Hydrogen-bond-directed highly stereoselective synthesis of Z-enamides via Pd-catalyzed oxidative amidation of conjugated olefins

Article abstract of DOI:10.1021/ja0639315

An efficient procedure for the preparation of Z-enamides has been developed, involving the reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide, phosphonate, and ketone groups. The notable preference for the formation of Z-enamides is presumably due to the presence of an intramolecular hydrogen bond between the amido proton and the carbonyl oxygen. The energy difference between two plausible σ-alkylamidopalladium intermediates, leading to Z- and E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The β-hydride elimination step is assumed to be a stereochemistry-determining step in the overall oxidative amidation process, with the energy level for the transition state leading to the Z-enamide being 5.35 kcal/mol lower than that leading to the E-isomer. The efficiency of photoisomerization between Z- and E-enamides was observed to be largely dependent on the substrates' substituents, and certain E-enamides could be obtained in synthetically useful yields by photoirradiation of Z-isomers. Synthetic application of the present method was successfully demonstrated by a direct formal synthesis of cis-CJ-15,801.

Full text of DOI:10.1021/ja0639315

Published on Web 09/02/2006
Hydrogen-Bond-Directed Highly Stereoselective Synthesis of
Z-Enamides via Pd-Catalyzed Oxidative Amidation of
Conjugated Olefins
Ji Min Lee, Doo-Sik Ahn, Doo Young Jung, Junseung Lee, Youngkyu Do,
Sang Kyu Kim,* and Sukbok Chang*
Contribution from the Center for Molecular Design and Synthesis, Department of Chemistry and
School of Molecular Science (BK21), Korea AdVanced Institute of Science and Technology
(KAIST), Daejeon 305-701, Republic of Korea
Received June 14, 2006; E-mail: sangkyukim@kaist.ac.kr; sbchang@kaist.ac.kr
Abstract: An efficient procedure for the preparation of Z-enamides has been developed, involving the
reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that
certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in
nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields
with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad
substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide,
phosphonate, and ketone groups. The notable preference for the formation of Z-enamides is presumably
due to the presence of an intramolecular hydrogen bond between the amido proton and the carbonyl oxygen.
The energy difference between two plausible σ-alkylamidopalladium intermediates, leading to Z- and
E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The â-hydride elimination
step is assumed to be a stereochemistry-determining step in the overall oxidative amidation process, with
the energy level for the transition state leading to the Z-enamide being 5.35 kcal/mol lower than that leading
to the E-isomer. The efficiency of photoisomerization between Z- and E-enamides was observed to be
largely dependent on the substrates’ substituents, and certain E-enamides could be obtained in synthetically
useful yields by photoirradiation of Z-isomers. Synthetic application of the present method was successfully
demonstrated by a direct formal synthesis of cis-CJ-15,801.
aspergillamides,6c chondriamides,6d salicylihalamides,6e apicu-
laren A,6f TMC-95A-D,6g crocacins,6h lansiumamide A,6i
storniamides,6j and enamidoin.6k In addition, enamides serve as
highly versatile synthetic intermediates, especially in the forma-
tion of heterocycles and in asymmetric synthesis for the
generation of secondary or tertiary chiral amines.7 As a result,
several protocols have been devised for the preparation of
Introduction
Hydrogen bonds serve as one of the most essential motifs
both in molecular recognition and for defined organization of
important molecules in chemistry and biology.1 Although
numerous examples of hydrogen-bonding-driven approaches
have been reported in crystal engineering and self-assembly,2
the use of this noncovalent interaction in catalysis has been less
frequently investigated. In fact, only in recent years have
hydrogen bonds been utilized as a key feature to control activity
and/or selectivity in certain catalytic transformations,3 such as
Diels-Alder, epoxidation, aldol, Michael, hydrogenation, and
cycloaddition reactions.4
(4) (a) Bassani, D. M.; Darcos, V.; Mahony, S.; Desvergne, J.-P. J. Am. Chem.
Soc. 2000, 122, 8795-8796. (b) Schuster, T.; Bauch, M.; Du¨rner, G.; Go¨bel,
M. W. Org. Lett. 2000, 2, 179-181. (c) Rankin, K. N.; Gauld, J. W.; Boyd,
R. J. J. Am. Chem. Soc. 2001, 123, 2047-2052. (d) Thadani, A. N.;
Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5846-5850. (e) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062-
2064.
Enamides are widely present as a key structural moiety in
numerous natural products,5 such as palytoxin,6a terpeptin,6b
(5) Yet, L. Chem. ReV. 2003, 103, 4283-4306.
(6) (a) Moore, R. E.; Bartolini, G. J. Am. Chem. Soc. 1981, 103, 2491-2494.
(b) Kagamizono, T.; Sakai, N.; Arai, K.; Kobinata, K.; Osada, H.
Tetrahedron Lett. 1997, 38, 1223-1226. (c) Toske, S. G.; Jensen, P. R.;
Kauffman, C. A.; Fencial, W. Tetrahedron. 1998, 54, 13459-13466. (d)
Davyt, D.; Entz, W.; Fernandez, R.; Mariezcurrena, R.; Mombru, A. W.;
Saldana, J.; Dominguez, L.; Coll, J.; Manta, E. J. Nat. Prod. 1998, 61,
1560-1563. (e) Erickson, K. L.; Beutler, J. A.; Cardellina, I. I., J. H.;
Boyd, H. M. R. J. Org. Chem. 1997, 62, 8188-8192. (f) Kunze, B.; Jansen,
R.; Sasse, F.; Hofle, G.; Reichenbach, H. J. Antibiot. 1998, 51, 1075-
1080. (g) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.;
Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990-
995. (h) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot.
