Direct cyanation of picolinamides using K4[Fe(CN)6] as the cyanide source

Article abstract of DOI:10.1246/cl.150111

The efficient, simple, and environment-friendly route of direct cyanation of picolinamides has been developed with nontoxic K₄[Fe(CN)₆] as the cyanide source through Pdcatalyzed C-H bond activation. A series of N-(naphthalene-1- yl)picolinamide derivatives were successfully transformed to the corresponding cyanation products. The cyanation mechanism has also been speculated.

Full text of DOI:10.1246/cl.150111

Received: February 4, 2015 | Accepted: February 25, 2015 | Web Released: March 6, 2015
CL-150111
Direct Cyanation of Picolinamides Using K4[Fe(CN)6] as the Cyanide Source
Dinghui Guan,1,2 Lu Han,1,2 Lulu Wang,1,2 He Song,1,2 Wenyi Chu,*1,2 and Zhizhong Sun*1,2
1School of Chemistry and Materials Science, Heilongjiang University, Harbin 150080, P. R. China
2Key Laboratory of Chemical Engineering Process and Technology for High-efficiency Conversion,
College of Heilongjiang Province, Harbin 150080, P. R. China
(E-mail: wenyichu@hlju.edu.cn, sunzz@hlju.edu.cn)
The efficient, simple, and environment-friendly route of
direct cyanation of picolinamides has been developed with
nontoxic K4[Fe(CN)6] as the cyanide source through Pd-
catalyzed C-H bond activation. A series of N-(naphthalene-1-
yl)picolinamide derivatives were successfully transformed to the
corresponding cyanation products. The cyanation mechanism
has also been speculated.
reagent aryl (cyano) iodonium triflates need to be equipped
under a nitrogen atmosphere and stored in a refrigerator.
An alternative reagent for direct cyanation of C-H bonds was
N-cyano-N-phenyl-p-toluenesulfonamide (NCTS);9 the reaction
carried out with the reagent also needs the inert gas atmosphere
and is incompatible with atom economy.
Although much effort and remarkable progress has been
made in this area, some drawbacks remain with these reactions.
The major drawback is the notorious toxicity of cyanating
reagents including KCN, CuCN, Zn(CN)2, and TMSCN, which
often resulted in inconvenient operations. Additionally, the
cyanating reagents for C-H bond functionalization are usually
complex and are not readily handled.
Aromatic nitriles have been attracting increasing attention
due to their presence as the structural motifs in natural products,
agrochemicals, and pharmaceuticals.1 The cyano group was also
widely applied in functional-group transformations, including
the formation of aldehydes, amines, tetrazoles, and their carboxy
derivatives.2 Aromatic nitriles are commonly synthesized by
two classical methods: Sandmeyer3 and Rosenmund-von Braun4
reactions. However, both reactions require toxic copper(I)
cyanide as the cyano source and occur under harsh conditions.
The nucleophilic cyanation of aryl halides with metal cyanide5
and TMSCN6 as cyanating reagents have emerged as alternative
routes to preparing nitriles (Scheme 1).
Potassium hexacyanoiron(II) (K4[Fe(CN)6]) as an inexpen-
sive, easily obtained, and relatively nontoxic reagent has
attracted considerable attention for the nucleophilic cyanation
of aryl halides.10 To the best of our knowledge, there are only a
few reports11 on C-H bond cyanation using K4[Fe(CN)6] as the
cyanating reagent. Consequently, we turned our attention to
developing a C-H bond activation methodology based on the use
of K4[Fe(CN)6] as a cyanide source. We report our results here.
N-(Naphthalene-1-yl)picolinamides possess good potential
bioactivities12 and are used as intermediates of agrochemicals
and pharmaceuticals. Due to the intrinsic directing effect of
picolinamides in C-H bond functionalization reactions,13 N-
(naphthalene-1-yl)picolinamide was the chosen substrate reacted
with K4[Fe(CN)6] to examine the cyanation reaction conditions
(Table 1).
Initially, the reaction was carried out under Pd(OAc)2 as
catalyst and Cu(OAc)2 as oxidant in DMSO at 130 °C, the
desired cyanation product was obtained in 72% yield after
24 h (Table 1, Entry 3). Several other oxidants were then
evaluated, and results showed that Cu(OAc)2 was superior to
BQ, Cu(OTf)2, and Cu(TFA)2 (Table 1, Entries 1-5). Among the
transition-metal catalysts we examined, Pd(OAc)2 showed the
highest activity for this reaction (Table 1, Entries 3 and 6-8).
Moreover, the use of MeCN and DMF as solvents did not
improve the yield of desired product; it was presumed that the
solubility of K4[Fe(CN)6] in these two solvents were poor
relative to DMSO (Table 1, Entries 3, 8, and 9). Yield decreased
when temperature was changed to 110 °C; it was speculated
that the main reason was that low temperature hindered the
dissociation of cyano group from K4[Fe(CN)6] (Table 1,
Entry 10). When the reaction was carried out under a N2
atmosphere, the yield decreased to 21%. Control experiments
showed that the reaction failed to give the desired product in the
absence of Pd(OAc)2 or Cu(OAc)2 (Table 1, Entries 11 and 12).
We next turned our attention to reducing the quantity of
K4[Fe(CN)6]. Since one molar equivalent of K4[Fe(CN)6]
corresponds to a sixfold excess, we tried reducing its quantity
Moreover, directing-group-assisted transition-metal-cata-
lyzed C-H bond activation reactions have enabled the direct
cyanation of aromatic C-H bonds.7 Wang and co-workers8
described the iron(II)-catalyzed direct cyanation of arenes. The
a) Nucleophilic cyanation under transition-metal catalyst
X
CN
Pd, Cu, Ni, Rh
CN- source
additive
R
R
•Toxic cyanating reagent
•Harsh reaction conditions
b) Directing groups assisted C-H cyanations:
DG
DG
CN
Pd or Cu
additive
DG=directing groups
•Complex cyanating reagents
•Inert gas atmosphere
NC OTf
I
Ph
Ts
N
CN
F3C
CF3
hypervalent iodine(III) reagent
NCTS
DFCT
Scheme 1. Different approaches to the synthesis of aromatic
nitriles derivatives.
Chem. Lett. 2015, 44, 743–745 | doi:10.1246/cl.150111
© 2015 The Chemical Society of Japan | 743

