Toward Customized Tetrahydropyran Derivatives through Regioselective α-Lithiation and Functionalization of 2-Phenyltetrahydropyran

In this contribution, the first direct and efficient functionalization of the preformed 2-phenyltetrahydropyran (2-PhTHP) nucleus by electrophilic interception of the corresponding α-lithiated derivative by employing sBuLi as the base and THF as the solvent at –78 °C was explored. The presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) proved to be critical to governing reaction feasibility both in polar and apolar solvents and for improving the yield of the reaction. Both carbon- and heteroatom-based halides were found to be competent electrophiles for this transformation, as well as aliphatic and aromatic aldehydes and ketones, isocyanates, and carboxylic acid derivatives. The combination of hexane/TMEDA lowered the rate of racemization of α-lithiated optically active 2-PhTHP, which thereby enabled calculation of its barrier to inversion at –78 °C.