Synthesis of unsymmetrical ketones by palladium-catalyzed cross-coupling reaction of carboxylic anhydrides with organoboron compounds

Article abstract of DOI:10.1246/bcsj.75.137

On the basis of fundamental studies on oxidative addition of carboxylic anhydrides to zerovalent palladium complexes to yield acyl(carboxylato)bis(tertiary phosphine)palladium(II) complexes and their reactions with organoboronic acids to yield ketones, a novel catalytic process has been developed. This converts carboxylic anhydrides and organoboron compounds into ketones catalyzed by palladium complexes under mild conditions. The process provides a general, versatile, synthetic method to produce various symmetrical and unsymmetrical ketones with aromatic, aliphatic, and heterocyclic groups. The catalytic cycle is proposed to comprise (a) oxidative addition of a carboxylic anhydride to produce an acyl(carboxylato)palladium intermediate, (b) transmetallation with an organoboron compound to give an acyl(organo)palladium intermediate, and (c) its reductive elimination to yield a ketone. Not only homogeneous catalyst systems but also heterogeneous systems were found to give ketones under mild conditions.

Full text of DOI:10.1246/bcsj.75.137

Bull. Chem.
Soc. Jpn.
75
1
© 2002 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 75, 137–148 (2002)
137
The Chemical
Society of Ja-
pan
The Chemical
Society of Ja-
pan
OB
1
15
Synthesis of Unsymmetrical Ketones by Palladium-Catalyzed
Cross-Coupling Reaction of Carboxylic Anhydrides with Organoboron
Compounds
Pd-Catalyzed Ketone Synthesis from Anhydrides
R. Kakino et al.
2002
137
148
BCSJA8
0009-2673
01308
9
Ryuki Kakino, Sayaka Yasumi, Isao Shimizu, and Akio Yamamoto*
Department of Applied Chemistry, Graduate School of Science and Engineering and Advanced Research Institute for
Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555
(Received September 3, 2001)
3
2001
9
27
On the basis of fundamental studies on oxidative addition of carboxylic anhydrides to zerovalent palladium com-
plexes to yield acyl(carboxylato)bis(tertiary phosphine)palladium(Ⅱ) complexes and their reactions with organoboronic
acids to yield ketones, a novel catalytic process has been developed. This converts carboxylic anhydrides and organobo-
ron compounds into ketones catalyzed by palladium complexes under mild conditions. The process provides a general,
versatile, synthetic method to produce various symmetrical and unsymmetrical ketones with aromatic, aliphatic, and het-
erocyclic groups. The catalytic cycle is proposed to comprise (a) oxidative addition of a carboxylic anhydride to produce
an acyl(carboxylato)palladium intermediate, (b) transmetallation with an organoboron compound to give an acyl(orga-
no)palladium intermediate, and (c) its reductive elimination to yield a ketone. Not only homogeneous catalyst systems
but also heterogeneous systems were found to give ketones under mild conditions.
2001
3.2.1
Cross-coupling processes of aryl or alkenyl halides with or-
ganometallic compounds of main group elements catalyzed by
palladium complexes have found extensive use in organic syn-
thesis.1 The reason of the utility of the palladium complex as
catalyst arises from the ease of oxidative addition of organic
halides to Pd(0) complexes, ready transmetallation to give di-
organopalladium species and the subsequent facile reductive
elimination to bring together the two organic entities. Howev-
er, the palladium-promoted catalytic processes involving the
oxidative addition of organic halides, despite their utility, en-
tail an intrinsic problem that the halogen used has to be re-
moved eventually for preparation of compounds containing no
halogen atoms. An approach to make the process more atom-
efficient and environmentally benign is to start from com-
pounds without halogen and design a particular synthetic
methodology involving cleavage of a specific bond in the start-
ing material. To utilize cleavage of a carbon–oxygen bond in
an organic compound by palladium and to make use of the re-
activity of the organopalladium compound thus produced ap-
pear as one of the most promising ways to realize a halogen-
free catalytic process. However, cleavage of C–O bonds in ox-
ygen-containing organic compounds by palladium complexes
has not been well utilized except for the process using allylic
carboxylates and carbonates.2
[(phenoxo)(trifluoroacetyl)bis(trimethylphosphine)palladium-
(Ⅱ)] 2a.4 On the other hand, acetic anhydride underwent the
cleavage of the acyl-oxygen bond to give trans-[(acetato)-
(acetyl)bis(tertiary phosphine)palladium(Ⅱ)] 3a and 3b, as
shown in Scheme 1.5
In both processes the cleavage of the acyl–O bond promoted
by the palladium complexes yields reactive acylpalladium
complexes, which can be utilized for synthesis of various car-
bonyl-containing compounds.
Based on the fundamental studies on cleavage of the C–O
bonds in acid anhydrides on interaction with Pd(0) complexes,
we have previously developed novel catalytic hydrogenation
processes to convert a variety of carboxylic anhydrides into the
corresponding aldehydes under mild conditions.5 Later we ex-
panded the method to include direct hydrogenation of carboxy-
As an extension of our long-standing interest in the promo-
tion of the C–O bond cleavage by transition metal complexes,3
we found ready cleavage of the acyl–oxygen bond in elec-
tronegative carboxylic esters4 and carboxylic anhydrides5 on
interaction with Pd(0) complexes. Phenyl trifluoroacetate re-
acted with a coordinatively unsaturated palladium complex,
[Pd(styrene)(PMe3)2]6 1a, prepared in situ by thermolysis of
trans-[PdEt2(PMe3)2]7 in the presence of styrene, to give trans-
Scheme 1. Cleavage of C–O bond in phenyl trifluoroacetate
and acetic anhydride.

138 Bull. Chem. Soc. Jpn., 75, No. 1 (2002)
Pd-Catalyzed Ketone Synthesis from Anhydrides
lic acids into aldehydes at the cost of less reactive carboxylic
anhydrides such as pivalic (2,2-dimethylpropanoic) anhydride
added as an activator of the carboxylic acid (Eq. 1).8
In the previous paper we described the palladium-catalyzed
synthesis of perfluoroalkyl ketones using aryl perfluoroalkane-
carboxylates as shown below.19
(2)
(1)
Another conceivable target for applying the elementary pro-
cess of the acyl–oxygen bond cleavage to organic synthesis is
synthesis of ketones. The acylpalladium species such as 3
generated in the oxidative cleavage of carboxylic anhydride
can be subjected to transmetallation to yield an acyl(alkyl)pal-
ladium species, which may liberate ketone on reductive elimi-
nation.
The catalytic process provides a convenient route to perfluo-
roalkyl ketones from phenyl perfluoroalkanecarboxylates and
organoboron compounds under neutral conditions. However,
the process is not applicable to ketone synthesis from ordinary
carboxylic esters without the electronegative fluorine substitu-
ents because of their reluctance to oxidative addition to a Pd(0)
species.
