An improved palladium(II)-catalyzed method for the synthesis of aryl ketones from aryl carboxylic acids and organonitriles

Article abstract of DOI:10.1016/j.tetlet.2014.02.109

A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed. The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.

Full text of DOI:10.1016/j.tetlet.2014.02.109

Tetrahedron Letters 55 (2014) 2376–2380
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An improved palladium(II)-catalyzed method for the synthesis of aryl
ketones from aryl carboxylic acids and organonitriles
⇑
Linda Axelsson, Jean-Baptiste Veron, Jonas Sävmarker, Jonas Lindh, Luke R. Odell, Mats Larhed
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed.
The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the
use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with
a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 25 September 2013
Revised 7 January 2014
Accepted 26 February 2014
Available online 6 March 2014
Keywords:
Palladium
Nitrile
Aryl ketone
Decarboxylation
Flow chemistry
The use of aryl carboxylic acids as aryl palladium precursors has
attracted significant attention. Compared to other aryl sources, aryl
carboxylic acids offer a number of significant advantages including
wide commercial availability, low cost, low toxicity, and high
chemical stability. Moreover, gaseous CO2 is the only byproduct
produced when the aryl palladium species is formed. Since the
groundbreaking decarboxylative Heck-type reaction reported by
Myers and co-workers in 2002, a multitude of palladium(II)-cata-
lyzed decarboxylative reactions, including Heck-type and cross-
coupling processes, have been discovered.1–6
Numerous natural products and pharmaceuticals contain an
aryl ketone, often with a substituent at one or both ortho posi-
tions.7,8 Furthermore, they often serve as precursors to various
important heterocyclic systems including imidazoles,9 isoxaz-
oles,10 indoles,11 and pyrazoles.12 Previously, the synthesis of aryl
ketones from benzoic acids has been limited to harsh methods
requiring stoichiometric organolithium reactants,13 or Friedel–
Crafts acylations14 that are often moisture sensitive and suffer
from a lack of regio- and chemoselectivity. More recently, arylst-
annanes have been used to prepare sterically hindered aryl ketones
from acid chlorides, however this procedure suffers from the draw-
backs associated with handling toxic tin by-products.15 Thus, the
development of new methods for the preparation of aryl ketones
is of significant interest.
The palladium-catalyzed insertion of nitriles, first discovered in
1970,16 is an attractive strategy for generating the aryl ketone
motif due to the often widespread availability and low cost of
the nitrile reaction partners. Thus, effective protocols are available
utilizing a range of aryl palladium precursors.17–22 In 2010, Lindh
et al.23 published the synthesis of aryl ketones from aryl carboxylic
acids via a Pd(II)-catalyzed decarboxylation followed by addition to
a nitrile, protonation of the ketimine intermediate, and hydrolysis
to give the aryl ketone product. Importantly, sterically congested
aryl ketones could be synthesized as the benzoic acid needs to have
an activating ortho substituent to facilitate the decarboxylation
process. To complement the suggested mechanism based on MS-
detected cationic palladium complexes (Fig. 1),23 DFT calculations
on sterically congested aromatic substrates have been carried out
to improve the detailed understanding of the process.24
However, in the protocol of Lindh et al., the nitriles were used as
solvents and the scope was thus limited to liquid substrates.23
Accordingly, we sought to expand the scope of this procedure to
enable the use of solid nitriles as reaction partners and to decrease
the amount of nitrile required for a productive reaction. As a start-
ing point for our investigation, 2,6-dimethoxybenzoic acid (1a,
0.5 mmol) and phenylacetonitrile (2d, 5 equiv), were chosen as
model substrates for a solvent screen, since these substrates were
among the most high yielding in the previous study.23 A catalytic
system consisting of Pd(O2CCF3)2 (8 mol %) and 6-methyl-2,20-
bipyridine, (9.6 mol %) was employed. Among the solvents evalu-
ated25 a mixture of THF/water (10/1) performed best and product
3d was isolated in 68% yield (Table 1, entry 4), after microwave
⇑
Corresponding author. Tel.: +46 18471 4667; fax: +46 18471 4474.
