Synthesis of Symmetrical Trisubstituted Olefins by Cross Metathesis

Article abstract of DOI:10.1021/ol0259793

(Matrix Presented) Trisubstituted alkenes have been prepared via intermolecular olefin cross-metathesis (CM) between α-olefins and symmetrically 1,1-disubstituted olefins using an imidazolylidene ruthenium benzylidene complex. Of particular interest is th

Full text of DOI:10.1021/ol0259793

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1939-1942
Synthesis of Symmetrical Trisubstituted
Olefins by Cross Metathesis
Arnab K. Chatterjee, Daniel P. Sanders, and Robert H. Grubbs*
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
rhg@its.caltech.edu
Received April 5, 2002
ABSTRACT
Trisubstituted alkenes have been prepared via intermolecular olefin cross-metathesis (CM) between r-olefins and symmetrically 1,1-disubstituted
olefins using an imidazolylidene ruthenium benzylidene complex. Of particular interest is the synthesis of isoprenoid/prenyl groups by a
simple solvent-free CM reaction with isobutylene. In addition, prenyl groups can also be installed by a cross-metathesis of 2-methyl-2-butene
with a variety of r-olefins at room temperature with low catalyst loadings.
Trisubstituted carbon-carbon double bonds are present in a
diverse set of organic molecules and the development of new
methods for their synthesis remains an ongoing challenge
in synthetic organic chemistry. A wide variety of methods
have been investigated to date, with Wittig olefinations being
the most common.1 However, the exclusive use of olefin
starting materials to generate trisubstituted olefins, instead
of using more reactive aldehyde functionalities, would
provide a method that is orthogonal to Wittig chemistry.
The olefin metathesis reaction has gained prominence in
synthetic organic chemistry as a reliable method for olefin
formation.2 The commercial availability of well-defined
single-component homogeneous catalysts, such as Mo-
(CHCMe2Ph)(NAr)[OCMe(CF3)2]2 1 developed by Schrock
et al.3 and ruthenium benzylidene catalyst (PCy3)2Cl2-
RuCHPh 2,4 has made the olefin metathesis reaction practical
for small molecule synthesis. In particular, ring-closing
metathesis (RCM) reactions have been widely utilized in the
construction of a variety of organic molecules.
The intermolecular variant of olefin metathesis, olefin
cross-metathesis (CM), has received less attention in the
literature due to a perceived lack of selectivity and olefin
stereoselectivity.5 However, renewed interest in this area has
led to the recent development of new methods in selective
CM. Most of this work has been made possible by a new
family of ruthenium metathesis catalysts similar to 2, where
a phosphine ligand has been replaced by a 1,3-dimesityl-
4,5-dihydroimidazolylidene ligand.6
(3) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; Dimare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875. (b) Bazan, G. C.;
Khosravi, E.; Schrock, R. R.; Feast, W. J.; Gibson, V. C.; O’Regan, M. B.;
Thomas, J. K.; Davis, W. M. J. Am. Chem. Soc. 1990, 112, 8378. (c) Bazan,
G. C.; Oskam, J. H.; Cho, H. N.; Park, L. Y.; Schrock, R. R. J. Am. Chem.
Soc. 1991, 113, 6899.
(4) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Schwab, P.; Grubbs, R. H.; Ziller,
J. W. J. Am. Chem. Soc. 1996, 118, 100. (c) Belderrain, T. R.; Grubbs, R.
H. Organometallics 1997, 16, 4001.
(5) Leading references using 1 and 2 in CM: (a) Crowe, W. E.; Goldberg,
D. R. J. Am. Chem. Soc. 1995, 117, 5162. (b) Brummer, O.; Ruckert, A.;
Blechert, S. Chem. Eur. J. 1997, 3, 441. (c) Blackwell, H. E.; O’Leary, D.
J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 58.
(1) (a) Burke, S. D.; Hong, J.; Lennox, J. R.; Mongin, A. P. J. Org.
Chem. 1998, 63, 6952. (b) Breit, B.; Zahn, S. K. Angew. Chem., Int. Ed.
1999, 38, 969. (c) Wang, Q.; Wei, H.; Schlosser, M. Eur. J. Org. Chem.
1999, 3263.
(2) (a) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013. (b) Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (c) Kotha, S.;
Sreenivasachary, N. Ind. J. Chem. B 2001, 40, 763.
10.1021/ol0259793 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/04/2002

