Preparation of soluble and insoluble polymer supported IBX reagents.

Article abstract of DOI:10.1016/S0960-894X(02)00264-0

A series of soluble and insoluble polymer supported versions of the versatile oxidizing reagent IBX has been prepared. Each of the reagents were evaluated for their efficiency in the conversion of benzyl alcohol to benzaldehyde. Results from this study were that the soluble, non-crosslinked polystyrene supported IBX reagent gave the best rate of conversion to benzaldehyde, while the macroporous polymer supported IBX resin provided a superior rate of conversion to benzaldehyde when compared with a gel type resin. The macroporous IBX reagent was also shown to convert a series of alcohols to the corresponding aldehydes and ketones.

Full text of DOI:10.1016/S0960-894X(02)00264-0

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2047–2049
Preparation of Soluble and Insoluble Polymer Supported
IBX Reagents
Neal N. Reed, Mercedes Delgado, Kristina Hereford,
Bruce Clapham and Kim D. Janda*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA92037, USA
Received 5 November 2001; accepted 1 February 2002
Abstract—A series of soluble and insoluble polymer supported versions of the versatile oxidizing reagent IBX has been prepared.
Each of the reagents were evaluated for their efficiency in the conversion of benzyl alcohol to benzaldehyde. Results from this study
were that the soluble, non-crosslinked polystyrene supported IBX reagent gave the best rate of conversion to benzaldehyde, while
the macroporous polymer supported IBX resin provided a superior rate of conversion to benzaldehyde when compared with a gel
type resin. The macroporous IBX reagent was also shown to convert a series of alcohols to the corresponding aldehydes and
ketones. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
attractive feature of polymer bound reagents is that they
can be isolated from the reaction without work up using
a simple filtration to yield a solution of pure product.
This technology is now being used to great effect in the
parallel synthesis of libraries of compounds for use in
drug discovery programs. Additionally, the preparation
of polymer bound reagents is important industrially
since the spent reagent can be potentially reused after
recovery and regeneration. Finally, many explosive
reagents have been made safe by conversion into a resin
bound version and notable examples include a polymer
Hypervalent iodine reagents are valuable tools in syn-
1
thetic organic chemistry. One important application of
these reagents is the oxidation of alcohols to the corre-
sponding carbonyls. In particular, Dess-Martin period-
inane (DMP) has received much attention since it is
2
efficient, mild reagent for this oxidation. The precursor
to DMP, o-iodosobenzoic acid (IBX) 1 has also been
utilized for the conversion of alcohols to aldehydes and
ketones. In fact, it is now preferred to DMP in many
instances since it does not cleave 1,2-diols, is con-
veniently handled, and is stable to storage for prolonged
periods. Additionally, many new elegant oxidative
transformations using IBX have been recently repor-
ted. One drawback to the use of IBX is its solubility,
IBX reactions are performed in either homogeneous
DMSO solutions or heterogeneous slurries with other
solvents. There is also an additional safety concern
when using hypervalent iodine reagents in that they are
potentially explosive and this may have precluded larger
7
bound sulfonyl azide reagent for diazotransfer reac-
8
tions and an azodicarboxylate reagent for Mitsunobu
3
reactions. Because of the proven utility of IBX and its
solubility and safety issues, it is an ideal candidate for
the preparation of polymer bound analogues. Reported
herein are our efforts for the preparation and appli-
cation of both soluble and insoluble polymer supported
IBX reagents.
4
5
scale applications of IBX or related oxidants.
Results and Discussion
Polymer supported reagents and catalysts are currently
6
The strategy for the preparation of a polymer bound
version of the IBX reagent is outlined in Figure 1.
undergoing a renaissance in synthetic chemistry. An
We envisaged that hydroxy-iodobenzoic acid 3 would
be an ideal substrate to prepare a polymer bound IBX
reagent, this through attachment via an aryl ether linkage.
*
2
Corresponding author. Tel.: +1-858-784-2516; fax: +1-858-784-
595; e-mail: kdjanda@scripps.edu
0
960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00264-0

