Amine derivatives, acetoacetyl

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

Compounds with Reactive Methylene Groups. In this group the coupling components with the greatest industrial importance are the A-acetoacetyl derivatives of aromatic amines (acetoacetarylides) CH3COCH2CONHAr. Anilines substituted by halogen, alkyl, alkoxy, nitro, and acylamino groups are most suitable (e.g., Napthol AS-IRG). 

N-Protection in peptide synthesis. Diketene reacts with an amino ester hydrochloride in ethanol at 0-5° in the presence of 1 equivalent of sodium ethoxide or a tertiary amine to give the often crystalline and easily purified N-acetoacetyl derivative (1). After peptide synthesis the protective group is removed by treatment with phenylhydrazine, which affords l-phenyl-3-methyl-5-pyrazolone. 

Trautwein and co-workers described an efficient method for the solid-phase s thesis of TV-substituted pyrroles, including tetrasubstituted pyrroles. Highly substituted pyrroles are functional components of compounds such as atorvastatin (Lipitor), an HMG-CoA reductase inhibitor used for lowering cholesterol. Reaction of p-ketoamides 29, prepared from polymer bound acetoacetamide using a series of primary amines in trimethylorthoformate (not shown), with a-bromoketone derivatives 30 in the presence of 2,6-di-tertbutylpyridine (DTBP) and DMF yielded pyrroles 31 with diverse functionality in high purity. The authors found that polystyrene Rink amide resin was the best solid support because it was able to withstand the acetoacetylation conditions required to produce the polymer bound acetoacetamide. 

The acetoacetyl derivatives are obtained by the reaction of the amine with diketene . In the case of amino acid ester hydrochlorides the presence of one equivalent of sodium methoxide or of a tertiary base is necessary. The group is removed by applying the conditions of the Knorr synthesis of pyrazol derivatives from various /3-keto esters and their derivatives . The protecting group is removed in acetic acid by using an equimolar amount of phenylhydrazine (reaction 3). 

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