Dicarbonyl Compounds Claisen Condensations

Claisen condensation org chem 1. Condensation, in the presence of sodium ethox-ide, of esters or of esters and ketones to form p-dicarbonyl compounds. 2. Condensation of arylaldehydes and acylphenones with esters or ketones In the presence of sodium ethoxide to yield unsaturated esters. Also known as Claisen reaction. klas-3n kand-on sa-shon ... 

Unfortunately neither reaction will work The black route requires a controlled condensation between two different enolizable esters—a recipe for a mixture of products. The simple alkylation route above removes the need for control. The green route requires a condensation between an unsymmetrical ketone and diethyl carbonate. This condensation will work all right, but not to give this product. As you saw on p. 730, Claisen condensations prefer to give the less substituted dicarbonyl compound, and condensation would occur at the methyl group of the ketone on the right to give the other unsymmetrical keto-ester. 

The 1,3-dicarbonyl components can be replaced by an enol ether, which can be prepared by Claisen condensation from an ortho ester and a reactive methylene compound. ... 

The term condensation refers to the joining of two molecules with the splitting out of a smaller molecule. The Claisen condensation is used extensively in the synthesis of dicarbonyl compounds. In biochemistry it is used to build fatty acids in the body. The Dieckmann condensation, the crossed Claisen condensation, and others (with other carbanions) cire variations of the Claisen condensation. In this section we briefly look at these variations. 

The Claisen condensation is one method of synthesizing (3-dicarbonyl compounds, specifically a (3-keto ester. This reaction begins with an ester and occurs in two steps. In the first step, a strong base, such as sodium ethoxide, removes a hydrogen ion from the carbon atom adjacent to the carbonyl group in the ester. (Resonance stabilizes the anion formed from the ester.) The anion can then attack a second molecule of the ester, which begins a series of mechanistic steps until the anion of the (3-dicarbonyl compound forms, which, in the second reaction step (acidification), gives the product. 

The conversion of the substituted 1,3-dicarbonyl compound into homophthalic acid is remarkably facile loss of the acetyl group by a retro-Claisen condensation and hydrolysis of the ester group are complete in a few minutes in aqueous sodium hydroxide. The overall synthesis of homophthalic acids from o-bromobenzoic acids occurs in high yield and provides an attractive route. 

Key Mechanism 22-12 The Claisen Ester Condensation 1071 22-13 The Dieckmann Condensation A Claisen Cyclization 1074 22-14 Crossed Claisen Condensations 1074 22-15 Syntheses Using /3-Dicarbonyl Compounds 1077 22-16 The Malonic Ester Synthesis 1079 22-17 The Acetoacetic Ester Synthesis 1082 22-18 Conjugate Additions The Michael Reaction 1085 Mechanism 22-13 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

Claisen condensations usually give 1,3-dicarbonyl products, with one I saturated carbon between two carbonyl groups. Michael additions commonly give 1,5-dicarbonyl products, with three saturated I carbons between two carbonyl I groups. When you need a compound with three carbons between two carbonyl groups,... 

The keto-aldehyde can be made by a simple Claisen ester condensation (Chapter 28) using the enolate of the methyl ketone with ethyl formate (HCC Et) as the electrophile. It actually exists as a stable enol, like so many 1,3-dicarbonyl compounds (Chapter 21). 

The five-membered ring pyrazoles are even simpler as the starting material is a 1,3-dicarbonyl compound available from the aldol or Claisen ester condensations. 

Following the methods we have established so far in this chapter, we can remove the hydrazine portion to reveal a 1,3-dicarbonyl compound. In fact, this is a tricarbonyl compound, a diketo-estcr, because of the ester already present and it contains 1,2- 1,3-, and 1,4-dicarbonyl relationships. The simplest synthesis is by a Claisen ester condensation and we choose the disconnection so that the electrophile is a reactive (oxalate) diester that cannot enolize. The only control needed will then be in... 

When you need to synthesize a p-hydroxy ketone or aldehyde or an a,p-unsaturated ketone or aldehyde, use an aldol reaction. When you need to synthesize a p-diketone or p-keto ester, use a Claisen reaction. When you need to synthesize a 1,5-dicarbonyl compound, use a Michael reaction. The Robinson annulation is used to synthesize polycyclic molecules by a combination of a Michael reaction with an aldol condensation. 

In the Claisen condensation, the enolate of the p dicarbonyl compound is treated with H3+ to yield the neutral product. 

The importance of a-diazo ketones as synthetic intermediates has led to the development of a number of general methods for their preparation.5 Particularly popular approaches include the acylation of diazo alkanes and the base-catalyzed "diazo group transfer" reaction of sulfonyl azides with 8-dicarbonyl compounds.6-7 While direct diazo transfer to ketone enolates is usually not a feasible process,8-9 diazo transfer to simple ketones can be achieved in two steps by employing an indirect deformylative diazo transfer strategy in which the ketone is first formylated under Claisen condensation conditions, and then treated with a sulfonyl azide reagent such as p-toluenesulfonyl azide.6a,6c,9,i0,11... 

When o-phcnylenediamine reacts with aliphatic or aliphatic-aromatic ketones the initially formed benzimidazolines can be thermally decomposed, losing a hydrocarbon fragment to yield 2-substituted benzimidazoles [81, 131]. While this method does not appear to have major synthetic importance, the analogous reaction with a, 6-diketonc has some application [132]. Presumably it involves an acid-catalysed retro-Claisen condensation of the S-dicarbonyl compound. When acetylacetonc is used, acetone is formed. The process, then, offers an unambiguous approach to compounds such as 2-methyl-4-nitrobenzimidazoles (not available by direct nitration). Neither the numbers of substituents on the arylenediamine nor their natures appear to affect yields or reaction times significantly. 

Reaction of sugar lactone with ester enolate (the Claisen condensation) gives -keto ester, the resulting 1,3-dicarbonyl compound immediately reacts with the hydroxyl group present in the same molecule to afford a lactol with an axial hydroxyl group. In a recent example shown in O Scheme 4 [8], the product of the reaction was further transformed to the corresponding nitrile or amide by addition of cyanide or a Ritter reaction with benzonitrile in the presence of TMSOTf as a Lewis acid. 

The Reformatsky -Claisen variant is complicated by various side reactions, e.g., the condensation of the zinc enolate derived from acetic esters to yield 1,3-dicarbonyl compounds, known byproducts in the classical Reformatsky reaction. This side reaction is depressed by a-alkyl substitution of the ester. 

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