One-pot synthesis of benzoylacetonitriles through sequential Pd-catalyzed carbonylation and decarboxylation

Article abstract of DOI:10.1016/j.tetlet.2015.12.050

Benzoylacetonitrile were prepared through sequential carbonylation and decarboxylation. The palladium-catalyzed carbonylation of aryl iodides and methyl cyanoacetate using Mo(CO)₆ as a carbon monoxide source afforded beta-keto cyanoesters, and then the subsequent reaction with Li/H₂O produced the desired benzoylacetonitriles.

Full text of DOI:10.1016/j.tetlet.2015.12.050

Tetrahedron Letters 57 (2016) 239–242
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of benzoylacetonitriles through sequential
Pd-catalyzed carbonylation and decarboxylation
⇑
Sunwoo Lee , Han-Sung Kim, Hongkeun Min, Ayoung Pyo
Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzoylacetonitrile were prepared through sequential carbonylation and decarboxylation. The palla-
dium-catalyzed carbonylation of aryl iodides and methyl cyanoacetate using Mo(CO)6 as a carbon
monoxide source afforded beta-keto cyanoesters, and then the subsequent reaction with Li/H2O pro-
duced the desired benzoylacetonitriles.
Received 20 October 2015
Revised 3 December 2015
Accepted 9 December 2015
Available online 10 December 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Benzoylacetonitrile
Palladium
Decarboxylation
Carbonylation
Aryl iodide
Introduction
O
ArCN
CH3CN
+
+
NaCN
X
c)
O
a)
Ar
Benzoylacetonitrile is an important building block because it can
be converted to a variety of heterocyclic compounds such as
cytosine,1 triazole,2 imidazole,3 furan,4 aminopyrazole,5 aminoisox-
azole,6 isoxazole,7 and pyridine.8 In addition, it has been
employed as a starting material for the preparation of biologically
active materials, such as antimicrobial,9 antineoplastic,10 and
anti-inflammatory agents,11 and HIV inhibitors.12 A number of
preparation methods have been developed as shown in
O
X = Br, Cl
Br
N
CN
e)
d)
Ar
b)
O
Ar
O
+
CH3CN
Ar
Y
Ar
NMe2
Y = OMe, OEt, NMe(OMe)
Scheme 1. Classical methods for the synthesis of benzoylacetonitriles.
Scheme 1. The substitution of
a-haloacetophenones with cyanide
(Scheme 1a),13 the coupling of an ester (or N-methoxy-N-methyl-
benzamide) and acetonitrile in the presence of a strong base
(Scheme 1b),14 the reaction between benzonitriles and acetonitrile
(Scheme 1c),15 the ring opening of 3-bromoisoxazole (Scheme 1d),16
and the reaction of enaminones with hydroxylamine hydrochloride
(Scheme 1e) have been employed to produce benzoylacetonitriles.17
Recently, we first reported the synthesis of benzoylacetonitriles
through palladium-catalyzed carbonylation with aryl halides and
trimethylsilyl acetonitrile (Scheme 2a).18 Palladium-catalyzed car-
bonylation has been used in the synthesis of carbonyl compounds
such as amides, esters, and ketones via the couplings of aryl halides
and nucleophiles in the presence of carbon monoxide.19 Although
it is a simple and straightforward method, the handling of carbon
monoxide gas requires special equipment and is a safety issue. In
order to address the use of toxic carbon monoxide, we developed
an alternative method that utilizes Mo(CO)6 as a carbon monoxide
surrogate. A number of carbonylation methods using Mo(CO)6 have
been reported.20 Although these two methods provided straight-
forward protocols for the synthesis of benzoylacetonitriles from
aryl halides, they required trimethylsilyl acetonitrile, which may
give rise to cost issues. Therefore, the development of a synthetic
method that uses much less expensive reagents is still in demand.
To meet this requirement, we focused our attention on the car-
bonylation of aryl iodides with methyl cyanoacetate (2) and the
subsequent decarboxylation.
The palladium-catalyzed coupling reaction of aryl halides with
alkyl cyanoacetates has been reported by other groups.21 However,
the carbonylation of aryl halides and cyanoacetate in the presence
of a carbon monoxide has never been reported. Here, we first
report the direct synthesis of benzoylacetonitriles through the car-
⇑
Corresponding author.
E-mail address: sunwoo@chonnam.ac.kr (S. Lee).
http://dx.doi.org/10.1016/j.tetlet.2015.12.050
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

