Cyanation of aryl chlorides with potassium hexacyanoferrate(II) catalyzed by cyclopalladated ferrocenylimine tricyclohexylphosphine complexes

Article abstract of DOI:10.1055/s-2007-970741

Cyanation of aryl chlorides with potassium hexacyanoferrate(II) catalyzed by cyclopalladated ferrocenylimine tricyclohexylphosphine complex has been described. This method is applicable to both activated and deactivated aryl chlorides. The corresponding aryl nitriles were isolated in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970741

LETTER
543
Cyanation of Aryl Chlorides with Potassium Hexacyanoferrate(II) Catalyzed
by Cyclopalladated Ferrocenylimine Tricyclohexylphosphine Complexes
Cyanation of
Aryl
i
Chlorid
-
es nan Cheng, Zheng Duan,* Ting Li, Yangjie Wu*
Chemistry Department, the Key Lab of Chemical Biology and Organic Chemistry of Henan Province, the Key and Open Lab of Applied
Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. of China
Fax +86(371)67979408; E-mail: duanzheng@zzu.edu.cn; E-mail: wyj@zzu.edu.cn
Received 9 October 2006
We have focused on the cyclopalladation of ferro-
Abstract: Cyanation of aryl chlorides with potassium hexacyano-
cenylimines 1 (Figure 1) and their application in organic
ferrate(II) catalyzed by cyclopalladated ferrocenylimine tricyclo-
synthesis, and found that the dimeric cyclopalladated
hexylphosphine complex has been described. This method is
ferrocenylimines were effective in the Heck reaction12
applicable to both activated and deactivated aryl chlorides. The
corresponding aryl nitriles were isolated in good to excellent yields and Suzuki reaction of aryl halides.13 The corresponding
tricyclohexylphosphine (PCy3) complex 2 (Figure 1)
showed higher catalytic activities in Suzuki coupling
reaction with aryl chlorides.14
Key words: cyclopalladium, cyanation, aryl chloride, catalysis,
coupling
Here, we would like to report the first efficient catalytic
cyanation of inexpensive aryl chlorides4,9,15,16 with potas-
sium hexacyanoferrate(II) using Pd–PCy3 complex 2a.
Aryl nitriles are of significant interest in organic chemis-
try. The versatile transformations of nitrile function make
them important intermediates in the synthesis of poly-
amides, amidines, imidoesters, biologically active mole-
cules.1,2 Moreover, aryl nitriles themselves are an integral
part of herbicides, pesticides, dyes, natural products and
pharmaceuticals.3
An initial reaction condition screening was performed on
the model cyanation reaction of 4-chlorotoluene with
potassium hexacyanoferrate(II). In this study the perfor-
mance of different cyclopalladium compounds which
have been developed in our group, such as 1a,b,17 their
combination with triphenylphosphine and the tricyclohex-
ylphosphine adducts 2a–d14 were examined. The typical
results were listed in Table 1. The dimeric catalysts 1a
and 1b showed low activities (Table 1 entries 1–3). When
10 mol% triphenylphosphine and 1 mol% 1a were added
to the reaction mixture, the conversion of 4-chlorotoluene
was increased dramatically to 84% (Table 1 entry 4).
Pd-catalyzed cyanation of aryl halides has been studied
extensively. Generally, the cyanide sources used in the
cyanation reaction were alkali cyanides (KCN or NaCN),
acetone cyanohydrin, TMSCN (trimethylsilylcyanide)
and Zn(CN)2.4,5 Recently, potassium hexacyanoferrate(II)
{K4[Fe(CN)6]} has been used as a cheap and environ-
ment-friendly cyanation reagent for catalyzed cyanation
of aryl halides. Beller and co-workers reported the first
example of palladium-catalyzed cyanation of aryl halides
using potassium hexacyanoferrate(II).6,7 Weissman im-
proved this method and developed a ligand-free cyanation
method.8 Using 1,8-bis(diisopropylphosphino)triptycene
as a ligand, Grossman and Gelman developed a mild and
air-stable cyanation reaction.9 Very recently, the palladi-
um-catalyzed cyanation in ionic liquids under microwave
irradiation using potassium hexacyanoferrate(II) was re-
ported.10 The microwave irradiation reduced the reaction
time considerably and the catalyst system could be reused
several times. Copper-catalyzed cyanation of aryl halides
using potassium hexacyanoferrate(II) has also been re-
ported.11 However, all these methods have been limited to
aryl bromides or iodides. Only cyanation of activated aryl
chlorides have been reported in these reports. To the best
of our knowledge, no efficient method involving potassi-
um hexacyanoferrate(II) has been reported for cyanation
of aryl chlorides.
