Synthesis of Azole-Substituted Propanamides

All reagents and solvents were of general purpose or analytical grade and purchased from Sigma‐Aldrich, Fisher Scientific, Fluka, Alfa Aesar and Acros. Lanosterol and fluconazole were supplied by Sigma‐Aldrich. Ni²⁺‐NTA agarose affinity chromatography matrix was obtained from Qiagen. ¹H and ¹³C NMR spectra were recorded with a Bruker Avance DPX500 spectrometer operating at 500 and 125 MHz, with Me₄Si as internal standard. Mass spectra (HRMS) were determined by the Engineering and Physical Sciences Research Council National Mass Spectrometry Service Centre at Swansea University (Swansea, UK). Elemental analysis was performed by MEDAC Ltd (Chobham, Surrey, UK); HPLC (Method A, Cardiff University) was performed on a Shimadzu LC‐2030C Plus C18 Rapid Resolution 250×4.6 mm, 5 μm particle size using a 7–10 min gradient of water/methanol 5 : 95 (Method B, University of Bath) was performed on a Zorbax Eclipse Plus C18 Rapid Resolution 2.1×50 mm, 1.8 μm particle size using a 7.5 minute gradient method 5 : 95 water: methanol with 0.1 % formic acid as additive. Gradient column chromatography was performed with silica gel 60 (230‐400 mesh; Merck) and TLC was carried out on precoated silica plates (kiesel gel 60 F₂₅₄, BDH). Compounds were visualised by illumination under UV light (254 nm) or by the use of vanillin stain followed by heating. Melting points were determined on an electrothermal instrument and are uncorrected. All solvents were dried prior to use and stored over 4 Å molecular sieves, under nitrogen. All the compounds were≥95 % pure.
General procedure for the preparation of azoles (5 and 12) and alkene elimination products (6 and 13). To a stirred solution of azole (imidazole or triazole or tetrazole; 4 equiv) in dry CH₃CN (2 mL/mmol of azole) was added potassium carbonate (4 equiv), and the mixture was heated for 1 h at 45 °C. After cooling to room temperature, mesylate (4 or 11; 1 equiv) was added and the reaction was heated at 70 °C for 4 h then stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue was extracted with EtOAc (35 mL/mmol of mesylate), washed with brine (3×35 mL/mmol of mesylate) and water (3×35 mL/mmol of mesylate). The organic layer was dried (MgSO₄) and evaporated under vacuum to give the crude product, which was purified by gradient column chromatography. Alkene (6 or 13) was eluted first with petroleum ether/EtOAc system, followed by the azole product (5 or 12) on changing the system to CH₂Cl₂/MeOH.
N‐Benzyl‐2‐phenylacrylamide (6 a, R¹=R²=H). Prepared from 3‐(benzylamino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 a; 0.48 g, 1.44 mmol) and purified by petroleum ether/EtOAc gradient column chromatography eluting with 70 : 30 v/v. Product was obtained as a white solid, yield 0.27 g (62 %); m.p. 78–80 °C; TLC (petroleum ether/EtOAc 1 : 1, v/v), R_f=0.78; ¹H NMR ([D₆]DMSO): δ 8.74 (t, J=5.9 Hz, 1H, NH), 7.43 (m, 2H, Ar), 7.35 (m, 7H, Ar), 7.26 (m, 1H, Ar), 5.79 (s, 1H, C=CHaHb), 5.68 (s, 1H, C=CHaHb), 4.40 (d, J=6.1 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.70 (C, C=O), 145.65 (C, C=CH₂), 140.07 (C, Ar), 137.18 (C, Ar), 128.79 (2×CH, Ar), 128.77 (2×CH, Ar), 128.57 (CH, Ar), 127.61 (2×CH, Ar), 127.52 (2×CH, Ar), 127.21 (CH, Ar), 118.17 (C=CH₂), 42.81 (NHCH₂); HRMS (ESI), m/z calcd for C₁₆H₁₆NO ([M+H]⁺), 238.1257; found: 238.1226.
N‐(4‐Fluorobenzyl)‐3‐(1H‐imidazol‐1‐yl)‐2‐phenylpropanamide (5 b, R¹=4‐F, R²=H) andN‐(4‐fluorobenzyl)‐2‐phenylacrylamide (6 b, R¹=4‐F, R²=H). Prepared from 3‐((4‐fluorobenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 b; 0.70 g, 1.98 mmol) and purified by gradient column chromatography eluting the alkene (6 b) with petroleum ether/EtOAc 70 : 30 v/v, followed by the imidazole (5 b) with CH₂Cl₂/MeOH 90 : 10 v/v. N‐(4‐Fluorobenzyl)‐3‐(1H‐imidazol‐1‐yl)‐2‐phenylpropanamide (5 b) was obtained as a cream solid, yield 0.22 g (34 %); m.p. 100–102 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.61 (t, J=5.9 Hz, 1H, NH), 7.53 (brs, 1H, imid), 7.40 (d, J=7.05 Hz, 2H, Ar), 7.34 (t, J=7.4 Hz, 2H, Ar), 7.29 (t, J=7.2 Hz, 1H, Ar), 7.11 (brs, 1H, imid), 7.03 (m, 4H, Ar), 6.88 (brs, 1H, imid), 4.63 (dd, J=9.7, 13.4 Hz, 1H, CHCHaHb), 4.29 (dd, J=6.4, 15.3 Hz, 1H, NHCHaHb), 4.24 (dd, J=5.7, 13.4 Hz, CHCHaHb), 4.10 (dd, J=5.5, 15.2 Hz, NHCHaHb), 4.02 (dd, J=5.8, 9.6 Hz, CHCHaHb); ¹³C NMR ([D₆]DMSO): δ 171.06 (C, C=O), 162.52 and 160.60 (C,C−F), 137.94 (C, Ar), 135.63 (C, Ar), 130.15 (CH, imid), 130.09 (CH, imid), 129.38 (CH, Ar), 129.32 (CH, Ar), 128.93 (2×CH, Ar), 128.27 (2×CH, Ar), 127.86 (CH, Ar), 115.66 (CH, imid), 115.40 (CH, Ar), 115.23 (CH, Ar), 53.33 (CHCH₂imid), 48.88 (CHCH₂imid), 41.80 (NHCH₂); LRMS (ES, m/z): 324.15 [C₁₉H₁₈FN₃O+H]⁺; HRMS (ESI), m/z calcd for C₁₉H₁₉FN₃O ([M+H]⁺), 324.1507; found: 324.1507; HPLC (Method A): 98.0 %, t_R=4.87 min. N‐(4‐Fluorobenzyl)‐2‐phenylacrylamide (6 b) was obtained as a white solid, yield 0.25 g (39 %); m.p. 108–110 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.79; ¹H NMR ([D₆]DMSO): δ 8.74 (t, J=5.4 Hz, 1H, NH), 7.43 (d, J=7.7 Hz, 2H, Ar), 7.36 (m, 5H, Ar), 7.17 (t, J=8.9 Hz, 2H, Ar), 5.79 (s, 1H, C=CHaHb), 5.69 (s, 1H, C=CHaHb), 4.38 (d, J=6.0 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.68 (C, C=O), 162.60 and 160.67 (C, C−F), 145.60 (C, Ar), 137.16 (C, Ar), 136.27 (C, C=CH₂), 129.67 (CH, Ar), 129.61 (CH, Ar), 128.79 (2×CH, Ar), 128.58 (CH, Ar), 127.53 (2×CH, Ar), 118.29 (C=CH₂), 115.57 (CH, Ar), 115.40 (CH, Ar), 42.16 (NHCH₂); elemental analysis calcd (%) for C₁₆H₁₄FNO (255.2911): C 75.28, H 5.53, N 5.48; found: C 75.34, H 5.32, N 5.55.
