Synthesis of 2-Aryl-3,4,5,6-tetrachloropyridines and 2,6-Diaryl-3,4,5- trichloropyridines by Site-Selective Suzuki-Miyaura Reactions of Pentachloropyridine

Article abstract of DOI:10.1055/s-0029-1219951

The first Suzuki-Miyaura reactions of pentachloropyridine are reported. The reaction with two equivalents of arylboronic acids gave 2,6-diaryl-3,4,5- trichloropyridines, while the reaction with one equivalent of arylboronic acid afforded 2-aryl-3,4,5,6-te

Full text of DOI:10.1055/s-0029-1219951

1528
LETTER
Synthesis of 2-Aryl-3,4,5,6-tetrachloropyridines and 2,6-Diaryl-3,4,5-
trichloropyridines by Site-Selective Suzuki–Miyaura Reactions of
Pentachloropyridine
S
ynthesis of 2-
e
A
ryl-3,4,5,
t
6-tetra
e
chloropyrid
r
ines and 2,6-D
E
iaryl-3,4, 5-trich
h
loropyridine
l
s
ers,a,b Sebastian Reimann,a,b Silke Erfle,a,b Alexander Villinger,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
Received 5 March 2010
tions of pentahalogenated pyridines have, to the best of
our knowledge, not yet been reported. Herein, we report
our preliminary results related to Suzuki–Miyaura reac-
tions of pentachloropyridine (1). The reactions provide a
Abstract: The first Suzuki–Miyaura reactions of pentachloropyri-
dine are reported. The reaction with two equivalents of arylboronic
acids gave 2,6-diaryl-3,4,5-trichloropyridines, while the reaction
with one equivalent of arylboronic acid afforded 2-aryl-3,4,5,6-tet-
rachloropyridines. The one-pot reaction of pentachloropyridine convenient approach to 2-aryl-3,4,5,6-tetrachloropyr-
with two different arylboronic acids resulted in the formation of 2,6-
idines and 2,6-diaryl-3,4,5-trichloropyridines. These
diaryl-3,4,5-trichloropyridines containing two different aryl groups.
products have only rarely been reported in the literature so
All reactions proceeded with very good site selectivity.
far and are not readily available.19
Key words: catalysis, palladium, Suzuki–Miyaura reaction, pyri-
Our starting point was to find suitable conditions for the
dine, regioselectivity
site-selective synthesis of 2-(4-methoxyphenyl)-3,4,5,6-
tetrachloropyridine (3a) by reaction of 1 with one equiva-
lent of (4-methoxyphenyl)boronic acid (2a, Scheme 1).
Pyridines are of considerable pharmacological relevance
After much optimization (Table 1), we have found that the
and occur in a number of natural products. Examples in-
best conversion and yield were obtained when the reac-
clude nicotinic acid and its derivatives, vitamin B6, and
tions were carried out using Pd(PPh3)4 (5 mol%) as the
various other molecules.1,2 We have recently reported that
catalyst and Cs2CO3 as the base. The reaction was carried
2-sulfonylpyridines3 and 4-hydroxy-4-(pyridyl)alk-3-en-
out at 20 °C in a 10:1 mixture of acetonitrile and water
2-ones4 exhibit antimicrobial activity. Pyridines possess
(entry 12). Similar results were obtained when toluene
several applications, for example, as drugs, fluorescent
was used as the solvent (entry 7). However, the use of
chemosensors, and fluorophores.5 Classic syntheses of
K3PO4 instead of Cs2CO3 proved to be unsuccessful (entry
pyridines often rely on base-mediated cyclocondensations
13, excellent conversion, but low yield). An excess of 2a
(e.g., the Hantzsch reaction).2,6 Despite their great utility,
(2.2 equiv) had to be employed. The yield decreased when
these methods may have drawbacks when specific substi-
only 1.5 equivalents of 2a were employed (entry 16). In-
tution patterns and labile functionalities are incorporated.
