M.J. Myllyma¨ki et al. / European Journal of Medicinal Chemistry 44 (2009) 4179–4191
4187
5.1.18. Procedure for preparation of 18a–e
7.50 (dd, 1H, J ¼ 2.4, 1.5 Hz), 7.39 (td, 1H, J ¼ 7.7, 1.2 Hz), 7.30–7.18
(m, 6H), 6.98 (ddd, 1H, J ¼ 8.1, 2.6, 1.0 Hz), 4.65–4.57 (m, 1H), 4.35 (t,
1H, J ¼ 9.0 Hz), 4.17 (dd, 1H, J ¼ 8.6, 7.2 Hz), 3.23 (dd, 1H, J ¼ 13.7,
4.9 Hz), 2.75 (dd, 1H, J ¼ 13.7, 9.0 Hz); 13C NMR (CDCl3) 164.8, 156.4,
137.6, 129.7, 129.3, 128.6, 128.3, 126.6, 120.2, 119.4, 115.2, 72.0, 67.2,
41.5; Anal. C16H15NO2 (C, H, N).
5.1.18.1. (S)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenol (18a). Zinc
chloride (48 mg, 0.35 mmol, 10 mol-%) was melted in a 50 mL flask
under high vacuum. 3-Cyanophenol (413 mg, 3.46 mmol, 100 mol-
%) and chlorobenzene (10 mL) were added and heated up to reflux
under argon atmosphere. (S)-2-Aminopropanol (510 mL, 6.5 mmol,
190 mol-%) was added and the mixture was refluxed for 22 h. The
mixture was cooled to rt and filtered through a pad of silica with
EtOAc and purified by FC (33% EtOAc in hex) and recrystallized from
EtOAc:hex giving 18a (317 mg, 52%) as white needles: mp. 125–
5.1.24. (S)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenyl
cyclohexyl-carbamate (5c)
White crystals (120 mg, 56%): mp. 152–155 ꢀC; Rf 0.46 (10% Et2O
126 ꢀC; Rf (50% EtOAc in hex) 0.31; [
a]
D 48 (c ¼ 0.5, CDCl3); 1H NMR
in CH2Cl2); [
a
]
5.8 (c ¼ 0.5, CHCl3); 1H NMR (CDCl3) 7.78 (d, 1H,
D
(CDCl3) 9.45 (br s, 1H), 7.45 (dd, 1H, J ¼ 2.3, 1.6 Hz), 7.30 (td, 1H,
J ¼ 7.7,1.3 Hz), 7.18 (t,1H, J ¼ 7.9 Hz), 6.95 (ddd,1H, J ¼ 8.1, 2.5,1.0 Hz),
4.53 (dd,1H, J ¼ 9.4, 8.0 Hz), 4.45–4.36 (m,1H), 3.96 (t,1H, J ¼ 7.9 Hz),
1.33 (d, 3H, J ¼ 6.6 Hz); 13C NMR (CDCl3) 164.6, 156.9, 129.6, 128.0,
119.8, 119.5, 115.1, 74.2, 61.2, 21.1; Anal. C10H11NO2 (C, H, N).
J ¼ 7.8 Hz), 7.70 (t,1H, J ¼ 1.8 Hz), 7.39 (t,1H, J ¼ 8.0 Hz), 7.33–7.21 (m,
6H), 4.93 (d,1H, J ¼ 7.6 Hz), 4.62–4.54 (m,1H), 4.34 (t,1H, J ¼ 8.9 Hz),
4.13 (dd, 1H, J ¼ 8.3, 7.5 Hz), 3.61–3.51 (m, 1H), 3.23 (dd, 1H, J ¼ 13.7,
5.1 Hz), 2.72 (dd,1H, J ¼ 13.7, 8.9 Hz), 2.05–1.97 (m, 2H),1.78–1.70 (m,
2H),1.66–1.61 (m,1H),1.43–1.32 (m, 2H),1.28–1.14 (m, 3H); 13C NMR
(CDCl3) 163.3, 153.3, 151.0, 137.9, 129.2, 129.2, 129.0, 128.6, 126.5,
125.0,124.7,121.6, 71.9, 67.9, 50.2, 41.8, 33.2, 25.4, 24.7; Rt 57 min, 98
ee-%; Anal. C23H26N2O3 (C, H, N).
