Ketones, hydroxy from diketones

Oxidations of hydroxy ketones to diketones occur frequently in steroidal alcohols. If the alcoholic group, usually secondary, is remote enough from the keto group, its oxidation takes place independently and is achieved by the same reagents that are used for the oxidation of alcohols. A solution of chromium trioxide in aqueous sulfuric acid oxidizes 5-pregnen-3p-ol-20-one in acetone solution at room temperature within 2-5 min to 5-pregnen-3,20-dione in 90% yield [579]. Similarly, lip-hydroxytestosterone 17-acetate is transformed by chromium trioxide in 80% acetic acid at room temperature in 30 min into 11-ketotestosterone 17-acetate in 92% yield [807]. 

Products detected or isolated from these oxidations include the corresponding a-hydroxy ketone and a-diketone and also adipic acid (from cyclohexanone) in up to 95 % yield. However, IrCI gives a-chloroketone in quantitative yield . Evidently when the rate of oxidation exceeds enolisation attack is on the keto form, probably via a complex, although this is definite only for Ce(IV) perchlorate, to give a radical, e.g. 

Symmetrical and unsymmetrical benzoins have been rapidly oxidized to benzils in high yields using solid reagent systems, copper(II) sulfate-alumina [105] or Oxone-wet alumina [105, 106] under the influence of microwaves (Scheme 6.32). Conventionally, the oxidative transformation of a-hydroxy ketones to 1,2-diketones is accomplished by reagents such as nitric acid, Fehling s solution, thallium(III) nitrate (TTN), ytterbium(III) nitrate, ammonium chlorochromate-alumina and dayfen. In addition to the extended reaction time, most of these processes suffer from drawbacks such as the use of corrosive acids and toxic metals that generate undesirable waste products. 

The scope of the reaction was considerably enlarged in 1935, when Clutterbuck and Reuter6 observed that the compound tetrahydroterrein, derived from the mold metabolite terrein, consumes more than the calculated amount of periodate per mole. They found that 1,2-diketones and a-hydroxy ketones are also oxidized under the conditions used by Malaprade. Although this type of oxidation had been earlier noted [in a study7 of the action of periodate on 1,3-dihydroxy-2-propanone (dihydroxyace-tone)], Clutterbuck and Reuter made a more thorough exploration of the reaction.6 In a series of model compounds, Ri and R2 were varied from... 

Preparation and phytochemical reduction of 2,2 -thenoin and 2,2 -thenil have been studied in the authors laboratory (20a). It has been shown that 2,2 -thenoin gives a color reaction similar to that shown by benzoin and other acyloin condensation products in- the presence of alcoholic alkali. The hydroxy ketone may be oxidized by iodine in the presence of sodium methoxide to give the diketone, 2,2 -thenil, in excellent yields. Phytochemical reduction was shown also to be applicable to both compounds. It is significant that thenoin differs from benzoin, since reduction products were not obtained enzymatically from the latter. 

Utsukihara, T., Nakamura, H., Watanahe, M. and Horiuchi, C.A., Microwave-assisted synthesis of a-hydroxy ketone and a-diketone and pyrazine derivatives from a-halo and a,a -dibromo ketone. Tetrahedron Lett., 2006, 47, 9359. 

The ketone 73 was reduced chemo- and diastereoselectively and protected to provide the silyl ether 74. The ester function was then deprotonated to the corresponding ester enolate (75) that was alkylated with methyl iodide exclusively from the Re face of the enolate to afford the bicycle 76 (Scheme 11). The substrate for the retro-aldol reaction (77) was prepared by a sequence that consists of seven functional and protecting group transformations. The retro-aldol reaction converted the bicyclic yS-hydroxy ketone 77 into the 1,3-diketone 69 via the alkoxide (78) in very good yield. 

Both the diketone and the cleavage products were shown to arise from an a-hydroxy ketone intermediate (benzoin), 5. 