terestingly, the employment of dry acetonitrile, in the
To address these limitations, the application of palladium-
presence of Cs2CO3, K2CO3, KOt-Bu, or K3PO4, proved to
catalyzed cross-coupling reactions to halogenated pyr-
be unsuccessful in terms of yield (entries 8–11). Moderate
idines can be advantageous. In recent years, site-selective
yields were obtained when a mixture of toluene and water
reactions of polyhalogenated heterocycles have been
was used as the solvent (entries 14 and 15). The employ-
studied.7,8 Cross-coupling reactions of 2,5-dibromopyri-
ment of the monophosphine biaryl ligand X-Phos,20 which
dine include aminations,9 and Stille,10 Suzuki,11 Negishi,12
often gives excellent results for Suzuki reactions of aryl
Sonogashira,13 and Kumada couplings.14 In all cases, the
chlorides, gave unsatisfactory results (entries 1–6).
first reaction occurs at the more electron-deficient posi-
tion C-2. Recently, Handy and co-workers reported the
Cl
Cl
first double Suzuki couplings of 2,5- and 2,3-dibromopyr-
idine.15 Pentachloropyridine represents an inexpensive
and interesting polyfunctionalized substrate. Nucleophilic
aromatic substitution reactions of this substrate with O-,
N-, and S-nucleophiles have been reported.16 Only a few
reactions with carbon nucleophiles have been studied
which include the reaction with enamines17a and
DMAP.17b Metal-halide exchange reactions have also
been reported.18 Palladium-catalyzed cross-coupling reac-
ArB(OH)2
Cl
Ar
Cl
Cl
Cl
Cl
Cl
Cl
2a–f
i
N
N
1
3a–f
Scheme 1 Synthesis of 3a–f. Reagents and conditions: (i) 2a–f (2.2
equiv), Pd(PPh3)4 (5 mol%), MeCN–H2O (10:1), Cs2CO3 (1.2 equiv),
20 °C, 20 h.
The reaction of 1 with arylboronic acids 2a–f, using our
optimized conditions (Table 1, entry 12), afforded the 2-
aryl-3,4,5,6-tetraarylpyridines 3a–f in 33–67% yield
(Table 2, Scheme 1).21,22 The best yields were obtained
SYNLETT 2010, No. 10, pp 1528–1532
Advanced online publication: 25.05.2010
DOI: 10.1055/s-0029-1219951; Art ID: D06310ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

LETTER
Synthesis of 2-Aryl-3,4,5,6-tetrachloropyridines and 2,6-Diaryl-3,4,5-trichloropyridines
1529
Table 1 Optimization of the Synthesis of 3a
Entry
1
Catalyst
Solvent
2a (equiv)
2.2
Temp (°C) Base
Cs2CO3
Conversion (3a, %)a Yield of 3a (%)b
Pd(OAc2/X-Phos
Pd(OAc)2/X-Phos
Pd(OAc)2/X-Phos
Pd(OAc)2/X-Phos
Pd(OAc)2/X-Phos
Pd(OAc)2/X-Phos
Pd(PPh3)4
toluene
80
80
80
80
80
80
20
20
20
20
20
20
20
20
20
20
55
56
68
73
65
86
88
74
44
100
71
89
100
66
80
95
15
7
2
THF
2.2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOt-Bu
K3PO4
3
dioxane
2.2
3
4
MeCN
2.2
28
20
7
5
toluene–THF
DMF
2.2
6
2.2
7
toluene
2.2
78
5
8
Pd(PPh3)4
MeCN
2.2
9
Pd(PPh3)4
MeCN
2.2
5
10
11
12
13
14
15
16
Pd(PPh3)4
MeCN
2.2
15
10
79
33
43
46
71
Pd(PPh3)4
MeCN
2.2
Pd(PPh3)4
MeCN–H2O
MeCN–H2O
toluene–H2O
toluene–H2O
MeCN–H2O
2.2
Cs2CO3
K3PO4
Pd(PPh3)4
2.2
Pd(PPh3)4
2.2
Cs2CO3
K3PO4
Pd(PPh3)4
2.2
Pd(PPh3)4
1.5
Cs2CO3
a Conversion.
