Palladium-Catalyzed Cyanation of Aryl Halides Using Formamide and Cyanuric Chloride as a New “CN” Source

Article abstract of DOI:10.1002/ejoc.202000117

A new source of “CN” employing formamide and cyanuric chloride is introduced for the cyanation reactions. The treatment of formamide and 2,4,6-trichloro-1,3,5-triazine (TCT; cyanuric chloride) afforded an efficient cyanating agent which it can be used as a nontoxic, readily available, and non-expensive reagent in the cyanation transformations. In this study, palladium-catalyzed cyanation of aryl halides was successfully accomplished using this new “CN” source in high yields.

Full text of DOI:10.1002/ejoc.202000117

A Journal of
Accepted Article
Title: Palladium-Catalyzed Cyanation of Aryl Halides using Formamide
and Cyanuric Chloride as a New “CN” Source
Authors: Esmaeil Niknam, Farhad Panahi, and Ali Khalafi-Nezhad
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000117
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000117
Supported by

10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
Palladium-Catalyzed Cyanation of Aryl Halides using Formamide
and Cyanuric Chloride as a New “CN” Source
Esmaeil Niknam, [a] Farhad Panahi, * [a] and Ali Khalafi-Nezhad* [a]
[a]
E. Niknam, Prof. Dr. F. Panahi, Prof. Dr. A. Khalafi-Nezhad
Department of Chemistry, College of Sciences
Shiraz University
Shiraz 71454, Iran
E-mail: Panahi@shirazu.ac.ir; khalafi@chem.susc.ac.ir
URL: F. Panahi https://scholar.google.com/citations?hl=en&user=sYuOPlwAAAAJ
URL: A. Khalafi-Nezhad https://scholar.google.com/citations?hl=en&user=TBzpC54AAAAJ
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: A new source of “CN” employing formamide and cyanuric
chloride is introduced for the cyanation reactions. The treatment of
formamide and 2,4,6-trichloro-1,3,5-triazine (TCT; cyanuric chloride)
afforded an efficient cyanating agent which it can be used as a
nontoxic, readily available and non-expensive reagent in the
cyanation transformations. In this study, palladium-catalyzed
cyanation of aryl halides was successfully accomplished using this
new “CN” source in high yields.
as NaCN, KCN, CuCN, K4Fe(CN)6 and Zn(CN)2 are well known
in the cyanation reactions. In the case of organic cyanide
sources, there are good results with cyanating agents such as
cyanohydrin, acetonitrile, malononitrile and benzyl cyanide.1-3
However, some of the available cyanide sources suffer from
some drawbacks to be used in cyanation reactions including
high toxicity, low solubility, less reactivity, high sensitivity to
moisture, high pricing, and formation of metal wastes in a
stoichiometric amount.4 Due to these limitations, the discovery of
new sources of “CN”, especially its in situ generation from
simple and readily available regents, is highly considered in
recent years.5-11 The safety of these combined cyanating
reagents has attracted much attention and has made it an
important topic in this field.8a,c,9b Yu’s group reported the use of
nitromethane as the cyanide source for the cyanation of 2-
phenylpyridine.5 A combined cyanide source using ammonia and
DMF was disclosed for the C-H cyanation of 2-arylpyridine,
electron-rich arenes, aryl boron compounds, indoles and
organosilanes.6 DMF was also used as a cyanide source alone.7
Also, a combination of DMF and NH4X (X = HCO3, I) was
illustrated for the cyanation of aryl halides.8 In addition, dimethyl
sulfoxide (DMSO) in combination with NH4HCO3 was also
worked well as CN source for the cyanation of the 3-position of
indole.9a DMSO in combination with urea in the presence of
CuF2 was used as “CN” source in the cyanation of aryl iodides.9b
Formamide in the presence of POCl3 was also produces a
cyanide source for the cyanation of aryl halides (Scheme 1, a).10
Very recently a nickel-catalyzed process was developed using
formamide to generate “CN” source for cyanation reactions
(Scheme 1, b).11 In this study we disclosed a new nontoxic
cyanide source using combination of formamide and 2,4,6-
trichloro-1,3,5-triazine (TCT; cyanuric chloride) (Scheme 1, c).
This precursor is an efficient and operationally simple cyano
source that it generates cyanuric acid as a byproduct which is
simply removable from the reaction mixture.
Introduction
Benzonitriles are an important class of organic compounds with
a broad applications which serve as raw material in pharmaticual,
natural products, advanced materials, dyes and agriculture
chemicals (Figure 1).1
CN
NC
O
O
N
NH
H2N
CN
Me
OH
N
N
O
N
N
HN
N
H
Me
NC
Bunitrolol
(beta-adrenergic antagonist)
Rilpivirine
(anti HIV)
Alogliptin (anti-diabetic)
O
NC
N
OH
S
CN
NC
B
NH2
11CH3
O
N
N
O
CH3
DASB
Crisaborole
(for the treatment of eczema) Perampanel (antiepileptic)
(a radioligand in neuroimaging)
Figure 1. The chemical structure of some biologically important benzonitrile
derivatives
These compounds also have been used as valuable
precursors for the synthesis of amines, aldehydes, ketones,
carboxylic acids, imines and etc.2 To prepare benzonitrile
derivatives, different reactions and methodologies were
developed. Sandmeyer reaction, Rosenmund-von Braun
reaction, transition metal catalyzed cyanation reactions and C-H
bond functionalization of arenes are well-known aryl cyanation
methods.3 In the cyanation reactions, both organic and inorganic
cyanide sources have been used. Metal cyanating agents such
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10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
O
14
15
16
17
18
19
20
21
22
23
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
-
Pd/C(3)
Pd/C(3)
130
130
130
130
130
130
130
120
145
130
40[c]
78[c,d]
52[c,e]
84[c,f]
83[c]
C
POCl3
[Ni]
a)
b)
N
H2
H
CN
Dinesh et al.
Yang et al.
"
" source
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
O
Pd/C(3)
C
N
H2
H
CN
"
" source
Pd/C(3.5)
Pd/C(4.0)
Pd/C(3.5)
Pd/C(3.5)
Pd/C(3.5)
Pd/C(3.5)
Pd/C(3.5)
O
TCT
Pd
C
CN
86[c,g]
83[c,h]
78[c,i]
84[c]
c)
"
" source
This work
N
H2
H
Scheme 1. The use of formamide as “CN” precursor.
In continuation of our program on application of TCT in
organic transformations,12,13 it was found that its combination
with formamide produces a stable salt, which it can be used as a
safe, easily handling reagent in the cyanation reactions. To the
best of our knowledge there is no report in the literature on the
use of this reagent in the cyanation reactions. In this study, TCT-
formamide salt was used for the cyanation of aryl halides using
a Pd-catalyzed process.
