G Model
CCLET 4309 No. of Pages 3
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Y. Hu et al. / Chinese Chemical Letters xxx (2017) xxx–xxx
Table 1
oxygen [28]. Tao reported Cu(NO3)2/TEMPO-catalyzed aerobic
ammoxidation of alcohols to nitriles in DMSO at 80 ꢀC under O2
[29]. Muldoon employed Cu(OTf)2/TEMPO/bpy in the transforma-
tion of alcohols to nitriles using air instead of pure oxygen [30].
Despite the advantages of these protocols, the use of pure oxygen
or expensive ligand has limited their application in synthetic
chemistry. Very recently, Batra et al. also reported a facile method
for the synthesis of nitriles from primary alcohols catalyzed by Fe
(NO3)3 in the presence of TEMPO [31]. In this context, our group is
particularly interested in Cu/TEMPO catalytic systems and its
application in nitrile synthesis. It is still highly desirable to develop
an efficient, safe, and more practical catalyst system for the
oxidative synthesis nitriles from alcohols under ambient con-
ditions. Moreover, as reported that 4-hydroxy-2,2,6,6-tetramethyl-
piperidyl-1-oxy (4-HO-TEMPO) was cheaper and more active than
TEMPO in the aerobic oxidation of alcohols [32,33]. Herein, we
Optimization of the reaction conditions for the conversion of benzyl alcohol into
benzonitrile.a
Entry
Catalyst
Ligand
Additive
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
–
–
3
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
0
0
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr2
CuCl2
Cu(OAc)2
Cu(NO3)2
Cu(OTf)2
CuI
CuCl
CuCl
CuCl
CuCl
–
–
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
41
67
58
82
89
92
83
79
80
85
88
90
95
89
80
25
trace
0
Et3N
DBU
DMAP
Bipy
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
9
10
11
12
13
14
15
16
17
18
19
20c
report
a highly practical CuCl/DABCO/4-HO-TEMPO catalyst
system for the direct synthesis of nitriles from alcohols and
aqueous ammonia with air as the oxidant at room temperature
(Scheme 1). This approach exhibits broad substrate scope and a
variety of nitriles are obtained in moderate to good yields.
Initially, we employed benzyl alcohol (1a) as model substrate to
optimize the reaction conditions in the presence of air at room
temperature. The optimal results including catalyst, ligand,
additive and solvent were summarized in Table 1. As shown in
Table 1, copper salt and TEMPO were crucial for the reaction, and
no benzonitrile was observed in the absence of CuCl or TEMPO
(Table 1, entries 1 and 2). In order to improve the stability and
chemoselectivity of the catalyst system, the influence of different
N-containing ligands such as Et3N, 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU), N,N-dimethylpyridin-4-amine (DMAP), 2,20-bipyridine
(Bpy) and 1,4-diazabicyclo[2.2.2]octane (DABCO) were investigat-
ed (Table 1, entries 3–8). To our delight, DABCO turned out to
perform best in the model reaction, and an exciting isolated yield
of 2a was obtained in 92%. Next, we tested other copper salts such
as CuBr2, CuCl2, Cu(OAc)2, Cu(NO3)2, Cu(OTf)2 and CuI, all of them
gave good yield of 2a (Table 1, entries 9–14). Notably, CuCl showed
higher catalytic reactivity in combination with DABCO and TEMPO.
When 4-HO-TEMPO (4) was used instead of TEMPO (3), the desired
product 2a was provided up to 95% yield (Table 1, entry 15). Then,
we explored the influence of various solvents on this reaction. It
was found that CH3CN showed the best efficiency compared with
other solvents such as DMSO, DMF, dioxane and toluene (Table 1,
entries 16–19). However, the desired product was not observed
when the reaction was carried out under nitrogen, indicating that
the importance of molecular oxygen as the terminal oxidant
(Table 1, entry 20).
Dioxane
Toluene
CH3CN
CuCl
CuCl
a
Reaction conditions: 1 mmol of benzyl alcohol, 5 mol% copper catalyst, 5 mol%
additive, 10 mol% ligand, 3.0 equiv. of aq. NH3 (25%–28%, w/w), 2 mL of solvent, air
balloon, r.t., 24 h.
b
Isolated yield.
Under N2.
c
With the optimal reaction conditions in hand, the substrate
scope and the limitation of this catalytic system were explored and
the results were summarized in Scheme 2. It was observed that
both electron-donating groups and electron-withdrawing groups
were well tolerated in the reactions. As shown in Scheme 2,
primary benzylic alcohols bearing electron-donating groups such
as methyl, methoxyl, tert-butyl gave the desired products in
Scheme 2. Oxidative conversion of alcohols to nitriles.
excellent yields (Scheme 2, 2b–2e). However, the electron-
withdrawing groups such as –F, –Cl, Br, –NO2, –CF3 and –OCF3
substituted benzylic alcohols provided comparably low yields of
the corresponding nitriles (Scheme 2, 2f–2m). Of particular note
was that benzylic alcohols bearing thioether and acetyl amino
functional groups were smoothly converted into the desired
products in 88% and 90% yields, respectively (Scheme 2, 2n and 2o).
For the disubstituted and trisubstituted benzylic alcohols, they
were also suitable in this transformation with good efficiency
(Scheme 2, 2p–2t). It was noteworthy that 4-phenylbenzonitrile,1-
naphthylnitrile and 2-naphthylnitrile were obtained in moderate
Scheme 1. Synthesis of nitriles from alcohols and aqueous ammonia.
Please cite this article in press as: Y. Hu, et al., Practical CuCl/DABCO/4-HO-TEMPO-catalyzed oxidative synthesis of nitriles from alcohols with