A versatile ruthenium catalyst for C-C bond formation by C-H bond activation

Article abstract of DOI:10.1002/anie.200603786

(Chemical Equation Presented) Easily modified: the electronic and steric properties of a ruthenium catalyst highly active for C-H bond activation (see scheme) can be modified by fine-tuning the ligand. This makes this catalytic system very versatile as it

Full text of DOI:10.1002/anie.200603786

Communications
such processes, along with, in certain cases, [Ru3(CO)12].[7] No
other ruthenium complexes with such high catalytic activity
have been found even though several attempts have been
made to prepare analogous compounds.[8] One exception
concerns the use of the highly reactive and unstable complex
[RuH2(H2)(PCy3)2] (Cy = cyclohexyl) developed by Chaudret
et al.[9]
À
C H Bond Activation
DOI: 10.1002/anie.200603786
À
AVersatile Ruthenium Catalyst for C C Bond
Formation by C H Bond Activation**
À
We report herein the generation of low-valent and flexible
RØmi Martinez, Reynald Chevalier, Sylvain Darses,*
and Jean-Pierre Genet*
À
ruthenium catalysts in situ that are highly active in C H bond
activation, particularly in the Murai reaction.Our initial idea
was to generate {RuH2} species as precursors to the ruthe-
nium(0) catalyst[10] from commercial or easily available
ruthenium(II) sources by reaction with a hydride donor.
The activity of various catalytic systems was evaluated by the
reaction of a-tetralone (1a) with triethoxyvinylsilane (2a) in
toluene at 1408C (Scheme 1).
[1]
À
Catalytic processes involving C H bond activation are
highly desirable as they allow the functionalization of more-
easily available starting materials (atom economy concept[2])
and also because they produce clean reactions (reduced
amounts of salts).In the field of C C bond formation by C H
activation, several catalytic reactions have been developed
recently involving mainly low-valent transition metals,[1] such
as palladium, rhodium, and particularly ruthenium com-
plexes, which have been extensively used in this field.[3]
The most active catalysts involve low-valent ruthenium
complexes with oxidation states 0 or II, such as [Ru(cod)-
À
À
Scheme 1. Use of an in situ generated ruthenium catalyst in the Murai
reaction.
(cot)]
(cod = cyclooctadiene,
cot = cyclooctatetraene),
[Ru3(CO)12], [RuH2(PPh3)4], and [RuH2(CO)(PPh3)3],
because of their high activity both in stoichiometric and
catalytic reactions.[3] However, these low-valent catalyst
precursors have low activity and/or are generally air- and
moisture-sensitive and must therefore be stored under an
inert atmosphere at low temperature to prevent their
decomposition.Moreover, their synthesis is generally not
obvious and requires several preparative and purification
steps from commercially available RuCl3.Furthermore, their
preparation does not allow the complexation of a large variety
of ligands, which limits their scope.The generation of low-
valent active ruthenium species in situ under mild conditions
would therefore be a highly desirable improvement in terms
of simplicity, flexibility, and scope of these catalytic systems.
We tested the feasibility of this approach in one of the
We were pleased to find that the reaction between easily
available [{Ru(p-cymene)Cl2}2] and a formate salt generated a
highly active catalyst that provided the expected coupling
adduct in quantitative yield in the presence of triphenylphos-
phane as ligand (Table 1, entry 2).Among the various
possible counter cations for the formate salts,[11] sodium and
thallium were found to be the best as they gave faster initial
reaction rates.However, because of the high toxicity of
thallium derivatives, only the sodium salt was used in
subsequent studies.Thus, reaction of ketone 1a with tri-
Table 1: Ligand screening in the Murai-type reaction.[a]
À
most efficient ruthenium(0)-catalyzed processes involving C
Entry
Ligand
Conversion [%][b]
after 3 h after 21 h
H bond activation, namely the Murai reaction.[4] This
reaction, and its subsequent variations,[5,6] involves C H
À
bond activation in the ortho position of an electron-with-
drawing substituent, such as oxo, imino, or cyano, and
subsequent insertion of an alkene.The ruthenium complex
[RuH2(CO)(PPh3)3] has been found to be the most active in
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
none
PPh3
0
99
3
97
0
90
54
16
1
2
2
0
0
0
100
94
100
0
93
94
55
62
8
P(p-tolyl)3
P(m-tolyl)3
P(o-tolyl)3
P(4-CF3C6H4)3
P(4-MeOC6H4)3
P(2-furyl)3
PCyPh2
PCy2Ph
PCy3
P(OEt)3
P(OPh)3
dppe
[*] R. Martinez, Dr. R. Chevalier, Dr. S. Darses, Prof. J.-P. Genet
Laboratoire de Synth›se SØlective Organique (UMR 7573, CNRS)
Ecole Nationale SupØrieure de Chimie de Paris
11 rue P&MCurie, 75231 Paris cedex 05 (France)
Fax: (+33)1-4407-1062
5
0
0
0
E-mail: sylvain-darses@enscp.fr
jean-pierre-genet@enscp.fr
0
0
[**] This work was supported by the Centre National de la Recherche
Scientifique (CNRS). R.M. thanks the Minist›re de l’Education et de
la Recherche for a grant. R.C. thanks Rhodia-Silicone for financial
support. We thank Dr. GØrard Mignani (Rhodia-Silicone) for fruitful
discussions.
