The first example for cyanation of arylboronic acids with nontoxic and inexpensive K4[Fe(CN)6]

Article abstract of DOI:10.1246/cl.2012.719

Nontoxic and inexpensive K₄[Fe(CN)₆] is first introduced as a cyanating agent to cyanation of arylboronic acids. The present method is simple, practical, and allowed a wide range of substrates including functionalized phenylboronic acids, 1-naphthylboronic acid as well as heterocyclic boronic acids to be smoothly converted into the corresponding products in moderate to high yields.

Full text of DOI:10.1246/cl.2012.719

doi:10.1246/cl.2012.719
Published on the web June 30, 2012
719
The First Example for Cyanation of Arylboronic Acids
with Nontoxic and Inexpensive K4[Fe(CN)6]
Xinzhe Tian,* Yanpei Sun, Chuanhua Dong, Kaixuan Zhang, Tengfei Liang, Yu Zhang, and Chaodong Hou
School of Chemical Engineering and Pharmaceutics, Henan University of Science and Technology,
Luoyang 471003, Henan, P. R. China
(Received March 7, 2012; CL-120198; E-mail: zzutxz@mail.haust.edu.cn)
Table 1. Cyanation of phenylboronic acida
Nontoxic and inexpensive K4[Fe(CN)6] is first introduced
as a cyanating agent to cyanation of arylboronic acids. The
present method is simple, practical, and allowed a wide range
K4[Fe(CN)6], I2, K2CO3
B(OH)2
CN
Catalyst, 6 h, 160 °C
Entry
Catalyst
Yield/%b
of substrates including functionalized phenylboronic acids,
1-naphthylboronic acid as well as heterocyclic boronic acids to
be smoothly converted into the corresponding products in
moderate to high yields.
1
2
3
Cu(OAc)2¢H2O
15
8
3
Cu(OAc)2¢H2O/DMEDAc
Pd(OAc)2
d
4
Pd(OAc)2/PPh3
4
5
6
7
8
Cu(OAc)2¢H2O/Pd(OAc)2
Cu(NO3)2¢3H2O/Pd(OAc)2
CuSO4¢5H2O/Pd(OAc)2
CuCl2¢2H2O/Pd(OAc)2
CuO/Pd(OAc)2
CuCN/Pd(OAc)2
CuI/Pd(OAc)2
CuBr/Pd(OAc)2
78
19
0
9
4
0
4
8
5
Aryl nitriles are an important class of compounds in
synthetic chemistry because they not only constitute the key
components of a range of pharmaceuticals, agrochemicals, and
dyes,1 but also can be easily converted into various classes of
compounds such as nitrogen-containing heterocycles, aldehydes,
amines, amidines, acids, and acid derivatives.2 As a result, their
preparation has attracted considerable attention. One of the most
convenient methods for the synthesis of aryl nitriles is the direct
reaction between aryl halides and CuCN known as Rosenmund-
von Braun reaction.3 However, such a strategy does not meet
today’s criteria of sustainable synthesis owing to stoichiometric
amounts of metal waste, which has prompted chemists to
develop some transition-metal-catalyzed methods for the syn-
thesis of benzonitriles including cyanation of aryl halides,4-8
direct cyanation of heteroarenes,9 as well as electrophilic
cyanation of organolithium, organomagnesium, and organozinc
reagents.10
9
10
11
12
13
14
Cu2O/Pd(OAc)2
Cu(OAc)2¢H2O/Pd(OAc)2/DMEDAc
31
aReaction conditions: phenylboronic acid (1 mmol), K4[Fe-
(CN)6] (0.5 mmol), K2CO3 (1 mmol), I2 (1 mmol), copper salt
(0.3 mmol), Pd(OAc)2 (0.01 mmol), under N2, NMP (1.5 mL),
160 °C, 6 h. bDetermined by GC. c0.3 mmol DMEDA. d0.02 mmol
PPh3 was used (DMEDA: N,N¤-dimethyl-1,1-ethanediamine). See
Supporting Information for details.22
Another promising alternative to the synthesis of aryl
nitriles is the cyanation of more stable and readily available
arylboronic acids with benzyl thiocyanate,11 Zn(CN)2,12 p-
toluenesulfonyl cyanide,13 CuCN, or TMSCN14 as the cyanating
agent. K4[Fe(CN)6] has significant advantages over the above-
mentioned cyanide sources from environmental and economic
perspectives, and has been widely used as the cyanating agent
for the transition-metal-catalyzed direct cyanation of hetero-
arenes,15 three-component arylcyanation of internal alkynes,16
