Ruthenium-catalyzed cyclization of ketoxime acetates with DMF for synthesis of symmetrical pyridines

Article abstract of DOI:10.1021/ol501183z

A novel ruthenium-catalyzed cyclization of ketoxime carboxylates with N,N-dimethylformamide (DMF) for the synthesis of tetrasubstituted symmetrical pyridines has been developed. A methyl carbon on DMF performed as a source of a one carbon synthon. And NaHSO₃ plays a role in the reaction.

Full text of DOI:10.1021/ol501183z

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Cyclization of Ketoxime Acetates with DMF for
Synthesis of Symmetrical Pyridines
Mi-Na Zhao, Rong-Rong Hui, Zhi-Hui Ren, 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
S
* Supporting Information
ABSTRACT: A novel ruthenium-catalyzed cyclization of
ketoxime carboxylates with N,N-dimethylformamide (DMF)
for the synthesis of tetrasubstituted symmetrical pyridines has
been developed. A methyl carbon on DMF performed as a
source of a one carbon synthon. And NaHSO3 plays a role in the
reaction.
yridines represent an important class of hererocycles which
are prevalent in natural products, functional materials, and
Scheme 1. Transition-Metal-Catalyzed Synthesis of
Pyridines from Ketoxime Carboxylates
P
medicinal chemistry.1 Particularly, a number of symmetrical
pyridines have been discovered to have good biological
activity.2 Over the past decades, various methods, such as
condensation of amines and carbonyl compounds,3 transition-
metal-catalyzed cycloaddition reactions,4 and cycloisomeriza-
tion reactions5 have been established for the synthesis of
pyridines. However, these methods are mainly focused on
versatile unsymmetrical substituted pyridines;6 a general
protocol for the synthesis of valuable symmetrical pyridines
has rarely been developed.7
Recently, transition-metal-catalyzed coupling of ketoxime
carboxylates with alkenylboronic acids, alkynes, or alkenes has
emerged as a straightforward method to synthesize substituted
pyridines,8 in which the N−O bond cleavage of the ketoxime
carboxylates acts as an internal oxidant to make the reactions
proceed under mild redox-neutral conditions (Scheme 1, eqs 1
and 2). Inspired by some of these works, we have developed an
efficient copper-catalyzed cyclization of ketoxime acetates with
aldehydes for the synthesis of symmetrical pyridines (Scheme 1,
eq 3).9a However, the reaction is mainly limited in the synthesis
of 2,4,6-trisubstituted symmetrical pyridines.
DMF is a popular polar solvent. Recently, DMF has been
employed as a promising reactant in organic transformations
such as formylation,10 amination,11 and cyanation reactions.12
Insertion of arynes into the CO bond of DMF has been
discovered in multicomponent reactions.13 Very recently, a Rh-
catalyzed direct α-methylation of ketones by DMF has also
been disclosed.14 However, to our knowledge, employing DMF
as a source of a one carbon synthon to perform a cyclization
reaction has rarely been reported.15 In this paper, we have
developed a novel and efficient ruthenium-catalyzed cyclization
of ketoxime carboxylates with DMF for the synthesis of 2,3,5,6-
tetrasubstituted symmetrical pyridines (Scheme 1, eq 4).
When we studied reactions of propiophenone oxime acetate
1a in DMF, an unexpected 3,5-dimethyl-2,6-diphenylpyridine
2a was observed in 9% yield in the presence of the [Ru(p-
cymene)Cl2]2 catalyst (Table 1, entry 1). The symmetrical
pyridine formation reveals that DMF may undergo the
cyclization reaction with propiophenone oxime acetate 1a
acting as a carbon source. This interesting result encouraged us
to optimize the reaction conditions to provide a general
protocol for the synthesis of tetrasubstituted symmetrical
pyridines which are less accessible by traditional methods.
Therefore, various additives were screened to examine if they
could improve the reaction efficiency. Similar to our previous
finding in the copper-catalyzed reaction of ketoximes,9
NaHSO3 could dramatically improve the yield of pyridine 2a
to 60%. Other additives, such as Na2SO3 and Na2S2O4, were
inferior to NaHSO3 (Table 1, entries 2−4). Optimizing with
various ruthenium catalysts, such as Ru(acac)3, RuCl3, Ru-
(cod)Cl2, and Ru3(CO)12, revealed that Ru(cod)Cl2 was the
Received: April 24, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Table 2. Ru-Catalyzed Cyclization of Aryl Ethyl Ketoxime
Acetates with DMF
a
entry
[Ru] catalyst
additive
t (°C)
yield (%)
1
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
Ru(acac)3
−
120
120
120
120
120
120
120
120
120
140
100
9
16
22
60
35
51
73
53
0
2
Na2SO3
3
Na2S2O4
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
4
5
6
RuCl3·xH2O
Ru(cod)Cl2
7
8
Ru3(CO)12
9
−
10
11
Ru(cod)Cl2
72
26
Ru(cod)Cl2
a
Reaction conditions: 1a (0.4 mmol), catalyst (5 mol %), additive (1.5
equiv), DMF (2 mL), 5 h, in air; isolated yields.
most effective catalyst for this reaction, improving the yield of
2a to 73% (Table 1, entries 5−8). Additionally, no reaction
occurred in the absence of a ruthenium catalyst, thus indicating
that a ruthenium catalyst is essential for this reaction (Table 1,
entry 9). Furthermore, the reaction temperature was also
varied; the experiments show that the optimal temperature for
the reaction is 120 °C (Table 1, entries 10−11).
