Isomerizing ethenolysis as an efficient strategy for styrene synthesis

Article abstract of DOI:10.1002/chem.201301336

A shrinking chain: A bimetallic system consisting of [{Pd(μ-Br)(tBu ₃P)}₂] and a ruthenium metathesis catalyst has been found to efficiently promote the cross-metathesis between substituted alkenes and ethylene, while continuously migrating the double bond along the alkenyl chain (see scheme). When alkenylarenes, such as the natural products eugenol, safrol, or estragol, were treated with this catalyst under an ethylene atmosphere, they were cleanly converted into the corresponding styrenes and propylene gas. Copyright

Full text of DOI:10.1002/chem.201301336

COMMUNICATION
DOI: 10.1002/chem.201301336
Isomerizing Ethenolysis as an Efficient Strategy for Styrene Synthesis
Sabrina Baader, Dominik M. Ohlmann, and Lukas J. Gooßen*[a]
Functionalized styrenes are valuable building blocks for
the synthesis of pharmaceutically active compounds,[1] fine
chemicals,[2] and polymers.[3] Classically, styrenes are ac-
cessed by elimination reactions, carbonyl alkenylation (by
using phosphorus-, silicon-, or titanium-based reagents), or
the partial reduction of terminal alkynes.[4] Contemporary
methods[5] for the synthesis of functionalized styrenes in-
clude transition-metal-catalyzed cross-couplings of aryl elec-
trophiles with vinyltin,[6] -silicon,[7] or -boron reagents,[8] or
of arylmagnesium[9] or -boron reagents[10] with vinyl electro-
philes, as well as Heck reactions of aryl electrophiles with
ethylene or its synthons.[11] However, all of these established
synthetic methods have inherent limitations such as the for-
mation of large quantities of waste salts resulting from the
use of aryl halide substrates or stoichiometric amounts of or-
ganometallic reagents.
In many cases, arenes with longer alkenyl chains, particu-
larly allylarenes, are more easily accessible than their vinyl
counterparts.[12,13] Several allylarenes are available from nat-
ural sources, for example, eugenol, safrol, estragol, or meth-
yleugenol.[14] A potential method to tap into this substrate
class as a resource for the synthesis of valuable, functional-
ized styrenes would be to first migrate the double bond into
conjugation with the arene, and
strates for cross-metathesis, and there are only a few reports
of successful ethenolysis reactions.[17]
A one-pot process for the isomerization and ethenolysis
of alkenylarenes with orthogonal tandem catalysis[18] ap-
peared even further out of reach. The recent discovery that
the dimeric palladium(I) complex [{PdACTHNUTRGNEUNG
(m-Br)tBu3P}2][19] is a
uniquely active isomerization catalyst,[20] which retains its
activity in the presence of state-of-the-art alkene metathesis
catalysts without lessening their activity, finally set the stage
for the development of efficient one-pot isomerizing alkene
metatheses.[21] This catalyst promotes self- and cross-meta-
thesis reactions of unsaturated fatty acids, for example, with
ethylene, thus giving access to alkenes and unsaturated
mono- and dicarboxylates with adjustable chain-length dis-
tributions.[22]
Starting from arenes bearing unsaturated side chains as
the substrate, an isomerizing ethenolysis may, in contrast, be
directed so that rather than a product mixture, vinylarenes
are formed selectively. Although the double bond migrates
towards the arene ring, the alkyl substituent on the alkene
could be removed continuously by ethenolysis. With excess
ethylene, vinylarenes should finally form along with a mix-
ture of volatile alkenes, as exemplified in Scheme 1.
then perform a cross-metathesis
with ethylene.[15]
However, even if performed
in two separate steps, substan-
tial hurdles would have to be
overcome before such a process
could be achieved. Although
the conjugated position would
be expected to be favored, the
double-bond migration step is
still likely to result in a hard-to-
Scheme 1. General principle of an isomerizing ethenolysis.
separate equilibrium mixture of
isomers, especially when performed at elevated tempera-
To probe the viability of this concept, 4-phenyl-1-butene
(1) was treated with excess ethylene in the presence of the
Pd/Ru catalyst combination employed in the isomerizing
ethenolysis of fatty acids (Scheme 1).[21] Unfortunately, the
reactions stopped at the propenylarene 5 stage. Control ex-
tures.[16] Moreover, b-substituted vinylarenes are tough sub-
[a] S. Baader, Dr. D. M. Ohlmann, Prof. Dr. L. J. Gooßen
Fachbereich Chemie, Technische Universitꢀt Kaiserslautern
Erwin-Schrçdinger-Straße 54, 67663 Kaiserslautern (Germany)
Fax : (+49)631-205-3921
periments revealed that [{PdACHTNUGTRNEUNG(m-Br)tBu3P}2} effectively pro-
motes the double-bond migration in 2, so that an equilibri-
um mixture containing predominantly the conjugated
isomer 3 forms within minutes. Consequently, the stalling of
the reaction had to be caused by insufficient activity of the
ruthenium catalyst (Ru-8, Figure 1) for mediating the final
E-mail: goossen@chemie.uni-kl.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301336.
