Synthesis of 2,6-diaryl-3-(trifluoromethyl)pyridines by regioselective Suzuki-Miyaura reactions of 2,6-dichloro-3-(trifluoromethyl)pyridine

Article abstract of DOI:10.1016/j.tetlet.2013.01.031

The Suzuki-Miyaura reaction of 2,6-dichloro-3-(trifluoromethyl)pyridine with 1 equiv of arylboronic acids resulted in site-selective formation of 2-aryl-6-chloro-3-(trifluoromethyl)pyridine. Due to electronic reasons, the reaction takes place at the steri

Full text of DOI:10.1016/j.tetlet.2013.01.031

Tetrahedron Letters 54 (2013) 1669–1672
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Synthesis of 2,6-diaryl-3-(trifluoromethyl)pyridines by regioselective
Suzuki–Miyaura reactions of 2,6-dichloro-3-(trifluoromethyl)pyridine
Shahzad Ahmed a,b, Muhammad Sharif a,b,c, , Khurram Shoaib a,b, Sebastian Reimann a,c, Jamshed Iqbal d,
⇑
Tamás Patonay e, Anke Spannenberg c, Peter Langer a,c,
⇑
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, Pakistan
c Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
d Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan
e Department of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The Suzuki–Miyaura reaction of 2,6-dichloro-3-(trifluoromethyl)pyridine with 1 equiv of arylboronic
acids resulted in site-selective formation of 2-aryl-6-chloro-3-(trifluoromethyl)pyridine. Due to elec-
tronic reasons, the reaction takes place at the sterically more hindered position. The one-pot reaction
with two different arylboronic acids afforded 2,6-diaryl-3-(trifluoromethyl)pyridine containing two dif-
ferent aryl substituents. The reactions proceeded smoothly in the absence of phosphane ligands.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 December 2012
Revised 5 January 2013
Accepted 8 January 2013
Available online 16 January 2013
Keywords:
Catalysis
Suzuki–Miyaura reaction
Regioselectivity
Palladium
Organofluorine compounds
Highly-functionalized pyridines, including aryl and heteroaryl
substituted derivatives, are widespread in pharmaceutical and
agrochemical chemistry.1 On the other hand, fluorinated and
trifluoromethylated heterocycles are also of great importance in
medicinal chemistry, due to the metabolic stability of the C–F
bond and the considerable lipophilicity and bioavailability of
fluorinated heterocycles.2 Trifluoromethylated pyridines are of
special relevance in medicinal and agricultural chemistry. For
example, 2,6-diaryl-4-trifluoromethyl-pyridines represent prom-
ising mGluR2 antagonists3 and anti-cancer agents.4 Picoxystrobin,
a 2-trifluoromethylpyridine derivative developed by DuPont, is a
widely used fungicide.
Classical syntheses of pyridines are based on formal [5+1]
cyclocondensations of 1,5-dicarbonyl compounds with ammonia
or related nitrogen sources,5 on the Diels–Alder reaction of dieno-
philes with azines,6 and on the cyclocondensation of enamine
derivatives with dielectrophiles.7 Pyridines are also available by
transition-metal catalyzed reactions, such as gold-catalyzed reac-
tions of propargyl vinyl ethers,8 b-ketoesters and propargylam-
ines,9 and [4+2] or [2+2+2] cycloadditions of alkynes, dienes, or
nitriles.10 Suzuki or Sonogashira reactions have also been widely
used.11 Despite the utility of these methods, the synthesis of tri-
fluoromethyl substituted pyridines is still a challenging task. The
trifluoromethylation of heterocycles can be carried out by Pd- or
Cu-catalyzed reactions with Me3SiCF3.12 Other methods for the
synthesis of trifluoromethyl substituted pyridines include oxida-
tive C–H trifluoromethylation,13 photoredox catalyzed reactions,14
and rhenium-catalyzed trifluoromethylations using hypervalent
iodine derivatives.15 4-Trifluoromethylpyridines are also available
by multi-step syntheses using ethyl trifluoroacetate as a building
block.16
In recent years, site-selective Suzuki–Miyaura reactions17 of
polyhalogenated heterocycles have been studied.18 Recently, we
reported Suzuki–Miyaura reactions of 2,4-dichloro-1-(trifluoro-
methyl)-benzene and 1,4-dibromo-2-trifluoromethyl-benzene.19
The reactions proceeded with very good site-selectivity at the
sterically less hindered position. Herein, we report what are, to
the best of our knowledge, the first Suzuki–Miyaura reactions of
2,6-dichloro-3-(trifluoromethyl)pyridine.20 These reactions, which
proceed smoothly in the absence of phosphane ligands, allow for a
site-selective synthesis of various arylated 3-trifluoromethylpyri-
dines which are not readily available by other methods.
