eugenol.demethylation.sibx, biotransformation
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ORGANIC
LETTERS
A Stabilized Formulation of IBX (SIBX)
for Safe Oxidation Reactions Including a
New Oxidative Demethylation of
Phenolic Methyl Aryl Ethers
2003
Vol. 5, No. 16
2903
-
2906
Aur lie Ozanne,
†
Laurent Pouys gu,
†,‡
Dominique Depernet,
§
Bruno Franc
ü
ois,
§
and St phane Quideau*
,†,‡
Institut Europ
´
en de Chimie et Biologie, 16 a
enue Pey-Berland,
F-33607 Pessac, France, Laboratoire de Chimie des Substances V
´
g
´
tales,
Centre de Recherche en Chimie Mol
´
culaire, Uni
V
ersit
´
Bordeaux 1,
351 cours de la Lib
´
ration, F-33405 Talence Cedex, France, and
SIMAFEX, 16 a
V
V
enue des Fours-
`
-Chaux, F-17230 Marans, France
s.quideau@iecb-polytechnique.u-bordeaux.fr
Received June 4, 2003
ABSTRACT
SIBX is a nonexplosive formulation of IBX that can be used as a suspension in a variety of standard organic solvents such as refluxing EtOAc
and THF to oxidize safely alcohols into aldehydes and ketones. The use of hot THF is limited to the oxidation of allylic and benzylic alcohols.
Most yields are comparable to those obtained with IBX or DMP. SIBX can also be used to perform oxygenative demethylation of 2-methoxyarenols
into orthoquinones and catechols.
The utility of hypervalent iodine(V) compounds such as the
Dess
of DMP and IBX are limited because both reagents suffer
from major safety concerns related to their violent decom-
position under impact and/or heating.
2d,5
Modified IBX-like
reagents have been introduced as nonexplosive oxidants,
6,9
Martin periodinane reagent (DMP)
1
and its benzio-
doxole oxide precursor 2-iodoxybenzoic acid (IBX)
1b,2
has
been amply evidenced by many successful demonstrations
of their selectivity in oxidation reactions.
2b,3
These
ì
5
-iodanes
have also found uses in many other synthetic transformations
3c,4
and often constitute environmentally benign alternatives to
heavy metal-based systems. However, industrial applications
-
(3) (a) Varvoglis, A.
Hyper
V
alent Iodine in Organic Synthesis
; Academic
Press: San Diego, CA, 1997. (b) Wirth, T.; Hirt, U. H.
Synthesis
1999
,
1271-1287. (c) Wirth, T.
Angew. Chem., Int. Ed. Engl.
2001
,
40
, 2812-
2814. (d) More, J. D.; Finney, N. S.
Org. Lett.
2002
,
4
, 3001-3003. (e)
Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V. D.; Rao,
K. R.
J. Org. Chem.
2003
,
68
, 2058-2059. (f) Wirth, T.
Top. Curr. Chem.
2003
,
224
, 185-208.
(4) (a) Zhdankin, V. V.; Stang, P. J.
Chem. Re
V
.
2002
,
102
, 2523-2584.
(b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L.
J. Am.
Chem. Soc.
2002
,
124
, 2245-2258 and previous papers in the same series.
(c) Wu, Y.; Huang, J.-H.; Shen, X.; Hu, Q.; Tang, C.-J.; Li, L.
Org. Lett.
2002
,
4
, 2141-2144. (d) Bose, D. S.; Srivinas, P.
Synlett
1998
, 977-978.
(e) Bose, D. S.; Narsaiah, A. V.
Synth. Commun.
1999
,
29
, 937
†
Institut Europ´en de Chimie et Biologie.
‡
Laboratoire de Chimie des Substances V´g´tales.
§
SIMAFEX.
(1) (a) Dess, D. B.; Martin, J. C.
J. Org. Chem.
1983
,
48
, 4155
4156.
(b) Dess, D. B.; Martin, J. C.
J. Am. Chem. Soc.
1991
,
113
, 7277-7287.
(2) (a) Hartmann, C.; Meyer, V.
Chem. Ber.
1893
,
26
, 1727
-
1732. (b)
Frigerio, M.; Santagostino, M.
Tetrahedron Lett.
1994
,
35
, 8019-8022.
(c) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G.
J. Org. Chem.
1995
,
60
, 7272-7276. (d) Frigerio, M.; Santagostino, M.; Sputore, S.
J.
Org. Chem.
1999
,
64
, 4537
-
941.
(5) (a) Plumb, J. B.; Harper, D. J.
