The palladium catalysed Suzuki coupling of 2- and 4-chloropyridines

Article abstract of DOI:10.1055/s-1999-2533

The Suzuki coupling of 2- and 4-chloropyridines with arylboronic acids is successfully performed under Pd(PPh₃)₄ catalysis. Moderate to good yields are obtained with 4-chloropyridines while 2-chloropyridines give excellent yields. The corresponding pyridine N-oxides react in the same manner. An easy and cheap access to arylpyridines, a class of compound with medicinal interest, is thus achieved.

Full text of DOI:10.1055/s-1999-2533

LETTER
45
The Palladium Catalysed Suzuki Coupling of 2- and 4-Chloropyridines
Olivier Lohse,* Philippe Thevenin¥ and Erwin Waldvogel
Novartis Pharma AG, Chemical and Analytical Development, K-684.1.15, CH-4002 Basel, Switzerland
Fax +41-61-696-2711; E-mail: olivier.lohse@pharma.novartis.com
Received 16 October 1998
K2CO3, 5% Pd(PPh3)4) gave the best result (entry 3). The
reaction was scaled up to 10 g and Pd(OAc)2 was a used
as a cheaper source of palladium, yielding 81% of analyt-
ically pure 2-phenylpyridine (entry 4).17 Arylboronic ac-
Abstract: The Suzuki coupling of 2- and 4-chloropyridines with
arylboronic acids is successfully performed under Pd(PPh3)4 catal-
ysis. Moderate to good yields are obtained with 4-chloropyridines
while 2-chloropyridines give excellent yields. The corresponding
pyridine N-oxides react in the same manner. An easy and cheap ac- ids bearing electron-withdrawing groups (entry 5) or
cess to arylpyridines, a class of compound with medicinal interest,
is thus achieved.
electron-donating groups (entry 8–10) gave good yields of
biaryls. We also compared the reactivity of 2-chloro-5-ni-
tropyridine with that of 1-chloro-4-nitrobenzene.18 The
Key words: chloropyridines, Suzuki coupling, biaryl, palladium
pyridine substrate was completely consumed after 2 hours
at reflux, yielding 78% of biaryl (entry 6), whereas the
benzene halide had only reacted to 70% extent after 8
hours. This clearly demonstrated the activating effect of
the nitrogen on the aromatic ring.
The current interest in 2- and 4-arylpyridines is based on
their pharmacological activities and their potential useful-
ness as therapeutic agents for the treatment of various dis-
eases.1-3 They have been studied as cardiotonic agents,4
gastric secretion inhibitors,5 potential reactivators of ace-
tylcholinesterase poisoned with organophosphorus
compounds6 and have been used as intermediates for the
preparation of 6-arylpyridine semicarbazone insecti-
cides.7 During the course of chemical development activ-
ities, we became interested in 4-aryl-2-carboxypyridines
and required a short synthesis that would allow making
large quantities of compounds via an ecologically sound
and safe process.8 The Suzuki coupling is a powerful tool
for the synthesis of substituted biaryls. High yields are ob-
tained when using aryl bromides, iodides or triflates as
coupling partner with boronic acids.9 Usually, aryl chlo-
rides do not react except when they are activated with
electron-withdrawing groups.10,11 Since chloropyridines
are readily available and are “activated” aryl chlorides, we
became interested in studying their reactivity in the palla-
dium catalysed Suzuki coupling. The interest in using aryl
chlorides in cross-coupling reactions stems from the fact
that they are both the least expensive and the most widely
available aryl halides. In the case of 2- and 4-halo-
pyridines, the chloro compounds show a better stability in
comparison with the bromo or iodo derivatives. Many of
the methods used to include aryl chlorides in catalysed
carbon-carbon bond-forming reactions are limited by the
need for substrates that are activated by electron-with-
drawing substituents11,12 or by complex transition metal
fragments.13 We report here that simple 2- and 4-chloro-
pyridines react smoothly in Pd(PPh3)4 catalysed Suzuki
coupling.
Scheme 1
We first investigated the coupling of 2-chloropyridine
with phenylboronic acid (Scheme 1). Under standard
conditions14 (toluene, K2CO3, 5% Pd(PPh3)4) 80% conver-
sion was obtained after 18h at reflux (Table 1, entry 1).
