Synthesis of 2-pyridones and iminoesters via Rh(III)-catalyzed oxidative coupling between acrylamides and alkynes

Article abstract of DOI:10.1021/ol102306c

Catalytic oxidative coupling between acrylamides and alkynes was achieved using 0.5 mol % loading of [RhCp*Cl₂]₂ with Cu(OAc)₂ as an oxidant. 2-Pyridones, iminoesters, and substituted indoles could be obtained as a result

Full text of DOI:10.1021/ol102306c

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5462-5465
Synthesis of 2-Pyridones and
Iminoesters via Rh(III)-Catalyzed
Oxidative Coupling between
Acrylamides and Alkynes
Yan Su, Miao Zhao, Keli Han, Guoyong Song,* and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian, P. R. China 116023
xwli@dicp.ac.cn; songgy129@gmail.com
Received September 25, 2010
ABSTRACT
Catalytic oxidative coupling between acrylamides and alkynes was achieved using 0.5 mol % loading of [RhCp*Cl2]2 with Cu(OAc)2 as an
oxidant. 2-Pyridones, iminoesters, and substituted indoles could be obtained as a result of the electronic and steric effects of the substituents
in the acrylamides.
Pyridones are a valuable building block in natural product
synthesis,1 and they represent one of the most important
classes of heterocycles that are known to exhibit a wide range
of biological activities.2 Consequently, various methods have
been developed, and the construction of substituted 2-pyri-
done rings is generally achieved using acyclic starting
materials with a Michael addition being the key step.3
However, they typically involve harsh conditions and can
be incompatible with sensitive functional groups. Metal
catalysis is one of the most straightforward methods for
constructing pyridone rings.4 For example, Padwa developed
an important methodology of 2-pyridone synthesis starting
from diazo compounds using Rh(II) catalysts.5 A well-known
strategy to construct 2-pyridone rings is based on a [2 + 2
+ 2] cycloaddition between alkynes and isocyanates, and
these reactions can be catalyzed by Rh(I),6 Co(I),7 and
Ru(II)8 complexes. Tanaka recently developed synthetic
methods to access substituted 2-pyridones via intramolecular
hydrovinylation of N-alkenyl alkynylamides using Au(I) or
(5) (a) Harris, J. M.; Padwa, A. Org. Lett. 2003, 5, 4195. (b) Straub,
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(c) Lee, E. E.; Rovis, T. Org. Lett. 2008, 10, 1231. (d) Tanaka, K.; Wada,
A.; Noguchi, K. Org. Lett. 2005, 7, 4737.
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T. Chem. Pharm. Bull. 1985, 33, 2731.
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D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127,
3473. (b) Eichberg, M. J.; Dorta, R. L.; Lamottke, K.; Vollhardt, K. P. C.
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10.1021/ol102306c  2010 American Chemical Society
Published on Web 10/29/2010

