Formation of enamides via palladium(II)-catalyzed vinyl transfer from vinyl ethers to nitrogen nucleophiles

Article abstract of DOI:10.1021/ol0494360

Matrix presented. Palladium(II) complexes catalyze the formation of enamides via the formal cross-coupling reaction between nitrogen nucleophiles and vinyl ethers. These vinyl transfer reactions proceed in good yields with amide, carbamate, and sulfonamide nucleophiles, and the optimal catalyst is (DPP)Pd(OCOCF₃)₂ (DPP = 4,7-diphenyl-1,10-phenanthroline).

Full text of DOI:10.1021/ol0494360

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1845-1848
Formation of Enamides via
Palladium(II)-Catalyzed Vinyl Transfer
from Vinyl Ethers to Nitrogen
Nucleophiles
Jodie L. Brice, James E. Meerdink, and Shannon S. Stahl*
UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706
stahl@chem.wisc.edu
Received March 25, 2004
ABSTRACT
Palladium(II) complexes catalyze the formation of enamides via the formal cross-coupling reaction between nitrogen nucleophiles and vinyl
ethers. These vinyl transfer reactions proceed in good yields with amide, carbamate, and sulfonamide nucleophiles, and the optimal catalyst
is (DPP)Pd(OCOCF3)2 (DPP ) 4,7-diphenyl-1,10-phenanthroline).
Recent developments in palladium(0)-catalyzed carbon-
nitrogen bond formation have led to numerous useful
synthetic methodologies, particularly for the cross-coupling
of allyl,1 aryl,2 and vinyl3,4 halides and related electrophiles
with amine and amide nucleophiles. These reactions are
initiated by oxidative addition of a C-X bond (X ) halide,
acetate, triflate) at a palladium(0) center. Palladium(II)-
catalyzed transformations have also been developed for C-N
bond formation, and both oxidative and nonoxidative reac-
tions are known.5 Examples include allylic substitution,6
rearrangement of allylic imidates,7 and hydroamination8 and
oxidative amination8-10 of alkenes. This report describes a
new method for carbon-nitrogen bond formation involving
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10.1021/ol0494360 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/05/2004

