Application of polymer-supported triphenyl phosphine in the palladium-catalyzed cyanation reaction under microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2004.09.184

A variety of aryl nitriles were prepared in excellent yields from the palladium acetate catalyzed coupling of aryl halides with Zn(CN)₂ using polymer-supported triphenyl phosphine as the ligand and dimethylformamide as solvent under microwave irradiation conditions.

Full text of DOI:10.1016/j.tetlet.2004.09.184

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8895–8897
Application of polymer-supported triphenyl phosphine
in the palladium-catalyzed cyanation reaction under
microwave conditions
Rajiv R. Srivastava* and Scott E. Collibee
Department of Combinatorial/Parallel Synthesis Albany Molecular Research, Inc., PO Box 15098, Albany, NY 12212-5098, USA
Received 27 August 2004; revised 28 September 2004; accepted 28 September 2004
Abstract—A variety of aryl nitriles were prepared in excellent yields from the palladium acetate catalyzed coupling of aryl halides
with Zn(CN)2 using polymer-supported triphenyl phosphine as the ligand and dimethylformamide as solvent under microwave irra-
diation conditions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Substituted benzonitriles are an integral part of dyes,
natural products, herbicides, agrochemicals, and pharma-
ceuticals.1 In organic synthesis, nitriles play a crucial
role as theycan be easilyconverted into a varietyof
functional groups2 such as acids, esters, and amides,
etc. In medicinal chemistry, nitriles are very useful as
theycan be transformed into a varietyof biologically
important structures such as tetrazoles, triazoles, oxa-
zoles, thiazoles, oxazolidinones, to name just a few.
For example, tetrazoles are veryoften used as the meta-
cused microwave flash heating continues to find greater
applications in parallel synthesis and in drug discovery
processes. Recentlymicrowave heating has been proven
to be veryeffective in accelerating the cyanation reac-
tions.8 Leadbeater and co-workers8b,c have shown that
classical Rosenmund–von Braun cyanation reaction
could be completed in minutes (as compared to hours
under traditional heating) under microwave condition.
8d
Similarlythe reaction times for nickel
and palla-
dium8e,f mediated cyanation reactions have also been
greatlyimproved under microwave heating.
3
bolicallystable bioisosteres of the carboxylic groups.
In general, aryl nitriles are synthesized from aryl halides
and stoichiometric amounts of copper(I) cyanide
(Rosenmund–von Braun reaction),4 on an industrial
scale via amoxidation of the corresponding toluenes,5a
or from aniline5b via diazotization and a subsequent
Sandmeyer reaction. Nickel-6 and palladium-catalyzed7
methods have been developed as milder alternatives to
the classical Rosenmund–von Braun nitrile synthesis,
but these transition metal catalyzed reactions take sev-
eral hours. Microwave-induced reaction rate enhance-
ment has become a powerful tool in organic synthesis
because of milder reaction conditions, better selectivity,
and associated ease of manipulation. Automated and fo-
Rapid development of combinatorial chemistryand ro-
botic parallel synthesis has led to a growing demand for
fast reactions and efficient purification procedures. The
major problems associated with the broad application
of currently known transition metal catalyzed cyanation
reactions in high throughput synthesis is the removal of
homogeneous palladium catalyst and dissociated ligand
by-products that add purification steps in the synthesis.
Another disadvantage with the current palladium-cata-
lyzed cyanation reaction is catalyst poisoning. Mecha-
nistic studies have revealed that cyanides form very
stable complexes with transition metal catalysts9 and
thus relativelyhigh quantities of catalysts are needed
to compensate for the poisoned catalyst.
Because of the need for more environmentallybenign
chemistryand the desire to develop simplified protocols
for rapid screening methods, there is a need for hetero-
geneous catalysis systems to address the bottleneck
Keywords: Aryl halides; Nitriles; Palladium; Heterogeneous catalyst;
Microwave irradiation.
*
Corresponding author. Tel.: +1 518 464 0279; fax: +1 518 464
0289; e-mail: rajiv.srivastava@albmolecular.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.184

