A RuH2(CO)(PPh3)3-catalyzed regioselective arylation of aromatic ketones with arylboronates via carbon-hydrogen bond cleavage

Article abstract of DOI:10.1021/ja043334n

When the reaction of aromatic ketones with arylboronates (arylboronic acid esters) using RuH₂-(CO)(PPh₃)₃ (3) as a catalyst was conducted in toluene, the corresponding arylation product was obtained in moderate yields. In this case, a nearly equivalent amount of a benzyl alcohol derived from a reduction of an aromatic ketone was also formed. The use of aliphatic ketones, such as pinacolone and acetone, as an additive or a solvent dramatically suppressed the reduction of the aromatic ketones and, as a result, ortho-arylation products were obtained in high yield based on the aromatic ketones. In these reactions, the aliphatic ketone functioned as a scavenger of ortho-hydrogens of the aromatic ketones and the B(OR)₂ moiety of the arylboron compound (HB species). A variety of aromatic ketones, such as acetophenones, acetonaphthones, tetralones, and benzosuberone, could also be used in this coupling reaction. Several arylboronates containing electron-donating (NMe₂, OMe, and Me) and -withdrawing (CF ₃ and F) groups were also applicable to this coupling reaction. Intermolecular competitive reaction using pivalophenone-d₀ and -d₅ and intramolecular competitive reaction using pivalophenone-d₁ were carried out using 3 as a catalyst. The k _H/k_D value for the intermolecular competitive reaction was substantially different, compared with intramolecular competitive reaction. This strongly suggests the production of an intermediate where the ketone carbonyl is coordinated to the ruthenium involved in this catalytic reaction. ¹H and ¹¹B NMR studies using 2′-methylacetophenone, phenylboronate (2), and pinacolone (6) indicate that 6 functions effectively as a scavenger of the HB species.

Full text of DOI:10.1021/ja043334n

Published on Web 04/02/2005
A RuH2(CO)(PPh3)3-Catalyzed Regioselective Arylation of
Aromatic Ketones with Arylboronates via Carbon-Hydrogen
Bond Cleavage
Fumitoshi Kakiuchi,*,†,‡ Yusuke Matsuura,† Shintaro Kan,† and Naoto Chatani†
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan, and PRESTO, JST, 4-1-8 Honcho Kawaguchi, Saitama, Japan
Received November 4, 2004; E-mail: kakiuchi@chem.eng.osaka-u.ac.jp.
Abstract: When the reaction of aromatic ketones with arylboronates (arylboronic acid esters) using RuH2-
(CO)(PPh3)3 (3) as a catalyst was conducted in toluene, the corresponding arylation product was obtained
in moderate yields. In this case, a nearly equivalent amount of a benzyl alcohol derived from a reduction
of an aromatic ketone was also formed. The use of aliphatic ketones, such as pinacolone and acetone, as
an additive or a solvent dramatically suppressed the reduction of the aromatic ketones and, as a result,
ortho-arylation products were obtained in high yield based on the aromatic ketones. In these reactions, the
aliphatic ketone functioned as a scavenger of ortho-hydrogens of the aromatic ketones and the B(OR)2
moiety of the arylboron compound (HB species). A variety of aromatic ketones, such as acetophenones,
acetonaphthones, tetralones, and benzosuberone, could also be used in this coupling reaction. Several
arylboronates containing electron-donating (NMe2, OMe, and Me) and -withdrawing (CF3 and F) groups
were also applicable to this coupling reaction. Intermolecular competitive reaction using pivalophenone-d0
and -d5 and intramolecular competitive reaction using pivalophenone-d1 were carried out using 3 as a
catalyst. The kH/kD value for the intermolecular competitive reaction was substantially different, compared
with intramolecular competitive reaction. This strongly suggests the production of an intermediate where
1
the ketone carbonyl is coordinated to the ruthenium involved in this catalytic reaction. H and 11B NMR
studies using 2′-methylacetophenone, phenylboronate (2), and pinacolone (6) indicate that 6 functions
effectively as a scavenger of the HB species.
Introduction
to C-C multiple bonds. In the case of the arylation of C-H
bonds, this approach is not applicable. Such a reaction usually
The development of highly efficient, selective catalytic
reactions involving C-H bond cleavage has been a subject of
considerable interest in organic and organometallic chemistry.
During the past decade, a variety of reactions that involve C-H
bond transformations have been developed.1,2 Among these, the
catalytic conversion of C-H bonds to C-C bonds is one of
the most useful transformations, because of the importance of
C-C bond formation in organic synthesis. To date, several
different types of transition-metal-catalyzed C-C bond forma-
tion have been reported, involving alkylation with olefins,3-5
alkenylation with acetylenes,6,7 carbonylation with olefins and
carbon monoxide,8 and the hydroacylation of olefins and
acetylenes.9 These reactions involve the addition of C-H bonds
requires the coupling of C-H bonds with Ar-X bonds. To date,
several examples of the arylation of C-H bonds in arenes using
aryl halides or aryl pseudo-halides have been reported.10-18
The first example of this type of reaction was reported by
Chiusoli in 198510 and involved the reaction of bromobenzene
with norbornene using Pd(PPh3)4 as a catalyst to give 1,2,3,4,-
4a,12b-hexahydro-1,4-methanotriphenylene (eq 1). de Meijere
† Osaka University.
subsequently reported a similar biarylation reaction in which
aryl halides were reacted with norbornene using a palladium
catalyst.11 Since these pioneering studies, several studies with
respect to catalytic arylations of C-H bonds have been
reported.12-18 In 1997, Miura achieved an important advance
in this area.12 When the reactions of aromatic carbonyl
compounds such as ketones,12d amides,12e and aldehydes12d with
aryl halides were carried out with the aid of a palladium complex
as the catalyst, C-C bond formation took place between the R
carbon of the carbonyl functionality and the ortho carbon in
‡ PRESTO.
