Room-temperature regioselective c-H/olefin coupling of aromatic ketones using an activated ruthenium catalyst with a carbonyl ligand and structural elucidation of key intermediates

Article abstract of DOI:10.1021/ja104918f

Mechanistic studies of the ruthenium-catalyzed reaction of aromatic ketones with olefins are presented. Treatment of the original catalyst, RuH ₂(CO)(PPh₃)₃, with trimethylvinylsilane at 90 °C for 1-1.5 h afforded an activ

Full text of DOI:10.1021/ja104918f

Published on Web 11/29/2010
Room-Temperature Regioselective C-H/Olefin Coupling of
Aromatic Ketones Using an Activated Ruthenium Catalyst
with a Carbonyl Ligand and Structural Elucidation of Key
Intermediates
Fumitoshi Kakiuchi,†,* Takuya Kochi,† Eiichiro Mizushima,‡ and Shinji Murai*,§
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan, PRESTO, JST, 4-1-8 Honcho Kawaguchi,
Saitama 332-0012, Japan, and Nara Institute of Science and Technology, 8916-5 Takayama,
Ikoma, Nara 630-0019, Japan
Received June 5, 2010; E-mail: kakiuchi@chem.keio.ac.jp
Abstract: Mechanistic studies of the ruthenium-catalyzed reaction of aromatic ketones with olefins are
presented. Treatment of the original catalyst, RuH2(CO)(PPh3)3, with trimethylvinylsilane at 90 °C for 1-1.5
h afforded an activated ruthenium catalyst, Ru(o-C6H4PPh2)(H)(CO)(PPh3)2, as a mixture of four geometric
isomers. The activated complex showed high catalytic activity for C-H/olefin coupling, and the reaction of
2′-methylacetophenone with trimethylvinylsilane at room temperature for 48 h gave the corresponding ortho-
alkylation product in 99% isolated yield. The activated catalyst was thermally robust and showed excellent
catalytic activity under refluxing toluene conditions. 1H and 31P NMR studies of the C-H/olefin coupling at
room temperature suggested that an ortho-ruthenated complex, P,P′-cis-C,H-cis-Ru(2′-(6′-MeC6H4C-
(O)Me))(H)(CO)(PPh3)2, participated in the reaction as a key intermediate. Isotope labeling studies using
acetophenone-d5 indicated that the rate-limiting step was the C-C bond formation, not the C-H bond
cleavage, and that each step prior to the reductive elimination was reversible. The rate of C-H/olefin coupling
was found to exhibit pseudo first-order kinetics and to show first-order dependence on the ruthenium complex
concentration.
Introduction
products. Since then, the chemistry of transition-metal-catalyzed
regioselective functionalization via unreactive C-H bond cleav-
Transition-metal-catalyzed regioselective functionalizations
via cleavage of normally unreactive carbon-hydrogen bonds
have attracted much attention due to their synthetic utility and
are now regarded as powerful tools in organic synthesis.1 In
the catalytic cycles of the reactions, carbon-hydrogen bond
cleavage by transition metal catalysts is, of course, one of the
key steps. Several mechanisms for this step are considered to
be involved in catalytic C-H functionalizations, and oxidative
addition of C-H bonds is one such mechanism. A variety of
catalytic functionalizations have been developed via oxidative
addition of C-H bonds, such as alkylations, 2-5 alkenylations,6,7
acylations,8 arylations,9 silylations,10 and borylations.11
Oxidative addition of C-H bonds plays a particularly
valuable role in catalytic C-H addition to C-C multiple bonds,
because after C-H bond cleavage, a hydride ligand remains
on the metal and can be directly used for C-H bond formation.
In 1993, highly efficient, catalytic, regioselective alkylation of
aromatic ketones via oxidative addition of ortho C-H bonds
or equivalent processes was reported.2a The multiple step
processes gave overall results equivalent to direct oxidative
addition. The reaction employed RuH2(CO)(PPh3)3 (1) as a
catalyst and showed a reasonably wide substrate scope and high
functional group compatibility, providing excellent yields of
age has been explored rapidly and intensively, and a huge
number of methods have been developed for catalytic C-H
functionalization.1 On the other hand, ruthenium-catalyzed
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† Keio University.
‡ PRESTO, JST.
§ Nara Institute of Science and Technology.
9
10.1021/ja104918f  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 17741–17750 17741

A R T I C L E S
Kakiuchi et al.
aromatic ketone/olefin coupling has also been studied by many
researchers, and ruthenium catalysts other than complex 1 have
been found for C-H/olefin coupling. In addition, several
suggestions have been provided for the catalytic intermediates
of ruthenium-catalyzed coupling.
In an early investigation, transfer of the hydride ligands of
RuH2(CO)(PPh3)3 (1) to an olefin gave a catalytically active
species, and it was proposed that the dehydrogenation of 1 is
the key step for the generation of an active catalyst.2c Concur-
rently, Weber and co-workers also observed partial hydrogena-
tion of olefins in the application of C-H/olefin coupling to step-
growth polymerization and suggested that the reduction of the
olefin may be involved in the formation of catalytically active
species.They also found that treatment of 1 with a stoichiometric
amount of styrene (2) prior to step-growth polymerization
provided a catalytically active species. In both studies, coordi-
Figure 1. Structures of ortho-ruthenated intermediates.
natively unsaturated ruthenium(0) species were considered to
be the active catalyst, but the structure was not experimentally
determined.