Anhydrous conditions15 (DMF, K3PO4) proved to be infe-
rior (entry 2). Finally, the Gronowitz conditions16 (DME,
4-Chloropyridine was also treated with arylboronic acids
using Pd(PPh3)4 as a catalyst (Scheme 2). Although the re-
action was slower than in the 2-chloro series, the yields
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46
O. Lohse et al.
LETTER
Another recent improvement in the palladium catalysed
cross-coupling reaction is the observation of an accelerat-
ing “copper effect” in the Stille coupling23a which was
also reported for the Suzuki coupling of some 4-trifluo-
romethylsulfonyloxycoumarins.23b We therefore treated
N-methyl 4-chloropicolinamide with phenylboronic acid
under catalysis of a copper/palladium mixture (1%
Scheme 2
were good to moderate with both electron rich (Table 2, Pd(OAc)2, 0.5% CuI, 4% Pd(o-tolyl)3). The coupling pro-
entry 1-3) or electron poor arylboronic acids (entry 4).
ceeded twice as fast in the presence of copper during the
first hour but it then slowed down. The addition of another
0.5% CuI had no effect and only 63% conversion was ob-
tained after 20 hours at reflux (entry 10).
We next focused our attention to the coupling of 4-chlo-
ropicolinic acid derivatives19 with phenylboronic acid
(Table 2, entry 5-10). The methyl ester was hydrolysed
under basic aqueous conditions and no biaryl product was Lastly, 2- and 4-chloropyridine N-oxide were reacted with
obtained (entry 5). Under anhydrous fluoride mediated phenylboronic acid (DME/H2O/K2CO3/5% Pd(PPh3)4) to
coupling conditions20, the expected product was obtained give 2- and 4-phenylpyridine N-oxide, in 70% and 65%
but in only 50% yield (entry 6). The t-butyl ester was sta- yield respectively (Scheme 3). No reaction was observed
ble and yielded 81% of biaryl under standard procedure when Pd(OAc)2/PPh3 was used.
(entry 7). N-methyl 4-chloropicolinamide reacted
smoothly with 1% Pd(OAc)2/4 P(o-tolyl)3, reaching 97%
conversion after 20 hours and gave 63% of biaryl (entry
8). Interestingly, the iodo derivative did not react faster
under the same reaction conditions.
Scheme 3
During the course of our studies, we also made the follow-
ing interesting observation. Due to its cost and oxidative
lability, tetrakis(triphenylphosphine)palladium (0) is un-
suitable for a large-scale process and it was our goal to re-
place it by in-situ generated Pd(0). Amatore et al. have
shown that one equivalent of triphenylphosphine is oxi-
dised to triphenylphosphine oxide during the reduction of
palladium acetate to Pd(0).24a Indeed, when we used
Pd(OAc)2 in combination with PPh3 as a catalyst system,
we always observed the formation of the phosphine
oxide25 (GC-MS, HPLC). However, when the more
crowded tri-o-tolylphosphine was used as a ligand, we
never observed the formation of its oxide. Instead, a
stoichiometric amount (based on palladium) of biphenyl
was reproducibly obtained by dimerisation of the arylbo-
ronic acid.26 Thus, it appears that, in the case of P(o-
tolyl)3, it is not the phosphine but the boronic acid that re-
duces Pd(OAc)2 to Pd(0).27
Recently, new palladium catalysts13d and nickel
catalysts13b have allowed the Suzuki coupling of chloro-
arenes in good yields. Chloropyridines incorporating elec-
tron withdrawing substituants were also shown to react
smoothly when using Pd(dppb)Cl2.12e We could demon-
strate that simple 2- and 4-chloropyridines were reactive
enough to give good yields of biaryls under Pd(PPh3)4 ca-
talysis. The reaction was easy to scale up and Pd(PPh3)4
could then advantageously be replaced by in situ generat-
ed Pd(0) from Pd(OAc)2 and PPh3, which showed even
greater reactivity.24b 4-Chloropicolinic acid derivatives
Recently, phosphine-free catalytic systems have been
claimed as a major improvement of the Suzuki coupling.21
When the reaction of N-methyl 4-chloropicolinamide
with phenylboronic acid was conducted with 0.5%
Pd2(dba)3 (1% Pd(0)) and no ligand, only 16% conversion
was observed after 20 hours at reflux (entry 9). The pico-
linamide probably binds to the palladium(0) and forms an
unproductive complex.22 Upon addition of P(o-tolyl)3
(4%), the reaction was accelerated but did not go above
50% conversion.
