Efficient synthesis of 6-aryl-2-chloronicotinic acids via Pd catalyzed regioselective suzuki coupling of 2,6-dichloronicotinic acid

Article abstract of DOI:10.1002/jhet.5570450646

(Chemical Equation Presented) A regioselective Suzuki coupling of 2,6-dichloronicotinic acid with aryl boronic acids to synthesize 6-aryl-2-chloronicotinic acids is described. Regioselectivity was achieved in aqueous dioxane using the routinely used catalyst Pd(PPh₃) ₄.

Full text of DOI:10.1002/jhet.5570450646

Nov-Dec 2008
1847
Efficient Synthesis of 6-Aryl-2-chloronicotinic Acids via Pd
Catalyzed Regioselective Suzuki Coupling
of 2,6-Dichloronicotinic Acid
Mingliang Ma [a], Chengwei Li[a], Xiaoyan Li [a], Ke Wen [a]*, Yahu A. Liu [b]
[a] Key Laboratory of Brain Functional Genomics, MOE & STCSM, Shanghai Institute of Brain Functional
Genomics, East China Normal University, Shanghai 200062, China
[b] Medicinal Chemistry, ChemBridge Research Laboratories, Inc., San Diego, CA 92127, USA
Received November 14, 2007
Pd(PPh )
3 4
O
Na CO
O
2
3
OH
B
H O
2
+
OH
OH
dioxane
Ar
OH
o
100 C, 16 h
Cl
N
Cl
Ar
N
Cl
1
2
3
A regioselective Suzuki coupling of 2,6-dichloronicotinic acid with aryl boronic acids to synthesize 6-
aryl-2-chloronicotinic acids is described. Regioselectivity was achieved in aqueous dioxane using the
routinely used catalyst Pd(PPh3)4.
J. Heterocyclic Chem., 45, 1847 (2008).
INTRODUCTION
substitution of the chlorine atoms of 2,6-dichloronicotinic
acid derivatives with aryl groups via the Suzuki coupling
reaction [5]. In this report [5], Yang et al. focused on the
selective introduction of aryl groups at position 2 of
2,6-dichloronicotinamide as well as methyl 2,6-dichloro-
nicotinate by employing a special Pd catalyst (PXPd2).
Regioselectivity at position 2 over position 6 was achieved
with best ratio of 9 to 1 in the case of an amide and 2.5 to 1
in the case of methyl ester. Yang et al also found that the
ratio of 6-phenyl product to 2-phenyl product of Suzuki
reaction of phenyl boronic acid with methyl
dichloronicotinate has been between 1:1.7 and 5:1 with
using broadly diversified Pd catalysts. At the beginning of
our study, we tried to explore region-selective Suzuki
coupling on methyl 2,6-dichloro-nicotinate. There was not
much success in finding reaction conditions with decent
regioselectivity. Considering the difficulties we
encountered and what was reported by Yang et al., we
believed that it would not be feasible to achieve good
selectivity by playing different catalysts, bases or solvents.
We were inclined to explore a different approach to
improve selectivity. Because there was no report about
introduction of aryl group to the simplest substrate in the
series, 2,6-dichloronicotinic acid, we decided to carry out
the Suzuki reaction on 2,6-dichloronicotinic acid under one
of the most commonly employed conditions. Actually,
according to Yang and co-workers, the best selectivity of 6-
phenyl product over 2-phenyl product was 5 to 1 when the
reaction was conducted in THF with using Pd(PPh3)4 as
catalyst and K2CO3 as base [5]. In our study, Suzuki
coupling of arylboronic acids with 2,6-dichloronicotinic
Pyridine derivatives appear as important motifs in
biological active compounds as well as therapeutic agents
[1]. 2,6-Dichloronicotinic acid and its derivatives are
readily accessible and can serve as useful starting
materials in the preparation of pyridino-containing
biologically active small molecules [2]. Selectively
replacing one of the two chloride atoms at the 2- or
6-position of these compounds by different functional
groups will lead to access of a pool of diversified
pyridines [3]. Although progress has been made on the
selective substitution of the 2- or 6-chloro atoms of the
2,6-dichloronicotinic acid and its derivatives by alkoxy
and amino groups via nucleophilic SNAr reaction, there
are very rare examples of selective substitution of the
chloride atoms by aryl groups. Herein we report a method
of selective substitution of 6-Cl of 2,6-dichloronicotinic
acid.
RESULTS AND DISCUSSION
During the course of our medicinal chemistry research,
we encountered a need for introducing aryl group at the
position 6 of 2,6-dichloronicotinic acid, its ester and amide
derivatives. The only one example of such reactions (a
patent) is
a
substitution of 6-Cl of ethyl 2,6-
dichloronicotinate with a phenyl group via the Suzuki
coupling reaction [4]. The Suzuki reaction conducted in
DME by employing Pd(PPh3)4 as catalyst afforded the
6-phenyl product in 34% yield with a 6:1 ratio of the
6-phenyl product to the 2,6-diphenyl product. Besides this
patent, there is only one literature report on the selective