NMR studies carried out by Hiraki and co-workers suggested
that treatment of 1 with 2 and 3′-trifluoromethylacetophenone
(3) generates several ruthenium complexes involving P,P′-cis-
C,H-cis-Ru(C6H3(CF3)C(O)CH3)(H)(CO)(PPh3)2 (4a), P,P′-
trans-C,H-cis-Ru(C6H3(CF3)C(O)CH3)H(CO)(PPh3)2 (4b), and
P,P′-trans-C,H-trans-Ru(C6H3(CF3)C(O)CH3)H(CO)(PPh3)2 (4c)
(Figure 1).13 The structures of these complexes were not
determined solely by the NMR analyses, but were proposed
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17742 J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010

C-H/Olefin Coupling of Aromatic Ketones
A R T I C L E S
evidence for or against the coordination of a CO ligand in
metalated species. Fogg and co-workers prepared an ortho-
ruthenated benzophenone complex, Ru(C6H4C(O)Ph)(H)(CO)-
(dcypb) (7) (dcypb ) 1,4-bis(dicyclohexylphosphino)butane;
Cy2P(CH2)4PCy2) (Figure 2) and examined its catalytic activity
for alkylation of aromatic ketones.15 However, complex 7
showed only low catalytic activity, and they proposed that it
was in the catalytic sink for the alkylation of aromatic ketones.
Koga, Morokuma, and co-workers conducted theoretical
calculations on ruthenium-catalyzed C-H/olefin coupling.12
They used benzaldehyde and ethylene as substrates and
Ru(CO)(PH3)n as a catalyst and showed that the coordination
of the carbonyl oxygen to the ruthenium center decreased the
activation energy of the C-H bond cleavage step. Based on
their calculation using the carbonyl complex, the C-H bond is
so easily cleaved that the rate-determining step is the C-C bond
formation, not the C-H bond cleavage.
This Article describes a detailed investigation of the RuH2(CO)-
(PPh3)3-catalyzed coupling of aromatic ketones with alkenes,
including spectroscopic analyses of intermediates and kinetic
studies. Several features of C-H/olefin couplings were revealed:
(1) Catalytically active intermediates possess a carbonyl ligand
during catalysis; (2) reaction of RuH2(CO)(PPh3)3 with an olefin
provides a catalytically active species, Ru(o-C6H4PPh2)(H)-
(CO)(PPh3)2 (8); and (3) the activated ruthenium catalyst 8 with
a carbonyl ligand shows excellent catalytic activity for C-H/
olefin coupling and even catalyzes the reaction at room
temperature.
Figure 2. Structures of previously synthesized ortho-ruthenated complexes.
taking the electronic effects of the ligands into account.13 Under
their reaction conditions, ortho-ruthenated acetophenone com-
plexes 4a-c were observed as minor isomers, along with a large
amount of starting complex 1, and 4b was considered more
active as a catalyst than 4a and 4c. The authors speculated that
one carbonyl ligand was attached to the catalytically active
species, but the presence was not confirmed spectroscopically.
Several related ortho-ruthenated aromatic ketone complexes
have also been synthesized by other research groups (Figure
2).4,14,15 Chaudret and co-workers synthesized an ortho-ruth-
enated benzophenone complex, P,P′-cis-C,H-trans-Ru(o-
C6H4C(O)Ph)(H)(CO)(PCy3)2 (5), having tricyclohexylphos-
phine as axial ligands (Figure 2).4 Complex 5 showed essentially
zero catalytic activity, and on the basis of this observation and
Trost’s results on a related C-H/olefin coupling, using conju-
gated alkenes instead of aromatic ketones,they proposed that
the binding of the CO ligand to the ruthenium suppressed the
catalytic activity of the ruthenium complex. Subsequently,
Whittlesey and co-workers synthesized P,P′-trans-C,H-cis-Ru(o-
C6H4C(O)Me}(H)(CO)(PPh3)2 (6) and determined its structure
by X-ray crystallography.14 Complex 6 did not catalyze C-H/
olefin coupling, and the authors stated it was highly likely that
alternative isomers of 6 could be involved in the catalytic
pathways, although their results did not provide definitive
Results and Discussion
Generation of Highly Active Species for Alkylation of
C-H Bonds with Olefins. This study was initiated with the
reaction of ruthenium catalyst 1 with olefins to determine the
structure of the activated ruthenium complex. On the basis of
the accumulated results concerning RuH2(CO)(PPh3)3-catalyzed
coupling reactions of aromatic compounds with olefins, tri-
methylvinylsilane (9), which is the most reactive among the
olefins screened, was chosen as an activator of 1. When the
reaction of 1 with 9 was carried out in benzene-d6 at room
temperature, a significant amount of a white precipitate was
formed, and the only ruthenium species observable by 31P NMR
was 1, remaining in the solution even after 7 days. By contrast,
the reaction at 90 °C provided several new ruthenium species,
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1
and the resulting mixture was analyzed by H and 31P NMR
spectroscopy (eq 1).
(11) (a) Waltz, K. M.; He, X.; Muhoro, C.; Hartwig, J. F. J. Am. Chem.
Soc. 1995, 117, 11357–11358. (b) Waltz, K. M.; Hartwig, J. F. Science
1997, 277, 211–213. (c) Chen, H.; Schlecht, S.; Semple, T. C.;
Hartwig, J. F. Science 2000, 287, 1995–1997. (d) Cho, J.-Y.; Iverson,
C. N.; Smith, M. R., III. J. Am. Chem. Soc. 2000, 122, 12868–12869.
(e) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith,
M. R., III. Science 2002, 295, 305–308. (f) Ishiyama, T.; Takagi, J.;
Ishida, K.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 390–391. (g)
Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem.,
Int. Ed. 2002, 41, 3056–3058. (h) Hartwig, J. F. In ActiVation and
Functionalization of C-H Bonds; Goldberg, K. I., Goldman, A. S.,
Eds.; ACS Symposium Series 885; American Chemical Society:
Washington, DC, 2004; pp 136-154. (i) Hartwig, J. F.; Lawrence,
J. D. In Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-
VCH: Weinheim, 2005; Vol. 2, pp 605-615. (j) Ishiyama, T.; Miyaura,
N. Pure Appl. Chem. 2006, 78, 1369–1375.
Two hydride signals of 1 at -8.60 (ddt, JHP ) 75.1, 5.8,
29.2 Hz) and at -6.76 ppm (ddt, JHP ) 14.8, 5.8, 31.1 Hz)
9
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A R T I C L E S
Kakiuchi et al.
