Rhodium-catalyzed one-pot synthesis of substituted pyridine derivatives from α,β-unsaturated ketoximes and alkynes

Article abstract of DOI:10.1021/ol7028367

(Chemical Equation Presented) A rhodium-catalyzed chelation-assisted C-H activation of α,β-unsaturated ketoximes and the reaction with alkynes to afford highly substituted pyridine derivatives is described.

Full text of DOI:10.1021/ol7028367

ORGANIC
LETTERS
2008
Vol. 10, No. 2
325-328
Rhodium-Catalyzed One-Pot Synthesis
of Substituted Pyridine Derivatives from
r,â-Unsaturated Ketoximes and Alkynes
Kanniyappan Parthasarathy, Masilamani Jeganmohan, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received November 23, 2007
ABSTRACT
A rhodium-catalyzed chelation-assisted C−H activation of r,â-unsaturated ketoximes and the reaction with alkynes to afford highly substituted
pyridine derivatives is described.
Recently, considerable research activity has been directed
toward the metal-catalyzed C-H bond activation and
subsequent carbon-carbon bond formation in organic syn-
thesis.1 These reactions are environmentally friendly and
atom-economical when compared with the other conventional
methods such as carbon-halide functionalization.2,3
Chelation-assisted activation of the ortho aromatic or
alkenyl C-H bond by a transition metal complex is a
promising and practical method in modern organic synthe-
sis.1,3 Various directing groups, such as aldehyde, ketone,
imine, alcohol, amine, carboxylic acid, and nitrile, have been
used to activate the ortho aromatic or alkenyl C-H bond.
This method has been used for the functionalization of arenes
and alkenes1,3-6 via coupling reactions with organic halides
or organometallic reagents1f,4 and via an addition reaction
with carbon-carbon multiple bonds (alkynes or alkenes).5
However, only very few examples are known for the catalytic
activation of alkenyl C-H bond.6 Moreover, these reactions
are mostly limited to â-alkylation of enones, imines, and
2-vinyl pyridines by alkenes.6 Very recently, Bergman and
Ellman reported a rhodium-catalyzed alkylation of R,â-
unsaturated aldimines by various alkenes.7 In the paper, two
examples using alkynes as the substrates for the alkenylation
of an aldimine were also included. Our continuous interest
in metal-catalyzed cyclization reactions8 prompted us to
explore the possibility of R,â-unsaturated ketoximes with
alkynes. Herein, we wish to report a new method for the
synthesis of highly substituted pyridines from R,â-unsatur-
(5) (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem.
Soc. 2003, 125, 1698. (b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N.
J. Am. Chem. Soc. 2005, 127, 5936. (c) Masui, K.; Ikegami, H.; Mori, A.
J. Am. Chem. Soc. 2004, 126, 5074 and references therein. (d) Cao, C.; Li,
Y.; Shi, Y.; Odom, A. L. Chem. Commun. 2004, 2002. (e) Kuninobu, Y.;
Kawata, A.; Takai, K. J. Am. Chem. Soc. 2005, 127, 13498. (f) Kuninobu,
Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006, 128,
202.
(6) (a) Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S. Chem. Lett.
1995, 681. (b) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem.sEur. J. 2002,
8, 2422. (c) Jun, C.-H.; Moon, C. W.; Kim, Y. M.; Lee, J.; Lee, H.
Tetrahedron Lett. 2002, 43, 4233. (d) Lim, S.-G.; Ahn, J.-A.; Jun, C. H.
Org. Lett. 2004, 6, 4687. (e) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2001, 123, 2685. (f) Kakiuchi, F.; Tanaka, Y.; Sato, T.;
Chatani, N.; Murai, S. Chem. Lett. 1995, 79. (g) Kakiuchi, F.; Sato, T.;
Kakiuchi, F.; Chatani, N.; Murai, S. Chem. Lett. 1995, 893. (h) Chatani,
N.; Kamitani, A.; Murai, S. J. Org. Chem. 2002, 67, 7014.
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128, 5604.
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V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (c) Kakiuchi, F.;
Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (d) Pastine, S. J.; Gribkov,
D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220. (e) Godula, K.;
Sames, D. Science 2006, 312, 67. (f) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174.
(2) (a) Tsuji, J. Transition Metal Reagents and Catalysts: InnoVations
in Organic Synthesis; Wiley: New York, 2002. (b) Lautens, M.; Klute,
W.; Tam, W. Chem. ReV. 1996, 96, 49. (c) Ojima, I.; Tzamarioudaki, M.;
Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635.
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2006, 128, 11748 and references therein.
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3113 references therein.
10.1021/ol7028367 CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/20/2007

