Intramolecular carbolithiation reactions heterocycles

Although the synthesis of dihydrobenzofuran derivatives seems to be not possible by this anionic cyclization methodology, there are some particular examples in which these heterocycles are prepared by an intramolecular carbolithiation reaction. In this respect Baldwin and coworkers described in 1980 the preparation of 350 by rearrangement of 349 when it was treated with BuLi in THF/TMEDA (Scheme 91)151. The most likely explanation starts with an orf/zo-lithiation giving a dilithium intermediate, which undergoes an intramolecular 5-exo carbolithiation reaction affording a 3-lithiomethyldihydrobenzofuran... 

An intramolecular carbometallation of a carbon-carbon triple bond generally leads to a five-membered carbo- or heterocycle possessing an exocyclic carbon-carbon double bond. The selectivity of this transformation has been reviewed thoroughly in the previous edition of this book and in several comprehensive reviews [3b, 59,122). In the past decade, intramolecular carbolithiation reactions have been studied both experimentally and computationally. For example, Maddaluno et al. [123] examined... 

Carbon—carbon bond formation by an intramolecular carbolithiation (anionic cycliza-tion) reaction to give heterocyclic systems has been gaining increasing use in organic... 

On the other hand, alkenyl aryllithiums can undergo diastereoselective cyclizations in very good yields. Pedrosa and coworkers163 reported that chiral 2-(o-bromophenyl)-substitutedperhydro-l,3-benzooxazines 281, initially transformed to the aryllithium derivative, gave the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of the heterocycle (Scheme 87). By adding 2 equivalents of TMEDA to the aryllithium derivative 1,3-benzooxazines 281 prepared at —90 °C,... 

DFT computations showed that the intramolecular addition of the aryllithium generated from 425 occurs on the central carbon atom of the allenic moiety to yield the intermediate 427 from which lithium ethoxide is eliminated to furnish the benzofuran product 426. Both cyclization processes were found to pass through low-lying transition states, as it would be expected for fast reactions at low temperatures [123]. Further explorations on the anti selectivity in the intramolecular carbolithi-ation by DFT computations revealed additional details regarding the mechanism of this carbocyclization and led the authors to conclude that such a transformation is controlled by the appropriate molecular editing [123]. The synthesis of functionalized heterocycles can be relatively easy to achieve by intramolecular carbometallation reactions. For example, Kunz and Knochel [124] recently reported the preparation of benzothiophene scaffolds 429 by copper-catalyzed carbomagnesiation ofalkynyl thioethers 428 (Scheme 10.148). 

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