We wish to report here one other type of palladium-cata-
lyzed ketone synthesis using the C–O bond cleavage of car-
boxylic anhydrides coupled with transmetallation employing
organoboron compounds without using a base (Eq. 3). The
present process using the cleavage of carboxylic anhydrides is
complementary to the process using perfluoroalkanecarboxy-
lates and has a wider scope in application to synthesis of vari-
ous ketones that may not be prepared by conventional methods
such as Friedel–Crafts acylation processes.14
By far the most commonly used methods for the synthesis
of ketones are (i) the nucleophilic addition of organometallic
reagents to carboxylic acid derivatives,9 (ii) oxidation of alco-
hols,10,11,12,13 and (iii) the Friedel–Crafts acylation reaction of
aromatic compounds.14 However, these preparative methods
entail some problems and limitations. For example, synthesis
of ketones from organometallic reagents of electropositive
metals such as lithium and magnesium and carboxylic acid de-
rivatives often proceeds in low yields because of the addition
of the organometallic reagents to the ketone produced to form
tertiary alcohols.15 Many useful reactions are known in partial
oxidation of secondary alcohols to ketones, such as the Swern
oxidation,11 and oxidation by heavy metal salts such as PCC12
and MnO2.13 However, in these processes stoichiometric
amounts of oxidizing agents are required, with concomitant
formation of undesirable by-product(s). The Friedel–Crafts
acylation reactions, which are one of the most important pro-
cesses for the synthesis of aromatic ketones, are generally car-
ried out by using more than a stoichiometric amount of anhy-
drous aluminum trichloride as a Lewis acid. From an industri-
al point of view, the reaction is less desirable because of the
highly corrosive conditions and the concomitant formation of a
large amount of waste. In addition, Friedel–Crafts reactions
display ortho and para selectivity and are not suitable for prep-
aration of aryl ketones with a meta substituent.
Among various palladium-catalyzed cross-coupling pro-
cesses using organic halides as the starting compounds, the
protocol using organoboron compounds (Suzuki–Miyaura pro-
cess) has recently been utilized most widely by synthetic
chemists.16 The process gives the coupling products usually in
high yields, is tolerant to functional groups, and shows excel-
lent stereochemistry. In addition, most organoboron com-
pounds are nontoxic, inert to air and moisture, thermally sta-
ble, and can be recrystallized from water or alcohol.
The Suzuki–Miyaura coupling has been employed for ke-
tone synthesis as well.17,18 Representative preparative methods
of ketones reported so far are (i) carbonylative cross-coupling
reaction of haloarenes with organoboron compounds,17 and (ii)
cross-coupling reaction of acyl halides with various organobo-
ron compounds.18 However, these methods also entail some
problems. The major problem of the Suzuki–Miyaura protocol
is the requirement of a stoichiometric amount of a base to drive
the coupling reactions. Thus these processes are not usable for
the synthesis of ketones sensitive to a base, beside the inherent
environmental problems and the defect of low atom efficiency.
(3)
Results
Stoichiometric Reaction of trans-[(Acetato)(acetyl)bis-
(trimethylphosphine)palladium(ꢀ)] (3a) with Phenylboron-
ic Acid. We have previously reported that 2a,4 generated by
the trifluoroacetyl–OPh bond cleavage in phenyl trifluoroace-
tate on oxidative addition to 1a6 (Scheme 1), reacted readily
with phenylboronic acid at room temperature to liberate phen-
yl trifluoromethyl ketone (Eq. 4).19 The reaction is considered
to proceed through transmetallation, followed by reductive
elimination.
(4)
We found further that the trans-[(acetato)(acetyl)bis(meth-
yldiphenylphosphine)palladium(Ⅱ)] 3b5a readily reacted with
phenylboronic acid at room temperature in a manner similar to
Eq. 4 to liberate acetophenone (Eq. 5).
(5)

R. Kakino et al.
Bull. Chem. Soc. Jpn., 75, No. 1 (2002) 139
The above result on the stoichiometric reactions of the acyl–
O bond cleavage indicated the feasibility of application of the
C–O bond cleavage of carboxylic anhydrides to catalytic syn-
thesis of ketones in the presence of a palladium catalyst. In
fact, examination of the catalytic processes revealed that gen-
eral and convenient palladium-catalyzed processes of synthe-
sizing a variety of ketones from carboxylic anhydrides and or-
ganoboron compounds could be realized.
Catalytic Processes to Prepare Ketones from Carboxylic
Anhydrides and Organoboronic Acids. (a) Examination
of Catalyst Systems. Treatment of benzoic anhydride with
phenylboronic acid at 80 °C in dioxane in the presence of 0.02
molar amount of [Pd(PPh3)4] 4 per benzoic acid for 5 h gave
98% yield of benzophenone. Table 1 summarizes the effects
of the catalyst systems for the ketone synthesis under the stan-
dardized conditions as stated above.
Various palladium catalysts with tertiary phosphine ligands
proved effective in synthesizing benzophenone. Of other tran-
sition metal complexes examined, nickel,20 platinum,21 and
rhodium22 complexes were ineffective (Runs 12–14). The na-
ture and molar amounts of the tertiary phosphine ligands added
to the catalyst system were noted to affect the yield of ben-
zophenone. Palladium complexes such as [Pd(dba)2] and
Pd(OAc)2 without added tertiary phosphine ligands did not cat-
alyze the ketone synthesis (Runs 4 and 5). These palladium
compounds, however, developed suitable catalytic activities
when they were used in combination with tertiary phosphine
ligands as shown in Runs 6 and 7, whereas addition of four
equivalents of more basic tributylphosphine to Pd(OAc)2 sup-
pressed the catalytic activity almost completely (Run 11). The
results suggest that a catalytically active, coordinatively unsat-
urated zerovalent palladium species having a limited number
of the supporting tertiary phosphine ligands of appropriate co-
ordinating abilities is generated in the catalytic system. Zerov-
alent palladium complexes such as [Pd(PPh3)4], [Pd(PMe-
Ph2)4], and [Pd(PCy3)2] (Runs 1, 3, and 8) were found effective
as catalysts, but addition of three equivalents of PPh3 per mol
of [Pd(PPh3)4] caused a decrease in the ketone yield (Run 2).
The presence of four tertiary phosphine ligands such as
PMePh2, having higher coordinating ability than PPh3, lowered
the yield of the ketone (Run 3), whereas coordinatively unsat-
urated Pd(0) complex [Pd(PCy3)2] (Run 8) was found to be as
effective as [Pd(PPh3)4]. Employment of ditertiary phosphine
ligands such as 1,1ꢀ-bis(diphenylphosphino)ferrocene (DPPF)
and 1,4-bis(diphenylphosphino)butane (DPPB) added to
[Pd(dba)2] also gave moderate yields of the ketone (Runs 9 and
10). Although palladium(Ⅱ) acetate alone was not effective,
addition of triphenylphosphine to the system developed some
catalytic activity. This may be ascribed to in situ generation of
a triphenylphosphine-coordinated Pd(0) species by reduction
of palladium acetate with triphenylphosphine.23
(b) Effects of Solvent and Temperature. The effects of
the solvent and reaction temperature on the yields of ben-
zophenone produced by the palladium-catalyzed reaction of
benzoic anhydride with phenylboronic acid are summarized in
Table 2. In the reaction catalyzed by [Pd(PPh3)4] 4 the ben-
zophenone formation was slow at room temperature in diox-
ane, but at higher temperatures of 60 and 80 °C, higher yields
were obtained, whereas at still higher temperature of 100 °C a
slight decrease in the yield was observed (Runs 1–4).
The effects of other solvents on the yields of the coupling
reaction of benzoic anhydride with phenylboronic acid at 80
°C are shown in Runs 5–10. Dioxane was found to be most
suitable as solvent, followed by THF, which gave a slightly
lower yield at refluxing temperature. Employment of acetone,
toluene and 1-methyl-2-pyrrolidinone (NMP) gave moderate
yields of the ketone. Hexane was found to be less appropriate,
probably because of its poor ability to dissolve the catalyst sys-
tem.
