Methyl ketone synthesis, acetyl chloride

This reaction was first reported by Nenitzescu in 1931. It is the formation of an a,p-unsaturated ketone directly by aluminum chloride-promoted acylation of alkenes with acyl halides. Therefore, it is known as the Darzens-Nenitzescu reaction (or Nenitzescu reductive acylation), or Nenitzescu acylation. Under such reaction conditions, Nenitzescu prepared 2-butenyl methyl ketone from acetyl chloride and 1-butene and dimethylacetylcyclohex-ene from acetyl chloride and cyclooctene. However, in the presence of benzene or hexane, the saturated ketones are often resolved, as supported by the preparation of 4-phenyl cyclohexyl methyl ketone from the reaction of cyclohexene and acetyl chloride in benzene, and the synthesis of 3- or 4-methylcyclohexyl methyl ketone by refluxing the mixture of cycloheptene and acetyl chloride in cyclohexane or isopentane. This is probably caused by the intermolecular hydrogen transfer from the solvent. In addition, owing to its intrinsic strain, cyclopropyl group reacts in a manner similar to an oleflnic functionality so that it can be readily acylated. It should be pointed out that under various reaction conditions, the Darzens-Nenitzescu reaction is often complicated by the formation of -halo ketones, 3,)/-enones, or /3-acyloxy ketones. This complication can be overcome by an aluminum chloride-promoted acylation with vinyl mercuric chloride, resulting in a high purity of stereochemistry. ... 

Al-Thebeiti and El-Zohary [101] have reported an efficient synthesis of a new series of spiroazetidin-2-one derivatives incorporated with quinazoline (Scheme 30). 3-Amino-2-methyl-3//-quinazolin-4-one 117 was treated with cyclic ketones 118 to afford the corresponding cycloalkylidene-3-aminoquinazolinone derivatives 119 in good yields. The reaction of the compounds 119 with chloro-acetyl chloride in the presence of triethylamine as a catalyst yielded the spiroaz-etidin-2-ones 120. 

The conclusive proof that in acetone there are two methyl groups present is in the synthesis of acetone from acetic acid and acetyl chloride, reactions which we shall soon study. With this conclusive proof our formula, as we have written it, must be correct and our ideas in regard to the oxidation of compounds containing hydrogen linked to carbon are probably correct also. The steps in the oxidation are probably as we have indicated, viz., that hydrogen is first converted into hydroxyl and when as a result of such oxidation, two hydroxyls are linked to one carbon the compound loses water, leaving one oxygen doubly linked to the carbon. This enables us to understand the facts that only primary alcohols on oxidation yield aldehydes, secondary alcohols yield ketones, while tertiary alcohols yield neither aldehydes nor ketones. 

Modified Darzens reaction. The original Darzens synthesis of u./3-unxaturated ketones3 involved the addition of acid chlorides to cyclohexenes in the presence of aluminum chloride or stannic chloride followed by dehydrohalogenation. For example, the addition of acetyl chloride to cyclohexene affords l-acetyl-2-chlorocyclohexane, which on dehydrohalogenation (dimethylaniline) gives methyl cyclohexenyl ketone. 

This method for the synthesis of higher-carbon ketoses is based on the reaction of diazomethane with an acid chloride to give a diazomethyl ketone which, on hydrolysis (or acetolysis), furnishes a hydroxy (or acetoxy) methyl ketone. The reaction was first applied in the sugar field in 1938 and has since been widely used in the synthesis of ketoses by Wolfrom and coworkers. As developed by Wolfrom, the synthesis uses fully acety-lated derivatives in the following stages aldose — acetylated aldonic acid acetylated aldonyl chloride acetylated diazomethyl ketose — acetylated ketose — ketose. The method is illustrated in the synthesis of D-galacto-heptulose (10). ... 

One of the most common uses of [ C]acetyl chloride is its Lewis acid- (AICI3, SnCLi) catalyzed Friedel-Crafts reaction with aromatic or heteroaromatic substrates to produce labeled aryl/heteroaryl methyl ketones. As these intermediates are subject to several types of transformations, they have been used as key intermediates for the synthesis of a wide variety of a,)8-functionalized aryl/heteroaryl alkyl target compounds. For example, aryl/ heteroaryl methyl ketones can be (a) halogenated in the methyl group to provide substrates for reaction with carbon or nitrogen nucleophiles, (b) deprotonated so as to react with appropriate electrophilic partners, (c) subjected to stereoselective carbonyl group reduction to alcohols, or (d) reduced to aryl/heteroaryl alkyls. Such transformations can be conducted sequentially in many combinations. 

---