b GC-yield (n-hexadecane was used as the internal standard).
for the reactions of 1 with (4-methoxyphenyl)boronic acid The reaction of 1 with 4.4 equivalents of arylboronic acids
(2a) and for phenylboronic acid (2e). The yields de- 2c–h, in the presence of Pd(PPh3)4 (5 mol%) and Cs2CO3
creased when sterically hindered boronic acids (2b,c) or (2.4 equiv), afforded the 2,6-diaryl-3,4,5-trichloropyr-
electron-poor boronic acids (2d,f) were employed. In all idines 4a–f in 45–65% yield (Scheme 2, Table 3).23,24
reactions, unreacted starting material was recovered (10– During the optimization, it proved to be important to use
15%). A reaction at position C-6 or at another position an excess of the boronic acid and to carry out the reaction
was not observed. However, attack at position 6 and for- at 90–100 °C instead of 20 °C. The main side reaction was
mation of 2,6-diaryl-3,4,5-trichloropyridines were ob- the formation of biaryls by dimerization of two molecules
served when the reactions were carried out under more of the arylboronic acid. In addition, a small amount of un-
forcing conditions (higher temperature, longer reaction reacted starting material was recovered (<5%).
time).
The second coupling required considerably more forcing
conditions compared to the first one. This can be ex-
plained by the fact that the presence of an aryl group lo-
cated at the pyridine moiety results in some deactivation
of the pyridine moiety (with regard to the second Suzuki
reaction), due to the electron-donating properties of the
aryl group.
Table 2 Synthesis of 3a–f
2, 3
a
Ar
Yield of 3 (%)a
4-MeOC6H4
2-naphthalene
2-MeOC6H4
4-FC6H4
67
46
33
50
62
38
b
c
Cl
Cl
ArB(OH)2
Cl
Ar
Cl
Ar
Cl
Cl
Cl
Cl
d
2c–h
e
Ph
i
N
N
f
4-MeCOC6H4
1
4a–f
a Yields of isolated products.
Scheme 2 Synthesis of 4a–f. Reagents and conditions: (i) 2a–f (4.4
equiv), Pd(PPh3)4 (5 mol%), MeCN–H2O (10:1), Cs2CO3 (2.4 equiv),
90–100 °C, 20 h.
Synlett 2010, No. 10, 1528–1532 © Thieme Stuttgart · New York

1530
P. Ehlers et al.
LETTER
Table 4 Synthesis of 5a–c
Table 3 Synthesis of 4a–f
Yield of 4 (%)a
2
5
a
b
c
Ar1
Ar2
Yield of 5 (%)a
2
c
d
e
f
4
a
b
c
d
e
f
Ar
a,d
a,f
f,h
4-MeOC6H4
4-MeOC6H4
4-MeCOC6H4
4-FC6H4
4-MeCOC6H4
4-MeC6H4
40
23
48
2-MeOC6H4
4-FC6H4
52
52
65
45
45
62
Ph
a Yields of isolated products.
4-MeCOC6H4
3,4-(MeO)2C6H3
4-MeC6H4
g
In conclusion, we have reported the synthesis of 2-aryl-
3,4,5,6-tetrachloropyridines and 2,6-diaryl-3,4,5-trichlo-
ropyridines by the first Suzuki–Miyaura reactions of
pentachloropyridine. The one-pot reaction of pentachlo-
ropyridine with two different arylboronic acids afforded
2,6-diaryl-3,4,5-trichloropyridines containing two differ-
ent aryl groups. All reactions proceed with very good site
selectivity. Our current studies are directed towards func-
tionalization of the remaining chloride groups.
h
a Yields of isolated products.
