Direct formation of 2,3,5-trichloropyridine and its nucleophilic displacement reactions in ionic liquid

Article abstract of DOI:10.1081/SCC-200039365

Reaction of trichloroacetaldehyde and acrylonitrile in the presence of a catalytic amount of copper (I) chloride in ionic liquid afforded 2,3,5-trichloropyridine, fluprination of which with KF and CsF in ionic liquid afforded 3,5-dichloro-2-fluoropyridihe and 5-chloro-2,3-dichloropyridine. Reaction of 2,3,5-trichloropyridine, 3,5-dichloro-2-fluoropyridine, or 5-chloro-2,3-dichloropyride with 2-(4-hydroxyphenoxy) propionates in ionic liquid afforded the corresponding 2-aryloxylpropionates in good yields.

Full text of DOI:10.1081/SCC-200039365

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Direct Formation of
2,3,5‐Trichloropyridine and
its Nucleophilic Displacement
Reactions in Ionic Liquid
Ping Zhong a , Huanan Hu a b & Shengrong Guo a b
a Department of Chemistry , Wenzhou Normal
College , Xueyuanzhong Road, Wenzhou, 325027,
P. R. China
b Department of Chemistry , Jiangxi Normal
University , Nanchang, P. R. China
Published online: 10 Jan 2011.
To cite this article: Ping Zhong , Huanan Hu & Shengrong Guo (2004) Direct
Formation of 2,3,5‐Trichloropyridine and its Nucleophilic Displacement Reactions
in Ionic Liquid, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:23, 4301-4311, DOI: 10.1081/
SCC-200039365
To link to this article: http://dx.doi.org/10.1081/SCC-200039365
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4301–4311, 2004
Direct Formation of 2,3,5-Trichloropyridine
and its Nucleophilic Displacement Reactions
in Ionic Liquid
Ping Zhong,1, Huanan Hu, and Shengrong Guo1,2
1,2
*
1Department of Chemistry, Wenzhou Normal College, Wenzhou,
P. R. China
2Department of Chemistry, Jiangxi Normal University, Nanchang,
P. R. China
ABSTRACT
Reaction of trichloroacetaldehyde and acrylonitrile in the presence of a
catalytic amount of copper (I) chloride in ionic liquid afforded 2,3,5-
trichloropyridine, fluorination of which with KF and CsF in ionic liquid
afforded 3,5-dichloro-2-fluoropyridine and 5-chloro-2,3-dichloropyridine.
Reaction of 2,3,5-trichloropyridine, 3,5-dichloro-2-fluoropyridine, or 5-
chloro-2,3-dichloropyride with 2-(4-hydroxyphenoxy)propionates in ionic
liquid afforded the corresponding 2-aryloxylpropionates in good yields.
Key Words: Trichloroacetaldehyde; Acrylonitrile; 2,3,5-Trichloropyri-
dine; Ionic liquid; Nucleophilic displacement reactions.
*
Correspondence: Ping Zhong, Department of Chemistry, Wenzhou Normal College,
Xueyuanzhong Road, Wenzhou 325027, P. R. China; E-mail: zhongp@wznc.zj.cn.
4301
DOI: 10.1081/SCC-200039365
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4302
Zhong, Hu, and Guo
2,3,5-Trichloropyridine can be used as an intermediate for the production
of herbicidal active substances.[1,2] Proposed processes for its production have
been widely diverse and have included both the selection chlorination of
intermediate compounds, the selective dechlorination of higher chlorinated
pyridines, and other routes. For example, 2,3,5-trichloropyridine can be pre-
pared by the vapor phase chlorination of 3,5-dichloropyridine.[3] It can also
be prepared by reacting 3,5-dichloro-2-pyridone at 75–808C with phosgene
in the presence of a dimethyl formamide (DMF).[4] 2,3,5-Trichloropyridine
can also be prepared by reacting 2,3,4,5-tetrachloropyridine using zinc dust
in an alkanephosphonic acid dialkyl ester[5] or by the directly reacting penta-
chloropyridine or 2,3,5,6-tetrachloropyridine with metallic zinc in the pre-
sence of a strongly alkaline aqueous solution and a water-immiscible
reaction medium[6] and so on.[7,8] But the Lewis acid catalyzed addition of tri-
chloroacetaldehyde to acrylonitrile is the most notable and well-known
method for the large-scale production of this compound.[9]
The mechanism of this reaction has been studied, and a two-step reaction
has been proposed. 2,4,4-Trichloro-4-formylbutyronitrile is produced by the
addition of trichloroacetaldehyde to acrylonitrile under nitrogen atmosphere.
