Pd/C-catalyzed cyanation of aryl halides in aqueous PEG

Article abstract of DOI:10.1002/ejoc.200800295

An environmentally friendly Pd/C-PEG-H₂O system was developed for the cyanation of aryl halides under microwave irradiation. A wide range of aryl bromides, iodides, and some activated chlorides were demonstrated to be cyanated smoothly by using nontoxic K₄[Fe(CN)₆] ·3H₂O as the cyanide source. There is no phosphorus- or nitrogen-containing ligand or solvent involved. Moreover, this reaction can be carried out without the protection of inert atmosphere. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800295

FULL PAPER
DOI: 10.1002/ejoc.200800295
Pd/C-Catalyzed Cyanation of Aryl Halides in Aqueous PEG
Gong Chen,[a] Jiang Weng,[a] Zhanchao Zheng,[a] Xinhai Zhu,[a] Yaoyao Cai,[a] Jiwen Cai,[a]
and Yiqian Wan*[a]
Keywords: Palladium / Cyanides / Water chemistry / Microwaves / Sustainable chemistry
An environmentally friendly Pd/C–PEG–H2O system was de-
veloped for the cyanation of aryl halides under microwave
irradiation. A wide range of aryl bromides, iodides, and some
activated chlorides were demonstrated to be cyanated
smoothly by using nontoxic K4[Fe(CN)6]·3H2O as the cyanide
source. There is no phosphorus- or nitrogen-containing li-
gand or solvent involved. Moreover, this reaction can be
carried out without the protection of inert atmosphere.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
dium-catalyzed cyanation reactions with the use of
K4[Fe(CN)6] as a cyanide source were almost always carried
out in a highly polar amide solvent such as DMF, NMP, or
DMAC under an inert gas atmosphere.[9,11,12] The utiliza-
tion of K4[Fe(CN)6] in copper-catalyzed cyanation reac-
tions of aryl halides has also been realized. However, amine
ligands as well as long reaction times were required in these
copper-catalyzed protocols.[13]
Introduction
Aryl nitriles are important building blocks of numerous
pharmaceuticals, herbicides, natural products, and dyes.[1]
In addition, nitriles are very useful intermediates in organic
synthesis, because they can be easily converted into other
functional groups.[2] For these reasons, much attention has
been given to the development of efficient and practical
methods for the synthesis of aryl nitriles. Of these transfor-
mations, transition-metal-mediated cyanation of aryl ha-
lides represents one of the most convenient approaches.[3]
Typical procedures utilized toxic inorganic or organic cya-
nide sources, such as alkali cyanides,[4] Zn(CN)2,[5] CuCN,[6]
TMSCN,[7] and acetone cyanohydrin.[8] In most cases, vari-
ous ligands were developed to maintain or improve the ac-
tivity of the metal catalysts. However, the ligands are often
toxic, expensive, and hard to be removed from the product.
Recently, an attractive improvement was made by Beller
and coworkers.[9] Nontoxic, inexpensive, and easily handled
K4[Fe(CN)6] was, for the first time, introduced as a cyanide
source to the cyanation reaction,[10] although a phosphane
ligand was still necessary. Further modifications of the orig-
inal protocol led to ligand-free versions soon after.[11] To
ensure that the transformations were carried out smoothly,
however, dehydrating or grinding the K4[Fe(CN)6]·3H2O
into fine particles was a prerequisite. In addition, some elec-
tron-rich aryl bromides, for example, 4-bromoanisole, often
encountered problematic and incomplete conversion.[11b,11c]
It is noteworthy that the solvent showed a significant influ-
ence on the reaction. To the best of our knowledge, palla-
Being the solvent of life, water is necessarily a nontoxic
and economic solvent. As such, it has frequently been pro-
moted as an alternative solvent in academic and industrial
labs. In addition, the utilization of water as a solvent in
transition-metal-catalyzed coupling reactions often greatly
facilitates the workup procedure and avoids drying solvents
and starting materials.[14] Although some experiments
showed that small amounts of water or hydrate in the cya-
nide source was tolerated by the catalytic system in cyan-
ation reactions,[5c–5f,11b,12a] only two papers described the
transition-metal-catalyzed cyanation reaction in water in
the absence of an amide cosolvent. One of these reported
procedures involved the utilization of toxic NaCN as a cya-
nide source, water–heptane as a biphasic solvent, and sulfo-
nated phosphane as a palladium ligand to accomplish the
cyanation of aryl iodides and activated aryl bromides.[15]
The other paper also used toxic NaCN or CuCN as a cya-
nide source, whereas the substrate scope was limited to aryl
iodides.[16] Thus, the development of an efficient and envi-
ronmentally friendly catalytic system for transition-metal-
catalyzed cyanation reactions in water is still attractive.
