Efficient synthesis of p-quinols using catalytic hypervalent iodine oxidation of 4-arylphenols with 4-iodophenoxyacetic acid and oxone

Article abstract of DOI:10.1248/cpb.57.643

Efficient synthesis of p-quinols (2) using catalytic hypervalent iodine oxidation of 4-arylphenols (1) with 4-iodophenoxyacetic acid (3) and Oxone was developed. Reaction of 1 with a catalytic amount of 3 in the presence of Oxone as a co-oxidant in tetrahydrofuran or 1,4-dioxane-water gave the corresponding 2 in excellent yields.

Full text of DOI:10.1248/cpb.57.643

June 2009
Communications to the Editor
Chem. Pharm. Bull. 57(6) 643—645 (2009)
643
tetrahydrofuran (or 1,4-dioxane)–water (Chart 2).
Efficient Synthesis of p-Quinols Using
Catalytic Hypervalent Iodine Oxidation
of 4-Arylphenols with
We first examined 4-phenylphenol (1a) as a model sub-
strate (Table 1). Treatment of 1a and 0.1 eq of 3 and 4 eq of
Oxone® in acetonitrile–water (2 : 1) at room temperature for
24 h gave 2a in only 38% yield. Addition of water shortened
the reaction time, although yields were not improved (entries
2, 3). Next we investigated the solvent effect of other water-
soluble organic solvent on the catalytic reactions. A similar
reaction of 1a in acetone–water (1 : 2) gave an almost identi-
cal result to that in acetonitrile–water (entry 4). Use of 2,2,2-
trifluoroethanol (TFE), which is known to be an efficient sol-
vent in catalytic hypervalent iodine reactions,29,31,38) gave
high yield (76%) of 2a, but needed a longer reaction time
(entry 5). However, it is interesting that an unfamiliar solvent
in hypervalent iodine chemistry, tetrahydrofuran (THF) gave
a better result than TFE did (entry 6). Use of 1,4-dioxane
shortened the reaction time with a lower reaction yield (entry
7). When the reaction was conducted in a 1 : 5 mixture of
THF–H2O, the reaction was completed within 5 h. The best
yield was obtained (entry 8). Further addition of water to the
THF–H2O solvent system was ineffective (entry 9). The cat-
4-Iodophenoxyacetic Acid and Oxone®
Takayuki YAKURA* and Masanori OMOTO
Graduate School of Medicine and Pharmaceutical Sciences,
University of Toyama; Sugitani, Toyama 930–0194, Japan.
Received March 10, 2009; accepted April 3, 2009; published online
April 6, 2009
Efficient synthesis of p-quinols (2) using catalytic hypervalent
iodine oxidation of 4-arylphenols (1) with 4-iodophenoxyacetic
acid (3) and Oxone® was developed. Reaction of 1 with a cat-
alytic amount of 3 in the presence of Oxone® as a co-oxidant in
tetrahydrofuran or 1,4-dioxane–water gave the corresponding 2
in excellent yields.
Key words p-quinol; 4-iodophenoxyacetic acid; Oxone®; catalytic hy-
pervalent iodine oxidation; 4-arylphenol
Development of efficient methods for synthesis of p- alytic oxidation proceeded even in water alone, but a longer
quinols is quite important in synthetic organic chemistry reaction time, unfortunately, was required (entry 10). We
because they are structural components of numerous natu- then changed the amounts of 3 and Oxone® (entries 11—15).
ral products1—4) as well as pharmacologically active com- When the amount of Oxone® was reduced to 1 eq in a 1 : 5
pounds5—7) and useful synthetic intermediates.8,9) A com- mixture of THF–H2O, the reaction was completed after 13 h
monly used methods for preparation of p-quinols is 4- to give 86% yield of 2a. A similar reaction with 0.05 eq of 3
substituted phenol oxidation. Among many reported oxidants and 4 eq of Oxone® required 8 h to finish the reaction afford-
for the oxidation of phenols,10—17) hypervalent iodine(III) ing 2a in 85% yield. When 1a was treated with 0.025 eq of 3
oxidants such as phenyliodine(III) diacetate (PIDA) and
phenyliodine(III) trifluoroacetate (PIFA) are typically
used18—21) because of the non-toxic nature of hypervalent io-
dine(III) reagents and the method’s simplicity.22—26) However,
this approach often gives low yields of the desired product
because of competitive oligomerization, especially in the
case of oxidation of 4-arylphenols. For example, Felpin re-
ported in 2007 that the oxidation of 4-phenylphenol (1a)
with PIDA gave the corresponding p-quinol (2a) in 43%
yield. In fact, PIFA caused much more complication than
PIDA to reduce the yield to 17% (Chart 1).27) We recently
Chart 2
reported a catalytic hypervalent iodine oxidation of 4-
Table 1. Oxidation of 1a with 3 and Oxone®a)
alkoxyphenols to p-quinones using a catalytic amount of
4-iodophenoxyacetic acid (3) with Oxone® (2KHSO5·
KHSO4·K2SO4) as a co-oxidant.28,29) This oxidation system
has the following advantages. The reaction proceeds under
mild conditions. Oxone® is an inorganic, water-soluble, com-
mercially available, and inexpensive co-oxidant that has low
toxicity.30) Moreover, the solubility of 3 in alkaline solution
makes its separation and recovery steps easier to carry out
without a purification step. As part of our study for develop-
ment of catalytic hypervalent iodine oxidations,31—45) we re-
port herein an efficient synthesis of p-quinols directly from
4-arylphenols using catalytic amount of 3 and Oxone® in
3
(eq)
Oxone
(eq)
Time
(h)
Yield of
2a (%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.025
0.01
None
4
4
4
4
4
4
4
4
4
4
1
4
4
4
4
CH3CN–H2O (2 : 1)
CH3CN–H2O (1 : 1)
CH3CN–H2O (1 : 2)
Acetone–H2O (1 : 2)
24
2.5
1
38
35
43
46
76
80
60
89
2
CF3CH2OH–H2O (1 : 2) 12
THF–H2O (1 : 2)
1,4-Dioxane–H2O (1 : 2)
THF–H2O (1 : 5)
THF–H2O (1 : 10)
H2O
THF–H2O (1 : 5)
THF–H2O (1 : 5)
THF–H2O (1 : 5)
THF–H2O (1 : 5)
THF–H2O (1 : 5)
10
3
5
8
81
16
13
8
13
24
54 (30)b)
86
85
88
53 (26)b)
No reaction
a) Reactions were carried out at room temperature. b) Parentheses are recovery of
1a.
Chart 1
∗ To whom correspondence should be addressed. e-mail: yakura@pha.u-toyama.ac.jp
© 2009 Pharmaceutical Society of Japan

