Hydroxylation of Ketones

Ketones having at least one hydrogen next to the carbonyl group can be hydroxylated to form a-hydroxy ketones (acyloins). Acetophenone is oxidized to a-hydroxyacetophenone by o-iodosobenzoic add. In the presence of potassium hydroxide and methanol, dimethyl acetal is obtained, which on subsequent hydrolysis gives the hydroxy ketone in 83% yield (equation 400) [790], 

The conversion of ketones into a-hydroxy ketones can be achieved by the oxidation of enolates or enol ethers. A special reagent for enolates is the oxodiperoxy molybdenum complex with pyridine and hexamethylphos-phoramide. The reaction is applied to aromatic aliphatic ketones and cyclic ketones and furnishes 34-81% yields of a-hydroxy ketones with up to 26% of a-diketones (equation 401) [531]. 

Trimethylsilyl enol ethers prepared in 60-91% yields from ketone enolates and trimethylsilyl chloride are converted into a-hydroxy ketones by chromyl chloride in 62-82% yields (equation 402) [676] (equation 340). 

Hydroxylations of steroidal and unsaturated steroidal ketones in different positions are accomplished by microorganisms, a fact that shows how much ahead microorganisms are in synthetic chemistry as far as regio- 

The biochemical hydroxylations are carried out under the conditions required for the cultivation of individual microorganisms. The common denominator in the cultivation of microorganisms is an aerated aqueous solution containing nutrient material, buffered to the required pH, and kept at a temperature of 26 to 28 °C for a few days or weeks. The products are isolated by extraction with dichloromethane, chloroform, ethyl acetate, and the like. The yields are usually low, and chromatography is often used in isolations. 

---

The hydroxyl group in alcohol 122 is then oxidized. Deprotonation of this ketone with KHMDS (1 eq.), followed by the addition of Davis oxaziridine (see Chapter 4 for a-hydroxylation of ketones)28 (2 eq.) allows the stereo-controlled introduction of the C-10 oxygen from the less hindered enolate face, providing only the (i )-hydroxyketone 123. Subsequent reduction of 123 with excess LAH provides the tetra-ol 124. Treatment of this compound with imidazole and TBSC1 followed by PPTS and 2-methoxypropene provides in one operation the acetonide 125 with 91% yield (Scheme 7-37). 

Asymmetric a-hydroxylation of ketones 97 through phase transfer catalysis under alkaline conditions was realized by use of the Merck catalyst 7 (R=4-CF3, X=Br)[721 as well as the chiral azacrown ether 98[731 in conjunction with molecular oxygen, as shown in Scheme 30. The highest enantioselectivity of 79% ee was attained in the a-hydroxylation of the tetralone 100 by use of the Merck cata-... 

The procedure reported here provides a convenient method for the a-hydroxylation of ketones which form enolates under the reaction conditions. The reaction has been applied successfully to a series of para-substituted acetophenones, 1-phenyl-1-propanone, 3-pentanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclododecanone, 2-methyl cyclohexanone, 2-norbornanone and benzalacetone. In the case of a steroidal example it was shown that a carbon-carbon double bond and a secondary hydroxyl group are not oxidized. A primary amino function, as in the case of p-aminoacetophenone, is not affected.5 Similarly, a tertiary amino ketone such as tropinone undergoes the a-hydroxy at ion reaction.5... 

Ketones can be a hydroxylated in good yields, without conversion to the enolates, by treatment with the hypervalent iodine reagents162 o-iodosobenzoic acid163 or phenyliodoso acetate PhI(OAc)2 in methanolic NaOH.164 The latter reagent has also been used on carboxylic esters.165 02 and a chiral phase transfer catalyst gave enantioselective a hydroxylation of ketones, if the a position was tertiary.166... 

The CCl4-HF-SbF5 system developed by Jouannetaud and co-workers and used in the selective fluorination of imines (see Section 5.10.1) can be applied in the oxygenation of ketones and carboxamides as well. The hydroxylation of ketones is selective [Eq. (5.229)], provided that a five- or six-membered cyclic carboxonium ion preventing fluorination is involved.534,659 Fluorination, however, may be a side reaction with product distributions depending on quenching conditions (aqueous Na2CC>3 or HF-pyridine). Similar features are characteristic of the transformation of carboxamides.659... 