Table 1. Effect of Homogeneous Catalysts on the Cross-
Coupling Reaction of Benzoic Anhydride with Phenylbo-
ronic Acid
Table 2. Effects of Solvents and Temperature on the Cross-
Coupling Reaction of Benzoic Anhydride with Phenylbo-
ronic Acid
Run
Catalyst
Yield/%a)
1
2
3
[Pd(PPh3)4]
98
72
66
0
[Pd(PPh3)4] + 3PPh3
[Pd(PMePh2)4]
[Pd(dba)2]
4
Run
Temp/°C
Solvent
Yield/%a)
5
Pd(OAc)2
0
1
2
3
4
5
6
7
8
9
r. t.
60
80
100
reflux
reflux
80
80
80
reflux
dioxane
dioxane
dioxane
dioxane
acetone
hexane
toluene
acetonitrile
NMPb)
5
73
99
91
59
5
77
24
62
92
6
7
8
9
10
11
12
13
14
[Pd(dba)2] + 4PPh3
Pd(OAc)2 + 4PPh3
[Pd(PCy3)2]
82
77
95
76
64
trace
trace
0
[Pd(dba)2] + 1DPPFb)
[Pd(dba)2] + 1DPPBc)
Pd(OAc)2 + 4PnBu3
[Ni(cod)2] + 2PPh3
[Pt(PPh3)4]
[Rh(PPh3)3Cl]
0
10
THF
a) Determined by GC using nC14H30 as an internal
standard.
b) DPPF is 1,1ꢀ-bis(diphenylphosphino)ferrocene.
c) DPPB is 1,4-bis(diphenylphosphino)butane.
a) Determined by GC using nC14H30 as an internal
standard.
b) N-methyl-2-pyrrolidinone.

140 Bull. Chem. Soc. Jpn., 75, No. 1 (2002)
Pd-Catalyzed Ketone Synthesis from Anhydrides
Table 3. Synthesis of Unsymmetrical Ketones by the Palladium-Catalyzed Cross-Coupling of Carboxylic Anhydrides with Orga-
noboronic Acids
Run
1
R1
R2
Methoda) Yield/%b) Run
R1
R2
Methoda) Yield/%b)
A
A
A
B
B
A
A
A
98
9
10
11
12
13
14
15
16
A
A
A
A
C
A
A
C
99 (96)
99 (97)
99 (97)
79 (61)
54 (48)
97
2
3
4
5
6
7
8
98
81
99 (64)
95
94 (73)
99
84 (88)
44
87
a) Method A: 2 mol% of [Pd(PPh3)4] was used. Reaction time, 5 h.
Method B: 5 mol% of [Pd(PPh3)4] was used. Reaction time, 10 h.
Method C: 5 mol% of [Pd(PPh3)4] was used. Reaction time, 24 h.
b) GC yields based on acid anhydrides and isolated yields are in the parentheses.
(c) Scope and Limitation. On the basis of the above
mentioned results, we chose [Pd(PPh3)4] 4 as the standard cata-
lyst and examined the applicability of the present method to
synthesis of various unsymmetrical ketones by carrying out the
experiments under the standardized procedure, i. e., in dioxane
at 80 °C with use of various anhydride substrates in combina-
tion with various organoboronic acids commercially avail-
able. The results are summarized in Table 3.
Various aromatic carboxylic anhydrides having electron-do-
nating as well as an electron-withdrawing substituent at the
para or meta position in benzoic anhydride can be catalytically
converted into the corresponding ketones, usually in excellent
yields, on treatment with organoboronic acids in the presence
of 4 (Runs 1–13). p-Chlorobenzoic anhydride was trans-
formed selectively into 4-chlorobenzophenone without under-
going the C–Cl bond cleavage24 (Run 8).
ronic acids. It is noted that the present method is applicable to
2-thienylboronic acid that is known as a poor arylating reagent
in the conventional Suzuki–Miyaura coupling because of its
inclination to deboronation.25 Although longer reaction time
and usage of an extra molar amount of the palladium catalyst
were required to complete the reaction (Run 4), 2-thiophenyl
phenyl ketone was obtained in an excellent yield in 10 h. Or-
ganoboronic acid such as trans-β-styrylboronic acid having the
double bond that may interact with the palladium species could
be also used (Run 5).
Aliphatic carboxylic anhydrides such as acetic anhydride
and hexanoic anhydride (caproic anhydride) are converted
smoothly into alkyl aryl ketones with 4 in combination with
organoboronic acids (Runs 14, 15), whereas a bulky aliphatic
carboxylic anhydride such as 2,2-dimethylpropanoic anhydride
(pivalic anhydride) was much less reactive, as shown in Run
16. Some steric hindrance was also noted on the side of orga-
The present method allows the use of a variety of organobo-

R. Kakino et al.
Bull. Chem. Soc. Jpn., 75, No. 1 (2002) 141
noboronic acids, as evidenced in the lower yield of unsymmet-
rical ketone in coupling of p-toluic anhydride with 2,6-dimeth-
ylphenylboronic acid with the palladium catalyst (Run 13).26
A somewhat decreased yield was also noted in the reaction of
toluic anhydride with 2-methylphenylboronic acid having a
methyl substituent at the ortho postion (Run 12).
Organoboron compounds other than organoboronic acids
were also examined. Employment of sodium tetraphenyl-
borate27 in a quantity somewhat higher than equimolar amount
in combination with the benzoic anhydride yielded benzophe-
none in 95%. A moderately high yield of benzophenone
(64%) from benzoic anhydride was obtained even when 1/3
molar amount of NaBPh4 was employed in the presence of 4,
the result indicating that two phenyl groups in NaBPh4 were
used in the transfer process. The use of 2-phenyl-1,3,2-
dioxaborinane28 as the alkylating reagents was ineffective (Eq.
6).
Scheme 3. Cleavage of C–O bond in acetic anhydride.
lates.19 The catalytic cycle is composed of elementary pro-
cesses of (i) oxidative addition of a carboxylic anhydride to a
coordinatively unsaturated Pd(0) species A, formed from a cat-
alyst precursor D, with the C–O bond cleavage to give an
acyl(carboxylato)palladium species B; (ii) transmetallation
with an organoboron compound such as organoboronic acid to
give an acyl(alkyl)palladium species C; and (iii) reductive
elimination of ketone as the coupling product regenerating the
Pd(0) species A, which further carries the catalytic cycle to
produce the product ketone.
(6)
As indicated in the effect of tertiary phosphines on the
yields of ketones in the cross-coupling process in Table 1, the
active species A involved in the catalytic cycle seems to have a
vacant site for undergoing the oxidative addition with the an-
hydride. Such a notion is based on several pieces of experi-
mental evidence. Examination of the 31P{1H} NMR spectra of
[Pd(PMePh2)4] 5 in dioxane in the presence of an equimolar
quantity of added acetic anhydride at room temperature indi-
cated the inertness of the coordinatively saturated species 5 to
oxidative addition of acetic anhydride. In contrast, the coordi-
natively unsaturated Pd(0) complex [Pd(styrene)(PMePh2)2]
1b29 having two PMePh2 ligands undergoes ready oxidative
addition of acetic anhydride with the C–O bond cleavage to
give trans-[(acetato)(acetyl)bis(dimethylphenylphosphine)pal-
ladium(Ⅱ)]5a 3b (Scheme 3), which corresponds to B in
Scheme 2.