1994, 47, 881-886. (i) Lin, J.-H. Phytochemistry 1989, 28, 621-622. (j)
Palermo, J. A.; Brasco, M. F. R.; Seldes, A. M. Tetrahedron 1996, 52,
2727-2734. (k) Koshino, S.; Koshino, H.; Matsuura, N.; Kobinata, K.;
Onose, R.; Isono, K.; Osada, H. J. Antibiot. 1995, 48, 185-187.
(1) (a) Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin,
D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37-44.
(b) Alkorta, I.; Rozas, I.; Elguero, J. Chem. Soc. ReV. 1998, 27, 163-170.
(c) Wormer, P. E. S.; van der Avoird, A. Chem. ReV. 2000, 100, 4109-
4143. (d) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48-76.
(2) For selected recent reviews, see: (a) Subramanian, S.; Zaworotko, M. J.
Coord. Chem. ReV. 1994, 137, 357-401. (b) Ariga, K.; Kunitake, T. Acc.
Chem. Res. 1998, 31, 371-378. (c) Sherrington, D. C.; Taskinen, K. A.
Chem. Soc. ReV. 2001, 30, 83-93. (d) Desiraju, G. R. Acc. Chem. Res.
2002, 35, 565-573. (e) Choi, K.; Hamilton, A. D. Coord. Chem. ReV. 2003,
240, 101-110.
(3) (a) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710. (b) Schreiner,
P. R. Chem. Soc. ReV. 2003, 32, 289-296. (c) Taylor, M. S.; Jacobsen, E.
N. Angew. Chem., Int. Ed. 2006, 45, 1520-1543.
9
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J. AM. CHEM. SOC. 2006, 128, 12954-12962
10.1021/ja0639315 CCC: $33.50 © 2006 American Chemical Society

Highly Stereoselective Synthesis of Z-Enamides
A R T I C L E S
enamides. Conventional approaches include addition of amides
to alkynes,8 condensation of ketones or aldehydes with amides,9
elimination of alcohols from N-(R-alkoxyalkyl)amides,10 dehy-
dration of hemiaminal,11 acylation of imines,12 Curtius rear-
rangement of R,â-unsaturated acyl azides,13 and elimination of
â-hydroxy-R-silylamides (Peterson reaction).14
On the other hand, several catalytic routes have been also
investigated, such as isomerization of N-allylamides by Fe, Rh,
or Ru complexes15 and Rh-catalyzed â-hydride elimination of
diazoamides.16 Additionally, metal-mediated C-N bond forma-
tion has been an area of great interest, and some protocols have
been developed, including Ru- or Cu-catalyzed addition of
amides to alkynes17 and coupling of vinyl (pseudo)halides with
amides using Pd18 or Cu species.19 Despite the numerous
examples for the catalytic synthesis of enamides, such reactions
often suffer from either low yield or difficulty in preparing
necessary vinyl halides. More importantly, stereocontrol of the
double bond presents an additional challenge, particularly when
Z-enamides are required.20-23 This is especially noteworthy,
considering that significant progress has been made recently in
direct oxidative amination of olefins with simple amines.24 For
example, Hirai et al. previously reported an amidation protocol
using a stoichiometric palladium complex.25 Murahashi and co-
workers later demonstrated that enamides could be readily
obtained by the reaction of amides or carbamates with olefins
using Pd and Cu cocatalysts under an oxygen atmosphere.26
However, reaction of lactams or cyclic carbamates afforded
predominantly E-enamides, whereas a mixture of isomeric
enamides was obtained with acyclic amides. More recently, Stahl
et al. have contributed to a significant advance by expanding
the scope of the nucleophiles, including oxazolidinone, phthal-
imide, secondary amide, and sulfonamide, in amination of
simple olefins via either Markovnikov or anti-Markovnikov
manner by the choice of catalyst system, although the require-
ment for excess amounts of certain types of olefins and low
product yields in some cases leave room for further improve-
ments.27,28
Despite the recent progress, there are still several issues to
be addressed, such as substrate scope, stereoselectivity, and
mildness of reaction conditions for the efficient preparation of
enamides. Therefore, direct oxidatiVe amidation of alkenes
instead of Vinyl halides would be highly desirable, especially if
it yields high stereoselectiVity in the formation of enamides
under mild conditions. In this article, we reveal our studies on
the development of such a straightforward method for producing
Z-enamides with high stereoselectivity through a hydrogen-
bond-directed approach (eq 1).29
(7) (a) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679-1681. (b)
Burk, M. J. Acc. Chem. Res. 2000, 33, 363-372. (c) Sibi, M. P.; Asano,
Y. J. Am. Chem. Soc. 2001, 123, 9708-9709. (d) Blaser, H.-U.; Malan,
C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003,
345, 103-151.
(8) Mo¨hrle, H.; Kilian, R. Tetrahedron 1969, 25, 5745-5753.
(9) (a) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett. 1993, 34,
1479-1482. (b) Dupau, P.; Le Gendre, P.; Brueau, C.; Dixneuf, P. H.
Synlett 1999, 1832-1834.
(10) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.-i.;
Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697-6703. (b)
Torii, S.; Inokuchi, T.; Kubota, M. J. Org. Chem. 1985, 50, 4157-4160.
(11) (a) Wang, X.; Porco, J. A., Jr. J. Org. Chem. 2001, 66, 8215-8221. (b)
Bayer, A.; Maier, M. E. Tetrahedron 2004, 60, 6665-6677.
(12) (a) Boeckman, R. K., Jr.; Goldstein, S. W.; Walters, M. A. J. Am. Chem.
Soc. 1988, 110, 8250-8252. (b) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817-3856. (c) Kinderman, S. S.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001,
3, 2045-2048.
(13) (a) Brettle, R.; Mosedale, A. J. J. Chem. Soc., Perkin Trans. 1 1988, 2185-
2195. (b) Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett 2000, 397-
399. (c) Stefanuti, I.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2000,
41, 3735-3738.