palladium(II)-catalyzed vinyl transfer from vinyl ethers to
nitrogen nucleophiles.11
Table 1. Catalyst Screening Resultsa
During our recent studies on the palladium(II)-catalyzed
oxidative amination of olefins (for example, eq 1),10b we
observed that ethyl vinyl ether undergoes nonoxidative vinyl
transfer to the nitrogen nucleophile (eq 2). This reaction
represents a C-N cross-coupling reaction in which the vinyl
ether is the electrophilic partner. However, palladium(0)-
catalyzed cross-coupling reactions are generally incompatible
with an aerobic atmosphere, and vinyl ethers are not expected
to undergo efficient oxidative addition to palladium(0). The
limited precedent for this class of reactions, together with
growing synthetic interest in enamides,12 prompted us to
investigate this reactivity further.
entry
catalyst
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(PhCN)2PdCl2
Pd(OCOCF3)2
(DPP)Pd(OCOCF3)2
(DPP)Pd(OAc)2
(DPP)PdCl2
(phen)Pd(OCOCF3)2
(tmeda)Pd(OCOCF3)2
(PPh3)2Pd(OCOCF3)2
1
2
c
100
39
<1
91
38
6
6
0
<1
5
2
d
e
f
(diphos)Pd(OCOCF3)2
Na2PdCl4
Hg(OAc)2
HgSO4
HgCl2
Hg(OCOCF3)2
26
a Reaction conditions: 1.0 equiv of 2-oxazolidinone, 10 equiv of BVE,
0.05 equiv of catalyst, 75 °C, open to air, 3 min. b Yields determined by
1H NMR with 1,3,5-tri-tert-butylbenzene internal standard. c DPP ) 4,7-
diphenyl-1,10-phenanthroline. d phen ) phenanthroline. e tmeda ) tetra-
methylethylenediamine. f diphos ) 1,2-bis(diphenylphosphino)ethane.
A series of palladium(II) catalysts were explored to
improve upon the reaction catalyzed by (PhCN)2PdCl2. The
vinylation of 2-oxazolidinone was used to investigate the
effects of both counterions and neutral donor ligands on
palladium(II). The higher boiling point of butyl vinyl ether
(BVE) relative to ethyl vinyl ether (eq 2) generally makes it
a more convenient substrate in these reactions. BVE also
served as the solvent in the reactions.
Recent results by Schlaf and co-workers on vinyl transfer
to alcohols13 prompted us to include complexes bearing
phenanthroline ligands (Table 1), and the (4,7-diphenyl-1,10-
phenanthroline)palladium(II) trifluoroacetate complex, (DPP)-
Pd(OCOCF3)2, displayed the highest catalytic activity. Use
of this catalyst resulted in a quantitative yield within 3 min
(Table 1, entry 3). Nearly identical activity is obtained if
this catalyst is prepared in situ. The (phen)Pd(OCOCF3)2
complex (entry 6) also displays high activity, but its low
solubility can lead to lower yields under certain conditions.
Mercuric salts are known to promote vinyl transfer to oxygen
nucleophiles (alcohols and carboxylic acids);14 however,
these complexes proved to be less effective (Table 1, entries
11-14).
With the optimal catalyst in hand, we examined the scope
of this reactivity with a series of nitrogen nucleophiles (Table
2). The reactions with saturated primary and secondary
amines (e.g., morpholine and benzylamine) were unsuccess-
ful under these conditions, possibly because of the ability
of these reactants to coordinate strongly to palladium(II). A
Table 2. Formation of Various Enamidesa
(9) (a) Hegedus, L. S. J. Mol. Catal. 1983, 19, 201-211. (b) van
Benthem, R. A. T. M.; Hiemstra, H.; Longarela, G. R.; Speckamp, W. N.
Tetrahedron Lett. 1994, 35, 9281-9284. (c) Ro¨nn, M.; Ba¨ckvall, J.-E.;
Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749-7752. (d) Larock, R.
C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996,
61, 3584-3585. (e) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int.
Ed. 2002, 41, 164-166.
(10) (a) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.-I.
Tetrahedron Lett. 1992, 33, 6643-6646. (b) Timokhin, V. I.; Anastasi, N.
R.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 12996-12997.
(11) For a similar reaction using vinyl acetate, see: Bayer, E.; Geckeler,
K. Angew. Chem., Int. Ed. Engl. 1979, 18, 533-534.
(12) (a) Yet, L. Chem. ReV. 2003, 103, 4283-4306. (b) Xiong, H.; Hsung,
R. P.; Shen, L.; Hahn, J. M. Tetrahedron Lett. 2002, 43, 4449-4453. (c)
Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773-782.
(13) (a) Handerson, S.; Schlaf, M. Org. Lett. 2002, 4, 407-409. (b)
Bosch, M.; Schlaf, M. J. Org. Chem. 2003, 68, 5225-5227.
a Reaction conditions: 1 equiv of nucleophile, 10 equiv of BVE, 5 mol
% of (DPP)Pd(OCOCF3)2, 75 °C, open to air. b Isolated yield after flash
column chromatography. c Ethyl vinyl ether used as the vinyl donor; room
temperature.
1846
Org. Lett., Vol. 6, No. 11, 2004

