An efficient synthesis of enamides from ketones

Article abstract of DOI:10.1021/ol7028788

A new synthesis of enamides from ketones is disclosed that involves a phosphine-mediated reductive acylation of oximes. The resulting enamides are isolated in good yields (up to 89%) and excellent purity, permitting a subsequent hydrogenation to access en

Full text of DOI:10.1021/ol7028788

ORGANIC
LETTERS
2008
Vol. 10, No. 3
505-507
An Efficient Synthesis of Enamides from
Ketones
Hang Zhao, Charles P. Vandenbossche, Stefan G. Koenig,
Surendra P. Singh,* and Roger P. Bakale
Chemical Process Research and DeVelopment, Sepracor Inc., 84 Waterford DriVe,
Marlborough, Massachusetts 01752
surendra.singh@sepracor.com
Received November 29, 2007
ABSTRACT
A new synthesis of enamides from ketones is disclosed that involves a phosphine-mediated reductive acylation of oximes. The resulting
enamides are isolated in good yields (up to 89%) and excellent purity, permitting a subsequent hydrogenation to access enantiopure acetamides
at catalyst loadings practical for large-scale applications.
Chiral amines and their derivatives represent an important
class of biologically active compounds and serve an impor-
tant role as resolving agents, chiral auxiliaries, and ligands
for enantioselective syntheses. Consequently, methods to
synthesize amines in high enantiomeric purity are of
considerable interest. In recent years, significant progress has
been made to access chiral amines catalytically by the
asymmetric hydrogenation of enamides, with considerable
attention paid to the development of new metal-ligand
complexes for this type of transformation.1 As a result, a
significant number of catalysts have become available for
evaluation along these lines. Yet, despite the progress made
in the area of asymmetric hydrogenation, methods to access
the required enamides, especially those derived from benzylic
ketones, are still limited.2
condensation of amides with ketones3 (usually acetamide),
(2) reaction of N-H imines derived from ketones or nitriles
with appropriate electrophiles4 (such as acyl chlorides or
anhydrides), (3) transition metal-catalyzed coupling of
derivatives such as vinyl halides,5 triflates,2f,6a or tosylates6b
with amides, and (4) reductive acylation of ketoximes2a,b with
iron metal in the presence of acyl donors (as above). This
last approach is often the method of choice to prepare
enamides at smaller scale. However, this method is not
amenable to scale-up and adaptation in the pharmaceutical
industry. Herein, we report a general method for the synthesis
of enamides via ketoximes, which are easily accessible from
the corresponding ketones.
In 1975, Barton et al.7a reported the conversion of ketoxime
1 into enamide 3 by refluxing with excess acetic anhydride
and pyridine (Scheme 1). Under thermal conditions, ho-
There are four common approaches for the preparation of
enamides starting from the corresponding ketones: (1) direct
(3) (a) Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling,
U. H.; Frey, L.; Karady, S.; Shi, Y.-J.; Verhoeven, T. R. J. Org. Chem.
1995, 60, 4324. (b) Dupau, P.; Le Gendre, P.; Bruneau, C.; Dixneuf, P. H.
Synlett 1999, 1832.
(4) Savarin, C. G.; Boice, G. N.; Murray, J. A.; Corley, E.; DiMichele,
L.; Hughes, D. Org. Lett. 2006, 8, 3903 and references cited therein.
(5) (a) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577. (b) Jiang, L.;
Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (c) Shen,
R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333. (d) Ogawa, T.; Kiji, T.; Hayami,
K.; Suzuki, H. Chem. Lett. 1991, 1443.
(1) Reviews: (a) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.;
Steiner, H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103. (b) Van denBerg,
M.; Haak, R. M.; Minnaard, A. J.; de Vries, A. H. M.; Vries, J. G.; Feringa,
B. L. AdV. Synth. Catal. 2002, 344, 1003.
(2) (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) Neugnot, B.; Cintrat, J.-C.; Rousseau, B. Tetrahedron 2004,
60, 3575. (e) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6,
1845. (f) Harrison, P.; Meek, G. Tetrahedron Lett. 2004, 45, 9277. (g) Willis,
M. C.; Brace, G. N.; Holmes, I. P. Synth 2005, 3229.
(6) (a) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P. Org.
Lett. 2003, 5, 4749. (b) Klapars, A.; Campos, K. R.; Chen, C.-y.; Volante,
R. P. Org. Lett. 2005, 7, 1185.
10.1021/ol7028788 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/01/2008

