A stabilized formulation of IBX (SIBX) for safe oxidation reactions including a new oxidative demethylation of phenolic methyl aryl ethers

Article abstract of DOI:10.1021/ol0349965

(Matrix presented) 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.

Full text of DOI:10.1021/ol0349965

ORGANIC
LETTERS
2
003
Vol. 5, No. 16
903-2906
A Stabilized Formulation of IBX (SIBX)
for Safe Oxidation Reactions Including a
New Oxidative Demethylation of
Phenolic Methyl Aryl Ethers
2
Aur e´ lie Ozanne, Laurent Pouys e´ gu, Dominique Depernet,§
†
†,‡
§
,†,‡
Bruno Fran c¸ ois, and St e´ phane Quideau*
Institut Europ e´ en de Chimie et Biologie, 16 aVenue Pey-Berland,
F-33607 Pessac, France, Laboratoire de Chimie des Substances V e´ g e´ tales,
Centre de Recherche en Chimie Mol e´ culaire, UniVersit e´ Bordeaux 1,
351 cours de la Lib e´ ration, F-33405 Talence Cedex, France, and
SIMAFEX, 16 aVenue des Fours- a` -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
of DMP and IBX are limited because both reagents suffer
from major safety concerns related to their violent decom-
1
Dess-Martin periodinane reagent (DMP) and its benzio-
1
b,2
2d,5
doxole oxide precursor 2-iodoxybenzoic acid (IBX) has
position under impact and/or heating. Modified IBX-like
reagents have been introduced as nonexplosive oxidants,6
,9
been amply evidenced by many successful demonstrations
of their selectivity in oxidation reactions.2 These λ -iodanes
b,3
5
3c,4
(3) (a) Varvoglis, A. HyperValent Iodine in Organic Synthesis; Academic
Press: San Diego, CA, 1997. (b) Wirth, T.; Hirt, U. H. Synthesis 1999,
have also found uses in many other synthetic transformations
and often constitute environmentally benign alternatives to
heavy metal-based systems. However, industrial applications
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.
†
Institut Europ e´ en de Chimie et Biologie.
Laboratoire de Chimie des Substances V e´ g e´ tales.
SIMAFEX.
‡
§
(4) (a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 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, 937-941.
(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.
(
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.
995, 60, 7272-7276. (d) Frigerio, M.; Santagostino, M.; Sputore, S. J.
Org. Chem. 1999, 64, 4537-4538.
(
(
(
1
1
0.1021/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.
2). Our results are for the most part in agreement with More
3d
and Finney’s observations. 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.
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-
7
xybenzoic acid itself (49%). 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.
Table 2. Solvent Optimizationa
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
solvent
EtOAc
time (h)
temp (°C)
yield (%)
1.3
0.5
2.0
0.5
1.5
17.0
1.0
0.5
77
82
56
60
80
rt
90
96
90
99
100
92
2
b,c
CH CN
an alcohol in DMSO, in which it readily dissolves (Table
, entry 1). In search of another solvent system that would
3
acetone
THF
1
PhCH3
CH2Cl2
NMP
rt
rt
68
66
Table 1. Oxidation of Selected Alcohols with SIBX in NMP
or DMSO
DMSOb
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
b
c
for 2 h with 1.2 equiv of SIBX. DMSO. NMP.
allow reactions to be performed rapidly at room temperature,
8
N-methylpyrrolidone (NMP) was used. 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
3
d
recently been proven wrong by More and Finney, who
observed that suspensions of IBX in heated solutions of
piperonyl alcohol (9) in common organic solvents furnished
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. In THF/
DMSO (9:1) at room temperature.
b
3
d
the corresponding aldehyde 10 in satisfactory yields. We
repeated the same solvent optimization with SIBX (Table
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
(
6) (a) Stickley, S. H.; Martin, J. C. Tetrahedron Lett. 1995, 36, 9117-
9
120. (b) Zhdankin, V. V.; Smart, J. T.; Zhao, P.; Kiprof, P. Tetrahedron
Lett. 2000, 41, 5299-5302. (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
8 in 6 h (Table 4, entry 1), and 23 and 25 into 24 and 2612
over 2 h in 93% and 77% yield, respectively (Table 4, entries
3 and 4).
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)
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
(
Table 3, entry 2), which is otherwise readily oxidized into
3d
3d