(14) (a) Ager, D. J. Synthesis 1984, 384-398. (b) Ager, D. J. Org. React. 1990,
38, 1-223. (c) Fu¨rstner, A.; Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001,
3, 3955-3957.
(15) (a) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139-2145. (b)
Sergeyev, S.; Hesse, M. Synlett 2002, 1313-1317. (c) Sergeyev, S. A.;
Hesse, M. HelV. Chim. Acta 2003, 86, 750-755.
(16) Muthusamy, S.; Gunanathan, C.; Babu, S. A. Synthesis 2002, 471-474.
(17) (a) Kondo, T.; Tanaka, A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc., Chem.
Commun. 1995, 413-414. (b) Zhou, Y.-G.; Yang, P.-Y.; Han, X.-W. J.
Org. Chem. 2005, 70, 1679-1683. (c) Goossen, L. J.; Rauhaus, J. E.; Deng,
G. Angew. Chem., Int. Ed. 2005, 44, 4042-4045.
Results and Discussion
At the outset of our studies on the oxidative amidation
reaction, benzamide (1) and ethyl acrylate (2) were chosen as
model substrates, and various reaction conditions were subse-
quently examined (Table 1). We were especially interested in
(18) For recent examples, see: (a) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.;
Volante, R. P. Org. Lett. 2003, 5, 4749-4752. (b) Brice, J. L.; Meerdink,
J. E.; Stahl, S. S. Org. Lett. 2004, 6, 1845-1848. (c) Klapars, A.; Campos,
K. R.; Chen, C.-y.; Volante, R. P. Org. Lett. 2005, 7, 1185-1188. (d) Willis,
M. C.; Brace, G. N.; Holmes, I. P. Synthesis 2005, 3229-3234. Review:
(e) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973-986.
(19) For recent examples, see: (a) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki,
H. Chem. Lett. 1991, 1443-1446. (b) Shen, R.; Porco, J. A., Jr. Org. Lett.
2000, 2, 1333-1336. (c) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman,
B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889-7901. (d) Jiang,
L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667-
3669. (e) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron
Lett. 2003, 44, 4927-4931. (f) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004,
6, 577-580. (g) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809-1812.
(h) Sun, C.; Camp, J. E.; Weinreb, S. M. Org. Lett. 2006, 8, 1779-1781.
(20) For the formation of Z-enamides relying on a rearrangement-hydrolysis
of R-silylallyl amides, see: (a) Zhang, X.; Houk, K. N.; Lin, S.;
Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 5111-5114. (b) Lin, S.;
Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.; Danishefsky,
S. J. J. Am. Chem. Soc. 2004, 126, 6347-6355.
(23) Porco et al. demonstrated that copper-catalyzed coupling of primary amides
with E-vinyl iodides bearing a â-amide group afforded Z-enamides albeit
in rather low yields (18-25%). It was reasoned that the stereocontrol was
related to the higher acidity of the N-H in conjugated amides, thus leading
to the formation of an intramolecular H-bond. Han, C.; Shen, R.; Su, S.;
Porco, J. A., Jr. Org. Lett. 2004, 6, 27-30.
(24) For intramolecular oxidative amination reactions, see: (a) van Benthem,
R. A. T. M.; Hiemstra, H.; Longarela, G. R.; Speckamp, W. N. Tetrahedron
Lett. 1994, 35, 9281-9284. (b) Ro¨nn, M.; Ba¨ckvall, J.-E.; Andersson, P.
G. Tetrahedron Lett. 1995, 36, 7749-7752. (c) Larock, R. C.; Hightower,
T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-
3585. (d) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002,
41, 164-166. (e) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2003, 42, 2892-2895.
(25) Hirai, H.; Sawai, H. Bull. Chem. Soc. Jpn. 1970, 43, 2208-2213.
(26) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.-I. Tetradedron Lett.
1992, 33, 6643-6646.
(27) (a) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2003,
125, 12996-12997. (b) Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi,
N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868-2869. (c) Timokhin,
V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888-17893.
(28) For a recent example of Pd-catalyzed intramolecular oxidative amidation
of an unactivated double bond using p-benzoquinone as a reoxidant, see:
Abbiati, G.; Beccalli, E.; Broggini, G.; Martinelli, M.; Paladino, G. Synthesis
2006, 73-76.
(21) For an example of the oxidation of â-amido esters to Z-enamides using
Dess-Martin periodinate, see: Nicolaou, K. C.; Mathison, C. J. N. Angew.
Chem., Int. Ed. 2005, 44, 5992-5997.
(22) Kish et al. also reported that the cis/trans isomerization was induced under
photochemical conditions in a solvent-dependent manner and approximated
that a 6.5:1 ratio of the trans- and cis-isomers was obtained in DMF. Suh,
E. M.; Kishi, Y. J. Am. Chem. Soc. 1994, 116, 11205-11206.
9
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A R T I C L E S
Lee et al.
Table 1. Optimization of the Reaction Conditions in the Oxidative
Amidationa
entry
solvent
conv (yield, %)b
Z/Ec
1
2
3
4
5
6
7
8
DMF
DMSO
DME
THF
dioxane
1,2-dichloroethane
toluene
chlorobenzene
chlorobenzene (w/o Cu)
chlorobenzene
chlorobenzene
<5 (0)
<5 (0)
91 (86)
78 (67)
83 (60)
50 (34)
65 (37)
56 (47)
10 (<5)
7 (<5)
46 (41)
8 (<5)
2.4:1
3.0:1
4.8:1
>30:1
>30:1
>30:1
9
10d
11e
12
>30:1
chlorobenzene (N2)
a Reaction conditions: a mixture of benzamide (1 equiv), ethyl acrylate
(3.0 equiv), PdCl2(PhCN)2 (5.0 mol %), and CuCl (10 mol %) in the
indicated solvent (0.2 M) was stirred at 70 °C for 48 h under 1 atm of O2.
