Synthetic process development and scale up of palladium-catalyzed alkoxycarbonylation of chloropyridines

Article abstract of DOI:10.1021/op010012k

2,3-Dichloropyridines undergo a mono- or a dicarbonylation in the presence of carbon monoxide, an alcohol, and a palladium catalyst, affording selectively either alkyl 3-chloropyridine-2-carboxylates or dialkyl pyridine-2,3-dicarboxylates in good yields, depending on the reaction conditions. For instance, the process could be scaled up for the monoalkoxycarbonylation of 2,3-dichloro-5-(trifluoromethyl)pyridine, affording in high yield and selectivity the corresponding 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate.

Full text of DOI:10.1021/op010012k

Organic Process Research & Development 2001, 5, 572−574
Synthetic Process Development and Scale Up of Palladium-Catalyzed
Alkoxycarbonylation of Chloropyridines
Roger Crettaz, Je´roˆme Waser, and Yves Bessard*
Department of Process Research, LONZA Ltd., P.O. Box CH-3930, Visp, Switzerland
Abstract:
2,3-Dichloropyridines undergo a mono- or a dicarbonylation
in the presence of carbon monoxide, an alcohol, and a palladium
catalyst, affording selectively either alkyl 3-chloropyridine-2-
carboxylates or dialkyl pyridine-2,3-dicarboxylates in good
yields, depending on the reaction conditions. For instance, the
process could be scaled up for the monoalkoxycarbonylation
of 2,3-dichloro-5-(trifluoromethyl)pyridine, affording in high
yield and selectivity the corresponding 3-chloro-5-(trifluoro-
methyl)pyridine-2-carboxylate.
Figure 1.
alkoxycarbonylation of 2,3-dichloro-5-(trifluoromethyl)py-
ridine (4) using previously developed reaction conditions.8
Furthermore, the process could be successfully scaled up
from mmol routine labscale to molar scale.
The Carbonylation Reaction Concept
Palladium-mediated coupling reactions have become
important tools in synthetic organic chemistry.9,10 The
functionalization of aryl molecules with carbon monoxide
to yield carbonyl compounds represents a rapidly growing
area of investigation. Among the carboxylic acid derivatives
accessible by this chemistry, esters are certainly the most
reported in the literature. Primarily this is due to experimental
convenience; the alcohol can be often used as solvent, and
the ester formed is sufficiently stable for isolation and
purification purposes. In general, these transformations are
successful with aryl bromides or iodides.
Nevertheless, this concept has only been seldom applied
to heteroaryl molecules, although the carbonylation of
heterocyclic halides could provide an attractive method for
the synthesis of esters and amides of heterocyclic carboxylic
acids derived from pyridine,11 pyrazine,12 or quinoline.13
However, most procedures reported in recent years used
expensive iodo- or bromoheterocycles14,15 as starting materi-
als. Indeed, only a few examples of alkoxycarbonylation of
chloropyridines can be found in the literature, and the yields
are usually fairly low, and the reaction conditions are
relatively harsh.16-18
Introduction
Chlorinated picolinic acids and pyridine-2,3-dicarboxylic
acids are useful intermediates1-3 to the agrochemical industry
as precursors for herbicides such as 3.4 In continuation of
our program directed to the development of synthetic
methods in heterocyclic chemistry,5 we were interested in
the preparation of esters of pyridinecarboxylic acids of
structure 1 or 2 by alkoxycarbonylation of the dichloropy-
ridine 4 (Figure 1).
We aimed to take advantage of the particular reactivity
of 2-halopyridines in Heck-type reactions6 and speculated
that the presence of a carboxylic group in the 2-position of
a 3-halopyridine could provide sufficient activation7 to allow
for carbonyl insertion into the carbon-halogen bond. Fol-
lowing this reasoning, 2,3-dihalogenopyridines such as 4
could serve as convenient starting materials for the prepara-
tion of either 1 or 2 (Figure 1). We wish to report here the
application of this concept to the efficient preparation of
3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid de-
rivatives 1 and 5-(trifluoromethyl)pyridine-2,3-dicarboxylic
acid derivatives 2, achieved by selective mono- or double-
* Author for correspondence. Telephone: (41) 27 948 5800. Fax: (41) 27
948 6180. E-mail: yves.bessard@lonzagroup.com.