Pd(II) catalysts.9 Very recently, Tsuji reported a related
2-quinolones synthesis via Ir(I)-catalyzed annulation reac-
tions between carbamoyl chlorides and alkynes.10
lectivity. We now report the synthesis of all these three
categories of products in Rh(III)-catalyzed oxidative cou-
pling, and the product formation is controlled by the steric
and electronic effects of the substituent in the N-aryl ring
and in the olefin unit.
We commenced our studies with the screening of reaction
conditions for the coupling between N-phenyl methacryla-
mide and PhCtCPh. Our previous studies indicated that
oxidative coupling between PhCtCPh and the structurally
related N-phenyl benzamide can be successfully achieved
using [RhCp*Cl2]2 as a catalyst and Ag2CO3 as an oxidant.14
Indeed, 2-pyridone 3aa was isolated in 68% yield when this
combination was used in MeCN at 110 °C (entry 1, Table
1). The yield was significantly improved when acetone was
In the past decade, catalytic activation of C-H bonds
has become an increasingly important strategy for the
elaboration of readily available simple substrates in an
atom-economic fashion.11 Recently, the groups of Jones,
Fagnou, Miura and Satoh, Glorius, Rovis, and Li have
independently reported Rh(III)-catalyzed oxidative cou-
pling between alkynes and arenes bearing heteroatom
directing groups.12-14 The C-H activation of arenes is
directed to the ortho positions, and this method allows the
synthesis of various heterocycles including indoles,13j
pyrroles,13c isoquinolones,13a,d,e,14 isoquinolines,13h,m and
isocoumarins.13f Our14 and other’s13a,d,e recent studies in-
dicated that isoquinolones can be efficiently synthesized from
the oxidative coupling reactions between alkynes and ben-
zamides using Rh(III) catalysts and Cu(II) or Ag(I) oxidants.
Along the same lines, an efficient and selective synthesis of
related 2-pyridones via oxidative insertion of alkynes into
acrylamides would constitute a powerful method (eq 1).
Table 1. Synthesis of Pyridone 3aa under Different Conditionsa
entry cat. loading
oxidant
temp (°C) solvent yield
1
2
3
4
4 mol %
4 mol %
4 mol %
0.5 mol %
Ag2CO3
Ag2CO3
Ag2CO3
Cu(OAc)2
110
90
100
100
MeCN
68%
86%
92%
94%
acetone
acetone
acetone
a Conditions: 1a (5.0 mmol), diphenylacetylene (1.3 equiv), oxidant (1.5
equiv of Ag2CO3 or 2.2 equiv of Cu(OAc)2), catalyst, solvent (3 mL), 12 h,
isolated yield.
We reasoned that when N-aryl acrylamides are used as
substrates C-H activation can take place either in the aryl
ring or at the ꢀ position of the olefin unit. Therefore,
pyridones, iminoesters, and N-acyl indoles are the three
possible products (eq 1), as a result of different chemose-
used as a solvent even at a lower temperature (entry 3).
However, a rather high loading (4 mol %) of [RhCp*Cl2]2
is necessary for a full conversion when Ag2CO3 was used.
Moving to Cu(OAc)2 as an oxidant, we were delighted to
find that 3aa was isolated in 94% yield using only 0.5 mol
% loading of the catalyst when the reaction was conducted
in acetone (entry 4). Reactions performed using benchtop
acetone without the extrusion of air afforded products in
nearly indentical yields.
The coupling of various acrylamides with internal alkynes
was examined under the optimized conditions (Scheme 1).
Substrate 1a reacted similarly with a symmetrically substi-
tuted diaryl alkyne to give 3ab in high yield. A thiophenyl-
substituted alkyne can also be used but with lower reactivity,
and 3ac was isolated in 53% yield. Surprisingly, dialkyl-
substituted alkynes such as 4-octyne only gave complicated
reactions with unidentifiable products. In contrast, mixed
alkyl- and aryl-substituted unsymmetrical alkynes are suitable
coupling partners. Thus PhCtCMe readily participated in
this reaction, and products 3jd and 3jd′ were isolated as a
mixture of regioisomers (7:1 ratio) in excellent yield.15 The
selectivity was slightly decreased when PhCtCnPr was
employed to give 3ke and 3ke′ in a 5:1 ratio, where the
(9) (a) Imase, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett. 2008,
10, 3563. (b) Imase, H.; Suda, T.; Shibata, Y.; Noguchi, K.; Hirano, M.;
Tanaka, K. Org. Lett. 2009, 11, 1805.
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(11) For leading reviews on metal-catalyzed C-H functionalization, see:
(a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. ReV. 2010, 110,
624. (b) Sun, C.-L.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (c) Chen,
X.; Engle, K. M.; Wang, D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.,
Int. Ed. 2009, 48, 9792. (e) Xu, L.-M.; Yang, Z.; Shi, Z.-J. Chem. Soc.
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Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 3013. (h)
Satoh, T.; Miura, M. Top. Organomet. Chem. 2008, 24, 61. (i) Ritleng, V.;
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.
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2010, 132, 6908. (b) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2010, 12, 2068. (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, N.; Hirano, K.; Satoh, T.;
Miura, M. Chem. Lett. 2010, 39, 744. (f) Mochida, S.; Shimizu, M.; Hirano,
K.; Satoh, T.; Miura, M. Chem. Asian J. 2010, 5, 847. (g) Mochida, S.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 6295. (h)
Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050. (i) Umeda,
N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47,
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Jones, W. D. J. Am. Chem. Soc. 2008, 130, 12414. (l) Ueura, K.; Satoh, T.;
Miura, M. Org. Lett. 2007, 9, 1407. (m) Fukutani, T.; Umeda, N.; Hirano,
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Chem. 2010, DOI: 10.1021/jo101596d.
.
(15) The regiochemistry of the major isomer 3jd was confirmed by the
correlation between the pyridine ring C-H and the two CH3 groups in
NOESY spectroscopy (see Supporting Information).
Org. Lett., Vol. 12, No. 23, 2010
5463

