Construction of β-haloenamides via direct copper-promoted coupling of lactams with 2-chloro and 2-bromo vinyliodides

Article abstract of DOI:10.1021/ol060093a

Cu(I)-catalyzed coupling of lactams with (E)-2-chlorovinyliodides or (E)-2-bromovinyliodides produces the corresponding β-haloenamides in moderate to excellent yields.

Full text of DOI:10.1021/ol060093a

ORGANIC
LETTERS
2
006
Vol. 8, No. 9
779-1781
Construction of
â-Haloenamides via
1
Direct Copper-Promoted Coupling of
Lactams with 2-Chloro and 2-Bromo
Vinyliodides
Cuixiang Sun, Jason E. Camp, and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
Received January 12, 2006
ABSTRACT
Cu(I)-catalyzed coupling of lactams with (E)-2-chlorovinyliodides or (E)-2-bromovinyliodides produces the corresponding
moderate to excellent yields.
â
-haloenamides in
Several alkaloids isolated from the marine bryozoan Chartel-
la papyracea incorporate an array of unusual functional groups,
1
including a â-halogenated enamide moiety (Figure 1). Due
2
to their unique structures, both the chartellines (1-3) and
3
chartellamides (4 and 5) have attracted attention as synthetic
targets. However, little work to date has focused on formation
of the â-chloroenamide moiety found in the chartellines and
the â-bromoenamide of the chartellamides. We are currently
exploring synthetic approaches to these marine metabolites and
now describe some of our initial results for the efficient con-
struction of the haloenamide portions of these natural products.
There has been a substantial amount of recent work
dedicated to the synthesis of stereochemically well-defined
Figure 1. The chartellines and chartellamides.
4
5
enamides and enamide-containing natural products via
metal-catalyzed coupling of vinyl halides with amides and
lactams. Buchwald et al. have developed a mild and
convenient improved procedure for the stereocontrolled
(1) (a) Anthoni, U.; Bock, K.; Chevolot, L.; Larsen, C.; Nielsen, P. H.;
Christophersen, C. J. Org. Chem. 1987, 52, 5638-5639. (b) Anthoni, U.;
Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C. J. Org. Chem.
1
987, 52, 4709-4712. (c) Chevolot, L.; Chevolot, A.-M.; Gajhede, M.;
Larsen, C.; Anthoni, U. J. Am. Chem. Soc. 1985, 107, 4542-4543. (d)
Nielsen, P. H.; Anthoni, U.; Christophersen, C. Acta Chem. Scand. 1988,
B42, 489-491.
N-vinylation of amides with vinyl halides using copper(I)
catalysis with N,N′-dimethylethylenediamine as the ligand.6
(2) (a) Lin, X.; Weinreb, S. M. Tetrahedron Lett. 2001, 42, 2631-2633.
(b) Lin, X. Ph.D. Thesis, The Pennsylvania State University, 2002. (c) Baran,
P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed. 2005, 44, 3714-
(4) For a review see: Dehli, J. R.; Legros, J.; Bolm, C. Chem Commun.
2005, 973-986. See, for example: (a) Shen, R.; Lin, C. T.; Porco, J. A.,
Jr. J. Am. Chem. Soc. 2002, 124, 5650-5651. (b) Wang, X.; Porco, J. A.,
Jr. J. Am. Chem. Soc. 2003, 125, 6040-6041. (c) Han, C.; Shen, R.; Su,
S.; Porco, J. A., Jr. Org. Lett. 2004, 6, 27-30. (d) Pan, X.; Cai, Q.; Ma, D.
Org. Lett. 2004, 6, 1809-1812.
3
717. (d) Nishikawa, T.; Kajii, S.; Isobe, M. Synlett 2004, 2025-2027. (e)
Nishikawa, T.; Kajii, S.; Isobe, M. Chem. Lett. 2004, 33, 440-441. (f)
Sun, C. Ph.D. Thesis, The Pennsylvania State University, 2005.
(
3) Pinder, J. L.; Weinreb, S. M. Tetrahedron Lett. 2003, 44, 4141-
4
143.
1
0.1021/ol060093a CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/30/2006