Synlett 1999, No. 1, 45–48 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Palladium Catalysed Suzuki Coupling of 2- and 4-Chloropyridines
47
spectively.12b 4-Chloroquinoline reacts 7.5 times faster than 4-
chloropyri-dine for the same displacement reaction.12b
(12) a) For a general discussion concerning the reactivity of aro-
matic heterocycles towards nucleophilic substitution at car-
bon, see: Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic
Chemistry, 3rd ed.; Chapman & Hall: London, 1995; p. 24.
b) Chapman, N. B.; Russel-Hill, D. Q. J. Chem. Soc. 1956,
1563. c) For examples of coupling reactions of chloroquino-
lines, see: Ciufolini, M. A.; Mitchell, J. W.; Roschangar, F.
Tetrahedron Lett. 1996, 37, 8281.; Dunn, S. H.; McKillop, A.
J. Chem. Soc., Perkin Trans. I 1993, 8, 879.; Ali, N. M.;
McKillop, A.; Mitchell, M. B.; Rebelo, R. A.; Wallbank, P. J.
Tetrahedron 1992, 37, 8117. d) For examples of coupling re-
actions of chloropurines, see: Gundersen, L.-L. Tetrahedron
Lett. 1994, 35, 3155. e) Mitchell, M. B.; Wallbank, P. J. Tetra-
hedron Lett. 1991, 32, 2273. f) Rocca, P.; Marsais, F.; Godard,
A.; Quéguiner, G. Tetrahedron Lett. 1993, 34, 2937.
(13) a) Gouda, K.; Hagiwara, E.; Hatanaka, Y.; Hiyama, T. J. Org.
Chem. 1996, 61, 7232. b) Indolese, A. F. Tetrahedron Lett.
1997, 38, 3513. c) Saito, S.; Sakai, M.; Miyaura, N. Tetrahe-
dron Lett. 1996, 37, 2993. d) Beller, M.; Fischer, H.; Herr-
mann, W. A.; Öfele, K.; Brossmer, C. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1848. e) Firooznia, F.; Gude, C.; Chan, K.;
Satoh, Y. Tetrahedron Lett. 1998, 39, 3985.
were shown to be particularly good substrates for palladi-
um catalysed Suzuki coupling.
Acknowledgement
We thank K. Killius and M. Weibel for their technical assistance
and A. Brodbeck for the preparation of large quantities of 4-chloro-
picolinic acid.
References and Notes
¥) Present address: KTH - Royal Institute of Technology,
Department of Chemical Engineering and Technology,
S-10044 Stockholm, Sweden.
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(17) For small scale experiments, we recommend the use of com-
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Typical procedure: 10 g 2-chloropyridine (1 eq.; 88.1
mmol), 12.9 g phenylboronic acid (1.2 eq.; 105.8 mmol) and
2.31 g triphenylphosphine (0.1 eq.; 8.81 mmol) were dissol-
ved in 1,2-dimethoxyethane (100 mL). 120 mL of a 2M
K2CO3 (2.7 eq.; 240 mmol) aqueous solution were added and
the mixture was purged with argon. Palladium acetate (0.494
g; 0.025 eq.) was added and the mixture was refluxed for 18
hours. The two phases were then separated and the aqueous
phase was extracted with ethyl acetate (3X 250 mL). The com-
bined organic phases were washed with water (250 mL) and
brine (250 mL) and were dried over MgSO4. After evaporation
of the solvent, the oily residue was purified by bulb-to-bulb di-
stillation (110°C, 1 mbar) to afford 11.15 g of pure 2-phenyl-
pyridine (81 %).
