Convenient approaches to 4-trifluoromethylpyridine

Article abstract of DOI:10.1021/op000109r

A number of approaches to the synthesis of 2-chloro-and 2,6-dichloro-4-trifluoromethylpyridine are described. The first method for 2-chloro-and 2,6-dichloro-4-trifluoromethylpyridine is based on commercially available ethyl trifluoroacetate. An alternative access to 2,6-dichloro-4-trifluoromethyl pyridine uses trifluoroacetaldehyde as starting material. 2-Chloro-4-trifluoromethylpyridine is prepared from ethyl(trifluoroacetylvinyl)ether in two steps.

Full text of DOI:10.1021/op000109r

Organic Process Research & Development 2001, 5, 531−534
Convenient Approaches to 4-Trifluoromethylpyridine
Biao Jiang,*,†,‡ Wennan Xiong, Xiaobing Zhang, and Fangjiang Zhang
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
54 Fenglin Lu, Shanghai 200032, China, and Engineering Research Center in Organic Synthesis,
Chinese Academy of Sciences, Synica Chemicals, 476 Zhenbei Road, Shanghai 200062, China
†
‡
‡
3
Abstract:
temperature, high pressure, use of toxic and corrosive
A number of approaches to the synthesis of 2-chloro- and 2,6-
dichloro-4-trifluoromethylpyridine are described. The first
method for 2-chloro- and 2,6-dichloro-4-trifluoromethylpyridine
is based on commercially available ethyl trifluoroacetate. An
alternative access to 2,6-dichloro-4-trifluoromethyl pyridine uses
trifluoroacetaldehyde as starting material. 2-Chloro-4-trifluo-
romethylpyridine is prepared from ethyl(trifluoroacetylvinyl)-
ether in two steps.
hydrogen fluoride, low reactivity, low selectivity, limited
scope and formation of by-products. More convenient and
effective synthetic methods to prepare the trifluoromethylated
pyridine are increasingly required. The use of easily available
trifluoromethylated building blocks has often been found to
be the best choice rather than those direct methods. Thus,
we devised and improved several convenient synthetic
methodologies for 2-chloro- and 2,6-dichloro-4-trifluoro-
methylpyridine from commercially available building blocks
under mild conditions.
Introduction
Results and Discussion
Many trifluoromethylated pyridines, or their derivatives,
have shown remarkable biological activity, and they have
been widely used in a variety of fields ranging from
medicinal to agricultural applications. 2-Chloro- or 2,6-
dichloro-4-trifluoromethylated pyridines are versatile inter-
mediates in the synthesis of biologically active trifluoromethyl-
The first approach to 2-chloro-4-trifluoromethyl-pyridine
(7) and 2,6-dichloro-4-trifluoromethylpyridine (10) starts with
the commercially available ethyl trifluoroacetate (1), which
was based on the suitable use of the dialdehyde 4 as a key
intermediate (Scheme 1). Ethyl trifluoroacetate (1) was
1
reacted with allylmagnesium bromide to form 4-hydroxy-
2
containing compounds. Only a few approaches to the
5
4
-trifluoromethyl-1,6-heptadiene (3) in 92% yield. Ozo-
preparation of trifluoromethylated pyridines have been
2
nolysis of diene 3 and subsequent addition of Me S afforded
3
developed. General procedures reported for the synthesis
dialdehyde 4, which was cyclized in ammonia-saturated
methanol solution to yield 4-trifluoromethylpyridine (5).
Oxidation of pyridine 5 with m-CPBA produced N-oxide 6.
Chlorination of N-oxide 6 with thionyl chloride under reflux
gave the desired 2-chloro-4-trifluoromethylpyridine 7 in 62%
yield. Dialdehyde 4 was further converted into diacid 8 by
oxidation with 30% hydrogen peroxide in formic acid under
reflux. Heating the diacid 8 with urea at 200 °C gave
of chloro-trifluoromethyl pyridine are: (1) by reaction of
3a
methylpyridines with chlorine and HF, (2) reaction of
trichloromethylpyridines with HF in the presence of an
antimony catalyst,3 or (3) Reaction of pyridine carboxylic
acids with MoF
alternative method involves directly introducing a trifluo-
c
3
d
6
at high temperature and pressure. An
4
romethyl group into pyridine by utilizing CF
However, these methods have some drawbacks such as high
3 3
I or CF Cl.
