Regio- and Stereoselective Electrochemical Alkylation of Morita-Baylis-Hillman Adducts
Giulio Bertuzzi*, Giada Ombrosi and Marco Bandini*
*Center for Chemical Catalysis -C3-, Alma Mater Studiotum - Università di Bologna, Via Selmi 2, 40126 Bologna, Italy,
Email: giulio.bertuzzi2
unibo.it, marco.bandiniunibo.it
G. Bertuzzi, G. Ombrosi, M. Bandini, Org. Lett., 2022, 24, 4354-4359.
DOI: 10.1021/acs.orglett.2c01529
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Abstract
Exposure of N-acyloxyphthalimides (redox-active esters) to galvanostatic electroreductive conditions enables a general regio- and stereoselective alkylation of Morita-Baylis-Hillman compounds in high yields. The method offers wide functional group tolerance.
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proposed mechanism
Details
The document discusses a novel electrochemical method for the regio- and stereoselective alkylation of Morita−Baylis−Hillman (MBH) adducts using N-acyloxyphthalimides (redox-active esters, RAEs) under galvanostatic electroreductive conditions. This method employs a sacrificial zinc anode and a graphite cathode, with tetraethylammonium tetrafluoroborate (TEABF4) as the supporting electrolyte in DMF. The process yields densely functionalized cinnamate and oxindole derivatives with high efficiency (up to 80%) and broad functional group tolerance. The study highlights the advantages of electrochemical synthesis, such as mild conditions, high selectivity, and the avoidance of toxic organometallic reagents. Optimization of reaction conditions revealed that lower current values significantly improve yields by minimizing side reactions. The methodology was successfully applied to various MBH acetates and carbonates, demonstrating its generality and scalability. Control experiments and mechanistic studies suggest that the high E-selectivity of the products is due to the exclusive SN2′ radical trapping. The research provides a green and practical approach to synthesizing α-substituted α,β-unsaturated esters or ketones, offering a complementary alternative to existing photocatalytic strategies. The authors acknowledge financial support from the University of Bologna and the PRIN-2017 project.
Optimized general procedure for the eChem alkylation of MBH adducts
The ElectraSyn vial (5 mL), equipped with a stir bar, was charged with MBH acetate (0.15 mmol), redox-active ester (0.30 mmol) and TEABF4 (65.1 mg, 0.30 mmol). The ElectraSyn vial cap, equipped with anode (Zn) and cathode (graphite) was inserted into the mixture and closed with a rubber septum. The vessel was evacuated and backfilled with N2 three times, then dry DMF (3 mL) was added, and the solution bubbled with N2 (balloon) under stirring for 1 min. The reaction mixture was electrolyzed (under N2, balloon) at a constant current of 2 mA, until a total charge of 0.60 F (4 F/mol) was reached (ca. 8 h). The ElectraSyn vial cap was removed, and the electrodes and vial were rinsed with EtOAc (10 mL) and HCl(aq) (1M, 10 mL), which were combined with the crude mixture in a separatory funnel. Then, the organic layer was separated, the aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic layers were washed with HCl(aq) (0.1 M, 3 x 10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was finally purified by flash chromatography (nHex/Et2O mixtures).
Key Words
ID: J54-Y2022