240
S. Lee et al. / Tetrahedron Letters 57 (2016) 239–242
Table 2
Previous our works
a)
Optimization of the carbonylationa
O
I
cat. Pd
CN
R
Me3Si
CN
+
O
O
R
I
cat. Pd/Ligand
Mo(CO)6
CO or Mo(CO)6
CN
O
3
1
+
CN
MeO
OMe
Base, solvent
1a
2
4
This work
b)
R
120 oC, 12 h
O
I
Yieldb (%)
CN
MX
O
Entry
Catalyst
Ligand
Base
Solvent
cat. Pd
Mo(CO)6
+
3
R
CN
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd2(dba)3
PPh3
dppb
PPh3
dppb
PPh3
dppb
dppf
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
DMSO
40
54
36
57
55
87
60
70
62
61
73
51
81
53
- CO2
- MeX
MeO
O
OMe
1
2
I
Pd2(dba)3
Scheme 2. Synthesis of benzoylacetonitriles through carbonylation.
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
Table 1
Xantphos
BINAP
dppb
Na2CO3
Na2CO3
K2CO3
Optimization of Krapcho decarboxylationa
9
10
11
12
13
14
O
O
dppb
dppb
dppb
dppb
Cs2CO3
Na3PO4
Na2CO3
Na2CO3
MX
CN
CN
130 oC, solvent
O
I
OMe
- CO2
3a
- MeX
a
Reaction conditions: iodobenzene (0.3 mmol), methyl cyanoacetate (0.6 mmol),
Mo(CO)6 (0.3 mmol), palladium catalyst (0.015 mmol), ligand (0.015 mmol), and
Entry
MX
Solvent
Yieldb (%)
base (0.6 mmol) were reacted in NMP (1.0 mL) at 120 °C for 12 h.
b
Isolated yield.
1
2
3
4
5
6
7
8
NaCN
NaCl
LiCl
KI
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
NMP/H2O
NMP/H2O
43
90
84
43
55
23
43
38
77
88
51
91
methyl 2-cyano-3-oxo-3-phenylpropanoate, in the subsequent
reaction. First, we employed Pd(PPh3)2Cl2, which had shown good
activity in the coupling reaction in the presence of Mo(CO)6, as the
palladium catalyst. When PPh3 and 1,4-bis(diphenylphosphino)
butane (dppb) were used as ligands, desired carbonyl compound
4 was formed in 40% and 54% yields, respectively (entries 1 and
2). When the palladium catalyst was changed to Pd2(dba)3 with
PPh3 and dppb as ligands, the yields did not improve (entries 3
and 4). When [(allyl)PdCl]2 was employed as the palladium cata-
lyst, the reactions with PPh3 and dppb as ligands afforded the
desired product in 55% and 87% yields, respectively (entries 5
and 6). However, other chelating phosphine ligands such as
1,10-bis(diphenylphosphino)ferrocene (dppf), Xantphos, and BINAP
were not superior to dppb and did not give satisfactory results
(entries 7–9). When K2CO3, Cs2CO3, and Na3PO4 were used as bases
instead of Na2CO3, the desired product was formed in 61%, 73%,
and 51% yield, respectively (entries 10–12). The reaction in DMF
gave an 81% yield of the product (entry 13). However, the reaction
in DMSO, which is a good solvent in the decarboxylation, did not
give a satisfactory result (entry 14).
Finally, we combined the carbonylation and the decarboxylation
for the sequential one-pot synthesis of benzoylacetonitriles. The
optimized conditions were as follows: aryl iodide, methyl cyanoac-
etate, Mo(CO)6, [(allyl)PdCl]2, dppb, and Na2CO3 were reacted in
NMP at 120 °C for 12 h, and then LiI/H2O was added to the resulting
mixture and stirred at 130 °C for 6 h. To evaluate this methodology,
a variety of aryl iodides was tested under the optimized conditions.
As shown in Table 3, moderate yields were obtained in most cases.
As expected, iodobenzene provided the desired benzoylacetonitrile
in 76% isolated yield (entry 1). Methyl-, ethyl-, and methoxy-
substituted iodobenzenes gave desired products 3b, 3c, and 3d in
70%, 71%, and 69% yields, respectively (entries 2–4). Halide-
substituted aryl iodides afforded the desired benzoylacetonitriles
in yields ranging from 55% to 71% (entries 5–11). 4-Iodoacetophe-
none gave desired product 3l in 57% yield (entry 12). 2-Naphthyl
iodide and 2-thiophenyl iodide provided corresponding products
3m and 3n in 83% and 44% yields, respectively (entries 13 and
14). However, aryl iodides bearing ester or cyano groups did not
give the desired products (entries 15 and 16).23
LiI
NaCN
NaCl
LiCl
KI
LiI
NaCl
LiI
9
10
11
12
a
Reaction conditions: I (0.3 mmol) and MX (0.6 mmol) were reacted at 120 °C for
6 h.
b
Determined by gas chromatography with an internal standard.
bonylation of aryl halides with alkyl cyanoacetates and a subse-
quent decarboxylation.
To achieve this goal, we first attempted to find the optimized
conditions for the decarboxylation of methyl 2-cyano-3-oxo-
phenylpropanoate (I), which can be obtained through the coupling
reaction of an aryl halide and the corresponding cyanoacetate in
the presence of a carbon monoxide source. This decarboxylation
of an ester bearing an electron-withdrawing group at the
b-position is known as the Krapcho reaction.22 The results are sum-
marized in Table 1.
When NaCN, NaCl, and LiCl, which showed good activity in the
Krapcho decarboxylation, were employed in DMSO, desired pro-
duct 3a was formed in 43%, 90%, and 84% yields, respectively
(entries 1–3). However, KI and LiI gave product 3a in 43% and
55% yields, respectively (entries 4 and 5). Bearing in mind the sub-
sequent reaction, the decarboxylation was tested in DMF, which
was a good solvent in the palladium-catalyzed carbonylation for
the synthesis of benzoylacetonitriles. We found that NaCN, NaCl,
and LiCl provided lower yields of the product than they did in
DMSO (entries 6–8). KI and LiI showed good yields in DMF (entries
9 and 10). When the reaction was conducted in NMP (N-methyl-2-
pyrrolidinone), NaCl was inferior to LiI (entries 11 and 12).
In order to accomplish the one-pot sequential synthesis of
benzoylacetonitriles, we attempted the palladium-catalyzed car-
bonylation of an aryl iodide and a cyanoacetate in the presence
of Mo(CO)6 (Table 2). As a model reaction, iodobenzene and methyl
cyanoacetate were tested in the synthesis of the intermediate,

