3.2. Synthesis of N-(aryl)-1-(hydroxyalkyl)pyrrolidine-2-carboxamide Derivatives (Compounds 2a–2g and
3a–3g)
3.2.1. Synthesis of N-(4-chlorophenyl)pyrrolidine-2-carboxamide (1a)
To a solution of Boc-Pro-OH (1 mmol) and p-chloro-aniline (1 mmol) dissolved in anhydrous DMF (15 mL) were added TBTU (1.1 mmol), HOBt (1.1 mmol), and N, N-diisopropylethylamine (DIPEA) (1.1 mmol). The reaction mixture was stirred for 12 h at room temperature. After solvent removal, the residue was dissolved in ethyl acetate and extracted with 10% citric acid, 5% NaHCO3 , and brine. The organic phase was dried with Na2 SO4 , filtered, and evaporated to dryness. The residue was purified on a silica gel column using DCM/MeOH (9.5/0.5 v/v) as an eluent. The crystallization with diethyl ether provided the Boc protected product that was dissolved in 40% TFA in DCM (10 mL) and the mixture was stirred at room temperature for 2 h. After evaporation of the solvent, the desired product 1a was obtained as a white solid by crystallization with diethyl ether (yield 47%, calculated on two steps). Using the above described procedure intermediates 1b–1g were prepared starting from 4-hexylaniline (1b), 4-heptylaniline (1c), 4-octylaniline (1d), α-naphtylamine (1e), 2-aminobiphenyl (1f), and 4-aminobiphenyl (1g).
A solution of 2-bromoethanol (1 mmol) and NaI (1.5 mmol) dissolved in 15 mL of DMF was stirred under reflux for 30 min. Then, a solution of 1a (1 mmol) and K2 CO3 (1.5 mmol) in 10 mL of DMF was added drop wise. After 12 h, the reaction mixture was cooled at room temperature, the solid was filtered off, and the solvent was evaporated under vacuum. The obtained residue was dissolved in ethyl acetate and the solution was extracted with brine. The organic phase was then dried with Na2 SO4 , filtered, and evaporated under vacuum, furnishing an oily residue. This residue was purified by chromatography on a silica gel column using a mixture of DCM/MeOH (9.5/0.5; v/v) as an eluent, thus obtaining the final product 2a as an oil. Yield: 67%. 1 H-NMR δ = 9.77 (s, 1H, -NH), 7.54 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 3.76–3.71 (m, 1H), 3.66–3.63 (m, 1H), 3.27–3.26 (m, 1H), 3.17–3.15 (m, 1H), 2.85–2.80 (m, 1H), 2.70–2.66 (m, 1H), 2.40–2.36 (m, 1H), 2.22–2.17 (m, 1H), 1.98–1.96 (m, 1H), 1.79–1.73 (m, 2H); 13 C-NMR δ = 173.45, 136.99, 131.47, 129.11, 120.84, 68.18, 61.07, 57.89, 54.32, 30.87, 24.70. ESI-MS calculated: 268.74; Found: 269.3 [M + H]+ . Anal. (C13 H17 ClN2 O2 ), C, H, N.
EJCHEM_Volume 61_Issue Conference Issue (14th Ibn Sina Arab Conference on Heterocyclic Chemistry and Its Applications (ISACHC 2018), 30 March-2 April 2018, Hurgada, Egypt)._Pages 1-8
