Cyclization by Intramolecular Carbolithiation of Alkyl- and Vinyllithiums Prepared by the Action of Aromatic Radical Anions on Phenyl Thioethers. High Stereoselectivity in the Cyclization Accelerated by an Allylic Lithium Oxyanion¹

Abstract

The reductive lithiation of alkyl and vinyl phenyl thioethers by aromatic radical anions is shown to be the most general method yet known for preparing organolithiums capable of intramolecular carbometalation of unactivated alkenes to produce five-membered rings and in one case a four-membered ring (in a far higher yield than known cases). The relative rates of cyclization for alkyllithiums are secondary > tertiary > primary, and the yields are very high. In the secondary case, the stereoselectivity is extremely high, producing a cyclopentylmethyllithium with a trans-2-alkyl substituent. A remarkable finding is that for all of the organolithiums a lithium oxyanionic group in the proximal allylic position to the alkene greatly accelerates the cyclization and leads almost exclusively to a trans relationship between the CH(2)Li group and the OLi group, the opposite relationship from that observed in intramolecular carbolithiations by allyllithiums. A mechanistic rationale for this divergence is discussed. One of the two types of proximal homoallylic lithium oxyanions exerts an analogous effect. An intriguing limitation, even occurring with the highly reactive secondary organolithium and in the presence of an allylic oxyanionic group, is the failure of intramolecular carbolithiation when a methyl group is at the terminus of the alkene.

Advances in Carbolithiation

“…However, it should be noted that this model was found not to be accurate enough to predict the stereochemical outcome for the cyclization of secondary unsaturated organolithium species 62, easily generated by reductive lithiation of the sulfide 61 (Scheme 11.17). Indeed, the major isomer of the carboxylic acid 64 isolated in good yield after trapping the intermediate 63 with CO 2 was almost exclusively trans (trans/cis > 40 : 1) [43]. The proposed transition states for this cyclization have been studied computationally [44].…”

“…The proposed transition states for this cyclization have been studied computationally [44]. Reductive lithiation followed by intramolecular carbolithiation of oligosubstituted (phenylsulfanyl)alkenes analogous to the one discussed previously was applied to the synthesis of substituted cyclopentanols and cyclobutanols [43,45].…”

Carbometallation Reactions

“…The stereochemistry of the cyclization step was confirmed by transformation of 156a to the known ester 156b. This cyclization was found to furnish almost exclusively the trans diastereomer (trans/cis, >40 : 1) [43]. Proposed transition states for this cyclization were studied by computational methods [44].…”

“…The observed stereoselectivities of the intramolecular additions of a carbon-lithium bond across a nonactivated double bond most likely occurs through a transition state that resembles a chair conformation of cyclohexane in which any substituents prefer to occupy pseudoequatorial positions (Scheme 10.50) [42], and this was confirmed computationally for the transition state in the cyclization of 150 and the intermediate 151. However, this model does not predict the correct stereochemical outcome for the cyclization of the secondary unsaturated organolithium species 154 generated by reductive lithiation of the sulfide 153 (Scheme 10.51) [43].…”

“…Under the optimized conditions, product 181 was isolated as a 30 : 1 : 0 mixture of diastereomers, and the major diastereomer was determined to be trans,cis-181 by nOe experiments. Considering the models previously proposed for the carbolithiation step [43,45], the authors could rationalize the stereochemical outcome of this reaction [49]. The optimized conditions for the sequential aminolithiation/carbolithiation cyclization were applied to the synthesis of several other allyl-and homoallylaminoalkenes (Scheme 10.60).…”