Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4283
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N-(4-Hydroxyphenethyl)-2,2-diphenylacetamide (25). H NMR
(400 MHz, CDCl3) δ 7.26 (m, 6H), 7.15 (d, 4H, J=6.7 Hz), 6.85
(d, 2H, J=8.3 Hz), 6.68 (d, 2H, J=8.3 Hz), 5.82 (s, 1H), 4.87 (s,
1H), 3.48 (t, 2H, J=6.8 Hz), 2.66 (t, 3H, J=6.8 Hz). HRMS (ESI
(MþH)þ m/z) calcd for C22H22NO2 332.1651, found 332.1642.
N-(4-Hydroxyphenethyl)-2-(6-methoxy-3-oxo-2,3-dihydro-1H-
inden-1-yl)acetamide (26). 1H NMR (400 MHz, CDCl3) δ 7.66 (d,
1H, J=8.5 Hz), 7.01 (d, 2H, J=8.3 Hz), 6.93 (dd, 2H, J=3.8,
12.3 Hz), 6.77 (d, 2H, J=8.4 Hz), 5.32 (s, 1H), 3.88 (s, 3H), 3.80
(dd, 1H, J=7.6, 14.7 Hz), 3.54 (m, 1H), 3.41 (m, 2H), 2.87 (dd,
1H, J=7.3, 18.7 Hz), 2.73 (m, 2H), 2.63 (dd, 1H, J=4.8, 14.4 Hz),
2.27 (dd, 1H, J=9.8, 13.9 Hz). HRMS (ESI (MþH)þ m/z) calcd
for C20H22NO4 340.1549, found 340.1533.
3.91 (s, 3H), 3.64 (dd, 1H, J=6.3, 13.4 Hz), 3.38 (ddd, 2H, J=
6.4, 16.3, 19.2 Hz), 2.57 (t, 2H, J=6.5 Hz), 1.57 (d, 3H, J=
7.1 Hz). HRMS (ESI (M þ H)þ m/z) calcd for C22H24NO3
350.1756, found 350.1754.
(S)-2-(3-Benzoylphenyl)-N-(4-hydroxyphenethyl)propanamide
(36). 1H NMR (400 MHz, CDCl3) δ 7.77 (m, 2H), 7.66 (m, 2H),
7.59 (m, 1H), 7.46 (m, 4H), 6.81 (d, 2H, J=8.5 Hz), 6.68 (m, 2H),
5.54 (t, 1H, J=5.6 Hz), 3.56 (q, 1H, J=7.1 Hz), 3.41 (m, 2H),
2.62 (t, 2H, J=6.8 Hz), 1.51 (d, 3H, J=7.2 Hz). HRMS (ESI
(MþH)þ m/z) calcd for C24H24NO3 374.1756, found 374.1749.
(()-2-(3-Benzoylphenyl)-N-(4-hydroxyphenethyl)propanamide
(37). 1H NMR (400 MHz, CDCl3) δ 7.77 (m, 2H), 7.66 (m, 2H),
7.60 (m, 1H), 7.47 (m, 4H), 6.82 (m, 2H), 6.68 (m, 2H), 5.48
(t, 1H, J=6.0 Hz), 3.55 (q, 1H, J=7.1 Hz), 3.46 (m, 1H), 3.36
(dq, 1H, J=6.8, 13.4 Hz), 2.63 (t, 2H, J=6.8 Hz), 1.51 (d, 3H, J=
7.2 Hz). HRMS (ESI (M þ H)þ m/z) calcd for C24H24NO3
374.1756, found 374.1750.
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N-(4-Hydroxyphenethyl)-3-phenylpropanamide (27). H NMR
(400 MHz, CDCl3) δ 7.28 (m, 2H), 7.19 (dd, 3H, J=6.5, 13.3 Hz),
6.94 (d, 2H, J=8.3 Hz), 6.75 (d, 2H, J=8.4 hz), 5.32 (m, 1H), 3.43
(dd, 2H, J=6.6, 12.9 Hz), 2.94 (t, 2H, J=7.6 Hz), 2.65 (t, 2H, J=
6.8 Hz), 2.42 (t, 2H, J=7.6 Hz). HRMS (ESI (MþH)þ m/z) calcd
for C17H20NO2 270.1494, found 270.1504.
(R)-N-(4-Hydroxyphenethyl)-2-(6-methoxynaphthalen-2-yl)
propanamide (38). 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, 2H,
J=5.9, 8.6 Hz), 7.57 (s, 1H), 7.28 (m, 1H), 7.16 (m, 2H), 6.74
(d, 2H, J=8.5 Hz), 6.56 (d, 2H, J=8.5 Hz), 5.41 (s, 1H), 3.92 (s,
3H), 3.64 (q, 1H, J=7.2 Hz), 3.45 (dq, 1H, J=6.6, 13.1 Hz),
3.34 (td, 1H, J=6.7, 13.0 Hz), 2.58 (t, 2H, J=6.8 Hz), 1.58 (d,
3H, J = 7.2 Hz). HRMS (ESI (M þ H)þ m/z) calcd for
N-(4-Hydroxyphenethyl)cinnamamide (28). 1H NMR (400 MHz,
CDCl3) δ 7.62 (d, 1H, J=15.6 Hz), 7.48 (s, 2H), 7.36 (m, 3H), 7.09
(d, 2H, J=8.5 Hz), 6.80 (d, 2H, J=8.5 Hz), 6.31 (d, 1H, J=15.6 Hz),
5.58 (m, 1H), 3.62 (d, 2H, J=6.1 Hz), 2.82 (t, 2H, J=6.9 Hz).