The Suzuki–Miyaura reaction of commercially available
2,6-dichloro-3-(trifluoromethyl)pyridine (1) with arylboronic acids
2a–n (0.9 equiv) afforded the 6-chloro-2-phenyl-3-(trifluoro-
methyl)pyridines 3a–n in moderate to good yields and with very
⇑
Corresponding authors.
E-mail address: Peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.031

1670
S. Ahmed et al. / Tetrahedron Letters 54 (2013) 1669–1672
ArB(OH)2
2a-n
ArB(OH)2
2a-f
CF3
Cl
CF3
Cl
CF3
CF3
Ar
i
i
Cl
N
Cl
N
Cl
N
Ar
Ar
N
3a-n
4a-f
1
1
Scheme 1. Synthesis of 3a–n. Conditions: (i), 1 (1.0 equiv), 2a–n (0.9 equiv), K3PO4
(1.5 equiv), Pd(OAc)2 (2 mol %), H2O/DMF (1:1), 20 °C, 12 h.
Scheme 2. Synthesis of 4a–f. Conditions: (i), 1 (1.0 equiv), 2a–f (2.2 equiv), K3PO4
(2.5 equiv), Pd(OAc)2 (2 mol %), H2O/DMF (1:1), 20 °C, 12–16 h.
Table 1
Table 2
Synthesis of 3a–n
Synthesis of 4a–f
2,3
Ar
3a (%)
2
4
Ar
4a (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
C6H5
87
92
69
65
78
72
78
82
61
68
71
65
63
71
b
c
d
a
i
a
b
c
d
e
f
4-MeC6H4
4-(Acetyl)C6H4
4-(F3CO)C6H4
C6H5
4-(MeO)C6H4
4-EtC6H4
70
68
58
68
63
76
4-MeC6H4
4-(Acetyl)C6H4
4-(F3CO)C6H4
3,5-Me2C6H3
4-EtC6H4
4-(EtO)C6H4
4-tBuC6H4
4-(MeO)C6H4
4-FC6H4
f
a
Yields of isolated products.
3-MeC6H4
2-Thienyl
4-PhC6H4
1) Ar1B(OH)2
CF3
Ar1
CF3
2) Ar2B(OH)2
3,5-(F3C)2C6H3
Ar2
N
i
a
Cl
N
Cl
Yields of isolated products.
5a-
1
Scheme 3. One-pot synthesis of 5a–c. Conditions: (i), (1) 1 (1.0 equiv), 2h,e,o
(1.0 equiv), K3PO4 (1.5 equiv), Pd(OAc)2 (2 mol %), H2O/DMF (1:1), 20 °C, 8 h; (2)
2a,k,e (1.2 equiv), Pd(OAc)2 (2 mol %), H2O/DMF (1:1), 50 °C, 8 h.
Table 3
Synthesis of 5a–c
2
5
Ar1
Ar2
5a (%)
h,a
e,k
o,e
a
b
c
4-tBuC6H4
3,5-Me2C6H3
4-(Vinyl)C6H4
C6H5
3-MeC6H4
C6H5
65
54
59
a
Yields of isolated products.
conditions as given for the synthesis of 3a–n, afforded the 2,6-dia-
ryl-3-trifluoromethyl-pyridines 4a–f in good yields (Scheme 2, Ta-
ble 2).24
The one-pot reaction of 1 with two different arylboronic acids
(sequential addition) afforded the unsymmetrical 2,6-diphenyl-3-
trifluoromethyl-pyridines 5a–c containing two different aryl
groups (Scheme 3, Table 3).25 The reactions were again carried
out under similar conditions as given for the synthesis of 3a–n.
