Aerobic oxidative deprotection of benzyl-type ethers under atmospheric pressure catalyzed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)/tert-butyl nitrite

Article abstract of DOI:10.1016/j.tetlet.2013.01.045

A facile and efficient protocol for the oxidative deprotection of benzyl-type ethers has been developed. The reaction was performed with catalytic amounts of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tert-butyl nitrite (TBN) under atmospheric pressure of O₂. Under the optimal reaction conditions, a variety of p-methoxybenzyl (PMB), p-phenylbenzyl (PPB), and benzyl (Bn) ethers can be deprotected to their corresponding alcohols in excellent conversions and selectivities.

Full text of DOI:10.1016/j.tetlet.2013.01.045

Tetrahedron Letters 54 (2013) 1579–1583
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aerobic oxidative deprotection of benzyl-type ethers under atmospheric
pressure catalyzed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(
DDQ)/tert-butyl nitrite
a,
⇑
a
a
a
a
a
a,b,
⇑
Zhenlu Shen , Lili Sheng , Xiaochu Zhang , Weimin Mo , Baoxiang Hu , Nan Sun , Xinquan Hu
a
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, China
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient protocol for the oxidative deprotection of benzyl-type ethers has been developed.
The reaction was performed with catalytic amounts of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
Received 5 November 2012
Revised 7 January 2013
Accepted 11 January 2013
Available online 17 January 2013
2
(DDQ) and tert-butyl nitrite (TBN) under atmospheric pressure of O . Under the optimal reaction condi-
tions, a variety of p-methoxybenzyl (PMB), p-phenylbenzyl (PPB), and benzyl (Bn) ethers can be depro-
tected to their corresponding alcohols in excellent conversions and selectivities.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Deprotection
2
,3-Dichloro-5,6-dicyano-1,4-benzoquinone
(
DDQ)
tert-Butyl nitrite (TBN)
Oxygen
Benzyl-type ether
The selective and efficient protection and deprotection of hy-
droxyl groups play a crucial role in organic synthesis, as these
methods have been extensively utilized in different areas of
complex syntheses of natural products, pharmaceutical chemicals,
cleavage of benzyl-type ethers remains a popular protocol. Among
these oxidants, DDQ is used most frequently. An example of
oxidative deprotection of PMB ethers with DDQ in large-scale can
be found in the synthesis of discodermolide by Novartis.14
However, the use of stoichiometric DDQ results in the isolation
problem because of the concomitant by-product 2,3-dichloro-5,6-
dicyano-hydroquinone (DDHQ). To avoid this inherent disadvan-
tage, a combination of catalytic amount of DDQ and a less-
expensive co-oxidant is an interesting alternative. Several inor-
ganic oxidants can be acted as the co-oxidant to regenerate DDHQ,
1
and materials. Protection of hydroxyl groups as benzyl-type
2
ethers has long been developed as a valuable reaction, which is
mainly due to that benzyl-type protecting groups provide a
number of significant advantages such as ease of introduction, sta-
bility toward both acidic and basic reaction conditions, and relative
insensitivity to various oxidizing and reducing agents. These ben-
zyl-type protecting groups include benzyl (Bn), diphenylmethyl,
trityl, p-methoxybenzyl (PMB), m-methoxybenzyl, p-phenylbenzyl
1
5
16
and the combination of DDQ–FeCl
3
,
DDQ–Mn(OAc)
can be effectively used for the removal of PMB
or 3,4-dimethoxybenzyl group. However, using of great
3
,
or
1
7
DDQ–MnO
2
(
PPB), p-halobenzyl, 3,5-dimethoxylbenzyl, and 2-naphthylmethyl,
a
3
etc. There are various methods for the removal of benzyl-type
protecting groups. Lewis acids, including SnCl –PhSH,
4
AlCl
or Ce(OTf)
amount of these inorganic oxidants brings new environmental
effluents.
4
5
6
7
8
3
–EtSH, CeCl –BF
3
Á7H
2
O–NaI, NaCNBH
3
ÁEt
3 2
O, ZrCl
4
–CH
3
CN,
In the recent years, using the catalytic oxidationsystems employ-
ing catalytic amounts of DDQ and a co-catalyst with molecular oxy-
gen serving as the terminal oxidant to replace the stoichiometric
DDQ has received interests. These catalytic oxidation systems have
remarkable environmental and economic benefits, and have been
9
3
–CH NO , etc, have been introduced to facilitate the
3
2
cleavage of benzyl-type ethers. TfOH, a Bronsted acid, also can
mediate p-methoxybenzyl group demasking.10 The use of
stoichiometric oxidants, such as 2,3-dichloro-5,6-dicyano-
1
1
12
18
1
,4-benzoquinone (DDQ), ceric ammonium nitrate (CAN), or
successfully applied in oxidative dehydrogenation, alcohol oxida-
phenyliodine bis(trifluoroacetate) (PIFA),13 for the oxidative
tion, and oxidative cross-dehydrogenative coupling reactions.
19
20
21
With our previous TEMPO-catalyzed aerobic oxidation, we re-
cently reported DDQ/tert-butyl nitrite (TBN) catalyst system for
the aerobic oxidation of alcohols and oxidative deprotection of
⇑
Corresponding authors. Tel.: +86 571 88320416; fax: +86 571 88320103.
E-mail addresses: zhenlushen@zjut.edu.cn (Z. Shen), xinquan@zjut.edu.cn
2
2
PMB ethers in autoclave. For the purpose of simplifying the
(
X. Hu).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.045

