Rh(III)-catalyzed tandem oxidative olefination-michael reactions between aryl carboxamides and alkenes

Article abstract of DOI:10.1021/ol102241f

Rh(III)-catalyzed oxidative coupling reactions between benzamides or heteroaryl carboxamides and olefins have been developed. The vinylation product can further undergo a Michael reaction leading to γ-lactam in the case of electron-withdrawing olefins.

Full text of DOI:10.1021/ol102241f

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5430-5433
Rh(III)-Catalyzed Tandem Oxidative
Olefination-Michael Reactions between
Aryl Carboxamides and Alkenes
Fen Wang,† Guoyong Song,† and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian, P. R. China 116023
xwli@dicp.ac.cn
Received September 19, 2010
ABSTRACT
Rh(III)-catalyzed oxidative coupling reactions between benzamides or heteroaryl carboxamides and olefins have been developed. The vinylation
product can further undergo a Michael reaction leading to γ-lactam in the case of electron-withdrawing olefins.
Pioneered by Fujiwara and Moritani, oxidative olefination
of arenes using alkenes (the oxidative Heck reaction)
represents an atom-economic strategy to directly function-
alize arenes (eq 1).1 This process is highly attractive in that
no prior functionalization of the arene is necessary.2 A survey
of recent reports on oxidative Heck reactions reveals that
palladium catalysts are most commonly used, as in the
seminal work of Yu3 and others.4,5 Significantly, Yu and
co-workers even discovered the oxidative C(sp3)-H olefi-
nation of N-aryl carboxamides.3a Nevertheless, the N-aryl
groups are limited to highly electron-withdrawing ones in
this case.
pathway for their high functional group tolerance and wide
range of synthetic utility.7 However, rhodium-catalyzed
oxidative C-H functionalization has been less well-
studied. Matsumoto and Yoshida achieved an oxidative
Heck reaction between benzene and ethylene using cy-
clometalated Rh(III) catalysts.8 More recently, Miura and
Satoh9 and Glorius6 reported important Rh(III)-catalyzed
oxidative Heck reactions with Cu(II) oxidants (eq 2-4).9
(4) (a) Song, C. X.; Cai, G.-X.; Farrell, T. R.; Jiang, Z. P.; Li, H.; Gan,
L. B.; Shi, Z.-J. Chem. Commun. 2009, 6002. (b) Cai, G.; Fu, Y.; Li, Y.;
Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (c) Boele, M. D. K.;
van Strijdonck, G. P. F.; der Vries, A. H. M.; Kamer, P. C. J.; de Vries,
J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (d)
Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
(e) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009,
131, 13888. (f) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125,
9578. (g) Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc.
2003, 125, 1476. (h) Wu¨rtz, S.; Rakshit, S.; Neumann, J. J.; Dro¨ge, T.;
Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 7230.
Rhodium catalysts stand out in the area of C-C
coupling reactions that proceed via a C-H activation
† These authors contributed equally to this work.
(1) (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.
Chem. Res. 2001, 34, 633.
(5) (a) Ma, S.; Yu, S. Tetrahedron Lett. 2004, 45, 8419. (b) Liu, C.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250. (c) Grimster,
N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2005, 44, 3125. (d) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12,
1972.
(2) For the applications of oxidative Heck reactions in natural product
synthesis, see: (a) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames,
D. J. Am. Chem. Soc. 2002, 124, 11856. (b) Tsai, A. S.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6316.
(3) (a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 3680. (b) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 9886. (c) Lu, Y.; Wang, D.-H.; Engle, K.-M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 5916. (d) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-
H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460. (e) Wang, D.-H.; Engle,
K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315. (f) Li, J.-J.; Mei, T.-
S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452.
(6) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982.
(7) For a recent review, see: Colby, D. A.; Bergman, R. G.; Ellman,
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2002, 206, 272.
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74, 7094. (b) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407.
10.1021/ol102241f  2010 American Chemical Society
Published on Web 11/01/2010