Table 1. Optimization of reaction conditionsa
Table 3. Scope of cyanation of picolinamide derivatives with
K4[Fe(CN)6]a
O
O
catalyst
oxidant
N
N
O
10 mol% Pd(OAc)
1.2 equiv Cu(OAc)
O
2
N
N
+
K4[Fe(CN)6]
NH
NH CN
2
solvent, temp.
+
K [Fe(CN) ]
4 6
NH
NH CN
DMSO, 130°C
1
2
3
Entry Catalyst
Oxidant
Solvent Temp/°C Yield/%b
4
5
1a-j
2a-j
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CuI/phen
Rh2(OAc)4 Cu(OAc)2
RuCl3
Pd(OAc)2
Pd(OAc)2
®
BQ
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
DMF
130
130
130
130
130
130
130
110
130
110
130
130
12
N.R.
72 (21c)
52
34
N.R.
60
32
42
61
0
K2S2O8
Cu(OAc)2
Cu(TFA)2
Cu(OTf)2
K2S2O8
O
N
O
O
O
N
N
N
NH CN
NH CN
NH CN
NH CN
NO
2
X
X
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
®
X = Cl 80%
X = Br 76%
X = I 70 %
X = Cl 76%
X = Br 70%
X = I 68%
2b
2c
2d
2f
2g
2h
2a 85%
2e 89%
10
11
12
DMSO
DMSO
DMSO
(78%b)
0
O
O
O
aReaction conditions: N-(naphthalene-1-yl)picolinamide (0.4 mmol),
K4[Fe(CN)6] (1 equiv), catalyst (10 mol %), oxidant (1.2 equiv) in
solvent (6 mL) for 24 h. BQ: 1,4-Benzoquinone, MeCN: acetonitrile.
N
N
N
O
N
NH CN
NH CN
NH CN
NH CN
bIsolated yield. The reaction was under a N2 atmosphere.
c
R
NO
NHAc
2
NHAc
Table 2. Optimization of the quantity of K4[Fe(CN)6]a
R = H 74%
R = Cl 73%
2j
2k
2i 85%
2l 72%
2m 70%
N
O
10 mol% Pd(OAc)2
1.2 equiv Cu(OAc)2
O
N
N
N
Cl
NH
O
N
+
K4[Fe(CN)6]
NH
NH CN
O
NH
O
NH
NH
O
NH
DMSO, 130°C
O
1n
1o
1p
1q
1r
Equivalent of
K4[Fe(CN)6]
Entry
Yield/%b
aReaction conditions:
1
(0.4 mmol), K4[Fe(CN)6] (0.25 equiv),
Cu(OAc)2 (1.2 equiv) and Pd(OAc)2 (10 mol %) in DMSO (6 mL) at
1
2
3
4
0.17
0.25
0.25
0.5
63
85 (70c)
51d
b
130 °C for 6 h. The reaction was expanded to 4 mmol scale for 1a.
position (Table 3, 2b-2d), the yield was higher than when the
location was at C-4 position (Table 3, 2f-2h). For substrates
with strong electron-withdrawing groups at C-5 and C-4
positions, the yields went up to 89% (Table 3, 2e) and 85%
(Table 3, 2i), respectively. These may be caused by the
electronic effect. To our delight, the good tolerance of halogen
atoms makes the cyanation products susceptible to conversion to
various useful functional groups by different reaction routes.
More importantly, deiodination products have not been detected
(Table 3, 2d and 2h). When introducing another directing group
(acetyl amino group) to the aromatic ring, only the C-8
cyanation product isomer can be detected (Table 3, 2l and
2m). It is suggested that the directing effect of picolinamide
was stronger than that of acetyl amino group. Especially, when
the substrate expanded to 4-mmol scale, the yield also can rise
to 70%.
Additionally, some other amides were also examined.
Unfortunately, the substrates 1n-1r failed to give the desired
cyanation products under the optimal conditions or other
conditions. The main reason was hypothesized: these structures
could not coordinate with catalyst to form cyclometalated
