Highly regio- and stereoselective ruthenium(II)-catalyzed direct ortho -alkenylation of aromatic and heteroaromatic aldehydes with activated alkenes under open atmosphere

Article abstract of DOI:10.1021/ol3000684

Various aromatic and heteroaromatic aldehydes reacted with activated alkenes in the presence of a catalytic amount of [{RuCl₂(p-cymene)} ₂], AgSbF₆, and Cu(OAc)₂?H₂O to give substituted alkene derivat

Full text of DOI:10.1021/ol3000684

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1134–1137
Highly Regio- and Stereoselective
Ruthenium(II)-Catalyzed Direct
ortho-Alkenylation of Aromatic and
Heteroaromatic Aldehydes with Activated
Alkenes under Open Atmosphere
Kishor Padala and Masilamani Jeganmohan*
Department of Chemistry, Indian Institute of Science Education and Research,
Pune 411021, India
mjeganmohan@iiserpune.ac.in
Received January 12, 2012
ABSTRACT
Various aromatic and heteroaromatic aldehydes reacted with activated alkenes in the presence of a catalytic amount of [{RuCl2(p-cymene)}2],
AgSbF6, and Cu(OAc)2 H2O to give substituted alkene derivatives in a highly regio- and stereoselective manner. The corresponding alkene
3
derivatives were further converted into unusual four-membered cyclic ketones or a polycyclic isochromanone derivative via a photochemical
rearrangement. Notably, the catalytic reaction was conducted under an open atmosphere.
The transition-metal-catalyzed chelation-assisted CꢀH
bond activation and subsequent alkenylation at the ortho
position of the aromatic ring with alkenes is a practical
and highly atom-economical method to synthesize highly
substituted olefins in organic synthesis.1 This chemistry
has been broadly applied to synthesize various natural
products, drugs, and materials.1 In this regard, an initial
effort has been paid by Fujiwara’s group for the develop-
ment of alkenylation of electron-rich aromatic CꢀH bonds
with alkenes in the presence of palladium complexes.2
Later, several palladium-catalyzed directing group assisted
couplings of aromatic CꢀH bonds with alkenes have been
(1) Selected reviews: (a) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111,
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r
10.1021/ol3000684
Published on Web 02/08/2012
2012 American Chemical Society

