Alcohol Dieckmann condensation

Condensations Highly atom economical since small molecules of water or alcohol are liberated Atom economy increases as the molecular weights of the combining fragments increases For cyclization reactions such as the Dieckmann condensation and the synthesis of cyclic ethers from straight chain diols the atom economy increases with increasing ring size... 

Tetracyclic keto ester 467, prepared earlier (253), was treated with the anion of diethyl methoxycarbonylmethylphosphonate in dimethylformamide. The reaction supplied the unsaturated ester 492, which was catalytically hydrogenated to diester 493. Dieckmann condensation of 493 yielded two nonenolizable keto esters (494 and 495), which could be separated by fractional crystallization. Sodium borohydride reduction of 18a-methoxyyohimbinone (494) gave two alcohols (496 and 497) in a ratio of about 10 1 at the same time, reduction of 180-methoxyyohimbinone (495) furnished another two stereoisomeric alcohols (498 and 499) in approximately equal amounts. Demethylation of the four stereoisomers (496-499) resulted in the corresponding 18-hydroxyyohimbines (500-503)... 

Fiesselmann and Pfeiffer114 passed HCI at 0° through acetoacetic ester and thioglycolic ester in alcohol to obtain triethyl /5,/J-bis(carbo-methoxymethylthio)butyrate (169) Dieckmann condensation reportedly furnished ethyl 3,4-dihydroxy-6a-methyI-3a,6a-dihydro-thieno[2,3-ft]-thiophene-2-carboxylate (170) [Eq. (48)]. 

The base-catalyzed intramolecular condensation of a diester. The Dieckmann Condensation works well to produce 5- or 6-membered cyclic i-keto esters, and is usually effected with sodium alkoxide in alcoholic solvent. 

A synthesis of 4-hydroxy-substituted TIQ has been developed in connection with plant isoquinolines (169,170), and the glycine ester route used for a similar purpose (171) is shown in Fig. 23. Reaction of the benzyl bromide 85 with N-methylglycine ester gave 86 the ketoester 87 was obtained on Dieckmann condensation. Alkaline hydrolysis of ester 87 followed by treatment with mineral acid gave ketone 88 alcohol 89 was obtained on reduction of 88 with sodium borohydride. 

The synthetic route to 619 is a rather lengthy 27-step sequence outlined in Scheme 87 [192]. The first key reaction is a Wittig olefination of 606 with phosphorane 620 to give 621 with > 98% Z-selectivity. Subsequent Claisen rearrangement of the free alcohol 622 provides 623 with >98% stereoselectivity. Dieckmann condensation followed by decarboxylation gives the thermodynamically more stable ran -cyclopentanone 624 trans cis ratio = 7 1). 

The product this time is a 3-ketoester. A suitable base would be the alkoxide that is derived from the parent alcohol of the ester, because it does not matter if the ester undergoes transesterification that is, where one alkoxy moiety is exchanged for another. Note that, instead of the anionic adduct just picking up a proton, a alkoxide anion is eliminated on the formation of the carbonyl group. If both ester groups are in the same molecule, then an internal condensation reaction is possible. This is called the Dieckmann cyclisation, and works best when the ring formed contains five, six or seven members. 

Bixchler Napiralski, Dieckmann cyclization [15], Suzuki reaction [48], Wittig reaction, ozonolysis, condensation, esterification, nucleophilic substitution [49], Henry reaction, 1.3-dipolar cyclo-addition, electrophilic addition [50], oxidation chloride -> aldehyde [50], sulfide —> sulfone [51], alcohol —> ketone, Arbuzov reaction (phosphine-phosphorox-ide) [52], reduction hydration [45], ester -> alcohol [49, 53]... 

In 1887, Claisen and Lowman reported that the condensation of 2 mol of an ester, such as ethyl acetate, in the presence of base gave the p-keto ester, ethyl acetoacetate (ethyl 3-oxobutanoate equation 1). The intramolecular equivalent was recognized by Dieckmann in 1894. He found that heating an adipic acid ester with sodium and a trace of alcohol led to cyclization, with the formation of a cyclopentanone (equation 2). The reaction was, at an early stage, extended to the acylation of ketones. Claisen himself reported the base-catalyzed reaction of acetophenone and ethyl benzoate to give dibenzoylmethane in 1887. This reaction, too, has an intramolecular parallel. The acylation of ketones with esters and other acid derivatives is sometimes called a Claisen condensation, although this usage is criticized by some writers and avoided by others. A widely used example of ketone acylation is the synthesis of a-formyl (hydroxymethylene) ketones (equation 3). Intramolecular variants of this reaction include the classical synthesis of dimedone (Scheme 1). 

A second synthesis has been described of slaframine (11), the amine which causes excessive salivation in livestock foraging on red clover infected with Rhizoctomia leguminicola. Condensation of L(-l-)-glutamic acid with acrylonitrile, followed by esterification, gave ethyl iV-()5-ethoxycarbonylethyl)-5-oxopyrrolidine-2-car-boxylate (12), which on Dieckmann cyclization, hydrolysis, and decarboxylation afforded the racemic 3-oxopyrrolidine acid (13). Platinum-catalysed hydrogenation of the hydrochloride of (13) in methanol solution gave the alcohol-ester... 

A process which should have produced norlupinane was worked through by Clemo and Ramage. They condensed ethyl piperidine-2-carboxylate withy-bromobutyronitrile and, as the resultingy-2-carbethoxy-piperidinobutyronitrile could not be cyclised, hydrolysed it with alcoholic hydrogen chloride to the dicarboxylic ester (XXIII), which by the Dieckmann reaction, gave ethyl l-ketooctahydropyridocoline-2-carboxylate (XXIV). This on boiling with dilute sulphuric acid furnished 1-kcto-... 

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