dppf
0
[a] Reactions conducted with 1 mmol of 1a, 2 equiv of 2a, 2.5 mol%
[{Ru(p-cymene)Cl2}2], and 3 equiv of ligand compared to Ru for
monodentate ligands (1 equiv for bidentate ligands), in toluene at
1408C. [b] Conversion determined by GC. dppe=1,2-bis(diphenylphos-
phino)ethane, dppf=1,1’-bis(diphenylphosphino)ferrocene.
Supporting Information for this article is available on the WWW
under http://www.angewandte.org or from the author.
8232
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 8232 –8235

Angewandte
Chemie
ethoxyvinylsilane (2a) in the presence of 5 mol% [{Ru(p-
cymene)Cl2}2], 15 mol% triphenylphosphane, and 30 mol%
NaHCO2 in toluene at 1408C afforded the expected product
in quantitative yield in less than two hours, a result that
compares well with those obtained with the classical complex
[RuH2(CO)(PPh3)3].
confirmed by the reaction with another aromatic ketone,
namely 1-acetonaphthone (1b; Figure 1b).Once again, a very
fast reaction was achieved with three equivalents of triphe-
nylphosphane, whereas with two equivalents an induction
period was observed.It is also of note that ketone 1b is even
more reactive than 1a—100% conversion was obtained in
less than 20 minutes.
We next decided to conduct a ligand screening to further
improve the reactivity of this catalytic system and to
demonstrate its versatility (see Table 1 for selected exam-
ples).From these results, it appears that only a few ligands are
suitable, mainly tri(aryl)phosphanes (Table 1, entries 2–7).
The bidentate ligands tested did not produce any catalytic
activity (Table 1, entries 14 and 15) and the highest conver-
sions were achieved with triphenylphosphane (Table 1,
entry 2).It is also of note that the degree of steric hindrance
provided by the phosphane ligand has a strong influence on
the reaction course (the reactivity decreases with an increase
of the cone angle[12]).Thus, tri( o-tolyl)phosphane (Table 1,
entry 5) did not allow the formation of the expected adduct,
whereas quantitative conversion was achieved under identical
conditions with the meta or para isomers (Table 1, entries 3
and 4).The electronic nature of the ligand also greatly
influences the kinetic course of the reaction, with electron-
donating substituents retarding the coupling (Table 1, com-
pare entries 6 and 7).Indeed, from these preliminary results it
appears that electron-poor and nonhindered tri-
(aryl)phosphane ligands are the most suitable for this
reaction.
Under these optimal conditions, very high yields of
coupling products were achieved for a variety of aromatic
methyl ketones (Table 2).All reactions were conducted with
two equivalents of alkene, which explains the formation of
disubstituted products, but, by careful control of the number
of equivalents, it was possible, in many cases, to obtain the
mono-substituted acetophenones exclusively.As shown in
Table 2, these conditions are compatible with a bromo
Table 2: The Murai reaction with the herein presented in situ generated
ruthenium catalyst.[a]
Entry
1
2
a
Product
Time [h]
1
Yield [%][b]
100 (85/15)
We next turned our attention to determining the optimal
ratio between the triphenylphosphane ligand and the ruth-
enium(II) precursor, with a-tetralone (1a) as the aromatic
ketone (Figure 1a).The reaction conducted with one equiv-
2
3
4
a
a
a
2
0.5
20
92 (50/50)
100 (75/25)
70[c] (100/0)
5
a
1.5
99[d] (100/0)
6
7
8
9
a
a
b
c
4
2
85
100
97
Figure 1. Influence of the amount of triphenylphosphane on the
reaction profile for ketones 1a (a) and 1b (b). Gray circles: 1 equiv;
gray rhombi: 2 equiv; black squares: 3 equiv; black triangles: 4 equiv.
