Selective Electrosynthetic Hydrocarboxylation of α,β‐Unsaturated Esters with Carbon Dioxide

Abstract The carboxylation of low‐value commodity chemicals to provide higher‐value carboxylic acids is of significant interest. Recently alternative routes to the traditional hydroformylation processes that used potentially toxic carbon monoxide and a transition metal catalyst have appeared. A significant challenge has been the selectivity observed for olefin carboxylation. Photochemical methods have shown a viable route towards the hydrocarboxylation of α,β‐unsaturated alkenes but rely on the use of an excess reducing or amine reagent. Herein we report our investigations of an electrochemical approach that is able to hydrocarboxylate α,β‐unsaturated alkenes with excellent regioselectivity and the ability to carboxylate hindered substrates to afford α‐quaternary center carboxylic acids. The reported process requires no chromatography and the products are purified by simple crystallization from the reaction mixture after work‐up.


General Experimental
Reagents: Commercially available materials (electrolytes, reducing agents, acrylates) were used without further purification. Substrates were purchased from commercial sources and used as received. Anhydrous N,N-dimethylformamide and toluene were purchased from Sigma-Aldrich and dried over 3Å molecular sieves prior to use. Tetraethylammonium iodide was also purchased from Sigma-Aldrich. Deuterated solvents were purchased from Fluorochem UK Ltd.
Analytical Methods: All infrared spectra were obtained using a Perkin-Elmer Spectrum 65 FT-IR spectrophotometer; thin film spectra were acquired using sodium chloride plates. All 1 H and 13 C NMR spectra were measured at 400 and 100 MHz using a Bruker Avance 400 MHz spectrometer, a Jeol ECS 400 MHz spectrometer or at 500 and 125 MHz on a Jeol ECZ 500 MHz spectrometer. The solvent used for NMR spectroscopy was CDCl3 (unless stated otherwise) using TMS (tetramethylsilane) as the internal reference. Chemical shifts are given in parts per million (ppm) and J values are given in Hertz (Hz).
Analysis by GCMS utilised a Shimadzu QP2020, GC-2010 Plus, using a 15 m x 0.25 mm DB-5 column and an electron impact low resolution mass spectrometer, acids were converted to their corresponding methyl esters using TMSdiazomethane prior to sampling. Melting points were recorded using a Stuart Scientific melting point apparatus SMP3 and are uncorrected. All chromatographic manipulations used silica gel as the adsorbent. Reactions were monitored by GCMS or using thin layer chromatography (TLC) on aluminium backed plates with Merck Kiesel 60 F254 silica gel. TLC visualised by UV radiation at a wavelength of 254 nm. Purification by column chromatography used Apollo Scientific 60 40-63μm silica gel.
Headspace GC-MS analysis of CO2 reduction was carried out on an Agilent 5977 GC-MS with a HP5-MS column 30 m long, 0.25 mm diameter, with 5% phenyl-methyl siloxane stationary phase, 0.25 m thick. The programme was set with a 2-minute hold time at 40 ºC followed by a ramp to 200 ºC for 10 minutes. The headspace sample was introduced via a gas tight syringe.
Electrode electrochemical reactions were carried out using a 10mL reaction vial using a carbon anode and a carbon cathode supplied by IKA and the current was supplied from an IKA ElectraSyn 2.0 S-4

Procedure for preparing acrylates via Wittig and Horner-Wadsworth-Emmons reaction
General Procedure I: In a microwave vial (2-5 mL), Methyl (triphenylphosphoranylidene)acetate S2 (0.835 g, 2.5 mmol) and the aldehyde or ketone S1 were dissolved in toluene (3 mL). The reaction was ran for 10 min at 150 o C. The reaction mixture was placed in a RBF (100 mL ) and 5 g silica gel added. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane/AcOEt on silica gel affording acrylates 1.
General Procedure II: In 250 mL RBF, sodium hydride (0.240 g, 10 mmol) was suspended in THF (50 mL ) and trimethyl phosphonoacetate S3 (1.62 mL, 10 mmol) was added dropwise. The reaction was then stirred under reflux for 1 hr at 60 o C then the corresponding ketone 1 (10 mmol) was dissolved in THF (10 mL) and added to the reaction carefully dropwise then the reaction was left under reflux overnight. After that, the reaction was cooled to rt, and 99% methanol (10 mL) of was added and around 10 g of silica gel. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane/AcOEt on silica gel affording acrylates 1.

