A versatile method for the synthesis of diaryl and alkyl aryl ketones via palladium-catalysed cross-coupling reaction of arylboronic acids with acyl chlorides

Article abstract of DOI:10.1002/aoc.3269

An efficient catalytic system using 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride and PdCl₂ was developed for the cross-coupling reaction of arylboronic acids with acyl chlorides. The catalytic amount of this homogeneous catalytic system affords the corresponding diaryl and alkyl aryl ketones in good to excellent yields under mild reaction conditions.

Full text of DOI:10.1002/aoc.3269

Full Paper
Received: 26 October 2014
Revised: 30 November 2014
Accepted: 4 December 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3269
A versatile method for the synthesis of diaryl
and alkyl aryl ketones via palladium-catalysed
cross-coupling reaction of arylboronic acids
with acyl chlorides
a
b
Fatemeh Rafiee * and Abdol R. Hajipour
2
An efficient catalytic system using 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride and PdCl was developed for the cross-
coupling reaction of arylboronic acids with acyl chlorides. The catalytic amount of this homogeneous catalytic system affords
the corresponding diaryl and alkyl aryl ketones in good to excellent yields under mild reaction conditions. Copyright © 2015 John
Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: palladium catalyst; cross-coupling reaction; arylboronic acid; aryl ketone
[
28,29]
[25]
and co-workers
and Gooßen and Ghosh
independently.
Introduction
Gooßen and co-workers reported efficient procedures for the
coupling of arylboronic acids with carboxylic acids using
pivalic anhydride,
Aryl ketones constitute the key components of various commercial
compounds, including natural products, biologically active com-
pounds, pharmaceuticals, cosmetics, dyes, fragrances, agrochemi-
[
26]
[30]
disuccinimidyl carbonate
and dimethyl
[
31]
dicarbonate as activating agents.
[
1–5]
cals and functional materials.
A traditional method for the
Bumagin and co-workers described the synthesis of aromatic
ketones via ligandless and phosphine-free palladium-catalysed
coupling of acyl chlorides with arylboronic acids in aqueous
acetone. There are several alternative procedures for this
cross-coupling reaction under various conditions, such as in
preparation of aryl ketones is Friedel–Crafts acylation, which suffers
from low regioselectivity, difficulty of regioisomer separation, re-
lease of large amounts of waste, harsh reaction conditions and in-
[
32]
[6]
compatibility with electron-deficient functional groups.
[
33,34]
[35–37]
The acylation of carbon nucleophiles of organometallic reagents
such as magnesium, lithium, zinc, copper, tin, cadmium or bismuth
with carboxylic acids and their derivatives is an important C–C
aqueous media,
anhydrous reaction
and solvent-free
[
38]
conditions.
Generally, the combination of palladium catalysts with phos-
phine and carbene ligands results in high efficiency in coupling
reactions. However, most phosphine ligands are air-sensitive, ex-
pensive and require an inert environment and high catalyst loading
of palladium source in carrying out the reaction. Although carbene
ligands are more stable than phosphines, they must be synthesized
through multi-step processes. Thus the development of efficient
phosphine-free palladium catalytic systems remains a potentially
promising field in organic synthesis.
[
7–12]
bond-forming reaction for the preparation of aryl ketones.
983 Rapoport and co-workers reported the formation of α-amino
ketones from various α-N-acylated amino acids and organolithium
In
1
[13]
or organomagnesium reagents. In 1998 Fukuyama and co-workers
described an efficient methodology for the palladium-catalysed
synthesis of ketones from reaction of thiol esters and organozinc
[
39]
[14]
reagents. However, these methods have typical disadvantages in-
cluding usage of toxic reagents, high temperature and long reaction
time, low yields due to the formation of tertiary alcohols as side prod-
[
40]
[15,16]
ucts and inferior tolerance of functional groups.
Recently, palladium-catalysed cross-coupling of boronic acids
with carboxylic derivatives has been developed as a powerful pro-
Results and Discussion
In continuation of our recent investigations on the synthesis and
applications of the palladium complex of 1-benzyl-4-aza-1-
[
17–26]
tocol for the regioselective synthesis of aromatic ketones.
This
approach is superior to the previous methods in terms of reaction
conditions, selectivity, efficiency and functional group compatibility
and also non-toxicity, thermal, air and moisture stability and com-
mercial availability of organoboron compounds as starting mate-
rials. Liebeskind and Srogl in 2000 developed a mild and general
method for the palladium-catalysed, copper-mediated coupling of
thiol esters and boronic acids under base-free conditions. The
first developments of palladium-catalysed cross-coupling of anhy-
drides with boronic acids have been investigated by Yamamoto
*
Correspondence to: Fatemeh Rafiee, Department of Chemistry, Faculty of Science,
Alzahra University, Vanak, Tehran, Iran. E-mail: f.rafiee@alzahra.ac.ir
a Department of Chemistry, Faculty of Science, Alzahra University, Vanak, Tehran,
[
27]
Iran
b Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan
University of Technology, Isfahan 84156, Iran
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.

