Ruthenium-catalyzed tandem allylic substitution/isomerization: A direct route to propiophenones from cinnamyl chloride derivatives

Article abstract of DOI:10.1039/b801159a

A tandem nucleophilic substitution/redox isomerization catalyzed by a single ruthenium catalyst leads to the direct transformation of allylic chlorides into propiophenones. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Full text of DOI:10.1039/b801159a

View Article Online / Journal Homepage / Table of Contents for this issue
LETTER
www.rsc.org/njc | New Journal of Chemistry
Ruthenium-catalyzed tandem allylic substitution/isomerization: a direct
route to propiophenones from cinnamyl chloride derivatives
Marion Helou, Jean-Luc Renaud,* Bernard Demerseman, Franc¸ ois Carreaux and
Christian Bruneau*
Received (in Montpellier, France) 22nd January 2008, Accepted 28th March 2008
First published as an Advance Article on the web 15th April 2008
DOI: 10.1039/b801159a
A tandem nucleophilic substitution/redox isomerization cata-
lyzed by a single ruthenium catalyst leads to the direct trans-
formation of allylic chlorides into propiophenones.
nucleophilic substitution of allylic substrates by C-, N- and
O-nucleophiles to form branched products.8 With these ideas
in mind, we were interested in performing a sequence of
catalytic reactions to directly transform allylic substrates into
ketones.
Rapid and economical catalytic syntheses of target com-
pounds promoted by a single catalyst precursor are of utmost
interest with respect to green chemistry and sustainable devel-
opment. Efforts are therefore being made to generate well-
defined catalysts with multifunctional activities, with the
objective of performing successive transformations in a single
pot via tandem, cascade or sequential catalytic reactions.1
Among the variety of ruthenium complexes that have been
used for the redox isomerization of allylic alcohols into
ketones,2 ruthenium(II) complexes with a cyclopentadienyl
type ligand and ruthenium(IV) complexes featuring an allylic
ligand have emerged as very efficient catalytic systems. The
mononuclear RuCpCl(PPh3)2, Ru(indenyl)Cl(PPh3)2, [RuCp-
(MeCN)3]PF6, [RuCp(MeCN)2(PR3)]PF6 and RuCpCl(di-
phosphine)3 complexes have shown good catalytic activities
for the isomerization of aliphatic and aromatic allylic alcohols
into ketones or aldehydes at 65–100 1C. The binuclear ruthe-
nium catalyst [(Ru(CO)2)2(H)(C5Ph4OHOC5Ph4)] is also very
efficient for this type of isomerization and has led to faster
reactions than with the previous examples.4 More recently,
RuCp*Cl(Ph2PCH2CH2NH2)5 and Ru(C5MePh4)X(CO)2
(X = Br, Cl)6 complexes have been shown to be very active
Cp-containing ruthenium isomerization catalysts, which oper-
ate close to ambient temperature with a large scope of
substrates.
We report here the direct transformation of cinnamyl
derivatives into propiophenones, useful precursor substrates
leading towards biologically-active substances, via a regio-
selective substitution by hydroxide ion, followed by isomer-
ization catalyzed by [RuCp*(MeCN)3]PF6, as shown in
eqn (1).
ð1Þ
The reaction of phenylboronic acid (2), which has already
been used in ruthenium-catalyzed C–C bond formation in
Heck- and Suzuki–Miyaura-type reactions,9 and aromatic
arylation,10 did not lead to phenyl group transfer but to
regioselective hydroxy group transfer onto the allylic moiety.
In addition, this transfer was followed by the Cp*Ru-cata-
lyzed isomerization of the initial allylic alcohol into the
corresponding ketone. Thus, when 0.5 mmol of para-benzyl-
oxycinnamyl chloride (1) and 0.6 mmol of 2 (1.2 equiv.) were
reacted in 1 ml of acetonitrile at room temperature for 16 h in
the presence of 2.6 equiv. of K2CO3 and 0.015 mmol of
[RuCp*(MeCN)3]PF6 (3 mol%), para-benzyloxypropiophe-
none (3) was isolated in 87% yield as the sole reaction product
(eqn (2)).