treatment with 6 N NaOH in the presence of a catalytic
amount of tetrabutylammonium hydroxide, the diacetyl
species was converted into the desired product 5.
Scheme 1. Barton Protocol for Enamide Synthesis
With the optimal reaction conditions identified for sub-
strate 4, the scope of the reaction was investigated (Tables
2 and 3). In all cases, the oximes were prepared from the
Table 2. Enamides from Benzylic Ketonesa via Oximes
molytic cleavage of the N-O bond of oxime acetate 2 was
proposed as a plausible mechanism. We envisioned that the
presence of an oxophilic reagent would enable this trans-
formation to proceed under milder conditions. Indeed, when
ketoxime 4 was treated with triphenylphosphine and acetic
anhydride at stoichiometric levels in toluene at reflux,
complete conversion to enamide 5 was observed.
A screening of phosphines revealed that trialkyl as well
as triaryl phosphines were effective for this transformation
(Table 1, entries 1-6). However, sterically hindered promot-
Table 1. Effect of Phosphine on the Rate of Enamide
Formationa
reaction
time (h)
entry
phosphine
% yieldb
1
2
3
4
5
6
7
8
Ph3P
14
14
16
16d
14
38
38
38
78
89
89
84
72
78
trace
trace
DPPEc
Et3P
(n-Bu)3P
(n-Oct)3P
(Cy)3P
(t-Bu)3P
(EtO)3P
a Reaction conditions: (i) NH2OH‚HCl (1.2 equiv), NaOAc (1.2 equiv)
solvent, reflux; (ii) Et3P (1.2 equiv), Ac2O (1.2 equiv), toluene, reflux.
b Crude yield of ketoxime. c Unoptimized isolated yield of enamide from
ketoxime after column chromatography.
a Reaction conditions: phosphine (1.2 equiv), Ac2O (1.2 equiv), toluene,
reflux. b Isolated yield of enamide from ketoxime after chromatography.
c 0.6 equiv of DPPE was used. d Reaction was run in o-xylene.
corresponding ketones based on literature precedence9 and
used in the subsequent reaction without further purification.
Both benzylic and non-benzylic ketoximes may be easily
converted to enamides via this method. Ketoximes derived
from substituted and electron-rich R-tetralones gave good
yields of enamide (Table 2, entries 1-3). Other alkylaryl
ketoximes also provided reasonable yields of enamide (Table
2, entries 4-6). Even acyclic ketoximes such as a 1,1-
disubstituted variant gave a moderate yield of enamide (Table
2, entry 7). Additionally, indanone-derived ketoxime gave
78% yield of enamide (Table 2, entry 8).
ers such as tri-tert-butylphosphine, and triethyl phosphite did
not provide adequate conversion (Table 1, entries 7 and 8).
The best results were obtained when triethylphosphine, tri-
n-butylphosphine, or diphenylphosphinoethane (DPPE) was
used (Table 1, entries 2-4). Despite its pyrophoric nature,
triethylphosphineswhich we utilize as a more easy-to-handle
50% solution in tolueneswas our preferred reagent due to
the water-soluble nature of the phosphine oxide byproduct.
Optimization of the solvent revealed that toluene, o-xylene,
and chlorobenzene were superior to 1,4-dioxane and aceto-
nitrile. The initial reaction mixture generally consisted of
both desired monoacetyl 5 and diacetyl products.8 By simple
For the non-benzylic systems, ketoximes derived from
4-substituted cyclohexanones worked to a similar extent as
(8) Up to 8-10 area % of diacylated product by HPLC was observed.
(9) For standard protocol see: Bousquet, E. W.; Carothers, W. H.;
McEwen, W. L. Organic Synthesis; Wiley and Sons: 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. 1991, 56, 1393.
(7) (a) Boar, R. B.; McGhie, J. F.; Robinson, M.; Barton, D. H. R.;
Horwell, D. C.; Stick, R. V. Chem. Commun. 1975, 1237. (b) Baldwin, J.
E.; Aldous, D. J.; O’Neil, I. A. Tetrahedron Lett. 1990, 31, 2051.
506
Org. Lett., Vol. 10, No. 3, 2008

