Copper-catalysed amidation of 2-chloro-pyridines

Article abstract of DOI:10.1039/c3ra43368d

The simple and inexpensive N,N-dimethylcyclohexane-1,2-diamine/CuI catalytic system provides a versatile, easy and efficient access to an array of N-(2-pyridin-2-yl)-amides from 2-chloro-pyridine derivatives. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra43368d

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DOI: 10.1039/C3RA43368D
Copper-catalysed amidation of 2-chloro-pyridines.
Lionel Nicolas, Patrick Angibaud, Ian Stansfield, Lieven Meerpoel, Sébastien Reymond*
and Janine Cossy*
ESPCI ParisTech, Laboratoire de Chimie Organique, CNRS UMR7084, 10 Rue
Vauquelin, 75231, Paris Cedex 05, France.
H
N
N
R3
H
R3
(5 mol%)
CuI (5 mol%)
N
Cl
N
N
R2
HN
R2
R1
R1
+
O
K2CO3 (2 equiv)
1,4 dioxane
170 °C, 24 h
O
(1.5 equiv)
21-96%

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DOI: 10.1039/C3RA43368D
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Copper-catalysed amidation of 2-chloro-pyridines.
Lionel Nicolas,a Patrick Angibaud,b Ian Stansfield,b Lieven Meerpoel,c Sébastien Reymond*a
and Janine Cossy*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Table 1 Ligand screening in the amidation of 2ꢀchloropyridine
The simple and inexpensive N,N-dimethylcyclohexane-1,2-
diamine/CuI catalytic system provides a versatile, easy and
efficient access to an array of N-(2-pyridin-2-yl)-amides from
2-chloro-pyridine derivatives.
H
N
Cl
N
N
Ph
[Cu] / ligand
H2N
+
O
K2CO3 (3 equiv)
1,4-dioxane, 24 h
O
(1.5 equiv)
50
Entrya [Cu]
Ligand
(mol%)
T
(°C)
Yieldb
10
Amide formation is ubiquitous in organic chemistry as many
biologicallyꢀrelevant synthetic and natural products incorporate
an amide moiety. Among amides, Nꢀheteroaryl amides constitute
one important class of pharmacophores used in medicinal
chemistry and, recently, Nꢀ(2ꢀpyridinꢀ2ꢀyl)ꢀamide derivatives
(mol%)
O
O
Ph
Ph
1
CuI (50)
100
100
100
ꢀ
ꢀ
ꢀ
(50)
15 were reported to block sodium channels which are involved in
neuronal regulation with potential applications in the treatment of
pain, arrhythmia or epilepsy.1 Nonꢀcatalytic amidations of
2ꢀamino heterocycles as well as metalꢀcatalysed amidations of
aryl halides are existing to access amide derivatives.2 However,
20 despite considerable progresses in palladiumꢀ and copperꢀ
catalysed CꢀN bond formation,3ꢀ5 broadening the scope of
electrophiles and nucleophiles that can be used in these reactions,
only few methods are able to achieve the amidation of aryl
chlorides, and a few examples are reported for the amidation of
25 2ꢀchloroꢀpyridine derivatives which are less reactive than their
brominated counterparts.6 Herein, we would like to report a
general method for the catalytic amidation of chloroꢀpyridine
derivatives derivatives involving a cheap and simple catalytic
system based on CuI and transꢀN,Nꢀdimethylꢀcyclohexaneꢀ1,2ꢀ
30 diamine.6bꢀc,f,7,8,9
COOH
N
2
3
4
CuI (50)
CuI (50)
CuI (50)
H
(50)
O
N
OH
(50)
H
N
N
H
100 48%
100 82%
(50)
H
N
5
CuI (50)
N
H
L (50)
a c = 1 M; b isolated yield.