The cyclization of 2,4,4-trichloro-4-formylbutyronitrile in the presence of
dry HCl or Lewis acid has afforded 2,3,5-trichloropyridine (Scheme 1).
However, those reported methods included some unsatisfied conditions,
such as long time, high temperature, and pressure. Recently, we found that
the usage of the room temperature ionic liquids as solvent with a catalytic
amount of Lewis acid in one step directly synthesized 2,3,5-trichloropyridine
1 and accelerated the formation of 1 remarkably, including being environmen-
tally more benign, and having generality, simplicity of the methodology, ease
of product isolation, higher yield, and potential for recycling ionic liquids
(Scheme 2).
Room-temperature ionic liquids[10] such as [Bmim][BF4] are finding growth
in applications as alternative reaction media for organic transformations.
Scheme 1.

2,3,5-Trichloropyridine
4303
Scheme 2.
Recent examples of such organic transformations include Diels–Alder
reactions,[11] Friedel–Crafts reactions,[12] Heck reactions,[13] nucleophilic
substitution,[14] and so on.
Generally, the fluoropyridines were prepared in dimethyl sulfoxide or
dimethyl sulfone by the action of anhydrous potassium fluoride, usually 2
molesofpotassiumfluorideforeachatomofhalogentobereplaced, ontheappro-
priate halopyridine.[15] But, the nucleophilic displacement reactions of hetero-
cyclic compounds in ionic liquids have not been reported. It was found that
3,5-dichloro-2-fluoropyridine 2 and 5-chloro-2,3-difluoropyridine 3 can be pre-
pared by 2,3,5-trichloropyridine 1 with an effective amount of KF or CsF in an
ionic liquid, such as [Bmim][BF4], at an elevated temperature under substantially
anhydrous conditions with removal of the difluoropyridine product essentially as
it is formed. 5-Chloro-2,3-difluoropyridine 3 is also prepared by fluorinating
3,5-dichloro-2-fluoropyridine 2 under favorable conditions (Scheme 3).
Reaction of 2,3,5-trichloropyridine 1, 3,5-dichloro-2-fluoropyridine 2, or
5-chloro-2,3-difluoropyridine 3 with 2-(4-hydroxyphenoxy)-propionates 4
Scheme 3.

4304
Zhong, Hu, and Guo
and K2CO3 in [Bmim][BF4] afforded 2-[4-(3,5-dichloropyridin-2-yloxy)-
phenoxy]-propionates, 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-
propionates 5 (Scheme 4, Table 1).
Under basic conditions, hydrolysis of 5 gave their acids. For example,
2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid 6 could be
given from 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionates
5d (Scheme 5).
