Efficient and fast method for the preparation of Diaryl Ketones at room temperature

Article abstract of DOI:10.1055/s-0033-1341070

Palladium-catalyzed cross-coupling reaction of arylboronic acids with acid chlorides at room temperature under phosphine-free conditions affords the corresponding aromatic ketones in excellent yields within short times. This synthetic method overcomes common disadvantages of Friedel-Crafts acylation procedures and is compatible with both electron-donating and electron-withdrawing substituents on the aryl ring of the acyl chlorides. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341070

LETTER
▌A
letter
Efficient and Fast Method for the Preparation of Diaryl Ketones at Room
Temperature
Preparation of Diaryl Ketones
Abdol Reza Hajipour,*a,b Raheleh Pourkavehb
a
Department of Pharmacology, University of Wisconsin Med. Sch., 1300 University Avenue, Madison, WI 53706-1532, USA
b
Pharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran
Fax +98(311)3912350; E-mail: haji@cc.iut.ac.ir
Received: 08.01.2014; Accepted after revision: 04.03.2014
Here we wish to report the synthesis and characterization
of a new air- and moisture-stable Pd(II) complex contain-
ing 1-benzyl-3-(1-benzyl-1-methylpyrrolidin-1-ium-2-yl)-
pyridin-1-ium with general formula [DBNT][PdCl4]
Abstract: Palladium-catalyzed cross-coupling reaction of aryl-
boronic acids with acid chlorides at room temperature under phos-
phine-free conditions affords the corresponding aromatic ketones in
excellent yields within short times. This synthetic method over-
comes common disadvantages of Friedel–Crafts acylation proce- (Scheme 1). The DBNT ammonium salt was prepared
dures and is compatible with both electron-donating and electron-
withdrawing substituents on the aryl ring of the acyl chlorides.
from the reaction of benzyl chloride and (–)-nicotine and
the resulting ammonium salt was then reacted with palla-
Key words: palladium, aromatic ketone, acid chloride, arylboronic
acid, room temperature
dium chloride in dried acetone at reflux temperature to
prepare the catalyst. The application of the resulting cata-
lyst was investigated in the Suzuki type cross-coupling re-
action. The effect of tetraalkylammonium salts on the
Diaryl ketones have many uses in the pharmaceutical, fra- activity and stability of palladium catalysts has been de-
grance, dye, and agrochemical industries.1 However, al- scribed by Jeffery.33 This quaternary nicotinium cation
though there are numerous synthetic methods available stabilized the Pd(0) species during the reaction by pre-
for the preparation of such compounds,2–9 many of these venting formation of unreactive palladium black.
approaches have significant drawbacks. Friedel–Crafts
acylation10–12 can suffer from a lack of regioselectivity,13
and incompatibility with several functional groups,
Ph
Me
N+
Me
2–
1. PhCH2Cl
PdCl4
whereas cross-coupling reactions of organotin,14–16
organobismuth,17,18 organozinc,19–21 and Grignard
reagents22 with an activated acid derivative can suffer
from low yields due to the formation of tertiary alcohol,23–25
and can require toxic reagents, long reaction times, and
high temperature.
N
N+
N
2. PdCl2, acetone
Ph
Scheme 1 Preparation of catalyst
With this new catalyst, the cross-coupling reaction of ar-
ylboronic acids with acid chlorides took place at room
temperature under phosphine-free32 and copper-free34
conditions, which led to the formation of a range of aro-
matic ketones. It is important to note that phosphine-free
palladium-catalyzed synthesis of unsymmetrical ketones
was first suggested by Bumagin et al. in 1981 for the car-
bonylation and acyldemetalation of organotin and later in
1997–2004 for Suzuki acyldeboration.35–40
Organometallic reagents act as efficient nucleophiles for
cross-coupling reactions, for example in 1972 the Ni-cat-
alyzed reaction of organomagnesium reagents with alke-
nyl and aryl halides was reported by Kumada, Tamao, and
Corriu.26,27 However, among transition metals, palladium
is a well-known catalyst that has been frequently used for
the formation of carbon–carbon bonds.28 Other discover-
ies were reported by Migita and Stille for organostan-
nans,29 Murahashi for organolithium, and Hiyama for
organosilicon compounds.30 Hadach and McCarthy found
a new synthetic methodology based on Pd-catalyzed
cross-coupling reaction of acid chlorides with arylboronic
acids,31 with the advantages of this method being mild re-
action conditions, compatibility with different functional
groups,8 non-toxicity, stability toward heat, air,32 and
moisture, and because the starting materials are available
commercially.
Our initial studies focused on the effect of solvent, base,
and the amount of catalyst on the cross-coupling reaction
of acid chlorides with arylboronic acids. To optimize
these factors we chose the reaction of phenylboronic acid
and benzoyl chloride as a model.
After carrying out the coupling reaction in a range of sol-
vents, CHCl3 was chosen as the best solvent (Table 1). In
cyclohexane, the desired ketone was not produced, and in
PEG-200 and water, due to the hydrolysis of benzoyl
chloride, a large amount of benzoic acid was detected. In
toluene, biphenyl was obtained as a by-product. Biphenyl
can be produced by two pathways: the homocoupling of
the boronic acids, and decarbonylative coupling between
the acyl chloride and the boronic acid.34
SYNLETT 2014, 25, 000A–000E
Advanced online publication: 07.04.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341070; Art ID: ST-2014-B0018-L
© Georg Thieme Verlag Stuttgart · New York