Yields of a-hydroxy ketones by enolate hydroxylation with 1 are generally in the range 45-80% the a-diketone is sometimes obtained in addition in 5-26% yield. For unknown reasons, these hydroxylations often do not go to completion, and 5-15% of the carbonyl substrate is recovered. Yields are poor from hydroxylations of methyl ketones. 

The unsaturated diketones that are obtained from the /1-hydroxy ketones in Figure 12.19 by proton-catalyzed dehydration according to the E2 mechanism are of considerable importance ... 

Bridgehead bicyclic cyclopropanols or cyclopropyl silyl ethers 103 (R=H) cleaved to ring-expanded mixtures of cyclic (1-hydroxy ketones 105 and (1-diketones 106 in good overall yields catalyzed by 10 mol% of VO(acac)2 in the presence of oxygen (Fig. 32) [191, 192]. With 3-substituted substrates 103 (R=Me), mixtures of bicyclic endoperoxide hemiketals 104B and (1-hydroxy ketones 105 arose. In separate experiments it was shown that 105 is not oxidized to 106 under the reaction conditions, and thus the products most likely form from... 

Primary benzylic alcohols (equation 10) can be oxidized in the presence of saturated primary alcohtris using a catalyst derived from ammonium cerium(IV) nitrate supported on charcoal with air as the cooxidant (under these conditions a-hydroxy ketones are oxidized to a-diketones). ... 

Tetronic acids. N,N -Carbonyldiimidazole (1) can serve as an equivalent of C=0 in a synthesis of tetronic acids from dianions of a-hydroxy ketones or a -diketones. ... 

Diols may be prepared by reduction of a-diketones or a-hydroxy ketones such as biacetyl, benzoin, and benzil. Substituted benzoins containing methoxyl and p-dimethylamino groups have been reduced catalytically over platinum oxide and by sodium amalgam and alcohol. Levorotatory propylene glycol is made from acetol, CHjCOCHjOH, by an enzymatic reduction with yeast. ... 

Hydroxy ketones of the type RCOCHjCHOHCHj are formed in 35-66% yields by partial catalytic hydrogenation of the corresponding /S-diketones over Raney nickel at KX) . Aromatic a-hydroxy ketones (benzoins) are prepared from the corresponding a-diketones (benzils) by catalytic reduction or by reduction with magnesium-magnesium iodide mixture. ... 

The earliest synthesis of imidazole was achieved by Debus from glyoxal, formaldehyde and ammonia (Scheme 70), and many of the classical methods of Imidazole synthesis were based on this general type of reaction. Initially, most syntheses utilized a-diketones, but in the 1930s it was shown that a-hydroxy ketones could serve equally well provided that some oxidizing agent (e.g. ammoniacal copper(II) acetate, citrate or sulfate) was incorporated in the reaction mixture. Further improvement used ammonium acetate in acetic acid as the nitrogen source. 

Some of the problems associated with the synthesis of a-dicarbonyl starting materials have been alleviated by the use of propane-1,3-dithiol, which reacts with aldehydes to give cyclic thioacetals. With butyllithium the resulting stable dithiane anions (134) can be transformed into a-diketones or a-hydroxy ketones (Scheme 73). A further approach to such compounds is found in the reaction of a-ketonitrate esters with sodium acetate (Scheme 73), while aryl a-diketones are also available from a-ketoanils (prepared from the cyanide-ion-catalyzed transformation of aromatic aldimines) (70AHC(12)103). 

When a-diketones react with a mixture of formamide and formaldehyde at 180-200 °C it is not possible to detect a-hydroxy ketones during the reaction. It seems, therefore, that the formaldehyde cannot be acting as a reducing agent, and that imidazole formation must be a consequence of generation of ammonia from formamide, and subsequent reaction between the diketone, ammonia and formaldehyde. The major advantage here over earlier methods lies in the reduced decomposition of the a-diketone, which normally results in reduction in yields and mixtures of products. 

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