Cyanation of Anilines to Aryl Nitriles Using tert-Butyl Isocyanide: A Simple and Copper-free Procedure

Article abstract of DOI:10.1002/bkcs.11848

In this manuscript, a simple and copper-free procedure for the synthesis of aryl nitrile derivatives from anilines is described. Under the improved protocol, the anilines were reacted with tert-butyl isocyanide under a mild reaction condition without the use of solvents and copper catalyst to synthesize benzonitriles. This copper-free Sandmeyer-type reaction could tolerate a range of anilines bearing different functional groups and also can be conducted even without the exclusion of air. In addition, this method has afforded the aryl nitriles in moderate to good yields (52–81%). The obtained results in this study reveal that the tert-butyl isocyanide as a potential cyanide source for the cyanation reaction.

Full text of DOI:10.1002/bkcs.11848

Article
DOI: 10.1002/bkcs.11848
BULLETIN OF THE
P. W. Chia et al.
KOREAN CHEMICAL SOCIETY
Cyanation of Anilines to Aryl Nitriles Using tert-Butyl Isocyanide:
A Simple and Copper-free Procedure
‡
‡
§
Poh Wai Chia,†,‡, Fu Siong Julius Yong, Habsah Mohamad, and Su-Yin Kan
*
†Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, Malaysia
‡Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Terengganu, Malaysia.
*E-mail: pohwai@umt.edu.my
§Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus, Malaysia
Received June 15, 2019, Accepted July 15, 2019
In this manuscript, a simple and copper-free procedure for the synthesis of aryl nitrile derivatives from
anilines is described. Under the improved protocol, the anilines were reacted with tert-butyl isocyanide
under a mild reaction condition without the use of solvents and copper catalyst to synthesize benzonitriles.
This copper-free Sandmeyer-type reaction could tolerate a range of anilines bearing different functional
groups and also can be conducted even without the exclusion of air. In addition, this method has afforded
the aryl nitriles in moderate to good yields (52–81%). The obtained results in this study reveal that the
tert-butyl isocyanide as a potential cyanide source for the cyanation reaction.
Keywords: tert-butyl isocyanide, Metal-free, Aryl nitrile, Aniline, Solvent-free, Cyanation
Introduction
reactions.23–27 Herein, we would like to report on the use of
tert-butyl isocyanide as cyano source for the conversion of ani-
lines to aryl nitriles (Figure 1). The advantages of this method
including metal-free reaction, simplicity of the protocol, mild
reaction condition and the yield of the final products were
obtained in moderate to good yields (52–81%).
Aryl nitriles are valuable class of compounds. They are
mainly found as core moieties in variety of compounds, such
as medicinal, agricultural, natural products, materials, and
dyes.1,2 Moreover, aryl nitriles are versatile intermediates, as
it can be easily transformed into a variety of functional
groups including aldehydes, ketones, amide, carboxylic
acids, and so on, which render this class of compounds a
useful intermediate in organic synthesis.3 Owing to their vast
application in biology and chemistry fields, there has always
been a continuous interest devoted to the development of
methodology for the synthesis of aryl nitriles.4,5
Traditionally, the synthesis of aryl nitriles rely heavily on
the Sandmeyer6 and Rosenmund-von Braun methods.7 In addi-
tion, a variety of procedures were also generated based on the
use of transition metals for the synthesis of aryl nitriles includ-
ing KCN,8 NaCN,9 ZnCN,10 K4[Fe(CN)6],11 Pd/K4[Fe
(CN)6],12 and so on. Other non-metallic cyanide sources that
were used for synthesis of aryl nitriles were also reported, such
as the arenediazonium o-benzenedisulfonimides,13 acid/azide,14
I2/TBHP,15 NIS/TMSN3,16 and so on. However, most these
methods suffer some drawbacks, in which it involve the use of
metals, acid, require the prior preparation of reagent and harsh
reaction condition.
