Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes

Abstract

Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C 2v point group with six faces�two triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, Ag I -catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.

Silver(I)-Catalyzed Synthesis of Cuneanes from Cubanes and their Investigation as Isosteres

“…This investigation began with a survey of reaction conditions for the rearrangement of cubane 1,4-dimethyl ester 1a to 2,6-disubstituted cuneane 2a (Table ). Consistent with results reported in the literature, ,,,, we found silver salts to be effective in promoting this reaction. In most cases, none of the alternative 1,3-disubstituted cuneane 3a was detected in these reactions.…”

“…From a brief examination of silver­(I) salts and solvents, the use of AgNTf 2 (10 mol %) in CH 2 Cl 2 at room temperature was identified as being effective in giving 1,3-disubstituted cuneanes in generally good yields and high regioselectivities, despite the same combination giving poor regioselectivity in the rearrangement of cubane 1a at 50 °C (Table , entry 10). These results are of significance because there were no prior examples of the selective synthesis of 1,3-disubstituted cuneanes containing two different substituents. , …”

“…Next, we examined the silver­(I)-catalyzed rearrangements of 1,4-disubstituted cubanes containing only one electron-withdrawing group (Scheme ). When we initiated this study, rearrangements of this class of cubane to cuneanes had not been described, and it was therefore of interest to determine the efficiency and regiochemical outcomes of these reactions. , We found that these reactions occur much more readily than the reactions shown in Scheme and give 1,3-disubstituted cuneanes as the major products, rather than 2,6-disubstituted cuneanes . From a brief examination of silver­(I) salts and solvents, the use of AgNTf 2 (10 mol %) in CH 2 Cl 2 at room temperature was identified as being effective in giving 1,3-disubstituted cuneanes in generally good yields and high regioselectivities, despite the same combination giving poor regioselectivity in the rearrangement of cubane 1a at 50 °C (Table , entry 10).…”

“…Cuneanes are interesting caged hydrocarbons that have been largely overlooked. − First described by Cassar, Halpern, and Eaton in 1970, cuneanes are prepared by the σ bond rearrangement of cubanes, catalyzed by Ag­(I), ,,,, Pd­(II), , Li­(I), or Au­(I) (Figure C). The aqueous media-induced rearrangement of cubane-1,4-dicarboxylic acid to cuneane-2,6-dicarboxylic acid has also been reported…”

“…The regioselectivity of the rearrangement is strongly dependent on the electronic character of the cubane substituents. Potential applications of cuneanes as isosteres in medicinal chemistry are suggested and the synthesis of a cuneane analogue of the anticancer drug sonidegib was achieved …”