As part of our ongoing research interest in aqueous
cross-coupling reactions,[17] we herein wish to report our
investigation on Pd/C-catalyzed cyanation of aryl halides
with the use of nontoxic and commercially available
K4[Fe(CN)6]·3H2O directly as the cyanide source in aque-
ous polyethylene glycols (PEGs) under microwave irradia-
tion without protection of an inert atmosphere.
[a] School of Chemistry and Chemical Engineering, Sun Yat-Sen
University,
Guangzhou 510275, P. R. China
Fax: +86-020-84112245
E-mail: ceswyq@mail.sysu.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3524–3528

Pd/C-Catalyzed Cyanation of Aryl Halides in Aqueous PEG
Table 1. Optimization of the reaction conditions.[a]
Results and Discussion
Cyanation of 4-bromoanisole was chosen as a model re-
action to optimize the reaction conditions. The results are
summarized in Table 1. Initially, the cyanation reaction was
carried out in pure water under microwave irradiation at
140 °C for 30 min in the presence of Pd/C (10 mol-%),
K4[Fe(CN)6]·3H2O (0.33 equiv.), Na2CO3 (20 mol-%), and
KI (1 equiv.). Unfortunately, no desired product was de-
tected (Table 1, Entry 1). This might be caused by the poor
solubility of 4-bromoanisole in water and should be circum-
vented by the addition of surfactant. Polyethylene glycols
(PEGs) are known to be nontoxic, recyclable, thermally
stable, and inexpensive media for the use as phase-transfer
catalysts (PTCs), and they may even be applicable in bio-
medical protocols.[18] In view of green chemistry, utilization
of PEGs as PTCs was one of the best options. Hence, a
variety of PEGs with different chain lengths were investi-
gated both as cosolvents and PTCs under the same reaction
conditions (Table 1, Entries 2–7). As shown in Table 1,
PEG4000 was the most efficient in promoting the reaction
(Table 1, Entry 5). Other PEGs with longer chain lengths,
such as PEG2000, PEG6000, and PEG10000, also im-
proved the conversion of the starting material remarkably,
but they were less efficient than PEG4000. PEGs with
shorter chain lengths, such as PEG600 and PEG1000, had
lower activity. The influence of the ratio between PEG and
water on the reaction was then further studied (Table 1, En-
tries 8–13). The results indicated that the appropriate quan-
tity of water was crucial for success of the reaction. Utiliza-
tion of pure PEG4000 as the solvent only gave trace
amounts of product (Table 1, Entry 13), and the addition
of small amounts of water was also not effective (Table 1,
Entry 12). However, when the mass ratio between water and
PEG4000 was 1:2, the yield dramatically increased to 55%
Entry Solvent [b]
Catalyst
Base
Time Conv. Yield
[min] [%][c]
[%][c]
1
Pure water
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
PdCl2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO
30
30
30
30
30
30
30
30
30
3
trace
Ͻ5
9
2
3
4
5
6
7
8
9
10
11
12[d]
13
14
15
16
17[e]
18
19
20
21
22
23[f]
PEG600/H2O (1:1)
PEG1000/H2O (1:1)
PEG2000/H2O (1:1)
PEG4000/H2O (1:1)
PEG6000/H2O (1:1)
PEG10000/H2O (1:1)
PEG4000/H2O (1:2)
PEG4000/H2O (2:1)
PEG4000/H2O (4:1)
PEG4000/H2O (7:1)
PEG4000