1848
M. Ma, C. Li, X. Li, K. Wen and Y. A. Liu
Vol 45
Table 1
6-Aryl-2-chloronicotinic acids (3) from Regioselective Suzuki Coupling
of 2,6-dichloronicotinic acid with aryl boronic acids (2).
3
Ar
Yield [a]
%
1H NMR (CDCl3)
ESI-MS
m/z (MH+)
Molecular
Formula
Analysis % [b]
ꢀ
Calcd./Found
C
H
N
3a
3b
phenyl
81
72
7.49-7.53 (3H), 7.92 (d, J = 8.1 Hz,
1H), 8.09 (m, 2H), 8.28 (d, J = 8.1 Hz,
1H)
2.31 (s, 3H), 2.34 (s, 3H), 7.20 (d, J =
10.3 Hz, 1H), 7.73 (m, 1H), 7.83 (d, J
= 8.1Hz, 1H), 7.85 (s, 1H), 8.25 (d, J
= 8.1 Hz, 1H)
234
262
C12H8ClNO2
C14H12ClNO2
61.69
61.94
3.45
3.46
5.99
5.97
3,4-dimethylphenyl
64.25
64.45
4.62
4.64
5.35
5.33
3c
3-chlorophenyl
69
79
7.42-7.49 (2H), 7.95 (d, J = 8.1 Hz,
1H), 8.01 (m, 1H), 8.12 (s, 1H), 8.32
(d, J = 8.1 Hz, 1H)
3.88 (s, 3H), 7.05 (m, 1H), 7.41 (m,
1H), 7.63 (m, 1H), 7.64 (s, 1H), 7.91
(d, J = 8.1 Hz, 1H), 8.30 (d, J = 8.1
Hz, 1H)
268
264
C12H7Cl2NO2
C13H10ClNO3
53.76
53.87
2.63
2.63
5.22
5.21
3d
3-methoxyphenyl
59.22
59.38
3.82
3.83
5.31
5.29
3e
3f
4-fluoro-2-
methoxyphenyl
65
78
63
70
3.90 (s, 3H), 6.83 (m, 1H), 6.95 (m,
1H), 7.90 (m, 1H), 7.97 (d, J = 8.1 Hz,
1H), 8.25 (d, J = 8.1 Hz, 1H)
3.75 (s, 3H), 3.91 (s, 3H), 7.18-7.20
(2H), 7.13 (m, 1H), 7.89 (d, J = 8.1
Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H)
4.04 (s, 3H), 7.37 (m, 1H), 7.63 (m,
1H), 8.21 (d, J = 8.0 Hz, 1H), 8.52 (d,
J = 8.0 Hz, 1H)
7.53-7.57 (2H), 7.89 (m, 1H), 7.94-
8.02 (2H), 8.06 (d, J = 8.1 Hz, 1H),
8.18 (dd, J = 8.7 and 1.8 Hz, 1H), 8.33
(d, J = 8.1 Hz, 1H), 8.61 (s, 1H)
282
294
300
284
C13H9ClFNO3
C14H12ClNO4
C13H8ClF2NO3
C16H10ClNO2
55.43
55.62
3.22
3.24
4.97
4.95
2,3-
dimethoxylphenyl
57.25
57.36
4.12
4.14
4.77
4.74
3g
3h
3,5-difluoro-2-
methoxyphenyl
52.11
52.31
2.69
2.72
4.67
4.65
2-naphthalenyl
67.74
67.85
3.55
3.57
4.94
4.92
[a] Calculated on the basis of the re-crystallized solid products. [b] Performed with re-crystallized solid products.
1H) and ~8.3 ppm (d, J = 8.1 Hz, 1H) which stand for two
protons H4 and H5 of the pyridine core [5]. Because there
is no reported NMR data for acid 3a, we transformed 3a
into the methyl ester 4a in order to do a direct comparison
of 4a’s NMR data to the reported ones. Therefore, methyl
ester 4a was made from 3a by refluxing in MeOH in the
presence of H2SO4 (Scheme 2). The chemical shifts
observed in the H1 NMR spectrum of compound 4a was
found to be identical with what was reported [5].
acid was conducted in the common solvent dioxane
together with water. Inexpensive Na2CO3 was used as the
base and the catalyst was the most commonly used
Pd(PPh3)4. To our delight, only the desired 6-aryl
regioisomers were obtained as exclusive products (Scheme
1). Eight arylboronic acids were examined and the results
are listed in Table 1. The yields of the reactions are from
good to excellent. All products were pure enough for
further coupling reactions with amines to make amides or
for esterification. They could also be crystallized easily
from a mixed solvent of EtOAc and methanol if special
purity is required.
Scheme 2
O
O
H2SO4
MeOH
OH
O
Scheme 1
N
Cl
N
Cl
refluxing, 6 h
Pd(PPh3)4
O
Na2CO3
H2O
dioxane
O
OH
B
3a
4a
OH
+
OH
Ar
OH
100 oC, 16 h
Cl
Ar
N
Cl
N
Cl
1
Although the structural elucidation based on H NMR
of 4a was persuasive, unambiguous evidence for such
assignment was still needed. Hence, single crystals of 3a
with X-ray diffraction quality were grown by slow
evaporation from a mixed solvent of EtOAc and MeOH.
1
2
3
The structural assignment was clearly supported by
1
chemical shifts in H NMR of ~7.9 ppm (d, J = 8.1 Hz,