Discussion
On the basis of the fundamental studies on the stoichiomet-
ric processes involving oxidative addition of carboxylic anhy-
dride to Pd(0) compounds and the subsequent reaction of the
acyl(carboxylato)palladium complexes with organoboronic ac-
ids, we propose the catalytic cycle shown in Scheme 2 to ac-
count for the catalytic formation of ketones from carboxylic
anhydrides and organoboronic compounds.
The essential part in the mechanism is similar to the mecha-
nism of ketone synthesis from phenyl perfluoroalkanecarboxy-
The oxidative addition of an anhydride to A to give B and
the reductive elimination process to give A from B are revers-
ible. Addition of two equivalents of methyldiphenylphosphine
to the THF-d8 solution of 3b caused the rapid formation of 5
and acetic anhydride (Eq. 2), indicating that the reductive elim-
ination with coupling of the acetyl and acetato ligands takes
places readily in the presence of an extra amount of a tertiary
phosphine.30 The results show the presence of an equilibrium
shown in Eq. 2. This equilibrium lies far to the right, on the
side of C–O bond formation.
(7)
The transmetallation of the acetate ligand in 3b on treatment
with phenylboronic acid in dioxane takes place readily at room
Scheme 2. Catalytic cycle for the formation of ketones.

142 Bull. Chem. Soc. Jpn., 75, No. 1 (2002)
Pd-Catalyzed Ketone Synthesis from Anhydrides
Fig. 2. Time course of the coupling reaction of (PhCO)2O or
(p-MeOC6H4CO)2O with PhB(OH)2 catalyzed by
[Pd(PPh3)4] carried out at 80 ˚C in dioxane.
Fig. 1.
Time courses of the coupling reaction of (p-
MeOC6H4CO)2O and PhB(OH)2 catalyzed by [Pd(PPh3)4]
or [Ph(η3-C3H5)Cp] + 2PPh3 in dioxane carried out at 80
˚C.
Table 4. Reactivity of p-Substituted Benzoic Anhydrides
Relative to Benzoic Anhydride and Their Hammett Sub-
stituent Values
temperature to liberate acetophenone, as shown in Eq. 5. The
result suggests that the reductive elimination of the ketone
from C is also a rapid process.
These results point to the importance of the pre-equilibrium
process between the active species A and its catalyst precursor
D, shown outside of the main catalytic cycle in Scheme 2.
For comparing the reactivities of palladium complexes hav-
ing the coordinative unsaturation and saturation, we have ex-
amined the time courses of the reactions of p-anisic anhydride
with phenylboronic acid at 80 °C in the presence of
[Pd(PPh3)4] and a coordinatively unsaturated catalyst system
prepared from the mixture of [(η5-cyclopentadienyl)(η3-al-
lyl)palladium] 6 with two equivalents of PPh3. The ketone for-
mation was observed to proceed much faster in the initial peri-
od with the latter catalyst system having the coordinative un-
saturation than with 4 having four PPh3 ligands (Fig. 1).
These results suggest the importance of the generation of a
catalytically active, coordinatively unsaturated species to react
with a carboxylic anhydride in the catalytic process. The re-
quirement of a moderately high reaction temperature to pro-
mote the catalytic process with 4 may be mainly associated
with the necessity to generate a coordinatively unsaturated and
thermally stable species to carry the reaction in the presence of
a supporting ligand(s).
For gaining further insight into the mechanism of the cata-
lytic process, we next examined the reaction course of the ke-
tone synthesis. Figure 2 exhibits time-courses of the reactions
of benzoic anhydride and p-anisic anhydride, respectively,
with phenylboronic acid in the presence of [Pd(PPh3)4] 4 in di-
oxane at 80 °C.
The reaction of benzoic anhydride with phenylboronic acid
catalyzed by 4 proceeded smoothly to give benzophenone al-
most quantitatively in 1 h, whereas the reaction of 4-methoxy-
Y
Hammett σp
P(Y)/P(H)
log(P(Y)/P(H))
MeO
Me
H
−0.27
−0.17
0
0.55
0.72
1
−0.26
−0.14
0
Cl
0.227
1.6
0.19
a) Determined by GC using nC14H30 as an internal
standard.
benzoic anhydride proceeded more slowly, to be completed in
3 h at 80 °C. The result in Fig. 2 shows that introduction of an
electron-donating substituent such as OMe group at the para
position in benzoic anhydride decreases the reaction rate in the
coupling reaction.
More direct comparison of the reactivities of various car-
boxylic anhydrides can be achieved by carrying out competi-
tion experiments by using equimolar mixtures of benzoic an-
hydride and various para-substituted benzoic anhydrides in re-
actions with phenylboronic acid catalyzed by 4 (Table 4). In
Table 4 are compared relative product yields, P(Y)/P(H) of the
ketone having theY substituent at the para position versus ben-
zophenone, produced after heating for 5 h in dioxane at 80 °C.
The results indicate that the carboxylic anhydride having the
more electron-withdrawing para substituent reacts faster than
the benzoic anhydride derivative having the more electron-re-
leasing para substituent.

R. Kakino et al.
Bull. Chem. Soc. Jpn., 75, No. 1 (2002) 143
Table 5. Effect of Heterogeneous Catalysts on the Cross-
Coupling Reaction of Benzoic Anhydride with Phenylbo-
ronic Acid
Run Pd-catalyst
Yield/%a)
1
2
3
4
5
6
Pd/C (10% wt)
Pd/BaSO4 [reduced] (5% wt)
Pd/BaSO4 [unreduced] (5% wt)
Pd/C (10% wt) + 4PPh3
Pd/BaSO4 [reduced] (5% wt) + 4PPh3
Pd/BaSO4 [unreduced] (5% wt) + 4PPh3
25
14
33
66
43
94
a) Determined by GC using nC14H30 as an internal
standard.
The result indicates that the aroyl part in the mixed anhy-
dride 7 reacted preferentially with the palladium complex in
the catalytic system. On the basis of these results, we devel-
oped a catalytic process to convert carboxylic acids directly
into ketones by combining the exchange process of the carbox-
ylic acid with an acid anhydride having a less reactive acyl en-
tity under mild conditions without using a base. The results
will be the subject of a separate report.
Fig. 3. Hammett plot for the relative reactivities of various
para-substituted benzoic anhydridesd to benzoic anhydride
in the cross-coupling reaction.
Figure 3 demonstrates the results of the competition experi-
ments using the three pairs of para-substituted symmetric ben-
zoic anhydrides and benzoic anhydride carried out at 80 °C in
the presence of [Pd(PPh3)4] as the catalyst. The plot of loga-
rithms of the relative yields of the ketones against Hammett σp
constants showed a reasonably good linear relationship (r2 =
0.996) with a ρ value of 0.89. The positive ρ value suggests
that cross-coupling reaction proceeds faster with carboxylic
anhydride having the more electron-withdrawing groups.
Although more detailed studies are required to draw definite
conclusions concerning the rate-determining step in the cata-
lytic cycle, it is clear that the oxidative addition of carboxylic
anhydride to the coordinatively unsaturated palladium(0) spe-
cies constitutes the most important step to control the catalytic
cycle under the experimental conditions where an equilibrium
between the catalyst precursor D and active species A is
present.
