Synthesis of enamides via CuI-catalyzed reductive acylation of ketoximes with NaHSO33

Article abstract of DOI:10.1021/jo1022348

CuI-catalyzed reductive acylation of ketoximes for preparation of enamides was reported. A broad scope of enamides was obtained in high yields with NaHSO₃ used as the terminal reductant.

Full text of DOI:10.1021/jo1022348

pubs.acs.org/joc
Synthesis of Enamides via CuI-Catalyzed Reductive
Acylation of Ketoximes with NaHSO3
SCHEME 1. Strategies for the Synthesis of Enamides
,
Zheng-Hui Guan,* Zhi-Yuan Zhang, Zhi-Hui Ren,
†
†
†
†
Yao-Yu Wang, and Xumu Zhang
‡
†
Key Laboratory of Synthetic and Natural Functional
Molecule Chemistry of Ministry of Education, Department
of Chemistry & Materials Science, Northwest University,
Xi’an 710069, P. R. China, and Department of Chemistry
‡
and Chemical Biology, Rutgers University, Piscataway,
New Jersey 08854, United States
guanzhh@nwu.edu.cn
In addition to transition-metal-catalyzed cross-coupling
4
reactions (eqs 1 and 2) and addition of an organometallic
Received November 9, 2010
5
6
reagent to a nitrile (eq 3), reductive acylation of ketoximes
eq 4) has proven to be the most direct approach for the
(
synthesis of enamides (Scheme 1). Iron powder was initially
used as the stoichiometric reducing reagent in this trans-
6
formation. However, this procedure usually involved a un-
6
,7
controllable exothermic reaction and low yields. Recently,
alternative protocols for reductive acylation of ketoximes
8
have emerged with the use of pyrophoric Et P or Fe(OAc)
7
2
3
as the stoichiometric reducing reagents. We have previously
developed the Rh/C-catalyzed hydroacylation of ketoximes
9
for the preparation of enamides. Despite these efforts, the
CuI-catalyzed reductive acylation of ketoximes for pre-
paration of enamides was reported. A broad scope of
enamides was obtained in high yields with NaHSO used
development of a practical catalytic procedure for the synth-
esis of enamides under mild reaction conditions is still
required. In connection with the recent investigation of Cu-
3
as the terminal reductant.
1
0-12
catalyzed oxime transformations,
we envision that it
may be possible to conduct a catalytic reductive acylation
process using an inexpensive Cu catalyst and a proper
reductant. In this paper, we report a practical catalytic
process for the CuI-catalyzed reductive acylation of ketox-
imes employing NaHSO as the economical terminal reduc-
3
tant. This process proceeds under mild reaction conditions
and gives a broad scope of enamides in high yields.
Enamides and their derivatives are versatile and powerful
building blocks in organic synthesis, especially for the en-
antioselective hydrogenation to prepare various chiral
1
amines and for stereoselective C-C and C-N bond-for-
mation reactions. Additionally, the enamide moiety is also a
key substructure in various classes of natural products and
2
Acetophenone oxime 1a was chosen as a test substrate in
the initial experiments to optimize the reaction conditions. A
variety of formate salts such as HCO Na, HCO K, and
3
pharmaceutical lead compounds. There are a number of
methods for the synthesis of enamides; however, enamide
formation in a practical manner is still a challenge.
2
2
HCO NH were screened as the reducing reagent with CuI
2
4
(
1) (a) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753. (b)
Zhang, X.; Huang, K.; Hou, G.; Cao, B.; Zhang, X. Angew. Chem., Int. Ed.
010, 49, 6421. (c) Erre, G.; Enthaler, S.; Junge, K; Addis, D.; Beller, M. Adv.
Synth. Catal. 2009, 351, 1437. (d) Shi, L.; Wang, X.; Sandoval, C. A.; Wang,
Z.; Li, H.; Wu, J.; Yu, L.; Ding, K. Chem.;Eur. J. 2009, 15, 9855. (e)
Imamoto, T.; Itoh, T.; Yoshida, K.; Gridnev, I. D. Chem. Asian J. 2008, 3,
(5) (a) O’Shea, P. D.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau,
C.; Roy, A.; Shultz, C. S. J. Org. Chem. 2009, 74, 4547. (b) Savarin, C. G.;
Boice, G. N.; Murry, J. A.; Corley, E.; DiMichele, L.; Hughes, D. Org. Lett.
2006, 8, 3903 and references therein.
(6) (a) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C. J. J. Am.
Chem. Soc. 2005, 127, 15644. (b) Zhu, G.; Casalnuovo, A. L.; Zhang, X.
J. Org. Chem. 1998, 63, 8100. (c) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org.
Chem. 1998, 63, 6084.
2
1
636. (f) Hu, A. G.; Fu, Y.; Xie, J.; Zhou, H.; Wang, L. X.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2002, 41, 2348. (g) Gridnev, I. D.; Yasutake, M.;
Higashi, N.; Imamoto, T. J. Am. Chem. Soc. 2001, 123, 5268.
(2) (a) Chang, L.; Kuang, Y.; Qin, B.; Zhou, X.; Liu, X.; Lin, L.; Feng, X.
Org. Lett. 2010, 12, 2214. (b) Matsubara, R.; Kobayashi, S. Acc. Chem. Res.
(7) Tang, W.; Capacci, A.; Sarvestani, M.; Wei, X.; Yee, N. K.; Senanayake,
C. H. J. Org. Chem. 2009, 74, 9528.
2
2
008, 41, 292. (c) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129,
92. (d) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew.
(8) Zhao, H.; Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale,
R. P. Org. Lett. 2008, 10, 505.
Chem., Int. Ed. 2007, 46, 5565. (e) Terada, M.; Machioka, K.; Sorimachi, K.
Angew. Chem., Int. Ed. 2006, 45, 2254.
(9) Guan, Z.-H.; Huang, K.; Yu, S.; Zhang, X. Org. Lett. 2009, 11, 481.
(10) (a) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (b)
Zhang, Z.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2008, 10, 3005. (c) Liu, S.; Yu,
Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947.
(11) (a) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676. (b)
Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572. (c)
Zaman, S.; Mitsuru, K.; Ab, A. D. Org. Lett. 2005, 7, 609.
(12) (a) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505. (b)
Narasaka, K. Pure Appl. Chem. 2002, 74, 143.
(3) (a) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577. (b) Vidal, J. P.;
Escale, R.; Girard, J. P.; Rossi, J. C.; Chantraine, J. M.; Aumelas, A. J. Org.
Chem. 1992, 57, 5857.
(
4) (a) Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109. (b)
Klapars, A.; Campos, K. R.; Chen, C.-y.; Volante, R. P. Org. Lett. 2005, 7,
185. (c) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (d) Jiang, L.; Job,
G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667.
1
DOI: 10.1021/jo1022348
r 2010 American Chemical Society
Published on Web 12/14/2010
J. Org. Chem. 2011, 76, 339–341 339

