Synthesis of benzoyl cyanide through aerobic photooxidation of benzyl cyanide using carbon tetrabromide as a catalyst

Article abstract of DOI:10.1039/c5ra13269j

We developed a synthetic method toward benzoyl cyanide through aerobic photooxidation of benzyl cyanide in the presence of carbon tetrabromide under visible light irradiation with fluorescent lamps.

Full text of DOI:10.1039/c5ra13269j

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Synthesis of benzoyl cyanide through aerobic photooxidation of
benzyl cyanide using carbon tetrabromide as a catalyst
Y. Sugiura,a Y. Tachikawa,a Y. Nagasawa,a N. Tadaa and A. Itoha
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We developed
a
synthetic method toward benzoyl cyanide source with photoirradiation.16 However, benzyl cyanide is less
through aerobic photooxidation of benzyl cyanide in the presence stable than benzyl amide; therefore, we considered that the
of carbon tetrabromide under visible light irradiation with oxidation of benzyl cyanide would be possible under these
fluorescent lamps.
mild conditions. After investigating the ideal reaction
conditions, we found that the photooxidation of benzyl
cyanides occurred in the presence of carbon tetrabromide
(CBr4) and water with irradiation using fluorescent lamps
Acyl cyanide is a useful synthetic intermediate in organic synthesis
as it can be utilized in a variety of transformations as both CO and
CN functionalities. For instance, effective cycloaddition of azides
with benzoyl cyanides affords benzoyltetrazols.1 Furthermore, it can
be used in the synthesis of oxazoles2,3,4 and tetrazolinones.5 In
general, benzoyl cyanides are synthesized by cyanation of benzoyl
chloride using AgI6 or oxidation of mandelonitrile by various
methods.7 In addition, aroyl cyanides are synthesized via the
formation of cyanohydrin nitrate intermediates using AgNO3.8
Furthermore, oxidation of benzyl cyanide has been used for the
synthesis of benzoyl cyanide; however, most of these reactions
require expensive and environmentally hazardous transition metal
catalysts such as ruthenium or vanadium. 9,10,11,12
(Scheme 1). Here we report
a detailed study of the
photooxidation of benzyl cyanides to benzoyl cyanides.
O
O2, h
ν
(fluorescent lamp)
CBr4
CN
CN
R
R
Scheme 1. Photo-oxidation of benzyl cyanide
To explore this approach, we selected benzyl cyanide (1a) as
the test substrate to optimize the reaction conditions (Table 1).
We first compared the effect of additives with K2CO3 as the
base, TFA as the acid, or no additives. From this, we found that
TFA dramatically improved the yield of 2a, while oxidation in
the presence of K2CO3 did not proceed at all (entries 1–3). Thus,
we screened solvents and bromine sources in the presence of
TFA and molecular oxygen under photoirradiation from
fluorescent lamps (entries 4–21). From this, we found that
benzoyl cyanide (2a) was produced most efficiently and in the
best yield using 0.2 equivalents of CBr4 as the catalyst and
ethyl acetate as the solvent (entry 2). Next, we examined other
acids as additives, which produced benzoyl cyanides in low to
moderate yields (entries 22–24). We also found that H2O was
Because of the increasing demand for more environmentally
benign syntheses, molecular oxygen has received much attention
because it is more atom-efficient than other oxidants such as toxic
heavy metals or complex organic reagents. In addition, molecular
oxygen is inexpensive and theoretically produces only water as the
end product of oxidation.13 However, to the best of our knowledge,
there has been no investigation of the catalytic oxidation of benzyl
cyanide to benzoyl cyanide under metal-free conditions using
molecular oxygen as the terminal oxidant.
In contrast, the effective use of visible light is important for
environmental load-reducing reactions as it exudes no residue
and has neither shape nor weight. As such, it is an important
component in the examination of environmentally benign
processes.14 As a result, we have been studying the aerobic
photooxidation of various substrates using molecular oxygen
and visible light from fluorescent lamps.15 For instance, we
previously reported the photooxidation of a benzyl amide to
the corresponding imide using catalytic amounts of a bromine
the best additive as
a proton source (entry 25–28).
Furthermore, the best yield of benzoyl cyanide was obtained
when 1.5 equivalents of water was used (entry 27).
Table 2 shows the scope and limitations of the oxidation of
benzyl cyanide under the optimized reaction conditions (entry
27).17 As the crude products are labile and we couldn’t purify
them by flush column chromatography or Kugelrohr
1
distillation,18,19 they were characterized by H NMR (Table 2,
a.Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax: +81-58-230-8108; E-mail: itoha@gifu-pu.ac.jp
yield 1) and isolated as the corresponding carboxylic acids
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Table 1. Study of Reaction Conditions.a
Table 2. Scope and Limitation.