Recent studies on Rh(III)-catalyzed oxidative C-C, C-N,
and C-O coupling reactions by Satoh and Miura, Fagnou,
Jones, Glorius, and Zhang has revealed that in most cases
proximal heteroatom-directing groups such as amide,6,10
pyridyl,9a,11 imine,12 hydroxyl,13 and carboxyl9b,14 are
important both to facilitate the activation of C(sp2)-H bonds
and to direct the selectivity to the ortho position. Considering
that amides are readily available and amide functionality
offers sufficient assistance, oxidative functionalization of
acetanilides has been well studied.5d,6,10a,15 In contrast to
the specific selectivity of C-H functionalization in aceta-
nilides, C-H functionalization of N-aryl benzamides may
be complicated by chemoselectivity in terms of which arene
undergoes C-H cleavage, and this substrate was not studied
until very recently by us16 and others in Rh catalysis,10d,e
although Pd-catalyzed C-H activation of N-aryl amides has
been reported to occur at the carboxylic acid unit.17 As a
continuation of our studies, we now report C-H olefination
of such benzamides at the C-aryl ring. More importantly,
when electron-poor olefins are utilized, the coupled products
may further undergo in situ Michael addition to give
γ-lactams.
Scheme 1. Rh(III)-Catalyzed Tandem Oxidative
Olefination-Michael Reactions between Benzamides and
Alkenesa b
,
a Reaction conditions: benzamide, olefin (2 equiv), Ag2CO3 (2 equiv),
[RhCp*Cl2]2 (4 mol %), MeCN (5 mL), sealed tube under nitrogen, 110
°C, 12 h. b 2a ) benzyl acrylate; 2b ) ethyl acrylate; 2c ) methyl acrylate;
2d ) butyl acrylate; 2e ) tert-butyl acrylate; 2f ) acrylonitrile; 2g ) ethyl
vinyl ketone.
higher temperatures (125 °C) but with lower catalyst loading
(2 mol %) only gave lower yields (64%). This reaction is
proposed to go by the oxidative olefination of the ortho C-H
bond in the C-aryl ring, followed by intramolecular hy-
droamination (Michael addition).3a,f,9b The scope of this
reaction is outlined in Scheme 1. Benzamides with electron-
donating or -withdrawing groups afforded lactams in high
isolated yield. Furthermore, N-o-tolyl benzamide (1e) also
reacts to give the coupled product in 89% isolated yield,
indicating tolerance of the steric bulk in the N-aryl group. It
is noteworthy that the halide substituent (1h) can be tolerated
without any Heck coupling byproduct being detected, which
highlights an advantage of rhodium catalysis compared to
palladium catalysis. To examine the regioselectivity of this
reaction, substrates 1i and 1j were allowed to react under
the standard conditions to give 3i and 3j, respectively, where
C-H functionalization occurred at the less sterically hindered
We initiated our investigation with the coupling between
benzamide 1a and benzyl acrylate. Gratifyingly, the use of
[Cp*RhCl2]2 as the single catalyst and Ag2CO3 as the oxidant
in MeCN or acetone yielded lactam 3aa (110 °C, sealed tube,
12 h) in 94% yield (Scheme 1). Reactions performed at
(10) (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 16474. (b) Guimond, N.; Gouliaras, C.;
Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (c) Rakshit, S.; Patureau,
F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (d) Hyster, T. K.;
Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565. (e) Mochida, S.; Umeda,
(13) Uto, T.; Shimizu, M.; Ueura, K.; Tsurugi, H.; Satoh, T.; Miura,
M. J. Org. Chem. 2008, 73, 298.
(14) (a) Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2009, 74, 3478. For a recent review, see: (b) Satoh., T.; Ueura, K.; Miura,
M. Pure Appl. Chem. 2008, 80, 1127.
N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2010, 39, 744
.
(15) (a) Phipps, R. J.; Gaunt, M. Science 2009, 323, 1593. (b) Lyons,
T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147. (c) Yang, S.; Li, B.;
Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. (d) Zaitsev, V. G.;
Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156.
(11) (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem.,
Int. Ed. 2008, 47, 4019. (b) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am.
Chem. Soc. 2008, 130, 12414. (c) Guan, Z.-H.; Spinella, S. M.; Yu, S.;
Liang, Y.-M.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 729. (d) Morimoto,
(16) Song, G.; Chen, D.; Pan, C.-L.; Crabtree, R. H.; Li, X. J. Org.
Chem. DOI: 10.1021/jo101596d.
K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2068
.
(12) (a) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050.
(b) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Commun. 2009, 5141.
(17) (a) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965.
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1275.
Org. Lett., Vol. 12, No. 23, 2010
5431