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H. Crabtree, Dalton Trans. 2001, 2437-2450. (d) Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. ReV. 2002, 102, 1731-1770. (e) Labinger, J. A.; Bercaw,
J. E. Nature 2002, 417, 507-514. (f) Miura, M.; Nomura, M. In Cross-
Coupling Reactions; Springer: Berlin, Germany, 2002; p 211-241.
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S., Ed.; Springer-Verlag: Berlin, 1999; Vol. 3, pp 47-79. (b) Kakiuchi,
F.; Murai, S. Acc. Chem. Res. 2002, 35, 826-834. (c) Kakiuchi, F.; Chatani,
N. AdV. Synth. Catal. 2003, 345, 1077-1101. (d) Kakiuchi, F.; Chatani,
S. In Topics in Organometallic Chemistry; Bruneau, C., Dixneuf, P. H.,
Eds.; Springer-Verlag: Berlin, 2004; Vol. 11, pp 45-79. (e) Kakiuchi, F.
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9
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J. AM. CHEM. SOC. 2005, 127, 5936-5945
10.1021/ja043334n CCC: $30.25 © 2005 American Chemical Society

Arylation of Aromatic Ketones with Arylboronates
A R T I C L E S
the benzene ring toward the carbonyl group. In this case, the
coordination of the carbonyl group to palladium was important
for the success of this regioselective arylation. They also re-
ported the arylation of phenols,12a-c naphthols,12b and arylmeth-
anols.12f Dyker reported that the palladium-catalyzed arylation
of sp3 C-H bonds proceeded via a similar reaction pathway.
In their studies, the palladium-catalyzed reaction of 1-tert-
butyl-2-iodobenzene gave the cyclization product, i.e., 7,7-di-
methylbicyclo[4.2.0]octa-1,3,5-triene.13 Sames recently reported
on the phenylation of alkane segments using Ph2Si(OH)Me with
the aid of Pd(OAc)2/Cu(OAc)2/benzoquinone.14 In this case, the
palladium(II) species functioned as a catalyst. Oi reported that,
in the case of the arylation of 2-arylpyridines and arylimines
with aryl halides, RuCl2(PPh3)3 exhibited good catalytic activ-
ity.15 They proposed that a Ru(IV) species derived from an
oxidative addition of an aryl halide to the Ru(II) species served
as the catalytically active species. In 2003, Bedford reported
that the RhCl(PPh3)3-catalyzed arylation of phenols with aryl
halides can be achieved using phosphinite (PR2(OAr)) as a
cocatalyst.16 The important points of this reaction are the
exchange of phenols with the arylated phenoxy moiety on the
phosphinite and the generation of electrophilic Rh(III) species
via the oxidative addition of aryl halides to the Rh(I) complex.
Sharp reported that the arylation of 3-carbethoxyfuran and
3-carbomethoxythiophene with an aryl bromide proceeded at
the 2-position.17 The arylation of thiazole with an aryl iodide
using PdCl2(PPh3)2/CuI as a catalyst was reported by Mori.18
In all of these reactions mentioned above, C-H bond cleavage
took place via an electrophilic substitution pathway. Thus,
Ar-M-X species which were formed by the oxidative addition
of aryl halides or pseudo-halides to the corresponding low-valent
transition-metal complex functioned as an electrophile. The
hydrogens of the ortho C-H bonds should be removed as
protons.
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A R T I C L E S
Kakiuchi et al.
species to the corresponding rhodium(III) species by the
halogenated solvent. Thus, the C-H bond cleavage step would
proceed via an electrophilic substitution reaction.21 This is
unique in the arylation of C-H bonds, but its applicability is
restricted. Recently, we reported on the ruthenium-catalyzed
arylation of ortho C-H bonds in aromatic ketones with
arylboronates (arylboronic acid esters), in which ortho arylation
products were obtained in good yields (eq 2).20 In this arylation
to the arylation product, this coupling reaction gave the benzyl
alcohol, formed by the addition of the HB species to the car-
bonyl group of the aromatic ketone. To suppress this undesired
reduction of aromatic ketones, the reaction was carried out in
the presence of an aliphatic ketone, which was employed as a
scavenger of the HB species. Among the aliphatic ketones
examined, pinacolone (3,3-dimethyl-2-butanone) showed the
highest activity for the C-H/ArB(OR)2 coupling in many cases.
In some cases, acetone could also be used as a scavenger of
the HB species. This arylation reaction using arylborons can
be applied to a variety of combinations of aromatic ketones and
arylboronates. In many cases, the corresponding ortho-arylation
products were obtained in high to excellent yields based on the
aromatic ketones. The importance of the coordination of ketone
carbonyl to the ruthenium center was revealed by means of inter-
and intramolecular competitive reactions using deuterium-
t
labeled pivalophenones. The formation of Bu(Me)CH(OB-
(OR)2) by addition of the HB species to pinacolone was verified
1
by H and 11B NMR and GC/MS spectroscopy.
Reactions of 2′-Methylacetophenone with Phenylboron
Compounds: Optimization of Reaction Conditions. The
reaction of 2′-methylacetophenone (1) with 5,5-dimethyl-2-
phenyl[1,3,2]dioxaborinane (2) was carried out in refluxing
toluene using RuH2(CO)(PPh3)3 (3) as a catalyst (run 1 in eq
3). When 1 equiv of ketone was used, the corresponding ortho-
reaction, a nearly equivalent amount of alcohol derived from
the reduction of the starting ketone was obtained as a byproduct.