Reaction of the Unsymmetrical Anhydride with Arylbo-
ronic Acids Catalyzed by [Pd(PPh3)4] 4. To compare the
relative reactivities of the acyl entities in the mixed carboxylic
anhydrides toward palladium-catalyzed ketone synthesis, we
have treated the mixed anhydride, p-toluic pivalic anhydride 7,
with phenylboronic acid at 80 °C for 1 day in the presence of 4
as the catalyst. The reaction of phenylboronic acid used in a
quantity somewhat higher than equimolar amount in combina-
tion with the p-toluic pivalic anhydride gave 4-methylben-
zophenone in 80%, together with 10% of the 2,2-dimethylpro-
piophenone (Eq. 8).
Application to Heterogeneous Systems.
Recently, the
effect of addition of ligands not only to homogeneous catalyst
systems but also to heterogeneous catalysts to control the reac-
tion courses is attracting increasing attention.31 In practical
systems, heterogeneous catalysts possess obvious advantages
over the homogeneous systems in ease of separation of the cat-
alysts and the product. We found that by suitable combination
of the heterogeneous palladium catalyst with triphenylphos-
phine ligand, effective catalyst systems could be developed, as
shown in Table 5.
The commercially available palladium deposited on activat-
ed carbon and barium sulfate (reduced as well as unreduced
samples) showed modest catalytic activities (Runs 1–3). Addi-
tion of PPh3 gave rise to higher activity. The combination of
Pd/BaSO4 (unreduced) used in the presence of 4 equiv of PPh3
gave as high as 94% yield of benzophenone in dioxane at 80
°C (Run 6).
Evaluation of the Utility of the Present Process in Or-
ganic Synthesis. The ketone synthesis utilizing the Suzuki–
Miyaura coupling employing the systems composed of either
acyl halides with organoboronic acids or aryl halides with or-
ganoboronic acids under CO atmosphere has been already de-
veloped.17,18 But the process using acyl chlorides is less desir-
able than the present method in that the preparation of acyl
chlorides is required in the first place and the addition of a base
is necessary to drive the coupling reaction. The present pro-
cess uses the acyl entity in carboxylic anhydride and requires
no carbon monoxide to be externally introduced, thus offering
operational ease.
There are other useful processes of ketone synthesis using
thioesters as the acyl entity as developed by Fukuyama,32
Terfort,33 and Liebeskind.34 The present method provides a di-
rect route of synthesizing ketones without synthesizing the thi-
ol ester derivatives, from which the thiolate parts have to be
(8)

144 Bull. Chem. Soc. Jpn., 75, No. 1 (2002)
Pd-Catalyzed Ketone Synthesis from Anhydrides
graph. Elemental analyses were performed by the Materials Char-
acterization Central Laboratory of Waseda University.
discarded after their use for ketone synthesis. The necessity of
prior preparation of carboxylic anhydrides is one disadvantage
of the present method. However, we recently found the route
to overcome the disadvantage by activating carboxylic acids in
combination with another anhydride, notably dimethyl dicar-
bonate. Treatment of carboxylic acids with dimethyl dicarbon-
ate leads to mixed anhydrides, which undergo the C–O bond
cleavage process and further transmetallation with organobo-
ron compounds to yield unsymmetrical ketones in excellent
yields, as will be reported separately.35
In the Suzuki–Miyaura coupling of organic halides or or-
ganic triflates with aryl-, alkenyl-, and alkylboronic acids or
esters, addition of a base such as NaOEt, KOAc, and NaOH is
necessary to drive the reactions.16 In the Suzuki–Miyaura cou-
pling the effect of addition of the base was accounted for as re-
placement of the halide ligand in the catalyst intermediate with
the alkoxide, carboxylate, or hydroxide ligand that is more sus-
ceptible to transmetallation with the oxophilic organoboron
compounds than a halide.36 In the present case, on the other
hand, use of carboxylic anhydride gives the acyl(carboxy-
late)palladium intermediate suitable for the direct transmetal-
lation process with the oxophilic organoboron compounds,
thus eliminating the necessity of adding an extra base.37
Reagents. All organoboron compounds were commercial
products (Aldrich) and were used without further purification.
Benzoic anhydride (Tokyo Kasei Kogyo Co.), acetic anhydride
(Tokyo Kasei Kogyo Co.), 2,2-dimethylpropionic anhydride (Ald-
rich), and hexanoic anhydride (Tokyo Kasei Kogyo Co.) were
commercial products, and were used directly. All carboxylic an-
hydrides except for benzoic anhydride, acetic anhydride, 2,2-dim-
ethylpropionic anhydride, and hexanoic anhydride were synthe-
sized by the reaction of acyl halides with the corresponding car-
boxylic acids in the presence of pyridine. p-MeC6H4COOCOtBu
was prepared by treating p-toluic acid with pivaloyl chloride in the
presence of pyridine.
[Pd(PPh3)4],38 [Pd(PMePh2)4],29,39
[Pd(PCy3)2],40 [Pd(styrene)(PMePh2)2],29 [(η5-cyclopentadie-
nyl)(η3-allyl)palladium]41 were prepared by the reported proce-
dures. [Pd2(dba)3] was prepared following a synthesis report42 and
was used without recrystallization of the crude precipitate ob-
tained at the end of the synthesis. Pd(OAc)2 (Aldrich), 10% Pd/C
(Kojima Chemicals Co.), 5% Pd/BaSO4/(reduced) (Aldrich), and
Pd/BaSO4/(unreduced) (Aldrich) were used as received from com-
mercial suppliers. All tertiary phosphines were commercial prod-
ucts and were used without further purification.
trans-[PdAc(OAc)(PMePh2)2] 3b was prepared as previously
reported5a by the reaction of [Pd(styrene)(PMePh2)2]29 1b with
acetic anhydride.
Conclusion
Reaction of trans-[PdAc(OAc)(PMePh2)2] with Phenylbo-
ronic Acid (Eq. 5). To a dioxane solution (5 cm3) of trans-
[PdAc(OAc)(PMePh2)2] (300 mg, 0.493 mmol), phenylboronic
acid (72.0 mg, 0.591 mmol) was added at room temperature. The
mixture was stirred for 4 h at room temperature. The GC and GC-
MS analysis of the products was performed with nC14H30 as an in-
ternal standard. Formation of acetophenone (67%) was con-
formed. Acetophenone was characterized by GC-MS by compar-
ing with an authentic sample (Tokyo Kasei Kogyo Co.). GC-MS
m/z (rel intensity) 120 (47), 105 (100), 77 (98).
Effect of Homogeneous Catalysts (Table 1). A typical pro-
cedure is as follows (Run 8). A dioxane solution (5 cm3) contain-
ing [Pd(PCy3)2] (13.3 mg, 0.0199 mmol), benzoic anhydride (226
mg, 0.999 mmol), and phenylboronic acid (147 mg, 1.21 mmol) in
a 25 cm3 Schlenk tube was heated under argon at 80 °C for 5 h.
The yields of benzophenone were determined by GC using
nC14H30 as an internal standard. Benzophenone was characterized
by GC-MS by comparison with an authentic sample (Tokyo Kasei
Kogyo Co.).
On the basis of the fundamental studies on the elementary
processes involving oxidative addition of a carboxylic anhy-
dride to a Pd(0) complex and on the transmetallation of the
product with an organoboronic acid to give a ketone, we de-
vised a novel type of catalytic process to convert carboxylic
anhydrides and organoboron compounds into ketones without
using a base. In view of the paucity of atom-efficient and envi-
ronmentally benign useful processes to synthesize unsymmet-
rical ketones under mild conditions, the present method pro-
vides a convenient new route to selective production of ketones
under mild conditions. Dissociation of a tertiary phosphine
ligand from a coordinatively saturated species to generate a co-
ordinatively unsaturated species has been confirmed as an im-
portant factor to control the reaction rate of the catalysis. It
was also revealed on the basis of competition reactions that ox-
idative addition of the carboxylic anhydride substrate to a
Pd(0) species constitutes the turn-over limiting step in the cata-
lytic cycle, if other experimental conditions are kept constant.
