Deprotonation dipole-stabilized

Dimethylpropanoyl)-l, 2,3,4-tetrahydroisoquinolincs 16 form dipole-stabilized lithium carbanions on deprotonation, but their addition to aldehydes or methyl ketones proceeds nevertheless with low simple diastereoselectivity22 23. However, a high preference for the formation of the w-diastereomer is observed after transmetalation with magnesium bromide22"24. 

Configurational stability has also been confirmed for various metalated carbamates by Hoppe and coworkers. Remarkably, carbamate-protected alcohols such as 20 are deprotonated enantioselectively, when treated with i-butyllithium in the presence of (—)-sparteine. The lithium carbenoids like 21 (R = alkyl) thus generated turn out to retain their configuration (equation 11). Similar results have been obtained for a-lithiated amines and carbamate protected amines " . As a rule, dipole stabilization of the organolithium compounds in general also enhances the configurational stability of a-oxygen-substituted lithium carbenoids. 

As indicated in Section ni.B, deprotonation of a carbamate affords a dipole-stabilized a-amino-organolithium that can be transmetalated with copper salts to form cuprates, thereby expanding the versatility of the organolithium. Suitable electrophiles include enones, alkenyl, alkynyl, allenyl and dienyl carboxylic acid derivatives, nitriles and sulfoxides. Dieter and coworkers have shown that the same process can be accomplished via transmetalation of a stannane (Scheme 36). The procedure is particularly... 

Deprotonation is the most convenient manner for the generation of alkyllithium derivatives. However, most of the potential precursors have insufficient acidity. Notable exceptions are those substrates which lead to dipole-stabilized carbanions , among them O-alkyl iV,A-dialkylcarbamates 15 ° and A-Boc-(cyclo)alkylamines 18 ° (equation 5). A... 

Dipole-Stabilization is a term coined by Beak to describe the situation that results when a carbanion is stabilized by an adjacent dipole. Such a situation arises when, for example, an amide is deprotonated a to nitrogen. The chemistry of these systems has been reviewed, - so only a few pertinent points will be made here. Firstly, metalation occurs syn to the carbonyl oxygen, and when the system is cyclic, the equatorial proton is removed selectively, and the electrophile attacks equatorially, as shown in equation (5), 24, 25 Thus, in contrast to nitrosamines, amide anions give the less stable equatorial product. 4,i25... 

The mechanism of the deprotonation of dipole-stabilized anions has been studied in detail. It has been shown by IR spectroscopy that a preequilibrium exists between the butyllithium base and the amide or amidine, forming a coordination complex prior to deprotonadon. A recent mechanistic study has shown that, in cyclohexane solvent, this prior coordination is between the amide (or added TMEDA) and aggregated s-butyllithium, and that the effect of the coordination is to increase the reactivity of the complex. The diastereoselectivity of proton removal in chiral benzylic systems has also been examined,but since the anions invert, this selectivity is of little consequence in the alkylation step. 

Alkyl arenecarbothioates (42), on the other hand, undergo deprotonation at the 5-alkyl group. The resulting dipole-stabilized carbanions may be acylated by the starting compound (42) to form 5-(2-oxoal-kyl) arenethioates (equation 37). ... 

A number of heterocyclic IV-alkyllactams have been metalated to dipole-stabilized anions, and the yields of addition to carbonyls are reasonably good. An experimental and theoretical study of the competitive metalation to form enolates or dipole-stabilized anions of a series of alicyclic -benzyllactams has been reported by Meyers and Still.Experimentally, the regioselectivity of the deprotonation varies inconsistently with ring size. Specifically 5-, 6- and 11-membered rings are deprotonated in the ring to form enolates (29), whereas 7- and 8-membmd rings are deprotonated at the IV-benzyl to form dipole-... 

When the a-protons are allylic or benzylic, the selectivity of the deprotonation is attenuated by the competing stereoelectronic requirements of allylic activation and dipole stabilization. Stabilization of a... 

Virtually all of the synthetic applications of chiral dipole-stabilized organolithiums reported to date have the C— Li bond in an allylic or benzylic system. The most important consequence of this fact is that the two stereoisomers shown in Figure 3 can interconvert by pyramidal inversion. Therefore, the stereoselectivity of the deprotonation is irrelevant to the stereoselectivity as manifested in the product dia-stereomer ratio. The source of the selectivity in the organolithium alkylation step has not been determined. The available data do not permit a distinction between at least three possibilities thermodynamic control as determined by the equilibrating organolithium diastereomers, - kinetic control according to Curtin-Hammett kinetics,or increased carbon-lithium covalency at low temperature. ... 

Lithiation takes place more readily if the dipole-stabilized anions are further activated by an adjacent aromatic ring or a double bond and, in fact, many such compounds are most conveniently deprotonated using the less reactive -BuLi. ... 

The pA of 1,3-dithiane is 36.5 (Cs" ion pair in THF). The value for 2-phenyl-1,3-dithiane is 30.5. There are several factors which can contribute to the anion-stabilizing effect of sulfur substituents. Bond dipole effects contribute but carmot be the dominant factor because oxygen substituents do not have a comparable stabilizing effect. Polarizability of sulfur can also stabilize the carbanion. Delocalization can be described as involving 3d orbitals on sulfur or hyperconjugation with the a orbital of the C—S bond. MO calculations favor the latter interpretation. An experimental study of the rates of deprotonation of phenylthionitromethane indicates that sulfur polarizability is a major factor. Whatever the structural basis is, there is no question that thio substituents enhance... 

The chelate formation in lithium complexes 17 or 20 contributes to stabilization. Enhancement of kinetic acidity arises from the formation of pre-complexes 16 and 19, respectively. Here, already a dipole is induced and, in addition, proton exchange can proceed intramolecularly via a five- or six-membered ring. Despite these favourable features, the acidity of alkyl carbamates 15 is lower than those of the 1-proton in butane n-BuLi does not lead to deprotonation. In order to suppress carbonyl attack, a branched amino residue NR2 such as diisopropylamino (in Cb) or 2,2,4,4-tetramethyl-l,3-oxazolidin-3-yl (in Cby) is essential. A study on the carbenoid nature of compounds 17 was undertaken by Boche and coworkers. ... 

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