Heterocycles lithiated, stability

The relative stability of lithiated thiopyrans seems to depend upon the heterocyclic ring substitution. Thus, a-lithiated 2,6-diphenyl-2//-thiopyran 16 rearranges into the y-lithiated derivative 17 (Scheme 5) (82JOC680), while the reverse transformation occurs on lithiation of 2,6-diphenyl-4-diethylphosphonylthiopyran (80JOC2453). 

Attempts to extend this process to the related 2-pyridone system have been less successful, with only a small proportion of C-6 lithiation being observed with l-methyl-2-pyridone [85CC1021 88JCS(P1)1]. In fact, the major mode of reaction involves lithiation of the exocyclic methyl group, to give a carbanionic species that is dipole-stabilized by the heterocyclic amide group (Scheme 120) (83MI1). 

Of course, epoxides can also undergo many modes of chemistry in which the heterocyclic ring remains intact. One such example is the addition of lithiated oxazolinyl epoxides (114) onto carbonyl compounds, providing a synthesis of trisubstituted oxiranes (116). In this case the oxazolinyl group not only confers stability to the lithiate, but also provides an opportunity to introduce chiral auxiliaries <01JOC3049>. 

Bromo- and iodo-heterocycles react rapidly with alkyllithiums, even at temperatures as low as -100°C, to give the lithio-heterocycle. Where alternative exchanges are possible, the site of reaction is governed by the stability of the anion formed, just as for direct lithiation by deprotonation. Exchange of fluorine is unknown and of chlorine, rare enough to assume that it is inert. 

This survey describes how the chemistry of lithiated oxygen heterocycles has been fruitfully exploited, particularly over the last 10 years, for the preparation of more (stereodefined) functionalized derivatives and products derived from them. Also, how they have contributed to natural product synthesis and molecules of relevant pharmaceutical interest. The genesis of the reactive lithiated intermediates (especially a- and orf/io-lithiated (hetero)arylepoxides, -oxetanes and -tetrahydrofurans) requires a careful choice of the experimental conditions in terms of solvents and temperature in order them to be successfully intercepted by electrophiles. The study of the aggregation and solvation of certain chiral functionalized lithiated oxygen heterocycles has provided further hints about the factors affecting their configurational stability and... 

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