Me
Me
N
R
N
R
Pd
Cl
Fe
Fe
Pd
Cl
PCy3
2
2a R = 4-EtOC6H4
2b R = 4-MeOC6H4
2c R = 4-MeC6H4
2d R = c-Hex
1a R = 4-MeC6H4
1b R = 4-MeOC6H4
Figure 1 Catalysts of cyclopalladated ferrocenylimine
Increasing the loading of 1a to 2 mol% did not notably
improve the conversion (Table 1 entry 5). This result en-
couraged us to examine the electron-rich tricyclohexyl-
phosphine (PCy3) as a ligand to facilitate the aryl–Cl bond
activation.18 To our delight, tricyclohexylphosphine
complexes showed excellent performance. The cyanation
reaction proceeded very well and excellent conversions
(98%) were obtained in the presence of 2 mol% of 2a
(Table 1 entry 7). Further examinations revealed that
2b–d had the similar activities. In the presence of 2 mol%
2b–d, respectively, more than 97% 4-chlorotoluene was
converted into the corresponding cyanation products
SYNLETT 2007, No. 4, pp 0543–0546
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-970741; Art ID: W20806ST
© Georg Thieme Verlag Stuttgart · New York

544
Y.-n. Cheng et al.
LETTER
(Table 1 entries 8–10). This indicated that the presence of obtained with DMAc/Na2CO3, which was used for Pd-
triphenylphosphine (PPh3) and tricyclohexylphosphine catalyzed cyanation of aryl bromides with potassium
(PCy3) facilitated the oxidative addition to C–Cl bond and hexacyanoferrate(II)8 (Table 1 entries 13 and 14). Both
protected the active palladium center from deactivation in NMP/Na2CO3 and DMF/K3PO4 were found to be effec-
the catalytic cycle. This could be confirmed by the fact tive. Reactions in NMP/Na2CO3 showed higher efficiency
that the reaction mixture rapidly changed into black when (Table 1 entries 6, 7, and 17). Due to high bond energy of
it was heated without phosphine. Beller and co-workers C–Cl of aryl chloride,7,18 a relatively higher reaction
reported that a decreased amount of catalyst could inhibit temperature (140 °C) was essential for successful con-
agglomeration of molecular palladium complexes to ‘pal- versions.
ladium black’ and led to higher yield of cyanation reaction
After optimizing the reaction conditions, we studied the
of aryl bromide.6 But in our reaction, only low conver-
scope and the possible limitations of this reaction. Gener-
sions were obtained with decreased amount of 2a (Table 1
ally, 2 mol% 2a and 0.22 equivalents K4[Fe(CN)6]·3H2O
entry 19).
were used. The reaction was conducted in 1 mL NMP
Next, we investigated the effect of solvent and base. The combined with 1 equivalent Na2CO3 at 140 °C for 16–24
combination of DMF/Cs2CO3, which had been applied hours.19 The results are summarized in Table 2. As
extensively to Suzuki reaction of aryl chloride,13 was not expected, activated aryl chlorides 3g–k were smoothly
suitable for our procedure and provided only 35% conver- converted into the corresponding 4g–k in good yields
sion (Table 1 entry 16). Only moderate conversion was (Table 2 entries 7–9, and 11). Electron-neutral 3a, mildly
Table 1 Cyanation of 4-Chlorotoluene with K4[Fe(CN)6] in the Presence of Cyclopalladium Catalysta
K4[Fe(CN)6]⋅3H2O/cat.