Ruthenium(IV) complexes bearing the bis(allyl) dodeca-
2,6,10-triene-1,12-diyl (L1)7a or 2,7-dimethylocta-2,6-dien-
1,8-diyl (L2)7b ligand in RuCl2(L1), [RuCl2(L2)]2,
RuCl2(L)(L2) and RuCl(L2)(MeCN)2]SbF6 (L = CO, phos-
phine, tBuNC, MeCN or PhNH2) have also shown very high
turnover frequencies in the redox isomerization of allylic
alcohols into carbonyl compounds, both in organic solvents
and in water at 75 1C.
On the other hand, ourselves and others have shown that
Cp*Ru(II) complexes are able to activate allylic halides and
carbonates, and generate Ru(IV) species bearing an allylic
ligand, which are efficient catalysts for the regioselective
ð2Þ
We showed that no reaction took place in the absence of
either the ruthenium catalyst or 2, which indicates that the
boronic acid was the hydroxide source and that the reaction
was catalyzed by a ruthenium species. Without a boron
activator, no reaction took place. Cesium carbonate and
potassium fluoride had a positive effect on the reactivity,
and the best results were obtained with potassium carbonate.
´
UMR 6226, Sciences Chimiques de Rennes, CNRS-Universite de
Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France. E-mail:
jean-luc.renaud@univ-rennes1.fr. E-mail: christian.bruneau@univ-
rennes1.fr; Fax: +33 (0)223236939; Tel: +33 (0)223236283
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2008
New J. Chem., 2008, 32, 929–931 | 929

View Article Online
When water was used as a hydroxide source under basic
conditions, no reaction took place, and when the reaction
was carried out with 2 in the presence of K2CO3, introduced as
an aqueous solution (0.5 M), the yields drastically decreased.
We anticipate that this transformation took place via, firstly,
allylic activation by [RuCp*(CH3CN)3]PF6, resulting in the
regioselective formation of the internal allylic alcohol 4,
followed by isomerization into ketone 3, catalyzed by the
metal species generated from the same ruthenium precursor.
According to the definitions proposed by Fogg and dos
Santos,1a this sequence corresponds to an auto-tandem cata-
lytic transformation. Indeed, we showed that the reaction at
room temperature was fast, and that branched alcohol 4 was
present at the beginning of the reaction but disappeared
completely after 3 h, whereas no linear alcohol, 5, could be
detected. After a 1.5 h reaction time, substrate 1 was com-
pletely converted into 3 and 4 in a 54 : 46 ratio, and after 3 h
only 3 was observed. In a parallel experiment, we showed that
the linear alcohol 5 was isomerized into the corresponding
aldehyde under our catalytic conditions, but that the reaction
was much slower, as only 67% conversion of 5 into the
aldehyde was obtained after 16 h at room temperature. This
is in line with previous results from the literature, which point
out the higher reactivity of internal allylic alcohols when
forming ketones than primary alcohols when forming
aldehydes.6,7
However, the delivery of the nucleophile via a boron inter-
mediate is less common. It has been exemplified in a few cases
by the palladium-catalyzed substitution of 1,3-diphenylprope-
nyl acetate by an alkoxy group using B(OR)3 in the presence of
K2CO3 or KF as an additive,12 and in the intramolecular
delivery of an alkoxy nucleophile from a borate formed in
situ.13 An interaction between the Lewis acid site of the
boronic acid and a halide, leading to a borate-type intermedi-
ate, might favour the controlled delivery of the hydroxy group
to the reactive allylic ligand.
In conclusion, we have described a new example of tandem
catalysis initiated by Cp*-ruthenium catalysts14 based on the
allylic substitution and isomerization of allylic derivatives,
which affords propiophenones directly from cinnamyl chloride
derivatives at room temperature. Aromatic ketones are avail-
able by Friedel–Crafts synthesis, but even though pure syn-
thetic relevance is not the strongest point of this new
methodology, this sequence represents the first example of
such a one-pot transformation of allylic substrates into pro-
piophenones in the presence of ruthenium catalysts in organic
solvents under mild conditions, with an unexpected role for 2,
which may offer an alternative to hydroxide sources and
aqueous media.
Under the catalytic conditions of eqn (2), the propiophe-
nones 6–8 were obtained in good yields after a 16 h reaction
time from para-methoxy-, para-dimethylamino- and 2,4,6-
trimethoxy-phenylprop-3-en-1-yl chloride, respectively.
