Diesters, intramolecular condensation -

The intramolecular condensation reaction of diesters, the Dieckmann condensation, works best for the formation of 5- to 7-membered rings larger rings are formed with low yields, and the acyloin condensation may then be a faster competitive reaction. With non-symmetric diesters two different products can be formed. The desired product may be obtained regioselectively by a modified procedure using a solid support—e.g with a polystyrene 10 ... 

Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones (Section 23.6). Called the Dieckmann cyclization, the reaction works best on 1.6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic /3-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic /3-keto ester. 

Thiepane (35) has been synthesized by an intramolecular radical addition of the thiyl radical (equation 59) which was generated by photolysis of a thiol (71TL2025). Similarly, C—S bond formation has been achieved (equation 60) by an intramolecular condensation of 6-mercaptohexanoic acid to give the thiolactone, thiepan-2-one (135) (64MI51700). A Dieckmann-type base-catalyzed cyclization of a diester precursor followed by acid-catalyzed hydrolysis and decarboxylation has been used in the synthesis of thiepan-3-one (41) as indicated in equation (61) (52JA917). 

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. 

The Dieckmann condensation is usually defined to include only intramolecular condensations of diesters. ... 

The Dieckmann intramolecular condensation of diesters, which is used for the formation of rings B, C, and, particularly, D, has found incomparably wider use. In this reaction, cyclic )3-keto esters are first formed in the synthesis of ring C (93) —(94) they are immediately methylated further (Scheme 8), and in the synthesis of ring D (95) — (98) cyclization to compound (96) is followed by saponification and decarboxylation (Scheme 82). Instead of cyclization of diesters of type (95) in the presence of alk-... 

The intramolecular Claisen condensation of diesters, or Dieckman reaction, occurs readily to give five- or six-membered rings, and it has been extensively used for cyclopentanone and cyclohexanone derivatives. 

The intramolecular version of ester condensation is called the Dieckmann condensation.217 It is an important method for the formation of five- and six-membered rings and has occasionally been used for formation of larger rings. As ester condensation is reversible, product structure is governed by thermodynamic control, and in situations where more than one product can be formed, the product is derived from the most stable enolate. An example of this effect is the cyclization of the diester 25.218 Only 27 is formed, because 26 cannot be converted to a stable enolate. If 26, synthesized by another method, is subjected to the conditions of the cyclization, it is isomerized to 27 by the reversible condensation mechanism. 

Another important reductive coupling is the conversion of esters to a-hydroxyketones (acyloin condensation).267 This reaction is usually carried out with sodium metal in an inert solvent. Good results have also been obtained for sodium metal dispersed on solid supports.268 Diesters undergo intramolecular reactions and this is also an important method for the preparation of medium and large carbocyclic rings. 

A synthesis of the monoterpene alkaloid ( )-actinidine has been accomplished through the intramolecular cycloaddition of a substituted pyrimidine (81JCS(P1)1909). Condensation of the diester (756) with formamidine provided the pyrimidine precursor (757) which when heated at its melting point (203 °C) underwent cycloaddition with elimination of isocyanic acid to produce the pyridone (758). Conversion of the pyridone into the chloropyridine was effected with phosphoryl chloride. The chlorine atom was then removed by hydrogenoly-sis over palladium on charcoal to afford the racemic alkaloid (759 Scheme 175). 

Similar in style to the above are the base-catalyzed intramolecular cyclizations of diesters (116) and substituted salicylaldehydes (117), Dieckmann and Perkin condensations, respectively (36JCS212, 36JCS419, 40JCS787). 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

One typical radical reaction is a coupling reaction. Oxidative decarboxylation coupling reaction of carboxylic acids by electrolysis (Kolbe electrolysis), intramolecular coupling reaction of diesters with Na (acyloin condensation), formation of pinacols from ketones or aldehydes with Na or Mg are well known classical methods [1,2]. Recently, oxidative... 

Gutman,50 in his process route, which did not report any yields, hydrogenated the pyridine ring first to access the piperidine moiety and constructed the indanone ring system via an intramolecular Friedel-Crafts acylation (Scheme 5). Hydrogenation of diester 31, obtained from condensation of 4-pyridine carboxaldehyde and dimethyl malonate, followed by benzylation of the piperidine intermediate afforded A-benzylated piperidine 32. Alkylation of 32 with 3,4-dimethoxybenzyl chloride (33) and subsequent hydrolysis gave dicarboxylic acid 34. Subjection of 34 to strong acid resulted in intramolecular Friedel-Crafts acylation and in situ decarboxylation to provide 3. 

Dieckmann reaction (Section 23.9) the intramolecular Claisen condensation reaction of a 1,6-or 1,7-diester, yielding a cyclic p-keto ester. 

Intramolecular acyloin condensation [71] of the diester 90 under dilution conditions with sodium in toluene and with addition of trimethylsilyl chloride led to the bis(trimethylsilyl)en-diol ether 91 (29% yield) which was transformed subsequently in several steps to [l.l.l.ljparacyclophane 92 [71a]. 

The Claisen reaction is a carbonyl condensation that occurs between two ester components and gives a /3-keto ester product. Mixed Claisen condensations between two different esters are successful only when one of the two partners has no acidic a hydrogens (ethyl benzoate and ethyl formate, for instance) and thus can function only as the acceptor partner. Intramolecular Claisen condensations, called Dieckmann cyclization reactions, provide excellent syntheses of five- and six-membered cyclic /3-keto esters starting from 1,6- and 1,7-diesters. 

The Dieckmann condensation is an intramolecular variant of the Claisen condensation where a diester is converted to a 3-ketoester. Typically, an alkoxide is used as the base to form the enolate which attacks the remaining ester to form the carbocycle. Five- and six-membered rings are formed readily with this method. Reviews (a) Davis, B. R. Garrett, P. J. In Comprehensive Organic Synthesis, Trost, B. M. Fleming, 1. Eds. Pergamon Press Oxford, 1991 Vol. 2, Chapter 3.6 Acylation of Esters, Ketones, and Nitriles, pp. 806-829. (b) Schaefer, J. P Bloomfield, J. J. Org. React. 1967,15, 1-203. 

Bycroft was able to achieve the synthesis of 110 via a slightly modified route (Scheme 1.22). ° Condensation of benzyl 7-hydroxyoctanoate (108) with 3,5-dimethoxyphenylacetyl chloride provided the expected diester 109. Hydrogenolysis of the benzyl ester gave the desired acid, which was induced to close to the lactone via intramolecular Friedel-Crafts acylation to afford 110. 

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