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L. Kiefer et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
by a saturated aqueous solution of sodium potassium tartrate.
After 30 min, the mixture was extracted with ethyl acetate (3ꢂ),
the combined organic extracts were dried over sodium sulfate
and the solvents were removed under vacuum. The residue was
purified by flash chromatography (silica gel, AcOEt/heptane/MeOH
46:50:4), affording compound 33 (80% yield, orange oil); 1H NMR
(300 MHz, CDCl3) d (ppm) 1H NMR 8.42 (br s, 1H), 8.16 (d,
J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H),
7.70 (d, J = 7.6 Hz, 1H), 7.54–7.49 (m, 3H), 7.08 (t, J = 7.9 Hz, 1H),
7.97 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 7.9 Hz, 1H), 6.42 (s, 1H), 4.73
(q, J = 6.7 Hz, 1H), 3.95 (s, 3H), 3.92 (d, Jgem = 14.0 Hz, 1H), 3.87
(d, Jgem = 14.0 Hz, 1H), 1.55 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d (ppm) 152.9, 140.6, 137.2, 136.4, 134.0, 131.3, 129.0,
127.4, 125.9, 125.6, 125.4, 123.0, 122.6, 122.2, 119.0, 104.2, 99.6,
97.2, 55.3, 53.0, 44.8, 23.4; HRESMS Calcd for C22H23N2O [M+H]+:
331.1810. Found: 331.1824.
1H), 6.20 (d, J = 2.2 Hz, 1H), 4.71 (q, J = 6.6 Hz, 1H), 4.06 (s, 3H),
3.93 (s, 3H), 3.90 (s, 3H), 3.91 (d, Jgem = 14.2 Hz, 1H), 3.84 (d,
Jgem = 14.2 Hz, 1H), 1.55 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d (ppm) 149.0, 140.5, 138.6, 137.7, 137.5, 134.0, 131.3,
129.0, 127.4, 125.8, 125.6, 125.4, 124.2, 124.1, 122.9, 122.6,
100.3, 97.1, 61.4, 61.0, 56.4, 53.0, 44.8, 23.4; HRESMS Calcd for
C
24H27N2O3 [M+H]+: 391.2022. Found: 391.2028.
Hydrochloride of 36: mp 147–151 °C (decomposition);
[
a
]
D = ꢀ14.5 (c 0.7, MeOH); Anal. Calcd for C24H27ClN2O3ꢁ0.6 H2O:
C, 64.53; H, 6.23; N, 6.27. Found: C, 64.16; H, 6.39; N, 5.97.
5.2.18. (R)-N-[(5-Fluoro-1H-indol-2-yl)methyl]-1-(1-naphthyl)
ethanamine (37)
Compound 37 was prepared by the same method described for
the synthesis of 33 starting from 24 (87% yield, yellow oil); 1H NMR
(300 MHz, CDCl3) d (ppm) 8.16 (dd, J1 = 6.0, J2 = 3.0 Hz, 1H), 7.93
(dd, J1 = 6.0, J2 = 3.0 Hz, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.71 (d,
J = 7.4 Hz, 1H), 7.57–7.51 (m, 3H), 7.23 (d, J = 2.5 Hz, 1H), 7.21
(dd, J1 = 9.1, J2 = 1.5 Hz, 1H), 6.92 (dt, J1 = 9.1, J2 = 2.5 Hz, 1H), 6.27
(d, J = 1.2 Hz, 1H), 4.73 (q, J = 6.6 Hz, 1H), 3.92 (d, Jgem = 14.4 Hz,
1H), 3.86 (d, Jgem = 14.4 Hz, 1H), 1.97 (br s, 1H), 1.58 (d, J = 6.6 Hz,
For biological evaluation, the hydrochloride salt of 33 was pre-
pared by dissolving it in methanol, adding methanolic HCl until the
solution was acidic, adding pentane and collecting the solid precip-
itate formed by filtration; mp 213.5–215 °C (decomposition);
[
a
]
D = ꢀ22.2 (c 1.0, MeOH); Anal. Calcd for C22H23ClN2Oꢁ0.1H2O:
C, 71.67; H, 6.34; N, 7.60. Found: C, 71.55; H, 6.42; N, 7.42.