Table 1. 1H and 31P NMR Spectral Data (benzene-d6, 22 °C) for
Complexes 8a-d
complex
1H NMR spectral data
31P NMR spectral data
8a
δ -8.18 (dt, JHP ) 83.6, 26.5 Hz) δ -35.3 (t, JPP ) 15.2 Hz)
δ 52.1 (d, JPP ) 15.2 Hz)
8b
8c
8d
δ -5.82 (ddd, JHP ) 84.9, 30.2,
δ -36.3 (dd, JPP ) 26.9,
21.4 Hz)
21.9 Hz)
δ 31.4-31.9 (overlapped
with signals of 8c)
δ 42.2 (dd, JPP ) 21.9,
18.5 Hz)
Figure 3. 31P{1H} NMR spectra of a mixture of complexes 8a-d formed
by treatment of 1 with 9 (162 MHz, benzene-d6, 22 °C).
δ -5.57 (ddd, JHP ) 85.6, 28.5,
19.9 Hz)
δ -28.1 (dd, JPP ) 242.2,
18.3 Hz)
δ 31.4-31.9 (overlapped
with signals of 8b)
δ 54.4 (dd, JPP ) 242.2,
17.4 Hz)
The observations from the NMR and IR experiments sug-
gested that the reaction of 1 with 9 afforded several isomers
of ruthenium complex 8, possibly via dehydrogenation by
the olefin and ortho-ruthenation of one of three PPh3.
Attempts were made to isolate complex 8 in a pure form,
but were unsuccessful, probably due to its instability.
Complex 8 was therefore generated in situ by the treatment
of 1 with 9 for use in the following experiments.
δ -3.15 (td, JHP ) 25.9, 18.6 Hz) δ -34.0 (dd, JPP ) 242.4,
23.9 Hz)
δ 49.7 (dd, JPP ) 23.9,
16.2 Hz)
δ 60.7 (dd, JPP ) 242.4,
16.2 Hz)
Catalytic Addition of C-H Bonds in Aromatic Ketones to
Olefins Using Activated Ruthenium Complex 8 as a Catalyst
under Mild Reaction Conditions. To examine the catalytic
activity of 8 for C-H/olefin coupling, a reaction of 2′-
methylacetophenone (10) with 9 was carried out at room
temperature using in situ-generated complex 8 as a catalyst (eq
2). The coupling reaction of 10 with 9 took place with only 2
mol % of catalyst 8, even at room temperature, to give the
corresponding ortho-alkylation product 11 in 99% isolated yield.
On the other hand, when the same reaction of 10 with 9 was
conducted using 1 as a catalyst at room temperature, no coupling
product was observed. These results suggest that high reaction
temperature (90 °C) was necessary for the generation of
catalytically active species 8, but not for the actual C-H/olefin
coupling between 10 and 9, which could be catalyzed by 8 even
at room temperature.
had completely disappeared from the 1H NMR spectrum after
1.5 h, and four new hydride signals having spin-spin
coupling with phosphorus nuclei appeared at -8.18 (8a),
-5.82 (8b), -5.57 (8c), and -3.15 (8d) ppm in a ratio of
2.6:1.0:1.3:1.3 (Table 1). The 31P NMR spectrum also
suggested that four ruthenium phosphine complexes were
present in the mixture, along with a small amount of
triphenylphosphine and triphenylphosphine oxide, and two
or three phosphine signals were observed for each complex
(Figure 3). The 31P NMR spectral data are listed in Table 1.
The high field shifts (-35.3, -36.3, -28.1, and -34.0 ppm)
suggested the presence of an ortho-metalated triphenylphos-
phine (PPh3) on each ruthenium center.16 Similar 1H and 31
P
NMR results were also obtained when the reaction was
1
carried out in toluene-d8. Investigation into the H and 31P
NMR area ratios and coupling constants led us to assign the
structures of ruthenium complexes 8a-d to be the ones drawn
in eq 1. Correlations between hydrides and phosphorus atoms
located at trans positions to each other in 8a-c were also
observed in the 1H-31P HMQC spectrum of the mixture and
are in good agreement with the assigned structures. The
presence of a carbonyl ligand of major isomer 8a was
confirmed by the 13C NMR spectrum. The signal of the
ruthenium-bound aromatic carbon and the CO ligand ap-
peared at 173.6 (td, JC-P ) 14.1 and 6.6 Hz) and 207.1 ppm
(td, JC-P ) 13.2 and 6.6 Hz), respectively, and the assignment
was also supported by the 1H-13C HMBC analysis. The
solution-phase IR spectrum of the mixture showed a peak at
1918 cm-1, supporting the existence of a carbonyl ligand.17
Acetophenone (12) was also coupled with 9 using in situ-
generated 8 at room temperature to give 2,6-dialkylation
product 14 in 96% yield (eq 3). In this reaction, the
corresponding 1:1 addition product 13 was observed in the
early stage, and, as the reaction proceeded, the amount of
13 was decreased and that of 1:2 coupling product 14 was
increased. As reported previously, when the reaction of 12
with 9 was conducted in refluxing toluene using 1 as a
catalyst, 14 was formed as a major product, even in the early
stage of the catalytic reaction.2b,c
(12) (a) Matsubara, T.; Koga, N.; Musaev, D. G.; Morokuma, K. J. Am.
Chem. Soc. 1998, 120, 12692–12693. (b) Matsubara, T.; Koga, N.;
Musaev, D. G.; Morokuma, K. Organometallics 2000, 19, 2318–2329.
(13) Hiraki, K.; Ishimoto, T.; Kawano, H. Bull. Chem. Soc. Jpn. 2000, 73,
2099–2108.
(14) Jazzer, R. F. R.; Mahon, M. F.; Whittlesey, M. K. Organometallics
2001, 20, 3745–3751.