B
A. R. Hajipour, R. Pourkaveh
LETTER
Our next aim was to find the optimal base. To this end,
both organic and inorganic bases were examined, and
the results revealed that organic bases such as Et3N and
1,4-diazabicyclo[2.2.2]octane (DABCO) gave poor
yields; K2CO3 was chosen as an optimum base.
Table 1 Optimizing the Cross-Coupling of Phenylboronic Acid with
Benzoyl Chloridea
Entry Solvent
Base
Cat.
Time
Yield
(%)b
(mol%) (min)
1
2
CHCl3
NaHCO3
K2HPO4
DABCO
Et3N
1
35
35
35
35
35
5
5
70
Finally, the amount of catalyst was examined, with the re-
sults showing that 1 mol% was sufficient. Reducing the
amount of catalyst led to increased reaction times and in-
creasing it further led to the formation of biphenyl by-
product.
CHCl3
1
3
CHCl3
1
n.r.c
10
4
CHCl3
1
With the optimal conditions in hand, the reaction of a
range of acid chlorides with phenylboronic acid and 4-me-
thoxy phenylboronic acid was examined. Electron-donat-
ing acid chlorides and arylboronic acids afforded the
corresponding ketone in higher yields within short times.
5
CHCl3
K2CO3
t-BuOK
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1
100
90
6
CHCl3
1
7
CHCl3
1
35
35
35
15
8
toluene
1,4-dioxane
cyclohexane
PEG-200
H2O–TBAB
CHCl3
1
84
It is important to note that aliphatic acyl chlorides coupled
with arylboronic acids to give the desired ketones in high
yields. Comparing entry 4 with 5 in Table 2 shows that
acyl chlorides bearing an electron-donating substituent re-
quired longer reaction times because of a slower reduc-
tive-elimination step. In fact, electron-withdrawing
substituents on the acid chloride gave the corresponding
ketones in higher yields and shorter reaction times com-
pared with acid chlorides bearing electron-donating sub-
stituents. As shown in Table 2, entry 8, use of furan-2-
carbonyl chloride as a heteroaromatic acid chloride gave
the corresponding ketone in high yields within short reac-
tion time.
9
1
80
10
11
12
13
14
1
n.r.c
25
1
10
55
35
35
1
40
1.7
0.5
90
CHCl3
50
a Reaction conditions: benzoyl chloride (4 mmol, 0.46 mL), phenyl-
boronic acid (2 mmol, 0.243 g), base (4.5 mmol), solvent (2 mL), cat-
alyst, r.t.
b Determined by GC analysis.
c No reaction.
In summary, we have found a convenient method for the
formation of ketones through Pd-catalyzed cross-coupling
reaction of acid chlorides with arylboronic acids.41 These
reactions proceed without any activator in short times at
room temperature.
Table 2 Palladium-Catalyzed Cross-Coupling of Boronic Acids with Acyl Chloridesa
B(OH)2
O
O
cat.
Ph
Me
N+
K2CO3, cat. (1 mol%)
CHCl3, r.t
2–
PdCl4
+
N+
R1
R2
R2
R1
Ph
Entry
Arylboronic acid
Acid chloride
Ketone
Time (min)
35
Yield (%)b
100
O
O
B(OH)2
1
2
Cl
O
Cl
I
O
B(OH)2
B(OH)2
38
15
90
79
I
O
O
Cl
Cl
Cl
3
Cl
Cl
Synlett 2014, 25, A–E
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of Diaryl Ketones
C
Table 2 Palladium-Catalyzed Cross-Coupling of Boronic Acids with Acyl Chloridesa (continued)
B(OH)2
O
O
cat.
Ph
Me
N+
K2CO3, cat. (1 mol%)
CHCl3, r.t
2–
PdCl4
+
N+
R1
R2
R2
R1
Ph
Entry
Arylboronic acid
Acid chloride
Ketone
Time (min)
55
Yield (%)b
O
O
O
B(OH)2
4
100
Cl
Cl
MeO
OMe
NO2
O
O
O
B(OH)2
B(OH)2
5
6
8
92
95
O2N
O
Cl
10
F
F
O
O2N
NO2
B(OH)2
Cl
7
5
93
NO2
NO2
O
B(OH)2
B(OH)2
O
O
8
9
10
45
80
89
Cl
O
O
O
Cl
O
B(OH)2
B(OH)2
O
10
11
12
38
40
55
92
94
80
Cl
O
O
Cl
Cl
Cl
O
O
B(OH)2
Cl
MeO
MeO
MeO
I
I
MeO
MeO
O
O
B(OH)2
B(OH)2
Cl
Cl
Cl
13
14
40
78
80
Cl
Cl
O
O
Cl
180
MeO
MeO
OMe
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, A–E

