Ruthenium-catalyzed tandem enyne-cross metathesis-cyclopropanation: three-component access to vinyl cyclopropanes

Article abstract of DOI:10.1016/j.tetlet.2008.07.119

Substituted vinylcyclopropanes are prepared through a ruthenium-catalyzed, tandem three-component coupling between an olefin, alkyne, and diazoester. Grubbs' 2nd generation (NHC) ruthenium complexes in the presence of ethylene effect a stereoselective enyne-cross metathesis between alkynes and olefins to generate 1,3-substituted dienes. The slow introduction of diazoacetates to this reaction mixture then allows for the regioselective cyclopropanation of the resulting diene. When the olefin reaction partner is just ethylene (i.e., R′ = H), the tandem process is less efficient. In this case, the byproducts provide unique insight into possible catalyst decomposition pathways.

Full text of DOI:10.1016/j.tetlet.2008.07.119

Tetrahedron Letters 49 (2008) 5714–5717
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Tetrahedron Letters
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Ruthenium-catalyzed tandem enyne-cross metathesis–cyclopropanation:
three-component access to vinyl cyclopropanes
*
Ryan P. Murelli, Silvia Catalán, Michael P. Gannon, Marc L. Snapper
Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467-3860, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted vinylcyclopropanes are prepared through a ruthenium-catalyzed, tandem three-component
coupling between an olefin, alkyne, and diazoester. Grubbs’ 2nd generation (NHC) ruthenium complexes
in the presence of ethylene effect a stereoselective enyne-cross metathesis between alkynes and olefins
to generate 1,3-substituted dienes. The slow introduction of diazoacetates to this reaction mixture then
allows for the regioselective cyclopropanation of the resulting diene. When the olefin reaction partner is
just ethylene (i.e., R0 = H), the tandem process is less efficient. In this case, the byproducts provide unique
insight into possible catalyst decomposition pathways.
Received 1 July 2008
Accepted 15 July 2008
Available online 26 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Ruthenium alkylidenes 1–4 (Fig. 1) are well recognized and
widely used catalysts for olefin metathesis.1 To extend the syn-
thetic utility of these ruthenium complexes, recent efforts have
aimed at developing new, non-metathesis catalytic transforma-
tions with these ruthenium complexes.2,3 When combined with
olefin metathesis, these new ruthenium-catalyzed tandem pro-
cesses allow for the formation of multiple bonds in a single reac-
tion vessel that previously required several steps to accomplish.4
Recently, we reported that alkylidene 1 could effect the cyclo-
propanation of dienes generated from an enyne ring-closing
metathesis by addition of a diazo ester (Eq. 1).5 Using this proce-
dure, we were able to gain access to cycloalkenyl cyclopropanes di-
rectly from enynes. Given the importance of vinyl cyclopropanes as
reactive functionalities in variety of transformations,6 we reasoned
that further development of this process was warranted. Herein,
we describe a three-component, tandem enyne-cross metathesis/
cyclopropanation that allows for the preparation of a diverse array
of substituted vinyl cyclopropanes (Eq. 2).
MesN
Cl
NMes
Cl
MesN
Cl
NMes
Cl
MesN
Cl
NMes
Cl
PCy3
Cl
Me
Me
Ru
Ru
Ru
Ru
Cl
Ph
Ph
PCy3
PCy3
i-PrO
PCy3
1
2
3
4
Figure 1. Commercially available ruthenium-based olefin metathesis catalysts.
Several advancements are worth noting in the development of
this enyne-cross metathesis/cyclopropanation.7 For one, enyne-
ring-closing has been shown to be successful with ruthenium com-
plex 1; however, more active catalysts are typically required to
perform the enyne-cross metathesis (ECM). In addition, the cross
metathesis generally leads to a mixture of Z- and E-olefin isomers.8
When the enyne-cross metathesis is run in the presence of catalyst
2 under an atmosphere of ethylene, however, the E-selectivity of
the newly formed olefin can be improved significantly.9
enyne ring-closing metathesis/cyclopropanation
R2
Unfortunately, our initial enyne ring-closing metathesis/cyclo-
propanation studies indicated that NHC-complex 2 was ineffective
R1
R1
R
N2
ð1Þ
ð2Þ
R2
1, ethylene
PhH, 75 °C
X
X
as
a cyclopropanating agent under the conditions examined
X
n
n
(Scheme 1). The added diazoester was rapidly consumed leading
to significant quantities of maleate and fumarate,10 and the result-
ing diene formed in the enyne ring-closing metathesis at times
underwent a secondary cross metathesis to generate triene 11.
We assumed that alkylidene 2 (or derivative thereof) was capable
of cyclopropanating; however, the rapid dimerization of the diazo-
ester interfered with the desired mode of reactivity.
n
R
R
5
6
enyne cross-metathesis/cyclopropanation
R2
R2
R3
2, ethylene
R3
N2
R
R
R1
Δ
R
R1
7
R1
9
8
As shown in Scheme 2, when the NHC-alkyli dene 4 was used in
an enyne-cross metathesis between aromatic acetylene 7a and
octane, diene 12 was generated stereoselectively.11 By keeping
the concentration of the diazoacetate to a minimum, the desired
* Corresponding author. Tel.: +1 617 552 8096; fax: +1 617 552 1442.
E-mail address: marc.snapper@bc.edu (M. L. Snapper).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.119

