Palladium-catalyzed carbonylative cross-coupling reactions of pyridine halides and aryl boronic acids: A convenient access to α-pyridyl ketones

Article abstract of DOI:10.1016/S0040-4039(01)00544-5

The proper choice of solvent, catalyst precursor and CO pressure enables the easy and selective transformation of mono- and dihalopyridines into phenyl pyridyl ketones in 81-95% yields.

Full text of DOI:10.1016/S0040-4039(01)00544-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3689–3691
Palladium-catalyzed carbonylative cross-coupling reactions of
pyridine halides and aryl boronic acids: a convenient access to
a-pyridyl ketones
Samuel Couve-Bonnaire, Jean-Franc¸ois Carpentier,* Andre´ Mortreux and Yves Castanet*
Laboratoire de Catalyse de Lille associe´ au CNRS, Groupe de Chimie Organique Applique´e,
Ecole Nationale Supe´rieure de Chimie de Lille, B.P. 108-59652 Villeneuve d’Ascq, France
Received 29 March 2001; accepted 30 March 2001
Abstract—The proper choice of solvent, catalyst precursor and CO pressure enables the easy and selective transformation of
mono- and dihalopyridines into phenyl pyridyl ketones in 81–95% yields. © 2001 Elsevier Science Ltd. All rights reserved.
a-Pyridyl ketones are very useful intermediates in the
synthesis of various natural products and drugs.1 Dif-
ferent methodologies have been proposed to access this
important class of products.2 However, most of them
used unfriendly reagents, had poor overall yields and/or
were only effective with specific substrates. In view of
our current interest in the carbonylation of pyridine
halides,3 we envisioned the palladium-catalyzed cross-
coupling reaction between halopyridines, carbon
monoxide and aryl boronic acids as a general, practical
route toward aryl pyridyl ketones. To our knowledge,
the only two previous attempts in this direction were
limited to 2-pyridyl halides and led only to modest
yields into 2-benzoylpyridine.4
Table 1. Palladium-catalyzed carbonylative cross-coupling reaction of monohalogenated pyridines and phenyl boronic acida
Entry
Substrate
Catalyst
P(CO) (bar)
Temp. (°C)
Timeb (h)
Product
Conversionc (%) Selectivityc (%)
precursor
1d
2d
3
1a
1a
1a
3a
3b
3b
5
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(Pcy3)2
PdCl2(PPh3)2
PdCl2(Pcy3)2
PdCl2(Pcy3)2
PdCl2(Pcy3)2
1
5
5
5
5
5
5
5
5
80
80
80
20
5
2
2
2
4
4
4
–
6
2
2
2
4
100
100
100
100
100
100
0
100
80
100
100
36
25
75
90 (80)
95 (82)
82
85
–
91 (80)
35
62
24
20
20
26
24
20
24
20
20
70
4
100
120
120
120
120
120
120
120
150
5
6e
7
8
9
10
11
12
5
1b
1b
1b
3c
5
50
5
93
53
a Unless otherwise stated: 0.03 mmol Pd catalyst precursor, 1.0 mmol halopyridine, 1.1 mmol (0.134 g) PhB(OH)2, 3.0 mmol (0.414 g) K2CO3, 20
mL THF.
b Reaction time was not necessarily optimized.
c Determined by quantitative GLC; direct non-carbonylative cross-coupling products account for the balance; figures in parentheses are isolated
yields of >95% pure product.
d Anisole (20 mL) was used as solvent.
e Reaction carried out in the presence of 3.0 mmol of KI.
Keywords: carbonylation; cross-coupling; ketones; palladium; pyridines.
* Corresponding authors. Tel.: +33 (0)320 434 927; fax: +33 (0)320 436 585. ; e-mail: yves.castanet@ensc-lille.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00544-5

