Pd(OAc)2-catalyzed ligand-free cyanation of diaryliodonium salts with K4[Fe(CN)6]

Article abstract of DOI:10.1016/j.tetlet.2012.10.036

An effective palladium-catalyzed cyanation of diaryliodonium salts with K₄[Fe(CN)₆] in DMF at 130 °C has been developed, affording the aryl nitriles in high yields via ligand-free process.

Full text of DOI:10.1016/j.tetlet.2012.10.036

Tetrahedron Letters 53 (2012) 6954–6956
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Tetrahedron Letters
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Pd(OAc)2-catalyzed ligand-free cyanation of diaryliodonium salts with
K4[Fe(CN)6]
Li Liu a, Jian Li b, , Jiao Xu b, Jiang-tao Sun b
⇑
a Analytical center, Chang Zhou University, Changzhou 213164, PR China
b School of Pharmaceutical Engineering & Life Sciences, Chang Zhou University, Changzhou 213164, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2012
Revised 22 September 2012
Accepted 9 October 2012
Available online 16 October 2012
An effective palladium-catalyzed cyanation of diaryliodonium salts with K4[Fe(CN)6] in DMF at 130 °C has
been developed, affording the aryl nitriles in high yields via ligand-free process.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diaryliodonium salts
Pd(OAc)2
Cyanation reaction
K4[Fe(CN)6]
Aryl nitriles are important building blocks for constructing
pharmaceuticals, natural products, dyes, and herbicides.1 More-
over, they are valuable motifs for the conversion to other func-
tional groups such as benzoic acids/esters, amines, amides,
imidoesters, benzamidines, aldehydes, and nitrogen-containing
heterocycles in organic synthesis.2 In the past century, a consider-
able effort has been directed toward the development of efficient
and selective methods for preparation of aryl nitriles.
Traditional synthetic methods for the synthesis of aryl nitriles
are the Rosenmund-von Braun and Sandmeyer reactions, which
convert aryl iodides/bromides and aryldiazonium, respectively,
into corresponding nitriles using stoichiometric CuCN at high
temperature (e.g., 220–550 °C) under high pressure.3
Recent developments in the transition-metal-catalyzed process
for the preparation of aryl nitriles from aryl halide including palla-
dium, copper, or nickel-complexes have been explored to be effec-
tive catalysts for this reaction.
Among these, palladium salts were widely investigated for the
cyanation of aryl halides. As early as in 1973, Takagi et al. reported
the first palladium-catalyzed cyanation of aryl halides.4 In 2000, Jin
and Confalone reported palladium-catalyzed cyanation of aryl
chlorides using toxic reagent Zn(CN)2 as the cyanating source.5 In
2004, Beller and co-workers introduced K4[Fe(CN)6] as an efficient
cyanating agent under Pd/dppf system for the first time.6 In 2007,
Littke et al. demonstrated mild cyanation conditions (95 °C in
general) for aryl chlorides using the Buchwald-type ligand,
racemic-2-di-tert-butylphosphino-1,10-binaphthalene.7 Very re-
cently, Hajipour et al. described a palladacycle complex involved
cyanation reaction under both conventional and microwave irradi-
ation conditions using K4[Fe(CN)6].8
Unfortunately, all the above catalytic reactions are inefficient in
the absence of ligands. There has been a limited literature report
regarding the cyanation of aryl chlorides mediated by K4[Fe(CN)6]
without ligand. It is highly desirable to develop a ligand-free pro-
cess to further improve the efficiency and generality of the prepa-
ration of aryl nitriles.
Diaryliodonium salts serve as versatile arylating agents with a
variety of nucleophiles because of their highly electron-deficient
nature and excellent leaving-group ability.9 Recent years have wit-
nessed an increasing development of diaryliodonium salts.10 It dis-
closed both metal-catalyzed and metal-free direct arylations of
versatile compounds, such as indoles, pyrroles, phenols, carboxylic
acids, aniline, and carbonyls.11–16 Recently, our group developed a
new Heck-type reaction of acrylate with diaryliodonium salts
without the aid of ligand and base,17 which inspired us to develop
a cyanation system of diaryliodonium salts in the absence of
ligand.
We initiated our investigations using diphenyliodonium salt 1a
and K4[Fe(CN)6] as model substrates. Various reaction conditions
were tested for the cyanation of diphenyliodonium salt 1a
(Table 1). First, these two coupling partners were reacted in DMF
at room temperature for 24 h with 5 mol % of CuI, only 5% of cya-
nated product 2a was detected (Table 1, entry 1). Gratifyingly,
when Pd(OAc)2 was employed, the desired compound was formed
in 35% yield. We increased the temperature form 25 to 60 and
⇑
Corresponding author. Fax: +86 519 8633 4597.
E-mail address: lijianchem@gmail.com (J. Li).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.036