HRMS (ESI (MþH)þ m/z) calcd for C17H18NO2 268.1338, found
268.1327. HPLC purity 92%.
C
22H24NO3 350.1756, found 350.1743.
(1SR,2SR)-N-(4-Hydroxyphenethyl)-2-phenylcyclopropane-
carboxamide (29). 1H NMR (400 MHz, CDCl3) δ 7.26 (t, 2H,
J=7.6 Hz), 7.18 (t, 1H, J=7.3 Hz), 7.05 (m, 4H), 6.78 (d, 2H,
J=8.3 Hz), 5.70 (s, 1H), 3.51 (m, 2H), 2.75 (t, 2H, J=7.0 Hz),
2.49 (m, 1H), 1.62 (m, 1H), 1.52 (m, 1H), 1.23 (m, 2H). HRMS
(ESI (M þ H)þ m/z) calcd for C18H20NO2 282.1494, found
282.1491.
N-(4-Hydroxyphenethyl)-1,2,3,4-tetrahydronaphthalene-2-car-
boxamide (30). 1H NMR (400 MHz, CDCl3) δ 7.06 (m, 6H), 6.79
(d, 2H, J=8.5 Hz), 5.64 (t, 1H, J=5.1 Hz), 3.52 (dd, 2H, J=6.9,
14.3 Hz), 2.85 (m, 6H), 2.46 (m, 1H), 2.03 (d, 1H, J=10.2 Hz),
1.86 (m, 1H). HRMS (ESI (MþH)þ m/z) calcd for C19H22NO2
296.1651, found 296.1641.
N-(4-Hydroxyphenethyl)-2-(5-methoxy-1H-indol-3-yl)aceta-
mide (31). 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.27 (d,
1H, J=8.7 Hz), 6.89 (m, 3H), 6.62 (dd, 4H, J=8.5, 22.2 Hz),
5.88 (s, 1H), 3.64 (s, 2H), 3.35 (t, 2H, J=5.7 Hz), 2.53 (t, 2H,
J=6.7 Hz). HRMS (ESI (MþH)þ m/z) calcd for C19H21N2O3
325.1552, found 325.1545.
2-(5-(Benzyloxy)-1H-indol-3-yl)-N-(4-hydroxyphenethyl)aceta-
mide (32). 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 1H, J=7.5 Hz),
7.38 (t, 1H, J=7.5 Hz), 7.31(dd, 1H, J=4.5, 8.0 Hz), 6.99 (dd, 1H,
J=9.1, 11.5 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.55 (d, 1H, J=8.3 Hz),
5.08 (s, 1H), 3.64 (s, 0H), 3.33 (m, 1H), 2.52 (t, 1H, J=6.6 Hz).
HRMS (ESI (M þ H)þ m/z) calcd for C25H25N2O3 401.1865,
found 401.1855.
(2S)-2-(3-(Hydroxy(phenyl)methyl)phenyl)-N-(4-hydroxyphe-
nethyl)propanamide (39). A solution of 36 (0.016 g, 0.043 mmol)
in MeOH (2 mL) was treated with NaBH4 (0.002 g, 0.047 mmol).
The resulting mixture was stirred for 2 h at rt. The reaction
mixture was quenched with 4 mL of water and extracted with
EtOAc (10 mL). The extract was washed with water (3ꢀ5 mL)
and brine (1 ꢀ 5 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash-column chromatography over silica gel (Biotage SP4,
12þS column, eluting with hexane/ethyl acetate gradient 10-
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80%) to give 39 (0.013 g, 81%). H NMR (400 MHz, CDCl3)
δ 7.27 (m, 8H), 7.10 (dd, 1H, J=3.8, 7.1 Hz), 6.76 (dd, 2H, J=
4.3, 8.4 Hz), 6.66 (d, 2H, J=8.4 Hz), 5.74 (s, 1H), 5.56 (m, 1H),
3.42 (m, 2H), 3.27 (dt, 1H, J=6.5, 13.1 Hz), 2.56 (m, 2H), 1.44
(dd, 3H, J=2.7, 7.2 Hz). HRMS (ESI (MþH)þ m/z) calcd for
C24H26NO3 376.1913, found 376.1912.