standard reaction conditions, incomplete conversion was
observed, and the major product (4pa) was identified as an
Scheme 1
.
Oxidative Coupling of N-Substituted Acrylamides
1
indole on the basis of its characteristic H and 13C NMR
and Internal Alkynesa
data (eq 2). No full conversion could be reached even though
the reaction was conducted at a high (4 mol %) loading of
[RhCp*Cl2]2 in acetone or MeCN. Eventually a full conver-
sion could be reached when [RhCp*(MeCN)3](PF6)2 (5 mol
t
%) was used as a catalyst in AmOH at 120 °C, and 4pa
was isolated as the major product in 60% yield. Synthesis
of indoles or pyrroles via Rh(III)-catalyzed oxidative cou-
pling has been reported.13c,j
During our exploration of the scope of the acrylamide that
bears a bulky N-aryl group, substrate 1o with an N-mesityl
substituent has been applied. As expected, this reaction was
slow with low conversion, and only one product was detected
and isolated in 13% yield. Interestingly, this product was
identified as an iminoester 5oa (eq 3). In the 13C NMR spectrum,
the CdN resonates at δ 151.9, to the higher field of the carbonyl
signals in pyridones 3aa-3na. In addition, the iminoester ring
proton (para to the oxygen) resonates as a quartet (δ 6.78, 4JH-H
a Reaction conditions: acrylamide, alkyne (1.5 equiv), 2.2 equiv of
Cu(OAc)2, 0.5 mol % of catalyst, acetone, 100 °C, 12 h, isolated yield.
1
) 1.5 Hz) in the H NMR spectrum. The highly bulky
N-substituent renders any C-N bond formation unfavorable,
and consequently C-O bond formation occurred, where ap-
parent NH to OH tautomerization of the acrylamide is involved.
This interesting strategy to construct heterocycles that involves
tautomerization of amides and anilines has been increasingly
explored in both intramolecular and cross-coupling reactions
in palladium or copper catalysis.16
decreased selectivity is plausibly ascribed to the increased
steric bulk of the nPr group. However, essentially no coupling
occurred when PhCtCSiMe3 was used under the same
conditions. The scope of the acrylamide was further defined
using PhCtCPh as the coupling partner. Methacrylamides
bearing a wide variety of N-aryl groups can be applied. Both
electron-donating (3ba, 3ca, 3ea) and -withdrawing (3da,
3ga, 3ha, 3ia) N-aryl groups in methacrylamides can be
tolerated, and the 2-pyridone products were isolated in
excellent yield. These products were fully characterized; the
carbonyl group resonates within a narrow range of δ
162-163 in the 13C NMR spectra, and it offers diagnostic
handles for structure elucidation. The isolation of 3ca in high
yield indicates that the steric bulk of the N-o-tolyl group
can be tolerated. Furthermore, the N-substituent is not limited
to an aryl group, and N-benzyl-substituted acrylamide (1l)
reacted similarly to give pyridone 3la in good yield.
The effects of the substituent in the olefin unit of the
acrylamide were further explored. The substituent at the
R-position seems to have a big effect. N-Methyl 2-pheny-
lacrylamide reacted similarly with PhCtCPh to give 3ma
in 77% yield (Scheme 1). However, when acrylamide with
an unsubstituted olefin unit (1n) is used, a sluggish reaction
was observed and 3na was isolated in only 48% yield. The
substituent at the ꢀ-position has an even more pronounced
effect. When a phenyl group is introduced into the ꢀ-position
of acrylamide (trans-cinnamide), no coupling product could
be detected, and the starting materials were fully recovered.
In contrast, when trans-crotylamide 1p was subjected to the
In addition to the formation of iminoester through steric
control of the N-aryl group, the selectivity of pyridone versus
iminoester formation could also be tuned by the electronic
effects of the N-aryl group. We reasoned that introduction
of an electron-withdrawing group into the N-aryl group of
acrylamides should enhance the acidity of the NH proton,
and consequently, NH to OH tautomerization of the amide
functionality is expected to proceed at a lower kinetic barrier.
As a result, the likeliood of oxidative C-O bond formation
that yields an iminoester is enhanced. Indeed, the reaction
of 1q and PhCtCPh under the standard conditions afforded
both 2-pyridone 3qa and iminoester 5qa in 52% and 21%
(16) (a) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411.
(b) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272. (c) Inamoto,
K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147. (d) Joyce,
L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792. (e) Garc´ıa-Fortanet, J.; Kessler,
F.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 6676.
5464
Org. Lett., Vol. 12, No. 23, 2010