EXPERIMENTAL
Melting points are uncorrected. Thin-layer chromatography (TLC) was
performed using precoated silica gel 60 GF254 (0.25 mm), column chromato-
graphy was performed using silica gel (100–200 mesh), infrared (IR) spectra
were recorded on a Bruker VECTOR55 instrument, and 1H NMR and
13C NMR spectra were recorded on a FT-Bruker AT-300 instrument using
tetramethylsilane (TMS) as an internal standard. MS spectra were recorded
on a Finnigan DECAX-30000 LCQ DecaXP plus instrument. 1-Butyl-3-
methylimidazolium tetrafluoroborate ([Bmim]BF4) and 2-(4-hydroxy-
phenoxy)-propionates 4 were prepared according to the procedures
reported.[16,17]
Synthesis of 1-Butyl-3-Methylimidazoliumtetrafluoroborate
([Bmim]BF4)
A mixture of n-Butyl chloride (0.4 mol), N-methylimidazole (0.4 mol)
and toluene (100 mL) was stirred at refluxing temperature for 1 or 2 days
under nitrogen. The mixture was cooled to ice temperature, and then the
mixture appeared in two layers, spilling out the topper, and acetone (50 mL)
was added causing precipitation of 1-butyl-3-methyl imidazolium halide salt
Scheme 4. R1 ¼ Cl, or F; 5a: R2 ¼ Cl, R3 ¼ C2H5; 5b: R2 ¼ F, R3 ¼ C2H5; 5c:
R2 ¼ Cl, R3 ¼ CH3; 5d: R2 ¼ F, R3 ¼ CH3; 5e: R2 ¼ Cl, R3 ¼ CH2C6H5;
5f: R2 ¼ Cl, R3 ¼ CH2COC6H5; 5g: R2 ¼ Cl, R3 ¼ CH2CO2C2H5; 5h: R2 ¼ Cl,
;;
R3 ¼ CH2 C CH.

2,3,5-Trichloropyridine
4305
Table 1. Reaction of 1, 2, or 3 with 2-(4-hydroxyphenolic) propionates.
Entry
R1
R2
R3
Product
Yield (%)
1
2
Cl
F
Cl
Cl
F
C2H5
C2H5
C2H5
CH3
CH3
CH3
CH3
5a
5a
5b
5c
5c
5d
5d
5e
5f
75
82
81
77
85
80
70
76
75
77
75
3
F
4
Cl
F
Cl
Cl
F
5
6
7Ã
F
F
F
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH2C6H5
9
CH2COC6H5
CH2CO2C2H5
CH2C;CH2
10
11
5g
5h
ÃWithout ionic liquids.
as a white solid. This solid was recovered by filtration and washed with ethyl
ether. To prepare the tetrafluoroborate salts, the 1-butyl-3-methyl imidazolium
halide salt (0.32 mol) was added to a suspension of NaBF4 (1.2 equiv.) in
acetone (150 mL) with a mechanical stirrer. After the mixture was stirred
for 48 h at room temperature, the sodium halide precipitate was removed by
filtration, and the filtrate was concentrated to oil by rotary evaporation. This
oil still contained some 1-butyl-3-methyl imidazolium halide, because it
gave a precipitate when mixed with aqueous silver nitrate.
Synthesis of 2,3,5-Trichloropyridine 1
A one-neck reaction flask was charged with [Bmim]BF4 (5 mL), tri-
chloroacetaldehyde (14.7 g, 0.1 mol), acrylonitrile (5.3 g, 0.1 mol), copper(I)
chloride (0.5 g, 0.005 mol), and acetonitrile (20 ml). Heated at 1208C with a
stirrer, the reaction was monitored by TLC until consumption of the material.
After completion of the reaction, the combined reaction mixture was
Scheme 5.

4306
Zhong, Hu, and Guo
concentrated in vacuo, then distilled with steam, in the process of which the
2,3,5-trichloropyridine was given. The yield is 7.48 g (41% of theory).
2,3,5-Trichloropyridine (1): A white solid. m.p. 49–508C (lit.[11]: 49–
1
508C). H NMR: d ¼ 8.30 (d, J ¼ 2.0 Hz, 1H), 7.82 (d, J ¼ 2.0 Hz, 1H);
13C NMR: d ¼ 147.3 (1C), 145.9 (1C), 138.1 (2C), 130.8 (1C). MS
m/z ¼ 182.2. IR (nmax, KBr): 3040, 1560, 1230, 1120, 1030 cm21
.
