation of the methyl group of 8 with chromium trioxide under acidic conditions,20 followed by esterification of the resulting carboxylic acid 9, gave the methyl ester 10 in 40% overall yield. Oxidation at the C2-position of the quinoline ring of 10 was accomplished by a two-step sequence to yield 2-hydroxyquinoline derivative 12:21 oxidation of the nitrogen atom with m-chloroperbenzoic acid, followed by rearrangement of the resulting N-oxide using acetic anhydride. Finally, chlorination of 12 gave the desired 2-chloro-6-methoxycarbonylquinoline (4c) in 98% yield.

Having the 6-substituted quinoline derivatives 4b and 4c in hand, nucleophilic aromatic substitution with the known alcohol 3 was investigated as shown in Scheme 3. After several attempts, the conditions for coupling the quinolines, including commercially available 2-chloroquinoline (4a), and secondary alcohol 3 were established as follows. Refluxing quinoline derivatives 4a and 4b with 3 (2 equiv) and sodium hydride (2.2 equiv) in N,N-dimethylacetamide for 16 h under argon gave the corresponding target molecules 2a and 2b in 81% and 46% yields, respectively. Nucleophilic aromatic substitution of 4c and 3 in the presence of sodium hydride occurred at 0 °C to give target analogue 2c in 67% yield. Hydrolysis of methyl ester 2c with lithium hydroxide afforded the quinoline carboxylic acid derivative 2d in 70% yield.

Next, fluorescence properties of the synthetic analogues were analyzed. The excitation and emission wavelengths along with Stokes’ shifts and quantum yields22 of 2a–2d in MeOH are displayed in Table 1. Although quantum yields of analogues 2a, 2c, and 2d unfortunately were extremely low, that of analogue 2b having a dimethylamino group exhibited a reasonable value (0.321). These spectral results indicate that analogue 2b will be applicable for the investigation of the mode of action of pyriproxyfen.

In conclusion, we designed four fluorescence pyriproxyfen analogues and synthesized them by using nucleophilic aromatic substitution reactions. The analogues 2a–2d exhibited different fluorescence properties. It appeared that analogue 2b would be a useful fluorescence analogue for biological investigation of pyriproxyfen. Biological studies of this synthetic analogue are now in progress.

EXPERIMENTAL
(E)-N-[4-(Dimethylamino)phenyl]-3-ethoxyacrylamide (6).
To a stirred solution of 4-(dimethylamino)aniline (5) (5.00 g, 36.7 mmol) and triethylamine (6.50 mL, 4.71 g, 46.6 mmol) in toluene (125 mL) was added dropwise a solution of 3-ethoxyacryloyl chloride19 (4.94 g, 36 7 mmol) in toluene (25 mL) at 100 °C, and the reaction mixture was refluxed for 2 h. After the solvent was removed in vacuo, THF (100 mL) was added to the residue. The resulting suspension was filtered, and the filtrate was evaporated in vacuo. The obtained residue was recrystallized from AcOEt to give 618 (4.29 g, 21.0 mmol, 57%) as pale yellow needles. m.p. 152–153 ºC (from AcOEt); IR (KBr): 3297, 3260, 1657, 1611, 1524, 1345, 1253, 1239, 1152, 811 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.33 (t, J = 6.8 Hz, 3H), 2.93 (s, 6H), 3.80–4.08 (br m, 2H), 5.31 (d, J = 12.0 Hz, 1H), 6.68­–6.71 (br m, 2H), 6.85–7.03 (br s, 1H), 7.26–7.52 (br m, 2H), 7.60 (d, J = 12.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 14.5, 40.9 (2C), 66.9, 99.3, 113.0 (2C), 121.7 (2C), 128.5, 147.6, 160.1, 165.1; HRMS (ESI–TOF): calcd for C13H19N2O2 ([M + H]+) 235.1447, found 235.1464.