This suggests that the hydrogen of the ortho C-H bond is
removed as a hydride and is then transferred to the ketone
carbonyl. From this observation, we proposed that the C-H
bond was cleaved via an oxidative addition to a ruthenium(0)
species to give an aryl-Ru-H species. Thus, the mechanism
of the C-H bond cleavage step in our coupling reaction appears
to be different from the other precedent examples.
In our arylation reaction, one of the most important steps is
the generation of a ruthenium-alkoxy (Ru-OR) species, a key
intermediate in the transmetalation which appeared to be formed
by the addition of a Ru-H species to a carbonyl group in
aromatic ketones. For each molecule of arylation product
formed, one molecule of the aromatic ketones should be reduced
to a benzyl alcohol derivative. Therefore, the reduction of one
molecule of the ketone to the corresponding alcohol is an
inevitable side reaction. This reduction is the most serious, open
issue of our arylation protocol, and a variety of efforts have
been made to suppress this side reaction. We found that some
aliphatic ketones, such as pinacolone and acetone, could
effectively function as an acceptor of the hydrogen of the ortho
C-H bond in aromatic ketones and the B(OR)2 moiety of
arylboronates Ar-B(OR)2 (hereafter abbreviated as HB species),
thus suppressing the reduction of the aromatic ketones.
In this paper, we report that the ruthenium-catalyzed arylation
of aromatic ketones with arylboronates in the presence of an
aliphatic ketone as an acceptor of HB species gives an ortho-
arylated aromatic ketone in high yield, based on the aromatic
ketone. A plausible reaction pathway for this arylation reaction
is proposed.
phenylation product 4 was obtained in 47% yield (0.47 mmol)
(run 1 in eq 3). In this case, a nearly equivalent amount (40%
yield, 0.4 mmol)) of (2-methylphenyl)ethyl alcohol (5), a
reduction product of 1, which was formed by a hydrolysis of
5,5-dimethyl-2-(1-o-tolylethoxy)[1,3,2]dioxaborinane during the
workup, was obtained as a byproduct. When a 2-fold excess of
ketone 1 was used, 4 was obtained in 82% yield, based on
phenylboronate 2 (run 2 in eq 3).
The catalytic activities of some ruthenium and rhodium
complexes were investigated under the same reaction conditions
as used in run 2 in eq 3. When the reaction of 1 with 2 was
conducted in refluxing toluene for 20 h using a ruthenium
complex such as Ru(CO)2(PPh3)3, Ru(CO)3(PPh3)2, RuHCl-
(CO)(PPh3)3, and RuHCl(CO)(PPh3)3/CsF, coupling product
4 was obtained in 33%, 19%, 0%, and 29% yields, respec-
tively. For the present phenylation reaction, (η5-C5Me5)Rh-
(C2H3SiMe3)2, which showed catalytic activity for the alkylation
of aromatic ketones with olefins,4f was ineffective as a catalyst.
Among the complexes screened, RuH2(CO)(PPh3)3 (3) exhibited
the highest activity. Therefore, 3 was used in the coupling
reaction described below.
Results and Discussion
When the reaction of aromatic ketones with arylboronates
(Ar-B(OR)2) was conducted in refluxing toluene with the aid
of RuH2(CO)(PPh3)3 as a catalyst, the ortho-arylation of the
aromatic ketone occurred via C-H bond cleavage. In addition
(21) Oi, S.; Sakai, K.; Inoue, Y. Abstract of Papers, 51st Symposium on
Organometallic Chemistry, Japan, Tokyo, Japan; Kinki Chemical Society,
Japan: Osaka, 2004; Abstract B202.
9
5938 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Arylation of Aromatic Ketones with Arylboronates
A R T I C L E S
Table 1. Screening of Aliphatic Ketone as a Scavenger
Scheme 1. Hypotheses for Conversion of a Ru-H Bond to a
Ru-OR Bond
% yieldb
run
aliphatic ketone
pKEa value
4c
8d
1
2
3
4
5
6
pinacolone (6)
8.76
8.33
7.51
7.43
7.33
6.38
8.76
8.76
8.76
67
65
17
7
29
13
64g
85g
81g
72
61
10
37
15
NR
66g
76g
-
acetone
2-heptanonee
3-pentanone
3-methyl-2-butanone
cyclohexanone
6
6
6
7f
8h
9i
a From ref 25. b GC yield. c Reaction conditions: 2′-methylacetophenone
1 (1 mmol), phenylboronate 2 (1 mmol), toluene (1 mL), aliphatic ketone
(2 mmol), RuH2(CO)(PPh3)3 (3) (0.02 mmol), reflux or 110 °C (sealed tube),
20 h. d Reaction conditions: pivalophenone 7 (1 mmol), 2 (1 mmol),
pinacolone 6 (0.5 mL, 4 mmol), 3 (0.02 mmol), reflux or 110 °C (sealed
tube), 20 h. e The value of the pKE for 2-butanone is used, neglecting the
effect of the alkyl chain length. f 6 (0.5 mL). g Isolated yield. h 6 (1 mL).
i 6 (2 mL).
good acceptors of Ru-H species. Though the ability of the HB
species to serve as a scavenger was not certainly consistent with
the order of the pKE values, the higher contribution of the keto
form appeared to be suitable for the addition of the Ru-H spe-
cies to the carbonyl group to give the Ru-OR species. The
activity of aliphatic ketones as a scavenger was also examined
using 2,2-dimethylpropiophenone (pivalophenone) (7). When
the reaction was conducted in pinacolone or acetone, the coup-
ling product 8 was obtained in high yields as well as the reaction
of 1. On the basis of hypothesis 2, we examined the protonation
of the Ru-H bond with an alcohol or a carboxylic acid23 such
as tert-butyl alcohol, hexafluoro-2-propanol, phenol, acetic acid,
trifluoroacetic acid, and benzoic acid. Unfortunately, no reaction
or a substantial decrease in yield was observed. We also inves-
tigated the possibility of â-alkoxy elimination (hypothesis 3 in
Scheme 1). When the arylation was conducted in the presence
of vinyl alcohols or allyl methyl carbonate, no improvement in
activity was observed. On the basis of these results, we
employed pinacolone 6 as the scavenger of the HB species.
