Oxidation of 4-arylphenol trimethylsilyl ethers to p-arylquinols using hypervalent iodine(III) reagents

Article abstract of DOI:10.1016/j.tetlet.2006.11.073

An efficient synthesis of p-arylquinols by the oxidation of 4-arylphenol trimethylsilyl ethers with phenyliodine(III) diacetate (PIDA) is reported. This protocol greatly improved the yield of p-quinol by minimizing oligomer side products compared to the o

Full text of DOI:10.1016/j.tetlet.2006.11.073

Tetrahedron Letters 48 (2007) 409–412
Oxidation of 4-arylphenol trimethylsilyl ethers to
p-arylquinols using hypervalent iodine(III) reagents
Fran c¸ ois-Xavier Felpin*
Universit e´ Bordeaux-I, Laboratoire de Chimie Organique et Organom e´ tallique, 351 Cours de la Lib e´ ration,
3
3405 Talence Cedex, France
Received 19 October 2006; revised 8 November 2006; accepted 10 November 2006
Available online 30 November 2006
Abstract—An efficient synthesis of p-arylquinols by the oxidation of 4-arylphenol trimethylsilyl ethers with phenyliodine(III) di-
acetate (PIDA) is reported. This protocol greatly improved the yield of p-quinol by minimizing oligomer side products compared
to the oxidation of free phenol with hypervalent iodine(III) reagents. The innocuity of phenyliodine(III) diacetate associated with
the mild conditions make the method highly competitive over metal-mediated oxidation reactions. The proposed reaction mecha-
nism is discussed and compared to the generally accepted mechanism of 4-substituted phenols to explain the yield improvement.
ꢀ
2006 Elsevier Ltd. All rights reserved.
p-Quinols are important skeletons found in many bio-
Table 1. Study of phenol protecting group
1
logically active natural products as well as being impor-
2
RO
Hypervalent
Iodine
O
tant intermediate skeletons in multi-steps synthesis. On
OH
the other hand, Westwell et al. reported p-quinols based
antitumor agents, which represent structurally new and
original skeletons. Westwell et al. prepared p-quinols
CH
0 °C to rt
CN-H O
3 2
2
3
by dearomatization of phenols using Phenyliodine(III)
bis-trifluoroacetate (PIFA) as the oxidating agent. How-
ever, yields of the required p-quinols were low due to the
generation of radical species that might lead to
unwanted by-products. Consequently, although attrac-
tive due to the non toxic nature of hypervalent iodine(III)
reagents and the simplicity of the method,4 this
approach is often hampered by limited yields as a result
of competitive ortho oxidation and/or oligomerization
processes. As part of a program directed at the discovery
of new anticancer agents, we were interested in the
incorporation of p-quinol skeletons in our own struc-
Entry
R
Substrate Hypervalent iodine Yield (%)
1
2
3
4
5
6
7
8
H
H
CH
CH
CH SO
CH SO
Si(CH
Si(CH
1
1
3
3
4
4
5
5
PhI(OAc)
PhI(OCOCF
PhI(OAc)
PhI(OCOCF
PhI(OAc)2
2
43
17
3
3
)
2
2
3
2
Trace
Trace
0
0
82
3
)
3
2
3
2
PhI(OCOCF3)2
PhI(OAc)
PhI(OCOCF
3
)
3
2
3
)
3
3
)
2
35
5
corresponding p-arylquinol 2 in higher yield than 43%
entry 1). We observed extensive oligomerization dra-
matically decreasing the yields of isolated p-arylquinol
. Phenyliodine(III) bis-trifluoroacetate (PIFA) has a
tures. For this purpose, we have re-examined the hyper-
valent iodine(III) mediated oxidation of phenol
derivatives.
(
2
deleterious effect on the yield causing much more oligo-
merization than phenyliodine(III) diacetate (PIDA)
We first selected 4-phenyl phenol 1 as a model substrate
in the presence of water as nucleophile (Table 1). De-
spite numerous attempts, we were unable to isolate the
(entry 1 vs 2). We believe that the side products are formed
as a result of the formation of a highly reactive phe-
noxonium ion (vide infra). With the intention to mini-
mize this intermediate, we envisaged the oxidation of
the corresponding protected phenol. Although oxidative
dealkylation has been reported for the formation of qui-
Keywords: p-Arylquinols; Hypervalent iodine(III) reagents; Oxidation;
Dearomatization.
*
Tel.: +33 5 40 00 62 87; fax: +33 5 40 00 62 86; e-mail:
fx.felpin@lcoo.u-bordeaux1.fr
6
nones, phenol methyl ether 3 was found to be mostly
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.073

