Benzylic lithiation

Tellurium-catalysed decomposition of a-lithiated benzylic sulphones into 1,2-diarylethylenes... 

Enantiomerically pure a-lithiated ethers have been prepared from stannanes and turned out to react with electrophiles under retention. The configurational stability of the hthium carbenoid 19 has been deduced from equation 10 . Lithiated benzyl methyl ether, chelated by a chiral bis(oxazoline) ligand, proved itself to be configurationally stable as welP . ... 

Epoxide 6 is attacked nucleophilically by the lithiated benzyl ether. 

The lithiated benzylic ether prepared from 79 is a carbon nucleophile. Under boron trifluoride catalysis10 it attacks diepoxide 6. In the process, the alkyl lithium reagent adds in a stepwise fashion to diepoxide 6, whereby the first addition is significantly more rapid than the second.7 One thus obtains only the monoadduct 24... 

The stereochemical course in addition of lithiated benzyl cyanide and propioni-trile to aromatic Schiff bases has been investigated and the origin of the stereochemical results has been discussed.44 A carbanionic intermediate with an adjacent (g stereogenic centre, formed as a result of fast isomerization of the initially formed azanions, has been proved to be involved in the formation of the stereochemical ratios. 

We suggest that the structure of lithiated 48, as shown by structure 48a (only the monomeric species is considered) in Scheme 2, may be similar to that of lithiated benzyl phenyl sulfone.53 One would expect the benzylic carbon of 48a to be close to planar and the phenyl substituent to be anti to the bulky Wfert-butyldiphenylsilyl moiety. The nonbonding orbital at the benzylic carbon would be approximately coplanar with the S-CH3 a bond as a result of a stabilizing nc-a s-c interaction. Electrophilic attack on 48a should occur from the less hindered diastereoface, i.e., anti to the S-CH3. An open transition state 53 in which R of the aldehyde and the phenyl substituent of 48a are anti is consistent with the stereochemical outcome. 

Denmark and coworkers [354] have examined the alkylation of a-lithiated benzyl carbanions generated from diastereoisomeric chiral phosphonamides 1.96 and 5.10. The stereoselectivity of this process depends on the configuration at phosphorus, and it is alway higher when starting from 1.96. It is believed that planar benzylic anions are alkylated on their least sterically hindered face. Strong support for this rationale derives from the X-ray crystal structure of A. After hydrolysis and treatment of the products with diazomethane, (R)- or (S)-dimethyl phosphonates can be obtained (Figure 5.6). Hanessian and coworkers [311, 312] performed similar alkylations of phosphonamides 1.74 (Y = Me, Cl) derived from (RJR)- or ( ,.S)-trans-cyclohexanediamines bearing a C2 axis of symmetry. The reaction of the intermediate anionic species on its less hindered face, followed by... 

The intermediates obtained react in the usual way with various electrophiles to give the expected derivatives in excellent yields. The hydroxyalkylation of lithiated benzyl trimethylsilane is immediately followed by a Peterson-elimination of Me3SiOLi to give the olefin. 

The first a-oxybenzyllithium compound, which offered these problems, was the lithiated benzyl carbamate 244 (Fig. 4), but it could not be tuned to useful selectivities [64,149]. 

Toru and coworkers have reported a highly enantioselective reaction of a-lithiated benzyl phenyl sulfide with various electrophiles [41,42], in which the most efficient chiral Hgand was a bis(oxazohne). High enantioselectivities were obtained in the reaction with various carbonyl compounds, although the reaction with alkyl haUdes and carbon dioxide showed somewhat lower enantioselectivity (Table 1). Cumene was the best solvent giving the highest ee, whereas toluene slightly lowered the enantioselectivity. 

Table 1. Enantioselective reaction of a-lithiated benzyl phenyl sulfide 1) n-BuLi...

M,M-dibenzylamino)-3-phenylpropanal, TMEDA or the enantiopure bis(oxa-zoline), confirmed a dynamic kinetic resolution pathway for this reaction. Ab initio calculations showed that the C-Li bond prefers the conformation antiperi-planar to the S-Cjpj bond [42] due to the n-o negative hyperconjugation of a-lithiated benzyl phenyl sulfide, as described in Sect. 1.3 (Fig. 13). Thus, this enantioselective reaction was assumed to proceed through a four-membered cyclic transition state stabilized by the negative hyperconjugation. 

Fig.13. Calculation of relative stability of conformers of a-lithiated benzyl phenyl sulfide-TMEDA complexes...

When the substituent of the benzyl sulfide was changed from the phenyl to a pyridyl group, a drastic change in reaction features was observed. -BuLi abstracts the proton without a ligand. Furthermore, the enantioselective reaction of a-lithiated benzyl 2-pyridyl sulfide with electrophiles gives the products with reversed stereochemistry to that obtained in the reaction of the a-lithiated benzyl phenyl sulfide (Table 2). 

The reaction of a-lithiated benzyl 2-pyridyl sulfide was proved to proceed through a dynamic thermodynamic resolution pathway by the experiments us-... 

Fig. 14. Stability of a-lithiated benzyl 2-pyrldyl sulfide-bls(oxazollne) complexes...

The Sg2 reaction on the 5p -like hybridized carbanion tends to proceed with inversion of the stereochemistry [45]. It is reasonable that a-thio carbanions, having higher s character than a-oxy carbanions, more frequently invert the stereochemistry on the anionic carbon in the reaction with electrophiles. As in the case of a-lithiated benzyl 2-pyridyl sulfide, the reaction of a-lithiated benzyl 2-quinolyl sulfide also proceeds through a dynamic thermodynamic resolution pathway. The quinolyl group is an excellent protecting group of thiols [46] and can be removed to yield the corresponding chiral thiols without racemization (Tables) [47]. 

The literature reveals that both retention and inversion of the configuration have been observed for the reactions of lithiated benzylic and related systems with various electrophiles.[14] hi most cases no solid-state structure of the corresponding lithium alkyl could be determined to confirm the absolute configuration of the stereogenic metalated carbon center. The stereochemical course of the reaction of our lithium alkyl with the electrophile iodomethane in toluene can be understood on the basis of the solid-state structure of compound (R,S)-2, which was crystallized from the same solvent as was used in the substitution reaction with the alkyl iodide, in combination with computational studies. 

Oxetane (trimethylene oxide) reacts with aryllithiums, with 1-naphthyl-methylpotassium and with a-lithiated benzyl isocyanideJ" Yields exceeding 80% can be achieved. 

The first stereoselective application of the NOP reaction is described in Scheme 6 (16,34). (l/, 2/ )-NH-Cbz trifluoronorephedrine 26 was synthesized with high stereocontrol starting from lithiated (/ -benzyl p-tolyl sulfoxide 24, used as chiral a-... 

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