(15) Drouin, S. D.; Amoroso, D.; Yap, G. P. A.; Fogg, D. E. Organome-
tallics 2002, 21, 1042–1049.
For the regioselective alkylation of 2-acetylthiophene, com-
plex 8 generated in situ also functioned as an effective catalyst,
but a slightly higher reaction temperature (40 °C) and a
prolonged reaction period were necessary to attain high product
yield (eq 4).
(16) (a) Appleton, T. G.; Bennett, M. A.; Tomkins, I. B. J. Chem. Soc.,
Dalton Trans. 1976, 439–440. (b) Cole-Hamilton, D. J.; Wilkinson,
G. J. Chem. Soc., Dalton Trans. 1977, 797–804. (c) Garrou, P. E.
Chem. ReV. 1981, 81, 229–266. (d) Mohr, F.; Prive´r, S. H.; Bhargava,
S. K.; Bennett, M. A. Coord. Chem. ReV. 2006, 250, 1851–1888.
(17) Roper, W. R.; Wright, L. J. J. Organomet. Chem. 1982, 234, C5–C8.
9
17744 J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010

C-H/Olefin Coupling of Aromatic Ketones
A R T I C L E S
Scheme 1. Detection of an Intermediate in the Reaction of 10 with
9 Using 8 as a Catalyst
The choice of olefins is an important factor in the achievement
of the C-H alkylation reaction. One of the major limitations
of RuH2(CO)(PPh3)3-catalyzed C-H alkylation is the low
reactivity of olefins having allylic hydrogens, due to double-
bond isomerization to internal hydrogens, which are unreactive
in this reaction.2c The use of 8 as the catalyst was expected to
suppress the undesired double-bond isomerization because of
high catalyst activity, even under the milder reaction conditions.
Unfortunately, however, when the reaction of 10 with 1-hexene
was carried out at room temperature, isomerization of 1-hexene
to 2- and 3-hexenes proceeded, and no coupling product was
obtained, even after 7 days. Thus, ruthenium-catalyzed double-
bond isomerization is more facile than C-H alkylation, even
at room temperature.
C-H Alkylation with 9 Using 8 as a Catalyst under Low
Catalyst Loading Conditions. Catalytic efficiency (turnover
numbers) of in situ-generated complex 8 for C-H alkylation
was examined under low catalyst loading conditions. When the
reaction of 10 with 9 was conducted at room temperature after
0.1 mol % of 1 was treated with 9 at 90 °C for 1.5 h, C-H
alkylation proceeded only sluggishly. When the reaction tem-
perature was increased to 120 °C, 10 was completely consumed
after 20 h, and the corresponding ortho-alkylation product 11
was isolated in 99.4% yield (994 turnover numbers) (eq 5).18
in the reaction mixture. The 31P NMR spectrum showed that
the amount of 8 was reduced, and a new species 15, bearing
two PPh3 ligands in a cis configuration (δ 35.1, JPP ) 18.3 Hz
and δ 39.1, JPP ) 18.3 Hz), was observed in the reaction mixture
(Figure 4b). Ketone 10 was completely converted to alkylation
product 11 after 5 days. At this point, ortho-ruthenated complex
15 disappeared, and all of the peaks corresponding to 8a-d
re-emerged on the 31P NMR spectrum (Figure 4c). When 0.2
mmol of ketone 10 was added again to the reaction mixture,
the signals of 15 gradually regenerated (Figure 4d). This
indicates that complexes 8 and 15 participate in the coupling
reaction of 10 with 9 as key intermediates.
The Reaction of 10 with 9 Using Ru(CO)2(PPh3)3 (16) as a
Catalyst. Previous research has established that Ru(CO)2(PPh3)3
(16) can also be used as a catalyst for the alkylation of aromatic
ketones under refluxing toluene conditions.2a,c When C-H
alkylation was carried out using catalyst 8 at room temperature,
16 was gradually formed, as shown in Figure 4. Thus, there
was a possibility that complex 16 functioned as a catalyst for
the alkylation of 10 with 9 at room temperature. To examine
the catalytic activity of 16 at room temperature, the reaction of
10 with 9 was conducted in the presence of 16 as a catalyst (eq
6). However, no coupling product was obtained, even after 48 h,
and catalytically active species were not generated from 16 at
room temperature.
Chaudret’s4 and Leitner’s5a,b groups independently reported
the RuH2(H2)(PCy3)2-catalyzed alkylation of aromatic ketones
with ethylene at room temperature. This complex functioned
as a catalyst under mild reaction conditions such as room
temperature, but at a higher reaction temperature, the complex
was decomposed, and the C-H alkylation did not proceed.4
On the other hand, complex 8 generated in situ showed high
catalytic activity at both room and high (120 °C) reaction
temperatures and should be considered as a more thermally
robust catalyst.
Monitoring of the Catalytic Reaction of 2′-Methylacetophe-
none (10) with Trimethylvinylsilane (9) by NMR Spectroscopy.
To probe the intermediate structures of room-temperature
catalytic C-H/olefin coupling using 8, the reaction of 2′-
methylacetophenone (10) with vinylsilane 9, using catalyst 8
generated in situ, was performed at room temperature in
benzene-d6 (Scheme 1).
Elucidation of the Structure of the Ortho-Ruthenated
2′-Methylacetophenone Complex by NMR Spectroscopy. The
structure of ortho-ruthenated 2′-methylacetophenone complex
1
1
15 was determined by H, 31P, 13C, and H-13C HMBC NMR
spectra in benzene-d6. As mentioned above, in the 31P{1H} NMR
spectrum, the two phosphorus atoms are coupled to each other,
and their small spin-spin coupling constant (JPP ) 17.0 Hz in
benzene-d6) indicates the cis configuration of the two phosphine
1
ligands. The H NMR spectrum of 15 displayed the hydride
ligand at -5.82 ppm as a doublet of doublets, due to the
coupling with two phosphine ligands (JHP ) 91.9, 24.6 Hz).