cyanation of benzyl chlorides,17 and cyanation of aryl halides,7
whereas previous attempts to introducing such a green agent to
the cyanation of arylboronic acids were unsuccessful.12 There-
fore, our attention was drawn to developing a procedure for
cyanation of arylboronic acids with nontoxic and inexpensive
K4[Fe(CN)6] as the cyanating agent, and the results are reported
here. It is worth noting that during preparation of this manuscipt,
Chang and co-workers reported a copper-mediated method for
cyanation of aryl C-B using ammonium iodide and DMF.18
Their method suffers from at least two drawbacks: the use of as
much as 2 equiv copper salt and 2 equiv acetic acid is less
attractive for applications, and the use of high-boiling solvent is
adverse for the separation and purification of the product.
In our initial study, the cyanation of phenylboronic acid
was chosen as a model reaction to demonstrate the catalytic
effectiveness of various copper and palladium compounds. As
shown in Table 1, the cyanation with 30 mol % Cu(OAc)2¢H2O
as the catalyst gave the desired cyanation product in only 15%
yield. Similar results were observed using DMEDA/Cu(OAc)2¢
H2O, a typical and effective catalyst system for the cyanation of
aryl halides with K4[Fe(CN)6].7f Both Pd(OAc)2 and PPh3/
Pd(OAc)2 were also less catalytically active. To our delight,
a combination of Pd(OAc)2 and Cu(OAc)2¢H2O improved the
cyanation to a satisfactory extent (Table 1, Entry 5). Surpris-
ingly, Pd(OAc)2 in combination with other copper salts includ-
ing Cu(NO3)2¢3H2O, CuSO4¢5H2O, CuCl2¢2H2O, CuO, CuCN,
CuI, CuBr, and Cu2O was less effective as the catalysts for the
cyanations.
After finding a suitable catalyst system, we optimized other
critical parameters such as additive, solvent, reaction time, and
temperature. Only 9% yield of benzonitrile was obtained in the
absence of inorganic base, suggesting that the use of the base
was necessary. Of the screened bases, K2CO3 was the most
effective one. The effectiveness of Na2CO3 was comparable to
that of K2CO3, whereas other bases such as KF, NaOH, and
K3PO4¢3H2O gave the desired product in poor yields. The
cyanations were highly dependent on the type of solvent. The
experimental results showed that high-boiling and polar solvents
including NMP (N-methyl-2-pyrrolidone), DMF, and DMSO
Chem. Lett. 2012, 41, 719-721
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

720
Table 2. Cyanation of various arylboronic acids catalyzed by
Cu(OAc)2¢H2O/Pd(OAc)2
were optimal in terms of the yield and selectivity of the
reactions. Attempts to develop a procedure for the cyanation
with environmentally benign water as the solvent were not
successful. For instance, only 7% yield of benzyl cyanide was
obtained under condition of H2O as the solvent, 160 °C and 6 h.
We tried to reduce the loading amount of Cu(OAc)2¢H2O
to 10 mol %, but found that this was not possible without
sacrificing product yield even if the reaction time was prolonged
to 20 h. The same was true when we tried to decrease the ratio of
K4[Fe(CN)6] to phenylboronic acid. Changing K4[Fe(CN)6] to
K3[Fe(CN)6] decreased the yield from 89% to 18% under the
conditions showed in Entry 1, Table 2. Whether decreasing or
increasing the loading amount of I2 led to a decrease in the yield
of the cyanation product, thus 1 equiv of iodine was used in the
experiments. The cyanation reactions proceeded in high yields
for as short as 2 h, yet the experimental results were less
reproducible in such a case, which prompted us to perform the
following reactions for 6 h. Our experimental results showed that
the presence of oxygen slightly prevented phenylboronic acid
from being cyanated. Thus an inert ambience condition was
selected to perform the reactions.