reported by the groups of Yu, Miura, and others.3,4 In
2009, Yu’s group reported nondirected meta-selective al-
kenylation of aromatics in the presence of palladium
complexes.5 Recently, rhodium(III)-catalyzed chelation-
assisted oxidative alkenylation at the ortho position of
aromatic CꢀH bonds with alkenes has been demonstrat-
ed.6 And very recently, a few examples of ruthenium(II)-
catalyzed chelation-assisted ortho-alkenylation of aromatic
and heteroaromatic acids with alkenes have been described.7
The directing groups frequently used in this Heck-type
alkenylation reaction include amine, COOH, phenol, OH,
oxime, imine, amide, pyridyl, ketone, and ester groups.
Despite such significant diversity of directing groups, a
weakly coordinating CHO-directed ortho-alkenylation of
substituted aromatics with alkenes has not been explored
in the literature.8
reactions is crucial to make this type of reaction beneficial
to organic synthesis. Moreover, in most of the metal-
catalyzed CꢀH bond activation reactions, a stoichiometric
amount of oxidant is used to regenerate the active catalyst.
These oxidants most likely oxidize aldehydes into acids
subsequently ina facile manner. These types of competitive
reactions seriously restrict the scope of aldehydes in CꢀH
bond functionalization reactions. Recently, we demon-
strated a ruthenium-catalyzed coupling of aromatic and
heteroaromatic ketones with alkenes and cyclization of
aromatic and heteroaromatic ketones and acids with al-
kynes in the presence of a catalytic amount of silver salt
and Cu(OAc)2 H2O.10 In these reactions, Cu(OAc)2 H2O
provided the acetate source to the ruthenium species in
order to facilitate ortho-metalation by concerted depro-
tonation metalation pathway.1c These reactions were
moisture-insensitive, and the remaining amount of active
Cu(OAc)2 source was regenerated by oxygen or atmo-
sphere. These results prompted us to explore the possibility
3
3
A number of competitive reactions such as decarbonyla-
tion and hydroacylation could be possible in the coupling
of substituted aldehydes with alkenes in the presence
of metal complexes.9 Thus, the control of the competitive
of using a catalytic amount of Cu(OAc)2 H2O as a termi-
3
nal oxidant in the Heck-type coupling of aromatic alde-
hydes with alkenes. Herein, we wish to report oxidative
coupling of aromatic aldehydes with alkenes in the pre-
sence of a catalytic amount of [{RuCl2(p-cymene)}2],
(4) (a) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47,
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G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964. (h) Amino acid
ligand accelerated CꢀH bond activation: Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137.
AgSbF6, and Cu(OAc)2 H2O, giving alkene derivatives
3
in good to moderate yields under open atmosphere in a
highly regio- and stereoselective manner. The catalytic
reaction was also compatible with heteroaromatic alde-
hydes. It is important to note that no decarbonylation
of aldehydes, hydroacylation of aldehydes with alkenes,
and oxidation of aldehydes to acids were observed in
the reaction. The observed alkene derivatives were further
converted into unusual four-membered cyclic ketones or
polysubstituted isochromanone derivatives via a photo-
chemical rearrangement.
(5) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
5072.
(6) (a) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362.
(b) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 16474. (c) Umeda, N.; Hirano, K.; Satoh,
T.; Miura, M. J. Org. Chem. 2009, 74, 7094. (d) Sun, Z.-M.; Zhang, J.;
Manan, R. S.; Zhao, P. J. Am. Chem. Soc. 2010, 132, 6935. (e) Mochida,
S.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 5776. (f)
Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
6908. (g) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc.
2010, 132, 9585. (h) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 9982. (i) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int.
Ed. 2011, 50, 1064. (j) Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.;
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J. Y.; Chang, S. Org. Lett. 2011, 13, 2372. (l) Wang, F.; Song, G.; Li, X.
Org. Lett. 2010, 12, 5430. (m) Muralirajan, K.; Parthasarathy, K.;
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Jayakumar, J.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed.
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(7) Alkenylation: (a) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706. (b) Ackermann, L.;
Pospech, J. Org. Lett. 2011, 13, 4153. (c) Ackermann, L.; Wang, L.;
Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14, DOI: 10.1021/ol203251s.
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14, DOI: 10.1021/ol2032575. Cyclization: (e) Ackermann, L.; Lygin,
A. V.; Hofmann, N. Org. Lett. 2011, 13, 3278. (f) Ackermann, L.; Lygin,
A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379. (g)
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ol2034614.
When piperonal (1a) was treated with methyl acrylate
(2a) in the presence of a catalytic amount of [{RuCl2(p-
cymene)}2] (3 mol %), AgSbF6 (20 mol %) and Cu(OAc)2
3
H2O (50 mol %) in 1,2-dichloroethane at 100 °C for 16 h
under open atmosphere, a substituted alkene derivative
3a was observed in 47% isolated yield with very high
E-stereoselectivity. The catalytic reaction was also highly
regioselective. In the substrate 1a, there are two ortho
aromatic CꢀH bonds for coupling. Very selectively, the
alkenylation reaction takes place at the sterically hindered
CꢀH bond of 1a moiety predominately. In order to im-
prove the yield, the catalytic reaction was carried out with
longer reaction time (24 h), higher reaction temperature
(130 °C), and more ruthenium catalytic loading (10 mol %).
However, in these conditions, no improvement in the yield
of 3a was observed. Then, the reaction was carried out with
an excess amount of methyl acrylate (2a) (6.0 equiv). The
catalytic reaction proceeded well and gave 3a in 84%
isolated yield. The reaction did not proceed in the absence
of either copper source or silver salt. Notably, the present
(8) Alkylation: (a) Kakiuchi, F.; Sato, T.; Igi, K.; Chatani, N.; Murai,
S. Chem. Lett. 2001, 386. Arylation: (b) Terao, Y.; Kametani, Y.; Wakui,
H.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2001, 57, 5967. (c)
Gurbuz, N.; Ozdemir, I.; Cetinkaya, B. Tetrahedron Lett. 2005, 46, 2273.
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2004, 43, 340. (d) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res.
2008, 41, 222. (e) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am. Chem.
Soc. 2007, 129, 2082. (f) Willis, M. C. Chem. Rev. 2010, 110, 725.
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Ravi Kiran, C. G.; Jeganmohan, M. Eur. J. Org. Chem. 2012, 417. (c)
Ravi Kiran, C. G.; Jeganmohan, M. Chem. Commun. 2012, 48, 2030.
Org. Lett., Vol. 14, No. 4, 2012
1135

