Synthesis of fluorescence pyriproxyfen analogues as juvenile hormone agonists

Article abstract of DOI:10.3987/COM-11-12232

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. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-11-12232

HETEROCYCLES, Vol. 83, No. 7, 2011
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HETEROCYCLES, Vol. 83, No. 7, 2011, pp. 1649 - 1658. © The Japan Institute of Heterocyclic Chemistry
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*
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences,
1432–1
Horinouchi,
Hachioji,
Tokyo
192-0392,
Japan
(e-mail:
itohisa@toyaku.ac.jp)
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.10ꢀꢀIt 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

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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.
R
O
O
O
N
O
N
O
O
pyriproxyfen (1)
pyriproxyfen analogues 2a: R = H
2b: R = –NMe2
2c: R = –CO2Me
2d: R = –CO2H
Figure 1. Structures of pyriproxyfen (1) and its fluorescence analogues 2a–2d
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.
O
OH
O
R
3
O
+
O
N
R
O
Cl
N
pyriproxyfen analogues 2a: R = H
2b: R = –NMe2
2c: R = –CO2Me
4a: R = H
4b: R = –NMe2
4c: R = –CO2Me
Scheme 1. Synthetic plan for pyriproxyfen analogues 2a–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.

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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.
OEt
a
b
c
N
N
N
N
H2N
O
N
H
HO
N
Cl
N
5
7
4b
6
Me
CO2Me
CO2H
d
e
f
N
N
N
9
8
10
CO2Me
CO2Me
CO2Me
g
h
N
O
HO
N
Cl
N
12
4c
11
Scheme 2. Syntheses of 6-substituted-2-chloroquinoline derivatives 4b and 4c. Reagents and Conditions:
a) 3-ethoxypropenoylchloride, Et3N, toluene, reflux, 2 h, 57%; b) conc. H2SO4, 50 °C, 24 h. 45%; c) POCl3,
reflux, 3 h, 58%; d) CrO3, conc. H2SO4, H2O, reflux, 24 h, 40% (based on recovered 8); e) p-TsOH, MeOH,
reflux, 24 h, 99%; f) mCPBA, CHCl3, rt, 18 h, 94%; g) Ac2O, 100 °C, then H2O, rt, 72 h, 74%; h) POCl3,
reflux, 3 h, 98%.
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

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in 70% yield.
R
R
O
a
O
N
Cl
N
O
O
OH
4a: R = H
pyriproxyfen analogues 2a: R = H
2b: R = –NMe2
O
4b: R = –NMe2
3
4c: R = –CO2Me
2c: R = –CO2Me
2d: R = –CO2H
b
Scheme 3. Syntheses of pyriproxyfen analogues 2a–2d. Reagents and Conditions: a) 3, NaH, N,N-
Dimethylacetamide, reflux, 16 h, 81% from 4a to 2a; 46% from 4b to 2b; 0 °C, 15 min, 67% from 4c to 2c;
b) LiOH, THF–H2O, rt, 48 h, 70%.
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.
Table 1. Fluorescence spectral data for pyriproxyfen analogues 2a–2d
Analogues
Maximum wavelength (nm)
Stokes' shift (nm)
Quantum yield
Excitation
Emission
2a
2b
239
250
343
461
104
211
0.015
0.321
2c
247
246
343
345
96
99
0.005
0.005
2d
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).

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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): !
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): !
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,
1
1200, 1117, 842, 816, 584 cm–1; H NMR (300 MHz, CDCl3): ! 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),
13
11.4–11.7 (br s, 1H); C NMR (75 MHz, CDCl3): ! 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): ! 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): ! 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.

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HETEROCYCLES, Vol. 83, No. 7, 2011
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): ! 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,
13
1.7 Hz, 1H), 13.0–13.5 (br s, 1H); C NMR (75 MHz, DMSO-d6): ! 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): ! 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): ! 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

HETEROCYCLES, Vol. 83, No. 7, 2011
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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): ! 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): ! 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): ! 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),
13
11.17–11.28 (br s, 1H); C NMR (75 MHz, CDCl3): ! 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): ! 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):
! 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.

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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): ! 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): ! 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,
1
991, 968, 872, 845, 820, 752, 692, 623 cm–1; H NMR (300 MHz, CDCl3): ! 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,
13
1H); C NMR (75 MHz, CDC3): ! 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;

HETEROCYCLES, Vol. 83, No. 7, 2011
1657
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): ! 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 =
13
8.8, 2.0 Hz, 1H), 8.47 (d, J = 1.9 Hz, 1H); C NMR (75 MHz, CDCl3): ! 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): ! 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,
13
1H), 8.29 (dd, J = 8.8, 1.8 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H); C NMR (75 MHz, CDCl3): ! 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.

1658
HETEROCYCLES, Vol. 83, No. 7, 2011
ACKNOWLEDGEMENTS
This work was supported in part by a grant for private universities from MEXT of Japan.
REFERENCES AND NOTES
1. M. Hatakoshi, N. Agui, and I. Nakayama, Appl. Ent. Zool., 1986, 21, 351.
2. T. S. Dhadialla, G. R. Carlson, and D. P. Le, Annu. Rev. Entomol., 1998, 43, 545.
3. H. Oouchi and P. Langley, J. Pestic. Sci., 2005, 30, 50.
4. I. Ishaaya, A. De Cock, and D. Degheele, J. Econ. Entomol., 1994, 87, 1185.
5. I. Ishaaya and A. R. Horowitz, J. Econ. Entomol., 1992, 85, 2113.
6. T.-X. Liu and T.-Y. Chen, Entomol. Exp. Appl., 2001, 98, 295.
7. T.-X. Liu and P. A. Stansly, J. Econ. Entomol., 1997, 90, 404.
8. K. Kamimura and R. Arakawa, Jpn. J. Sanit. Zool., 1991, 42, 249.
9. C. H. Schaefer and F. S. Mulligan, III, J. Am. Mosq. Control Assoc., 1991, 7, 409.
10. P. G. Koehler and R. J. Patterson, J. Econ. Entomol., 1991, 84, 917.
11. R. McKinlay, J. A. Plant, J. N. B. Bell, and N. Voulvoulis, Environment International, 2008, 34,
168.
12. D. M. Schreinemachers, Environ. Health Perspect., 2003, 111, 1259.
13. C. A. Mackenzie, A. Lockridge, and M. Keith, Environ. Health Perspect., 2005, 113, 1295.
14. S. M. Zala and D. J. Penn, Anim. Behav., 2004, 68, 649.
15. V. F. Garry, Toxicol. Appl. Pharmacol., 2004, 198, 152.
16. P. Nicolopoulou-Stamati and M. A. Pitsos, Hum. Reprod. Update, 2001, 7, 323.
17. N. Meki, Y. Oogami, and O. Magara, Jpn Kokai Tokkyo Koho, 1991, 03034951.
18. C. Janiak, S. Deblon, and L. Uehlin, Synthesis, 1999, 959.
19. L. F. Tietze, C. Schneider, and M. Pretor, Synthesis, 1993, 1079.
20. G. Campiani, S. Butini, C. Fattorusso, S. Franceschini, I. Z. Thale, K. S. Nielsen, J. Scheel-Krüeger,
and L. S. Madsen, US Pat. Appl. 2010/0087445 A1.
21. J. E. Heemskerk, J. M. Mccall, and K. D. Barnes, WO 2009/042907 A1.
22. Quantum yields were measured on an absolute PL quantum yield measurement system (Photonic
Multi-Channel Analyzer C10027, Hamamatsu Photonics K.K.).