Carbanions, heterocycle-stabilized

Sulfur stabilized carbanions Heterocycle stabilized carbanions... 

In the formation of the first synthetic intermediate in Sequence D, the very effective Verley-Doebner modification of the fundamental Knoevenagel condensation is used. This modification uses malonic acid in place of the conventional ester to promote enoUzation. In addition, the heterocyclic amine, pyridine, functions as both the base catalyst and the solvent. A cocatalyst, P-alanine (an amino acid), is also introduced. Mechanistically, the reaction closely resembles the aldol condensation in that in both cases a carbanion is generated by abstraction, by base, of a proton alpha to a carbonyl group. The resulting carbanion is stabilized as an enolate anion (see below). 

The most useful reactions combine carbanion nucleophiles with activated aziridines. For example, the ring expansion which occurs on treatment of aziridines (219) with malonate salts typifies the heterocyclic synthesis possible. The conversion is quite general since many analogous transformations have been observed in which different carbanion stabilizing substituents were employed (73S546). 

Heterocyclic carbanions stabilized by ylid formation, or by resonance that places the negative charge on a heteroatom, are specifically excluded. In addition, heterocyclic systems that do not depend on additional stabilization factors for their initial deprotonation, continued existence, or subsequent reaction with electrophilic substrates are discussed in less detail. 

However, dipole stabilization is less significant as an aid to carbanion formation with unsaturated azaheterocycles, since the nitrogen lone-pair electrons are normally incorporated into the 77-electron system of the heterocycle, and are therefore less readily available for donation to the substituent group. In fact, dipole-stabilization can even be a hindrance in some systems where exocyclic ip -carbanion formation is competitive with internal ip -carbanion formation. In these cases it is the heterocycle itself that is responsible for the dipole-stabilization of the external carbanion. 

Attempts to extend this process to the related 2-pyridone system have been less successful, with only a small proportion of C-6 lithiation being observed with l-methyl-2-pyridone [85CC1021 88JCS(P1)1]. In fact, the major mode of reaction involves lithiation of the exocyclic methyl group, to give a carbanionic species that is dipole-stabilized by the heterocyclic amide group (Scheme 120) (83MI1). 

The intramolecular addition of carbon nucleophiles to alkenes has received comparatively little attention relative to heterocyclization reactions. The first examples of Pd-catalyzed oxidative carbocyclization reactions were described by Backvall and coworkers [164-166]. Conjugaled dienes with appended al-lyl silane and stabilized carbanion nucleophiles undergo 1,4-carbochlorination (Eq. 36) and carboacetoxylation (Eq. 37), respectively. The former reaction employs BQ as the stoichiometric oxidant, whereas the latter uses O2. The authors do not describe efforts to use molecular oxygen in the reaction with allyl silanes however, BQ was cited as being imsuccessful in the reaction with stabihzed car-banions. Benzoquinone is known to activate Ti-allyl-Pd intermediates toward nucleophilic attack (see below. Sect. 4.4). In the absence of BQ, -hydride eUm-ination occurs to form diene 43 in competition with attack of acetate on the intermediate jr-allyl-Pd" species to form the 1,4-addition product 44. 

Diphenylmethylcarbanions. The carbanions based on diphenyknethane (pKa = 32) (6) are useful initiators for vinyl and heterocyclic monomers, especially alkyl methacrylates at low temperatures (94,95). Addition of lithium chloride or lithium /W -butoxide has been shown to narrow the molecular weight distribution and improve the stability of active centers for anionic polymerization of both alkyl methacrylates and tert-huXyi acrylate (96,97). Surprisingly, these more stable carbanions can also efficiendy initiate the polymerization of styrene and diene monomers (98). 

L. B. Dipole stabilized carbanions in series of cyclic aldonitrones. Aldonitrone metalation and dimerization in LDA and BuLi solutions. Heterocyclic Comm. 1998, 4, 261-270. 

Terminal perfluoroolefins have two fluorine atoms at the double bond. The carbon atoms of the latter bear a significant positive charge, and the nucleophilic agents easily replace the fluorine atoms at the multiple bond. The reactions of binucleophilic reagents with terminal perfluoroolefins form heterocyclic systems. The first step of the reaction involves a nucleophilic attack at the carbon atom of the double bond, generating a carbanion. The latter is stabilized by elimination of the fluoride ion and formation of a new double bond. Subsequent cyclization by the intramolecular attack of the nucleophilic center at the double bond leads to the formation of a heterocyclic system. For example, when a reaction mixture of hexafluoropropylene and sodium dialkylaminodithiocarbamate in dimethylacetamide is heated with aqueous sodium tetraphenylborate, one obtains the tetraphenylborate salt of 2-dialkylamino-4-trifluoromethyl-4,5-difluoro-l,3-dithiolan-2-yl (78JFC(12)193). This compound is formed by intramolecular cyclization of the S-nucleophilic center. 

If a molecule has a multiple bond and a nucleophilically mobile chlorine atom, then the fluoride ion attacks the double bond, generating a carbanion stabilized by two trifluoromethyl groups, and intramolecular nucleophilic cyclization forming a five-membered heterocycle 48 is possible. 

These non-classical Wittig reactions of esters have been used to prepare a number of oxygen-containing heterocycles.35 Phosphonate stabilized carbanions, for example, those derived from dimethyl methylphophonate, also react with esters to give, in this case, a P-keto phophonate which can react further with aldehydes and ketones. 

The relative electronegativity of heteroatoms directly bonded to the carbanion also contribute to the overall stabilization. This is best illustrated by the reaction of o-benzodithiol (II) with tetrachloroethylene. Of the two possible cycloaddition routes, that leading to the thermodynamically less stable five-membered heterocycle prevails, perhaps owing to the greater stability of carb-... 

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