Ruthenium-catalyzed oxidative C - H bond olefination of N -methoxybenzamides using an oxidizing directing group

Article abstract of DOI:10.1021/ol2032575

Ruthenium-catalyzed oxidative C - H bond olefination of N-methoxybenzamides using an oxidizing directing group with a broad substrate scope is reported. The reactions of N-methoxybenzamides with acrylates in MeOH and styrene (or norbornadiene) in CF₃

Full text of DOI:10.1021/ol2032575

ORGANIC
LETTERS
2012
Vol. 14, No. 3
736–739
Ruthenium-Catalyzed Oxidative CÀH Bond
Olefination of N-Methoxybenzamides Using
an Oxidizing Directing Group
Bin Li,*,† Jianfeng Ma,† Nuancheng Wang,† Huiliang Feng,† Shansheng Xu,† and
Baiquan Wang*,†,‡
State Key Laboratory of Element-Organic Chemistry, College of Chemistry,
Nankai University, Tianjin 300071, P. R. China, and State Key Laboratory of
Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
nklibin@nankai.edu.cn; bqwang@nankai.edu.cn
Received December 8, 2011
ABSTRACT
Ruthenium-catalyzed oxidative CÀH bond olefination of N-methoxybenzamides using an oxidizing directing group with a broad substrate scope is
reported. The reactions of N-methoxybenzamides with acrylates in MeOH and styrene (or norbornadiene) in CF3CH2OH afforded two types of products.
Transition-metal-catalyzed direct CÀH bond transfor-
mations have attracted significant interest, because these
approaches allow the use of cheaper and more readily
available starting materials.1 Generally, the use of an
external oxidant is required to regenerate the catalyst in
the oxidative CÀH bond functionalization reaction. Con-
sequently, stoichiometric amounts of the reduced external
oxidant are produced as waste, and harsh oxidative reac-
tion conditions are required. In the past two years, the use
of an oxidizing directing group that acts as both a directing
group and an (internal) oxidant has emerged in this field.2
This efficient method has been independently developed in
palladium- and rhodium-catalyzed CÀH bond transfor-
mation reactions by the research groups of Cui and Wu,3
Hartwig,4 Yu,5 Guimond and Fagnou,6 and Glorius.7
Recently, we first applied this strategy in the synthesis of
† Nankai University.
‡ Chinese Academy of Sciences.
(1) For selected recent reviews about CÀH bond functionalizations,
see: (a) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992. (b) Ackermann, L.
Chem. Rev. 2011, 111, 1314. (c) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624. (d) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147. (e) Willis, M. C. Chem. Rev. 2010, 110, 725.
(f) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503.
(g) Topics in Current Chemistry, C-H Activation; Yu, J.-Q., Shi, Z.-J.,
Eds.; Springer: Berlin, 2010; Vol. 292. (h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Commun. 2010, 46, 677. (i) Jazzar, R.; Hitce, J.; Renaudat, A.;
Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654.
(j) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096.
(k)Giri, R.;Shi, B.-F.;Engle, K. M.;Maugel, N.;Yu, J.-Q.Chem. Soc. Rev.
2009, 38, 3242. (l) Ackermann, L.; Vicente, R; Kapdi, A. Angew. Chem., Int.
Ed. 2009, 48, 9792. (m) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094. (n) Thansandote, P.; Lautens, M.
Chem.;Eur. J. 2009, 15, 5874. (o) Daugulis, O.; Do, H.-Q.; Shabashov, D.
Acc. Chem. Res. 2009, 42, 1074. (p) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett
2008, 949 and references therein.
(2) For a highlight, see: Patureau, F. W.; Glorius, F. Angew. Chem.,
Int. Ed. 2011, 50, 1977.
(3) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc.
2009, 131, 13888.
(4) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676.
(5) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010,
132, 12862.
(6) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2011, 133, 6449.
(7) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem.
Soc. 2011, 133, 2350.
r
10.1021/ol2032575
Published on Web 01/18/2012
2012 American Chemical Society