Table 3. Enamides from Non-Benzylic Ketonesa via Oximes
Scheme 2. Preparation of Enamide 9 from Ketone 6
anhydride, full conversion to enamide 9 occurred.13 Con-
versely, when ketoxime 7 was treated with triethylphosphine,
formation of the imine by deoxygenation of ketoxime 7 was
not observed.
a Reaction conditions: (i) NH2OH‚HCl (1.2 equiv), NaOAc (1.2 equiv)
solvent, reflux; (ii) Et3P (1.2 equiv), Ac2O (1.2 equiv), toluene, reflux.
b Crude yield of ketoxime. c Unoptimized isolated yield of enamide from
ketoxime after column chromatography. d Low yield is due to physical loss
during isolation. e Only geometric isomer depicted was isolated.
In summary, we have developed a new, proficient method
to access enamides from ketones, especially difficult benzylic
substrates. The methodology adds a valuable alternative to
the currently limited number of methods for accessing
enamides efficiently. It should allow for further exploitation
of the plethora of catalysts and encourage use of asymmetric
hydrogenation as a practical approach to access chiral amines.
the benzylic systems (Table 3, entries 1 and 2). Entries 3
and 4 demonstrate that further substitution can be tolerated
in furnishing tetrasubstituted enamide products. In addition,
entry 3 illustrates that the reaction conditions are compatible
with sensitive nitrile functionality in the substrate.
Acknowledgment. We thank Dr. Zhi-Dong Jiang, Sepra-
cor Inc., for help with high-resolution mass spectroscopy
analysis. Also, we thank Professor Alan R. Katritzky,
University of Florida, for helpful discussions.
In a related manner, the preparation of enamide 9 from
ketone 6 has been successfully demonstrated at multikilogram
scale10 as an intermediate in a process for the manufacture
of 10, a drug candidate under development (Scheme 2).
Importantly, 9 was isolated from this process by crystalliza-
tion without further purification, and was suitable for large-
scale hydrogenation with a practical catalyst loading.11
Supporting Information Available: Experimental details
and physical characterization data of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
We are working toward broadening our understanding of
the reaction mechanism. On the basis of LC-MS data, we
believe that oxime acetate 8 is the reactive substrate for the
OL7028788
(12) Oxime acetate 8 was made by combining oxime 7 with pyridine
o
formation of enamide 9. Also, when pure oxime acetate12
8
and acetic anhydride at 0 C. The resulting slurry was quenched with ice
water to yield a yellow solid, which was further treated with 10% HCl/
EtOH to yield a white solid. 1H NMR (400 MHz, CDCl3) δ 8.25 (m, 1H),
7.33 (m, 3H), 7.17 (m, 1H), 6.93 (m, 1H), 6.87 (m, 1H), 4.13 (m, 1H),
2.83 (m, 2H), 2.25 (s, 3H), 2.22 (m, 1H), 2.06 (m, 1H). 13C NMR (100
MHz, CDCl3) δ 168.8, 160.4, 143.6, 141.2, 132.7, 131.2, 130.7, 130.5,
130.3, 129.2, 129.1, 127.8, 127.5, 125.8, 43.9, 29.2, 22.7, 19.8.
(13) In a qualitative experiment, full conversion from 8 to 9 was observed.
However, based on LC-MS, the reaction profile was inferior (81 area %
purity) when compared to the standard conditions.
was treated with triethylphosphine in the absence of acetic
(10) The process was scaled up to manufacture over 75 kg of enamide
9 at pilot scale in 86% isolated yield from ketone 6 in 99.5 area % purity
by HPLC.
(11) The enamide 9 was successfully hydrogenated at a substrate/catalyst
ratio of 2000:1 at pilot scale.
Org. Lett., Vol. 10, No. 3, 2008
507