a
Temperature
Time
/h
Entry
Substrate
Yield/%b
/ C
°
1d
2
3
160
140
120
6
6
24
89
70
16
B(OH)2
4d
5
160
160
6
6
74
76
H3C
B(OH)2
B(OH)2
H3C
6d
7
160
140
120
6
6
90
76
69
B(OH)2
B(OH)2
8d
24
9
10
11
160
120
100
6
10
24
82
86
37
F
Cl
B(OH)2
B(OH)2
12
13
160
140
10
6
77
12
In some cases, a small amount of biphenyl from dimeriza-
tion of phenylboronic acid was obtained.19 In addition, a by-
product from iodination of phenyl cycle by cleaving the C-H
bonds was observed.20 Another iodination by-product was from
cleavage of the B(OH)2 group, revealing that the role of iodine
was to be reacted with phenylboronic acid to afford iodoben-
zene, and the cyanation was a stepwise reaction where
conversion of phenylboronic acid into iodobenzene was fol-
lowed by the cyanation of the resulting iodobenzene to yield the
desired product (Scheme 1). In accord with this hypothesis, the
iodination product was obtained in moderate yield in the absence
of K4[Fe(CN)6] (Scheme 2). Copper-catalyzed iodination of
phenylboronic acid is known,21 and our experimental results
showed that the Pd/Cu system was effective for the formation of
iodobenzene (Scheme 2). Thus the catalyst for the iodination
step may be the mixture of copper salts and palladium salts.
Copper- or palladium-catalyzed cyanation of iodobenzene is also
well known,7 and the catalytic activity of palladium is often
higher than that of copper salts.7 In fact, Pd/Cu system-mediated
cross-coupling has been reported,15 and our experimental results
showed that the cyanation of iodobenzene in the presence of Pd/
Cu system did occur. Based on these results, the catalyst for the
cyanation step may be the mixture of copper salts and palladium
salts. In addition, the CN in the product turns out to be from
K4[Fe(CN)6],7 so MCN represents K4[Fe(CN)6] in Scheme 1.
With the above results in mind, we decided to examine the
scope and limitations of the cyanation protocol by testing a
variety of representative arylboronic acids, and the results are
shown in Table 2. Several phenylboronic acids with alkyl
substituents in the benzene ring were converted into the desired
products in excellent yields (Table 2, Entries 1-8). Fluorinated
and trifluoromethylated phenylboronic acids were also suitable
substrates, and their cyanation gave the pharmaceutically
interesting products in high yields even at temperatures as
low as 120 °C (Table 2, Entries 10 and 21). Moreover, more
challenging functionalized phenylboronic acids were also
compatible with the present cyanation conditions (Table 2,
Entries 13, 17, 18, and 25). The cyanation of 1-naphthylboronic
acid required higher reaction temperature and catalyst loading
H2N
F
14d
15
160
140
120
6
6
89
88
62
B(OH)2
B(OH)2
16
24
F
17
18
140
160
6
6
35
44
O
OMe
O
B(OH)2
B(OH)2
19
20
21
22
160
140
120
100
6
6
24
24
86
90
82
46
F3C
B(OH)2
B(OH)2
23
24
160
140
12
10
58
45
MeO
O2N
25
140
6
46
B(OH)2
26c,d
27
180
160
6
12
76
48
28
29
160
140
6
6
28
37
N
B(OH)2
B(OH)2
B(OH)2
30
31
160
120
6
24
45
52
O
32
33
160
140
6
6
36
35
S
aReaction conditions: arylboronic acid (1 mmol), K4[Fe(CN)6]
(0.5 mmol), Cu(OAc)2¢H2O (0.3 mmol), Pd(OAc)2 (0.01 mmol),
K2CO3 (1 mmol), I2 (1 mmol), under N2, DMSO (1.5 mL). bDe-
termined by GC. c0.5 mmol of Cu(OAc)2¢H2O was used. dIsolated
yield is respectively 60% (Entry 1), 62% (Entry 4), 75%
(Entry 6), 71% (Entry 8), 63% (Entry 14), and 71% (Entry 26).
