Ketones self-condensation

Bases lb. Id, and 9b catalyze the nitroaldol reaction with ketones and aldehydes at room temperature in the presence of MgS04 in generally superior yields [Eq. (14)] [123]. Moreover, ketone self-condensation was not problematic under our conditions. In a comparison of the effectiveness of Id with le and If in these reactions, le and If were more efficacious [71]. 

We know what the disconnection must be, since we have been given one starting material. This looks like an enolate alkylation, and we need to use a specific enolate to stop the ketone self-condensing. The best enolate equivalent will be one that is not too basic, to avoid competing ehmination. The simplest solution is probably to use a keto-ester, easily made by Claisen condensation with diuethyl carbonate. After alkylation, the ester group is removed by decarboxylation. 

Aldol Reaction (Ketone Self-Condensation Shown)... 

O-alkyl-3-oxothionoesters were prepared by reaction of the sodium enolate with (EtOCS)2S in a ratio of 2.1 1. Hydrolysis of the intermediate gives the oxothionoester. However, the products are often contaminated with the products of ketone self condensation. Conversely, sonication of the reaction mixture gave good yields of the pure product in this case [196] (Scheme 90). 

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 selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

The situation is similar for other ketones Special procedures for aldol addition and self condensation of ketones have been developed but are rarely used... 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

MIBK is a flammable, water-white Hquid that boils at 116°C. It is sparingly soluble in water, but is miscible with common organic solvents. It forms an a2eotrope with water as shown in Table 2. Condensation of MIBK with another methyl ketone can produce ketones containing 9—15 carbons. For example, condensation with acetone produces diisobutyl ketone, and self-condensation of two MIBK molecules produces 2,6,8-trimethyl-4-nonanone [123-17-1]. Condensation with 2-ethylhexanal gives 1-tetradecanol (7-ethyl-2-methyl-4-undecanol), avaluable surfactant intermediate (58). 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

Treatment of a-hydroxy-ketones or -aldehydes with ammonium acetate (65BSF3476, 68BSF4970) results in the formation of dihydropyrazines, presumably by direct amination of the hydroxyketone followed by self-condensation (79AJC1281). Low yields of pyrazines have been noted in the electrolysis of ketones in admixture with KI and ammonia, and again it appears probable that the a-aminoketone derived by way of the a-iodoketone is the intermediate (69CI(L)237>. 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

The Friedlander reaction is quite versatile. The primary limitation on the o-aminobenzaldehyde component is preparation of the starting material as one might expect, these compounds are prone to self-condensation. Both electron rich and electron poor o-aminobenzocarbonyl compounds undergo the Friedlander reaction. When ketone partner 2 has only one available reactive methyl or methylene or is symmetrical, only one product is obtained. Even when two products can be formed, it is possible to choose reaction conditions such that only one product is isolated vide infra). The reaction can be promoted by acid catalysis, sometimes with improved results. 

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 ... 

The self-condensation is largely suppressed in reactions with those ketones 2, that are activated by an electron-withdrawing substituent or R". The carbonyl activity is then increased, and the enamine-intermediate 5 is favored over the imine 4, by conjugation with the electron-withdrawing group. ... 

The product supplied by Matheson, Coleman and Bell was used as received. Lower yields were obtained when a molar equivalent of diethyl carbonate was utilized, possibly because of self-condensation of the ketone. 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

Reaction of 2-aminobenzophenone with acetyl acetone in the presence of Bi(OTf)3 (5 mol%) results in the formation of 3-acetyl-2-methyl-4-phenylquinoline [117]. Various 1,3-diketones, acyclic ketones and cyclic ketone undergo the condensation with 2-aminoaryl ketones. The scope and generality of this process is illustrated with respect to various 2-aminoaryl ketones and a wide array of a-methylene ketones, and the results are summarized in Table 6. This method is free from side reactions such as the self-condensation of ketones, which is normally observed under basic conditions. Unlike reported methods, the present protocol does not require high temperature or drastic conditions to produce quinoline derivatives. 

The self-condensation is largely suppressed in reactions with those ketones 2, that are activated by an electron-withdrawing substituent or The carbonyl... 

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