6-(Dimethylamino)quinolin-2-ol (7).
To stirred conc. H2SO4 was added 6 (600 mg, 2.56 mol) in small portions at 0 °C, and the reaction mixture was allowed to warm to 50 °C. After stirring for 6 days at 50 °C, the mixture was made basic by addition to 5 M NaOH aqueous solution. The mixture was extracted by AcOEt (3 x 300 mL), washed with brine, and concentrated in vacuo. The residue was purified by column chromatography (CHCl3–MeOH–28% NH4OH, 360:9:1) to give 718 (290 mg, 1.54 mmol, 60%) as pale yellow needles. m.p. 238–239 ºC (from CHCl3); IR (KBr): 3440, 3143, 2986, 2898, 2831, 1657, 1620, 1508, 1428, 1367, 1200, 1117, 842, 816, 584 cm–1; 1H NMR (300 MHz, CDCl3): δ 2.97 (s, 6 H), 6.67 (d, J = 9.5 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 7.08 (dd, J = 9.0, 2.7 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 9.5 Hz, 1H), 11.4–11.7 (br s, 1H); 13C NMR (75 MHz, CDCl3): δ 41.1 (2C), 108.9, 117.0, 118.5, 120.8, 121.3, 130.8, 140.6, 146.7, 164.0; HRMS (ESI–TOF): calcd for C11H13N2O ([M + H]+) 189.1028, found 189.1020.

2-Chloro-6-(dimethylamino)quinoline (4b).
A suspension of 7 (257 mg, 1.27 mmol) in phosphorus oxychloride (3.75 mL) was refluxed under argon. After stirring for 3 h, excess phosphorus oxychloride was removed by distillation at atmosphere, and ice (50 mg) was added to the residue. The residue was made basic by adding 10% Na2CO3 aq. at pH 8–9, and the resultant 4b18 (165 mg, 0.798 mmol, 58%) was obtained as yellow crystals by filtration. m.p. 75–76 ºC (from CHCl3); IR (KBr): 2885, 2812, 1623, 1577, 1514, 1451, 1367, 1246, 1194, 1153, 1136, 1096, 1068, 940, 846, 814, 713, 642, 543, 474 cm–1; 1H NMR (300 MHz, CDCl3): δ 3.07 (s, 6H), 6.77 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 9.4, 2.8 Hz, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 40.4 (2C), 104.6, 119.6, 122.0, 128.2, 128.8, 136.8, 141.3, 145.7, 148.6; HRMS (ESI–TOF): calcd for C11H12ClN2 ([M + H]+) 207.0689, found 207.0680.

Quinoline-6-carboxylic acid (9).
To a stirred solution of 6-methylquinoline (8) (500 mg, 3.50 mmol) in H2O (5 mL) was added conc. H2SO4 (1.3 mL) and chromium trioxide (1.35 g, 1.35 mmol), then the reaction mixture was refluxed for 24 h. After addition of H2O (15 mL), the reaction mixture was extracted with AcOEt (9 x 100 mL), dried over MgSO4, and concentrated in vacuo. The resultant solid was recrystallized from hexane–MeOH to afford 9 (119 mg, 0.687 mmol, 20%) as colorless needles. The organic layer was evaporated in vacuo and the resultant solid was recrystallized from H2O–hexane to recover 8 (123 mg, 0,710 mmol, 20%) as colorless crystals. Compound 9: m.p. 243–247 ºC (from hexane–MeOH); IR (KBr): 2778, 2432, 2374, 2347, 1906, 1702, 1629, 1506, 1462, 1328, 1277, 1217, 1195, 1098, 807, 789, 754, 637, 525 cm–1; 1H NMR (300 MHz, DMSO-d6): δ 7.63 (dd, J = 8.3, 4.2 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.8, 1.9 Hz, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.68 (d, J = 1.7 Hz, 1H), 9.02 (dd, J = 4.2, 1.7 Hz, 1H), 13.0–13.5 (br s, 1H); 13C NMR (75 MHz, DMSO-d6): δ 123.2, 128.2, 129.6, 129.7, 130.3, 131.9, 138.5, 150.3, 153.6, 167.9; HRMS (ESI–TOF): calcd for C10H8NO2 ([M + H]+) 174.0555, found 174.0556.

