One-pot synthesis of stilbenes from alcohols through a wittig-type olefination reaction promoted by nickel nanoparticles

Article abstract of DOI:10.1055/s-0029-1217333

A series of stilbenes has been synthesised in one pot from benzyl alcohols and benzylidenetriphenylphosphorane through a Wittig-type olefination reaction in the presence of nickel nanoparticles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217333

LETTER
1579
One-Pot Synthesis of Stilbenes from Alcohols through a Wittig-Type
Olefination Reaction Promoted by Nickel Nanoparticles
Synthesis of
S
r
tilbenes
a
from
A
lcoh
n
ols cisco Alonso,* Paola Riente, Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Química Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: falonso@ua.es; E-mail: yus@ua.es
Received 30 January 2009
Dedicated to Professor Santiago Olivella on occasion of his 65th birthday
powder and a catalytic amount of an arene as reducing
agent.14 These nanoparticles were applied to different
functional-group transformations,15 and more recently, to
the hydrogen-transfer reduction of carbonyl compounds16
and reductive amination of aldehydes.17 Additionally, we
recently reported for the first time that nickel, in the form
of nanoparticles (NiNP), was a potential alternative to the
use of noble-metal-based catalysts for the a-alkylation of
ketones and indirect aza-Wittig reaction with alcohols.18
These reactions involved the hydrogen transfer from the
alcohol to the intermediate a,b-unsaturated ketone or im-
ine, respectively, proceeding in short reaction times and in
the absence of any added ligand, hydrogen acceptor or
base, under mild conditions (Scheme 1).
Abstract: A series of stilbenes has been synthesised in one pot from
benzyl alcohols and benzylidenetriphenylphosphorane through a
Wittig-type olefination reaction in the presence of nickel nanoparti-
cles.
Key words: alcohols, Wittig, olefination, stilbenes, nickel nano-
particles
The Wittig reaction1 is one of the fundamental and most
reliable methods in synthetic organic chemistry. In a clas-
sic Wittig reaction, a phosphorus ylide reacts with a car-
bonyl compound to give the corresponding alkene and
phosphane oxide.2 In general, alcohols are cheaper and
commercially more abundant than the corresponding al-
dehydes. Thus, the oxidation of primary alcohols to alde-
hydes and subsequent Wittig reaction is a common
practice in organic synthesis. In some cases, however, al-
dehydes may be difficult to handle because of their vola-
tility, toxicity, or high reactivity. A variety of procedures
for the in situ oxidation–Wittig olefination of primary al-
cohols have been developed to overcome this problem
with Swern,3 MnO2,4 Dess–Martin,5 BaMnO4,6 IBX,7
TPAP,8 PCC,9 SO3·py,10 and BAIB[bis(acetoxy)iodoben-
zene]–TEMPO11 as oxidising systems. Most of these pro-
cedures involve stabilised ylides and, though all are
carried out in one pot, some of them are sequential. There-
fore, the course of the alcohol oxidation needs monitoring
before the ylide addition. Williams et al. reported, for the
first time, the so-called indirect ‘Wittig’ olefination from
alcohols for the formation of carbon–carbon single
bonds.12 This methodology coupled a Wittig-type olefina-
tion with a crossover transfer hydrogenation under iridi-
um or ruthenium catalysis. Stabilised ylides and
phosphonates were combined with benzyl alcohols lead-
ing, mainly, to products with a new carbon–carbon single
bond, together with variable amounts of the correspond-
ing aromatic aldehydes and alkenes.
NiNP, R2COMe
THF, reflux
O
R2
R1
R1
OH
NiNP, Ph3P=NPh
THF, reflux
Ph
R1
N
H
Scheme 1 a-Alkylation of ketones and indirect aza-Wittig reaction
with primary alcohols promoted by nickel nanoparticles
In view of the above precedents, we were intrigued about
the behaviour of the nickel nanoparticles in Wittig-type
reactions using alcohols as phosphorus ylide partners. As
a result of our studies, we wish to report herein what, to
the best of our knowledge, is the first metal-promoted
selective Wittig olefination reaction with alcohols in
which there is no standard redox step.
