Enolizable

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The ff-oxidation of carbonyl compounds may be performed by addition of molecular oxygen to enolate anions and subsequent reduction of the hydroperoxy group, e.g. with triethyl phosphite (E.J. Bailey, 1962 J.N. Gardner, 1968 A,B). If the initially formed a-hydroperoxide possesses another enolizable a-proton, dehydration to the 1,2-dione occurs spontaneously, and further oxidation to complex product mitctures is usually observed. 

The methyl ketone shown in the example can enohze in only one direction and typifies the kind of reactant that can be converted to a carboxylic acid in synthetically accept able yield by the haloform reaction When C 3 of a methyl ketone bears enolizable hydro O... 

A mixed aldol condensa tion in which an aromatic aide hyde reacts with an enolizable al dehyde or ketone... 

In mordant dyes, phenols, naphthols, and enolizable carbonyl compounds, such as pyrazolones, are generally the couplers. As a rule, 2 1 metal complexes are formed ia the afterchroming process. A typical example of a mordant dye is Eriochrome Black T (18b) which is made from the important dyestuff iatermediate nitro-l,2,4-acid, 4-amiQO-3-hydroxy-7-nitro-l-naphthalenesulfonic acid [6259-63-8]. Eriochrome Red B [3618-63-1] (49) (Cl Mordant Red 7 Cl 18760) (1, 2,4-acid — l-phenyl-3-methyl-5-pyrazolone) is another example. The equiUbrium of the two tautomeric forms depends on the nature of the solvent. 

Although some authors propose that an enolizable /3-dicarbonyl system is essential for inflammatory activity, two analogues in which this hydrogen atom at carbon 4 has been substituted, suxibuzone (717) and pipebuzone (718), are used as antiinflammatory agents, and the latter also possesses antipyretic and analgesic properties. However, these compounds are probably not active per se and their activity is due to metabolism to phenylbutazone. 

Me3Si)2NH, Me3SiCl, Pyr, 20°, 5 min, 100% yield. ROH is a carbohydrate. Hexamethyldisilazane (HMDS) is one of the most common sily-lating agents and readily silylates alcohols, acids, amines, thiols, phenols, hydroxamic acids, amides, thioamides, sulfonamides, phosphoric amides, phosphites, hydrazines, and enolizable ketones. It works best in the presence of a catalyst such as X-NH-Y, where at least one of the group X or Y is electron-withdrawing. ... 

A-/-Butyldimethylsilyl-7V-methyltrifluoroacetamide, CH3CN, 5 min, 97-100% yield.This reagent also silylates thiols, amines, amides, carboxylic acids, and enolizable carbonyl groups. 

The ester, formed from the acid (COCE, toluene then CH2=CHCH2CH20H, acetone, —78° warm to rt, 70-94% yield), can be cleaved by ozonolysis followed by Et3N or DBU treatment (79-99% yield), the ester is suitable for the protection of enolizable and base-sensitive carboxylic acids. ... 

The in situ cyanosilylation of p-an1saldehyde is only one example of the reaction which can be applied to aldehydes and ketones in general. - The simplicity of this one-pot procedure coupled with the use of inexpensive reagents are important advantages over previous methods. The silylated cyanohydrins shown in the Table were prepared under conditions similar to those described here. Enolizable ketones and aldehydes have a tendency to produce silyl enol ethers as by-products in addition to the desired cyanohydrins. The... 

Deuteriums in the enolizable positions of a,/3-unsaturated keto substrates are unaffected during the course of the reduction. This extends the applicability of this procedure to the preparation of y-labeled ketones by subjecting the substrates to hydrogen-deuterium exchange (section ll-C) prior to reduction. This technique has been utilized for the preparation of the y-labeled ketones (156), (157) and (158). " The deuteriums in the a-positions of these ketones are back exchanged (section 11-B) after the reduction. 

A recent communication described the cleavage of 17a-hydroperoxy-20-keto steroids with base to give 17-ketoandrostanes in good yield. Since such hydroperoxides are now accessible from 20-ketopregnanes in one step vide infra), this constitutes a convenient two-step degradation process. In practice, the intermediate hydroperoxide need not be isolated. Other enolizable... 

