Copper-Catalyzed coupling of oxime acetates with aldehydes: A new strategy for synthesis of pyridines

Article abstract of DOI:10.1021/ol202290y

Copper-catalyzed coupling of oxime acetates with aldehydes offers a new strategy for the synthesis of highly substituted pyridines. This novel method tolerates a wide range of functionality and allows for rapid elaboration of the oxime acetates into a variety of substituted pyridines.

Full text of DOI:10.1021/ol202290y

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5394–5397
Copper-Catalyzed Coupling of Oxime
Acetates with Aldehydes: A New Strategy
for Synthesis of Pyridines
Zhi-Hui Ren, Zhi-Yuan Zhang, Bing-Qin Yang, Yao-Yu Wang, and Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of
Education, Department of Chemistry & Materials Science, Northwest University, Xi’an
710069, P. R. China
guanzhh@nwu.edu.cn
Received August 24, 2011
ABSTRACT
Copper-catalyzed coupling of oxime acetates with aldehydes offers a new strategy for the synthesis of highly substituted pyridines. This novel
method tolerates a wide range of functionality and allows for rapid elaboration of the oxime acetates into a variety of substituted pyridines.
Oximes and their derivatives are valuable synthetic
building blocks.1 They are well-known fruitful candidates
for the Beckmann rearrangement reactions to prepare
amides2 or for the dehydration reactions to produce
nitriles.3 Recently, transition metal catalyzed coupling
reactions using oximes and their derivatives as substrates
have emerged. Coupling of oximes with aryl halides or
arylboronic acids have been used for construction of the
synthetic useful O-arylhydroxylamines.4 Alternatively,
attractive elegant strategies for the coupling of oxime
carboxylates with boronic acids (eq 1),5 arynes (eq 2),6 or
aromatic CꢀH bonds (eq 3)7 were recently explored for
efficient construction of a series of aza-heterocycles
(Scheme 1). Cleavage of the NꢀO bond in oxime carbox-
ylates by a low valent transition metal, such as Pd(0) and
Cu(I), shows a new promising approach to nitrogen-con-
taining compounds. Despite these advances, the develop-
ment of new methodologies for transition metal catalyzed
coupling of the electrophilic oxime carboxylates with
alternative electrophiles remains largely unrealized. The
challenges of the reactions include the following: (1)
cleavage of the NꢀO bond in oxime carboxylates involves
two pathways: oxidative addition and radical process; (2)
coupling of two electrophiles is subject to an efficient
reducing agent in the reaction system.
(1) (a) Sukhorukov, A. Y.; Ioffe, S. L. Chem. Rev. 2011, 111, 5004. (b)
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Alonso, D. A.; Najera, C. Chem. Soc. Rev. 2010, 39, 2891. (c) Himo, F.;
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Substituted pyridines are one of the most prevalent
heterocycles in many natural products, pharmaceuticals,
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r
10.1021/ol202290y
Published on Web 09/13/2011
2011 American Chemical Society