F. Rafiee and A. R. Hajipour
azoniabicyclo[2.2.2]octane chloride with palladium chloride
2-Thenoyl chloride and 2-furoyl chloride as heteroaromatic acyl
chlorides (Table 2, entries 8 and 9), acetyl chloride and phenylacetyl
chloride as aliphatic acyl chlorides (Table 2, entries 11 and 12 and
16–18) and also cinamoyl chlorides (Table 2, entries 20–22) couple
with arylboronic acids in good yields. Cross-coupling reactions of
acyl chlorides with electron-donating arylboronic acids such as 4-
methoxy and 4-methylphenylboronic acid give higher yields with
shorter reaction times. Also thiophen-2-ylboronic acid as a
heteroarylboronic acid couples with benzoyl chlorides in good
yields (Table 2, entries 10 and 19).
[41–44]
2 2 6
((BeDABCO) Pd Cl ),
we now report the extension of this
complex as an efficient and highly active homogeneous catalyst
for the cross-coupling reaction of various acyl chlorides with
phenylboronic acid under phosphine-free conditions (Scheme 1).
In order to search for better experimental conditions, the cross-
coupling of phenylboronic acid and benzoyl chloride was chosen
as a model reaction to optimize the effects of solvent, base, temper-
ature and amount of catalyst (Table 1).
As evident from Table 1, K CO as base, toluene as solvent and
2
3
0
.4mol% of catalyst give the best results for enhanced selectivity
A general catalytic cycle for this cross-coupling reaction is pre-
[
18]
toward benzophenone and for preventing the formation of
undesirable biaryl by-products. Biphenyls can be produced using
two pathways: the homocoupling of phenylboronic acids and
the decarbonylative coupling between acyl chloride and
sented in Scheme 2. Potassium carbonate as a co-catalyst facili-
tates the reduction of palladium(II) species and has a positive
[
47]
effect on the reaction. Also a negatively charged base, such as
potassium carbonate, is needed in different cross-coupling reac-
tions of organoboronic acids. It is found that the base accelerates
the transmetallation rate. The negatively charged base coordinates
[45]
phenylboronic acid.
Several solvents, namely N-methyl-2-
pyrrolidone (NMP), N,N-dimethylformamide (DMF), methanol,
dioxane, toluene and water, were examined. When DMF is used
as a polar solvent, the selectivity for aryl ketone is decreased and
leads to the formation of biphenyl. When methanol is used as
solvent, methyl benzoate is obtained in significant amounts. A
lower yield of benzophenone is produced in aqueous solvents
and water due to the partial hydrolysis of benzoyl chloride and
formation of significant amounts of benzylic anhydride and
[48]
to the boron atom thus increasing its nucleophilicity. The effect
of tetraalkylammonium salts on the activity and stability of palla-
[
49]
dium catalysts has been described by Jeffery. BeDABCO quater-
