Addition of carbon-based nucleophiles to cyclic six-membered oxocarbenium ions generally occurs via highly-selective axial attack. Selectivities are exceedingly high with nucleophiles such as allyltrimethyl silane and triethylsilane, but lower with stronger nucleophiles. Recent work suggests competing SN1 and SN2 reaction mechanisms can occur, but depend upon Lewis acid activator, and relative reactivities of the nucleophiles.  In order to probe stereoelectronic effects at the electrophilic carbon, we incorporated electron-donating and withdrawing moieties (e.g., R1 = Me, Et, Pr, Bu, trifluoromethyl, 4-trifluoro-methylphenyl-, etc.) into the cyclization precursors. Nucleophilic reagents such as enol ethers were also synthesized with trifluoromethyl moieties adjacent to the nucleophilic double bond.  Although overall selectivities were excellent for axial attack using alkyl-substituted ketone starting materials,  trifluoromethyl ketone reactants decompose under the reaction conditions, indicating that the strongly electron-withdrawing group prevents oxocarbenium ion formation. 

Cyclization-addition reactions toward trisubstituted tetrahydropyrans: Effects of substitution on electrophilic substrate and nucleophile

244th National Meeting (2012)

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