Novel and efficient synthesis of p-quinones in water via oxidative demethylation of phenol ethers using hypervalent iodine(III) reagents

Article abstract of DOI:10.1016/S0040-4039(01)01407-1

A new method for preparing p-quinone derivatives from phenol ether derivatives in water using the hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA) was developed. The present reaction proceeds in good to excellent yields under mild reaction conditions. This oxidation is expected to be environmentally benign since it uses recyclable poly-bis(trifluoroacetoxyiodo)styrene (PBTIS) in water.

Full text of DOI:10.1016/S0040-4039(01)01407-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6899–6902
Novel and efficient synthesis of p-quinones in water via oxidative
demethylation of phenol ethers using hypervalent iodine(III)
reagents
Hirofumi Tohma, Hironori Morioka, Yu Harayama, Miki Hashizume and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 21 June 2001; revised 23 July 2001; accepted 27 July 2001
Abstract—A new method for preparing p-quinone derivatives from phenol ether derivatives in water using the hypervalent
iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA) was developed. The present reaction proceeds in good to
excellent yields under mild reaction conditions. This oxidation is expected to be environmentally benign since it uses recyclable
poly-bis(trifluoroacetoxyiodo)styrene (PBTIS) in water. © 2001 Elsevier Science Ltd. All rights reserved.
The synthesis of quinones is important in organic
chemistry because they are not only useful intermedi-
ates, but also many are pharmacologically active com-
presence of alcohols and H O. These involve the reac-
2
tions of phenols, in which the phenolic oxygen reacts
with the iodine center of PIFA. Although similar
preparative methods of quinones from phenols using
1
pounds. Among various preparations of quinone
2
12
derivatives, oxidative dealkylation (especially demethyl-
iodine(III) reagents have also been reported, the oxi-
ation) of hydroquinone dimethyl ethers is one of the
most effective methods. This is because methyl ethers of
phenol derivatives are stable under various reaction
conditions and can be converted to the desired
quinones in the later stages of a synthetic scheme. Thus
far, oxidative demethylation has been achieved by using
dative demethylation of phenol ethers that have no
phenolic OH groups (hydroquinone dimethyl ethers)
using hypervalent iodine reagents has never been
reported, probably due to their low reactivity in com-
parison with metal oxidants. Very recently, we have
shown that iodine(III) reagents can be remarkably acti-
3
4
13
cerium(IV) ammonium nitrate (CAN), nitric acid, sil-
vated in water by micellar effect or hydrophobic
5
14
ver(II) oxide (AgO)–mineral acid, manganese dioxide
effect. We report herein the first example of oxidative
6
7
(
MnO )–nitric acid, cobalt(III) fluoride (CoF ) and
demethylation reaction of hydroquinone dimethyl ether
derivatives in water using PIFA or poly-bis(tri-
fluoroacetoxyiodo)styrene (PBTIS) in the absence of
additives.
2
3
8
NBS–H SO . However, total syntheses of naturally
2
4
occurring complex quinones sometimes need milder
reaction conditions and the pharmaceutical and agro-
chemical industries are seeking environmentally benign
methods free of metal waste. Hypervalent iodine
reagents have been used extensively in organic synthe-
ses as a result of their low toxicity, ready availability
First, we examined the oxidation of 1,4-dimethoxyben-
zene (1a) using PIFA. Interestingly, after optimization
of the reaction conditions, the reaction was found to
proceed smoothly in water (containing a small amount
of MeOH as a co-solvent) to give p-benzoquinone (2a)
9
and easy handling. As a continuation of our studies on
hypervalent iodine chemistry, we have already reported
various oxidation reactions of phenol and phenol ether
derivatives using phenyliodine(III) bis(trifluoroacetate)
15
quantitatively, while either deficiency or absence of
16
water caused side reactions as well as low yield of 2a.
10
(
PIFA) and phenyliodine(III) diacetate (PIDA).
Among them, we have developed efficient oxidation
Next, we compared this reaction with typical oxidative
demethylation methods using CAN or AgO–HNO3
reactions of p-alkoxyphenols leading to p-quinone
1
1a
11b
monoacetals
and p-quinones
using PIFA in the
(
Table 1).
Although hypervalent iodine oxidations required long
reaction time in all cases, Table 1 shows that the
present reaction gave the best results when PIFA or
*
Corresponding author. Tel.: +81-6-6879-8225; fax: +81-6-6879-8229;
e-mail: kita@phs.osaka-u.ac.jp
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01407-1