5.1.19. (S)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenyl
cyclopentyl-carbamate (4c)
White crystals (83 mg, 51%): mp. 139–142 ꢀC; Rf (15% Et2O in
CH2Cl2) 0.33; [
a
]
D ꢁ54 (c ¼ 0.5, CHCl3); 1H NMR (CDCl3) 7.77 (d, 1H,
5.1.25. (R)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenol (18d)
White waxy solid (267 mg, 41%): mp. 108–111 ꢀC; Rf 0.21 (15%
J ¼ 7.7 Hz), 7.70 (s, 1H), 7.38 (t,1H, J ¼ 8.0 Hz), 7.24 (d,1H, J ¼ 8.1 Hz),
5.04 (d, 1H, J ¼ 6.6 Hz), 4.51 (dd, 1H, J ¼ 9.3, 8.1 Hz), 4.41–4.32 (m,
1H), 4.09–4.00 (m, 1H), 3.94 (t, 1H, J ¼ 7.9 Hz), 2.06–1.97 (m, 2H),
1.75–1.56 (m, 4H), 1.53–1.44 (m, 2H), 1.35 (d, 3H, J ¼ 6.6 Hz); 13C
NMR (CDCl3) 162.7, 160.1, 153.7, 151.0, 129.1, 125.0, 124.6, 121.6, 74.1,
62.0, 53.0 (rotam. 52.1), 33.1 (rotam. 33.6), 23.5, 21.4; Anal.
C16H20N2O3 (C, H, N).
Et2O in CH2Cl2); [
a
]
D ꢁ40 (c ¼ 0.5, CHCl3); 1H NMR (CDCl3) 8.50 (br
s, 1H), 7.50 (dd, 1H, J ¼ 2.3, 1.5 Hz), 7.36 (td, 1H, J ¼ 7.7, 1.1 Hz), 7.29–
7.18 (m, 6H), 6.97 (ddd, 1H J ¼ 8.2, 2.5, 0.9 Hz), 4.66–4.57 (m, 1H),
4.34 (t, 1H, J ¼ 9.0 Hz), 4.17 (dd, 1H, J ¼ 8.5, 7.3 Hz), 3.24 (dd, 1H,
J ¼ 13.7, 4.8 Hz), 2.75 (dd, 1H, J ¼ 13.7, 9.2 Hz); 13C NMR (CDCl3)
165.0, 156.6, 137.5, 129.7, 129.3, 128.6, 128.2, 126.6, 120.1, 119.5,
115.2, 72.0, 67.0, 41.4; Anal. C16H15NO2 (C, H, N).
5.1.20. (S)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenyl
cyclohexyl-carbamate (5a)
5.1.26. (R)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenyl
cyclohexyl-carbamate (5d)
White crystals (94 mg, 65%): mp. 133–135 ꢀC; Rf (50% EtOAc in
hex) 0.40; [
a
]
D
ꢁ49 (c ¼ 0.5, CHCl3); 1H NMR (CDCl3) 7.77 (d, 1H,
White crystals (152 mg, 57%): mp. 153–155 ꢀC; Rf 0.38 (13% Et2O
J ¼ 7.7 Hz), 7.70 (s, 1H), 7.38 (t, 1H, J ¼ 7.9 Hz), 7.26–7.23 (m, 1H),
4.92 (d, 1H, J ¼ 7.3 Hz), 4.51 (dd, 1H, J ¼ 9.2, 8.2 Hz), 4.42–4.32 (m,
1H), 3.94 (t, 1H, J ¼ 7.9 Hz), 3.61–3.51 (m, 1H), 2.05–1.97 (m, 2H),
1.78–1.70 (m, 2H), 1.66–1.59 (m, 1H), 1.43–1.32 (m, 2H), 1.35 (d, 3H,
J ¼ 6.6 Hz), 1.28–1.15 (m, 3H); 13C NMR (CDCl3) 162.8, 153.4, 151.0,
129.1 (2C), 125.0, 124.6, 121.6, 74.1, 62.0, 50.1, 33.2, 25.4, 24.7, 21.4;
Rt 60 min, 93 ee-%; Anal. C17H22N2O3 (C, H, N).