With the optimized reaction conditions established, the
scope of the reaction was investigated (Table 2). This
transformation proved to be a general method for the
preparation of tetrasubstituted symmetrical pyridines. Propio-
phenone oxime acetates with electron-donating or -with-
drawing groups on aryl rings, such as methyl, tert-butyl, fluoro,
chloro, and bromo, all gave the corresponding symmetrical
pyridines 2b−2i in good yields, thus implying that the
electronic nature of the substrates has little influence on the
reaction (Table 2, entries 1−9). However, the steric effect plays
a role in the reaction. The desired symmetrical pyridine 2f was
obtained only in 24% yield when ortho-methyl substituted
propiophenone oxime acetate 1f was employed as the substrate
(Table 2, entry 6). In addition, the 1-(naphthalen-2-yl)propan-
1-one oxime acetate 1j also reacted smoothly to give the
desired naphthyl substituted symmetrical pyridine 2j in 68%
yield (Table 2, entry 10).
Next, a series of phenyl alkyl ketoxime acetates were
investigated to extend the substrate scope (Table 3). Ketoxime
acetates derived from butyrophenone, valerophenone, and α-
tetralone reacted smoothly to give the desired symmetrical
pyridines 2k−2m in moderate to good yields (Table 3, entries
1−3). Tetraphenylpyridine 2n was also obtained in 50% yield
when 1,2-diphenylethanone oxime acetate 1n was used as the
substrate (Table 3, entry 4). Notably, the corresponding ketone
was observed as the main byproduct in the above reactions.
Furthermore, acetophenone oxime acetates which may provide
2,6-disubstituted symmetrical pyridines were studied as the
substrates. Expectedly, 2,6-diarylpyridines 2o−2q were afforded
in reasonable yields under standard conditions (Table 3, entry
5). However, the 2,6-dithienylpyridine 2r was obtained in only
30% yield (Table 3, entry 6). And no reaction occurred when
(E)-1-(pyridin-2-yl)ethanone oxime acetate 1s or butan-2-one
oxime acetate 1t was employed as the substrates (Table 3,
a
Reaction conditions: 1 (0.4 mmol), Ru(cod)Cl2 (5 mol %), NaHSO3
(1.5 equiv), DMF (2 mL), 120 °C, in air; isolated yields.
entries 7−8). It should be noted that different propiophenone
oxime carboxylates, such as propionate, tert-butyrate, and
benzoate, with the exception of pentafluorobenzoate, show
similar reactivity to that of acetate (Table 3, entries 9−12).
To gain insight into the reaction mechanism, a deuterium
labeling experiment was carried out. The reaction became
considerably slower under the conditions to afford 4-deuterated
pyridine 2o in 30% yield when DMF-d7 was used as the solvent
(Scheme 2, eq 5). This result confirmed that the carbon on the
4-position of the pyridine ring should indeed come from DMF.
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Table 3. Ru-Catalyzed Cyclization of Various Ketoxime
Carboxylates with DMF
Scheme 2. Investigation of the Reaction Mechanism
a
results indicate that the carbon unit should be provided by a
methyl carbon on DMF.
On the basis of the aforementioned results and previous
studies, a tentative mechanism for the reaction is proposed in
Scheme 3. Oxidation of DMF by Ru(II) gives an iminium
Scheme 3. A Tentative Mechanism for Ru-Catalyzed
Cyclization of Ketoxime Carboxylates with DMF
species A and Ru(0).12 Subsequently, oxidative addition of
ketoxime acetate 1 to Ru(0) generates an imino-Ru(II)
complex B, which undergoes tautomerization to afford an
enamino-Ru(II) complex C.9 Then, nucleophilic addition of C
to species A produces an imine intermediate D. Condensation
of imine intermediate D with a second ketoxime acetate 1 gives
an intermediate E.9 Nucleophilic substitution of E by NaHSO3
followed by intramolecular cyclization of the intermediate F
forms a dihydropyridine intermediate G. Finally, Ru-catalyzed
oxidative aromatization of intermediate G in the presence
oxygen generates the desired pyridine product 2. Alternatively,
nucleophilic substitution by the NaHSO3 step could occur prior
to the condensation.
In summary, we have developed a novel Ru-catalyzed
cyclization of ketoxime carboxylates with DMF for the synthesis
of tetrasubstituted symmetrical pyridines. A methyl carbon on
DMF performed as a source of a one carbon synthon in the
reaction. The reaction is a good protocol for the rapid
elaboration of readily available ketoxime acetates into a variety
of valuable tetrasubstituted symmetrical pyridines under mild
a
Reaction conditions: 1 (0.4 mmol), Ru(cod)Cl2 (5 mol %), NaHSO3
(1.5 equiv), DMF (2 mL), 120 °C, in air; isolated yields.
Further, the reaction occurred as well when DMSO or
hexamethylphosphoramide (HMPA) was used as the solvent
albeit in low yield. However, the reaction did not occur when
N,N-diethylformamide was employed (Scheme 2, eq 6). These
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ASSOCIATED CONTENT
■
S
* Supporting Information
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Detailed experimental procedures and spectral data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: guanzhh@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the National
Natural Science Foundation of China (21272183 and
21002077) and Fund of the Rising Stars of Shanxi Province
(2012KJXX-26).
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