Anions Dieckmann condensation

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

Besides the Michael addition-initiated domino reactions presented here, a multitude of other anionic domino reactions exist. Many of these take advantage of an incipient SN-type reaction (for a discussion, see above). In addition to the presented SN/Michael transformations [97, 98, 100], a SN/retro-Dieckmann condensation was described by Rodriguez and coworkers, which can be used for the construction of substituted cycloheptanes as well as octanes [123]. Various twofold SN-type domino... 

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)... 

Anionic resin capture of solution-phase library products has also been reported. The anion exchange resin A-26 hydroxide 6 was used in a dual capacity to mediate Dieckmann condensations of solution-phase library intermediates and also to affect resin capture of the formed tetramic acids as polymer-bound intermediates (Scheme 7).79 Rinsing, followed by tri-... 

Dihydrofuranones can be generated by Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates. The resulting intramolecular Dieckmann condensation yields substituted furanone rings (Scheme 82) (57HCA1157). 

A very useful method for generating 3 (2H)- dihydrofuranones is based on the Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates (Scheme 82). The intermediate anion attacks the adjacent ester moiety via a Dieckmann condensation reaction to produce a substituted furanone ring which usually bears useful functionality. Overall yields of 45-60% have been obtained for this reaction. 

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 anion from (70.5) attacks the nitrile group and a 4-aminopyridine ring is formed in this example, the product is related to the antibacterial agent nalidixic acid. 5-Phenyl esters are useful in regioselectively directing a Dieckmann condensation of the diesters (70.6) to carbacephems. Dieckmann reactions usually requite heating but the enaminic ester (70.7) undergoes cyclization without external heat. 

This type of enolate anion reaction occurs among esters in the Claisen (Section 15.3A) and Dieckmann condensations (Section 15.3B). 

The mechanism of a Dieckmann condensation is identical to the mechanism we described for the Claisen condensation. An anion formed at the a-carbon of one ester in Step 1 adds to the carbonyl of the other ester group in Step 2 to form a tetrahedral carbonyl addition intermediate. This intermediate ejects ethoxide ion in Step 3 to regenerate the carbonyl group. Cyclization is followed by formation of the conjugate base of the j8-ketoester in Step 4, just as in the Claisen condensation. The j8-ketoester is isolated after acidification with aqueous acid. 

Identify the a-carbon for each ester group. Convert one of the a-carbons to an enolate anion and show it adding to the other carbonyl carbon. Because Dieckmann condensations occur with nucleophilic acyl substitution, the —OR group of the carbonyl being attacked Is eliminated from the final product. It often helps to number the atoms in the enolate anion and the ester being attacked. 

Addition of enolate anions derived from aldehydes or ketones (aldol reactions) and esters (Claisen and Dieckmann condensations) to the carbonyl groups of other aldehydes, ketones, or esters. 

The intra-molecular Claisen condensation is called a Dieckmann condensation, and it generates a cyclic compound 58,99,101,118. Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or add derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation 59, 60, 61, 62, 69, 99,108,110,112, 113,119,124. 

There are few mechanistic studies for the Dieckmann condensation. " The reaction can simply be described as an intramolecular Claisen condensation and hence entirely reversible. The summation of the consensus for its mechanism is as follows the reaction is initiated by anion formation through the abstraction of the most acidic proton on the a-carbon to one of the di-... 

In 1999, Shindo and Sato reported an interesting one-pot tandem [2 + 2]-cycloaddition-Dieckmann condensation. The condensation is a unique approach for the synthesis of functionalized 5- and 6-membered rings. The reaction proceeds by first treating the 3molate anions of structure 41, which is formed readily in situ from its corresponding o,a-dibromo esters with 4 equiv of tert-BoLi at -78 C. The reaction is warmed up to 0 °C, followed by the addition of y-keto-esters of structure 40 in THF, after which the temperature is then lowered to -78 C, and the reaction then proceeds at that temperature. After workup and with no purification, acid-catalyzed decarboxylation in benzene follows to give compounds of structure 42 in good yields. 

The Thorpe-Ziegler cyclization is characterized by a relatively straightforward mechanism. As demonstrated below, deprotonation of dinitrile 1 results in the formation of the anionic species 2. Intramolecular cyclization in a manner similar to the well-known Dieckmann condensation yields 3. Workup under aqueous conditions then produces imine 4, which immediately tautomerizes to the conjugated enamine 5. 

Note that aldol, Claisen, and Dieckmann condensations all give primary products with oxygens in a 1,3 relationship. The Michael reaction with enolate anions gives products with oxygens in a 1,5 relationship. These relationships are a consequence of the polarization of the reagents. In aldol, Claisen, and Dieckmann condensations, the carbonyl carbon is positive and the a-position is negative. 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

Crossed Claisen reactions with two different esters, each of which has a-H atoms, are seldom useful synthetically as there are, of course, four possible products. Crossed Claisen reactions are, however, often useful when one of the two esters has no a-H atoms, e.g. HCOzEt, ArC02Et, (C02Et)2, etc., as this can act only as a carbanion acceptor. Such species are in fact good acceptors, and the side reaction of the self-condensation of the other, e.g. RCH2C02Et, ester is not normally a problem. Intramolecular Claisen reactions, where both C02Et groups are part of the same molecule [e.g. (123)], are referred to as Dieckmann cyclisations. These work best, under simple conditions, for the formation of the anions of 5-, 6- or 7-membered cyclic / -ketoesters... 

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