Preparation and reactivity of polymer-supported 2-iodylphenol ethers, an efficient recyclable oxidizing system

Article abstract of DOI:10.1021/jo7015746

(Chemical Equation Presented) Preparation of new recyclable polymer-supported oxidizing reagents based on 2-iodylphenol ethers is described. The synthesis employs commercially available aminomethylated polystyrene or Merrifield resin and affords polymer-supported 2-iodylphenol ethers with loading up to 0.86 mmol/g with respect to IO₂ groups. The new reagents effect clean and efficient conversion of a wide range of alcohols, including heteroatomic and unsaturated structures, to the corresponding carbonyl compounds. Recycling of the resins is possible with minimal loss of activity after several reoxidations.

Full text of DOI:10.1021/jo7015746

various derivatives of IBX, which are highly soluble and
nonexplosive, have been developed recently.2,3 Several variants
of polymer-supported IBX-based reagents have also been
prepared, and their usefulness as efficient oxidizing reagents
was demonstrated by several research groups.4,5 The polymer-
supported IBX derivatives are especially attractive because of
the low explosiveness and the preparative advantage of the
attachment of a chemical reagent to a solid matrix.5 Particularly
promising oxidizing systems are represented by polymer-
supported IBX amides5d-f 1 and N-(2-iodylphenyl)acylamides5g,h
(NIPA resin, 2).
Preparation and Reactivity of Polymer-Supported
2-Iodylphenol Ethers, an Efficient Recyclable
Oxidizing System
Rashad R. Karimov, Zeinul-Gabiden M. Kazhkenov,
Matthew J. Modjewski, Eric M. Peterson, and
Viktor V. Zhdankin*
Department of Chemistry and Biochemistry, UniVersity of
Minnesota Duluth, Duluth, Minnesota 55812
Vzhdanki@d.umn.edu
ReceiVed July 19, 2007
Recently, we have reported the preparation, X-ray structure,
and oxidative properties of 2-iodylphenol ethers 3, which are
readily available, soluble, and stable IBX analogues having a
pseudocyclic four-membered ring motif.6 Herein, we report the
facile synthesis of polymer-supported 2-iodylphenol ethers and
their reactivity toward oxidation of a broad range of alcohols.
To create a 2-iodylphenol ether scaffold and to ensure proper
immobilization to resin through amide and ether bonds, 4-hy-
droxybutanoic acid and 1,4-butanediol moieties were chosen,
respectively, as linkers. Preparation of these linkers was achieved
through easy steps with excellent yields. Thus, reaction of
commercially available 2-iodophenol 4 with ethyl 4-bromobu-
tanoate gave ester 5, which was afterward saponified to afford
acid 6. Acid 6 was subsequently coupled to aminomethylated
polystyrene with HOBt/DIC to yield resin 8 (Scheme 1). To
block any possible free amino groups the resin was treated with
an excess of acetic anhydride and pyridine.
Preparation of new recyclable polymer-supported oxidizing
reagents based on 2-iodylphenol ethers is described. The
synthesis employs commercially available aminomethylated
polystyrene or Merrifield resin and affords polymer-sup-
ported 2-iodylphenol ethers with loading up to 0.86 mmol/g
with respect to IO2 groups. The new reagents effect clean
and efficient conversion of a wide range of alcohols,
including heteroatomic and unsaturated structures, to the
corresponding carbonyl compounds. Recycling of the resins
is possible with minimal loss of activity after several
reoxidations.
Since 2-iodophenol can be easily attached to the halomethy-
lated polymers through a simple nucleophilic substitution, we
(2) (a) Macikenas, D.; Skrzypczak-Jankun, E.; Protasiewicz, J. D. Angew.
Chem., Int. Ed. 2000, 39, 2007-2010. (b) Meprathu, B. V.; Justik, M. W.;
Protasiewicz, J. D. Tetrahedron Lett. 2005, 46, 5187-5190. (c) Thottumkara,
A. P.; Vinod, T. K. Tetrahedron Lett. 2002, 43, 569-572. (d) Thottumkara,
A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett. 2005, 7, 2933-2936. (e)
Dess, D. B.; Martin, J. C. J. Org. Chem. 1991, 113, 7277-7287. (f) Stickley,
S. H.; Martin, J. C. Tetrahedron Lett. 1995, 36, 9117-9120.
Hypervalent iodine(V) compounds, namely, 2-iodoxybenzoic
acid (IBX) and its acetylation product, Dess-Martin periodinane
(DMP), are now employed extensively in organic synthesis as
highly selective reagents for the oxidation of alcohols to
carbonyl compounds as well as for a variety of other syntheti-
cally useful oxidative transformations.1 Despite their importance,
IBX and DMP are not perfect reagents and have some
disadvantages. IBX is potentially explosive and is insoluble in
common organic solvents, while DMP is highly sensitive to
moisture and decomposes upon prolonged storage with the
formation of partially hydrolyzed insoluble products. Therefore,
(3) (a) Zhdankin, V. V.; Koposov, A. Y.; Netzel, B. C.; Yashin, N. V.;
Rempel, B. P.; Ferguson, M. J.; Tykwinski, R. R. Angew. Chem., Int. Ed.
