Application of polymer-supported triphenylphosphine and microwave irradiation to the palladium-catalyzed cyanation of aryl triflates

Article abstract of DOI:10.1080/00397910601039044

A variety of aryl nitriles were prepared in excellent yield from the palladium(II) acetate-catalyzed cross-coupling of aryl triflates and zinc cyanide under microwave irradiation conditions. To facilitate purification, polymer-supported triphenylphosphine was used as the palladium ligand. Comparison to the corresponding thermal conditions revealed much shorter reaction times with comparable yields. Copyright Taylor & Francis Group, LLC.

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Application of Polymer‐Supported
Triphenylphosphine and Microwave
Irradiation to the Palladium‐Catalyzed
Cyanation of Aryl Triflates
a
a
a
Rajiv R. Srivastava , Andrew J. Zych , David M. Jenkins , Hong‐Jun Wang
a
a
a
,
Zhen‐Jia Chen, & David J. Fairfax
a
Department of Medicinal Chemistry, Albany Molecular Research, Inc.,
Albany, New York, USA
Version of record first published: 06 Feb 2007.
To cite this article: Rajiv R. Srivastava , Andrew J. Zych , David M. Jenkins , Hong‐Jun Wang , Zhen‐Jia Chen,
&
David J. Fairfax (2007): Application of Polymer‐Supported Triphenylphosphine and Microwave Irradiation to
the Palladium‐Catalyzed Cyanation of Aryl Triflates, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:3, 431-438
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Synthetic Communications , 37: 431–438, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601039044
Application of Polymer-Supported
Triphenylphosphine and Microwave
Irradiation to the Palladium-Catalyzed
Cyanation of Aryl Triflates
Rajiv R. Srivastava, Andrew J. Zych, David M. Jenkins,
Hong-Jun Wang, Zhen-Jia Chen, and David J. Fairfax
Department of Medicinal Chemistry, Albany Molecular Research, Inc.,
Albany, New York, USA
Abstract: A variety of aryl nitriles were prepared in excellent yield from the palladium(II)
acetate–catalyzed cross-coupling of aryl triflates and zinc cyanide under microwave
irradiation conditions. To facilitate purification, polymer-supported triphenylphosphine
was used as the palladium ligand. Comparison to the corresponding thermal conditions
revealed much shorter reaction times with comparable yields.
Keywords: aryl triflates, heterogeneous catalyst, microwave irradiation, nitriles,
palladium, thermal heating
INTRODUCTION
In organic synthesis, nitriles play a crucial role as a moiety that can be easily
converted into a variety of other functional groups such as acids, esters, and
[
amides. Furthermore, the nitrile functionality can be transformed into a
1]
[2a]
[2b]
variety of biologically important structures such as oxazoles, thiazoles,
[
triazoles, oxadiazoles, and tetrazoles, the later of which is often used
2c]
[2d]
[2e]
[3]
in medicinal chemistry as a bioisostere for the carboxylic moiety. Classifi-
cally, aryl nitriles are synthesized from aryl halides and stoichiometric
Received in the USA February 19, 2006
Address correspondence to Rajiv R. Srivastava, Department of Medicinal
Chemistry, Albany Molecular Research, Inc., P.O. Box 15098, Albany, NY 12212-
5
098, USA. Tel.: þ1 518 464 0279; Fax: þ1 518 464 0289. E-mail: rajiv.
srivastava@albmolecular.com
4
31