Chem. Eng. News
1990
,
July 16
,3.
(b) Ireland, R. E.; Liu, L.
J. Org. Chem.
1993
,
58
, 2899.
-
-
4538.
10.1021/ol0349965 CCC: $25.00
© 2003 American Chemical Society
Published on Web 07/09/2003
but their preparation necessitates additional steps.
6a,b,9
It thus
became desirable to find a means of stabilizing IBX to enable
its safe utilization in chemical synthesis.
Research conducted at SIMAFEX led to a nonexplosive
white-powder formulation of IBX composed of a mixture
of benzoic acid (22%), isophthalic acid (29%), and
o
-iodo-
xybenzoic acid itself (49%).
7
In this letter, we wish to
highlight the performances of this new oxidizing system,
which we referred to as SIBX for “Stabilized IBX”, in
alcohol and phenol oxidation reactions for comparison with
those of IBX and DMP.
We started our investigation by searching for the most
appropriate solvent system to accommodate the use of SIBX.
Like IBX, SIBX is not soluble in most standard organic
solvents, so we initially evaluated its capacity of oxidizing
an alcohol in DMSO, in which it readily dissolves
2b,c
(Table
1, entry 1). In search of another solvent system that would
2). Our results are for the most part in agreement with More
and Finney’s observations.
3d
Among noteworthy differences
is the fact that the oxidation worked very well in THF and
toluene. THF actually emerged as the best solvent in this
study, affording the highest yield of
10
in the shortest period
of time.
Table 2.
Solvent Optimization
a
solvent
time (h)
temp (°C)
yield (%)
EtOAc
1.3
77
90
CH
3
CN
0.5
82
96
acetone
2.0
56
90
THF
0.5
60
99
PhCH
3
1.5
80
100
CH
2
Cl
2
17.0
rt
92
NMP
1.0
rt
68
Table 1.
Oxidation of Selected Alcohols with SIBX in NMP
DMSO
b
0.5
rt
66
or DMSO
a
All reactions were carried out on a 1.0-mmol scale.
b
SIBX in solution;
SIBX in suspension in all of the other reaction solvents used.
Another series of benzylic and allylic alcohols was then
submitted to SIBX in suspension in THF at 60
C to furnish
the corresponding aldehydes or ketones (Table 3). Initial
°
Table 3.
SIBX-Mediated Oxidation of Benzylic and Allylic
Alcohols
a
All reactions were carried out on a 10-mmol scale at room temperature
for 2 h with 1.2 equiv of SIBX.
b
DMSO.
c
NMP.
allow reactions to be performed rapidly at room temperature,
N
-methylpyrrolidone (NMP) was used.
8
Although SIBX is
only sparingly soluble in NMP, oxidation of a selection of
primary
and
secondary
alcohols
worked
well
at
room
temperature on multigram scales (Table 1).
The common perception that IBX must be completely
dissolved for expressing its full oxidizing reactivity has
recently been proven wrong by More and Finney,
3d
who
observed that suspensions of IBX in heated solutions of
piperonyl alcohol (
9
) in common organic solvents furnished
the corresponding aldehyde
10
in satisfactory yields.
3d
We
repeated the same solvent optimization with SIBX (Table
a
Reactions were carried out in THF on a 0.5- to 1.0-mmol scale at 60
°C for 0.5-1 h with 1.2 equiv of SIBX per alcohol function.
b
In THF/
DMSO (9:1) at room temperature.
attempts to oxidize geraniol (
19)
under these conditions,
however, led to the formation of an insoluble white gel from
which no product could be extracted. Geranial (
20
) was
nevertheless obtained in a high yield by performing the
oxidation in a 9:1 THF/DMSO solvent mixture at room
-
9120. (b) Zhdankin, V. V.; Smart, J. T.; Zhao, P.; Kiprof, P.
Tetrahedron
Lett.
2000
,
41
, 5299
(6) (a) Stickley, S. H.; Martin, J. C.
Tetrahedron Lett.
1995
,
36
, 9117
5302. (c) Zhdankin, V. V.; Koposov, A. Y.; Netzel,
B. C.; Yashin, N. V.; Rempel, B. P.; Ferguson, M. J.; Tykwinski, R. R.
Angew. Chem.
2003
,
115
, 2244
-
-
2246.