nary ammonium in this catalyst stabilizes the Pd(0) species by
preventing the formation of unreactive palladium black.
[
46]
benzoic acid as by-products. Moderate yields are afforded using
the bases Cs CO , Na CO , NaHCO , K PO and t-BuOK. No desired
product is observed when Et N is used in this coupling reaction.
Table 1. Optimization of reaction conditions for Suzuki-type
a
2
3
2
3
3
3
4
cross-coupling reaction
3
Decreasing the amount of base leads to a decrease in the yield of
benzophenone.
Increasing the reaction temperature in this cross-coupling
reaction results in a small increase in yield. Although an increase
of temperature from 60 to 80 °C has a positive effect on the
conversion in shorter reaction time, more biphenyl by-product is
observed.
Entry Solvent
Base
Temp. Catalyst Time
°C) (mol%) (min)
Conversion (%)
(
b
Product By-product
A low palladium concentration usually leads to a long period of
reaction. Increasing the amount of palladium catalyst shortens the
reaction time, but does not increase the yield of benzophenone.
There is no reaction in the absence of catalyst.
1
2
3
4
5
6
7
8
9
DMF
K2CO3
K2CO3
K2CO3
rt
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
50
30
70
10
12
74
70
98
43
65
2
NMP
MeOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
80
rt
c
—
Dioxane K2CO3
H2O K2CO3
24
30
98
50
78
57
69
d
With the optimized reaction conditions in hand, we extended the
scope to a variety of acid chlorides with phenylboronic acids. The
results are shown in Table 2. Under the optimized reaction
conditions, a variety of aryl ketones are obtained in high yields
and the competitive hydrolysis for most of the acyl chlorides and
biaryl formation appear to be minimized. Benzoyl chlorides with
both electron-releasing and electron-withdrawing substituents
can be converted into the corresponding ketones in good to
excellent yields. However, acyl chlorides bearing electron-donating
groups are reacted in longer times due to a slower reductive
elimination step.
Toluene K2CO3
Toluene t-BuOK
Toluene Cs CO
30
20
34
20
10
18
10
2
3
Toluene Na CO
2
3
10
11
12
13
14
15
Toluene NaHCO3
Toluene NEt3
Toluene K3PO4
Toluene K2CO3
Toluene K2CO3
Toluene K2CO3
—
52
90
e
—
—
—
0.3
0.5
0.4
0.4
0.4
83
98
98
90
42
8
2
16
17
18
19
Toluene
Toluene
Toluene
Toluene
K
2
CO
CO
CO
CO
3
K
2
3
2
K
2
3
10
7
f
K
2
3
a
Reaction conditions: benzoyl chloride (0.75 mmol), phenylboronic
acid (0.6 mmol), base (1 mmol), solvent (2 ml), catalyst 1, room
temperature (rt).
b
By-product was biphenyl.
c
By-products were biphenyl and methyl benzoate.
d
By-products were biphenyl and benzoic acid.
e
Base (0.6 mmol).
f
Scheme 1. Cross-coupling reaction of acyl halides with phenylboronic
acids using catalyst (1).
2
PdCl /BeDABCO (in 1:1 ratio) was used as catalyst.
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2015)