site, although (reversible) C-H activation may take place
at both positions ortho to the amide directing group.10a In
sharp contrast, the olefination of 1k gave a mixture of two
regioisomers 3k and 3k′ in 10:1 ratio, with the major product
being derived from the ortho C-H activation at the more
hindered position. Similar results were also observed for
amide 1l, where 3l and 3l′ were isolated in 1:4 ratio as
analytically pure compounds. This observed selectivity is
most plausibly ascribed to the directing effect of the meta
heteroatom and/or the electronic effect of the aryl ring. The
range of olefin substrates can also be extended to other
acrylates, an enone, and acrylonitrile (Scheme 1). In all cases,
only monovinylation products can be detected, in contrast
to the divinylation of benzoic acids observed by Satoh and
Miura.9b This result also indicates that the amide functionality
in the product cannot function as an efficient directing group
to achieve further ortho C-H activation. Thus, the observed
single lactam product might be ascribed to the fast Michael
reaction that traps the olefination intermediate (vide infra).
We reasoned that when using electron-neutral or electron-
rich olefins this reaction should stop after the olefination
stage. Indeed, when 1a was allowed to react with styrene
under the same conditions, the corresponding stilbene
products could be detected (GC-MS). However, they cannot
be isolated in analytically pure form using column chroma-
tography. Fortunately, switching from styrene to p-chlo-
rostyrene (1 equiv) leads to the successful isolation of stilbene
4 (62% GC yield and 42% isolated yield, eq 5), together
with the recovery of the starting benzamide (30%).
nolone, where two products have been isolated and fully
characterized (eq 7). In the reaction of 6 and benzyl acrylate,
a monovinylation product (7a) and an N-alkyl product (7b)
were isolated in 42% and 46% yield, respectively. In both
products, the C-H activation takes place at the 8-position,
facilitated by the proximal O atom of the amide moiety. No
further intramolecular oxidative Colefin-Oamide coupling was
observed for product 7a, even though an excess of Ag2CO3
was provided. When isolated 7a was allowed to react
(MeCN, 110 °C) with benzyl acrylate under the same
reaction conditions ([Cp*RhCl2]2, 4 mol %, and Ag2CO3, 2
equiv), product 7b was isolated in 35% yield, together with
the complete recovery of 7a. These results indicate that
product 7a can be an intermediate leading to the N-alkyl
product 7b. However, the alternative Michael reaction-
oxidative olefination sequence is also possible.
Extension of this reaction to heteroaryl carboxamides
turned out to be successful under the standard conditions.
Furyl-2-carboxamide (8) undergoes a somewhat sluggish
reaction with benzyl acrylate to give an olefin product 9 in
46% yield (eq 8); however, this reaction is clean, and the
unreacted substrate 8 can be recovered (44%). Indolyl-3-
carboxamide (10) readily reacts with benzyl acrylate to give
11 in high isolated yield (eq 9), and here even the N-methyl
amide is reactive enough. In neither case did further Michael
reaction take place. It should be noted that the amide-
directing group in 10 is necessary as evidenced by the
absence of any reaction when simple N-methyl indole was
allowed to react with acrylates under these conditions. This
is in contrast to the observed Pd(II)-catalyzed oxidative
coupling between N-methyl indole and butyl acrylate at the
3-position using Cu(OAc)2 as oxidant.19 Thiophenyl-2-
carboxamide (12) readily reacted with benzyl acrylate, and
both olefin (13a) and Michael reaction products (13b) were
To better define the substrate scope, 1-naphthamide 1l was
subjected to the same reaction conditions. Surprisingly,
although the expected lactam 5b can still be obtained, the
major product is an imidoester (5a), resulting from a double
oxidative coupling reaction which involves sequential C-H
olefination and intramolecular oxidative C-O formation (eq
6). Optimization of the reaction conditions by simply
providing an access of Ag2CO3 leads to the isolation of 5a
and 5b in 65% and 29% yield, respectively. The structure
of 5a was elucidated using NMR (1H and 13C) and IR
spectroscopy and HRMS (see Supporting Information for the
characterization of 5a). We noted that directed activation of
the C-H bond at the 8-position of 1-substituted naphthalenes
is rare.18
The scope of this reaction can be further extended to
1-hydroxyisoquinoline 6, which is essentially an isoqui-
(18) (a) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 78. (b) Ka¨ım, L. E.; Gamez-Montan˜o, R.; Grimaud,
L.; Ibarra-Riverab, T. Chem. Commun. 2008, 1350. (c) Harayama, T.; Sato,
T.; Hori, A.; Abe, H.; Takeuchi., Y. Synthesis 2004, 9, 1446.
5432
Org. Lett., Vol. 12, No. 23, 2010

