Reactive Deep Eutectic Solvents for EDC-mediated Amide Synthesis

The sustainability of amide bond formation is an ever-present topic in the pharmaceutical industry, as it represents the common motif in many clinically approved drugs. Despite many procedures for accomplishing eco-friendly amide synthesis having been developed, this transformation still remains a contemporary challenge. Herein, we report a greener approach for amide synthesis by using Reactive Deep Eutectic Solvents (RDESs) acting as both the reaction medium and reactants. The procedure not only avoids the use of hazardous solvents but also provides operationally simple product recovery with high purity and efficiency, without chromatographic purification. This approach was efficiently applied to the synthesis of a key intermediate in the production of an active pharmaceutical ingredient like atenolol. The green metrics of the gram-scale procedure were compared to the conventional industrial strategy showing an advancement in the greening of amide synthesis.


General information
All starting materials were purchased from Aldrich (Merck) and used without further purification unless stated otherwise.Thin layer chromatography (TLC) was carried out on Schleicher&Schuell F1400/LS 254 plates coated with a 0.2 mm layer of silica gel; detection by UV254 light.Mass spectra (EI) were obtained at 70 eV on a Shimazdu QP-5000 spectrometer, giving fragment ions in m/z with relative intensities (%) in parentheses. 1 H NMR (300 MHz) spectra were recorded on Bruker AC-300 NMR spectrometers respectively in proton coupled mode. 13C NMR (75.5 MHz) spectra were recorded on Bruker AC-300 NMR spectrometer respectively in proton decoupled mode at 20 °C.Chemical shifts are given in δ (parts per million) and coupling constants (J) in Hertz.HPLC analysis were performed to determine the ee % value (DIACEL Chiralcel OD-H, n-hexane:2-propanol = 90:10 (1 mL/min), tr = 13.4 min (R) and tr = 18.1 min (S), 99 % ee, S-enantiomer).

General procedure: amide synthesis in RDES
EDC.HCl ChCl:R 1 COOH (1:1), 0.5-2h, 40 °C The different RDESs were prepared by mixing choline chloride and the carboxylic acid (benzoic, phenyl acetic or 4-hydroxyphenylacetic acid) in a round-bottom flask under inert atmosphere in a 1:1 molar ratio.The resulting mixture was magnetically stirred at 60-80 °C, until a clear liquid was observed.The obtained DESs were directly used without further purification.In a typical procedure, 1mmol of the coupling reagent was added to a ChCl: carboxylic acid (1:1)-based RDES.After stirring at 50°C for 10-15 minutes, the amine was added in equimolar ratio and the resulting mixture was vigorously stirred at the given temperature for an additional time (30-60 min).The progress of the reaction was monitored by TLC and GC/MS analysis.Upon completion, 2 mL of H 2 O were added.The resulting aqueous suspension was then extracted with ethyl acetate (3 × 2 mL).The organic phases were dried over sodium sulphate, followed by evaporation under reduced pressure to give the corresponding amides.The reaction conversions were determined by GC/MS analysis.Spectral data were in accordance with the literature (See ESI).138.0, 134.6, 129.4, 129.0, 128.6, 127.4, 126.5, 43.7, 43.5 ppm.EIMS m/z (%): 225 (M +. , 30), 91 (100), 77 (5), 65 (15) The characterization data of the compound 3a matched previous reports    6, 137.9, 134.7, 129.7, 129.3, 129.1, 128.9, 127.7, 127.3, 120.4, 44.6The characterization data of the compound 3b matched previous reports S2 .
The characterization data of the compound 5a matched previous reports S10
The characterization data of the compound 5b matched previous reports S11
The characterization data of the compound 5e matched previous reports S11