Aromatic ketone reduction products

A number of derivatives of compound A were prepared that included acetates, ethers, olefin reduction products, aldehyde and ketone reduction products, aromatic decarbonylated derivatives, and derivatives where the aldehyde was converted to a methyl ester [122]. 

Unsaturated hydrocarbons are present in nearly all products of the Clemmensen reduction of aromatic ketones and must be removed, if the hydrocarbon is requiral pure, by the above process. Secondary alcohols, often produced m small amount are not appreciably steam-volatile. 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

Contaminants and by-products which are usually present in 2- and 4-aminophenol made by catalytic reduction can be reduced or even removed completely by a variety of procedures. These include treatment with 2-propanol (74), with aUphatic, cycloaUphatic, or aromatic ketones (75), with aromatic amines (76), with toluene or low mass alkyl acetates (77), or with phosphoric acid, hydroxyacetic acid, hydroxypropionic acid, or citric acid (78). In addition, purity may be enhanced by extraction with methylene chloride, chloroform (79), or nitrobenzene (80). 

Residual aromatic ether concentrations are determined from the absorbance at 278 mfi of the crude reduction products in methanol solution. Steroidal ether concentrations of 1 mg/ml are employed. The content of 1,4-dihydro compound is determined, when possible, by hydrolysis to the a, -unsaturated ketone followed by ultraviolet analysis. A solution of the crude reaction product (usually 0.01 mg/ml cone) in methanol containing about 1/15 its volume of water and concentrated hydrochloric acid respectively is kept at room temperature for 2 to 4 hr. The absorbance at ca. 240 mfi is measured and, from this, the content of 1,4-dihydro compound can be calculated. Longer hydrolysis times do not increase the absorbance at 240 mp.. 

Another example of the reduction of functional groups is that of aromatic ketones. At the mercury electrode, a radical-type intermediate is formed as the primary product ... 

Purely aromatic ketones generally do not give satisfactory results pinacols and resinous products often predominate. The reduction of ketonic compounds of high molecular weight and very slight solubility is facilitated by the addition of a solvent, such as ethanol, acetic acid or dioxan, which is miscible with aqueous hydrochloric acid. With some carbonyl compounds, notably keto acids, poor yields are obtained even in the presence of ethanol, etc., and the difficulty has been ascribed to the formation of insoluble polymolecular reduction products, which coat the surface of the zinc. The adffition of a hydrocarbon solvent, such as toluene, is beneficial because it keeps most of the material out of contact with the zinc and the reduction occurs in the aqueous layer at such high dilution that polymolecular reactions are largdy inhibited (see Section IV,143). 

The isolated double bonds in the dihydro product are much less easily reduced than the conjugated ring, so the reduction stops at the dihydro stage. Alkyl and alkoxy aromatics, phenols, and benzoate anions are the most useful reactants for Birch reduction. In aromatic ketones and nitro compounds, the substituents are reduced in preference to the Dissoiving-Memi... 

New chiral oxazaborolidines that have been prepared from both enantiomers of optically active inexpensive a-pinene have also given quite good results in the asymmetric borane reduction of prochiral ketones.92 Borane and aromatic ketone coordinate to this structurally rigid oxazaborolidine (+)- or (—)-94, forming a six-membered cyclic chair-like transition state (Scheme 6-41). Following the mechanism shown in Scheme 6-37, intramolecular hydride transfer occurs to yield the product with high enantioselectivity. With aliphatic ketones, poor ee is normally obtained (see Table 6-9). 

Reduction of nonconjugated aromatic ketones gave at metal cathodes (e.g., tin, copper, silver, palladium, zinc) the cis isomers (ds-H/OH) of cycKzed products in high diastereoselectivity. The electroreduction of 5-phenylpentan-2-one led to 70% of an exclusively ds-hexahydronaphthalene... 

All reducing agents used for reductions of aliphatic and aromatic ketones can be used for reduction of cyclic ketones to secondary alcohob (pp. 107 and 109). In fact, reduction of cyclic ketones is sometimes easier than that of both the above mentioned categories [262]. What is of additional importance in the reductions of cyclic ketones is stereoselectivity of the reduction and stereochemistry of the products. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

This side reaction cannot be avoided when reducing aliphatic ketones, but in the aromatic series either product can be obtained by varying the conditions of the reduction. An alkaline reduction favours alcohol production pinacones are formed when acid reducing agents are employed (see Preparation 16). 

Several studies have been made of the effect of added metal ions on the pinacol/alcohol ratio. Addition of antimony(m) chloride in catalytic amounts changes the product of the electrochemical reduction of acetophenone in acidic alcohol at a lead electrode from the pinacol in the absence of added metal salt to the secondary alcohol in its presence53. Antimony metal was suspected to be an intermediate in the reduction. Conversely, addition of Sm(in) chloride to DMF solutions of aromatic aldehydes and ketones54 and manganese(II) chloride to DMF solutions of hindered aromatic ketones55 results in selective formation of pinacols in excellent yields. When considering these results one should keep in mind the fact that aromatic ketones tend to form pinacols in DMF even in the absence of added metal ions1,29,45. 

Another example concerning the reduction of carbonyl compounds also relates to the salt effect theme. Shaefer and Peters (1980), Simon Peters (1981,1982,1983,1984), Rudzki et al. (1985), and Goodman and Peters (1986) described photoreductions of aromatic ketones by amines. In this case, the addition of excess NaC104 results in considerable retardation, even prevention, of final product formation. The two fundamental steps in this photoreduction consist of rapid electron transfer from the amine to the photoactivated ketone (in its triplet state), followed by the slow transfer of proton from the amine cation radical to the carbonyl anion radical ... 

The unsubstituted hydrazones derived from aromatic ketones and aldehydes are converted to the corresponding alkyl chlorides, in high yield, under Swern oxidation conditions. In this unusual oxidation/reduction sequence, the substrate undergoes a net reduction. Unsubstituted hydrazones derived from cyclohexyl ketones yielded elimination products. The mechanism in Scheme 7 has been postulated.111... 

Samarium metal, in the presence of various additives such as ammonium chloride or bromide, induces reductive dimerizations of aromatic ketones to give 1,2-diols, with some diastereoselectivity, and with some alcohol (i.e. reduced ketone) by-product.164 The syn-selectivity observed in many cases may be due to samarium chelation of the... 

A new chiral acyloxyborohydride has been prepared by combining sodium borohy-dride with a tartaric acid-based reagent. This reagent effects the reduction of aromatic ketones to provide the product alcohols in ees of 93-98%. Several aliphatic ketones were also reduced with moderate to excellent enantioselectivity. A mechanism has been provided with supporting calculations for the proposed active species and tran- sition state.262... 

Borane reduction of a variety of aromatic ketones using 5-10 mol% of 5-methyl catalyst 11 proceeded in >95% yield and in 80-97% ee. a-Haloketones were generally more reactive (90-97% ee) than simple ketones, which required higher temperatures (0°C compared to -20°C) to react to completion and led to lower enantioselectivities (80-90% ee).118 A complementary study by Umani-Ronchi and co-workers37 described the borane reduction of cyclic and acyclic ketones using catalyst 10. All products were obtained in >89% yield and >85% ee. Cyclic and hindered ketones led to the highest enantioselectivities (up to 96% ee) at room temperature. 

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