N‐(4‐Chlorobenzyl)‐3‐(1H‐imidazol‐1‐yl)‐2‐phenylpropanamide (5 c, R¹=4‐Cl, R²=H). Prepared from 3‐((4‐chlorobenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 c; 0.38 g, 1.0 mmol) and purified by gradient column chromatography eluting the imidazole (5 c) with CH₂Cl₂/MeOH 90 : 10 v/v. Product was obtained as a cream solid, yield 0.20 g (56 %); m.p. 136–138 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v), R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.67 (t, J=5.8 Hz, 1H, NH), 7.52 (s, 1H, imid), 7.40 (m, 2H, Ar), 7.35 (m, 2H, Ar), 7.29 (m, 3H, Ar), 7.11 (s, 1H, imid), 6.96 (d, J=8.2 Hz, 2H, Ar), 6.88 (s, 1H, imid), 4.63 (dd, J=9.9, 13.3 Hz, 1H, CHCHaHb), 4.30 (dd, J=6.4, 15.5 Hz, 1H, NHCHaHb), 4.23 (dd, J=5.6, 13.4 Hz, CHCHaHb), 4.10 (dd, J=5.4, 15.5 Hz, NHCHaHb), 4.03 (dd, J=5.7, 9.7 Hz, CHCHaHb); ¹³C NMR ([D₆]DMSO): δ 171.2 (C, C=O), 138.5 (C, Ar), 137.9 (C, Ar), 131.7 (C, C−Cl), 129.2 (3×CH, Ar (2) and imid (1)), 129.0 (2×CH, Ar), 128.6 (3×CH, Ar (2) and imid (1)), 128.3 (2×CH, Ar), 127.9 (CH, Ar), 120.0 (CH, imid), 53.3 (CHCH₂imid), 50.8 (CHCH₂imid), 41.8 (NHCH₂); elemental analysis calcd (%) for C₁₉H₁₈ClN₃O⋅0.1H₂O (341.6215): C 66.80, H 5.37, N 12.30; found: C 66.44, H 5.07, N 12.39; HPLC (Method A): 99.0 %, t_R=4.94 min.
N‐(4‐Chlorobenzyl)‐2‐(4‐chlorophenyl)‐3(1H‐imidazol‐1‐yl)propanamide (5 d, R¹=R²=4‐Cl) andN‐(4‐chlorobenzyl)‐2‐(4‐chlorophenyl)acrylamide (6 d, R¹=R²=4‐Cl). Prepared from 3‐((4‐chlorobenzyl)amino)‐2‐(4‐chlorophenyl)‐3‐oxopropyl methanesulfonate (4 d; 0.44 g, 1.09 mmol) and purified by gradient column chromatography eluting the alkene (6 d) with petroleum ether/EtOAc 70 : 30 v/v, followed by the imidazole (5 d) with CH₂Cl₂/MeOH 90 : 10 v/v. Imidazole 5 d was further purified by recrystallization from CH₃CN. N‐(4‐Chlorobenzyl)‐2‐(4‐chlorophenyl)‐3(1H‐imidazol‐1‐yl)propanamide (5 d) was obtained as a brown solid, yield 0.11 g (26 %); m.p. 160–162 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.66 (t, J=5.9 Hz, 1H, NH), 7.50 (s, 1H, imid.), 7.40 (m, 4H, Ar), 7.29 (d, J=8.5 Hz, 2H, Ar), 7.09 (s, 1H, imid.), 6.98 (d, J=8.5 Hz, 2H, Ar), 6.86 (s, 1H, imid.), 4.59 (dd, J=9.4, 13.5 Hz, 1H, CHCHaHb), 4.29 (dd, J=6.4, 15.4 Hz, 1H, NHCHaHb), 4.24 (dd, J=6.1, 13.5 Hz, 1H, CHCHaHb), 4.10 (dd, J=5.4, 15.5 Hz, 1H, NHCHaHb), 4.05 (dd, J=6.1, 9.4 Hz, 1H, CHCHaHb); ¹³C NMR ([D₆]DMSO): δ 170.78 (C, C=O), 138.41 (C, Ar), 138.06 (CH, imid), 136.78 (C, Ar), 132.59 (C, C−Cl), 131.75 (C, C−Cl), 130.16 (2×CH, Ar), 129.23 (2×CH, Ar), 128.92 (2×CH, Ar), 128.68 (CH, imid), 128.57 (2×CH, Ar), 119.95 (CH, imid), 52.59 (CHCH_2‐imid), 48.66 (CHCH₂imid), 41.85 (NHCH₂); elemental analysis calcd (%) for C₁₉H₁₇Cl₂N₃O (374.2688): C 60.97, H 4.58, N 11.22; found: C 60.99, H 4.50, N 11.20; HPLC (Method A): 96.3 %, t_R=2.53 min. N‐(4‐Chlorobenzyl)‐2‐(4‐chlorophenyl)acrylamide (6 d) was obtained as an off‐white solid, yield 0.09 g (22 %); m.p. 108–110 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.73; ¹H NMR ([D₆]DMSO): δ 8.80 (t, J=5.9 Hz, 1H, NH), 7.45 (m, 4H, Ar), 7.41 (d, J=8.5 Hz, 2H, Ar), 7.33 (d, J=8.5 Hz, 2H, Ar), 5.84 (s, 1H, C=CHaHb), 5.76 (s, 1H, C=CHaHb), 4.37 (d, J=6.1 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.27 (C, C=O), 144.20 (C, C=CH₂), 139.02 (C, Ar), 135.98 (C, C−Cl), 133.27 (C, C−Cl), 131.80 (C, Ar), 129.55 (2×CH, Ar), 129.46 (2×CH, Ar), 128.80 (2×CH, Ar), 128.74 (2×CH, Ar), 119.40 (C=CH₂), 42.26 (NHCH₂); elemental analysis calcd (%) for C₁₆H₁₃Cl₂NO (306.1908): C 62.76, H 4.28, N 4.57; found: C 63.07, H 4.30, N 4.61.