S. Lee et al. / Tetrahedron Letters 57 (2016) 239–242
241
Table 3
Krapcho Decarboxylation
Carbonylation
Synthesis of benzoylacetonitrilesa
O
Ar
I
Pd(0)
CN
2.5 mol% [(allyl)PdCl]2
O
LiI (2.0 eq)
O
Ar
Ar
I
5 mol% dppb
CN
CN
I
+
O
C
MeO
O
OMe
Ar
Na2CO3 (2.0 eq)
H2O
Ar Pd
I
130 oC, 6 h
Mo(CO)6
Entry
1
Ar
Pd CHCN
MeI
NMP, 120 oC, 12 h
Mo(CO)6
heat
A
C
O
OMe
CO2
CO
R
Product
Yieldb (%)
76
O
O
I
O
O
3a
3b
3c
Ar
C
Pd I
CH2CN
CN
CN
MeO
Base
Ar
B
O
Me
I
Me
2
3
70
71
CH2CN
O
Scheme 3. Proposed mechanism.
Et
I
Et
CH2CN
OMe
I
OMe
O
4
3d
69
decarboxylation. Methyl cyanoacetate, which is less expensive
than trimethylsilyl acetonitrile, reacted with an aryl iodide and
Mo(CO)6 in the presence of a palladium catalyst to give a beta-keto
cyanoester, which was treated with LiI/H2O to provide the benzoy-
lacetonitrile in a moderate to good yield. The utilization of Mo(CO)6
and a cyanoacetate as the carbon monoxide and acetonitrile
source, respectively, provided a convenient-handling and low-cost
reaction method for the synthesis of benzoylacetonitriles from aryl
iodides. To the best of our knowledge, this is the first Letter of
sequential carbonylation and decarboxylation for the synthesis of
benzoylacetonitriles.
CH2CN
O
F
I
I
I
F
5
6
7
3e
3f
61
63
71
CH2CN
O
Cl
Cl
CH2CN
O
Br
Br
Br
Br
3g
CH2CN
O
8
9
3h
3i
62
62
I
CH2CN
F
F
O
I
Acknowledgments
CH2CN
F
F
Cl
Cl
This work was supported by the LG Yonam Culture Foundation
fellowship for a visiting scholar. Spectral data were obtained from
the Korea Basic Science Institute, Gwangju branch.
O
I
10
11
3j
59
55
CH2CN
Cl
Cl
Cl
Cl
O
3k
3l
References and notes
Cl
Cl
I
CH2CN
O
O
O
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I
12
13
57
83
Me
Me
CH2CN
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I
3m
CH2CN
O
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14
15
3n
3o
3p
44
0
S
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CH2CN
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CH2CN
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16
0
CH2CN
a
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and H2O (3.0 mL) were added and stirred at 130 °C for 6 h. The conversion of all aryl
iodides was >99%.
b
Isolated yield.
The proposed reaction pathway is shown in Scheme 3. The aryl
iodide reacts with palladium to give oxidative aryl palladium com-
plex A, and then carbon monoxide, which is generated from Mo
(CO)6, is inserted into palladium complex A toproduceacyl palladium
complex B. This acyl palladium complex reacts with methyl cyanoac-
etate in the presence of a base to give palladium complex C, and then
carbonylated compound I is formed through reductive elimination.
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a one-pot synthesis of
benzoylacetonitriles through sequential carbonylation and

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