Screening of Phenylboron Compounds. In transition-metal-
catalyzed coupling reactions using organoboron compounds such
as the Suzuki-Miyaura coupling, the substituent on the boron
atom influences the reactivity and stability of the boron
compounds.26 To determine the optimal substituent on the boron
atom, the coupling reaction of 1 with several phenylboron
compounds was examined (Table 2). When the reaction of 1
with 2 was carried out in refluxing pinacolone, 4 was obtained
in 85% isolated yield (run 1). In the case of the reaction with
phenylboronic acid, a trace amount of 4 was obtained (run 2).
When the reaction was conducted in the presence of potassium
fluoride,27 the yield was improved to 26% (run 3), but ketone
1 was recovered only in 34% yield. This suggests that ketone
1 also functioned as a scavenger of the HB species. Reactions
using 2-phenyl[1,3,2]dioxaborolane 9 (run 4), 4,4,5,5-tetra-
methyl-2-phenyl[1,3,2]dioxaborolane 10 (run 5), and 2-phen-
yl[1,3,2]dioxaborinane 11 (run 6), gave 4 in 60%, 46%, and
62% yields, respectively. Phenylboronate 2 had the highest
phenylating ability among the phenylboron compounds screened.
In this phenylation, the formation of benzyl alcohol 5 is an
inevitable side reaction under the reaction conditions shown in
eq 3. This suggests that the addition of the Ru-H bond to the
carbonyl group in the aromatic ketone is a key step in this
coupling reaction. Thus, the generation of a ruthenium-alkoxide
(Ru-OR) species is essential in the transmetalation step. We
propose that, in place of the reduction of aromatic ketones with
the Ru-H species, the following three protocols appeared to
be effective for the conversion of the Ru-H to the Ru-OR
species: (i) the addition of the Ru-H to a carbonyl group in
aliphatic ketones (hypothesis 1 in Scheme 1),22 (ii) protonation
of the Ru-H species with alcohols or carboxylic acids
(hypothesis 2 in Scheme 1),23 and (iii) a â-alkoxy elimination24
from the â-alkoxy(ethyl)ruthenium intermediate formed by the
hydroruthenation to a vinyl ether or allyl carbonate (hypothesis
3 in Scheme 1).
We verified the possibility of hypothesis 1 using several
aliphatic ketones, such as 3,3-dimethyl-2-butanone (pinacolone)
(6), acetone, 2-heptanone, 3-pentanone, 3-methyl-2-butanone,
and cyclohexanone (Table 1). The findings show that pinacolone
6 exhibited the highest activity for the coupling reaction.
Acetone could also be used as a scavenger of the HB species,
but its efficiency and generality were slightly lower than those
of 6. These ketones have large pKE values (pinacolone, pKE )
8.76; acetone, pKE ) 8.33), indicating a large contribution by
the keto form.25 Thus, these ketones can potentially function as
(22) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley &
Sons: New York, 1994; Chapter 2. (b) Takaya, H.; Ohta, T.; Noyori, R.
In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim, 1993;
Chapter 1. (c) Brunner, H.; Zettlmeier, W. Handbook of EnantioselectiVe
Catalysis; VCH: Weinheim, 1993. (d) Noyori, R.; Takaya, H. Acc. Chem.
Res. 1990, 23, 345.
(23) (a) Field, L. D.; Hambley, T. W.; Yau, B. C. K. Inorg. Chem. 1994, 33,
2009-2017. (b) Osakada, K.; Ohshiro, K.; Yamamoto, A. Organometallics
1991, 10, 404-410.
(24) (a) Ito, H.; Nakamura, T.; Taguchi, T.; Hanazawa, Y. Tetrahedron 1995,
51, 4507-4518. (b) Bedjeguelal, K.; Bolitt, V.; Sinou, D. Synlett 1999,
762. (c) Hara, R.; Ura, Y.; Huo, S.; Kasai, K.; Suzuki, N.; Takahasahi, T.
Inorg. Chim. Acta 2000, 300-302, 741-748.
(26) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147-168. (c) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633-9695.
(27) Wright, S. W.; Hangeman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59,
6095-6097.
(25) Keeffe, J. R.; Kresge, A. J.; Schepp, N. P. J. Am. Chem. Soc. 1990, 112,
4862-4868.
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5939

A R T I C L E S
Kakiuchi et al.
Table 2. Screening of Phenylboronatesa
ortho position inhibited the second C-H bond cleavage. The
reaction of 2′-R,R,R-trifluoromethylacetophenone (15) gave the
coupling product 16 in 61% yield (run 5). In this case, 15 and
16 were reduced to some extent. Our proposed explanation for
this is that the electron-withdrawing CF3 group increases the
electrophilicity of the carbonyl group in the starting material
15 and in the coupling product 16. The methoxy and fluoro
groups at the 4′-position in the aromatic ring remained intact
in the coupling products (runs 6 and 7). These results suggest
that the electronic nature of the substituent on the aromatic ring
does not exert a large affect on the reactivity of these ketones.
Naphthalene derivatives can also be used in this reaction. The
reaction of 1-acetonaphthone with 2 gave the expected 2-phenyl-
1-acetonaphthone in 78% yield (run 8). In the case of the
reaction of 2-acetonaphthone (17) using 1.1 equiv of 2, 1-phenyl-
(18), 3-phenyl- (19), and 1,3-diphenylacetonaphthones (20) were
obtained in 5% (0.05 mmol), 46% (0.46 mmol), and 16% (0.16
mmol) yields, respectively (run 9). When 2 equiv of 2 was used
for this coupling reaction, the reaction afforded a mixture of
19 and 20 in 12% and 55% yields, respectively (run 10). It is
noteworthy that C-C bond formation also took place at the
â-position, although in the alkylation of 17 with triethoxyvi-
nylsilane, C-C bond formation occurs only at the R position.