2048
N. N. Reed et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2047–2049
Figure 1. Strategy used to prepare polymer supported IBX reagents.
In our approach (Scheme 1), 5-hydroxy-2-anthranilic
acid was converted to hydroxy-iodobenzoic acid 4 using
a Sandmeyer reaction according to literature prece-
dent. Carboxylic acid 4 was then converted to the
corresponding ester 5 in quantitative yield using a
Fisher esterification reaction.
ꢀ
ꢀ
Scheme 1. (a) (i) NaNO
2
, aqueous H
2
SO
CO
O, MeOH rt, 12 h; (e) Bu
4
, 0 C; (ii) KI, 90 C, 57%;
ꢀ
(
(
b) EtOH, HCl, reflux; (c) Cs
2
3
,
DMF, 70 C, 14 h;
9
2.
d) Ba(OH) 8H
2
4
N-Oxone, 5 equiv,
MeSO H 5 equiv, CH Cl , 2 h.
3
2
2
In search of an optimal polymer bound version of the
IBX reagent, several different types of supports were
investigated. These supports were an insoluble poly-
styrene gel-type JandaJel resin 6a, a macroporous poly-
styrene ArgoPore resin 6b, a soluble, non-crosslinked
polystyrene resin 6c and soluble poly(ethylene glycol)
Scheme 2. (a) 8a–c, CH
2
2
Cl .
salts, since isolation of the polymer by precipitation
from methanol would have quenched the freshly gener-
ated reagent. The PEG bound oxidant 8d also proved
troublesome, precipitation of the polymer from diethyl
ether was accompanied by co-precipitation of the oxone
salts, because of this the PEG oxidant 7d was dropped
from the study.
(PEG 3400) support 6d. The common building block 5
was reacted with either chloromethyl functionalized
polystyrenes 6a–c or mesylate functionalized PEG 3400
6
d in the presence of cesium carbonate in DMF to form
the desired aryl ether. The corresponding polymer
bound iodocarboxylic acids 7a–d were then unmasked
by barium hydroxide mediated hydrolysis. Each of the
resins were found to be loaded in the following amounts
With the synthesis of three polystyrene supported
reagents 8a–c in hand, a comparison of their activity in
the oxidation of benzyl alcohol to benzaldehyde was
examined. Here, two equivalents of the support bound
oxidants 8a–c were shaken with a solution of benzyl
alcohol in methylene chloride (Scheme 2).
À1 À1
a (0.7 mmol g ), 7b (0.9 mmol g ), 7c (0.3 mmol
7
À1
À1
g
), and 7d (0.4 mmol ) as determined by either
NMR (soluble resins) or elemental analysis of insoluble
supports.
The critical oxidation of the support bound iodoacids 7
to the corresponding polymer supported IBX reagent 8
proved difficult to optimize. Initial attempts centered
around the macroporous resin supported iodoacid 7b
and the PEG supported iodoacid 7d since the prepar-
ation of IBX is commonly accomplished in aqueous
conditions and these supports are well known to work
well in water. Unfortunately, neither the traditional
Homogenous non-crosslinked polystyrene supported
reagent 8c was superior with 100% conversion to pro-
duct (determined by GC) after only 1 h. For the inso-
luble polymers, the macroporous ArgoPore supported
reagent proved best, and thus oxidation of benzyl alcohol
gave 93% conversion to benzaldehyde after 2.5 h that
rose to 100% after 4 h. The gel-type polymer supported
reagent, however, only gave 75% conversion after 2.5 h
and failed to increase after extended reaction time.
2
conditions of potassium bromate in sulfuric acid nor
1
0
the recently described Oxone oxidation procedure
gave the desired oxidants 8. We were aware of a recent
report where tetrabutylammonium hydroxide had been
used in place of sodium hydroxide with great effect for
the reaction of a polystyrene bound substrate.1 This
led us to examine the use of the tetrabutylammonium
Table 1.
1
% Conversationa
Alcohol
Product
1
2
salt of Oxone in organic solvents for the oxidation of
a to 8a, however, these conditions also failed to pro-
9
9
7
vide the desired oxidant. After further experimentation,
we found that addition of one equivalent of methane
50, 78b
1
3
sulfonic acid to the oxidation reaction enabled con-
version to the desired polymer bound oxidant as esti-
1
4
mated by IR spectroscopy. Using these conditions,
each of the polymer supported iodoacids 7a–d were
converted to the corresponding oxidants 8a–d. The
insoluble polymer bound oxidants were easily isolated
by simple filtration, however, the soluble polymer sup-
ported reagents were more difficult to isolate cleanly.
For example, the non-crosslinked polystyrene supported
oxidant 8c required extraction into methylene chloride
and washing with brine to remove unwanted oxone
4
5c
9
9
a
% Conversion estimated by GC after 4 h.
After 6 h.
No further increase in yield was observed.
b
c

