Ketones, a-, substitution

Selenides (see also Hydroxy selenides, Ketones-a-Substituted ketones)... 

The glycidic esters are of interest primarily because upon hydrolysis aud decarboxylation they aflFord aldehydes (if ClCHjCOOEt is used) or ketones (if substituted chloroacetic esters- ClCHRCOOEt are employed) having a higher carbon content than the original aldehyde or ketone. Thus (I) gives o-phenyl-propionaldehyde or hydratropaldehyde (II) ... 

The first reaction was involved in a synthesis of morphine, the starting ketone being made by reduction of a substituted naphthalene O. Amer. Chem. Soc., 1950, 72, 3704). No doubt an epoxide could have been used as the electrophile. 

Active methylene or methine compounds, to which two EWGs such as carbonyl, alko.xycarbonyl, formyl, cyano, nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59]. 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is earned out with a /3-keto ester, /9-diketone, malonate, Q-formyl ketones, a-cyano and Q-nitro esters, cya noacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

Preparation of Amines. Amines are prepared by heating aUphatic, aromatic, or cycHc ketones with ammonium formate, formamide, or an A/-substituted ammonium formate at 165—190°C (Leuckart reaction). For example, cx-methylbenzylamine is prepared by the reaction of acetophenone with ammonium formate. 

Reactions. Heating an aqueous solution of malonic acid above 70°C results in its decomposition to acetic acid and carbon dioxide. Malonic acid is a useful tool for synthesizing a-unsaturated carboxyUc acids because of its abiUty to undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic acids are formed from the reaction of malonic acid and benzaldehyde derivatives (1). If aUphatic aldehydes are used acryhc acids result (2). Similarly this facile decarboxylation combined with the condensation with an activated double bond yields a-substituted acetic acid derivatives. For example, 4-thiazohdine acetic acids (2) are readily prepared from 2,5-dihydro-l,3-thiazoles (3). A further feature of malonic acid is that it does not form an anhydride when heated with phosphorous pentoxide [1314-56-3] but rather carbon suboxide [504-64-3] [0=C=C=0], a toxic gas that reacts with water to reform malonic acid. 

Hydroxyl Group. The OH group of cyanohydrins is subject to displacement with other electronegative groups. Cyanohydrins react with ammonia to yield amino nitriles. This is a step in the Strecker synthesis of amino acids. A one-step synthesis of a-amino acids involves treatment of cyanohydrins with ammonia and ammonium carbonate under pressure. Thus acetone cyanohydrin, when heated at 160°C with ammonia and ammonium carbonate for 6 h, gives a-aminoisobutyric acid [62-57-7] in 86% yield (7). Primary and secondary amines can also be used to displace the hydroxyl group to obtain A/-substituted and Ai,A/-disubstituted a-amino nitriles. The Strecker synthesis can also be appHed to aromatic ketones. Similarly, hydrazine reacts with two molecules of cyanohydrin to give the disubstituted hydrazine. 

Hydrolysis of Enol Esters. Enzyme-mediated enantioface-differentiating hydrolysis of enol esters is an original method for generating optically active a-substituted ketones (84—86). If the protonation of a double bond occurs from one side with the simultaneous elimination of the acyl group (Fig. 3), then the optically active ketone should be produced. Indeed, the incubation of l-acetoxy-2-methylcyclohexene [1196-73-2] (68) with Pichia... 

Moreover, fermentation of various a-substituted cycloalkanone enol esters results in optically active six-, eight-, ten-, and twelve-membered ring ketones with 70—96% ee (84). Isolated enzymes catalyze similar transformations, bacillus coagulans and Candida glindracea]i 2Lse OF (Meito Sangyo) hydrolyze a number of cycHc and acycHc enol esters, giving ketones in 40—80% yield and 14—85% ee (85,86). 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

The procedure described is essentially that of Shioiri and Yamada. Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis. It has been used for racemlzatlon-free peptide syntheses, thiol ester synthesis, a modified Curtius reaction, an esterification of a-substituted carboxylic acld, formation of diketoplperazines, alkyl azide synthesis, phosphorylation of alcohols and amines,and polymerization of amino acids and peptides. - Furthermore, diphenyl phosphorazidate acts as a nitrene source and as a 1,3-dipole.An example in the ring contraction of cyclic ketones to form cycloalkanecarboxylic acids is presented in the next procedure, this volume. 