The nickel nanoparticles (NiNP) were generated from an-
hydrous nickel(II) chloride, lithium powder, and a catalyt-
ic amount of DTBB (4,4¢-di-tert-butylbiphenyl, 5 mol%)
in THF at room temperature.14 A preliminary study was
carried out using benzyl alcohol and benzylidenetriphe-
nylphosphorane (generated from commercially available
benzyltriphenylphosphonium chloride and n-BuLi) as
model substrates in order to optimise the amount of cata-
lyst and compare with other nickel catalysts (Table 1). A
blank experiment in the absence of any nickel catalyst led
to the unmodified starting materials (entry 1). We were
On the other hand, and due to our ongoing interest on ac-
tive metals,13 we studied a mild methodology for the fast
synthesis of nickel(0) nanoparticles, from different nick-
el(II) chloride containing systems in THF, using lithium
SYNLETT 2009, No. 10, pp 1579–1582
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217333; Art ID: D03609ST
© Georg Thieme Verlag Stuttgart · New York

1580
F. Alonso et al.
LETTER
delighted to observe that our NiNP, in a 1:1 NiNP/sub- With regard to the stereochemistry, it is well known that
strate ratio, afforded stilbene in 77% isolated yield as a ca. semistabilised ylides, such as benzyl ylides, usually yield
1:1 cis/trans mixture after six hours at reflux (entry 2). At- mixtures of Z- and E-isomers.22 In particular, the reactions
tempts to decrease the NiNP/substrate ratio were, howev- with benzylidenetriphenylphosphorane and aromatic al-
er, unsuccessful (entry 3). It is noteworthy that under the dehydes are practically nonselective. A slight increase in
same conditions as in entry 2, the commercially available favour of the Z-stereoisomer (ca. 60:40) was described in
Raney nickel (entry 4), Ni-Al alloy (entry 5), and Ni/ the presence of a lithium salt,22 whereas a catalytic
SiO2–Al2O3 (entry 6) did not work at all.
amount of 18-crown-6 was reported to improve notably
the Z stereoselectivity.23 In our study, Z/E mixtures of stil-
benes were also obtained with low stereoselectivity, with
the E-isomer being normally the major one (up to ca. 1:4,
entry 5). In some cases, the purification step by column
chromatography allowed the separation of both stereoiso-
mers (entries 1–4, 6, and 12). Moreover, the isomerisation
of Z- to E-stereoisomers can be easily accomplished under
iodine catalysis.24 Thus, when a 57:43 Z/E mixture of 1-
(4-methoxyphenyl)-2-phenylethene was treated with a
catalytic amount of iodine in hexane at reflux, a quantita-
tive conversion into the corresponding E-stereoisomer
was achieved (Scheme 3).
Table 1 Wittig-Type Olefination of Benzyl Alcohol and Ben-
zylidenetriphenylphosphorane in the Presence of Different Nickel
Catalysts
Ni catalyst
Ph3P
Ph
+
Ph
OH
Ph
Ph
THF, reflux
Entry
Ni catalyst/substrate (mmol) Time (h) Yield (%)a
1
2
3
4
5
6
none
24
6
0
77b
0
NiNP 1:1
NiNP 1:10
24
24
24
24
Raney Ni 1:1
Ni–Al alloy 1:1
Ni/SiO2–Al2O3 1:1
0
Ph
Ph
I2 (cat.), hexane
0
reflux, 16 h
MeO
MeO
0
Z/E = 57:43
100% E
a GLC yield, unless otherwise stated.
Scheme 3 Iodine-catalysed Z/E isomerisation of 1-(4-methoxyphe-
nyl)-2-phenylethene
b Isolated yield after column chromatography as a ca. 1:1 cis/trans
mixture.
We must point out that the success of this olefination
methodology resides in the fact that hydrogen transfer
from the alcohol to the corresponding stilbene is not an ef-
fective process. In fact, we have never detected the re-
duced stilbene. This unexpected behaviour might be
attributed to a loss of the catalyst activity during the reac-
tion or to a preferential hydrogen transfer to some other
species present in the reaction medium. Experiments to
test the possible hydrogen transfer from benzyl alcohol to
either the phosphorus ylide of triphenylphosphane oxide
failed. In addition, we found out that the hydrogen transfer
from benzyl alcohol to added stilbene was substantially
depleted in the presence of the phosphorus ylide, triphe-
nylphosphane oxide, or triphenylphosphane.25 Moreover,
an increase in the size of the NiNP from 2.5 1.5 nm to
8–20 nm (before and after a standard reaction, respective-
ly) was observed by transmission electron microscopy.