as a base, instead of K2CO3, led to a slightly decreased yield
(74%) whereas the use of Cs2CO3 lowered the yield to 36%
55 (Table 2, entries 5ꢀ6). When DMF was used as the solvent,
Nꢀ(pyridinꢀ2ꢀyl)benzamide was isolated in 48% yield, and when
DME was utilised, the yield was similar to the one obtained with
1,4ꢀdioxane (85%) (Table 2, entries 7ꢀ8). A decrease of the
catalytic loading in both CuI and ligand L from 50 mol% to
60 10 mol% dramatically decreased the yield in the crossꢀcoupling;
Nꢀ(pyridinꢀ2ꢀyl)benzamide was isolated in 71% yield with
25 mol%, and in 28% yield with a 10 mol% catalytic loading
(Table 2, entries 9ꢀ10). Gratifyingly, when the reaction was
performed with 10 mol% of CuI and 10 mol% of L in
Initially,
a catalytic amidation of 2ꢀchloropyridine with
benzamide was examined to tune up the reaction conditions
(Table 1). Initial trials involving CuI (50 mol%) and
1,3ꢀdiphenylpropanꢀ1,3ꢀdione, proline or N,Nꢀdimethylglycine as
35 ligands (50 mol%) did not lead to any conversion of the starting
materials (Table 1, entries 1ꢀ3). However, the use of N,Nꢀ
dimethylꢀethylenediamine as ligand (50 mol%) provided Nꢀ
(pyridinꢀ2ꢀyl)benzamide in 48% yield (Table 1, entry 4), and the
yield was increased to 82% when N,Nꢀdimethylcyclohexaneꢀ1,2ꢀ
40 diamine (50 mol%) was used (Table 1, entry 5).
Having identified N,Nꢀdimethylcyclohexaneꢀ1,2ꢀdiamine (L)
as the best ligand, the optimisation of the amidation of
2ꢀchloropyridine with benzamide was achieved (Table 2). Other
copper sources such as CuO, CuBr, Cu2O or Cu(OAc)2•H2O were
45 evaluated (Table 2, entries 1ꢀ4), however they displayed lower
catalytic activities than CuI (Table1, entry 5). The use of K3PO4
65 1,4ꢀdioxane in
a sealed tube at 170 °C, Nꢀ(pyridinꢀ2ꢀ
yl)benzamide was isolated in 81% yield (Table 2, entry 11) and,
at this temperature, the amount of K2CO3 could be reduced to 2
equivalents. It was possible to decrease the catalytic charge to
5 mol% of CuI and 5 mol% of L as Nꢀ(pyridinꢀ2ꢀyl)benzamide
70 was still obtained in good yield (69%) (Table 2, entry 12). With
2 mol% of CuI and 2 mol% of L, the yield was 60% however,
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Table 2 Optimisation of the catalyst for the amidation of
2ꢀchloropyridine
Table 3 Amidation of 2ꢀchloropyridine with various amides
R2
N
CuI (5 mol%)
L (5 mol%)
N
R1
N
Cl
R2HN
R1
H
N
Cl
+
N
N
Ph
[Cu] / L
H2N
O
K2CO3 (2 equiv)
1,4 dioxane, 170 °C
24 h
+
O
O
solvent, base
24 h
O
(1.5 equiv)
(1.5 equiv)
Entrya,b
1
Amide
Product
Yieldc
72%
Entry
[Cu] L (mol%)
(mol%)
Base
(equiv)
Solventa
T
(°C)
Yieldb
OMe
OMe
H
N
(50)
(50)
1
2
3
4
CuO (50)
CuBr (50)
K2CO3 (3) 1,4ꢀdioxane 100 11%
K2CO3 (3) 1,4ꢀdioxane 100 23%
K2CO3 (3) 1,4ꢀdioxane 100 38%
K2CO3 (3) 1,4ꢀdioxane 100 26%
N
H2N
O
O
Cu2O (50) (50)
(50)
Cu(OAc)2ꢀ
H2O (50)
CuI (50)
CuI (50)
CuI (50)
CuI (50)
CuI (25)
CuI (10)
CuI (10)
CuI (5)
CuI (2)
ꢀ
H
N
N
H2N
2
3
66%
57%
(50)
(50)
(50)
(50)
(25)
(10)
(10)
(5)
5
6
7
8
K3PO4 (3) 1,4ꢀdioxane 100 74%
Cs2CO3 (3) 1,4ꢀdioxane 100 36%
K2CO3 (3)
K2CO3 (3)
O
O
NO2
NO2
DMF
DME
150 38%
85 85%
H
N
N
H2N
9
K2CO3 (3) 1,4ꢀdioxane 100 71%
K2CO3 (3) 1,4ꢀdioxane 100 28%
K2CO3 (2) 1,4ꢀdioxane 170c 81%
K2CO3 (2) 1,4ꢀdioxane 170c 69%
K2CO3 (2) 1,4ꢀdioxane 170c 60%d
O
O
10
11
12
13
14
15
Cl
Cl
Cl
Cl
H
N
N
4
5
H2N
69%
83%
(2)
-
O
O
K2CO3 (2) 1,4ꢀdioxane 170c
K2CO3 (2) 1,4ꢀdioxane 170c
K2CO3 (2) 1,4ꢀdioxane 170c
ꢀ
ꢀ
ꢀ
N
N
-
CuI (10)
H
N
N
(10)
H2N
16
ꢀ
a
b
c = 1 M; isolated yield; c reaction performed in a sealed tube;
O
O
O
5
d after 60 h of reaction.