The structure of product 4c was independently confirmed
by X-ray crystal structure analysis (Figure 1).25 The phe-
nyl groups and the pyridine moiety are twisted out of
plane.
The one-pot reaction of 1 with two different arylboronic
acids afforded the 2,6-diaryl-3,4,5-trichloropyridines 5a–
c, containing two different aryl groups (Scheme 3,
Table 4).26,27 Products 5a and 5c were isolated in accept-
able yields. The symmetrical products 4 were formed as
side products in low yield. In addition, a small amount of
starting material was recovered. The yield of 48% of 5c
corresponds to approx. 70% yield per cross-coupling step.
The yield of 5b was relatively low. This can be explained
by the fact that an excess of the first boronic acid [4-
(MeO)C6H4] had to be used which is still present in the re-
action mixture when the second boronic acid [the rather
electron-poor and unreactive boronic acid 4-
(MeCO)C6H4] was added. Therefore, some formation of
4a as a side product cannot be avoided.
Acknowledgment
Financial support from the Interdisciplinary Faculty of the Univer-
sity of Rostock (scholarship for S. R.) is gratefully acknowledged.
References and Notes
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Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
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McKillop, A.; Katritzky, A. R.; Rees, C. W., Eds.; Elsevier
Science: Oxford, 1984, Chapt. 2.05, 165. For recent
pyridine syntheses, see: (b) Dash, J.; Lechel, T.; Reissig, H.-
U. Org. Lett. 2007, 9, 5541; and references cited therein.
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9, 1335; and references cited therein.
(7) For reviews of cross-coupling reactions of polyhalogenated
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Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur.
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Malik, I.; Villinger, A.; Langer, P. Tetrahedron Lett. 2009,
50, 4962. (e) Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger,
A.; Langer, P. Adv. Synth. Catal. 2009, 351, 1595.
Figure 1 Crystal structure of 4c
Ar1B(OH)2
Cl
Cl
Ar2B(OH)2
Cl
Cl
Cl
Cl
Cl
Cl
2c–h
Ar1
N
Ar2
i
N
1
5a–c
Scheme 3 Synthesis of 5a–c. Reagents and conditions: (i) 1) 2a–f
(2.2 equiv), Pd(PPh3)4 (5 mol%), MeCN–H2O (10:1), Cs2CO3 (2.4
equiv), 80 °C, 2 h; 2) 2a–f (2.2 equiv), 80 °C, 12 h.
Synlett 2010, No. 10, 1528–1532 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aryl-3,4,5,6-tetrachloropyridines and 2,6-Diaryl-3,4,5-trichloropyridines
1531
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Pliushchev, M.; Sciotti, R. J.; Wiedeman, P. E.; Djuric, S. W.
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Houpis, I. N.; Volante, R. P. Tetrahedron Lett. 2001, 42,
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mg), dissolved in a 10:1 mixture of MeCN (2 mL) and H2O
(0.2 mL) was stirred for 10 min. Subsequently, the boronic
acid 2 (2.2 equiv) was added. The solution was stirred for 20
h at r.t. To the reaction mixture was added brine, and the
organic and the aqueous layer were separated. The latter was
extracted with CH2Cl2 (3×). The combined organic layers
were dried (Na2SO4), filtered, and the solution was
concentrated in vacuo. The residue was purified by column
chromatography (hexane–CH2Cl2).
