An efficient copper-catalyzed coupling reaction of pyridin-2-ones with aryl and heterocyclic halides based on Buchwald's protocol

Article abstract of DOI:10.1016/j.tetlet.2004.04.019

An efficient copper-catalyzed coupling reaction based on the Buchwald's protocol has been established for pyridin-2-ones with aryl iodides, aryl bromides, and heterocyclic bromides.

Full text of DOI:10.1016/j.tetlet.2004.04.019

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4257–4260
An efficient copper-catalyzed coupling reaction of pyridin-2-ones
with aryl and heterocyclic halides based on Buchwald’s protocol
Chun Sing Li* and Darryl D. Dixon
Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., PO Box 1005, Pointe-Clarie Dorval, Quebec,
Canada H9R 4P8
Received 17 March 2004; accepted 6April 2004
Abstract—An efficient copper-catalyzed coupling reaction based on the Buchwald’s protocol has been established for pyridin-2-ones
with aryl iodides, aryl bromides, and heterocyclic bromides.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Pyridin-2-one is an important component of many
pharmacological active substances1 and N-aryl substi-
tution is frequently a key structural feature. Our ability
to synthesize these N-aryl substituted pyridin-2-ones in a
diverse and efficient manner would therefore offer the
possibility to broaden the scope of SAR studies.
N-arylation of amines under the copper-catalyzed Ull-
mann reaction usually requires drastic reaction condi-
tions and produces moderate yields of the desired
products.2 However, improved conditions for the
N-arylation of heterocyclic compounds have been
reported.3;4 Lam has also developed a copper-catalyzed
cross-coupling reaction of N-heterocyclic compounds
with aryl boronic acids to give N-aryl substituted het-
erocycles in fair to excellent yields.5 Scope of this
N-arylation has been studied with different substituted
pyridin-2-ones.6 Recently, Buchwald has developed an
efficient copper-catalyzed system for the amination and
amidation of aryl and heterocyclic halides.7 This copper-
catalyzed system provides an opportunity to easily access
a number of N-aryl heterocyclic analogs, but the poten-
tial of this copper-catalyzed system in the synthesis of N-
aryl substituted heterocyclic system has not yet been fully
investigated. One recent example is the application to the
synthesis of a N-aryl oxazolidinone,8 which is a key
structural feature of a new class of oxazolidinone
antibiotics. Herein, we report our application of the
Buchwald copper-catalyzed system to the cross-coupling
reaction of pyridin-2-ones with aryl halides and discuss
the scope and limitation of this synthetic reaction.
Buchwald’s group has extensively investigated effects of
ligands and bases on the copper-catalyzed coupling
reaction.9 We were pleased to see that N,N0-dimethyl-
ethylenediamine as the ligand and K3PO4 as the base
could be conveniently used and gave very satisfactory
results in our present study. Other ligands such as 1,2-
diaminocyclohexanane were less effective although this
ligand was successful in the oxazolidinone synthesis.8
Replacement of K3PO4 with CsCO3 gave poorer yield of
the coupling product. The following conditions were
used throughout this study: A screw cap 2-dram vial was
charged with 1,4-dioxane (1.5 mL), pyridin-2-one
(1 mmol), and aryl halide (1.2 mmol). CuI (40 mg,
0.2 mmol), N,N0-dimethyethylenediamine (44 L, 0.4
mmol), and K3PO4 (425 mg, 2 mmol) were added. The
mixture was then flushed with nitrogen, capped and
placed in an oil bath at 110 ꢁC, and stirred for 16–24 h.
After cooling to room temperature, the mixture was
diluted with water and extracted with ethyl acetate.
Purification over silica gel and elution with hexanes–
ethyl acetate provided the desired coupling product.10
The coupling reaction of some representative pyridin-2-
ones and aryl iodides were summarized in Table 1.
Yields were in general very good. There were two
exceptions. While a mild electron-withdrawing sub-
stituent on the pyridin-2-one such as a carboxylic ester
in 1d posed no problem in the coupling reaction, a
strong electron-withdrawing substituent such as nitro
Keywords: Pyridin-2-ones; Aryl halides; Copper-catalyzed coupling
reaction.
* Corresponding author. Tel.: +1-514-428-3217; fax: +1-514-428-4900;
e-mail: chunsing_li@merck.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.019