ruthenium-catalyzed open atmosphere reaction is inexpen-
sive and environment-friendly for synthesizing 2-formyl
phenylalkeno-derivatives 3 in a highly regio- and stereo-
selective manner.
in the reaction, giving an alkenylated product 3m in 40%
yield. The reaction of 1-napthaldehyde (1h) with 2a gave
the corresponding coupling product, 3n, in 41% yield.
Under similar reaction conditions, 2-napthaldehyde (1i)
reacted with 2a to give an alkenylated product 3o regiose-
lectively in 43% yield, in which C3ꢀH of 2-napthaldehyde
was involved in the coupling reaction with 2a selectively.
The catalytic reaction was also tested with 4-cyano ben-
zaldehyde and 4-methylester benzaldehyde. However, in
these reactions, no expected coupling products were ob-
served. It appears that the yield of this catalytic reaction
is highly sensitive to the type of substituent used on the
aromatic ring of aldehydes. Electron-rich substituents such
as dioxole, OMe, Me, and NMe2 on the aromatic ring gave
the highest product yield, while the electron-withdrawing
substituents such as Cl, CN, and CO2Me afforded the
lowest yield or no product.
Scheme 1. Alkenes Scopea
a All reactions were carried out using aldehydes 1a and 1b (1.0 mmol),
alkenes 2 (2aꢀb in 6.0 mmol and 2cꢀf in 5.0 mmol), [{RuCl2(p-cymene)}2]
Scheme 2. Aldehydes Scopea
(3 mol %), AgSbF6 (20 mol %), and Cu(OAc)2 H2O (50 mol %) in
3
DCE at 100 °C for 16 h. Reported yields are for the isolated products.
b The reaction was carried out in tert-BuOH. c Cu(OAc)2 H2O
(2.0 mmol) was used for the reaction.
3
The scope of the present alkenylation reaction was
further extended to various substituted activated alkenes
(Scheme 1). Piperonal (1a) underwent alkenylation reac-
tion with ethyl acrylate (2b) under similar reaction condi-
tions to afford 3b in 78% yield. Likewise, n-butyl acrylate
(2c), tert-butyl acrylate (2d), and cyclohexyl acrylate
(2e) afforded alkenylation products 3cꢀe in 75, 68, and
79% yields, respectively. An acrylic acid was also a good
coupling partner for this reaction. Thus, acrylic acid (2f)
underwent coupling with piperonal (1a) to give an alkeny-
lated product 3f in 62% yield. These reactions were also
highly regio- and stereoselective as like 3a, whereas 3,4-
dimethoxy benzaldehyde (1b) reacted with methyl acrylate
(2a) to give an different type of regioselective product 3g
in 72% yield with very high E-stereoselectivity. In the sub-
strate 1b also, there are two ortho aromatic CꢀH bonds for
coupling. Very selectively, the alkenylation reaction takes
place predominately at the sterically less hindered CꢀH
bond of 1b moiety. Similarly, 1b reacted with ethyl acrylate
(2b) to provide an alkenylated product 3h in 67% yield in a
highly regio- and stereoselective manner.
a All were carried out using aldehydes 1 (1.0 mmol), methyl acrylate
(2a) (6.0 mmol), [{RuCl2(p-cymene)}2] (3 mol %), AgSbF6 (20 mol %),
and Cu(OAc)2 H2O (50 mol %) in 1,2-dichloroethane at 100 °C for 16 h
3
under open atmosphere.
Heterocyclic aldehydes were also compatible for the
present CꢀH bond activation reaction (Scheme 3). Thus,
1-methylindole-3-carboxaldehyde (1j) and 3-formylthio-
phene (1k) reacted with 2a to give the corresponding cou-
pling products 3p and 3q in 69 and 67% yields, respectively.
The reaction tolerates a variety of functional groups such as
Br, Cl, OMe, S, dioxole, and NMe2 on the aromatic and
heteroaromatic ring of aldehydes (Schemes 2 and 3).
Scheme 3. Heteroaromatic Aldehydes Scope
This alkenylation reaction was successfully extended to
various aromatic aldehydes 1 with methyl acrylate (2a)
(Scheme 2). Thus, treatment of 4-methoxy benzaldehyde
(1c), 4-methyl benzaldehyde (1d), and 4-dimethylamino
benzaldehyde (1e) with methyl acrylate (2a) gave the cor-
responding alkenylated compounds 3iꢀk in 60, 46, and
39% yields, respectively. In the reaction of 4-dimethyl-
amino benzaldehyde (1e) with 2a, in addition to mono
alkenylation product 3k in 39% yield, bis alkenylation
product 3k0 was also observed in 49% yield. 4-Chloro
benzaldehyde (1f) also reacted with n-butyl acrylate (2c)
to provide a 2-formyl phenylalkeno-derivative 3l in a low
25% yield. 2-Methoxy benzaldeyde (1g) also participated
A synthetic application of product 3 in organic synthesis is
shown in Scheme 4. The 2-formyl phenylalkeno-derivatives 3
were further converted into unusual four-membered cyclic
1136
Org. Lett., Vol. 14, No. 4, 2012