45[c,i]
[a] Reaction conditions: 4-bromoanisole (1.0 mmol), TCT-formamide salt (0.35
mmol), base (2.0 mmol), catalyst (3.0 mol %), PPh3 (6.0 mol %), and solvent
(2.0mL). [b] Isolated yield. [c] TCT was used instead of TCT-formamide salt.
[d] 6.0 mol % dppe used as ligand. [e] No ligand was used. [f] 7.0 mol % of
PPh3 used as ligand. [g] 1.5 mmol of base was used. [h] 1mmol base was
used. [i] 30 mol% of PPh3 ligand was used.
Initially, in DMF solvent in the absence of any direct cyanide
source 70% yield of 3a was produced (Table 1, entry 1). By
change of solvent to formamide, the reaction yield was
enhanced to 78 % (Table 1, entry 2). Other solvents were also
checked and no superiority in the reaction yield was observed,
thus formamide was used as solvent for this reaction (Table 1,
entries 3-6). By distinguishing formamide as the best solvent for
this reaction (among tested solvents) we hypothesized the
cyanation reaction using one-pot approach. To our surprise the
one-pot procedure (using TCT instead of TCT-formamide salt)
worked well and afforded to 80% of isolated product after 12h
(Table 1, entry 7). Then, different sources of palladium were
used, but no superiority was observed in the reaction yield
(Table 1, entries 8 & 9). Therefore, Pd/C as an available and
cheap palladium catalyst source was selected for this reaction.14
The type of base was also investigated and K2CO3 as the
best one was distinguished (Table 1, entries 10-14). No change
in the reaction yield was observed by the use of 1,2-bis
(diphenylphosphino) ethane (dppe) ligand and consequently
PPh3 as readily available ligand was selected (Table 1, entry 15).
In the absence of phosphine ligand the reaction yield was
decreased to 52 % (Table 1, entry 16). The catalyst loading was
evaluated and 3.5 mol% of the catalyst recognized as optimum
(Table 1, entries 17 & 18). The amount of base was also
checked and result shows that 1.5 mmol of K2CO3 was sufficient
to obtain high yield (Table 1, entry entries 19 & 20). It seems
that, the reaction temperature of higher than 130 ºC is essential
for the formation of cyanide source from TCT and formamide, so
that the reaction yield was decreased at lower temperature
(Table 1, entry 21). In addition, at higher temperature of 140 ºC,
no enhancement in the reaction yield was observed (Table 1,
entry 22).
Results and Discussion
We investigated the cyanation of 1-bromo-4-methoxybenzene
(1a) using TCT-formamide reagent (2a) in the presence of Pd/C
catalyst system as a model reaction (Table 1).
Table 1. Optimization of the reaction conditions [a]
CN
Br
Cl
N
Cl
O
Catalyst (3.0 mol %)
NH2
+
N
N
C
H
Ligand (6.0 mol %)
Solvent (2 mL)
Base (2 eq)
Cl
OMe
OMe
1a
130 oC, 12h
2a
3a
Catalyst
Yield 3a
entry
solvent
base
Temp(ºC)
(mol %)
(%)[b]
1
2
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Pd/C(3)
Pd/C(3)
Pd/C(3)
Pd/C(3)
Pd/C(3)
Pd/C(3)
Pd/C(3)
Pd(OAc)2(3)
PdCl2(3)
Pd/C(3)
Pd/C(3)
Pd/C(3)
Pd/C(3)
130
130
130
130
130
130
130
130
130
130
130
130
130
70
78
HCONH2
DMAC
3
66
4
Toluene
DMSO
30
5
64
6
PEG-300
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
HCONH2
55
7
80[c]
71[c]
74[c]
62[c]
78[c]
75[c]
74[c]
8
9
In an experiment in order to show that the reaction is
homogeneous or heterogeneous in practice, the amount of PPh3
was increased to 30 mol% and it was found a remarkable
decreasing in the reaction yield (Table 1, entry 23). Since, the
PPh3 ligand can strongly block the active centres of the Pd
catalyst, representing a homogeneous Pd-catalyzed cyanation
process.
10
11
12
13
Na2CO3
Cs2CO3
Et3N
2
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10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
In order to further prove that the “CN” unit is come from
formamide component, some other experiments were also
accomplished and results are summarized in Scheme 2. In the
absence of TCT, no benzonitrile product observed,
demonstrating the activation role of TCT to form “CN” source.
No product was observed using only TCT or 1,3,5-triazine-2,4,
6-triol (4; as byproduct of the reaction)15 confirming that they
cannot act as source of “CN”, alone. In this light, 2,4,6-triamino-
1,3,5-triazine was also checked, possibly it can form “CN”
source, but no aryl nitrile product was detected. These
experiments confirmed that the “CN” unit is not originated from
triazine ring. Based on our experiments, only, using both TCT
and formamide components together the cyanation reaction was
carried out. The release of cyanide ion was distinguished using
picrate impregnated indicator paper upon heating formamide
and TCT under optimized reaction conditions. By increasing the
amount of TCT to 0.5 equivalents the reaction yield was
enhanced to 90%. It is not possible to obtain aryl cyanide using
DMF instead of formamide under optimized reaction
conditions.13
In order to show the formation of cyanide ion using TCT-
formamide salt, some NMR experiments was accomplished. In
an experiment TCT-formamide was treated with base in DMSO-
d6 solvent and it was heated until 130 °C and it was analyzed by
NMR. The 13C NMR show that the peak at 150.0 ppm which is
related to the formamide part was completely removed and a
peak at 163.1 ppm remained with a little change in chemical shift,
corresponding to the triazine ring. This experiment has same
results, when in addition to base, Pd source was also used. Also
some peaks between 125-130 ppm were observed which can be
corresponded to the cyanide ion species. More importantly, no
peaks observed in the range of 160 ppm, which is related to the
cyanate (-OCN) formation. The generation of cyanate is possible
through the oxidation of TCT-formamide reagent, to be served
as cyanating agent (see supporting information).14
derivatives were tested and high yields of products were
obtained. Our results showed that, the type of substituents in
viewpoint of the electronic and/or steric difference is not more
important factor in the cyanation of aryl halides using TCT-
formamide salt. Also, the optimized reaction conditions are
compatible with a variety of functional groups such as amine
(3c,k,n,o,w,x,y), halogens (3e,f,q), keto (3g,u), aldehyde (3h),
nitro (3j,p,q), cyano (3m) and ether (3a,ac-ag). The position of
substituents on aromatic ring not have remarkable effects on the
reaction yields (3k,n,o).
In the case of bihalides the cyanation were selectively
accomplished on more active C-halogen bond to afford
corresponding
halogen-substituted
benzonitriles
(3e,f,q).
Polyaromatic aryl halides were easily cyanated using this new
“CN” source under optimized conditions without any problem
(3r-t). Some of the synthetic aryl halides incorporating various
heterocycles including morpholine (3w), piperidine (3x),
piperazine (3y), imidazole (3z), indole (3aa), carbazole (3ab)
were examined in the cyanation reaction and the corresponding
nitrile derivatives produced in good to excellent yields. Moreover,
bromo-functionalized aryl-aryl ether compounds afforded the
aryl-nitrile products (3ad-ag). Under optimized reaction
conditions aryl chloride derivatives were also checked and
moderate to good yields of products were obtained (3h,j,p).