isoquinolones from N-methoxybenzamides via ruthenium-
catalyzed CÀH bond activation at room temperature.8
The MizorokiÀHeck reaction9 is one of the most im-
portant metalÀcatalyzed CÀC bond-forming processes.
As an attractive alternative, the FujiwaraÀMoritani
reaction10 is the oxidative olefination of normally unreac-
tive aryl CÀH bonds. In recent reports, palladium11 and
rhodium12 complexes are the most frequently used cat-
alysts in the FujiwaraÀMoritani reaction. However, the
analogous ruthenium-catalyzed processes13 were less
explored, except the elegant contributions from the
research groups of Milstein,14 Miura and Satoh,15 and
Yi.16 Very recently, [{RuCl2(p-cymene)}2] catalyzed CÀH
bond activation reactions of aromatic acids and aryl
ketones with olefins were reported by the research groups
ofAckermann13c and Jeganmohan,13f respectively. Herein,
we disclose our development of a ruthenium-catalyzed
oxidative CÀH bond olefination using the CONH(OMe)
group6a,17 as an oxidizing directing group. We found that
the reaction of N-methoxybenzamides with acrylates in
MeOH and styrene (or norbornadiene) in CF3CH2OH
afforded two types of products.
Our success in the ruthenium-catalyzed CÀH bond
annulations of N-methoxybenzamides with alkynes
using an oxidizing directing group8a prompted us to
examine their reactions with alkenes. Initially, the
reactions of N-methoxybenzamide (1a) with activated
alkenes were examined. To our delight, treatment of 1a
(1.0 equiv) with n-butyl acrylate (2a) (1.8 equiv) in
the presence of 5.0 mol % of [{RuCl2(p-cymene)}2]
and 30 mol % of NaOAc in CH3OH at 60 °C for 4 h
gave the Heck-type product 3aa in 87% yield with
excellent E-stereoselectivity (Scheme 1). The structure
of 3aa was confirmed by 1H and 13C NMR analysis and
mass spectrometry. No desired product was obtained in
the absence of a ruthenium catalyst or acetate. The
acetate is crucial for the cyclometalation step1b and
the regeneration of the catalyst.8a Other salts, such as
K2CO3, were unsuitable for the reaction.
With the optimized conditions in hand, we then inves-
tigated the reaction of various substituted benzamides
1 with 2a (Scheme 1). Both electron-rich and -poor
N-methoxybenzamides participated well in this reaction
and gave the corresponding alkene derivatives 3aaÀ3ma in
moderate to excellent yields. It is noteworthy that
many important functional groups on the aromatic ring
of benzamides 1, such as methoxy, fluoro, chloro, bromo,
iodo, nitro, ester, and acetyl substituents (3daÀ3la), were
compatible in the present catalytic reaction. These findings
offer the opportunity for further coupling to afford more
complicated molecules. Extension of this reaction to hetero-
aryl carboxamides turned out to be successful. N-Methoxy-
1-methyl-indolyl-2-carboxamide (1n) and N-methoxythio-
phenyl-2-carboxamide (1o) reacted withn-butylacrylate to
yield 3na and 3oa in good yield (Scheme 1). Moreover,
various acrylates, such as methyl acrylate (2b), ethyl
acrylate (2c), tert-butyl acrylate (2d), and benzyl acrylate
(2e), efficiently reacted with 1a to produce the correspond-
ing Heck-type products 3abÀ3ae in good to excellent
yield (Scheme 1). As a result of the use of an oxidizing
directing group, the reactions were completely ortho-
and mono-olefination selective in all cases. This is in
contrast to the use of an external oxidant together with
a directing group in the established metal-catalyzed
olefination methods.11,12
(8) Li, B.; Feng, H.; Xu, S.; Wang, B. Chem.;Eur. J. 2011, 17,
12573. Very recently, a ruthenium-catalyzed annulation in H2O as the
solvent was reported: (b) Ackermann, L.; Fenner, S. Org. Lett. 2011,
13, 6548.
(9) For recent reviews, see: (a) The MizorokiÀHeck Reaction; Oestreich,
€
M., Ed.; Wiley: Chichester, 2009. (b) Brase, S.; de Meijere, A. In Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: New York, 2004; Chapter 5.
(10) For first report, see: (a) Moritani, I.; Fujiwara, Y. Tetrahedron
Lett. 1967, 8, 1119. For reviews, see: (b) Jia, C.; Kitamura, T.; Fujiwara,
Y. Acc. Chem. Res. 2001, 34, 633. (c) Beccalli, E. M.; Broggini, G.;
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Wang, G.-W. Chem. Commun. 2011, 47, 12789. (b) Li, Y.; Leow,
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Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
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Org. Lett., Vol. 14, No. 3, 2012
737