Nov-Dec 2008
M. Ma, C. Li, X. Li, K. Wen and Y. A. Liu
1849
washed with brine (10 mL), dried over Na2SO4 and
evaporated to afford 3b (220.8 mg, 84%). Compound 3b was
crystallized in mixed solvent of EtOAc /MeOH (5:1) to result in
crystalline solid (198 mg, 72%).
As expected, the single-crystal structure of 3a clearly
shows the phenyl group at position 6 of this compound
(Figure 1).
Esterification of 3a into methyl 2-chloro-6-phenyl-
nicotinate (4a). To solution of 2-chloro-6-phenylnicotinic acid
(3a) (58.4 mg, 0.25 mmol) in methanol (50 mL) was added
concentrated sulfuric acid (98%, 0.2 mL) resulting in a mixture
which was refluxed for 6 h and then concentrated. The residue
was partitioned between aqueous Na2CO3 solution (80 mL) and
EtOAc (40 mL) and the aqueous phase was extracted with
EtOAc (3 ꢀ 20 mL). The combined organic extracts were
washed with brine (10 mL) and dried over Na2SO4, evaporated
1
to afford 4a (37.8 mg, 61%). H NMR (CDCl3) ꢀ 3.97 (s, 1H),
7.47-7.53 (3H), 7.73 (d, J = 8.1 Hz, 1H), 8.04-8.07 (2H), 8.24
(d, J = 8.1 Hz, 1H); ESI-MS m/z 248 (MH+).
Acknowledgement. This work was supported by grants from
Shanghai Commission for Science and Technology (06Pj14034,
06DZ19002), Ministry of Education (106078), and Ministry of
Science and Technology of China (973 Project,
2003CB716600).
Figure 1. Crystal structure of 2-chloro-6-phenyl-nicotinic acid (3a).
In summary, we have described a simple regioselective
method for generation of 6-aryl-2-chloro-nicotinic acids
starting from commercially available 2,6-dichloro
nicotinic acid and arylboronic acids under Suzuki
coupling condition catalyzed by Pd(PPh3)4. This method
could be easily adapted in the synthesis of 6-aryl
substituted nicotinic acids, from which their amide or
ester derivatives could be readily made.
REFERENCES AND NOTES
[1a] Lukevits, E. Chem. Heterocyclic Compd. 1995, 31, 639-650.
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Ed.; Academic Press: New York, 1987; Vol 31. [f] Micetich, R. G.
Pyridine and Its Derivatives: Supplement; Abramovitch, R.A. Ed.; John
Wiley and Sons: New York, 1974.
EXPERIMENTAL
[2a] Dropinski, J. F.; Akiyama, T.; Einstein, M.; Habulihaz,
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1
General Remarks. H NMR spectra were recorded on a 300
MHz Bruker spectrometer and are reported in ppm. 2,6-
Dichloronicotinic acid (97%) was obtained from Aldrich. All
other commercially available solvents and reagents were used
without further purification. Brine refers to a saturated aqueous
sodium chloride solution. Solvent removal was accomplished by
a rotary evaporator operating at vacuum (40-50 Torr).
Representative Procedure: 6-(3,4-Dimethylphenyl)-2-
chloronicotinic acid (3b). A mixture of 2,6-dichloronicotinic
acid (1) (198 mg, 97%, 1 mmol), 3,4-dimethylphenylboronic
acid (2) (178.8 mg, 1.2 mmol), Pd(PPh3)4 (53 mg, 0.05 mmol)
and Na2CO3 (318 mg, 3 mol) in a mixed solvent of dioxane (15
mL) and H2O (5 mL) was purged with N2 and heated at 100 °C
for 16 h. After cooling to room temperature, the reaction mixture
was poured into Na2CO3 solution (10%, 100 mL) and the
aqueous phase was washed with EtOAc (2 ꢀ 20 mL), acidified
to pH = 1 with concentrated HCl (12 N) and extracted with
EtOAc (3 ꢀ 30 mL). The organic extracts were combined,
[5] Yang, W.; Wang, Y.; Corte, J. R. Org. Lett. 2003, 5,
3131.