General method for reductive amination. Preparation of 3a-f
Catalyst - Pd/active carbon (0.05 g; 10%, Aldrich®) was added to a solution of 2-phenylimidazole-4-carbaldehyde (0.40 g; 2.3 mmol) and α‑amino acid ester (2.3 mmol) in dry methanol (15 mL) and triethylamine (0.35 mL; 2.4 mmol). The solution was degassed and saturated with hydrogen in an autoclave at 1 MPa at 55 °C for 2 h. The catalyst was filtered off, washed with methanol and the filtrate concentrated in vacuo. The crude product was purified by CC (SiO2; ethyl acetate/methanol 4:0.7).
(2S)-Methyl 2-[(2-phenyl-1H-imidazol-4-yl)methylamino]propanoate (3a). Prepared from (S)-alanine methyl ester hydrochloride in 56% yield; m.p. 145-146 ºC; [α]D20 = -8.9 (c 0.05, CH3OH); 1H-NMR: δ = 1.34 (3H, d, J = 7.0, CH3), 3.50 (1H, q, J = 7.0, CHNH), 3.70 (3H, s, OCH3), 3.77 (1H, d, J = 13.8, CH2NH), 3.83 (H, d, J = 13.8, CH2NH), 7.07 (1H, s, HIm), 7.37 (1H, t, J = 7.4, ArH), 7.44 (2H, t, J = 7.4, ArH,), 7.85 (2H, d, J = 7.4, ArH); 13C-NMR: δ = 18.5 (CH3), 44.5 (CH2NH), 52.7 (OCH3), 56.60 (CHNH), 122.1 (C5Im), 126.5 (ArH), 130.0 (ArH), 130.1 (ArH), 131.4 (Arq), 137.6 (C4Im), 148.3 (C2Im), 176.4 (COOCH3); Elemental analysis (%) calcd. for C14H17N3O2: C 64.85, H 6.61, N 16.20; found: C 64.90, H 6.58, N 16.23.
(2S)-Methyl 3-methyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]butanoate (3b). Prepared from (S)-valine methyl ester hydrochloride in 73% yield; m.p. 141-142 ºC; [α]D20 = -22.8 (c 0.05, CH3OH); 1H-NMR: δ = 0.91 (3H, d, J = 6.9, (CH3)2), 0.94 (3H, d, J = 6.9, (CH3)2), 1.91-1.97 (1H, m, CH(CH3)2), 3.11 (1H, d, J = 5.8, CHNH), 3.65 (3H, s, OCH3), 3.67 (1H, d, J = 14.0, CH2NH), 3.77 (1H, d, J = 14.0, CH2NH), 6.99 (1H, s, HIm), 7.36 (1H, t, J = 7.5, ArH), 7.42 (2H, t, J = 7.5, ArH), 7.84 (2H, d, J = 7.5, ArH); 13C-NMR: δ 19.3 ((CH3)2), 32.7 (CH(CH3)2), 45.3 (CH2NH), 52.4 (OCH3), 67.5 (CHNH), 122.2 (C5Im), 126.4 (ArH), 129.8 (ArH), 130.1 (ArH), 131.6 (Arq), 138.2 (C4Im), 148.1 (C2Im), 176.5 (COOCH3); Elemental analysis (%) calcd. for C16H21N3O2: C 66.88, H 7.37, N 14.62; found: C 66.91, H 7.33, N 14.60.
(2S)-Methyl 4-methyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]pentanoate (3c). Prepared in 34% yield from (S)-leucine methyl ester hydrochloride; m.p. 115-117 °C; [α]D20 = -22.0 (c 0.05, CH3OH); 1H-NMR: δ = 0.85 (3H, d, J = 6.6, (CH3)2), 0.92 (3H, d, J = 6.6, (CH3)2), 1.47-1.52 (2H, m, CH2CH), 1.66-1.70 (1H, m, CH(CH3)2), 3.38 (1H, t, J = 7.2, CHNH), 3.67 (3H, s, OCH3), 3.68 (1H, d, J = 13.9, CH2NH), 3.79 (1H, d, J = 13.9, CH2NH), 7.01 (1H, s, HIm), 7.37 (1H, t, J = 7.5, ArH), 7.44 (2H, t, J = 7.5, ArH), 7.84 (2H, d, J = 7.2, ArH); 13C-NMR: δ = 23.0 (CH3)2), 23.1 (CH3)2), 26.2 (CH(CH3)2), 43.7 (CH2CH), 45.0 (br, CH2NH), 52.4 (OCH3), 60.2 (CHNH), 122.2 (C5Im), 126.5 (ArH), 129.9 (ArH), 130.1 (ArH), 131.6 (Arq), 148.2 (C2Im), 177.2 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C17H23N3O2: C 67.75, H 7.69, N 13.94; found: C 67.73, H 7.72, N 13.98.
