Simple ruthenium precatalyst for the synthesis of stilbene derivatives and ring-closing metathesis in the presence of styrene initiators

Article abstract of DOI:10.1002/adsc.200600493

The ruthenium complex RuCl₂(p-cymene)(IMes) was found to be an efficient precatalyst, with styrene as an initiating species, for the alkene metathesis of various styrenes into symmetrical and unsymmetrical stilbene derivatives and for the ring-closing metathesis reaction of a sterically hindered olefin leading to a tetrasubstituted cycloolefin.

Full text of DOI:10.1002/adsc.200600493

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DOI: 10.1002/adsc.200600493
Simple Ruthenium Precatalyst for the Synthesis of Stilbene
Derivatives and Ring-Closing Metathesis in the Presence of
Styrene Initiators
Cheikh Lo,a Renan Cariou,a CØdric Fischmeister,a,* and Pierre H. Dixneufa,*
a
Catalyse et OrganomØtalliques, UMR 6226 CNRS, UniversitØ de Rennes 1, Institut Sciences Chimiques de Rennes, Av.
GØnØral Leclerc, 35042 Rennes Cedex, France
Fax : (+33)-(0)2-23-23-69-39; phone: (+33)-(0)2-23-23-62-80; e-mail: cedric.fischmeister@univ-rennes1.fr or
pierre.dixneuf@univ-rennes1.fr
Received: September 28, 2006; Revised: December 20, 2006
This paper is dedicated to Professor Masakatsu Shibasaki on the occasion of his 60th birthday.
À
Abstract: The ruthenium complex RuCl
cymene)(IMes) was found to be an efficient preca-
A
We recently reported the intramolecular vinyl C H
A
bond activation of an N-vinyl-N-heterocyclic carbene-
ruthenium(II) intermediate leading to a bidentate
NHC-alkenyl ruthenium complex (Scheme 1).[10]
talyst, with styrene as an initiating species, for the
alkene metathesis of various styrenes into symmet-
rical and unsymmetrical stilbene derivatives and for
the ring-closing metathesis reaction of a sterically
hindered olefin leading to a tetrasubstituted cyclo-
olefin.
Keywords: alkene metathesis; N-heterocyclic car-
benes; ring-closing metathesis; ruthenium; stil-
benes; styrenes
Stilbene derivatives, in particular hydroxy- or alkoxy-
subtituted ones are gaining importance due to their
biological activities for the prevention of cancer or
cardiovascular diseases.[1] They are also an important
family of building blocks for the design of conjugated
À
Scheme 1. Intramolecular vinyl C H bond activation.
In an attempt to explore the intermolecular version
materials with optical properties.[2] Wittig or Wittig– of this transformation, styrene was reacted with the
Horner reactions[3] constitute a priviledged approach readily available ruthenium complex RuCl
for the synthesis of stilbene derivatives but they gen- cymene)
(IMes) 1[11] [IMes=1,3bis(2,4,6-trimethylphe-
G
AHCTREUNG
erate stoichiometric amounts of phosphine oxides nyl)imidazol-2-ylidene]. This reaction resulted in the
hence requiring fastidious purification. Catalytic reac- stereoselective formation of E-stilbene in very good
tions such as Heck or Suzuki couplings can be used as yield, thus suggesting a self-metathesis reaction. Here
more efficient ways to synthesize stilbene deriva- we describe several aspects of RuCl
A
tives.[4] More recently catalytic olefin metathesis[5] ap-
AHCTREUNG
peared as a tool of choice for the efficient and stereo- actions. In the absence of an alkene metathesis car-
selective synthesis of stilbene derivatives thanks to bene initiator, complex 1 acts as a pre-catalyst for the
the emergence of very active catalysts for cross-meta- metathesis transformation of various styrene deriva-
thesis.[6] In particular, the ruthenium-based second tives into the corresponding stilbenes including un-
generation Grubbs catalyst has been shown to effi- symmetrical ones. We show the dual ring-closing
ciently promote the self- and cross-metathesis of sty- metathesis (RCM) vs. cycloisomerisation activity of 1
rene derivatives.[7] Other complexes based on molyb- and that, in the presence of styrene as an activator,
denum[8] or osmium[9] have also been described as ef- complex 1 is effective for the RCM of a sterically hin-
ficient catalysts for this transformation.
dered diene.