1
580
Z. Shen et al. / Tetrahedron Letters 54 (2013) 1579–1583
DDQ, TBN
reaction conditions are summarized in Table 2. PMB ethers of
P-O-R
R
OH
1-octanol, 2-octanol, and cyclohexanol (1b–d) underwent a com-
plete deprotection of PMB group to furnish the corresponding alco-
hols in excellent selectivity (entries 2–4). When PMB ethers 1e and
O -Balloon
2
P: benzyl-type protecting group,
PMB, PPB or Bn
1
f with high steric hindrance were subjected to deprotection,
increasing the catalyst loading was needed (entries 5 and 6).
PMB ethers containing a heterocyclic moiety (1g–i) could also be
fully deprotected. The successful deprotection of 1g showed that
the oxidative deprotection can endure the Boc group (entry 7).
2
Scheme 1. Oxidative deprotection of benzyl-type ethers with DDQ/TBN/O .
equipment and extending the substrate scope, we investigated the
aerobic oxidative deprotection of several benzyl-type ethers at
atmospheric pressure of O in the presence of DDQ/TBN (Scheme 1).
2
The successful results are described in this Letter.
In our initial screening experiments, oxidative deprotection of
PMB ether 1a with DDQ/TBN/O was selected as the model reac-
2
tion. The optimized results of the influence of various parameters
including solvent, the amounts of DDQ and TBN, reaction time,
and reaction temperature are summarized in Table 1. Firstly, the
reaction was carried out in different solvents with 5 mol % DDQ
Diacetone-D-glucose 2j, bounding two acid-sensitive isopropyli-
dene group as well as a glycosidic ring, could be obtained from
its PMB ether 1j in 94% isolated yield (entry 10). The substrates
with two different hydroxyl protecting groups (1l–o) were also
submitted to the oxidative deprotection reactions. The results
showed that using this procedure the PMB ethers were selectively
cleaved, giving the corresponding alcohols without affecting the
other functional groups (entries 12–15). In case of entry 16, the
PMB ether of p-chlorophenol (1p) gave very poor conversion
(<5%) in deprotection under our reaction condition. Similar result
was obtained when the PMB ether of phenol was used as the sub-
strate. Thus, we thought that this method might be proposed to
selectively deprotect alkyl PMB ether in the presence of aryl PMB
ether, and PMB ether of 4-(2-hydroxyethyl)phenol (1q) with two
PMB groups was subjected to the oxidative deprotection. The de-
sired product 2q was obtained in 81% isolated yield (entry 17).
Comparing with PMB group, the PPB group is more compatible
2
and 5 mol % TBN under atmospheric pressure of O in balloon at
1
00 °C. Results in Table 1 showed the solvent can greatly affect
the oxidative deprotection of PMB ether. It was found that
chlorobenzene, ethylene glycol diethyl ether, and 1,1,2,2-tetrachlo-
roethane led to excellent conversion of 1a and selectivity to 2-
phenylethanol (entries 1, 2, 5). Chlorobenzene might be the most
suitable solvent, in which oxidative deprotection of 1a could be
completed in 1.5 h. In ethylene glycol monoethyl ether, moderate
conversion of 1a was obtained in 3 h (entry 3). Other solvents such
as ethylene glycol, xylenes, DMF, and n-BuOH, resulted in poor
conversions (entries 4, 6–8). Further study indicated that decreas-
ing the load of DDQ and TBN from 5 to 3 mol %, a longer reaction
time was needed and the selectivity to 2-phenylethanol was
slightly decreased. Afterward, the effect of reaction time was inves-
tigated. At 80 °C, the reaction rate was slowed down, and a 96%
conversion of 1a was obtained in 3.5 h. When the reaction temper-
ature was increased to 120 °C, the reaction time could be shorten
to 1 h, while the selectivity to 2-phenylethanol was decreased to
1
1c
under acidic conditions. Thus, the oxidative deprotection of a ser-
ies of PPB ethers catalyzed with DDQ/TBN under dioxygen atmo-
sphere (balloon) at 100 °C was studied. The results are listed in
Table 3. It was found that all the PPB ethers (3a–n) could be com-
pletely deprotected in an appropriate reaction time with excellent
selectivities (entries 1–14). It should be noted that a longer reaction
timewas needed to completedeprotection ofa PPB ether thanthat of
a PMB ether. For example, for the cleavage of 1-octyl PPBether and 1-
octyl PMB ether, the reactions were complete in 5 h (Table 2, entry 2)
and 3 h (Table 1, entry 2), respectively. When PPB ether 3j was used
as the substrate, dosage of DDQ and TBN should be increased to
12 mol % to shorten the reaction time and maintain the selectivity
to 2j. Relatively low isolated yield of 2j (80%) was due to the hydro-
lysis of isopropylidene groups in the weak acidic reaction system.
Then, the cleavage of benzyl protecting group of alcohols was
performed in the same way. Bn ethers of 2-phenylethanol (4a) and
1-octanol (4b) were successfully deprotected to give the desired
alcohols (entries 15 and 16). Thus, we believe that other benzyl-type
9
5% (entry 11). On the basis of these experimental data, we con-
cluded that 5 mol % of DDQ and 5 mol % TBN in chlorobenzene at
1
00 °C were suitable for oxidative deprotection of PMB ether under
23
2
atmospheric pressure of O .
PMB is almost the most frequently used alcohol protecting
group in the type of benzyl series, and the results of oxidative
deprotection of a variety of PMB ethers with the optimized
Table 1
Optimization of reaction conditions for the oxidative deprotection of 1aa
DDQ, TBN
OH
OPMB
O -Balloon
2
1a
2a
Entry
Solvent
PhCl
DDQ (mol %)
TBN (mol %)
T (°C)
Time (h)
Conv. (%)
Select. (%)
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
5
3
5
5
5
5
5
5
5
5
5
5
3
5
5
100
100
100
100
100
100
100
100
100
80
1.5
3
3
3
3
6
6
6
3
100
99
67
11
92
10
29
28
100
96
>99
>99
90
90
94
74
85
94
98
98
95
EtO(CH
EtO(CH
2
)
)
2
OEt
OH
2
2
HOCH
2
CH
2
OH
CHCl CHCl
2
2
Xylenes
DMF
n-BuOH
PhCl
PhCl
PhCl
1
1
0
1
3.5
1
120
100
a
Reaction conditions: 1a (2 mmol), solvent (5 mL), DDQ (5 mol %), TBN (5 mol %), O2 (balloon, 1 atm). The conversion and selectivity were determined by GC with area
normalization.

