Stereodivergent Quaternization of 2‐Alkyl‐2‐p‐tolylsulfinylacetonitriles: NMR Spectroscopic Evidence of Planar and Pyramidal Benzylic Carbanions

Abstract

Enantiomerically enriched alpha,alpha-disubstituted phenylacetonitriles have been readily prepared by stereoselective quaternization of 2-alkyl-2-[2-(p-tolylsulfinyl)phenyl]acetonitriles with different alkylating electrophiles in the presence of bases. The use of potassium hexamethyldisilazane (KHMDS)/[18]crown-6 ether and NHMDS with alkyl halides afforded S,S(S) and R,S(S) diastereoisomers, respectively, in high enantiomeric purities, thus providing stereodivergent processes for synthesizing both isomers. The dependence of the stereochemical course of the reactions on the experimental conditions (mainly on the counterion) has been rationalized by assuming a planar or pyramidal structure for the benzylic carbanions. This hypothesis has been supported by NMR spectroscopic studies, which permit one to assign a chelated pyramidal structure to the sodium benzylic carbanions and an almost planar naked carbanionic structure to the potassium benzylic carbanions generated in the presence of [18]crown-6 ether.

Modular, Catalytic Enantioselective Construction of Quaternary Carbon Stereocenters by Sequential Cross-Coupling Reactions

“…The absolute configuration of the enantiomers of 32 was established by ozonolysis and oxidation (Jones reagent) to the derived carboxylic acid followed by comparison of optical rotation to that for the known compound. 16 …”

Stereodivergent routes in organic synthesis: marine natural products, lactones, other natural products, heterocycles and unnatural compounds

“…2-Alkyl-2-p-tolylsulfinylacetonitriles were diastereodivergently alkylated using different reaction conditions by García Ruano, Martín-Castro and coworkers. 138 Using NHMDS as base, the alkylation of the resulting carbanion gave mainly one diastereomer, whereas with KHDMS and 18-crown-6 ether opposite alkylation occurred (Scheme 93). This reversal diastereoselectivity in the quaternization process was explained by formation of carbanions I and II, a chelated pyramidal structure for the sodium of the benzylic carbanion and an almost planar naked carbanionic structure for the potassium benzylic carbanion in the presence of 18-crown-6 ether, respectively.…”

Stereocontrolled Addition of Scrambling ortho-Sulfinyl Carbanions: Easy Access to Homopropargylamines and α-Allenylamines

“…Interestingly, the use of HMPA afforded 3a , along with the corresponding allene, as a major product for the first time (Table , entry 5). This result suggested an important contribution from a plausible association between the base and the recently generated carbanion, favoring the generation of one product over another. Subsequently, we decided to change the configuration of the aldimine to the corresponding ( R )-2a , rendering 4a with high diastereoselectivity when LHMDS or KHMDS were used (Table , entries 7 and 8), while no conversion with LDA was observed (Table , entry 6).…”

“…In a different context, the use of optically active sulfoxides as chiral auxiliaries has been exploited over the last decades; this exploitation is due to their great stability and high stereocontrol in several synthetic transformations. Over the last years, our group has highlighted the peculiar behavior of the ortho -sulfinyl carbanions generated by the use of bases, such as LDA or diverse MHMDS, toward the stereocontrolled generation of new C–C single bonds between sterically hindered nucleophile–electrophile pairs . Taking this information into account, we considered the possibility of taking advantage of the delicate equilibrium of ortho -sulfinyl propargyl carbanions, designing a chemodivergent procedure based on a remotely controlled activation, to selectively achieve the γ-functionalization (Scheme , pathway A, top) or the ε-functionalization (Scheme , pathway B, bottom) of the described benzyl-propargyl scaffolds in the presence of the same electrophile.…”

“…We started our studies with the optimization of the addition of alkyne 1 to aldimines 2 . In previous reports, we have established the use of LDA as an efficient deprotonating reagent, triggering the formation of the corresponding benzyl carbanion. Therefore, we performed the reaction of 1 in front of aldimine ( S )-2a , observing the formation of 3a as the only product with an extraordinary diastereomeric ratio (Table , entry 1).…”