After addition of 1.0 equiv of the first arylboronic acid, the mixture
was stirred for 8–10 h at 20 °C. Subsequently, the second arylbo-
ronic acid was added (1.2 equiv). At the same time, it proved to
be important to add fresh catalyst (2 mol %). The mixture was sub-
sequently stirred at an elevated temperature (50 °C, 8 h) to com-
plete the reaction.
Palladium catalyzed cross-coupling reactions of polyhalogenat-
ed substrates usually proceed regioselectively in favor of the steri-
cally less hindered and electronically more deficient position.18 In
case of pyridine 1, the Suzuki–Miyaura reactions proceeded regio-
selectively in favor of the electronically more deficient position 2
which is sterically more hindered than position 6, due to the prox-
imity of the CF3 substituent (Scheme 4). Surprisingly, Suzuki–
Miyaura reactions of 2,4-dichloro-1-trifluoromethyl-benzene (6),
the benzene analogue of 1, follows the opposite selectivity pat-
tern:26 the first attack occurred at the sterically less hindered posi-
tion 4 instead of the electronically more deficient position 2. In
Figure 1. Molecular structure of 3g in the crystal. Displacement ellipsoids are
drawn at the 30% probability level.
good regioselectivity (Scheme 1, Table 1). The formation of the
opposite regioisomers was not observed. The synthesis of 3a has
been previously reported.21 The best yields were obtained using
0.9 equiv of the arylboronic acid, Pd(OAc)2 (2 mol %) as the catalyst,
and K3PO4 (1.5 equiv) as the base. The use of a phosphane ligand
was not necessary. The reactions were carried out in a mixture of
H2O and DMF (1:1) at 20 °C.22 Both electron rich and poor arylbo-
ronic acids were successfully employed. No systematic trend was
observed for the influence of the type of arylboronic acid on the
yield.
The structures of all products were elucidated by spectronic
techniques and 2D NMR experiments (NOESY, HMBC). The struc-
ture of 3g was independently confirmed by X-ray crystal structure
analysis (Fig. 1).23
The Suzuki–Miyaura reaction of 1 with 2.2 instead of 0.9 equiv
of arylboronic acids 2a–d,f,i, carried out under otherwise identical

S. Ahmed et al. / Tetrahedron Letters 54 (2013) 1669–1672
1671
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CF3
CF3
1
2
Cl
N
1
Cl
1
Cl
Cl
2
6
Scheme 4. Different regioselectivity observed for substrates 1 and 6.
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case of pyridine 1, the electronic effect overrides the steric effect,
while the opposite is true for benzene derivative 6. The reason
for this difference remains unclear at present. The reason might
be associated to the fact that the presence of the ring nitrogen en-
hances both the electron deficiency of the arene as well as offering
a potential complexation site for the catalyst.
In conclusion, we have reported Suzuki–Miyaura reactions of
2,6-dichloro-3-(trifluoromethyl)pyridine which provide a conve-
nient approach to various arylated pyridines. The regioselectivity
in favor of position 2 is based on electronic grounds and is opposite
to the regioselectivity observed for 2,4-dichloro-1-trifluoromethyl-
benzene.
14. (a) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224; (b) Ye, Y.; Sanford,
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Suzuki, A.; Yamamoto, Y. Chem. Lett. 2011, 40, 894; (d) Kotha, S.; Lahiri, K.;
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polybrominated substrates (a) Schröter, S.; Stock, C.; Bach, T. Tetrahedron
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Financial support by the Higher Education Commission Pakistan
and by the DAAD (scholarships for S.A. and K.S.) is gratefully
acknowledged. Financial support by the European Social Fund
(EFRE program) is also acknowledged. The work was also sup-
ported by the TÁMOP-4.2.1/B-09/KONV-2010-007 project. The
project is implemented through the New Hungary Development
Plan, co-financed by the European Social Fund and the European
Regional Development Fund.
Synthesis 2009, 1405; For
a simple guide for the prediction of the site-
References and notes
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20. For the reaction of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine with
arylboronic acids, see: Janssen Pharmaceuticals, Bartolome-Nebreda, J. M.;
MacDonald, G. J.; Van Gool, M. WO2010/12758 A1, 2010.
