Oxidations with Immobilized Periodinanes

In recent years hypervalent iodine compounds have experienced extensive investigations yielding many results of practical synthetic importance. Supported iodi-nanes, i.e. iodoso or iodine(III) reagents, have been prepared by several groups, mainly as the bis-acetoxyiodoso derivatives [15-18] or as the respective dihalogeno compounds [19]. Iodoso reagents are employed in the oxidation of hydroquinones and phenols that have been exploited in the formation of spiroketals from a variety of tyrosines.

In contrast, periodinanes (i.e. iodoxo or iodine(V) reagents), preferably as the 1-hydroxy-(1H)-benzo-1,2-iodoxol-3-one-1-oxide (2-iodoxybenzoic acid, IBX) [20, 21] or its acetylation product, the Dess-Martin reagent [22], have been widely used for oxidation of sensitive and complex alcohols. Periodinanes have not yet been prepared on a polymer support; a silica-supported IBX has been reported recently

The limitations of oxoammonium resins in the oxidation of nitrogen-containing moieties prompted investigation of polymer-supported periodinanes as poten-

Ibx Reagent
Fig. 3.6.5. Polymer-supported IBX can be activated and recycled with monoperoxy sulfonic acid (Caro's acid). The reagent is capable of alcohol oxidations, dehydrogenations, and radical cyclization reactions.

tial alternatives [15]. To obtain a functional iodine(V) reagent, a derivative of 2-iodobenzoic acid was required which would be suitable for immobilization yet retain oxidation properties similar to those of the parent compound. 5-Hydroxy-2-iodobenzoic acid esters can be efficiently immobilized on chloromethyl polystyrene via the phenoxide. The alkoxy derivatives have been prepared and oxidized to the iodoso derivative, but not to the iodoxo derivative. Methyl 5-hydroxy-2-iodobenzoate was obtained in two steps from 3-hydroxyanthranilic acid by a Sandmeyer reaction followed by esterification with thionyl chloride in methanol. It was coupled to chloromethyl polystyrene crosslinked with 1% divinylbenzene (1.20 mmol g-1) by using cesium carbonate as base (Figure 3.6.5). The loading of the resin was determined by elemental analysis and was close to the theoretical value (98%). Saponification was effected by treatment with potassium trimethylsilanoxide in THF, yielding resin 4.

Oxidation of 4 to resin 5 has been investigated under different conditions. Initial screening of oxidizing activity was conducted by HPLC analysis of the reaction with piperonyl alcohol as test substrate. Generation of monoperoxysulfonic acid (i.e. Caro's acid) was identified as the best oxidation conditions. By using an equi-molar mixture of tetrabutylammonium oxone with methylsulfonic acid (DCM, RT, 3 h) resin 5 was furnished with a high oxidizing activity of 0.8 mmol g-1. Resin 5 was characterized by IR spectroscopy, elemental analysis, and MAS NMR. Elemental analysis indicated a loading of 0.84 mmol g-1, corresponding to a yield of 94% relative to the initial loading and taking into account the mass increase of the resin. No loss of iodine was observed under the strongly acidic reaction conditions. The oxidizing polymer 5 was stable towards air and moisture and could be stored without loss of activity.

The oxidation properties of periodinane reagent 5 (1.75 equiv., DCM, RT, 3 h) were investigated by reaction with a collection of a variety of alcohols including benzylic, allylic, and primary and secondary alcohols, including the unsaturated terpene alcohols citronellol and geraniol, and the carbamate-protected amino-alcohols Fmoc-Phe-ol and Fmoc-Ile-ol. All reactions were followed by GC-MS or by HPLC (215 and 280 nm). Products were identified by NMR spectroscopy and by mass spectrometry (EI, 70 eV); isolated yields were determined by weight. Most alcohols were converted to the respective aldehyde or ketone products in good to excellent yields and purities. After extensive washing resin 5 that had not been used at elevated temperatures could be recycled by repeated oxidation. In addition to the oxidation of alcohols, further important transformations effected by IBX were investigated with resin 5. Cyclohexanol reacted with 5 in a closed vessel (2.3 equiv., DCM, 2 h, 65 °C) yielding the a,j5-unsaturated cyclohexenone via cyclo-hexanone and a postulated iodine-enol ether intermediate [24]. The unsaturated carbamate 6 was treated with reagent 5 (4 equiv., THF/DMSO 10:1, 90 °C, 16 h) to effect radical cyclization affording product 7 in 30% yield [25]. It should be noted that IBX at elevated temperatures can oxidize benzylic positions, which are abundant in the polystyrene backbone of 4; this might account for a competing reaction pathway.

Resin 5 was prepared as the first polymer-supported periodinane reagent. The resin was obtained with high loading (0.8 mmol g_1) and was capable of converting a collection of diverse alcohols including complex and sensitive structures efficiently and in good to excellent yields to the respective carbonyl compounds. The a,jS-desaturation of carbonyl compounds and the radical cyclization of an unsatu-rated carbamate were also demonstrated. The novel reagent is likely to find broad application in polymer-assisted solution phase synthesis. The new oxidizing resin should also be well suited to integration into parallel polymer-supported reaction sequences and to conversion of compound libraries.

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