(1) Nishiyama, R.; Fujikawa, K.; Yokomichi, I.; Haga, T.; Koyanagi, T. (Ishihara
Sangyo Kaisha, Ltd.). Eur. Pat. Appl. EP 34917; Chem. Abstr. 1982, 96,
19977.
Results and Discussion
On the basis of knowledge gained from previous findings,8a
the reactivity of a monochloropyridine was first tested at 10
mmol scale with 2-chloro-5-(trifluoromethyl)pyridine (5) to
(2) Nagao, K. (Osaka Soda Co., Ltd.). Eur. Pat. Appl. EP 299362; Chem. Abstr.
1989, 110, 173105.
(3) Hamprecht, G.; Fuchs, E.; Gerber, M.; Walter, H.; Wesphalen, K.-O. (BASF
A.-G.). Ger. Offen. DE 4343923; Chem. Abstr. 1995, 123, 228159.
(4) Brunner, H.-G. (Ciba-Geigy A.-G.). Eur. Pat. Appl. EP 353187; Chem. Abstr.
1990, 113, 40462.
(8) Bessard, Y.; Roduit, J.-P. Tetrahedron 1999, 55, 393. (b) Bessard, Y.;
Crettaz, R. Tetrahedron 1999, 55, 405. (c) Bessard, Y.; Crettaz, R.
Heterocycles 1999, 51, 2589.
(5) Alkoxycarbonylation of 2,3-dichloropyridines: Bessard, Y.; Stucky, G.;
Roduit, J.-P. (Lonza AG.). Eur. Pat. Appl. EP 820987; Chem. Abstr. 1998,
128, 140617. (b) Selective monoalkoxycarbonylation of 2,3-dichloropy-
ridines: Bessard, Y.; Stucky, G.; Roduit, J.-P. (Lonza AG.). Eur. Pat. Appl.
EP 820986; Chem. Abstr. 1998, 128, 154017. (c) Alkoxycarbonylation of
2,6-dichloropyridines: Bessard, Y.; Roduit, J.-P. (Lonza AG.). Eur. Pat.
Appl. EP 864565; Chem. Abstr. 1998, 129, 216519.
(9) For a review of carbonylations, see: Colquhoun, D. M.; Thompson, D. J.;
Twigg; M. V. Carbonylation, Direct Synthesis of Carbonyl Compounds;
Plenum Press: New York, 1991.
(10) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W. J. Mol. Catal.
1995, 104, 17.
(11) Murata, N.; Sugihara, T.; Kondo, Y.; Sakamoto, T. Synlett 1997, 298.
(12) Takeuchi, R.; Suzuki, K.; Sato, N. Synthesis 1990, 923.
(13) Ciufolini, M. A.; Mitchell, J. W.; Roschangar, F. Tetrahedron Lett. 1996,
37, 8281.
(6) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318.
(7) Takeuchi, R.; Suzuki, K.; Sato, N. J. Mol. Catal. 1991, 66, 277.
572
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10.1021/op010012k CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 11/16/2001

Scheme 2
Table 1. Effect of temperature on the carbonylation reactiona
entry
reaction conditionsb
ligand/catalyst
4 [%]
1a [%]
2a [%]
yieldc [%]
1
2
3
4
5
120 °C/2 h
80 °C/2 h
100 °C/2 h
80 °C/5 h
150 °C/2 h
dppb/PdCl2(Ph3P)2
dppf/Pd(II)Ac
dppf/Pd(II)Ac
dppf/Pd(II)Ac
dppf/Pd(II)Ac
59
32
-
32
68
97
99
-
9
-
-
-
3
-
92 (1a)
92 (2a)
-
1
>99
-
a The values reported correspond to relative GC (crude reaction mixture) integration results. b Reaction conditions:
3
mol
%
of ligand (dppf: 1,1′-
bis(diphenylphosphino)ferrocene; dppb: 1,4-bis(diphenylphosphino)butane) and 0.5 mol % of catalyst (Pd(II)Ac: palladium acetate); ethanol; 15 atm CO. The temperature
given is the bath temperature (internal temperature is ∼15 °C less). c Isolated yield after flash chromatography.
