Efficient ring-closing metathesis of alkenyl bromides: The importance of protecting the catalyst during the olefin approach

Article abstract of DOI:10.1021/ja108253f

We present the first productive ring-closing metathesis reaction that leads to the construction of cyclic alkenyl bromides. Efficient catalysis employing commercially available Grubbs II catalyst is possible through appropriate modification of the starting bromoalkene moiety.

Full text of DOI:10.1021/ja108253f

Published on Web 10/11/2010
Efficient Ring-Closing Metathesis of Alkenyl Bromides: The Importance of
Protecting the Catalyst during the Olefin Approach
Michele Gatti, Emma Drinkel, Linglin Wu, Ivano Pusterla, Fiona Gaggia, and Reto Dorta*
Organic Chemistry Institute, UniVersity of Zurich (UZH), Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
Received September 13, 2010; E-mail: dorta@oci.uzh.ch
solution and in nearly stoichiometric quantity (>90% against an internal
Abstract: We present the first productive ring-closing metathesis
reaction that leads to the construction of cyclic alkenyl bromides.
Efficient catalysis employing commercially available Grubbs II
catalyst is possible through appropriate modification of the starting
standard) after the reaction was styrene. While the overall mechanism
by which GII decomposes is speculative at this point, the generation
of styrene (and the lack of reactivity between 2 and GII) strongly
points to a reaction scenario where initial cross metathesis of the
bromoalkene moiety.
unsubstituted olefin in 1 with the benzylidene moiety of GII preceeds
decomposition of the catalyst.10 This in turn would mean that the
alkenyl bromide unit only reacts irreversibly with the active ruthenium
species when it is forced into close proximity to the metal center.11
The advent of alkylidene-based ruthenium metathesis catalysts
featuring high functional group tolerance greatly contributed to the
affirmation of alkene metathesis as one of the most important tools
to manipulate a C-C double bond.1 In particular RCM (ring-closing
metathesis) has been widely explored and applied in the synthesis
of complex natural products.2 Less developed, but highly desirable,
are versions of this reaction in which one of the two olefins bears
heteroatom substituents. To date, a number of dienes containing
enol ethers and enamines have been studied,3 but good results in
RCM were only obtained with high catalyst loadings and the
applicability is restricted to a limited number of substrates. The
synthesis of cyclic alkenyl halides, which could subsequently
undergo an array of coupling reactions, represents another appealing
version of the RCM reaction. Pioneering work in this field has been
reported by the Weinreb group,4a,b who have shown that cyclic
chloroalkenes could indeed be generated, albeit high catalyst
loadings were again necessary for acceptable reactivity (10 mol
%). This methodology has more recently been employed by Grubbs
and Stoltz et al. in the successful synthesis of a specific natural
compound.4c,d Unfortunately, the more useful alkenyl bromide
substrates are known to be completely inactive with both Schrock-
type as well as first- and second-generation Grubbs-type catalysts.5,6
In this report, we describe our effort toward the synthesis of
carbo- and heterocyclic five-, six-, and seven-membered alkenyl
halides via the RCM reaction of the corresponding dienes. Specif-
ically, we show how appropriate protection of the starting alkenyl
halide group not only leads to efficient RCM of alkenyl chlorides
but also enables the unprecedented and highly efficient construction
of cyclic bromoalkenes.
Figure 1. Stoichiometric reactivity of model substrates 1 and 2.
Table 1. Influence of Olefin Substitution on Catalytic Activitya
mol %
GIIb
T
(°C)
t
(h)
yield
(%)c
entry
R1
R2
solvent
1 (1)
2 (3)
3 (4)
4 (5)
5 (6)
H
H
Me
H
H
Ph
2
2
2
2
2
benzene
benzene
benzene
benzene
benzene
60
60
60
60
60
24
24
24
0.5
24
0
0
70
>98 (90)
0
Me
Me
Ph
H
a All the reactions were performed with
a
0.1
M
substrate
concentration. The substrate was added via syringe to a solution of
catalyst preheated in an oil bath for 2 min. b For a screening of different
solvents and catalysts, see the Supporting Information. c Yields based on
NMR analysis. Isolated yield in parentheses.
Initial exploratory studies were carried out with malonate-derived
alkenyl bromide 1. As previously reported,4a,5 both GI (Grubbs I) and
GII (Grubbs II) were completely ineffective for the RCM of 1 as were
HovII (Hoveyda-Grubbs II) and BleII (Blechert II).7 To possibly gain
insight into what prevents catalytic turnover with 1, we mixed
equimolar amounts of 1 and GII in C6D6 and compared results with
a mixture of GII and the analogous substrate (2) that lacks the second
terminal olefin unit (Figure 1). Rather unexpectedly, NMR spectros-
copy of this latter mixture did not show appreciable amounts of
decomposition of GII (and of 2) over a period of 2 days, whereas
substrate 1 was able to completely destroy the precatalyst. During the
course of the reaction, a color change to red-brown was observed with
concomitant formation of a white precipitate which when analyzed
turned out to be clean SIMes ·HBr.8,9 Another byproduct identified in
Given these unexpectedly insightful stoichiometric studies, we
reasoned that, by simply introducing one or two substituents to the
terminal position of the bromoalkene, we could reduce its ability
to destroy the catalyst and be able to catalytically generate cyclic
bromoalkenes via RCM.12,13
As a first attempt, we tested a substrate featuring a geminal
dimethyl substitution (Table 1, entry 2) that proved to be unreactive
in RCM, most probably due to the low propensity of a tetrasub-
stituted olefin to approach the metal center and bind to it. In contrast,
the introduction of a single substituent Z to the bromine atom turned
out to be highly beneficial. In the presence of a methyl group (Table
1, entry 3) formation of a substantial amount of product was
observed from NMR analysis;14 when a substrate featuring a
Z-configured terminal phenyl group was employed, full conversion
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J. AM. CHEM. SOC. 2010, 132, 15179–15181 15179