6
pyridinediol 9. Chlorination of pyridinediol 9 with phos-
phorus oxychloride under reflux afforded 2,6-dichloro-4-
trifluoromethylpyridine 10 in 30% yield.
*
Author to whom correspondence may be sent. E-mail: jiangb@pub.sioc.ac.cn.
Fax: +86-21-64166128.
†
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
An alternative route to 2,6-dichloro-4-trifluoromethylpy-
ridine is outlined in Scheme 2. It has been reported that
condensation of trifluoroacetaldehyde with 2 mol of cy-
anoacetamide and subsequent hydrolysis and decarboxylation
Chemistry, Chinese Academy of Sciences.
‡
Engineering Research Center in Organic Synthesis, Chinese Academy of
Sciences, Synica Chemicals
1) (a) Filler, R. Biochemical Aspects of Fluorine Chemistry; Kodansha: Tokyo,
982. (b) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
(
1
7
afforded the diacid 11. Diacid 11 was dehydrated to give
Chemistry; John Wiley & Sons: New York, 1991.
(
2) (a) Cox, J. M.; Gillen, K. J.; Ellis, R. M.; Vohra, S. K.; Smith, S. C.;
Matthews, I. R. WO 9637466, 1996; Chem. Abstr. 1997, 126, 104006. (b)
Toki, T. T.; Tsujii, Y.; Yoshida, K.; Nakamura, Y.; Imai, O.; Kimura, T.
JP 63048268, 1988; Chem. Abstr. 1988, 109, 210902. (c) Fenstermacher,
M. R.; Novoroske, R. L. EP 4434, 1979; Chem. Abstr. 1980, 92, 94255.
3) (a) Nishiyama, R.; Fujikawa, K.; Yokomichi, I.; Tsujii, Y.; Nishimura, S.
EP 42,696, 1981; Chem. Abstr. 1982, 96, 181153. (b) Kaisha, I. S. JP
cyclic anhydride 12. Amination of cyclic anhydride 12 led
to the monoamide of glutaric acid, which on dehydration
8
gave the glutarimide 14. Treatment of the glutarimide 14
with phosphorus pentachloride and phosphorus oxychloride
(
9
gave the 2,6-dichloropyridine 10 in 65% yield.
5
8010569, 1983; Chem. Abstr. 1983, 98, 179229. (c) Fung, A. P.; Wilson,
C. A.; Fujioka, G. S.; Werner, J. A. EP 110,690, 1984; Chem. Abstr. 1984,
01, 171106. (d) Shustov, L. D.; Nikolenko, L. N.; Senchenkova, T. M.
(5) Scallen, T. J.; Morrow, C. J. U.S. Patent 4,169,944, 1979; Chem. Abstr.
1980, 92, 59181.
1
Zh. Obshch. Khim. 1983, 53, 103.
4) (a) Naumann, D.; Wikes, B.; Kischkewitz, J. J. Fluorine Chem. 1985, 30,
(6) Crockett, G. C.; Swanson, B. J.; Anderson, D. R.; Koch, T. H. Synth.
Commun. 1981, 11, 447.
(
7
3. (b) Juergen Kobayashi, Y.; Kumadaki, Y.; Ohsawa, A.; Murakami, S.;
Nakano, T. Chem. Pharm. Bull. 1978, 26, 1247. (c) Maki, Y. JP patent
4079283, 1979; Chem. Abstr 1980, 92, 6416.
(7) Gootjes J.; Nauta, W. T. Recl. TraV. Chim. Pays-Bas 1965, 84, 1183.
(8) Rabjohn, N. Organic Syntheses; John Wiley & Sons: New York, 1963;
Collect. Vol. 4, p 496..