11
14
52
57
40
43
17
57
40
41
4
37
51
37
39
15
55
36
40
3
30
30
30
Pure PEG4000
PEG4000/H2O (7:1)
PEG4000/H2O (7:1) Pd(OAc)2 Na2CO3
30
4
3
Na2CO3
30
30
30
33
16
0
32
15
0
PEG4000/H2O (7:1)
PEG4000/H2O (2:1)
PEG4000/H2O (2:1)
PEG4000/H2O (2:1)
PEG4000/H2O (2:1)
PEG4000/H2O (2:1)
PEG4000/H2O (2:1)
PEG4000/H2O (2:1)
CuI
Na2CO3
Na2CO3
No base
Na2CO3
K3PO4
KOH
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
30
30
31
41
67
70
66
89
99
28
40
61
62
40
88
98
120
120
120
120
120
NaF
NaF
[a] Reaction conditions: 4-bromoanisole (0.5 mmol, 1 equiv.),
K4[Fe(CN)6]·3H2O (0.33 equiv.), Pd/C (10 wt.-%, 10 mol-%), KI
(1 equiv.), base (20 mol-%), solvent (1.5 g), 140 °C, microwave irra-
diation. [b] Mass ratio in parentheses. [c] GC yield. [d] H2O
(3 equiv.) was added. [e] No KI was added. [f] NaF (1 equiv.) was
used.
of crown ethers.[18] Probably, the PEG and K+ from
K4[Fe(CN)6] formed complexes and brought the [Fe(CN)6]4–
fragment to the organic substrate. In addition, K4[Fe(CN)6]·
3H2O has a good solubility in water. Furthermore, water is
a good placeholder ligand for palladium and is particularly
effective in ligand-free reactions. Because of the high con-
centration in aqueous solvents (giving a huge excess over
the palladium catalyst), water is able to displace other labile
(Table 1, Entry 9). Nevertheless,
a lower amount of
PEG4000 had a detrimental effect on the reaction (Table 1,
Entries 5, 8). As mentioned above, in the absence of PEG,
the transformation was completely halted (Table 1, En-
try 1).
It should be noted that KI was beneficial to some extent
for the cyanation reaction of aryl bromides (Table 1, En-
try 17), because it could convert the aryl bromide into the
more reactive aryl iodide by a palladium-catalyzed halide-
exchange reaction.[19] However, when KI was used as an
additive here, incomplete conversion of the starting material
still remained a problem and even the reaction time was
prolonged to 2 h under microwave irradiation (Table 1, En-
try 19); the yield of the dehalogenation product also in-
creased at the same time. Finally, a weaker base gave some
advantages over strong bases in the conversion to the de-
sired products. As shown in Table 1, the conversion of 4-
bromoanisole increased to 99% when Na2CO3 was replaced
with NaF, and the byproducts were suppressed to less than
1% as well (Table 1, Entry 23).
Table 2. Cyanation reaction in various solvent.[a]
Entry
Solvent[b]
Conv. [%][c]
Yield [%][c]
1
2
3
4
5
6
7
8
9
NMP/H2O (2:1)
DMF/H2O (2:1)
DMAc/H2O (2/1)
Toluene/H2O (2:1)
Dioxane/H2O (2:1)
CH3CN/H2O (2:1)
H2O[d]
7
5
10
3
2
6
55
2
99
6
4
10
2
1
6
52
1
98
H2O[e]
PEG4000/H2O (2:1)
[a] Reaction conditions: 4-bromoanisole (0.5 mmol, 1 equiv.),
K4[Fe(CN)6]·3H2O (0.33 equiv.), Pd/C (10 wt.-%, 10 mol-%), KI
(1 equiv.), NaF (1 equiv.), solvent (1.5 g), 140 °C, 2 h, microwave
irradiation. [b] Mass ratio in parentheses. [c] GC yield. [d] TBAB
It is well documented that PEGs can serve as PTCs, as
the poly(ethylene oxide) chains in PEGs can form com-
plexes with the metal ions in a manner similar to that (1 equiv.) was added. [e] SDS (1 equiv.) was added.