E-mail address: mats.larhed@orgfarm.uu.se (M. Larhed).
http://dx.doi.org/10.1016/j.tetlet.2014.02.109
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

L. Axelsson et al. / Tetrahedron Letters 55 (2014) 2376–2380
2377
Table 1
ArCOO-
ArCOOH
Ar
Optimization of the conditions for the Pd(II)-catalyzed decarboxylative addition of
2,6-dimethoxybenzoic acid (1a) and nitriles 2a–e producing 3a–e
1
R
N Pd
N
N
NH
O
Ar
R
Ar
R
3
Ar
O
Ar
N Pd
N
N
R
O
N Pd
N
Entry
1
R
Product
Isolated yield
(%)
Me
3a 71a,b
Ar
N Pd
N
R
CN
2a
CO2
2
2
3
4
Pr
3b 64c,b
3c 82a,b
3d 68d
Figure 1. The proposed mechanism supported by MS-detected cationic palladium
complexes.23
2b
(MW) heating26 at 130 °C for four hours followed by hydrolysis
with formic acid.
Ph
The addition of TFA has previously been shown to be beneficial
for the palladium-catalyzed synthesis of aryl ketones from aryl
sulfinates and organonitriles,19 and we reasoned that this may also
improve our current reaction, as addition of an acid helps to pro-
tonate and liberate the ketimine from the intermediate Pd-com-
plex (a role otherwise given solely to the benzoic acid). In
addition, TFA facilitates the hydrolysis of the ketimine to form
the ketone.23,24 Gratifyingly, the addition of one equivalent of
TFA led to an increase in the isolated yield of 3d (89%) and allowed
the reaction time to be shortened to 30 minutes as well as promot-
ing in situ hydrolysis (Table 1, entry 6).
2c
Bn
5
6
7
8
9
2d
86c
89a,b
84e
76f
94a
Notably, using the new protocol afforded aryl ketones 3a–c in
isolated yields that were either better (3c) or in the same range
as the previous study.23 Reducing the amount of nitrile from five
to two equivalents had only a slight effect on the yield in some
cases, for example 3d was isolated in 86% yield compared to 89%
when two and five equivalents of 2d were used, respectively (Ta-
ble 1, entries 5 and 6). In other reactions the effect was more pro-
nounced: two equivalents of 2-(4-bromophenyl)acetonitrile (2e)
provided 3e in 78% yield, whereas five equivalents gave 3e in a
94% yield (Table 1, entries 9 and 10). Unfortunately, the presence
of large amounts of excess nitrile often led to difficulties during
the purification process and therefore most of the reactions were
conducted using two equivalents of nitrile.
In an attempt to reduce catalyst loading the synthesis of 3d was
conducted with Pd(O2CCF3)2 (4 mol %) and ligand (4.8%) instead of
8 mol % and 9.6%, respectively. This resulted in a slight decrease in
the yield from 86% to 84% (Table 1, entries 5 and 7). A further de-
crease to 2 mol % of Pd-catalyst produced 3d in a lower 76% yield
(Table 1, entry 8). The synthesis of 3k was not affected by the
reduction to 4 mol % of the Pd-catalyst (Table 2, entries 6 and 7).
When the reaction was carried out with less reactive substrates
(see Table 3) there was a notable difference in conversion (accord-
ing to LC–MS analysis) between 4% and 8 mol % of Pd-catalyst.
Accordingly, in order to develop and evaluate a robust protocol,
most of the experiments in Tables 1 and 2 were run with 8 mol %
of Pd(O2CCF3)2.
