Synthesis of enamides via Rh/C-catalyzed direct hydroacylation of ketoximes

Article abstract of DOI:10.1021/ol802665v

(Chemical Equation Presented) Enamides were efficiently prepared via a novel Rh/C-catalyzed direct hydroacylation of ketoximes. Up to 88% isolated yield of enamides were obtained with this method. Subsequent asymmetric hydrogenation of the enamides with Rh/DuanPhos complex gave the corresponding chiral amine in excellent enantioselectivities (up to 99.7% ee).

Full text of DOI:10.1021/ol802665v

ORGANIC
LETTERS
2009
Vol. 11, No. 2
481-483
Synthesis of Enamides via Rh/
C-Catalyzed Direct Hydroacylation of
Ketoximes
Zheng-Hui Guan,‡ Kexuan Huang,† Shichao Yu,† and Xumu Zhang*,†
Department of Chemistry and Chemical Biology and Department of Pharmaceutical
Chemistry, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854-8020, and State Key Laboratory of Applied Organic
Chemistry, Lanzhou UniVersity, Lanzhou 730000, China
xumu@rci.rutgers.edu
Received November 18, 2008
ABSTRACT
Enamides were efficiently prepared via a novel Rh/C-catalyzed direct hydroacylation of ketoximes. Up to 88% isolated yield of enamides were
obtained with this method. Subsequent asymmetric hydrogenation of the enamides with Rh/DuanPhos complex gave the corresponding chiral
amine in excellent enantioselectivities (up to 99.7% ee).
Enamides and their derivatives are versatile synthetic
intermediates in synthetic organic chemistry for the prepara-
tion of chiral amines, amino acids, and various heterocyclic
compounds.1 Furthermore, the enamide moiety is also a key
substructure in various classes of natural products and
pharmaceutical drug lead compounds.2 In the past decade,
we have been interested in the development of asymmetric
hydrogenation for the synthesis of enantiomerically pure
amines from enamides.3 However, the synthesis of the
required highly substituted enamide precursors in an efficient
manner is still a challenge.
Conventionally, protocols for the preparation of enamides
mainly consist of (1) direct condensation of amides with
ketones,4 (2) transition-metal-catalyzed coupling of vinyl de-
rivatives with amide,5 and (3) reaction of N-H imines derived
from ketones or nitriles with appropriate electrophiles.6 Al-
though successful in a limited number of cases, direct conden-
sation of a ketone with an amide to provide an enamide is not
a general transformation. The transition-metal-catalyzed cou-
pling reactions require additional steps to form the necessary
vinyl substrates or access to the properly functionalized coupling
† Rutgers University.
‡ Lanzhou University.
(1) (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029, and references
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Studer, M. AdV. Synth. Catal. 2003, 345, 103. (c) Huang, H.; Zheng, Z.;
Luo, H.; Bai, C.; Hu, X.; Chen, H. J. Org. Chem. 2004, 69, 2355, and
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10.1021/ol802665v CCC: $40.75
Published on Web 12/15/2008
2009 American Chemical Society