Therefore, we can conclude that catalyst deactivation very
likely, accounts for this particular performance.
NiNP (1 equiv)
Ph3P
Ph
+
Ar
OH
Ar
Ph
THF, reflux
Scheme 2 Reagents and conditions: alcohol (1 mmol), phosphorus
ylide (1 mmol), NiNP (1 mmol), THF (4 mL).
The optimised reaction conditions (Scheme 2) were ex-
tended to a variety of benzyl alcohols (Table 2).19 Both the
reaction time and yield were shown to be very dependent
on the electronic character and position of the substituent.
For instance, 4-methylbenzyl alcohol and 3-methylbenzyl
alcohol provided the corresponding stilbenes in high
yields after eight hours (entries 2 and 3). In contrast, 2-
methylbenzyl alcohol (entry 4) did not react under the
standard conditions. Interestingly, the expected stilbene
could be formed when the phosphorus ylide was in situ
generated from benzyltriphenylphosphonium chloride
and metal lithium in a one-pot reaction.20 The electron-
deficient trifluoromethyl-substituted benzyl alcohols dis-
played lower reactivity, furnishing the corresponding ole-
fins in moderate yields after longer heating (entries 5 and
6). Moderate-to-good yields of methoxy-substituted stil-
benes were achieved (entries 7–9), the reaction being fast-
er when the substituent was located at the para- and meta-
positions. Other benzyl alcohols such as furan-2-ylmetha-
nol or some polymethoxylated benzyl alcohols furnished
the expected alkenes in good isolated yields (entries 10–
12). The latter results are promising in relation with the
synthesis of resveratrol analogues.21
In summary, we have demonstrated that nickel, in the
form of nanoparticles, can promote the Wittig-type reac-
tion of benzyl alcohols and benzylidenetriphenylphospho-
rane in THF under reflux. The corresponding stilbenes are
obtained in modest-to-high isolated yields, depending on
the electronic character of the substituent and position in
the aromatic ring. The Z/E mixtures can be separated, in
some cases, by column chromatography or quantitatively
transformed into the E-stereoisomers by iodine-catalysed
isomerisation. To the best of our knowledge, this is the
first metal-mediated chemoselective Wittig-type olefina-
Synlett 2009, No. 10, 1579–1582 © Thieme Stuttgart · New York

LETTER
Synthesis of Stilbenes from Alcohols
1581
Table 2 Wittig-Type Olefination of Benzyl Alcohols and Benzylidenetriphenylphosphorane Promoted by Nickel Nanoparticles
Entry
1
Alcohol
Time (h)
6
Producta
Z/Eb
Yield (%)c
77
Ph
OH
OH
51:49
(Z = 36, E = 41)
Ph
81
OH
2
3
8
8
36:64
42:58
(Z = 31, E = 50)
Ph
Ph
86
(Z = 41, E = 45)
28
4d
44:56
21:79
OH
4
5
(Z = 18, E = 10)
Ph
OH
30
41
F3C
F3C
Ph
OH
51
6
7
8
24
4
25:75
57:43
53:47
(Z = 13, E = 38)
CF3
CF3
Ph
OH
67
62
MeO
MeO
Ph
Ph
OH
OH
4
OMe
OMe
9
20
6
36:64
51:49
83
70
OMe
OH
OMe
10
Ph
O
O
MeO
MeO
Ph
Ph
OH
OH
11
12
15
24
24:76
47:53
67
OMe
OMe
OMe
MeO
MeO
MeO
MeO
70
(Z = 30, E = 40)
OMe
a All isolated products were ≥95% pure (GLC and/or 1H NMR).
b Z/E ratio determined from the reaction crude by GLC and/or 1H NMR.
c Isolated yield after column chromatography, in parenthesis the isolated yield for each stereoisomer.
d Benzylidenetriphenylphosphorane was in situ generated from benzyltriphenylphosphonium chloride and metal Li.
tion reaction with alcohols, in which there is no standard
redox step.26 Moreover, the reaction proceeds in the ab-
sence of any additive as a hydrogen acceptor. Further
research to widen the scope of this methodology to other
alcohols and phosphorus ylides is under way.