N‐(2,4‐Dichlorobenzyl)‐3‐(1H‐imidazol‐1‐yl)‐2‐phenylpropanamide (5 e, R¹=2,4‐Cl, R²=H) andN‐(2,4‐dichlorobenzyl)‐2‐phenylacrylamide (6 e, R¹=2,4‐Cl, R²=H). Prepared from 3‐((2,4‐dichlorobenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 e; 0.5 g, 1.24 mmol) and purified by gradient column chromatography eluting the alkene (6 e) with petroleum ether/EtOAc 80 : 20 v/v, followed by the imidazole (5 e) with CH₂Cl₂/MeOH 90 : 10 v/v. N‐(2,4‐Dichlorobenzyl)‐3‐(1H‐imidazol‐1‐yl)‐2‐phenylpropanamide (5 e) was obtained as a cream solid, yield 0.34 g (74 %); m.p. 55–57 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.68 (t, J=5.8 Hz, 1H, NH), 7.56 (d, J=2.1 Hz, 1H, Ar), 7.54 (brs, 1H, imid), 7.41 (d, J=7.2 Hz, 2H, Ar), 7.36 (t, J=7.4 Hz, 2H, Ar), 7.30 (t, J=7.2 Hz, 1H, Ar), 7.23 (dd, J=2.1, 8.4 Hz, 1H, Ar), 7.13 (brs, 1H, imid), 6.90 (brs, 1H, imid), 6.75 (d, J=8.4 Hz, 1H, Ar), 4.63 (dd, J=9.8, 13.4 Hz, 1H, CHCHaHb), 4.31 (dd, J=6.2, 16.0 Hz, 1H, NHCHaHb), 4.23 (dd, J=5.7, 13.4 Hz, 1H, CHCHaHb), 4.16 (dd, J=5.4, 16.0 Hz, 1H, NHCHaHb), 4.10 (dd, J=5.7, 9.8 Hz, 1H, CHCHaHb)); ¹³C NMR ([D₆]DMSO): δ 171.32 (C, C=O), 137.72 (C, Ar), 135.52 (C, Ar), 133.34 (C, C−Cl), 132.63 (C, C−Cl), 130.12 (2×CH, Ar (1) and imid (1)), 128.97 (3×CH, Ar), 128.30 (2×CH, Ar), 127.94 (2×CH, Ar (1) and imid (1)), 127.51 (2×CH, Ar (1) and imid (1)), 53.21 (CHCH₂imid), 48.86 (CHCH₂imid), 40.01 (NHCH₂); elemental analysis calcd (%) for C₁₉H₁₇Cl₂N₃O⋅0.2 H₂O (377.87184): C 60.39, H 4.64, N 11.12; found: C 60.04, H 4.46, N 10.85; HPLC (Method A): 96.20 %, t_R=3.20 min. N‐(2,4‐Dichlorobenzyl)‐2‐phenylacrylamide (6 e) was obtained as a cream solid, yield 0.05 g (11 %); m.p. 66–68 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v), R_f=0.85; ¹H NMR ([D₆]DMSO): δ 8.76 (t, J=5.8 Hz, 1H, NH), 7.63 (d, J=2.1 Hz, 1H, Ar), 7.47 (m, 3H, Ar), 7.34 (m, 5H, Ar), 5.83 (s, 1H, C=CHaHb), 5.75 (s, 1H, C=CHaHb), 4.44 (d, J=5.9 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.87 (C, C=O), 145.33 (C, C=CH₂), 137.04 (C, Ar), 136.02 (C, C−Cl), 133.41 (C, C−Cl), 132.67 (C, Ar), 130.58 (CH, Ar), 129.06 (CH, Ar), 128.82 (2×CH, Ar), 128.63 (CH, Ar), 127.85 (CH, Ar), 127.58 (2×CH, Ar), 118.73 (C=CH₂), 40.01 (NHCH₂); LRMS (ESI, m/z): 308.0417 [C₁₆H₁₃³⁷Cl₂NO+H]⁺, 306.0447 [C₁₆H₁₃³⁵Cl₂NO+H]⁺, 158.98 [C₇H₅³⁵Cl₂]⁺; HRMS (ES), m/z calcd for C₁₆H₁₄³⁵Cl₂NO ([M+H]⁺), 306.0447; found: 306.0449; and calcd for C₁₆H₁₄³⁷Cl₂NO ([M+H]⁺), 308.0417; found: 308.0418.
2‐(4‐Chlorophenyl)‐N‐(2,4‐dichlorobenzyl)‐3‐(1H‐imidazol‐1‐yl)propanamide (5 f, R¹=2,4‐diCl, R²=Cl) and 2‐(4‐chlorophenyl)‐N‐(2,4‐dichlorobenzyl)acrylamide (6 f, R¹=2,4‐diCl, R²=Cl). Prepared from 2‐(4‐chlorophenyl)‐3‐((2,4‐dichlorobenzyl)amino)‐3‐oxopropyl methanesulfonate (4 f; 0.54 g, 1.24 mmoL) and purified by gradient column chromatography eluting the alkene (6 e) with petroleum ether/EtOAc 60 : 40 v/v, followed by the imidazole (5 e) with CH₂Cl₂/MeOH 90 : 10 v/v. 2‐(4‐Chlorophenyl)‐N‐(2,4‐dichlorobenzyl)‐3‐(1H‐imidazol‐1‐yl)propanamide (5 f) was obtained as a white solid, yield 0.21 g (41 %); m.p. 148–150 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.69 (t, J=5.7 Hz, 1H, NH), 7.56 (d, J=2.2 Hz, 1H, Ar), 7.50 (brs, 1H, imid), 7.41 (m, 4H, Ar), 7.26 (dd, J=2.1, 8.3 Hz, 1H, Ar), 7.10 (brs, 1H, imid), 6.88 (brs, 1H, imid), 6.79 (d, J=8.4 Hz, 1H, Ar), 4.58 (dd, J=9.5, 13.4 Hz, 1H, CHCHaHb), 4.30 (dd, J=6.1, 15.9 Hz, 1H, NHCHaHb), 4.23 (dd, J=6.0, 13.5 Hz, 1H, CHCHaHb), 4.16 (dd, J=5.5, 15.9 Hz, 1H, NHCHaHb), 4.10 (dd, J=6.0, 9.5 Hz, 1H, CHCHaHb); ¹³C NMR ([D₆]DMSO): δ 170.96 (C, C=O), 138.02 (CH, imid), 136.64 (C, Ar), 135.41 (C, Ar), 133.40 (C, C−Cl), 132,69 (C, C−Cl), 132.63 (C, C−Cl), 130.24 (CH, Ar), 130.19 (2×CH, Ar), 129.00 (CH, Ar), 128.94 (2×CH, Ar), 128.74 (CH, imid), 127.57 (CH, Ar), 119.92 (CH, imidazole), 52.47 (CHCH₂), 48.68 (CHCH₂), 40.58 (NHCH₂); HRMS (ESI), m/z calcd for C₁₉H₁₇Cl₃N₃O ([M+H]⁺), 408.0438; found: 408.0432; HPLC (Method A): 99.6 %, t_R=4.56 min. 2‐(4‐Chlorophenyl)‐N‐(2,4‐dichlorobenzyl)acrylamide (6 f) was obtained as a white solid, yield 0.19 g (37 %); m.p. 104–106 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.87; ¹H NMR ([D₆]DMSO): δ 8.81 (t, J=5.8 Hz, 1H, NH), 7.62 (d, J=2.1 Hz, 1H, Ar), 7.46 (dd, J=8.9, 16.3 Hz, 5H, Ar), 7.39 (d, J=8.3 Hz, 1H, Ar), 5.88 (s, 1H, C=CHaHb), 5.80 (s, 1H, C=CHaHb), 4.43 (d, J=5.9 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.43 (C, C=O), 143.97 (C, C=CH₂), 135.91 (C, Ar), 135.88 (C, C−Cl), 133.41 (C, C−Cl), 133.30 (C, C−Cl), 132.69 (C, Ar), 130.60 (CH, Ar), 129.49 (2×CH, Ar), 129.07 (CH, Ar), 128.81 (2×CH, Ar), 127.86 (CH, Ar), 119.69 (C=CH₂), 40.49 (NHCH₂); HRMS (ESI), m/z calcd for C₁₆H₁₂Cl₃NONa ([M+Na]⁺), 361.9882; found: 361.9880.