The JHP values suggest that the hydride ligand is located at the
trans position of one of the phosphines and the three ligands,
and the hydride and the two phosphines coordinate to the
ruthenium in a meridional fashion. The structures satisfying the
1H and 31P NMR observations are shown as complexes 15 and
17 in Figure 5, and, at this point, the relationship between the
other three ligands cannot be established. The 13C NMR
spectrum showed the signals of the CO ligand, the ketone
carbonyl group, and the ruthenium-bound aryl group at 210.3,
209.8, and 208.4, respectively, and the assignment was supported
To a benzene-d6 solution of 8, generated by the reaction of
1 (0.02 mmol) with 9 (0.2 mmol, 10 equiv) at 90 °C for 1.5 h
(Figure 4a) were added 10 (0.1 mmol) and 9 (0.1 mmol, total
0.3 mmol) at room temperature, and the progress of the reaction
1
was monitored by H and 31P NMR spectroscopy. After 6 h,
the C-H alkylation proceeded, but free ketone 10 still remained
(18) Darses and co-workers recently reported highly efficient C-H
alkylation of aromatic ketones using an in situ-generated ruthenium
catalyst. See ref 3.
9
J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010 17745

A R T I C L E S
Kakiuchi et al.
Figure 4. 31P{1H} NMR monitoring of the catalytic reaction of ketone 10 with vinylsilane 9 using 8 as a catalyst at room temperature. (a) The mixture of
8a-d generated by the reaction of RuH2(CO)(PPh3)3 (1) with 9. (b) The reaction mixture at 6 h after addition of 10 and an extra amount of 9. (c) The
reaction mixture after 5 days. (d) The mixture at 3 h after further addition of 10.
One of the major differences between the two experiments
(runs 1 and 2 in eq 7) is that the catalytic reaction was performed
in the presence of one more equivalent of PPh3 than that of
Whittlesey and co-workers, because, as compared to 6, 1 had
one more phosphine on the ruthenium. To examine the pos-
sibility that the third PPh3 ligand participates in the catalyst
regeneration, C-H alkylation was carried out using 6 as a
catalyst in the presence of 1 equiv of PPh3 (run 3 in eq 7).
However, there was no improvement in the observed catalytic
efficiency. This result shows that the low catalytic activity of 6
cannot be attributed to the small PPh3/Ru ratio on the catalyst.
Figure 5. Possible structures of the ortho-ruthenated intermediate.
Comparison with Hiraki’s Reaction Systems. As mentioned
in the Introduction, Hiraki and co-workers previously studied
by the HMBC spectrum. The presence of the coupling (JCP
)
the reaction mechanism of RuH2(CO)(PPh3)3-catalyzed C-H
alkylation using 3′-trifluoromethylacetophenone (3) and styrene
(2).13 They examined the reaction of 3 (0.37 mmol) with 2 (0.2
mmol) in the presence of 1 (0.04 mmol) at 70 °C without
preactivation of 1. Several ruthenium complexes were observed
by 1H and 31P NMR spectroscopy. In this case, in addition to a
large amount of unreacted complex 1, three ortho-ruthenated
acetophenone complexes were observed as minor products. In
consideration of the 1H and 31P NMR spectral data and the trans
influence of the ligands, they proposed the structures of these
three ortho-ruthenated complexes, as shown in Figure 1.13 While
two phosphines on complex 4a coordinate to the ruthenium at
the cis position to each other, 4b and 4c possess the phosphines
in a trans configuration. The geometry around the ruthenium
center of 4a proposed by Hiraki and co-workers was similar to
that of 15 observed in the present NMR studies. Complex 4a
isomerized to P,P′-trans-C,H-cis isomer 4b during the reaction
at high temperature, but they claimed that the geometry of 4b
produced more catalytically active species than 4a, and the
isomerization that occurred only at high temperature is the key
step for highly efficient C-H/olefin coupling.
67.7 Hz) between the aryl carbon and one of the phosphorus
atoms indicates the trans configuration of these two ligands.
Therefore, the other two ligands, the ketone carbonyl group and
the carbon monoxide, should be located at the cis position of
both phosphines, and the structure of 15 was determined as
shown in Figure 5.
Comparison of the Catalytic Activities of 6 and 1. Whittlesey
and co-workers synthesized an ortho-ruthenated acetophenone
complex, P,P′-trans-C,H-cis-Ru(H)(o-C6H4C(O)CH3)(CO)-
(PPh3)2 (6) and examined the catalytic activity of 6 for the
alkylation of 2′-methylacetophenone (10) with triethoxyvinyl-
silane, but the product yield was poor, even under toluene reflux
conditions (run 1 in eq 7).14 As reported earlier, the coupling
of 10 with triethoxyvinylsilane afforded 93% yield of the product
when 1 was used as a catalyst.2c
In the present study, however, the kinetically favorable cis-
isomer 15 was observed to be involved in the catalytic reaction.
In addition, trans-isomer 6 exhibited almost no catalytic activity
9
17746 J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010

C-H/Olefin Coupling of Aromatic Ketones
A R T I C L E S
Scheme 2. A Plausible Reaction Pathway for the C-H Alkylation of Aromatic Ketones Using 8
at either room or toluene reflux temperature. This is critically
different from Hiraki’s proposal, and the intermediacy of the
P,P′-cis-C,H-cis isomers may explain the discrepancy between
the plausibility of the presence of Ru(H)(o-C6H4C(O)-
CH3)(CO)(PPh3)2 in the catalytic cycle and the observed
inactivity of the P,P′-trans-C,H-cis isomers.