Cl
N
Cl
Pd/C (3.5 mol%)
PPh3 (7.0 mol%)
Ar
CN
Ar
X
+
N
N
R
R
C
N
H2 (2.0 mL)
H
O
Cl
K2CO3 (1.5 mmol)
130 (oC), 12h
1 mmol
CN
0.50 mmol
NO2
CN
NH2
H2
N
R
CN
O2N
CN
3n: X = Br, 69%
3a: R = OMe, X = I, 87 %
X = Br, 86 %
3b: R = Me, X = Br, 82%
3p
: X = Br, 89%
X = Cl, 78%
3o
: X = Br, 64%
3c
: R = NMe2, X =Br, 80%
CN
CN
3d: R = H, X = I, 80%
O2
Cl
N
X = Br, 77%
3e: R = Cl, X = I, 85%
CN
X = Br, 79%
3f
: R = Br, X = Br, 70%
3q: X = Br, 74%
3r: X =Br, 91%
3s: X = Br, 90%
3g: R = COCH3, X = Br, 95%
3h
: R = CHO, X = Br, 87%
X = Cl, 77%
Br
CN
O
CN
HO
N
OH
Cl
N
Cl
3i
: R = CF3, X = Br, 90%
3j: R = NO2, X = I, 90%
X= Br, 81%
Pd/C (3.5 mol %)
+
+
N
N
N
N
PPh3 (7.0 mol %)
HCONH2 (2 mL)
K2CO3 (1.5 mmol)
130 oC, 12h
NC
3u: X = Br, 85%
X = Cl, 76%
3t: X = Br, 85%
OH
3k
: R = NH2, X = I, 65%
OMe
"
Cl
OMe
3l: R = OH, X = I, 75%
3m
4
3a
: R = CN, X = Br, 86%
[a]
CN
[a]
Ph
N
N
3a
CN
(%)
CN
N
CN
CN
" source
3a
CN
" source
"
(%)
O
N
3y: X = Br, 85%
3v
: X = Br,91%
HCONH2
3x
: X = Br, 87%
0
TCT
TCT
(0.35 mmol)
HCONH2
(0.5 mmol) HCONH2
+
85
3w X = Br, 88%
+
TCT (0.5 mmol)
0
90
N
CN
N
CN
N
CN
PhO
N
CN
0[b]
0[c]
1,3,5-triazine-2,4,6-triol (4)
(0.6 mmol)
HCONH2
+
90
TCT
3ac: X = Br, 90%
3z X = Br, 15h, 82%
3aa
X = Br, 86%
Ph
TCT(0.5 mmol)
HCONMe2
+
3ab
2,4,6-triamino-1,3,5-triazin
: X = Br, 15h, 84%
0[d]
CN
CN
O
Scheme 2. Control experiments for the cyanation of aryl halides using TCT-
formamide as “CN” source. Reaction conditions: 4-bromoanisole (1.0 mmol),
TCT (0.35-0.6 mmol), K2CO3 (1.5 mmol), Pd/C (3.5 mol %), 7.0 mol % PPh3,
formamide (2.0 mL). [a] Yields corresponds to the isolated products. [b] 0.5
mmol of 4 was used as “CN” source. [c] 0.5 mmol of 2,4,6-triamino-1,3,5-
triazin was used as “CN” source. [d] DMF was used as solvent.
CN
O
O
CN
O
3ad: X = Br, 88%
3ag: X = Br, 89%
3ae X = Br, 92%
3af: X = Br, 91%
Scheme 3. Synthesis of aryl cyanides using TCT and formamide as
a
combined cyanide source. Reaction conditions: aryl halide (1.0 mmol), TCT
(0.5 mmol), K2CO3 (1.5 mmol), catalyst (3.5 mol %), PPh3 (7.0 mol %) and
formamide (2.0 mL) at 130 oC. Yield corresponds to isolated products.
With the optimized cyanation conditions in our hand, the
substrate scope was investigated (Scheme 3). Cyanation of 1-
bromo-4-methoxybenzene and its iodo analog afforded to 3a in
high yields. Then, different bromobenzene and iodobenzene
In order to show that TCT-formamide slat is also effective in
the cyanation reaction as an alternative for the in situ method we
3
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10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
also investigated the cyanation of some aryl halides TCT-
formamide slat and results are summarized in Scheme 4. As
shown in Scheme 4, the reaction yields are same to the in situ
method and in some cases the yield is better.
Experimental Section
General
Chemicals were purchased from Fluka and Aldrich companies and used
without further purification. The known products were characterized by
comparison of their spectral and physical data with those reported in the
literature. 1H (250 MHz), (400MHz), (500 MHz) and 13C NMR (62.5 MHz),
(100MHz), (125 MHz) spectra were recorded on a Brucker (250 MHz)
Avance DRX and Brucker (400 MHz) Avance DRX in deutrated solvents.
FT-IR spectroscopy (Shimadzu FT-IR 8300 spectrophotometer), were
employed for characterization of the products. Melting points were
determined in open capillary tubes in a Buchi melting point B-545. The
reaction monitoring was accomplished by TLC on silica gel PolyGram
SILG/UV254 plates. Column chromatography was carried out on
H
Pd/C (3.5 mol%)
N
O
N
C
H
Ar
CN
Ar
X
+
PPh3 (7.0 mol%)
formamide (2.0 mL)
K2CO3 (1.5 mmol)
130 (oC), 12h
R
R
N
N
H
Cl
1 mmol
0.50 mmol
CN
F3
C
CN
CN
MeO
CN
3b: X = Br, 85%
Me
3i
: X = Br, 88%
3a: X = Br, 83%
3d: X = Br, 82%
CN
CN
O2N
CN
−230 mesh).
columns of silica gel 60 (70
3j
: X = Br, 92%
3v
: X = Br,88%
3r: X =Br, 88%
Synthesis and Characterization of TCT-formamide salt (I). Into two-
necked round-bottomed flask (10 mL) equipped with a condenser, TCT
(0.18 g, 1.0 mmol), and formamide (4.0 mL) was added and the mixture
was stirred for 6h at 100oC. After allowing the mixture to cool down to
room temperature, precipitate was filtered and then washed with acetone
(3×10 mL). The purified product was dried in an oven at 100 oC for 12 h
to afford the TCT-formamide salt (I) (0.30 g, 94%) as a brown solid. This
compound is soluble in water and DMSO and insoluble in ethyl acetate
and acetone.1H NMR (500 MHz, DMSO) δ 11.13 (s, 3H), 7.94 (dd, J =
13.5, 1.7 Hz, 1H), 7.64 – 7.04 (m, 5H).13C {1H} NMR (126 MHz, DMSO) δ
Scheme 4. Synthesis of aryl cyanides using TCT-formamide reagent.