3‐(1H‐Imidazol‐1‐yl)‐N‐(4‐methylbenzyl)‐2‐phenylpropanamide (5 g, R¹=4‐CH₃, R²=H) andN‐(4‐methylbenzyl)‐2‐phenylacrylamide (6 g, R¹=4‐CH₃, R²=H). Prepared from 3‐((4‐methylbenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 g; 0.7 g, 2.0 mmol) and purified by gradient column chromatography eluting the alkene (6 g) with petroleum ether/EtOAc 70 : 30 v/v, followed by the imidazole (5 g) with CH₂Cl₂/MeOH 90 : 10 v/v. 3‐(1H‐Imidazol‐1‐yl)‐N‐(4‐methylbenzyl)‐2‐phenylpropanamide (5 g) was obtained as a cream solid, yield 0.03 g (5 %); m.p. 134–136 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v), R_f=0.0; ¹H NMR ([D₆]acetone): δ 7.72 (brs, 1H, NH), 7.52 (brs, 1H, imid.), 7.44 (d, J=7.0 Hz, 2H, Ar), 7.32 (m, 3H, Ar), 7.11 (brs, 1H, imid.), 7.04 (d, J=7.9 Hz, 2H, Ar), 6.95 (d, J=8.0 Hz, 2H, Ar), 6.91 (brs, 1H, imid.), 4.76 (dd, J=9.3, 13.6 Hz, 1H, CHCHaHb), 4.37 (dd, J=6.2, 14.8 Hz, 1H, NHCHaHb), 4.28 (dd, J=5.7, 13.6 Hz, 1H, CHCHaHb), 4.23 (dd, J=5.6, 15.0 Hz, 1H, NHCHaHb), 4.09 (dd, J=5.7, 9.3 Hz, 1H, CHCHaHb), 2.27 (s, 3H, CH₃); ¹³C NMR ([D₆]acetone): δ 170.50 (C, C=O), 137.77 (C, Ar), 136.18 (C, Ar), 136.01 (C, Ar), 128.80 (2×CH, Ar), 128.55 (3×CH, Ar (2) and imid (1)), 128.39 (CH, imid), 127.98 (3×CH, Ar (2) and imid (1)), 127.48 (2×CH, Ar), 127.18 (2×CH, Ar), 54.00 (CHCH₂imid), 49.20 (CHCH₂imid), 42.24 (NHCH₂) 20.10 (CH₃); HRMS (ESI), m/z calcd for C₂₀H₂₂N₃O ([M+H]⁺), 320.1786; found: 320.1757; HPLC (Method A): 95.5 %, t_R=2.49 min. N‐(4‐Methylbenzyl)‐2‐phenylacrylamide (6 g) was obtained as an off‐white solid, yield 0.38 g (59 %); m.p. 92–94 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v), R_f=0.78; ¹H NMR ([D₆]DMSO): δ 8.69 (t, J=6.0 Hz, 1H, NH), 7.43 (m, 2H, Ar), 7.35 (m, 3H, Ar), 7.20 (d, J=8.0 Hz, 2H, Ar), 7.15 (d, J=7.9 Hz, 2H, Ar), 5.78 (s, 1H, C=CHaHb), 5.66 (s, 1H, C=CHaHb), 4.35 (d, J=6.1 Hz, 2H, NHCH₂), 2.29 (s, 3H, CH₃); ¹³C NMR ([D₆]DMSO): δ 168.63 (C, C=O), 145.68 (C, C=CH₂), 137.19 (C, Ar), 137.04 (C, Ar), 136.23 (C, Ar), 129.31 (2×CH, Ar),128.78 (2×CH, Ar), 128.55 (CH, Ar), 127.63 (2×CH, Ar), 127.50 (2×CH, Ar), 118.06 (C=CH₂), 42.54 (NHCH₂), 21.14 (CH₃); elemental analysis calcd (%) for C₁₇H₁₇NO (251.3274): C 81.24, H 6.82, N 5.57; found: C 81.35, H 7.06, N 5.53.
3‐(1H‐Imidazol‐1‐yl)‐2‐phenyl‐N‐(4‐(trifluoromethyl)benzyl)propanamide (5 h, R¹=4‐CF₃, R²=H) and 2‐phenyl‐N‐(4‐(trifluoromethyl)benzyl)acrylamide (6 h, R¹=4‐CF₃, R²=H). Prepared from 3‐oxo‐2‐phenyl‐3‐((4‐(trifluoromethyl)benzyl)amino)propyl methanesulfonate (4 h; 0.58 g, 1.44 mmol) and purified by gradient column chromatography eluting the alkene (6 h) with petroleum ether/EtOAc 70 : 30 v/v, followed by the imidazole (5 h) with CH₂Cl₂/MeOH 90 : 10 v/v. 3‐(1H‐Imidazol‐1‐yl)‐N‐(4‐(trifluoromethyl)benzyl)‐2‐phenylpropanamide (5 h) was obtained as a brown amorphous solid, yield 0.02 g (4 %); TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]acetone): δ 7.87 (brs, 1H, NH), 7.50 (m, 4H, Ar (3) and imid. (1)), 7.33 (m, 2H, Ar (1) and imid. (1)), 7.21 (m, 4H, Ar (3) and imid. (1)), 7.11 (m, 2H, Ar), 4.67 (dd, J=9.8, 12.8 Hz, 1H, CHCHaHb), 4.38 (dd, J=6.2, 15.6 Hz, 1H, NHCHaHb), 4.22 (d, J=5.3 Hz, 1H, CHCHaHb), 4.20 (t, J=5.2 Hz, 1H, NHCHaHb), 4.05 (dd, J=5.3, 8.9 Hz, 1H, CHCHaHb); ¹³C NMR ([D₆]acetone): δ 170.85 (C, C=O), 143.94 (C, Ar), 137.47 (C, Ar), 128.64 (3×CH, Ar), 128.31 (CH, imid), 128.28 (C, Ar), 128.25 (CH, imid), 127.99 (3×CH, Ar), 127.63 (CH, Ar), 127.60 (2×CH, Ar), 127.49 (CH, imid), 125.07 & 125.04 (CF₃), 53.82 (CHCH₂imid), 49.89 (CHCH₂imid), 42.03 (NHCH₂); ¹⁹F NMR ([D₆]acetone): δ −62.87; HRMS (ESI), m/z calcd for C₂₀H₁₉F₃N₃O ([M+H]⁺), 374.1506; found: 374.1475; HPLC (Method A): 97.7 %, t_R=3.47 min. 2‐Phenyl‐N‐(4‐(trifluoromethyl)benzyl)acrylamide (6 h) was obtained as an off‐white solid, yield 0.32 g (59 %); m.p. 88–90 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.74; ¹H NMR ([D₆]DMSO): δ 8.83 (t, J=6.0 Hz, 1H, NH), 7.72 (d, J=8.1 Hz, 2H, Ar), 7.54 (d, J=8.0 Hz, 2H, Ar), 7.43 (d, J=6.8 Hz, 2H, Ar), 7.36 (m, 3H, Ar), 5.81 (s, 1H, C=CHaHb), 5.73 (s, 1H, C=CHaHb), 4.48 (d, J=6.1 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.81 (C, C=O), 145.46 (C, =C=), 144.97 (C, Ar), 137.10 (C, Ar), 128.81 (2×CH, Ar), 128.61 (CH, Ar), 128.30 (3×CH, Ar), 127.80 (C, Ar), 127.57 (3×CH, Ar), 125.69 & 125.66 (CF₃), 118.60 (C=CH₂), 42.55 (NHCH₂); ¹⁹F NMR ([D₆]DMSO): δ −60.78; elemental analysis calcd (%) for C₁₇H₁₄F₃NO⋅0.1 H₂O (307.10042): C 66.49, H 4.66, N 4.56; found: C 66.43, H 4.75, N 4.48.