Claisen-Schmidt reaction (Section 18.10) A mixed aldol condensation in which an aromatic aldehyde reacts with an enolizable aldehyde or ketone. 

As one might expect, most of the reported cases of Camps quinoline syntheses involve reactions in which only one of the carbonyl groups is enolizable, thus eliminating the regioselectivity problem. 

The addition of the a-carbon of an enolizable aldehyde or ketone 1 to the carbonyl group of a second aldehyde or ketone 2 is called the aldol reaction It is a versatile method for the formation of carbon-carbon bonds, and is frequently used in organic chemistry. The initial reaction product is a /3-hydroxy aldehyde (aldol) or /3-hydroxy ketone (ketol) 3. A subsequent dehydration step can follow, to yield an o ,/3-unsaturated carbonyl compound 4. In that case the entire process is also called aldol condensation. 

The reaction can be performed with base catalysis as well as acid catalysis. The former is more common here the enolizable carbonyl compound 1 is depro-tonated at the a-carbon by base (e.g. alkali hydroxide) to give the enolate anion 5, which is stabilized by resonance ... 

Since various substituents are tolerated, the Friedlander reaction is of preparative value for the synthesis of a large variety of quinoline derivatives. The benzene ring may bear for example alkyl, alkoxy, nitro or halogen substituents. Substituents R, R and R" also are variable. The reaction can be carried out with various carbonyl compounds, that contain an enolizable a-methylene group. The reactivity of that group is an important factor for a successful reaction. 

The enolate anion 1 may in principle be generated from any enolizable carbonyl compound 4 by treatment with base the reaction works especially well with /3-dicarbonyl compounds. The enolate 1 adds to the a ,/3-unsaturated compound 2 to give an intermediate new enolate 5, which yields the 1,5-dicarbonyl compound 3 upon hydrolytic workup ... 

The dehydration reaction leads by an Ea process to 8 and is promoted by the tertiary, benzylic nature of the OH group at Ce and its antiperiplanar trans relationship to the H atom at Csg. Furthermore, one of the cannonical forms of the enolizable 0-dicarbonyl system present at Cn and Cia has a double bond in the C ring. Thus, dehydration leads to aromatization of the C ring, and this factor must provide some of the driving force for the reaction. 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

Phenyl-l-benzothiepin-3,5(2//,4//)-dione (8) (see Section 2.1.3.1.) is the precursor of 3,5-di-oxy-substituted 1-benzothiepins. The enolizable diketone can be transformed by acylation, alkylation, substitution or reduction reactions. 

The Barbier-type modification17, in which the allyl Grignard reagent is produced in the presence of a carbonyl compound, seems not to be suitable for enolizable aldehydes. Some... 

The present procedure illustrates the facile demethylation of methyl aryl ethers by lithium diphenylphosphide.3 This reaction is specific for methyl ethers and may be carried out in the presence of ethyl ethers in high yield.4 Use of excess reagent allows cleavage in the presence of enolizable ketones.5 In the present case, the cleavage may be performed without protection of the aldehyde, but two equivalents of reagent are required, and the yield is reduced to ca. 60%. 

Enolizable compounds can be used for Meerwein reactions provided that the keto-enol equilibrium is not too far on the side of the ketone for example, P-dicar-bonyl compounds such as acetylacetone are suitable (Citterio and Ferrario, 1983). The arylation of enol esters or ethers (10.12) affords a convenient route for arylating aldehydes and ketones at the a-carbon atom (Scheme 10-48). Silyl enol ethers [10.12, R = Si(CH3)3] can be used instead of enol ethers (Sakakura et al., 1985). The reaction is carried out in pyridine. 

In azo couplings with carbonyl compounds, three tautomeric products are possible, compared with only two for phenols and aromatic amines (discussed in Section 12.1). The ketohydrazone 12.75 is most often dominant, but for easily enolizable 1,3-dicarbonyl compounds (X=CO-R and similar structures) the azoenol 12.76 is the major product. The azoketone 12.77 is often postulated as primary product, but has rarely been identified in an unambiguous fashion using modern methods. The CH2 group should be easily detectable in the lH NMR spectrum. 

Note. This sequence succeeds with both aldehydes and ketones, but fails with readily enolizable ketones and enones. 

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