10
78c
11
12
60g
45h
a
A
microwave vial was charged with Pd(O2CCF3)2 (8 mol %), 6-methyl-2,20-
bipyridine (9.6 mol %), and THF (2 mL), and the mixture was stirred for 5 min. 2,6-
Dimethoxybenzoic acid (1 mmol), nitrile (5 equiv), TFA (1 equiv), and H2O (200 lL)
were added and the mixture exposed to MW heating for 30 min at 130 °C.
b
The highest yields obtained by Lindh et al. were 94% for 3a, 73% for 3b, 20% for
3c, and 73% for 3d.
Likea but nitrile (2 equiv).
c
Likea but no TFA, only conducted on a 0.5 mmol scale, 130 °C for 4 h, followed
d
by addition of formic acid (1 mL) and the mixture was heated to 130 °C for 15 min.
Likea but nitrile (2 equiv), Pd (4 mol %) and ligand (4.8 mol %).
e
Likea but Pd (2 mol %) and ligand (4.8 mol %).
f
g
h
Likea but nitrile (1 equiv), 2,6-dimethoxybenzoic acid (2 equiv).
Continuous-flow scale-out example using a flow of 0.5 mL/min of the reaction
mixture, corresponding to 2 min in the MW heated zone, and with the temperature
set at 210 °C. The stock solution consisted of 0.71 M 1a (yield determining) in THF
with 10% water, 2e (5 equiv), TFA (25 equiv), Pd(O2CCF3)2 (4 mol %), and 6-methyl-
2,20-bipyridine (9.6 mol %). The yield is based on the work-up of an aliquot of 14 mL
of the solution with the theoretical yield of 1 mmol of 3e.
yield of 3h (50%, Table 2, entry 3) due to the competing Pd(II)-cat-
alyzed insertion of the aldehyde,27,28 which furnished an alcohol in
trace amounts that could be detected by LC–MS analysis. Heterocy-
clic nitriles were also well tolerated and the electron-rich furan-2-
carbonitrile (2j) gave 3j in 68% yield, whereas the yield obtained
with electron-poor nicotinonitrile (2k) was slightly higher, 82%
(Table 2, entries 5 and 6).
To our surprise the sterically hindered aryl ketone 3i was iso-
lated in 38% yield, despite the presence of two ortho-methoxy
groups on the benzoic acid and an ortho-bromo substituent on
the benzonitrile (Table 2, entry 4). Full chemoselectivity was
Having identified suitable conditions, we next set about explor-
ing the scope and limitations of the method (Table 2). The protocol
seemed robust concerning electronic effects as the electron-rich
nitrile 2f provided 3f in a 72% yield, whereas 3g was isolated in
73% yield using the electron-poor nitrile 2g (Table 2, entries 1
and 2). The aldehyde-containing nitrile 2h returned only a modest

2378
L. Axelsson et al. / Tetrahedron Letters 55 (2014) 2376–2380
Table 2
subsequent cyclization, was detected by LC–MS analysis. In an at-
tempt to minimize byproduct formation, the number of equiva-
lents of TFA was reduced from ten to three and dry THF was
used, however, this strategy was only partly successful providing
3m in 53% yield (Table 2, entry 11).
Scope and limitations of the Pd(II)-catalyzed decarboxylative addition of 2,6-
dimethoxybenzoic acid 1a and nitriles 2f–m producing 3f–m
In cases where the nitrile is more expensive or more precious
than the carboxylic acid, it may be desirable to reverse the stoichi-
ometry and use the nitrile as the limiting reagent. When nitrile 2e
(2 mmol) was reacted with benzoic acid 1a (1 mmol) it had a neg-
ative impact on the reaction outcome (78% vs 60%, Table 1, entries
10 and 11).
Entry
1
R
Product
Isolated yield
(%)
If the benzoic acid is available in excess concentration, prob-
lems with the competing background decarboxylation reaction de-
crease, but if the organonitrile is present in excess it is beneficial
for coordination and insertion of the nitrile into the Pd-complex.
Which of these two factors are the most important for the reaction
outcome may differ with the benzoic acids and nitriles used.