3‐(1H‐Imidazol‐1‐yl)‐N‐(4‐methoxybenzyl)‐2‐phenylpropanamide (5 i, R¹=4‐OCH₃, R²=H) andN‐(4‐methoxybenzyl)‐2‐phenylacrylamide (6 i, R¹=4‐OCH₃, R²=H). Prepared from 3‐((4‐methoxybenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 i; 0.67 g, 1.85 mmol) and purified by gradient column chromatography eluting the alkene (6 i) with petroleum ether/EtOAc 60 : 40 v/v, followed by the imidazole (5 i) with CH₂Cl₂/MeOH 90 : 10 v/v. 3‐(1H‐Imidazol‐1‐yl)‐N‐(4‐methoxybenzyl)‐2‐phenylpropanamide (5 i) was obtained as a brown solid, yield 0.17 g (27 %); m.p. 102–104 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.52 (t, J=5.8 Hz, 1H, NH), 7.53 (brs, 1H, imid), 7.39 (d, J=7.2 Hz, 2H, Ar), 7.34 (t, J=7.4 Hz, 2H, Ar), 7.28 (t, J=7.2 Hz, 1H, Ar), 7.09 (brs, 1H, imid), 6.93 (d, J=8.6 Hz, 2H, Ar), 6.87 (brs, 1H, imid), 6.79 (d, J=8.6 Hz, 1H, Ar), 4.62 (dd, J=9.6, 13.4 Hz, 1H, CHCHaHb), 4.24 (ϕt, J=5.6, 4.3 Hz, 1H, NHCHaHb), 4.22 (t, J=5.8 Hz, 1H, CHCHaHb), 4.06 (dd, J=5.4, 14.9 Hz, 1H, NHCHaHb), 4.00 (dd, J=5.8, 9.5 Hz, 1H, CHCHaHb), 3.71 (s, 3H, CH₃); ¹³C NMR ([D₆]DMSO): δ 170.89 (C, C=O), 158.64 (C, C‐OCH₃), 138.05 (C, Ar), 131.30 (C, Ar), 128.90 (2×CH, Ar (1) and imid (1)), 128.77 (2×CH, Ar (1) and imid (1)), 128.28 (2×CH, Ar (1) and imid (1)), 127.81 (CH, Ar), 114.05 (2×CH, Ar), 55.52 (OCH₃), 53.31 (CHCH₂imid), 48.91 (CHCH₂imid), 41.99 (NHCH₂); LRMS (ES+TOF, m/z): 336.17 [C₂₀H₂₁N₃O₂+H]⁺; HRMS (ES+TOF), m/z calcd for C₂₀H₂₂N₃O₂ ([M+H]⁺), 336.1712; found: 336.1715; HPLC (Method A): 95.9 %, t_R=5.07 min. N‐(4‐Methoxybenzyl)‐2‐phenylacrylamide (6 i) was obtained as an off‐white solid, yield 0.31 g (50 %); m.p. 100–102 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.64; ¹H NMR ([D₆]DMSO): δ 8.66 (t, J=5.9 Hz, 1H, NH), 7.43 (d, J=4.7 Hz, 2H, Ar), 7.36 (m, 3H, Ar), 7.25 (d, J=8.7 Hz, 2H, Ar), 6.91 (d, J=8.7 Hz, 2H, Ar), 5.77 (s, 1H, C=CHaHb), 5.65 (s, 1H, C=CHaHb), 4.33 (d, J=6.1 Hz, 2H, NHCH₂), 3.75 (s, 3H, CH₃); ¹³C NMR ([D₆]DMSO): δ 168.58 (C, C=O), 158.66 (C, C‐OCH₃), 145.72 (C, C=CH₂), 137.22 (C, Ar), 132.02 (C, Ar), 129.00 (2×CH, Ar), 128.78 (2×CH, Ar), 128.54 (CH, Ar), 127.50 (2×CH, Ar), 118.04 (C=CH₂), 114.18 (2×CH, Ar), 55.53 (CH₃), 42.27 (NHCH₂); elemental analysis calcd (%) for C₁₇H₁₇NO₂ (267.3268): C 76.38, H 6.41, N 5.24; found: C 76.35, H 6.30, N 5.13.
N‐(3,4‐Dimethoxybenzyl)‐3‐(1H‐imidazol‐1‐yl)‐2‐phenylpropanamide (5 j, R¹=3,4‐diOCH₃, R²=H) andN‐(3,4‐dimethoxybenzyl)‐2‐phenylacrylamide (6 j, R¹=3,4‐diOCH₃, R²=H). Prepared from 3‐((3,4‐dimethoxybenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 j; 0.52 g, 1.30 mmol) and purified by gradient column chromatography eluting the alkene (6 j) with petroleum ether/EtOAc 60 : 40 v/v, followed by the imidazole (5 j) with CH₂Cl₂/MeOH 90 : 10 v/v. N‐(3,4‐Dimethoxybenzyl)‐3‐(1H‐imidazol‐1‐yl)‐2‐phenylpropanamide (5 j) was obtained as a pale yellow oil, yield 0.25 g (51 %); TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.55 (t, J=5.8 Hz, 1H, NH), 7.53 (brs, 1H, imid), 7.41 (d, J=7.2 Hz, 2H, Ar), 7.34 (t, J=7.4 Hz, 2H, Ar), 7.28 (t, J=7.3 Hz, 1H, Ar), 7.09 (brs, 1H, imid), 6.85 (brs, 1H, imid), 6.80 (d, J=8.2 Hz, 1H, Ar), 6.60 (d, J=1.8 Hz, 1H, Ar), 6.56 (dd, J=1.8, 8.2 Hz, 1H, Ar), 4.64 (dd, J=9.6, 13.5 Hz, 1H, CHCHaHb), 4.23 (dd, J=7.5, 13.5 Hz, 1H, CHCHaHb), 4.16 (d, J=5.8 Hz, 2H, NHCHaHb), 4.01 (dd, J=5.7, 9.5 Hz, 1H, CHCHaHb), 3.70 (s, 3H, CH₃), 3.58 (s, 3H, CH₃); ¹³C NMR ([D₆]DMSO): δ 170.93 (C, C=O), 149.10 (C, COCH₃), 148.17 (C, COCH₃), 138.16 (C, Ar), 131.88 (C, Ar), 128.93 (3×CH, Ar (2) and imid (1)), 128.52 (CH, imid), 128.27 (3×CH, Ar (2) and imid (1)), 127.81 (CH, Ar), 119.55 (CH, Ar), 112.05 (CH, Ar), 111.14 (CH, Ar), 56.02 (OCH₃), 55.67 (OCH₃), 53.35 (CHCH₂imid), 48.80 (CHCH₂imid), 42.21 (NHCH₂); LRMS (ES+TOF, m/z): 366.18 [C₂₁H₂₃N₃O₃ + H]⁺; HRMS (ES+ TOF), m/z calcd for C₂₁H₂₄N₃O₃ ([M+H]⁺), 366.1818; found: 366.1826; HPLC (Method A): 99.9 %, t_R=4.81 min. N‐(3,4‐Dimethoxybenzyl)‐2‐phenylacrylamide (6 j) was obtained as white solid, yield 0.09 g (23 %); m.p. 102–104 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.64; ¹H NMR ([D₆]DMSO): δ 8.66 (t, J=6.0 Hz, 1H, NH), 7.44 (m, 2H, Ar), 7.36 (m, 3H, Ar), 6.92 (m, 2H, Ar), 6.84 (dd, J=1.9, 8.2 Hz, 1H, Ar), 5.78 (s, 1H, C=CHaHb), 5.65 (s, 1H, C=CHaHb), 4.33 (d, J=6.1 Hz, 2H, NHCH₂), 3.75 (s, 3H, CH₃), 3.74 (s, 3H, CH₃); ¹³C NMR ([D₆]DMSO): δ 168.68 (C, C=O), 149.13 (C, C‐OCH₃), 148.21 (C, C‐OCH₃), 145.75 (C, C=CH₂), 137.19 (C, Ar), 132.52 (C, Ar), 128.79 (2×CH, Ar), 128.57 (CH, Ar), 127.45 (2×CH, Ar), 119.74 (CH, Ar), 117.87 (C=CH₂), 112.24 (CH, Ar), 111.69 (CH, Ar), 56.05 (CH₃), 55.86 (CH₃), 42.54 (NHCH₂); elemental analysis calcd (%) for C₁₈H₁₉NO₃ (299.3530): C 72.71, H 6.44, N 4.71; found: C 72.59, H 6.46, N 4.82.
