Aminoketone 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. 

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 ... 

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). 

Ring-fused systems have also been prepared using this bond formation approach. Treat-ent of the /3-aminoketone (281) with lead tetraacetate gave the isoxazole system (282 ... 

By similar procedures diazirines were prepared not only from simple aliphatic ketones but also from hydroxyketones and )3-aminoketones (B-67MI50800), and so were a large number of diazirines from steroidal ketones (65JA2665). Permanganate, bromine, chlorine and hypochlorite were used as oxidants. A one-step preparation of diazirines from ketones like 3-nonanone, ammonia and chlorine has been claimed in a patent (66USP3290289). 3,3-Diazirinedicarboxylic acid derivatives like (286) were obtained directly from oxime tosylates by the action of two moles of O-ethoxyamine (81AG(E)200). 

When the 1-monoximes or dioximes of 4-acetyl-l-tetralones are hydrogenated in the presence of palladium, mixtures of diastereoisomeric 1-aminotetralones are formed. The m-aminoketone isomers readily form dehydrobenzoisoquinuclideines (3,4-disubstituted-1,4-dihydro-1,4-ethano-isoquinolines). Quaternary immonium salts prepared from these bicyclic imines are then converted by bases to bicyclic enamines [2,4-disubstituted-3-alkylidene-1,4-ethano-1,2,3,4-tetrahydroisoquinolines (25)]. 

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

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 ... 

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. 

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... 

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

The sulfenimines have been shown to be highly useful building blocks for the preparation of trifluoromethylated amines, aminoketones, and aminoalkano-ates as illustrated in Scheme 6.19. 

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 bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

A number of other simple cyclic amine targets with oxygen substitution have been prepared using a nitrone cycloaddition strategy to provide both the N- and 0-functionalities. These include the pyrrolidines darlinine 193 and analogues (248), (+)-preussin (194) (249) and the piperidines (—)-allosedamine (195) (250), and the related structure 196 (251) as well as analogous (3-aminoketones (Fig. 1.4) (252). 

Bupropion is an aminoketone that exerts its therapeutic effect through the inhibition of norepinephrine and dopamine reuptake. Bupropion s receptor occupancy profile shows an absence of anticholinergic and antihista-minic effects (Cusack et ah, 1994). Bupropion is absorbed rapidly from the gastrointestinal tract, and peak blood levels are achieved within 2 hours for regular release and 3 hours for sustained-release preparations = 10 hours). Bupropion undergoes extensive first-pass metabolism in the liver, yielding three active metabolites hydrobupropion, threohydroxybu-propion, and erythrohydrobupropion. The half-lives of the active metabolites are approximately 20 + hours (Preskorn, 1993). 

Methyl-2-aminobenzophenone can be prepared similarly by substituting toluene for benzene. The yield of crude material, m.p. 85-88°, is 70%. On recrystallization from 95% ethanol, using 5 ml. per g., there is obtained, in two crops, a 70% recovery of 4/-methyl-2-aminobenzophenone, m.p. 92-93°. Because of the higher temperature required in the steam distillation (cf. Note 5), the sulfonamide is obtained in a form difficult to purify. As a result the crude aminoketone usually contains 1-2 g. of aluminum oxide. 

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... 

Several pyrimidine aminoketones 108 (Scheme 32) have been prepared for potential use as intermediates in the synthesis of pharmaceutically interesting pyrimido-l,4-diazepines (86S886 87AP704). 

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