Synthesis of 3,5-Dichloro-2-Fluoropyridine 2 and
5-Chloro-2,3-Difluoropyridine 3
In a 100 ml flask was placed 2,3,5-trichloropyridine 1 (10.95 g,
0.06 mmol), KF (6.97 g, 0.12 mol), CsF (3.04 g, 0.02 mol), 0.5 g K2CO3, and
40 mL [Bmim]BF4. The stirred mixture was heated to 2008C for 10 h. The
product was extracted with Et2O (3 Â 25 ml) after the reaction was completed.
The combined ethereal phases were evaporated under reduced pressure, and
the crude product was purified by column chromatography on silica gel and
elution with 5 : 1 petroleum ether (60–908C) and ethyl acetate to give
3,5-dichloro-2-fluoropyridine 2 (3.60 g, 36.1% of theory) and 5-chloro-2,3-
difluoropyridine 3 (1.89 g, 21.0% of theory).
Synthesis of 5-Chloro-2,3-Difluoropyridine 3 with 3,5-
Dichloro-2-Fluoropyridine 2
In a 50 ml flask was placed 2-fluoro-3,5-dichloropyridine 2 (6.65 g,
0.04 mmol), CsF (9.3 g, 0.061 mol), 0.4 g K2CO3, and 20 mL [Bmim]BF4.
After the mixture was heated at 100–1108C/200 mmHg for 8 h, the product
was extracted with Et2O (3 Â 25 ml). The combined ethereal phases were
evaporated under reduced pressure, and the crude product was purified by
column chromatography on silica gel and elution with 5 : 1 petroleum ether
(60–908C) and ethyl acetate to give 2-fluoro-3,5-dichloropyridine 2 (0.60 g)
and 5-chloro-2,3-difluoropyridine 3 (3.75 g, 68.8% of theory).
3,5-Dichloro-2-fluoropyridine 2: A white solid. m.p. 38–398C (lit.[18]
:
38–398C). 1H NMR: d ¼ 8.01 (d, J ¼ 2.0 Hz, 1H), 7.44 (d,
J ¼ 2.0 Hz, 1H); 13C NMR: d ¼ 156.6 (1C), 146.5 (1C), 138.6 (1C),
131.3 (1C), 119.5 (1C). MS m/z ¼ 165.7. IR (nmax, KBr): 3045,
1568, 1235, 1130, 1035 cm21
.
5-Chloro-2,3-difluoropyridine 3: An oil (lit.[19]: boil 135–1368C, or
1
70–738C/85 mmHg20). H NMR: d ¼ 7.94 (d, J ¼ 2.1 Hz, 1H), 7.51

2,3,5-Trichloropyridine
4307
(d, J ¼ 2.1 Hz, 1H); 13C NMR: d ¼ 156.7 (1C), 151.2 (1C), 141.7 (1C),
129.2 (1C), 123.6 (1C). MS m/z ¼ 149.3. IR (nmax, KBr): 3035, 1558,
1225, 1125, 1025 cm21
.
Synthesis of 2-[4-(3,5-Dihalopyridin-2-yloxy)-
Phenoxy]-Propionate 5
To a stirred mixture of 2-(4-hydroxyphenoxy)-propionates 4 (0.05 mol),
K2CO3 (6.91 g, 0.05 mol), and 20 mL [Bmim]BF4 was added drop-wise a
solution of 2,3,5-trichloropyridine 1, or 3,5-dichloro-2-fluoropyridine 2, or
5-chloro-2,3-difluoropyridine 3 (0.05 mol) in 15 ml of acetonitrile, and the
mixture was heated at a temperature of 50–608C during 40 h. The mixture was
then poured into ice water. The organic material was extracted with ethyl
acetate, washed with a saturated salt solution, dried over magnesium sulfate,
filtered, and evaporated. The oily residue was purified by column chromato-
graphy on silica gel and elution with 3 : 1 petroleum ether (60–908C) and
ethyl acetate to give 2-[4-(3,5-dihalopyridin-2-yloxy)-phenoxy]-propionic
acid and its esters 5.