Guan et al.
JOCNote
TABLE 1. Optimizing Reaction Conditions
a
TABLE 2. CuI-Catalyzed Reductive Acylation of Acyclic Ketoximes
for Preparation of Enamides
a
entry
catalyst
CuI
reductant
HCO
solvent
yield (%)
1
2
3
4
5
6
7
8
9
2
M
toluene
toluene
DMF
1,4-dioxane
EtOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
70
36
64
0
83
20
0
54
8
0
35
9
5
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
NaHSO
NaHSO
NaHSO
NaHSO
NaHSO
3
3
3
3
3
Na
Na
Na
2
2
2
SO
3
S
S
2
O
O
3
2
4
10
11
12
13
14
15
16
17
18
a
K
2
S
Na NO
2
3
NaHSO
NaHSO
NaHSO
NaHSO
NaHSO
NaHSO
NaHSO
3
3
3
3
3
3
3
Cu
2
O
Cu(OAc)
2
0
0
5
0
Pd(PPh
Pd/C
3
)
4
Pd(OAc)
2
2
Reaction conditions: 1a (0.5 mmol), Ac O (1.0 mmol), reductant
(
1.5 mmol), and catalyst (10 mol %) in solvent (5 mL) under Ar at 120 °C
for 24 h.
as the catalyst. Unfortunately, no reaction was observed
after several attempts (Table 1, entry 1). To our delight, the
desired enamide 2a was obtained in 70% yield in the presence
of NaHSO in toluene with CuI used as the catalyst (Table 1,
3
entry 2). Therefore, a variety of solvents and reducing
reagents were screened for better efficiency in this transfor-
mation. DCE was found to be the most effective (Table 1,
entries 2-6). Optimization of the reducing reagents revealed
that Na SO , Na S O , and K S were inferior (Table 1,
2
3
2
2
4
2
entries 7, 9, and 10), albeit Na S O and Na NO showed
2
2
3
2
3
no reactivity (Table 1, entries 8 and 11). Further experiment
showed that CuI was the best catalyst for this transforma-
1
1
tion; other copper or palladium precursors, such as CuBr,
CuCl, Cu O, Cu(OAc) , Pd(PPh ) , Pd/C and Pd(OAc) ,
2
2
3 4
2
were found to be inferior (Table 1, entries 12-18).
Under the optimized conditions for this CuI-catalyzed
reductive acylation process, we have explored the substrate
scope (Table 2). The reductive procedure displayed good
functional group tolerance and gave the acyclic enamides in
good to excellent yields. Acyclic ketoximes with Cl, F, MeO,
and Me, even with sensitive Br, NH , and NO were tolerated
a
Reaction conditions: ketoxime 1 (0.5 mmol), Ac
NaHSO (1.5 mmol), and CuI (10 mol %) in DCE (5 mL) under Ar at
2
O (1.0 mmol),
3
b
1
20 °C. 1-(4-Aminophenyl)ethanone oxime 1d was used directly as the
substrate. Ac O was replaced by propionic anhydride (1.0 mmol).
2
c
2
2
under the reaction conditions (Table 2, entries 2-11). For
the electronic effects of this transformation, we found that
electron-rich ketoximes showed more reactivity and gave
slightly higher yields than electron-deficient ketoximes
as the substrate (Table 2, entry 16). However, only acetanilide
that resulted from Beckmann rearrangement of acetophenone
oxime 1a was observed when trifluoroacetic anhydride
was used.
(Table 2, entries 2-8). Interestingly, the enamide 2d was
isolated in 95% yield with 1-(4-aminophenyl)ethanone
oxime 1d as the substrate (Table 2, entry 4). The enamide
The cyclic ketoximes were investigated as well for extend-
ing the substrate scope (Table 3). Satisfactorily, the CuI-
catalyzed reductive acylation proceeded smoothly. Both
R-tetralones-derived ketoximes 1q, 1r and indanones-derived
ketoximes 1s, 1t exhibited good reactivity in the transfor-
mation, and the desired enamides 2q-2t were obtained in
good to excellent yields (Table 3, entries 1-4). It is note-
worthy that ketoximes 1u, 1v derived from cyclohexanone or
2
electron-withdrawing NO substitutent at the ketoxime 1h
h was also formed in 58% yield, albeit with a strong
2
(Table 2, entry 8). Furthermore, the tri- and tetrasubstituted
acyclic enamides 2n and 2o were obtained in good yields in
the transformation (Table 2, entries 14-15). N-Propyl en-
amide 2p was achieved when propionic anhydride was used
3
40 J. Org. Chem. Vol. 76, No. 1, 2011