set up the preliminary reaction conditions. The reaction was
carried out in ethanol under 15 atm of carbon monoxide, in
the presence of palladium acetate (0.5 mol %) and 1,1′-bis-
(diphenylphosphino)ferrocene (3 mol %) using sodium
acetate as a base (2 equiv) (Scheme 1).
monoxide, in the presence of palladium acetate (0.5 mol %)
and 1,1′-bis(diphenylphosphino)ferrocene (3 mol %) using
sodium acetate as a base (2 equiv). Table 1 shows a summary
of reaction conditions and the corresponding results.
Using these reaction conditions, ethyl 3-chloro-5-(tri-
fluoromethyl)pyridine-2-carboxylate (1a) was then prepared
on a 0.5 mol scale by alkoxycarbonylation of 2,3-dichloro-
5-(trifluoromethyl)pyridine (4). To test its robustness, the
process was repeated three times, and in each case GC
analysis of the reaction mixture showed complete conversion
of the starting material 4 after 5 h at 80 °C. Very good
selectivity was also obtained, with only 1% of diethyl
5-(trifluoromethyl)pyridine-2,3-dicarboxylate (2a) present in
the reaction mixture. After filtration of insoluble salts, ethyl
3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate was iso-
lated with 94% yield by high vacuum distillation (see
Experimental Section).
Scheme 1
GC analysis of the reaction mixture showed that the
conversion was complete in 2 h at 100 °C. Following
isolation and chromatographic purification, ethyl 5-(trifluo-
romethyl)-pyridine-2-carboxylate (6a) was obtained in 93%
yield.
In the case of 2,3-dichloro-5-(trifluoromethyl)pyridine (4),
both the mono- and the dicarboxylate could be expected
(Scheme 2). The carbonylation occurring first at the
2-position,8a the selectivity could be directed by controlling
the temperature and the reaction time.
Even at relatively low temperature, the dichloropyridine
4 was totally transformed to the monocarboxylate 1a.
Selectivity was also high since less than 1% of dicarboxylate
2a could be detected by GC analysis. Indeed, after 5 h at 80
°C, ethyl 3-chloro-5-(trifluoromethyl)-pyridine-2-carboxylate
(1a) could be isolated in 92% yield after flash chromatog-
raphy. Logically, a higher temperature was necessary for the
exclusive formation of the dicarboxylate 2a. In this case,
after 2 h at 150 °C, diethyl 5-(trifluoromethyl)pyridine-2,3-
dicarboxylate (2a) could be isolated by flash chromatography
also in 92% yield. In both cases, the reaction was carried
out on a 10 mmol scale in ethanol under 15 atm of carbon
Conclusions
A process has been developed to prepare pyridine mono-
and dicarboxylates by alkoxycarbonylation of 2,3-dichloro-
pyridines. The process was scaled up from 10 mmol (routine
laboratory experiments) to 0.5 mol, affording ethyl 3-chloro-
5-(trifluoromethyl)pyridine-2-carboxylate with high selec-
tively and yield.
Experimental Section
General Procedures. Reagents and solvents were reagent
grade and used as received. All reactions were conducted
under nitrogen. Melting points were determined on a Bu¨chi
1
535 apparatus and have not been corrected. H NMR (400
MHz) spectra were recorded on a VARIAN spectrometer.
Chemical shifts are reported as parts per million relative to
tetramethylsilane. Coupling constants (J) are given in hertz.
Alkoxycarbonylation of 2-Chloro-5-(trifluoromethyl)-
pyridine (5). Synthesis of Ethyl 5-(trifluoromethyl)-
pyridine-2-carboxylate (6a). The reaction was carried out
in a 100-mL stainless steel autoclave equipped with a
magnetic stirring bar. The reagents were charged into a
Teflon liner in the following order: ethanol (20 mL), sodium
acetate (1.70 g, 20 mmol), 2-chloro-5-(trifluoromethyl)-
(14) Chambers, R. J.; Marfat, A. Synth. Commun. 1997, 27, 515.