410
F.-X. Felpin / Tetrahedron Letters 48 (2007) 409–412
unreactive in our studies (entries 3 and 4). Mesyl pro-
tecting group also inhibited the oxidative dearomatiza-
tion (entries 5 and 6). Then, we studied the reactivity
(Table 2). With a variety of phenols or their trimethyl-
silyl ether derivatives in hand, we studied the hypervalent
iodine(III)-mediated dearomatization, in the presence of
water as nucleophile, with three different methods: (A)
oxidation of 4-arylphenol trimethylsilyl ethers with
PIDA, (B) oxidation of 4-arylphenol trimethylsilyl
ethers with PIFA and (C) oxidation of 4-arylphenols
with PIDA. As expected, method A (e.g., oxidation of
4-arylphenol trimethylsilyl ethers with PIDA) proved
to be the most efficient way to obtain p-arylquinols as
the only identifiable product by TLC. In most cases,
we found a spectacular positive effect for the yield when
the oxidation was carried out on protected phenols as
illustrated by the most impressive one in entry 5. While
7
of trimethylsilyl ether 5. Although the oxidation of 5
with PIFA gave disappointing low yields causing exten-
sive oligomerization (entry 8), we found that the use of
PIDA led to the desired p-arylquinol 2 in an excellent
yield and purity (entry 7). These results are of impor-
tance since trimethylsilyl ethers are easily accessible by
a simple heating of the free phenols with HMDS in
8
the presence of pyridine.
We then examined the impact of the structure of the
4
-arylphenol derivatives on the reaction outcome
Table 2. Screening of 4-arylphenol derivatives oxidation
RO
O
Method A, B or C
OH
R2
R2
R1
R = Si(CH3)3 : Method A or B
R = H
R1
: Method C
Entry
Substrate
Product
Yield (%)
Method
a
A
B
C
RO
O
OH
1
82
35
43
R = H
: 1
2
R = Si(CH ) : 5
3
3
RO
O
O
OH
OH
2
3
76
56
38
R = H
: 6
16
R = Si(CH ) : 7
F
F
3
3
RO
0
0
0
R = H
: 8
17
R = Si(CH ) : 9
3
3
OCH3
OCH3
OCH3
OCH3
RO
O
OH
4
78
70
49
R = H
: 10
18
R = Si(CH ) : 11
3
3
NO2
NO2
Br
Br
RO
O
O
5
6
OH
OH
70
66
59
62
0
R = H
: 12
19
R = Si(CH ) : 13
3
3
RO
44
R = H
: 14
20
R = Si(CH ) : 15
3
3
a
Method A: oxidation of 4-arylphenol trimethylsilyl ethers with PIDA; Method B: oxidation of 4-arylphenol trimethylsilyl ethers with PIFA;
Method C: oxidation of 4-arylphenol with PIDA.