b Determined by 1H NMR using an internal standard (anisole) and combined
isolated yields of both isomers. c Isomeric ratio of crude reaction mixture
determined by 1H NMR. d CuCl2 (10 mol %) was used instead of CuCl.
e Benzoquinone (1.0 equiv) was used instead of CuCl.
applying Wacker-type reaction conditions30 because it was
envisioned that the protocol would eventually be amenable to
a practical process. It was observed that solvent polarity has a
dramatic effect on the efficiency as well as selectivity in the
conversion. For example, when the reaction was carried out in
DMF or DMSO, it was quite sluggish and a negligible
conversion was observed after 48 h using a Pd/Cu cocatalyst
system (entries 1 and 2). On the other hand, although the
reaction took place readily in 1,2-dimethoxyethane (DME),
tetrahydrofuran (THF), or dioxane at 70 °C under an oxygen
atmosphere (1 atm), the corresponding enamides were produced
as a mixture of Z- and E-enamide 3, the former being the major
isomer (entries 3-5).
On the other hand, selective formation of Z-enamide (Z/E
>30:1) was observed in a relatively less polar solvent such as
toluene, 1,2-dichloroethane, and chlorobenzene, although the
conversion rate was slightly lower (entries 6-8). Among those
media, the use of chlorobenzene resulted in the highest yield
of Z-3. While the reaction was sluggish in the absence of Cu
cocatalyst (entry 9), CuCl was superior to other copper salts
examined, such as Cu(OAc)2, Cu(OTf)2, and CuI (<10%
conversion). Interestingly, copper(II) chloride, the more typically
used cocatalyst in Wacker-type reactions, displayed much lower
efficiency compared to CuCl (entry 10). When benzoquinone
(1.0 equiv) was used as a reoxidant instead of CuCl cocatalyst,
Figure 1. ORTEP drawings of (Z)-3 and (E)-3.
the rate was only slightly lower, albeit with high stereoselectivity
(entry 11). The oxygen atmosphere was essential for achieving
high efficiency, as demonstrated in entry 12. Palladium catalysts
other than PdCl2(PhCN)2 displayed lower activity in general,
although the Z-selectivity was not changed in chlorobenzene
under otherwise the same conditions. For example, conversion
with Pd(OAc)2 was 11%; Pd(PPh3)4, 36%; (cod)PdCl2, 38%;
Pd(dba)2, 6%; and [1,1′-(Ph2P)2ferrocene]Cl2Pd, <5%. Pal-
ladium complexes bearing N-heterocyclic carbene (NHC)
ligands, such as IPrPd(allyl)Cl, [IPrPdCl2]2, and IPrPd(O2-
CCF3)2(OH2) [IPr ) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene], which have received much attention due to their air
and moisture stability and increased catalytic activity, turned
out to be ineffective in our case.31
The chemical shift of the amido hydrogen of the isolated Z-3
was at 11.5 ppm (CDCl3), while that of E-3 appears at 8.9 ppm,
strongly suggesting that an intramolecular hydrogen bond exists
in the Z-isomer.32 In fact, this was confirmed from crystal
structure analysis of each isomer (Figure 1). The distance of
the hydrogen bond (NsH‚‚‚O) in Z-3 was determined to be
2.007 Å from the solid structure, which is in the range of
reported intramolecular H-bonds,33 and the angle of the hydrogen-
bonded NsH·‚‚O was determined to be 135.1°.
(29) For selected examples of related works from this laboratory, see: (a) Chang,
S.; Yang, S. H.; Lee, P. H. Tetrahedron Lett. 2001, 42, 4833-4835. (b)
Chang, S.; Lee, M.; Kim, S. Synlett 2001, 1557-1558. (c) Na, Y.; Park,
S.; Han, S. B.; Han, H.; Ko, S.; Chang, S. J. Am. Chem. Soc. 2004, 126,
250-258. (d) Park, S.; Kim, M.; Chang, S. AdV. Synth. Catal. 2004, 346,
1638-1640. (e) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. ReV.
2004, 33, 302-312. (f) Hwang, L. K.; Na, Y.; Lee, J.; Do, Y.; Chang, S.
Angew. Chem., Int. Ed. 2005, 44, 6166-6169.
(30) For general accounts of the Wacker reaction, see: (a) Tsuji, J. Synthesis
1984, 369-384. (b) Tsuji, J. New J. Chem. 2000, 24, 127-135. (c) Henry,
P. M. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i., Ed.; John Wiley & Sons, Inc.: New York, 2002; Vol. 3, pp
2119-2139. (d) Takacs, J. M.; Jiang, X.-t. Curr. Org. Chem. 2003, 7, 369-
396. (e) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. ReV. 2005, 105,
2329-2363.
(31) (a) Jensen, D. R.; Schultz, M. J.; Mueller, J. A.; Sigman, M. S. Angew.
Chem., Int. Ed. 2003, 42, 3810-3813. (b) Jensen, D. R.; Sigman, M. S.
Org. Lett. 2003, 5, 63-65. (c) Rogers, M. M.; Wendlandt, J. E.; Guzei, I.
A.; Stahl, S. S. Org. Lett. 2006, 8, 2257-2260.
(32) For discussions of H-bonds in related compounds, see: (a) Gilli, P.;
Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122, 10405-
10417. (b) Vargas, R.; Garza, J.; Friesner, R. A.; Stern, H.; Hay, B. P.;
Dixon, D. A. J. Phys. Chem. A 2001, 105, 4963-4968. (c) Papenek, P.;
Fischer, J. E.; Murthy, N. S. Macromolecules 2002, 35, 4175-4182. (d)
Lei, Y. X.; Casarini, D.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2003,
68, 947-959.
(33) (a) Kang, Y. K. J. Phys. Chem. B 2000, 104, 8321-8326. (b) Eckert, J.;
Barthes, M.; Klooster, W. T.; Albinati, A.; Aznar, R.; Koetzle, T. F. J.