Continuous flow microwave-assisted organic synthesis, CF-
MAOS, can be used as a practical method for producing large quan-
tities without the drawbacks of large-scale batch synthesis, that is,
safety considerations, need for special and bulky equipment, etc.,
while still maintaining the shorter reaction times and energy effi-
ciency associated with microwave chemistry.29–31 Thus, an effort
was made to include an example using a non-resonant microwave
system for CF-MAOS.29 A model reaction with 2,6-dimethoxyben-
zoic acid (1a) and 2-(4-bromophenyl)acetonitrile (2e) was chosen
for a scale-out using a straight tubular reactor made of borosilicate
glass (3 mm inner diameter, 200 mm long).
Unfortunately, Pd(0) precipitation on the reactor inner wall led
to problems with local superheating and rupture of the reactor.32,33
An increase in ligand concentration and decrease in Pd loading did
not give a stable system amenable to safe and reliable upscaling.
Although the addition of the palladium reoxidant, p-benzoquinone,
led to a reduction in palladium precipitation, it also resulted in a
significant decrease in product formation (according to GC-MS
analysis). Finally, increasing the amount of TFA to 25 equivalents
made upscaling possible at 0.5 mL/min, 210 °C and provided aryl
ketone 3e in a moderate 45% yield (Table 1, entry 12). Further opti-
mization needs to be performed in order to use flow chemistry as
an upscaling opportunity using this protocol.
Next, an effort was made to further expand the batch reaction
scope and evaluate additional benzoic acids using a selection of
the nitriles from Tables 1 and 2. Thus, four diverse benzoic acids
and four nitriles were chosen for investigation and the resulting
(hetero)aryl ketone products are presented in Table 3. During ini-
tial attempts using the optimized conditions we noted a decrease
in reactivity when using other less electron-rich carboxylic
acids,30,34 and therefore five equivalents of nitrile were used. The
reactions were MW heated for one hour at 130 °C in order to
achieve full conversion.
Rewardingly, most of the reactions occurred efficiently with
various heterocyclic acids and nitriles. When 3-ethoxythiophene-
2-carboxylic acid (1b) or 4-acetyl-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid (1c) was heated with the nitriles, 2-phenylacetonitrile
(2d), 2-(4-bromophenyl)acetonitrile (2e), furan-2-carbonitrile (2j),
and nicotinonitrile (2k), the reactions gave full conversion and the
heteroaryl ketones 3n, 3o, 3v, 3w, 3z, and 3ab were isolated in
moderate to good yields, 48–73% (Table 3).
3f
72a
73a
2
3g
3
4
5
3h
3i
50a
38a
68a
3j
6
7
82a
83b
3k
3l
8
42a
9
47c
10
11
3m 37d
53e
a
A
microwave vial was charged with Pd(O2CCF3)2 (8 mol %), 6-methyl-2,20-
bipyridine (9.6 mol %), and THF (2 mL), and the mixture was stirred for 5 min. 2,6-
Dimethoxybenzoic acid (1 mmol), nitrile (2 equiv), TFA (1 equiv), and H2O (200 lL)
were added and the mixture exposed to MW heating for 30 min at 130 °C.
Likea but nitrile (5 equiv), Pd (2 mol %), and ligand (4.8 mol %).
b
Likea but nitrile (1 equiv), 2,6-dimethoxybenzoic acid (2 equiv), and TFA
c
(10 equiv), 1 h, 130 °C.
Likea but nitrile (2 equiv), TFA (10 equiv), 1 h 130 °C.
d
Likea but nitrile (2 equiv), TFA (3 equiv), no H2O addition, dry THF, 1 h 130 °C.
e
obtained with both 3e and 3i without any Pd(0)-catalyzed reac-
tions on the bromine. The use of dicyanide 2l produced 3l in a
modest 42% yield and the diarylated compound was detected in
trace amounts (according to LC–MS analysis, Table 2, entry 8).