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Table 1. Ethenolysis of isoeugenol (7).[a]
Entry
Ru catalyst
Solvent
Conversion
[%]
8a
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
Ru-1
Ru-2
Ru-3
Ru-4
Ru-5
Ru-6
Ru-7
Ru-8
Ru-4
Ru-4
Ru-4
Ru-4
Ru-4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeOH
NMP
46
51
>99
>99
>99
30
57
41
82
62
39
35
44[b]
55[b]
47[b]
26
31
35
0[b]
62
acetone
diglyme
THF
82
>99
>99
80
93
96
[a] Reaction conditions: compound 7 (0.25 mmol), Ru catalyst (3 mol%),
solvent (1 mL), ethylene (10 bar), 608C, 16 h. Yields were determined by
GC using n-hexadecane as the internal standard. [b] Dehydrodiisoeu
ol was detected as a side product.
ACHTUNGTRENNUNGgen-
AHCTUNGTRENNUNG
Figure 1. Metathesis and isomerization catalysts (Cy=cyclohexyl, Mes=
mesityl, Tol=tolyl).
Table 2. Isomerizing ethenolysis of eugenol (9a).[a]
step, that is, the ethenolysis of the less reactive, conjugated
double bond in 3 or 5.
We thus approached the development of the desired
transformation by examining the final ethenolysis step
alone, and used the alk-2-enylarene isoeugenol (7) as the
model substrate. The unprotected hydroxy group in 7 pres-
ents a particular challenge for the catalyst.[23] Numerous
ruthenium-based catalysts were investigated (Figure 1), in
particular, those that are known to promote ethenolysis.[24]
These include first- and second-generation Grubbs- and
Hoveyda-type catalysts (Ru-1,[25] Ru-2,[26] Ru-3,[27] Ru-4,[28]
and Ru-5[29]), and indenylidene ruthenium complexes, such
as Ru-6,[30] Ru-7,[31] and Ru-8.[32]
Under the reaction conditions used for the isomerizing
ethenolysis of fatty acids (toluene, 608C, ethylene (10 bar),
Ru-8 (3 mol%), Pd-1 (0.75 mol%)) most catalysts gave low
conversions (Table 1, entries 1, 2, and 6–8). With Ru-3, Ru-
4, and Ru-5, the yields were better, but dimerization of 7,
with formation of dehydrodiisoeugenol,[33] became a major
side reaction (Table 1, entries 3–5). This and other unwanted
side reactions, for example, stilbene formation, were effec-
tively suppressed by switching to polar, aprotic solvents such
as ethers (Table 1, entries 9–12). With the use of catalyst
Ru-4 in combination with THF as the solvent, full conver-
sion and near-quantitative yield of 8a was finally achieved
(Table 1, entry 13).
Entry
p
t
Pd-1
[mol%]
Conversion
[%]
8a
[%]
A
G
1
2
10
10
10
10
5
16 h
16 h
16 h
4 h
16 h
15 min
16 h
0.5
0.1
0.5
0.5
0.5
0.5
0
>99
>99
>99
>99
>99
>99
44
97
92
91
87
83
90
33
3[b]
4
5
6[c]
7
10
10
[a] Reaction conditions: compound 9a (0.25 mmol), Ru-4 (3 mol%),
THF (1 mL), ethylene (10 bar), 608C, 16 h. Yields were determined by
GC using n-hexadecane as internal standard. [b] Ru-4 (1 mol%). [c] By
using microwave irradiation.
commercial value than the starting material eugenol (9a,
16 E/100 g).[34]
The desired transformation proceeded in near-quantita-
tive yield even when the Pd loading was reduced to
0.1 mol% or the Ru loading to 1 mol% (Table 2, entries 1–
3). At 10 bar and 608C, the conversion approached comple-
tion after only 4 h, whereas the reaction required 16 h at
5 bar (Table 2, entries 4 and 5). Microwave irradiation
strongly accelerated the reaction; thus, compound 9a was
converted in high yield in only 15 min, even when using
only 5 bar of ethylene (Table 2, entry 6). A control experi-
ment revealed that in the absence of the isomerization cata-
lyst, the desired product was also formed in small quantities.