To determine the relative reactivity of these two C-H bonds,
2-pivalonaphthone (21) was used in this coupling reaction
because the pivaloyl group suppressed the second C-H bond
cleavage or C-C bond formation. Thus, in this case, the mono
coupling product was obtained exclusively. In this case, R- and
â-phenylation products (22 and 23, respectively) were obtained
in 17% and 64% yields, respectively (run 11). We attribute this
regioselectivity to steric repulsion between the ruthenium center
and the hydrogen at the peri-position (the 8-position) or among
the phenyl group and the ruthenium atom and the hydrogen at
the 8-position, which would disturb C-C bond formation at
the 1-position (Figure 1). Fused aromatic ketones, i.e., R-tetra-
lone 24, 1-benzosuberone 26, and 2,2-dimethyl-R-tetralone,
exhibited a high reactivity. The reaction of ketone 24 gave the
phenylation product 25 in 92% yield. In this case, 24 was
recovered in 6% yield. Among the aromatic ketones examined,
1-benzosuberone (26) showed the highest reactivity. The reac-
tion of 26 with 2 gave the phenylation product 27 in 98% yield.
The reaction of 2,2-dimethyl-R-tetralone also gave the coupling
product in 91% yield, but a prolonged reaction period (20 h)
was required to attain this high yield. This suggests that steric
congestion around the carbonyl group retarded the reactivity
of the ketone substantially.
a Reaction conditions: 2′-methylacetophenone 1 (1 mmol), phenylbor-
onate (1.1 mmol), pinacolone (6) (1.0 mL), RuH2(CO)(PPh3)3 (3) (0.02
mmol), reflux, 1 h. b KF (1 mmol) was added.
After further optimization of the reaction conditions, we
adopted 2 mol % RuH2(CO)(PPh3)3 (3), aromatic ketone (1
mmol), and arylboronates (1.1 equiv) in refluxing pinacolone
(6) (1 mL) as the standard reaction conditions (eq 4).
Phenylation Reactions of Various Aromatic Ketones. The
applicability of aromatic ketones for use in this arylation reaction
was examined using phenylboronate 2 (Table 3). In the case of
the reaction of acetophenone 12 using equimolar amount of 2
in refluxing pinacolone, a mixture of mono- and diphenylation
products was obtained in 17% (13, 0.17 mmol) and 39% (14,
0.39 mmol) yields based on 12, respectively (run 1). When an
excess amount (2.2 mmol) of 2 was used in the coupling reaction
of 12, diphenylation product 14 was formed in 89% yield along
with a 3% yield of 13 (run 2). In the reaction of 2-methyl-1-
phenylpropan-1-one, the 1:2 coupling product was also formed
as the major product (run 3). A similar product selectivity was
observed in the ruthenium-catalyzed reactions of aromatic
ketones,3a-c esters,3d and nitriles3g with olefins. It has been
proposed that these alkylation reactions proceed without the
dissociation of the 1:1 coupling product from the ruthenium
center. These observations provide for a scenario in which the
second C-C bond formation takes place without the dissociation
of the 1:1 coupling product from the ruthenium. When an
aromatic ketone with a sterically hindered tert-butyl group on
the carbonyl group was used, product selectivity was dramati-
cally changed. In the case of pivalophenone (7), the correspond-
ing mono phenylation product 8 was obtained in 76% yield as
the sole product (run 4). The large steric repulsion between the
tert-butyl group and the ortho phenyl group introduced at the
Reaction of 1-Benzosuberone 26 with Arylboronates. The
applicability of arylboronates was examined using ketone 26,
which exhibited the highest reactivity. Some selected results
are listed in Table 4. The reaction with arylboronates containing
an electron-donating group such as methoxy and N,N-dimethy-
lamino groups gave the corresponding arylation products in 88%
and 84% yields, respectively (runs 1 and 2 in Table 4). Reactions
with p-fluoro- and p-trifluoromethylphenylboronates also pro-
vided arylation products in good yields (75% and 84% yields,
respectively). These results indicate that the electronic nature
of the substituent on the aromatic ring does not greatly affect
reactivity. In the case of reactions with sterically hindered aryl-
boronates, it would appear that the reactivity of the boronates
is low. Interestingly, however, coupling reactions using 2-tolyl-
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5940 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Arylation of Aromatic Ketones with Arylboronates
A R T I C L E S
Table 3. Aromatic Ketone Generalitya
a Reaction conditions: aromatic ketone (1 mmol), phenylboronate (2) (1.1 mmol), RuH2(CO)(PPh3)3 (3) (0.02 mmol), pinacolone (1.0 mL, 8 mmol),
reflux. b Isolated yield. c 2 (1 mmol). d 2 (2.2 mmol). e 2 (2 mmol), pinacolone (0.5 mL). f 2 (2 mmol). g Products 22 and 23 were isolated in 81% yield as
a mixture with a ratio of 21:79, respectively. h 2 (1.5 mmol), pinacolone (0.5 mL). i 2 (1.2 mmol), pinacolone (0.5 mL).