L. Liu et al. / Tetrahedron Letters 53 (2012) 6954–6956
6955
Table 1
Table 2
Optimization of the model reactiona
Cyanation of diaryliodonium salts with K4[Fe(CN)6]a
X
I
OTf
Pd(OAc)2 (5 mol%)
CN
CN
I
K2CO3 (2 equiv.)
Catalyst
Solvent
K4[Fe(CN)6]
+
+
R
K4[Fe(CN)6]
R
DMF,130 oC
1a
2a
1
2
Yieldb (%)
Entry
Catalyst
X
Base
Solvent
T (°C)
Yieldb (%)
Entry
Substrate
Product
1
2
3
4
5
6
7
8
CuI
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTs
Br
—
—
—
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAC
DMSO
NMP
Toluene
25
25
60
5
35
46
50
91
23
45
61
54
83
74
64
87
74
42
47
CN
OTf
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
I
1
2
91
130
130
130
130
130
130
130
130
130
130
140
130
110
K2CO3
Na2CO3
Cs2CO3
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2a
1a
CN
OTf
I
9c
10
11
12
13
14
15
16
F
85
83
F
2b
CN
1b
Cl
OTf
OTf
OTf
OTf
OTf
I
Cl
3
Cl
2c
a
Diphenyliodonium salt (0.5 mmol) and K4[Fe(CN)6] (184.2 mg, 0.5 mmol) were
mixed in solvent (1 mL) at rt before the addition of Pd(OAc)2 (5 mol %) and base
1c
OTf
I
(1 mmol), then heating to 130 °C for 2 h.
CN
b
Isolated yield.
TBAB (1 mmol) was added.
c
Br
4
5
6
89
87
92
Br
2d
130 °C, the yield was promoted to 46% and 50% after 2 h. It is noted
that when 2 equiv of K2CO3 was used, 91% yield of desired com-
pound was obtained, which shows that the catalytic process goes
more smoothly under base conditions. The screening of bases with
Pd(OAc)2 revealed that K2CO3 was much better than other bases,
such as Na2CO3 and Cs2CO3, even under a more stronger base
NaOH (Table 1, entries 6–8). In order to increase the solubility of
the K2CO3 in the system, 2 equiv of TBAB was added, it was disap-
pointing that a lower yield was observed but 31% yield of bromo-
benzene was found.
1d
CN
OTf
I
EtOOC
2e
EtOOC
O2N
1e
OTf
I
CN
O2N
2f
Further studies were thus carried out about the influence of dif-
ferent diphenyliodonium anions, which showed that satisfactory
results could be obtained with diaryliodonium 4-methylbenzene-
sulfonate, bromide, and chloride salts (Table 1, entries 10–12).
Moreover, the search for different solvents disclosed that the reac-
tion proceeded well in DMF and DMAC (Table 1, entries 13–16), so
we chose DMF as solvent in our system.
With optimized reaction conditions in hand, we probed the
scope of diaryl iodonium salts with K4[Fe(CN)6] employing
5 mol % of Pd(OAc)2 in DMF at 130 °C with the presence of
K2CO3. The results are summarized in Table 2.
1f
CN
OTf
I
7
8
91
64
2g
1g
Me
Me
OTf
CN
I
The reaction scope was subsequently explored by using various
asymmetrical diaryliodonium salts 1 which were prepared with
appropriate iodoarene and mesitylene (Table 2).18 The salts bear-
ing common functional groups in p-position were well tolerated
under standard conditions, such as fluorine, chlorine, bromine, ni-
tro, phenyl, and ester groups. Cyanated products 2 were obtained
in moderate to high yields (entries 2–7). It is noted that the diaryli-
odonium salts with an electron-withdrawing group resulted in
better yield (Table 2, entries 5 and 6) than that with an electron-
2h
1h
CN
OTf
OTf
I
9
80
85
Me
Me
2i
1i
O2N
CN
O2N
I
10
donating group (Table 2, entries
8 and 9). Likewise, ortho-
2j
substituted salts posed no problem in this reaction, as exemplified
by o-methyl product (entry 8). Steric bulk in the meta-position was
very well tolerated, as demonstrated by cyanation with salt meta-
nitro to yield high congested product (entry 10).
1j
a
General procedure for cyanation reaction of diaryliodonium salt.
Isolated yield.
b
The plausible mechanism of the cyanation reaction is depicted
in Scheme 1. At first, an oxidative addition occurred of Pd(OAc)2
with diaryliodonium salts in the reaction system to trigger the first
catalytic cycle, after the reaction between 3 and K4[Fe(CN)6], the
intermediate 4 is achieved. Finally, the reductive elimination of