and various kinds of functional materials.8 Although a
variety of approaches toward substituted pyridines have
been developed,9 versatile and efficient methods for the
construction of pyridine rings which are compatible with
various functional groups and using readily available
starting materials remain highly desirable. Herein, we
report a novel and efficient strategy for Cu-catalyzed
coupling of oxime acetates with aldehydes for the synthesis
of highly substituted pyridines (Scheme 1, eq 4).
Table 1. Optimization of Conditions for Cu-Catalyzed Cou-
pling of Oxime Acetate with Aldehydea
entry
catalyst
additive
solvent
DMSO
yield (%)
Scheme 1. Transition Metal Catalyzed Coupling Reactions of
Oxime Carboxylates
1
CuI
ꢀ
30
79
89
77
61
60
78
42
35
32
0
2
CuI
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
Na2SO3
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
3
CuBr
CuCl
Cu2O
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
ꢀ
4
5
6
7
8
1,4-Dioxane
Toluene
DMSO
DMSO
DMSO
9
10
11
12
NaHSO3
NaHSO3
Pd2(dba)3
0
a Reaction conditions: acetophenone oxime acetate 1a (0.9 mmol),
benzaldehyde 2a (0.3 mmol), catalyst (10 mol %), and additive (0.9
mmol) in solvent (5 mL) under Ar at 120 °C for 2.5 h.
Furthermore, control experiments confirmed that no reac-
tion occurred in the absence of a copper catalyst or in the
presence of a Pd2(dba)3 catalyst (Table 1, entries 11ꢀ12).
These results indicate that the Cu species did indeed act as
the catalyst for cleavage of the NꢀO bond in oxime
carboxylates in the reaction.
We began our study by investigating the coupling reac-
tion of acetophenone oxime acetate 1a with benzaldehyde
2a. We were pleased to find that 2,4,6-triphenylpyridine
3aa was formed in 30% yield accompanied by acetophe-
noneasthe only byproductinthe presenceofaCuIcatalyst
in DMSO (Table 1, entry 1). The structure of the product
3aa was unambiguously confirmed by X-ray diffraction
analysis (see Supporting Information). This interesting
result encouraged us to optimize the reaction conditions
to give a general protocol for the synthesis of substituted
pyridines. Therefore, different additives, copper catalysts,
and solvents were screened for inhibition of the acetophe-
none formation (Table 1). To our delight, NaHSO3 was
discovered to efficiently inhibit the hydrolysis of oxime
acetate,10 and the yield of 2,4,6-triphenylpyridine 3aa was
dramatically improved (Table 1, entry 2). Screening of
copper catalysts, such as CuCl, CuBr, Cu2O, and Cu(OAc)2,
revealed that CuBrwas the most effective in the presence of
NaHSO3 (Table 1, entries 3ꢀ6). Other solvents such as
NMP, 1,4-dioxane, and toluene are less effective (Table 1,
entries 7ꢀ9). And low conversion was observed when
Na2SO3 was employed as the additive (Table 1, entry 10).
Under the optimized conditions for the Cu-catalyzed
coupling of oxime acetates with aldehydes, the scope ofthis
pyridine formation has been investigated. This transfor-
mation displayed high functional group tolerance and
proved to be a quite general methodology. Oxime acetates
with methyl, methoxyl, fluoro, chloro, and bromo groups
on aryl rings all gave good to excellent yields of the
corresponding pyridines (Table 2). Aryl chlorides and
bromides were inert under the conditions suggesting that
the Cu(I) catalyst preferentially reacts with the NꢀO bond
of the oxime acetate over the CꢀX bonds (Table 2, entries
5ꢀ6). For the electronic effects of the transformation, the
electron-rich oxime acetates showed better reactivity and
gave slightly higher yields than electron-deficient ones
(Table 2, entries 2ꢀ10). In addition, the 2-acetylnaphtha-
lene oxime acetate 1k and benzylideneacetone oxime acet-
ate 1l also underwent the desired reaction to give the
corresponding pyridines 3ka and 3la in good yields respec-
tively (Table 2, entries 11ꢀ12). An extensive investigation
of the reaction shows that the fully substituted pyridines
were achieved by using R-tetralone oxime acetates 1mꢀ1n
or indanone oxime acetates 1oꢀ1p as substrates (Table 2,
entries 13ꢀ16).
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Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570. (c)
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
129, 10096. (d) Yoshida, K.; Kawagoe, F.; Hayashi, K.; Horiuchi, S.;
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€ €
Baffoe, J.; Landge, S. M.; Torok, B. Synthesis 2008, 3423.
Various aldehydes were explored as well to extend
the substrate scope, and the results are illustrated in
(10) Guan, Z.-H.; Zhang, Z.-Y.; Ren, Z.-H.; Wang, Y.-Y.; Zhang, X.
J. Org. Chem. 2011, 76, 339.
Org. Lett., Vol. 13, No. 19, 2011
5395