5
1
0.1021/op000109r CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Vol. 5, No. 5, 2001 / Organic Process Research & Development
•
531
Published on Web 06/28/2001

Scheme 1a
Scheme 3a
a
2
Reagents and conditions: (a) ClCH CN, Zn, TMSCl, THF, 3 h; (b) concd
HCl, reflux, 74%; (c) POCl
3
, 3 h, 60%.
1
7 and further cyclization by nucleophilic substitution to
afford 4-trifluoromethyl pyridone 18. Chlorination of the
pyridone 18 resulted in the desired product 7 in good yield
a
Reagents and conditions: (a) Mg, THF, 50 °C, 3 h, 92%; (b) O
/MeOH, reflux, 24 h, 70%; (d) MCPBA,
, reflux, 3 h, 62%; (f) 30% H , HCOOH, 70
, 200 °C, 8 h, 32%; (h) POCl , reflux, 10 h,
3 2 2
, CH Cl /
(Scheme 3).
MeOH, -78 °C, 24 h, 90%; (c) NH
CH Cl , rt, 10 h, 73%; (e) SOCl
C, 10 h, 75%; (g) NH CONH
0%.
3
In conclusion, we have demonstrated a number of novel
2
2
2
2 2
O
3
°
3
2
2
and convenient routes to 2-chloro- or 2,6-dichloro-4-trifluo-
romethylpyridine, which can be readily obtained in multi-
hundred gram quantities. These methods are superior to the
other methods with respect to: ease of preparation, com-
mercial availability of the starting materials, milder condi-
tions, high selectivity, and high yield.
Scheme 2a
Experimental Section
All melting points were measured with a WRS-1A digital
melting point apparatus, without correction. IR spectra were
1
determined with a Shimadzu IR-440 spectrometer.
H
1
3
NMR and C NMR spectra were recorded on a Bruker
AM-300 instrument. The chemical shifts are expressed in
ppm, and coupling constants are given in Hz. Low-resolution
MS spectra were obtained on a VG-Quattro or HP-5969A
spectrometer, and high-resolution MS spectra were recorded
on a Finnigan MAT-95 spectrometer. Elemental analyses
were carried out on a Heraeus Rapid-CHNO instrument.
Column chromatography was performed on silica gel H (10-
40 µm). Reagents purchased commercially were used without
further purification. Solvents were dried using standard
procedures.
a
Reagents and conditions: (a) Cyanacetamide, EtOH, piperidine, reflux, then
O, reflux; (C) NH ‚H O, rt; (d) 220-230 °C, 1.5 h,
, reflux, 10 h, 65%.
2
3
0% HCl, reflux; (b) Ac
0%; (e) POCl , PCl
2
3
2
3
5
Ethyl(trifluoroacetylvinyl)ether 15 is a versatile synthon
for convenient introduction of trifluoromethyl group into
heterocyclic compounds.10 There are several reports on the
use of alkyl(trifluoroacetylvinyl)ethers to synthesize 6-tri-
fluoromethylated pyridines.11 We have found that chloro-
acetonitrile reacts with 15 in tetrahydrofuran as solvent, in
the presence of zinc powder and trimethylchlorosilane, to
produce the â-trimethylsilyloxynitrile 16 accompanied by
the elimination product 17. The mixture of 16 and 17 was
heated at reflux in concentrated HCl to give 4-trifluoro-
methyl-2-pyridone 18 in one pot. We suggest that the mech-
anism of heterocyclization involves Reformatsky reaction to
give intermediate 16, which undergoes elimination to give
4-Hydroxy-4-trifluoromethyl-1,6-heptadiene (3). A mix-
ture of allyl bromide 2 (14.5 g, 120 mmol) and ethyl
trifluoroacetate 1 (7.1 g, 50 mmol) was added dropwise to a
stirred solution of magnesium (2.9 g, 120 mmol) in anhy-
droues THF (50 mL) under N
heated at 50 °C for 3 h. The reaction was quenched with
saturated NH Cl. The product was extracted from the
aqueous layer with ethyl acetate and washed with brine. The
combined organic extracts were dried with Na SO and
2
. The reaction mixture was
4
2
4
concentrated in vacuo. The crude product was distilled in
(
9) Choi, Y. M.; Kucharczyk, N.; Norbert, D. R. J. Labelled Compd.