N. N. Reed et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2047–2049
2049
From these findings a series of oxidations of additional
substrates using the macroporous polymer supported
oxidant 7b were also examined (Table 1). A solution of
each alcohol was shaken with 2 equiv of 7b and the
conversion to product was estimated after 4 h by GC. p-
Nitrobenzyl alcohol gave complete conversion after 4 h,
however, the less reactive p-methoxybenzylalcohol was
only converted to 50% yield after 4 h. 2-Decanol was
converted to 2-decanone in 45% yield after 4 h, how-
ever, no further conversion to product was observed
even after extending the reaction time. Finally, cyclo-
hexanol was smoothly converted to cyclohexanone in
excellent yield.
Skaggs Institute for Chemical Biology. B.C. is a Skaggs
postdoctoral fellow.
References and Notes
1
. (a) Wirth, T.; Hirt, U. H. Synthesis 1999, 8, 1271. (b) Var-
voglis, A. Tetrahedron 1997, 53, 1179.
. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
2
3. (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994,
35, 8019. (b) Frigerio, M.; Santagostino, M.; Sputore, S.; Pal-
misano, G. J. Org. Chem. 1995, 60, 7272.
4
. (a) Wirth, T. Angew. Chem. Int. Ed. 2001, 40, 2812. (b)
Chaudhari, S. S. Synlett 2000, 278.
5. Plumb, J. B.; Harper, D. J. Chem. Eng. News 1990, 68, 3.
6. (a) Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron
2001, 57, 4367. (b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.;
Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.;
Scott, J. S.; Storer, I. R.; Taylor, S. J. J. Chem. Soc., Perkin
Trans. 1 2000, 23, 3815.
7. (a) Green, G. M.; Peet, N. P.; Metz, W. A. J. Org. Chem.
2001, 66, 2509. (b) Roush, W. R.; Feitler, D.; Rebek, J., Jr.
Tetrahedron Lett. 1974, 15, 1391.
Conclusion
In summary,15 we have developed a series of polymer
supported IBX reagents. Our findings were that: (1) The
soluble, non-crosslinked polystyrene supported reagent
gave the greatest rate of conversion of alcohol to alde-
hyde. (2) The macroporous ArgoPore reagent was
superior to the gel supported reagent for this same
reaction. (3) The macroporous reagent was found to
convert a series of alcohols to the corresponding alde-
hydes and ketones in good to excellent yields. Investi-
gations of alternative supported versions of IBX and
applications of the polymer supported IBX reagents
reported is ongoing in our laboratory and will be
reported in due course.
8. Arnold, L. D.; Assil, H. I.; Vederas, J. C. J. Am. Chem.
Soc. 1989, 111, 3973.
9
1
1
1
1
1
. Moss, R. A.; Alwis, K. W.; Shin, J.-S. J. Am. Chem. Soc.
984, 106, 2651.
0. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
999, 64, 4537.
1. Harikrishnan, L. S.; Showalter, H. D. H. Synlett 2000, 9,
339.
12. Trost, B. M.; Braslau, R. J. Org. Chem. 1988, 53, 532.
13. The addition of methane sulfonic acid forms Caro’s acid
(monoperoxysulfuric acid) in situ, which is a stronger oxidant
than Oxone alone.
1
appearance of the acid carbonyl at 1710 cm
4. The progress of oxidation was measured by a dis-
À1
and the
appearance of a broad carbonyl peak at approximately 1630
À1
cm
.
1
5. (a) Note added to proof: After submission of our manu-
script the following papers appeared describing similar
approaches to polymer supported IBX reagents. Mulbaier,
Acknowledgements
¨
We gratefully acknowledge financial support from the
National Institutes of Health (GM-56154), The Scripps
Research Institute, Aventis Pharmaceuticals, and The
M.; Giannis, A. Angew. Chem. Int. Ed. 2001, 40, 4393. (b)
Sorg, G.; Mengei, A.; Jung, G.; Rademann. J. Angew. Chem.,
Int. Ed. 2001, 40, 4395.