Ruthenium-catalyzed olefin cross metathesis of styrenes as an alternative to the Heck and cross-coupling reactions

Article abstract of DOI:10.1002/1615-4169(200208)344:6/7<634::AID-ADSC634>3.0.CO;2-K

The use of olefin cross metathesis as a method for the formation of styrenyl-olefins is described using allylic substituted olefins and electron-deficient olefins. These methods provide an orthogonal method to alternative olefination strategies, such as the Heck reaction. These methods have also been employed in the total synthesis of 3-flavanols.

Full text of DOI:10.1002/1615-4169(200208)344:6/7<634::AID-ADSC634>3.0.CO;2-K

COMMUNICATIONS
Ruthenium-Catalyzed Olefin Cross Metathesis of Styrenes as an
Alternative to the Heck and Cross-Coupling Reactions
Arnab K. Chatterjee, F. Dean Toste, Tae-Lim Choi, Robert H. Grubbs*
Arnold and Mabel Beckman Laboratories for Chemical Synthesis, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, California 91125, USA
Fax: ( ‡ 1)-626-564-9297, e-mail: rhg@caltech.edu
Received: March 26, 2002; Accepted: May 25, 2002
employing olefin cross metathesis as an alternative entry
Abstract: The use of olefin cross metathesis as a
method for the formation of styrenyl-olefins is
described using allylic substituted olefins and elec-
tron-deficient olefins. These methods provide an
orthogonal method to alternative olefination strat-
egies, such as the Heck reaction. These methods
have also been employed in the total synthesis of 3-
flavanols.
into this class of molecules (Scheme 1, equation 2).
Notably, this reaction should be amenable to utilizing
simple olefins as coupling partners and as such should
circumvent some of the aforementioned limitations.
Olefin metathesis has developed into a highly useful
reaction for the synthesis of complex organic molecules
by ring-closing metathesis (RCM) and ring-opening
metathesis polymerization (ROMP). Due to the com-
mercial availability of well-defined single component
catalysts Mo(CHCMe2Ph)(NAr)[OCMe(CF3)2]2 (1)[3]
and (PCy3)2Cl2RuCHPh (2),[4] organichcemists have
subjected highly valuable substrates, in many cases
synthesized in multi-step processes, to RCM and ROMP
reactions. On the other hand, olefin cross metathesis
(CM) has been underutilized when compared to other
Keywords: cross metathesis; 3-flavanols, N-hetero-
cyclic carbene (NHC) ligands; homogeneous catal-
ysis; ruthenium; styrenes
Functionalized styrenes are important building blocks metathesis processes and this is due primarily to the lack
for organicsynthesis. Therefore, preparation of these
of product selectivity and olefin stereoselectvity.[5]
compounds must allow for variation in both the However, styrenes represent one of the classes of olefins
aromaticand olefinicportions of the styrene. Since the
used in CM with ill-defined catalyst systems,[6] 1[7] and
olefin often undergoes further manipulation, it is 2,[8] because of high trans selectivity in the cross product
imperative that the alkene geometry is controlled during and the slow dimerization of styrene to stilbene,
the coupling reaction. The Heck reaction,[1] and cross- allowing for selective cross-coupling. In all these cases,
coupling reactions such as the Suzuki reaction,[2] have an excess of styrene was used in the reaction to consume
often been employed because of the availability of aryl as much terminal olefin as possible. However, CM
halides and boronic acids and because of excellent products were only obtained in moderate yields and
control of the olefin geometry (Scheme 1, equation 1). only terminal olefins are employable in CM with 1 and 2.
However, the latter is often limited by access to the Therefore, increasing the efficiency and substrate scope
coupling partners (vinyl halides and triflates). On the of styrene CM reactions would be advantageous in
other hand, the Heck reaction employs simple olefins as organicsynthesis as a viable alternative to Heck and
coupling partner; however, the reaction operates best other cross-coupling methods. With the recent advent of
with olefins substituted with electron-withdrawing imidazolylidene-based catalysts systems, such as 3, there
groups. The commercial availability of a large number has been an expanded set of reports of successful CM. In
of styrenes prompted us to examine the possibility of fact, the range of electron-deficient olefins that partic-
ipate in CM with 3 now include a,b-unsaturated carbon-
yl-containing olefins,[9] vinylphosphonates,[10] vinylsul-
fones,[11] and perfluorinated alkane[12] containing olefins.
With these successes in hand, we wished to investigate
styrene CM with catalyst 3.
To this end, we examined the cross metathesis
reaction of styrene with a variety of cross partners using
ruthenium alkylidene 3 (Scheme 2). Reaction of styrene
with 2 equivalents of homoallylicbenzoate 4, catalyzed
by 5 mol % of 3, affords the substituted styrene 5 in 81%
X
Br
X
B(OH)2
X
Br
(1)
(2)
X
X
Scheme 1. Alternative styrene olefination strategies.
634
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/02/3446+7-634 637 $ 17.50-.50/0
Adv. Synth. Catal. 2002, 344, No. 6+7

