Cubane Electrochemistry: Direct Conversion of Cubane Carboxylic Acids to Alkoxy Cubanes Using the Hofer–Moest Reaction under Flow Conditions

Abstract

The highly strained cubane system is of great interest as a scaffold and rigid linker in both pharmaceutical and materials chemistry. The first electrochemical functionalisation of cubane by oxidative decarboxylative ether formation (Hofer–Moest reaction) was demonstrated. The mild conditions are compatible with the presence of other oxidisable functional groups, and the use of flow electrochemical conditions allows straightforward upscaling.

Development and Assembly of a Flow Cell for Single‐Pass Continuous Electroorganic Synthesis Using Laser‐Cut Components

“…[7] This mode of operation significantly simplifies the technical requirements of the setup, as a three-electrode electrochemical cell or a potentiostat are not required (an inexpensive adjustable power supply can be employed instead). [17] Moreover, the reaction selectivity can still be optimized by tuning the current density at the electrodes.…”

“…[16] These types of electrode materials (Pt and C) have also been previously utilized for Hofer-Moest reactions in continuous flow mode. [17] In our investigation, graphite was selected as the anode material and stainless steel as the cathode. Preliminary batch experiments showed that these materials perform well in the presence of a catalytic amount of NaOMe as the base for the electrolysis of 1.…”

Synthetic Advances in the C–H Activation of Rigid Scaffold Molecules

“…Along the same line, the electrochemical functionalization of 4-substituted cubane-1-carboxylic acids 33, 34, and 67 was reported. 62 The electrolysis of 4-substituted cubane-1-carboxylic acids 33, 34, and 67 initially formed the radical, which was oxidized further to yield the carbocation. The resultant carbocation reacted with nucleophiles (alcohols) to afford cubane derivatives.…”

“…The anodic oxidation of 4-(methoxycarbonyl)cubane-1-carboxylic acid (67) using a C/PVDF anode (200 mA, 0.5 mL/min) in the presence of methanol and Et 3 N yielded methyl 4-methoxycubane-1-carboxylate. 62 N. Grover, M. O. Senge…”

Taking electrodecarboxylative etherification beyond Hofer–Moest using a radical C–O coupling strategy

“…Further anodic oxidation of these intermediates results in highly reactive carbocations, which are prone to rearrangement, elimination or coupling with any nucleophile in their proximity 47,48 . High selectivity can only be achieved if the radical and the positive charge are stabilised by electron-donating substituents 49,50 , resonance 51,52 or conjugation with α-O 53,54 , α-N 55,56 or α-S substituents 57 . Still, the O-nucleophile is often added in large excess.…”