2003, 42, 2194-2196. (b) Zhdankin, V. V.; Litvinov, D. N.; Koposov, A.
Y.; Ferguson, M. J.; McDonald, R.; Tykwinski, R. R. J. Chem. Soc., Chem.
Commun. 2004, 106-107. (c) Zhdankin, V. V.; Koposov, A. Y.; Litvinov,
D. N.; Ferguson, M. J.; McDonald, R.; Luu, T.; Tykwinski, R. R. J. Org.
Chem. 2005, 70, 6484-6491. (d) Koposov, A. Y.; Zhdankin, V. V. Synthesis
2005, 22-24.
(4) For a review on polymer-supported hypervalent iodine reagents,
see: Togo, H.; Sakuratani, H. Synlett 2002, 1966-1975.
(5) (a) Mu¨lbaier, M.; Giannis, A. Angew. Chem., Int. Ed. 2001, 40, 4393-
4394. (b) Sorg, G.; Mengel, A.; Jung, G.; Rademann, J. Angew. Chem.,
Int. Ed. 2001, 40, 4395-4397. (c) Reed, N. N.; Delgado, M.; Hereford,
K.; Clapham, B.; Janda, K. D. Bioorg. Med. Chem. Lett. 2002, 12, 2047-
2049. (d) Lei, Z.; Denecker, C.; Jegasothy, S.; Sherrington, D. C.; Slater,
N. K. H.; Sutherland, A. J. Tetrahedron Lett. 2003, 44, 1635-1637. (e)
Chung, W.-J.; Kim, D.-K.; Lee, Y.-S. Tetrahedron Lett. 2003, 44, 9251-
9254. (f) Chung, W.-J.; Kim, D.-K.; Lee, Y.-S. Synlett 2005, 2175-2178.
(g) Ladziata, U.; Willging, J.; Zhdankin, V. V. Org. Lett. 2006, 8, 167-
170. (h) Ladziata, U.; Zhdankin, V. V. Synlett 2007, 527-537.
(6) Koposov, A. Y.; Karimov, R. R.; Geraskin, I. M.; Nemykin, V. N.;
Zhdankin, V. V. J. Org. Chem. 2006, 71, 8452-8458.
(1) (a) Varvoglis, A. HyperValent Iodine in Organic Synthesis; Academic
Press: London, 1997. (b) HyperValent Iodine Chemistry; Wirth, T., Ed.;
Springer-Verlag, Berlin, 2003. (c) Ochiai, M. In Chemistry of HyperValent
Compounds; Akiba, K., Ed.; VCH Publishers, New York, 1999. (d) Tohma,
H.; Kita, Y. AdV. Synth. Catal. 2004, 346, 111-124. (e) Wirth, T. Angew.
Chem., Int. Ed. 2005, 44, 3656-3665. (f) Ladziata, U.; Zhdankin, V. V.
ARKIVOC 2006, ix, 26-58. (g) Zhdankin, V. V.; Stang, P. J. Chem. ReV.
2002, 102, 2523-2584. (h) Zhdankin, V. V. Curr. Org. Synth. 2005, 2,
121-145. (i) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006,
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161-234.
10.1021/jo7015746 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/20/2007
J. Org. Chem. 2007, 72, 8149-8151
8149

TABLE 1. Oxidation of Alcohols with Reagents 10 and 11a
SCHEME 1. Synthesis of Polymer-Supported 2-Iodophenol
Ethers 8 and 9
SCHEME 2. Oxidation of Resins 8 and 9
a All oxidations were carried out with 1 equiv of reagents 10 or 11 in
dry DCE under reflux for specified time, unless otherwise noted. The resin
was removed by filtration and washed with dry DCE. The resulting filtrates
were analyzed by GC-MS. b (Z)-Isomer (4%) was also detected as a side
product. c (Z)-Isomer (3%) was also detected. d Oxidation was carried out
with 0.5 equiv of resins 10 and 11. e 4-(Methylsulfinyl)benzaldehyde (13%),
[4-(methylthio)phenyl]methanol (7%), and [4-(methylsulfinyl)phenyl]metha-
nol (3%) were detected. f 4-(Methylsulfinyl)benzaldehyde (11%), [4-(me-
thylthio)phenyl]methanol (9%), and [4-(methylsulfinyl)phenyl]methanol
(5%) were detected.
have also investigated Merrifield resin as a solid support. This
resin is cheaper than aminomethylated polystyrene and is more
stable to the typical acidic oxidation conditions that have
previously been used for the oxidation of known polymer-
supported reagents.5 Although direct attachment of 2-iodophenol
4 to Merrifield resin was unsuccessful, the readily available
alcohol 7 was successfully coupled to the Merrifield resin via
ether link to yield polymer 9 (Scheme 1).