Scheme 1. Results of Ruthenium-Catalyzed Oxidative CÀH
Scheme 2. Results of Ruthenium-Catalyzed Oxidative CÀH
Olefination with Acrylic Acid Estersa
Olefination with Phenylethylene and 2,5-Norbornadienea
a Isolated yield. b6 mol %of [RuCl2(p-cymene)]2 was used. c7.5 mol %
of [RuCl2(p-cymene)]2 was used.
a Isolated yield. b70 °C.
product was observed under the optimized reaction con-
ditions described above. The same reaction was examined
with other solvents. After some trials, we were surprised to find
that the reaction worked smoothly in 2,2,2-trifluoroethanol
(TFE) and afforded 3,4-dihydroisoquinolinone deriva-
tive 6aa in 75% isolated yield with a higher catalyst
loading (10 mol %) (Scheme 2).19 However, treatment
of 1a with n-butyl acrylate 2a in TFE still gave the
Heck-type product 3aa. Notably, Glorius has reported
that the rhodium-catalyzed reaction of 1a with acrylates/
styrene afforded ortho-olefinated products.7 Replace-
ment of the N-methoxy group of 1a by the N-pivalate
group led to the formation of 3,4-dihydroisoquinolinone
derivatives.6b,7 Under the reaction conditions in TFE,
various substituted styrenes (4bÀ4e) with either electron-
donating or -withdrawing groups and norbornadiene (5a)
were good candidates for this reaction and produced
6abÀ6ae and 7aa in moderate to high yield (Scheme 2).
4-Methyl and 4-methoxy substituted benzamides 1b and 1d
also reacted well with 4-tert-butylstyrene (4c) and norborna-
diene (5a) to give 3,4-dihydroisoquinolinone derivatives 6bc,
6dc, 7ba, and 7ca in 47À87% yield, respectively (Scheme 2).
Disappointedly, other strained alkenes, such as norbornene
and cyclohexene, were not suitable substrates for this reaction
and gave the desired products in very low yield (<5%) under
We then studied the regioselectivity of this reaction.
Examination of the meta-substituted benzamide scope
revealed that the conversion of meta-substituted 1m and
the β-naphthyl derivative 1p was largely controlled by
steric interactions. The former afforded 3ma as the sole
product (Scheme 1), whereas the latter yielded 3pa-1 as a
major regioisomer (eq 1). In contrast, when substrates
1q and 1r with electronegative heteroatoms in the meta-
position were applied, significant amounts of regioisomers
3qa-2 and 3ra-2 were produced through CÀH bond transfor-
mations at the 2-position of the arenes (eq 2). The observed
site selectivity of different substrates was in agreement with
that found by Ackermann8b,13g and us,8a which resulted from
the CÀH bond acidity1b or RuÀC bond stability.18
Subsequently, we tested the catalytic reaction with sty-
renes and norbornadiene. No corresponding alkenylated
(18) (a) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010, 110,
749. (b) Clot, E.; Megret, C.; Eisenstein, O.; Perutz, R. N. J. Am. Chem.
Soc. 2009, 131, 7817.
(19) Under otherwise identical conditions, approximately 10% and
40% of 6aa was obtained in the reaction of 1a and styrene (4a) catalyzed
by 5.0 and 7.5 mol % of [{RuCl2(p-cymene)}2], respectively.
738
Org. Lett., Vol. 14, No. 3, 2012

the optimized reaction conditions. The structures of com-
plexes 6ad and 7ca were further confirmed by X-ray diffrac-
tion analysis (Figure 1).
In summary, we have developed the first ruthenium-
catalyzed oxidative CÀH bond olefination of N-methox-
ybenzamides using an oxidizing directing group with a
broad substrate scope. The catalytic reaction is exclusively
ortho- and mono-olefination selective. The use of an inter-
nal oxidant results in a mild reaction condition and a clean
process. Intriguingly, the reactions with acrylate esters in
MeOH afford olefinated benzamides, whereas with styrenes
or norbornadiene in TFE provide 3,4-dihydroisoquinolinone
derivatives as products. Moreover, the present reaction
adds to the rapidly expanding repertoire of internal
oxidant directed CÀH bond activation reactions.2À8 Me-
chanistic studies of the reaction were indicative of an
irreversible CÀH bond metalation step via acetate assis-
tance. Further studies to explore ruthenium-catalyzed
oxidative CÀH bond transformations and clearly under-
stand the reaction pathway are in progress and will be
reported in due course.
Figure 1. X-ray diffraction analysis of complexes 6ad (a) and 7ca
(b). Thermal ellipsoids are shown at the 30% level. Hydrogen
atoms have been omitted for clarity.
Finally, we conducted experiments with isotopically
labeled substrates to probe the working mode of the reac-
tion. Reaction with deuterated starting material 1a-[D5]
was examined, and no H/D exchange was detected (eq 3).
Furthermore, a kinetic isotope effect (KIE) of kH/kD ≈ 2.1
was observed in the intermolecular isotopic study (eq 4). It
is suggested that, under the reaction conditions, the CÀH
bond metalation step is probably irreversible and involved
in the rate-determining step.13c On the basis of the above
data, we proposed the reaction proceeds by an initial
intermolecular carboruthenation of alkene via rate-
determining CÀH bond ruthenation and subsequently
reductive elimination for product formation (Scheme 3).
Scheme 3. Proposed Mechanism (Cy = p-Cymene)
Acknowledgment. Support of this work by NSFC
(21072097, 21072101, 20872066) is gratefully acknowledged.
Supporting Information Available. General experimen-
tal procedures, full spectroscopic data for all new com-
pounds, and CIF files giving X-ray structural information
for 6ad and 7ca. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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