Methyl quinoline-6-carboxylate (10).
To a stirred solution of 9 (189 mg, 1.09 mmol) in MeOH (20 mL) was added p-TsOH monohydrate (415 mg, 2.18 mmol), and the mixture was refluxed for 12 h. The reaction mixture was quenched by addition of sat. NaHCO3 aq. (20 mL), and the mixture was extracted with AcOEt (3 x 40 mL). The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. The resultant residue was purified by column chromatography (hexane–AcOEt, 1:1) to afford 10 (202 mg, 1.08 mmol, 99%) as a white solid. The solid was recrystallized from AcOEt to give colorless prisms. m.p. 83–84 ºC (from AcOEt); IR (KBr): 1718, 1625, 1596, 1461, 1440, 1358, 1323, 1285, 1256, 1204, 1181, 1125, 1101, 974, 916, 847, 797, 786, 470 cm–1; 1H NMR (300 MHz, CDCl3): δ 3.94 (s, 3H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.25 (dd, J = 8.3, 1.5 Hz, 1H), 8.30 (dd, J = 8.8, 1.8 Hz, 1H), 8.59 (d, J = 1.8 Hz, 1H), 9.00 (dd, J = 4.2, 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 52.4, 121.8, 127.4, 128.1, 128.9, 129.8, 131.0, 137.3, 150.0, 152.5, 166.6; HRMS (ESI–TOF): calcd for C11H10NO2 ([M + H]+) 188.0712, found 188.0708.

Methyl quinoline-6-carboxylate N-oxide (11).
To a stirred solution of 10 (65.0 mg, 0.347 mmol) in CHCl3 (4 mL) was added mCPBA (121 mg, 0.701 mmol), and then the reaction mixture was stirred at room temperature under Ar. After stirring for 16 h, the mixture was quenched by addition of sat. NaHCO3 aq. (10 mL), and washed with H2O. The organic layer was dried over MgSO4, and the solvent was removed. The resulting residue was purified by column chromatography (AcOEt–MeOH, 1:1) to afford 11 (66.0 mg, 0.325 mmol, 94%) as a white solid. The solid was recrystallized from CHCl3 to give colorless prisms. m.p. 145–147 ºC (from CHCl3); IR (KBr): 3058, 1718, 1622, 1573, 1457, 1433, 1361, 1294, 1260, 1222, 1203, 1178, 1102, 774, 578, 497 cm-1; 1H NMR (300 MHz, CDCl3): δ 4.01 (s, 3H), 7.38 (dd, J = 8.5, 6.1 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 8.34 (dd, J = 9.1, 1.7 Hz, 1H), 8.60 (d, J = 6.1 Hz, 1H), 8.63 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 52.4, 120.0, 121.7, 126.3, 129.5, 129.7, 130.1, 130.7, 136.8, 142.9, 165.4; HRMS (ESI–TOF): calcd for C11H10NO3 ([M + H]+) 204.0661, found 204.0670.

Methyl 2-hydroxyquinoline-6-carboxylate (12).
A solution of 11 (186 mg, 0.916 mmol) in Ac2O (15 mL) was heated to 100 °C, and the mixture was stirred for 18 h. H2O (15 mL) was added to the reaction mixture at room temperature, and then this mixture was stirred for 72 h at the same temperature. The mixture was extracted with CHCl3 (3 x 30 mL), and the combined organic layers were dried over MgSO4. The solvent was removed in vacuo, and the resulting residue was purified by column chromatography (CHCl3–MeOH–28% NH4OH, 450:9:1) to afford 12 (137 mg, 0.675 mmol, 74%) as a white solid. The solid was recrystallized from CHCl3 to give colorless needles. m.p. 251–253 ºC (from CHCl3); IR (KBr): 3449, 3428, 1720, 1672, 1656, 1626, 1569, 1279, 1256, 1211, 545 cm–1; 1H NMR (300 MHz, CDCl3): δ 3.96 (s, 3H), 6.74 (d, J = 9.5 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 9.5 Hz, 1H), 8.17 (dd, J = 8.6, 1.8 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 11.17–11.28 (br s, 1H); 13C NMR (75 MHz, CDCl3): δ 52.3, 115.9, 119.3, 122.4, 124.7, 130.3, 131.4, 141.2, 141.4, 164.3, 166.2; HRMS (ESI–TOF): calcd for C11H10NO3 ([M + H]+) 204.0661, found 204.0661.