Experimental
General procedure
In a Schlenk tube, 0.5 mmol of cinnamyl chloride, 0.6 mmol of
boronic acid, 1.3 mmol of K2CO3 and 0.015 mmol of
[Cp*Ru(CH3CN)3]PF6 (3 mol%) were added to 1 ml of
acetonitrile under an argon atmosphere. The reaction mixture
was then stirred for 16 h at room temperature. In the case of 3,
this reaction time was optimized to a much shorter 3 h. The
product was isolated by purification over silica gel with a 9 : 1
heptane/diethyl ether mixture as the eluent. NMR analyses
were performed in CDCl3 on a 200 MHz Bruker spectrometer.
The isolated propiophenones are known compounds and their
NMR analyses are in agreement with published data.
1-(4-Benzyloxyphenyl)propan-1-one (3). 1H NMR (200
MHz, CDCl3): d 8.00 (d, 2H, J = 8.8 Hz), 7.50–7.30 (m,
5 H), 7.00 (d, 2H, J = 8.8 Hz), 5.10 (s, 2H), 2.95 (q, 2H,
J = 7.3 Hz) and 1.20 (t, 3H, J = 7.3 Hz).
1-(4-Methoxyphenyl)propan-1-one (6). 1H NMR (200
MHz, CDCl3): d 8.00 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J =
8.8 Hz), 3.95 (s, 3H), 3.05 (q, 2H, J = 7.3 Hz) and 1.20 (t, 3H,
J = 7.3 Hz).
1-(4-Dimethylaminophenyl)propan-1-one (7). 1H NMR
(200 MHz, CDCl3): d 8.00 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H,
J = 8.8 Hz), 3.00 (s, 6H), 2.95 (q, 2H, J = 7.3 Hz) and 1.20
(t, 3H, J = 7.3 Hz).
It is noteworthy that though all the cinnamyl substrates
tested under the catalytic conditions of eqn (2) led to allylic
alcohols, only those with a phenyl ring substituted by one or
several groups having an electron-donating mesomeric effect
(alkoxy, dialkylamino) underwent the isomerization reaction.
On the other hand, treatment with cinnamyl chloride or 3-
naphthylprop-2-enyl chloride at room temperature led to the
formation of the branched allylic alcohols 9 and 10 in 77 and
90% yields, respectively, with high regioselectivity (branched/
linear ratio = 98 : 2 and 100 : 0, respectively).11 Even after 16
h at 90 1C, only 18% of propiophenone was formed, alongside
the 57% of branched 1-phenylprop-2-en-1-ol (9) and 25% of
linear 3-phenylprop-2-en-1-ol, showing that the allylic alcohol
intermediates with no electron-donating substituents were not
easily isomerized into carbonyl compounds.
As far as the mechanisms of these tandem reactions are
concerned, the ruthenium-catalyzed isomerization of allylic
alcohols into carbonyl compounds is well documented.3b,6,7b
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2008
930 | New J. Chem., 2008, 32, 929–931

View Article Online
1-(2,4,6-Trimethoxyphenyl)propan-1-one (8). 1H NMR
(200 MHz, CDCl3): d 6.10 (s, 2H), 3.85 (s, 9H), 2.95 (q, 2H,
J = 7.3 Hz) and 1.20 (t, 3H, J = 7.3 Hz).
8 (a) M. D. Mbaye, B. Demerseman, J.-L. Renaud, L. Toupet and C.
Bruneau, Angew. Chem., Int. Ed., 2003, 42, 5066; (b) M. D. Mbaye,
B. Demerseman, J.-L. Renaud, L. Toupet and C. Bruneau, Adv.
Synth. Catal., 2004, 346, 835; (c) J.-L. Renaud, C. Bruneau, B.
Demerseman and M. D. Mbaye, Curr. Org. Chem., 2006, 10, 115;
(d) C. Bruneau, J.-L. Renaud and B. Demerseman, Chem.–Eur. J.,
2006, 12, 5178; (e) B. M. Trost, P. L. Fraisse and Z. T. Ball, Angew.