isolated (eq 10). The differences observed for these heteroaryl
carboxamides and benzamides with respect to Michael
reactions are likely caused by the differences of the stereo-
electronic effects of the olefin intermediate/product.
acidic NH give a higher rate and (2) essentially no reaction
was observed for PhC(O)NHMe, PhC(O)NH(Mes), and
PhC(O)N(Me)Ph. The strong influence of the N-substituent
on the reaction rate, particularly the poor reactivity of
PhC(O)NHMe, seems inconsistent with oxygen coordina-
tion.22
In conclusion, we have successfully developed a Rh(III)-
catalyzed synthesis of γ-lactams from oxidative coupling of
benzamides or heteroaryl carboxamides with electron-poor
olefins. In these reactions, the ortho C-H bonds in the C-aryl
rings undergo selective activation to give the vinylation
products, followed by intramolecular Michael reactions.
2-Heteroaryl carboxamides can undergo oxidative coupling
with or without subsequent Michael addition. The oxidative
coupling between benzamides and styrenes gives olefination
products. The simplicity of this catalyst system and the high
regio- and chemoselectivity of the synthesis of lactams should
find broader applications, especially in natural product
synthesis.
To probe the reaction mechanism, competitive reactions
have been carried out. An equimolar amount of
p-MeOC6H4C(O)NHPh, p-BrC6H4C(O)NHPh, and benzyl
acrylate was allowed to react under the standard condi-
tions. Benzamides with electron-poor groups in the C-aryl
ring tend to react in slight preference (Supporting Infor-
mation). Likewise, the competitive reaction between
PhC(O)NH(p-FC6H4) and PhC(O)NH(p-OMeC6H4) also
leads to the conclusion that this coupling reaction is
favored for benzamides with electron-poor N-aryl groups
(see the Supporting Information).20 The fact that benza-
mides with electron-poor N-aryl groups react at a higher
rate also suggests that the Michael reaction cannot be the
turnover limiting step for the catalytic cycle.
Although there is no formal N-H cleavage (prior to the
Michael reaction) in the olefination of benzamides, (revers-
ible) metalation seems to take place on the nitrogen rather
than on oxygen.21 This hypothesis is consistent with the facts
that (1) withdrawing N-aryls (and C-aryls) and hence more
Acknowledgment. Financial support from the Dalian
Institute of Chemical physics, Chinese Academy of Sciences,
is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008,
10, 1159.
(20) We would have liked to obtain information on the cleavage of the
ortho C-H bond from kinetic isotope effect (KIE) experiments. However,
KIE data could not be obtained from inter- or intramolecular competition
since heating protonated and deuterated benzamide (C6D5C(O)NHPh) in
equimolar ratios in the absence of acrylate resulted in scrambling of
deuterium into the ortho sites of both benzamides, which indicates that the
ortho C-H activation here is a reversible process. See ref 12.
(21) Nitrogen coordination in benzamide substrates has been recently
proposed in related coupling reactions. See ref 10d.
OL102241F
(22) The methyl group in PhC(O)NHMe makes the amide oxygen more
coordinating and should make amide oxygen a stronger chelator, favoring
oxygen-directed C-H cleavage if oxygen metalation is followed. However,
this does not seem to be consistent with the experimental results.
Org. Lett., Vol. 12, No. 23, 2010
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