series of less basic nucleophiles, however, were effective,
including chiral derivatives of 2-oxazolidinone (entries 2-3)
and 2-pyrrolidinone (entry 4). The primary nucleophile,
trifluoractamide (entry 5), is also successful, although the
product is rather sensitive to acidic conditions and elevated
temperatures. Ethyl vinyl ether was used in place of BVE
to facilitate product purification. The lower reaction tem-
peratures required by this substrate led to a longer reaction
time, but the product could be obtained in good yield. Use
of other primary nucleophiles, acetamide and p-toluene-
sulfonamide, resulted in low conversion (10-30%). N-
Alkylated p-toluenesulfonamides proved to be effective
substrates, as both TsNHMe and the tosylated â-alanine
methyl ester proceed in good yield to the enamide product
(entries 6 and 7).
excess BVE. Attempts to prevent acetal formation by adding
catalytic or stoichiometric amounts of base15b (i.e., triethyl-
amine and Na2CO3) were only moderately successful, in part,
because the base also hinders the formation of the desired
enamide. Only minor amounts of aminal product (e5%, eq
6) form in these reactions.17
In palladium-catalyzed vinyl transfer to alcohols and
carboxylic acids (eq 3),13,15 the reactions take place under
equilibrium control. Therefore, the vinyl ether substrate is
generally employed in large excess (g20 equiv) to favor
product formation. In principle, excess substrate is not
required in the present reactions because formation of the
vinyl amide is thermodynamically favored. Density func-
tional calculations estimate the equilibrium constant for eq
4 to be in the range of 103.16 Use of a 1:1 ratio of BVE and
1 results in g80% yield of the vinyl transfer product, 2, when
the reaction is conducted in dimethoxyethane or toluene as
the solvent. The formation of a dibutylacetal side product,
which can arise from palladium-(or acid-)catalyzed addition
of butanol to BVE (eq 5), reduces the yield under these
conditions. This complication can be overcome by using
These reactions differ from the recently developed pal-
ladium(0)-catalyzed cross-coupling methods for carbon-
nitrogen bond formation in that the catalyst appears to remain
in the +2 oxidation state throughout the reaction. Qualitative
support for this mechanism is provided by the following
experimental observations. The optimal catalysts, phenan-
throline-palladium(II) complexes, are the same as those
identified for vinyl transfer to oxygen nucleophiles, car-
boxylic acids, and alcohols.13,15b,d A recent competition study
by Jung and co-workers18 suggests that molecular oxygen
reacts more rapidly with palladium(0) than aryl iodides. Vinyl
ethers should be even less reactive than aryl iodides toward
oxidative addition to palladium(0). This observation, together
with the fact that these reactions proceed as effectively under
pure oxygen or air than under an inert atmosphere, argue
against the intermediacy of palladium(0). In fact, the presence
of air can have a beneficial effect by rescuing any catalyst
that is reduced to palladium(0) during the reaction.13,19,20
Palladium(II)-catalyzed reactions with alkenes also generally
have more severe steric constraints than those with palladium-
(0).15c Indeed, the reaction of ethyl 1-propenyl ether (3)
proceeds much more slowly than that with vinyl ether
substrates. Although the reaction between BVE and 1 is
complete within three minutes (Table 1, entry 3), the reaction
between 1 and 3 is only 48% complete after 24 h under
comparable conditions.21
(14) (a) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79,
2828-2833. (b) Hopff, H.; Wyss, U.; Lu¨ssi, H. HelV. Chim. Acta 1960,
43, 135-140. (c) Slinckx, G.; Smets, G. Tetrahedron 1966, 22, 3163-
3171. (d) Hopff, H.; Osman, M. A. Tetrahedron 1968, 24, 2205-2214.
(15) (a) McKeon, J. E.; Fitton, P.; Griswold, A. A. Tetrahedron 1972,
28, 227-232. (b) McKeon, J. E.; Fitton, P. Tetrahedron 1972, 28, 233-
238. (c) Henry, P. M. Acc. Chem. Res. 1973, 6, 16-24. (d) Ketterling, A.
A.; Lisitsyn, A. S.; Nosov, A. V.; Likholobov, V. A. Appl. Catal. 1990,