Me
Cl
Me
CN
solvent, base, 140 °C
Entry
1
Solvent
Base
Catalyst
Catalyst loading (Pd mol%) Conversion (%)b
NMPc
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMAcd
DMAc
DMF
DMF
DMF
NMP
NMP
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
1a
1
5
9
2
1a
2
3
1b
2
3
4
1a + PPh3 (10%)
1
84
87
89
98
97
97
97
85
62
75
72
71
35
89
82
32
5
1a + PPh3 (10%)
2
6
2a
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
2a
2a
1
7
2
8
2
9
2
10
11
12
13
14
15
16
17
18
19
2
2
t-BuOK
Na2CO3
K2CO3
2
2
2
Na2CO3
Cs2CO3
K3PO4
2
2
2
Na2CO3
Na2CO3
0.5
0.1
a Reaction conditions: 1 mmol 4-chlorotoluene, 0.22 mmol K4[Fe(CN)6]·3H2O, 1 mL solvent, 1 mmol base, 140 °C for 18 h.
b Conversion is determined by GC using n-undecane as an internal standard.
e NMP: N-methyl-2-pyrrolidone.
d DMAc: N,N-dimethylacetamide.
Synlett 2007, No. 4, 543–546 © Thieme Stuttgart · New York

LETTER
Cyanation of Aryl Chlorides
545
electron-rich 3b and 3d worked well and moderate to vealed that the steric hindrance of substrates had little ef-
good yields were obtained (Table 2 entries 1, 2, and 4). fect on this cyanation reaction. 2-Chlorotoluene (3b), 2,6-
Remarkably, even electron-rich 3f also showed good reac- dimethylchlorobenzene (3c) and 1-chloronaphthalene (3l)
tivity, the corresponding 4f could be isolated in 66% yield afforded products in good to excellent yields (Table 2
(Table 2 entry 6). Though only 47% yield was obtained entries 2, 3, and 12). Surprisingly, although a nitro group
for 4-chloroanisole (3e) under the optimized conditions, can activate the C–Cl bond of chloride-substituted
the result could be improved to 72% when DMAc/K2CO3 nitrobenzene in most Pd-catalyzed C–C, C–N coupling
system was used (Table 2 entry 5). 3-Chloropyridine (3j) reactions,14,20,21 however, 4-nitrochlorobenzene (3m) did
also exhibited satisfactory reactivity and 4j was isolated in not give any desired product in this cyanation reaction.
82% yield (Table 2 entry 10). Further investigation re-
Table 2 Cyanation of Aryl Chlorides Catalyzed by Cyclopalladium Compound 2aa
K4[Fe(CN)6 ]⋅3H2O/2a (2 mol%)
Cl
CN
NMP, Na2CO3, 140 °C
R
R
4
3
Entry
1
Aryl chloride
Time (h)
18
Product
Yield (%)b
81
3a
3b
4a
4b
Cl
CN
Me
Cl
Me
CN
2
3
18
18
79
80
Me
Cl
Me
Me
CN
Me
3c
4c
4
5
3d
3e
18
24
4d
4e
71
Me
Cl
Me
CN
47 (72)c
MeO
Cl
MeO
CN
OMe
Cl
OMe
CN
6
3f
24
4f
66
7
8
9
3g
3h
3i
16
16
16
4g
4h
4i
81
80
88
Me(O)C
MeO2C
EtO2C
CN
Me(O)C
MeO2C
EtO2C
Cl
Cl
CN
Cl
CN
10
11
3j
18
16
4j
82
73
Cl
CN
N
N
3k
4k
NC
Cl
NC
CN
CN
Cl
12
13
3l
16
24
4l
97
0
3m
4m
O2N
Cl
O2N
CN
a Reaction conditions: 1 mmol substrate, 0.22 mmol K4[Fe(CN)6]·3H2O, 2 mol% catalyst, 1 mmol Na2CO3 and 1 mL NMP, 140 °C reaction
temperature.
b Isolated yield.
c Yield with DMAc/K2CO3 is given in parentheses.
Synlett 2007, No. 4, 543–546 © Thieme Stuttgart · New York

546
Y.-n. Cheng et al.