isolated yield, respectively (eq 4). The selectivity of imi-
noester versus pyridone can be further improved when a
combination of [RhCp*Cl2]2 (4 mol %) and Ag2CO3 (1.5
equiv) was used, and iminoester 5qa was isolated as the
major product in 61% yield.
In most cases, the coupling reaction proceeded smoothly with
0.5 mol % loading of [RhCp*Cl2]2 in common solvents.
Products in three categories, namely, 2-pyridone, iminoesters,
and a substituted indole, have been obtained as a result of
the electronic and steric effects of the substituents in the
N-aryl groups and in the olefin unit. In most cases 2-pyri-
dones were obtained as the oxidative coupling product. The
formation of iminoesters was favored for a substrate bearing
a bulky N-aryl group. Both 2-pyridone and iminoester
products were obtained for an acrylamide bearing a nitro-
functionalized N-aryl group. The ꢀ-substituents of the
acrylamides showed pronounced effects. No coupling reac-
tion was detected for an N-aryl trans-cinnamide, while the
coupling of N-aryl trans-crotylamide (1p) afforded an indole
product, where C-H activation occurred at the ortho position
in the N-aryl ring, instead of at the ꢀ vinylic position. An
amount of 2 equiv of alkynes was oxidatively incorporated
to give a tricyclic product when simple methacrylamide was
used. The versatility and the wide scope of this coupling
reaction should find applications in the synthesis of complex
organic molecules such as natural products.
In addition to the coupling of alkynes with secondary
acrylamides, the coupling of primary methacylamide and
PhCtCPh proceeded smoothly under the same conditions.
Interestingly, tricyclic product 6 was obtained in 51% yield (eq
5), which corresponds to the oxidative incorporation of two
alkyne units, and thus 4 equiv of Cu(OAc)2 was provided.
Formation of 6 is proposed to involve the formation of a
2-pyridone intermediate that bears an NH group, followed by
oxidative insertion of the second equivalent of PhCtCPh. A
similar type of reaction has been reported by us and others.13e,14
Acknowledgment. We thank the Dalian Institute of
Chemical Physics, Chinese Academy of Sciences, for
financial support.
Supporting Information Available: Detailed synthetic
procedures, characterization data, and NMR spectra of all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, we have successfully developed Rh(III)-
catalyzed oxidative coupling between acrylamide and alkynes.
OL102306C
Org. Lett., Vol. 12, No. 23, 2010
5465