Elucidation of Precoordination of the Ketone Carbonyl
to the Ruthenium Center: Competitive Reactions Using
Deuterium-Labeled Pivalophenones. In our previous study
concerning the alkylation of C-H bonds in aromatic ketones
and esters with olefins (C-H/olefin coupling), we proposed
Figure 1. Steric repulsion between the peri-hydrogen and the ruthenium
that the carbonyl group coordinates to the ruthenium based
complex.
on deuterium-labeling experiments using acetophenone-d5
(12-d5)3c and methyl benzoate-d5 (29-d5).3i These deuterium-
(run 5) and 1-naphthylboronates (run 6) afforded the corre-
labeling experiments indicated that the H/D exchange oc-
curred between the ortho positions of 12-d5 and 29-d5 and at
the vinylic positions of triethoxyvinylsilane. The regioselectivity
of the H/D exchange was consistent with the regioselectivity
of the C-C bond formation in the products. From these
observations, in the case of the RuH2(CO)(PPh3)3-catalyzed
C-H/olefin coupling, the precoordination of the carbonyl group
would be predicted to be involved prior to the C-H bond
cleavage.
sponding arylation product in 96% and 92% yields, respectively.
The reason for the high yields of these reactions is not clear at
present, but steric congestion around the biaryl framework in
the coupling products appears to prevent the Ru-H species from
attacking at the carbonyl group. Thus, the reduction of the
coupling product was effectively suppressed by the bulky biaryl
framework. Unfortunately, however, the highly hindered 2,4,6-
trimethylphenylboronate was inactive under these reaction
conditions.
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5941

A R T I C L E S
Kakiuchi et al.
Table 4. Reaction of 1-Benzosuberone 26 with Arylboronatesa
Scheme 2. Jones’ Protocol for Competitive Deuterium-Labeling
Experiments
a Reaction conditions: 1-benzosuberone 26 (1 mmol), boronate (1.2
mmol), RuH2(CO)(PPh3)3 (3) (0.02 mmol), pinacolone (0.5 mL, 4 mmol),
reflux, 1 h. b Isolated yield.
On the contrary, Brookhart found that, in the case of
(η5-C5Me5)Rh(C2H3SiMe3)2-catalyzed reaction of 12-d5 with
trimethylvinylsilane, the H/D exchange occurred at the para-
and the meta-positions but not at the ortho-position and that
C-C bond formation took place at the ortho-position.4f On the
basis of these results, they proposed that C-H (or C-D) bond
cleavage proceeded without the coordination of the carbonyl
and that the coordination of the ketone carbonyl to the rhodium
participated in the C-C bond formation step, i.e., in the
reductive elimination step and not in the C-H bond cleavage
step.
for kH/kD in both the inter- and intramolecular competitive
reactions should be nearly the same. On the other hand, if the
present reaction involves the coordination of the ketone carbonyl
to the ruthenium prior to C-H bond cleavage, the kH/kD values
in these labeling experiments should be different.
On the basis of our hypothesis, we examined both inter-
(Scheme 3) and intramolecular (Scheme 4) competitive reac-
tions. The reactions of 7-d0 and 7-d5 with p-methoxyphenyl-
boronate (28) were conducted under the reaction conditions
shown in Scheme 3. The reactions were stopped at 40% and
47% conversions (runs 1 and 2, respectively). In the case of
run 1, the coupling products 30-d0 and 30-d4 were obtained in
The results of our and Brookhart’s deuterium-labeling experi-
ments described above indicate that the regioselectivity of C-C
bond formation in the product does not always provide accurate
information with respect to the role of the directing group in
the catalytic cycle. To reveal the role of the ketone carbonyl in
the present arylation reaction, we applied the Jones’ protocol
of deuterium-labeling experiments28 to our reaction. The out-
line of Jones’ protocol is illustrated in Scheme 2 along with
their experimentally derived kH/kD values. Jones postulated the
η2-arene complex as the intermediate prior to C-H bond
cleavage on the basis of these deuterium-labeling competi-
tive reactions on the basis of the observation of substantially
different kH/kD values in intermolecular competitive reactions
of C6H6 and C6D6 with (η5-C5Me5)Rh(PMe3), compared with
the intramolecular competitive reaction of 1,3,5-C6D3H3 with
(η5-C5Me5)Rh(PMe3).
1
40% total yield based on 28. The H NMR and the GC/MS
spectra of the products indicated that the arylation products
30-d0 and 30-d4 were obtained in almost the same ratio
(30-d0/30-d4 ) 1.06). This ratio indicates a ratio of kH/kD, i.e.,
a kinetic isotope effect (KIE) ) 1.06. In the case of run 2, a
similar value of kH/ kD, i.e., KIE ) 1.09, was observed. The
intramolecular competitive reactions were examined using
2′-deuteriopivalophenone (7-d1) (runs 3 and 4 in Scheme 4). In
the case of run 3, the reaction of 7-d1 with 28 gave 30-d1 and
30-d0 in 50% total yield based on 28. The ratio of 30-d1 and
30-d0, indicative of the KIE (kH/kD), was found to be 1.41. When
the reaction was stopped at 74% conversion (run 4), the KIE
value (kH/kD ) 1.49) was almost the same as that in run 3. Thus,
these kH/kD values were different between the inter- (Scheme
3) and intramolecular (Scheme 4) competitive reactions. These
observations indicate that an intermediate such as I or II in
Figure 2 is produced prior to C-H bond cleavage. On the
basis of the basicity of the ketone carbonyl oxygen compared
with the π-electrons of the benzene ring and the regioselectivity
We modified these inter- and intramolecular competitive
reactions using deuterium-labeled pivalophenones. Our hypoth-
esis is as follows. If, in the present coupling reaction of aromatic
ketones with arylboronates, C-H bond cleavage proceeds
without coordination of the ketone carbonyl group, the values
(28) (a) Jones, W. D.; Feher, F. J. J. Am. Chem. Soc. 1986, 108, 4814-4819.
(b) Jones, W. D.; Feher, F. J. Acc. Chem. Res. 1989, 22, 91-100.