2904
Org. Lett.,
Vol. 5, No. 16,
2003
temperature (Table 3, entry 5). In all cases, yields were
comparable with those obtained with DMP or IBX (Table
3). Although these SIBX-mediated oxidations are usually not
sensitive to air or moisture, all reactions were carried out
under nitrogen. This precaution was especially useful for the
conversion of benzyl alcohol (
13
) into benzaldehyde (
14
)
(Table 3, entry 2), which is otherwise readily oxidized into
benzoic acid.
3d
This over-oxidation was particularly prob-
lematic, since one of the IBX stabilizers is benzoic acid.
Oxidation of the vicinal diol
15
occurred without oxidative
cleavage to furnish the desired diketone
16
in 92% yield
(Table 3, entry 3).
9
We then turned our attention to the oxidation of a selection
of aliphatic alcohols in THF (Table 4). Cycloheptanol
(21
)
8
in 6 h (Table 4, entry 1), and
23
and
25
into
24
and
26
12
over2hin93%and77%yield, respectively (Table 4, entries
3 and 4).
The use of suspensions of SIBX in inert solvents such as
EtOAc (Table 4), or even in THF in the case of allylic and
benzylic alcohol oxidations (Table 3), shares the technical
advantages already noted for IBX under similar reaction
conditions.
3d
First, no silica gel chromatography was required
to purify products, for the carboxylic acid stabilizers are
efficiently removed by slightly basic aqueous washes.
Second, the main IBX byproduct, that is iodosylbenzoic acid
(IBA), can be recovered by filtration and recycled via
oxidation into IBX with oxone.
3d
Our continuing interest in the oxidation chemistry of
arenols
13
then led us to examine the behavior of phenolic
alcohols in the presence of SIBX (Table 5). The 4-hy-
Table 4.
SIBX-Mediated Oxidation of Aliphatic Alcohols
Table 5.
SIBX-Mediated Oxidation of Phenolic Alcohols
a
Reactions were carried out in EtOAc on a 0.5- to 1.0-mmol scale at
reflux temperature for 2-6 h with 1.2 equiv of SIBX per alcohol function.
b
See Table 1 for comparison; a large-scale reaction was also performed
overnight on 10 g (i.e., 64 mmol) of
7
to furnish
8
in 90%.
c
In THF at 60
°C for 0.5 h.
was oxidized into cycloheptanone (
22
) in a good yield of
77% in only 30 min in THF at 60
C (Table 4, entry 2). Of
particular note is the fact that no dehydrogenation product
was observed. This is in contrast to observations made by
Nicolaou et al.
4b,10
°
,
â
-unsaturated
carbonyl compounds from saturated alcohols with use of IBX
in DMSO. Here, even when performing the reaction in
DMSO at 60 or 90
on the formation of
R
C with 2 to 3 equiv of SIBX,
10b
only
cycloheptanone (
22
) was observed. Other secondary and
primary alcohols such as menthol (
7
), 3-phenylpropanol (
23
),
and 1,9-nonanediol (
25
) were not converted in good yields
into carbonyl compounds under the aforementioned condi-
tions, because SIBX reacted with THF. We indeed verified
that SIBX (100 mg in 1.0 mL of the indicated solvent under
nitrogen) is not stable over a prolonged period of time either
in THF at 60
°
a
Reactions were carried out on a 0.7- to 1.0-mmol scale with 1.2 to 2.1
equiv of SIBX.
C. Ring-opened
aldehydic products were observed in hot THF after1hand
SIBX was consumed over2hinhottoluene to cleanly
furnish benzaldehyde. The SIBX formulation is thus no
different than straight IBX in the sense that solvent oxidation
may occur,
3d,9
but this problem appears limited to the less
reactive substrates such as aliphatic primary alcohols.
3f,11
Aliphatic alcohols were thus oxidized by using 1.2 equiv of
SIBX in refluxing ethyl acetate (Tables 2 and 4), a solvent
also selected for IBX-mediated oxidations by More and
Finney.
3d
Under these conditions,
7
was cleanly oxidized into
°
C or in toluene at 80
°
b
In refluxing EtOAc; [phenol] ) 0.14 M.
c
In THF at room
temperature; [phenol]
)
0.05 M.
d
Workup with aq. Na
2
S
2
O
4
.
droxymethylphenol
27
was cleanly oxidized into the aldehyde
28
in refluxing EtOAc (entry 1). The steric demand of the
two
tert
-butyl groups adjacent to the phenolic hydroxyl group
certainly prevented any reaction at this locus. Furthermore,
the aldehyde function likely deactivated the arenol ring
toward any secondary phenol oxidation. Phenols bearing
electron-withdrawing groups such as carbonyl-based and
Org. Lett.,
Vol. 5, No. 16,
2003
2905
nitro functions, are known to resist IBX oxidations.