Phys. Chem. B 2001, 105, 19-24 and refs 32a,c.
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Highly Stereoselective Synthesis of Z-Enamides
A R T I C L E S
Table 2. Effects of Additives on the Oxidative Amidationa
when 2 or 1 equiv of ethyl acrylate was used under otherwise
the same conditions, the product yield was 59% or 36%,
respectively, compared to 72% with 3 equiv (entry 11).
Under the optimized conditions, the oxidative amidation was
next investigated using a range of primary amides and conju-
gated olefins (Table 3). It turned out that primary amides of
aryl, alkenyl, and alkyl adducts all reacted readily with olefins
conjugated with any of the functional groups examined which
are capable of hydrogen bonding with amido NH protons. More
importantly, the enamide products were generated exclusively
in Z-form in all cases investigated; no traces of E-isomers were
observed. When benzamide was allowed to react with ethyl
acrylate or N,N-dimethylacrylamide using PdCl2(PhCN)2 (5 mol
%), CuCl (10 mol %), and TEMDP (10 mol %) in chloro-
benzene at 70 °C under oxygen (48 h), the corresponding
Z-enamides were obtained in good yields (entries 1 and 2). Since
substituted vinylphosphonates have been frequently utilized as
important synthetic intermediates,36 we were interested in the
oxidative amidation of those compounds. When diethyl vinyl-
phosphonate was employed to react with benzamide, we were
pleased to observe that the corresponding amidovinyl phospho-
nate was produced in a pure Z-form with a synthetically
acceptable yield (entry 3). The amido proton of the produced
N-[2-diethylphosphoryl-(Z)-ethenyl]benzamide appeared at 11.4
entry
additive
yield (%)b
1
2
3
4
5
6
7
8
47
<5
<5
<5
16
LiBr
(n-Bu)4N+Cl-
pyridine
NaHCO3
IPrc
31
triethylamine
PPh3
P(O)Ph3
P(O)(n-Oct)3
[(EtO)2P(O)]2CH2
HMPA
<5
<5
68
9
10
11
12
74d
72
64d
a Reaction conditions: a mixture of benzamide (1 equiv), ethyl acrylate
(3.0 equiv), CuCl (10 mol %), and PdCl2(PhCN)2 (5.0 mol %) in
chlorobenzene (0.2 M) was stirred at 70 °C for 48 h under 1 atm of O2.b In
all cases, the ratio of Z/E-3 was >30:1 and the isolated yield is that of Z-3.
c IPr ) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. d A cyclized ena-
mide was also obtained in ca. 10% yield, along with the desired Z-enamide
(ref 35).
Although excellent stereoselectivity was observed for the
formation of Z-3 in relatively nonpolar solvents, reaction rates
were retarded when compared to those in DME, THF, or
dioxane, as shown in Table 1. This was mainly attributed to
the formation of Pd(0) black from the palladium complex during
the course of the catalytic cycles. In order to suppress such
precipitation, various additives were subsequently investigated
(Table 2).34 It was observed that certain types of salts or bases
significantly inhibited the reaction of benzamide with ethyl
acrylate (entries 2-5). The addition of free carbene and tertiary
amine, which are known to stabilize the catalyst, did not improve
the yield (entries 6 and 7). In contrast, we found that, whereas
the addition of phosphines or phosphonites resulted in complete
inhibition, their oxides displayed notable promoting effects to
accelerate the reaction rates and increase the product yields
(entries 8-12). In fact, formation of palladium black was not
observed in the presence of the beneficial additives. Among
those examined, tetraethyl methylenediphosphonate (TEMDP)
was chosen for the subsequent studies because it also inhibits
formation of a side product (cyclized enamide) that is presum-
ably formed by an intramolecular activation of the ortho proton
of benzamide followed by a cyclization pathway.35 Hexameth-
ylphosphoramide (HMPA) displayed slightly inferior additive
effects relative to phosphine oxides or TEMDP. It should be
mentioned that the presence of additives did not change the
stereoselectivity in the oxidative amidation; Z-enamides were
still produced exclusively. The use of less than 3 equiv of olefins
to amides resulted in decreased product yields. For example,
1
ppm (CDCl3) in the H NMR spectrum, implying again that a
strong intramolecular H-bond exists in the product and that this
is mainly responsible for the stereochemical outcome in this
reaction.37 As expected, the chemical shift of N-H in the
E-isomeric vinylphosphonate (obtained from photoisomerization
of Z-enamide, vide infra) was upfield (10.1 ppm) relative to
that of Z-enamide. When methyl vinyl ketone was used, the
reaction afforded the corresponding Z-enamide in a moderate
yield but with excellent stereoselectivity, again under the same
conditions (entry 4). In contrast to terminal olefins that afforded
moderate to good yields of enamides, reactions with internal
olefins were sluggish, resulting in lower product yields. For
example, when ethyl trans-crotonate was applied, the Z-enamide
was obtained in 14% yield, presumably due to the steric
hindrance (entry 5).38 It was observed that generally labile
groups in Pd catalysis were tolerant under the present oxidative
amidation conditions, as demonstrated by the reactions with
4-bromobenzamide (entries 6 and 7).
A range of vinylic amides were also readily reacted with
conjugated olefins to afford conjugated enamides in good yields
with excellent stereoselectivity for the formation of Z-isomers.
For example, oxidative amidation of ethyl acrylate and acryl-
amide took place smoothly when cinnamamide was employed,
to afford the corresponding Z-enamides in high yields (entries
8 and 9). Likewise, R-substituted vinylic amides such as
methacrylamide underwent oxidative coupling with various
conjugated olefins efficiently and selectively (entries 10-12).
It turned out that the presence of R-substituents in the corre-
(34) Vogl, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38,
1570-1577.
(35) The side product was determined to be ethyl 3-oxo-∆1R-isoindolineacetate.