Chem. Lett. 2012, 41, 719-721
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

721
MCN
MI
13, 648. b) A. R. Hajipour, K. Karami, G. Tavakoli, A.
Pirisedigh, J. Organomet. Chem. 2011, 696, 819. c) C.
DeBlase, N. E. Leadbeater, Tetrahedron 2010, 66, 1098.
d) M. Islam, P. Mondal, K. Tuhina, A. S. Roy, S. Mondal,
D. Hossain, J. Organomet. Chem. 2010, 695, 2284. e) K.
Chattopadhyay, R. Dey, B. C. Ranu, Tetrahedron Lett. 2009,
50, 3164. f) T. Schareina, A. Zapf, M. Beller, Tetrahedron
Lett. 2005, 46, 2585. g) T. Schareina, A. Zapf, M. Beller,
Chem. Commun. 2004, 1388.
I2
I
CN
B(OH)2
Catalyst 1
Catalyst 2
Scheme 1. Proposed pathway for the cyanation.
0.3 mmol Cu(OAc)2·H2O, 0.01 mmol Pd(OAc)2
B(OH)2
I
1 mmol K2CO3, 1 mmol I2, N2, 1.5 mL NMP, 160 °C, 6 h
1 mmol
53%
Scheme 2. Iodination of phenylboronic acid.
8
9
For selected examples of using Zn(CN)2, see: a) H. Yu, R. N.
Richey, W. D. Miller, J. Xu, S. A. May, J. Org. Chem. 2011,
76, 665. b) M. Shevlin, Tetrahedron Lett. 2010, 51, 4833. c)
F. G. Buono, R. Chidambaram, R. H. Mueller, R. E.
Waltermire, Org. Lett. 2008, 10, 5325. d) A. Littke, M.
Soumeillant, R. F. Kaltenbach, III, R. J. Cherney, C. M.
Tarby, S. Kiau, Org. Lett. 2007, 9, 1711.
a) S. Ding, N. Jiao, J. Am. Chem. Soc. 2011, 133, 12374. b)
X. Ren, J. Chen, F. Chen, J. Cheng, Chem. Commun. 2011,
47, 6725. c) J. Kim, S. Chang, J. Am. Chem. Soc. 2010, 132,
10272. d) H.-Q. Do, O. Daugulis, Org. Lett. 2010, 12, 2517.
e) B. V. S. Reddy, Z. Begum, Y. J. Reddy, J. S. Yadav,
Tetrahedron Lett. 2010, 51, 3334. f) X. Jia, D. Yang, S.
Zhang, J. Cheng, Org. Lett. 2009, 11, 4716.
for a satisfactory yield (Table 2, Entry 26). A moderate yield
was obtained in the case of electron-rich phenylboronic acid
with a methoxy group in the meta-position of the boronic acid
group (Table 2, Entry 23).
In conclusion, nontoxic and inexpensive K4[Fe(CN)6] was
demonstrated to be an effective cyanating agent for the
cyanation of arylboronic acids with Pd(OAc)2/Cu(OAc)2¢H2O
as the catalyst. The experimental results showed that high-
boiling and polar solvents including NMP, DMF, and DMSO
were optimal in terms of the yield and selectivity of the
reactions, and the use of the inorganic base was necessary. A
wide range of substrates including fluorinated, trifluoromethyl-
ated, alkylated, chlorinated, methoxylated, and acylated phenyl-
boronic acids and 1-naphthaleneboronic acid, as well as
heteroarylboronic acids were smoothly converted into the
corresponding products in moderate to high yields in the case
of 100-180 °C and 6-24 h.
10 a) P. Anbarasan, H. Neumann, M. Beller, Chem.®Eur. J.