S
S
H
N
N
N
H2N
H2N
6
7
8
75%
96%
78%
after 60 h of reaction (Table 2, entry 13). We have to point out
that in the absence of either CuI or L, no conversion of the
starting material was observed under the reaction conditions
O
O
H
N
10 (Table 2, entries 14ꢀ16).10
O
N
Having obtained optimized conditions for the crossꢀcoupling
of 2ꢀchloropyridine with benzamide (5 mol% of CuI and 5 mol%
of L, 2 equiv of K2CO3, 170 °C, 1,4ꢀdioxane, 24 h), the reaction
of 2ꢀchloropyridine was evaluated with several aromatic,
15 heteroaromatic and aliphatic amides, and the results are reported
in Table 3. Aromatic amides such as 4ꢀmethoxybenzamide,
4ꢀmethylbenzamide or 4ꢀnitrobenzamide provided the
corresponding crossꢀcoupling products in 72ꢀ57% yield (Table 3,
entries 1ꢀ3), the electronꢀpoor 4ꢀnitrobenzamide leading to the
20 lowest yield (57%) (Table 3, entry 3). When 3,4ꢀdichloroꢀ
benzamide was engaged in the amidation of 2ꢀchloropyridine, the
crossꢀcoupling was chemoselective and the expected amide was
obtained in 69% yield (Table 3, entry 4). Heteroaromatic amides
such as nicotinamide or thiopheneꢀ2ꢀcarboxamide are suitable in
25 the crossꢀcoupling with 2ꢀchloropyridine as the corresponding
amides were isolated with good yields of 83% and 75%
respectively (Table 3, entries 5 and 6). Aliphatic amides such as a
primary amide, butyramide, or a secondary amide, piperidinꢀ2ꢀ
one, provided the expected Nꢀ(pyridinꢀ2ꢀyl)amides in 96% and
30 78% yields respectively (Table 3, entries 7ꢀ8).
N
HN
O
O
a c = 1 M; b reaction performed in a sealed tube; c isolated yield.
40
yl)benzamide was obtained in 92% yield (Table 4, entry 1),
whereas with 2ꢀchloroꢀ3ꢀmethoxypyridine, no crossꢀcoupling
product was isolated and the starting material was recovered
(Table 4, entry 2). The reaction of 2ꢀchloroꢀ5ꢀchloropyridine was
45 chemoselective and the expected monoꢀamide was obtained
selectively, however in 45% isolated yield for 75% conversion of
the starting dihalopyridine (Table 3, entry 3). When
2,4ꢀdichloropyridine was used, the corresponding monoꢀamide
was obtained chemoselectively and, in this case, the isolated yield
50 was 32%, for 72% conversion of the starting 2,4ꢀdichloroꢀ
pyridine (Table 3, entry 4). In contrast, the use of 2ꢀchloroꢀ4ꢀ
iodopyridine led to the expected diamide in 32% yield and only
traces of the monoꢀamide were observed (Table 3, entry 5).
Concerning 2ꢀchloroꢀ4ꢀbromopyridine, the diamide product was
55 isolated in only 21% yield, and only traces of the monoꢀamide
were observed (Table 3, entry 6). Worthy of note is the reaction
of 3ꢀchloropyridine which was unreactive under the reaction
conditions (Table 3, entry 7). Finally, 2ꢀchloropyrazine and 2ꢀ
chloroquinoline successfully reacted with benzamide, and the
At this stage, the amidation of other pyridyl halides with
benzamide was examined, under the optimized conditions
(5 mol% of CuI and 5 mol% of L, 2 equiv of K2CO3, 170 °C,
35 1,4ꢀdioxane, 24 h), and the results are reported in Table 4. When
2ꢀchloroꢀ5ꢀmethoxypyridine was used, Nꢀ(5ꢀmethoxypyridinꢀ2ꢀ
2
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Table 4 Amidation of various halogenoꢀheteroaromatics
Acknowledgements
CuI (5 mol%)
L (5 mol%)
N
N
20 Janssen Research & Development, a Division of JanssenꢀCilag, is
gratefully acknowledged for financial support.