Scheme 1. CM of Symmetrical Disubstituted Olefins
The high activity of these catalyst systems now allows
R-olefins as well as 1,2-disubstiuted olefin starting materials
for CM of R,â-unsaturated carbonyl olefins,7 vinylphospho-
nates,8 and vinylsulfones.9 In addition, we also reported the
cross-metathesis of terminal olefin with 1,1-disubstiuted
olefins.10 Unfortunately, these reactions exhibited low olefin
stereoselectivity and required moderately high catalyst load-
ings and reaction temperatures. In addition, only methyl
groups as the second geminal substituent were reported in
our initial work. We anticipated that the use of identical
substituents on the geminal carbon would expand the
substrate scope, without being complicated by the issue of
poor stereoselectivity. In this Letter, we report the convenient
CM of symmetrical 1,1-disubstituted olefins with a variety
of CM partners, including an isoprenoid synthetic route by
the homologation of R-olefins with isobutylene or 2-methyl-
2-butene.11
(entry 1). Also, the reactions tolerate substrates that could
Table 1. Cross-Metathesis with Isobutylene Using 3
Our initial work began with the cross-metathesis of
isobutylene with terminal olefins (Table 1).12 These reactions
offer a convenient alternative to the use of Ph3PdC(CH3)2
and the corresponding aldehyde to form prenyl functionality.
Prenyl groups are a ubiquitous structural element in many
natural products13 and are also frequently employed in ene
chemistry. For example, the reaction works well with simple
ring close as demonstrated in the homoallylic hepatadiene
case (entry 2). Senecioic acid derivations are also readily
available from the CM reaction with the corresponding
acrylate ester (entry 3). In addition, a protected secondary
allylic alcohol is well tolerated and provides the CM product
in quantitative yield (entry 5). With these results in hand,
we investigated other symmetrically substituted olefins and
found that both methylenecyclohexane and 2-methylene-1,3-
dibenzoate work well as CM partners with 5-hexenyl acetate
(Scheme 1). Since the 1,1-disubstituted olefin does not
dimerize, it can be fully recovered and used in subsequent
CM reactions.
Interestingly, we did observe a background dimerization
of a small amount of isobutylene to tetramethylethylene, but
this did not affect the CM efficiency. The CM efficiency is
surprising since the catalyst loadings are very low relative
to the amount of bulk olefin in the reaction, with an effective
catalyst loading of 0.0001 mol %. The inability of the 1,1-
disubstituted olefin to readily homodimerize allows it to serve
(6) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543.
(7) (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783. (b) Choi, T.-L.; Chatterjee, A. K.; Grubbs,
R. H. Angew. Chem., Int. Ed. 2000, 39, 1277. (c) Choi, T.-L.; Lee, C. W.;
Chatterjee, A. K.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 10417.
(8) Chatterjee, A. K.; Choi, T.-L.; Grubbs, R. H. Synlett 2001, 1034.
(9) Grela, K.; Bieniek, M. Tetrahedron Lett. 2001, 42, 6425.
(10) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751.
(11) Some of these olefins have been demonstrated in other CM systems
from this group, see: ref 7c and Goldberg, S. D.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 807.
(12) Typical isobutylene CM procedure: To an oven dried, 100 mL
Fischer-Porter bottle with Teflon stir bar, ruthenium metathesis catalyst
(15.0 mg, 0.018 mmol, 1.0 mol %) was added. The bottle was capped with
a rubber septum and flushed with dry nitrogen and cooled to -78 °C (or
temperature sufficient to freeze substrate). Substrate (1.0 mmol) was injected
into the bottle. Once the substrate was frozen, a pressure regulator was
attached to the bottle. The bottle was evacuated and backfilled with dry
nitrogen 3 times. Subsequently, isobutylene (5-10 mL, 50-100 equiv) was
condensed into the bottle. The bottle was backfilled to ∼2 psi with nitrogen,
sealed, and allowed to slowly warm to room temperature, at which time it
was transferred to an oil bath at 40 °C. After stirring for 12-18 h, the
bottle was removed from the oil bath and allowed to cool to room
temperature. The isobutylene was slowly vented off at room temperature
until the pressure apparatus could be safely disassembled. The remaining
mixture was taken up in organic solvent for subsequent silica gel
chromatography and/or spectrographic characterization.
(13) The following paper provides an excellent application of the methods
described in this Letter in an allyl to prenyl conversion, see: Spessard, S.
J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943.
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Org. Lett., Vol. 4, No. 11, 2002