Radiopharm. 1987, 24 (1), 1.
vacuo to give a colorless oil 3 (8.31 g, 92%); bp 37-39 °C
5
19
1
(
10) (a) Gorbunova, M. G.; Gerus, I. I.; Kukhar, V. P. J. Fluorine Chem. 1993,
(10 mmHg). F NMR (CDCl
3
) δ 2.2 (s, CF
3
). H NMR
65, 25. (b) Gerus, I. I.; Gorbunova, M. G.; Kukhar, V. P. J. Fluorine Chem.
(
(
CDCl
KBr) νmax 3463, 2984, 1643, 1179, 1150 (CF
3
) δ 5.84 (m, 2H), 5.22 (m, 4H), 2.47 (m, 4H). IR
1
994, 69, 195.
-
1
3
) cm . MS
(
11) (a) Brown, S. M.; Bowden, M. C.; Parsons, T. J.; McNeilly, P.; Fraine, P.
J. Org. Process Res. DeV. 1997, 1, 370. (b) Cocco, M. T.; Congiu, C.;
Onnis, V.; Bernard, A. M.; Piras, P. P. J. Heterocycl. Chem. 1996, 33,
+
+
(EI) m/z 180 (M , 1), 163 (M - OH, 11), 91 (47), 69 (CF
0), 41 (100). Anal. Calcd for C O: C, 53.33; H, 6.11.
Found: C, 53.40; H, 6.22.
3
,
9
8 11 3
H F
1
771. (c) Cocco, M. T.; Congiu, C.; Onnis, V. J. Heterocycl. Chem. 1995,
3
2, 543.
532
•
Vol. 5, No. 5, 2001 / Organic Process Research & Development

3
-Hydroxy-3-trifluoromethyl-1,5-pentanedialdehyde (4).
of 11 (4 g, 20 mmol) and acetic anhydride (15 mL) was
refluxed for 14 h. The excess acetic anhydride was removed
in vacuo. Then ammonia water (30 mL) was added and the
mixture stirred at room temperature overnight. The aqueous
layers were exstracted with ethyl acetate (3 × 80 mL). The
combined organic extracts were washed with 1 N HCl (75
3
(8.31 g, 46 mmol) was dissolved in CH Cl and MeOH
2
2
and cooled to -78 °C. Oxygen-containing ozone was passed
through the solution. After 48 h, ozone was no longer
absorbed, and the excess ozone was purged with nitrogen.
The mixture was allowed to warm to room temperature.
Dimethyl sulfide was added and the mixture stirred at room
temperature for 2 h. The solvent and methyl sulfide were
removed in vacuo to afford the crude product 4 (7.6 g, 90%)
which was used directly in the next reaction without
purification.
mL) and brine (2 × 50 mL), dried (anhydrous Na
2 4
SO ), and
concentrated to give a crude reaction mixture which was used
directly in the next reaction without purification. The crude
product was heated at 220-230 °C until water no longer
distilled. The reaction mixture was cooled to ambient
temperature and dissolved in water (10 mL). The solution
was boiled for 30 min with about 0.5 g of charcoal. The
charcoal was removed by filtration. The dry residue was
4-Trifluoromethyl-pyridine (5). 4 (7.6 g, 41.3 mmol)
was added to the saturated ammonia-methanol solution (100
mL). The mixture was refluxed for 24 h. The solvent was
evaporated in vacuo, and the residue was purified with
crystallized from 95% ethanol to give product 14 (1.1 g,
3a 19
19
column chromatography to give 5 (4.25 g, 70%).