Results and Discussion
For the optimization study, we began the model reaction
by adding sodium nitrite (5 mmol) into a 50 mL round
bottom flask that was suspended with a mixture of ani-
line (1.00 mmol) and concentrated acetic acid (3–5
drops) at rt. The reaction mixture was left for stirring for
1 h and the progress of the reaction was monitored by
TLC. Under this reaction condition, the 3a was obtained
in good yield (61%) (Table 1, entry 2). An increase in
the amount of sodium nitrite used has increased the yield
of 3a (Table 1, entry 2). The best yield of 3a (81%
yield) was obtained when 10 mmol of sodium nitriꢀte was
used and the reaction mixture was heated at 50 C for
1 h (Table 1, entry 3). When prolonged the reaction time
and high temperature (>50 ꢀC) were employed, we
found that these reaction conditions did not led to a bet-
ter yields of 3a (Table 1, entry 4–6). In this study, we
have also explored the synthesis of 3a using different
solvent (DMF, DMSO, CH3CN, and CH3OH) under the
identical reaction condition. However, the yields of 3a
were found to be decreased (30% for DMF, 45% for DMSO,
42% for CH3CN, and 7% for CH3OH) (Table 1, entries
7–10). With all these results in hand, the optimized reaction
condition was determined (Table 1, entry 3).
Isocynides are useful C1 building blocks in organic synthe-
sis. In particular, isocyanides were found to be a powerful pre-
cursors in the work of multicomponent reaction, namely the
Passerine17–19 and Ugi20–22 reactions. In recent years, iso-
cyanides have been used as a cyano source for the construction
of C─O, C─C, C─N bonds and aldehydes through the inser-
tion of isocyanides into C–X bonds via palladium-catalyzed
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KOREAN CHEMICAL SOCIETY
previous work:
CN
NH2
NaNO2 , TEMPO or DPPH
CN
I
Pd, Oxidant, additive
tert-butyl isocyanide, AcOH
1 hr, 0-50
t-Bu
N C
R1
R1
°C
12 h
Figure 2. Aryl radical trapping experiment using TEMPO
or DPPH.
this work:
NH2
CN
NaNO2, AcOH
t-Bu
N C
solvent-free, 0-50 °C
C
R1
R1
N2
B
NH2
N2OAc
NaNO2
AcOH
R1 = Electron-withdrawing and electron-donating groups
OAc
Figure 1. Synthetic route towards the preparation of aryl nitriles.
C
N
A
Next, we have investigated the general applicability of
the current method to synthesize a range of benzonitrile
derivatives using the optimized reaction condition. The
current method work well for electro-withdrawing and
electro-donating groups at the ortho- and para-positions,
such as the chloro (3b and 3g), bromo (3c and 3h), fluoro
(3i and 3d), methyl (3f), nitro (3e), and methoxy (3j)
(Figure 2). In all the cases, the benzonitriles were purified
over silica gel column chromatography and the yields of
the final products were found to be in moderate to good
yields (52–81%). In particular, anilines bearing the
electron-withdrawing and electron-donating groups at the
para-position afforded the benzonitriles 3b-f in moderate
to good yields within 1 h reaction time (Table 2). How-
ever, the anilines bearing the substituents (both electron-
withdrawing and electron-donating groups) at the ortho-
position experienced a decrease in reaction yields, which
might be due to the issue of steric hindrance adjacent to
the reactive site (3g–3j). Other non-aromatic amines were
also subjected to the similar reaction condition. However,
none of it react even after prolong reaction time (24 h).
The current method was regarded as unprecedented, in
which no solvents and copper metal were required in the
preparation of benzonitriles (3a–3j). In addition, the ben-
zonitriles were synthesized under mild condition and rea-
sonable reaction time. All the synthesized benzonitriles
(CH3)3C-OAc
D
CN
3a
Figure 3. A plausible mechanism for the formation of 3a via radi-
cal intermediate.
