Carbanions condensation

Non-oligomeric and air- or moisture-sensitive chemistries such as cycloadditions, cyclizations, and carbanion condensations have already been successfully enabled on solid support, and some recent examples are discussed below. It is anticipated that these studies will be further extended in combinatorial formats and libraries subjected to HTS in the near future. 

Aromatic 8-sultones (167) may be prepared from alkanesulfonyl salicylaldehydes (168) by intramolecular carbanion condensation (Scheme 69). 

The reaction mechanism consists of formation of a Schiff base by pyridoxal phosphate with a reactive amino group of the enzyme entry of glycine and formation of an enzyme-pyridoxal phosphate-glycine-Schiff base complex loss of a proton from the a carbon of glycine with the generation of a carbanion condensation of the carbanion with succinyl-CoA to yield an enzyme-bound intermediate (a-amino-yS-ketoadipic acid) decarboxylation of this intermediate to ALA and liberation of the bound ALA by hydrolysis. ALA synthesis does not occur in mature erythrocytes. 

Z3.3. The Feist-Benary Furan Synthesis. In this synthesis, an aldol-type carbonyl-carbanion condensation and a halogen displacement by an enol are employed to bring two molecules together in a ring stmc-ture, and in this sense it resembles the Knorr synthesis. The reactants are an alpha-haloketone and a ketoester (like ethyl acetoacetate). The mechanistic details remain unclear, but a logical mechanism is shown in Scheme 4.34. This assumes the carbonyl condensation occurs first before the halogen displacement, but the reverse may be tme. 

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

Thioglycohc acid is recommended as a cocatalyst with strong mineral acid in the manufacture of bisphenol A by the condensation of phenol and acetone. The effect of the mercapto group (mercaptocarboxyhc acid) is attributed to the formation of a more stable carbanion intermediate of the ketone that can alkylate the phenol ring faster. The total amount of the by-products is considerably reduced (52). 

Inductive and resonance stabilization of carbanions derived by proton abstraction from alkyl substituents a to the ring nitrogen in pyrazines and quinoxalines confers a degree of stability on these species comparable with that observed with enolate anions. The resultant carbanions undergo typical condensation reactions with a variety of electrophilic reagents such as aldehydes, ketones, nitriles, diazonium salts, etc., which makes them of considerable preparative importance. 

Although most of the reactions of preparative importance involving the a-alkyl carbanions are usually carried out under controlled conditions with NHa /NHs being used as the base, a number of reactions using less severe conditions are known, both in the pyrazine and quinoxaline series. In the case of alkylquinoxalines, where an increased number of resonance possibilities exist, mildly basic conditions are usually employed in condensation reactions. 

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

Since the final proton transfer is essential for a successful condensation, it is important to understand what factors drive the proton transfer. Examine the electrostatic potential map of the carbanion, and draw all of the resonance contributors that are needed to describe this ion. How does this ion differ from the others Which product, if either, would be expected from the following condensation Explain. 

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

In contrast to the facile condensation of o-nitrotoluene with diethyl oxalate, other a-alky] nitrobenzenes are sluggish to react with diethyl oxalate or fail to react at all. It has been suggested that this is due both to steric and electronic factors effected by the alky] group, which destabilizes the methylene group in regard to formation of the carbanion. ... 

The thenyl cyanides are of great importance for the preparation of thiophene derivatives. Because of the acidifying effects of both the thienyl and of the cyano groups, carbanions are easily obtained through the reaction with sodamide or sodium ethoxide, which can be alkylated with halides, carbethoxylated with ethyl carbonate, or acylated by Claisen condensation with ethyl... 

The carbanions derived from acylthiophenes have been condensed with aldehydes,and, through the Claisen condensation with esters, thienylsubstituted -diketones have been obtained. 2-Thenoyl trifluoroacetone, first prepared by Reid and Calvin through the Claisen condensation of 2-acetylthiophene with ethyl trifluoracetate, has become an extremely useful chelating agent for the extraction of numerous elements from strongly acidic solutions, The tautomeric form which dominates in aqueous solution is the ketone hy-drate. Other thiophenes have also proved useful for analytical purposes. ... 

Base catalyzed condensation of 2-azidobenzaldehyde 796 with cyano-carbanions in piperidine or NaOEt in ethanol afforded tetrazoloquinolines... 

The cyanide ion plays an important role in this reaction, for it has three functions in addition to being a good nucleophile, its electron-withdrawing effect allows for the formation of the carbanion species by proton transfer, and it is a good leaving group. These features make the cyanide ion a specific catalyst for the benzoin condensation. 

A somewhat more complex side chain is incorporated by alkylation of the carbanion of the substituted cyanoacetate, 148, with 2-chloroethylmethyl sulfide. Condensation of the resulting cyanoester (149) with thiourea followed by hydrolysis of the resulting imine (150) affords methitural (151)... 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

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