Sodium Dieckmann condensation

In its present form, intermediate 12 is not a viable substrate for the crucial Dieckmann condensation it must undergo prior epimerization at C-16. When intermediate 12 is treated with sodium methoxide in hot methanol, enolization at C-16 occurs and an equilibrium is established between 12 and a diastereomeric substance, intermediate 11. Once formed, 11 can either revert back to 12 through the planar enolate form, or it can participate in a productive cyclization reaction to give a new six-membered ring. Under these conditions, the desired transformations take place with exceptional facility to give, after acidification of the reaction medium, enol ester 10. 

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)... 

Catalytic hydrogenation of the triple bond (Pd/C) and oxidation of the acetal in acid medium led to lactone 13. which could be cyclised directly to the tricyclic intermediate 5. according to a Dieckmann condensation induced by sodium methylsulphinylmethylide in DMSO. The cyclisation takes place through intermediate 14. Compound 5 was a diastereomeric mixture still, but on treatment with aqueous alkali, at room temperature, gave a crystalline compound in about 30-35% yield, to which the cis-anti-cis- configuration was assigned (in fact an equilibration through the intermediate A may take place). 

This interesting reaction is especially useful for the synthesis of medium- and large-ring compounds from dicarboxylic esters, and is effective for ring sizes that cannot be made by the Dieckmann condensation or decarboxylation (Section 18-1 OB). Radical anions formed by addition of sodium to the ester... 

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. 

Intramolecular ester condensation reactions are called Dieckmann condensations and are very useful ring-forming reactions. Examples are shown in the following equations. In the second equation the yield is only 54% if sodium ethoxide is used as the base. 

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. 

To most organic chemists the term Claisen condensation implies the self-condensation of esters in the presence of sodium ethoxide to give 0-ketoesters. A Dieckmann condensation is a special Claisen condensation in which an ester of a dibasic acid undergoes intramolecular condensation to produce a cyclic jS-ketoester. From the point of view of mechanism, however, this idea of a Claisen condensation is perhaps unnecessarily limited, for there are a number of extremely closely related reactions which involve compounds other than esters, and bases other than sodium ethoxide. In all these transformations, the essential feature of the reaction is the addition of a carbanion to a carbonyl group, followed by the loss of a negative ion from the seat of reaction. 

Dieckmann condensation. At the time of submission of an Organic Syntheses procedure for the cyclization of diethyl adipate to 2-carboethoxycyclopentanone, the reaction had been effected with sodium, sodium amide, and sodium ethoxide. Pinkney selected sodium, conducted the reaction at 110-115° for 7 hrs., and... 

The indole-2-carboxylate (70.2) undergoes a Dieckmann condensation usine sodium in benzene. An excess of lithium bis(trimethyl ily )atni()Q (LB At thf at -78 C for 5 min cyclizes the thio ester (70.3) to the stereoisomer shown as the only product. The same base has been used (30671 to svnthe ir biologically promising carbapenems. 

Carboxylic Acids and their Derivatives.—2,3-Seco-A -unsaturated dicarboxylic acids (443), obtained by ozonolysis of 2-hydroxymethylene-4-en-3-ones, have been considered rather resistant to cyclisation to form the A-nor-3-en-2-one system (444). Two convenient methods for achieving such a reaction are now described. Dieckmann condensation of the dimethyl ester (445) was successful with sodium hydride, in toluene containing a little methanol. The 5-methoxy-carbanion (446), resulting from conjugate addition of methoxide ion, is suggested as a possible activated intermediate. Alternatively, the diacid (in the B-nor-series)... 

Synthesis of pyrrolizidines by Dieckmann condensation continues to receive wide attention. It is a useful method for producing pyrrolizidines with oxygen substituents and has been exploited in a number of syntheses by Viscontini and co-workers. For their attempted preparation of 1,7-dioxopyrrolizidine, the very unstable 3-oxopyrrolidine was required as an intermediate.29 This compound was stabilized by ketalization (37), and by this means N-substituted 3-oxopyrrolidines are readily accessible. The 1,7-dioxopyrrolizidine was synthesized as the sodium enolate (38) as shown in Scheme 3. The dione itself is unstable and could not be isolated. Analogous Michael addition of the pyrrolidine (37) to a-chloroacrylic ester gave the corresponding 5,6-dihydropyrrolizine as the sodium salt (39).30 Treatment of this salt with acid produced a very stable H-bonded aromatic species. 

