Amides 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. 

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... 

The biosynthesis of tenuazonic acid was studied using [l-14C]-labeled acetate. N-acetoacetyl-L-isoleucine (7) was detected by radioactive trapping, indicating that amide formation, rather than carbon-carbon bond formation is probably the first step. None of the simple tetramic acid (8)... 

N-Acetoacety lotion. The N-acetoacetylation of amides with diketene is markedly improved if it is carried out in the presence of iodotrimcthylsilanc (generated in situ). The reactive reagent is probably a. 

The heterocycle 43 was needed as an intermediate in a cytochalasan synthesis.10 Disconnection of the 1,3-diCO relationship between the two ketones reveals the amide 44 that is the acetoacetyl derivative of phenylalanine ethyl ester 45. 

The classical method for tert-butyl esterification involves nnineral add catalyzed addition of the amino acid to isobutene. Both, N-protected, e.g. Z-Xaa-OH, and unprotected amino acids form tert-butyl esters with isobutene in the presence of catalytic amounts of sulfuric acid or TosOH. " Another efficient method is the transesterification of an acetic acid tert-bvXy ester catalyzed by perchloric acid. " Amide tert-butylation was recognized as a side reaction in the presence of perchloric acid, but could be completely suppressed by using sulfuric acid. Both methods, acid-catalyzed addition to isobutene and the transesterification of acetic add terf-butyl esters, result in simultaneous terf-butyl-ation of hydroxy and sulfanyl groups. A synthetic route to Z-Thr-OtBu, Z-Ser-OtBu, and Z-Hyp-OtBu without conconnitant O-alkylation involves the hydroxy protection by the acetoacetyl group, which is readily cleaved by treatment with 2 equivalents of hydrazine in EtOH for 30 minutes. ... 

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-... 

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. 

N-Acetoacetylation with diketene of N-silylcarboxylic acid amides... 

A soln. of N-trimethylsilyl-2-pyrrolidone and diketene in dry benzene refluxed 4 hrs. in the presence of a catalytic amount of triethylamine, a little water added, and warmed 10 min. at 60° on a water bath -> N-acetoacetyl-2-pyrrolidone. Y 89%. F. e. and different reaction with silylated prim, amides s. Y. Yamamoto and H. Kimura, Chem. Pharm. Bull. 24, 1236 (1976). 

The conformational properties of polypeptides containing j3-keto-amide groups in the side chain, such as acetoacetylated poly-L-lysine, poly-L-ornithine and poly-L-diaminobutyric acid, have been recently investigated in our laboratory [1 ]. 

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