as both a reaction solvent and as an effective cross partner.
These factors allow for selective CM to the trisubstituted
olefinic product.
methods (entry 3). Substituted allylbenzenes (entries 4 and
5) are also well tolerated in the reaction. Particularly
interesting is the CM of phenolic allylbenzene (entry 5),
where CM is a convenient alternative to aromatic Claisen
chemistry that would initially require the synthesis of tertiary
phenoxy ether. One general note is the ease of performing
these reactions: no solvent is required, all reagents are
handled on the bench, and only ambient temperatures are
needed to afford CM products in excellent yield.
At this point, we were interested in understanding the
excellent CM observed with 2-methyl-2-butene and decided
to investigate the likely propagating species in these reac-
tions. While the reaction of 3 with isobutylene produces the
ruthenium isopropylidene and styrene as the kinetic prod-
ucts,18 reaction with 2-methyl-2-butene results in the exclu-
sive formation of the ruthenium ethylidene complex and â,â-
dimethyl styrene as the kinetic products.19 These results
indicate that the general reaction pathway for 2-methyl-2-
butene cross-metathesis is that shown in Scheme 2.
However, the background dimerization of isobutylene to
tetramethylethylene prompted us to investigate the use of
2,3-dimethyl-2-butene as a more convenient CM partner,
since it is a liquid at room temperature (bp 73 °C).
Unfortunately, this did not provide a synthetically useful
amount of CM product, but we were able to use 2-methyl-
2-butene (bp 35-38 °C) as a useful CM partner. In fact, we
were surprised to see very efficient CM with this substrate
at room temperature (Table 2).14 This reaction represents the
Table 2. Cross Metathesis with 2-Methyl-2-butene Using 3
Scheme 2. Proposed 2-Methyl-2-butene CM Reaction
Pathway
first CM reaction that involves the productive CM of
trisubstituted olefins at room temperature.15-17 Our previous
results required higher catalyst loadings (5 mol %) and
refluxing CH2Cl2 to obtain productive CM yields. The
substrate scope in these CM is quite general, including
allylphosphonates (entry 1) which allow for an efficient
synthesis of prenyl diene reagents. In addition to amenability
of an electron-deficient styrene (entry 2), unprotected alde-
hydes work well, allowing direct orthogonality to Wittig
(14) Typical 2-methyl-2-butene procedure (Table 2, entry 4): Pen-
tafluoroallylbenzene (225 µL, 1.468 mmol) from Aldrich Chem. Co. and
2-methyl-2-butene (3.2 mL) from Aldrich Chem. Co. were added simul-
taneously via syringe to a stirring solution of catalyst 3 (1.25 mg, 0.015
mmol, 1.0 mol %) under a nitrogen atmosphere. The flask was allowed to
stir at room temperature for 12 h. The reaction mixture was then reduced
in volume to 0.5 mL and purified directly on a silica gel column (2 × 10
cm), eluting with 20:1 hexane:ethyl acetate to provide the cross-metathesis
product (316 mg, 1.337 mmol, 91% yield) as a viscous oil.
(15) Thermodynamically controlled disproportionation of 2-methyl-2-
butene and the step-growth ADMET polymerization of 2-methyl-1,5-
hexadiene have been reported with 1: Konzelman, J.; Wagener, K. B.
Macromolecules 1995, 28, 4686.
(16) While the ruthenium benzylidene 2 does not react with trisubstituted
olefins, the more reactive ruthenium enoic carbene (Cl2(PCy3)2RudCHCO2-
Cy) undergoes one turnover with 2-methyl-2-pentene to generate the
ruthenium propylidene and dimethyl-substituted cyclohexyl acrylate. Ulman,
M.; Belderrain, T. R.; Grubbs, R. H. Tetrahedron Lett. 2000, 41, 4689.
(17) Metathesis depolymerization of polyisoprene has been previously
reported with 3: Craig, S. W.; Manzer, J. A.; Coughlin, E. B. Macromol-
ecules 2001, 34, 7929.
Due to the higher reactivity of terminal olefins toward CM,
a significant portion of the terminal olefin may homodimerize
before the CM reaction with 2-methyl-2-butene can compete
(represented by R1 ) R2). Cross-metathesis with 2-methyl-
(18) The ruthenium isopropylidene was eventually consumed and finally
only ruthenium methylidene was observed. Ruthenium isopropylidene: 31P
NMR (C6D6): δ ) 19.94 (s). 1H NMR (C6D6): δ ) 2.85 (s, 6H, ortho
CH3), 2.57 (s, 6H, ortho CH3), 2.26 (s, 6H, RudC(CH3)2), 2.21 (s, 3H,
para CH3), 2.14 (s, 3H, para CH3). For complete spectroscopic characteriza-
tion of the ruthenium methylidene, see ref 6b.
(19) The ruthenium ethylidene was confirmed by independent generation
of the complex by reaction of 3 with cis-2-butene or propene. 31P NMR
1
(C6D6): δ ) 29.05 (s). H NMR (C6D6): δ ) 19.03 (q, J ) 5.7 Hz, 1H,
RudCHCH3), 2.81 (s, 6H, ortho CH3), 2.57 (s, 6H, ortho CH3), 2.18 (s,
3H, para CH3), 2.10 (s, 3H, para CH3), 1.91 (d, J ) 5.7 Hz, 3H,
RudCHCH3). This is consistent with the results shown with 2-methyl-2-
pentene and Cl2(PCy3)2RudCHCO2Cy. See ref 16.
Org. Lett., Vol. 4, No. 11, 2002
1941