ated ketoximes and alkynes via a rhodium-catalyzed C-H
activation of R,â-unsaturated ketoxime. Pyridines are im-
portant classes of heterocyclic compounds. The pyridine core
is present in various natural products and biologically active
compounds.9 In addition, the starting materials of ketoximes
can be prepared readily from the corresponding ketones and
hydroxylamine.10
Table 1. Results of the Reaction of R,â-Unsaturated
Ketoximes with Alkynesa
Treatment of R,â-unsaturated ketoxime 1a having methyl
substituents at R- and â-carbons with diphenylacetylene 2a
in the presence of 3 mol % of RhCl(PPh3)3 in toluene at
130 °C for 3 h gave a highly substituted pyridine derivative
3a in 92% isolated yield (Table 1, entry 1). To the best of
our knowledge, this is the first report using oxime as a
directing group for the activation of an alkenyl C-H bond
followed by a series of reaction steps leading to the synthesis
of N-heteroaromatic compounds.11 The formation of product
3a can be viewed as a â-alkenylation of oxime 1a to provide
a 1-azatriene intermediate, followed by a 6π-cyclization and
dehydration (vide infra). Alternatively, product 3a might has
been formed via [4 + 2] Diels-Alder cycloaddition of 1a
with 2a, followed by dehydration.12 In order to clarify it,
the present reaction was carried out in the absence of rhodium
catalyst in toluene at 150 °C for 15 h, and no 3a was
obtained. The result indicates that the rhodium catalyst is
necessary for the present reaction.
Under similar reaction conditions, several alkyl-substituted
R,â-unsaturated ketoximes also react with alkynes 2a to give
the corresponding substituted pyridines. Thus, propenyl
methyl ketoxime 1b and propenyl ethyl ketoxime 1c gave
3b and 3c in 80 and 74% yields, respectively (entries 2 and
3). Similarly, methyl vinyl ketoxime 1d and propyl vinyl
ketoxime 1e afforded the corresponding pyridine derivatives
3d and 3e in moderate 63 and 62% yields, respectively
(entries 4 and 5). In addition, R,â-unsaturated cyclic alkenyl
oxime, 1-acetylcyclopentene oxime 1f, reacted with 2a
providing 3f in 94% yields (entry 6). Interestingly, even
oxime 1g having a [2.2.1] bicyclic moiety reacted efficiently
with 2a to afford the corresponding pyridine derivative 3g
in 68% yield (entry 7).
In addition to diphenylacetylene 2a, di(2-thienyl)acetylene
2b also reacts smoothly with unsaturated ketoximes. For
example, the reaction of 2b with 1f provided highly
substituted pyridine derivative 3h in 89% yield (entry 8).
The present catalytic reaction was also successfully extended
(9) (a) Jones, G. Pyridine and their Benzoderivatives: Synthesis. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5, pp 167-243. (b)
Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379.
(c) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (d) Varela, J. A.;
Saa, C. Chem. ReV. 2004, 104, 3787. (e) Movassaghi, M.; Hill, M. D.;
Ahmad, O. K. J. Am. Chem. Soc. 2007, 129, 10096.
(10) (a) Shinada, T.; Yoshihara, K. Tetrahedron Lett. 1995, 36, 6701.
(b) Booth, S. E.; Jenkins, P. R.; Swain, C. J.; Sweeney, J. B. J. Chem.
Soc., Perkin Trans. 1 1994, 3499.
(11) (a) Palladium-catalyzed O-methyl oxime as a directing group for
activation of the sp3 C-H bond followed by oxygenation with PhI(OAc)2:
Desai, L. V.; Hull, K. L.; Sanford, S. M. J. Am. Chem. Soc. 2004, 126,
9542. (b) Oxime as a directing group for activation of the ortho aromatic
C-H bond in a stoichiometric amount of palladium complex: Bezsoudnoba,
E. Y.; Ryabov, A. D. J. Organomet. Chem. 2001, 622, 38.
(12) (a) Boger, D. L.; Ichikawa, S.; Jiang, H. J. Am. Chem. Soc. 2000,
122, 12169 and references therein. (b) Boger, D. L.; Corbett, W. L.; Curran,
T. T.; Kasper. A. M. J. Am. Chem. Soc. 1991, 113, 1713.
a Unless otherwise mentioned, all reactions were carried out using oximes
1 (1.0 mmol), alkyne 2 (1.1 mmol), Rh(PPh3)3Cl (3 mol %), and toluene
(2.0 mL) at 130 °C for 3 h. b Isolated yields. c Reaction time was 12 h.
d 2-Thienyl. e Reaction time was 6 h.
326
Org. Lett., Vol. 10, No. 2, 2008