N‐(4‐Chlorobenzyl)‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanamide (5 k, R¹=4‐Cl, R²=H). Prepared from 3‐((4‐chlorobenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 c; 0.59 g, 1.61 mmol) and purified by gradient column chromatography eluting the triazole (5 k) with petroleum ether/EtOAc 10 : 90 v/v. Product was obtained as a white solid, yield 0.22 g (40 %); m.p. 113–115 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 8.72 (t, J=6.0 Hz, 1H, NH), 8.32 (s, 1H, triaz), 7.99 (s, 1H, triaz), 7.20 (m, 5H, Ar), 7.28 (d, J=8.4 Hz, 2H, Ar), 6.97 (d, J=8.5 Hz, 2H, Ar), 4.83 (dd, J=9.2, 13.8 Hz, 1H, CHCHaHb), 4.44 (dd, J=6.5, 13.5 Hz, 1H, CHCHaHb), 4.27 (m, 2H, CHCHaHb+NHCHaHb), 4.08 (dd, J=5.5, 15.6 Hz, NHCHaHb); ¹³C NMR ([D₆]DMSO): δ 170.74 (C, C=O), 151.99 (CH, triaz), 145.08 (CH, triaz), 138.58 (C, Ar), 137.94 (C, C−Cl), 137.47 (C, C−Cl), 131.68 (C, Ar), 129.9.36 (CH, Ar), 129.07 (2×CH, Ar), 129.02 (2×CH, Ar), 128.78 (CH, Ar), 128.54 (2×CH, Ar), 128.23 (CH, Ar), 51.56 (CHCH₂triaz), 51.10 (CHCH₂triaz), 41.72 (NHCH₂); elemental analysis calcd (%) for C₁₈H₁₇ClN₄O (340.8115): C 63.44; H, 5.03; N, 16.43 ; found: C 63.22; H, 5.01; N, 16.33; HPLC (Method A): 99.7 %, t_R=4.91 min.
tert‐Butyl (4‐((2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanamido)methyl)phenyl)carbamate (5 l, R¹=NHBoc, R²=H) andtert‐butyl (4‐((2‐phenylacrylamido)methyl)phenyl)carbamate (6 l, R¹=NHBoc, R²=H). Prepared from 3‐((4‐((tert‐butoxycarbonyl)amino)benzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 k; 0.62 g, 1.39 mmol) and purified by gradient column chromatography eluting the alkene (6 l) with petroleum ether/EtOAc 60 : 40 v/v, followed by the imidazole (5 l) with CH₂Cl₂/MeOH 90 : 10 v/v. tert‐Butyl (4‐((2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanamido)methyl)phenyl)carbamate (5 l) was obtained as a pale yellow oil, yield 0.49 g (84 %); TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR (CDCl₃): δ 7.80 (s, 1H, triazole), 7.76 (s, 1H, triazole), 7.18 (m, 7H, Ar), 6.81 (d, J=8.5 Hz, 2H, Ar), 6.61 (s, 1H, NH), 6.10 (t, J=5.6 Hz, 1H, NHCHaHb), 4.83 (dd, J=8.7, 13.6 Hz, 1H, CHCHaHb), 4.23 (ddd, J=6.1, 14.7, 21.0 Hz, 2H, CHCHaHb and NHCHaHb), 4.11 (dd, J=5.5, 9.2, 14.8 Hz, 1H, NHCHaHb), 3.97 (dd, J=6.2, 8.7 Hz, 1H, CHCHaHb), 1.39 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): δ 170.26 (C, C=O), 152.79 (C, C=O), 151.99 (CH, triaz), 144.21 (CH, triaz), 137.77 (C, Ar), 135.96 (C, Ar), 132.12 (C, Ar), 129.25 (2×CH, Ar), 128.35 (CH, Ar), 128.14 (3×CH, Ar), 127.81 (2×CH, Ar), 118.75 (CH, Ar), 80.60 (C(CH₃)₃), 54.71 (CHCH₂), 52.05 (CHCH₂), 42.15 (NHCH₂), 28.33 (C(CH₃)₃); HRMS (ESI), m/z calcd for C₂₃H₂₈N₅O₃ ([M+H]⁺), 422.2218; found: 422.2187; HPLC (Method A): 99.7 %, t_R=4.82 min. tert‐Butyl (4‐((2‐phenylacrylamido)methyl)phenyl)carbamate (6 l) was obtained as white solid, yield 0.06 g (9 %); m.p. 136–138 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.7; ¹H NMR (CDCl₃): δ 7.38 (m, 5H, Ar), 7.33 (d, J=8.5 Hz, 2H, Ar), 7.21 (d, J=8.5 Hz, 2H, Ar), 6.53 (s, 1H, NH), 6.21 (d, J=1.3 Hz, 1H, C=CHaHb), 5.97 (brs, 1H, NH), 5.65 (d, J=1.3 Hz, 1H, C=CHaHb), 4.49 (d, J=5.6 Hz, 2H, NHCH₂), 1.53 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): δ 167.07 (C, C=O), 152.73 (C, C=O), 144.61 (C, C=CHaHb), 137.77 (C, Ar), 136.97 (C, Ar), 132.60 (C, Ar), 128.77 (2×CH, Ar), 128.57 (CH, Ar), 128.50 (3×CH, Ar), 128.82 (2×CH, Ar), 122.64 (C=CH₂), 118.78 (CH, Ar), 80.64 (C(CH₃)₃), 43.46 (NHCH₂), 28.34 (C(CH₃)₃); HRMS (ESI), m/z calcd for C₂₁H₂₅N₂O₃ ([M+H]⁺), 353.1876; found: 353.1860.
N‐(4‐Chlorobenzyl)‐2‐phenylacrylamide (6 c, R¹=4‐Cl, R²=H). Prepared from 3‐((4‐chlorobenzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (4 c; 0.38 g, 1.03 mmol) and purified by gradient column chromatography eluting the alkene (6 c) with petroleum ether/EtOAc 70 : 30 v/v. Product was obtained as a white solid, yield 0.09 g (23 %); m.p. 118–120 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.75; ¹H NMR ([D₆]DMSO): δ 8.76 (t, J=5.9 Hz, 1H, NH), 7.38 (m, 9H, Ar), 5.79 (s, 1H, C=CHaHb), 5.69 (s, 1H, C=CHaHb), 4.37 (d, J=6.1 Hz, 2H, NHCH₂; ¹³C NMR ([D₆]DMSO): δ 168.72 (C, C=O), 145.53 (C, C=CH₂), 139.13 (C, Ar), 137.12 (C, Ar), 131.77 (C, C−Cl), 129.54 (2×CH, Ar), 128.80 (2×CH, Ar), 128.73 (2×CH, Ar), 128.59 (CH, Ar), 127.54 (2×CH, Ar), 118.40 (C=CH₂), 42.22 (NHCH₂); elemental analysis calcd (%) for C₁₆H₁₄ClNO (271.7457): C 70.72, H 5.19, N 5.15; found: C 70.44, H 5.16, N 5.04.