mediate 6. β-Hydride elimination from intermediate 6 in
the presence of Cu(OAc)2 H2O gives the final product 3
and regenerates the active ruthenium species for the next
catalytic cycle. In the reaction, the remaining amount of
active Cu(OAc)2 source was regenerated under oxygen or
atmosphere from the reduced copper source.
3
Scheme 4. Photochemical Rearrangement
Scheme 5. Proposed Mechanism
ketones and a polysubstituted isochromanone derivative via a
photochemical rearrangement.11 Thus, when irradiation of 3a
in a benzene solution with a 450 W medium pressure mercury
vapor lamp for 8.0 h was performed, a four-membered cyclic
ketone 4a was observed in 67% yield. Similarly, the irradiation
of 3g under similar reaction conditions for 8 h gave a four-
membered cyclic ketone 4b in 63% yield. Surprisingly, with the
irradiation of 3i in a benzene solution with a 450 W medium
pressure mercury vapor lamp for 5.0 h, a polysubstituted
isochromanone derivative 4c was observed in 76% yield.11
But, 3j under similar reaction conditions gave a four-mem-
bered cyclic ketone 4d in 69% yield. It is important to point out
that isochromanone derivatives are widely occurring natural
products that show various biological activities.10c,11
In conclusion, we have demonstrated a ruthenium-
catalyzed ortho-alkenylation of aromatic and heteroaro-
matic aldehydes with activated alkenes to afford substituted
alkene derivatives in good to moderate yields. Further
extension of the CꢀH bond activation of other chelating
group substituted aromatics and functionalization with
other π-components and detailed mechanistic investigations
are in progress.
A plausible mechanistic rationale of coupling of aro-
matic and heteroaromatic aldehydes with alkenes is pro-
posed in Scheme 5. The catalytic reaction is likely initiated
by the removal of chloride ligand by Agþ salt from
[{RuCl2(p-cymene)}2] complex. Coordination of the car-
bonyl oxygen of 1 to the ruthenium cationic species
followed by ortho-metalation provides a five-membered
ruthenacycle 5.1c Coordinative insertion of alkene 2 into
the Ruꢀcarbon bond of ruthenacycle 5 affords an inter-
Acknowledgment. We thank the Indian Institute of
Science Education and Research, Pune, India, for the
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
(11) Xia, W.; Shao, Y.; Gui, W.; Yang, C. Chem Commun. 2011, 47,
11098 and references therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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