Methyl 2-chloroquinoline-6-carboxylate (4c).
A suspension of 12 (109 mg, 0.537 mmol) in phosphorus oxychloride (7 mL) was refluxed under argon. After stirring for 3 h, excess phosphorus oxychloride was removed by distillation at atmosphere, and ice (100 mg) was added to the residue. The residue was made basic by adding 10% Na2CO3 aqueous solution at pH 8–9, and the mixture was extracted with CHCl3 (3 x 100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was recrystallized from CHCl3 to afford 4c (116 mg, 0.525 mmol, 98%) as colorless needles. m.p. 134–136 ºC (from CHCl3); IR (KBr): 1727, 1584, 1454, 1310, 1279, 1196, 1187, 1140, 1103, 1091, 818, 788, 750 cm–1; 1H NMR (300 MHz, CDCl3): δ 3.99 (s, 3H), 7.45 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.31 (dd, J = 8.8, 1.7 Hz, 1H), 8.56 (d, J = 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 52.5, 123.3, 126.0, 128.6, 128.9, 130.2, 130.5, 139.9, 149.7, 153.0, 166.2; HRMS (ESI–TOF): calcd for C11H9ClNO2 ([M + H]+) 222.0322, found 222.0311.

2-[1-(4-Phenoxyphenoxy)propan-2-yl]oxyquinoline (2a).
To a solution of 1-(4-phenoxyphenoxy)propan-2-ol 317 (122 mg, 0.499 mmol) in N,N-dimethylacetamide (2 mL) was added NaH (24.0 mg, 55% dispersion in mineral oil, 0.549 mmol) at 0 °C, and this suspension was stirred at room temperature for 0.5 h. A solution of 2-chloroquinoline (4a) (41.0 mg, 0.250 mmol) in N,N-dimethylacetamide (2 mL) was added to the reaction mixture at room temperature, and then the mixture was refluxed for 16 h. The reaction mixture was quenched by addition of H2O (10 mL), and extracted with AcOEt (3 x 30 mL). The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. The residue was purified by column chromatography (hexane–AcOEt, 10:1) to afford 2b (75.6 mg, 0.204 mmol, 81%) as a colorless oil. IR (neat): 3047, 2927, 2934, 2873, 1619, 1605, 1590, 1574, 1504, 1488, 1473, 1428, 1393, 1344, 1311, 1276, 1257, 1224, 1155, 1112, 1045, 987, 870, 843, 824, 755, 692 cm–1; 1H NMR (400 MHz, CDCl3): δ 1.57 (d, J = 6.4 Hz, 3H), 4.13 (dd, J = 10.0, 5.2 Hz, 1H), 4.30 (dd, J = 10.0, 5.1 Hz, 1H), 5.87 (qdd, J = 6.4, 5.2, 5.1 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.94–6.97 (m, 2H), 6.98–7.01 (m, 4H), 7.02–7.07 (m, 1H), 7.28–7.33 (m, 2H), 7.38 (ddd, J = 7.9, 7.1, 1.2 Hz, 1H), 7.62 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.72 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 17.1, 69.3, 70.9, 113.6, 115.9 (2C), 117.6 (2C), 120.8 (2C), 122.4, 124.1, 125.2, 127.3, 127.4, 129.5, 129.6 (2C), 138.9, 146.5, 150.3, 155.3, 158.6, 161.4; HRMS (ESI–TOF): calcd for C24H22NO3 ([M + H]+) 372.1600, found 372.1604.

6-Dimethylamino-2-[1-(4-phenoxyphenoxy)propan-2-yl]oxyquinoline (2b).
To a solution of 1-(4-phenoxyphenoxy)propan-2-ol 3 (472 mg, 1.94 mmol) in N,N-dimethylacetamide (6 mL) was added NaH (93.0 mg, 55% dispersion in mineral oil, 2.13 mmol) at 0 °C, and this suspension was stirred at room temperature. After stirring for 0.5 h at room temperature, a solution of 2-chloroquinoline 4b (200 mg, 0.960 mmol) in N,N-dimethylacetamide (6 mL) was added to the reaction mixture at room temperature, and then the mixture was refluxed for 16 h. The reaction mixture was quenched by addition of H2O (15 mL), and extracted with AcOEt (3 x 40 mL). The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. The residue was purified by column chromatography (hexane–AcOEt, 8:1) to afford 2b (75.6 mg, 0.204 mmol, 81%) as a pale yellow oil. IR (neat): 1601, 1505, 1489, 1471, 1396, 1365, 1275, 1247, 1222, 1196, 1158, 1110, 1084, 1044, 991, 968, 872, 845, 820, 752, 692, 623 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.57 (d, J = 6.4 Hz, 3H), 3.03 (s, 6H), 4.12 (dd, J = 10.0, 5.4 Hz, 1H), 4.31 (dd, J = 10.0, 4.9 Hz, 1H), 5.75–5.88 (m, 1H), 6.82–6.90 (m, 2H), 6.94–7.10 (m, 7H), 7.27–7.36 (m, 3H), 7.74 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H); 13C NMR (75 MHz, CDC3): δ 17.1, 41.2 (2C), 68.8, 70.9, 107.0, 113.4, 115.9 (2C), 117.5 (2C), 119.2, 120.8 (2C), 122.3, 126.1, 127.7, 129.6 (2C), 137.6, 139.8, 147.4, 150.1, 155.3, 158.5, 159.2; HRMS (ESI–TOF): calcd for C26H27N2O3 ([M + H]+) 415.2022, found 415.2011.