(22) 2,3,4,5-Tetrachloro-6-(4-methoxyphenyl)pyridine (3a)
Starting with 2a (1.1 mmol), Pd(PPh3)4 (5 mol%, 29 mg),
Cs2CO3 (0.9 mmol, 290 mg), and 1 (0.5 mmol, 126 mg) in
MeCN (2 mL) and H2O (0.2 mL), 3a was isolated by column
chromatography (hexane–CH2Cl2 = 4:1) as a white solid
(108 mg, 67%), mp 129–130 °C. 1H NMR (300 MHz,
CDCl3): d = 3.86 (s, 3 H, OCH3), 6.98 (d, 3J = 9.0 Hz, 2 H,
Ar), 7.70 (d, 3J = 9.0 Hz, 2 H, Ar). 13C NMR (75 MHz,
CDCl3): d = 55.4 (OCH3), 113.6 (CH), 128.1, 128.2, 128.8
(CAr/Hetar), 131.1 (CH), 143.0, 147.1, 154.6, 160.8 (CAr/Hetar).
IR (ATR): 3015 (w), 2955 (w), 2923 (w), 2853 (w), 2728
(w), 2553 (w), 1607 (w), 1505 (s), 1350 (m), 1320 (br, s),
1288 (s), 1084 (s), 815 (s) cm–1. MS (EI, 70 eV): m/z (%) =
323 (100) [M+], 321 (78), 280 (19), 278 (15), 245 (13), 243
(13), 210 (6), 208 (9). HRMS (EI, 70 eV): m/z calcd for
C12H7ONCl4: 320.92763; found: 320.927630. Anal. Calcd
for C12H7Cl4NO (323.0): C, 44.62; H, 2.18; N, 4.34. Found:
C, 44.84; H, 2.21; N, 4.33.
(23) General Procedure for the Synthesis of 4a–f
A solution of Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (2.4
equiv, 391 mg), and pentachloropyridine (0.5 mmol, 126
mg) in MeCN (2 mL) and H2O (0.2 mL) was stirred for 10
min at 20 °C. Subsequently, the boronic acid 2 (2.4 equiv)
was added at 20 °C. The solution was stirred for 20 h at 90–
100 °C. The workup was carried out as described for the
synthesis of 3a–f.
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J. E.; Boothby, C. E.; Koehler, A.; Friend, R. H.; Holmes,
A. B. J. Am. Chem. Soc. 2004, 126, 7041. (b) Vice, S.;
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McCombie, S.; Miller, M.; Nazareno, D.; Palani, A.; Tagat,
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Carpentier, J.-F.; Mortreux, A.; Castanet, Y. Tetrahedron
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Yang, C.; Reider, P. J. Tetrahedron Lett. 2001, 42, 6811.
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Roberti, M.; Rondanin, R.; Baruchello, R.; Grisolia, G.;
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Tolomeo, M. Tetrahedron Lett. 2003, 44, 3005.
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(24) 3,4,5-Trichloro-2,6-diphenylpyridine (4c)
Starting with Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (1.2
mmol, 391 mg), 1 (0.5 mmol, 126 mg), and 2e (1.2 mmol,
146 mg) in MeCN (2 mL) and H2O (0.2 mL), 4e was isolated
as a white solid (109 mg, 65%), mp 168–170 °C; reaction
temperature 100 °C. 1H NMR (300 MHz, CDCl3): d = 7.34–
7.40 (m, 2 H, CH), 7.44–7.50 (m, 4 H, CH), 7.61–7.65 (m, 4
H, CH). 13C NMR (75 MHz, CDCl3): d = 127.2, 127.3, 128.8
(CHAr), 129.7, 141.2, 144.7, 146.5 (CHetar). IR (ATR): 3058
(w), 2921 (m), 1731 (m), 1529 (s), 1486 (br, s), 1369 (s),
1329 (s), 1297 (s), 1200 (br, s), 1067 (m), 883 (m), 817 (s),
771 (s), 737 (s), 708 (s), 691 (s), 599 (s) cm–1. MS (EI, 70
eV): m/z (%) = 340 (68) [M]+, 294 (11), 302 (11), 299 (20),
298 (100), 263 (13), 227 (30), 160 (25), 149 (11). HRMS
(EI, 70 eV): m/z calcd for C17H10Cl3N: 332.98733; found:
332.98738. Anal. Calcd for C17H10NCl3 (334.63): C, 61.02;
H, 3.01; N, 4.19. Found: C, 61.35; H, 3.24; N, 3.89.