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22. Synthesis of 6-chloro-2-(4-ethoxyphenyl)-3-(trifluoromethyl)-pyridine (3g):
A
DMF/water solution (1:1, 2 mL per 1 mmol of 1) of K3PO4 (1.5 mmol),
Pd(OAc)2 (2 mol %), and arylboronic acid 2a–n (0.9 mmol) was stirred at
room temperature for 8–12 h (tlc control). After completion of the reaction, the
mixture was extracted with CH2Cl2 and the combined organic layers were
dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (silica gel, EtOAc/heptane = 1:4).
Starting with 1 (216 mg, 1.00 mmol), K3PO4 (165 mg, 1.50 mmol), Pd(OAc)2
(2 mol %), 4-ethoxyphenylboronic acid (149 mg, 0.90 mmol), and a solution of
DMF and water (1:1, 5 mL), 3g was isolated as a white solid (235 mg, 78%),
mp = 74–75 °C. 1H NMR (300 MHz, CDCl3): d = 1.36 (t, 3H, CH3), 4.01 (q, 2H,
CH2), 6.87 (d, J = 8.91 Hz, 2H, ArH), 7.30 (dd, J = 8.37, J = 0.75 Hz, 1H, ArH), 7.40
(d, J = 8.46 Hz, 2H, ArH), 7.90 (d, J = 8.51 Hz, 1H, ArH). 13C NMR (75.46 MHz,
CDCl3): d = 13.7 (CH3), 62.5 (OCH2), 113.1 (CH), 115.3 (d, 1JCF = 252.42 Hz, CF3),
120.9 (CH), 122.0 (q, 2JCF = 63.26, Hz, C), 124.3(C), 126.6 (C), 127.9 (C), 129.1(C),
4
3
129.3 (d, JCF 1.95 Hz CH), 136.6 (q, JCF = 5.01 Hz CH), 152.3 (C), 157.9 (d,
JCF = 2.82 Hz, C), 159 (C). 19F NMR (282.4 MHz, CDCl3): d = À57.02 (CF). IR (ATR,
3. Mcarthur, S. G.; Goetschi, E.; Wichmann, J.; Woltering, T. J. PCT Int. Appl. 2007,
WO 2007110337 A1 20071004.
cmÀ1):
m = 3064 (w), 2980 (m), 2877 (w), 1660 (w), 1544 (w), 1140 (m), 816 (s).
MS (EI, 70 eV): m/z (%) 301 (57) [M+], 273 (100), 238 (12). HRMS (EI) calcd for
14H11ClF3NO [M+]: 301.04758, found 301.04758.
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C
23. CCDC-915015 contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ; Fax: (+44)1223 336 033; or
deposit@ccdc.cam.ac.uk.
24. Synthesis of 2,6-bis(4-methoxyphenyl)-3-(trifluoromethyl)-pyridine (4e): A DMF/
water solution (1:1, 2 mL per 1 mmol of 1) of K3PO4 (1.5 mmol), Pd(OAc)2
(2 mol %), and arylboronic acid 2 (2.2 mmol) was stirred at room temperature
for 8–12 h (tlc control). After completion of the reaction, the mixture was
extracted with CH2Cl2 and the combined organic layers were dried (Na2SO4),
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1672
S. Ahmed et al. / Tetrahedron Letters 54 (2013) 1669–1672
filtered and the filtrate was concentrated in vacuo. The residue was purified by
column chromatography (silica gel, EtOAc/heptane = 1:4). Starting with
(216 mg, 1.0 mmol), K3PO4 (345 mg, 2.5 mmol), Pd(OAc)2 (2 mol %), 4-
methoxyphenylboronic acid (334 mg, 2.20 mmol), and solution of DMF and
extracted with CH2Cl2 and the combined organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The residue was purified by
