Carbonyl compounds 3-aminoketones

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 aminoketone 1, required as starting material, can be obtained by a Neber rearrangement from a A -tosylhydrazone. Another route to a-aminoketones starts with the nitrosation of an a-methylene carbonyl compound—often in situ—to give the more stable tautomeric oxime 7, which is then reduced in a subsequent step to yield 1 ... 

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 ... 

Toward carbonyl compounds, the behavior of nonstabilized arsonium ylides such as methylene or ethylidene triphenylarsorane is similar to that of sulfonium ylides (10, II, 13, 97). When an arsonium ylide was reacted with aminoketones in a cold 1 1 DMSO-THF solution a smooth reaction took place and the corresponding 3-substituted indoles were obtained in fair to good yields (II). 

The Knorr synthesis is generally suitable for the synthesis of a range of substituted pyrroles utilising a-aminoketones (or keto esters as illustrated above) with carbonyl compounds containing an active methylene group. 

Upon reaction with amino acids, in the Strecker degradation, unstable imines are formed, which may easily decarboxylate, leaving an enamine, which upon hydrolysis yields an aldehyde from the amino acid and an a-aminoketone from the di-carbonyl-compound. 

The condensation of carbonyl compounds with a-aminoketones gives pyrroles by a Ilac cycli-zation known as the Knorr pyrrole synthesis. In most examples the carbonyl compounds are fi-ketoesters or )S-diketones (Scheme 45). 

The classical method of obtaining a-aminoketones for Knorr synthesis is by nitrosation of the carbonyl compound, followed by in situ reduction with zinc <82JOC3059,82jpc52i7>. An alternative is to prepare A(-methoxy-A(-methylamides of A-protected (Boc, Cbz) amino acids. These react with Grignard reagents to give protected a-aminoketones which can be deprotected and used in the Knorr synthesis (Scheme 46) <93H(35)843>. 

The addition of a-sulfinyl carbanions to carbonyl compounds followed by further functional group modification has proved to be an efficient and highly stereoselective approach to epoxides, a-aminoketones, a-aminoaldehydes, a-hydroxy esters, and allylic and propargylic alcohols [76-80]. 

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... 

Two papers from Gnichtef demonstrate the utility of oximes of a-aminoketones [e.g. (135)] for preparing small heterocycles [e.g. (136)—(138)]. In both examples imidazoline iV-oxides can be formed if the anft-forms of the oximes are reacted with carbonyl compounds as shown. 

Reactions with Carbonyl Compounds Followed by Insertion Reactions. IV-Substituted -aminoketones react with TMSC(Li)N2 to give 2-pyrroUne derivatives via the alkylidene carbene intermediates by intramolecular N-H insertion, analogously to the reaction of -acyl-A(-tosylanilines with TMSC(Li)N2 (eq 21). Dehydrogenation of the 2-pyrrolines with active Mn02 (CMD, chemical manganese dioxide, produced for battery manufacture) affords the corresponding pyrroles (eq 24). ... 

The importance of the Mannich reaction stems from the synthetic utility of the resulting aminoketones. Thermal decomposition of the amines or the derived quaternary salts leads to a-methylene ketones. The decomposition of the quaternary salts is particularly facile, and they can be used as in situ sources of many a,j3-unsaturated carbonyl compounds. These are useful synthetic intermediates, for... 

Patent applications from Pfizer disclosed 1,5-diaryl-pyrazoles bearing bioisosteric replacements for the 3-carboxamide moiety. One application showed that the amide could be replaced by a-aminoketones as exemplified by compound (416) [284]. The corresponding alcohols and their ethers were also described, including compounds that allowed the amine substituent and ether to form a ring system, such as a morpholine unit. This application also allowed for the replacement of the 1,5-diaryl-pyrazole by a 1,2-diaryl-imidazole bearing a 3-carbonyl substituent, as exemplified by compound (417). A further patent application from Pfizer claims compounds in which imidazoles replace the 3-carboxamide moiety in the 1,5-diaryl-pyrazole... 

Nicotine Nicotine, l-methyl-2-(3-piridyl)pirrolidine (13.1.27), is an alkaloid that is isolated from the plant Nicotiana (Nicotiana tabacum, Nicotiam rustica, and others) and can be synthesized in varions ways [33-36]. In particular, it is proposed to proceed from nicotinic acid ethyl ester, which is condensed with iV-methylpyrrolidone, giving l-methyl-2-nicotinoyl pyrrolidone-2 (13.1.23). Acidic hydrolysis of this compound leads to an opening of the pyrrolidine ring giving the intermediate (13.1.24), which under the reaction conditions is decarboxylated to the /-aminoketone (13.1.25). The carbonyl group is reduced to an alcohol and the resnlting prodnct (13.1.26) undergoes dehydration to nicotine (13.1.27). 

In the Mannich reaction, a carbonyl component usually formaldehyde, a secondary amine and a CH-acidic compound react together to form 3-aminoketones. The classical method for the formation of (3-aminoketones suffers from many disadvantages such as drastic reaction conditions, formation of undesired side products, little or no stereo-or regioselectivity and low yields. In 2000, Gadhwal and co-workers developed the first microwave-assisted Mannich protocol24 (Scheme 5.10). 

The problems involved are exemplified here by Knorr s pyrrole synthesis (A. Gossauer, 1974). It has been known for almost a century that a-aminoketones (C2N components) react with 1,3-dioxo compounds (C2 components) to form pyrroles (C4N-heterocycles). A side-reaction is the cyclodimerization of the a-aminoketones to yield dihydropyrazines (C4Nj), but this can be minimized by keeping the concentration of the ar-aminoketone low relative to the 1,3-dioxo compound. The first step in Knorr s pyrrole synthesis is the formation of an imine. This depends critically on the pH of the solution. The nucleophilicity of the amine is lost on protonation, whereas the carbonyl groups are activated by protons. An optimum is found around pH 5, where yields of about 60% can be reached. At pH 4 or 6 the yield of the pyrrole may approach zero. The ester groups of /7-keto esters do not react with the amine under these conditions. If a more reactive 1,3-diketone is used, it has to be symmetrical, otherwise mixtures of two different imines are obtained. The imine formed rearranges to an enamine, which cyclizes and dehydrates to yield a 3-acylpyrrole as the normal Knorr product (A. Gossauer, 1974 G.W. Kenner, 1973 B). 

Another group of applications consists of electrosynthesis of substances that can be otherwise synthesized only with difficulty. The chemical reduction of p-aminoketones is complicated by the elimination of these compounds. A polarographic two-electron wave in acidic solution, corresponding to the reduction of carbonyl grouping to p-aminoalcohol... 

P-Aminoketones 511 are employed mostly as pharmaceuticals, many of them currently in use. Investigations of their properties are of continuing interest in several branches of medicinal chemistry (Fig. 76, Chap. Moreover, these compounds are precursors of a substantial group of derivatives equally important in pharmacology, namely, the y-aminoalcohols 512, which arc readily prepared by hydrogenation or addition of organometal to the carbonyl group. - ... 

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