(36) For a review on the utility of vinylphosphonates, see: (a) McReynolds,
M. D.; Dougherty, J. M.; Hanson, P. R. Chem. ReV. 2004, 104, 2239-
2258. (b) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. ReV. 2004, 104,
6177-6216. (c) Maffei, M. Curr. Org. Synth. 2004, 1, 355-375.
(37) The chemical shift of the N-H proton is not dependent upon the
concentration of isolated Z-enamide sample. Therefore, the possibility of
a contribution from an intermolecular H-bond seems to be quite low.
(38) When ethyl cis-crotonate and ethyl trans-cinnamate were applied, the
corresponding enamides were not produced, which suggests that the vinyl
substituents at the â position with respect to the carbonyl group of
conjugated olefins might significantly inhibit the progress of the reaction.
9
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A R T I C L E S
Lee et al.
Table 3. Oxidative Catalytic Amidation of Conjugated Olefins with Primary Amidesa
a In all cases, selectivity of Z/E-isomer was >30:1, except for entry 26. b Isolated yields after silica gel chromatography. c 10 mol % of PdCl2(PhCN)2 and
20 mol % of both CuCl and TEMDP were used. d Z/E-isomeric ratio was 2.1:1, and the isolated yield is that of Z-enamide.
sponding Z-enamides did not interfere with the intramolecular
hydrogen bond, as judged by the chemical shifts of amido
protons in these cases (ca. 11 ppm in CDCl3).
Aliphatic primary amides turned out to be another feasible
type of substrate, producing Z-enamides selectively by reaction
with conjugated olefins. However, in these cases, while stereo-
selectivity was still high for the formation of Z-enamides, the
reactivity was generally lower than that of aromatic or vinylic
amides, and larger amounts of catalysts were required to obtain
satisfactory product yields. For example, while 63% yield of a
Z-enamide was obtained from reaction of acetamide with ethyl
acrylate with the use of 5 mol % of PdCl2(PhCN)2, the yield
was increased to 82% by using 10 mol % of the same Pd species
(compare entries 13 and 14). Under the same conditions,
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Highly Stereoselective Synthesis of Z-Enamides
A R T I C L E S
Table 4. Photoisomerization of Several Z-Enamides
irradiation (more than 8 h) did not change the isomerization
ratio, implying that a photoequilibrium was established under
these conditions.40
Interestingly, among various solvents examined, the use of
DMF or methanol, which is known to disrupt intramolecular
hydrogen bonds,41 gave a lower isomerization ratio (E/Z ) 1.3-
1.5:1) compared to that obtained in chloroform. The efficiency
of the photoisomerization was observed to depend significantly
also on the type of substituents on the enamides employed.
Whereas higher ratios of photoisomerization were observed with
ester or ketonyl moieties (entries 1 and 2), the E/Z ratio was
sharply decreased with enamides having amido or phosphoryl
groups at R2 (entries 3 and 4). Interestingly, it was seen that a
Z-enamide bearing an aliphatic amide was much less efficiently
isomerized into the E-enamides, as illustrated in entry 5. Further
spectroscopic and dynamic studies on the electronically excited
states of enamides would be quite desirable for the quantitative
explanation of our results shown in Table 4.
entry
R1
R2
E/Z (%)a
1
2
3
4
5
Ph
Ph
Ph
Ph
CO2CH2CH3
COCH3
CON(CH3)2
P(O)(OCH2CH3)2
CO2CH2CH3
4.9:1 (74)
5.4:1 (80)
1.5:1 (56)
0.42:1 (31)
0.25:1 (14)
t-Bu
a Ratio determined by H NMR of the crude mixture, and the isolated
yield is that of E-isomer.
1
acetamide was also readily reacted with other conjugated olefins
to provide the corresponding Z-enamides in high yields (entries
15 and 16). Bulkier aliphatic amides such as phenylacetamide
and trimethylacetamide underwent oxidative amidation without
difficulty to afford the corresponding Z-enamides in good yields
(entries 17-20). The amido proton peaks of Z-enamides
obtained from the aliphatic amides appear at 10.2-11.8 ppm,
depending on the substituents, while those of the E-isomers are
found upfield (ca. 8 ppm). This indicates again that an
intramolecular hydrogen bond exists in Z-enamides formed from
aliphatic amides. The tolerance of functional groups toward the
reaction conditions turned out to be respectable. Indeed,
reactions of aliphatic amides substituted with halide, silyloxy,
or acetoxy groups took place without problems, as demonstrated
in entries 21-25.
In Scheme 1, a plausible catalytic cycle for the present
oxidative amidation is outlined using acetamide (4) and ethyl
acrylate (2) as representative substrates, although several details
remain to be elucidated.42 The reaction is believed to be initiated
by the displacement of the benzonitrile ligand of the palladium
complex precursor, [PdCl2(PhCN)2], by the double bond of
conjugated alkene 2, forming a palladium-olefin complex,
either A or B. The palladium-olefin complex is then susceptible
to intermolecular nucleophilic attack by amide 4, which is
presumably coordinated to the palladium complex prior to the
nucleophilic attack,43 leading to amidopalladation adducts C and/
or D upon loss of HCl.44
It was observed that, when carbamates were employed as
substrate, both efficiency and selectivity were significantly
decreased. For example, urethane reacted with ethyl acrylate to
afford a mixture of enamides (Z/E, 2.1:1) with a moderate
chemical yield (entry 26). Presumably, this can be ascribed to
the lower acidity of the carbamate N-H proton compared to
amides and, therefore, lower stabilization of a putative σ-alky-
lamidopalladium adduct, leading to Z-isomers (vide infra).23 On
the other hand, it turned out that unconjugated simple aliphatic
olefins and styrene derivatives were not viable substrates for
the oxidative amidation reaction under the presently employed
conditions.