(8) Title compounds have been prepared by numerous methods,
few of them being selective and none of them being attractive
for large scale synthesis; via Grignard addition to 1-(alkoxy-
carboxy)-pyridinium salts: Webb, T. R. Tetrahedron Lett.
1985, 26, 3191; via nucleophilic addition of aryl Grignard or
copper reagents at the 2- or 4-position of pyridine, followed by
oxidation of the resulting dihydropyridines: Comins, D. L.;
Smith, R. K.; Stround, E. D. Heterocycles 1984, 22, 339; via
diethyl(4-pyridyl)borane: Ishikura, M.; Ohta, T.; Terashima,
M. Chem. Pharm. Bull. 1985, 33, 4755; via palladium cross-
coupling using tin reagents (Stille coupling) or bromopyri-
dines.6
(9) For a recent review on catalytic cross-coupling reactions in
biaryl synthesis, see: Stanforth, S. P. Tetrahedron 1998, 54,
263. For a review on Suzuki coupling, see: Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457.
(10) The low reactivity of aryl chlorides in cross-coupling reac-
tions is generally ascribed to their reluctance to oxidatively
add to Pd(0). For discussions, see: a) Grushin, V. V.; Alper, H.
Chem. Rev. 1994, 94, 1047. b) Reference 9.
(18) Fitton, P.; Rick, E. A. J. Organomet. Chem. 1971, 28, 287.
(19) Lohse, O. Synth. Commun. 1996, 26, 2017.
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1994, 59, 6095.
(21) a) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034.
b) Moreno-Mañas, M.; Pajuelo, F.; Pleixats, R. J. Org. Chem.
1995, 60, 2396.
(22) a) Catalyst inhibition upon addition of pyridine has been ob-
served in the Pd(0)/P(o-tolyl)3 catalysed amination of aryl bro-
mides: Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61,
7240. b) For an example of a cationic palladium/dipicolinate
complex, see: Espinet, P.; Miguel, J. A.; Garcia-Granda, S.;
Miguel, D. Inorg. Chem. 1996, 35, 2287. c) Curiously, no
change of colour was observed upon addition of N-methyl 4-
chloropicolinamide to a toluene or DME solution of
Pd2(dba)3. When P(o-tolyl)3 was subsequently added, the
colour of the solution changed, indicating the formation of a
palladium-phosphine complex.
(11) The order of reactivity of the aryl halides (I > Br >> Cl) to-
wards addition to Pd(PPh3)4 suggests that this has some simi-
larity to aromatic nucleophilic substitution in which breaking
of the bond to the leaving group is rate determining.10,18 One
would therefore predict that the presence of electron-with-
drawing groups would increase the overall reaction rate. Some
bicyclic heteroaryl chlorides may be regarded as specially ac-
tivated.12a For example, 2-chloroquinoline and 2-chloropyri-
midine react 3x102 and 7x105 times faster than 2-
chloropyridine for nucleophilic displacement with EtO-, re-
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48
O. Lohse et al.
LETTER
(23) a) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebes-
kind, L. S. J. Org. Chem. 1994, 59, 5905. b) Boland, G. M.;
Donnelly, D. M. X.; Finet, J.-P.; Rea, M. D. J. Chem. Soc.,
Perkin Trans. I 1996, 21, 2591
(24) a) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics
1992, 11, 3009. b) Smith, G. B.; Dezeny, G. C.; Hughes, D. L.;
King, A. O.; Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151.
(25) Although three equivalents of phosphine are theoretically
enough to form the active Pd(PPh3)2 catalytic species, we
always used four equivalents to avoid precipitation of palladi-
um black.24b
(26) Self coupling of arylboronic acids has been described when
the cross coupling is very slow. It has been turned into a useful
synthetic method for the preparation of symmetrical biaryls:
see Moreno-Mañas, M.; Pérez, M.; Pleixats, R. J. Org. Chem.
1996, 61, 2346 and literature cited therein.
(27) This reaction had already been observed in 1966: Davidson,
J. M.; Triggs, C. Chem. & Ind. 1966, 457.
Synlett 1999, No. 1, 45–48 ISSN 0936-5214 © Thieme Stuttgart · New York