2-butene produces the ruthenium ethylidene and the gemi-
nally dimethyl-substituted product. Depending upon the
nature of R2, this trisubstituted olefin may be kinetically
resistant to further metathesis. The ruthenium ethylidene
reacts with another equivalent of olefin to regenerate the
appropriate ruthenium alkylidene and release a methyl-
substituted olefin. In the case where R1 ) H or CH3, this
volatile propene or 2-butene boils off to effectively remove
the methyl groups from the reaction and drives the reaction
toward the desired product.20 If significant amounts of the
terminal olefin have homodimerized, methyl-substituted
olefins (R1 ) R2) may be produced in this step which are
gradually converted to the thermodynamically favored and
desired geminally dimethyl-substituted olefin in subsequent
cycles. Higher molecular weight homologues of 2-methyl-
2-butene such as 2-methyl-2-pentene and 2-methyl-2-hexene
may be used as well; however, the heavier fragments are
more difficult to drive out of the system at room temperature,
resulting in a larger fraction of ethyl- and propyl-substituted
products. For certain olefins, such as the allylic benzoate
(entry 5, Table 1), CM with 2-methyl-2-butene results in a
6:1 mixture of dimethyl- and methyl-substituted products
which cannot be driven to produce the desired cross-product
in high conversion.21 For these olefins, CM with isobutylene
is the better route to the desired cross-product.
Unlike the examples shown in Table 1, when it is
unfavorable for the olefin (such as acrylates) to cross onto
the ruthenium, a second reaction pathway, illustrated in
Scheme 3, is primarily responsible for the observed product
distribution. In this system, the 2-methyl-2-butene is the more
reactive olefin and crosses onto the catalyst to produce the
ruthenium ethylidene complex. This can react with the
terminal olefin to produce a methyl-substituted olefin and
ruthenium methylidene. The methylidene can react with the
large excess of 2-methyl-2-butene to produce isobutylene and
regenerate the ethylidene. In this pathway, the isobutylene
boils off and effectively removes the geminal methyl groups
from the reaction, resulting in the preferential generation of
Scheme 3. Proposed CM Reaction Pathway with Poor Olefins
methyl-substituted olefin. With these olefins, the 2-methyl-
2-butene may serve as practical substitute for propene or
2-butene in CM. This pathway is exemplified by the CM of
n-butyl acrylate with 2-methyl-2-butene in which trans-n-
butyl crotonate is produced in 83% conversion by 1H NMR.
In conclusion, the cross-metathesis reactions between
symmetrical disubstituted olefins and terminal olefins em-
ploying ruthenium alkylidene 3 have been presented. Of
particular interest is the convenient conversion of terminal
olefins to prenyl groups. This method allows for an efficient
one-step formation of trisubstituted olefins under mild
reaction conditions and low catalyst loadings and further
demonstrates the utility of olefin metathesis in organic
synthesis.
Acknowledgment. The authors would like to thank Dr.
Eric F. Connor, Dr. F. Dean Toste, Dr. Jennifer A. Love,
John P. Morgan, and Tina M. Trnka for useful discussions
and encouragement. Support has been generously provided
by the National Institutes of Health.
(20) In fact, trace amounts of the 1,2-disubstiuted olefin (<5%) are
1
detectable by H NMR in the reactions with 2-methyl-2-butene.
(21) Column chromatography yielded a 6:1 ratio of dimethyl-substituted
to methyl-substituted cross-products. Resubjection of the product mixture
to CM conditions with 2-methyl-2-butene failed to improve the conversion
of the dimethyl-substituted product.
OL0259793
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Org. Lett., Vol. 4, No. 11, 2002