intermediates, which leads to the failure of the following steps
in common catalytic cycles to achieve the desired products.
76
aReaction conditions: N-(naphthalene-1-yl)picolinamide (0.4 mmol),
Pd(OAc)2 (10 mmol %), K4[Fe(CN)6], Cu(OAc)2 (1.2 equiv) in DMSO
(6 mL) for 6 h. bIsolated yield. cThe catalyst loading was reduced to
5 mol %. dThe temperature was reduced to 110 °C and the reaction was
prolonged to 24 h.
to a stoichiometric equivalent, the yield was dropped to 63%
(Table 2, Entry 1). Increasing the K4[Fe(CN)6]-to-substrate ratio
to 0.25:1 allowed us to retain an 85% yield; 70% yield of
product was obtained even when the loading of Pd(OAc)2
was decreased to 5 mol % (Table 2, Entry 2). Yield did not
improved when 0.5 equivalent of K4[Fe(CN)6] was used
(Table 2, Entry 4). As a result, the final optimal reaction con-
ditions were described as: picolinamides (0.4 mmol), Pd(OAc)2
(10 mol %), K4[Fe(CN)6] (0.25 equiv), and Cu(OAc)2 (1.2 equiv)
in DMSO (6 mL), heated at 130 °C for 6 h.
The C-H cyanation reaction was successfully extended to
various substrates 1, and the results were listed in Table 3 (see
also Supporting Information). A number of substituted 2-
picolinamides can be converted to corresponding cyanation
products in good yields. When R substituent located at C-5
744 | Chem. Lett. 2015, 44, 743–745 | doi:10.1246/cl.150111
© 2015 The Chemical Society of Japan

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Cu(I)
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Pd(OAc)2
Cu(II)
C-H
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addition
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CN
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Scheme 2. Proposed catalytic cycle.
Based on known metal-catalyzed C-H bond activation
reactions14 and our experimental results, the preliminary mecha-
nism has been speculated (Scheme 2). First, intermediate A was
formed by the coordination of Pd(OAc)2 with substrate 115 and
C-H bond cyclometalation. Then, intermediate A underwent
an oxidative addition with the free “CN” dissociated from
K4[Fe(CN)6]16 to produce the intermediate B, which was
followed by a reductive elimination to result in the cyanation
product 2 and the catalyst was regenerated under the oxidation
by Cu(II) to finish the catalytic cycle.
In conclusion, an efficient, simple, nontoxic, and environ-
ment-friendly C-H bond cyanation reaction directed by picoli-
namide was developed. A series of N-(naphthalene-1-yl)picoli-
namide derivatives were synthesized. A detailed investigation
into the reaction mechanism is currently underway.
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This work was supported by Fund of Natural Science
Foundation of Heilongjiang Province of China (No. B201208).
Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 743–745 | doi:10.1246/cl.150111
© 2015 The Chemical Society of Japan | 745