Ethyl 2-[4-(3,5-dichloropyridin-2-yloxy)-phenoxy]-propionate 5a: An
1
oil. H NMR: d ¼ 7.94 (d, J ¼ 1.3 Hz, 1H), 7.74 (d, J ¼ 1.3 Hz, 1H), 7.05
(d, J ¼ 8.9 Hz, 2H), 6.90 (d, J ¼ 8.9 Hz, 2H), 4.71 (q, J ¼ 6.7 Hz, 1H), 4.23
(q, J ¼ 7.1 Hz, 2H), 1.62 (d, J ¼ 6.7 Hz, 3H), 1.26 (t, J ¼ 7.1 Hz, 3H);
13C NMR: d ¼ 171.20 (1C), 157.79 (1C), 154.80 (1C), 147.51 (1C), 143.37
(1C), 138.65 (1C), 125.35 (1C), 122.40 (1C), 119.32 (2C), 116.23 (2C),
73.08 (1C), 60.53 (1C), 18.78 (1C), 14.20 (1C); MS m/z ¼ 356.1; IR (nmax
,
film): 3030, 1760, 1550, 1210, 1100 cm21. Anal. Calcd. for C16H15Cl2NO4:
C, 53.95; H, 4.24; N, 3.93. Found: C, 53.61; H, 4.15; N, 3.63.
Ethyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionate
1
5b: An oil. H NMR: d ¼ 7.92 (m, 1H), 7.72 (m, 1H), 7.04 (d, J ¼ 8.6 Hz,
2H), 6.90 (d, J ¼ 8.6 Hz, 2H), 4.71 (q, J ¼ 6.6 Hz, 1H), 4.22 (q, J ¼ 7.0, 2H),
1.61 (d, J ¼ 6.6 Hz, 3H), 1.25 (t, J ¼ 7.0 Hz, 3H); 13C NMR: d ¼ 169.24
(1C), 158.13 (1C), 157.02 (1C), 153.51 (1C), 151.26 (1C), 140.03 (1C),
130.22 (1C), 122.71 (1C), 119.68 (2C), 117.51 (2C), 73.13 (1C), 60.85
(1C), 19.49 (1C), 14.46 (1C); MS m/z ¼ 339.6; IR (nmax, film): 3035, 1765,
1555, 1220, 1120 cm21. Anal. Calcd. for C16H15ClFNO4: C, 56.56; H, 4.45;
N, 4.12. Found: C, 56.25; H, 4.38; N, 4.08.
Methyl 2-[4-(3,5-dichloropyridin-2-yloxy)-phenoxy]-propionate 5c:
1
An oil. H NMR: d ¼ 7.95 (d, J ¼ 1.5 Hz, 1H), 7.75 (d, J ¼ 1.5 Hz, 1H),
7.04 (d, J ¼ 8.8 Hz, 2H), 6.92 (d, J ¼ 8.8 Hz, 2H), 4.73 (q, J ¼ 6.8 Hz, 1H),
3.94 (s, 3H), 1.60 (d, J ¼ 6.8 Hz, 3H); 13C NMR: d ¼ 169.95 (1C), 157.82
(1C), 157.02 (1C), 153.90 (1C), 140.10 (1C), 130.21 (1C), 130.24 (1C),

4308
Zhong, Hu, and Guo
122.40 (1C), 119.32 (2C), 116.23 (2C), 73.08 (1C), 51.65 (1C), 18.78 (1C);
MS m/z ¼ 342.3; IR (nmax, film): 3020, 1755, 1560, 1220, 1120 cm21
.
Anal. Calcd. for C15H13Cl2NO4: C, 52.65; H, 3.83; N, 4.09. Found: C,
52.43; H, 3.64; N, 4.00.
Methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionate
1
5d: A white solid. m.p. 63–648C. (lit.[21]: 63–648C). H NMR: d ¼ 7.94
(m, 1H), 7.74 (m, 1H), 7.00 (d, J ¼ 8.6 Hz, 2H), 6.90 (d, J ¼ 8.6 Hz, 2H),
4.72 (q, J ¼ 6.6 Hz, 1H), 3.92 (s, 3H), 1.62 (d, J ¼ 6.6 Hz, 3H); 13C NMR:
d ¼ 170.02 (1C), 157.98 (1C), 157.24 (1C), 152.65 (1C), 142.37 (1C),
138.65 (1C), 125.35 (1C), 124.77 (1C), 119.55 (2C), 117.51 (2C), 73.41
(1C), 51.24 (1C), 19.48 (1C); MS m/z ¼ 325.6; IR (nmax, film): 3030, 1755,
1550, 1225, 1130 cm21
.
Benzyl 2-[4-(3,5-dichloropyridin-2-yloxy)-phenoxy]-propionate 5e:
1
An oil. H NMR: d ¼ 7.96 (d, J ¼ 2.3 Hz, 1H), 7.77 (d, J ¼ 2.3 Hz, 1H),
7.33 (m, 5H), 7.04 (d, J ¼ 9.0 Hz, 2H), 6.92 (d, J ¼ 9.0 Hz, 2H), 5.22
(s, 2H), 4.79 (q, J ¼ 6.8 Hz, 1H), 1.67 (d, J ¼ 6.8 Hz, 3H); 13C NMR:
d ¼ 170.01 (1C), 157.81 (1C), 155.79 (1C), 148.53 (1C), 143.37 (1C),
138.63 (1C), 137.01 (1C), 128.86 (1C), 125.33 (2C), 122.41 (2C), 119.32
(1C), 117.28 (2C), 117.05 (2C), 116.22 (1C), 74.12 (1C), 67.23 (1C), 19.49
(1C); MS m/z ¼ 418.9; IR (nmax, film): 3035, 1755, 1550, 1200,
1120 cm21. Anal. Calcd. for C21H17Cl2NO4: C, 60.30; H, 4.10; N, 3.35.
Found: C, 59.92; H, 4.02; N, 3.28.
2-Oxo-2-phenylethyl
2-[4-(3,5-dichloropyridin-2-yloxy)-phenoxy]-
propionate 5f: A yellow solid. m.p. 53–558C. 1H NMR: d ¼ 7.96
(d, J ¼ 2.4 Hz, 1H), 7.90 (m, 5H), 7.74 (d, J ¼ 2.4 Hz, 1H), 7.09
(d, J ¼ 9.1 Hz, 2H), 7.02 (d, J ¼ 9.1 Hz, 2H), 5.45 (s, 2H), 4.93 (q, J ¼ 6.8 Hz,
1H), 1.78 (d, J ¼ 6.8 Hz, 3H); 13C NMR: d ¼ 171.46 (1C), 167.13 (1C), 157.81
(1C), 154.86 (1C), 147.47 (1C), 143.37 (2C), 138.66 (2C), 125.32 (1C),
122.36 (4C), 119.32 (1C), 116.23 (4C), 72.92 (1C), 61.00 (1C), 18.60 (1C);
MS m/z ¼ 446.8; IR (nmax, KBr): 3035, 1760, 1550, 1210, 1100cm21. Anal.
Calcd. for C22H17Cl2NO5: C, 59.21; H, 3.84; N, 3.14. Found: C, 59.02; H,
3.74; N, 3.68.