This was not unexpected as the metathesis catalyst Ru-4
itself promotes double-bond migration, albeit at low reac-
tion rates (Table 2, entry 7).[35]
As a next step, we combined the optimal catalyst Ru-4
with the isomerization catalyst Pd-1 and attempted the syn-
thesis of 8a through isomerizing ethenolysis starting directly
from eugenol (9a). This transformation is a good example
of the potential economic impact of this transformation, as
the vinylarene 8a (465 E/100 g) is of substantially higher
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Isomerizing ethenolysis
COMMUNICATION
When the new protocol (Ru-4 (3 mol%), Pd-1
(0.5 mol%), THF, 608C, ethylene (10 bar)) was applied to
the previously unsuccessful isomerizing ethenolysis of 4-
phenyl-1-butene (1), quantitative conversion was observed,
and styrene was obtained in 92% yield (Scheme 1). This
result demonstrates that the catalyst is sufficiently active to
convert even longer-chain alkenylarenes into the corre-
sponding vinylarenes through a cooperative isomerization/
metathesis process.
The scope of the new transformation was further investi-
gated by starting from various allylarenes bearing a wide
range of functionalities, such as hydroxy, ether, ester, and
halo groups (Table 3). The substrates include the natural
Scheme 2. Isomerizing ethenolysis of other allylic substrates.
In conclusion, isomerizing ethenolysis with a bimetallic
ruthenium/palladium catalyst system has been shown to be
an advantageous strategy for accessing vinylarenes and re-
lated compounds. It is of particular value in the context of
incorporating naturally occurring allylarenes, some of which
are available on the ton scale, into the chemical value chain.
After a reasonable amount of optimization, a cost-effective
process for this transformation should be possible. Potential
future applications of this reaction type include the conver-
sion of allyl chains that have been enantioselectively instal-
led at quaternary carbon centers[37] into their vinyl counter-
parts.
Table 3. Isomerizing ethenolysis of allylarenes.[a]
Product
Yield
[%]
Product
Yield
[%]
85
93
87[b]
Experimental Section
92
89
90
94
General procedure: A headspace vial (10 mL) with a stirring bar was
charged with metathesis catalyst Ru-4 (18.8 mg, 3.00 mol%) and isomeri-
zation catalyst Pd-1 (4.08 mg, 0.50 mol%), closed with a septum cap, and
purged with ethylene. THF (4 mL) and the allylarene (1.00 mmol) were
added through a syringe. The reaction vessel was placed in an autoclave,
pressurized with ethylene (10 bar), and stirred at 608C for 16 h. After
cooling and depressurizing, the solvent was removed in vacuo, and the
crude product was purified by column chromatography (SiO2, diethyl
ether/n-pentane gradient).
92
95[c]
87
95[c]
[a] Reaction conditions: 9a–j (1 mmol), Ru-4 (3 mol%), Pd-1
(0.5 mol%), THF (4 mL), ethylene (10 bar), 608C, 16 h. [b] On
a
Acknowledgements
10 mmol scale. [c] For this volatile styrene, the yield was determined by
GC analysis using n-hexadecane as the internal standard.
We thank NanoKat, the Collaborative Research Centre SFB/TRR 88
“3MET” and the Deutsche Bundesstiftung Umwelt (fellowship to S.B.)
for financial support, and Umicore AG for the donation of chemicals. We
also thank Patricia Podsiadly for technical assistance.
products eugenol (9a), safrol (9b), estragol (9c), and meth-
yleugenol (9d). In all cases, high yields were obtained. For
9a, it was confirmed that good yields are also obtained on a
preparative scale.
Keywords: ethenolysis · isomerization · olefin metathesis ·
renewable resources · styrenes
The applications of isomerizing ethenolyses are not limit-
ed to the synthesis of vinylarenes. After minimal optimiza-
tion, the protocol allowed the conversion of easily accessible
molecules with allyl-substituted quaternary carbon atoms
into the corresponding vinyl derivatives (Scheme 2). Exam-
ples include allylated malonates, homoallyl alcohols, and un-
saturated carboxylic acids. This indicates that isomerizing
metatheses may evolve into a generally applicable synthetic
tool to introduce vinyl groups into organic molecules. This
strategy benefits from the broad spectrum of efficient
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Received: April 9, 2013
Published online: June 17, 2013
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