Secondly, Dieckmann condensation of diester 211 with sodium hydride in benzene, followed by hydrolysis and decarboxylation. 

Two types of sodium hydride are available commercially a dry, granular material about 8 to 200 mesh in size, and a semidispersion of micronsized crystals in mineral oil. The oil-dispersed sodium hydride is the safer and easier to handle, as the high reactivity of the hydride is protected by the oil. The principal use of sodium hydride is to carry out condensation and alkylation reactions which proceed through the formation of a car-banion (base-catalyzed). The sodium hydride dispersion has been evaluated in comparison with dry sodium hydride, sodium metal, soda-mide, and sodium methylate. Yields and reaction rates in the self-condensation of esters, ester-keto condensations, and the Dieckmann condensation have been outstandingly superior. Amines can be successfully alkylated by a new technique employing polar solvents. Dehalogenations do not occur, nor does reduction unless there is no a-hydrogen present. Acyloin formation and reduction side reactions do not interfere when sodium hydride is used. 

The Dieckmann condensation of esters and thioesters is mediated by sodium hydride (eq 20). Conditions for the latter are significantly more mild than for the former, and the yields are higher. 

The synthesis scheme is described in two process patents [70] Dieckmann condensation applied to ethyl adipate leads to the salt of 2-ethoxycarbonylcyclopenta-none (Scheme 17.12). From this compound, methylation at position 2 followed by a rearrangement under basic medium brings the methyl group to position 5. The salt obtained is directly benzylated with 4-chlorobenzyl chloride. A second methylation then occurs directly at position 5 and a subsequent decarboxylation allows access to the key carbonyl cyclopentanone with all the required substituents present. The last step consists of a one-pot Corey-Chaykovsky epoxidation reaction in which are successively added to the triazolyl sodium formed in situ, the cyclopentanone and the trimethylsulfoxonium bromide. 

The reductive coupling of carbonyl compounds with active metals (Na, Mg, Al) yields pinacols. An electron transfer from the metal surface to the carbonyl oxygen (ketyl formation), a soft-soft interaction, is undoubtedly involved. The conversion of esters to acyloins (22, 23) on the surface of metallic sodium is well known. Here the enediolate products can be trapped in situ by Me3SiCl (24). The chlorosilane does not interfere with the coupling, yet it effectively removes the alkoxide ions and neutralizes the enediolate ions immediately on formation. The elimination of RO is imperative, for otherwise Claisen or Dieckmann condensations would compete with the normal course of reaction. These complicating processes require a hard base (e.g. RO ) to abstract a proton from the starting esters, whereas the desired coupling is accomplished by a soft base which is the electrons on the metal surface. 

In the synthesis of blennolide C (897) (Scheme 13.12), the sequence commenced from methyl-substituted chromenone 926 with 2-trimethylsiloxyfuran (930), followed by deprotection to the chromones 928 and 929. It was found that the contrast in selectivities at different temperatures was even greater than determined previously. The lactenone was reduced with nickel chloride hexahydrate and sodium borohydride to lactone 930, with Dieckmann condensation following again, in order to deliver blennolide C (897). 

An intramolecular Claisen condensation is called a Dieckmann condensation. For example, when diethyl hexanedioate is heated with sodium ethoxide, subsequent acidification of the reaction mixture gives ethyl 2-oxocyclopentanecarboxylate ... 

An intramolecular Claisen condensation of a dicarboxylic ester to give a five- or six-membered ring is known as a Dieckmann condensation. In the presence of one equivalent of sodium ethoxide, diethyl hexanedioate (diethyl adipate), for example, undergoes an intramolecular condensation to form a five-membered ring ... 

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