C O M M U N I C A T I O N S
Table 2. RCM Reactions Generating Cyclic Alkenyl Bromides and
Chlorides
relevant and in line with the idea of correctly protecting the alkenyl
bromide during its approach to the metal, incorporation of a terminal
phenyl group E to the halide (Table 1, entry 5) did not lead to any
product formation under otherwise identical reaction conditions.15
The scope of the reaction was then explored with a wider range
of bromoalkene derivatives, and the results are summarized in Table
2. Overall, five-membered and especially six-membered rings were
generated in good to excellent isolated yields within short reaction
times. Indeed, less than 2 mol % of GII seem to suffice for efficient
ring closing as evidenced from data collected for substrate 10 (Table
2, entry 5). Vastly improved results as compared to data in the
literature4a were obtained when applying the same concept to the
construction of representative cyclic alkenyl chlorides 9a and 14a
(Table 2, entries 4 and 9). Likewise, the synthesis of six-membered
tetrasubstituted cyclic chloroalkenes 15a and 16a proceeded with
remarkable ease and in high yield when employing a higher catalyst
loading (Table 2, entries 10 and 11).16 Unfortunately, an attempt
to generate the analogous tetrasubstituted cyclic alkenyl bromide
gave only trace amounts of product. For the synthesis of seven-
membered rings (substrates 17-19), the disposition of the substit-
uents proved to be important and efficient catalysis was only
possible with substrates 18 and 19, where a stronger Thorp-Ingold
effect is to be expected (Table 2, entries 13 and 14).17 Indeed, when
trying to ring-close substrate 17, relatively clean conversion (50%
isolated yield) to the six-membered product 13a was observed,
meaning that an unusually efficient olefin isomerization step occurs
before the expected metathetical ring closure.18
The last two entries in Table 2 (15 and 16) again underline the
importance of correctly substituting the starting alkenyl bromide
and the strikingly different reactivity of the resulting diene, as both
E-configured olefins 19 and 20 did not generate the desired RCM
products.19
Figure 2. Proposed catalytic cycle for the RCM of bromoalkenes.
In conclusion, we have developed a catalytic method (Figure 2)
to access cyclic alkenyl bromides via the ruthenium-catalyzed ring-
closing metathesis reaction using synthetically useful catalyst
loadings of GII (Grubbs II). The starting diene compounds are
easily accessible and should make the present protocol attractive
as a methodology for the construction of more elaborate molecular
structures.
The concept of sterically protecting double bonds that would
otherwise irreversibly react and deactivate metathesis-active cata-
lysts should not be applicable to only alkenyl halides, and studies
aimed at developing this idea further are currently underway.
a All the reactions were performed using 0.16 mmol of substrate with
a 0.1 M substrate concentration except entries 11-13 (0.01 M). b Shelf
lives of all compounds at -25 °C are at least 6 months without
decomposition. c Isolated yield after column chromatography. d Reac-
tions performed in benzene gave slightly lower yields. The main product
of the reaction was compound 13a.
Acknowledgment. We thank the Alfred Werner Foundation
(R.D.), the Swiss National Foundation (L.W.), the Roche Research
Foundation (E.D.), and the University of Zurich (M.G., E.D.) for
financial support.
was observed and product 5a was obtained in 90% isolated yield
using 2 mol % of GII (Table 1, entry 4). Mechanistically most
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C O M M U N I C A T I O N S
(9) To our knowledge, this is the first example where a second-generation
ruthenium catalyst decomposes via formal loss of the NHC ligand. For