R. P. Murelli et al. / Tetrahedron Letters 49 (2008) 5714–5717
5715
4 (10 mol %),
ethylene (1 atm),
PhMe, rt
N2
CO2Et
TsN
TsN
TsN
2, ethylene
PhH, 75 °C
TsN
CO2Et
n
-Hex
10
n-Hex
MeO
MeO
MeO
7a
12, 86%
8a (6 equiv.)
NTs
+
EtO2C
EDA (7 equiv.)
CO2Et
CO2Et
CO2Et
EtO2C
CO2Et
75 °C
11
CO2Et
-Hex
Scheme 1. Previous cyclopropanation results with alkylidene 2.
n
-Hex
n
13, 33%
9a
MeO
55% (1.9:1 dr)
diene cyclopropanation could compete effectively with the diazo-
ester dimerization. Slow addition of ethyl diazoacetate to this reac-
tion mixture at elevated temperatures converted diene 12 to a
vinyl cyclopropane 9a as a 1.9:1 mixture of diastereomers in 55%
isolated yield. While this is the first NHC ruthenium complex that
led to cyclopropanated products, significant quantities of diethyl
maleate and fumarate byproducts were also generated. Unfortu-
Scheme 2. Preliminary ECM/cyclopropanation results.
nately, these dienophilic side products reduced the yield of 9a by
consuming diene 12 through a competitive Diels–Alder reaction
(?13).12
Table 1
Tandem ECM/cyclopropanation
CO2R"
CO2R"
N2
4, ethylene
R
R
R'
R
R'
R'
Entry
1
Alkyne
Olefin
Product
Yield (%) (E:Z)
CO2Et
Ph
n-Hex
55–66 (1.7:1)
Ph
7b
8a
9a
n
-Hex
CO2Et
2
8a
8a
53–63 (1.9:1)
MeO
7a
n
-Hex
MeO
9b
CO2Et
3
4
<5
F3C
7c
n-Hex
F3C
9c
CO2Et
OTBS
8
7a
55 (1.9:1)
8b
OTBS
8
MeO
9d
CO2Et
OBn
6
5
6
7b
7b
46 (1.5:1)
Ph
8c
OBn
6
9e
CO2t-Bu
8a
8a
66–76 (1.9:1)
Ph
9f
n
-Hex
MeO2C
CO2Me
7
8
7b
25
Ph
9g
n
-Hex
CO2Et
n-Bu
Ph
45–50 (1:1)
n
-Bu
9h
7d
8d
Ph