benzoic acid. 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
conditions. 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
(
Table 3, entry 3).9
3
d
We then turned our attention to the oxidation of a selection
of aliphatic alcohols in THF (Table 4). Cycloheptanol (21)
oxidation into IBX with oxone.
Our continuing interest in the oxidation chemistry of
1
3
arenols 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
c
overnight on 10 g (i.e., 64 mmol) of 7 to furnish 8 in 90%. In THF at 60
°
C for 0.5 h.
was oxidized into cycloheptanone (22) in a good yield of
7% in only 30 min in THF at 60 °C (Table 4, entry 2). Of
7
particular note is the fact that no dehydrogenation product
was observed. This is in contrast to observations made by
Nicolaou et al.4
b,10
on the formation of R,â-unsaturated
carbonyl compounds from saturated alcohols with use of IBX
in DMSO. Here, even when performing the reaction in
1
0b
DMSO at 60 or 90 °C with 2 to 3 equiv of SIBX, 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 °C or in toluene at 80 °C. Ring-opened
aldehydic products were observed in hot THF after 1 h and
SIBX was consumed over 2 h in hot toluene to cleanly
furnish benzaldehyde. The SIBX formulation is thus no
different than straight IBX in the sense that solvent oxidation
a
Reactions were carried out on a 0.7- to 1.0-mmol scale with 1.2 to 2.1
equiv of SIBX. b In refluxing EtOAc; [phenol] ) 0.14 M. c In THF at room
temperature; [phenol] ) 0.05 M. Workup with aq. Na2S2O4.
d
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
3
d,9
may occur, but this problem appears limited to the less
3
f,11
reactive substrates such as aliphatic primary alcohols.
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
3d
Finney. Under these conditions, 7 was cleanly oxidized into
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
orthoquinol monoketal C and it better supports the excellent
regioselectivity observed in this oxygenative demethylation.
The same chemistry rationalizes the IBX-mediated ortho-
14a
oxygenation of phenols recently described by Pettus et al.
14b
and by us. 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.
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
1
5
similar to that can be achieved with periodates. 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
2 2 4
followed by a reductive workup with Na S O to prevent
any degradation of the reactive orthoquinone product,
furnished catechol 34 in a remarkable 77% yield (entry 4).
Acknowledgment. We wish to thank SIMAFEX and the
Association Nationale de la Recherche Technique (CIFRE
No. 301/2002) for their financial support and Aur e´ lie
Ozanne’s graduate research assistantship.
A mechanistic description of this IBX-mediated demethy-
lation is depicted in Scheme 1. We view this reaction as an
Supporting Information Available: Experimental details
and characterization data for all compounds. This material
is available free of charge via Internet at http://pubs.acs.org.
Scheme 1
OL0349965
(7) Depernet, D.; Fran c¸ 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, 43, 569-572.
10) (a) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem.,
(
(
Int. Ed. 2002, 41, 993-996. (b) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P.
S. J. Am. Chem. Soc. 2000, 122, 7596-7597.
(11) Lei, Z.; Denecker, C.; Jegasothy, S.; Sherrington, D. C.; Slater, N.
K. H.; Sutherland, A. J. Tetrahedron Lett. 2003, 44, 1635-1637.
(
12) Roels, J.; Metz, P. Synlett 2001, 6, 789-790.
(13) (a) Quideau, S. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
ionic process during which phenol A first adds to the iodine-
VCH: Weinheim, Germany, 2002; pp 539-573. (b) Quideau, S.; Pouys e´ gu,
L. Org. Prep. Proc. Int. 1999, 31, 617-680. (c) Quideau, S.; Feldman, K.
S. Tetrahedron: Symposium-in-Print 2001, 57, ix-x.
5
(V) center of IBX to give the λ -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
(
14) (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2002, 4, 285-288. (b) Quideau, S.; Pouys e´ gu, L.;
Deffieux, D.; Ozanne, A.; Gagnepain, J.; Fabre, I.; Oxoby, M. ARKIVOC
2
003, 6, 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.
5
from the λ -iodanyl moiety of B is the route (b) we favor
(
3
because it involves the formation of a more stable λ -iodanyl
2906
Org. Lett., Vol. 5, No. 16, 2003