546
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Simple Ruthenium Precatalyst for the Synthesis of Stilbene Derivatives
Table 1. Self-metathesis of styrene derivatives.[a]
There were some indications that complex 1 could
promote catalytic alkene metathesis: Nolan reported
one example of RCM activity of complex 1 with di-
ethyl diallylmalonate[11] and Noels pointed out the ac-
tivity of complex 1 for the ROMP of cyclic olefins
with or without addition of a diazo compound
(N2CHSiMe3) as a carbene initiator[12] and for the
ATRP of acrylate derivatives and styrene.[13]
The formation of stilbene was first revealed by the
stoichiometric reaction of complex 1 with styrene at
808C in toluene. The catalytic synthesis of symmetri-
cal stilbenes by self-metathesis was then screened
with a series of styrene derivatives bearing electron-
donating and electron-withdrawing substituents
(Table 1). Typically, the reactions were carried out for
3 h at 808C in toluene and afforded only stilbene de-
rivatives with the E-configuration.[14] The results show
that a strong electron-withdrawing substituent totally
inhibits the reaction (entries 7 and 8) in contrast to a
strong-donating one (entry 6). The weak electron-
withdrawing bromide substituent does not prevent the
reaction, except for the meta-derivative (entry 3).
The effect of light was found to be determining for
the outcome of the reaction since no conversion of
styrene was observed when the reaction was per-
Entry
R
Conversion [%][b] Isolated yield [%]
1
2
3
4
5
6
7
8
H
93
78
0
84
76
-
2-bromo
3-bromo
4-bromo
2,4-dimethyl 89
4-methoxy
4-nitro
82
77
87
76
-
80
0
4-cyano
0
-
[a]
5 mol% of 1, toluene, 808C, 3 h.
Determined by GC after 3 h.
[b]
formed in total darkness.[15] However, the combina- react with the generated catalyst. The synthesis of un-
tion of daylight and long distance artificial lighting symmetrical stilbene derivatives was then investigated
ensured good activity as well as reproductibility. Light (Scheme 2).
is expected to promote the arene decoordination to
Various substitution patterns have been obtained
afford an active, coordinatively unsaturated rutheni- with very good conversions of substrates and with a
um(II) species. The self-metathesis of the sterically selectivity always in favour of the unsymmetrical stil-
hindered a-methylstyrene was attempted but no con- bene derivative (Table 2). When a-methylstyrene was
version was observed suggesting that this substrate is used in combination with styrene, the only product
not suitable to either activate the precatalyst 1 or to obtained was stilbene hence showing that the steric
Scheme 2. Synthesis of unsymmetrical stilbenes.
Table 2. Synthesis of unsymmetrical stilbene derivatives.[a]
Entry
A (1 equiv)
B (1 equiv)
Conv. A [%][b]
Conv. B [%][b]
AA[c]
AB[c]
BB[c]
1
2
3
4
5
6
7
styrene
styrene
styrene
styrene
4-bromostyrene
4-bromostyrene
4-bromostyrene
4-methoxystyrene
4-bromostyrene
2,4-dimethylstyrene
a-methylstyrene
4-methoxystyrene
2-bromostyrene
91
92
91
92
86
92
91
92
92
92
-
86
88
93
30
34
13
100
27
28
24
49(38)
46[d]
21
20
42
-
25
14
24
45[d]
-
38(33)
58(51)
52[d]
2,4-dimethylstyrene
[a]
Reaction conditions: 1, 5 mol%, toluene, 808C, 24 h.
Determined by GC.
Product distribution determined by GC, (isolated yield).
Products could not be separated by column chromatography.
[b]
[c]
[d]
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Cheikh Lo et al.
hindrance of a-methylstyrene prevents its transforma-
tion by metathesis. Indeed, in the present case an
alkene metathesis catalyst is generated as shown by
the conversion of styrene into stilbene (entry 4).