O2, h
O
O2, hν (fluorescent lamp)
ν
(VIS)
bromo source, additive
CN
CN
CBr4 (0.2 eq)
Substrate
Product 1
solvent, 20 h
H2O (1.5 eq)
AcOEt (5 mL), 20 h
2
1
1a
2a
entry
Bromo source
(equiv)
Solvent
EtOAc
Additive
(equiv)
-
Conversion
H2O, conc.H2SO4
reflux, 103 ºC, 30 min
product 1 conversionb product 2
(%)b
Product 2
3
1
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
6
entry time (h)
yieldc
2
EtOAc
EtOAc
hexane
cyclohecane
THF
TFA (0.1)
K2CO3 (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
AlCl3 (0.1)
AcOH (0.1)
HBF4 (0.1)
H2O (0.5)
H2O (1.0)
H2O (1.5)
H2O (2.0)
69
3
0
O
O
1
20
20
20
40
65
20
20
20
20
65
65
110
20
74
73
88
45
68
64
53
34
25
71
37
28
0
73
4
3
CN
2a
OH
3a
5
7
O
O
6
43
2
72
71
49
60
67
46
40
19
21
34
16
CN
OH
7
CHCl3
0
Cl
Br
2b
Cl
Br
3b
8
CH2Cl2
acetone
i-PrOH
MeOH
neat
trace
trace
0
9
O
O
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
CN
OH
2c
3c
trace
trace
0
O
O
O
O
4d
5d
6
48% aq HBr (0.2)
NBS (0.2)
KBr (0.2)
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
CN
OH
7
2d
3d
F
F
4
CN
OH
NaBr (0.2)
AgBr (0.2)
MgBr2 (0.2)
CBr4 (0.1)
CBr4 (0.3)
CBr4 (0.4)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
CBr4 (0.2)
4
trace
trace
trace
55
2e
3e
Cl
Br
Cl
Br
O
O
CN
OH
2f
3f
16
O
O
25
7
CN
OH
3g
40
2g
Cl
O
Cl
O
61
70
8
CN
OH
68
Cl
Cl
Cl
Cl
Cl
Cl
O
2h
3h
74
O
O
O
71
CN
OH
9
a Reaction conditions: 1a (0.3 mmol), bromo source (0.2 equiv) and additive in
2i
3i
Cl
Cl
b
solvent was stirred and irradiated externally with fluorescent lamps for 20 h.
Conversion yields, determined by 1H-NMR with 1,1,2,2-tetrachloroethane as an
internal standard.
O
O
10d
11e
12e
13
CN
OH
2j
3j
Ph
Ph
after hydrolysis of in the presence of sulfuric acid (Table 2,
yield 2). As a result, benzoic acid was obtained in 73% isolated
yield (entry 1). The corresponding benzoyl cyanides were
detected when electron withdrawing groups were present on
the benzene ring (entries 2–9). In particular, 4-chlorobenzyl
cyanide and 4-bromobenzyl cyanide gave the corresponding
benzoyl cyanides in good yields (entries 2 and 3). In contrast,
oxidation of 4-fluorobenzyl cyanide was difficult; thus, an
increase in the time and amount of CBr4 used was necessary
(entry 4). 3-Chlorobenzoyl cyanide and 3-bromobenzoyl
cyanide were obtained in moderate yields (entries 5 and 6).
Both 2-chlorobenzyl cyanide and 2,4-dichlorobenzyl cyanide
provided the corresponding products in modest yields because
of steric reasons (entries 7 and 8). 3,4-Dichlorobenzoyl cyanide
resulted in a low yield (entry 9). Substrates with an electron
donating group, 4-methoxy, or 1-naphthaleneacetonitrile were
converted to the desired products in low yields when CBr4 was
increased and reaction time was extended (entries 11 and 12).
Unfortunately, aliphatic cyanide was not oxidized (entry 13).
CN
OH
2k
3k
MeO
MeO
O
CN
O
OH
3l
2l
O
CN
aReaction conditions: Substrate (0.3 mmol), bromo source and additive (1.5 eq) in
solvent was stirred and irradiated externally with fluorescent lamps for 20 h. The
solvent was removed by rotary evaporation, then we took 1H NMR. After dryness
by rotary evaporation again, it was added H2O(140 mL) and conc. H2SO4 (150 mL).
The mixture was stirred under reflux for 30 min. b Conversion yields, determined
by 1H-NMR with 1,1,2,2-tetrachloroethane as an internal standard. isolated
yields. d 0.4 equiv of CBr4. e 0.8 equiv of CBr4.
c
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To determine the reaction mechanism, we performed several
control experiments. Under air, the oxidation proceeded
slightly with 89% of the starting material and 8% of the
intermediate being recovered (equation 1). Under an argon
atmosphere, the oxidation did not proceed at all (equation 2).
These results suggest the necessity of sufficient molecular
oxygen for this oxidation. The oxidation also did not proceed at
all in the dark (equation 3); thus, photoirradiation is required
for this oxidation. Without CBr4, the reaction did not proceed
at all; thus, CBr4 is essential for the oxidation (equation 4).