in CH2Cl2); [
a
]
D
ꢁ7.4 (c ¼ 0.5, CHCl3); 1H NMR (CDCl3) 7.78 (d, 1H,
J ¼ 7.7 Hz), 7.7 (m, 1H), 7.39 (t, 1H, J ¼ 8.0 Hz), 7.33–7.20 (m, 6H),
4.93 (d, 1H, J ¼ 8.0 Hz), 4.62–4.53 (m, 1H), 4.33 (t, 1H, J ¼ 8.9 Hz),
4.13 (dd, 1H, J ¼ 8.3, 7.5 Hz), 3.62–3.50 (m, 1H), 3.23 (dd, 1H, J ¼ 13.7,
5.1 Hz), 2.71 (dd, 1H, J ¼ 13.7, 8.9 Hz), 2.05–1.97 (m, 2H), 1.77–1.70
(m, 2H), 1.66–1.58 (m, 1H), 1.43–1.32 (m, 2H), 1.28–1.14 (m, 3H); 13C
NMR (CDCl3) 163.3, 153.3, 151.0, 137.9, 129.2, 129.2, 129.0, 128.5,
126.5, 125.0, 124.7, 121.6, 71.9, 67.9, 50.1, 41.8, 33.2, 25.4, 24.7; Rt
22 min, 99 ee-%; Anal. C23H26N2O3 (C, H, N).
5.1.21. (R)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenol (18b)
White needles (283 mg, 57%): mp. 126–127 ꢀC; Rf (50% EtOAc in
hex) 0.19; [
a
]
D ꢁ46 (c ¼ 0.5, CHCl3); 1H NMR (CDCl3) 9.46 (br s, 1H),
5.1.27. (S)-3-(4-((1H-Indol-3-yl)methyl)-4,5-dihydrooxazol-2-
yl)-phenol (18e)
7.44 (dd, 1H, J ¼ 2.4, 1.6 Hz), 7.29 (td, 1H, J ¼ 7.7, 1.3 Hz), 7.18 (t, 1H,
J ¼ 7.9 Hz), 6.95 (ddd, 1H, J ¼ 8.1, 2.6, 1.0 Hz), 4.53 (dd, 1H, J ¼ 9.5,
8.1 Hz), 4.45–4.36 (m, 1H), 3.96 (t, 1H, J ¼ 7.9 Hz), 1.33 (d, 3H,
J ¼ 6.6 Hz); 13C NMR (CDCl3) 164.5, 156.9, 129.6, 127.9, 119.8, 119.5,
115.0, 74.2, 61.1, 21.1; Anal. C10H11NO2 (C, H, N).