Reaction conditions: aryl halide (1.0 mmol), TCT-formamide (0.5 mmol, 0.12
g), K2CO3 (1.5 mmol), catalyst (3.5 mol %), PPh3 (7.0 mol %) and formamide
(2.0 mL) at 130 oC. Yields correspond to isolated product.
A plausible reaction mechanism for the cyanation of aryl
halides using TCT-formamide reagent was proposed (Scheme
5).9, 11 The reaction of formamide with TCT forms imminium salt
(I), which it was isolated and characterized (see supporting
information). This salt probably in the presence of a base can
form a formimidate intermediate (II). The intermediate II in the
presence of base can release cyanide source, probably through
a rearrangement. The oxidative addition of aryl halide to Pd(0)
generates a palladated intermediate (III). The ligand exchange
of CN with halide afforded to Pd(II) species (IV). Finally, the
reductive elimination of intermediate IV delivers the cyanation
product and regenerates Pd(0).
163.14, 150.02. IR (KBr) ν: 3402, 3209, 3047, 1720, 1418, 1396, 1056,
16
779, 540cm-1. It decomposed at above 300 oC.
General procedure for the cyanation of aryl halide using TCT-
formamide reagent
Method A: Into two-necked round-bottomed flask (10 mL) equipped with
a condenser, aryl halide (1.0 mmol), Pd/C (3.5 mol %, 0.075 g), PPh3
(7.0 mol %, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol, 0.2 g),
and formamide (2.0 mL) was added and the mixture was stirred for 10
minutes at 25-30oC. Then the resulting mixture was stirred in an oil bath
for 12-14 h at 130 oC. After allowing the mixture to cool down to room
temperature, water (4.0 mL) was added and then the organic layer
extracted with ethyl acetate (3×10 mL).The extracted organic layers were
dried over anhydrous Na2SO4 and evaporated under vacuum. The crude
product was purified by column chromatography, eluting with n-hexane/
EtOAc (v/v), to afford the pure product.
O
N
Cl
C
H
N
H
N
N
H
N
OH
N
N
Ar
X
H
Ar
B:
N
O
N
Pd
X
C
H
Method B: The procedure was same to method A, only instead of TCT
C
N
H
N
N
Cl
H
(III)
B:
(V)
Pd(0)
the TCT-formamide salt (0.5 mmol, 0.12 g) was used.
(I)
H
B:H
N
O
N
Ar
C
X
Spectral data for all synthesized compounds
B:
CN
N
N
Pd
H
(II)
CN
B:H
Cl
Ar
(IV)
4-Methoxybenzonitrile (3a). According to the general procedure, a
mixture of 4-bromoanisole (1.0 mmol, 0.19 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol,
0.2g), and formamide (2.0 mL) was stirred at 130 ºC for 12h.The workup
process was same tothe general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc20:2
(v/v) to afford the pure compound 3a (110 mg, 86% yield) as a white solid.
1H NMR (250 MHz, CDCl3):δ 7.57 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 8.5 Hz,
2H), 3.85 (s, 3H). IR (KBr) ν: 3023, 2977, 2955, 2900, 2841, 2602, 2560,
2218, 1904, 1770, 1606, 1510, 1368, 1361, 1304, 1258, 1176, 1144,
1114, 1023, 958, 829, 808, 715, 682, 645cm-1.The spectral data and
physical properties were identical to that previously reported. M.p 53-55
ºC [Lit. 51-53ºC].[17]
Scheme 5. Proposed reaction mechanism for the cyanation reaction with
TCT-formamide reagent.
Conclusion
In summary, we have introduced a new procedure for the
production of a cyano unit from two readily accessible resources
including cyanuric chloride and formamide. The cyanation
reaction in the presence of this new cyanide source represents
an expedient and safe process for the cyanation of the aryl
halides. This new developed safe cyanide source may have
potential utility in other cyanation reactions.
4-Methylbenzonitrile (3b). According to the general procedure,
a
mixture of 4-bromotoluene (1.0 mmol, 0.17 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5mmol,
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane/EtOAc 20:1
(v/v) to afford the pure compound 3b (96 mg, 82% yield).1H NMR (250
MHz, CDCl3): δ7.49 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 2.39 (s,
3H, CH3). IR (KBr) ν: 3039, 2877, 2715, 2229, 1921, 1792, 1608, 1508,
1490, 1275, 1177, 1120, 1042, 1022, 951, 817, 761, 706, 605cm-1.The
spectral data and physical properties were identical to that previously
reported. Colorless oil.[18]
solid.1H NMR (250 MHz, CDCl3):δ 8.04 (d, J = 8.7 Hz, 2H), 7.77 (d, J =
8.7 Hz, 2H), 2.64 (s, 3H). IR (KBr) ν: 3085, 2923, 2854, 2229, 1944, 1689,
1604, 1558, 1404, 1357, 1257, 1110, 1072, 1018, 956, 833, 640, 594 cm-
1. The spectral data and physical properties were identical to that
previously reported. M.p. 55-57 oC [Lit. 58-59 oC].[21]
4-Cyanobenzaldehyde (3h). According to the general procedure, a
mixture of 4-bromobenzaldehyde (1.0 mmol, 0.18 g), Pd/C (3.5 mol%,
0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3
(1.5mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h.
The workup process was same to the general procedure. The crude
product was purified by column chromatography, eluting with n-
hexane/EtOAc 20:3 (v/v) to afford compound 3h (115 mg, 87% yield) as
a white solid. 1H NMR (250 MHz, CDCl3):δ10.08 (s, 1H), 7.98 (d, J = 8.5
Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H). IR (KBr) ν: 3085, 3047, 2862, 2754,
2221, 2167, 1704, 1566, 1442, 1296, 1172, 1010, 833, 740, 617, 547 cm-
1. The spectral data and physical properties were identical to that
previously reported. M.p. 100-101oC [Lit. 98-99 oC].[21]
4-(Dimethylamino) benzonitrile (3c). According to the general
procedure, a mixture of 4-bromo-N,N-dimethylaniline (1.0 mmol, 0.20 g),
Pd/C (3.5 mol %, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol,
0.092 g), K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at
130 ºC for 12h. The workup process is same to the general procedure.