14
More
electron-rich 4-hydroxymethyl-2-methoxyphenols such as
29
and its vinylogous derivative
31
led to vanillin (
30
) and
coniferaldehyde (
32
) in moderate yields (entries 2 and 3).
These aldehydes also failed to undergo any oxidation with
SIBX, so the inefficiency of their preparation from
29
and
31
is probably due to a competing phenolic oxidation prior
to the transformation into aldehydes.
The outcome of such a phenolic oxidation could not be
delineated from the reactions with
29
and
31
, but we
surmised that a formal demethylation of these 2-methoxy-
phenols into orthoquinones could be operational in a manner
similar to that can be achieved with periodates.
15
This
hypothesis was verified by treating eugenol (
33
) with SIBX
in THF at room temperature for 16 h. A mildly basic
hydrolysis of the reaction mixture, which was immediately
followed by a reductive workup with Na
2
S
2
O
4
to prevent
any degradation of the reactive orthoquinone product,
furnished catechol
34
in a remarkable 77% yield (entry 4).
A mechanistic description of this IBX-mediated demethy-
lation is depicted in Scheme 1. We view this reaction as an
orthoquinol monoketal
C
and it better supports the excellent
regioselectivity observed in this oxygenative demethylation.
The same chemistry rationalizes the IBX-mediated ortho-
oxygenation of phenols recently described by Pettus et al.
14a
and by us.
14b
Four other examples of this new demethylation
reaction are shown in Table 5 (entries 5
8). Dehydroeugenol
(
35
) was converted into catechol
36
in 89% yield (entry 5).
An excellent yield was obtained in the case of the demethy-
lation of the silyloxy derivative
39
without loss of the silyl
group (entry 7). Finally, the demethylation of 2-methoxy-
naphthol (
41
) gave rise to the stable naphthoquinone
42
,
which could be isolated as such in high yield (entry 8).
Another aspect of the versatility of IBX has thus been
unveiled by performing these SIBX-mediated oxygenative
demethylations of 2-methoxyphenols into orthoquinones and
catechols.
-
Acknowledgment.
We wish to thank SIMAFEX and the
Association Nationale de la Recherche Technique (CIFRE
No.
301/2002)
for
their
financial
support
and
Aur´lie
Ozanne’s graduate research assistantship.
Supporting Information Available:
Experimental details
and characterization data for all compounds. This material
Scheme 1
OL0349965
(7) Depernet, D.; Fran ü ois, B. WO 02/057210 A1, PCT/FR02/00189
,
US 2002/0107416;
Chem. Abstr.
2002
, 137, 109123. Explosive tests were
negative in compliance with the 92/69-A14 EEC directive. SIBX is available
at
SIMAFEX,
contact
dominique.depernet@simafex.com
or
benoitj@
simafex.com for further inquiries.
(8) Frigerio, M; Santagostino, M; Sputore, S. EP 0/658/533 A1;
Chem.
Abstr.
1995
, 123, 285513.
(9) mIBX
)
modified IBX, see:
Thottumkara, A. P.; Vinod, T. K.
Tetrahedron Lett.
2002
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, 569
572.
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Angew. Chem.,
Int. Ed.
2002
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, 993
-
996. (b) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P.
S.
J. Am. Chem. Soc.
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, 7596-7597.
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K. H.; Sutherland, A. J.
Tetrahedron Lett.
2003
,
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, 1635-1637.
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Synlett
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, 789
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Modern Arene Chemistry
; Astruc, D., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 539-573. (b) Quideau, S.; Pouys´gu,
L.
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, 617-680. (c) Quideau, S.; Feldman, K.
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T. R. R.
Org. Lett.
2002
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ARKIVOC
2003
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, 106-119.
(15) (a) Adler, E.; Hernestam, S.
Acta Chem. Scand.
1955
,
9
, 319-334.
(b) Adler, E.; Magnusson, R.
Acta Chem. Scand.
1959
,
3
, 505-519.
-
ionic process during which phenol
A
first adds to the iodine-
(V) center of IBX to give the
ì
5
-iodanyl intermediate
B
. The
molecule of water hence eliminated could serve as an oxygen
source, but this route (a) would produce directly a reactive
orthoquinone
E
. The intramolecular delivery of an oxygen
from the
ì
5
-iodanyl moiety of
B
is the route (b) we favor
because it involves the formation of a more stable
ì
3
-iodanyl
2906
Org. Lett.,
Vol. 5, No. 16,
2003
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