8896
R. R. Srivastava, S. E. Collibee / Tetrahedron Letters 45 (2004) 8895–8897
issues of purification associated with soluble ligands and
catalyst removal (recovery). Although adoption of
microwave conditions8 have improved on the reaction
time for the palladium-catalyzed cyanation reaction,
use of soluble catalysts and ligands require purification
steps to remove the ligands. Also, recoveryof catalyst
remains a major challenge when reactions are performed
on large scales. We envisioned that a heterogeneous cata-
lyst system in combination with microwave heating
would be ideally suited for the synthesis of aryl nitriles
in combinatorial chemistryapplications. Various ssy-
tems of solid-supported catalysts10 have been prepared
and applied successfullyin organic snythesis, but to
the best of our knowledge, there is no report of hetero-
geneous palladium-catalyzed cyanation reaction. In the
present studywe focused our studies on polymer-sup-
ported palladium catalysts for cyanation reactions.
Several solid-supported palladium catalysts are known
in the literature and have been widelyused in organic
synthesis.10 Some of these heterogeneous palladium cata-
lysts (or corresponding ligands) are commercially avail-
able although at high cost. For the present studywe
choose to utilize readilyavailable polmy er-supported
triphenyl phosphine resin. This inexpensive heterogene-
ous ligand is available through a varietyof commercial
sources. The desired heterogeneous catalyst was pre-
pared bymixing the resin supported triphenyl phosphine
and Pd(OAc)2 in dimethylformamide solvent. Initial
studies revealed that premixing of the catalyst and lig-
and was essential for the optimal catalytic activity. In
a typical experiment polymer-supported triphenylphos-
phine resin (50mg, 0.15mmol, 3mmol of triphenylphos-
phine per gram of resin, Aldrich) was taken up into
dimethylformamide (3mL) along with Pd(OAc)2
Table 1. Polymer-supported Pd-catalyzed cyanation of aryl halides
CN
PPh2, Pd(OAc)2
Zn(CN)2, DMF
X(Br, I)
R
R
Microwave @ 140 oC
1 a-k
2 a-h
lEhnatlridyeAsr(y
1)
Productsa (2)
Microwave heating
Timeb (min) Yieldc,d (%)
X
CN
1
2
a X = I
b X = Br
a
30
30
99
95
O2N
O2N
MeO
X
MeO
CN
CN
3
4
c X = I
d X = Br
b
30
30
92
98
H2N
H2N
5
e
c
50
92
I
O
O
X
CN
6
7
f X = I
g X = Br
d
30
30
96
89
Me
Me
O
O
I
CN
8
h
e
30
91
MeO
MeO
HO
HO
Br
CN
CN
9
i
j
f
50
30
93
H2N
N
H2N
N
10
g
84e
MeO
I
N
Br
MeO
NC
N
11
k
h
50
96
N
H
N
H
a Confirmed by 1H NMR and MS.
b Reaction times not optimized.
c Isolated yield.
d Aryl halides were completely consumed in the reaction as determined by TLC.
e Product tends to sublime under high vacuum.

R. R. Srivastava, S. E. Collibee / Tetrahedron Letters 45 (2004) 8895–8897
8897
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(15mg, 0.07mmol) in a 5mL glass microwave reactor
tube. The solution was purged with nitrogen and then
tube was closed with a septum. The mixture was stirred
for 2h. During this time the yellow color of Pd(OAc)2
solution was transferred to the beads leaving behind a
colorless solution. This is an indication of formation
of a palladium–phosphine complex (that such a complex
is formed on the resin and acts as catalyst is further sup-
11
ported bycontrol experiments).
The septum was re-
moved from the tube and aryl halide (1mmol) along
with Zn(CN)2 (1.0mmol) was added and once again
the solution was purged with nitrogen and tube was
closed with the septum. The reaction mixture was ex-
posed to microwave irradiation12 at 140ꢁC for 30–
50min (Table 1). After the reaction was judged to be
complete (TLC analysis), the solution was cooled to
room temperature and the liquid was filtered through
a glass frit to remove the resin and the resin was washed
with ether (3 · 10mL). The combined organic fractions
were washed with water (3 · 5mL), brine (1 · 10mL),
and dried (MgSO4). The solvent was then concentrated
on a rotaryevaporator to obtain the desired nitriles in
excellent yield and in high purity (>90%) as determined
by 1H NMR and HPLC (monitored at 254nm) analysis.
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In summary, we have successfully demonstrated the use
of commercially available polymer-supported triphenyl
phosphine in the palladium-catalyzed synthesis of aryl
nitriles. Microwave irradiation was used as the energy
source. A varietyof electron rich and electron deficient
aryl iodides and bromides were efficiently converted into
their corresponding nitriles. Products were obtained in
high yields and in excellent purity without the need of
anypurification. This methodologyhas a potential
application in parallel synthesis. More detailed study is
under wayto studythe scope and limitations of this
methodology.
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Acknowledgements
The authors thank Dr. Brian T. Gregg and Dr. William
G. Earleyfor helpful discussions and constant
encouragement.
11. Control experiments: (a) reaction was performed with
Pd(OAc)2 (15mol%), Zn(CN)2 (1.0equiv) in DMF at
140ꢁC for 30min without polymer-supported triphenyl-
phosphine. Under this condition 1b yielded only trace
amounts of 2a. (b) In another control experiment, removal
of the solution from the resin (after premixing with
Pd(OAc)2) followed byaddition of fresh solvent, 1b, and
Zn(CN)2 gave the desired nitrile, 2b, in quantitative yield.
12. Reactions were run in EmrysTM Optimizer from Personal
Chemistry(now Biotage) in a 5mL glass tube.
References and notes
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Pharmaceutical Substances: Synthesis, Patents, Applica-
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