to aliphatic alkynes 2c-e. Thus, 1a reacted with but-2-yne
2c to give the corresponding 2,3,4,5,6-pentamethylpyridine
3i in 76% yield (entry 9). It is interesting to note that oxime
1h with a phenyl group at the â-carbon reacted smoothly
with hex-3-yne 2d to give the expected pyridine derivative
3j in 75% yield (entry10) but failed to react with diphenyl-
acetylene 2a. The steric repulsion between the phenyl groups
in 1h and 2a likely accounts for the failure of the reaction.
Similarly, 1-acetylcyclohexene oxime 1i reacted nicely with
oct-4-yne 2e to give the pyridine derivative 3k in 81% yield
(entry 11). It is noteworthy that the reaction of R,â-unsatu-
rated aldoxime with alkynes under similar conditions did not
give the expected pyridine products. Further studies are
required to understand the reaction.13
Scheme 2. Proposed Mechanism for the Reaction of
R,â-Unsaturated Ketoximes with Alkynes
To understand the regioselectivity of the present reaction,
unsymmetrical alkynes 2f-i were investigated (Scheme 1).
Scheme 1. Rhodium-Catalyzed Reaction of
1-Acetylcyclohexene Oxime 1i with Unsymmetrical Alkynes
2h,i
electrocyclization15 and elimination of water to give the final
pyridine derivative 3.
To support the proposed mechanism in Scheme 2, we tried
to isolate the key product intermediate 7 from R,â-unsatur-
ated ketoximes and alkyne 2a by lowering the reaction
temperature or shortening the reaction time, but the attempt
failed. Fortunately, when we extended the catalytic reaction
to acetophenone oxime (1j) with 2a, intermediate product 8
was isolated in 92% yield in 3 h. Further, when 8 was re-
fluxed in toluene at 150 °C for 6 h, the corresponding iso-
quinoline derivative 9 was isolated in 90% yield (Scheme
3). The isolation of 8 and its conversion to product 9 supports
strongly the proposed mechanism in Scheme 2.
1-Phenyl-2-(trimethylsilyl)acetylene (2f) efficiently reacted
with 1f in a high regioselective manner, providing desilylated
pyridine derivative 3l in 80% yield in which the Ph group
was attached to C-4 of 3l (Table 1, entry 12). In a similar
way, phenylacetylene 2g gave single regioisomeric product
3l in 51% yield (Table 1, entry 12). Internal alkyne, 1-phenyl-
1-propyne (2h), underwent an addition and cyclization
reaction with 1i to give regioisomeric products 3m and 3m′
in 48 and 30% yields (Scheme 1), respectively. The regio-
chemistries of 3m and 3m′ were confirmed by NOE
experiments. Similarly, 1-phenyl-1-butyne (2i) also afforded
two regioisomers 3n and 3n′ in 75% combined yield with a
78:22 ratio (Scheme 1).
Scheme 3. Mechanistic Evidence
On the basis of known metal-catalyzed directing-group-
assisted C-H bond activation reactions,1,4-7 a possible
reaction mechanism is proposed to account for the present
catalytic reaction (Scheme 2). The first step involves
coordination of the oxime nitrogen of 1 to the rhodium metal
followed by oxidative insertion of the alkenyl C-H bond to
form a hydrometallacycle 5.14 Addition of the rhodium-
hydride bond to a coordinated alkyne gives 6. Subsequent
reductive elimination affords C-H addition product 7 and
regenerates the catalyst. Product 7 then undergoes 6π-
In conclusion, we have developed a rhodium-catalyzed
chelation-assisted C-H activation of R,â-unsaturated ketox-
ime and the reaction with alkynes to afford substituted
pyridine derivatives in good to excellent yields. The method
provides an opportunity for the placement of all five sub-
(13) Park, S.; Choi, Y.-A.; Han, H.; Yang, S. H.; Chang, S. Chem.
Commun. 2003, 1936.
(14) Jun, C.-H.; Moon, C. W.; Hong, J.-B.; Lim, S. G.; Chung, K.-Y.;
Kim, Y.-H. Chem.sEur. J. 2002, 8, 485.
(15) (a) Trost, B. M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473. (b)
Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem. 2001,
66, 3099 and references therein.
Org. Lett., Vol. 10, No. 2, 2008
327

stituents (C2-C6) of pyridine in one pot. In addition, this
appears to be the first report to describe addition of an alkenyl
C-H bond to alkynes followed by cyclization and elimina-
tion. The present protocol is also successfully applied to the
synthesis of an isoquinoline derivative. Further extension of
the reaction to other oximes and alkynes, the application of
this methodology in natural product synthesis, and the
detailed mechanistic investigation are in progress.
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China (NSC-94-2113-M-007-011) for
support of this research.
Supporting Information Available: General experimen-
tal procedure and characterization details. This material is
available free of charge via the Internet at http://pubs.acs.org.
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