F NMR
30%): mp 136-138 °C. F NMR (CDCl
6.6 Hz). H NMR (CDCl
3
) δ -3.4 (d, J )
+
1
(
9
CDCl
7 (22), 78 (19), 57 (100).
-Trifluoromethyl-1-oxo-pyridine (6). A solution of 5
4.25 g, 28.9 mmol) in CH Cl was added m-CPBA (9.36 g,
7.8 mmol), and the mixture was stirred at ambient temper-
ature for 10 h, diluted with CH Cl , and washed with
saturated sodium sulfite, 2N NaOH, and saturated NaCl. It
was dried over NaSO and then concentrated in vacuo. The
residue was purified by column chromatography on silica
3
): δ -13 (s). MS (EI) m/z 147 (M , 3.5), 127 (10),
3
1
) δ 8.60 (brs, 1H), 2.85-3.03 (m,
3
4H), 2.62-2.7 (m, 1H). C NMR (CDCl
3
) δ 169.2, 125.6
4
(q, J ) 276.7 Hz), 35.1 (q, J ) 29.8 Hz), 30.6. IR (KBr) ν
+
(
5
2
2
3202, 3098, 1698, 1130. MS (EI) m/z 181 (M , 12), 138
(23), 69 (8), 42 (100). HRMS (EI) calcd for C
138.02925. Found 138.02948.
5 5 3
H F O
2
2
2,6-Dichloro-4-trifluoromethyl-pyridine (10). Method
1: A mixture of 9 (1.79 g, 10 mmol) and phosphorus
oxychloride (10 mL) was heated to reflux for 10 h. The
excess phosphorus oxychloride was removed by distillation
under reduced pressure. The residue was poured onto ice
4
19
gel to give product 6 (3.42 g, 73%). F NMR (CDCl ): δ
13 (s). MS (EI): m/z 163 (M , 100), 147 (M - O, 7),
44 (M - F, 18), 139 (20), 69 (10).
3
ic Acid (8). To 4 (6 g, 33 mmol) was added 30% hydrogen
peroxide (11.4 mL) and 98% formic acid (23 mL). The
reaction mixture was refluxed overnight. The formic acid
was evaporated in vacuo. The residue was purified by column
chromatography on silica gel to afford 8 (5.3 g, 75%): mp
3
+
+
-
1
+
water and extracted with CH
phase was washed with saturated NaHCO
(15 mL). After drying (Na SO ), concentration in vacuo
2
Cl
2
(3 × 20 mL). The organic
-Hydroxy-3-trifluoromethyl-1,5-pentanedicarboxyl-
3
(10 mL) and brine
2
4
afforded a residue that was purified by flash chromatography
to give the desired 10 (0.65 g, 30%) as a colorless oil.3a
Method 2: A mixture of 14 (5.43 g, 30 mmol) and phos-
phorus oxychloride (30 mL) was heated to reflux for 8 h.
The excess phosphorus oxychloride was removed by distil-
lation under reduced pressure. The residue was poured onto
5
19
1
00-102 °C (lit. mp 102-105 °C). F NMR (CD
3
COCD
) δ 3.11-2.91 (m, 4H).
) δ 207.5, 127.23 (q, J ) 285 Hz),
3.7 (q, J ) 28.5 Hz), 37.15. IR (KBr) νmax 3436, 3065,
3
)
1
δ 5.0 (s, CF
3
). H NMR (CD
3 3
COCD
1
3
C NMR (CD COCD
3
3
ice water and extracted with CH
organic phase was washed with saturated NaHCO
and brine (30 mL). After drying (Na SO ), concentration in
vacuo afforded a residue that was purified by flash chroma-
2
Cl
2
(3 × 50 mL). The
7
1
1
3
(30 mL)
-
1
+
741, 1691, 1168 cm . MS (EI) m/z 217 (M + 1, 21),
99 (M - OH, 50), 181 (69), 129 (63), 69 (CF
100).