Electrocarboxylation of acrylates using a nonsacrificial electrochemical cell
General Procedure III: Substrate (1.0 mmol) was added to a solution of Et4NI (128 mg, 0.5 mmol) and TEOA (149 mg, 1.0 mmol) in DMF (5 mL). The resulting mixture was flushed with CO2 and kept under a positive pressure of CO2. The mixture was electrolysed at a constant voltage of 10V in a single compartment cell containing carbon cathode and carbon anode with stirring for 4h. The crude reaction mixture was acidified by addition of HCl/H2O (1:1, 2 mL) and extracted with diethylether (3 x 5mL). The combined organic phases were washed with brine, dried over MgSO4 and filtered. The solvent was then removed under reduced pressure and the crude material was recrystalised by hexane.

4-(2-methoxy-2-oxoethyl)tetrahydro-2H-pyran-4carboxylic acid (2ae).
Following the general procedure III using Procedure for electrochemical flow reaction: In 50 mL Erlenmeyer flask, acrylate 1ag (1 g, 7.8 mmol) was added to a solution of Et4NI (1 g, 3.9 mmol) and TEOA (1.16 g, 7.8 mmol) in DMF (25 mL). The resulting mixture was flushed with CO2 and kept under a positive pressure of CO2. The mixture was electrolysed at a constant voltage of 10V through a vapourtech ion electrochem reactor containing carbon cathode and carbon anode in closed cycle with speed of 0.5 mL/min for 4 h. The crude reaction mixture was acidified by addition of HCl/H2O (1:1, 10 mL) and extracted with diethylether (3 x 15mL). The combined organic phases were washed with brine, dried over MgSO4 and filtered. The solvent was then removed under reduced pressure and the crude material was recrystalised by hexane affording 2ag (1.1g, 80.8%).

Deuterium Labelling Studies
Following the general procedure III but using 10 eq of D2O instead of TEOA and starting with Methyl 3,3-dimethylacrylate affording the deuterated product [D]2q.

Procedure for gas chromatography batch calibration
Additives were individually analysed by gas chromatography to determine retention times. Calibration solutions with 16 compounds (1.0 mmol of each compound in 20 mL of chloroform) were subsequently prepared, ensuring compounds with similar retention times were separated. Standard gas chromatography calibration using anthracene as a standard was undertaken, and calibration lines produced for each additive.

Calibration for reaction yield
The calibration line for determination of the yield using gas chromatography analysis is given. Calibration was undertaken using anthracene as the standard.

Protocol for batch screening and analysis
Two calibration solutions containing 8 additives (1.0 mmol of each additive) and standard (1.0 mmol, anthracene) in chloroform (20 mL) are prepared, and analyzed.
Example GC method, compounds, retention times and chromatograms are provided: The relative integrals of the additive to the standard can be used for a semi-quantitative determination of the amount of additive present in a reaction mixture.
The standard reaction is performed and the product isolated. Calibration of the product (1.0 mmol) against the standard (1.0 mmol) is undertaken.
The standard reaction is prepared 16 times containing one additive (1.0 mmol). After the given reaction time, the standard is introduced to each reaction (1.0 mmol), and analysis by the selected method undertaken.
The yield of the reaction and the amount of additive remaining as determined by comparison with the calibration is reported in the following   Blank DMA GC-MS Spectra: DMA (0.1 mL) was placed into a GC-MS vial and diluted to 1.0 mL with EtOH (10% v/v), c.H2SO4 (0.02 mL) was added and the vial top screwed into place. The vial was placed in an oven for 10 minutes at 60 ºC along with a gas tight syringe. The vial was then allowed to cool for 5 minutes and 1.0 mL of the head space in the vial drawn into the syringe and immediately injected into the GC-MS.