Methyl on the Bridge: 2-Methyl Propellane as Precursor for 1,3-Substituted 2-Methylated Bicyclo[1.1.1]Pentanes

Bicyclo[1.1.1]pentanes (BCPs) have emerged as isosteric replacements for mono- and para-substituted benzene rings in medicinal and materials applications, involving substitution at the BCP bridgehead (1,3-positions). BCP functionalization at the 2-position is much less straightforward and currently under intense investigation. Herein, we report a synthetic route to 2-methyl BCPs allowing for functionalization at the 1,3-positions, with the novel 2-methyl[1.1.1]propellane as a key intermediate. Next to an optimization for the synthesis of 2-Me-propellane, this work contains an investigation of its reactivity leading to 1,2-disubstituted and 1,2,3-trisubstituted BCP derivatives. Compared to nonsubstituted propellane, the synthesis of 2-methyl propellane was lower-yielding, and its ring-opening reactions proceeded in similar or lower yields, with radical-based reactions generally giving the best results. A preliminary study of selected physicochemical properties was conducted to assess the impact of the introduction of a bridge-methyl group, showing an expected increase of about 0.5 logP units and featuring lower melting points.