(3a–3j) were characterized using NMR (1H and 13C) and
GC–MS spectroscopic methods.
Furthermore, we have explored the mechanistic details of
the conversion of anilines to benzonitriles (3a–3j), by syn-
thesizing 3a in the presence of TEMPO. When the synthe-
sis of 3a was conducted in equimolar concentration of
TEMPO, the benzonitrile of 3a was not observed. Simi-
larly, the use of excess of DPPH also did not give rise to
the formation of 3a (Figure 2). These results indicate that
the formation of benzonitriles involving the intermediate
radicals. The products of radical trap experiment were iso-
lated and studied using NMR and GCMS analyses. Under
the identical reaction condition, the starting material was
observed, along with some other unidentified side products.
It is note-worthy that the desired product was not observed
in this radical trap experiment. The result of this was differ-
ent from a previous reported literature.28 These differences
Table 1. The optimization of reaction condition for 3a.
Entry
Solvent (mL)
NaNO2 (mmol)
Time (min)
Temperature (ꢀC)
Yielda (%)
1
2
3
4
5
6
7
8
9
—
5
5
30
60
60
60
120
60
60
60
60
60
rt
rt
30
61
81
70
68
67
30
45
42
7
—
—
10
20
10
10
10
10
10
10
50
50
50
90
50
50
50
50
—
—
—
DMF (1.0)
DMSO (1.0)
CH3CN (1.0)
CH3OH (1.0)
10
a Isolated yield of product 3a.
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Simple and Copper-free method of Cyanation Using Tert-Butyl Isocyanide
KOREAN CHEMICAL SOCIETY
Table 2. Isolated yields and the synthesis of benzonitriles 3a.
Entry
1
Compound
Substrate
Product
Yielda (%)
3a
81
NH2
CN
2
3
4
5
6
3b
3c
3d
3e
3f
73
Cl
NH2
Cl
Br
CN
71
Br
NH2
NH2
NH2
CN
72
F
F
CN
68
O2N
O2N
CN
67
CN
NH2
7
8
3g
3h
3i
56
NH2
CN
Cl
Br
F
Cl
55
NH2
NH2
NH2
CN
Br
9
52
CN
F
10
3j
58
CN
O
O
11
3k
—
—
NH2
(continued overleaf )
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Simple and Copper-free method of Cyanation Using Tert-Butyl Isocyanide
KOREAN CHEMICAL SOCIETY
Table 2 (continued)
Entry
12
Compound
Substrate
Product
Yielda (%)
3l
—
—
NH2
a Isolated yield of product 3a.
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ꢀ
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Based on our understanding of Sandmeyer-type and radi-
cal reactions, a plausible mechanism for the formation of
3a was proposed as shown in Figure 3. It would appear that
the aniline is first reacted with sodium nitrite to form diazo-
nium salt (intermediate A). Next, the diazonium salt
decompose to form the acetoxy radical (B), aryl radical (C)
and nitrogen. The aryl radical (C) then abstracts the cyano
group from the tert-butyl isocyanide to produce the desired
product 3a. While the tert-butyl radical generated in this
reaction, which could further reacts with the acetoxy radical
(B) to form ester (D) and the [M+1] of ester (D) was con-
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Conclusion
We have developed a simple and copper-free method for the
synthesis of benzonitriles. This copper-free Sandmeyer-type
reaction could tolerate a range of anilines bearing different
functional groups and also can be conducted even without the
exclusion of air. In addition, this method has afforded the aryl
nitriles in moderate to good yields (52–81%). The obtained
results in this study reveal that the tert-butyl isocyanide as a
potential cyanide source for the cyanation reaction.
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Acknowledgments. The author is grateful to the Universiti
Malaysia Terengganu for its research facilities and the pub-
lication cost of this paper was supported by the Korean
Chemical Society.
Supporting Information. Additional supporting informa-
tion may be found online in the Supporting Information
section at the end of the article.
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