Methyl 2-[1-(4-phenoxyphenoxy)propan-2-yl]quinoline-6-carboxylate (2c).
To a solution of 1-(4-phenoxyphenoxy)propan-2-ol 3 (80.0 mg, 0.327 mmol) in N,N-dimethylacetamide (2 mL) was added NaH (15.0 mg, 55% dispersion in mineral oil, 0.344 mmol) at 0 °C, and this suspension was stirred at room temperature for 0.5 h. Next, a solution of 2-chloroquinoline 4c (36.0 mg, 0.163 mmol) in N,N-dimethylacetamide (2 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred for 15 min at 0 °C. The reaction mixture was quenched by addition of H2O (10 mL), and extracted with AcOEt (3 x 30 mL). The combined organic layers were dried over MgSO4, and the solvent was removed. The residue was purified by column chromatography (hexane–AcOEt, 3:1) to afford 2c (47.0 mg, 0.110 mmol, 67%) as a colorless oil. IR (neat): 1720, 1622, 1605, 1504, 1489, 1472, 1396, 1278, 1221, 1095, 691 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.56 (d, J = 6.4 Hz, 3H), 3.97 (s, 3H), 4.14 (dd, J = 10.0, 4.9 Hz, 1H), 4.28 (dd, J = 10.0, 5.3 Hz, 1H), 5.80–5.94 (m, 1H), 6.91–6.99 (m, 7H), 7.00–7.07 (m, 1H), 7.27–7.34 (m, 2H), 7.83 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 9.8 Hz, 1H), 8.22 (dd, J = 8.8, 2.0 Hz, 1H), 8.47 (d, J = 1.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 16.9, 52.0, 69.8, 70.8, 114.4, 115.8 (2C), 117.6 (2C), 120.8 (2C), 122.4, 124.2, 125.7, 127.4, 129.4, 129.6 (2C), 130.4, 139.8, 149.0, 150.3, 155.1, 158.4, 162.9, 166.9; HRMS (ESI–TOF): calcd for C26H24NO5 ([M + H]+) 430.1654, found 430.1643.

2-[1-(4-Phenoxyphenoxy)propan-2-yl]quinoline-6-carboxylic acid (2d).
To a stirred solution of 2c (35.0 mg, 81.6 µmol) in THF (2 mL) was added 1 M LiOH aqueous solution (1 mL) at room temperature, and this mixture was stirred at room temperature for 48 h. The reaction mixture was neutralized by addition of acetic acid at pH 6–7, extracted with AcOEt (3 x 15 mL), and dried over MgSO4. The solvent was removed in vacuo, and the resulting residue was purified by column chromatography (hexane–AcOEt, 5:1) to afford 2d (24.0 mg, 57.8 µmol, 70%) as a colorless gum. IR (neat): 2922, 1690, 1622, 1606, 1505, 1489, 1472, 1395, 1280, 1222, 822, 692 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.57 (d, J = 6.4 Hz, 3H), 4.15 (dd, J = 10.0, 4.9 Hz, 1H), 4.28 (dd, J = 10.0, 5.3 Hz, 1H), 5.81–5.96 (m, 1H), 6.90–7.08 (m, 8H), 7.26–7.34 (m, 2H), 7.86 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 8.29 (dd, J = 8.8, 1.8 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 16.9, 70.0, 70.8, 114.7, 115.8 (2C), 117.6 (2C), 120.8 (2C), 122.5, 124.3, 124.7, 127.6, 129.6 (2C), 129.7, 131.4, 139.9, 149.6, 150.4, 155.1, 158.4, 163.2, 171.3; HRMS (ESI–TOF): calcd for C25H22NO5 ([M + H]+) 416.1498, found 416.1486.

ACKNOWLEDGEMENTS
This work was supported in part by a grant for private universities from MEXT of Japan.

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