D
A. R. Hajipour, R. Pourkaveh
LETTER
Table 2 Palladium-Catalyzed Cross-Coupling of Boronic Acids with Acyl Chloridesa (continued)
B(OH)2
O
O
cat.
Ph
Me
N+
K2CO3, cat. (1 mol%)
CHCl3, r.t
2–
PdCl4
+
N+
R1
R2
R2
R1
Ph
Entry
Arylboronic acid
Acid chloride
Ketone
Time (min)
25
Yield (%)b
O
O
O
O
B(OH)2
15
16
91
Cl
MeO
MeO
MeO
MeO
NO2
O2N
O2N
NO2
B(OH)2
Cl
20
92
NO2
NO2
O
B(OH)2
B(OH)2
B(OH)2
O
Cl
17
18
19
20
45
60
48
26
91
88
95
94
Cl
Cl
MeO
MeO
MeO
Cl
OMe
O
O
Cl
OMe
O
O
Cl
MeO
O
O
O
B(OH)2
Cl
Cl
MeO
O2N
Cl
OMe
O
NO2
B(OH)2
21
32
87
Cl
Cl
NO2
NO2
a Reaction conditions: acyl chloride (4 mmol), arylboronic acid (2 mmol), K2CO3 (4.5 mmol, 0.621 g), solvent (2 mL), catalyst (1 mol%, 0.023
g), r.t.
b Determined by GC analysis.
(7) Zhang, L.; Wu, J.; Shi, L.; Xia, C.; Li, F. Tetrahedron Lett.
Supporting Information for this article is available online at
2011, 52, 3897.
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Synlett 2014, 25, A–E
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of Diaryl Ketones
E
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(41) Preparation of Catalyst; General Procedure: (–)-Nicotine
(1 mmol, 0.16 mL) and benzyl chloride (4 mmol, 0.46 mL)
were mixed under solvent-free conditions and the reaction
mixture was heated at 70 °C for 6 h. The reaction mixture
was treated with CH2Cl2 (5 × 6 mL) to remove the unreacted
materials and the organic phase was separated. The residue
(0.340 g, 82%) was mixed with PdCl2 (0.177 g PdCl2 per
0.415 g dibenzylated nicotinium salt) in acetone and heated
at reflux for 12 h. The supernatant was decantated and
washed with acetone (3 × 5 mL) to produce the catalyst
(0.530 g, 91%) as a brown powder.
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Tetrahedron 2013, 69, 2565.
Suzuki-Type Cross-Coupling Reaction; Typical
Procedure: An oven-dried round-bottom flask was charged
with phenylboronic acid (4 mmol, 0.487 g), benzoyl chloride
(2 mmol, 0.23 mL), K2CO3 (4.5 mmol, 0.621 g), CHCl3 (2
mL), and [DBNT][PdCl4] (1 mol%, 0.023 g). The reaction
mixture was stirred at r.t. for 35 min, then the solution was
extracted with water and EtOAc and separated by column
chromatography (silica gel; EtOAc–hexanes, 1:9).
All products are known compounds and were characterized
by comparing their FT-IR and 1H NMR spectra with those
reported in the literature (see Yu et al.9).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, A–E