column chromatography (silica gel, EtOAc/heptane = 1:3). Starting with
1
1
(108 mg, 0.5 mmol), K3PO4 (118 mg, 1.5 mmol), Pd(OAc)4 (2 mol %), 4-tert-
butylphenylboronic acid (106 mg, 1.0 mmol), and a DMF/water solution (1:1,
4 mL) and subsequent addition of K3PO4 (118 mg, 1.5 mmol), Pd(OAc)4
(2 mol %), phenylboronic acid (104 mg, 1.2 mmol), and a DMF/water solution
(1:1, 2 mL), 5a was isolated as a colorless oil (124 mg, 70%). 1H NMR (300 MHz,
CDCl3): d = 1.30 (s, 9H, CH3), 7.40 (m, 3H, ArH), 7.42 (d, J = 8.70, 2H, ArH), 7.53
(m, 2H, ArH) 7.72 (dd, J = 8.32, J = 0.76 Hz, 1H, ArH), 7.95 (d, J = 8.70, 2H, ArH),
8.02 (d, J = 8.43, 1H, ArH). 13C NMR (75.46 MHz, CDCl3): d = 31.2 (3CH3), 34.8
water (1:1) (2 mL), 4e was isolated as
a colorless solid (226 mg, 63%),
mp = 104–105 °C. 1H NMR (300 MHz, CDCl3): d = 3.87 (s, 3H, CH3), 3.88 (s,
3H, CH3), 6.98 (d, J = 1.70, Hz, 2H, ArH), 7.01 (d, J = 1.70 Hz, 2H, ArH), 7.58 (d,
J = 8.60, 2H, ArH), 7.71 (d, J = 8.60, Hz, 1H, ArH), 8.03–8.10 (m, 3H, ArH). 13C
NMR (75.46 MHz, CDCl3): d = 55.3 (OCH3), 55.3 (OCH3), 113.4 (2CH), 114.2
1
(2CH), 116.6 (CH), 124.1 (d, JCF = 273.1 Hz, CF3), 128.8 (2CH), 130.4 (d,
JCF = 2.11 Hz, 2CH), 130.5 (CH), 132.4 (C), 135.7 (q, 3JCF = 4.85, Hz, C), 157.6 (C),
158.7 (2C), 160.1 (C), 161.3 (C). 19F NMR (282.4 MHz, CDCl3): d = À57.04 (CF).
1
(C) 117.7 (2CH), 122.8 (d, JCF = 259.04 Hz, CF3), 125.8 (3CH), 127.1 (2CH),
IR (ATR, cmÀ1):
m
= 3075 (w), 2969 (w), 2846 (w), 1605 (m), 1581 (m), 1510
127.9 (2CH), 128.7 (C), 128.9 (d, JCF 1.70 Hz CH), 135.1(C), 135.6 (q,
4
(m), 1249 (s), 1124 (s), 1019 (s), 828 (s). MS (EI, 70 eV): m/z (%) 359 (100) [M+],
316 (8). HRMS (EI) calcd for C20H16F3NO2 [M+]: 359.11276, found 359.11258.
25. Synthesis of 2-(4-tert-butylphenyl)-6-phenyl-3-(trifluoromethyl)-pyridine (5a). A
DMF/water solution (1:1, 4 mL per 1 mmol of 1), K3PO4 (1.5 mmol), Pd(OAc)2
(2 mol %), and arylboronic acid 2f (1.2 mmol) was stirred at room temperature
for 8–10 h. Subsequently, arylboronic acid 2a (1.2 mmol), K3PO4 (1.5 mmol),
and Pd(OAc)2 (2 mol %) were added and the reaction mixture was stirred at
50 °C for 8–10 h. After completion of the reaction (tlc control), the mixture was
3JCF = 4.93 Hz CH), 139.7 (C), 153.4 (C), 158.0 (C), 159.3 (C). 19F NMR
(282.4 MHz, CDCl3): d = À56.79 (CF). IR (ATR, cmÀ1):
m = 3059 (w), 2962 (w),
2903 (w), 2868 (w), 1610 (w), 1587 (m), 1574 (m), 1455 (w), 1307(s), 1111 (s),
1098 (s), 1026 (s), 1018 (s), 826 (s), 767 (m), 697 (m). MS (EI, 70 eV): m/z (%)
355 (23) [M+], 340 (100). HRMS (EI) calcd for C22H20F3N [M+]: 355.15424,
found 355.15430.
26. Ali, I.; Siyo, B.; Hassan, Z.; Malik, I.; Ullah, I.; Ali, A.; Nawaz, M.; Iqbal, J.;
Patonay, T.; Villinger, A.; Langer, P. J. Fluorine Chem. 2013, 145, 18.