Ketones intramolecular condensations

An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acld in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acrtophenone phenylhydrazone (I) gives 2-phenyllndole (I V). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction ... 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

For unsymmetrieal ketones, two eondensation produets are possible. For example, intramolecular condensation of 2,7-octadione may lead to products which follow from the two possible enolates. 

As noted above, a convenient pathway to cinno-lines consists of intramolecular condensation of a diazonium group with a ketonic methyl group, or alternately with a double bond. The analogous reaction with an amide nitrogen leads to 1,2,3-benzotriazines, such as 198. Reaction of isatoic anhydride with N-aminomorpholine affords the hydrazide 196 then, treatment with nitrous acid yields initially the diazonium salt (197). Under the reaction conditions... 

Fig. 6.25. Simplified mechanism of two degradation reactions between peptides and reducing sugars occurring in solids, a) Maillard reaction between a side-chain amino (or amido) group showing the formation of an imine (Reaction a), followed by tautomerization to an enol (Reaction b) and ultimately to a ketone (Reaction c). Reaction c is known as the Amadori rearrangement (modified from [8]). b) Postulated mechanism of the reaction between a reducing sugar and a C-terminal serine. The postulated nucleophilic addition yields an hemiacetal (Reaction a) and is followed by cyclization (intramolecular condensation Reaction b). Two subsequent hydrolytic steps (Reactions c and d) yield a serine-sugar conjugate and the des-Ser-peptide...

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 biosynthesis of the polyketide moiety is thought to involve the condensation of coenzyme A esters of acetic acid with malonyl coenzyme A to give thiol esters of 3-keto acids. Further Claisen condensations with malonyl coenzyme A add further ketone units, leading to 3,5-diketo, 3,5,7-triketo acids and so on as their thiol esters. Intramolecular condensations subsequently afford heterocyclic or aromatic structures (Scheme 275). 

An interesting fur n synthesis based on acid-catalyzed intramolecular condensation has been reported by Fritel and Bamnger,t> a using l(2-epoxy-l (2-oxoprcpyl -cyclohexane. Attack is bolievcd by these authors to be led by the enolic form of the ketone, as shown in... 

Reaction LV. Intramolecular condensation of Phenylhydrazones of Aldehydes, Ketones and Ketonic Adds by heating with Hydrochloric Acid or Zinc Chloride (Fischer). (B., 19, 1563 26, R., 14 E.P., 385605.)— This is an important method of preparation for the alkylindols. The reactions occurring are somewhat complicated, since both a rearrangement and the elimination of ammonia take place. 

Intramolecular condensation of either 2-formylpyrrole or 2-benzoylpyrrole with phenacyl bromide gave pyrrolizin-3-ones 52a39 and 52b,40 respectively. JV-Acylpyrroles presumably are intermediates. Similarly, 5-alkoxy-2-for-mylindoles (53) were converted to benzopyrrolizines (54) by treatment with methyl vinyl ketone in the presence of trimethylbenzylammonium hydroxide in dioxane 41 From diketone 55 a mixture of pyrrolizines [56a (25%) and 56b (11%)] was obtained.42... 

A two-step, one-pot process has been developed for the synthesis of aza-indoles under dielectric heating conditions [31]. In the first step, aminopy-ridines and ketones were condensed either at room temperature (in the case of aza-indoles 19-20) or under dielectric heating at 160-220 °C to yield intermediate enamines 18. Subsequent microwave-assisted intramolecular Heck reactions furnished the corresponding 4-, 5-, 6- or 7-azaindoles in moderate to good yields (Scheme 9). 

Ketones are less reactive electrophiles than aldehydes. Therefore, the aldol condensation of ketones is not often used because the equilibrium is unfavorable. However, the intramolecular condensation of diketones is useful if the size of the resulting ring is fa-... 

Hydrogenation of hydroxyimino ketones or esters maybe accompanied by the formation of cyclic products, especially at elevated temperatures, as a result of inter- or intramolecular condensation in the course of hydrogenation. 

Although enamines readily undergo intramolecular condensation with ketones (Section VI.D) the only intermolecular reaction we are aware of is that with diethyl ketomalonate156. Whereas cyclic ketone enamines gave the aldol product, with enamines of acyclic ketones only the morpholine enamine of pentan-3-one gave the aldol product (73). The more reactive pyrrolidine enamine cyclysed onto the ester group to give the... 

Ketones containing a double bond have also been prepared by the reaction of unsaturated acyl halides with aromatic hydrocarbons in the usual Friedel-Crafts manner. Acylation of benzene and its homologs with /S,/S-dimethylacroyl chloride leads to dimethylvinyl aryl ketones, (CHj)jC = CHCOAr (75-90%). °° The latter compounds are stable and do not undergo intramolecular condensation. 

Intramolecular Condensation of o-Aminobenzyl Ketones and Related Compounds... 

Trichlorotitanium enolates are directly prepared from a ketone, TiCU, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-129], ketones [129], and imines [130,131], Intramolecular condensation with esters is also known [132-137], Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SNl-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123], Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138], Aminoalkylation of trichlorotitanium enolates with (a-chloroalkyl)amine has been performed analogously [139,140],... 

Diazo ketones also possess an electrophilic diazo group, and hence are susceptible to diazo-coupling reactions with suitable soft nucleophiles. Examples are given in equations (11) and (12). Phospha-zines such as (19) are useful synthetic intermediates in their own right. The carbon terminus of the 1,3-dipole possesses nucleophilic properties and can participate in aldol-type reactions with the particularly electrophilic carbonyl groups in 1,2-di- and 1,2,3-tri-carbonyl compounds. Intramolecular condensations occur with greater ease (equation 13). Reaction of diazo ketones of the type summarized in equations (9)-(12) have been thoroughly reviewed. ... 

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. 

Clemmensen reaction. The Clemmensen method of reduction (1913) consists in refluxing a ketone with amalgamated zinc and hydrochloric acid. Acetophenone, for example, is reduced to ethylbenzene. The method is applicable to the reduction of most aromatic-aliphatic ketones to at least some aliphatic and alicyclic ketones, to the y-keto acids obtainable by Friedel-Crafts condensations with succinic anhydride (succinolylation), and to the cyclic ketones formed by intramolecular condensation. 

Elbs reaction. Formation of anthracenes by intramolecular condensation of diaryl ketones containing a methyl or methylene substituent adjacent to the carbonyl group. 

Robinson annellation reaction. Formation of six-membered-ring ,(i-iinsaturatcd ketones by condensation of cyclohexanones with methyl vinyl ketone or its equivalents, followed by an intramolecular aldol condensation. 

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