(2S,3S)-Methyl 3-methyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]pentanoate (3d). Prepared from (2S,3S)-isoleucine methyl ester hydrochloride in 38% yield; m.p. 93-98 °C; [α]D20 = -9.2 (c 0.05, CH3OH); 1H-NMR: δ = 0.87-0.93 (6H, m, CHCH3 and CH2CH3), 1.17-1.24 (1H, m, CH2CH3), 1.50-1.55 (1H, m, CH2CH3), 1.70-1.72 (1H, m, CHCH3), 3.23 (1H, d, J = 5.7, CHNH), 3.65 (3H, s, OCH3), 3.67 (1H, d, J = 14.0, CH2NH), 3.77 (1H, d, J = 14.0, CH2NH), 6.99 (1H, s, HIm), 7.36 (1H, t, J = 7.4, ArH), 7.43 (2H, t, J = 7.4, ArH), 7.84 (2H, d, J = 7.8, ArH); 13C-NMR: δ = 12.0 (CH2CH3), 15.9 (CHCH3), 27.1 (CH2CH3), 39.7 (CHCH3), 45.3 (CH2NH), 52.1 (OCH3), 66.1 (CHNH), 122.2 (C5Im), 126.7 (ArH), 129.9 (ArH), 130.1 (ArH), 131.6 (Arq), 148.2 (C2Im), 176.4 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C17H23N3O2: C 67.75, H 7.69, N 13.94; found: C 67.72, H 7.73, N 13.96.
(2S)-Methyl 3-phenyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]propanoate (3e). Prepared from (S)-phenylalanine methyl ester hydrochloride in 66% yield; m.p. 165-166 °C; [α]D20 = -13.4 (c 0.05, CH3OH); 1H-NMR: δ = 2.94 (2H, 2, J = 9.7, CH2Ph), 3.58 (3H, s, OCH3), 3.61 (1H, t, J = 7.1, CHNH), 3.68 (1H, d, J = 14.0, CH2NH), 3.78 (1H, d, J = 14.0, CH2NH), 6.92 (1H, s, HIm), 7.14-7.30 (5H, m, Ph), 7.36 (1H, t, J = 7.0, ArH), 7.43 (2H, t, J = 7.7, ArH), 7.81 (2H, d, J = 7.3, ArH); 13C-NMR: δ = 40.4 (CH2Ph), 45.2 (br, CH2NH), 52.3 (OCH3), 63.3 (CHNH), 122.3 (C5Im), 126.5 (ArH), 127.9 (Ph), 129.6 (Ph), 129.9 (ArH), 130.1 (ArH), 130.4 (Ph), 131.5 (Arq), 138.6 (Phq), 148.2 (C2Im), 176.0 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C20H21N3O2: C 71.62, H 6.31, N 12.53; found: C 71.65, H 6.25, N 12.59.
(2S)-Methyl 2-phenyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]ethanoate (3f). Synthesized from (S)-glycine methyl ester hydrochloride in 23% yield; m.p. 157-158 °C; [α]D20 = -16.7 (c 0.05, CH3OH); 1H-NMR: δ = 3.63 (3H, s, OCH3), 3.73 (2H, s, CH2NH), 4.47 (1H, s, CHNH), 7.00 (1H, s, HIm), 7.28-7.44 (8H, m, ArH and Ph), 7.84 (2H, d, J = 7.4, ArH); 13C-NMR: δ = 44.3 (CH2NH), 52.8 (OCH3), 65.7 (CHNH), 122.4 (C5Im), 126.5 (ArH), 129.7 (Ph), 129.5 (Ph), 129.9 (Ph), 130.0 (ArH), 130.1 (ArH), 131.5 (Arq), 139.1 (Phq), 148.3 (C2Im), 174.6 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C19H19N3O2: C 71.01, H 5.96, N 13.08. Found: C 71.07, H 6.03, N 12.99.
General procedure for the preparation of 4a-f
Method A
Thionyl chloride (5 mL; 69 mmol) was added dropwise to a stirred and ice-cooled suspension of 5 (1.0 g; 5.3 mmol) in dry THF (200 mL). The reaction mixture was refluxed for 6 h, all of the volatiles evaporated in vacuo and the crude acylchloride used in the next step without further purification. A solution of the amine 6a-f (4.7 mmol) in dry THF (30 mL) was added dropwise to a stirred and ice-cooled solution of the above acylchloride (1 g; 4.8 mmol) in dry THF (180 mL), followed by gradual addition of triethylamine (1.5 mL, 10.7 mmol) as rapidly as pH doesn’t exceed 7. The reaction mixture was stirred for 12 h at 25 ºC, the precipitated triethylamine hydrochloride filtered off, the filtrate concentrated in vacuo and the residue purified by CC (SiO2; ethyl acetate/methanol 4:0.7).