The crude product was purified by column chromatography, eluting with
n-hexane/EtOAc 20:4 (v/v) to afford the pure compound 3c (117 mg,
80% yield) as a white solid. 1H NMR (250 MHz, CDCl3): δ 7.44 (d, J = 9.2
Hz, 2H), 6.61 (d, J = 9.0 Hz, 2H), 3.02 (s, 6H). IR (KBr) ν: 2907, 2869,
2823, 2211, 2159, 1900, 1606, 1557, 1525, 1446, 1417, 1371, 1325,
4-(Trifluoromethyl)benzonitrile (3i). According to the general procedure,
a mixture of 1-bromo-4-(trifluoromethyl)benzene (1.0 mmol, 0.22 g), Pd/C
(3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g),
K2CO3(1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC
for 12h.The workup process is same to the general procedure. The crude
product was purified by column chromatography, eluting with n-
hexane/EtOAc 20:2 (v/v) to afford compound 3i (154 mg, 90% yield) as a
light yellow solid.1H NMR (250 MHz, CDCl3):δ7.80 (d, J = 8.5 Hz, 2H),
7.73 (d, J = 8.5 Hz, 2H). IR (KBr) ν: 3110, 3089, 3060, 3013, 2237, 1796,
1623, 1416, 1399, 1387, 1323, 1162, 1139, 1108, 1068, 1018, 863, 839,
784, 729, 597, 547cm-1. The spectral data and physical properties were
identical to that previously reported. M.p 38-39 oC [Lit. 36-38 oC].[19]
-1
1226, 1172, 1138, 1122, 1066, 1003, 941, 819, 786, 655, 645, 545cm
.
The spectral data and physical properties were identical to that
previously reported. M.p. 71-73 oC [Lit. 74- 75 oC].[19]
Benzonitrile (3d). According to the general procedure, a mixture of
bromobenzene (1.0 mmol, 0.16 g), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0
mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (2.5 mmol, 0.17 g), and
formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup process
was same to the general procedure. The crude product was purified by
column chromatography, eluting with n-hexane to afford the pure
compound 3d (79 mg, 77% yield).1H NMR (250 MHz, CDCl3): δ 7.61-
7.66 (m, 2H), 7.56-7.60 (m, 1H), 7.42-7.49 (m, 2H). IR (KBr) ν: 3062,
2923, 2229, 1689, 1596, 1488, 1450, 1388, 1288, 1188, 1064, 1026, 925,
840, 756, 686 cm-1. The spectral data and physical properties were
identical to that previously reported. Colorless oil.[11]
4-Nitrobenzonitrile (3j). According to the general procedure, a mixture
of 1-bromo-4-nitrobenzene (1.0 mmol, 0.20 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane/EtOAc 20:3
(v/v) to afford compound 3j (130 g, 90% yield) as a yellow solid. 1H NMR
(250 MHz, CDCl3): δ 8.35 (d, J = 9.0 Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H). IR
(KBr) ν: 3109, 2229, 1805, 1666, 1604, 1527, 1350, 1288, 1249, 1103,
1010, 856, 748, 678 cm-1. The spectral data and physical properties were
identical to that previously reported. M.p. 146-148oC [Lit. 148-150oC].[22]
4-Chlorobenzonitrile (3e). According to the general procedure,
a
mixture of 1-iodo-4-chlorobenzene (1.0 mmol, 0.24 g), Pd/C (3.5 mol%,
0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3
(1.5mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h.
The workup process is same to the general procedure. The crude
product was purified by column chromatography, eluting with n-
hexane/EtOAc 20:2 (v/v) to afford compound 3e (116 mg, 85% yield) as
a white solid. 1H NMR (250 MHz, CDCl3): δ 7.59 (d, J = 8.7 Hz, 2H), 7.45
(d, J = 8.7 Hz, 2H). IR (KBr) ν: 3085, 2221, 1905, 1643, 1596, 1481,
1396, 1265, 1164, 1087, 825, 702, 586cm-1.The spectral data and
physical properties were identical to that previously reported. M.p. 91-
93oC [Lit. 90-93oC].[19]
4-Aminobenzonitrile (3k). According to the general procedure,
a
mixture of 4-bromoaniline (1.0 mmol, 0.17 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane e/EtOAc 20:5
(v/v) to afford compound 3k (77 mg, 65% yield) as a white solid. 1H NMR
(250 MHz, CDCl3): δ 7.38 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H),
4.21 (s, 2H). IR (KBr) ν: 3471, 3371, 3209, 2214, 1627, 1512, 1450,
1311, 1172, 1134, 833, 686, 624, 547 cm-1. The spectral data and
physical properties were identical to that previously reported. M.p. 85-87
oC [Lit. 87- 88 oC].[23]
4-Bromobenzonitrile (3f). According to the general procedure, a mixture
of 1, 4-dibromobenzene (1.0 mmol, 0.23 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process was same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc 20:2
(v/v) to afford compound 3f (126 mg, 70% yield) as a white solid. M.p. 1H
NMR (250 MHz, CDCl3):δ7.84 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.7Hz, 2H).
IR (KBr) ν: 2923, 2229, 2160, 1620, 1442, 1265, 1149, 864, 840, 609
cm-1. The spectral data and physical properties were identical to that
previously reported. 109-111oC [Lit. 110-113o C].[20]
4-Hydroxybenzonitrile (3l). According to the general procedure,
a
mixture of 4-bromophenol (1.0 mmol, 0.17 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc 20:5
(v/v) to afford compound 3l (89 mg, 75% yield) as a white solid. 1H NMR
(250 MHz, CDCl3): δ 7.55 (d, J = 8.7 Hz, 2 H), 6.99 (s, 1H, OH), 6.94 (d,
J = 8.75Hz, 2 H). IR (KBr) ν: 3290, 3079, 2885, 2804, 2662, 2581, 2444,
2233, 1904, 1791, 1613, 1602, 1560, 1540, 1508, 1449, 1439, 1375,
1364, 1326, 1284, 1249, 1222, 1208, 1192, 1105, 836, 819, 701, 668 cm-
4-Acetylbenzonitrile (3g). According to the general procedure, a mixture
of 4-bromo acetophenone (1.0 mmol, 0.20 g), pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process was same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane/EtOAc 20:5
(v/v) to afford compound 3g (138 mg, 95% yield) as a Light yellow
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
1. The spectral data and physical properties were identical to that
previously reported. M.p. 111-112 oC [Lit. 110-111 oC].[21]
1-Naphthonitrile (3r). According to the general procedure, a mixture of
1-bromonaphtalene (1.0 mmol, 0.21 g), Pd/C (3.5 mol%, 0.075 g), PPh3
(7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5mmol, 0.2 g),
and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc 20:1
(v/v) to afford compound 3r (140 mg, 91% yield) as a white solid.1H NMR
(400 MHz, CDCl3): δ 8.12 (d, J= 8.0 Hz,1H), 7.95 (d, J= 8.0 Hz,1H), 7.83-
7.78 (m,2H), 7.58-7.51 (m, 2H), 7.43-7.39 (m, 1H). IR (KBr) ν: 3058,
2222, 1604, 1504, 1396, 1242,801, 772 cm-1. The spectral data and
physical properties were identical to that previously reported. M.p. 35-37
oC [Lit. 36-38oC].[26]
Terephthalonitrile (3m). According to the general procedure, a mixture
of 4-bromobenzonitrile (1.0 mmol, 0.18 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc 20:2
(v/v) to afford compound3m (110 mg, 86% yield) as a white solid. 1H
NMR (250 MHz, CDCl3): δ 7.79 (s, 4H). IR (KBr) ν: 3199, 2230, 1681,
1417, 1290, 1121, 1095, 1016, 956, 862, 774, 675, 563, 544cm-1. The
spectral data and physical properties were identical to that previously
reported. M.p. 224-226oC [Lit. 225-227 oC].[21]
Phenanthrene-9-carbonitrile (3s). According to the general procedure,
a mixture of 1-bromonaphtalene (1.0 mmol, 0.21 g), Pd/C (3.5 mol%,
0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5
mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The
workup process is same to the general procedure. The crude product
was purified by column chromatography, eluting with n-hexane/EtOAc
20:2(v/v) to afford compound 3s (183 mg, 90% yield) as a yellow solid.