BTI is suitable for the direct hydroxylation of ketones. Aliphatic, aromatic and heterocyclic ketones in acetonitrile-water and trifluoroacetic acid afforded a-hydroxymethyl ketones (in the range of 70%), whereas a-methylene ketones, such as propiophenone, gave less satisfactory yields. 

Alkyl iodides upon oxidation by BTI in presence of lithium perchlorate afforded alkyl perchlorates in a reaction where trifluoroacetate competed with perchlorate [55] a-iodoketones were directly converted into a-hydroxyketones [56]. This transformation gave better yields than an analogous hydroxylation of ketones directly with BTI (Section 4.2). 

A catalytic route using a manganese (III) complex has been developed for a-hydroxylation of ketones avoiding the use of water or a protic solvent mixtures of a-hydroxyketones and their silyl derivatives were formed in excellent yield. By using a chiral pyrrolidine-based manganese (III) complex as catalyst, asymmetric oxidation was effected, with enantiomeric excess varying from 14 to 62% [30], Another kind of a-functionalized ketones resulted from silyl enol ethers which after the addition of IOB.BF3 were treated with triethyl phosphite a-ketophosphonates were obtained in this way [31] ... 

HYDROXY-1-CYCLOHEXENE-1-CARBOXALDEHYDE 1-CYCLOHEXENE-1 -CARBOXALDEHYDE, 3-HYDROXY- (67252-14-6), 67, 205 (S)-(+)-3-HYDROXY-2,2-DIMETHYLCYCLOHEXANONE Cyclohexanone, 3-hydroxy-2,2-dimethyl-, (S)- (87655-21-8), 68, 56 Hydroxylamine, N-phenyl-, 67, 187 a-Hydroxylation of ketones, 66, 138... 

One of the oldest methods for effecting the a-hydroxylation of ketones utilizes transition metal salts, the most widely employed being lead tetraacetate (LTA). Treatment of enolizable ketones with LTA (usually at reflux in acetic acid or benzene) affords the corresponding a-acetoxy derivatives. Originally a radical mechanism was proposed (Scheme 1), but elsewhere it has been suggested that an incipient or-ganolead species is involved prior to conversion to the a-acetoxy derivative by inter- or intra-molecular nucleophilic attack (Scheme 2). 

Much of the preceding discussion concerning the a-hydroxylation of ketones is relevant for ester and lactone substrates. Many examples have featured B-keto esters and these are clearly relevant. Reference should be made to these sections. 

The procedure developed by Moriarty for the a-hydroxylation of ketones using iodosylbenzene or its diacetate has been extended fw use with esters.Thus treatment of methyl or ethyl esters with iodosylbenzene diacetate in a two-phase system (benzene/aqueous KOH) generates the a-hydroxy acid, while reaction in methanol in the presence of sodium methoxide provides the a-methoxy ester, (Scheme 19). Oxidation of the fnt acid was unsuccessful (Section 2.3.2.6). Both variations proceed in similar, moderately good yields, in a fashion mechanistically analogous to Ae reaction with ketones. 

Recent introduction of these reagents as a source of electrophilic oxygen for a variety of oxidative processes was extended to the a-hydroxylation of ketone enolates (Section 2.4.2.1.Ziii), and, at the same time, to the analogous ester/lactone oxidations. 

In a maimer exactly analogous to the a-hydroxylation of ketone silyl enol ethers (Sections 2.3.2.1.3.i and 2.3.2.2.3.i) the corresponding ester silyl ketene acetals may be epoxidized by poacid and subsequently cleaved with fluoride to reveal the a-hydroxy ester.Yiel are good if hexanes are employed as solvent, while competing hydrolysis hampers the process in other media. The equivalent lactone hydroxylations are, however, not possible since hydrolysis is the dominant process even in hexane. This solvent limitation may prove restrictive to the widespread use of this technique. 

The dehydrogenation of steroidal and other ketones can be accomplished with (43) at elevated temperatures. Similar reactions with lactones and lactams have also been reported. Other interesting oxidations include the angular hydroxylation of ketones and the oxidation of benzylic hydrocarbons, as shown in Scheme 14. In some cases, the selenium reagent may be employed catalytically in the presence of a less expensive cooxidant that reoxidizes Se by-products back to the required Se oxidation state. 

---