3690
S. Cou6e-Bonnaire et al. / Tetrahedron Letters 42 (2001) 3689–3691
[Pd]
X
COPh
Ph
+ CO + PhB(OH)2
+
K2CO3
N
N
N
1a: X = 4-I; 1b: X = 4-Br
2: X = 4-COPh
4: X = 2-COPh
6: X = 3-COPh
3a: X = 2-I; 3b: X = 2-Br; 3c: X = 2-Cl
5: X = 3-Br
Scheme 1.
PdCl2(PCy3)2 (3 mol%)
PhB(OH)2 (2.2 eq)
+
Br
N
Br
Ph
N
COPh
PhCO
N
COPh
CO, K2CO3, THF
7
8
9
120 °C, 5 bar, 30 h; 100 % conv.
90 °C, 50 bar, 110 h; 100% conv.
63% : 26%
18% : 81%
Scheme 2.
Br
Br
+
COPh
PdCl2(PCy3)2 (3 mol%)
PhB(OH)2 (2.2 eq)
N
Br
PhCO
N
PhCO
N
CO, K2CO3, THF
10
11
12
120 °C, 5 bar, 2 h; 84 % conv.
120 °C, 5 bar, 42 h; 100% conv.
83% sel.
81% sel.
Scheme 3.
Table 1 shows that the proper choice of reaction con-
ditions and catalyst precursors enables the carbonyla-
tive cross-coupling of phenyl boronic acid (chosen as
a model reagent) with a variety of iodo- and bromo-
pyridines in high yields and selectivities (Scheme 1).
The reaction of 4-iodopyridine5 (1a) using anisole as
the solvent and under 1 bar of CO4a,c gave primarily
the direct non-carbonylative coupling product, and 4-
benzoylpyridine (2) was recovered with a poor final
yield (entry 1). The yield into 2 increased significantly
to 75% upon increasing the CO pressure to 5 bar
(entry 2). Using THF in place of anisole increased
the yield to 90% (entry 3) and had the obvious
advantage of an easier final work-up.† Under these
reaction conditions, 2-iodopyridine6 (3a) gave 2-ben-
zoylpyridine (4) in 95% yield (entry 4). On the other
hand, the reactivity of commercially available bromo-
pyridines proved much more variable. The carbonyla-
tive cross-coupling of 2-bromopyridine (3b) under the
above conditions occurred with satisfying selectivity
(82% into 4, entry 5), whereas 3-bromopyridine (5)
was completely inactive. In the latter case, activity
and high selectivity for 3-benzoylpyridine (6) were
restored when PdCl2(PCy3)2 was used as the catalytic
precursor instead of PdCl2(PPh3)2 (entry 8). For 4-
bromopyridine (1b), both the presence of the bulky
basic tricyclohexylphosphine ligand and rather high
CO pressure were required to attain a high selectivity
into 2 (entries 9–11).
Taking into account the good results obtained with
monobromopyridines, the work was extended to
dibromopyridines with the purpose of studying the
regioselectivity of the reaction. Under low CO pres-
sure (5 bar), 2,6-dibromopyridine (7) reacted to give,
in 63% yield, compound 8 resulting from the combi-
nation of direct cross-coupling and carbonylative
cross-coupling reactions (Scheme 2). Higher CO pres-
sure and lower temperature induced the selective for-
mation of the 2,6-dibenzoylpyridine (9), but with
rather low activity. In the case of 2,5-dibromopy-
ridine (10), under the same CO pressure (50 bar),
corresponding diketone 12 was obtained with similar
satisfying selectivity (Scheme 3). It is also noteworthy
that quenching the reaction at a low reaction time (2
h, 84% conversion) led selectively to 2-benzoyl-5-bromo-
pyridine (11). The high regioselectivity of thi
intermediary reaction clearly stems from the well-
† A typical procedure is as follows (entry 3): a suspension of 1a (0.205
g, 1.0 mmol), PhB(OH)2 (0.134 g, 1.1 mmol), K2CO3 (0.414 g, 3.0
mmol) and PdCl2(PPh3)2 (0.021 g, 0.03 mmol) in THF (20 mL) was
charged under nitrogen into a 50 mL stainless steel autoclave
equipped with a magnetic stirrer bar. After sealing, the reactor was
pressurized to 5 bar with CO and heated to 80°C. At the end of the
reaction, the reactor was cooled to room temperature and the
reaction mixture was analyzed by GLC to determine conversion
and selectivities. The reaction mixture was concentrated under
vacuum and the crude residue was chromatographed on silica using
AcOEt/heptane (1:1) as eluent, to yield analytically pure 2 as a pale
yellow solid (0.147 g, 80%). All of the reaction products described
in this paper were characterized by 1H, 13C NMR and MS, and
gave data in full accordance with the proposed structures.

S. Cou6e-Bonnaire et al. / Tetrahedron Letters 42 (2001) 3689–3691
3691
known electron-withdrawing effect of the pyridyl ring
that activates the 2-C–Br bond for oxidative addition
onto zerovalent palladium.
2. (a) Hlasta, D. J.; Court, J. J. Tetrahedron Lett. 1989, 30,
1773–1776; (b) Herrmann, C. K.; Sachdeva, Y. P.; Wolfe,
J. F. J. Heterocycl. Chem. 1987, 24, 1061–1065; (c)
Sakamoto, T.; Kondo, Y.; Murata, N.; Yamanaka, H.
Tetrahedron 1993, 49, 9713–9720; (d) Yamamoto, Y.;
Ouchi, H.; Tanaka, T. Chem. Pharm. Bull. 1995, 43,
1028–1030; (e) Tre´court, F.; Breton, G.; Bonnet, V.;
Mongin, F.; Marsais, F.; Queguiner, G. Tetrahedron Lett.
1999, 40, 4339–4342.
Current efforts are focused on the synthesis of targeted
molecules using this procedure and on its extension to
chloropyridines, an attractive although significantly
more demanding process (Table 1, entry 12).
3. (a) Douja, N.; Carpentier, J.-F.; Castanet, Y.; Biot, C.;
Brocard, J.; Mortreux, A. Tetrahedron Lett. 1999, 40,
3719–3722; (b) Couve-Bonnaire, S.; Carpentier, J.-F.; Cas-
tanet, Y.; Mortreux, A. Tetrahedron Lett. 1999, 40, 3717–
3718; (c) Couve-Bonnaire, S.; Carpentier, J.-F.; Mortreux,
A.; Castanet, Y. Adv. Synth. Catal. 2001, 343, 289–298.
4. (a) Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A.
Tetrahedron Lett. 1993, 34, 7595–7598; (b) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (c) Ishiyama,
T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J.
Org. Chem. 1998, 63, 4726–4731.
Acknowledgements
This work was supported by the Ministe`re de la
Recherche et de l’Enseignement Supe´rieur (grant to
S.C.B.) and by the CNRS.
References
1. (a) Comprehensive Heterocyclic Chemistry; Boulton, A. J.;
Mekillop, A., Eds.; Pergamon Press: Oxford, 1984; Vol. 2;
(b) De Kimpe, N.; Keppens, M.; Fonck, G. J. Chem. Soc.,
Chem. Commun. 1996, 635–636.
5. Coudret, C. Synth. Commun. 1996, 26, 3543–3547.
6. Corcoran, R. C.; Bang, S. H. Tetrahedron Lett. 1990, 31,
6757–6758.
.