Copper-catalyzed coupling of amides and carbamates with vinyl halides

Article abstract of DOI:10.1021/ol035355c

(Matrix presented) A general and efficient copper-catalyzed method for the amidation of vinyl bromides and iodides has been developed. This protocol uses a combination of 5 mol % copper iodide and 20 mol % N,N′-dimethyl ethylenediamine. Substrates bearing ester, silyl ether, and amino groups were successfully coupled under the reaction conditions. The double bond geometry of the vinyl halides was retained under the reaction conditions.

Full text of DOI:10.1021/ol035355c

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3667-3669
Copper-Catalyzed Coupling of Amides
and Carbamates with Vinyl Halides
Lei Jiang, Gabriel E. Job, Artis Klapars, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received July 21, 2003
ABSTRACT
A general and efficient copper-catalyzed method for the amidation of vinyl bromides and iodides has been developed. This protocol uses a
combination of 5 mol % copper iodide and 20 mol % N,N -dimethyl ethylenediamine. Substrates bearing ester, silyl ether, and amino groups
′
were successfully coupled under the reaction conditions. The double bond geometry of the vinyl halides was retained under the reaction
conditions.
Enamides are important synthetic intermediates,1 as well as
a structural component of many natural products.2 Conven-
tionally, protocols for their preparation include direct addition
of amides to alkynes,3 acylation of imines,4 the Curtius
rearrangement of R,â-unsaturated acyl azides,5 and the
olefination of amides.6 Although these protocols provide
access to enamides, they suffer from either low yield or lack
of stereocontrol on the double bond geometry. Transition-
metal-catalyzed C-N bond formation has been an area of
intensive research during the past 10 years.7 Most of the work
has concentrated on the formation of aromatic C-N bonds,
with only two examples of the palladium-catalyzed intramo-
lecular vinylation of an amide reported.8 In contrast, the
intermolecular vinylation of amides has been demonstrated
using copper as the catalyst or promoter.9 For example,
(6) For palladium-catalyzed C-N bond formation, see: (a) Hartwig, J.
F. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; p 1051. (b) Muci,
A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. For leading
references on the copper-catalyzed C-N bond formation, see: (a) Klapars,
A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (b)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (c) Klapars, A.;
Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727. (d) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001,
3, 4315. (e) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (f) Collman,
J. P.; Zhong, M. Org. Lett. 2000, 2, 1233.
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J.; Constantieux, T. Tetrahedron Lett. 1992, 33, 3903. (b) Cuevas, J.-c.;
Patil, P.; Snieckus, V. Tetrahedron Lett. 1989, 30, 5841.
(8) (a) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 111. For
palladium-catalyzed vinylation of azoles, see: (b) Lebedev, A. Y.; Izmer,
V. V.; Kazyul’kin, D. N.; Beletskaya, I. P.; Voskoboynikov, A. Z. Org.
Lett. 2002, 4, 623. For palladium-catalyzed vinylation of amines, see: (c)
Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem. Commun.
2002, 2362. (d) Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43,
9085.
(1) (a) Larock, R. C. ComprehensiVe Organic Transformations: A Guide
to Functional Group Preparations; Wiley-VCH: New York, 1999. (b)
Fu¨rstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem Eur. J. 2001, 7,
5286.
(2) (a) Galinis, D. L.; McKee, T. C.; Pannell, L. K.; Cardellina, J. H.,
II; Boyd, M. R. J. Org. Chem. 1997, 62, 8968. (b) McKee, T. C.; Galinis,
D. L.; Pannell, L. K.; Cardellina, J. H., II; Laasko, J.; Ireland, C. M.; Murray,
L.; Capon, R. J.; Boyd, M. R. J. Org. Chem. 1998, 63, 7805. (c) Suzumura,
K.-i.; Takahashi, I.; Matsumoto, H.; Nagai, K.; Setiawan, B.; Rantiamodjo,
R. M.; Suzuki, K.-i.; Nagano, N. Tetrahedron Lett. 1997, 38, 7573. (d)
Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y. Seto, H. J. Org. Chem.
1999, 64, 153. (e) Erickson, K. L.; Beutler, J.; Cardellina, J. H., II; Boyd,
M. R. J. Org. Chem. 1997, 62, 8188. (f) Dekker, K. A.; Aiello, R. J.; Hirai,
H.; Inagaki, T.; Sakakibara, T.; Suzuki, Y.; Thompson, J. F.; Yamauchi,
Y.; Kojima, N. J. Antibiot. 1998, 51, 14. (g) Kunze, B.; Jansen, R.; Sasse,
F.; Hofle, G.; Reichenbach, H. J. Antibiot. 1998, 51, 1075.
(3) (a) Mohre, H.; Kilian, R. Tetrahedron 1969, 25, 5745. (b) Kondo,
T.; Tanaka, A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc., Chem. Commun.
1995, 413.
(4) (a) Boeckmann, R. K., Jr.; Goldstein, S. W.; Walters, M. A. J. Am.
Chem. Soc. 1988, 110, 8250
(5) (a) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407. (b) Brettle, R.;
Mosedale, A. J. J. Chem. Soc., Perkin Trans. 1 1988, 2, 185.
(9) (a) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991,
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10.1021/ol035355c CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/09/2003