H2N
Ph
X +
NH
O
K2CO3 (2 equiv)
1,4 dioxane, 170 °C
24 h
Ph
A
A
O
(1.5 equiv)
Notes and references
a Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084,
10, rue Vauquelin, 75231 Paris Cedex 05, France.
Entrya,b Halogenopyridine
Product
Yieldc
92%
H
N
Cl
N
N
Ph
25 e-mail : janine.cossy@espci.fr;sebastien.reymond@espci.fr
Fax : (+33)140794660 ; Tel : (+33)140794659.
1
2
3
O
b Janssen Research & Development, a division of Janssen-Cilag, BP615-
Chaussée du Vexin, 27106 Val de Reuil-France.
MeO
MeO
N
Cl
c Janssen Research & Development, a division of Janssen Pharmaceutica
30 N.V. Turnhoutsweg 30, 2340 Beerse, Belgium.
ꢀ
ꢀ
OMe
Cl
H
N
N
N
Ph
† Electronic Supplementary Information (ESI) available: Experimental
procedures, spectroscopic data and NMR spectra for amide compounds.
See DOI: 10.1039/b000000x/
45%d
O
Cl
Cl
35
H
N
N
Cl
Cl
1 C. Ni, M. Park, B. Shao, L. Tafesse, J. Yao, M. Youngman, X. Zhou,
WO 2012/085650 A1, 2012.
N
Ph
4
32%e
O
2 The stoichiometric amidation of 2ꢀamino heterocycles is not always an
obvious reaction because of their low nucleophilicity. For examples, see:
40 a) A. R. Katritzky, H. ꢀY. He, K. Suzuki, J. Org. Chem., 2000, 65, 8210.
b) A. R. Katritzky, B. ElꢀDien M. ElꢀGendy, E. Todadze, A. A. A. Abdelꢀ
Fattah., J. Org. Chem., 2008, 73, 5442. c) K. Kim, K. Le, Synlett, 1999,
1957.
Cl
N
Cl
H
N
N
Ph
O
5
6
32%f
21%f
3 a) Topics in Organometallic Chemistry, Metal-catalyzed C(sp2)-N bond
45 Formation, A. Correa, C. Bolm, Springer: Berlin, Heidelberg, 2013. b)
Topics in Organometallic Chemistry, Assembly of N-Containing
Heterocycles via Pd- and Cu-Catalyzed C–N Bond Formation Reactions,
Y. Jiang, D. Ma, Springer: Berlin, Heidelberg, 2013. c) I. P. Beletskaya,
A. V. Cheprakov, Organometallics, 2012, 31, 7753.
50 4 For reviews on Pdꢀcatalysed CꢀN bond formations, see: a) J. F. Hartwig,
Nature, 2008, 455, 7211. b) de Meijere, A., Diederich, F., Eds. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; WileyꢀVCH: Weinheim,
2004. c) R. J. Lundgren, M. Stradiotto, Chem. Eur. J., 2012, 18, 9758. d)
E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Chem. Rev.,
55 2007, 107, 5318.
Ph
O
NH
I
O
H
N
Cl
N
N
Ph
O
Br
Ph
N
H
N
ꢀ
7
8
ꢀ
Cl
Cl
H
N
N
N
5 For reviews on Cuꢀcatalysed CꢀN bond formations, see: a) G. Evano, N.
Blanchard, T. Toumi, Chem. Rev., 2008, 108, 3054. b) I. P. Beletskaya,
A. V. Cheprakov, Coord. Chem. Rev., 2004, 248, 2337. c) F. Monnier, M.
Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954.
N
N
Ph
O
67%
O
H
N
N
Cl
60 6 For some examples, see : a) Q. Shen, S. Shekhar, J. P. Stambuli, J. F.
Hartwig, Angew. Chem., Int. Ed., 2005, 44, 1371. b) F. Halley, Y. Elꢀ
Ahmad, V. Certal, C. Venot, A. Dagallier, H. Strobel, K. Ritter, S. Ruf,
US 2009/0082329 A1, 2009. c) N. R. Irlapati, G. K. Deshmukh, V. P.
