Aminoketones, generation

Because the a-aminoketone is subject to self-condensation, the condensation with a P-dicarbonyl derivative (6) is usually carried out by generating the a-aminoketone in situ through reduction of an oximino derivative (7) 2iac ia glacial acetic acid is used as the reductant. For example, Knorr s pyrrole... 

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). 

Strecker aldehyde are generated by rearrangement, decarboxylation and hydrolysis. Thus the Strecker degradation is the oxidative de-amination and de-carboxylation of an a-amino acid in the presence of a dicarbonyl compound. An aldehyde with one fewer carbon atoms than the original amino acid is produced. The other class of product is an a-aminoketone. These are important as they are intermediates in the formation of heterocyclic compounds such as pyrazines, oxazoles and thiazoles, which are important in flavours. 

This is a fairly general reaction, and requires an amine plus an aldehyde (usually, but not necessarily, formaldehyde) together with an enolizable ketone, which together generate a P-aminoketone via an iminium system. The Mannich reaction is surprisingly... 

The elimination reaction can be followed only for pH > (pKvm — 2). The rate of the side reaction of the a,(i-unsaturated ketone increases with increasing pH and for phenylvinyl ketone becomes of importance at pH values above about 9. To study the elimination process unaffected by the hydration of the a,[3-unsaturated ketone generated, it was necessary to find a Mannich base the elimination of which would take place at pH << 9, i.e. with a.pKjtB 9. 3-Morpholinopropiophenone proved to be a suitable model (27) this compound has a pK B value of 6.8, so that constants ke and kaa at pH < 9 can be quantitatively evaluated without any effect from cleavage of the a,(3-unsaturated ketone. The validity of the kinetic equations corresponding to scheme (13) was proved both for the elimination of p-aminoketones (27) and for the addition of primary and secondary amines to a, (3-unsaturated ketones (28). 

Moreover, Hoveyda and coworkers have demonstrated that Mannich reactions between silyl enol ethers and aldimines are promoted by the chiral complex that was generated from AgOAc and an wo-Leu-derived phosphine ligand.26 When the reaction was conducted with trimethylsilyl enol ether and aldimine in the presence of AgOAc, /.so-Leu-derived phosphine ligand and 2-PrOH, the (3-aminoketone was obtained with high enantioselectivity (Schemes 9.15 and 9.16). 

The cyclization normally proceeds by initial enamine formation. Enamines of this type can also be generated by addition of a-aminoketones to dimethyl ethynedicarboxylate or methyl propiolate and they can be converted to pyrroles <62JOC3346, 64JA107, 68T1567,69X527,91JCS(Pi )337i >. Intermediates of both structures (18) and (19) have been observed. The condensations are usually carried out in hot acetic acid. 

A modified Knorr pyrrole synthesis was key to a practical synthesis of the potent 5-opioid agonist SB-342219 by GSK. SB-342219 is a selective 5-opioid agonist undergoing preclinical evaluation for the potential treatment of neuropathetic pain. The medicinal chemistry route used the conventional Knorr pyrrole synthesis. Condensation of the ketone with a-aminoketone, which was generated in situ by reduction of the requisite phenylhydrazone using zinc, gave the desired pyrrole in 63% yield. 

The reaction begins with conversion of the carbonyl compound (1) to the oxime (2), which is then treated with base to form the 2/f-azirine (3). Subsequent hydrolysis under acidic conditions generates the a aminoketone... 

As a result of the availability of a wide variety of aminoketone and ketomethy lene monomers that could be synthesized, and the ability of the Friedlander reaction to generate high molecular weight polymers under... 

As in (2), the Knorr synthesis proceeds via P-enaminone intermediates 47 and their cyclization to 48 [114]. Frequently, the required a-aminoketones are not employed as such (due to their instability) but generated in situ by reduction of a-oximino ketones or a-phenylhydrazono ketones 49/50 [115] ... 

Amine bases generated by the photolysis of carbamates, O-acyloximes, ammonium salts, formanilides, aminoimides, a-aminoketones, and amidines have been used to catalyze a wide range of different condensation polymerization reac-tions. Scheme 5 shows a mechanism for the photolysis of an O-acyloxime, 8, as a photolatent base to produce benzylamine. 

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