9
5942 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Arylation of Aromatic Ketones with Arylboronates
A R T I C L E S
Scheme 3. Intermolecular Competitive Reaction
Scheme 4. Intramolecular Competitive Reaction
of C-C bond formation, the coordination of the carbonyl group
(intermediate I)4e,l-n,29 is more plausible compared with the η2-
arene complex (intermediate II).30
1 in 18% yield, and trialkoxyborane 31 was formed in 82%
yield. No formation of 32 derived from the reduction of 1 by
Figure 2.
Plausible Pathway for the Reduction of Pinacolone. In the
present arylation reaction, pinacolone 6 appeared to be key for
suppressing the reduction of aromatic ketones. Thus, 6 served
as an effective scavenger of the HB species. To confirm that 6,
in fact, functioned as a scavenger of the HB species, we carried
out the reaction of 1 (0.1 mmol) with 2 (0.1 mmol) in pinacolone
6 (0.1 mL, 0.8 mmol) using catalyst 3 (0.01 mmol) at 115 °C
in an NMR tube (eq 5). After 1 h, 0.6 mL of benzene-d6 was
added to the reaction mixture, and 1H and 11B NMR spectra of
the reaction mixture were then collected. The 1H NMR spectrum
indicated that phenylation product 4 was formed in 82% yield,
the HB species was observed. The 11B NMR spectrum of the
reaction mixture indicated that the signal for 2 at δ 26.5 had
completely disappeared and a new signal appeared at δ 17.5,
which is close to a chemical shift of B(OMe)3 (δ 18.2). This
11B NMR spectrum indicated that a trialkoxyborane species was
formed during this reaction. The GC/MS spectrum showed a
base peak (m/z ) 199) consistent with M+ - Me (C11H23BO3
- CH3). These observations indicate that pinacolone 6 ef-
fectively functioned as an acceptor of the H and B(OCH2C(CH3)2-
CH2O) moieties (the HB species).
(29) (a) McGuiggan, M. F.; Pignolet, L. H. Inorg. Chem. 1982, 21, 2523-
2526. (b) Munshi, P.; Samanta, R.; Kumar, L. G. J. Organomet. Chem.
1999, 586, 176-183. (b) Chandra, M.; Sahay, A. N.: Pandey, D. S.; Puerta,
M. C.; Valerga, P. J. Organomet. Chem. 2002, 648, 39-48.
(30) (a) Sweet, J. R.; Graham, W. A. G. Organometallics 1983, 2, 135-140.
(b) Hackett, M.; Ibers, J. A.; Whitesides, G. M. J. Am. Chem. Soc. 1988,
110, 1436-1448. (c) Cordon, R.; Taube, H. J. Am. Chem. Soc. 1987, 109,
8101-8102.
To contradict the possibility that reduction product 31 was
formed by the transfer hydroboration from 32 to pinacolone
(Scheme 5), i.e., Meerwein-Ponndorf-Verley-type reduction,
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5943

A R T I C L E S
Scheme 5
Kakiuchi et al.
we examined the following control experiment. When the
reaction of 1 with 2 was carried out in refluxing toluene for 1.5
h, a mixture of phenylation product 4 and reduction product 32
was obtained (eq 6). Then, to the reaction mixture was added
Figure 3. A proposed reaction pathway.
ketones (e.g., acetophenones, acetonaphthones, and fused-
aromatic ketones) and arylboronates. Fused aromatic ketones
such as R-tetralones and 1-benzosuberone showed a high
reactivity for this arylation reaction. The electronic nature of
the substituent on the benzene ring in the arylboronates did not
greatly affect the reactivity. The kinetic isotope effects for the
intermolecular competitive reactions (kH/kD ) 1.06 and 1.09)
was different from that for the intramolecular one (kH/kD ) 1.41
and 1.49). These results indicate that the ketone carbonyl group
pinacolone 6 at the same temperature, and the resulting reaction
mixture was further refluxed for 16 h. The GC analysis of the
reaction mixture indicated that conversion of 32 to 31 did not
occur. This observation suggests that 31 is formed by the
reduction of 6 with the HB species directly.
A Plausible Reaction Pathway. On the basis of the
deuterium-labeling results and the NMR studies of the RuH2-
(CO)(PPh3)3-catalyzed arylation of aromatic ketones with aryl-
boron compounds, we propose the reaction pathway illustrated
in Figure 3. The reaction starts with the coordination of the
ketone carbonyl to intermediate B, as confirmed by the
deuterium-labeling experiments (Schemes 3 and 4), followed
by cleavage of C-H bonds to give the ortho-metalated
ruthenacycle C. The addition of the Ru-H in C to the carbonyl
group in pinacolone 6 leads to alkoxy-ruthenium intermediate
D. Transmetalation between alkoxy-ruthenium intermediate D
and 2 affords the diaryl ruthenium intermediate E and trial-
1
coordinates to the ruthenium prior to C-H bond cleavage. H
and 11B NMR studies using 1 and 2 indicated that pinacolone
6 effectively functioned as an acceptor of H and B(OCH2C(CH3)2-
CH2O) moiety (HB species). The catalytic arylation of aromatic
ketones via C-H bond cleavage using arylboron compounds
described here provides new opportunities for preparing a variety
of biaryl compounds. We anticipate that this type of coupling
reaction using organometalloid and organometallic reagents and
involving C-H bond cleavage will become a powerful new
synthetic protocol in organic synthesis.
1
koxyborane 31, which was detected by H and 11B NMR and
GC/MS spectroscopy (eq 5). A reductive elimination, forming
a C-C bond from E provides the coupling product and
regenerates the active species A.