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C. S. Li, D. D. Dixon / Tetrahedron Letters 45 (2004) 4257–4260
Table 1. Coupling reaction of pyridin-2-ones with aryl iodides
20 mol% CuI,
40 mol% Ligand,
2 equiv. K3PO4
X
H
N
O
X
+
Y
N
O
1,4-Dioxane, 110 o
16 - 24h
C
1.2 mmol
1 mmol
I
Y
3
1
2
(%) Yield of N-aryl pydirin-2-ones, 3
Pydridin-2-one 1
Aryl iodine 2, X ¼
4-Me 2a
3-OMe 2b
4-OMe 2c
4-CO2ET 2d
4-Cl 2e
2-Me 2f
H
N
O
1a
81
84
78
82
40
0
H
N
O
1b
1c
1d
94
87
77
78
82
92
91
90
69
92
81
95
85
75
Me
H
N
O
MeO
H
N
O
55
EtO2C
H
N
O
a
1e
6
8
90
6
7
83
50
Cl
H
N
O
1f
82
95
97
85
66
Me
O
H
Me
N
1g
Trace
Trace
H
N
O
1h
Trace
Trace
O2N
a 5% of dechlorinated product on the part of pyridin-2-one was also detected.
group in 1h11 impeded the coupling reaction. One of the
reasons might be due to reduced nucleophilicity of the
nitrogen atom on the pyridin-2-one. The coupling
reaction also failed with substrates containing a sub-
stituent next to one of the reacting centers such as 2-
iodo-toluene 2f and 6-methyl-pyridin-2-one 1g,12 most
likely due to steric effects. In general, a number of
electron-withdrawing and donating substituents, either
on the pyridin-2-one (1c13 and 1d) or the aryl iodide (2b,
2c, and 2d), were well tolerated. Although 4-chloro-1-
iodo-benzene 2e provided fair to good yield in the
coupling reaction, the coupling reaction with 4-bromo-
1-iodo-benzene was problematic. The bromine atom in
the coupling product was found to be labile and would
undergo a Finkelstein type reaction with iodide in the
mixture.14 The resulting iodide would then slowly lose
the iodine to give the reduced product.
(Scheme 1). An equimolar mixture of pyridin-2-one 1a,
aryl iodides 2c, 2a, and 2d was reacted under the present
conditions and gave pyridin-2-ones 4, 5, and 6 in a ratio
of 1:1.4:4.7. This result demonstrated that an aryl iodide
with an electon-withdrawing substitutent reacted more
readily than a neutral substituent, which was in turn
slightly more reactive than an aryl iodide with an elec-
tron-donating substituent.
Since aryl bromides are more readily commercially
available, we then tested the coupling reaction with aryl
bromides. This copper-catalyzed coupling reaction of
pyridin-2-one was equally successful with aryl bromides
(Table 2). Excellent yields of coupling products could
also be obtained.
The use of bromide in the copper-catalyzed coupling
reaction is particular suitable for heterocyclic substrates
since the corresponding iodides are not always accessi-
ble. Some of the coupling reactions of pyridin-2-one 1a
with heterocyclic bromides were summarized in Table 3.
We were curious about effect of substituents on the rate
of the coupling reaction and used a simple competition
experiment to evaluate these effects on the aryl iodide

C. S. Li, D. D. Dixon / Tetrahedron Letters 45 (2004) 4257–4260
4259
Table 3. Coupling reaction with heterocyclic bromides
OMe
Me
CO2Et
H
N
20 mol% CuI,
O
Het
N
H
40 mol% Ligand,
N
O
+
+
+
O
2 equiv. K3PO4
+
Het-Br
2d
1,4-Dioxane, 110 o
20 - 24 h
C
I
I
I
2a
2c
1a
1a
1 mmol of each substrates
(1.2 equiv.)
(1 equiv.)
Het-Br
% Yield
81
1,4-Dioxane, 110 oC,
15h,
70% yield based on
Pyridin-2-one
20 mol% CuI,
40 mol% Ligand,
2 eq. K3PO4
S
Br
S
OMe
Me
N
CO2Et
80
27
Br
N
S
N
1
O
O
N
O
+
+
Br
H
N
6
5
4
16
:
1.4
:
4.7
Br
Scheme 1.
10
N
The coupling reaction gave excellent yields with 2-
bromothiophene and 3-bromothiophene, but poorer
yields with nitrogen-containing heterocycles such as 2-
bromothiazole, 5-bromoindole, 8-bromoquinoline, and
3-bromopyridine.15 Coordination of the nitrogen atom
with the copper catalyst from these nitrogen-containing
heterocycles might impede the catalytic process.
Br
Br
N
8
OMe
20 mol% CuI,
Table 2. Coupling reaction with aryl bromides
H
40 mol% Ligand,
2 equiv. K3PO4
N
O
20 mol% CuI,
40 mol% Ligand,
2 equiv. K3PO4
Br
+
X
N
O
I
OMe
1,4-Dioxane, 110 o
7h
C
H
N
O
1a
10 mmol
2b
12 mmol
7
X
N
O
(75% yield)
1,4-Dioxane, 110 o
22h
C
1a
1 mmol
Scheme 2.
1,2 mmol
X
4-Me
4-OMe
82
4-CO2Et
91
Acknowledgements
% Yield of N-aryl pyridin-2-ones
88
We are thankful to NSERC for an Undergraduate
Student Research Award to Darryl D. Dixon and Dr.
Cameron Black for suggestions on the manuscript.
To test whether this coupling reaction could be scaled
up to gram quantity, we have carried out the coupling
reaction of pyridin-2-one 1a and 3-iodoanisole 2b on a
10 mmol scale (Scheme 2).16 The coupling product 7 was
obtained in 75% yield, which was comparable to the
1 mmol scale reaction (84% yield, Table 1).
References and notes
1. A few examples from the patent literature: (a) Farnesyl-
transferase inhibitor from Merck & Co., Inc. WO9828980;
(b) a-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid
(AMPA) receptor modulator from Eisai Co. Ltd.,
WO0196308; (c) p-38 MAP kinase inhibitor from Celltech
R&D Ltd., WO03033502 and from Bayer AG,
WO03076405; (d) Factor Xa antagonist from Merck Patent
GmbH, WO0040583.
2. For a review on copper-assisted nucleophilic substitution of
aryl halides: Lindley, J. Tetrahedron 1984, 40, 1433–1456.
3. Renger, B. Synthesis 1985, 856–860.
4. Sugahara, M.; Ukita, T. Chem. Pharm. Bull. 1997, 45,
719–721.
In conclusion, we have explored the copper-catalyzed
coupling reaction of pyridin-2-ones with aromatic
halides based on Buchwald’s protocol. This reaction has
the potential to scale up to a preparative scale. It gave
excellent yields with representative substituted pyridin-
2-ones and aryl halides containing either electron-
donating
or
electron-withdrawing
substituents.
Nonnitrogen containing heterocyclic bromides such
thiophene were well tolerated. However, a strong
electron-withdrawing substitutent such as a nitro group
at the 5-position of the pyridin-2-one 1h and a sub-
stituent next to the reactive centers on the pyridin-2-one
1g or the aryl halide 2f impeded the coupling reaction.
5. (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Averill, K. M.; Chan, D. M. T.; Combs, A. P. Synlett 2000,
674–676; (b) Lam, P. Y. S.; Vincent, G.; Clark, C. G.;

