The first examples of ring-closing olefin metathesis of vinyl chlorides

Article abstract of DOI:10.1021/ol034775z

(Matrix presented) Ring-closing metathesis (RCM) of olefinic vinyl chlorides can be effected by using the second generation Grubbs catalyst (10 mol %, Phil, 65°C) to produce a variety of carbocyclic and heterocyclic five-, six-, and seven-membered rings i

Full text of DOI:10.1021/ol034775z

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2505-2507
The First Examples of Ring-Closing
Olefin Metathesis of Vinyl Chlorides
Wenchun Chao and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
Received May 7, 2003
ABSTRACT
Ring-closing metathesis (RCM) of olefinic vinyl chlorides can be effected by using the second generation Grubbs catalyst (10 mol %, PhH, 65
°C) to produce a variety of carbocyclic and heterocyclic five-, six-, and seven-membered rings in excellent yields.
With the advent of functional group-compatible, well-
behaved transition-metal alkylidene catalysts over the past
decade, olefin metathesis has rapidly become one of the most
important and widely used methods in organic synthesis.1
In particular, ring-closing olefin metathesis (RCM) has been
extensively explored as an annulation strategy. This meth-
odology has been applied to construction of a variety of
carbocyclic and heterocyclic ring systems including macro-
cycles. Moreover, RCM chemistry has been used as a pivotal
step in several total syntheses of complex natural products.
Although a number of permutations of metathesis have been
described, relatively few examples have been reported
involving participation of heteroatom-substituted olefins. To
date, enol ethers of various types have been the most widely
utilized partners in such RCM reactions.2,3 Nitrogen-
substituted olefins such as enamides have also been used
successfully, but to a lesser degree.4 There are still some
unanswered mechanistic questions regarding these RCM
reactions. For example, it is unclear how crucial it is that
the transition metal catalyst first react with the nonheteroa-
tom-substituted olefin to avoid formation of a stable Fischer-
type carbene.2,5 However, there are some documented
instances where ruthenium Fischer carbene species can in
fact initiate RCM processes.6
In a recent publication, Grubbs and co-workers reported
that cross-coupling metathesis of vinyl halides with olefins
could not be effected.2 Despite these negative results, we
decided to investigate the possibility of doing RCM reactions
with vinyl halides since it seemed reasonable that the
intramolecularity of the process might offer a viable mecha-
nistic pathway. We also recognized the value of the metath-
esis products for subsequent transition-metal-mediated cou-
plings, as well as other reactions. Initial exploratory studies
were carried out with the vinyl chloride substrates shown in
(1) For recent reviews of olefin metathesis see: (a) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (c) Furstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012. (d) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037. (e) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900.
Lett. 2001, 42, 8023. Arisawa, M.; Theeraladanon, C.; Nishida, A.;
Nakagawa, M. Tetrahedron Lett. 2001, 42, 8029. van Otterlo, W. A. L.;
Ngidi, E. L.; Coyanis, E. M.; de Koning, C. B. Tetrahedron Lett. 2003, 44,
311. Whitehead, A.; Moore, J. D.; Hanson, P. R. Tetrahedron Lett. 2003,
44, 4275.
(2) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783.
(3) See, for example: Nicolaou, K. C.; Postema, M. H. D.; Claiborne,
C. F. J. Am. Chem. Soc. 1996, 118, 1565. Rainier, J. D.; Allwein, S. P. J.
Org. Chem. 1998, 63, 5310. Sturino, C. F.; Wong, J. C. Y. Tetrahedron
Lett. 1998, 39, 9623. Rainier, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron
Lett. 2001, 42, 179. Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron
(4) Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3, 2045.
(5) For a discussion see: Geissert, A. J.; Snyder, L.; Markham, J.; Diver,
S. T. Org. Lett. 2003, 5, 1793 and references cited.
(6) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153.
10.1021/ol034775z CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/13/2003