1H NMR (250 MHz, CDCl3):δ8.73-8.67 (m, 2H), 8.32-8.29 (m, 1H), 8.25
(s, 1H), 7.95- 7.91 (m, 1H), 7.84- 7.80 (m, 1H), 7.79- 7.74 (m, 2H), 7.71-
7.65 (m, 1H). IR (KBr) ν: 3071, 2219, 1616, 1448 1245, 1219, 950, 916,
744, 718, 620, 510, cm-1. The spectral data and physical properties were
identical to that previously reported. M.p. 105-107oC [Lit. 109oC].[22]
3-Aminobenzonitrile (3n). According to the general procedure,
a
mixture of 3-bromoaniline (1.0 mmol, 0.17 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc 20:5
(v/v) to afford compound 3n (82 mg, 69% yield) as a pale yellow solid. 1H
NMR (250 MHz, CDCl3): δ 7.22-7.15 (m, 1H), 6.99-6.95 (m, 1H), 6.87-
6.82 (m, 2H), 3.96 (s, 2H). IR (KBr) ν: 3400, 3325, 3218, 2234, 1600,
1490, 1476, 1457, 1313, 1295, 1167, 1157, 1068, 993, 976, 932, 895,
863, 788, 685cm-1. The spectral data and physical properties were
identical to that previously reported. M.p. 52-54 oC [Lit. 47-48 oC].[21]
Anthracene-9-carbonitrile (3t). According to the general procedure, a
mixture of 9-bromoanthracene (1.0 mmol, 0.26 g), Pd/C (3.5 mol%, 0.075
g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5 mmol,
0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc
20:2(v/v) to afford compound 3t (172 mg, 85% yield) as a green solid. 1H
NMR (400 MHz, CDCl3):δ8.51 (s, 1H), 8.31 (d, J = 8.5 Hz, 2H), 7.97 (d, J =
8.5 Hz, 2H), 7.64 (t, J = 8.2 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H). IR (KBr) ν:
3049, 3032, 2213, 1927, 1684, 1646, 1527, 1339, 1262, 1161, 1008, 954,
898, 855, 846, 780, 759, 730 cm-1. The spectral data and physical
properties were identical to that previously reported. M.p. 174-176 oC [Lit.
173-177oC].[27]
2-Aminobenzonitrile (3o). According to the general procedure,
a
mixture of 2-bromoaniline (1.0 mmol, 0.18 g), Pd/C (3.5 mol%, 0.075 g),
PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5mmol, 0.2
g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The workup
process is same to the general procedure. The crude product was
purified by column chromatography, eluting with n-hexane /EtOAc 20:5
(v/v) to afford compound 3o (76 mg, 64% yield) as a yellow solid. 1H
NMR (250 MHz, CDCl3): δ 7.31-7.18 (m, 2H), 6.68-6.61 (m, 2H), 4.36 (s,
2H). IR (KBr) ν: 3459, 3368, 3079, 3037, 2209, 2158, 1626, 1569, 1456,
1436, 1337, 1312, 1266, 1202, 1155, 1029, 847, 745cm-1. The spectral
data and physical properties were identical to that previously reported.
M.p. 49-51oC [Lit. 48-50 oC].[23]
4-Benzoylbenzonitrile (3u). According to the general procedure,
a
mixture of 9-bromobenzophenone (1.0 mmol, 0.26 g), Pd/C (3.5 mol%,
0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5
mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The
workup process is same to the general procedure. The crude product
was purified by column chromatography, eluting with n-hexane/EtOAc
20:5 (v/v) to afford compound 3u (176 mg, 85% yield) as a light white
solid. 1H NMR (250 MHz, CDCl3): δ 7.87 (d, J = 8.5 Hz, 2H): 7.81- 7.76
(m, 4H), 7.67-7.61 (m, 1H), 7.54-7.48 (m, 2H). IR (KBr) ν: 3065, 2229,
1743, 1650, 1550, 1535, 1519, 1458, 1311, 1280, 1110, 933, 856, 794,
694, 594, 586 cm-1. The spectral data and physical properties were
identical to that previously reported. M.p. 109-112oC [Lit. 111-113 oC].[19]
2, 4-Dinitrobenzonitrile (3p). According to the general procedure, a
mixture of 1-bromo-2, 4-dinitrobenzene (1.0 mmol, 0.25 g), Pd/C (3.5
mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g),
K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC
for 12h. The workup process is same to the general procedure. The
crude product was purified by column chromatography, eluting with n-
hexane /EtOAc 20:5 (v/v) to afford compound 3p (171 mg, 89% yield) as
a yellow to orange solid.1H NMR (250 MHz, CDCl3): δ 8.67 (d, J = 5.0 Hz,
1H), 8.18 (dd, J = 10.0 Hz, J = 2.0 Hz, 1H), 7.01 (d, J = 10.0 Hz, 1H). IR
(KBr) ν: 3078, 2245, 1612, 1512, 1326, 1211, 1118, 1056, 941, 817, 748,
586 cm-1. The spectral data and physical properties were identical to that
previously reported. M.p. 102-104oC [Lit. 104-105oC].[24]
[1, 1’-Biphenyl]-4-carbonitrile (3v). According to the general procedure,
a mixture of 4-bromo-1, 1’-biphenyl (1.0 mmol, 0.23 g), Pd/C (3.5 mol%,
0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g), K2CO3 (1.5
mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC for 12h. The
workup process is same to the general procedure. The crude product
was purified by column chromatography, eluting with n-hexane /EtOAc
20:1 (v/v) to afford compound 3v (163 mg, 91% yield) as a pale yellow
solid. 1H NMR (400 MHz, CDCl3): δ7.74-7.67 (m, 4H), 7.61-7.59 (m, 2H),
7.51-7.47 (m, 2H), 7.45-7.43 (m, 1H). IR (KBr) ν: 3029, 2227, 1631, 1596,
1095, 847 cm-1. The spectral data and physical properties were identical
to that previously reported. M.p. 83-85°C [Lit. 85-86 oC].[28]
4-Chloro-3-nitrobenzonitrile (3q). According to the general procedure,
a mixture of 4-bromo-1-chloro-2-nitrobenzene (1.0 mmol, 0.24 g), Pd/C
(3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g),
K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC
for 12h.Theworkup process is same to the general procedure. The crude
product was purified by column chromatography, eluting with n-hexane
/EtOAc 20:2 (v/v) to afford compound 3q (135 mg, 74% yield) as a white
solid. 1H NMR (250 MHz, CDCl3): δ 8.07- 8.02 (m, 1H) 7.59- 7.54 (m, 1H),
7.02 (d, J = 10.0 Hz, 2H). IR (KBr) ν: 3093, 2221, 1581, 1535, 1342,
1265, 1188, 1087, 964, 879, 810, 748 cm-1. The spectral data and
physical properties were identical to that previously reported. M.p. 99-
100oC [Lit. 98-101 oC].[25]
4-Morpholinobenzonitrile (3w). According to the general procedure, a
mixture of 4-(4-bromophenyl) morpholine (1.0 mmol, 0.24 g), Pd/C (3.5
mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g),
6
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10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC
for 12h. The workup process is same to the general procedure. The
crude product was purified by column chromatography, eluting with n-
hexane /EtOAc 20:3 (v/v) to afford compound 3v (165 mg, 88% yield) as
a yellowish solid. 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 12.0 Hz, 2H),
6.85 (d, J = 12.0 Hz, 2H), 3.84 (d, J = 4.0 Hz, 4H), 3.27 (d, J = 4.0 Hz,
4H). 13C {1H} NMR (100 MHz, CDCl3): δ 153.5, 133.5, 119.9, 114.1,
100.9, 66.5, 47.3. IR (KBr) ν: 3073, 2977, 2831, 2214, 1604, 1519, 1450,
1380, 1242, 1180, 1110, 925, 833 cm-1. The spectral data and physical
properties were identical to that previously reported. M.p. 80-82°C [Lit.