Although a complete understanding of the relationship
between the structures of the intermediates and the catalytic
activity for the RuH2(CO)(PPh3)3-catalyzed C-H alkylation
must await further extensive studies, the following features
can be addressed: (1) two PPh3 ligands coordinate to the
ruthenium center with cis configuration in the active inter-
mediate; (2) the hydride ligand is bound at the position trans
to one of the phosphine ligands and cis to the other; (3) the
CO ligand coordinates to the ruthenium throughout the
reaction; and (4) the geometry of the coordination of the PPh3
ligands to the ruthenium center is highly important for the
attainment of the efficient catalytic reaction of aromatic
ketones with olefins.
in 12-d5 and the three vinylic C-H bonds in 9. Partial
incorporation of deuterium atoms in exchange for each of the
three vinylic hydrogens was also confirmed by an independent
2H NMR experiment in C6H6. Although the material balance
with respect to deuterium atoms in the starting materials, as
well as to the product, could not be determined due to overlap
and the difficulty in quantifying the deuterium in the vinylsilane,
the partial H/D exchange among the ketone and the vinylsilane
supports the idea that each step prior to reductive elimination
is fast even at room temperature, and the reductive elimination,
that is, the C-C bond formation, is rate-limiting under the
reaction conditions.
Deuterium-Labeling Experiments. Deuterium-labeling ex-
periments were carried out to gain further understanding of
C-H/olefin coupling at room temperature. The reactions of
acetophenone-d0 (12) and acetophenone-d5 (12-d5) with 9 using
in situ-generated complex 8 were examined at room temperature
under pseudo first-order kinetic conditions, and the rate constants
of these reactions were measured. At 25 °C, the observed rate
constants were kobs(12) ) 1.15 × 10-5 s-1 (run 1 in eq 8) and
kobs(12-d5) ) 1.13 × 10-5 s-1 (run 2 in eq 8). The kinetic
deuterium isotope effect (KIE), kobs(12)/kobs(12-d5), was 1.02.
This small KIE value indicates that the C-H bond cleavage
step is not rate-limiting. This result is consistent with a previous
study concerning the reaction of 12-d5 with triethoxyvinylsilane
under toluene reflux conditions.2c The C-H bond cleavage is,
therefore, facile and not rate-limiting at both room and toluene-
reflux temperatures.
On the basis of the results of the NMR studies and the
deuterium-labeling experiments, a plausible reaction pathway
is proposed, as shown in Scheme 2. The initial step involves
the oxidative addition of an ortho C-H bond to the ruthenium
center to give the ortho-ruthenated complex A. Coordination
of an olefin to A affords B, followed by hydro-ruthenation of
the coordinating olefin, and provides alkylruthenium intermedi-
ates C and D. An equilibrium among A-D leads to H/D
exchange among the ortho C-H bonds in acetophenone and
the vinyl C-H bonds in the olefin. The coupling product and
the catalytically active species 8 are formed from intermediate
C through several steps.
Kinetic Studies of the Reaction of 10 with 9 at 25 °C. The
rate of alkylation of 2′-methylacetophenone (10) with trimeth-
ylvinylsilane (9), using in situ-generated complex 8 as a catalyst,
was measured at 25 °C by 1H NMR spectroscopy (eq 10). First,
the progress of the reaction with an excess amount of 9 was
monitored by measuring the concentration of coupling product
11 (Figure 6a), and the rate of the catalytic C-H addition was
found to exhibit pseudo first-order kinetics (Figure 6b). This
The reaction of 12-d5 with 1 equiv of 9 was carried out using
in situ-generated 8 as a catalyst at room temperature (eq 9).
The H NMR spectrum of the reaction mixture indicated that
1
partial H/D exchange proceeded among the two ortho C-D bonds
9
J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010 17747

A R T I C L E S
Kakiuchi et al.
Figure 6. (a) Time-conversion curve and (b) first-order plot for alkylation of 10 with 9. Reaction conditions: [10]0 ) 0.10 M, [9]0 ) 3.0 M, [Ru]0 ) 10
mM in benzene-d6, at 25 °C.
Table 2. Kinetic Data in the C-H Alkylation of 10 with 9 Using 8
[9]0 ([9]0 ) 4-5 M) (runs 8,9). Although the actual cause of
as a Catalyst
the dependence of the relationship on the olefin concentration
run
[1]0, M
[9]0, M
[PPh3], M
kobs × 105, s-1
is not clear at present, this result may suggest the possible
involvement of more than one vinylsilane in a catalytic cycle
and an increase in the amount of intermediates containing 9 at
high concentrations.
1
2
3
4
5
6
7
8
0.005
0.01
0.02
0.03
0.01
0.01
0.01
0.01
0.01
0.02
0.02
0.01
0.01
0.01
2.0
2.0
2.0
2.0
1.0
2.0
3.0
4.0
5.0
2.0
2.0
2.0
4.0
5.0
0
0
0
0
0
0
0
0
8.43 × 10-1
1.27
3.56
5.51
Figure 7c shows the effect of PPh3 added to the reaction
mixture. The addition of PPh3 (1-2 equiv to 1) retarded the
reaction, and increasing the equivalent of PPh3 linearly decreased
the rate of the alkylation (runs 3, 10, and 11). To minimize the
effect of dissociated PPh3 on the reaction rates, kinetic studies
were performed in the presence of an excess amount of PPh3
(5 equiv to 1) (entries 12-14). The rates of the catalytic
alkylation still exhibited pseudo first-order kinetics (Figure 8),
and the relationship between the rate constants and [9]0 appeared
to be closer to linear (Figure 9). These results suggest that this
C-H alkylation obeys first-order kinetics in the ketone con-
centration and near first-order kinetics in the vinylsilane
concentration, even in the presence of 5 equiv of PPh3.
4.61 × 10-1
1.27
2.50
3.39
3.89
2.14
9
0
10
11
12
13
14
0.02
0.04
0.05
0.05
0.05
2.81 × 10-1
2.16 × 10-2
3.56 × 10-2
5.02 × 10-2
means that the ketone consumption obeyed the pseudo first-
order rate law described as -d[10]/dt ) kobs[10],19 where kobs
is 2.50 × 10-5 s-1, if it is assumed that the amount of the
intermediates such as 15 is small enough to be ignored in the
calculation.