Ruthenium-Catalyzed Olefin Cross Metathesis of Styrenes
COMMUNICATIONS
N
N
Cl
Ru
3
Ph
Cl
PCy3
O
5% 3
5% 3
O
O
OBz
5
7
6
(81%)
(71%)
4
O
OBz
Scheme 2. Initial styrene CM using 3.
Table 1. Styrene cross metathesis with catalyst 3 (5 mol%).
yield as a single olefin isomer. The compatibility of the
benzoate functionality that may eliminate using basic
Wittig conditions is another advantage of the CM
method to these compounds. Similarly, reaction of ketal
6 with styrene produced cinnamyl ketone 7 in 71% also
as a single olefin isomer. Notably, this is the first example
of styrene CM in the presence of a fully substituted
allylic carbon atom, and does not affect the course of the
reaction. This prompted us to examine the cross meta-
thesis reaction of olefins bearing allylic substituents
which would not be tolerated in the Heck and cross-
coupling reactions, providing direct orthogonality to
those methods.
Allylic halides are not tolerated in the Heck and cross-
coupling reactions because of their propensity to under-
go ionization by palladium(0). On the other hand,
reaction of styrene with cis-butene-1,4-dichloride (2
equiv.), catalyzed by 5 mol % of 3, produced trans-
cinnamyl chloride 8 in 93% yield without any ionization
of the chloride (Table 1). Notably, the analogous
reaction catalyzed by the ruthenium bis-phosphine
catalyst 2 produced 8 in only 23% yield, and further
demonstrates the enhanced catalytic activity of 3. The
reaction can be extended to the production of cinnamyl
acetates. For example, 5 mol % of 3 catalyzes the
Isolated Yield
Styrene
Product
(E:Z ratio)[a]
Coupling Partner
Cl
Cl
93%
>20:1
8
Cl
AcO
OAc
83%
>20:1
9
MeO
OAc
MeO
AcO
AcO
OAc
OAc
81%
>20:1
10
OAc
OAc
93%
>20:1
11
Br
Br
Br
O
O
O
OEt
98%
>20:1
12
OEt
Br
O
99%
>20:1
13
14
N
N
OAc
45%
>20:1
OAc
3
3
[a] Determined by 1H and 13C NMR.
reaction of cis-butene-1,4-diacetate (2 equiv.) with 4- discovered that heteroaromatic compounds are also
methoxysytrene and 2-vinylnaphthelene to produce compatible for catalytic CM with 3, in the CM of 2-
cinnamyl acetates 9 and 10 in 83% and 81% yield, vinylpyridine with 5-hexenyl acetate to form 14 in
respectively. Substitution of a halide on the aromatic moderate yield, despite the ability of pyridine to serve as
ring of the styrene is also incompatible with the an excellent ligand for these catalytic complexes.[14]
palladium(0) methods because of the competing oxida-
This also prompted us to examine the use of ortho-
tive addition into the aryl-halide bond. In sharp contrast, alkoxysubstituted styrenes inCM. Similartothepyridine
the reaction of 4-bromosytrene with cis-butene-1,4- result described in Table 1, ortho-alkoxy groups in the
diacetate, catalyzed by 5 mol % of 3, afford 11 in 93% benzylidene have been observed to coordinate to the
yield as a single olefin isomer.
ruthenium center, and these substrates also have the
We also examined the cross metathesis of reaction of potential complication of catalyst inhibition.[15] We were
styrene with electron-poor olefins traditionally em- pleased to find that the reaction of 2-acetoxy-b-methyl-
ployed in the Heck reaction.[13] For example, 5 mol % of styrene (15a) with ethyl acrylate, catalyzed by 5 mol % of
3 catalyzes the reaction of 4-bromostyrene with ethyl 3, proceeded smoothly to afford cinnamate 16 in 87%
acrylate to afford ethyl cinnamate 12 in 98% yield as a yield (Scheme 3). Similarly, reaction of ortho-silyloxys-
single olefin isomer, and demonstrates a direct CM tyrene 15b with 1,4-cis-butene diacetate produced 17 as a
route to this compound. In addition, vinyl ketones are single olefin isomer in 94% isolated yield demonstrating
excellent CM partners with styrene as demonstrated in the compatibility of several different phenolic protecting
the quantitative CM to enone 13. Surprisingly, we groups to the CM conditions.
Adv. Synth. Catal. 2002, 344, 634 637
635

