Acylaminoketones

This reaction was first described by Gabriel in 1910 (40), when he warmed an acylaminoketone (197a) with an equimolecular amount of phosphorus pentasulfide. The reaction (Scheme 103) is similar to the preparation of other five-membered oxygen- and sulfur-containing rings from 1,4-dicarbonyl compounds. 

The Gabriel s synthesis is also applicable when a polysubstituted thiazole is required (381, 550). Thus 2,4,5-trisubstituted thiazoles are obtained by treating the corresponding a-acylaminoketones with phosphorus pentasulfide for a few minutes at 100°C (550) or at higher temperature for heavier substituents (381). (Table 11-31). 

TABLE 11-31. THIAZOLES FROM -ACYLAMINOKETONES AND PHOSPHORUS PENTASULFIDE (Gabriel s synthesis)... 

Another procedure for obtaining a-aminoketones is by reduction of a-nitrosoketones in the presence of the required carboxylic acid. Acylaminoketones are prepared either by reacting acids with the chlorhydrate of a-aminoketones according to the method of Pictet and Gauss (41) or by the action of acid anhydrides upon a-amino acids (550). 

The Gabriel s synthesis has been further extended to alkoxythiazoles. Thus 2-alkoxy (or aryloxymethyl) 5-methyl (or phenyl) thiazoles (200) were prepared by refluxing the corresponding acylaminoketone (199) in dry pr3ridine in the presence of P2S5 (Scheme 105) (409). 

These a-acylaminoketones also provided a convenient synthesis of thiazoles on treatment with phosphorus pentasulfide (Gabriel s method). Although yields range from 45 to 80%, substituents are usually restricted to alkyl, aryl and alkoxy derivatives. Thus, reaction of the a-acylaminoketone (4) with P4S1Q gave the thiazole (5), and thiazole (7) itself was prepared in this manner in 62% yield from formylaminoacetal (6) (14CB3163). The corresponding 5-ethoxy compound was obtained from the a-formamidoester and phosphorus pentasulfide in an inert solvent. 

An alternative method involves reaction of an a-acylaminoketone (12) with a primary amine and subsequent ring closure of the resultant Schiff s base (13) with phosphoryl chloride. This enables the introduction of a 1-substituent as in (14) to be carried out efficiently, and if the amine were replaced with a monosubstituted hydrazine, the imidazole derivative (IS) resulted (78LA1916). 

A noteworthy feature of this sequence of reactions is the 0 N migration of the acyl group and the final stabilization as the N-acylaminoketone. 

In the ring-closure reaction of a-acylaminoketones with hydrazines, some dihydro-1,2,4-triazines were obtained. The possible 1,2-, 2,3-, or 5,6-dihydro structures were excluded by IR spectroscopic studies however, this method, as well as the attempted preparation of fixed derivatives, failed to distinguish between... 

A parallel synthesis of novel pyrrole-oxazole analogues of the insecticide Pirate was performed through the dehydration of acylaminoketones with POCl3<06S1975>. 

Fiir die Umwandlung von a-Aminosauren in a-Acylaminoketone und C02 bei. der Einwirkung von Essigsaureanhydrid in Gegenwart einer... 

A-Acyl AAs, when transformed into a-acylaminoketones by the Dakin-West reaction, react with arylhydrazines, arylsulfonylhydrazines, or some primary amines to give the corresponding ketimines which undergo cyclodehydration with POCI3/PCI5 or TPP (Scheme 21) (78LA1916). 

In attempts to carry out the condensation of ketones with nitriles under Ritter reaction conditions, / -acylaminoketones 96-98 were obtained73. Ketones such as acetone, cyclohexanone, mesityl oxide, diacetone alcohol and acetophenone and its substituted derivatives were applied in this reaction (equation 34). 

Multisubstituted five-membered aromatic heterocycles are synthesized via this cascade protocol (equation 34). The cycloadditions of a-acyloxyketones 78a with lithium ynolates afford /3-lactone lithium enolates 79a, which spontaneously cyclize to give bicyclic compounds 80a. These intermediates, which are stable enough to be isolated, are treated with TsOH under heating to provide substituted furans 81a via decarboxylation and dehydration. Thiophenes (e.g. 81b) are also synthesized by the analogous scheme via intermediate 80b using a-acylthioketones (78b) as a substrate. In the synthesis of pyrroles using a-acylaminoketones as a substrate, the cyclization proceeded at —20 °C, and the -lactone was subsequently ring-opened via /3-elimination to furnish pyrroles in one-pot (equation 35). ... 

Alkaline cleavage of 2,4,4-trimethyl-5-phenyl-4//-imidazole 1-oxide gives oximes of a-acylaminoketones as products (80AHC(27)24l). 

Thiazoles were usually obtained by treating the corresponding a-acylaminoketones with phosphorus pentasulfide for a few minutes at IOO C... 

When primary amines react with a-acylaminoketones the resulting Schiff bases can be cyclized in the presence of phosphoryl chloride, phosphorus pentachloride, or triphenylphosphine and triethylamine in hexachloroethane to give 1-substituted imidazoles (11) (Scheme 2.1.4). The starting a-acyl-aminocarbonyls are readily prepared from a-amino acids by reduction with sodium amalgam [31, 32] or by the Dakin-West reaction [33, 34], which is most conveniently conducted in the presence of 4-(AUV-dimethylamino)pyridine (DMAP) as an acylation catalyst [35 37]. 

Thiazoles can also be derived from 1,4-dicarbonyl compounds, which are available through the N-H insertion reaction of rhodium carbenoids <05JA15644>. For example, the dirhodium(II) carboxylate-catalyzed reaction of diazocarbonyl compound 8 in the presence of primary amide 7 leads to the formation of a-acylaminoketone 9, which is converted into thiazole 10 by treatment with Lawessons reagent. Thiazole 10 serves as one of the six thiazole building blocks in the total synthesis of thiopeptide antibiotic amythiamicin D. 

Moreover, it has been shownthat under conditions of electrophilic catalysis by acetyl cations the addition of ketones to nitriles proceeds more rapidly than the self-condensation of ketones shown in equations 34-36, Thus, cyclohexanone reacts with both benzonitrile and acetonitrile in the presence of perchloric acid/acetic anhydride mixture to form A -acyliminium salts 186 which are then converted to the JV-acylimines 187. The -acylaminoketones 97" did not form the salts 186 in a control experiment... 

Via intermediates Acetylenedicarhoxylic acid ester syntheses s. 3, 704 jd-Keto-o-acylaminocarboxylic acid esters and a-acylaminoketones from a-acylaminocarboxylic acids via oxazolones s. 4, 804 v.L -f- <—... 

A convenient route to polysubstituted oxazoles was developed through a variation on the Robinson-Gabriel synthesis in which the key 1,4-dicarbonyl compounds were obtained by a rhodium carbene N-H insertion reaction. Dirhodium tetraacetate catalysed reaction of primary amides 103 and diazocarbonyl compounds 107 gave a-acylaminoketones 108, which were converted into 109 by cyclodehydration using the Wipf and Miller protocol <04T3967>. 

---