These results suggest that CBr4, photoirradiation, and
molecular oxygen are critical for this reaction. A catalytic
amount of BHT, which is a radical inhibitor, completely
suppressed the reaction (equation 5), suggesting that this
reaction most likely proceeds via a radical chain mechanism.
O2, hν (fluorescent lamp)
O
OH
CN
CBr4 (0.2 eq)
CN
CN
H2O (1.5 eq)
EtOAc (5 mL), 20 h
1a (0.3 mmol)
2a
4a
100
80
60
40
20
0
1a
2a
4a
0
10
20
Figure 1. Time cource.
The Conversions were determined by 1H-NMR with 1,1,2,2-tetrachloroethane as
an internal standard
Air, hν (fluorescent lamp)
O
CBr4 (0.2 eq)
(1)
(2)
(3)
CN
CN
H2O (1.5 eq)
EtOAc (5 mL), 20 h
Scheme 3 shows a further study on the availability of benzoyl
1a (0.3 mmol)
2a trace
cyanide (2a). The synthesis of
from benzoyl cyanide (2a) was previously reported.21 Thus, we
attempted to synthesize -cyanobenzyl benzoate (4a) in a
α-cyanobenzyl benzoate (4a)
Ar, hν (fluorescent lamp)
O
CBr4 (0.2 eq)
CN
CN
H2O (1.5 eq)
EtOAc (5 mL), 20 h
α
one-pot reaction using the aerobic photooxidation from benzyl
cyanide (1a) through benzoyl cyanide (2a). As a result, the
product was obtained in moderate yields.
1a (0.3 mmol)
2a 0%
O
O2, dark
CBr4 (0.2 eq)
CN
CN
H2O (1.5 eq)
EtOAc (5 mL), 20 h
Air, hν (fluorescent lamp)
O
1a (0.3 mmol)
2a 0%
CBr4 (0.2 eq)
CN
CN
O
H2O (1.5 eq)
O2, h
ν
(fluorescent lamp)
EtOAc (5 mL), 20 h
CN
CN
(4)
(5)
1a (0.3 mmol)
2a
H2O (1.5 eq)
EtOAc (5 mL), 20 h
O2, h
O
H
1a (0.3 mmol)
2a 0%
O
CN
ν
(fluorescent lamp)
(0.9 eq)
CBr4 (0.2 eq)
BHT (0.2 eq)
O
O
Et3N (40 mol%)
r.t. 10 min
CN
CN
H2O (1.5 eq)
5a 48 %
EtOAc (5 mL), 20 h
Scheme 3. Synthesis of a-cyanobenzyl benzoate.
1a (0.3 mmol)
2a 0%
Scheme 2. Study of Reaction Mechanism.
Conclusions
We also performed a time course experiment for the oxidation
of benzyl cyanide (1a) under the optimized reaction conditions
1
(Figure 1). Mandelonitrile (3a) was detected by H NMR in the
In conclusion, we developed a synthetic method for the
aerobic photooxidation of benzyl cyanide to benzoyl cyanide
using a catalytic amount of carbon tetrabromide in the
presence of water under photoirradiation from fluorescent
lamps. Although the detailed mechanism of this reaction was
not determined, it was proven that it most likely proceeds via
a radical chain reaction with H2O as the proton source. This
novel reaction is valuable as it uses inexpensive and harmless
molecular oxygen and visible light from general purpose
fluorescent lamps. The application of this photooxidation to
other reactions is now in progress in our laboratory.
early stages of the reaction, as well as small amounts of
benzoyl cyanide (2a). In the middle stages, benzoyl cyanide
(
2a)
was synthesized quickly, while the amount of
mandelonitrile (3a) decreased. After 20 h, the starting material
and mandelonitrile (3a) completely disappeared. Thus, it was
confirmed that mandelonitrile was synthesized first, while
benzoyl cyanide was synthesized gradually. This suggests that
mandelonitrile is the intermediate of this reaction.
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Notes and references
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17 General Procedure: A solution of benzyl cyanide (1a, 0.3
mmol), carbon tetrabromide (0.2 equiv), and H2O (1.5 equiv)
in dry EtOAc (5 mL) in a pyrex test tube, purged with an O2
balloon, was stirred and irradiated externally with
fluorescent lamps for 20 h. The reaction mixture was
concentrated in vacuo. Then 140 ꢀL of water and 150 ꢀL of
conc. H2SO4 were added. The mixture was stirred under
reflux for 30 min. After that the mixture was basified by 10%
NaOH and extracted with ether. Water layer was acidified by
2N HCl and extracted with ether. Organic layer was
evaporated and product was obtained. When the product is
not pure, it was purified by preparative TLC.
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4 | J. Name., 2012, 00, 1-3
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