Stabilized carbanions with alkyl halides

Reaction of stabilized carbanions (enolates) with alkyl halides (enolate alkylation)... 

Sulfur is one of the most frequently employed elements in organic synthesis. Typical functionalities containing sulfur atoms are illustrated below (la-ld) they all stabilize the adjacent carbanion, which serves as a nucleophile. The carbanion reacts with alkyl halides or adds to C—X ir-bonds (X = C, O, N, etc.) to form a C— bond, which is an essential process in organic synthesis. 

This chapter is devoted exclusively to the alkylation of the above mentioned organometallic reagents with alkyl halides, epoxides and oxetanes. It includes a large variety of organosulfur- and organoselen-ium-stabilized carbanions derived from saturated and unsaturated sulfides, selenides, sulfoxides, selen-oxides and sulfones as well as those carbanions bearing another heteroatomic moiety. The chapter excludes, however, those organometallics which can be viewed as a-thio and a-seleno enolates. 

Dimethyl-4,8-dioxaspiro[2.5]oct-l-ene is a synthetically useful precursor for cyclopropenones because of its stability and ready availability. The sodium derivative 1 of the cyclopropenone acetal in liquid ammonia reacted with alkyl halides giving alkyl-substituted cyclopropenone acetals 3. The lithiated cyclopropenone acetal 4 was generated by treating the cyclopropenone acetal with one equivalent of butyllithium in tetrahydrofuran. Reaction of the lithium carbanion 4 with alkyl halides proceeded cleanly in the presence of two equivalents of hexamethylphosphoric triamide (Table 1, entries 1-4). The lithium compound underwent nucleophilic addition to carbonyl compounds smoothly at — 70 C giving hydroxymethyl derivatives 5 (Table 1, entries 5-10). 

Introducing a heteroatom (X) into an organic molecule enhances the acidity of the proton adjacent to the heteroatom (H—C—X). A sulfur group makes the proton more acidic due to electron-withdrawing effects as well as by stabilization of the resulting carbanion by the d orbitals (see above).- 00,301 Several different sulfur-stabilized carbanions are known and have been used extensively in organic synthesis.Sulfur stabilized carbanions react with alkyl halides or with aldehydes and ketones in the same manner as other carbanions. 

In l-hthio vinyl sulfides (sec. 8.6) the sulfur atom stabilized the carbanion, allowing either alkylation or condensation reactions. The sulfonyl moiety can also stabilize a vinyllithium derivative. Vinyl sulfone (321), for example, was converted to the 1-lithio derivative with methyllithium.332 xhis organometallic reacted in the usual manner with alkyl halides (methyl iodide) to give the coupling product, 322. 

The relative stability of benzylic carbocations, radicals, and carbanions makes it possible to manipulate the side chains of aromatic rings. Functionalization at the benzylic position, for example, is readily accomplished by free-radical halogenation and provides access to the usual reactions (substitution, elimination) that we associate with alkyl halides. 

A very useful modification of the Wittig reaction involves the reaction of phosphonate-stabilized carbanions with aldehydes or ketones, which is known as the Homer-Wadsworth-Emmons (HWE) reaction [7, 151,152], This reaction was originally described by Homer et al. [153, 154] and further defined by Wadsworth and Emmons [155]. Phosphonate-stabilized carbanions are more nucleophilic and more basic than phosphonium ylides. They are prepared by the addition of suitable bases to the corresponding alkylphosphonates, which are readily accessible through the Michaelis-Arbuzov reaction of trialkyl phosphites with alkyl halides (usually a-halo carbonyl compounds) [143]. In contrast to the Wittig reaction, the HWE reaction yields phosphate salt byproducts that are water-soluble and hence are readily separated from the desired alkene products by simple extraction. 

An important complement to the Wittig reaction is the reaction of phosphonate carbanions with carbonyl compounds.151 The alkylphosphonate esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are more nucleophilic than an analogous ylide, and even when R is a carbanion-stabilizing substituent, they react readily with aldehydes and ketones to give alkenes. Phosphonate carbanions are generated by treating alkylphosphonate esters with bases such as sodium hydride, w-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.152... 

From oxidative cleavage of 1,2-diols and 1,2-amino alcohols Dibutyltin oxide, 95 By reaction of alkyl halides with sulfur-stabilized carbanions Methylthiomethyl p-tolyl sulfone, 192 From reduction of carboxylic acids Vilsmeier reagent, 341 From terminal alkenes by addition reactions... 

The ylide is prepared by deprotonating a triphenylalkylphosphonium salt with a strong base, commonly an organometallic base such as butyllithium or phenyllithium. The hydrogens on the carbon that is bonded to the phosphorus of the salt are somewhat acidic because the carbanion of the conjugate base (the ylide) is stabilized by the inductive effect of the positive phosphorus atom. In addition, a resonance structure with five bonds to phosphorus makes a minor contribution to the structure and provides some additional stabilization. The triphenylalkylphosphonium salt can be prepared by an SN2 reaction of triphenylphosphine with the appropriate alkyl halide (see Section 10.9). 

A treatment of 314 with LDA yielded a carbanion stabilized by boron and sulfur atom, which undergoes alkylation with organic halides and with methyl acrylate (Equation (93)).473... 

The phosphorus-stabilized carbanion is an ylide (pronounced ilL-id )—a molecule that bears no overall charge but has a negatively charged carbon atom bonded to a positively charged heteroatom. Phosphorus ylides are prepared from tri-phenylphosphine and alkyl halides in a two-step process. The first step is nucleophilic attack by triphenylphosphine on an unhindered (usually primary) alkyl halide. The product is an alkyltriphenylphosphonium salt. The phosphonium salt is treated with a strong base (usually butyllithium) to abstract a proton from the carbon atom bonded to phosphorus. 

In E2 elimination with bases like KOH and CH30Na, most alkyl halides give Saytzeflf orientation. Certain other compounds (quaternary ammonium salts, Sec. 23.5, for example) give Hofmann orientation. Alkyl sulfonates fall in between. With each kind of compound, orientation is affected—sometimes drastically—by the choice of base and solvent, and by stereochemistry. (The percentage of 1-hexene from 2-hexyl chloride, for example, jumps from 33% in CH ONa/ CH3OH to 91% in /-BuOK//-BuOH, evidently for steric reasons.) In all this, we should remember that orientation is a matter of relative stabilities of competing transition states these stabilities are determined by electronic factors—alkene character and carbanion character—with superimposed conformational factors. 

Alkylations of boron-stabilized carbanions have been carried out with primary alkyl halides containing acetal, alkene, alkyne, chloride, cyano, ester and tosylate groups, though a ketone group was not tolerated. ... 

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