Acknowledgment
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC; grant no. CTQ2007-65218 and Conso-
lider Ingenio 2010-CSD2007-00006). P.R. thanks the MEC for a
predoctoral grant.
Synlett 2009, No. 10, 1579–1582 © Thieme Stuttgart · New York

1582
F. Alonso et al.
LETTER
and monitored by GLC-MS. The resulting mixture was
References and Notes
diluted with EtOAc (10 mL), filtered through a pad
containing Celite, and the filtrate was dried over MgSO4.
The residue obtained after removal of the solvent (0.02 bar)
was purified by column chromatography (silica gel, hexane,
or hexane–EtOAc) to give the pure stilbene. The diastereo-
meric ratio was determined on the basis of the GC and 1H
NMR analyses.
Stilbene was characterized by comparison of its physical and
spectroscopic properties with those of a commercially
available sample (Aldrich). 1-(4-Methylphenyl)-2-phenyl-
ethene,27 1-(3-methylphenyl)-2-phenylethene,28 1-(2-
methylphenyl)-2-phenylethene,27 1-(4-trifluoromethylphenyl)-
-2-phenylethene,29 1-(3-trifluoromethylphenyl)-2-phenyl-
ethene,30 1-(4-methoxyphenyl)-2-phenylethene,31 1-(3-
methoxyphenyl)-2-phenylethene,31 1-(2-methoxyphenyl)-2-
phenylethene,32 1-(2-furyl)-2-phenylethene,33 1-(1,3-di-
methoxyphenyl)-2-phenylethene,31 and 1-(1,2,3-trimethoxy-
phenyl)-2-phenylethene34 were characterised by comparison
of their physical and spectroscopic data with those described
in the literature.
(1) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953,
580, 44.
(2) For reviews, see: (a) Maryanoff, B. E.; Reitz, A. B. Chem.
Rev. 1989, 89, 863. (b) Edmonds, M.; Abell, A. In Modern
Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH:
Weinheim, 2004, 1.
(3) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198.
(4) For a review, see: Taylor, R. J. K.; Reid, M.; Foot, J.; Raw,
S. A. Acc. Chem. Res. 2005, 38, 851.
(5) Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M. J. Org. Chem.
1997, 62, 9376.
(6) Shuto, S.; Niizuma, S.; Matsuda, A. J. Org. Chem. 1998, 63,
4489.
(7) Maiti, A.; Yadav, J. S. Synth. Commun. 2001, 31, 1499.
(8) MacCoss, R. N.; Balskus, E. P.; Ley, S. V. Tetrahedron Lett.
2003, 44, 7779.
(9) (a) Bressette, A. R.; Glover, L. C. IV Synlett 2004, 738.
(b) Shet, J.; Desai, V.; Tilve, S. Synthesis 2004, 1859.
(10) Pinacho Crisóstomo, F. R.; Carrillo, R.; Martín, T.; García-
Tellado, F.; Martín, V. S. J. Org. Chem. 2005, 70, 10099.
(11) Vatèle, J.-M. Tetrahedron Lett. 2006, 47, 715.
(12) For reviews, see: (a) Hamid, M. H. S. A.; Slatford, P. A.;
Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555.
(b) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J.
Dalton Trans. 2009, 753.
(13) For reviews, see: (a) Alonso, F.; Yus, M. Chem. Soc. Rev.
2004, 33, 284. (b) Alonso, F.; Yus, M. Pure Appl. Chem.
2008, 80, 1005.
(14) (a) Alonso, F.; Calvino, J. J.; Osante, I.; Yus, M. Chem. Lett.
2005, 34, 1262. (b) Alonso, F.; Calvino, J. J.; Osante, I.;
Yus, M. J. Exp. Nanosci. 2006, 1, 419.