2‐Phenyl‐N‐(4‐(phenylsulfonamido)benzyl)‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanamide (12 a, R¹=H) and 2‐phenyl‐N‐(4‐(phenylsulfonamido)benzyl) acrylamide (13 a, R¹=H). Prepared from 3‐oxo‐2‐phenyl‐3‐((4‐(phenylsulfonamido)benzyl)amino)propyl methanesulfonate (11 a; 0.32 g, 0.65 mmol) and purified by gradient column chromatography eluting the alkene (13 a) with petroleum ether/EtOAc 40 : 60 v/v, followed by the triazole (12 a) with CH₂Cl₂/MeOH 90 : 10 v/v. 2‐Phenyl‐N‐(4‐(phenylsulfonamido)benzyl)‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanamide (12 a) was obtained as a white solid, yield 0.06 g (19 %); m.p. 96–98 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 10.20 (brs, 1H, NHSO₂), 8.58 (t, J=5.9 Hz, 1H, NH), 8.30 (s, 1H, triazole), 7.92 (s, 1H, triazole), 7.73 (d, J=7.1 Hz, 2H, Ar), 7.61 (t, J=7.4 Hz, 1H, Ar), 7.54 (t, J=7.5 Hz, 2H, Ar), 7.31 (m, 5H, Ar), 6.93 (d, J=8.6 Hz, 2H, Ar), 6.79 (d, J=8.6 Hz, 2H, Ar), 4.80 (dd, J=9.1, 13.5 Hz, 1H, CHCHaHb), 4.42 (dd, J=6.6, 13.5 Hz, 1H, CHCHaHb), 4.18 (ddd, J=6.5, 15.4, 20.9 Hz, 2H, CHCHaHb+NHCHaHb), 3.97 (dd, J=5.8, 15.4 Hz, 1H, NHCHaHb); ¹³C NMR ([D₆]DMSO): δ 170.59 (C, C=O), 151.89 (CH, triazole), 145.63 (CH, triazole), 139.93 (C, Ar), 137.50 (C, Ar), 136.68 (C, Ar), 135.23 (C, Ar), 133.33 (CH, Ar), 129.70 (2×CH, Ar), 128.96 (2×CH, Ar), 128.21 (2×CH, Ar), 128.05 (2×CH, Ar), 127.91 (CH, Ar), 127.09 (2×CH, Ar), 120.51 (2×CH, Ar), 51.52 (CHCH₂), 51.08 (CHCH₂), 41.78 (NHCH₂); HRMS (ESI), m/z calcd for C₂₄H₂₄N₅O₃S ([M+H]⁺), 462.1594; found: 462.1613; HPLC (Method A): 99.9 %, t_R=4.68 min. 2‐Phenyl‐N‐(4‐(phenylsulfonamido)benzyl) acrylamide (13 a) was obtained as white waxy solid, yield 0.15 g (51 %); TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.46; ¹H NMR ([D₆]DMSO): δ 10.25 (brs, 1H, NHSO₂), 8.63 (t, J=6.0 Hz, 1H, NH), 7.77 (d, J=7.1 Hz, 2H, Ar), 7.60 (t, J=7.1 Hz, 1H, Ar), 7.54 (t, J=7.45 Hz, 2H, Ar), 7.36 (m, 5H, Ar), 7.16 (d, J=8.6 Hz, 2H, Ar), 7.06 (d, J=8.6 Hz, 2H, Ar), 5.76 (s, 1H, C=CHaHb), 5.64 (s, 1H, C=CHaHb), 4.27 (d, J=6.1 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.65 (C, C=O), 145.56 (C, C=CH₂), 140.00 (C, Ar), 137.13 (C, Ar), 136.71 (C, Ar), 135.84 (C, Ar), 133.33 (CH, Ar), 129.71 (2×CH, Ar), 128.77 (2×CH, Ar), 128.55 (CH, Ar), 128.42 (2×CH, Ar), 127.49 (2×CH, Ar), 127.11 (2×CH, Ar), 120.69 (2×CH, Ar), 118.18 (C=CH₂), 42.21 (NHCH₂); HRMS (ESI), m/z calcd for C₂₂H₂₁N₂O₃S ([M+H]⁺), 393.1267; found: 393.1255.
N‐(4‐((4‐Fluorophenyl)sulfonamido)benzyl)‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl) propanamide (12 b, R¹=4‐F) andN‐(4‐((4‐fluorophenyl)sulfonamido)benzyl)‐2‐phenylacrylamide (13 b, R¹=4‐F). Prepared from 3‐oxo‐2‐phenyl‐3‐((4‐(4‐fluorophenylsulfonamido)benzyl)amino)propyl methanesulfonate (11 b; 0.31 g, 0.62 mmol) and purified by gradient column chromatography eluting the alkene (13 b) with petroleum ether/EtOAc 50 : 50 v/v, followed by the triazole (12 b) with CH₂Cl₂/MeOH 90 : 10 v/v. N‐(4‐((3‐Fluorophenyl)sulfonamido)benzyl)‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl) propanamide (12 b) was obtained as a white solid, yield 0.09 g (30 %); m.p. 78–80 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 10.21 (brs, 1H, NHSO₂), 8.59 (t, J=5.9 Hz, 1H, NH), 8.31 (s, 1H, triazole), 7.93 (s, 1H, triazole), 7.79 (dd, J=5.2, 8.9 Hz, 2H, Ar), 7.34 (m, 7H, Ar), 6.93 (d, J=8.5 Hz, 2H, Ar), 6.81 (d, J=8.5 Hz, 2H, Ar), 4.81 (dd, J=9.1, 13.5 Hz, 1H, CHCHaHb), 4.43 (dd, J=6.6, 13.5 Hz, 1H, CHCHaHb), 4.19 (m, 2H, CHCHaHb+NHCHaHb), 3.99 (dd, J=5.4, 15.4 Hz, 1H, NHCHaHb); ¹³C NMR ([D₆]DMSO): δ 170.60 (C, C=O), 165.73 (C, Ar), 163.73 (C, Ar), 151.90 (CH, triazole), 143.33 (CH, triazole), 137.51 (C, Ar), 136.49 (C, Ar), 135.48 (C, Ar), 130.21 (CH, Ar), 130.13 (CH, Ar), 128.96 (2×CH, Ar), 128.22 (2×CH, Ar), 128.08 (2×CH, Ar), 127.90 (CH, Ar), 120.76 (2×CH, Ar), 117.00 (CH, Ar), 116.82 (CH, Ar), 51.53 (CHCH₂), 51.09 (CHCH₂), 41.78 (NHCH₂); elemental analysis calcd (%) for C₂₄H₂₂FN₅O₃S⋅0.1 H₂O (481.32942): C 59.89, H 4.65, N 14.55; found: C 59.52, H 4.49, N 14.26; HPLC (Method A): 99.9 %, t_R=4.69 min. N‐(4‐((4‐Fluorophenyl)sulfonamido)benzyl)‐2‐phenylacrylamide (13 b) was obtained as a white solid, yield 0.12 g (41 %); m.p. 136–138 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.5; ¹H NMR ([D₆]DMSO): δ 10.27 (brs, 1H, NHSO₂), 8.64 (t, J=6.1 Hz, 1H, NH), 7.81 (dd, J=5.2, 9.0 Hz, 2H, Ar), 7.36 (m, 7H, Ar), 7.17 (d, J=8.6 Hz, 2H, Ar), 7.06 (d, J=8.6 Hz, 2H, Ar), 5.76 (s, 1H, C=CHaHb), 5.64 (s, 1H, C=CHaHb), 4.28 (d, J=6.1 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.65 (C, C=O), 165.73 (C, Ar), 163.73 (C, Ar), 145.56 (C, C=CH₂), 137.13 (C, Ar), 136.50 (C, Ar), 136.09 (C, Ar), 130.22 (CH, Ar), 130.15 (CH, Ar), 128.76 (2×CH, Ar), 128.54 (CH, Ar), 128.47 (2×CH, Ar), 127.49 (2×CH, Ar), 120.93 (2×CH, Ar), 118.20 (C=CH₂), 117.02 (CH, Ar), 116.84 (CH, Ar), 42.20 (NHCH₂); HRMS (ESI), m/z calcd for C₂₂H₂₀FN₂O₃S ([M+H]⁺), 411.1173; found: 411.1173.