3H); 13C NMR (75 MHz, CDCl3)
d (ppm) 159.4–156.3 (d,
1JCF = 233.3 Hz), 140.5, 139.9, 134.0, 132.3, 131.3, 129.0, 128.8
5.2.15. (R)-N-[(4,6-Dimethoxy-1H-indol-2-yl)methyl]-1-(1-
naphthyl)ethanamine (34)
3
(d, JCF = 10.4 Hz), 127.5, 125.9, 125.6, 125.4, 122.8, 122.6, 111.1
3
2
(d, JCF = 9.9 Hz), 109.6–109.3 (d, JCF = 26.3 Hz), 105.0–104.7 (d,
Compound 34 was prepared by the same method described for
the synthesis of 33 starting from 21 (54% yield, dark orange oil); 1H
NMR (300 MHz, CDCl3) d (ppm) 8.33 (br s, 1H), 8.16 (dd, J1 = 6.4,
J2 = 3.2 Hz, 1H), 7.89 (dd, J1 = 6.4, J2 = 3.2 Hz, 1H), 7.79 (d,
J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.54–7.49 (m, 3H), 6.45 (d,
J = 1.7 Hz, 1H), 6.32 (d, J = 1.7 Hz, 1H), 6.22 (d, J = 1.7 Hz, 1H),
4.72 (q, J = 6.6 Hz, 1H), 3.91 (s, 3H), 3.84 (m, 5H), 1.54 (d,
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d (ppm) 157.2, 153.3,
140.6, 137.2, 134.8, 134.0, 131.3, 129.0, 127.4, 125.9, 125.6,
125.4, 123.0, 122.6, 113.3, 97.2, 91.5, 86.9, 55.7, 55.3, 53.0, 44.8,
23.4; HRESMS Calcd for C23H24N2NaO2 [M+Na]+: 383.1735. Found:
383.1747.
2JCF = 23.3 Hz), 100.0 (d, JCF = 4.9 Hz), 53.1, 44.7, 23.4; HRESMS
4
Calcd for C21H20FN2 [M+H]+: 319.1611. Found: 319.1614.
Hydrochloride of 37: mp 193–196 °C (decomposition);
[
a
]
D = ꢀ5.2 (c 0.8, MeOH); Anal. Calcd for C21H20ClFN2ꢁ0.1H2O: C,
70.72; H, 5.71; N, 7.85. Found: C, 70.53; H, 5.85; N, 7.75.
5.2.19. (R)-N-[(5-Methyl-1H-indol-2-yl)methyl]-1-(1-naphthyl)
ethanamine (38)
Compound 38 was prepared by the same method described for
the synthesis of 33 starting from 25 (65% yield, dark orange oil); 1H
NMR (300 MHz, CDCl3) d (ppm) 8.35 (br s, 1H), 8.17 (dd, J1 = 6.3,
J2 = 3.1 Hz, 1H), 7.93 (dd, J1 = 6.3, J2 = 3.1 Hz, 1H), 7.82 (d,
J = 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.58–7.52 (m, 3H), 7.38 (s,
1H), 7.23 (d, J = 8.1 Hz, 1H), 7.02 (dd, J1 = 8.1, J2 = 1.8 Hz, 1H),
6.25 (s, 1H), 4.74 (q, J = 6.6 Hz, 1H), 3.93 (d, Jgem = 14.1 Hz, 1H),
3.85 (d, Jgem = 14.1 Hz, 1H), 2.49 (s, 3H), 1.98 (br s, 1H), 1.57 (d,
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d (ppm) 140.6, 138.0,
134.2, 134.0, 131.3, 129.0, 128.8, 128.7, 127.4, 125.9, 125.7,
125.4, 122.9, 122.6, 119.8, 110.3, 99.6, 52.9, 44.8, 23.4, 21.4;
HRESMS Calcd for C22H23N2 [M+H]+: 315.1861. Found: 315.1858.
Hydrochloride of 38: mp 178–180 °C (decomposition);
Hydrochloride of 34: mp 154–156.5 °C (decomposition);
[
a
]
D = ꢀ12.8 (c 0.6, MeOH); Anal. Calcd for C23H25ClN2O2ꢁ0.6H2O:
C, 67.75; H, 6.48; N, 6.87. Found: C, 67.48; H, 6.17; N, 6.75.