Considering that Z/E-isomerization of enamides does not
occur under the reaction conditions, it is assumed that the
stereochemical outcome of the products is determined mainly
after the nucleophilic attack of amide on the palladium-olefin
complex.45 It was initially considered that two intermediates,
C and D, are generated without any preference for one over
the other and that they actually interconvert by σ-bond rotation.
However, the additional stability provided by intramolecular
H-bonding in intermediate C is expected to drive the equilibrium
between C and D toward the H-bonded intermediate C. In turn,
the intermediate C is likely to undergo â-hydride elimination
(via transition state E) more readily than the corresponding
It should be mentioned that a cis T trans isomerization of
the produced enamides does not occur under the reaction
conditions. On the other hand, it is known that stereoisomers
of Z- and E-enamides are interconverted by photoirradiation.39
This led us to investigate photoisomerization of the obtained
Z-enamides under various conditions by changing UV wave-
lengths and solvents. When a pure Z-3 enamide was irradiated,
the highest ratio of isomerization (E/Z ) 4.9:1) was observed
at 350 nm, and the E-3 isomer could be isolated in 74% yield,
along with recovered Z-3 (23%), after 8 h at room temperature
in chloroform (Table 4, entry 1). This result indicates that the
intramolecular H-bond present in Z-enamides does not inhibit
isomerization of the electronically excited enamides. Longer
(40) Photoirradiation of Z-3 in chloroform at 300 nm gave Z/E ) 1:1 within
10 min. However, after reaching Z/E ) ca. 3 in 1 h, both compounds
decomposed under longer irradiation. Photoirradiation of Z-3 in chloroform
at 250 nm resulted in decomposition of the starting material within 10 min.
The time course of photoirradiation at 350 nm was monitored every 1 h.
(41) (a) Lewis, F. D.; Stern, C. L.; Yoon, B. A. J. Am. Chem. Soc. 1992, 114,
3131-3133. (b) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9,
407-414 and ref 22.
(42) For recent reviews on Heck-type reactions, see: (a) Amatore, C.; Jutand,
A. J. Organomet. Chem. 1999, 576, 254-278. (b) Amatore, C.; Jutand, A.
Acc. Chem. Res. 2000, 33, 314-321. (c) Beletskaya, I. P.; Cheprakov, A.
V. Chem. ReV. 2000, 100, 3009-3066. (d) Dounay, A. B.; Overman, L. E.
Chem. ReV. 2003, 103, 2945-2964.
(43) Hartley, F. R. Chem. ReV. 1969, 69, 799-844.
(44) It can be also considered that the amidopalladation proceeds through
zwitterionic intermediates which are deprotonated by chloride anion to
afford anionic palladium species in analogy to Stahl’s aerobic oxidative
amination reactions, as demonstrated in ref 27.
(45) (a) Hegedus, L. S. Tetrahedron 1984, 40, 2415-2434. (b) Grushin, V. V.
Chem. ReV. 1996, 96, 2011-2034. (c) Stahl, S. S.; Thorman, J. L.; Nelson,
R. C.; Kozee, M. A. J. Am. Chem. Soc. 2001, 123, 7188-7189. (d)
Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc. 2002, 124,
766-767. (e) Lloyd-Jones, G. C.; Slatford, P. A. J. Am. Chem. Soc. 2004,
126, 2690-2691. (f) Muller, J. A.; Goller, C. P.; Sigman, M. S. J. Am.
Chem. Soc. 2004, 126, 9724-9734. (g) Hay, M. B.; Wolfe, J. P. J. Am.
Chem. Soc. 2005, 127, 16468-16476 and ref 42b.
(39) (a) Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421-452. (b) Lewis, F.
D.; Howard, D. K.; Oxman, J. D.; Upthagrove, A. L.; Quillen, S. L. J. Am.
Chem. Soc. 1986, 108, 5964-5968. (c) Robinson, A. J.; Stanislawski, P.;
Mulholland, D.; He, L.; Li, H.-Y. J. Org. Chem. 2001, 66, 4148-4152.
(d) Kuramochi, K.; Osada, Y.; Kitahara, T. Tetrahedron 2003, 59, 9447-
9454. (e) Nishio, T.; Tabata, M.; Koyama, H.; Sakamoto, M. HelV. Chim.
Acta 2005, 88, 78-86.
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A R T I C L E S
Lee et al.
Figure 2. Optimized geometry of σ-alkylpalladium(II) intermediates and transition states for â-hydride elimination (L ) PhCN).
Scheme 1
σ-alkylpalladium(II) species D (via transition state F), resulting
in the predominant formation of Z-enamides. The LPdHCl
species, which is generated from â-hydride elimination of the
σ-alkylpalladium(II) intermediates in addition to enamide
products, subsequently eliminates HCl to afford Pd(0), which,
after oxidation by the action of copper cocatalyst and molecular
oxygen in analogy to the Wacker process,30 re-enters into the
next catalytic cycle.
intermediates C and D, and transition states of â-hydride
elimination E and F (Figure 2) was carried out using the
correlated ab initio and density functional theory (DFT) method
B3LYP/LANL2DZ.46 As expected, the calculation showed that
isolated Z-5 is more stable than its E-5 isomer by 5.46 kcal/
mol,47 and coordinated species Z-5-LPdHCl is more stable than
its isomer E-5-LPdHCl by 6.18 kcal/mol, probably due to the
(46) Frisch, M. J.; et al. Gaussian 03; Gaussian, Inc.: Pittsburgh, PA, 2003.
(47) B3LYP/6-31G(d) is used for calculation of the energy level of final products
only.
To rationalize the stereochemical outcome of enamide forma-
tion, optimization of stereoisomeric Z/E-enamides, plausible key
9
12960 J. AM. CHEM. SOC. VOL. 128, NO. 39, 2006

Highly Stereoselective Synthesis of Z-Enamides
A R T I C L E S
Figure 3. Relative energy diagram of geometry-optimized lowest-energy conformers of two σ-alkylpalladium(II) intermediates C and D and transition
states of â-hydride elimination E and F shown in Scheme 1 (aenergy unit is kcal/mol).