partners, although they appear to be a reliable approach to the
stereoselective preparation of enamides. The addition of an
organometallic to a nitrile is a direct approach, but this method
is usually not preferred because of complex reaction mixtures
and low yields. Burk et al. and our group reported the reductive
acylation of ketoximes with iron in the presence of Ac2O to
prepare enamides.7 This approach was often the method of
choice at smaller scale. An alternative approach recently
reported by Singh and co-workers involves a phosphine-
mediated reductive acylation of ketoximes,8 but an atom-
economical and environmentally benign approach to construct
enamides would be the direct hydroacylation of ketoximes
(outlined in Scheme 1).
Table 1. Optimization of Hydrogenation Acylation of
Ketoximea
entry
catalyst
solvent
yield (%)b
1
2
3
4
5
6
7
8
Pd/C
Rh/C
Rh/Al2O3
Ru/C
PtO2
Pd/BaSO4
Pd/CaCO3
Raney Ni
Rh/C
Rh/C
Rh/C
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EtOH
tr (90)
83 (0)
78 (0)
10 (0)
tr (95)
tr (0)
Scheme 1
tr (0)
tr (0)
9
88 (0)
85 (0)
72 (0)
56 (0)
63 (0)
10
11
12
13
CH2Cl2
THF
EtOAc
Rh/C
Rh/C
Ac2O
There is only limited precedent for the hydroacylation of
ketoximes to date.9 The most general procedure was recently
a Reaction conditions: 1a (0.2 mmol), Ac2O (3 equiv), catalyst (0.5 mol
%), H2 (1 bar), in solvent (2 mL) at rt for 10 h. b Isolated yield; tr ) trace.
c The numbers in parentheses are the isolated yields of 3a.
remarkable reactivity, and 83% yield of the desired enamide
2a was obtained in this transformation (Table 1, entry 2).
Rh/Al2O3 was also effective (Table 1, entry 3), but very low
conversion was observed when Ru/C, Pd/BaSO4, Pd/CaCO3,
or Raney Ni was employed as the catalyst (Table 1, entries
4, 6-8). Furthermore, when Pd/C or PtO2 was used as
catalyst, the major product was the amide 3a (Table 1, entries
1, 5). Optimization of the solvent revealed that EtOH,
toluene, and CH2Cl2 were superior to THF and EtOAc (Table
1, entries 2, 9-12). Ac2O could also be directly used as
solvent, but the desired enamide 2a was only obtained in
moderate yield (Table 1, entry 13). In addition, the pressure
of hydrogen did not have a significant effect on the yield of
the transformation.
Having gained an understanding of the factors that
influence the hydroacylation of the ketoxime process, we
explored the scope of this method (Table 2). The ketoximes
were in all cases prepared from the corresponding ketones
on the basis of literature precedence8,10 and used in the
reaction without further purification.
Scheme 2. Asymmetric Hydrogenation of Enamides
published by Burgos et al. for the reductive acylation of
ketoximes using Ir/C and Rh/C as catalysts.9a However, the
reaction generally needs high temperature to proceed and gives
low yields of electron-rich indanone oximes. In this com-
munication, we have improved the synthetic method and
developed an efficient catalytic process for the Rh/C-catalyzed
hydroacylation of ketoximes. This process proceeds at room
temperature and gives the corresponding enamides in high
yields.
Our experiment was initially conducted by treating in-
danone oxime 1a with Ac2O in toluene. A variety of
transition metal catalysts were screened in the presence of
H2 (1 bar) (Table 1). To our delight, Rh/C shows particularly
Various indanone-derived ketoximes gave good yields of
enamide. Electron-rich indanone ketoximes show good reactiv-
ity and gave high yields of the corresponding enamides 2b,c
(Table 2, entries 2 and 3), and a tetrasubstituted cyclic enamide
2d can also be obtained in a high yield (Table 2, entry 4). An
extensive investigation of the reaction shows that R-tetralones-
derived ketoximes 1e-i also worked well when toluene/Ac2O
was employed as the solvent, and high yields of the desired
(6) (a) Savarin, C. G.; Boice, G. N.; Murry, J. A.; Corley, E.; DiMichele,
L.; Hughes, D. Org. Lett. 2006, 8, 3903, and references therein. (b) Van
den Berg, M.; Haak, R. M.; Minnaard, A. J.; de Vries, A. H. M.; Vries,
J. G.; Feringa, B. L. AdV. Synth. Catal. 2002, 344, 1003. (c) Burk, M. J.;
Lee, J. R.; Wang, Y. M. J. Am. Chem. Soc. 1996, 118, 5142. (d) Hua,
D. H.; Lagneau, N.; Wang, H.; Chen, J. Tetrahedron 1995, 6, 349.
(7) (a) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63,
6084. (b) Zhu, G.; Casalnuovo, A. L.; Zhang, X. J. Org. Chem. 1998, 63,
8100. (c) Laso, N. M.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996,
37, 1605. (d) Boar, R. B.; McGhie, J. F.; Robinson, M.; Barton, D. H. R.;
Horwell, D. C.; Stick, R. V. Chem. Commun. 1975, 1237.
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S.; Martin, J.; Perrin, F.; Bourdeau, F. U.S. Patent 2007129573, 2007. (b)
Bertrand, B.; Blanchet, S.; Burgos, A.; Martin, J.; Perrin, F.; Roussiasse,
S.; Derrien, Y. U.S. Patent 2007191640, 2007
.
(10) For standard protocol see: Bousquet, E. W.; Carothers, W. H.;
McEwen, W. L. Organic Synthesis; Wiley: New York, 1943; Collect. Vol.
II, pp 313-315. For a specific procedure, see: Homes, A. B.; Smith, A. L.;
Williams, S. F.; Hughes, L. R.; Lidert, Z.; Swithenbank, C. J. Org. Chem.
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R. P. Org. Lett. 2008, 10, 505.
1991, 56, 1393
.
482
Org. Lett., Vol. 11, No. 2, 2009

Table 2. Rh/C-Catalyzed Hydrogenation Acylation of Cyclic
Table 3. Rh/C-Catalyzed Hydrogenation Acylation of Acyclic
Ketoximesa
Ketoximesa
a Reaction conditions: 1 (0.2 mmol), Rh/C (1 mol %), H2 (1 bar), in
toluene/Ac2O (v/v ) 4/1) (2 mL) at rt for 10 h. b Isolated yield.
3). The desired enamides, even the tetrasubstituted enamides
2m,n, were achieved in good yields.
In a related manner, these enamides can be easily
transformed via an asymmetric hydrogenation step with Rh-
DuanPhos complex to afford the corresponding chiral amines
(with 100% conversion and up to 99.7% ee), the key
intermediates for drugs (Scheme 2).
In summary, we have developed a mild and general procedure
for the Rh/C-catalyzed direct hydroacylation of ketoximes for
preparation of enamides. This method combined with the related
asymmetric hydrogenation provides a practical protocol for the
synthesis of chiral amines. Current research is focused on
extending the scope and the asymmetric hydrogenation of more
challenging tetrasubstituted enamides. This progress will be
reported in due course.
a Reaction conditions: 1 (0.2 mmol), Ac2O (3 equiv), Rh/C (0.5 mol
%), H2 (1 bar), in EtOH (2 mL) at rt for 10 h. b Isolated yield. c Rh/C (1
mol %), toluene/Ac2O (v/v ) 4/1) (2 mL) was used as solvent.
enamides were obtained in these transformations. These results
were also superior to those obtained by using iron powder or
triethylphosphine as the reductant.7,8
Acknowledgment. We thank the NIH(GM 58832) and
China scholarship council for financial support.
For extending the substrate scope, we have investigated the
reactions of acyclic ketoximes as well (Table 3). Satisfactorily,
the hydroacylation proceeded smoothly. A variety of arene
substituents, including Me and sensitive Cl functionality, were
well tolerated in these transformations (Table 3, entries 2 and
Supporting Information Available: Experimental pro-
cedures and spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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