Versatile and mild HCl-catalyzed cationic imino Diels-Alder reaction for the synthesis of new tetrahydroquinoline derivatives

Abstract

Supporting informationContents:1-General experimental information (Pages 1-13) 2-1 H NMR and 13 C NMR spectra of N-benzyl-4-aryl tetrahydroquinolines 3a-3p, 3-1 H NMR and 13 C NMR spectra of 4-aryl tetrahydroquinolines 3a-3l, (Pages 11-41) 4-Single crystal X-Ray diffraction data for N-benzyl-4-aryl-3-methyl tetrahydroquinoline 6d General Experimental InformationAll reagents were purchased from Merck, J.T. Baker and Sigma and Aldrich Chemical Co. and used without further purification. The reaction progress was monitored using thin layer chromatography on PF254 TLC aluminum sheets from Merck. Column chromatography was performed using Silica gel (60-120 mesh). The melting points (uncorrected) were determined using a Fisher-Johns melting point apparatus. IR spectra were recorded on a FTIR Bruker Tensor 27 spectrophotometer coupled to a Bruker platinum ATR cell. Mass spectra were recorded on an ESI-IT Amazon X (Bruker Daltonics) with direct injection, operating in Full Scan mode at 300°C and 4500V in the capillary, using nitrogen as nebulizer gas with an influx of 8 L/min and 30 psi.NMR spectra ( 1 H and 13 C) were measured on a Bruker Ultrashield-400 spectrometer (400 MHz 1 H NMR and 100 MHz 13 C NMR), using CDCl 3 as solvent and reference. J values are reported in Hz; chemical shifts are reported in ppm (δ) relative to the solvent peak (residual CHCl 3 in CDCl 3 at 7.26 ppm for protons). Signals were designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets of doublets; t, triplet; td, triplet of doublets; q, quartet; m, multiplet; br., broad.General procedure for the synthesis of N-benzyl-4-aryl tetrahydroquinolines: All the reactions were performed at room temperature unless otherwise stated. In a round bottom flask, a 5 mL solution in anhydrous acetonitrile of Nbenzylaniline (1 mmol) and formaldehyde (37% in methanol) (1.1 mmol) was prepared and stirred for 10 minutes. A 5 mL solution of HCl 2N (1.1 mmol) in MeCN was then added and after stirring for 20 minutes, the dienophile (trans-anethole or isoeugenol) (1.1 mmol) was incorporated to the reaction mixture and was vigorously stirred. The reaction achieved completion within 2-21 hours (monitored by TLC). The mixture was poured into a saturated solution of NaHCO 3 (15 mL), extracted with ethyl acetate (3 x 15 mL) and dried over Na 2 SO 4 . The crude product

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

“…Thus, the total reaction time was reduced from 96 h to 15 min (Table 4) through microwave-assisted methodology and compound yields were 2.5-fold increase in comparison with conventional procedures. It must be considered that compound 18 was not obtained, only decomposition products were obtained [87]. Novel tetrahydroquinolines derivatives 17, 19, and 20 were obtained in excellent yields (83-89%) of isolated products.…”

“…Different N-propargyl tetrahydroquinolines(17)(18)(19)(20) were synthesized using acid-catalyzed three-component cationic imino Diels-Alder reaction[87][88][89] (Scheme 5).Molecules 2020, 25, 491 12 of 42 2.2.3. Synthesis of N-Propargyl Tetrahydroquinolines Different N-propargyl tetrahydroquinolines (17-20) were synthesized using acid-catalyzed three-component cationic imino Diels-Alder reaction [87-89] (Scheme 5).…”

“…of 1-vinyl-2-pyrrolidinone(16) were added to the mixture and irradiated with 7-8 bar, 850 watts of power at 160 • C for 15 min. The resulting solution was passed through a pad of silica and celite with ethyl acetate and the crude mixture was purified by flash column chromatography (silica gel, n-hexane/AcOEt, 9:1)[87,89].1-(8-Fluoro-4-(2-oxopyrrolidin-1-yl)-1-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-2-one (17). Brown oil; 85% yield; FT-IR (KBr) ν / cm −1 2924, 2098, 1743, 1681, 1604, 1489, 1381, 1134, 795; 1 H NMR (400 MHz, CDCl 3 ) δ 6.70 (dd, J = 14.2, 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 5.17 (dd, J = 9.8, 5.7 Hz, 1H), 3.92 (qd, J = 18.0, 2.4 Hz, 2H), 3.40 (ddt, J = 17.8, 11.5, 6.1 Hz, 2H), 3.20 (dtt, J = 17.2, 8.4, 4.1 Hz, 2H), 3.10 (dt, J = 9.8, 7.2 Hz, 2H), 3.01 (dt, J = 9.7, 6.6 Hz, 2H), 2.33 (d, J = 7.1 Hz, 2H), 2.30 (dd, J = 8.1, 3.6 Hz, 2H), 2.09 (t, J = 2.2 Hz, 1H), 1.84 (dt, J = 12.5, 6.3 Hz, 2H), 1.73 (dt, J = 6.4, 3.1 Hz, 4H); 13 C NMR (101 MHz, CDCl 3 ) δ 175.6, 169.9, 154.3, 151.8, 133.8, 126.8, 120.5, 113.1, 79.8, 72.5, 51.1, 48.1, 47.5, 43.1, 43.1, 32.3, 31.0, 24.3, 23.0, 20.8, 17.9; 19 F NMR (376 MHz, CDCl 3 ) δ −120.9; ESI-HRMS (m/z): calcd.…”

Efficient synthesis and antioxidant activity of novel N-propargyl tetrahydroquinoline derivatives through the cationic Povarov reaction

“…The preparation of new N -propargyl THQs 6a-g via domino Mannich addition/Friedel-Crafts intramolecular alkylation reactions catalyzed by InCl 3 , was effective under mild condition reactions using N-propargylamines with formaline (37% in methanol) and N -vinylformamide as an electron-rich alkene. Acetonitrile (CH 3 CN) was used as solvent based on previous reports (Romero Bohórquez et al., 2016; Abonia et al., 2013). Synthetic route and structures of final compounds are shown in Scheme 1.…”

“…Recently, we have been successfully exploring the cationic version of the Povarov reaction (a domino Mannich/Friedel-Crafts reaction). This method resulted highly efficient to access different N-derivatives of THQs (Romero Bohórquez et al., 2016; Acelas et al., 2017), including the synthesis of new N -allyl/propargyl 1,2,3,4-THQs, promissory dual inhibitors against AChE and BChE enzymes (Rodriguez et al., 2016).…”