F.-X. Felpin / Tetrahedron Letters 48 (2007) 409–412
411
the oxidation of free phenol 12 only led to oligomeriza-
tion by-products, a complete reversal of reactivity was
observed when the oxidation was performed on 4-aryl-
phenol trimethylsilyl ether 13, allowing the isolation of
p-arylquinol 19 in a good yield (70%). We also demon-
strated unambiguously that PIDA is much more efficient
than PIFA. We noted a higher reactivity of PIFA, lead-
ing to the consumption of starting material after few
minutes at 0 ꢁC probably due to partial instability of
Interestingly, we did not observe any change in the
outcome of the reaction, indicating that the free radical
species are not likely involved in this oxidation process.
In contrast, the oxidation of 4-arylphenol trimethylsilyl
ethers to p-arylquinols could not be explained by the
formation of the highly reactive phenoxonium ion.
Although a detailed understanding of the reaction
mechanism awaits further study, we postulated the for-
mation of a more stable C-iodonylated cyclohexa-
dienone 26 at C4 (Scheme 2). The resulting phenyliodono
9
TMS ether under these conditions. On the other hand,
PIDA-mediated oxidation required approximately 1 h
at 0 ꢁC and 2 h at room temperature to go to comple-
tion. For some reason, oxidation of the electron rich
substituted substrates 8 and 9 gave only degradation
products, irrespective of the method used (entry 3). In
the case of the less reactive 4-alkylphenol trimethylsilyl
ether 15, a significant enhancement of the yield was
reached (entry 6). However, the reaction required longer
reaction times (5 h) to fully consume the starting mate-
rial and TLC analysis of the crude reaction mixture
showed along with the expected p-arylquinol 20 uniden-
tified by-products, which were not observed with 4-
arylphenols.
5
group, which has a leaving ability 8 · 10 times
1
2
greater than a triflate group, could then act as a
powerful nucleofuge when substituted by water to give
the corresponding p-phenylquinol 2. Stabilization of
the partial positive charge at C4 by aryl group could
explain the origin of the high regioselectivity observed.
To support our hypothesis, it would be interesting to
take into consideration the results of entry 4 (Table 2).
While the yields of methods B and C are significantly
higher compared to other substrates, we did not observe
any improvement with method A. These results could be
explained by the ability of the 3-nitrophenyl substituent
in stabilizing the carbocation at C4. In the case of
method A, we suggest that the carbocation at C4 is
not formed, annihilating the influence of the 3-nitro-
phenyl group. Clearly, these observations support our
mechanistic explanations.
It has been postulated that intermediate 21 dissociates to
give a very reactive phenoxonium ion 22, which could
react either at C2 and/or C4 positions depending on
the stability of the resulting carbocations 23–24 (Scheme
1
0
1
). In the case of 4-arylphenols, the carbocation at C4
is highly favored leading to the formation of the
expected p-arylquinols. On the other hand, it has been
recently reported that free radical species could also be
involved in the oxidation of 2,6-dimethylphenol by
PIDA. In order to address this issue, the potent radical
scavenger TEMPO was added to the reaction mixture
during the oxidation of 4-phenylphenol by PIDA.
In summary, we have reported a highly efficient synthe-
sis of p-arylquinols by dearomatization of 4-arylphenol
trimethylsilyl ethers with PIDA. We demonstrated that
the protection of phenols as their trimethylsilyl deriva-
tives greatly improve the yields by minimizing undesired
oligomerization processes. We believe that such an
1
1
HO
Ph
O
O
PhI(OAc)2
I
-PhI
OAc
-
AcO
1
21
22
O
O
O
H O
2
OH
2
3
24
2
Scheme 1. Accepted mechanism of phenol oxidation to p-quinol using PIDA.
Ph
OAc
O
O
I
Me Si
Me Si
3
AcO
OAc
3
I
Ph
5
25
AcO
OH
OAc
O
O
I
Ph
δ
H
H
O
26
2
Scheme 2. Proposed mechanism of 4-arylphenol trimethylsilyl ethers oxidation using PIDA.

412
F.-X. Felpin / Tetrahedron Letters 48 (2007) 409–412
improvement can be explained by the formation of a
more stable C-iodonylated cyclohexadienone at C4
instead of a highly reactive phenoxonium ion as potential
intermediates. We are currently incorporating this
chemistry to conceptually novel structures in the aim
to find new antitumor agents.
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Acknowledgements
The author thanks Mr. Soumya Mitra (The Ohio State
University), Mr. Edouard Godineau (University Bor-
deaux 1), and Mrs. G e´ raldine Rousseau (University
Bordeaux 1) for helpful discussions. The University of
Bordeaux 1 and the Centre National de la Recherche
Scientifique (CNRS) are gratefully acknowledged for
financial support.
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. A control experiment in the absence of water showed that
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4