2010, 16, 4725. b) N. Sato, Q. Yue, Tetrahedron 2003, 59,
5831. c) Y.-q. Wu, D. C. Limburg, D. E. Wilkinson, G. S.
Hamilton, Org. Lett. 2000, 2, 795.
11 Z. Zhang, L. S. Liebeskind, Org. Lett. 2006, 8, 4331.
12 a) C. W. Liskey, X. Liao, J. F. Hartwig, J. Am. Chem. Soc.
2010, 132, 11389. b) L. Zhang, J. Wu, L. Shi, C. Xia, F. Li,
Tetrahedron Lett. 2011, 52, 3897.
The authors are thankful for the financial support from
the National Natural Science Foundation of China (Grant
No. 20003013).
13 P. Anbarasan, H. Neumann, M. Beller, Angew. Chem., Int.
Ed. 2011, 50, 519.
References and Notes
14 G. Zhang, L. Zhang, M. Hu, J. Cheng, Adv. Synth. Catal.
2011, 353, 291.
15 a) G. Yan, C. Kuang, Y. Zhang, J. Wang, Org. Lett. 2010, 12,
1052. b) X. Jia, D. Yang, W. Wang, F. Luo, J. Cheng, J. Org.
Chem. 2009, 74, 9470.
1
M. Sundermeier, A. Zapf, M. Beller, J. Sans, Tetrahedron
Lett. 2001, 42, 6707.
2
a) C. Yang, J. M. Williams, Org. Lett. 2004, 6, 2837. b) R. C.
Larock, Comprehensive Organic Transformations: A Guide
to Functional Group Preparations, Wiley-VCH, New York,
1989.
16 Y.-n. Cheng, Z. Duan, L. Yu, Z. Li, Y. Zhu, Y. Wu, Org. Lett.
2008, 10, 901.
3
4
5
a) M. Kim, S. J. Garibay, S. M. Cohen, Inorg. Chem. 2011,
50, 729. b) J. Lindley, Tetrahedron 1984, 40, 1433.
For a recent review, see: P. Anbarasan, T. Schareina, M.
Beller, Chem. Soc. Rev. 2011, 40, 5049.
For selected examples of using KCN or NaCN, see: a) A. V.
Ushkov, V. V. Grushin, J. Am. Chem. Soc. 2011, 133, 10999.
b) Y. Ju, F. Liu, C. Li, Org. Lett. 2009, 11, 3582. c) J. Zanon,
A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
2890.
17 Y. Ren, M. Yan, S. Zhao, Y. Sun, J. Wang, W. Yin, Z. Liu,
Tetrahedron Lett. 2011, 52, 5107.
18 J. Kim, J. Choi, K. Shin, S. Chang, J. Am. Chem. Soc. 2012,
134, 2528.
19 a) C. Adamo, C. Amatore, I. Ciofini, A. Jutand, H. Lakmini,
J. Am. Chem. Soc. 2006, 128, 6829. b) L. Wang, Z. Jiang, L.
Yu, L. Li, Z. Li, X. Zhou, Chem. Lett. 2010, 39, 764. c) J. F.
Cívicos, M. Gholinejad, D. A. Alonso, C. Nájera, Chem.
Lett. 2011, 40, 907.
6
7
For selected examples of using trimethylsilyl cyanide, see: a)
M. Sundermeier, S. Mutyala, A. Zapf, A. Spannenberg, M.
Beller, J. Organomet. Chem. 2003, 684, 50. b) Ch. R. Reddy,
P. P. Madhavi, A. S. Reddy, Tetrahedron Lett. 2007, 48,
7169.
20 R. M. Al-Zoubi, D. G. Hall, Org. Lett. 2010, 12, 2480.
21 G. Zhang, G. Lv, L. Li, F. Chen, J. Cheng, Tetrahedron Lett.
2011, 52, 1993.
22 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
For selected examples of using K4[Fe(CN)6], see: a) P. Y.
Yeung, C. M. So, C. P. Lau, F. Y. Kwong, Org. Lett. 2011,
Chem. Lett. 2012, 41, 719-721
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/