Eur. J. Org. Chem. 2008, 3524–3528
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G. Chen, J. Weng, Z. Zheng, X. Zhu, Y. Cai, J. Cai, Y. Wan
FULL PAPER
ligands from the coordination shell of palladium,[20] par- tries 1–6). This proved that the PEGs in this reaction not
ticularly cyanide, which poisons the catalyst and blocks the only served as polar cosolvents but also as PTCs. Inspired
cationic path. Thus, it was no surprise to us that the combi- by this result, we then tested two other representative sur-
nation of water and PEGs as the solvent led to a very factants including sodium dodecyl sulfate (SDS, anionic
smooth cyanation transformation.
surfactant) and tetrabutylammonium bromide (TBAB, cat-
Because most of the palladium-catalyzed cyanation reac- ionic surfactant). As shown in Table 2, TBAB also showed
tions using K4[Fe(CN)6] as the cyanide source were carried a beneficial effect on the reaction, but this might be due to
out in highly polar solvents such as DMF, NMP, and the fact that the ammonium cation has the ability to extract
DMAc, we examined various aqueous solvents to compare the cyanide anion (Table 2, Entry 7).[21] However, SDS was
with the PEG–water system. As shown in Table 2, the use almost inefficient (Table 2, Entry 8).
of other organic cosolvents, including NMP, DMF, DMAc,
Encouraged by these results, the cyanation reactions of
dioxane, toluene, and CH3CN, in place of PEG4000 had a various aryl halides were performed under microwave irra-
dramatic detrimental effect on the reaction (Table 2, En- diation to investigate the scope and limitation of the opti-
mum conditions. The cyanation of various aryl bromides
was first examined. As summarized in Table 3, both elec-
tron-rich and electron-deficient aryl bromides were con-
verted into the corresponding aryl cyanides smoothly
Table 3. Pd/C-catalyzed cyanation of aryl bromides in aqueous
PEG.[a]
within 3 h in good-to-excellent yields. The cyanation of hin-
Table 4. Pd/C-catalyzed cyanation of aryl halides in aqueous
PEG.[a]
[a] Reaction conditions: aryl bromide (0.5 mmol, 1 equiv.),
[a] Reaction conditions: aryl bromide (0.5 mmol, 1 equiv.),
K4[Fe(CN)6]·3H2O (0.33 equiv.), Pd/C (10 wt.-%, 10 mol-%), KI K4[Fe(CN)6]·3H2O (0.33 equiv.), Pd/C (10 wt.-%, 10 mol-%), NaF
(1 equiv.), NaF (1 equiv.), water (0.5 g), PEG4000 (1 g), 140 °C, mi-
crowave irradiation. [b] Isolated yield. [c] GC yield was 97%; the
product is volatile.
(1 equiv.), water (0.5 g), PEG4000 (1 g), 2 h, microwave irradiation.
[b] Isolated yield. [c] KI (1 equiv.) was used. [d] 4-Cyanobenzamide
was isolated in 52%.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3524–3528

Pd/C-Catalyzed Cyanation of Aryl Halides in Aqueous PEG
MS (EI) and 1H NMR spectroscopic data, which were also verified
by the literature data. 1H NMR spectra were recorded at room
temperature with a Varian Mercury-Plus 300 instrument with TMS
as an internal reference. Gas chromatography–mass spectra were
recorded with a Finnegan Voyager GC–MS instrument with an
electron impact mass selective detector.
dered o-bromotoluene (Table 3, Entry 8) and other het-
eroaryl bromides only needed a slightly higher reaction
temperature (Table 3, Entries 10, 11).
