Convenient preparation of trans-arylalkenes via palladium(II)-catalyzed isomerization of cis-arylalkenes

Article abstract of DOI:10.1021/jo015880u

A convenient method for the isomerization of cisarylalkenes to their trans isomers using a palladium(II) catalyst is described. The reaction conditions are mild and general across a range of arylalkenes. The synthesis of a trans-resveratrol derivative from a mixture of alkene isomers was also completed.

Full text of DOI:10.1021/jo015880u

J . Org. Chem. 2002, 67, 4627-4629
4627
Ta ble 1. Scop e of Isom er iza tion Rea ction
Con ven ien t P r ep a r a tion of
tr a n s-Ar yla lk en es via
P a lla d iu m (II)-Ca ta lyzed Isom er iza tion of
cis-Ar yla lk en es
J inquan Yu, Matthew J . Gaunt, and
J onathan B. Spencer*
University Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW, U.K.
jbs20@cam.ac.uk
Received J une 29, 2001
Abstr a ct: A convenient method for the isomerization of cis-
arylalkenes to their trans isomers using a palladium(II)
catalyst is described. The reaction conditions are mild and
general across a range of arylalkenes. The synthesis of a
trans-resveratrol derivative from a mixture of alkene isomers
was also completed.
The construction of carbon-carbon double bonds is a
fundamental reaction in organic chemistry.1 A wealth of
research has been directed toward the synthesis of
geometrically pure alkenes, and many elegant methods
have been developed.2 However, in many reactions, such
as the Wittig reaction or alkene metathesis, mixtures of
cis- and trans-alkenes are formed.2,3 Methods for isomer-
izing cis-alkenes to their trans isomers, such as radical4a
or photochemical processes,4b often involve relatively
harsh reaction conditions. Furthermore, in some photo-
chemical procedures the reverse isomerization of trans
to cis is observed.4c It would therefore be very useful to
have a reliable, mild, and facile method for the conversion
of alkene mixtures or cis-alkenes to geometrically pure
trans-alkenes. Herein, we report a convenient new method
for the preparation of trans-arylalkenes via palladium-
(II)-catalyzed isomerization of cis-alkenes under ambient
conditions.
Previous studies have demonstrated that palladium-
(II) salts can promote the migration of terminal double
bonds giving a mixture of disubstituted alkenes.5 This
has led to the proposal that the mechanism might involve
formation of either a carbocation or a π-allylic complex.5
a
Reagents and conditions: 10 mol % (MeCN)2PdCl2, CH2Cl2,
b
rt. After purification by flash silica gel chromatography.
c 10 mol % PdCl2(PhCN)2 was used as the catalyst.
* To whom correspondence should be addressed. Fax: +44 (01223)
336362.
We felt that this reactivity could be exploited for the
preparation of pure trans-alkenes from cis-alkenes if the
double bond could be prevented from migrating. If the
mechanism involves a carbocation then we postulated
that a stabilizing aryl substituent, conjugated to the
double bond, would facilitate the isomerization and
prevent the bond from migrating. To test this, a range
of alkene substrates were prepared by conventional
Wittig olefination. Mixtures of cis- and trans-alkenes
were obtained in each case. Isomerization of these alkene
mixtures was carried out with 10 mol % of bis(acetoni-
trile)palladium(II) chloride in a 0.5 M solution of alkene
in dichloromethane under an argon atmosphere. In most
cases, the reactions were complete in less than 24 h
(Table 1). The mixtures of cis- and trans-â-methyl
(1) Evans, D. A.; Trotter, B. W.; Cote, B.; Coleman, P. J .; Dias, L.
C.; Tyler, A. N. Angew. Chem., Int. Ed. Engl. 1997, 36, 2744.
(2) For review of the Wittig reaction, see: Maryanoff, B. E.; Reitz,
A. B. Chem. Rev. 1989, 89, 863. For an example of cis-selective alkene
formation in natural products synthesis, see: Evans, D. A.; Fitch, D.
M.; Smith, T. E.; Cee, V. J . Am. Chem. Soc. 2000, 122, 10033. For
examples of trans-selective alkene formation in natural products
synthesis, see: (a) Ley, S. V.; Brown, D. S.; Clase, J . A.; Fairbanks, A.
J .; Lennon, I. C.; Osborn, H. M. I.; Stokes, E. S. E.; Wadsworth, D. J .
J . Chem. Soc., Perkin Trans. 1 1998, 2259. (b) Evans, D. A.; Carter, P.
H.; Carreira, E. M.; Charette, A. B.; Prunet, J . A.; Lautens, M. J . Am.
Chem. Soc. 1999, 121, 7540. (c) Fleming, I.; Barbero, A.; Walter, D.
Chem. Rev. 1997, 97, 2063.
(3) For example, alkene metathesis reactions often deliver mixtures
of alkenes. Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.;
Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J . I. J .
Am. Chem. Soc. 1997, 119, 7960.
(4) For examples, see: (a) Bosanac, T.; Yang, J .; Wilcox, C. S. Angew.
Chem., Int. Ed. 2001, 40, 1875. Ali, M. A.; Tsuada, Y. Chem. Pharm.
Bull. 1992, 40, 2842. (b) Deter, D. F.; Chu, Y. W. J . Am. Chem. Soc.
1955, 77, 4410. (c) J acobsen, E. N.; Deng, L.; Furukawa, Y.; Martinez,
L. E. Tetrahedron 1994, 50, 4332.
(5) (a) Sen, A.; Lai, T.-W. Inorg. Chem. 1981, 20, 4036. (b) Sen, A.;
Lai, T.-W. Inorg. Chem. 1984, 23, 3257.
10.1021/jo015880u CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/07/2002