Effect of Solvent and Temperature (Table 2).
A
typical
Experimental
procedure is as follows (Run 4). A dioxane solution (5 cm3) con-
taining [Pd(PPh3)4] (57.9 mg, 0.0501 mmol), benzoic anhydride
(227 mg, 1.00 mmol), and phenylboronic acid (146 mg, 1.20
mmol) in a 25 cm3 Schlenk tube was stirred under argon at room
temperature and at 60 °C, 80 °C, and 100 °C, respectively, for five
hours. The effects of solvents were examined in hexane, toluene,
acetonitrile, 1-methyl-2-pyrrolidinone (NMP), THF, and dioxane
by carrying out the synthesis at 80 °C. The yields of benzophe-
General Procedures. All manipulations were carried out un-
der argon atmosphere using Schlenk tube techniques. Solvents
were purified by the usual methods under argon. NMR spectra
were recorded on a JEOL Lambda 500 or a JEOL AL-400 spec-
trometer for 1H (referenced to SiMe4 via residual solvent protons),
13C{1H} (referenced to SiMe4 via the solvent resonance), 19F (ref-
erenced to trifluoroacetic acid in CDCl3 as an external standard),
and 31P{1H} (referenced to 85% H3PO4 as an external standard)
NMR. Coupling constants (J values) are given in hertz (Hz), and
spin multiplicities are indicated as follows: s (singlet), d (doublet),
t (triplet), m (multiplet), vt (virtual triplet), and br (broad). Gas
chromatographic analyses (GC) were carried out on a GC-353
equipped with TC1 column (0.25 mm i.d. × 30 m), using N2 as
carrier gas. Low-resolution mass spectra were obtained with a
JEOL JMS-Automass 150 that is coupled with gas chromato-
n
none were determined by GC using C14H30 as an internal stan-
dard. Benzophenone was characterized by GC-MS by compari-
son with an authentic sample (Tokyo Kasei Kogyo Co.).
Synthesis of Unsymmetric Ketones (Table 3).
A typical
procedure is as follows (Run 10). A dioxane solution (5 cm3) con-
taining [Pd(PPh3)4] (23.2 mg, 0.0201 mmol), m-toluic anhydride
(254 mg, 0.999 mmol), and 2-naphthylboronic acid (206 mg, 1.20
mmol) in a 25 cm3 Schlenk tube was heated under argon at 80 °C

R. Kakino et al.
Bull. Chem. Soc. Jpn., 75, No. 1 (2002) 145
for five hours. After the reaction mixture was cooled, diethyl ether
and H2O were added and the aqueous layer was extracted with di-
ethyl ether. The combined ether solution was dried (MgSO4) and
the solvent was evaporated in vacuo. Purification of the residue by
column chromatography (hexane/Et2O = 9:1) gave the corre-
sponding product (239 mg; yield 97%).
(100).
3-Methyl-1ꢁ-benzonaphthone: (96%); 1H NMR (acetone-d6,
r. t., 400 MHz) δ 8.13–8.09 (m, 1H, aromatic H), 8.03 (m, 1H, ar-
omatic H), 8.01 (m, 1H, aromatic H), 7.68 (s, 1H, aromatic H),
7.59 (m, 1H, aromatic H), 7.58 (s, 1H, aromatic H), 7.57 (m, 1H,
aromatic H), 7.55–7.54 (m, 1H, aromatic H), 7.53–7.50 (m, 1H,
aromatic H), 7.49–7.47 (m, 1H, aromatic H), 7.41–7.37 (m, 1H,
aromatic H), 2.36 (s, 3H, CH3); 13C{1H} NMR (acetone-d6, r. t.,
100 MHz) δ 197.8 (s, carbonyl C), 139.1 (s, aromatic C), 139.1 (s,
aromatic C), 137.4 (s, aromatic C), 134.6 (s, aromatic C), 134.5 (s,
aromatic C), 131.6 (s, aromatic C), 131.5 (s, aromatic C), 130.9 (s,
aromatic C), 129.2 (s, aromatic C), 129.2 (s, aromatic C), 128.1 (s,
aromatic C), 128.1 (s, aromatic C), 127.8 (s, aromatic C), 127.1 (s,
aromatic C), 126.1 (s, aromatic C), 125.3 (s, aromatic C), 21.2 (s,
CH3). GC-MS m/z (rel intensity) 246 (73), 231 (38), 202 (10),
155 (98), 127 (100), 119 (64), 91 (56), 77 (12). Found: C, 87.36;
H, 5.25%. Calcd for C18H14O: C, 87.78; H, 5.73%.
3-Methyl-2ꢁ-benzonaphthone: (97%); 1H NMR (acetone-d6,
r. t., 400 MHz) δ 8.26 (s, 1H, aromatic H), 8.01–7.96 (m, 3H, aro-
matic H), 7.88–7.85 (m, 1H, aromatic H), 7.64–7.54 (m, 4H, aro-
matic H), 7.46–7.38 (m, 2H, aromatic H), 2,38 (s, 3H, CH3);
13C{1H} NMR (acetone-d6, r. t., 100 MHz) δ 196.4 (s, carbonyl
C), 138.9 (s, aromatic C), 138.7 (s, aromatic C), 135.9 (s, aromatic
C), 135.7 (s, aromatic C), 133.7 (s, aromatic C), 133.1 (s, aromatic
C), 132.1 (s, aromatic C), 130.9 (s, aromatic C), 130.1 (s, aromatic
C), 129.0 (s, aromatic C), 129.0 (s, aromatic C), 128.9 (s, aromatic
C), 128.5 (s, aromatic C), 127.8 (s, aromatic C), 127.6 (s, aromatic
C), 126.2 (s, aromatic C), 21.3 (s, CH3). GC-MS m/z (rel intensi-
ty) 246 (55), 231 (18), 202 (5), 155 (62), 127 (95), 119 (42), 91
(100), 77 (21). Found: C, 87.59; H, 5.68%. Calcd for C18H14O: C,
87.78; H, 5.73%.
The following unsymmetric ketones were synthesized by the
above general procedure.
Benzophenone: [119-61-9] (98%); Benzophenone was char-
acterized by GC-MS by comparison with an authentic sample (To-
kyo Kasei Kogyo Co.). GC-MS m/z (rel intensity) 182 (73), 105
(84), 77 (100).
3-Methoxy-3ꢁ-methylbenzophenone: (97%); 1H NMR (ace-
tone-d6, r. t., 400 MHz) δ 7.60 (s, 1H, aromatic H), 7.56–7.54 (m,
1H, aromatic H), 7.45–7.40 (m, 3H, aromatic H), 7.30 (m, 2H, ar-
omatic H), 7.21–7.19 (m, 1H, aromatic H), 3.85 (s, 3H, OCH3),
2.40 (s, 3H, CH3); 13C{1H} NMR (acetone-d6, r. t., 100 MHz) δ
196.1 (s, carbonyl C), 160.4 (s, aromatic C), 139.8 (s, aromatic C),
138.8 (s, aromatic C), 138.4 (s, aromatic C), 133.8 (s, aromatic C),
130.7 (s, aromatic C), 130.1 (s, aromatic C), 128.9 (s, aromatic C),
127.7 (s, aromatic C), 122.9 (s, aromatic C), 118.9 (s, aromatic C),
115.0 (s, aromatic C), 55.7 (s, OCH3), 21.3 (s, CH3). GC-MS m/z
(rel intensity) 226 (49), 211 (10), 195 (5), 135 (37), 119 (73), 107
(13), 91 (100), 77 (62). Found: C, 79.28; H, 6.26%. Calcd for
C15H14O: C, 79.62; H, 6.24%.