66, 123-132. (e) Dumlao, C. M.; Francis, J. W.; Henry, P. M. Organo-
metallics 1991, 10, 1400-1405.
(16) The equilibrium constant for eq 4 was calculated to be 1001 (gas
phase) and 1580 (diethyl ether: solvent dielectric ) 4.355). Density
functional theory (DFT) calculations using the B3a-LYPb functional with
the 6-31++G** basis set were employed with the Gaussian 98c suite of
programs to perform gas-phase geometry optimizations on the substrates
butyl vinyl ether and 1 and the corresponding products of the isodesmic
reaction illustrated in Table 1. Additional geometry optimization calculations
were performed using Tomasi’s dipole polarizable continuum modeld
(DPCM) with the specified dielectric of 4.355 corresponding to a diethyl
ether reaction medium. Optimized structures were verified to be at a local
minimum by calculation of the harmonic vibrational frequencies. (a) Becke,
A. D. Phys. ReV. A 1988, 38, 3098-3101. (b) Lee, C.; Yang, W.; Parr, R.
G. Phys. ReV. B 1988, 37, 785-789. (c) Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski,
V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.;
Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;
Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui,
Q.; Morokuma, K.; Salvador, P.; Dannenberg, J. J.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.;
Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.10;
Gaussian, Inc.: Pittsburgh, PA, 2001. (d) Miertus, S.; Scrocco, E.; Tomasi,
J. Chem. Phys. 1981, 55, 117-129. (e) Miertus, S.; Tomasi, J. Chem. Phys.
1982, 65, 239-245. (f) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem.
Phys. Lett. 1996, 255, 327-335.
These observations are consistent with the following
palladium(II)-catalyzed mechanism for vinyl transfer to
(17) For examples of palladium-catalyzed aminal formation (i.e., hy-
droamination of vinyl ethers), see: (a) Baig, T.; Jenck, J.; Kalck, P. J. Chem.
Soc., Chem. Commun. 1992, 1552-1553. (b) Cheng, X.; Hii, K. K.
Tetrahedron 2001, 57, 5445-5450.
(18) Jung, Y. C.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org. Lett.
2003, 5, 2231-2234.
(19) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am.
Chem. Soc. 2001, 123, 7188-7189.
(20) Ackerman, L. J.; Sadighi, J. P.; Kurtz, D. M.; Labinger, J. A.;
Bercaw, J. E. Organometallics 2003, 22, 3884-3890.
(21) The commercial source of 3 (Aldrich) consists of ∼2.5:1 ratio of
the cis- and trans-isomers. The relative reactivity of the two isomers is not
readily apparent. Such analysis is complicated by the use of a large excess
of 3 in the reaction (20-fold excess), side reactions that consume 3 (e.g.,
eqs 5 and 6), and the possibility of Pd-catalyzed equilibration of the isomers
under the reaction conditions via transvinylation with the alcohol product
(cf. eq 3).
Org. Lett., Vol. 6, No. 11, 2004
1847

is not yet established. Subsequent â-alkoxide elimination
yields the desired amination product.
Scheme 1. Proposed Mechanism for Palladium(II)-Catalyzed
In conclusion, our studies have led to the development of
a new process for the synthesis of enamides via vinyl transfer
from vinyl ethers. The (DPP)Pd(OCOCF3)2 catalyst is
effective with a variety of amide and tosylamide nucleo-
philes, and this straightforward methodology represents a new
palladium(II)-catalyzed example of C-N bond formation.
Vinyl Transfer to Nitrogen Nucleophiles
Acknowledgment. We acknowledge V. I. Timokhin for
providing the preliminary experimental observations and B.
V. Popp for conducting the DFT calculations. Funding for
this project was provided by the Dreyfus Foundation
(Teacher-Scholar Award), the NIH (RO1 GM67173-01),
and the Sloan Foundation (Research Fellowship).
Supporting Information Available: Experimental pro-
cedures, characterization data of products in Table 2, and
NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
nitrogen nucleophiles (Scheme 1). Carbon-nitrogen bond
formation arises from aminopalladation of the vinyl ether
substrate. Whether this step takes place via internal or
external attack of the nucleophile on the coordinated olefin
OL0494360
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Org. Lett., Vol. 6, No. 11, 2004