alent of PPh3 led to partial decomposition of the catalyst and
low conversion.At least two equivalents of triphenylphos-
phane were needed, with optimal reaction rates being
achieved with three equivalents of ligand.This result can be
compared with that obtained with the most active ruthenium
catalyst described for this reaction, namely [RuH2(CO)-
(PPh3)3].[4] Indeed, we have demonstrated that only the
triphenylphosphane ligand, in the stoichiometry described
above, is a requisite as CO is mainly a spectator ligand in the
[RuH2(CO)(PPh3)3] catalyst precursor.[13] The stoichiometry
of the added ligand compared to ruthenium was further
5
20
89
[a] Reactions conducted with 1 mmol of ketone 1, 2 equiv of vinylsilane 2,
2.5 mol% [{Ru(p-cymene)Cl2}2], and 15 mol% of PPh3, in toluene at
1408C. [b] Yields of isolated product, with the percentages of mono- and
disubstituted products in parentheses. [c] Regioselectivity 85/15.
[d] With 3 equiv of 2a.
Angew. Chem. Int. Ed. 2006, 45, 8232 –8235
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8233

Communications
substituent (Table 2; entry 4, no oxidative addition is
yield with high regioselectivity, the anti-Markovnikov adduct
being formed for the first time in a 95/5 ratio (Scheme 4).
It is also noteworthy that the reaction can be conducted
under solvent-free conditions, which makes it attractive from
observed) and with heterocyclic ketones (Table 2; entries 6
and 7).Moreover, a high regioselectivity was observed with
meta-substituted acetophenones (Table 2; entries 4 and 5),
with a complexing substituent (Table 2; entry 5) or steric
effects (Table 2; entry 4) also influencing the regioselectiv-
ity.[5] Other alkenylsilanes participated equally well in the
reaction (Table 2, entries 8 and 9).
The present reaction conditions are not limited to
acetophenones.For example, the a,b-unsaturated amide 4
reacts with vinylsilane 2a at 1208C to afford amide 5 in high
yield (Scheme 2).[14] The double bond in adduct 5 has been
isomerized to the b,g-position, with an 85/15 isomeric ratio of
this bond in favor of the (E) isomer.
Scheme 4. Coupling with styrene.
an environmental point of view, and it can be scaled-up easily
without altering the yields (Scheme 5).Indeed, reaction of
50 mmol of 1b (7.6 mL) with three equivalents of trimethoxy-
vinylsilane (2d, 23 mL) without any solvent afforded a 45%
yield of pure 3n with only 0.04 mol% of ruthenium (turnover
number (TON) = 1125).Adduct 3n was obtained directly by
distillation from the reaction mixture.
Scheme 2. The Murai reaction with an a,b-unsaturated amide.
The versatility of this in situ generated catalyst was further
confirmed by extending the reaction to other substrates,
particularly to imine derivatives.Indeed, under standard
Murai conditions, that is, with [RuH2(CO)(PPh3)3] as catalyst,
aromatic imines fail to react and the use of [Ru3(CO)12] has
proved to be more appropriate.[4,15,16] A rapid screening of
substrates revealed that aromatic aldimines react well with
our catalytic system.Indeed, reaction of 6 and vinylsilane 2a
in the presence of only one equivalent of triphenylphosphane
(instead of the usual three equivalents) compared to ruthe-
nium afforded the expected imine in 100% conversion and,
after hydrolysis, the expected aldehyde 7 in quantitative yield
(Scheme 3), with the reaction being 10-times faster than with
[Ru3(CO)12] under identical conditions.
À
Scheme 5. A large-scale C H bond activation reaction under solvent-
free conditions.
In summary, we have demonstrated for the first time the
possibility of generating a highly active ruthenium catalyst for
C H bond activation in situ from stable and easily available
À
ruthenium(II) sources and that this catalyst has a similar or
higher activity than the Murai catalyst, depending on the
substrates.The versatility of this catalytic system lies in the
fact that the electronic and steric properties of the catalyst can
be fine-tuned by varying the ligands, thus allowing the
functionalization of various substrates.Further work is
underway to extend the applications of this catalytic system,
and to determine the nature of the active ruthenium species
generated under these conditions.