Table 2. CuBr-Catalyzed Coupling of Oxime Acetates with
Benzaldehyde for Synthesis of Pyridinesa
Table 3. CuBr-Catalyzed Coupling of Acetophenone Oxime
Acetate with Aldehydes for Synthesis of Pyridinesa
a Reaction conditions: acetophenone oxime acetate 1a (0.9 mmol),
aldehyde 2 (0.3 mmol), CuBr (10 mol %), and NaHSO3 (0.9 mmol) in
DMSO (5 mL) under Ar at 120 °C for 2.5 h.
Table 3. Satisfactorily, the para-, meta-, and ortho-
substituted aromatic aldehydes all gave the desired
trisubstituted pyridines in good to excellent yields
(Table 3, entries 1ꢀ11). Ortho MeO and Cl substituted
benzaldehydes 2jꢀ2k proceeded smoothly to give the
corresponding pyridines 3ajꢀ3ak in good yields imply-
ing that this transformation was insensitive to steric
hindrance (Table 3, entries 9ꢀ10). In contrast with the
substituted oxime acetates, electron-deficient aromatic
aldehydes showed better reactivity and gave higher
yields of pyridines than electron-rich ones (Table 3,
entries 1ꢀ6). In addition, heteroaromatic aldehydes
exhibit similar reactivity with benzaldehydes. Coupling
a Reaction conditions: oxime acetate 1 (0.9 mmol), benzaldehyde
2a (0.3 mmol), CuBr (10 mol %), and NaHSO3 (0.9 mmol) in DMSO
(5 mL) under Ar at 120 °C for 2.5 h.
5396
Org. Lett., Vol. 13, No. 19, 2011

of 2-furaldehyde 2m with acetophenone oxime acetate
1a afforded 4-(furan-2-yl)-2,6-diphenylpyridine 3am in
86% yield (Table 3, entry 12). It is noteworthy that 2,6-
diphenylpyridine 3an was also achieved in 60% yield
when paraformaldehyde 2n was employed (Table 3,
entry 13).
Scheme 3. Proposed mechanism for Cu-Catalyzed Coupling of
Oxime Acetates with Aldehydes
For further extension of this methodology, the
cross-coupling of two different oxime acetates with
one aldehyde has been explored as well (Scheme 2).
The three triarylpyridines were obtained in high total
isolated yields (82ꢀ92%) in each of the reactions.
The pyridines 3ccꢀ3ff were isolated as the major
products (35ꢀ43%) suggesting that this protocol
could be used for preparation of unsymmetrical pyr-
idines directly.
Scheme 2. Cross-Coupling of Two Different Oxime Acetates
with Benzaldehydea
oxidation by Cu2þ affords the triarylpyridine 3.5a At the
same time, the active Cuþ is regenerated. Alternatively,
elimination of intermediate D could occur prior to the
condensation.
In summary, we have developed a novel and efficient
strategy for Cu-catalyzed coupling of oxime acetates
with aldehydes for the synthesis of highly substituted
pyridines. The NꢀO bond cleavage followed by multi-
ple CꢀC and CꢀN bond formations was achieved by
the copper catalyst under mild conditions. NaHSO3
was discovered as a good inhibitor of hydrolysis of
oxime acetates in this transformation. This novel meth-
od tolerates a wide range of functionality and allows for
rapid elaboration of the readily available oxime acet-
ates into a variety of symmetrical and unsymmetrical
substituted pyridines in good to excellent yields. Cur-
rent research is focused on extending the scope of the
reaction.
a Reaction conditions: oxime acetate 1c (0.45 mmol), oxime
acetate 1d, or 1eꢀ1f (0.45 mmol), benzaldehyde 2a (0.3 mmol), CuBr
(10 mol %), and NaHSO3 (0.9 mmol) in DMSO (5 mL) under Ar at
120 °C for 2.5 h.
The proposed mechanism of the present reaction is
illustrated in Scheme 3. Cleavage of the NꢀO bond of
the oxime acetate 1 by Cuþ gives the imine radical A, which
is supposed to react rapidly with another Cuþ to give
NꢀCu2þ species B.11,12 Tautomerization of B affords the
intermediate C, and nucleophilic addition of C to benzal-
dehyde forms imine intermediate D.12 Then, condensation
ofimineintermediateD with a secondoximeacetate 1 gives
the intermediate E. Elimination of intermediate E pro-
duces an aza-hexa-1,3,5-triene intermediate F. Thermal
electrocyclization of intermediate F followed by rapid
Acknowledgment. This paper is dedicated to Professor
Xumu Zhang on the occasion of his 50th birthday. We
thank the National Natural Science Foundation of China
(NSFC-21002077), Northwest University (PR09037,
NF0913), and Education Department of Shaanxi Provin-
cial Government (2010JK869) for financial support.
Supporting Information Available. Experimental pro-
cedures and spectral data for all products and X-ray data
of 3aa (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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A. J.; Owen, D. W.; Powell, N. I. J. Organomet. Chem. 1990, 398, 299.
(12) Takai, K.; Katsura, N.; Kunisada, Y. Chem. Commun. 2001,
1724.
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