4628 J . Org. Chem., Vol. 67, No. 13, 2002
Notes
Sch em e 1. Isom er iza tion of Deu ter iu m La beled
Styr en e
In the present case, a 1:1 mixture of isomers 4/5 was
obtained in 92% yield. However, isomerization of this
mixture using the palladium catalyst gave only the trans
isomer 5 of the resveratrol derivative in 94% yield. In a
similar experiment, the pure cis-alkene 4 was converted
to trans-5 in identical yield.
In summary, isomerization of double bonds conjugated
to aromatic systems in the presence of palladium(II) is
reported. This reaction should prove an attractive method
for the preparation of pure trans-arylalkenes due to the
mild reaction conditions.
Sch em e 2. Syn th esis of Resver a tr ol Der iva tivea
Exp er im en ta l Section
Gen er a l In for m a t ion . 1H NMR spectra were recorded in
deuteriochloroform, unless stated otherwise, at 250 MHz at
298 ( 3 K. 13C NMR spectra were recorded at 62.5 MHz.
Chemical shifts are quoted relative to residual solvent (7.25 ppm
for 1H and 77.0 ppm for 13C of CDCl3), and coupling constants
(J ) are given in Hz. High-resolution mass spectral (HRMS)
analyses were measured by means of EI, FAB, FIB, or ES
techniques. All anhydrous solvents were dried by standard
techniques and freshly distilled before use or purchased in
anhydrous form. All flash chromatography was carried out using
silica gel.
Gen er a l P r oced u r e for th e Isom er iza tion of cis-Alk en es.
A solution of the cis-alkene and bis(acetonitrile)palladium(II)
chloride (10 mol %) in dichloromethane (2 mL per mmol of
substrate) was stirred at room temperature for the appropriate
time. The reaction mixture was diluted with diethyl ether and
filtered through a short pad of Florisil, eluting with diethyl ether.
The solvent was removed under reduced pressure and the
residue purified by flash silica gel chromatography to afford the
trans-alkene.
a
Reagents and conditions: (a) n-BuLi, THF, -78 to 0 °C, 1 h
then 3,5-dimethoxybenzaldehyde, THF, -78 °C; (b) 10 mol %
(MeCN)2PdCl2, CH2Cl2 (0.5 M), rt, 12 h.
styrenes (entries 1a -c,e) were converted to the trans
isomer in good yield.
Styrene substrates with sterically bulky substituents
(entry 1f) could also be isomerized to the trans product,
although they required extended reaction times (24 h)
to reach total conversion. The trans isomer, however, was
still isolated in 90% yield. Substituted stilbene deriva-
tives could likewise be isomerized in good yield (entries
1g and 1h ). When the double bond was further polarized
by being conjugated to a carbonyl group the reaction was
significantly accelerated (entry 1i). In contrast the in-
troduction of a trifluoromethyl group in the para position
of the aromatic ring (entry 1d ) resulted in no conversion
to the trans-alkene. This is consistent with the benzylic
carbon being electron deficient in the transition state.
Syn th esis of tr a n s-An eth ole, 2a : 1 mmol scale (cis/trans,
1:1), 14 h, gave 133 mg, 90%, Rf ) 0.72 diethyl ether-hexane
2:98; colorless oil; 1H NMR (250 MHz, CDCl3) δ 7.30-7.23 (m, 2
H, J ) 8.0 Hz), 6.87-6.80 (m, 2 H, J ) 8.0 Hz), 6.39-6.30 (m,
1 H, J ) 16.0 Hz), 6.18-6.03 (dq, 1 H, J ) 16.0, 6.8 Hz), 3.80 (s,
3 H), 1.87-1.83 (dd, 3 H, J ) 6.8, 1.9 Hz). 1H NMR spectra were
identical to authentic material.
Syn t h esis of cis/tr a n s-4-Met h oxy-3′,5′-d im et h oxyst il-
ben e, 4/5. n-Butyllithium (3.85 mL of a 1.3 M solution in
hexanes, 5.0 mmol) was added dropwise to a stirred suspension
of 4-methoxybenzyltriphenylphosphonium chloride (2.10 g, 5
mmol) in anhydrous tetrahydrofuran (10 mL) at 0 °C under an
argon atmosphere. After the mixture was stirred for 1 h, the
reaction temperature was lowered to -78 °C and the 3,5-
dimethoxybenzaldehyde (0.821 g, 4.95 mmol) in tetrahydrofuran
(5 mL) was added to the red solution. Stirring was continued at
low temperature for another 2 h, allowed to warm to room
temperature, and stirred for 12 h.
The reaction mixture was diluted with hexane and poured
into dilute hydrochloric acid solution. The solution was extracted
with hexane, and the combined organic fractions were washed
with water, saturated sodium hydrogen carbonate solution, and
water. The organic portions were dried (MgSO4) and filtered,
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography (hexane
Rf ) cis 0.30, trans 0.23) to afford the stilbene as a 1:1 mixture
of isomers as a white solid (0.94 g, 94%).
cis-4-Meth oxy-3′,5′-d im eth oxystilben e 4: 1H NMR (250
MHz, CDCl3) δ 7.16-7.12 (d, 2 H, J ) 8.2 Hz), 6.73-6.68 (d, 2
H, J ) 8.2 Hz), 6.50-6.45 (d, 1 H, J ) 12.0 Hz), 6.40-6.35 (d,
1 H, J ) 120 Hz), 6.38-6.36 (m, 2 H), 6.35-6.22 (m, 1 H), 3.76
(s, 3 H), 3.60 (s, 6 H).
tr a n s-4-Meth oxy-3′,5′-d im eth oxystilben e 5: 1H NMR (250
MHz, CDCl3) δ 7.72-7.38 (d, 2 H, J ) 8.0 Hz), 7.01-6.95 (d, 1
H, J ) 17.0 Hz), 6.86-6.79 (d, 1 H, J ) 17.0 Hz), 6.83-6.80 (d,
2 H, J ) 8.0 Hz), 6.60-6.58 (m, 2 H), 6.33-6.30 (br, 1 H), 3.78
(s, 9 H). 1H NMR spectra were consistent with data in ref 8.
It is, however, worth noting that those substrates
containing allylic hydrogens could isomerize by bond
migration (the double bond moving out of conjugation and
back again) with the involvement of a π-allylic complex.5
To investigate this possibility, deuterated methyl styrene
d 3-1a was synthesized and isomerized under similar
conditions (Scheme 1). No deuterium was lost from or
transferred to the benzylic position, thus ruling out this
as a possible mechanism. Another possible explanation
for the isomerization is the trans addition of palladium
chloride to the double bond followed by rotation and syn-
â-elimination of the palladium chloride. At this stage, it
is not possible to distinguish between this mechanism
and that involving a carbocation.
The synthetic potential of this methodology was dem-
onstrated in the synthesis of trimethoxy resveratrol.
Resveratrol is currently attracting a great deal of interest
from the scientific community for its biological proper-
ties.6 The synthesis of stilbenes is readily achieved
through the Wittig reaction of a benzyl phosphonium salt
and benzaldehyde (Scheme 2). However, ylides generated
from benzyl phosphonium salts seldom deliver geo-
metrically pure alkenes.7
(6) J ang, M. S.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas, C.
F.; Beecher, W. W.; Fong, H. H. S.; Farnsworth, N. R.; Kingborn, A.
D.; Mehta, R. G.; Moon, R. C.; Pezzuto, J . M. Science 1997, 275, 218.
(7) Bellucci, G.; Chiappe, C.; Lo Moro, G. Tetrahedron Lett. 1996,
37, 4225.
(8) Alonso, E.; Ramo´n, D. J .; Yus, M. J . Org. Chem. 1997, 62, 417.