LETTER
(13) Zhang, J. L.; Zhao, L.; Song, M. P.; Mak, T. C. W.; Wu, Y.
J. J. Organomet. Chem. 2006, 691, 1301.
(14) Gong, J. F.; Liu, G. Y.; Du, C. X.; Zhu, Y.; Wu, Y. J. J.
Organomet. Chem. 2005, 690, 3963.
(15) Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J. Tetrahedron
Lett. 2001, 42, 6707.
(16) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
(17) Huo, S. Q.; Wu, Y. J.; Du, C. X.; Zhu, Y.; Yuan, H. Z.; Mao,
X. A. J. Organomet. Chem. 1994, 483, 139.
In summary, we developed an efficient method for
cyanation of less costly aryl chloride with environmental-
ly benign cyanide source – potassium hexacyano-
ferrate(II). A variety of activated or deactivated aryl
chlorides can be successfully converted into correspond-
ing cyanides.
Acknowledgment
(18) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176.
(19) General Procedure.
We thank the National Natural Science Foundation of China (No.
20472074) and the Innovation Fund for Outstanding Scholar of
Henan Province (No. 0621001100) for financial support. We thank
Dr. Weiguo Zhu, Mr. Janxun Kang for their excellent analytical
support and Prof. Junfang Gong, Xiuling Cui, Dr. Chen Xu for their
help.
A reaction vessel was charged with 1 mmol Na2CO3, 0.22
mmol K4[Fe(CN)6]·3H2O and 2% mol catalyst 2a. The
vessel was then evacuated and backfilled with N2 four times.
Then, 1 mmol aryl chloride in 1 mL NMP was added to the
vessel. The mixture was heated at 140 °C for 16–24 h. The
suspension was cooled down to r.t., diluted with 5 mL
CH2Cl2 and washed with 5 mL H2O. The aqueous layer was
extracted twice with CH2Cl2 (3 mL) and the combined
organic layers were dried over MgSO4. After evaporation of
the solvents the residue was subjected to TLC (hexane–
EtOAc). All prepared compounds were known and
identified by 1H NMR, 13C NMR and MS.
References and Notes
(1) Larock, R. C. Comprehensive Organic Transformations. A
Guide to Functional Group Preparation; VCH: New York,
1989.
(2) Cristau, H. J.; Ouali, A.; Spindler, J. F.; Taillefer, M. Chem.
Eur. J. 2005, 11, 2483.
Selected Data.
Compound 4c: 1H NMR (400 MHz, CDCl3): d = 2.53 (s, 6
H), 7.11 (d, J = 7.7 Hz, 2 H), 7.34 (dd, J = 7.7 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): d = 20.8, 113.3, 117.3, 127.3,
132.1, 142.1 ppm. MS (ESI): m/z = 154.1 [M + Na]+.
Compound 4e: 1H NMR (400 MHz, CDCl3): d = 3.87 (s, 3
H), 6.95 (d, J = 8.9 Hz, 2 H), 7.58 (d, J = 8.9 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3): d = 55.3, 103.7, 114.5, 119.0,
133.7, 162.6 ppm. MS (ESI): m/z = 156.0 [M + Na]+.
Compound 4i: 1H NMR (400 MHz, CDCl3): d = 1.42 (t,
J = 7.2 Hz, 3 H), 4.42 (q, J = 7.1 Hz, 2 H), 7.74 (d, J = 8.3
Hz, 2 H), 8.14 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (100
MHz, CDCl3): d = 14.0, 61.6, 116.0, 117.8, 129.8, 131.9,
134.1, 164.7 ppm. MS (ESI): m/z = 197.8 [M + Na]+.
Compound 4j: 1H NMR (400 MHz, CDCl3): d = 7.45 (m, 1
H), 7.98 (m, 1 H), 8.83 (m, 1 H), 8.91 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): d = 110.3, 116.5, 123.6, 139.3, 152.5,
153.0 ppm. MS (ESI): m/z = 105.0 [M + H]+.
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Synlett 2007, No. 4, 543–546 © Thieme Stuttgart · New York