Summary
Described here is the mechanistic investigation of the coupling
of aromatic ketones with alkenes catalyzed by 1. The presence
or absence of a carbonyl ligand on ruthenium during catalysis
and the effect on the catalytic activity have previously been
discussed by many researchers. The current study revealed that,
at least in this system, a carbonyl ligand is present on the
ruthenium center during the catalytic reaction, and the ruthenium
species with a carbonyl ligand shows excellent catalytic activity.
Heating was required for the generation of catalytically active
species 8 as a mixture of four geometric isomers, but by using
the active catalyst C-H/olefin coupling can be carried out at a
much lower temperature, such as room temperature. Catalyst 8
generated in situ also showed excellent catalytic activity at both
room and high (120 °C) reaction temperatures or at low catalyst
loading (0.1 mol %, 994 TON). The monitoring of the catalytic
reaction also showed the presence of an ortho-ruthenated
aromatic ketone complex bearing a carbonyl ligand (15) during
catalysis as an intermediate. The deuterium-labeling experiments
using acetophenone and acetophenone-d5 indicate that C-H (or
C-D) bond cleavage is not the rate-limiting step. The H/D
exchange reaction between acetophenone-d5 and vinylsilane 9
suggests that each step prior to the C-C bond formation is in
equilibrium. The relationship between the rate constants and
the vinylsilane concentrations is not linear, but the kinetic studies
under pseudo first-order conditions using an excess amount of
The rate constants, kobs, were measured using various
concentrations of 8, 9, and PPh3 and are listed in Table 2.
Because complex 8 was generated in situ by treating complex
1 with an excess amount of 9, and only the weight of 1 was
measured accurately as the ruthenium catalyst used for all the
experiments, the initial concentration of 1 [1]0 was used as the
amount of catalyst for the following descriptions. As [1]0
increased from 5 to 30 mM (runs 1-4), the kobs value became
larger, and the plot of the kobs values against [1]0 shows that
the relationship was almost linear (Figure 7a). An increase in
the concentration of vinylsilane 9 also accelerated the reaction,
but the relationship between the rate constants and the initial
concentration [9]0 appeared to be more complex. At low
concentration ([9]0 ) 1-3 M) (runs 5-7), the rate constants
appeared to be greater than first-order in [9]0 (Figure 7b), but
the degree of order becomes lower at a higher concentration of
(19) Kitamura, M.; Tsukamoto, M.; Bessho, Y.; Yoshimura, M.; Kobs, U.;
Widhalm, M.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6649–6667.
9
17748 J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010

C-H/Olefin Coupling of Aromatic Ketones
A R T I C L E S
Figure 7. Dependence of the initial concentration of the ruthenium complex ([1]0), the initial concentration of trimethylvinylsilane 9 ([9]0), and the concentration
of PPh3 added ([PPh3]) as a rate constant kobs in the alkylation of 10 with 9 at 25 °C. (a) Plotting kobs versus [1]0. Reaction conditions: [10]0 ) 0.10 M, [1]0
) 5.0-30 mM, [9]0 ) 2.0 M, benzene-d6. (b) Plotting kobs versus [9]0. Reaction conditions: [10]0 ) 0.10 M, [1]0 ) 0.01 M, [9]0 ) 1.0-5.0 M, benzene-d6.
(c) Plotting kobs versus equivalents of PPh3 added. Reaction conditions: [10]0 ) 0.10 M, [Ru]0 ) 0.02 M, [9]0 ) 2.0 M, PPh3 ) 0-2 equiv to the ruthenium
complex, benzene-d6.
Figure 9. Plotting kobs versus [9]0. Reaction conditions: [10]0 ) 0.10 M,
[1]0 ) 0.01 M, [9]0 ) 2.0-5.0 M, in the presence of 5 equiv of PPh3,
benzene-d6.
Figure 8. Dependence of initial concentration of trimethylvinylsilane 9
([9]0) on the rate constant kobs in alkylation of 10 with 9 at 25 °C in the
25360-32-1) and Ru(CO)2(PPh3)3 (16) (Registry Number: 25360-
presence of 5 equiv of PPh3. Plotting kobs versus [9]0. Reaction conditions:
32-1) were prepared using a method in the literature.2c 2′-
[10]0 ) 0.10 M, [1]0 ) 0.01 M, [9]0 ) 2.0-5.0 M, [PPh3] ) 0.05 M,
Methylacetophenone (10) (Registry Number: 577-16-2), acetophe-
none (12) (Registry Number: 98-86-2), 2-acetylthiophene (Registry
Number: 98-86-2), and acetophenone-d5 (12-d5) (Registry Number:
28077-64-7) were distilled from CaSO4. Trimethylvinylsilane (9)
(Registry Number: 754-05-2) was purchased from ShinEtsu Chemi-
cal and Industry Co. and distilled from CaH2.
benzene-d6, at 25 °C.
olefin show that the reaction is first-order in ketone and catalyst
concentrations.
Experimental Section
Generation of Ru(o-C6H4PPh2)(H)(CO)(PPh3)2 (8) from
RuH2(CO)(PPh3)3 (1). RuH2(CO)(PPh3)3 (1) (0.02 mmol), 1 mL
of benzene, and trimethylvinylsilane (9) (0.024 mmol) were placed
in an oven-dried 10 mL Schlenk flask. The resulting solution was
heated at 90 °C. After heating for 1-1.5 h, 1 was completely
converted to Ru(o-C6H4PPh2)(H)(CO)(PPh3)2 (8).
Reaction of 2′-Methylacetophenone (10) with Trimethylvinyl-
silane (9) at Room Temperature. RuH2(CO)(PPh3)3 (1) (0.02
mmol), 1 mL of toluene, and trimethylvinylsilane (9) (0.2 mmol)
1
General Information. H, 13C{1H }, 31P{1H }, and 2D NMR
spectra were recorded using JEOL JNM-EX270, JNM-EX400,
JNM-GSX400, and JNM ECX400 spectrometers. All manipulations
for NMR and kinetic studies were performed under a nitrogen
atmosphere in a nitrogen-filled glovebox using dry solvents and
glassware.