4
32
R. R. Srivastava et al.
amounts of cyanide salts such as copper(I) cyanide (Rosenmund–von Braun
[4b]
on an industrial scale via amoxidation of
[
raction ) or nickel–cyanide,
4a]
[
5a]
the corresponding toluenes,
or from aniline via diazotization and a sub-
Aryl nitriles can also prepared by the displa-
cement of aryl triflates with either sodium or potassium cyanide, although
[
5b]
sequent Sandmeyer reaction.
[6]
these methods have achieved only limited success.
catalyzed displacement of aryl halides with cyanide has recently become a
Transition-metal-
[
7]
milder alternative to classical Rosenmund–von Braun Synthesis. Zinc
cyanide has found widespread use as the alternate cyanide source, with the
reagent system composed of zinc cyanide, catalytic palladium tetrakis(triphe-
nylphosphine), and dimethylformamide, reported to be the method of choice
[
8,9]
for preparing aryl nitriles from aryl triflates.
cyanide sequestering of the catalyst still appears to be a significant problem
Despite these advances,
[
10]
in this reaction.
BACKGROUND
As part of a recent synthetic library effort, we desired a method for the expedi-
tious synthesis of a variety of aryl cyanides. The most direct route to our desired
target set was the palladium-mediated cyanation of aryl triflates, which could be
readily obtained from the corresponding phenols by standard means. However,
a major problem associated with the application of transition-metal-catalyzed
reactions to high throughput organic synthesis is the removal of the homo-
geneous palladium catalyst and corresponding dissociated ligands from the
reaction mixture. This can make the high-throughput purification process
even more challenging. We envisioned that a heterogeneous catalyst system
in combination with microwave heating would be ideally suited for the
synthesis of aryl nitriles in parallel fashion. Recently, we reported the utiliz-
ation of polymer-supported triphenylphosphine as a heterogeneous ligand in
[11]
palladium-catalyzed cyanation of aryl halides.
This heterogeneous catalyst
was prepared by simply mixing polymer-bound triphenylphosphine and
palladium acetate in dimethylformamide. This catalyst system was found to
be very effective in cyanating both electron-rich and electron-deficient aryl
halides under microwave conditions. In the present study, we report an
extension of this methodology to the cyanation of aryl triflates.
RESULTS AND DISCUSSION
A survey of the literature reveals several reports on the palladium-catalyzed
[
cyanation of triflates, but very limited studies have been carried out on
9]
[9a]
the microwave-promoted cyanation of triflates.
Furthermore, no literature
precedent exists on the use of heterogeneous catalysts for achieving such a
transformation. We now report that a heterogeneous palladium catalyst
derived from resin-bound triphenylphosphine and palladium acetate was

Cyanation of Aryl Triflates
433
equally effective in cyanating triflates both under thermal as well as under
microwave-induced conditions (Scheme 1).
A variety of aryl triflate substrates, containing both electron-withdrawing
and electron-donating substituents, were successfully cyanated under thermal
as well as under microwave conditions; results are summarized in Table 1.
In general, longer reaction times were needed for the completion of the
reaction under conventional heating conditions, whereas reactions were
complete within minutes when microwave irradiation was used as the energy
source. A temperature of 1208C was chosen for thermal heating whereas
microwave-induced reactions were performed at 50 W for 2–3 min with
internal reaction temperatures reaching 140–1558C. Under both sets of con-
ditions, complete conversion of the triflate to the corresponding nitrile was
observed with relatively low catalyst and zinc cyanide loading being
necessary. For comparison, 3 mol% of polymer-supported catalyst and 1 equiv-
alent of zinc cyanide were utilized in this study as compared to 7 mol% of
palladium and 2 equivalents of Zn(CN) , which are reported necessary for
2
[
9a]
similar transformations.
This result suggests that the heterogeneous
catalyst system is less prone to deactivation by solubilized cyanide than the cor-
responding homogeneous system. The desired nitriles were obtained in good
yield and in excellent purity (.90%) by a simple filtration followed by a
standard aqueous workup. This protocol completely avoided any detailed puri-
fication steps and is very amenable to high-throughput synthesis.
SUMMARY
In summary, the use of commercially available polymer-supported triphenyl-
phosphine as the ligand in the palladium-catalyzed cyanation of aryl triflates
has been demonstrated. Thermal as well as microwave irradiation conditions
afford the desired compounds in high yield and excellent purity without the
need of any further purification. This methodology has obvious potential in
the area of high-throughput synthesis.
EXPERIMENTAL
Commercially available reagents were used without further purification.
Triflates 1a, 1b, 1e–g, 1j, and 1k were obtained from commercial sources.
Scheme 1. Cyanation of aryl triflates.