Notes
Isom er iza tion of th e Tr im eth oxyr esver a tr ol Der iva tive,
J . Org. Chem., Vol. 67, No. 13, 2002 4629
114.2, 104.4, 99.7, 55.3. 1H NMR spectra was consistent with
data in ref 8.
4. A solution of the cis-alkene 4 (100 mg, 0.5 mmol) and bis-
(acetonitrile)palladium(II) chloride (13 mg, 0.05 mmol) in dichlo-
romethane (1 mL) was stirred at room temperature for 14 h.
The reaction mixture was diluted with diethyl ether and filtered
through a short pad of Florisil, eluting with diethyl ether. The
solvent was removed under reduced pressure and the residue
purified by flash silica gel chromatography (diethyl ether-
hexane 2:98, Rf ) 0.52) to afford the trans-5 as a white solid (92
mg, 92%): 1H NMR (250 MHz, CDCl3) δ 7.48-7.45 (d, 2 H, J )
8.7 Hz), 7.11-7.01 (d, 1 H, J ) 16.2 Hz), 6.96-6.86 (d, 1 H, J )
16.2 Hz), 6.93-6.90 (d, 2 H, J ) 8.7 Hz), 6.69-6.68 (m, 2 H),
6.42-6.41 (br, 1 H), 3.84 (s, 6 H), 3.83 (s, 3 H); 13C NMR (250
MHz, CDCl3) δ 161.0, 159.5, 139.8, 130.0, 128.8, 127.9, 126.6,
Ack n ow led gm en t. We thank the Royal Society for
a University Research Fellowship (J .B.S.) and The
Wellcome Trust (M.J .G.) and St. J ohn’s College, Cam-
bridge, for funding.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O015880U