Karche, S. M. Jachak, N. Sinha, V. P. Palle, R. K. Kamboj, WO
65 2012/056478 A1, 2012. d) S. Guo, Y. Wang, C. Sun, J. Li, D. Zhou, Y.
Wu, Y. Wu, Tetrahedron Lett., 2013, 54, 3233. e) H. Kakuta, X. Zheng,
H. Oda, S. Harada, Y. Sugimoto, K. Sasaki, A. Tai, J. Med. Chem., 2008,
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70 Y. He, Bioorg. Med. Chem. Lett., 2006, 16, 3430. g) G. B. W. L. Ligthart,
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Wang, C. ꢀK. Liang, M. ꢀk. Leung, Tetrahedron, 2005, 61, 2931.
7 For examples of Cuꢀcatalysed amidation of arylꢀhalides, see : a) A.
75 Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am. Chem. Soc.,
2001, 123, 7727. b) K. R. Crawford, A. Padwa, A., Tetrahedron Lett.,
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7421. e) W. Deng, Y. ꢀF. Wang, Y. Zou, L. Liu, Q.ꢀX. Guo, Tetrahedron
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J. Am. Chem. Soc., 2005, 127, 4120. g) W. Chen, J. Li, D. Fang, C. Feng,
C. Zhang, Org. Lett., 2008, 10, 4565. h) E. R.Strieter, B. Bhayana, S. L.
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85 5691. j) S. Jammi, S. Krishnamoorthy, P. Saha, D. S. Kundu, S.
N
Ph
9
88%
a c = 1 M; b reaction performed in a sealed tube; c isolated yield; d
e
25% of starting material recovered; 28% of starting material
5
recovered; f Only traces of monoꢀamide product were observed.
corresponding amides were produced in 67% and 88% yield
respectively (Table 3, entries 8ꢀ9).
Conclusions
10
In summary, we have described a straightforward method for
the amidation of 2ꢀchloropyridine derivatives with a cheap and
convenient CuI/N,Nꢀdimethylcyclohexaneꢀ1,2ꢀdiamine catalytic
system, which constitutes an interesting alternative to both the
reported Pdꢀcentered methods and Cuꢀcatalysed amidations of
15 2ꢀbromoꢀpyridine derivatives. This CꢀN bond formation is
general and can involve aromatic, heteroaromatic or aliphatic
amides, and various pyridine derivatives such as 2ꢀchloroꢀ
pyridines, as well as 2ꢀchloropyrazine and 2ꢀchloroquinoline.
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5
8
For selected examples involving the Cuꢀcatalysed amidation of
2ꢀbromoꢀpyridine, see : a) I. M. Bella, R. A. Bednarb, J. F. Fayb, S. N.
Gallicchioa, J. H. Hochmanc, D. R. McMastersd, C. MillerꢀSteinc, E. L.
10 Mooreb, S. D. Mosserb, N. T. Pudvahc, A. G. Quigleya, C. A. Salvatoreb,
C. A. Stumpa, C. R. Thebergea, B. K. Wongc, C. B. Zartmana, X. ꢀF.
Zhanga, S. A. Kaneb, S. L. Grahama, J. P. Vaccaa, T. M. Williamsa,
Bioorg. Med. Chem. Lett., 2006, 16, 6165. b) J. Li, Y. Zhang, D. Ma,
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Synthesis, 2008, 1359. e) X. Lv, W. Bao, J. Org. Chem. 2007, 72, 3863.
9
For references concerning mechanistic features of Cuꢀcatalysed CꢀN
bond forming reactions, see Ref 3c, 6f, 6h and : G. Lefèvre, G. Franc, A.
Tlili, C. Adamo, M. Taillefer, I. Ciofini, A. Jutand, Organometallics,
20 2012, 31, 7694.
10 The use of a large excess of primary amides such as benzamide was
shown to convert 2ꢀchloroquinolines and some halogenated quinolines,
pyrazines and pyridines into the corresponding amino derivatives. With a
large excess of acetamide (ca. 80 equiv.) it is possible to isolate the
25 corresponding 2ꢀacetamidoquinoline derivatives, however in modest
yields. See : a) T. Watanabe, E. Kikuchi, W. Tamura, Y. Akita, M.
Tsutsui, A. Ohta, Heterocycles 1980, 14, 287. b) F. Kóródi, Synth.
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