Solvents and Materials. Toluene was dried over CaH2 and was
distilled under nitrogen. RuH2(CO)(PPh3)3 (1) (Registry Number:
9
J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010 17749

A R T I C L E S
Kakiuchi et al.
were placed in an oven-dried 10 mL Schlenk flask. The resulting
solution was heated at 90 °C for 1 h, and the resulting reaction
mixture was then cooled to room temperature. To the solution were
added 2′-methylacetophenone (10) (1 mmol) and 9 (2 mmol), and
the resulting solution was then held at room temperature for 48 h.
Volatile materials were evaporated. Silica gel column chromatog-
raphy of the residue afforded ortho-alkylation product 11 in 99%
yield (0.2336 g, 0.997 mmol).
Reaction of Acetophenone (12) with 9 at Room Temperature.
In an oven-dried 10 mL Schlenk flask were placed 1 (0.02 mmol),
1 mL of toluene, and 9 (0.4 mmol). The resulting solution was
heated at 90 °C for 1 h, and the resulting reaction mixture was
then cooled to room temperature. Acetophenone (12) (1 mmol) and
9 (6 mmol) were added to the solution, and the resulting solution
was then held at room temperature for 120 h. Volatile materials
were evaporated. Silica gel column chromatography of the residue
afforded 14 in 96% yield (0.3066 g, 0.96 mmol).
Reaction of 2-Acetylthiophene with 9 at 40 °C. In an oven-dried
10 mL Schlenk flask were placed 1 (0.02 mmol), 1 mL of toluene,
and 9 (0.2 mmol). The resulting solution was heated at 90 °C for
1 h, and the resulting reaction mixture was then cooled to room
temperature. To the solution were added 2-acetylthiophene (1 mmol)
and 9 (2 mmol), and the resulting solution was heated at 40 °C for
72 h. Volatile materials were evaporated. Silica gel column
chromatography of the residue afforded 3-(2-trimethylsilylethyl)-
2-acetylthiophene in 74% yield (0.1676 g, 0.74 mmol).
Reaction of 10 with 9 under Low-Catalyst Loading Condi-
tions. In an oven-dried 10 mL Schlenk flask were placed 1 (0.002
mmol), 1 mL of toluene, and 9 (2 mmol). The resulting solution
was heated at 90 °C for 1.5 h, and then the resulting reaction mixture
was cooled to room temperature. To the solution was added 10 (2
mmol), and then the resulting solution was heated at 120 °C for
48 h. Volatile materials were evaporated. Silica gel column
chromatography of the residue afforded 11 in 99.4% yield (0.466
g, 1.99 mmol).
Kinetic Experiments. Kinetic investigations were studied at 25
°C. In an oven-dried Schlenk flask were placed 1 (18 mg, 0.02
mmol, 0.01 M), 1.02 mL of benzene-d6, and 9 (870 µL, 6.0 mmol,
3.0 M). This mixture was heated at 90 °C for 1.25 h, and the
reaction mixture was then cooled to room temperature (25 °C). Into
the resulting solution were placed anisole (internal standard for the
NMR yield, 11 µL, 0.10 mmol, 0.050 M) and 2′-methylacetophe-
none 10 (26 µL, 0.20 mmol, 0.10 M). A partial amount (ca. 0.6
mL) of this reaction mixture was transferred into a sealable NMR
tube, and this reaction mixture was held at 25 °C. The progress of
the reaction was monitored by 1H NMR spectroscopy. The
measurement was continued for 960 min. The observed reaction
rate was 2.50 × 10-5 s-1. The effects of the initial concentration
of catalyst, initial concentration of trimethylvinylsilane, and equiva-
lents of PPh3 on the reaction rates were measured in a similar
fashion.
Kinetic Deuterium Isotope Effect. The rate constants for the
reactions of acetophenone-d0 (12-d0) and -d5 (12-d5) with trimeth-
ylvinylsilane were measured under the following reaction condi-
tions: [1]0 ) 0.02 M, [12]0 ) 0.10 M, [9] ) 2.0 M, benzene-d6,
0
at 25 °C. While the reaction proceeded, the corresponding 1:2
addition product was also formed. To minimize the effect of
conversion of the monoalkylation product to the dialkylation
product, the rate constant kobs was calculated on the basis of the
yield of the corresponding monoalkylation product at the early stage
of the catalytic reaction. The rate constants for the reaction of 12-
d0 and 12-d5 were calculated to be 1.15 × 10-5 and 1.13 × 10-5
s-1, respectively. From these results, the kinetic deuterium isotope
effect was calculated to be kH/kD ) 1.02.
Deuterium Labeling Experiment Using 12-d5. The reaction of
12-d5 (0.40 mmol) with 9 (0.40 mmol) was carried out in 0.8 mL
of benzene-d6 at room temperature using 8 (0.040 mmol) as a
catalyst. The progress of the reaction was monitored by 1H NMR,
and, after 80 h, the conversion of the reaction reached 26%. The
percentage of the deuterium incorporation into the starting ketone
1H and 31P NMR Monitoring of the Catalytic Reaction of
10 with 9 at Room Temperature Using 8 as a Catalyst. In a
benzene-d6 solution of 8 (0.02 mmol) in a sealable NMR tube,
generated according to the procedure described above, were placed
10 (0.1 mmol) and an additional amount of 9 (0.1 mmol). The
reaction was carried out at room temperature, and the progress of
the reaction was monitored by 1H and 31P NMR spectroscopy. After
5 days, an additional 0.2 mmol of 10 was added to the reaction
mixture.
1
and the product was determined by the H NMR spectrum.
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and by The Science
Research Promotion Fund from The Promotion and Mutual Aid
Corporation for Private Schools of Japan.
JA104918F
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17750 J. AM. CHEM. SOC. VOL. 132, NO. 50, 2010