Experimental Section
General Information. 1H NMR and 13C NMR were recorded on a
JEOL JNM-EX270 spectrometer operating at 270 and 67.5 MHz,
respectively. 11B NMR was recorded on a JEOL ECP-400 spectrometer
operating at 128 MHz. 1H and 13C NMR signals are quoted relative to
internal CHCl3 (δ ) 7.26 and 77.0) or tetramethylsilane. 11B NMR
signals are quoted relative to BF3. 1H NMR data are reported as
follows: chemical shift in ppm (δ), multiplicity (s ) singlet, d )
doublet, t ) triplet, q ) quartet, hept ) heptet, m ) multiplet, br )
broad), coupling constant (Hz), relative intensity. 13C NMR data are
reported as follows: chemical shift in ppm (δ). IR spectra were
measured on a Hitachi 270-50 infrared spectrometer. GC/MS analyses
were performed on a Shimadzu GCMS QP-5000 gas chromatography
mass spectrometer.
Conclusion
The reaction of aromatic ketones with arylboronates was
conducted in refluxing pinacolone 6 with the aid of RuH2(CO)-
(PPh3)3 (3) as a catalyst to give the ortho arylation products in
good to excellent yields. This arylation of aromatic ketones
exclusively occurred at the position ortho to the carbonyl group.
The use of aliphatic ketones, especially pinacolone, as the
acceptor of the HB species is quite effective for suppressing
the undesired reduction of aromatic ketones. The substituent
on the boron atom in phenylboron compounds influences its
reactivity. Phenylboronate 2 derived from phenylboronic acid
and 2,2-dimethyl-1,3-propanediol showed the highest reactivity
among the phenylboron compounds screened. The present
arylation can be applied to various combinations of aromatic
GC Analysis. Conditions for the GC analysis were as follows:
Shimadzu GC-14A (equipped with CBP-10 25 m × 0.2 mm); initial
temperature, 70 or 120 °C; final temperature, 250 °C; rate, 10 °C/min;
injection temperature, 250 °C; detector temperature, 250 °C.
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5944 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Arylation of Aromatic Ketones with Arylboronates
A R T I C L E S
Solvents and Materials. Toluene was distilled under nitrogen over
CaH2. Aliphatic and aromatic ketones were distilled under nitrogen over
CaSO4. RuH2(CO)(PPh3)3 was prepared by previously described
method.3c
equipped with a reflux condenser connected to a nitrogen line, a rubber
septum, and a magnetic stirring bar. The flask was flame dried under
a stream of nitrogen. The ruthenium complex (0.02 mmol), 1 mL of
toluene, pivalophenone-d1 (1 mmol), and p-methoxyphenylboronate 28
(0.5 mmol) were then placed in the flask. The resulting mixture was
refluxed under a nitrogen atmosphere for 15 min. The reaction mixture
was analyzed by GC and GC/MS, and the ratio of the 30-d0 and 30-d1
in the reaction mixture was determined by GC/MS31 and 1H NMR
spectrometry. The products and the starting materials were isolated and
purified by alumina and silica gel column chromatography.
General Procedure. The apparatus used in the reactions consisted
of a 10-mL two-necked flask equipped with a reflux condenser
connected to a nitrogen line, a rubber septum, and a magnetic stirring
bar. The flask was flame-dried under a stream of nitrogen. The
ruthenium complex (0.02 mmol), 1 mL of pinacolone, aromatic ketone
(1 mmol), and arylboronic acid ester (1-1.5 mmol) were then placed
in the flask. The resulting mixture was refluxed under a nitrogen
atmosphere. The progress of the reaction was monitored by GC analysis
and the product was isolated and purified by alumina and/or silica gel
column chromatography.
Confirmation of the Direct Reduction of Pinacolone with HB
Species. The apparatus consisted of 10-mL two-necked flask equipped
with a reflux condenser connected to a nitrogen line, a rubber septum,
and a magnetic stirring bar. The flask was flame-dried under a stream
of nitrogen. The ruthenium complex (0.02 mmol), 1 mL of toluene,
2′-methylacetophenone (1) (1 mmol), and phenylboronate 2 (1 mmol)
were then placed in the flask. The resulting mixture was refluxed under
a nitrogen atmosphere for 1.5 h. The reaction mixture was analyzed
by GC. To the reaction mixture, pinacolone (2 mmol) was carefully
added at the same temperature using a syringe. The resulting reaction
mixture was refluxed for 16 h further, and the reaction mixture was
analyzed by GC.
Intermolecular Deuterium-Labeling Experiment Using Piv-
alophenone-d0 (7) and Pivalophenone-d5 (7-d5). The apparatus
consisted of a 10-mL two-necked flask equipped with a reflux condenser
connected to a nitrogen line, a rubber septum, and a magnetic stirring
bar. The flask was flame-dried under a stream of nitrogen. The
ruthenium complex (0.02 mmol), 1 mL of toluene, pivalophenone (7)
(0.5 mmol), pivalophenone-d5 (7-d5) (0.5 mmol), and p-methoxyphe-
nylboronate 28 (0.5 mmol) were then placed in the flask. The resulting
mixture was refluxed under a nitrogen atmosphere for 15 min. The
reaction mixture was analyzed by GC and GC/MS, and the ratio of the
30-d0 and 30-d4 in the reaction mixture was determined by GC/MS31
Acknowledgment. This work was supported, in part, by
PRESTO, JST. This work was supported, in part, by the Kurata
Memorial Hitachi Science and Technology Foundation granted
to F. K.
1
and H NMR spectrometry. The products and the starting materials
were isolated and purified by alumina and silica gel column chroma-
tography.
Supporting Information Available: Physical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Intramolecular Deuterium-Labeling Experiment using Pivalophe-
none-d1 (7-d1). The apparatus consisted of 10-mL two-necked flask
(31) Hesse, M.; Meier, H.; Zeeh, B. Spectroscopic Methods in Organic
Chemistry; Thieme: New York, 1997; pp 254-257.
JA043334N
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