4260
C. S. Li, D. D. Dixon / Tetrahedron Letters 45 (2004) 4257–4260
Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42,
3415–3418.
6. Mederski, W. W. K. R.; Lefort, M.; Germann, M.
Tetrahedron 1999, 55, 12757–12770.
*Decomposition of the diazonium salt was performed with
the conditions reported by Cohen: Cohen, T.; Dietz,
A. G.; Miser, J. R. J. Org. Chem. 1977, 42, 2053–
2058.
7. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727–7729.
14. Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
14844–14845.
8. Mallesham, B.; Rajesh, B. M.; Reddy, P. R.; Srinivas, D.;
Trehan, S. Org. Lett. 2003, 5, 963–965.
15. Ukita has also observed poorer reaction with 3-bromo-
pyridine, Ref. 4.
9. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421–7428.
10. All reported yields were based on isolated products, which
16. To a 50 mL round-bottomed flask was added pyridin-2-
one 1a (0.95 g, 10 mmol), 3-iodoanisole 2b (2.81 g,
12 mmol), CuI (0.4 g, 2 mmol), and 1,4-dioxane (15 mL).
The mixture was stirred for 5-10 min to dissolve 1a and 2b.
N,N0-dimethylethylenediamine (0.44 mL, 4 mmol) was
added, followed by K3PO4 (4.25 g, 20 mmol). The mixture
was flushed with N2, equipped with a reflux condenser,
and heated on a 110 ꢁC bath for 7 h. After cooling to room
temperature, the mixture was diluted with H2O, extracted
with EtOAc (3·). The EtOAc extracts were combined,
washed with brine, dried (MgSO4), and concentrated.
Chromatography over silics gel and elution with hexanes–
EtOAc (1:1), followed by 100 % of EtOAc gave 1.5 g (75%)
of the coupling product 7. 1H NMR (acetone-d6) d 7.52
(1H, d, J ¼ 6:8 Hz), 7.44 (1H, dt, J ¼ 8:8, 1.9 Hz), 7.39
(1H, t, J ¼ 8:0 Hz), 6.99–6.94 (m, 3H), 6.43 (1H, d,
J ¼ 9:2 Hz), 6.25 (1H, t, J ¼ 6:7 Hz), 3.83 (s, 3H); MS
(+ESl) m=z 202 (MHþ).
1
gave satisfactory H NMR and MS data.
11. In contrast, the copper-catalyzed coupling reaction of 1h
with 4-methylphenylboronic acid gave 38% yield of
coupling product, Ref. 6.
12. The copper-catalyzed coupling reaction of 1g also failed
with 4-methylphenylboronic acid, Ref. 6.
13. 1c was prepared according to the following scheme:
1. t-BuOK, BnOH, DMF
80 oC (77%)
N
Cl
N
OBn
2. Fe, NH4Cl,
O2N
H2N
O
EtOH, H2O
Refux (96%)
1. NaNO2, H2SO4,
then
*
H
N
CuO, Cu(NO3)2
(51%)
2. MeI, NaOH, DMF
0oC - r.t. (84%)
MeO
1c
3. H2, 10%Pd/C,
EtOH (83%)