A-Aminoketones, preparation

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

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). 

An alternative approach to the use of a-aminoketones involves acetals (72JOC221) and pyrazine-2,3-diones have been synthesized by this route (Scheme 58). The acetals are readily available from the phthalimido derivatives via the a-chloroketones. Hemiacetals have also served as a starting point for pyrazine synthesis, although in most cases hemiacetals are too labile to be easily prepared examples are common in the 2-amino-2-deoxy sugar series 2-amino-2-deoxy-D-glucose for example dimerizes to the pyrazine (101) when generated in situ from the hydrochloride salt (68JAP6813469). 

With excess ketone, the preparation of the aminoketone and subsequent condensation to a pyrrole can be conducted in one pot. In a side-reaction a-aminoketones can undergo a self-condensation to give pyrazines 8 ... 

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an a-aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In tlie present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

Isothiazoles can be prepared from thionyl chloride and a-aminoketones, a-iminoketones, a-iminonitriles, or acrylonitriles the reactions concerned have been discussed.62... 

Research Focus The preparation of a-aminoketones having high initiator activity, low odor, low migration, and that are reactive with adds, aldehydes, and ketones. 

Observations Although modified a-aminoketones were prepared in a single step, four... 

During attempts to synthesize a series of optically active, bicyclic a-aminoketones (195-198), Kuneida and co-workers found that racem-ization invariably took place during the saponification and decarboxylation of the /9-ketoester intermediates, prepared via Dieckmann reactions [Eqs. (26) and (27)].253... 

Two independent syntheses of 10-propargylFA (694) have recently been reported. In the first, the Boon-Leigh strategy was employed (Scheme 3.154) [284], Thus, alkylation of diethyl [p-(W-propargylamino)benzoyl]-L-glutamate (690) with the phthalimide (500) provided the masked a-aminoketone (692), which was further elaborated to (694) via the oxime (693) under standard conditions. Various reduced derivatives of (694) were also prepared. An alter-... 

Returning again to pyrroles, probably the most widely-used method for their preparation is the Knorr pyrrole synthesis, which is the condensation of a ketone 2.22 with an a-aminoketone 2.23 to give pyrrole 2.13, via enamine 2.24. A reasonable mechanism is shown below, although none of the intermediates is isolated. 

The a-aminoketones are often prepared by nitrosation of an active methylene group followed by reduction of the oxime to the amine (e.g. 2.25 to 2.26 to 2.27). 

The self-condensation of two molecules of an a-aminoketone to a 2,5-dihydropyrazine and subsequent oxidation represents an important method for the preparation of 2,5-disubstituted and 2,3,5,6-tetra-substituted pyrazines. The second step may proceed spontaneously in the presence of air, or be carried out with oxidizing agents such as hydrogen peroxide or mercuric chloride. The required a-aminoketones are by no means easily accessible intermediates and an alternative route to tetrasubstituted pyrazines has been developed which involves... 

Direct ring syntheses are also available for the preparation of hydroxypyrazines. Thus, haloacylation of an a-aminoketone, followed by reaction with ammonia and oxidation represents a general synthesis of 5,6-disubstituted and 3,5,6-trisubstituted 2-hydroxypyrazines.339 This is illustrated by the preparation of 5,6-dimethyl-2-hydroxy-pyrazine (Scheme 39). Hydroxypyrazines are very conveniently... 

Thioxo(or oxo)-6//-imidazol[l,2-c]quinazolines 147 were prepared from reactions of 2-isothio(or oxo)cyanatobenzonitrile 145 with various a-aminoketones 146 <03TL5965>. 

Although a-aminoketones readily form imidazoles when they cyclize in the presence of formamide [48], preparative difficulties (see Sections 2,1.1, 2.2.1 and 4.1) point to alternative use of their precursors, a-oximinoketones, which can be reduced by dithionite or using catalytic methods in formamide at 70-100°C. Subsequent ring closure is achieved merely by raising the temperature to 180°C. 

Many modified Marckwald procedures are available to prepare structurally diverse imidazoles most of them are focused on the preparation of an oe-aminoketone or its equivalents. For example, a regiospecific synthesis of trisubstituted imidazoles has been developed. Thus, treatment of BOC-protected a-amino acids 1265 with malonic monoester leads to a-aminoketones. After removal of the BOC protecting group, the resulted a-aminoketone salt 1266 will condense with isothiocyanates to form thioureas 1267. The intermediates 1285 undergo cyclodehydration under acidic conditions, yielding imidazole-2-thiones 1268 in good yields. Both reductive and oxidative desulfonation have been used to convert the imidazole-2-thiones 1268 into imidazoles (1269 or 1270) (Scheme 321) <2005TL7315>. 

Amidinylation of a-aminoketones 1287 with cyanamide or activated guanidines such as pyrazole derivative 1288 affords 2-aminoimidazoles 1289. This method has been applied to prepare L-aminohomohistidine, as shown in Scheme 327 <2004TL2779>. 

In the laboratory of E.B. Pedersen, several 2-methylsulfanyl-1H-imidazoles were prepared and tested for their activity against HIV-1 These compounds can be regarded as novel non-nucleoside reverse transcriptase inhibitors. The required a-aminoketone hydrochloride building blocks were prepared using the Dakin-West reaction. L-Cyclohexylalanine was dissolved in excess pyridine and propionic anhydride and was kept at reflux overnight. The resulting a-propionylamino ethyl ketone was hydrolyzed with concentrated hydrochloric acid and the a-aminoketone hydrochloride was heated with one equivalent of potassium thiocyanate in water to afford 4-cyclohexylmethyl-5-ethyl-1,3-dihydroimidazole-2-thione. This material was then advanced to 4-cyclohexylmethyl-1-ethoxymethyl-5-ethyl-2-methylsulfanyl-IH-imidazole. 

Imidazolines can exist as the 2-, 3-, or 4-isomers ((5)- 7)), and whereas (5) can exist as a pair of tautomers, any proton shift in (6) will give (7) by rearrangement. Hydrolysis of A(-unsubstituted 3-imidazolines (6) to a-aminoketones presumably occurs via (7). Nickel boride , prepared in situ, transforms 3-imidazolines into 2-imidazolines by double-bond migration <86H(24)287l>. 

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