644
Vol. 57, No. 6
Table 2. Catalytic Hypervalent Iodine Oxidation of p-Aryl Phenols (1)a)
Entry
1
Solventb)
Time (h)
Yield (%)
1
2c)
3
b
c
c
d
e
f
g
h
i
A
A
B
B
B
B
B
B
A
B
16
24
3
4
8
5
4
4
7
67
58
87
66
48
43
77
85
79
75
4
5d)
6
7
8d)
9d)
10
j
2
Chart 3
a) Reactions were carried out using 0.05 eq of 3 and 4 eq of Oxone® at room temper-
ature. b) A: THF–H2Oꢀ1 : 5, B: 1,4-dioxane–H2Oꢀ1 : 2. c) Reaction was carried
out using 0.2 eq of 3. d) Reaction was carried out using 0.1 eq of 3.
iodine(III) species might exist as an intermediate. A possible
catalytic cycle for this oxidation is shown in Chart 3.
and 4 eq of Oxone®, the reaction time was increased to 13 h Iodoarene would be oxidized by Oxone® to iodine(III)
(entry 13). Reaction using 0.01 eq of 3 was not finished after species.58) The resultant trivalent iodine species reacts with
24 h to afford 3a in 53% yield along with 26% of recovered 4-arylphenol to give cationic intermediate (A) stabilized by
1a (entry 14). Reaction of 1a with Oxone® in the absence of 4-aryl group and iodine(I) derivative, before its further oxi-
3 did not occur (entry 15).16)
dation to iodine(V) species. The intermediate (A) is then hy-
Various 4-substituted phenols (1b—j) were oxidized with drolyzed to p-quinol. In the case of the reaction of 1e having
0.05 eq of 3 and 4 eq of Oxone® to the corresponding p- electron-withdrawing cyano group, the weaker stabilization
quinols (Chart 2, Table 2).46) When 4-(4-tolyl)phenol (1b) of A is expected to decrease its reactivity to give low yield.
was treated with 0.05 eq of 3 and Oxone® in THF–H2O (1 : 5)
In summary, an efficient and practical method for the
at room temperature, the reaction was finished within 16 h to preparation of p-quinols using a novel catalytic hypervalent
give 67% of p-quinol (2b) (entry 1). A similar reaction of 4- iodine oxidation of phenols with 3 and Oxone® was devel-
(4-pivaloyloxymethylphenyl)phenol (1c) in THF–H2O pro- oped. Reaction of 4-arylphenols (1) with a catalytic amount
ceeded slowly to give 58% yield of the corresponding 2c of 3 in the presence of Oxone® as a co-oxidant in THF or
after 24 h stirring with 0.2 eq of 3. In contrust, 1c reacted 1,4-dioxane–water gave the corresponding p-quinols (2) in
more smoothly in 1,4-dioxane–H2O (1 : 2) than in THF–H2O excellent yields.
to afford 2c in 87% yield (entries 2, 3). Oxidation of 4-
bromo derivative (1d) in 1,4-dioxane–H2O gave the corre-
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