(15) Heck, R. F. (University of Delaware). U.S. Patent 4,128,554; Chem. Abstr.
1979, 90, 103676.
(16) Kudo, M. Shokubai (catalysts) 1994, 36, 580.
(17) Zhang, T. Y.; Scriven, E. F. V. (Reilly Industries, Inc.). Int. Pat. Appl. WO
93/18005; Chem. Abstr. 1994, 120, 106784.
(18) Suto, K.; Kudo, M.; Yamamoto, M. (Nihon Nohyaku CO., Ltd.). Eur. Pat.
Appl. EP 282266; Chem. Abstr. 1989, 111, 133974.
Vol. 5, No. 6, 2001 / Organic Process Research & Development
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573

pyridine (5) (1.80 g [97 area %], 10 mmol), 1,1′-bis-
(diphenylphosphino)ferrocene (166 mg, 0.30 mmol [3 mol
%]), and palladium acetate (12 mg, 0.05 mmol [0.5 mol %]).
The air in the autoclave was replaced with carbon monoxide
and the pressure adjusted to 15 atm. The reaction mixture
was then heated to 100 °C (jacket temperature), and the
reaction was carried out with stirring. After 2 h, the reaction
mixture was cooled to room temperature and filtered through
Celite. GC analysis indicated that the mixture consisted of
>99 area % of 6a. The mixture was concentrated under
vacuum, and the product was isolated by flash chromatog-
raphy on silica gel eluting with ethyl acetate/hexane (1:4)
affording 2.04 g (>99% GC area %) of 6a (93%). At higher
scale (>50 mmol scale), after filtration through Celite, the
mixture was concentrated under vacuum and the product was
isolated by high vacuum distillation (bp 50 °C/0.1 mmHg,
sublimation).
(20 mL), sodium acetate (1.70 g, 20 mmol), 2,3-dichloro-
5-(trifluoromethyl)pyridine (4) (2.16 g [97 area %], 10
mmol), 1,1′-bis(diphenylphosphino)ferrocene (166 mg, 0.30
mmol [3 mol %]), and palladium acetate (12 mg, 0.05 mmol
[0.5 mol %]). The air in the autoclave was replaced with
carbon monoxide and the pressure adjusted to 15 atm. The
reaction mixture was then heated to 80 °C (jacket temper-
ature), and the reaction was carried out with stirring. After
5 h, the reaction mixture was cooled to room temperature
and filtered through Celite. GC analysis indicated that the
mixture consisted of 98 area % of 1a. The mixture was
concentrated under vacuum, and the product was isolated
by flash chromatography on silica gel eluting with ethyl
acetate/hexane (1:4) affording 2.34 g (>99% GC area %)
of 1a (92%). At higher scale (>50 mmol scale), after
filtration through Celite, the mixture was concentrated under
vacuum and the product was isolated by high-vacuum
distillation (bp 50 °C/0.02 mmHg).
C9H8F3NO2 [219.17]. Appearance: white solid, mp 45-
48 °C.
C9H7ClF3NO2 [253.61]. Appearance: colourless oil.
1H NMR (CDCl3): δ 8.82 (1H, s); 8.06 (1H, s); 4.52 (2H,
q, J ) 7.1); 1.45 (3H, t, J ) 7.1).
1H NMR (CDCl3): δ 9.01 (1H, s); 8.27 (1H, d, J ) 8.1);
8.10 (1H, dd, J ) 8.1, 2.3); 4.52 (2H, q, J ) 7.1); 1.45 (3H,
t, J ) 7.1).
GC/MS (m/e): 254; 253 (M+); 234; 208; 181.