N‐(4‐((4‐Chlorophenyl)sulfonamido)benzyl)‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl) propanamide (12 c, R¹=4‐Cl) andN‐(4‐((4‐chlorophenyl)sulfonamido)benzyl)‐2‐phenylacrylamide (13 c, R¹=4‐Cl). Prepared from 3‐((4‐((4‐chlorophenyl)sulfonamido)benzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (11 c; 0.20 g, 0.41 mmol) and purified by gradient column chromatography eluting the alkene (13 c) with petroleum ether/EtOAc 50 : 50 v/v, followed by the triazole (12 c) with CH₂Cl₂/MeOH 90 : 10 v/v. N‐(4‐((4‐Chlorophenyl)sulfonamido)benzyl)‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl) propanamide (12 c) was obtained as an off‐white solid, yield 0.02 g (11 %); m.p. 122–124 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 10.27 (brs, 1H, NHSO₂), 8.59 (t, J=5.9 Hz, 1H, NH), 8.31 (s, 1H, triazole), 7.92 (s, 1H, triazole), 7.72 (d, J=8.8 Hz, 2H, Ar), 7.63 (d, J=8.8 Hz, 2H, Ar), 7.30 (m, 5H, Ar), 6.92 (d, J=8.6 Hz, 2H, Ar), 6.81 (d, J=8.6 Hz, 2H, Ar), 4.81 (dd, J=9.1, 13.5 Hz, 1H, CHCHaHb), 4.43 (dd, J=6.6, 13.5 Hz, 1H, CHCHaHb), 4.19 (m, 2H, CHCHaHb+NHCHaHb), 3.99 (dd, J=5.4, 15.4 Hz, 1H, NHCHaHb); ¹³C NMR ([D₆]DMSO): δ 170.60 (C, C=O), 151.89 (CH, triazole), 143.81 (CH, triazole), 138.76 (C, Ar), 138.21 (C, C−Cl), 137.51 (C, Ar), 136.33 (C, Ar), 135.61 (C, Ar), 129.89 (2×CH, Ar), 129.07 (2×CH, Ar), 128.96 (2×CH, Ar), 128.22 (2×CH, Ar), 128.12 (2×CH, Ar), 127.90 (CH, Ar), 120.85 (2×CH, Ar), 51.52 (CHCH₂), 51.09 (CHCH₂), 41.78 (NHCH₂); HRMS (ESI), m/z calcd for C₂₄H₂₃ClN₅O₃S ([M+H]⁺), 455.1119; found: 455.1143; HPLC (Method A): 99.9 %, t_R=4.75 min. N‐(4‐((3‐Chlorophenyl)sulfonamido)benzyl)‐2‐phenylacrylamide (13 c) was obtained as a white solid, yield 0.10 g (50 %); m.p. 164–166 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.73; ¹H NMR ([D₆]DMSO): δ 10.33 (brs, 1H, NHSO₂), 8.64 (t, J=6.1 Hz, 1H, NH), 7.75 (d, J=8.8 Hz, 2H, Ar), 7.63 (d, J=8.8 Hz, 2H, Ar), 7.36 (m, 5H, Ar), 7.18 (d, J=8.5 Hz, 2H, Ar), 7.05 (d, J=8.5 Hz, 2H, Ar), 5.76 (s, 1H, C=CHaHb), 5.64 (s, 1H, C=CHaHb), 4.28 (d, J=6.1 Hz, 2H, NHCH₂); ¹³C NMR ([D₆]DMSO): δ 168.67 (C, C=O), 145.55 (C, C=CH₂), 138.81 (C, Ar), 138.22 (C, C−Cl), 137.12 (C, Ar), 136.20 (C, Ar), 129.90 (2×CH, Ar), 129.08 (2×CH, Ar), 128.77 (2×CH, Ar), 128.55 (CH, Ar), 128.51 (2×CH, Ar), 127.49 (2×CH, Ar), 121.02 (2×CH, Ar), 118.20 (C=CH₂), 42.21 (NHCH₂); HRMS (ESI), m/z calcd for C₂₂H₂₀ClN₂O₃S ([M+H]⁺), 427.0884; found: 427.0872.
2‐Phenyl‐N‐(4‐(4‐methoxyphenylsulfonamido)benzyl)‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanamide (12 d, R¹=4‐OCH₃) and 2‐phenyl‐N‐(4‐(4‐methoxyphenylsulfonamido)benzyl)acrylamide (13 d, R¹=4‐OCH₃). Prepared from 3‐((4‐((4‐methoxyphenyl)sulfonamido)benzyl)amino)‐3‐oxo‐2‐phenylpropyl methanesulfonate (11 d; 0.40 g, 0.77 mmol) and purified by gradient column chromatography eluting the alkene (13 d) with petroleum ether/EtOAc 40 : 60 v/v, followed by the triazole (12 d) with CH₂Cl₂/MeOH 90 : 10, v/v. N‐(4‐((4‐Methoxyphenyl)sulfonamido)benzyl)‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl) propanamide (12 d) was obtained as a white solid, yield 0.07 g (17 %); m.p. 160–162 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.0; ¹H NMR ([D₆]DMSO): δ 10.05 (brs, 1H, NHSO₂), 8.58 (t, J=5.9 Hz, 1H, NH), 8.31 (s, 1H, triazole), 7.92 (s, 1H, triazole), 7.67 (d, J=9.0 Hz, 2H, Ar), 7.31 (m, 5H, Ar), 7.05 (d, J=9.0 Hz, 2H, Ar), 6.93 (d, J=8.5 Hz, 2H, Ar), 6.79 (d, J=8.5 Hz, 2H, Ar), 4.81 (dd, J=9.0, 13.4 Hz, 1H, CHCHaHb), 4.43 (dd, J=6.6, 13.5 Hz, 1H, CHCHaHb), 4.19 (m, 2H, CHCHaHb+NHCHaHb), 3.98 (dd, J=5.4, 15.4 Hz, 1H, NHCHaHb), 3.80 (s, 3H, OCH₃); ¹³C NMR ([D₆]DMSO): δ 170.59 (C, C=O), 162.85 (C, C‐OCH₃), 151.84 (CH, triazole), 145.04 (CH, triazole), 137.57 (CH, Ar), 136.97 (C, Ar), 135.00 (C, Ar), 131.74 (C, Ar), 129.31 (2×CH, Ar), 128.93 (2×CH, Ar), 128.22 (2×CH, Ar), 128.02 (2×CH, Ar), 128.87 (CH, Ar), 120.36 (2×CH, Ar), 114.81 (2×CH, Ar), 56.09 (OCH₃), 51.58 (CHCH₂), 51.18 (CHCH₂), 41.87 (NHCH₂); HRMS (ESI), m/z calcd for C₂₅H₂₆N₅O₄S ([M+H]⁺), 492.1706; found: 492.1695; HPLC (Method A): 99.99 %, t_R=4.68 min. N‐(4‐((4‐Methoxyphenyl)sulfonamido)benzyl)‐2‐phenylacrylamide (13 d) was obtained as a white solid, yield 0.17 g (44 %); m.p. 98–100 °C; TLC (petroleum ether/EtOAc 1 : 1 v/v); R_f=0.33; ¹H NMR ([D₆]DMSO): δ 10.11 (brs, 1H, NHSO₂), 8.63 (t, J=6.1 Hz, 1H, NH), 7.69 (d, J=9.0 Hz, 2H, Ar), 7.38 (m, 5H, Ar), 8.65 (d, J=8.7 Hz, 2H, Ar), 7.05 (d, J=8.8 Hz, 4H, Ar), 5.76 (s, 1H, C=CHaHb), 5.64 (s, 1H, C=CHaHb), 4.27 (d, J=6.1 Hz, 2H, NHCH₂), 3.79 (s, 3H, OCH₃); ¹³C NMR ([D₆]DMSO): δ 168.65 (C, C=O), 162.84 (C, C‐OCH₃), 145.56 (C, C=CH₂), 136.97 (C, Ar), 135.57 (C, Ar), 131.64 (C, Ar), 129.34 (2×CH, Ar), 128.76 (2×CH, Ar), 128.54 (CH, Ar), 128.38 (2×CH, Ar), 127.49 (2×CH, Ar), 120.43 (2×CH, Ar), 118.16 (C=CH₂), 114.82 (2×CH, Ar), 56.07 (OCH₃), 42.21 (NHCH₂); HRMS (ESI), m/z calcd for C₂₃H₂₃N₂O₄S ([M+H]⁺), 423.1379; found: 423.1368.