À
Scheme 3. C H bond activation of aldimines.
Received: September 14, 2006
Published online: November 16, 2006
To further demonstrate the versatility of the catalytic
system, we turned our attention to the extension of this
reaction to other alkenes.As reported previously, one of the
main limitations of the Murai reaction is the low number of
compatible alkenes and the lack of regioselectivity with other
alkenes.[5] For example, the reaction of ketone 1b with styrene
(8) affords the coupled product with a 60/40 linear/branched
product ratio (l/iso) using our catalyst (with three equivalents
of PPh3).[17] Once again a ligand screening proved to be
fruitful, and we were pleased to find that the use of
dicyclohexylphenylphosphane instead of triphenylphosphane
in the reaction of 1b with 8 gave the coupled product 9 in 92%
À
Keywords: alkenes · C H activation · homogeneous catalysis ·
ketones · ruthenium
.
[1] Reviews: a) A.E. Shilov, G.B. Shulꢀpin, Chem. Rev. 1997, 97,
2879 – 2932; b) F.Kakiuchi, S.Murai in Topics in Organometallic
Chemistry, Vol. 3 (Ed.: S. Murai), Springer, Berlin, 1999, pp.47 –
79; c) G.Dyker, Angew. Chem. 1999, 111, 1808 – 1822; Angew.
Chem. Int. Ed. 1999, 38, 1698 – 1712; d) Y.Guari, S.Sabo-
Etienne, B.Chaudret, Eur. J. Inorg. Chem. 1999, 1047 – 1055;
e) C.Jia, T.Kitamura, Y.Fujiwara,
633 – 639; f) V.Ritleng, C.Sirlin, M.Pfeffer, Chem. Rev. 2002,
Acc. Chem. Res. 2001, 34,
8234
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 8232 –8235

Angewandte
Chemie
102, 1731 – 1769; g) F.Kakiuchi, N.Chatani, Adv. Synth. Catal.
2003, 345, 1077 – 1101; h) A.R.Dick, M.S.Sanford, Tetrahedron
2006, 62, 2339 – 2463.
[16] For a related rhodium-catalyzed process see: a) C.-H. Jun, J.-B.
Hong, Y.-H. Kim, K.-Y. Chung, Angew. Chem. 2000, 112, 3582 –
3584; Angew. Chem. Int. Ed. 2000, 39, 3440 – 3442; b) C.-H. Jun,
C.W.Moon, J-.B.Hong, S-.G.Lim, K-.Y.Chung, Y-.H.Kim,
[2] a) B.M. Trost, Science 1991, 254, 1471 – 1477; b) B.M. Trost,
Angew. Chem. 1995, 107, 285 – 307; Angew. Chem. Int. Ed. Engl.
1995, 34, 259 – 281; c) B.M.Trost, Acc. Chem. Res. 2002, 35, 695 –
705; d) M. Eissen, R. Mazur, H.-G. Quebbemann, K.-H.
Pennemann, Helv. Chim. Acta 2004, 87, 524 – 535.
[3] a) M.A. Bennett, T.W. Matheson in Comprehensive Organo-
metallic Chemistry, Vol. 4 (Eds.: G. Wilkinson, F. G. A. Stone,
E.W. Abel), Pergamon, Oxford, 1982, p.931; b) D.F. Shriver,
M.I. Bruce in Comprehensive Organometallic Chemistry II,
Vol. 7 (Eds:. E.W.Abel, F.G.A.Stone, G.Wilkinson), Perga-
mon, Oxford, 1995; c) T.Naota, H.Takaya, S-.I.Murahashi,
Chem. Rev. 1998, 98, 2599 – 2660; d) T.Mitsudo, T.Kondo,
Synlett 2001, 309 – 321; e) B.M.Trost, F.D.Toste, A.B.Pinker-
ton, Chem. Rev. 2001, 101, 2067 – 2096; f) Ruthenium in Organic
Synthesis (Ed.: S.-I. Murahashi), Wiley-VCH, Weinheim, 2004;
Chem. Eur. J. 2002, 8, 485 – 492; c) S.-G. Lim, J.-A. Ahn, C.-J.
