Aminoketones, synthesis

V O I G H T a-Aminoketone Synthesis Synthesis of a-aminoketones from a-hydroxyketones (see 1st edition). 

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. 

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 -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

The usefulness of the Knorr synthesis arises from the fact that 1,3-dioxo compounds and a-aminoketones are much more easily accessible in large quantities than rational 1,4-difunctional precursors. Such practical syntheses are known for several important hetero-cycles. They are usually limited to certain substitution patterns of the target molecules. 

The synthesis of a-aminoketones can be achieved using a-halogenated ketones as starting material. These latter are converted into the hexamethylene tetraminium salts by the method of Mannich and Hahn (42). This reaction proceeds in two steps ... 

Knorr Synthesis. Condensation of an a-aminoketone with a carbonyl compound was first reported by Knott (20). This reaction and its modifications are among the most important and widely used methods for the synthesis of pyrroles. 

The principal difficulty associated with this type of synthesis is in the availability of a-aminoacyl compounds, e.g. a-aminoaldehydes, a-aminoketones, etc., and most type B syntheses rely on the generation of these compounds in situ, where the self-condensation occurs spontaneously. A large number of research groups have addressed themselves to this problem and a variety of routes are now available. 

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). 

Other methods of generating a-aminoketones in situ are common, if somewhat less general than the methods already described. 2-Nitrovinylpyrrolidine, which is readily available, yields 2,3-bis(3-aminopropyl)pyrazine on reduction and this almost certainly involves ring opening of the intermediate enamine to an a-aminoketone which then dimerizes under the reaction conditions (Scheme 59) (78TL2217). Nitroethylene derivatives have also served as a-aminoketone precursors via ammonolysis of the derived epoxides at elevated temperatures (Scheme 60) (76S53). Condensation of 1,1-disubstituted hydrazine derivatives with a-nitro-/3-ethoxyethylene derivatives has been used in the synthesis of l,4-dialkylamino-l,4-dihydropyrazines (Scheme 61) (77S136). 

One of the more important approaches to 1-azirines involves a similar base-induced cycloelimination reaction of a suitably functionalized ketone derivative (route c. Scheme 1). This reaction is analogous to route (b) (Scheme 1) used for the synthesis of aziridines wherein displacement of the leaving group at nitrogen is initiated by a -carbanionic center. An example of this cycloelimination involves the Neber rearrangement of oxime tosylate esters (357 X = OTs) to 1-azirines and subsequently to a-aminoketones (358) (71AHC-(13)45). The reaction has been demonstrated to be configurationally indiscriminate both syn and anti ketoxime tosylate esters afforded the same product mixture of a-aminoketones... 

BREDERECK Imidazole synthesis Synthesis o( imidazoles Irom (ormamide (acetamide) and a-diketones, a-ketols, a-aminoketones, a-oziminoketones... 

G A S T A L 0 I Pyrazine Synthesis Pyrazme synthesis from a-oximmokeiones via a-aminoketones... 

ROBINSON - GABRIEL OxazoleSynthesis Oxazole synthesis from amides of a-aminoketones... 

V 0 I Q H T a-Amlnokelone synthesis Synthesis ol o-aminoketones from a-hydroxykeiones. 

By a condensation reaction of an a-aminoketone 1 with a ketone 2, a pyrrole 3 can be obtained. This reaction is known as the Knorr pyrrole synthesis. 

Mainly C-substituted pyrroles have been synthesized by application of the Knorr pyrrole synthesis however N-substituted pyrroles can also be prepared, when starting with secondary aminoketones, e.g. bearing an N-methyl or N-phenyl substituent. 

A similar microwave-assisted cyclization in the presence of ammonium acetate of an a-ketoamide, obtained by acylation of an a-aminoketone, was recently described for the synthesis of the antifungal agent Nortopsedin D [46]. The problem of the instabiUty of the a-amino ketones was successfully resolved by in situ acylation of the amine derived from Staudinger reaction of the azide 50 with a phosphine (Scheme 16). This ketoamide was... 

Knoevenagel reaction org chem The condensation of aldehydes with compounds containing an activated methylene (=Cff2) group. ka ne va.nag al re.ak shan ) Knorr synthesis orgchem Acondensation reaction carried out In either glacial acetic acid or an aqueous alkali in which an a-aminoketone combines with an a-carbonyl compound to form a pyrrole possibly the most versatile pyrrole synthesis. nor, sin-th3-s3s ... 

Transformations on this support included the synthesis of aminoketones from supported chloroketones as weU as biarylaldehydes after Suzuki cross-couphng reactions of supported bromo-benzaldehydes [21]. This dendritic polyglycerol was... 

Chiral rra s-2,5-dialkylpyrrolidines, which were used for the synthesis of ant-venom pyrrolizidines, were prepared in the following manner, d-Alanine was transformed into an pentenylamine which, upon intramolecular amidomercuration, yielded 15 (90TA561 92JOC4401). From a protected AA amide, after a Grignard reaction and treatment of the aminoketone with ethyl acetoacetate, the tetrasubstituted pyrrole 16 was obtained [93H(35)843],... 

The first step is formation of a pyrrole ring system from two identical aminoketones. It is actually a Knorr pyrrole synthesis, but we do not need to identify it as such, just approach it logically. In fact, if we look back at the Knorr pyrrole synthesis, we shall see that, under chemical conditions, the reagents used here are not sufficiently reactive for the pyrrole synthesis we need a more activated compound, like ethyl acetoacetate. Furthermore, we could not possibly proceed without masking the carboxyls as esters. This underlines how a biosynthetic sequence might differ somewhat from a purely chemical synthesis. 

Ready access to a-aminoketones [92IJC(B)349] via the HTIB-mediated approach has offered a superior alternative to the most widely used Marck-wald s synthesis (1892CB2354) of 2-mercaptoimidazoles 138 (Scheme 40). This synthesis can be accomplished by following two experimental procedures involving single or multisteps as outlined in Scheme 40. This method is applicable to the synthesis of 4-(2-thienyl)imidazoles (138, R = 2-thienyl), as well [94IJC(B)116). 

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