AlCl3-Promoted Cyclization of β-Keto Derivatives with in situ Generated Enamines under Solvent-Free High Speed Ball Milling: An Efficient One-Pot Access to Polysubstituted 1,4-Dihydropyridines

Section 1.1 General InformationChalcones 1 and enamine 2a were prepared according to reported procedures. 1,2All other chemical reagents were obtained from commercial suppliers and used without further purification.The mixer mill MM 400 (Retsch GmbH, Germany) was used for all ball-milling reactions, and the reaction vessels are titanium-alloyed jars lined with PTFE (neat volume: 4 mL) or stainless jars (neat volume: 25 mL).The milling balls are titanium-alloyed of 6.0 mm in diameter or stainless of 8.0 mm in diameter.Analytical thin-layer chromatography was performed on glass plates pre-coated with silica gel impregnated with a fluorescent indicator (254 nm), and the plates were visualized by exposure to ultraviolet light.Column chromatography was performed on silica gel using EtOAc/petroleum ether as the eluent.Melting points were determined on a XT-4 binocular microscope (Beijing Tech Instrument Co., China) and are uncorrected. 1H NMR spectra were recorded on a Bruker AV300, AV400 or AV500 NMR instrument.Chemical shifts are reported in parts per million with the solvent resonance as the internal standard (CDCl 3 , δ 7.26). 13C NMR spectra were recorded on an NMR instrument operated at 125 MHz or 100 MHz with complete proton decoupling.Chemical shifts are reported in parts per million with the solvent resonance as the internal standard (CDCl 3 , δ 77.16).HR-MS were recorded on a Bruker MicroTOF-QII mass instrument (ESI). General Procedure for the Synthesis of Product 5 (5a as an Example)Aniline (3a, 0.55 mmol), ethyl acetoacetate (4a, 0.55 mmol), AlCl 3 (0.125 mmol), together with two titanium-alloyed balls of 6.0 mm in diameter, were introduced into a titanium-alloyed jar lined with PTFE (4 mL).The same mixture was also introduced into a second parallel jar.The two reaction vessels were sealed with screw caps, fixed on the vibration arms of a ball-milling apparatus (mixer mill MM400, Retsch GmbH, Haan, Germany) and were vibrated vigorously at a rate of 1800 rounds per minute (30 Hz) at room temperature for 30 minutes.After the vessels were opened, chalcone (1a, 0.5 mmol) and AlCl 3 (0.25 mmol) were added into the two parallel jars, respectively.The vessels were sealed again and continued to vibrate for 60 minutes (30 Hz).The resulted mixtures were combined and directly loaded on silica gel chromatography column for purification with EtOAc/petroleum ether as the eluent, affording the desired product 5a as white solid. General Procedure for the Synthesis of Product 6 (6a as an Example)