Inspired by the work of Wang et al.,22 an attempt was made to
synthesize 2-(2,6-dimethoxyphenyl)benzofuran using our new
protocol. However, it was necessary to increase the amount of
TFA to 10 equiv to promote complete in situ cyclization of the 1-
(2,6-dimethoxyphenyl)-2-(2-hydroxyphenyl)ethanone intermedi-
ate. This procedure afforded the desired product 3m in 37% and
47% yields, using an excess of either the nitrile or benzoic acid,
respectively (Table 2, entries 9 and 10). Competing formation of
benzofuran-2(3H)-one, via hydrolysis of the nitrile 2m and
In all the reactions involving 2-(4-bromophenyl)acetonitrile
(2e), difficulties in removing the excess nitrile during product puri-
fication were encountered. Thus, these reactions were conducted
using either two equivalents of nitrile (3r, 41% and 3s, 70%) or a
2:1 excess of the benzoic acid substrate (3t, 76% and 3u, 73%).
The less electron-rich carboxylic acids, 2,6-difluoro-4-methoxy-
benzoic acid (1d) and 3-bromo-2,6-dimethoxybenzoic acid (1e),
exhibited lower reactivity and full conversion of the starting

L. Axelsson et al. / Tetrahedron Letters 55 (2014) 2376–2380
2379
Table 3
Pd(II)-catalyzed reaction between benzoic acids 1b–e and nitriles 2d, 2e, 2j, and 2k producing ketones 3n–ad
Product
Isolated
yield (%)
Product
Isolated
yield (%)
Product
Isolated
yield (%)
Product
Isolated
yield (%)
61a
73a
68b
68b
41c
70c
76d
73d
36b
50d
59a
64a
75b
9b
48a
66a
26b
19d
a
A microwave vial was charged with Pd(O2CCF3)2 (8 mol %), 6-methyl-2,20-bipyridine (9.6 mol %) and THF (2 mL), and the mixture was stirred for 5 min. Benzoic acid 1b,
1c, 1d, or 1e (1 mmol), nitrile 2d, 2e, 2j, or 2k (5 equiv), TFA (1 equiv), and H2O (200 L) were added and the mixture exposed to MW heating for 1 h at 130 °C.
l
b
Likea but THF (500
Likea but nitrile 2e (2 equiv).
l
L) and H2O (50
l
L).
c
d
Likea but THF (500
lL), H2O (50 lL), benzoic acid 1b, 1c, 1d, or 1e (2 equiv) and nitrile 2e, 2j, or 2k (1 equiv).
material was not observed (according to LC–MS analysis). A four-fold
decrease in the amount of solvent improved the reaction outcome
providing 3p, 3q, and 3x in satisfactory yields, 68–75% (Table 3).
The disappointing yields of 26% and 9% for the synthesis of 3ac
and 3ad might be a consequence of nitrogen coordination to palla-
dium. Additionally, full conversion was not achieved in the synthe-
sis of (3-bromo-2,6-dimethoxyphenyl)(furan-2-yl)methanone (3y),
resulting in a low isolated yield of 36%. An attempt to improve the
yield by having the benzoic acid in excess gave a slight increase in
the isolated yield (50%). Finally, the same stoichiometry switch
provided 3ad in a slightly increased yield of 19%.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
109.
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Importantly, the reaction allowed the use of solid organonitriles
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34. Using the protocol described in Table 3, conditions,a we also tried to synthesize
aryl ketones using the following benzoic acids; 2,6-dimethoxynicotinic acid, 3-
methylbenzofuran-2-carboxylic acid, 2,4,5-trimethoxybenzoic acid, 3-
methylbenzo[b]thiophene-2-carboxylic acid, 4-methylthiazole-5-carboxylic
acid, 2,4,6-trimethylbenzoic acid, 2-methoxy-4-methylbenzoic acid, and 3-
methoxy-2-naphthoic acid. The aryl ketone products could be detected with all
these benzoic acids, but the four chosen for further expansion showed the best
conversion according to LC–MS analysis (Table 3).