Received: November 20, 2019 | Accepted: December 5, 2019 | Web Released: January 30, 2020
CL-190854
Mild Environment-friendly Oxidative Debenzylation
of N-Benzylanilines Using DMSO as an Oxidant
Tatsuro Yoshinaga,1 Takayuki Iwata,2 and Mitsuru Shindo*2
1Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
2Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
E-mail: shindo@cm.kyushu-u.ac.jp
Oxidative debenzylation of N-benzyl aromatic amines using
DMSO as a non-toxic oxidant and catalyzed by TsOH gave N-
phenylimines, which were spontaneously hydrolyzed to form
anilines and benzaldehydes in good yields. This reaction
employs mild, metal-free conditions. The conditions are also
suitable for the debenzylation of benzylphenylethers.
Table 1. Optimization of reaction conditions using model
substrate 1a.
t-Bu
t-Bu
TsOH•H2O
N
N
H
+ 5
DMSO
T °C, t h
Atmosphere
t-Bu
t-Bu
1a
2a
t-Bu
Keywords: Debenzylation
| DMSO | N-benzylanilines
O
t-Bu
OHC
3M HCl
rt, 1 h
+
+
N
H
NH2
t-Bu
The benzyl group is one of the most frequently used
protecting groups for amines and alcohols.1 Benzylation of these
groups is easily performed,2 and benzyl deprotection can be
carried out under various reaction conditions, such as (1)
catalytic hydrogenolysis using Pd/C or other heterogeneous
metal catalysts,3 (2) nucleophilic substitution using strong Lewis
acid like boron halides,4 silyl reagents,5 or other metal salts,6 (3)
oxidation using CAN,7 DDQ,8 or Oxone,9 or (4) reduction using
alkali metal naphthalenide.10 However, these debenzylation
reactions sometimes encounter significant problems including
difficulty in removing toxic residual metals, the use of hazardous
reagents, and the use of harsh reaction conditions that cause
undesired side reactions in multi-step syntheses. Therefore, a
milder, more environment-friendly, and simple deprotection
procedure would be very useful for organic syntheses. Herein,
we report a simple oxidative debenzylation of benzylic anilines
using DMSO as an oxidant.
t-Bu
3a
4a
5
Atmo- TsOH¢H2O DMSO Concentration
T
t
3a 4a
5
Entry
sphere (mol %) (equiv) of 1a (M) (°C) (h) (%) (%) (%)
c
1
2
3
4
5
6
7
8
9
O2
O2
O2
O2
O2
air
air
air
air
air
air
0
5.0
10
940
94
94
94
94
94
94
47
24
0.015
0.015
0.015
0.015
0.15
0.15
0.15
0.30
0.60
1.2
100 119 94 93
®
®
®
®
c
c
c
100
100
100
100
9
8
4
9
88 91
89 88
83 87
100
5.0
5.0
5.0
5.0
5.0
5.0
5.0
66 67 17
100 26 68 70 14
c
c
c
c
c
125 10 83 84
®
®
®
®
®
125
125
125
7
4
4
84 81
85 85
20 24
10a
11
12
2.4b
1.0
100 35 81 81
a1a was recovered in 51%. bDMSO:toluene = 1:5 was used as
c
solvent. Not detected.
During the course of our research into the synthesis of cyclic
amines, we noticed the generation of an imine side product from
a benzylic amine under heating in aerobic DMSO (Scheme 1).
Since the resulting imines were easily hydrolyzed to give amines
and aldehydes, we postulated that this oxidation would be useful
for debenzylation of benzylic amines.
In addition, this type of oxidation has not been utilized for
debenzylation, although there has been one report of the DMSO
oxidation of N-benzylammonium salts (Scheme 1).11 We there-
fore decided to develop a simple, oxidative debenzylation
reaction of benzylic amines.
The study began with debenzylation of N-benzylaniline 1a
as a model substrate (Table 1). Initially, 1a was heated at 100 °C
under oxygen atmosphere in DMSO without any additives
(Entry 1). The products were found to be a mixture of imine 2a,
aniline 3a, and benzaldehyde 4a. In order to allow easy
purification, imine 2a was completely hydrolyzed to 3a and 4a
before work-up. Although nothing happened at first, the reaction
started after one day, and finally 3a and 4a were obtained in
excellent yields after five days. We believed this was due to slow
thermal decomposition of DMSO to generate the acid necessary
to initiate the oxidation.12 Hence, a catalytic amount of TsOH
was added to the reaction, which resulted in dramatic accel-
eration of the reaction rate, and eliminated any initiation time
(Entries 2 and 3). In the presence of a stoichiometric amount of
TsOH, the reaction time was further shortened to 4 h (Entry 4).
A higher concentration of 1a in the presence of 5 mol %
TsOH, resulted in a 9-hour reaction and lower yields of 3a and
4a due to over-oxidation forming the undesired amide 5
(Entry 5). When the reaction was performed under air atmos-
phere, more than 1 day at 100 °C was required for it to reach
Scheme 1. Oxidative debenzylation using DMSO.
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