Z. Shen et al. / Tetrahedron Letters 54 (2013) 1579–1583
1581
Table 2
a
Oxidative deprotection of PMB ethers
DDQ, TBN
PMBO-R
R OH
O -Balloon
2
1
2
Entry
Substrate
Product
Time (h)
Conv. (%)
Select.b (%)
OPMB
OH
1
2
3
1.5
3
100
100
100
>99
>99
>99
1
a
2a
CH
3
(CH )
2 7
OPMB (1b)
CH
3
(CH )
2 7
OH (2b)
4.5
OPMB
OH
1
c
2c
OPMB
OPMB
OH
4
3.5
2
100
100
>99
>99
1
d
2d
OH
5c
1
f
e
2e
6c
3
100
>99
OPMB
OH
1
2f
OPMB
OH
7
8
2
1
100
100
>99 (95)
>99
N
N
Boc
OPMB
Boc
1
g
2g
2h
OH
O
O
1
h
9c
2.5
2
100
100
97 (84)
(94)
Cl
N
Cl
N
OPMB
O
OH
1
i
2i
O
O
O
O
O
1
0c
O
O
O
O
PMBO
HO
1
j
2j
1
1
1
1
1
1
2
3
4
5
PMBO(CH
MeO(CH
AcO(CH
BzO(CH
2
)
6
OPMB (1k)
OPMB (1l)
OPMB (1m)
OPMB (1n)
HO(CH
MeO(CH
AcO(CH
BzO(CH
2
)
6
OH (2k)
OH (2l)
6
3
4
3
2
100
100
100
100
100
>99
>99
>99 (93)
>99 (93)
98
2
)
6
2
)
6
)
2 6
2
)
6
OH (2m)
OH (2n)
)
2 6
2
)
6
MOMO(CH
)
2 6
OPMB (1o)
2 6
MOMO(CH ) OH (2o)
OPMB
OH
1
6
7
5
5
<5%
100
—
Cl
Cl
1
p
2p
OPMB
OH
1
(81)
PMBO
PMBO
1
q
2q
a
2
Reaction conditions: PMB ether (2 mmol), chlorobenzene (5 mL), DDQ (5 mol %), TBN (5 mol %), O (balloon, 1 atm), 100 °C. The conversion and selectivity were deter-
mined by GC with area normalization.
b
Values in parentheses are isolated yields.
DDQ (8 mol %), TBN (8 mol %).
c
protecting groups, which can be removed by stoichiometric DDQ,
will be demasked using this procedure. Compared with Bn and
PPB groups, PMB group was easy to demask. Entries 17 and 18
showed that the PMB group was selectively cleaved substantially
without affecting the Bn and PPB groups. The isolated yields of
2
TBN under atmospheric pressure of O . Under the optimal reac-
tion conditions, a variety of PMB, PPB, and Bn ethers can be
deprotected to their corresponding alcohols in high conversions
and selectivities. The substrates with different hydroxyl protect-
ing groups can selectively cleave the benzyl-type groups without
affecting the other functional groups. The notable features of this
methodology including environmental friendliness and opera-
tional simplicity make this protocol more resourceful for future
applications.
2 6 2 6
BnO(CH ) OH (2r) and PPBO(CH ) OH (2s) were 89% and 86%,
respectively.
In conclusion, we have developed a methodology for the oxi-
dative deprotection of benzyl-type ethers catalyzed with DDQ/