Table 1. Polymer-supported Pd-catalyzed cyanation of aryl triflates
a
b
Microwave heating
Thermal heating
c
Time (min)
d,e
Yield (%)
c
Time (h)
d,e
Yield (%)
Entry
1
Aryl triflate 1
Product 2
2.5
2
92
2
94
2
3
96 (97)
94
1.5
3
98 (96)
93
2
4
5
2
2
93
1.5
1.5
94
92 (95)
92 (91)
6
2.5
94 (91)
1.5
93 (89)

7
3
89
2.0
93
8
9
2.5
2.5
93
94
1.5
1.5
94
92
1
1
0
1
2
2
91 (93)
90 (94)
1.5
1.5
92 (90)
91 (96)
a
Reactions were performed at 50 W with target temperature reaching 140–1558C.
Reactions were carried out at 1208C in an oil bath.
b
c
Reaction times not optimized.
d
Isolated yield.
Yields in parentheses were obtained by using 3 mol% (as compared to 7 mol%) of catalyst.
e

4
36
R. R. Srivastava et al.
Triflates 1c, 1d, 1h, and 1i were prepared from the reaction of corresponding
phenols with triflic anhydride, and triethylamine in methylene chloride as
[
9c]
solvent.
Polymer-supported triphenylphosphine was purchased from the
Aldrich Chemical Company and used directly. Microwave reactions were
carried out in a EmrysTM Optimizer in a 5 mL glass tube. All products were
identified by comparison of observed spectral and physical data to those of
known samples. The purity of all products was measured by high performance
1
liquid chromatography (HPLC) analysis with UV detection at 254 nm. H and
1
C NMR spectra were recorded on 300-MHz Bruker (Avance 300) instrument.
3
General Procedure for the Cyanation of Triflates
A 5 mL glass microwave reactor tube was charged with polymer-supported
triphenylphosphine resin (50 mg, 0.15 mmol, 3 mmol of triphenylphosphine
per gram of resin), dimethylformamide (3 mL), and palladium(II) acetate
(
15 mg, 0.07 mmol). The suspension was purged with nitrogen, and the tube
was then sealed with a rubber septum. The mixture was stirred for 2 h
during which time the yellow color of the dissolved palladium(II) acetate dis-
sipated, affording a yellow suspension with a colorless supernatent. This
observation was taken as an indication of formation of the palladiumphos-
phine complex (an observation further supported by control experiments,
Control experiments: (a) Reaction was performed with Pd(OAc) (7 mol%)
2
and Zn(CN) (1.0 eq) in DMF at 50 W for 3 min without polymer-supportted
2
triphenylphosphine. Under this condition, 1b yielded only trace amounts of
2b. (b) In another control experiment, removal of the solution from the
resin [after premixing with Pd(OAc) ] followed by the addition of fresh
2
solvent, 1b, and Zn(CN) gave the desired nitrile, 2b, in quantitative yield.).
2
The septum was removed from the tube, and aryl triflate (1 mmol) along
with zinc(II) cyanide (1.0 mmol) were added. The solution again was
purged with nitrogen, and the tube was sealed with a rubber septum. The
reaction mixture was exposed to microwave irradiation at a power of 50 W
for the time delineated in Table 1. After the reaction was determined to be
complete by thin-layer chromatography (TLC) analysis, the solution was
cooled to room temperature. The liquid was filtered through a glass frit to
remove the resin, and the resin was washed with ether (3 ꢀ 10 mL). The
combined organic filtrates were washed with water (3 ꢀ 5 mL) and brine
(
1 ꢀ 10 mL) and dried (MgSO ). The solvent was then concentrated on a
4
rotatory evaporator to obtain the desired nitriles in excellent yield and in
1
high purity (.90%) as determined by H NMR and HPLC analyses.
ACKNOWLEDGMENTS
The authors thank Brian T. Gregg and William G. Earley for helpful
discussions.

Cyanation of Aryl Triflates
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