Chem., Int. Ed., 2002, 41, 1059; (f) T. Kondo, H. Ono, N. Satake,
T. Mitsudo and Y. Watanabe, Organometallics, 1995, 14, 1945; (g)
R. Hermatschweiler, I. Fernandez, P. S. Pregosin and F. Breher,
Organometallics, 2006, 25, 1440; (h) I. Fernandez, R. Hermatsch-
weiler, P. S. Pregosin, A. Albinati and S. Rizzato, Organometallics,
References
1 (a) D. Fogg and E. N. dos Santos, Coord. Chem. Rev., 2004, 248,
2365; (b) L. F. Tietze, Chem. Rev., 1996, 96, 115; (c) Metal
Catalyzed Cascade Reactions, Topics in Organometallic Chemistry,
ed. T. J. J. Muller, Springer, Berlin, Heidelberg, 2006, vol. 19; (d)
¨
A. Ajamian and J. L. Gleason, Angew. Chem., Int. Ed., 2004, 43,
2006, 25, 323; (i) S. Constant, S. Tortoioli, J. Muller and J. Lacour,
Angew. Chem., Int. Ed., 2007, 46, 2082.
¨
3754.
2 R. Uma, C. Crevisy and R. Gree, Chem. Rev., 2003, 103, 27.
´ ´
9 (a) E. J. Farrington, J. M. Brown, C. F. J. Barnard and E. Rowsell,
Angew. Chem., Int. Ed., 2002, 41, 169; (b) Y. Na, S. Park, S. B.
Han, H. Han, S. Ko and S. Chang, J. Am. Chem. Soc., 2004, 126,
250.
10 (a) F. Kakiuchi, Y. Matsuura, S. Kan and N. Chatani, J. Am.
Chem. Soc., 2005, 127, 5936; (b) F. Kakiuchi, S. Kan, K. Igi, N.
Chatani and S. Murai, J. Am. Chem. Soc., 2003, 125, 1698.
11 A. Bouziane, M. Helou, B. Carboni, F. Carreaux, B. Demerseman,
C. Bruneau and J.-L. Renaud, Chem.–Eur. J., 2008, 14, DOI:
10.1002/chem.200702030, in press.
3 (a) B. M. Trost and R. J. Kulawiec, Tetrahedron Lett., 1991, 32,
3039; (b) B. M. Trost and R. J. Kulawiec, J. Am. Chem. Soc., 1993,
115, 2027; (c) C. Slugovc, E. Ruba, R. Schmid and K. Kirchner,
¨
Organometallics, 1999, 18, 4230; (d) R. C. van der Drift, M. Vailati,
E. Bouwman and E. Drent, J. Mol. Catal. A: Chem., 2000, 159,
163; (e) R. C. van der Drift, M. Gagliardo, H. Kooijman, A. L.
Spek, E. Bouwman and E. Drent, J. Organomet. Chem., 2005, 690,
1044.
4 J.-E. Backvall and U. Andreasson, Tetrahedron Lett., 1993, 34,
5459.
¨
12 Y. Hamada, N. Seto, Y. Takayanagi, T. Nakano and O. Hara,
Tetrahedron Lett., 1999, 40, 7791.
13 (a) B. M. Trost, E. J. McEachern and F. D. Toste, J. Am. Chem.
Soc., 1998, 120, 12702; (b) B. M. Trost, B. S. Brown, E. J.
McEachern and O. Kuhn, Chem.–Eur. J., 2003, 9, 4442.
5 M. Ito, S. Kitahara and T. Ikariya, J. Am. Chem. Soc., 2005, 127,
6172.
6 B. Martin-Matute, K. Bogar, M. Edin, F. B. Kaynak and J.-E.
Backvall, Chem.–Eur. J., 2005, 11, 5832.
¨
7 (a) V. Cadierno, S. E. Garcia-Garrido and J. Gimeno, Chem.
Commun., 2004, 232; (b) V. Cadierno, S. E. Garcia-Garrido, J.
Gimeno, A. Varel-Alvarez and J. A. Sordo, J. Am. Chem. Soc.,
2006, 128, 1360.
14 C. Bruneau, S. Derien and P. H. Dixneuf, in Topics in Organome-
´
tallic Chemistry, ed. T. J. J. Muller, Springer, Berlin, Heidelberg,
2006, vol. 19, pp. 295–326.
¨
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2008
New J. Chem., 2008, 32, 929–931 | 931