Method B
Benzylchlorofomate (0.97 mL 6.8 mmol) was added dropwise to a solution of 5 (1.0 g; 5.3 mmol) and triethylamine (1.5 mL; 10.8 mmol) in dry THF (200 mL) under N2 at -10º. The reaction mixture was stirred for an additional 30 min whereupon a solution of amine 6a-f (5.2 mole) in dry THF (30 mL) was added. The reaction was stirred for 12 h at 25 ºC, the precipitated triethylamine hydrochloride filtered off, the filtrate concentrated in vacuo and the crude product purified by CC (SiO2; ethyl acetate/methanol 4:0.7).
(1S)-2-Phenyl-N-[1-(2-phenyl-1H-imidazol-4-yl)ethyl]-1H-imidazole-4-carboxamide (4a). This compound was synthesized from amine 6a in yields of 23 (method A) and 24% (method B), respectively; m.p. 134-135 °C; [α]D20 = +95.6 (c 0.05, CH3OH). 1H-NMR: δ = 1.62 (3H, d, J = 6.9, CH3), 5.32 (1H, q, J = 6.9, CHNH), 7.08 (1H, s, HImR), 7.31-7.43 (6H, m, ArH), 7.73 (1H, s, HImL), 7.84 (2H, d, J = 7.3, ArH), 7.89 (2H, d, J = 7.1, ArH). 13C-NMR: δ = 21.2 (CH3), 44.1 (CHNH), 118.4 (C5ImR), 123.4 (C5ImL), 126.7 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.0 (Arq), 131.4 (Arq), 137.2 (C4ImL), 143.1 (C4ImR), 148.4 (C2ImR), 148.9 (C2ImL), 164.2 (CONH). Elemental analysis (%) calcd. for C21H19N5O: C 70.57, H, 5.36; N, 19.59. Found: C, 70.55; H, 5.40; N, 19.54.
(1S)-N-[2-Methyl-1-(2-phenyl-1H-imidazol-4-yl)propyl]-2-phenyl-1H-imidazole-4-carboxamide (4b). This compound was synthesized from amine 6b in yields of 30 (method A) and 35% (method B), respectively; m.p. 127-128 °C; [α]D20 = +48.0 (c 0.05, CH3OH). 1H-NMR: δ = 0.95 (3H, d, J = 6.7, (CH3)2), 1.06 (3H, d, J = 6.7, (CH3)2), 2.29-2.35 (1H, m, CH(CH3)2), 5.04 (1H, d, J = 5.8, CHNH), 7.09 (1H, s, HImR), 7.30-7.44 (6H, m, ArH), 7.74 (1H, s, HImL), 7.85 (2H, d, J = 7.3, ArH), 7.91 (2H, d, J = 7.2, ArH). 13C-NMR: δ = 19.4 ((CH3)2), 20.4 ((CH3)2), 34.2 (CH(CH3)2), 54.1 (CHNH), 119.2 (C5ImR), 123.1 (C5ImL), 126.4 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.1 (Arq), 131.5 (Arq), 137.5 (C4ImL), 141.1 (C4ImR), 148.2 (C2ImR), 148.8 (C2ImL), 164.6 (CONH). Elemental analysis (%) calcd. for C23H23N5O: C 71.67, H 6.01, N 18.17. Found: C 71.66, H 5.97, N 18.20.
(1S)-N-[3-Methyl-1-(2-phenyl-1H-imidazol-4-yl)butyl]-2-phenyl-1H-imidazole-4-carboxamide (4c). This compound was synthesized from amine 6c in yields of 16 (method A) and 25% (method B), respectively; m.p. 155-157 °C; [α]D20 = +48.8 (c 0.05, CH3OH). 1H-NMR: δ = 0.99 (6H, deceptively t, J = 6.2, (CH3)2), 1.66-1.71 (1H, m, CH(CH3)2), 1.87 (2H, t, J = 6.9, CH2CH), 5.35 (1H, t, J = 7.5, CHNH), 7.07 (1H, s, HImR), 7.31-7.45 (6H, m, ArH), 7.73 (1H, s, HImL), 7.85 (2H, d, J = 7.2, ArH), 7.90 (2H, s, J = 7.2, ArH). 13C-NMR: δ = 22.8 ((CH3)2), 23.3 ((CH3)2), 26.4 (CH(CH3)2), 45.4 (CH2CH), 46.4 (CHNH), 118.7 (C5ImR), 123.0 (C5ImL), 126.6 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.1 (Arq), 131.6 (Arq), 138.1 (C4ImL), 142.3 (C4ImR), 148.4 (C2ImR), 148.8 (C2ImL), 165.1 (CONH). Elemental analysis (%) calcd. for C24H25N5O: C 72.16, H 6.31, N 17.53. Found: C 72.15, H 6.36, N 17.50.