other decomposition pathways, see: (a) Samojlowicz, C.; Bieniek, M.; Grela,
K. Chem. ReV. 2009, 109, 3708. (b) Vougioukalakis, G. C.; Grubbs, R. H.
Chem. ReV. 2010, 110, 1746, and references cited.
Supporting Information Available: Experimental procedures and
NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
(10) It is commonly assumed that alkenyl halides react very rapidly with the
ruthenium center, giving rise to Fischer-type carbene moieties; see
discussion in ref 4a and: Macnaughtan, M. L.; Johnson, M. J. A.; Kampf,
J. W. J. Am. Chem. Soc. 2007, 129, 7708.
References
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R. H.; Stoltz, B. M. Tetrahedron 2010, 66, 4668. This paper indeed indicates
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RCM of the corresponding alkenyl chloride substrates.
(11) In a separate experiment, we made sure that compound 2 does not react
with an equimolar amount of tricyclohexylphosphine. This excludes a
reaction scenario where the phosphine liberated from GII during the initial
CM of 1 attacks the bromoalkene via elimination of HBr.
(12) Terminal substitution has been successfully used in the past to minimize
unwanted secondary metathesis activity during RCM. For the first example,
see: (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324. For
more recent, selected examples where the geometry of a terminal phenyl
or methyl group affects reaction yields, see: (b) Kirkland, T. A.; Lynn,
D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904. (c) Ro¨lle, T.; Grubbs,
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(13) This strategy would also generate, after each catalytic cycle, a propagating
species more stable than a methylidene. For a discussion regarding the
advantages of a stable propagating species in solution, see ref 12b.
(14) The main byproduct was unreacted starting material.
(15) Screening of reaction conditions (solvents, precatalysts etc.) can be found
in the Supporting Information.
(16) Reference 4d reports a 24% yield of 16a starting from the non-phenylated
malonate derivative of 16 when employing 5 mol % of an optimized second-
generation ruthenium precatalyst.
(17) In these cases, the approach of the alkenyl bromide seems to be more
difficult resulting in lower activity. For an early example on the Thorpe-
Ingold effect in RCM, see: Fu¨rstner, A.; Langemann, K. J. Org. Chem.
1996, 61, 8746.
(18) Probably, a correct and swift approach of the bromoalkene is not possible
in this case. For earlier studies that show how olefin isomerization can
occur before RCM, see: (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.;
Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204. (b) Schmidt, B.
Eur. J. Org. Chem. 2004, 1865, and references cited therein.
(19) While compound 6 did not show any apparent reactivity, substrates 20
and 21 partially decomposed with concomitant formation of trace amounts
of product (< 10%). A detailed investigation on catalyst and substrate
decomposition pathways is underway.
(5) For Grubbs II (GII), see ref 4 and b. For Schrock and Grubbs I (GI), see:
Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(6) For recent efforts to use alkenyl halides in CM, see: (a) Sashuk, V.;
Samojlowicz, C.; Szadkowska, A.; Grela, K. Chem. Commun. 2008, 2468.
(b) Macnaughtan, M. L.; Gary, J. B.; Gerlach, D. L.; Johnson, M. J. A.;
Kampf, J. W. Organometallics 2009, 28, 2880.
(7) See the Supporting Information for details.
(8) The identity of the counterion (Br- or Cl-) was established through
comparison of the 1H NMR signal of the imidazolinium proton with
authentic samples of SIMes · HCl and SIMes · HBr recorded in CDCl3 at
the same concentration. See the Supporting Information for spectra.
JA108253F
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