(25) CCDC-771412 contain all crystallographic details of this
publication which are available free of charge at
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(17) (a) Suschitzky, H.; Wakefield, B. J.; Whitten, J. P. J. Chem.
Soc., Perkin Trans. 1 1980, 2709. (b) Schmidt, A.;
Mordhorst, T.; Nieger, M. Org. Biomol. Chem. 2005, 3,
3788.
(18) Julia, L.; Riera, J.; Teixido, R. J. Chem. Soc., Perkin Trans.
1 1991, 1101.
(19) (a) Binns, H.; Suschitzky, H. J. Chem. Soc. C 1971, 1223.
(b) Roedig, A.; Grohe, K.; Klatt, D.; Kleppe, H.-G. Chem.
Ber. 1966, 2813. (c) Bratt, J.; Iddon, B.; Mack, A. G.;
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www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
(26) General Procedure for the Synthesis of 5a–c
To a solution of Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (2.4
equiv, 391 mg), and pentachloropyridine (0.5 mmol, 126
mg) in MeCN (2 mL) and H2O (0.2 mL) was added the first
boronic acid (2.2 equiv). The solution was stirred for 2 h at
80 °C. After cooling to r.t., the second boronic acid (2.2
equiv) was added. The solution was stirred for 12 h at 80 °C.
(20) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3358; and references cited therein.
(21) General Procedure for the Synthesis of 3a–f
A solution of Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (1.8
equiv, 290 mg), and pentachloropyridine (0.5 mmol, 126
Synlett 2010, No. 10, 1528–1532 © Thieme Stuttgart · New York

1532
P. Ehlers et al.
LETTER
The workup was carried out as described for the synthesis of
3a–f.
(27) 1-{4-[3,4,5-Trichloro-6-(p-tolyl)pyrid-2-
3J = 8.2 Hz, 2 H, Ar), 7.77 (d, 3J = 8.6 Hz, 2 H, Ar), 7.98 (d,
3J = 8.6 Hz, 2 H, Ar). 13C NMR (75 MHz, CDCl3): d = 21.5
(CH3), 26.8 (CH3), 128.0 (CAr/Hetar), 128.1 (CH), 128.3,
128.8, 128.9 (CAr/Hetar), 128.9, 129.4 (CH), 129.6 (CAr/Hetar),
129.9 (CH), 134.7, 137.3, 139.7, 142.2 (CAr/Hetar), 197.7
(C=O). IR (ATR): 3339 (w), 3076 (w), 3031 (w), 2997 (w),
2921 (m), 2853 (w), 1674 (w), 1607 (s), 1523 (m), 1493 (m),
1357 (s), 1267 (s), 1186 (m), 959 (m), 815 (s) cm–1. MS (EI,
70 eV): m/z (%) = 389 (51) [M+], 378 (33), 376 (100), 374
(98), 346 (20), 276 (10), 240 (9), 187 (9). HRMS (EI, 70 eV):
m/z calcd for C20H14O1N1Cl3: 389.01355; found: 389.01319.
yl]phenyl}ethanone (5c)
Starting with 2f (1.1 mmol, 180 mg), 2h (1.1 mmol, 150 mg),
Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (1.2 mmol, 390 mg),
and 1 (0.5 mmol, 126 mg) in MeCN (2 mL) and H2O (0.2
mL), 5c was isolated by column chromatography (heptanes–
EtOAc = 10:1) as a colorless solid (93 mg, 48%), mp 190–
192 °C. 1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3 H, CH3),
2.58 (s, 3 H, CH3), 7.21 (d, 3J = 8.3 Hz, 2 H, Ar), 7.57 (d,
Synlett 2010, No. 10, 1528–1532 © Thieme Stuttgart · New York

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