5716
R. P. Murelli et al. / Tetrahedron Letters 49 (2008) 5714–5717
Our efforts to delineate the scope of this three-component cou-
pling process are summarized in Table 1. The tandem ECM/cyclo-
Ph
4 (5 mol%)
90 ˚C, ethylene;
Ph
+
CO2Et
ethyl diazoacetate
90 ˚C
propanation sequence works for
a range of aromatic and
30% yield
7b
13
Ph
aliphatic reaction partners, although some steric and electronic
limitations were observed. The cyclopropanation takes place
exclusively at the more sterically accessible 1,1-disubstituted ole-
fin over the 1,2-disubstituted olefin. In addition, while electron rich
and neutral aromatic acetylenes can be used successfully (entries 1
and 2), the electron poor p-trifluoromethyl substituted phenyl
acetylene 7c affords mainly the diene intermediate, with only trace
amounts of the desired cyclopropanated product (entry 3). The TBS
and benzyl protected alcohols 8b and 8c were also shown to be
amenable to these conditions (entries 4 and 5). For nearly all of
these substrates, there is a slight preference for the trans-substi-
tuted cyclopropyl isomer.13
Ph
Ph
CO2Et
CO2Et
Ph
Ph
CO2Et
14
15
16
4 (40 mol %)
Ph
7b
40% yield
ethylene, PhMe,
90 ˚C, 12 h
Ph
16
Scheme 3. Products arising from enyne-cross metathesis/cyclopropanations
between aromatic alkynes and ethylene.
Using t-butyl diazoacetate led to a slight increase in yields with
little change in stereoselectivity (entry 1 vs entry 6). In this case,
the additional steric hindrance of the bis-t-butyl maleate or fuma-
rate byproduct may slow down the Diels–Alder reaction. Con-
versely, the use of a diazo dimethyl malonate provided a lower
yield of the tandem product 9g. We reasoned that the highly elec-
tron-deficient byproduct resulting from dimerization of the diazo
precursor led to greater consumption of the diene intermediate
(entry 7).14 Aliphatic acetylenes can also be used along with aro-
matic olefins to give vinyl cyclopropanes in approximately 50%
overall yield (entry 8). In this case, the cyclopropanation step is less
stereoselective, perhaps due to the small steric difference between
the aliphatic chain and the vinyl group. In addition, if the excess
styrene is not converted to stilbene by warming the reaction with
a N2 purge before the slow addition of the diazoester, significant
quantities of the cyclopropanated styrene are also obtained.
When the enyne-cross metathesis/cyclopropanation was run
between aromatic alkynes and ethylene, the yield of the desired
vinyl cyclopropanated product was low.8i Scheme 3 illustrates
some of the products observed in this transformation. In addition
to the E- and Z-cyclopropanated diastereomers (13) and the
Diels–Alder cycloadducts 14, notable amounts of the regioisomeric
vinylcyclopropyl diastereomers 15 were also obtained. This is not
surprising, given the less hindered nature of the corresponding
diene. Less clear, however, was the origin of vinyl cyclopentene
16, which was isolated in approximately 5% yield.
Subsequent studies indicated that the addition of diazoacetate
was not necessary for the formation of vinyl cyclopentene 16. Fur-
thermore, when the catalyst loading was increased to 40 mol %
there was a corresponding increase in the yield of vinyl cyclopen-
tene 16 (40%). Also noteworthy was the loss of olefin metathesis
activity that corresponded to the generation of 16. Given these
observations, we suspect that the formation of 16 may be part of
a catalyst decomposition pathway unique to diene metatheses.15
Scheme 4 suggests a mechanism that accounts for the formation
of 16 at the expense of metathesis active ruthenium alkylidene 4.
In this alkylidene decomposition pathway, diene 17, generated
in the enyne-cross metathesis, reacts with vinyl alkylidene 18 to
produce divinyl metallacyclobutane 19. This intermediate could
undergo a retro-[2+2] to form the triene secondary cross metathe-
sis product (i.e., 11, Scheme 1) and the corresponding ruthenium
methylidene; however, a more facile [3,3]-sigmatropic rearrange-
ment (Cope rearrangement) could occur to provide intermediate
20. In this case, the Cope rearrangement is favored because the
phenyl substituents on diene 19 position the vinyl groups in a
bis-endo conformation that facilitates the strain-releasing ring
expansion. The resulting metallocyclooctadiene 20 can then isom-
erize to the corresponding metallocyclohexene 21, which can then
undergo a reductive elimination to generate vinyl cyclopentene 16
and a non-metathesis active ruthenium complex. In general, this
decomposition pathway may represent one of the challenges in
Ph
Ph
7b
4
PhMe, 90 °C, 12 h
Ph
Ph
17
Ph
16
red. elim.
- [Ru]
Ru
18
Ph
Ph
Ph
Ph
Cope
[Ru]
[Ru]
19
[Ru]
Ph
20
21
Ph
Cope
Ph
Ph
Ph
[Ru]
[Ru]
Ph
Scheme 4. Possible mechanism for the decomposition of metathesis catalyst 4 and
the formation of vinyl cyclopentene 16.
developing a general diene–diene cross metathesis as a useful
method for preparing trienes.
In summary, ruthenium-catalyzed tandem olefin metathesis/
cyclopropanations have been expanded to include enyne-cross
metatheses as a route to functionalized vinyl cyclopropanes. The
net result of this advancement is a three-component, one-pot
preparation of vinyl cyclopropanes from alkynes, alkenes, and dia-
zoacetates. Further investigations into the reaction mechanism as
well as catalyst decomposition pathways are underway.
Acknowledgments
The authors would like to thank the National Science Founda-
tion (CHE-0612875) for financial support. In addition, S.C.
acknowledges the Spanish government for a visiting student fel-
lowship. We are grateful to Materia for the gift of metathesis
catalyst.
Supplementary data
Supplementary data (experimental procedures and data on new
compounds are available (PDF)) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.07.119.
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partial conversion to the anticipated minor compound (cis).
not observed after
cross-metathesis
H
H
EtO2C
Ph
CO2Et
EtO2C
Ph
III (5 mol %),
H
octene (10 equiv)
n-Hex
n-Hex
neat, 90°C
Ph
KHMDS, THF,
rt; EtOH
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