4-Iodoanisole was also cyanated smoothly under the op-
timum conditions to give the corresponding aryl nitrile
(Table 4, Entry 1). We then tempted to carry out this reac-
tion under milder conditions, because aryl iodides often
showed to be more reactive than aryl bromides in transi-
tion-metal-catalyzed coupling reactions. As demonstrated
in Table 4, the cyanation reaction temperature of 4-iodoani-
sole could be slightly lowered down to 130 °C. Lower tem-
peratures led to lower yields of the target products as a
result of the incomplete consumption of the starting mate-
General Procedure for the Cyanation of Aryl Bromides under Micro-
wave Irradiation: A 10-mL glass tube was charged with Pd/C
(10 wt.-%, 53 mg, 10 mol-%), KI (83 mg, 0.5 mmol), K4[Fe(CN)6]·
3H2O (70 mg, 33 mol-%), NaF (20 mg, 0.5 mmol), and water
(0.5 g). The mixture was stirred for 3 min at room temperature.
Then, 4-bromoanisole (94 mg, 0.5 mmol) and PEG4000 (1 g) were
added. The vessel was sealed with a septum and placed into the
microwave cavity. The temperature of the mixture was ramped from
rial (Table 4, Entries 3, 4). Cyanation of other aryl iodides room temperature to 140 °C under microwave irradiation, which
took 40–60 s. Once 140 °C was reached, the reaction mixture was
held for 120 min. After allowing the mixture to cool to room tem-
perature, it was extracted with diethyl ether (3ϫ10 mL), and the
combined organic layer was dried with Na2SO4. The solvent was
removed under vacuum, and the residue was purified by
chromatography on silica gel to give the target product 4-methoxy-
benzonitrile (62 mg, yield 95%) as a white solid; the purity of the
also proceeded smoothly at 130 °C in good-to-excellent
yields within 2 h (Table 4, Entries 5–7).
Cyanation of aryl chlorides proved to be more difficult
than that of aryl bromides and iodides. Some activated aryl
chlorides, for example, 4-choroacetophone, can be partly
cyanated (Table 4, Entry 8). 4-Chlorobenzenitrile was also
able to react with K4[Fe(CN)6]. Nevertheless, only 4-cyano-
benzamide was isolated due to the hydrolysis of the desired
terephthalonitrile product (Table 4, Entry 9). Almost no cy-
anation reaction occurred by using electron-rich aryl chlo-
rides like 4-chloroanisole as the starting material (Table 4,
Entry 10).
The reusability of the Pd/C catalyst was also examined
by using the cyanation of 4-bromoanisole as a model. The
Pd/C catalyst was filtered and used in the second cycle. Un-
fortunately, the yield decreased to 15%, because of the in-
complete consumption of 4-bromoanisole.
1
compound was confirmed by H NMR and MS (EI) (see Tables 3
and 4).
All the compounds in this paper have been reported previously and
characterized by comparison with their reported data.
Supporting Information (see footnote on the first page of this arti-
cle): General procedure and spectroscopic data for the compounds
listed in Table 3.
Acknowledgments
We acknowledge the Guangdong Provincial Natural Science Foun-
dation (No. 04009718), the National High Technology Research
and Development Program of China (863 Program), No.
2006AA09Z446, and Sun Yat-Sen University Science Foundation
for financial support of this work. We also thank the CEM Corpo-
ration for providing the microwave Discover.
Conclusions
An environmentally friendly Pd/C–PEG–H2O system
was developed for the cyanation of aryl halides under mi-
crowave irradiation without the protection of an inert atmo-
sphere. A variety of aryl bromides and iodides were cya-
nated smoothly with a wide range of substrate scope in
good-to-excellent yields. It is noteworthy that nontoxic,
commercially available K4[Fe(CN)6]·3H2O was used directly
as the cyanide source without pretreatment. In addition,
there is no phosphorus- or nitrogen-containing ligand or
solvent involved. Therefore, our preliminary success was the
cue to establish a more convenient and environmental Pd-
catalyzed cyanation methodology, although the cyanation
of aryl chlorides and the reuse of the catalytic system still
remain troublesome.
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G. Chen, J. Weng, Z. Zheng, X. Zhu, Y. Cai, J. Cai, Y. Wan
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Received: March 19, 2008
Published Online: May 30, 2008
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Eur. J. Org. Chem. 2008, 3524–3528