Arnab K. Chatterjee et al.
COMMUNICATIONS
AcO
CO2Et
5% 3
OAc
OAc
CO2Et
5% 3
OR
OTBS
OAc
15a R = Ac
b R = TBS
17 (94%)
16 (87%)
Scheme 3. ortho-Phenol cross metathesis.
OMe
OMe
5 mol % 3
R'
MeO
OTBS
R
MeO
OTBS
18
20a R = 3,4-OMe (82%)
b R = 2-OMe (97%)
R
19a R = 3,4-OMe, R' = H
b R = 2-OMe, R' = Me
AD-mix-β
OMe
OMe
OH
OH
MeOH, HCl
MeO
O
OH
MeO
OTBS
R
R
22a R = 3,4-OMe (74%, 3.5:1 dr)
b R = 2-OMe (85%, 15:1 dr)
21a R = 3,4-OMe (86%)
b R = 2-OMe (94%)
Scheme 4. Cross metathesis route to 3-flavinols.
Experimental Section
With these results in hand, we examined application of
this method to the synthesis of 3-flavanols
(Scheme 4).[16] To this end, reaction of allylbenzene 18
with 3,4-dimethoxystyrene 19a, catalyzed by 5 mol % of
3 afforded 20a in 82% yield as a single trans olefin
isomer. Similarly, the reaction of b-methylstyrene 19b
with 18 produced 20b in 97% yield. Sharpless asym-
metricdihydroxylation of propenes 20a and 20b, with
AD-mix-b, afforded diols 21a and 21b in 86% and 93%
yield, respectively. Finally, reaction of the diols with
methanolic hydrochloric acid produced the flavanols in
good yields.[17] The 3,4-dimethoxyphenyl-substituted
flavanol (permethylcatechin) 20a was produced as a
3.5:1 mixture of trans:cis diastereomers. On the other
hand, the 2-methoxyphenyl group produced the flava-
nol with significantly better distereoselectivity (15:1).
These reactions provide a method for synthesizing a
large set of flavanols by employing other commercially
available styrene CM partners.[18]
In conclusion, we have demonstrated that the N-
heterocyclic carbene-based ruthenium complex 3 effi-
ciently catalyzes the cross-coupling of styrenes with a
variety of substituted olefins. As such, the cross-meta-
thesis reaction produces substituted styrenes with
excellent control of olefin geometry from readily
available starting materials. Furthermore, the cross
metathesis reaction is tolerant of aryl and allylic halides
which is complimentary to the Heck and cross-coupling
reactions.
General Procedures
Analytical thin-layer chromatography (TLC) was performed
using silica gel 60 F254 precoated plates (0.25 mm thickness)
with a fluorescent indicator. Flash column chromatography
was performed using silica gel 60 (230 400 mesh) from EM
Science. All other chemicals were purchased from the Aldrich
or TCI America and used as delivered unless noted otherwise.
CH2Cl2 was purified by passage through a solvent column prior
to use. Catalyst 3 was stored and manipulated on the bench.
NMR spectra were recorded on a Varian Mercury 300 MHz
NMR spectrometer.
Representative Cross Metathesis Procedure (for
Compound 17)
cis-2-Butene-1,4-diacetate from TCI America (95 mL,
0.51 mmol, 2.0 equiv.) was added via syringe to a stirring
solution of 3 (15 mg, 0.018 mmol, 5.7 mol %) and 2-tert-
butyldimethylsilyloxy-b-methylstyrene (76 mg, 0.31 mmol,
1.0 equiv.) in CH2Cl2 (2.0 mL, 0.15 M in styrene) under a
nitrogen atmosphere. The flask was fitted with a condenser and
refluxed under nitrogen for 12 hours. The reaction mixture was
then reduced in volume to 0.5 mL and purified directly on a
silica gel column (2 Â 10 cm), eluting with 20:1 hexane:ethyl
acetate to provide cross product 17 (Rf ˆ 0.51 in 9:1 hex-
ane:ethyl acetate) as a viscous oil; yield: 88 mg (0.29 mmol,
94%).
636
Adv. Synth. Catal. 2002, 344, 634 637

Ruthenium-Catalyzed Olefin Cross Metathesis of Styrenes
COMMUNICATIONS
[9] A. K. Chatterjee, J. P. Morgan, M. Scholl, R. H. Grubbs,
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[10] A. K. Chatterjee, T.-L. Choi, R. H. Grubbs, Synlett 2001,
1034.
[11] K. Grela, M. Bieniek, Tetrahedron Lett. 2001, 42, 6425.
[12] S. Imhof, S. Randl, S. Blechert, Chem. Commun. 2001,
1692.
[13] Similar CM partners have been employed in a sequential
metathesis and hydrogenation process: J. Louie, C. W.
Bielawski, R. H. Grubbs, J. Am. Chem. Soc. 2001, 123,
11312.
[14] M. S. Sanford, J. A. Love, R. H. Grubbs, Organometallics
2001, 20, 5314.
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[1] I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100,
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Adv. Synth. Catal. 2002, 344, 634 637
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