Scheme 2
intramolecular hydrogen bonding present only in the Z-isomer.
In addition, the energy difference between optimized amidopal-
ladation adducts C and D (Figure 3) was calculated to be 4.18
kcal/mol, sufficiently high to explain the favorable formation
of intermediate C. Furthermore, the energy difference between
transition states E and F for â-hydride elimination leading to
Z- and E-enamide, respectively, turned out to be 5.35 kcal/mol,48
which is again sufficiently large to ensure almost exclusive
generation of the Z-enamide. This led us to assume that
â-hydride elimination from the σ-alkylpalladium(II) intermedi-
ates, leading to enamide products, is a stereochemistry-
determining step in the overall oxidative amidation process.49
When a secondary amide was employed under otherwise the
identical conditions, the oxidative amidation of ethyl acrylate
was very sluggish and produced the E-enamide exclusively, but
in only poor yield (eq 2). This result may be explained by
also controls the stereoselectivity of the produced enamides,
most probably through the â-hydride elimination step.50
A novel N-acyl vinylogous carbamic acid, CJ-15,801, was
recently reported as an inhibitor of multiple-drug-resistant
(MDR) Staphylococcus aureus strains.51 We envisioned that our
method could be effectively utilized for the direct synthesis of
cis-CJ-15,801 by employing a functionalized amide and acrylic
ester (Scheme 2).52 When a suitable amide (6), derived from
R-(+)-pantolactone,53 was allowed to react with allyl acrylate
under the oxidative amidation conditions developed in this study,
the reaction took place readily to afford the corresponding
Z-enamide (Z-7) in good yield and with excellent stereoselec-
tivity (Z/E >30:1). Two acetate groups were then efficiently
deprotected under the standard conditions to afford Z-8 in
excellent yield, thus achieving a truly efficient and direct formal
synthesis of cis-CJ-15,801.54
considering that a putative H-bond does not exist in the
corresponding σ-alkylpalladium(II) intermediate (G); thus, only
the thermodynamically more stable E-enamide is formed in this
case. We believe that this result further supports our proposal
that an intramolecular H-bond in the plausible σ-alkylamidopal-
ladium intermediates not only accelerates the reaction rates but
(50) For an intuitive review on the issue of reactivity and selectivity in catalysis,
see: Zaera, F. Catal. Lett. 2003, 91, 1-10.
(51) Sugie, Y.; Dekker, K. A.; Hirai, H.; Ichiba, T.; Ishiguro, M.; Shiomi, Y.;
Sugiura, A.; Brennan, L.; Duignan, J.; Huang, L. H.; Sutcliffe, J.; Kojima,
Y. J. Antibiot. 2001, 54, 1060-1065.
(52) For the Cu-mediated N-vinylation of amides with (E)-allyl-â-iodoacrylate
for the synthesis of CJ-15,801 and its analogues, see ref 23.
(53) For the preparation of amide, see: Harris, S. A.; Boyack, G. A.; Folkers,
K. J. Am. Chem. Soc. 1941, 63, 2662-2667.
(48) Ea for F is 1.46 kcal/mol and Ea for E is 0.29 kcal/mol.
(49) For examples of â-hydride elimination as a rate-determining step by the
similar approach, see ref 45g.
(54) For the deallylation procedure from the same precursor to give free cis-
CJ-15,801, see ref 21.
9
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A R T I C L E S
Lee et al.
Conclusions
type of substituents of enamide substrates and solvents em-
ployed, and synthetically useful yields of E-enamides could be
obtained with Z-enamides having more acidic amido protons.
Considering its convenient reaction conditions and excellent
stereoselectivity, the present oxidative amidation procedure
should attract much interest as a synthetically feasible approach
for the preparation of Z-enamides from readily available starting
materials.
We have shown that Z-enamides can be efficiently prepared
in high yields and with excellent stereoselectivity by the direct
reaction of primary amides with conjugated olefins under
Wacker-type conditions. A wide range of amides are readily
reacted with acrylic esters, acrylic amides, alkyl vinyl ketones,
and vinyl phosphonate by the action of a Pd/Cu cocatalyst
system under an oxygen atmosphere, leading to the correspond-
ing enamides exclusively in the Z-form. The high stereoselec-
tivity observed in this study is mainly attributed to the favorable
â-hydride elimination from one plausible σ-alkylamidopalladium
intermediate which bears an intramolecular hydrogen bond. In
fact, the energy difference between two proposed amidopalla-
dation intermediates was calculated to be 4.18 kcal/mol, where
the intermediate having an intramolecular H-bond is more stable.
Moreover, a transition state of â-hydride elimination leading
to the Z-enamide was determined to be more stable by 5.35
kcal/mol compared to that resulting in the E-isomer, implying
that the stereochemistry-determining-step in the present oxida-
tive amidation reactions is closely related to the â-hydride
elimination of the σ-alkylamidopalladium intermediates. Ef-
ficiency in the photoisomerization of Z-enamides into the
corresponding E-isomers was observed to be dependent on the
Acknowledgment. This paper is dedicated to Professor
Sunggak Kim on the occasion of his 60th birthday. This research
was supported by the Center for Molecular Design and Synthesis
(CMDS) at KAIST and grant no. R01-2005-000-10381-0 from
the Basic Research Program and Korea Science and Engineering
Foundation (no. R01-2005-000-10117-0).
Supporting Information Available: Complete ref 46, experi-
1
mental procedures, characterization of products, copies of H
and 13C NMR spectra of the obtained enamides, X-ray crystal-
lographic data of Z-3 and E-3, and XYZ coordinates for the
calculated compounds/transition states (PDF, CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA0639315
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12962 J. AM. CHEM. SOC. VOL. 128, NO. 39, 2006