(15) (a) Alonso, F.; Osante, I.; Yus, M. Adv. Synth. Catal. 2006,
348, 305. (b) Alonso, F.; Osante, I.; Yus, M. Synlett 2006,
3017. (c) Alonso, F.; Osante, I.; Yus, M. Tetrahedron 2007,
63, 93. (d) Alonso, F.; Riente, P.; Yus, M. ARKIVOC 2008,
(iv), 8.
(16) (a) Alonso, F.; Riente, P.; Yus, M. Tetrahedron 2008, 64,
1847. (b) Alonso, F.; Riente, P.; Yus, M. Tetrahedron Lett.
2008, 49, 1939.
(20) Following the general procedure but using double the
amount of lithium metal (28 mg, 4 mmol) and adding
successively the phosphonium salt and the alcohol to the
NiNP suspension.
(21) For a review, see: Ferré-Filmon, K.; Delaude, L.;
Demonceau, A.; Noels, A. F. Coord. Chem. Rev. 2004, 248,
2323.
(22) Yamataka, H.; Nagareda, K.; Ando, K.; Hanafusa, T. J. Org.
Chem. 1992, 57, 2865.
(23) Belluci, G.; Chiappe, C.; Lo Moro, G. Tetrahedron Lett.
1996, 37, 4225.
(24) Zhang, W.; Go, M. L. Eur. J. Med. Chem. 2007, 42, 841.
(25) It is known that phosphorus compounds can bind strongly to
metal centres, therefore, blocking the access of the substrate
to the active site: Widegren, J. A.; Finke, R. G. J. Mol. Catal.
A: Chem. 2003, 198, 317.
(26) This assertion is made on the basis that in every redox
process a species is oxidised at the same time that the oxidant
agent is reduced. In the present case, we assume that
dehydrogenation of the alcohol occurs leading to the
intermediate aldehyde (the ‘oxidation’ product). However,
other species resulting from a reduction step are not
detected.
(27) Xi, Z.; Liu, B.; Chen, W. J. Org. Chem. 2008, 73, 3954.
(28) Ito, Y.; Uozu, Y.; Dote, T.; Ueda, M.; Matsuura, T. J. Am.
Chem. Soc. 1988, 110, 189.
(29) Wang, Z.; Wnuk, S. F. J. Org. Chem. 2005, 70, 3281.
(30) Cui, X.; Li, J.; Zhang, Z.-P.; Fu, Y.; Liu, L.; Guo, Q.-X.
J. Org. Chem. 2007, 72, 9342.
(17) Alonso, F.; Riente, P.; Yus, M. Synlett 2008, 1289.
(18) (a) Alonso, F.; Riente, P.; Yus, M. Synlett 2007, 1877.
(b) Alonso, F.; Riente, P.; Yus, M. Eur. J. Org. Chem. 2008,
4908.
(19) General Procedure for the Wittig-Type Olefination with
Alcohols Promoted by Nickel Nanoparticles
n-BuLi (1.6 M, 625 mL, 1.0 mmol) was added dropwise to a
suspension of commercially available benzyltriphenyl-
phosphonium chloride (583 mg, 1.5 mmol) in THF (2 mL) at
0 °C. While the corresponding ylide was being formed (ca.
20 min), nickel(II) chloride (130 mg, 1 mmol) was added
over a suspension of lithium (14 mg, 2 mmol) and DTBB (13
mg, 0.05 mmol) in THF (2 mL) at r.t. under argon. The
reaction mixture, which was initially dark blue, changed to
black indicating that nickel(0) had been formed. After 10
min, the requisite benzyl alcohol (1 mmol) and the initially
prepared ylide suspension were added to the NiNP
suspension. The reaction mixture was warmed up to reflux
(31) Roberts, J. C.; Pincock, J. A. J. Org. Chem. 2004, 69, 4279.
(32) Aksin, O.; Türkmen, H.; Artok, L.; Çetinkaya, B.; Ni, C.;
Büyükgüngör, O.; Özkal, E. J. Organomet. Chem. 2006,
691, 3027.
(33) Cahiez, G.; Gager, O.; Lecomte, F. Org. Lett. 2008, 10,
5255.
(34) Azzena, U.; Dettori, G.; Idini, M. V.; Pisano, L.; Sechi, G.
Tetrahedron 2003, 59, 7961.
Synlett 2009, No. 10, 1579–1582 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.