This methodology also allows the synthesis of 5-7-
substrates (Scheme 3). â-Lactam 14 reacted with iodo bromo
membered lactams via the intramolecular vinylation of
7
amides.
At the outset of our research, nothing had been reported
on metal-induced couplings of amides or lactams with 1,2-
dihaloalkenes. During the course of the studies outlined here,
Scheme 3
8
however, the Isobe group described a single example of such
a process. Thus, it was found that a 5:1 mixture of
halogenated enamides 8 and 9 could be obtained via coupling
of â-lactam 6 and (E)-â-chloro vinyliodide 7 with the
Buchwald conditions (Scheme 1).2
e
Scheme 1
compound 11 to give â-bromoenamide 15 in 39% isolated
yield (100% based upon recovered iodide). We were pleased
to find that tribrominated spiro-â-lactam 1611 coupled
smoothly and chemoselectively with simple iodo chloro
substrate 7 to produce â-chloroenamide 17 in moderate yield.
The couplings of some 4-dihalovinylimidazoles with
tribromo spiro-â-lactam substrates were also investigated
(Scheme 4). Reaction of the Boc-protected tribromo â-lactam
1
8 with imidazole 20 under the standard conditions resulted
Our initial investigations were aimed at both developing
the chemistry required to construct the requisite haloenamide
moieties and determining the functional group compatibility
of this methodology. Therefore, known (E)-1-chloro-2-
Scheme 4
9
iodovinylbenzene (7) and (E)-1-bromo-2-iodovinylbenzene
(
11)10 were coupled with 2-pyrrolidinone (10) with use of
the reaction conditions described by Buchwald for simple
vinyl iodides (Scheme 2). Treatment of the chloro compound
Scheme 2
7
and lactam 10 with 20 mol % of CuI, cesium carbonate,
and N,N′-dimethylethylenediamine in THF at 70 °C produced
the â-chloroenamide 12 in high yield as a single geometric
isomer. Moreover, the reaction was completely iodide
selective, and none of the coupling product analogous to 9
was detected in this case, or in any of the examples discussed
below. In the case of bromo iodo compound 11, however,
the yield of coupled product 13 was significantly lower (21%;
60% based on recovered starting iodide).
We next investigated the coupling of some spiro-â-lactams
structurally related to the chartellines with model dihalo
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Org. Lett., Vol. 8, No. 9, 2006

in formation of the haloenamide 21 in low yield due to the
lability of the protecting group in this system. However, the
more stable methyl-substituted analogue 19 coupled in high
yield with imidazole 20 to afford â-chloroenamide 22.
Scheme 6
5-Substituted imidazole 24 also reacted with BOM-protected
lactam 23 to produce coupled product 25 in 45% isolated
yield (67% based upon recovered 24). This compound is a
potentially useful intermediate for synthesis of chartelline
A (1).
Since the chartellines and chartellamides contain a 2-bro-
moimidazole moiety, we decided to explore the compatibility
of this functionality with the coupling methodology (Scheme
5). Thus, 2-pyrrolidinone (10) was coupled with 2-bro-
cursor 31 was prepared via a DCC-mediated esterification12
of pyroglutamic acid (29) with known (E)-1-iodo-2-chlo-
rovinyl alcohol 30. Iodo lactam 31 was then subjected to
the usual Buchwald conditions to afford seven-membered
bicycle 32 in moderate yield.
Scheme 5
1
3
In conclusion, we have developed a simple, efficient
method for the stereocontrolled synthesis of â-haloenamides
in moderate to good yields via the copper-catalyzed halogen-
selective N-vinylation of lactams with (E)-â-chloro and (E)-
â-bromo vinyliodides. This methodology can also be effected
intramolecularly, thereby providing interesting possibilites
for the total synthesis of the chartellines 1-3 and chartel-
lamides 4 and 5.
Acknowledgment. We are grateful to the National
Science Foundation (CHE-0404792) for financial support of
this research.
moimidazole 26 to afford the undesired lactam 27 as the
major product, along with a small amount of bis-lactam 28.
Finally, it was found that this methodology can also be
effected intramolecularly (Scheme 6). The cyclization pre-
Supporting Information Available: Experimental pro-
cedures for preparation of new compounds including spectral
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
(
5) For recent examples, see: (a) Shen, R.; Porco, J. A., Jr. Org. Lett.
2
000, 2, 1333-1336. (b) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B.
J.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3103-3106. (c) Coleman, R. S.;
Liu, P.-H. Org. Lett. 2004, 6, 577-580.
OL060093A
(6) Jieng, L.; Job, G. E.; Klapers, A.; Buchwald, S. L. Org. Lett. 2003,
5
, 3667-3669.
(9) Uemura, S.; Okazaki, H.; Onoe, A.; Okano, M. J. J. Chem. Soc.,
Perkin Trans. 1 1977, 676-680.
(
7) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035-2038.
(8) â-Chloro- and â-bromoenamides have previously been prepared by
(10) Synthesized from phenylacetylene and IBr using a variation of the
9
halogenation of enamides: (a) Shrestha-Dawadi P. B.; Lugtenburg, J. Eur.
J. Org. Chem. 2003, 4654-4663. (b) Brovarets, V. S.; Zyuz, K. V.;
Vydzhak, R. N.; Vinogradova, T. K.; Drach, B. S. Zh. Obshch. Khim. 1994,
methodology of Uemura. See the Supporting Information for experimental
details.
(11) For synthesis of the â-lactam and imidazole substrates see ref 2f,
and: Sun, C.; Lin, S.; Weinreb, S. M. J. Org. Chem. 2006, 71, ASAP.
(12) Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217-229.
(13) Bellina, F.; Colzi, F.; Mannina, L.; Rossi, R.; Viel, S. J. Org. Chem.
2003, 68, 10175-10177.
6
4, 1642-1651. (c) Diller, D.; Bergmann, F. Chem. Ber. 1977, 110, 2956-
2
957. (d) Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon, P.;
Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735-3745. (e) Scartoni,
V.; Tognetti, T. J. Heterocycl. Chem. 1984, 21, 1499-1503.
Org. Lett., Vol. 8, No. 9, 2006
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