Acylodeboronation of arylboronic acids
a
Table 2. Suzuki-type cross-coupling reaction of acyl chlorides using catalyst 1
b
Entry
RCOCl
ArB(OH)
2
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
PhCOCl
p-O N-C
m-MeO-C
p-MeO-C
p-Me-C
p-Cl-C
p-MeOC-C
PhB(OH)
PhB(OH)
PhB(OH)
PhB(OH)
PhB(OH)
PhB(OH)
PhB(OH)
PhB(OH)
PhB(OH)
2-Thiophen-B(OH)
PhB(OH)
PhB(OH)
p-MeO-C
p-Me-C
p-MeO-C
p-MeO-C
p-Me-C
p-MeO-C
2-Thiophen-B(OH)
PhB(OH)
p-MeO-C
p-Me-C
2
60
20
70
80
65
35
45
40
35
60
70
40
20
30
45
30
40
35
60
60
40
50
96
92
90
94
90
89
86
90
85
90
91
92
95
92
90
93
90
91
87
90
92
90
2
6
H
4
-COCl
-COCl
-COCl
-COCl
-COCl
-COCl
2
6
H
4
2
6
H
4
2
6
H
4
2
6
H
4
2
6
H
4
2
2-Thenoyl chloride
2-Furoyl chloride
PhCOCl
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
2
CH
3
COCl
COCl
2
PhCH
2
2
PhCOCl
PhCOCl
6
H
4
-B(OH)
-B(OH)
-B(OH)
2
6
H
4
2
6
p-MeO-C H
4
-COCl
6
H
4
2
CH
CH
3
COCl
COCl
6
H
4
-B(OH)
2
3
6
H
4
-B(OH)
2
PhCH
2
COCl
-COCl
6 4 2
H -B(OH)
p-Me-C
6
H
4
2
PhCH¼CHCOCl
PhCH¼CHCOCl
PhCH¼CHCOCl
2
6
H
4
-B(OH)
2
6
H
4
-B(OH)
2
a
Reaction conditions: acyl chloride (0.75 mmol), phenylboronic acid (0.6 mmol), K
2
CO
3
(1 mmol), toluene (2 ml), catalyst (0.4 mol%).
b
Isolated yield after column chromatography.
was used as an internal standard) with a Bruker Avance 500
instrument (Rheinstetten, Germany) and a Varian 400 NMR. FT-IR
spectra were recorded with a Jasco-680 (Japan) spectrophotome-
ter. Spectra of solids were obtained using KBr pellets. Vibrational
ꢀ
1
transition frequencies are reported in wavenumber (cm ). We
used GC (Agilent 6890 N) for examination of reaction completion
and yields. Palladium chloride, acyl chlorides and all chemicals were
purchased from Merck or Aldrich and were used as received.
(
BeDABCO)
2 2 6
Pd Cl complex was synthesized according to our
[27]
previous work.
Scheme 2. Proposed mechanism for the coupling of acyl halides with
phenylboronic acids.
General Procedure for Cross-Coupling of Acyl Halides with
Phenylboronic Acids
In a typical experiment, an oven-dried round-bottom flask was
charged with phenylboronic acid (0.6 mmol), benzoyl chloride
Conclusions
In this investigation, a general protocol was applied for the Suzuki-
type reaction of various acyl chlorides with phenylboronic acids
using catalytic amounts of (BeDABCO) Pd Cl complex to obtain
2 2 6
(0.75 mmol), K CO (1mmol), toluene (2ml) and (BeDABCO) Pd Cl
2 3 2 2 6
(0.4mol%). The reaction mixture was stirred at room temperature
for the required time and progress of the reaction monitored using
both TLC and GC. After the reaction was completed, the solution
was extracted with water and ethyl acetate. The organic phase
aryl ketones in good to excellent yields.
4
was dried over MgSO , filtered and concentrated under reduced
Experimental
pressure using a rotary evaporator. The residue was purified by
silica gel column chromatography (ethyl acetate–hexane, 1:9).
All products are known compounds and were characterized by
General
1
13
1
13
H NMR and C NMR spectra were recorded using 400MHz with
samples in CDCl solutions at room temperature (tetramethylsilane
comparing their m.p. and FT-IR, H NMR and C NMR spectra with
those found in the literature.
[
16,50–52]
3
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

F. Rafiee and A. R. Hajipour
[
[
24] B. W. Xin, Synth. Commun. 2008, 38, 2826.
25] L. J. Gooßen, K. Ghosh, Angew. Chem. Int. Ed. 2001, 40, 3458.
Acknowledgements
We gratefully acknowledge the partial financial support received
from the research council of Alzahra University. We also gratefully
acknowledge the funding support received for this project from
the Isfahan University of Technology (IUT), IR Iran and Isfahan
Science & Technology Town.
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