Scheme 1. Exploratory RCM Reactions of Vinyl Chlorides
Table 1. Ring-Closing Metathesis Reactions of Representative
Vinyl Chlorides7
Scheme 1. We were pleased to find that the RCM reactions
do indeed occur successfully in benzene at 65 °C using the
second generation Grubbs catalyst 2. With substrate 1, the
cyclization can be effected with 5 mol % of the catalyst to
afford the five-membered ring product 3 in good yield.
Increasing the catalyst loading to 20 mol % increased the
yield only slightly. It was found that by using 5 mol % of
the metathesis catalyst with substrate 4 the desired six-
membered-ring RCM product 5 was obtained but a substan-
tial amount of starting material remained. However, with 10
mol % of 2, vinyl chloride 5 is formed in high yield.
Increasing the amount of catalyst to 20 mol % produces only
a marginal increase in product yield. Therefore, subsequent
RCM reactions were performed by using 10 mol % of
catalyst 2 (vide infra).7,8
We have also examined the possibility of utilizing a vinyl
bromide in this process. Upon exposure of substrate 6 to
the reaction conditions, which were developed for the vinyl
chlorides, no reaction was observed (eq 1). It is possible here
that the vinyl bromide functionality in 6 reacts with the
Grubbs catalyst faster than the terminal alkene, producing
an unreactive Fischer-type carbene.
The scope of the vinyl chloride RCM reaction has been
explored with several additional substrates, and some of the
results are listed in Table 1. As can be seen, it is possible to
use the methodology to prepare a wide variety of five-, six-,
and seven-membered vinyl chloride-containing carbocyclic
and heterocyclic compounds in high yields. In addition, using
a 1,2-disubstituted olefin rather than a terminal one does not
seem to cause problems with the cyclization (cf. entries b
and c).
(7) General experimental procedure for RCM of vinyl chlorides: A
100-mL flask equipped with a condenser was flame dried in vacuo. The
vinyl chloride substrate (0.24 mmol) in dry benzene (60 mL) was added
and the solution was deaerated by bubbling argon through the mixture for
2 h. Second-generation Grubbs catalyst 2 (10 mol %) in 2 mL of dry benzene
was added through the condenser and the argon bubbling was continued
for an additional 30 min. The mixture was heated and stirred at 65 °C for
4-10 h until TLC showed the reaction was complete. The solvent was
removed in vacuo and the residue was purified by silica gel chromatography
to afford the desired metathesis product.
We have also briefly investigated the possibility of forming
larger rings by this process. Thus, exposure of vinyl chloride
7 to our optimized RCM conditions led to a complex mixture
rather than the desired eight-membered ring 8 (eq 2).
Moreover, all attempts to form a twelve-membered vinyl
chloride ring also failed.
(8) At room temperature no metathesis occurs, and at 50 °C the reaction
is very slow.
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Org. Lett., Vol. 5, No. 14, 2003

The metathesis products constructed by this methodology
have considerable potential for a wide range of further
transformations. Until recently, palladium-mediated couplings
of vinyl chlorides in most cases were not synthetically useful
processes.9 However, this situation has changed with the
recent important discovery of Fu and co-workers that using
tri-tert-butylphosphine as the metal ligand allows one to
efficiently utilize vinyl chlorides in Suzuki-Miyaura10a and
Negishi10b couplings. Thus, cyclization product 9 could be
arylated to afford 10 in high yield by using this methodology
(eq 3). In addition, it is also possible to convert vinyl
chlorides to the corresponding R-haloketones under mild
conditions.11 For example, using our recently reported
procedure,11 metathesis product 11 could be transformed to
R-chloroketone 12 in excellent yield using sodium hypochlo-
rite in a 5:2 mixture of acetone/acetic acid (eq 4).
generation Grubbs ruthenium catalyst 2 to afford cyclized
products in high yields. The process can be used to produce
a diverse series of five- to seven-membered carbocyclic and
heterocyclic systems. We are currently investigating further
variations of this methodology, as well as applications to
natural product total synthesis.
Acknowledgment. We are grateful to the National
Institutes of Health (GM-32299) for financial support of this
research.
In conclusion, we have shown that vinyl chlorides
participate in RCM reactions with use of the second
Supporting Information Available: Copies of proton and
carbon NMR spectra of metathesis products and compound
12. This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) For recent reviews see: Miyaura, N., Ed. Top. Curr. Chem. 2002,
219.
(10) (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020. (b) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
(11) VanBrunt, M. P.; Ambenge, R. O.; Weinreb, S. M. J. Org. Chem.
2003, 68, 3323 and references cited therein.
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