(1S,2S)-N-[2-Methyl-1-(2-phenyl-1H-imidazol-4-yl)butyl]-2-phenyl-1H-imidazole-4-carboxamide (4d). This compound was synthesized from amine 6d in yields of 13 (method A) and 34% (method B), respectively; m.p. 144-145 °C; [α]D20 = +36.0 (c 0.05, CH3OH). 1H-NMR: δ = 0.93 (3H, d, J = 6.7, CHCH3), 0.96 (3H, t, J = 7.5, CH2CH3), 1.25-1.30 (1H, m, CH2CH3), 1.68-1.73 (1H, m, CH2CH3), 2.09-2.14 (1H, m, CHCH3), 5.09 (1H, d, J = 8.2, CHNH), 7.09 (1H, s, HImR), 7.30-7.46 (6H, m, ArH), 7.73 (1H, s, HImL), 7.85 (2H, d, J = 7.4, ArH), 7.92 (2H, d, J = 7.3, ArH). 13C-NMR: δ = 11.8 (CH3CH), 16.6 (CH3CH2), 26.6 (CH2CH3), 40.4 (CHCH3), 52.8 (CHNH), 119.0 (C5ImR), 123.6 (C5ImL), 126.6 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.1 (Arq), 131.5 (Arq), 137.8 (C4ImL), 141.3 (C4ImR), 148.2 (C2ImR), 148.8 (C2ImL), 165.0 (CONH). Elemental analysis (%) calcd. for C24H25N5O: C 72.16, H 6.31, N 17.53. Found: C 72.23, H 6.25, N 17.61.
(1S)-2-Phenyl-N-[2-phenyl-1-(2-phenyl-1H-imidazol-4-yl)ethyl]-1H-imidazole-4-carboxamide (4e). This compound was synthesized from amine 6e in yields of 17 (method A) and 22% (method B), respectively; m.p. 187-188 °C; [α]D20 = +33.0 (c 0.05, CH3OH). 1H-NMR: δ = 3.23-3.35 (2H, m, CH2Ph), 5.49 (1H, t, J = 7.3, CHNH), 6.97 (1H, s, HImR), 7.11 (1H, t, J = 7.3, Ph), 7.19 (2H, t, J = 7.3, Ph), 7.22 (2H, d, J = 7.2, Ph), 7.32-7.44 (6H, m, ArH), 7.69 (1H, s, HImL), 7.86 (2H, d, J = 7.4, ArH), 7.89 (2H, d, J = 7.2, ArH). 13C-NMR: δ = 42.5 (CH2Ph), 50.1 (CHNH), 118.6 (C5ImR), 123.7 (C5ImL), 126.6 (ArH), 126.9 (ArH),, 127.6 (Ph), 129.4 (ArH), 129.9 (Ph), 130.0 (ArH), 130.1 (ArH), 130.5 (Ph), 131.1 (Arq), 131.5 (Arq), 137.9 (C4ImL), 139.5 (Phq), 141.6 (C4ImR), 148.4 (C2ImR), 148.8 (C2ImL), 164.5 (CONH). Elemental analysis (%) calcd. for C27H23N5O: C 74.81, H 5.35, N 16.16. Found: C 74.78, H 5.41, N 16.14.
(1S)-2-Phenyl-N-(1-phenylethyl)-1H-imidazole-4-carboxamide (4f). This compound was synthesized from commercially available (S)-1-phenylethanamine (6f) in yields of 44 (method A) and 42% (method B), respectively; m.p. 163-164 °C; [α]D20 = +142.0 (c 0.05, CH3OH). 1H-NMR: δ = 1.55 (3H, d, J = 7.0, CH3), 5.21 (1H, q, J = 7.0, CHNH), 7.22 (1H, t, J = 7.4, Ph), 7.31 (2H, t, J = 7.4, Ph), 7.39-7.48 (5H, m, ArH and Ph), 7.72 (1H, s, HIm), 7.91 (2H, d, J = 7.1, ArH). 13C-NMR: δ = 22.7 (CH3), 50.2 (CHNH), 122.8 (C5Im), 126.9 (ArH), 127.3 (ArH), 128.3 (Ph), 129.7 (Ph), 130.2 (ArH), 130.6 (Ph), 131.1 (Arq), 145.2 (Phq), 148.6 (C2Im), 164.2 (CONH). Elemental analysis (%) calcd. for C18H17N3O: C 74.20, H 5.88, N 14.42. Found: C 74.17, H 5.85, N 14.46.