Formation by Ketone—Base Condensation

The Schiff base or enamine reaction has been employed to modify aldehydes and ketones by condensation with a primary amine (reaction 1) and to condense primary amines with a carbonyl compound (reaction 2). A similar reaction between primary amines and carbon disulfide yields isothiocyanates or mustard oils (reaction 3). These three possibilities for derivative formation will be discussed in this chapter. 

Edited by K. Blau and J. M. Halket 1993 John Wiley Sons Ltd 

Of course, enamine formation by routes (1) and (2) involves the same reaction scheme. However, the pur-p oses and requirements for its application to the isolation, identification and quantitative determination of carbonyl compounds or amines differ. Therefore, (1) and (2) will be treated separately. 

Before the age of chromatography, the characterization of unknown compounds necessitated the preparation of crystalline derivatives with definite melting points. For this purpose, hydroxylamine and phenylhydrazine are not always ideal reagents, particularly for low molecular weight carbonyl compounds. These derivatives possess rather low melting points or may even be oils at room temperature. The oximes are often very soluble and therefore difficult to purify, and mixtures of stereoisomers may also be formed. With phenylhydrazine, variations in the reaction procedure can lead to different derivatives a-diketones yield mono- and dihydrazones 

The characterization of carbonyl derivatives by melting point is more easily effected with the different nitrophenylhydrazones or with the semicarbazones. Extensive melting point lists are also available for these derivatives [5], 

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While enamines can usually be obtained directly from ketones and secondary amines their formation by an indirect route may bo advantageous. The previously mentioned condensation of rnethyl ketones during azeotropic enamine formation has prompted the alklyation (J) or acylation and reduction (59) of Schiff s bases. A parallel method uses the formation and desulfurization of N-acylthiazolines followed by hydride reduetion (60,61). 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

The base-catalyzed self-condensation of diketene is a similar type of reaction and yields dehydroacetic acid together with the tripyranone (322) (49JOC460, B-68MI22400). Ring opening of diketene and attack of the oxyanion on a second molecule of diketene followed by an intramolecular condensation accounts for the formation of the pyranone. The selfcondensation of malonyl dichloride in the presence of a ketone, which acts as a weak base, is a similar reaction (52JCS4109). 

The formation of Schiff bases by the reaction of ketones with amines is more difficult. Acetophenone and other aryl alkyl ketones which are slow to react under the usual conditions will combine with aromatic amines at 160-180° in the presence of a zinc chloride-aniline salt. In another procedure, 2-acetylthiophene and aniline are condensed in boiling toluene with the aid of a water separator. ... 

Lactone formation, by intramolecular condensation of a-acetoxy-ketones in strongly basic media, has been examined systematically. Lithium di-isopropylamide in ether is effective as the base conditions must be chosen according to the reactant. Scheme 8 illustrates successful reactions, which afforded either the /3-hydroxy-y-lactone or the butenolide, depending upon the ease of adoption of the conformation necessary for elimination of water. The method appears to be limited to tertiary a-acetoxy-ketones. 

The MgyAlOx activity declines in the acetone oligomerization reaction due to a blockage of both basic and acid active sites by a carbonaceous residue formed by secondary aldol condensation reactions. The key intermediate species for coke formation are highly unsaturated linear trimers that are formed by aldol condensation of mesityl oxide with acetone and remain strongly bound to the catalyst surface. The catalyst surface acid-base properties determine the preferential formation of a given trimeric intermediate, which in turn defines the chemical nature of the carbon deposit. Aromatic hydrocarbons are the main component of coke formed on acidic Al-rich MgyAlOx samples whereas heavy a,P-unsaturated ketones preferentially form on basic Mg-rich catalysts. 

The Claisen condensation is the main method for synthesizing 1,3-dicarbonyl compounds. Analyze this reaction on the basis of its similarities to the aldol condensation (Section 18-5) It is an enolate + carbonyl process, so bond formation occurs between the a-carbon of one carbonyl compound (which may be cither an ester or a ketone) and the carbonyl carbon of another (an ester). Note the limitation Under the conditions given, the reaction works only when the 1,3-dicarbonyl product still possesses a hydrogen on the carbon between the two carbonyl groups. Dcprotnnation of this acidic H by excess base allows the equilibrium to shift to the product. 

Aldehydes and ketones may frequently be identified by their semicarbazones, obtained by direct condensation with semicarbazide (or amino-urea), NH,NHCONH a compound which is a monacidic base and usually available as its monohydrochloride, NHjCONHNH, HCl. Semicarbazones are particularly useful for identification of con jounds (such as acetophenone) of which the oxime is too soluble to be readily isolated and the phenylhydrazone is unstable moreover, the high nitrogen content of semicarbazones enables very small quantities to be accurately analysed and so identified. The general conditions for the formation of semicarbazones are very similar to those for oximes and phenylhydrazones (pp. 93, 229) the free base must of course be liberated from its salts by the addition of sodium acetate. 

Reactions with Aldehydes and Ketones. The base-catalyzed self-addition of acetaldehyde leads to formation of the dimer, acetaldol [107-89-1/, which can be hydrogenated to form 1,3-butanediol [107-88-0] or dehydrated to form crotonaldehyde [4170-30-3]. Crotonaldehyde can also be made directiy by the vapor-phase condensation of acetaldehyde over a catalyst (53). 

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 long known catalyses of some ketone condensation reactions by secondary amines, can be postulated to have their basis in the reactions of enamine intermediates with ketones. The unsuitability of methyl ketones for azeotropic enamine formation is based on this phenomenon. Recent studies in cyclization reactions have added further support to this concept (354). 

The mechanism of the Fiesselmann reaction between methylthioglycolate and a,P-acetylenic esters proceeds via consecutive base-catalyzed 1,4-conjugate addition reactions to form thioacetal Enolate formation, as a result of treatment with a stronger base, causes a Dieckmann condensation to occur providing ketone 8. Elimination of methylthioglycolate and tautomerization driven by aromaticity provides the 3-hydroxy thiophene dicarboxylate 9. 

Since the amine by-product formation was essentially derived from the reaction of an enamine or a ketone with iodoaniline, the direct use of a ketone as the substrate instead of an amine, would also be expected to yield the indole (Scheme 4.21). Indeed, we were gratified to find that direct condensation of o-iodoaniline 24 (77, R, = H) with cyclohexanone (in the presence of 5mol% Pd(OAc)2 and 3 equiv DAB CO as a base at 0.3 M and 105 °C afforded the tetrahydrocarbazole 81a in 77% yield with no other major impurities (Figure 4.4) [5], The use of DMF as a solvent is crucial to the success of this reaction other solvents such as acetonitrile and toluene were ineffective. 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Based on the three-dimensional structure of CHS, we proposed that the initiation/elongation/cyclization cavity serves as a structural template that selectively stabilizes a particular folded conformation of the linear tetraketide, allowing the Claisen condensation to proceed from C6 to Cl of the reaction intermediate.14 In contrast, CTAL formation can occur either in solution or alternatively while sequestered in the enzyme active site. In either case, enolization of the C5 ketone followed by nucleophilic attack on the Cl ketone with either a hydroxyl group (in solution) or the cysteine thiolate (enzyme bound) as the leaving group results in CTAL. Similar lactones are commonly formed as by-products of in vitro reactions in other PKS systems.36 38... 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

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