First synthesis and oxidative properties of polymer-supported IBX

A polymer-supported analogue of the IBX-reagent (1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide) has been synthesized. Synthesis and oxidative properties of this new and efficient reagent are described. With this reagent is it now possible to oxidize alcohols selectively to the corresponding ketones and aldehydes. Over oxidation to carboxylic acids has not been observed. This new reagent combines the advantages of polymer-supported reagents with those of the IBX reagent.


Introduction
][9][10][11] For these purposes, iodinanes like (diacetoxyiodo)-benzene, [bis(trifluoroacetoxy)iodo]-benzene, the Dess-Martin periodinane (DMP) and 1-hydroxy-1,2benziodoxol-3(1H)-one 1-oxide (IBX) 1 are particularly suitable.The advantages of these reagents are high efficiency, easy availability, mild reaction conditions and (with the exception of DMP) stability against moisture and oxygen.Furthermore they are environmentally safe and can be regenerated.The combination of these properties with the advantages of polymer supported reagents [12][13][14][15] is an attractive and worthwhile aim.Recently, we reported on synthesis and oxidative properties of two aminomethylpolystyrene bound (diacetoxyiodo)-benzene derivatives. 16In the context of these investigations we envisaged the development of a polymer supported IBX reagent.Here we present the synthesis of such an IBX derivative and show that it is a powerful oxidant with broad applicability.

Synthesis of the IBX-reagent
The synthesis of reagent 7 was accomplished starting from commercially available 2-amino-5hydroxybenzoic acid 2 (Figure 2).Treatment of compound 2 with NaNO 2 /H 2 SO 4 and excess KI afforded derivative 3, which was transformed to the tert-butylester 4 using N,N-dimethylformamide-di-tert-butyl acetal. 17fter alkylation of the phenolic hydroxy group with ethyl α-bromoacetate and subsequent hydrolysis with NaOH, compound 5 was obtained.This linker was subsequently coupled to aminopropylsilica gel with DIC/HOBt to give compound 6.Cleavage of the tert-butylester with trifluoroacetic acid and oxidation with oxone 18 afforded the final reagent 7. 19 Application of the reagent Now various primary and secondary alcohols can be oxidised with reagent 7 (Table 1).Whereas in the case of soluble IBX, DMSO as solvent is indispensable at room temperature, reagent 7 also works in THF.In comparison to DMSO, reactions proceed faster in that solvent.Even the presence of water (1-10%) has no negative influence on yield and reaction time.The products are obtained with high purity and the general yields are high to excellent.During oxidation of primary alcohols to the corresponding aldehydes no over oxidation to the carboxylic acid was detected.
It is particularly interesting that oxidation of 4a leads to 4b with only the primary hydroxy group oxidised, even if reagent 7 is added in threefold excess. 20In order to get some clues of that remarkable selectivity we tried to oxidise menthol and 3-methyl-2-butanol with reagent 6.The yields of the corresponding ketones were poor (<5%) and could not be increased even after longer reaction times (48h).On the other hand, 2-methylcyclohexanol 11a (racemic mixture) is oxidised easily and in high yield to 2-methylcyclohexanone 11b.The exact reason of this diverse reactivity is yet not fully understood and is subject of current investigations.

Conclusions
In summary, we have discovered a powerful and versatile oxidation system 21 which is particularly suitable for oxidation of alcohols under mild conditions to the corresponding aldehydes and ketones.This method combines the advantages of polymer-supported reagents with the advantages of IBX which is superior to the Dess-Martin reagent in stability, efficiency and versatility. 7The reduced form of reagent 7 is easily separated by simple filtration and can be regenerated by oxidation with oxone. 19The products are obtained in high purity.Side reactions were not detected.Finally our system could be suitable for the polymer-supported synthesis of amino sugars 20 and the cyclization of anilides. 21,22Currently we are focusing our investigations on these aspects.

Experimental Section
General Procedures. 1 H NMR (and 13 C NMR) spectra were recorded on a Bruker AC-250 (DRX-500) spectrometer with the solvent residual peak as internal standard.The GC/MS spectra were recorded on a HP 5890 Series II Gas Chromatograph coupled with HP 5972 Series Mass Selective Detector (specifications of the column: Macherey Nagel Optima 1/20 µm, 25 m x 0.2 mm ID).Mass spectra were recorded on a Finnegan Mat MS90 mass spectrometer.Elemental analysis was performed on a Heraeus CHN-O-RAPID.Iodometric analysis (titration with thiosulfate solution after pulping, starch solution as indicator) was performed in the Institut für Anorganische Chemie, Universität Karlsruhe, Germany.Merck silica gel 60 for column chromatography and Merck precoated TLC plates, silica gel F 254 for TLC were used.All starting materials and chemicals are commercially available and were used without further purification.All solvents were purified and, when necessary, dried in the usual way.Melting points were measured with a Büchi 530 and are not corrected.

2-Iodo-5-hydroxybenzoic acid (3).
To a stirred suspension of commercially available 2-amino-5-hydroxybenzoic acid (5.66 g, 37 mmol) in 100 ml of water is added slowly 6.7 ml of concentrated sulfuric acid.Thereafter a solution of NaNO 2 (3.8 g, 55.4 mmol, in 20 ml of water) is added dropwise, in doing so the suspension is cooled < 5°C with an ice/salt bath.After this addition a solution of KI (9.2 g, 55.4 mmol, in 20 ml of water) is added dropwise and the solution is heated to 95-100°C for one hour.Afterwards the solution is stirred at room temperature for about 12 h.The crude product is crystallized at 4°C from the reaction mixture and filtered off.For further purification it is necessary to recrystallize the product in boiling water to give 3 in 95 % yield (9.21 g, 35 mmol).Analytical data: melting point 188°C, R f 0.3 (hexane/ethyl acetate/acetic acid 1:1:0.02), 1 2)), EI-MS (90°C) calc.m/z 263.9, found m/z 263.9.

Table 1 .
Oxidations of Alcohols with Reagent 7