1
582
Z. Shen et al. / Tetrahedron Letters 54 (2013) 1579–1583
Table 3
a
Oxidative deprotection of benzyl-type ethers
Entry
1
Substrate
Product
Time (h)
Conv. (%)
100
Select.b (%)
>99
OPPB
2a
5
3
a
2
3
3
CH (CH
2 7
) OPPB (3b)
2b
2c
5
5
100
100
>99
>99
OPPB
3c
OPPB
OPPB
4
2d
2e
3
2
100
100
>99
>99
3d
5c
3e
6c
2f
4
100
>99
OPPB
3
f
OPPB
7
8
2g
2h
7
100
100
>99
>99
N
Boc
OPPB
3
g
4.5
O
3
h
9c
2i
2j
3
3
100
100
97 (82)
(80)
Cl
N
OPPB
O
3
i
O
O
1
0d
O
O
BPPO
3j
1
1
1
1
1c
2
3
4
PPBO(CH
MeO(CH
AcO(CH
BzO(CH
2
)
6
OPPB (3k)
OPPB (3l)
OPPB (3m)
2k
2l
2m
2n
6
5
6.5
5
100
100
100
100
>99
>99
>99 (97)
>99 (95)
2
)
6
2
)
6
2
)
6
OPPB (3n)
OBn
1
5
6
2a
3
100
>99
4
a
1
1
CH
BnO(CH
PPBO(CH
3
(CH
2
)
7
OBn (4b)
2b
BnO(CH
PPBO(CH
4
3
2.5
100
100
100
>99
97 (89)
(86)
7
2
)
6
OPMB (5a)
OPMB (5b)
2
)
6
OH (2r)
OH (2s)
c
1
8
2
)
6
2
)
6
a
2
Reaction conditions: PMB or Bn ether (2 mmol), chlorobenzene (5 mL), DDQ (5 mol %), TBN (5 mol %), O (balloon, 1 atm), 100 °C. The conversion and selectivity were
determined by GC or HPLC with area normalization.
b
Values in parentheses are isolated yields.
DDQ (8 mol %), TBN (8 mol %).
DDQ (12 mol %), TBN (12 mol %).
c
d
Acknowledgments
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0.1 mmol, 5 mol %), and 5 mL of chlorobenzene. Before reaction, air was
replaced by purging with a stream of O . Then the solution was stirred under
dioxygen atmosphere (balloon) at 100 °C for 1.5 h. After cooling to room
2
temperature, the sample from the reaction mixture was diluted with CH Cl ,
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2
000, 41, 10323.
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1
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and the conversion and selectivity were detected by GC without any
purification. The GC result showed that the reaction was completed.