The Dieckmann Reaction

Intramolecular Claisen reactions of dlesters form five- and six-membered rings. The enolate of one ester is the nucleophile, and the carbonyl carbon of the other is the electrophile. An intramolecular Claisen reaction is called a Dieckmann reaction. Two types of diesters give good yields of cyclic products. 

The mechanism of the Dieckmann reaction is exactly the same as the mechanism of an inter-molecular Claisen reaction. It is illustrated in Mechanism 24.5 for the formation of a six-membered ring. 

Problem 24.20 One synthesis of prostaglandin PGAj involved a Dieckmann reaction as a key step. What is the structure of X in the reactions drawn below  

Problem 24.21 What two p-keto esters are formed in the Dieckmann reaction of the following diester  

7-Diesters yield six-membered rings by the Dieckmann reaction. 

In Step [1], the base removes a proton to form an enolate, which attacks the carbonyl group of the second ester in Step [2], thus forming a new carbon-carbon bond. 

To complete the reaction, the proton between the two carbonyl groups is removed with base, and then protonation of the enolate re-forms the p-keto ester (Steps [4] and [5]). 

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Esters of dicarboxyUc acids having hydrogen on tbe 8 or e carbon atoms undergo intramolecular cyclisation when heated with sodium or with sodium ethoxide. This cyclisation is known as the Dieckmann reaction. It is essentially an application of the Claiseu (or acetoacetic eater) condensation to the formation of a ring system the condensation occurs internally to produce s... 

Synthesis This cyclisation version of the Claisen ester condensation is sometimes called the Dieckmann Reaction. 

The reverse Claisen reaction is common, especially with cyclic P-ketoesters, such as one gets from the Dieckmann reaction (see Section 10.8). If one only wants to hydrolyse the ester, it thus becomes necessary to use the rather less effective acid-catalysed hydrolysis method (see Section 7.9.2). 

The use of classical condensation reactions is important. Thus, the Dieckmann reaction (equation 38) and the Thorpe-Ziegler cyclization (equation 39) have been used for almost a century for the preparation of a wide range of monocyclic and benzo-fused heterocycles. The aldol condensation and related reactions have also been fairly widely exploited, especially for the synthesis of 4-quinolones (the Camps reaction, e.g. equation 40), and various extensions of this general approach are described in the monograph chapters. 

Ring expansion of the six-membered ketosulfide (371) produces both 5-thiocanone and 4-thiocanone [372 v 1700 cm-1 (neat)], but in low yields (70JOC584). The photochemistry of these ketones has been studied and leads to a variety of products in low yields (70JOC584). 3-Thiocanone (373 b.p. 66-68 °C/0.35 mmHg, v 1708 cm-1) is formed in 44% yield by the dihalide method, but in only 3% yield by the Dieckmann reaction under high dilution conditions (70JPR1058). 

Many of the standard methods of C-C bond formation in aliphatic systems can be extended to heterocyclic systems, e.g. the Dieckmann reaction (,cf 51 — 52) and alkylation of active methylene compounds (e.g. 53 —+ 54). 

An example of the application of the Dieckmann reaction to the preparation of 3-thiepanone is shown in Scheme 22 (52JA917). 

C-alkyl derivatives (280) are obtained by direct addition of an alkyl halide at the end of the Dieckmann reaction, in benzene or xylene. O-Alkyl derivatives (281) are obtained by reacting sodium amide with ester 278, previously isolated, in benzene, followed by addition of the... 

The conversion of esters (278) to 3(2//)-benzofuranones (279) by hydrolysis and decarboxylation (KOH in alcohol)279,668,674 is sometimes difficult. Direct conversion of esters (277) into benzofurans has recently been achieved by the action of NaBH4 on the product of the Dieckmann reaction (not isolated), followed by acidic hydrolysis (70% yield).681,682... 

Most of the possible oxoindolizidines have been prepared by the application of the Dieckmann reaction to various piperidyl and pyrrol-idinyl diesters. Winterfeldt and Hoffstadt used it to convert 166 into 167 in good yield.227 Alkaline hydrolysis followed by lithium aluminum hydride reduction gave the alcohol 168 [Eq. (23)]. 

The synthesis may thus be seen to be an intramolecular Claisen ester condensation, which is known as the Dieckmann reaction. The procedure is an important method for the synthesis of five- and six-membered ring systems, and the cyclic /2-keto ester product may be converted into the corresponding cyclic ketone by hydrolysis followed by decarboxylation (ketonic hydrolysis, see Section 5.8.5, p. 619). The base catalyst used in Expt 7.8 is sodium ethoxide, but sodium hydride as a 50 per cent dispersion in oil is a recommended alternative. 

HO attacks the more reactive carbonyl called the Dieckmann Reaction. 0 A... 

An improved synthesis of Uhle s ketone (54), a useful intermediate in ergoline synthesis, has been described,36 in which the closure of the ketone ring is accomplished by the Dieckmann reaction this route is also applicable to the homologous ketone. 

The intramolecular version of the Claisen ester condensation is sometimes known as the Dieckmann reaction, It provides an excellent route to heterocyclic ketones (cyclic ketones with heteroatoms in the ring very important in. . 

Many of the standard methods of C-C bond formation in aliphatic systems can be extended to heterocyclic systems, e.g., the Dieckmann reaction (cf. 66 67) and alkylation of active methylene compounds (e.g., 68 69). An example of the application of the Dieckmann reaction to the preparation of 3-thiepanone 70 is shown in Scheme 42 <1952JA917>. Several more recent examples of applications of the Dieckmann condensation in the synthesis of substituted 4- and 3-piperidones are discussed in CHEC-III . 

The Dieckmann reaction of Et02C(CH2)4CH(CH3)C02Et yields only one of the two possible cyclic p-keto esters. Draw structures for both possible products and explain why only one is formed. 

A variety of electron-withdrawing groups such as those in ketones, nitriles, and sulfones are also suitable for the Dieckmann reaction. " ... 

The amino acid derived carboxy group can be utilized as a functionality for further synthetic manipulations, e.g. for cyclization reactions to 1,3-bridged P-carbolines, using the Dieckmann reaction, a promising stereocontrolled approach to macroline-related alkaloids (Scheme 14). > ... 

Hromatka, O., Binder, D., Eichinger, K. Mechanism of the Dieckmann-reaction of methyl-3-(methoxycarbonylmethylthio)propionic acid methyl ester. Monatsh. Chem. 1973, 104,1520-1525. 

Claisen condensation The reaction of two ester molecules in the presence of the appropriate alkoxide base, followed by mild acid hydrolysis to yield the 3-ketoester. The cyclic version is called the Dieckmann reaction. 

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