Claisen condensation with amides

The dianion of acetoacetate undergoes Claisen condensations with tetramethyldiamide derivatives of dicarboxyhc acids to produce polyketides in the presence of BF3-OEt2 (eq 15). Similarly, 3,5-dioxoalkanoates are synthesized from tertiary amides or esters with the acetoacetate dianion in the presence of Bp3-OEt2 (eq 16). ... 

If only a single electron-withdrawing substituent is present, as with simple ketones, esters, and nitriles, the formation of alkyl derivatives in high yield requires careful control of reaction conditions. Use of bases that are strong enough to effect only partial conversion of the substrate to its anion can result in aldol-condensation reactions with ketones and Claisen condensations with esters (see Chapter 2 for discussion of these reactions). This problem can be partially avoided by use of very strong bases such as the amide, hydride, or triphenylmethyl anions. 

Scheme 7.4 Eschenmoser-Claisen rearrangement via condensation with amide acetals.

The a-ionization of 7-methylpteridines can also be utilized in aldol-type condensation reactions. 7-Methyl-pterin and -lumazine and 2,4-diaminopteridine condense readily in aqueous base with aromatic aldehydes to afford 7-alkylidenepteridines (77JOC2951). A Claisen condensation requires the protection of the acidic hydrogens of the amide bonds. 

Carboxylic esters can be treated with ketones to give p-diketones in a reaction that is essentially the same as 10-118. The reaction is so similar that it is sometimes also called the Claisen condensation, though this usage is unfortunate. A fairly strong base, such as sodium amide or sodium hydride, is required. Yields can be increased by the catalytic addition of crown ethers. Esters of formic acid (R H) give P-keto aldehydes. Ethyl carbonate gives P-keto esters. 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

The aniline nitrogen is then converted to the para-toluenesulfonamide (4-3). Reaction of this intermediate with ethyl co-chlorobutyrate in the presence of potassium carbonate then gives the alkylation product (4-4). Potassium tert-butoxide-catalyzed Claisen condensation of this diester leads to azepinone (4-5) as a mixture of methyl and ethyl esters resulting from alternate cyclization routes. A strong acid leads to the transient keto-acid, which then decarboxylates the toluensulfonyl group is lost under reaction conditions as well as affording the benzazepinone (4-6). This last intermediate is then acylated with the benzoyl chloride (4-7) to afford amide (4-8). 

Benzene and thiophene rings can of course often be interchanged in biologically active agents. The very broad structural latitude consistent with NSAID activity is by now a familiar theme as well. Preparation of the fused thiophene counterpart of the NSAID piroxicam (Chapter 11) starts with the reaction of thiophene (25-1), itself the product of a multistep sequence, with ethyl A-methylglycinate to give the sulfonamide (25-2). Treatment of that intermediate with a base leads to intramolecular Claisen condensation and thus the formation of the 3-ketoester (25-3). An amide-ester interchange with 2-aminopyridme (25-4) completes the synthesis of tenoxicam (25-5) [25]. 

However, a useful synthetic reaction can be achieved in the following way. First, the ester anion is formed in the absence of water without causing a Claisen condensation or other carbonyl addition. This can be done with ethyl ethanoate by treating it with lithium bis(trimethylsily])amide in oxacyclopentane solution at -80° ... 

Methylisothiazole-5-carboxylic acid has also been prepared by alkaline hydrolysis of the 5-nitrile. The 5-acids decarboxylate readily at or near their melting points but otherwise behave normally, forming acid chlorides, esters, amides, hydra-zides, and nitriles. The esters undergo the Claisen condensation to form ]8-ketoesters, and the nitriles form thioamides with hydrogen sulfide in pyridine. An anomalous reaction is the reduction of 5-cyano-... 

Combination of the reagents TiCU, BuaN, and TMSOTf, was reported to be effective for Claisen condensation, as exemplified in Eqs (42) and (43) [129]. When acyl-oxazolidinones were subjected to reaction with TiCU and a tertiary amine, homocoupling reaction at the a-position of the acyl group took place to give succinic acid derivatives [146], The lithium enolate of an ester or amide has been alkylated with an (N,C>)-acetal in the presence of Ti(0-/-Pr)4 (Eq. 44) [147,148]. 

In the presence of a strong base, the a carbon of a carboxylic ester or other acid derivative can condense with the carbonyl carbon of an aldehyde or ketone to give a p-hydroxy ester, ° amide, and so on., which may or may not be dehydrated to the a,p-unsaturated derivative. This reaction is sometimes called the Claisen reaction an rmfortunate usage since that name is more firmly connected to 16-85. Early reactions used hydroxide or an alkoxide base in water or alcohol solvents, where self-condensation was the major process. Under such conditions, the aldehyde or ketone was usually chosen for its lack of an a-proton. Much better control of the reaction was achieved when amide bases in aprotic solvents, such as ether or THE, were used. The reaction of tert-butyl acetate and in hexane... 

As with ketone enolate anions (see 16-34), the use of amide bases under kinetic control conditions (strong base with a weak conjugate acid, aprotic solvents, low temperatures), allows the mixed Claisen condensation to proceed. Self-condensation of the lithium enolate with the parent ester is a problem when LDA is used as a base, ° but this is minimized with LICA (lithium isopropylcyclohexyl amide).Note that solvent-free Claisen condensation reactions have been reported. ° ... 

Reaction of sugar lactone with ester enolate (the Claisen condensation) gives -keto ester, the resulting 1,3-dicarbonyl compound immediately reacts with the hydroxyl group present in the same molecule to afford a lactol with an axial hydroxyl group. In a recent example shown in O Scheme 4 [8], the product of the reaction was further transformed to the corresponding nitrile or amide by addition of cyanide or a Ritter reaction with benzonitrile in the presence of TMSOTf as a Lewis acid. 

A number of heterocycle-fused 1,5-diazocines have been reported. Kli-siecki and Sucharda treated an ethyl acetate solution of methyl nicotinate with sodium and obtained diazocine 126 (23RC251). In a more recent, but similar, report, Oakes and Rydon attempted a Claisen condensation of ethyl 3-aminopicolinate with ethyl acetate, but obtained instead the inter-molecular amidation product 127 (58JCS205). A similar result was reported by Brederick et al., who found that reaction of 4-amino-5-carbe-thoxypyrimidine with ethyl acetate in toluene in the presence of sodium... 

Segment C2 was synthesized from methyl (fi)-lactate as a starting material in the following three steps (I) acetylation with acetic anhydride and pyridine, (II) intramolecular Claisen condensation of 146 using lithium bis-(trimethylsilyl) amide, and (III) hydrogenation of the enolic olefin 147 in the presence of rhodium catalyst. The required diastereomer (segment C2) was... 

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