Guan et al.
JOCNote
TABLE 3. CuI-Catalyzed Reductive Acylation of Cyclic Ketoximes for
Preparation of Enamides
SCHEME 2. Proposed Mechanism for Cu-Catalyzed Enamides
Formation
a
reductant makes this practical transformation attractive in
both organic synthesis and industrial applications.
a
2
Reaction conditions: ketoxime 1 (0.5 mmol), Ac O (1.0 mmol),
Experimental Section
NaHSO
20 °C.
3
(1.5 mmol), and CuI (10 mol %) in DCE (5 mL) under Ar at
1
General Procedure for CuI-Catalyzed Reductive Acylation of
Ketoximes for Preparation of Enamides. A mixture of ketoxime 1
cyclopentanone also gave the desired enamides 2u and 2v,
respectively, in good yields (Table 3, entries 5 and 6).
In addition, the CuI-catalyzed reductive acetylation of aceto-
phenone oxime 1a was conducted at 100 mmol scale under the
standard conditions. As expected, the reaction proceeded to
give enamide 2a in 80% yield.
(
(
0.5 mmol), acetic anhydride (1.0 mmol, 102.0 mg), NaHSO3
1.5 mmol, 156.2 mg), and CuI (10 mol %, 9.1 mg) was stirred in
1
,2-dichloroethane (DCE, 5.0 mL) at 120 °C under Ar. After
completion of the reaction (detected by TLC), the reaction
mixture was cooled to room temperature, diluted with EtOAc
(25 mL), and washed with NaOH (2 N, 20 mL) and brine
A plausible mechanism for the Cu-catalyzed reductive
acylation of ketoximes is depicted in Scheme 2. First, acyla-
tion of ketoxime 1 gives an O-acetyloxime intermediate A.
Next, reduction of the O-acetyloxime A by Cu(I) affords
iminium anion intermediate D through a two-step electron
2 4
(20 mL). The organic layers were dried over anhydrous Na SO
and evaporated in vacuo. The desired enamide 2 was obtained
after purification by flash chromatography on silica gel with
hexane/ethyl acetate as the eluent.
1
Spectroscopic Data of Enamide 2b. H NMR (400 MHz,
1
2
transfer process (path a). Acylation of iminium anion D
followed by tautomerization of intermediate E produces
enamide 2. Alternatively, the cleavage of the N-O bond in
O-acetyloxime A to give iminium anion D could be achieved
by oxidative addition of A to Cu(I) followed by expulsion of
CDCl
6
3
) δ 7.31 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H),
.94 (bs, 1H), 5.81 (s, 1H), 5.05 (s, 1H), 2.38 (s, 3H), 2.11 (s, 3H).
1
3
C NMR (100 MHz, CDCl
25.9, 101.8, 24.5, 21.1.
3
) δ 169.0, 140.3, 138.6, 135.5, 129.3,
1
þ
10,11
[
CuX2] (path b).
The Cu(II) or Cu(III) species is
assumed to be reduced by NaHSO to regenerate the active
Acknowledgment. This research was supported by Na-
tional Natural Science Foundation of China (NSFC-
1002077), Northwest University (PR09037, NF0913),
and Education Department of Shaanxi Provincial Government
3
Cu(I) in the reaction.
2
In summary, we have developed a practical method for
synthesis of enamides by CuI-catalyzed reductive acylation
of ketoximes. This general procedure shows good functional
group tolerance and affords a broad scope of enamides in
high yields. A plausible mechanism was proposed in this
(2010JK869).
Supporting Information Available: Experimental proce-
dures and spectral data for all products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
paper, and the use of NaHSO as the economical terminal
3
J. Org. Chem. Vol. 76, No. 1, 2011 341