Oxopropoxymethyl 2-[4-(3,5-dichloropyridin-2-yloxy)-phenoxy]-pro-
pionate 5g: An oil. 1H NMR: d ¼ 7.96 (d, J ¼ 2.4 Hz, 1H), 7.76
(d, J ¼ 2.4 Hz, 1H), 7.08 (d, J ¼ 8.8 Hz, 2H), 6.96 (d, J ¼ 8.8 Hz, 2H), 4.85
(q, J ¼ 6.8 Hz, 1H), 4.70 (s, 2H), 4.24 (q, J ¼ 7.1 Hz, 2H), 1.70 (d, J ¼ 6.8 Hz,
3H), 1.29 (t, J ¼ 7.1 Hz, 3H); 13C NMR: d ¼ 191.34 (1C), 171.57 (1C), 154.95
(1C), 147.43 (1C), 143.39 (1C), 138.65 (1C), 128.88 (1C), 128.60 (1C),
127.72 (1C), 122.38 (2C), 116.23 (2C), 73.12 (1C), 66.33 (2C), 18.81 (2C);
MS m/z ¼ 414.0; IR (nmax, film): 3035, 1751, 1555, 1220, 1120cm21. Anal.
Calcd. for C18H17Cl2NO6: C, 52.19; H, 4.14; N, 3.38. Found: C, 51.91; H,
4.05; N, 3.30.

2,3,5-Trichloropyridine
4309
2-propynyl 2-[4-(3,5-dichloropyridin-2-yloxy)-phenoxy]-propionate
5h: A white solid. m.p. 67–698C. 1H NMR: d ¼ 7.93 (d, J ¼ 2.3 Hz, 1H), 7.73
(d, J ¼ 2.3 Hz, 1H), 7.04 (d, J ¼ 8.8 Hz, 2H), 6.91 (d, J ¼ 8.8 Hz, 2H), 4.77
(q, J ¼ 6.8 Hz, 1H), 4.74 (s, 2H), 2.49 (s, 1H), 1.63 (d, J ¼ 6.8 Hz, 3H); 13C
NMR: d ¼ 171.20 (1C), 157.82 (1C), 154.81 (1C), 147.51 (1C), 143.37 (1C),
138.68 (1C), 125.36 (1C), 122.41 (2C), 119.32 (1C), 116.24 (2C), 75.44
(1C), 73.13 (2C), 52.61 (1C), 18.43 (1C); MS m/z ¼ 366.4. IR (nmax, KBr):
3035, 1751, 1555, 1220, 1120cm21. Anal. Calcd. for C17H13Cl2NO4: C,
55.76; H, 3.58; N, 3.82. Found: C, 55.63; H, 3.46; N, 3.71.
Synthesis of 2-[4-(5-Chloro-3-Fluoropyridin-2-yloxy)-
Phenoxy]-Propionic Acid 6
To
a solution of 6.5 g (0.02 mol) of methyl 2-[4-(5-chloro-3-
fluoropyridin-2-yloxy)-phenoxy]-propionate in 30 ml of dioxane were added
21 ml of 1 N sodium hydroxide, and the mixture was stirred for 3 h at 358C.
Then it was poured onto an ice water mixture and acidified with 11 ml of 2
N hydrochloric acid. The organic material was extracted with ethyl acetate.
The organic layers were washed with a saturated salt solution and dried
over magnesium sulfate, filtered, and concentrated. The residue was purified
by column chromatography on silica gel and elution with 3 : 1 petroleum
ether (60–908C) and ethyl acetate to yield 5.1 g (81.8% of the theory) of
2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid 6.
2-[4-(5-Chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid 6:
A white solid. m.p. 95–968C. (lit.[22]: 95–968C). 1H NMR: d ¼ 12.2
(s, 1H), 7.90 (m, 1H), 7.70 (m, 1H), 7.05 (d, J ¼ 8.7 Hz, 2H), 6.91
(d, J ¼ 8.7 Hz, 2H), 4.70 (q, J ¼ 6.5 Hz, 1H), 1.60 (d, J ¼ 6.5 Hz, 3H); IR
(nmax, KBr): 3030, 1735, 1550, 1240 cm21
.
ACKNOWLEDGMENT
Project 20272043 was supported by The National Nature Science Foun-
dation of China. This work was also supported by The National Nature
Science Foundation of Zhejiang Province (M203001).
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Received in Japan March 31, 2004