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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
J = 12.2 Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H), 4.62 (dd, J = 9.1 Hz & Hz, 1H), 3.57 (s, 3H), 3.44-3.27 (m, 2H), 2.54 (s, 3VHie)w, A2r.t4icl1e-O2n.l2in6e
DOI: 10.1039/C9OB00554D
7.8 Hz, 1H), 3.44-2.27 (m, 2H), 2.55 (s, 3H), 2.22-2.05 (m, 1H), (m, 1H), 1.58 (quint, J = 7.3 Hz, 2H), 1.42-1.26 (m, 6H), 1.06 (d,
1.58 (quint, J = 7.2 Hz, 2H), 1.42-1.26 (m, 6H), 0.98 (d, J = 6.8 J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.87 (t, J = 7 Hz, 3H); 13
C
Hz, 3H), 0.92-0.84 (m, 6H); 13C NMR (101 MHz, CDCl3): δ = NMR (101 MHz, CDCl3): δ = 165.7, 163.8, 145.8, 137.4, 133.4
164.0, 156.3, 146.1, 136.4, 132.2, 130.0, 128.7, 128.3, 128.2, (q, J = 35 Hz), 132.4, 130.1, 127.7, 125.8, 123.6 (q, J = 283 Hz),
67.1, 52.8, 38.9, 33.4, 31.7, 30.2, 30.0, 26.9, 22.7, 19.6, 18.4, 50.9, 38.9, 33.4, 31.6, 30.3, 30.0, 26.8, 22.7, 19.6, 18.7, 14.1,
14.2, 9.9; HRMS (ESI): Calcd. for C24H37N4O3: 429.2865 [M+H]+, 9.8; HRMS (ESI): Calcd. for C24H34F3N4O2: 467.2634 [M+H]+,
found: 429.2860.
found: 467.2625.
(S)-2-(1-amino-2-methylpropyl)-N-hexyl-1,5-dimethyl-1H-
(S)-N-hexyl-1,5-dimethyl-2-(2-methyl-1-(4-
imidazole-4-carboxamide 8. In a 25 mL round bottom flask, to methylbenzamido)propyl)-1H-imidazole-4-carboxamide 2c.
a degassed solution of Cbz-protected amine (650 mg, 1.38 mp: 160 °C; IR (neat, cm-1): 3413, 3273, 2927, 2865, 1639,
mmol) in methanol, Pd/C (10 % w/w) was added and stirred 1593, 1507, 1463, 1372, 1321, 1231, 1189, 1117, 1047, 983,
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under hydrogen atmosphere for 3 hours. The reaction mixture 913, 838, 727, 643, 588, 553; H NMR (400 MHz, CDCl3): =
filtered through small bed of celite. The filtrate was 7.69 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.03 (t, J = 5.7
concentrated to obtain amine (407 mg, 96%) as colorless oil. IR Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 5.13 (t, J = 8.7 Hz, 1H), 3.55 (s,
(neat, cm-1): 3401, 2926, 2864, 1642, 1593, 1516, 1462, 1370, 3H), 3.34 (td, J = 13.5 & 7.3 Hz, 2H), 2.53 (s, 3H), 2.38 (s, 3H),
1321, 1271, 1230, 1126, 1051, 977, 937, 902, 733, 579; 1H 2.36-2.25 (m, 1H), 1.57 (quint, J = 7.3 Hz, 2H), 1.41-1.24 (m,
NMR (400 MHz, CDCl3): = 7.16 (br s, 1H), 3.67 (d, J = 6.8 Hz, 6H), 1.05 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.87 (t, J =
1H), 3.49 (s, 3H), 3.40-3.30 (m, 2H), 2.55 (s, 3H), 2.01 (sext, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ = 166.9, 164.0,
6.8 Hz, 1H), 1.58 (quint, J = 7.3 Hz, 2H), 1.41-126 (m, 6H), 0.98 146.2, 142.3, 132.3, 131.3, 130.0, 129.3, 127.1, 50.8, 38.8,
(d, J = 6.7 Hz, 3H), 0.91-0.84 (m, 6H); 13C NMR (101 MHz, 33.3, 31.6, 30.3, 30.0, 26.8, 22.7, 19.7, 18.7, 14.1, 9.8; HRMS
CDCl3): δ = 164.3, 148.8, 132.3, 129.7, 54.6, 38.9, 34.1, 31.7, (ESI): Calcd. for C24H37N4O2: 413.2916 [M+H]+, found:
30.2, 30.0, 26.9, 22.7, 20.0, 18.2, 14.2, 9.8; HRMS (ESI): Calcd. 413.2937.
for C16H31N4O: 295.2498 [M+H]+, found: 295.2498.