The cross-metathesis of 4-bromostyrene and 4-me-
thoxystyrene was repeated with a ten-fold excess of
styrene in order to improve the selectivity toward the
unsymmetrical product.[6,7,16] These conditions effi-
ciently and selectively produced the unsymmetrical
products (AB) with high conversions along with the
formation of stilbene (BB) and almost no self-meta-
thesis (AA)of the reagent used in default was observed
(Table 3).
Complex 1 was evaluated in the RCM of the bench-
mark substrate N,N-diallyl-4-methylbenzenesulfon-
amide 2. In that case the expected RCM product was
not obtained but an exo-methylene 5-membered ring
product 3 resulting from a cycloisomerisation reaction
was obtained instead (Scheme 3). It is thus evidenced
Scheme 4. RCM vs. cycloisomerisation. Reaction conditions:
a) 5 mol% of 1, toluene, 808C, 3 h. b) Same as a) + 10
mol% of phenylacetylene, toluene, 808C, 3 h. c) Same as a)
+ 25 mol% of styrene, toluene, 808C, 3 h. d) Same as a)
+ 25 mol% of styrene, 30 min at 908C before addition of 2.
When phenylacetylene (10 mol%) was added to 2
in the presence of precatalyst 1 the reaction produced
only the ring-closing metathesis product, thus likely
via a ruthenium-vinylidene complex. On the other
hand, an attempt with styrene (25 mol%, reaction c,
Scheme 3. Cycloisomerisation of diallyl-N-tosylamine.
that the nature of the olefin is responsible for the Scheme 4) failed to provide the RCM product but
transformation of 1 into an olefin metathesis cata- again the cycloisomerisation product was obtained.
lysts.[17] When such a transformation is not possible or Hence, we performed an activation step reacting 1 (5
not favoured, cycloisomerisation takes place, very mol%) and styrene (25 mol%) at 808C for 30 min
likely by oxidative coupling of the diene to the ruthe- before 2 was added (reaction d, Scheme 4). A gas
nium centre.[18]
chromatographic analysis of the reaction mixture
This type of reactivity was already observed with after 3 h showed the presence of both the RCM and
the in situ generated catalyst [RuCl2(p-cymene)]2/Im- cycloisomerisation products in approximatively the
G
esH2Cl/Cs2CO3 (molar ratio 1/2/4).[18a] It was also same amounts. It seems clear that two reactions are in
shown that the RCM activity vs. cycloisomerisation competition, the cycloisomerisation one being fav-
could be restored by adding an alkyne derivative to oured very likely because of the slow transformation
promote the formation of a ruthenium vinylidene of 1 into an olefin metathesis catalyst.
[Ru=C=CHR] initiating species.[18a] With this in mind
It was thus necessary to attempt the transformation
we considered the possibility to use a terminal alkyne of a substrate for which the cycloisomerisation is not
or styrene as activator to perform the RCM of the di- possible. The more sterically demanding diene 5 was
allyl-N-tosylamine 2 (Scheme 4).
reacted with 1 in the presence of styrene to furnish
Table 3. Synthesis of unsymmetrical stilbene derivatives.[a]
Entry
A (1 equiv.)
B (10 equivs.)
Conv. A [%][b]
AB[c]
AA[c]
1
2
4-bromostyrene
4-methoxystyrene
styrene
styrene
91
93
98
100
2
0
[a]
Reaction conditions: 1, 5 mol%, toluene, 808C, 24 h.
Determined by GC.
Product distribution determined by GC.
[b]
[c]
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Simple Ruthenium Precatalyst for the Synthesis of Stilbene Derivatives
ferred via a filter cannula into a Schlenk tube containing
1.06 g (1.78 mmol, 0.5 equivs.) of [RuCl2(p-cymene)]2 in
exclusively the RCM product 6 with a conversion of
70% (Scheme 5).
AHCTREUNG
25 mL of freshly distilled toluene. The reaction mixture was
stirred for 2 h at room temperature and the solvent evapo-
rated. The resulting brown product was washed sequentially
by 10 mL of diethyl ether and 10 mL of pentane. The com-
plex was purified by flash column chromatography on a
short plug of neutral activated alumina using dichlorome-
thane as the eluent to furnish after solvent evaporation 1 as
an orange-brown powder; yield: 1.61 g (76%). HR-MS:
m/z=575.1773, calcd. for [MÀCl]+: 575.1767; 1H NMR
3
(200.131 MHz; CDCl3): d=1.11 [d, 6H, JH,H =6.95 Hz, CH-
A
Scheme 5. RCM of a sterically hindered substrate.