6
900
H. Tohma et al. / Tetrahedron Letters 42 (2001) 6899–6902
Table 1. Comparison with other methods using CAN or AgO
Entry
Substrate
Reagent (equiv.)
Solvent
Reaction time
Yield of 2
a
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1i
PIFA (4.0)
CAN (3.0)
CAN (4.0)
PIDA (1.5)
CAN (3.0)
AgO (5.0)–HNO3
PIFA (1.5)
CAN (3.0)
H O
4 h
30 min
24 h
1 h
Quant.
57
21
2
CH CN–H O (1:1)
3
2
a
H O
2
a
H O
86
—
—
2
b
CH CN–H O (1:1)
3
2
b
Dioxane
a
H O
1.5 h
30 min
5 min
95
93
87
2
1i
1i
CH CN–H O (1:1)
Dioxane
3
2
AgO (5.0)–HNO3
a
2
3
.5 v/v% MeOH in H O.
2
a was mainly obtained (see Refs. 3 and 5).
b
1
7
PIDA was used even in the oxidation of 1b, which
was converted to dimeric product 3a when using CAN
or AgO. Incidentally, the oxidation reaction that uses
CAN in water was not effective for oxidative demethyl-
ation (entry 3, Table 1).
result, p-quinones were obtained in good yields when
using PBTIS in water, while the reaction proceeded
much more slowly than when PIFA was used (Table 3).
Table 2. Synthesis of p-quinones via oxidative demethyla-
tion of phenol ethers in water using PIFA
The present method is applicable to a variety of substi-
tuted phenol ethers (1a–m) and affords the correspond-
ing p-quinones (2a–m) in high yields as shown in Table
time yield
entry
substrate
product
O
(h)
(%)
R2
R3
2.
R1
quant.a
86b
OMe
(1a)
4
1
3
4
1
2
3
4
5
6
H
OMe
H
H
H
H
R1
R1
OMe OMe
Me OMe
CH2CO2MeOMe
(
1b)
1c)
(1d)
Interestingly, p-quinones were obtained selectively even
when using ortho-substituted phenol ethers (1g, h)
(
b
81
R3
R3
a
a
a
84
95
71
(
entries 7–8, Table 2). Furthermore, oxidation of indole
R2
OMe OMe Br (1e)
O 2a-f 24
derivatives also proceeded to give pharmacologically
important indoloquinone derivatives in good yields
OMe OAc
R4
H
R5
H
(1f)
1.5
O
OMe
R4
R5
R5
R4
(
entries 12, 13, Table 2). However, the oxidation of
OMe
(1g)
2g
2h 18
b
7
8
24
62
70
a
OMe OMe (1h)
meta-substituted phenol ethers (1n–p) did not yield
quinones but yielded the corresponding diaryliodonium
salts (4a–c) in high yields (entries 14–16, Table 2).
O
OMe
O
R6
R6
6
95c
9
R : H (1i)
2i 1.5
Next, we modified this system to develop a practical
and clean procedure for oxidative demethylation using
a polymer-supported hypervalent iodine(III) reagent.
R : Me (1j)
6
2j 0.5
92c
1
0
O
OMe
OMe
O
O
18
Polymer-supported hypervalent iodine reagents are
expected to be useful for pharmaceutical and agro-
chemical industries due to their versatility, low toxicity
97a
11
1k
2k 6
Et
Et
OMe
19
20
OMe
O
and high yields. Recently, Togo et al. and Ley et al.
demonstrated that poly-(diacetoxyiodo)styrene
PDAIS) shows similar reactivity to PIDA and utilized
R7 R : H (1l)
7
R 2l 1
7
1
2
3
4a
7
7
1
R : (CH ) NHCOCF
62(80)c,d
2
2
3
3
2m
(
MeO
N
N
(1m)
MeO
it as a replacement for previously reported iodine(III)
reagents. We have reported on a new and facile activa-
tion of PDAIS and PBTIS in water as well as in
OMe Ts
O
Ts
OMe
OMe
R8
R9
4a
4b
4c
2
2
2
97c
1
15
16
4
H
H
OMe (1n)
Me (1o)
OMe OMe
c
CH Cl and developed an environmentally benign oxi-
R8
R9
95
79
2
2
R8
R9
c
21
(1p)
dation of alcohols as well as an efficient biaryl cou-
+
I Ph
–OCOCF3
2
2
pling reaction. As an extension of our studies on the
practical utility of hypervalent iodine reagents, we then
investigated the use of recyclable poly-(diacyl-
oxyiodo)styrene for oxidative demethylation. As a
a
b
Reactions were performed with 4.0 equiv. PIFA. Reactions were performed with 1.5
c
d
equiv. PIDA. Reactions were performed with 1.5 equiv. PIFA. Yield in parenthesis
is based on the consumed starting material.

H. Tohma et al. / Tetrahedron Letters 42 (2001) 6899–6902
6901
Table 3. Synthesis of p-quinones via oxidative demethyla-
tion using PBTIS and the efficiency of recycled PBTIS
tools for the syntheses of various biologically active
natural products containing a quinone structure. Syn-
thetic application of this method is now underway in
our laboratory.
Entry
Substrate
Product
Reaction time Yield (%)
h)
(
1
2
3
4
5
1b
1c
1i
1i
1i
2b
2c
2i
2i
2i
16
12
74
71
95
95
94
Acknowledgements
24 (cycle 1)
27 (cycle 2)
32 (cycle 3)
This work was supported by the Grant-in-Aid for
Scientific Research (S) (No. 7690) and for Encourage-
ment of Young Scientists (No. 13771331) from the
Ministry of Education, Science, Sports and Culture,
Japan. H.T. also thanks the Hoh-ansha Foundation for
a research fellowship.
All reactions were carried out in H O:MeOH using 4.0 equiv. PBTIS
at 20°C.
2
Ph
Ph
X
+
H2O O Me
OMe
OMe I X MeO
X
O
O
I
PhIX2
R
R
R
R
HO
R
+
H
+
O
1
H O O Me
OMe
OMe
Me
2
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oxidation in water: To a stirred suspension of 1 (0.20
3
2
mmol) in H O (1.0 mL) containing a small amount of
2
30% H O aq. (5.0 mL) was added dropwise at 0°C. The
2 2
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2
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2
phy (SiO /n-hexane–AcOEt) gave pure 2.
to give PBTIS. Poly iodostyrene was readily prepared
from polystyrene standard (Mw=50,000 purchased from
Aldrich) by treatment with I /I O /50%H SO /nitroben-
2
Although the reaction also proceeded in water, the addi-
tion of a small amount of MeOH (<20% MeOH in H O)
2
2
2
5
2
4
18a
was found to be more effective for an enhancement of the
reaction rate. Addition of excess amount of MeOH deac-
tivated PIFA.
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