2
4
+
3
, 90), 42
1
9
(
tography to give 10 (4.2 g, 65%). F NMR (CDCl
3
) δ -13
1
+
4-Trifluoromethyl-2,6-pyridinediol (9). 8 (3.4 g, 15.7
(s). H NMR (CDCl
3
) δ 7.40 (s, 1H). MS (EI) m/z 215 (M ,
mmol) and urea (1.25 g, 20.8 mmol) was heated at 185 °C
until no more ammonia was evolved. The mixture was
dissolved in ethyl acetate and washed with brine dried over
10), 217 (6), 196 (6), 180 (100), 182 (32), 160 (29), 144
(8), 110 (15).
5-Ethoxy-3-trimethylsilyloxyl-3-trifluoromethyl-4-pen-
tenenitrile (16) and 5-Ethoxy-3-trifluoro-methyl-2,4-pen-
tadienenitrile (17). Trimethylchlorosilane (5.3 mL, 30
mmol) was added to the suspension of zinc powder (2 g, 30
4
NaSO and then concentrated in vacuo. The residue was
purified by column chromatography on silica gel to give
1
9
product 9 (0.9 g, 32%). F NMR (CD
3
OD) δ -13 (s).
+
MS (EI) m/z 179 (M , 19), 160 (4), 151 (13), 136 (100), 67
2
mmol) in anhydrous THF (30 mL) under N . After stirring
(
66).
for 0.5 h, a solution of chloroacetonitrile (1.27 mL, 20 mmol)
and ethyl (trifluoroacetylvinyl)ether (1.68 g, 10 mmol) in
anhydroues THF (15 mL) was added dropwise slowly to keep
the temperature at 40 °C. After stirring at room temperature
for 1.5 h, 2 N HCl (5 mL) was added to adjust pH 3. The
mixture was poured onto ice water. The product was
extracted with EtOAc (3× 50 mL), and the combined extracts
were washed with brine. The organic layer was dried over
4-Trifluoromethyl-2,6-piperidinedione (14). A mixture
of trifluoroacetaldehyde (1.96 g, 20 mmol) and cyanoaceta-
mide (2.8 g, 40 mmol) were refluxed in ethanol (15 mL)
with piperidine as a catalyst for 10 h. Then the ethanol was
removed. Hydrochloric acid (20%, 20 mL) was added. The
reaction mixture was refluxed for 6 h, diluted with ethyl
ether, washed with brine, dried over NaSO
4
, and then
concentrated in vacuo to obtain crude product 11. A mixture
2 4
anhydrous Na SO , filtered, and evaporated to dryness to
Vol. 5, No. 5, 2001 / Organic Process Research & Development
•
533

give a crude reaction mixture of 16 (5.1 g, 61%) and 17
1.4 g, 25%), which were separated by column chromatog-
6.9 Hz, 1H), 6.78 (d, J ) 0.85 Hz, 1H), 7.75 (d, J ) 7.0 Hz,
1H). IR (KBr) νmax 3151 (N-H), 2851, 1664 (CdO), 1621,
1072 (CF ) cm . MS (EI) m/z 163 (M , 100), 144 (M -
3
(
19
-1
+
+
raphy (petroleum ether/EtOAc, 5:1). 16: F NMR (CDCl
3
)
1
δ 3 (s). H NMR (CDCl
3
) δ 6.51 (d, J ) 12.8 Hz, 1H), 4.65
3
F, 12), 135 (83), 116 (99), 85 (25), 69 (CF , 15), 57 (15),
(d, J ) 12.8 Hz, 1H), 3.59 (m, 2H), 2.60 (q, J ) 16.67 Hz,
43 (15).
2
2
H), 1.09 (t, J ) 9.93 Hz, 3H), 0.00 (s, 9H). MS (EI) m/z
82 (M + 1, 1), 241 (62), 212 (10), 197 (42), 142 ((8), 99
2-Chloro-4-trifluoromethyl-pyridine (7). Method 1: A
mixture of 6 (1.5 g, 15.8 mmol) and thionyl chloride (20
mL) was stirred and heated slowly to reflux over a period
of 1.5 h. The solution was then heated under reflux for 1 h.