Large-Scale Synthesis of Ethyl 3-Chloro-5-(trifluo-
romethyl)pyridine-2-carboxylate (1a). The reaction was
carried out in a 2000-mL stainless steel autoclave (Bu¨chi
BEP, max pressure 100 atm, max temp 250 °C) equipped
with a mechanical stirrer. The reagents were charged in the
following order: ethanol (600 mL), anhydrous sodium acetate
(75.5 g, 920 mmol), 2,3-dichloro-5-(trifluoromethyl)pyridine
(4) (100.0 g [97 area %], 449 mmol), 1,1′-bis(diphenylphos-
phino)ferrocene (7.4 g, 13.3 mmol [3 mol %]), and palladium
acetate (530 mg, 2.4 mmol [0.5 mol %]). The air in the
autoclave was replaced with carbon monoxide and the
pressure adjusted to 15 atm. The reaction mixture was then
heated to 80 °C (jacket temperature), and the reaction was
carried out with stirring. After 5 h, the reaction mixture was
cooled to room temperature and filtered through Celite. GC
analysis indicated that the mixture consisted of 99 area %
of 1a and 1 area % of 2a. The mixture was concentrated
under vacuum to about 120 g of crude material.
The reaction was repeated two more times in the same
conditions giving always the same mixture of 99% of 1a
and 1% of 2a.
The concentrated reaction mixtures of the three experi-
ments were then together distilled under vacuum (68-70
°C/0.05 mmHg) affording, as a main fraction, 331.9 g of
3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (1a, 94%
yield, based on the three experiments) with a purity of 99.6%
(GC area %).
GC/MS (m/e): 219 (M+); 200; 175; 147; 126.
Bis-alkoxycarbonylation of 2,3-Dichloro-5-(trifluoro-
methyl)pyridine (4). Synthesis of Diethyl 5-(trifluoro-
methyl)pyridine-2,3-dicarboxylate (2a). The reaction was
carried out in a 100-mL stainless steel autoclave equipped
with a magnetic stirring bar. The reagents were charged into
a Teflon liner in the following order: ethanol (20 mL),
sodium acetate (1.70 g, 20 mmol), 2,3-dichloro-5-(trifluo-
romethyl)pyridine (4) (2.16 g [97 area %], 10 mmol), 1,1′-
bis(diphenylphosphino)ferrocene (166 mg, 0.30 mmol [3 mol
%]), and palladium acetate (12 mg, 0.05 mmol [0.5 mol %]).
The air in the autoclave was replaced with carbon monoxide
and the pressure adjusted to 15 atm. The reaction mixture
was then heated to 150 °C (jacket temperature), and the
reaction was carried out with stirring. After 2 h, the reaction
mixture was cooled to room temperature and filtered through
Celite. GC analysis indicated that the mixture consisted of
>99 area % of 2a. The mixture was concentrated under
vacuum, and the product was isolated by flash chromatog-
raphy on silica gel eluting with ethyl acetate/hexane (1:4)
affording 2.68 g (>99% GC area %) of 2a (92%). At higher
scale (>50 mmol scale), after filtration through Celite, the
mixture was concentrated under vacuum, and the product
was isolated by high-vacuum distillation (bp 80 °C/0.02
mmHg).
C12H12F3NO4 [291.23]. Appearance: colourless oil.
1H NMR (CDCl3): δ 9.00 (1H, s); 8.47 (1H, s); 4.50 (2H,
q, J ) 7.1); 4.42 (2H, q, J ) 7.1); 1.43 (3H, t, J ) 7.1);
1.40 (3H, t, J ) 7.1).
Acknowledgment
We thank our colleagues in the Chemical Research and
Development department for their support and especially Dr.
D. Michel as well as Dr. G. Paddon-Jones for their valuable
advice during the preparation of this manuscript.
GC/MS (m/e): 292; 291 (M+); 246; 218; 174; 147.
Mono-alkoxycarbonylation of 2,3-Dichloro-5-(trifluo-
romethyl)pyridine (4). Synthesis of Ethyl 3-chloro-5-
(trifluoromethyl)pyridine-2-carboxylate (1a). The reaction
was carried out in a 100-mL stainless steel autoclave
equipped with a magnetic stirring bar. The reagents were
charged into a Teflon liner in the following order: ethanol
Received for review February 6, 2001.
OP010012K
574
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Vol. 5, No. 6, 2001 / Organic Process Research & Development