The loadings of the resins 8 and 9 were determined by
elemental analysis and corresponded to 89% and 70% conver-
sion, respectively, when the mass increase is taken into account.
Oxidation of polymers 8 and 9 was initially performed with
3,3-dimethyldioxirane (Scheme 2, method A), as described for
the solution-phase synthesis of the monomeric 2-iodylphenol
ethers 3.6 Obtained resins 10 and 11 were characterized by IR
spectroscopy and elemental analysis. Oxidizing activity of
reagents 10 and 11 was measured by GC-MS analysis using
an excess of 4-methoxybenzyl alcohol as the test substrate under
reflux in 1,2-dichloroethane (DCE) for 3 h. Based on these
measurements, the loadings of resins 10 and 11 were found to
be 1.23 mmol/g and 0.81 mmol/g correspondingly with respect
to the IO2 groups. Since the dioxirane oxidation was effective,
but not very practical (3,3-dimethyldioxirane is unstable and
not readily available), we have tested the in situ generated
dioxirane as the oxidizing agent. The modified protocol (Scheme
2, method B) consists of treatment of resins 8 and 9 with oxone,
NaHCO3, and acetone at room temperature and affords resins
10 and 11 with only slightly lower loading levels (0.74-0.86
mmol/g for polymer 10 and 0.50-0.55 mmol/g for polymer
11). We have used this practical procedure (method B) for the
preparation of numerous batches of resins 10 and 11 in gram
quantities.
The oxidative properties of resins 10 and 11 were evaluated
by the reaction with various benzylic, allylic, primary, and
secondary alcohols (Table 1). All employed alcohols and the
samples of the respective carbonyl compounds were com-
mercially available. Reactions were performed in DCE under
reflux until complete disappearance of alcohol (monitored by
TLC). Conversions were measured by GC-MS with a prior
column calibration using authentic samples of reagents and
products. The reaction products were identified by direct
8150 J. Org. Chem., Vol. 72, No. 21, 2007

g, 15.3 mmol) in dry DMF (50 mL) under nitrogen was added NaH
(0.450 g, 18.8 mmol) and the mixture stirred for 15 min at 0 °C.
Then a suspension of Merrifield resin (loading 3.8 mmol/g, 4.0 g,
15.3 mmol) in 100 mL of dry DMF was added followed by KI
(0.200 g, 1.2 mmol). The resulting mixture was stirred for 3 days
at room temperature. Solids were filtered off, washed with DMF
(3 × 25 mL), MeOH (3 × 25 mL), water (3 × 25 mL), MeOH (3
× 25 mL), and CH2Cl2 (3 × 25 mL), and dried in vacuum to
constant weight. Yield: 4.1 g. IR: 1010, 1088, 1243, 1269, 1458,
1577, 1654, 2922, 3398 cm-1. Anal. Found: I, 18.64. Loading:
1.47 mmol/g (70% conversion when the mass change is considered).
General Procedure for the Oxidation of Resins 8 and 9
(Method B). In a 1000 mL flask were mixed NaHCO3 (15 g),
acetone (50 mL), and H2O and the mixture cooled to 5-7 °C with
ice. Then Oxone (30 g) was added in three portions over 15 min
and the mixture stirred at that temperature for an additional 40 min.
Appropriate resin (∼1 g; preswollen in 25 mL of CH2Cl2 for 1 h)
was then added. An additional 25 mL of CH2Cl2 was used to
completely transfer the resin. The resulting mixture was mixed for
3 days. Thereafter, polymer was filtered, washed with H2O (6 ×
50 mL), MeOH (6 × 10 mL), CH2Cl2 (3 × 10 mL), Et2O (3 × 10
mL), CH2Cl2 (3 × 10 mL), Et2O (3 × 10 mL), CH2Cl2 (3 × 10
mL), Et2O (3 × 10 mL), and agitated with 25 mL of CH2Cl2 for 6
h. The resin was filtered off and dried in vacuum to a constant
weight.
Polymer 10. Oxidation of resin 8 (1.011 g, 1.68 mmol) according
to the general procedure afforded 0.992 g of polymer 10, isolated
as off-white powder. IR: 752, 1027, 1117, 1156, 1231, 1267, 1453,
1542, 1642, 2364, 2917, 3393 cm-1. Anal. Found: I, 21.66. Loading
(IO2): 0.74-0.86 mmol/g based on 4-methoxybenzyl alcohol
oxidation (5 resin batches were prepared).