77- 78 oC].[29]
121.4, 118.5, 110.4, 109.3, 105.8. IR (KBr) ν: 3101, 2221, 1604, 1512,
1458, 1342, 1103, 840,748 cm-1. The spectral data and physical
properties were identical to that previously reported. M.p. 94-96 °C [Lit.
94-95oC].[32]
4-(9H-carbazol-9-yl) benzonitrile (3ab). According to the general
procedure, a mixture of 9-(4-bromophenyl)-9H-carbazole (1.0 mmol, 0.32
g), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol,
0.092 g), K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at
130 ºC for 15 h. The workup process is same to the general procedure.
The crude product was purified by column chromatography, eluting with
n-hexane /EtOAc 20:1 (v/v) to afford compound 3ab (225 mg, 84% yield)
as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 8.0 Hz,
2H), 7.91 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 7.0 Hz, 2H), 7.47-7.42 (m, 4H),
7.36-7.232 (m, 2H). 13C {1H} NMR (100 MHz, CDCl3): δ 142.0, 139.9,
133.9, 127.1, 126.4, 124.0, 121.0, 120.6, 118.4, 110.4, 109.5. IR (KBr) ν:
3055, 2221, 1596, 1512, 1450, 1334, 1226, 1172, 1110, 840, 756 cm-1.
The spectral data and physical properties were identical to that
previously reported. M.p. 174-176°C [Lit. 176-177oC].[33]
4-(Piperidin-1-yl) benzonitrile (3x). According to the general procedure,
a mixture of 1-(4-bromophenyl) piperidine (1.0 mmol, 0.24 g), Pd/C (3.5
mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g),
K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC
for 12h. The workup process is same to the general procedure. The
crude product was purified by column chromatography, eluting with n-
hexane /EtOAc 20:2 (v/v) to afford compound 3x (162 mg, 87% yield) as
a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 12.0 Hz,
2H), 6.80 (d, J = 12.0 Hz, 2H), 3.30-3.29 (m, 4H), 1.65-1.653 (m, 6H). 13
C
4-Phenoxybenzonitrile (3ac). According to the general procedure, a
mixture of 1-bromo-4-phenoxybenzene (1.0 mmol, 0.249 g), Pd/C (3.5
mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g),
K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC
for 12 h. The workup process is same to the general procedure. The
crude product was purified by column chromatography, eluting with n-
hexane /EtOAc 20:1 (v/v) to afford compound 3ac (176 mg, 90% yield)
as a white to yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.0
Hz, 2H), 7.45-7.41 (m, 2H), 7.28-7.23 (m, 1H), 7.09 (d, J = 8.0 Hz, 2H),
7.02 (d, J = 8.0 Hz, 2H). IR (KBr) ν: 3054, 2227, 1605, 1590, 1247, 1106,
871, 767 cm-1. The spectral data and physical properties were identical to
that previously reported. M.p. 42-44 °C [Lit. 42-43 oC].[28]
{1H} NMR (100 MHz, CDCl3): δ153.5, 133.4, 120.4, 114.0, 98.6, 48.3,
25.2, 24.2. IR (KBr) ν: 2936, 2854, 2214, 1604, 1512, 1450, 1350, 1249,
1180, 1126, 817 cm-1. The spectral data and physical properties were
identical to that previously reported. M.p. 57-59 oC [Lit. 54- 55 oC].[30]
4-(4-phenylpiperazin-1-yl) benzonitrile (3y). According to the general
procedure, a mixture of 1-(4-bromophenyl)-4-phenylpiperazine (1.0 mmol,
0.32 g), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5
mmol, 0.092 g), K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was
stirred at 130 ºC for 12h. The workup process is same to the general
procedure. The crude product was purified by column chromatography,
eluting with n-hexane /EtOAc 20:6 (v/v) to afford compound 3y (224 mg,
85% yield) as a white yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.52 (d,
J= 9.2 Hz, 2H), 7.33-7.29 (m, 2H), 6.96 (d, J= 7.6 Hz, 2H), 6.91 (d, J= 7.6
Hz, 2H), 3.49 (t, J = 5.6 Hz, 4H), 3.34 (t, J = 5.6 Hz, 4H). 13C {1H} NMR
(100 MHz, CDCl3): δ 153.3, 150.9, 133.56, 129.3, 120.5, 120.0, 116.4,
114.4, 100.6, 49.0, 47.3. IR (KBr) ν: 2923, 2831, 2214, 1596, 1512, 1450,
1388, 1342, 1226, 1180, 1087, 941, 763, 694 cm-1. The spectral data and
physical properties were identical to that previously reported. M.p. 168-
170 oC [Lit. 169-170 oC].[31]
4-([1, 1’-Biphenyl]-2-yloxy) benzonitrile (3ad). According to the general
procedure, a mixture of 2-(4-bromophenoxy)-1, 1’-biphenyl (1.0 mmol,
0.32 gr), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5
mmol, 0.092 g), K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was
stirred at 130 ºC for 12 h. The workup process is same to the general
procedure. The crude product was purified by column chromatography,
eluting with n-hexane /EtOAc 20:0.5 (v/v) to afford compound 3ad (239
mg, 88% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.51-
7.47 (m, 3H), 7.44-7.27 (m, 8H), 7.11 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0
Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3): δ 161.6, 151.2, 136.9, 134.8,
133.9, 131.7, 129.2, 129.0, 128.30, 127.6, 126.0, 121.8, 118.9, 117.2,
105.3. IR (KBr) ν: 3062, 2221.8, 1604, 1496, 1427, 1249, 1164, 1110,
840, 771, 740, 702 cm-1.The spectral data and physical properties were
identical to that previously reported.M.p. 128-130°C.[34]
4-(1H-imidazol-1-yl)benzonitrile (3z). According to the general
procedure, a mixture of 1-(4-bromophenyl)-1H-imidazole (1.0 mmol, 0.22
g), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol,
0.092 g), K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at
130 ºC for 15h. The workup process is same to the general procedure.
