Benzyllithium alkylation

Organolithium reagents in which the carbanion is delocalized are more useful than alkyllithium reagents in alkylation reactions. Allyllithium and benzyllithium reagents can be alkylated and with secondary alkyl bromides and a high degree of inversion of configuration is observed.78... 

Volume 8a of the Science of Synthesis series has reviewed the synthesis and applications in organic synthesis of the following organolithium compounds alkyl- and cycloalkyl-lithium,49 alkenyllithium,50 allyllithium,51 benzyllithium and (lithiomethyl) hetarenes,52 /-i-liihiocarboxylic acids and related compounds,53 and bis(organosulfan-yl)- and bis(organoselanyl)-methyllithium compounds.54... 

The high yyw-selectivity seems to be independent of the stereochemistry of the starting material, since the use of 39Z also resulted in the preferential formation of the svn-isomer in a similar ratio. To explain this, the authors proposed 5-membered cyclic benzyllithium species having a. sy 2-like carbon to which two lithium atoms coordinate from both upper and lower sites as shown in 43 (Scheme 18). Such a dilithiated species would selectively react with electrophiles from the opposite site of the O—Li substituent. Another intermediate, 44, in which the benzylic lithium is coordinated with the heteroatom, may also be considered53. Both intermediates are likely, since in each of them the steric hindrance between the phenyl group and the alkyl group is minimal. Assuming that the reaction with... 

The effect of a 3-substituent on the orientation of the addition of alkyl- and aryl-lithium compounds is interesting and salient results appear in Table 23. Attack at C-2 is favoured over that at C-6 unless either, or both, the C-3 substituent and the attacking alkyl group are very large. Reaction of isopropyllithium with 3-methylpyridine does not follow this trend. Benzyllithium is anomalous in that it attacks preferentially at C-4. A study of the relative rates of these alkylations revealed the remarkable fact that a 3-methyl or 3-ethyl group activates the 2-position (but not the 6-) towards attack by phenyllithium but not methyllithium. However, a 3-isopropyl and 3-cyclohexyl group deactivates C-2 relative to... 

Fig. 13. The reaction of 1,1-diphenylethylene with various lithium compounds in tetrahydrofuran. Variation of rate with formal concentration of lithium alkyl or aryl. (A) n-Butyllithium ( ) benzyllithium (- ) allyllithium (o) methyllithium ( ) vinyl-lithium (0) phenyllithium. Solvent tetrahydrofuran [101].

The halogen-metal exchange of secondary alkyl iodides leads mainly to hydrocarbons containing Wurtz-type coupling or elimination products [44], except in the case of benzyllithium derivatives which are easily generated from benzyl selenides [45]. 

The preparation of benzyllithium from benzyl halides and alkyllithiums is not feasible because the benzyllithium initially formed reacts with the starting benzyl halides, producing 1,2-diphenylethane. Metalation of toluene with n-BuLi in the presence of TMEDA at 30 °C results in a 92 8 ratio of benzyllithium and ring metalated products. Metalation of toluene with n-BuLi in the presence of potassium rert-butoxide, and treatment of the resultant organopotassium compound with lithium bromide, affords pure benzyllithium in 89% yield. Alternatively, benzyllithiums are accessible by cleavage of alkyl benzyl ethers with lithium metal. " ... 

Benzyl phenyl sulfides can be sequentially metallated and alkylated. The cleavage of the carbon-sulfur bond in the resulting product leads to a benzyllithium and lithium phenylthiolate. Alkylation of the former organometallic then produces an alkylbenzene (Scheme 15), but competing alkylation on the thiolate is however observed. 

Di(phenylthio)methyllithium and di(phenylthio)benzyllithium, which are synthesized from the corresponding carbon acids and /i-butyllithium in THF, have been monoalkylated with primary but not with secondary alkyl halides. Higher homologs have not found widespread use because of the difficulties encountered in their alkylation. " The successful alkylation of such compounds has been achieved by carrying out the reactions in TMEDA (1 equiv.) in hydrocarbons (Scheme 55, entry c). Even the presence of THF with TMEDA almost completely suppresses the alkylation. However, double... 

The stereochemistry of the reaction products is dependent on the nature of the a-sulfinyl carbanion. Thus (i) its kinetic acidity, controls the stereochemistry of the organometallics initially formed (ii) its thermodynamic acidity defines the stereochemistry or the conformation of the intermediate organometal-lic and (iii) reactivity of the organometallic towards the electrophile controls the stereochemistry of the product. The alkylation reaction has proved to be far more selective than is the metallation. Therefore the contribution of kinetic acidity can be neglected because the carbanion in THF has sufficient time to reorganize into its most stable conformation before it reacts with an electrophile. The a-sulfinyl benzyllithiums produced from S(srd) and S(r -(2) should adopt the more stable conformations shown in... 

The metalation of tetramethylsilane is another dramatic example of the effect of chelation on reactivity since both n-BuLi and sec-BuLi are nearly inert under the same conditions. Chelated sec-BuLi is the most reactive soluble metalating agent we have found. TMED Li-sec-Bu reacts with tetramethylsilane about 1000 times faster than TMED Li-n-Bu and yields purer product (47). Broaddus (48, 49) has discussed kinetic metalation of olefins and alkyl aromatic compounds using TMED LiBu, and he also observed the slow equilibration to the thermodynamically favored isomers. The extent of ring metalation in toluene and the conditions for isomerization to benzyllithium are discussed in Chapter 2, Smith. 

Compound 20 (X = Cl) reacts with alkyllithiums with complete retention, in contrast to the inversion observed with R3Si-Cl allyllithium or benzyllithium and alkyl Grignard reagents also cleave the Si-F bond of 20 (X = F) with retention rather than inversion as observed with 1-NpPhMeSi-F. 

It is not surprising that there are wide variations in the comparative reactivities of Li alkyls depending upon the differences in aggregation and ion-pair interactions. An example is benzyllithium, which is monomeric in tetrahydrofuran and reacts with a given substrate more than 104 times as fast as the tetrameric methyllithium.31 The monomeric TMED complexes... 

Some ethers react with metallic lithium in the same way as alkyl and aryl halides e.g., benzyllithium is obtained in good yield from alkyl benzyl ethers in tetrahydrofuran.49... 

Lithium alkyls in ether or benzene show a mean degree of association of from three to seven, whereas phenyl- and benzyllithium are dimeric in ether (17, 135). The lower degree of association in ether may stem from etherate formation. The structure of these auto-complexes may be analogous to that of beryllium and aluminum alkyls, or perhaps a lithium atom acts as a Lewis acid that is, Li [Li(C6H6)2]e. Wittig (135) favors this formulation over a phenyl bridging scheme. 

In our synthetic investigations we have noticed considerable differences in reactivity of the various types of polar organometallic intermediates towards alkyl halides and epoxides. Exceptionally high alkylation rates were observed in reactions of benzyllithium (or potassium) and allyllithiums (or potassium) with primary alkyl bromides in mixtures of THF and hexane. Under preparative conditions (concentration of reagents 0.5 to 0.8 mol/liter) the characteristic orange colour of benzylalkali solutions disappeared completely within a few seconds upon addition at — 90 °C of a slight excess of alkyl bromide. The allylic intermediates reacted with comparable ease. 

Homoleptic tetrabenzyl complexes are prepared by reaction between ThCU and benzyllithium in THF solution at low temperature (equation 53). It is unlikely that these complexes are -alkyls, since the X-ray structure of Cp Th(CH2Ph)3 revealed multihapto coordination of the benzyl ligand. 

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