Benzyllithiums configurational stability

The closely related a-(pyrid-2-ylthio)benzyllithium (257) has a higher configurational stability, and equilibration with the chiral ligand prior to the substitution step is required , indicating that a dynamic thermodynamic resolution is important (equation 61). Depending on the method of calculation, (7 )-257 255b was found to be by 1.42 to 1.92 kcalmoD ... 

Tertiary analogues 183 of 180 are also configurationally stable at -78 °C.80 182 can be deprotonated and kept for 8 h at -78 °C with little loss of enantiomeric purity. It is consequently possible to make either enantiomer of the protected amine 184 from the appropriate amine 182, of which both enantiomers are available by virtue of the invertive substitution reactions characteristic of tin electrophiles (see section 6.1.4).82 83 Tertiary O-substituted benzyllithiums also have high configurational stability (see above). 

Exceptions are the few secondary benzyllithiums which show configurational stability on the microscopic (but not macroscopic) timescale - in other words, they racemise slower than they react with electrophiles, though they still cannot be maintained in stereoisomerically pure form for periods of minutes or more. These are the carbamates 288 and the sulfones 289, discussed in sections 5.1.4 and 5.I.7.6 It is significant that both of these compound classes contain powerful lithium-coordinating oxygen atoms, which may hold the lithium counterion close to one face of the benzylic system.134-120... 

Three types of secondary benzyllithium are known which are configurationally stable on the macroscopic timescale, and they too each contain powerful lithium-coordinating oxygen atoms. One is the N-Boc amino substituted 180 discussed above.80 Partial configurational stability is evident in a close analogue of 180.81... 

Benzyl-type organolithium compoimds are stabilized by the mesomeric interaction of the negative charge of the carbanionic center with the aromatic n-system. The thermodynamic acidity of the benzylic compounds is 10 to 15 pK units higher than of the corresponding methyl derivatives [127]. Mesomeric stabilization requires a considerable flattening of the carbanionic center towards sp -hy-bridization [128]. As a consequence, the configurational stability is decreased, and - with few exceptions - most of the benzyllithium derivatives suffer from rapid racemization [Eq. (56)],see Sect. 3.2. 

Since carbohthiations usually proceed as syn additions, 458 is expected to be formed first. Due to the configurationally labile benzylic centre it epimerizes to the trani-substitu-ted chelate complex epi-45S. The substitution of epi-458 is assumed to occur with inversion at the benzylic centre. Sterically more demanding reagents (t-BuLi) or the well-stabilized benzyllithium do not add. The reaction works with the same efficiency when other complexing cinnamyl derivatives, such as ethers and primary, secondary, or tertiary amines, are used as substrates . A substoichiometric amount (5 mol%) of (—)-sparteine (11) serves equally well. The appropriate (Z)-cinnamyl derivatives give rise to ewf-459, since the opposite enantiotopic face of the double bond is attacked . 

Taking an example of a sulfur-stabilized benzyllithium compound, Hoffmann and coworkers performed two reactions of the racemic a-thio carbanion with a racemic or a chiral aldehyde [Eq. (3)] [17-19], and found that both reactions afford an identical diastereomeric ratio of the product. From these results, they have concluded that the sulfur-stabilized benzyllithium compound epimerizes faster than it reacts with the aldehyde, i.e., it is configurationally labile in THF at -78°C. 

All our calculations are in agreement with the results of dynamic C NMR studies by Fraenkel and co-workers. That group was able to show that the benzyllithium compound (R,5)-2 exists as a monomeric single diasteieomer in THF solution between -93 and +27 °C [5]. This again fits with the results of the trapping reactions at variable temperatures performed by Chan and our research group which prove a stability of configuration on at least the time scale of the reaction. 

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