After evaporation of the excess thionyl chloride, the resi-
+
(100). Anal. Calcd for C11
18 3 2
H F NO Si: C, 46.96; H, 6.45;
1
9
N, 4.98. Found: C, 46.68; H, 6.69; N, 5.31. 17: F NMR
1
(CDCl
3
) δ -13 (s). H NMR (CDCl ) δ 7.26 (d, J ) 12.92
3
Hz, 1H), 5.91 (d, J ) 12.93 Hz, 1H), 5.47 (s, 1H), 4.02 (q,
due was poured onto ice water and extracted with CH
(3 × 50 mL). The organic phase was washed with saturated
NaHCO (20 mL) and brine (30 mL). After drying
(Na SO ), concentration in vacuo afforded a residue that was
purified by flash chromatography to give the desired 7 (1.8
g, 62%) as a colorless oil. Method 2: A mixture of 18 (3
g, 18.4 mmol) and phosphorus oxychloride (30 mL) was
heated to reflux for 3 h. The excess phosphorus oxychloride
was removed by distillation under reduced pressure. The
residue was poured onto ice water and extracted with
2 2
Cl
J ) 7.06 Hz, 2H), 1.37 (t, J ) 6.94 Hz, 3H). MS (EI) m/z
+
1
91 (M , 32), 136 (100), 103 (56), 73 (65). Anal. Calcd for
3
C
H F
8 8 3
NO: C, 50.27; H, 4.22; N, 7.33. Found: C, 50.42;
H, 4.19; N, 7.51.
-Trifluoromethyl-2(1H)-pyridinone (18). Trimethyl-
2
4
3
a
4
chlorosilane (5.3 mL, 30 mmol) was added to the solution
of zinc powder (2 g, 30 mmol) in anhydrous THF (30 mL)
under N . After stirring for 0.5 h, a solution of chloroaceto-
2
nitrile (1.27 mL, 20 mmol) and ethyl(trifluoroacetylvinyl)-
ether (1.68 g, 10 mmol) in anhydrous THF (15 mL) was
added dropwise slowly to keep the temperature at 40 °C.
The mixture was refluxed for 2 h. After the mixture was
cooled to room temperature, concentrated HCl (5 mL) was
added. The mixture was refluxed for 1 h, then cooled to room
temperature, and poured onto ice water. The product was
extracted with EtOAc (3 × 50 mL), and the combined
extracts were washed with brine. The organic layer was dried
CH
saturated NaHCO
(Na SO ), concentration in vacuo afforded a residue that was
purified by flash chromatography to give the desired 7 (2.0
2
Cl
2
(3 × 50 mL). The organic phase was washed with
3
(20 mL) and brine (30 mL). After drying
2
4
1
9
1
g, 60%) as a colorless oil. F NMR -13 (s, CF
(CDCl ) δ 8.61 (d, J ) 5.13 Hz, 1H), 7.58 (s, 1H), 7.47 (d,
J ) 5.08 Hz, 1H). IR (KBr) νmax 1450, 1334, 1146 cm .
3
). H NMR
3
-
1
+
+
3
MS (EI) m/z 181 (M , 3.58), 146 (M - Cl, 100), 69 (CF ,
over anhydrous Na
2 4
SO , filtered, and evaporated to dryness
54), 126 (25).
to give the residue that could be used in the next reaction
without further purification. The residue was purified by col-
Acknowledgment
We are grateful to the Shanghai Municipal Committee
of Science and Technology for financial support.
12 19
umn chromatography to afford 18 (1.2 g, 74%).
F NMR
1
(CDCl
3 3
) δ -13 (s). H NMR (CDCl ) δ 6.49 (dd, J ) 1.6,
(
12) (a) Uekawa, T.; Takemura, S.; Enomoto, M.; Sakaki, M.; Sato, R.; Nagano,
E. EP 488220, 1992; Chem. Abstr. 1993, 118, 80944. (b) Dunn, A. D. J.
Fluorine Chem. 1999, 93, 153.
Received for review November 13, 2000.
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