Aldehydes alkyllithium

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

These reagents are not isolated but are used directly in reactions with aldehydes, after generation of ate complexes via the addition of an alkyllithium reagent or pyridine11. 2-(2-Propenyl)-1,3,2-dioxaborolane is also metalated upon treatment with lithium tetramethylpiperidide, but mixtures of a- and y-substitution products are obtained upon treatment of this anion with alkylating agents20. Consequently, this route to a-substituted allylboron compounds appears to be rather limited in scope. 

The yield of 17 is 50 62% in the reactions involving butyl- or. vw-butyllithium due to competitive transfer of the butyl or sec-butyl group. Yields of 17 are improved by using pyridine as the additive, but diastereoselectivity is not as high as when the alkyllithiums are employed. Without any additive, a complex mixture of syn- and anti-diastereomers plus products resulting from addition of the a-carbon of the substrate borane to the aldehyde are obtained. 

A solution of 1.3 equiv of alkyllithium in hexane is added to a mixture of 1 cquiv of the enimine and 1.4equiv of (1 R,2R)-l,2-dimethoxy-1,2-diphenylethane8 in toluene at — 78°C. The solution is stirred at either — 78 CC or — 45 °C (see table above) for 1 -13 h and then treated with an acetate buffer (pH 4.5) for 12 h. The usual workup gives the aldehyde, which is then reduced with NaBH4 in methanol to give the alcohol. 

A second class of organometallic derivatives, namely alkyllithium reagents, has been condensed onto aldehydes in the presence of chiral sulfur-containing... 

Scheme 3.68 Amino sulfide ligands for additions of alkyllithium reagents to aldehydes.

Addition to chiral acylsilanes.6 Addition of alkyllithium or Grignard reagents to a-chiral aldehydes shows only modest (about 5 1) syn-selectivity. In contrast, the same reagents add to chiral acylsilanes with high sy -selectivity to give, after... 

Enantioselective synthesis of R R2CHNH2.1 Alkyllithiums add stereoselec-tively to the C=N bond of SAMP hydrazones (2) of aldehydes. Reductive cleavage of the N—N bond of the products (3) affords either (R)- or (S)-4 with recovery of... 

The reaction was used for synthesis of (- )-norpseudoephedrine from a chiral a-hydroxy aldehyde (second example). The diastereoselectivity can be reversed by addition of alkyllithiums to a-trityloxy aldehydes, presumably because chelation with the oxygen atom is no longer possible. 

Selective alkylation of ketonesThis reagent forms a complex so much more rapidly with aldehydes than with ketones that selective alkylation of a keto group in the presence of an aldehyde group with an alkyllithium or Grignard reagent is possible. The opposite chemoselectivity is achieved with the bulky methylaluminum bis(2,6-di-f-butyl-4-phenoxide) (MAD, 13, 203 this volume). 

Likewise, the sulfoxide-metal exchange reaction of /3-acetoxy sulfoxides 164 (/3-mesyloxy sulfoxides can also be used), which are prepared from alkenyl aryl sulfoxides 163 and aromatic aldehydes, with a Grignard or alkyllithium reagent at low temperatures gives the allenes 162 in good to excellent yield (Scheme 5.24) [65],... 

Among other enantioselective alkylations, a series of 3-aminopyrrolidine lithium amides (67 derived from 4-hydroxy-L-proline) have been used to induce high ee% in the addition of alkyllithiums to various aldehydes. Structure-activity relationships are identified, and the role of a second chiral centre (in the R group) in determining the stereochemistry of the product is discussed. 

Enantiomeric excesses of up to 76% have been obtained for alkyllithium-aldehyde condensations using 3-aminopyrrolidine lithium amides as chiral auxiliaries. Addition of organolithiums to imines has been achieved with up to 89% ee, in the presence of C2-symmetric bis(aziridine) ligands. ... 

The most important reactions of alkyl substituents a and y to the ring heteroatom are those which proceed via base-catalyzed deprotonation. Treatment of 2- and 4-alkyl heterocycles with strong bases such as sodamide and liquid ammonia, alkyllithiums, LDA, etc., results in an essentially quantitative deprotonation and formation of the corresponding carbanions. These then react normally with a wide range of electrophiles such as alkyl halides and tosylates, acyl halides, carbon dioxide, aldehydes, ketones, formal-dehyde/dimethylamine, etc., to give the expected condensation products. Typical examples of these transformations are shown in Scheme 17. Deprotonation of alkyl groups by the use of either aqueous or alcoholic bases can also be readily demonstrated by NMR spectroscopy, and while the amount of deprotonation under these conditions is normally very small, under the appropriate conditions condensations with electrophiles proceed normally (Scheme 18). 

The enantioselective addition of alkyllithium to aldehyde in the presence of the lithium salt of diaminoalcohol (94) yielded optically active secondary alcohols as shown in Table 2. 

Compared with aldehydes, ketones and esters are less reactive electrophiles in the addition of dialkylzincs. This makes it possible to perform a unique reaction that cannot be done with alkyllithium or Grignard reagents, which are too reactive nucleophiles. For example, Watanabe and Soai reported enantio- and chemoselective addition of dialkylzincs to ketoaldehydes and formylesters using chiral catalysts, affording enantiomerically enriched hydroxyketones 30 (equation 12)43 and hydroxyesters 31 in 91-96% , respectively (equation 13). The latter are readily transformed into chiral lactones 3244. 

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