Polymer 11. Oxidation of resin 9 (1.000 g, 1.47 mmol) according
to the general procedure afforded 0.890 g of polymer 11, isolated
as off-white powder: IR 744, 1015, 1095, 1243, 1269, 1460, 1576,
1654, 1700, 2364, 2917, 3407 cm-1. Anal. Found: I, 16.43. Loading
(IO2): 0.50-0.55 mmol/g based on 4-methoxybenzyl alcohol
oxidation (four resin batches were prepared).
comparison of the retention times and MS data with those
obtained for authentic samples.
Although both reagents gave corresponding carbonyl com-
pounds with high conversion and purity, resin 10 performed
these oxidations faster in most cases. Both reagents showed good
selectivity toward oxidation of an alcohol group in the presence
of a sulfide group in 4-(methylthio)benzyl alcohol (entry 10).
The oxidizing reactivity of resins 10 and 11 is generally similar
to the monomeric 2-iodylphenol ethers 3,6 with noticeable
improvement in the selectivity of oxidation of 4-(methylthio)-
benzyl alcohol.
The reduced polymeric materials formed in the reaction of
resins 10 and 11 with alcohols can be collected and reoxidized
according to the procedure described above. A slow decline in
oxidative activity was observed after multiple recovery steps,
possibly due to iodine loss in the course of resin reoxidation.
In conclusion, we have prepared polymer-supported analogues
of 2-iodylphenol ethers. The synthesis of these reagents employs
commercially available aminomethylated polystyrene and Mer-
rifield’s resin, includes four or five simple steps, and affords
the resins 10 and 11 with good loadings of 0.74-0.86 and 0.50-
0.55 g/mmol, respectively. Reagents 10 and 11 effect clean and
selective oxidation of a wide range of alcohols, including
heteroatomic and unsaturated structures.
Experimental Section
Experimental details, analytical data, and spectra of compounds
5-7 can be found in the Supporting Information.
Attachment of 4-(2-Iodophenoxy)butanoic Acid to Aminom-
ethylated Polystyrene (Resin 8). 4-(2-Iodophenoxy)butanoic acid
(10.000 g, 32.5 mmol) was dissolved in dry DMF (25 mL), and
HOBt (1-hydroxy-1H-benzotriazole, 4.845 g, 35.75 mmol) was
added. The resulting mixture was stirred vigorously until all of the
solid material dissolved. The resulting solution was added to a
suspension of aminomethylated polystyrene (8.1 g, 32.5 mmol,
200-400 mesh, 2% cross-linked with divinylbenzene, loading 4.0
mmol/g) in 205 mL of dry DMF. Thereafter, DIC (diisopropylcar-
bodiimide, 4.9 mL, 32.5 mmol) was added, and the reaction mixture
was heated to 105 °C and was agitated at this temperature for 8 h.
Then the reaction mixture was cooled to rt and additionally stirred
for 8 h. Pyridine (5.5 mL, 67 mmol) and acetic anhydride (6.5 mL,
67 mmol) were then added, and the mixture was agitated for 2 h at
80 °C. Polymer 8 was filtered, washed with DMF (6 × 10 mL),
MeOH (6 × 10 mL), DMF (6 × 10 mL), MeOH (6 × 10 mL),
and CH2Cl2 (6 × 10 mL), and dried in vacuum to constant weight.
Yield: 14.126 g. IR: 1012, 1046, 1177, 1238, 1272, 1458, 1513,
1642, 2364, 2908, 3402 cm-1. Anal. Found: I, 21.04. Loading:
1.66 mmol/g (89% conversion when the mass change is considered).
Attachment of 4-(2-Iodophenoxy)butan-1-ol to Merrifield
Resin (Resin 9). To a solution of 4-(2-iodophenoxy)butan-1-ol (4.48
General Procedure for the Oxidation of Alcohols with
Polymers 10 and 11. To a vigorously stirred mixture of polymer
(0.02 mmol) in dry dichloroethane (DCE) (1 mL) was added the
appropriate alcohol (0.02 mmol), and the solution was refluxed until
complete disappearance of alcohol (monitored by TLC). Thereafter,
polymer was filtered and washed with dry DCE (3 × 2 mL). The
resulting filtrates were analyzed by GC-MS.
Acknowledgment. This work was supported by a research
grant from the National Science Foundation (CHE-0702734).
Supporting Information Available: General experimental
procedures, including spectroscopic and analytical data. This
material is available free of charge via the Internet at http:
//pubs.acs.org.
JO7015746
J. Org. Chem, Vol. 72, No. 21, 2007 8151