(S)-N-hexyl-2-(1-(4-methoxybenzamido)-2-methylpropyl)-
General procedure for synthesis of amides 2a-2f. In a 10 1,5-dimethyl-1H-imidazole-4-carboxamide 2d. mp: 151-153
mL round bottom flask, to a solution of carboxylic acid (1 °C; IR (neat, cm-1): 3403, 2957, 2928, 2864, 1638, 1600, 1503,
equiv.) in dry THF (1 mL), EDC·HCl (1.1 equiv.), HOBt (1.1 1462, 1372, 1311, 1252, 1178, 1114, 1031, 983, 914, 845, 770,
equiv.) were added and stirred for 15 minutes. Amine (1.1 729, 683, 641, 592, 555; 1H NMR (400 MHz, CDCl3): = 7.76 (d,
equiv.) in THF (1 mL) was added followed by the addition of J = 8.9 Hz, 2H), 7.04 (t, J = 5.8 Hz, 1H), 6.91 (d, J = 8.8, 2.4 Hz,
Et3N (1.2 equiv.). The reaction mixture stirred for 15 hours. 2H), 6.73 (d, J = 8.9 Hz, 1H), 5.13 (t, J = 8.7 Hz, 1H), 3.83 (s, 3H),
The THF was evaporated under vacuum. The residue was 3.45-3.27 (m, 2H), 2.53 (s, 3H), 2.41-2.24 (m, 1H), 1.57 (quint, J
dissolved in CH2Cl2 and extracted with water and brine. The = 7.3 Hz, 2H), 1.42-1.26 (m, 6H), 1.05 (d, J = 6.7 Hz, 3H), 0.93
organic layer was dried over Na2SO4 and filtered. The filtrate (d, J = 6.7 Hz, 3H), 0.87 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz,
was concentrated and purified by column chromatography CDCl3): δ = 166.5, 164.0, 162.5, 146.3, 132.4, 130.1, 129.0,
with silica gel eluting with 30-40% EtOAc/ petroleum ether to 126.4, 113.9, 55.5, 50.8, 38.9, 33.3, 31.7, 30.3, 30.0, 26.9, 22.7,
obtain the amide 2a-2f in good to excellent yields.
(S)-2-(1-(4-bromobenzamido)-2-methylpropyl)-N-hexyl-
1,5-dimethyl-1H-imidazole-4-carboxamide 2a. mp: 145 °C; IR
19.8, 18.8, 14.2, 9.9; HRMS (ESI): Calcd. for C24H37N4O3:
429.2865 [M+H]+, found: 429.2857.
(S)-2-(1-(4-(tert-butyl)benzamido)-2-methylpropyl)-N-
(neat, cm-1): 3404, 3282, 3061, 2957, 2926, 2863, 1639, 1592, hexyl-1,5-dimethyl-1H-imidazole-4-carboxamide 2e. mp: 140
1521, 1474, 1372, 1322, 1233, 1144, 1070, 1011, 980, 913, °C; IR (neat, cm-1): 3411, 2958, 2927, 2865, 1640, 1594, 1511,
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844, 733, 559; H NMR (400 MHz, CDCl3): = 7.67 (d, J = 8.7 1463, 1368, 1322, 1274, 1232, 1150, 1049, 983, 917, 851, 774,
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Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.02 (m, J = 5.7 Hz, 1H), 6.78 731, 643, 568; H NMR (400 MHz, CDCl3): = 7.74 (d, J = 8.5
(d, J = 9.2 Hz, 1H), 5.12 (dd, J = 9.0 & 8.2 Hz, 1H), 3.57 (s, 3H), Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.05 (t, J = 5.9 Hz, 1H), 6.77 (d,
3.44-3.27 (m, 2H), 2.55 (s, 3H), 2.36-2.25 (m, 1H), 1.59 (quint, J J = 9.1 Hz, 1H), 5.14 (t, J = 8.7 Hz, 1H), 3.56 (s, 3H), 3.45-3.27
= 7.3 Hz, 2H), 1.42-1.27 (m, 6H), 1.04 (d, J = 6.7 Hz, 3H), 0.93 (m, 2H), 2.55 (s, 3H), 2.42-2.25 (m, 1H), 1.58 (quint, J = 7.3 Hz,
(d, J = 6.7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H); 13C NMR (101 MHz, 2H), 1.43-1.27 (m, 15H), 1.05 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.7
CDCl3): δ = 166.0, 163.9, 146.0, 133.0, 132.4, 131.9, 130.1, Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ =
128.8, 126.5, 50.9, 38.9, 33.4, 31.6, 30.3, 30.0, 26.8, 22.7, 19.6, 166.9, 164.0, 155.4, 146.2, 132.4, 131.3, 130.1, 127.0, 125.7,
18.7, 14.1, 9.8; HRMS (ESI): Calcd. for C23H34BrN4O2: 477.1865 50.8, 38.9, 35.1, 33.4, 31.7, 30.3, 30.1, 26.9, 22.7, 19.8, 18.8,
[M+H]+, found: 477.1858.
(S)-N-hexyl-1,5-dimethyl-2-(2-methyl-1-(4-
(trifluoromethyl)benzamido)propyl)-1H-imidazole-4-
14.2, 9.9; HRMS (ESI): Calcd. for C27H43N4O2: 455.3386 [M+H]+,
found: 455.3391.
(S)-N-hexyl-1,5-dimethyl-2-(2-methyl-1-
carboxamide 2b. mp: 140 °C; IR (neat, cm-1): 3418, 3276, (perfluorobenzamido)propyl)-1H-imidazole-4-carboxamide
2960, 2865, 1639, 1592, 1521, 1463, 1409, 1372, 1324, 1231, 2f. mp: 126-127 °C; IR (neat, cm-1): 3419, 3270, 2960, 2928,
1166, 1124, 1067, 1018, 984, 912, 857, 771, 730, 691, 644, 2865, 1652, 1593, 1496, 1414, 1373, 1340, 1260, 1230, 1163,
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596, 552; H NMR (400 MHz, CDCl3): = 7.92 (d, J = 8.1 Hz, 1111, 1049, 989, 915, 861, 823, 730, 682, 645, 611, 575; H
2H), 7.70 (d, J = 8.2 Hz, 2H), 7.08-6.93 (m, 2H), 5.14 (t, J = 8.6 NMR (400 MHz, CDCl3): = 7.18 (d, J = 8.1 Hz, 1H), 7.0 (t, J =
6 | J. Name., 2012, 00, 1-3
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