Isolera one flash purification system

All reactions were carried out using oven dried glassware and magnetic stirring under an atmosphere of air unless otherwise stated. Reaction temperatures are reported as the temperature of the oil bath surrounding the vessel. Analytical thin layer chromatography was performed on silica gel aluminium plates with F-254 indicator and visualized by UV light (254 nm) and/or chemical staining with a KMnO4 solution or a phosphomolybdic acid solution. Flash chromatography was performed on Merck silica gel (40-63 mesh) either by standard technique or by Biotage Isolera One Flash Purification System (gradient of solvents; PE = petroleum ether, Et2O = diethyl ether). 1 H NMR spectra were recorded on a Bruker DXP 300 MHz spectrometer at 300.1 MHz, 13 C spectra at 75. PdCl2 was purchased from Sigma-Aldrich Ltd. Dry DMF (N,N-Dimethylformamide, in sealed bottle with molecular sieves) was purchased from Acros Organics Ltd. Reagent I was synthesized according to the literature procedure. 13 Acrylamides 1a, 10c 1b, 14 1c, 10c 1e-1f, 10c 1g, 14 1h-1i, 10c 1j, 14 1k-1l, 10c 1m, 14 1n, 10c 1p, 14 1q-1r, 10c 1s, 15 1t, 10c 1u 14 were synthesized according to the preview reports in the literature. Starting materials 1v, 16 3, 16 4 17 and 5 10b were prepared according to literature procedures.

General Remarks All reagents and solvents purchased were of the highest commercial quality and were used without further purification. 1 H-NMR spectra were measured at 400 MHz on a VARIAN 400-MR spectrometer or at 500 MHz on an Agilent INOVA-500 spectrometer, and 13 (link) C-NMR spectra were measured at 100 MHz on a VARIAN 400-MR spectrometer or at 125 MHz on an Agilent INOVA-500 spectrometer. High resolution mass spectra were recorded using a Jeol JMS-T100LP AccuTOF instrument. IR spectra were recorded using a JASCO FT/IR-4700 spectrometer in attenuated total reflection (ATR) mode at room temperature. Silica gel column chromatography was performed using Silica Gel 60 (spherical and neutral; 100 to 210 µm, 37560-79, Kanto Chemical Co., Japan) and the Isolera One flash purification system (Biotage, Sweden). After stirring overnight at reflux temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOEt (60 mL), and the solution was washed with water (40 mL×2) and brine (40 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified using the Isolera One system (hexane/ AcOEt) to afford 16 as a yellow oil (4435 mg, 81%).

Reagents were purchased from commercial sources and used without further purification. Melting points were determined with a Mettler Toledo MP70 apparatus.
Crude residues were purified with the indicated solvent as eluent by flash column chromatography carried out at medium pressure using silica gel (E. Merck, Grade 60, particle size 0.040 -0.063 mm, 230 -240 mesh ASTM) or IsoleraOne flash purification system from Biotage. Compounds were detected with UV light (254 nm). General procedure for compounds 1 -21, 30 -50: Following the procedure described by Pandey et al. 17 with some modifications. A mixture of the isatin derivative (1 eq), the corresponding amine derivative (1 eq) and MMT-K10 (20 mg for 1 mmol of the isatin derivative) and toluene if necessary, was heated under microwave irradiation (6 -90 min, 100 -110 ºC). After cooling to room temperature, ethyl acetate (50 mL) was added and the mixture was extracted with a saturated solution of NaHCO 3 (50 mL x 3).
Finally, the organic phase was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was chromatographed as indicated in each case.
In case the amine was in hydrochloride form, the amine derivative (1 eq) was stirred
with triethylamine (1 eq) and toluene (3 mL) for 1 h at room temperature.
, 0.5H), 7.01 (ddd, J = 8.9,