5.2.16. (R)-N-[(6-Methoxy-1H-indol-2-yl)methyl]-1-(1-naphthyl)
ethanamine (35)
Compound 35 was prepared by the same method described for
the synthesis of 33 starting from 22 (58% yield, orange oil); 1H
NMR (300 MHz, CDCl3) d (ppm) 8.35 (br s, 1H), 8.17 (dd, J1 = 6.4,
J2 = 3.4 Hz, 1H), 7.93 (dd, J1 = 6.4, J2 = 3.4 Hz, 1H), 7.81 (d,
J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.57–7.50 (m, 3H), 7.44 (d,
J = 8.3 Hz, 1H), 6.83 (d, J = 1.9 Hz, 1H), 6.80 (dd, J1 = 8.3,
J2 = 1.9 Hz, 1H), 6.24 (s, 1H), 4.73 (q, J = 6.6 Hz, 1H), 3.87 (m, 5H),
1.56 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d (ppm) 156.0,
140.6, 136.7, 136.6, 134.0, 131.3, 129.0, 127.4, 125.8, 125.6,
125.4, 122.9, 122.7, 122.6, 120.6, 109.3, 99.9, 94.5, 55.6, 52.9,
44.8, 23.4; HRESMS Calcd for C22H22N2NaO [M+Na]+: 353.1630.
Found: 353.1643.
[
a
]
D = ꢀ16.2 (c 1.0, MeOH); Anal. Calcd for C22H23ClN2ꢁ0.4 H2O: C,
73.06; H, 6.74; N, 7.74. Found: C, 73.21; H, 6.89; N, 7.36.
5.2.20. (R)-N-[(5-Benzyloxy-1H-indol-2-yl)methyl]-1-(1-
naphthyl)ethanamine (39)
Compound 39 was prepared by the same method described for
the synthesis of 33 starting from 26 (63% yield, orange oil); 1H
NMR (500 MHz, CDCl3) d (ppm) 8.32 (br s, 1H), 8.16 (dd, J1 = 6.4,
J2 = 3.2 Hz, 1H), 7.92 (dd, J1 = 6.4, J2 = 3.2 Hz, 1H), 7.81 (d,
J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.55–7.49 (m, 5H), 7.41 (t,
J = 7.3 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.12
(d, J = 2.4 Hz, 1H), 6.91 (dd, J1 = 8.8, J2 = 2.4 Hz, 1H), 6.23 (s, 1H),
5.12 (s, 2H), 4.72 (q, J = 6.7 Hz, 1H), 3.91 (d, Jgem = 14.3 Hz, 1H),
3.85 (d, Jgem = 14.3 Hz, 1H), 1.88 (br s, 1H), 1.56 (d, J = 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3) d (ppm) 153.3, 140.6, 138.8,
137.8, 134.0, 131.3, 131.1, 129.0, 128.9, 1284, 127.7, 127.5, 127.4,
125.9, 125.7, 125.4, 122.9, 122.6, 112.1, 111.3, 103.8, 99.9, 70.9,
53.0, 44.8, 23.5; HRESMS Calcd for C28H27N2O [M+H]+: 407.2123.
Found: 407.2119.
Hydrochloride of 35: mp 163.5–166 °C (decomposition);
[
a
]
D = ꢀ25.5 (c 1.1, MeOH); Anal. Calcd for C22H23ClN2Oꢁ0.6H2O:
C, 70.30; H, 6.44; N, 7.45. Found: C, 70.33; H, 6.77; N, 7.05.
5.2.17. (R)-N-[(5,6,7-Trimethoxy-1H-indol-2-yl)methyl]-1-(1-
naphthyl)ethanamine (36)
Compound 36 was prepared by the same method described for
the synthesis of 33 starting from 23 (53% yield, orange oil); 1H
NMR (300 MHz, CDCl3) d (ppm) 8.50 (br s, 1H), 8.16 (dd, J1 = 6.2,
J2 = 3.3 Hz, 1H), 7.90 (dd, J1 = 6.2, J2 = 3.3 Hz, 1H), 7.80 (d,
J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.55–7.49 (m, 3H), 6.78 (s,