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.

TLC was performed on aluminium-precoated plates coated with silica gel 60 with an F254 indicator; visualised under UV light (254 nm) and/or by staining with cerium ammonium molybdate (CAM). Flash column chromatography was performed with Sigma Aldrich 60 silica gel (40-63 micron).
Fourier-transform infrared (FT-IR) spectra are reported in wavenumbers (cm -1 ) and were recorded using a diamond ATR accessory, as solids or neat liquids. Separations were carried out using He as carrier gas with a flow rate of 2.48 mL min -1 through the column. A split injection was conducted using a split ratio of 100:1. The injection and detector temperatures were maintained at 280 and 295 °C, respectively. The oven temperature was initially held at 60 ºC and then programmed to increase at 10 ºC min -1 to 250 °C, where it was held for 2 min. The GC was calibrated using a range of solutions of known concentration of both the starting material and the product.    Ammonite cell assembled:

Optimisation of the reaction parameters for cubane decarboxylation
For the analysis of the crude mixtures, quantification by 1 H NMR was not possible as many of the protons of the formed cubane-type products overlap with each other. Therefore, the reaction conditions were studied by using calibrated GC with the starting material 1 and methyl 4-methoxy-1-cubanecarboxylate (7). Due to inadequate separation of methyl 4-methyl-1-cubanecarboxylate (9) and methyl 1-cubanecarboxylate (10), and the small amount of byproducts collected as a mixture, the GC was only calibrated using methyl 4-methoxy-1cubanecarboxylate (7). All optimisation reactions analysed by GC were carried out on 0.25 mmol scale. if necessary depending on the general procedure used, AcOH (15 µL, 0.25 mmol, 1 equiv.) were added to methanol to make up 2.5 mL total volume. This sample was pumped into the reactor using the specified conditions (flow rate and current), and collected in a 5 mL volumetric flask (dilution to C = 0.05 M). Once all the solution had passed through the reactor, pure methanol was passed through the reactor and collected in the same 5 mL volumetric flask until the total sample volume was 5 mL. Samples were analysed by calibrated GC to determine the corresponding yields. NOTE: GC yields reported are for the entire sample rather than steady state. Moreover, due to gas formation during the reaction (cathode: H 2 and anode: CO 2 ), the flow rate was not constant during electrolyses, and therefore, residence time changes during the course of the experiment.

GC Area Ratio
The following table shows the area ratio of byproducts compared to the main compound 7 under the optimised conditions using Pt and C/PVDF electrodes (see GC chromatogram above). The ratios were similar for other conditions screened.

3.3
A qualitative solubility study has been carried out in order to find homogenous conditions for the reaction.
General conditions: Concentration of starting material 1, c = 0.1 M, 0.5 equivalent of base.  Screening conditions using Platinum anode 3.4 When DBU and KOH were used, a large amount of solid deposit was observed on the working electrode. Potassium hydroxide is not soluble in other alcohols, which makes this base unsuitable for a wider scope of substrates.    Screening conditions with Carbon/PVDF anode 3.5 Base screening 3.5.1  Electrode stability in fluorinated solvents (Figure S12) 3.

5.3
The C/PVDF electrode was found to be incompatible with fluorinated solvents, as shown in Figure S12. Erosion of graphite has been previously reported in the literature when using fluorinated solvents such as HFIP or TFE.

Flow Setup Calculation for the current needed in the flow cell (I theo ) and charge applied (F) 4.1
The theoretical current (I theo ) needed for in a flow electrochemical process can be calculated using the following equation: Faraday's law applied to flow conditions: • n = number of electrons involved in the electrochemical process The current efficiency (CE) of the electrochemical process can be calculated using the following equation:

Platinum electrode 4.2
The Hofer-Moest reaction is to a 2-electron oxidation process (n = 2). The optimised conditions using a Pt electrode were identified as: Flow rate = 0.2 mL min -1 = 0.00333 mL s -1 Therefore, with the equation shown above, the theoretical current (I theo ) for this transformation can be calculated: But the applied cell current (I cell ) is 0.2 A, which means that a 3.1 fold excess of current is used. This is the stoichiometry of current required, and is represented by "a":

F (in Coulombs) is the charge applied to the electrochemical reaction with a Pt electrode"
Similarly, for the C/PVDF electrode: The current efficiency (CE) of the electrochemical process for a batch-type reaction can be calculated using: The Hofer-Moest reaction is to a 2-electron oxidation process (n = 2).
-Surface area: The surface area of the batch electrode used was 1.8 cm 2 .
-Current density: The cell averaged current density used was the same as for the reaction in the But the reaction required 180 min (10800 s) to achieve >95% conversion of starting material, which means that a 2 fold excess of current was used. This is the stoichiometry of current needed, and is represented by "a":

Experimental procedure (batch electrolysis):
The acid 1 (103 mg, 0.500 mmol) and Et 3 N (35 µL, 0.25 mmol) were dissolved in MeOH (5 mL) in a vial (see Figure S13). A C/PVDF anode and a stainless steel cathode (12 mm wide) were submerged in the solution, having a working surface of 1.8 cm 2 . The solution was stirred and a constant current of 18 mA was applied. An aliquot was analysed by GC after 2 F of charge was passed (90 min), and the amount of product 7 was estimated to be 25% (50% starting material 1 remaining). The electrolysis was continued for another 90 minutes (4.0 F in total), and analysed by GC. The amount of compound 7 was estimated to be 50% (GC yield) with full consumption of starting material. This is comparable to the GC yield obtained using the flow reactor conditions.

Cyclic Voltammetry
Cyclic voltammetry was carried out in a three electrode, two-compartment cell with a vitreous carbon disc (diameter 3 mm) working electrode, a Pt wire counter electrode and an aqueous SCE reference electrode mounted in a Luggin capillary. An Autolab PGStat204 potentiostat with Nova 1.9 software was used and responses were analysed using Nova 1.9 software. Potential scan rate 25 mV s -1 .  Potential scan rate 25 mV s -1 . Potential scan rate 25 mV s -1 .
If an oxidation or reduction is diffusion controlled, the peak heights between experiments should change by a factor equal to the square root of the change in scan rate. e.g. Going from 25 mV/s to 100 mV/s is a change by a factor of 4. Therefore, peak heights in these 2 experiments should differ by a factor of 2 (i.e. double or half) if the process occurring is diffusion controlled rather than being dependant on chemical rate or being mass transfer limited. According to the results shown in Figure S20, we can confirm that this process is diffusion controlled and does not depend on the rate of subsequent chemical steps.     Methyl 4-(1,1,1,3,3,3-hexafluoroisopropoxy

General procedure D for the synthesis of cubanecarboxylic acids
To a solution of the corresponding cubanecarboxylate ester in THF and powdered NaOH (between 1.0 -30.0 equiv.) was added portionwise. After 12 h, the solvent was evaporated and the obtained solid was dissolved in the minimum amount of water and washed with CH 2 Cl 2 . The aqueous phase was acidified with concentrated HCl (pH ≈ 1 -2) and extracted with CH 2 Cl 2 . The combined organic phase was dried over MgSO 4 and concentrated under reduced pressure to afford the cubanecarboxylic acid as a white powder. No further purification was carried out.