Borohydrides reduce a-substituted ketones to the corresponding a-substituted alcohols, and such products can be further reduced to olefins (see section VIII). Other reagents serve, through participation of the carbonyl group, to remove the substituent while leaving the ketone intact. The zinc or chromous ion reduction of a-halo ketones is an example of this second type, which is not normally useful for double bond introduction. However, when the derivative being reduced is an a,jS-epoxy ketone, the primary product is a -hydroxy ketone which readily dehydrates to the a,jS-unsaturated ketone. Since... 

A third type of reduction of a-substituted ketones is typified by the expulsion of the substituent and the reduction of the keto function to form an olefin. Wolff-Kishner reductions of a-hydroxy, a-acetoxy, " a-halo, °° and a-epoxy (see below) ketones are the most frequently encountered steroid examples of this general class. ... 

The opening of epoxides with neighboring keto groups, accompanied by vinylogous jS-elimination, has already been mentioned (section V). This is an extension of the jS-elimination reactions which occur when a,p- or jS,y-epoxy ketones are opened with acid or base. a,jS-Epoxy ketones give a-substituted a,jS-unsaturated ketones [(162), for example], and j5,y-epoxy ketones give y-substituted a,jS-unsaturated ketones [(163), for example] ... 

Enol ethers are readily attacked in buffered medium by electrophilic reagents such as halogens, A -haloamides, perchloryl fluoride and organic peracids to give a-substituted ketones. Similarly, electrophilic attack on... 

The effect of an a-substituted oxirane group on the optical rotatory dispersion of steroidal ketones should be interpreted with caution an inverted octant rule for a-epoxy ketones has been proposed/although recent data indicate that the normal octant rule may still be valid. 

OL Halogenation (Sections 18.2 and 18.3) Halogens react with aldehydes and ketones by substitution an a hydrogen is replaced by a halogen. Reaction occurs by electrophilic attack of the halogen on the carbon-carbon double bond of the enol form of the aldehyde or ketone. An acid catalyst increases the rate of enolization, which is the ratedetermining step. 

Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Primary amines undergo nucleophilic addition to the carbonyl group of aldehydes and ketones to form carbinol-amines. These carbinolamines dehydrate under the conditions of their formation to give A/-substituted imines. Secondary amines yield enamines. 

If a substituted aromatic hydrocarbon is used, the ketone gioLip then enteis the paia-position, or, if this is occupied, the oitho-position. Substituted aromatic acid chlorides may. also be used, and if the acid is dibasic and has two caiboxyl chloiide gioups, two molecules of the aromatic hydiocaibon may be. attached. If phosgene is used with two molecules of benzene, benzophenone is obtained. 

The secondary amines used in the preparation of enamines have been primarily simple dialkylamines or cyclic amines of five- or higher-membered rings. Azetidine (4) yields a stable enamine with cyclopentanone (28). No simple enamines formed by condensation of ethylenimine (5) or a substituted ethylenimine with an aldehyde or ketone have been reported. 

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. 

Darzens reaction can be used to efficiently complete the stereoselective synthesis of a"-substituted epoxy ketones. As an example, Enders and Hett reported a technique for the asymmetric synthesis of a"-silylated a,P-epoxy ketones. Thus, optically active a -silyl a-bromoketone 38 was treated with LDA followed by the addition of benzaldehyde to give a"-silyl epoxyketone 40 in 66% yield with good... 

Pulici and coworkers have reported a solid-phase variation of the Robinson-Gabriel for the production of parallel libraries of ox azole-containing molecules." The preparation is based on a solid supported 2-acylamino ketone 16 that can be cleaved by means of a volatile anhydride and cyclized in solution to obtain a substituted oxazole ring (17) that does not contain traces of the linker moiety. 

The Friedlander quinoline synthesis combines an a-amino aldehyde or ketone (1) with another aldehyde or ketone with at least one methylene a to the carbonyl (2) to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat. 

In similar fashion, A-substituted-2(3fT)-oxazolones were prepared directly from the hydroxy-ketone by reaction with urethanes in the presence of pyridine and dimethylformamide or by using isocyanates. 

Reversible interaction of the carbonyl group with an azine lone-pair (cf. 245) should facilitate substitution adjacent to the heteroatom by the anion of a )3-hydroxyethyl ketone. A similar cyclic intermediate (246) is presumably responsible for the cyclization of acetylene dicarboxylic esters with azines. Similar cyclic intermediates... 

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