ORGANIC
LETTERS
2005
Vol. 7, No. 6
1185-1188
Preparation of Enamides via
Palladium-Catalyzed Amidation of Enol
Tosylates
Artis Klapars,* Kevin R. Campos, Cheng-yi Chen, and Ralph P. Volante
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
Received February 2, 2005
ABSTRACT
A Pd-catalyzed coupling of enol tosylates and amides has been developed. Ligand screening revealed dipf as the most general ligand for this
transformation. A variety of enol tosylates were coupled to an array of enamides in 58 97% yield.
−
Enamides are valuable synthetic intermediates, particularly
in conjunction with asymmetric hydrogenation, which pro-
vides an efficient route to chiral amines.1 Regrettably,
methods for the preparation of enamides are relatively
scarce.2 While successful in a limited number of cases, direct
condensation of a ketone with an amide to provide an
enamide is not a general transformation.3 Transition-metal-
catalyzed coupling reactions offer a more reliable approach
to the stereoselective preparation of enamides. For example,
the copper-catalyzed coupling of amides with vinyl iodides
or bromides is an attractive method provided that the vinyl
iodide or bromide is available.4 In many cases, however,
preparation of the vinyl halides may be inconvenient.
Therefore, the use of enol sulfonates, readily available from
the corresponding ketones, may be preferred.
Our group recently reported a palladium-catalyzed ami-
dation of enol triflates using the Pd2dba3/Xantphos catalyst
system.5 We sought to extend this transformation to enol
tosylates, which offers two important advantages. First,
tosylating agents are generally less expensive and more
readily available than N-phenyltriflimide,6 the reagent used
to prepare enol triflates. Second, from a process development
perspective the crystallinity associated with enol tosylates
would provide a convenient means for isolation and purifica-
tion of the product.
(1) Review: Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner,
H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103.
Surprisingly few enol tosylates have been documented in
the literature, and no general procedure for their preparation
has been reported.7 We found that the best conditions for
the generation of enol tosylates involved enolization of a
ketone (using NaOtBu8 in NMP or alternatively KHMDS in
(2) (a) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63,
6084. (b) Neugnot, B.; Cintrat, J.-C.; Rousseau, B. Tetrahedron 2004, 60,
3575. (c) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6, 1845.
(d) Harrison, P.; Meek, G. Tetrahedron Lett. 2004, 45, 9277.
(3) (a) Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling,
U.-H.; Frey, L.; Karady, S.; Shi, Y.-J.; Verhoeven, R. J. Org. Chem. 1995,
60, 4324. (b) Dupau, P.; Le Gendre, P.; Bruneau, C.; Dixneuf, P. H. Synlett
1999, 1832.
(4) (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.
(5) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P. Org. Lett.
2003, 5, 4749.
(6) PhNTf2 is not available in bulk and produces PhNHTf as a byproduct
which may be difficult to remove.
10.1021/ol050117y CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/22/2005