Gray powder (140 mg, 35%): mp. 183–186 ꢀC; Rf (50% EtOAc in
hex) 0.20; [
a
]
D 59 (c ¼ 0.3, MeOH); 1H NMR (DMSO-d6) 10.85 (br s,
1H), 9.68 (s, 1H), 7.59 (d,1H, J ¼ 7.9 Hz), 7.33 (d,1H, J ¼ 8.0 Hz), 7.31–
7.19 (m, 4H), 7.06 (td, 1H, J ¼ 7.5, 1.1 Hz), 6.98 (td, 1H, J ¼ 7.4, 1.0 Hz),
6.93–6.89 (m, 1H), 4.64–4.55 (m, 1H), 4.38 (dd, 1H, J ¼ 9.4, 8.4 Hz),
4.07 (t, 1H, J ¼ 7.9 Hz), 3.13 (dd, 1H, J ¼ 14.8, 4.9 Hz), 2.82 (dd, 1H,
J ¼ 14.6, 8.1 Hz); 13C NMR (DMSO-d6) 162.1,157.3,136.1, 129.6, 128.8,
127.5, 123.4, 120.9, 118.5, 118.5, 118.4, 118.3, 114.4, 111.3, 110.4, 71.7,
66.6, 31.0; Anal. C18H16N2O2 (C, H, N).
5.1.22. (R)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenyl
cyclohexyl-carbamate (5b)
White crystals (46 mg, 27%): mp. 133–134 ꢀC; Rf (50% EtOAc in
hex) 0.24; [
a
]
45 (c ¼ 0.5, CDCl3); 1H NMR (CDCl3) 7.77 (d, 1H,
D
J ¼ 7.7 Hz), 7.70 (m, 1H), 7.38 (t, 1H, J ¼ 7.9 Hz), 7.24 (dd, 1H, J ¼ 8.1,
1.4 Hz), 4.94 (d, 1H, J ¼ 7.4 Hz), 4.51 (dd, 1H, J ¼ 9.3, 8.1 Hz), 4.42–
4.32 (m, 1H), 3.94 (t, 1H, J ¼ 7.9 Hz), 3.60–3.50 (m, 1H), 2.07–1.96
(m, 2H),1.78–1.70 (m, 2H), 1.66–1.57 (m, 1H),1.43–1.32 (m, 2H),1.35
(d, 3H, J ¼ 6.6 Hz), 1.27–1.15 (m, 3H); 13C NMR (CDCl3) 162.8, 153.4,
151.0, 129.1 (2C), 124.9, 124.6, 121.6, 74.1, 62.0, 50.1, 33.2, 25.4, 24.7,
21.4; Rt 22 min, 99 ee-%; Anal. C17H22N2O3 (C, H, N).
5.1.28. (S)-3-(4-((1H-Indol-3-yl)methyl)-4,5-dihydrooxazol-2-yl)-
phenyl cyclohexylcarbamate (7)
White crystals (35 mg, 35%): mp. 149–151 ꢀC; Rf 0.23 (10% Et2O
in CH2Cl2); [
a]
D 22 (c ¼ 0.5, CDCl3); 1H NMR (CDCl3) 8.11 (br s, 1H),
7.79 (d, 1H, J ¼ 7.8 Hz), 7.72 (s, 1H), 7.66 (d, 1H, J ¼ 7.8 Hz), 7.41–7.33
(m, 2H), 7.20 (td,1H, J ¼ 7.5,1.1 Hz), 7.13 (td,1H, J ¼ 7.4,1.0 Hz), 7.28–
7.24 (m, 1H), 7.04 (d, 1H, J ¼ 2.2 Hz), 4.94 (d, 1H, J ¼ 7.8 Hz), 4.75–
4.67 (m, 1H), 4.33 (t, 1H, J ¼ 8.9 Hz), 4.15 (t,1H, J ¼ 7.9 Hz), 3.62–3.51
(m, 1H), 3.36 (dd, 1H, J ¼ 14.5, 4.6 Hz), 2.88 (dd, 1H, J ¼ 14.6, 8.9 Hz),
2.05–1.97 (m, 2H), 1.78–1.70 (m, 2H), 1.67–1.58 (m, 1H), 1.43–1.32
5.1.23. (S)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenol (18c)
White waxy solid (446 mg, 52%): mp. 109–111 ꢀC; Rf (10% Et2O in
CH2Cl2) 0.14; [
a]
39 (c ¼ 0.5, CHCl3); 1H NMR (CDCl3) 7.92 (s, 1H),
D