(S)-2-(3-Benzylphenyl)-N-(4-hydroxyphenethyl)propanamide
(40). 1H NMR (400 MHz, CDCl3) δ 7.21 (m, 6H), 7.06 (dd, 3H,
J=7.8, 16.8 Hz), 6.79 (d, 2H, J=8.4 Hz), 6.70 (d, 2H, J=8.3
Hz), 5.41 (t, 1H, J=5.5 Hz), 3.94 (s, 2H), 3.44 (m, 2H), 3.32 (td,
1H, J=6.8, 13.0 Hz), 2.57 (m, 2H), 1.47 (d, 3H, J=7.2 Hz).
HRMS (ESI (M þ H)þ m/z) calcd for C24H26NO2 360.1964,
found 360.1951.
N-(4-Hydroxyphenethyl)-2-(2-phenoxyphenyl)acetamide (41).
1H NMR (400 MHz, CDCl3) δ 7.27 (m, 4H), 7.08 (m, 2H), 6.82
(m, 5H), 6.69 (d, 2H, J=8.5 Hz), 5.77 (s, 1H), 3.57 (s, 2H), 3.39
(q, 2H, J=6.7 Hz), 2.61 (t, 2H, J=6.8 Hz). HRMS (ESI (MþH)þ
m/z) calcd for C22H22NO3 348.1600, found 348.1599.
N-(4-Hydroxyphenethyl)-2-(3-phenoxyphenyl)acetamide (42).
1H NMR (400 MHz, CDCl3) δ 7.31 (ddd, 4H, J = 4.9, 8.2,
15.8 Hz), 7.12 (t, 1H, J=7.4 Hz), 7.00 (m, 2H), 6.90 (m, 4H), 6.83
(s, 1H), 6.71 (d, 2H, J=8.5 Hz), 5.41 (bs, 1H), 3.49 (s, 2H), 3.43
(dd, 2H, J = 6.6, 12.8 Hz), 2.65 (t, 2H, J = 6.8 Hz). HRMS
(ESI (M þ H)þ m/z) calcd for C22H22NO3 348.1600, found
348.1592.
2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-
N-(4-hydroxyphenethyl)acetamide (33). H NMR (400 MHz,
1
CDCl3þCD3OD) δ 7.64 (d, 2H, J=8.3 Hz), 7.52 (d, 2H, J=
8.4 Hz), 6.91 (dd, 2H, J=5.7, 8.1 Hz), 6.80 (d, 2H, J=8.4 Hz),
6.72 (dd, 1H, J=2.5, 9.0 Hz), 6.62 (d, 2H, J=8.4 Hz), 6.29 (s,
1H), 3.84 (s, 3H), 3.58 (s, 2H), 3.40 (dd, 2H, J=6.6, 12.7 Hz),
2.62 (t, 2H, J=6.8 Hz), 2.28 (s, 3H). HRMS (ESI (MþH)þ m/z)
calcd for C27H26N2O4Cl 477.1581, found 477.1571.
N-(4-Hydroxyphenethyl)-2-(4-isobutylphenyl)propanamide (34).
1H NMR (400 MHz, CDCl3) δ 7.10 (m, 4H), 6.83 (d, 2H,
J=8.5 Hz), 6.72 (d, 2H, J=8.6 Hz), 5.44 (t, 1H, J=5.4 Hz),
3.43 (ddq, 3H, J=7.0, 13.3, 26.0 Hz), 2.61 (m, 2H), 2.46 (d, 2H,
J=7.2 Hz), 1.85 (d p, 1H, J=6.8, 13.6 Hz), 1.49 (d, 3H, J=7.2 Hz),
0.91 (d, 6H, J=6.6 Hz). HRMS (ESI (MþH)þ m/z) calcd for
C21H28NO2 326.2120, found 326.2109.
N-(4-Hydroxyphenethyl)-2-(4-phenoxyphenyl)acetamide (43).
A solution of 36 (0.040 g, 0.107 mmol) and 10% Pd/C (0.002 g)
in methanol (3 mL) was stirred under H2 for 18 h at rt and
then filtered through a short pad of Celite. The solvent was
removed in vacuo, and the residue was flash-chromatographed
over silica gel (Biotage SP4, 12þS column, eluting with hexane/
ethyl acetate gradient 10-80%) to give 43 (0.035 g, 0.097 mmol,
(S)-N-(4-Hydroxyphenethyl)-2-(6-methoxynaphthalen-2-yl)pro-
panamide (35). 1H NMR (400 MHz, CDCl3) δ 7.68 (t, 2H,
J=7.8 Hz), 7.56 (s, 1H), 7.27 (d, 1H, J=8.4 Hz), 7.14 (m, 2H),
6.74 (d, 2H, J=8.3 Hz), 6.59 (d, 2H, J=8.4 Hz), 5.47 (s, 1H),
1
91% yield). H NMR (400 MHz, CDCl3) δ 7.35 (t, 2H, J =
7.9 Hz), 7.11 (m, 3H), 7.01 (m, 2H), 6.94 (dd, 2H, J=2.9, 8.5 Hz),
6.88 (dd, 2H, J=2.6, 8.4 Hz), 6.73 (dd, 2H, J=2.9, 8.4 Hz),