Table 1
Figure 1.
Ogawa reported9a the cross-coupling reaction between potas-
sium amides and vinyl bromides mediated by a stoichiometric
quantity of CuI.10 More recently, using CuTc (Tc )
thiophene-2-carboxylate) as a catalyst, Porco described9b
a
copper-catalyzed amidation of vinyl iodides to give enamides
in moderate yield. Both protocols only worked for terminal
vinyl halides. Moreover, they required the use of either
HMPA or NMP as solvent.
On the basis of our previous work on the copper-catalyzed
C-N bond formation of aryl halides,7a-c we felt that the use
of an appropriate ligand would allow us to realize a mild
and general procedure for the synthesis of enamides. Using
2-pyrrolidinone and 2-methyl-1-bromopropene as the pro-
totypical substrate combination, an initial ligand screen was
carried out with CuI as a catalyst and K2CO3 as a base. To
our delight, among the eight ligands examined, N,N′-
dimethylethylenediamine (7) and trans-N,N′-dimethyl-cy-
clohexyldiamine (8) gave excellent results. Of the bases
examined, K2CO3 turned out to give the best yield. The
combination of CuI, 7, and K2CO3 could be successfully
employed in a variety of solvents including THF, dioxane,
toluene, and DMF. Coupling reactions involving vinyl
bromides were carried out at 110 °C, and the process
generally went to completion in less than 16 h. To the best
of our knowledge, this is the first example of the copper-
catalyzed amidation of an unactivated vinyl bromide. A
variety of enamides have been prepared employing these
conditions, as shown in Table 1. Four-, five-, and six-
membered lactams were all viable substrates; the reaction
a Isolated yield average of two runs. b Rotameric mixture was isolated.
c 1.2 equiv of vinyl bromide was employed. d 10 mol % of CuI and 20 mol
% of 7 were employed.
of five-membered lactams was generally faster than those
of the others.11 Both cyclic amides and acyclic amides could
be combined with vinyl halides to give the desired enamides
in excellent yields. Notably, an amide with a free anilino
group was also successfully coupled using this catalytic
system (Table 1, entry 11). We found, however, that acyclic
secondary amides were not suitable substrates, most likely
because of their increased level of steric hindrance. In
contrast, this protocol was less sensitive to the size of the
(10) While this manuscript was being prepared, a paper utilizing a
stoichiometric quantity of CuTc and N,N′-dimethylethylenediamine was
reported: Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040.
(11) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035.
Org. Lett., Vol. 5, No. 20, 2003
3668

employed. This general protocol could also be applied to
the vinylation of carbamates (Table 1, entries 8-10).
The coupling of vinyl iodides was also examined with the
same catalyst system. The amidation of vinyl iodides was
found to proceed under mild conditions (<70 °C), and in
one case the reaction proceeded at room temperature. For
the amidation of vinyl iodides, the use of Cs2CO3 as a base
generally gave better results than K2CO3. As shown in Table
2, R,â-unsaturated amides were also viable substrates. More
importantly, the double bond geometry of the vinyl halides
was retained in the product. We also found that R,â-
unsaturated-â-iodoesters were successfully coupled with
amides to provide the dehydro-â-amino ester, a precursor
for â-amino acids.12 In these cases, it is important to stop
the reaction at the time indicated; extended heating results
in decomposition of the products.
Table 2.
In conclusion, we have developed a mild and efficient
protocol for the copper-catalyzed coupling of amides and
carbamates with vinyl bromides and iodides. This procedure
provides access to the structurally important enamide moiety.
The mild reaction conditions and increased scope relative
to previous methods, the operational simplicity, and the
functional group compatibility of this process should render
this protocol attractive to synthetic chemists.
a Isolated yield (average of two runs). b Reaction was run in DMF.
c K2CO3 was used as base. d The starting vinyl iodide contained ∼5% cis-
isomer.
Acknowledgment. We thank the NIH (GM 58160) for
funding. Pfizer, Merck, and Bristol-Myers Squibb are
acknowledged for additional unrestricted support. L.J. was
supported as a postdoctoral trainee of the National Cancer
Institute (NCI training grant CI T32CA09112).
vinyl halides used. For example, di- and trisubstituted vinyl
bromides performed well under the reaction conditions and
afforded the desired enamides in excellent yield. Particularly
important was that we were able to, for the first time,
accomplish the catalytic coupling of tetrasubstituted vinyl
bromides with an amide using a copper catalyst (Table 1,
entries 2-4). We note that the amidation of tetrasubstituted
vinyl bromides required slightly longer reaction time than
that of di- or tri-substituted substrates. Vinyl bromides
bearing a silyl ether moiety were also compatible under the
reaction conditions (Table 1, entries 6 and 7). It is also
important to note that a small amount of double vinylation
product was observed when an excess of vinyl halide was
Supporting Information Available: Experimental pro-
cedure and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035355C
(12) For a recent report on asymmetric hydrogenation of â-acylamido
acrylates, see: Holz, J.; Monsees, A.; Jiao, H.; You, J.; Kormarov, I. V.;
Fischer, C.; Drauz, K.; Borner, A. J. Org. Chem. 2003, 68, 1701.
Org. Lett., Vol. 5, No. 20, 2003
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