1,4-Ketols

Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions... 

Nitro alcohols form salts upon mild treatment with alkahes. Acidification causes separation of the nitro group as N2O from the parent compound, and results in the formation of carbonyl alcohols, ie, hydroxy aldehydes, from primary nitro alcohols and ketols from secondary nitro alcohols. 

BREDERECK Imidazole synthesis Synthesis o( imidazoles Irom (ormamide (acetamide) and a-diketones, a-ketols, a-aminoketones, a-oziminoketones... 

LIEBIG BenzyBc Aad Rearrangement Benzylic a<5ds by rearrangement of diketones (also a-ketol rearrangement)... 

WEIDENHAQEN Invdazotosynthesis Imidazole synthesis from a-ketols, formaldehyde and ammonia. 

IV. REDUCTION OF CONJUGATED ENONES AND DIENONES, SATURATED KETONES AND KETOL ACETATES. 

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

The reductive cleavage of ketol acetates involves addition of two electrons to the system with fragmentation into an acetate ion and a ketone carbanion... 

Protonation of the a-carbanion (50), which is formed both in the reduction of enones and ketol acetates, probably first affords the neutral enol and is followed by its ketonization. Zimmerman has discussed the stereochemistry of the ketonization of enols and has shown that in eertain cases steric factors may lead to kinetically controlled formation of the thermodynamically less stable ketone isomer. Steroidal unsaturated ketones and ketol acetates that could form epimeric products at the a-carbon atom appear to yield the thermodynamically stable isomers. In most of the cases reported, however, equilibration might have occurred during isolation of the products so that definitive conclusions are not possible. 

REDUCTIONS OF STEROIDS BY METAL-AMMONIA SOLUTIONS / 45 3, Reduction of Ketol Acetates... 

From the data available, calcium appears to be generally useful for the deacetoxylation of ketol acetates, whereas the utility of lithium is definitely established only for 17-acetoxy-20-ketopregnane derivatives. 

Occasionally a free ketol rather than its acetate may be cleaved successfully in other cases cleavage does not occur. Starr and Smith " have summarized the available data including that covering the reduction of vinylogs of ketols. The experimental findings may be rationalized in several ways, but no firm conclusions seem possible. Smith has discussed some of the pertinent factors that must control the reduction of ketols. 

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

A solution of the ketol diacetate (15 g, 0.028 mole) in toluene (200 ml) is dried by concentration to 150 ml at normal pressure. The solution is cooled to room temperature and then added with vigorous stirring to a solution of calcium turnings (4.2 g, 0.11 g-atom) in liquid ammonia (500 ml). The addition is made in 5 min, the mixture is stirred for a further 3 min, and excess calcium is then destroyed by the dropwise addition of bromobenzene ca. 4 ml). Water (5 ml) is added cautiously and the ammonia is allowed to evaporate. The toluene is removed by distillation on a steam-bath under reduced pressure and methanol (200 ml) is added to the residue, followed by a solution of potassium hydroxide (5 g) in water (10 ml). The mixture is boiled for 1 hr, water (50 ml) is added, and the mixture is warmed on the steam bath for 30 min in order to coagulate the product. Water (250 ml) and acetic acid (15 ml) are added, the mixture is cooled and the product filtered, washed thoroughly with water and dried to give 12.3 g of crude 11-ketotigogenin, mp 209-218° Md, -31°. 

J. E. StaiT, Metal Ammonia Reductions of Steroidal Enones, Saturated Ketones, and Ketols in Steroid Reactions, C. Djerassi, ed., Holden-Day, Inc., San Francisco, 1963, Chapter 7. 

Nickel peroxide is a solid, insoluble oxidant prepared by reaction of nickel (II) salts with hypochlorite or ozone in aqueous alkaline solution. This reagent when used in nonpolar medium is similar to, but more reactive than, activated manganese dioxide in selectively oxidizing allylic or acetylenic alcohols. It also reacts rapidly with amines, phenols, hydrazones and sulfides so that selective oxidation of allylic alcohols in the presence of these functionalities may not be possible. In basic media the oxidizing power of nickel peroxide is increased and saturated primary alcohols can be oxidized directly to carboxylic acids. In the presence of ammonia at —20°, primary allylic alcohols give amides while at elevated temperatures nitriles are formed. At elevated temperatures efficient cleavage of a-glycols, a-ketols... 

A solution of bismuth trioxide in hot glacial acetic acid provides a specific method for the oxidation of acyloins. " The reaction rate is dependent on the steric accessibility of the ketol system. A 2,3-ketol requires less than one hour for completion but an 11,12-ketol is not yet fully oxidized in thirty hours." The reaction is highly selective as a-keto acids, hydrazines and phenols are not oxidized. In a direct comparison with cupric acetate, this procedure is somewhat superior for the preparation of a 2,3-diketone from a 2-keto-3-hydroxy steroid. ... 

Many functional groups are stable to alkaline hydrogen peroxide. Acetate esters are usually hydrolyzed under the reaction conditions although methods have been developed to prevent hydrolysis.For the preparation of the 4,5-oxiranes of desoxycorticosterone, hydrocortisone, and cortisone, the alkali-sensitive ketol side chains must be protected with a base-resistant group, e.g., the tetrahydropyranyl ether or the ethylene ketal derivative. Sodium carbonate has been used successfully as a base with unprotected ketol side chains, but it should be noted that some ketols are sensitive to sodium carbonate in the absence of hydrogen peroxide. The spiroketal side chain of the sapogenins is stable to the basic reaction conditions. 

Alcoholic potassium hydroxide or sodium hydroxide are normally used to convert the halohydrins to oxiranes. Other bases have also been employed to effect ring closure in the presence of labile functional groups such as a-ketols, e.g., potassium acetate in ethanol, potassium acetate in acetone or potassium carbonate in methanol.However, weaker bases can lead to solvolytic side reactions. Ring closure under neutral conditions employing potassiunT fluoride in dimethyl sulfoxide, dimethylformamide or A-methyl-pyrrolidone has been reported in the patent literature. 

The 2,4-dinitrophenylhydrazone is formed in ethanolic hydrochloric acid dehydration will then take place on heating only if the ketol dinitrophenyl-hydrazone remains soluble in the reaction mixture. 

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