4-Methylbenzophenone: [134-84-9] (98%); 4-Methylben-
zophenone was characterized by GC-MS by comparison with an
authentic sample (Kanto Chemical Co.). GC-MS m/z (rel intensi-
ty) 196 (43), 181 (10), 119 (100), 105 (26), 91 (24), 77 (28).
4-Trifluoromethylbenzophenone: [728-86-9] (81%); 4-Tri-
fluoromethylbenzophenone was characterized by GC-MS by com-
parison with an authentic sample (ACROS). GC-MS m/z (rel in-
tensity) 250 (11), 173 (12), 145 (30), 125 (10), 105 (100), 77 (95).
1
2,4ꢁ-Dimethylbenzophenone: [1140-16-5] (61%); H NMR
(acetone-d6, r. t., 400 MHz) δ 7.65 (d, 2H, J = 8.06 Hz, aromatic
H), 7.43–7.39 (m, 1H, aromatic H), 7.33–7.32 (m, 1H, aromatic
H), 7.32 (d, 2H, J = 8.06 Hz, aromatic H), 7.28 (s, 1H, aromatic
H), 7.27 (s, 1H, aromatic H), 2.40 (s, 3H, 4ꢀ-CH3), 2.26 (s, 3H, 2-
CH3); 13C{1H} NMR (acetone-d6, r. t., 100 MHz) δ 197.7 (s, car-
bonyl C), 144.7 (s, aromatic C), 139.9 (s, aromatic C), 136.7 (s,
aromatic C), 135.9 (s, aromatic C), 131.5 (s, aromatic C), 130.6 (s,
aromatic C), 130.6 (s, aromatic C), 129.9 (s, aromatic C), 128.6 (s,
aromatic C), 125.9 (s, aromatic C), 21.6 (s, 4-CH3), 19.8 (s, 2-
CH3). GC-MS m/z (rel intensity) 209 (70), 195 (98), 178 (17),
165 (33), 152 (10), 119 (100), 91 (100). Found: C, 85.75; H,
6.82%. Calcd for C15H14O: C, 85.68; H, 6.71%.
2-Benzoylthiophene: [135-00-2]
(96%);
2-Benzoylth-
iophene was characterized by GC-MS by comparison with an au-
thentic sample (Tokyo Kasei Kogyo Co.). GC-MS m/z (rel inten-
sity) 188 (100), 171 (22), 160 (28), 111 (100), 105 (99), 77 (100).
Chalcone: [614-47-1] (95%); Chalcone was characterized by
GC-MS by comparison with an authentic sample (Tokyo Kasei
Kogyo Co.). GC-MS m/z (rel intensity) 208 (91), 179 (58), 165
(30), 131 (100), 105 (100), 77 (83).
4-Methoxy-4ꢁ-methylbenzophenone: (94%); 1H NMR (ace-
tone-d6, r. t., 400 MHz) δ 7.77 (d, 2H, J = 8.79 Hz, aromatic H),
7.64 (d, 2H, J = 8.06 Hz, aromatic H), 7.33 (d, 2H, J = 8.06 Hz,
aromatic H), 7.05 (d, 2H, J = 8.79 Hz, aromatic H), 3.89 (s, 3H,
OCH3), 2.41 (s, 3H, CH3); 13C{1H} NMR (acetone-d6, r. t., 100
MHz) δ 194.6 (s, carbonyl C), 163.8 (s, aromatic C), 143.1 (s, aro-
matic C), 136.4 (s, aromatic C), 132.7 (s, aromatic C), 131.0 (s, ar-
omatic C), 130.3 (s, aromatic C), 129.6 (s, aromatic C), 114.3 (s,
aromatic C), 55.9 (s, OCH3), 21.5 (s, CH3). GC-MS m/z (rel in-
tensity) 226 (30), 211 (10), 195 (5), 135 (63), 119 (30), 107 (12),
91 (100), 77 (44). Found: C, 79.17; H, 6.26%. Calcd for
C15H14O2: C, 79.62; H, 6.24%.
1
2,4ꢁ,6-Trimethylbenzophenone: (48%); H NMR (acetone-
d6, r. t., 400 MHz) δ 7.64 (d, 2H, J = 8.12 Hz, aromatic H), 7.33
(d, 2H, J = 8.12 Hz, aromatic H), 7.26 (t, 1H, J = 7.81 Hz, aro-
matic H), 7.12 (d, 2H, J = 7.81 Hz, aromatic H), 2.40 (s, 3H, 4ꢀ-
CH3), 2.04 (s, 6H, 2,6-CH3); 13C{1H} NMR (acetone-d6, r. t., 100
MHz) δ 199.4 (s, carbonyl C), 145.3 (s, carbonyl C), 140.8 (s, aro-
matic C), 135.5 (s, aromatic C), 134.4 (s, aromatic C), 130.4 (s, ar-
omatic C), 129.8 (s, aromatic C), 129.3 (s, aromatic C), 128.2 (s,
aromatic C), 21.6 (s, 4ꢀ-CH3), 19.3 (s, 2,6-CH3). GC-MS m/z (rel
intensity) 224 (26), 209 (100), 194 (12), 165 (7), 133 (25), 119
(33), 105 (22), 91 (32), 77 (26). Found: C, 85.40; H, 7.33%. Cal-
cd for C15H14O: C, 85.68; H, 7.19%.
4-Methoxybenzophenone: [611-94-9] (99%); 4-Methoxy-
benzophenone was characterized by GC-MS by comparison with
an authentic sample (Aldrich). GC-MS m/z (rel intensity) 212
(98), 181 (9), 135 (42), 105 (28), 92 (8) 77 (72).
Acetophenone: [98-86-2] (97%); Acetophenone was charac-
terized by 1H, 13C{1H} NMR, and GC-MS by comparison with an
1
authentic sample (Tokyo Kasei Kogyo Co.). H NMR (acetone-d6,
4-Chlorobenzophenone: [134-85-0] (87%); 4-Chloroben-
zophenone was characterized by GC-MS by comparison with an
authentic sample (Tokyo Kasei Kogyo Co.). GC-MS m/z (rel in-
tensity) 216 (9), 181 (4), 152 (3), 139 (30), 111 (41), 105 (72), 77
r. t., 400 MHz) δ 7.99–7.97 (m, 2H, aromatic H), 7.62–7.58 (m,
1H, aromatic H), 7.52–7.48 (m, 2H, aromatic H), 2.57 (s, 3H,
CH3); 13C{1H} NMR (acetone-d6, r. t., 100 MHz) δ 197.6 (s, car-
bonyl C), 138.0 (s, aromatic C), 133.6 (s, aromatic C), 129.2 (s,

146 Bull. Chem. Soc. Jpn., 75, No. 1 (2002)
Pd-Catalyzed Ketone Synthesis from Anhydrides
aromatic C), 128.8 (s, aromatic C), 26.6 (s, CH3). GC-MS m/z (rel
intensity) 120 (55), 105 (99), 77 (100).