6956
L. Liu et al. / Tetrahedron Letters 53 (2012) 6954–6956
4
KYZ1102100C) and the Priority Academic Program Development
of Jiangsu Higher Education Institutions.
ArI
Fe(CN)6
CN
OTf
AcO Pd OAc
4
Fe(CN)5(OTf)
[Ar2I]OTf
Ar
3
Supplementary data
1
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.036.
Pd(OAc)2
AcO Pd OAc
Ar
Catalyst
4
References and notes
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Scheme 1. Possible mechanism of the cyanation.
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intermediate 4 caused the desired cyanated products 2 and the
Pd(OAc)2, which is used for the next catalytic cycle. The entire pro-
cess of catalyst undergoes a Pd(II)-Pd(IV)-Pd(II) cycle.19
In conclusion, an efficient cyanation reaction has been devel-
oped with K4[Fe(CN)6] and diaryliodonium salts without the aid
of ligand. Various diaryliodonium salts 1 could perform the reac-
tion with readily available K4[Fe(CN)6] by 5 mol % of Pd(OAc)2 in
DMF with the presence of K2CO3, assembling aryl nitriles in up to
92% yields. Further investigations on further exploration of the
substrate scope and other synthetic utility of diaryliodonium salts
are currently underway.
General procedure for the cyanation reaction of diaryliodonium
salts with K4[Fe(CN)6]
A
mixture of diaryliodonium salt (0.5 mmol), K4[Fe(CN)6]
(184.2 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), K2CO3
(138.2 mg, 1 mmol), and DMF (1 mL) was taken in a 10 ml reaction
tube and heated at 130 °C for 2 h under vigorous stirring. After
completion of the reaction (observed on TLC or GC), the mass
was cooled to room temperature, and 5 ml of water was added.
The mixture was stirred for 10 min and extracted with ethyl ace-
tate (3 ꢀ 10 mL). The organic layer was washed with water and
dried over anhydrous sodium sulfate. Solvent was evaporated un-
der reduced pressure and the residue was purified on silica gel col-
umn by using petroleum ether and ethyl acetate as eluent to obtain
the pure product. All the compounds were analyzed by 1H NMR,
13C NMR, and mass spectra.
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Acknowledgments
We are grateful to the Grants from the Foundation of Chang
Zhou Municipal Bureau of Science and Technology (No.