Amines acetoacetylation

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. 

An amine-terminated poly ether (ATPE) is prepared as follows. Charge poly(tetramethylene oxide) diol (PolyTHF 1000, BASF, 75.96 g, 0.0759 m) to a 500-mL three-neck round-bottom flask fitted with a thermocouple, a mechanical stirrer, and a vacuum port. Add tert-butylacetoacetate (24.04 g, 0.1582 m) and apply vacuum. Heat at 175° C for 4 h, Fourier transform infrared (FTIR) analysis should indicate complete loss of the polyol OH absorption at 3300 cm. The room temperature viscosity of the product should be about 520 mPa-s. React this acetoacetylated product (85.5 g, 0.0649 m) with cyclohexylamine (14.5 g, 0.1465 m) at 110° C under vacuum for several hours. Cool the resultant cyclohexylaminocrotonate poly ether product to room temperature (1790 mPa-s at room temperature). 

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. 

Aliquat is an efficient catalyst for the acetoacetylation of amines by diketene. The initially formed amides react with an excess of the diketene to form, after cyclization of the secondary product, 1-substituted 3-acetyl-4-hydroxy-6-methylpyrid-2-ones [39]. Amides react under similar conditions with diketene to form A-acyl aceto-acetamides, which react further with a second molecule of diketene to yield, after cleavage of the A-acyl group, 3-acetyl-4-hydroxy-6-methylpyrid-2-one [39]. 

The amine or amide (50 mmol) and Aliquat (0.81 g, 2 mmol) in PhMe (20 ml) are stirred at 70-90 °C and diketene (6.73 g, 80 mmol) is added dropwise. The mixture is stirred for 8-10 h and then cooled, filtered, and evaporated. The residue is extracted with Et20 (3 x 25 ml) and the extracts are evaporated to yield the acetoacetylated product... 

N,N-Diphonylacetoacetomlde or Acetoacetyl-di phenyl amine, C6H5—N — CflH6... 

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. 

In the first step, Rink amide AM PS Resin was acetoacetylated with diketene. Treatment with primary amines resulted in polymer-bound enaminones which then underwent a Hantzsch reaction [30] with l,4-dibromo-2,3-butanedione under formation of 5-(2-bro-moacetyl)pyrroles which could be cleaved from the resin with 20 % TFA/CH2C12. 

Fig. 20.7. Solid-phase synthesis of pyrrole amides by the split-mix method a. acetoacetylation with dike-tene b. separation of the resin into 14 aliquots, enaminone formation with 14 different primary amines ...

The library of 140 pyrrole-3-carboxamides was synthesized following the split-mix protocol with 14 primary amines and 10 a-bromo-ketones as variable building blocks. In the first step Rink-Amide-AM-PS resin was acetoacetylated at —15 °C by addition of di-ketene to the resin suspended in CH2CI2. After 0.5 h at —15 °C and 2 h at room temperature the resin was washed and dried. A negative Kaiser test proved the complete conver-... 

The enzyme could be inactivated by NaBH4 in the presence of either acetoacetyl-CoA or acetyl-CoA. This observation strongly suggests that the reaction is through a Claisen condensation with an amine as the base and with an enzyme substrate ketimine as an intermediate [20]. A mechanism was postulated for the reaction as indicated in Fig. 2. 

Other nucleophiles, including thiols and amines, are also acetoacetylated under similar conditions to give )S-ketothioesters <90CPB2262> and )9-ketocarboxamides respectively <84CPB3848>. Intramolecular examples of these reactions are described above (see Section 6.08.5.2.1) <93JOC5011>. 

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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