The crude product was purified by column chromatography, eluting with
n-hexane/EtOAc/MeOH 20:4:1 (v/v) to afford compound 3z (139 mg,
82% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H),
4-([1, 1’-Biphenyl]-4-yloxy) benzonitrile (3ae). According to the general
procedure, a mixture of 4-(4-bromophenoxy)-1, 1’-biphenyl (1.0 mmol,
0.325 g), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5
mmol, 0.092 g), K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was
stirred at 130 ºC for 12 h. The workup process is same to the general
procedure. The crude product was purified by column chromatography,
eluting with n-hexane /EtOAc 20:0.5 (v/v) to afford compound 3ae (250
mg, 92 % yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ
7.64-7.62 (m, 4H), 7.59-7.57 (m, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.39-7.35
(m, 1H), 7.14 (d, J = 8.80 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H). 13C {1H} NMR
(100 MHz, CDCl3): δ 161.6, 154.3, 140.1, 138.3, 134.2, 128.9, 127.4,
127.0, 120.6, 119.0, 118.9, 118.0, 105.9. IR (KBr) ν: 3047, 2221, 1596,
1481, 1249, 1172, 1110, 1010, 825, 732, 694 cm-1. Anal. Calcd for
C19H13NO (271.32): C, 84.11; H, 4.83; N, 5.16; O, 5.90. Found: C, 84.17;
H, 4.77; N, 5.23. M.p. 99-102°C.
7.72 (d, J = 8.8 Hz, 2 H), 7.45 (d, J = 8.8 Hz, 2H), 7.19-7.18 (m, 2H). 13
C
{1H} NMR (100 MHz, CDCl3): δ 140.5, 135.39, 134.2, 131.6, 121.4, 117.8,
117.6, 112.2. IR (KBr) ν: 3124, 2229, 1689, 1604, 1510, 1303, 1265,
1056, 833, 771, 655, 547 cm-1.The spectral data and physical properties
were identical to that previously reported. M.p. 148-150 °C [Lit. 151-154
oC].[18]
4-(1H-indol-1-yl) benzonitrile (3aa). According to the general procedure,
a mixture of 1-(4-bromophenyl)-1H-indole (1.0 mmol, 0.27 g), Pd/C (3.5
mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5 mmol, 0.092 g),
K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was stirred at 130 ºC
for 12h. The workup process is same to the general procedure. The
crude product was purified by column chromatography, eluting with n-
hexane /EtOAc 20:1 (v/v) to afford compound 3aa (187 mg, 86% yield)
as a white solid. 1H NMR (400 MHz, CDCl3):δ7.81 (d, J = 8.4 Hz, 2H),
7.70 (d, J = 8.0 Hz, 1H), 7.65-7.60 (m, 3H), 7.34 (d, J = 4.0 Hz, 1H),
7.30-7.20 (m, 2H), 6.75 (dd, J = 3.6, J = 0.8 Hz, 1H). 13C {1H} NMR (100
MHz, CDCl3): δ 143.5, 135.2, 133.8, 130.0, 127.1, 123.8, 123.3, 121.6,
4-(Naphthalene-2-yloxy) benzonitrile (3af). According to the general
procedure, a mixture of 2-(4-bromophenoxy) naphthalene (1.0 mmol,
0.30 g), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5
mmol, 0.092 g), K2CO3 (1.5 mmol, 0.2 g), and formamide (2.0 mL) was
7
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10.1002/ejoc.202000117
European Journal of Organic Chemistry
FULL PAPER
stirred at 130 ºC for 12 h. The workup process is same to the general
procedure. The crude product was purified by column chromatography,
eluting with n-hexane /EtOAc 20:1 (v/v) to afford compound 3af (223 mg,
91 % yield) as a white to yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.93
(d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.65
(d, J = 8.0 Hz, 2H), 7.56-7.49 (m, 3H), 7.26 (dd, J = 8.8, J = 2.4 Hz, 1H),
7.09 (d, J = 8.8 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3): δ 161.6, 152.4,
134.3, 131.0, 130.5, 127.9, 127.3, 126.9, 125.6, 120.2, 118.8, 1181,
116.7, 106.0. IR (KBr)ν: 3055, 2221, 1589, 1504, 1465, 11357, 1247,
1164, 1118, 956, 825, 756 cm-1. The spectral data and physical
properties were identical to that previously reported. M.p. 100-102°C [Lit.
103-105 oC].[35]
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procedure, a mixture of 1-(4-bromophenoxy) naphthalene (1.0 mmol,
0.30 g), Pd/C (3.5 mol%, 0.075 g), PPh3 (7.0 mol%, 0.018 g), TCT (0.5
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89 % yield) as a white to yellow solid.1H NMR (400 MHz, CDCl3): δ 7.96-
7.91 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.53 (dd,
J = 8.0, 1.2 Hz, 1H), 7.50-7.45 (m, 2H), 7.14 (dd, J = 7.2, 0.8 Hz, 1H),
7.01 (d, J = 8.8 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3): δ 162.3, 150.4,
135.1, 134.2, 128.1, 126.9, 126.6, 125.8, 125.5, 121.6, 118.8, 117.5,
116.3, 105.8. IR (KBr) ν: 3055, 2221.8, 1596, 1496, 1388, 1242, 1164,
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The financial support of Shiraz University is gratefully
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Keywords: Cyanuric chloride • Cyanation • Combined “CN”
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8
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European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Cl
N
Cl
Pd/C (3.5 mol%)
N
N
H
Ar
X
Cl
CN
Ar
R
R
O
PPh3 (7.0 mol%)
K2CO3 (2.5 eq )
130 oC, 12-15 h
C
36 entries
64-95%
N
H
H
Combination of formamide and cyanuric chloride afforded a new combined “CN” source which is highly stable and safe and can be
used in organic cyanation transformation reactions instead of common cyanide sources. This study unfolds the efficient Pd-catalyzed
cyanation of aryl halides using TCT-formamide reagent as a new combined “CN” source.
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