(s, 6H, Mes-4-CH3), 2.56 [m, 1H, CH(CH3)2)], 4,66 (d, 2H,
3JH,H =5.86 Hz, C6H4), 5.07 (d, 2H, 3JH,H =5.86 Hz, C6H4),
6.93 (s, 2H, NCHCHN), 6.97 (s, 4H, Mes-3-CH); 13C NMR
(50.329 MHz; CDCl3): d=18.5 (CH3), 19.5 (CH3), 21.6
(CH3), 22.9 (CH3), 30.6 (CH), 86.1 (CH), 86.2 (CH), 96.2
(Cq), 103.3 (Cq), 125.6 (CH), 129.1 (CH), 136.6 (Cq), 139.1
(Cq), 139.2 (Cq), 172.2 (Cq).
This result reveals the potential of this catalyst pre-
cursor 1 since the RCM of a sterically hindered diene
is still a challenging reaction. Indeed, this transforma-
tion performed with well defined ruthenium-alkyli-
dene catalysts (Grubbs, Hoveyda, Grela) provided the
RCM product in a maximum 52% yield (cat: 5
mol%, CH2Cl2, reflux, 20 h).[19]
Crystallographic data (excluding structure factors) for the
structure of complex 1 have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC-602393. Copies of the data can be ob-
tained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax.: (internat.) +44–
1223/336–033; e-mail: mailto:deposit@ccdc.cam.ac.uk].
The activity of our system reaches that of these ref-
erence catalysts while being more easily prepared
since complex 1 is readily obtained from the commer-
cially available [RuCl2(p-cymene)]2 and 1,3-bis(2,4,6-
A
trimethylphenyl)imidazolidinium chloride (IMesHCl)
compounds. Although it is not possible at this stage to
define the nature of the catalytic species, it is clear
General Procedure for the Synthesis of Stilbene
Derivatives
that the formation of an alkene metathesis catalyst Complex 1 (17.5 mg, 0.03 mmol, 0.05 equivs.) and 0.6 mmol
of styrene derivative in 2 mL of toluene were stirred at
808C. Conversions were determined by gas chromatography
by measuring area ratios assuming identical response factors
for all the compounds. Some reactions have been repeated
with good reproducibility. The stilbene derivatives were iso-
lated by column chromatography on silica gel using a mix-
ture of heptane/dichloromethane as the eluent. 1H NMR
data of the following isolated stilbenes were in agreement
with reported values: 1,1’-(E)-ethene-1,2-diylbis(2-bromo-
benzene)[23] (Table 1, entry 2), 1,1’-(E)-ethene-1,2-diylbis(4-
from 1 requires the presence of styrene. There are a
few examples of alkene metathesis catalysts in situ
generated from metal complexes and olefins as in the
polymerisation of norbornene with RuCl3 in etha-
nol[20] or Ru(H2O)62+ in water.[21]
A
In conclusion, we have performed the synthesis of a
series of symmetrical and unsymmetrical stilbene de-
rivatives by olefin metathesis using a ruthenium cata-
lyst in situ generated from an easily available complex
RuCl
A
G
diylbis(2,4-dimethylbenzene)[25] (Table 1, entry 5), 1,1’-(E)-
also demonstrated that complex 1 with styrene as an
initiator efficiently promotes the RCM of a sterically
hindered diene.
Developments in this domain are underway and
will be reported in due course.
ethene-1,2-diylbis(4-methoxybenzene)[7b] (Table 1, entry 6),
1-methoxy-4-[(E)-2-phenylvinyl]benzene[26]
(Table 2,
entry 1),
1-bromo-4-[(E)-2-(4-methoxyphenyl)vinyl]ben-
zene[27] (Table 2, entry 5), 1-bromo-2-[(E)-2-(4-bromophe-
nyl)vinyl]benzene[28] (Table 2, entry 6).
Experimental Section
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