Jun, Org. Lett. 2004, 6, 4687 – 4690; d) R.K.Thalji, J.A.Ellman,
R.G.Bergman, J. Am. Chem. Soc. 2004, 126, 7192 – 7193.
[17] Similar results were obtained with the Murai catalyst
[RuH2(CO)(PPh3)3] (l/iso = 70/30): see ref.[5].
g) B.M. Trost, M.U. Frederiksen, M.T. Rudd,
Angew. Chem.
2005, 117, 6788 – 6825; Angew. Chem. Int. Ed. 2005, 44, 6630 –
6666.
[4] S.Murai, F.Kakiuchi, S.Sekine, Y.Tanaka, A.Kamatani, M.
Sonoda, N.Chatani, Nature 1993, 366, 529 – 530.
[5] a) F.Kakiuchi, S.Sekine, Y.Tanaka, A.Kamatani, M.Sonoda, N.
Chatani, S.Murai, Bull. Chem. Soc. Jpn. 1995, 68, 62 – 83; b) M.
Sonoda, F.Kakiuchi, N.Chatani, S.Murai, Bull. Chem. Soc. Jpn.
1997, 70, 3117 – 3128; c) review: F.Kakiuchi, S.Murai,
Chem. Res. 2002, 35, 826 – 834.
Acc.
[6] For the ruthenium-catalyzed coupling of aromatic ketones with
aryl boronates see: a) F.Kakiuchi, S.Kan, K.Igi, N.Chatani, S.
Murai, J. Am. Chem. Soc. 2003, 125, 1698 – 1699; b) F.Kakiuchi,
M.Usui, S.Ueno, N.Chatani, S.Murai, J. Am. Chem. Soc. 2004,
126, 2706 – 2707.
[7] One rhodium complex has also shown some interesting catalytic
activity, see: C.P.Lenges, M.Brookhart, J. Am. Chem. Soc. 1999,
121, 6616 – 6623.
[8] H.Kawano, R.Tanaka, T.Fujikawa, K.Hiraki, M.Onishi,
Chem. Lett. 1999, 401 – 402.
[9] a) Y.Guari, S.Sabo-Etienne, B.Chaudret,
J. Am. Chem. Soc.
1998, 120, 4228 – 4229; b) Y.Guari, A.Castellanos, S.Sabo-
Etienne, B.Chaudret, J. Mol. Catal. A 2004, 212, 77 – 82; c) J.
Matthes, S.Grꢁndemann, A.Toner, Y.Guari, B.Donnadieu, J.
Spandl, S.Sabo-Etienne, E.Clot, H-.H.Limbach, B.Chaudret,
Organometallics 2004, 23, 1424 – 1433; d) M.Grellier, L.Vend-
ier, B.Chaudret, A.Albinati, S.Rizzato, S.Mason, S.Sabo-
Etienne, J. Am. Chem. Soc. 2005, 127, 17592 – 17593, and
references therein.
[10] Studies on the Murai reaction mechanism: a) see ref.[5a]; b) T.
Matsubara, N.Koga, D.G.Musaev, K.Morokuma, J. Am. Chem.
Soc. 1998, 120, 12692 – 12693; c) T.Matsubara, N.Koga, D.G.
Musaev, K.Morokuma, Organometallics 2000, 19, 2318 – 2329;
d) R.F.R. Jazzar, M.F. Mahon, M.K. Whittlesey,
Organo-
metallics 2001, 20, 3745 – 3751.
[11] Only the zinc, cesium, thallium, and sodium formate salts
resulted in complete conversion.
[12] C.A.Tolman, Chem. Rev. 1977, 77, 313 – 348.
[13] For a discussion on the influence of the CO ligand see: B.M.
Trost, K.Imi, I.W.Davies, J. Am. Chem.Soc. 1995, 117, 5371 –
5372.
À
[14] C H bond activation of a,b-unsaturated esters and amides (one
example) has already been reported, see ref.[13].
[15] a) F.Kakiuchi, M.Yamauchi, N.Chatani, S.Murai, Chem. Lett.
1996, 111 – 112; b) F.Kakiuchi, T.Sato, T.Tsujimoto, M.
Yamauchi, N.Chatani, S.Murai, Chem. Lett. 1998, 1053 – 1054;
c) N.Chatani, A.Kamitani, S.Murai,
7014 – 7018.
J. Org. Chem. 2002, 67,
Angew. Chem. Int. Ed. 2006, 45, 8232 –8235
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8235