Competitive Reactions of Various para-Substituted Benzoic
Anhydrides and Benzoic Anhydride (Table 4, Fig. 3). A typi-
cal procedure is as follows. A dioxane solution (5 cm3) containing
[Pd(PPh3)4] (23.3 mg, 0.0202 mmol), benzoic anhydride (453 mg,
2.00 mmol), 4-methoxybenzoic anhydride (577 mg, 2.02 mmol),
and phenylboronic acid (122 mg, 1.00 mmol) in a 25 cm3 Schlenk
tube was heated under argon at 80 °C for 5 h. The GC analysis re-
vealed that 59.4% of benzophenone and 32.9% of 4-methoxyben-
zophenone were generated in the reaction mixture. On the basis
of the amounts of the two ketones, the relative reactivity of benzo-
ic anhydrides was determined as 0.55.
Cross-Coupling Reaction of Pivalic p-Toluic Anhydride
with Phenylboronic Acid (Eq. 3). A dioxane solution (5 cm3)
containing [Pd(PPh3)4] (58.0 mg, 0.0502 mmol), pivalic p-toluic
anhydride (220 mg, 0.999 mmol), and phenylboronic acid (147
mg, 1.21 mmol) in a 25 cm3 Schlenk tube was heated under argon
at 80 °C for 24 h. The yields of 4-methylbenzophenone and 2,2-
dimethylpropiophenone were determined by GC using nC14H30 as
an internal standard. 4-methylbenzophenone and 2,2-dimethyl-
propiophenone were characterized by GC-MS by comparing with
an authentic sample (Kanto Chemical Co. and Aldrich). 4-Meth-
ylbenzophenone: GC-MS m/z (rel intensity) 196 (32), 181 (8), 119
(100), 105 (30), 91 (36), 77 (41). 2,2-Dimethylpropiophenone:
GC-MS m/z (rel intensity) 162 (4), 105 (99), 77 (40).
Effect of Heterogeneous Catalysts (Table 5). A typical pro-
cedure is as follows (Run 6). A dioxane solution (5 cm3) contain-
ing [10 wt% Pd/BaSO4] (unreduced) (106 mg, 0.0498 mmol),
triphenylphosphine (52.3 mg, 0.199 mmol), benzoic anhydride
(226 mg, 0.999 mmol), and phenylboronic acid (146 mg, 1.20
mmol) in a 25 cm3 Schlenk tube was heated under argon at 80 °C
for 24 h. The yield of benzophenone was determined by GC using
nC14H30 as an internal standard. Benzophenone was characterized
by GC-MS by comparison with an authentic sample (Tokyo Kasei
Kogyo Co.). GC-MS m/z (rel intensity) 182 (100), 105 (82), 77
(88).
Hexanophenone: [942-92-7] (88%); Hexanophenone was
1
characterized by H, 13C{1H} NMR, and GC-MS by comparison
1
with an authentic sample (Tokyo Kasei Kogyo Co.). H NMR (ac-
etone-d6, r. t., 400 MHz) δ 8.01–7.98 (m, 2H, aromatic H), 7.61–
7.57 (m, 1H, aromatic H), 7.51–7.48 (m, 2H, aromatic H), 3.01 (t,
2H, J = 7.20 Hz, COCH2), 1.72–1.65 (m, 2H, CH2), 1.37–1.33
(m, 4H, CH2), 0.91–0.87 (m, 3H, CH3); 13C{1H} NMR (acetone-
d6, r. t., 100 MHz) δ 200.0 (s, carbonyl C), 138.0 (s, aromatic C),
133.4 (s, aromatic C), 129.2 (s, aromatic C), 128.6 (s, aromatic C),
38.8 (s, COCH2), 32.1 (s, CH2), 24.6 (s, CH2), 23.2 (s, CH2), 14.2
(s, CH3). GC-MS m/z (rel intensity) 176 (20), 133 (15), 120 (100),
105 (100), 91 (8), 77 (100).
2,2-Dimethylpropiophenone: [938-16-9] (44%); 2,2-Dime-
thylpropiophenone was characterized by GC-MS by comparison
with an authentic sample (Aldrich). GC-MS m/z (rel intensity)
162 (5), 105 (96), 77 (100).
Cross-Coupling Reaction of Benzoic Anhydride with Other
Organoboron Compounds (Eq. 1). A typical procedure using
NaBPh4 is given below. A dioxane solution (5 cm3) containing
[Pd(PPh3)4] (57.8 mg, 0.0500 mmol), benzoic anhydride (228 mg,
1.01 mmol), and sodium tetraphenylborate (110 mg, 0.321 mmol)
in a 25 cm3 Schlenk tube was heated under argon at 80 °C for 24
h. The yields of benzophenone were determined by GC using
nC14H30 as an internal standard. Benzophenone was characterized
by GC-MS by comparison with an authentic sample (Tokyo Kasei
Kogyo Co.). GC-MS m/z (rel intensity) 182 (100), 105 (82), 77
(98).
Reaction of [Pd(PMePh2)4] with Acetic Anhydride (Scheme
3). A dioxane solution (0.5 cm3) containing [Pd(PMePh2)4]
(15.2 mg, 0.0168 mmol), and acetic anhydride (1.84 mg, 0.0180
mmol) in an NMR tube was reacted under argon at room tempera-
ture for 23.5 h. 31P{1H} NMR analysis did not give any signal
corresponding to the oxidative adduct.
Reaction of trans-[PdAc(OAc)(PMePh2)2] with Methyl-
diphenylphosphine (Eq. 2). trans-[PdAc(OAc)(PMePh2)2]
(13.5 mg, 0.0222 mmol) was dissolved in THF-d8 (0.5 cm3) and
PMePh2 (8.93 mg, 0.0446 mmol) was added into the solution at
room temperature. The solution was shaken and subjected to
NMR observation after 5 min. The 1H and 31P{1H} NMR analysis
indicated the formation of [Pd(PMePh2)4] and Ac2O as major
products.
Time-Yield Curves of [( -Cyclopentadienyl)( -allyl)palla-
dium] 6 and [Pd(PPh3)]4] 4 (Fig. 1). A typical procedure is as
follows ([Pd(PPh3)4]). A dioxane solution (5 cm3) containing
[Pd(PPh3)4] (22.9 mg, 0.0198 mmol), 4-methoxybenzoic anhy-
dride (221 mg, 0.977 mmol), and phenylboronic acid (143 mg,
1.17 mmol) in a 25 cm3 Schlenk tube was heated under argon at
80 °C. At each interval, the tube was removed, and cooled in a
water bath immediately. The yields of 4-methylbenzophenone
were determined by GC using nC14H30 as an internal standard.
Time-Yield Curves in Formation of Benzophenone and 4-
Methoxybenzophenone (Fig. 2). A typical procedure for ob-
taining the time-yield curve in synthesis of 4-methoxybenzophe-
none is as follows. A dioxane solution (5 cm3) containing
[Pd(PPh3)4] (23.2 mg, 0.0201 mmol), 4-methoxybenzoic anhy-
dride (288 mg, 1.01 mmol), and phenylboronic acid (147 mg, 1.21
mmol) in a 25 cm3 Schlenk tube was heated under argon at 80 °C.
At each interval, the tube was removed from the oil bath and
cooled in a water bath immediately. The yields of benzophenone
were determined by GC using nC14H30 as an internal standard.
This study was supported by grants from the Ministry of Ed-
ucation, Science, Sports and Culture and from Nippon Zeon
Co., Ltd.
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