6.9 Hz, 2.00 H), 3.34 (t,s overlapping, 3.90 H), 3.11 (t, J = 7
Hz, 2.05 H), 2.34 (t, J = 6.1 Hz, 1.91 H); 13C NMR (100 MHz) δ
203.8, 168.1, 136.3, 127.3, 122.3, 122.1, 119.6, 118.5, 112.9, 111.4,
49.0, 44.4, 38.5, 23.7; IR (NaCl, film) 3283, 2924, 2854, 2362,
1726, 1644, 1489, 1644, 1489, 1457, 1350, 1227, 1095, 1011, 745
cm-1; HRMS (ESI) m/z calcd for C15H16N2O2 (M+Na)+
279.1104; found 279.1100.
1158, 1125, 1098, 1074, 1036 cm-1; HRMS (ESI) m/z calc’d for
C23H25Cl2N3O (M+H)+ 430.1447; found 430.1448.
N-(3,5-Dichlorobenzyl)-N-methylpiperidin-4-amine
(27a). A solution of tert-butyl 4-(methylamino)piperidine-
1-carboxylate (44 mg, 0.2 mmol), 3,5-dichlorobenzaldehyde
(53 mg, 0.3 mmol), acetic acid (12 mg, 0.2 mmol), and sodi-
um triacetoxyborohydride (85 mg, 0.4 mmol) in 1,2-
dichloroethane (2 mL) was stirred at room temperature for
18 h, whereupon the solution was diluted with 1 M NaOH
(15 mL) and extracted with Et2O (3 x 15 mL). The combined
organic extracts were dried (Na2SO4) and concentrated via
rotary evaporation. The crude material was purified by
flash chromatography eluting with hexane:EtOAc:Et3N
(95:5:1) to give 48 mg (64%) of tert-butyl 4-((3,5-
dichlorobenzyl)(methyl)amino)piperidine-1-carboxylate as
1-(2-(1H-Indol-3-yl)ethyl)-4-(methylamino)piperidin-
2-one (24). To a solution of ketone 23 (65 mg, 0.25 mmol)
in methanol (2.5 mL) was added methylamine (78 mg, 2.5
mmol, 33% wt. soln. in EtOH), AcOH (150 mg, 2.5 mmol),
and NaBH3CN (31 mg, 0.5 mmol), and the resulting mixture
was stirred for 16 h at room temperature, whereupon an
additional portion of NaBH3CN (31 mg, 0.5 mmol) was add-
ed. After stirring for an additional 3 h, the reaction was
diluted in 1 M HCl (50 mL) and washed with Et2O (50 mL).
The aqueous layer was treated with 1 M NaOH until the
solution turned cloudy and pH > 10, and the resulting mix-
ture was diluted with brine (20 mL) and extracted with
CH2Cl2 (3 x 50 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure.
The crude material was purified via column chromatog-
raphy, eluting with CH2Cl2:MeOH:Et3N (95 : 5 : 1) to yield
1
an opaque white oil. H NMR (400 MHz) δ 7.23 – 7.19
(comp, 3 H), 4.16 (s, 2 H), 3.50 (s, 2 H), 2.75 – 2.61 (comp, 2
H), 2.55 (tt, J = 11.5, 3.6 Hz, 1 H), 2.17 (s, 3 H), 1.83 – 1.70
13
(comp, 2 H), 1.45 (comp, 11 H). C NMR (100 MHz) δ 154.7,
143.9, 134.7, 126.9, 126.7, 79.4, 61.1, 57.0, 43.1, 37.7, 28.4, 27.9;
IR (NaCl, film) 2975, 2940, 2854, 2788, 1694, 1590, 1569,
1451, 1425, 1365, 1330, 1275, 1244, 1159, 1111, 1046, 1004 cm-1.
HRMS (ESI) m/z calcd for C18 H26Cl2N2O2 (M+H)+ 373.1444;
found 373.1454.
1
45 mg (66%) of 24 as a white foam. H NMR (400 MHz) δ
8.02 (s, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.37 (dt, J = 8.1, 1.0 Hz,
1 H), 7.20 (ddd, J = 8.1, 7.0, 1.3 Hz, 1 H), 7.13 (ddd, J = 7.9,
7.0, 1.1 Hz, 1 H), 7.06 (d, J = 2.3 Hz, 1 H), 3.66 (td, J = 7.1, 2.9
Hz, 2 H), 3.25 – 3.18 (m, 1 H), 3.16 – 3.08 (m, 1 H), 3.07 – 3.02
(comp, 2 H), 2.86 – 2.78 (m, 1 H), 2.68 (ddd, J = 17.1, 5.3, 1.8
Hz, 1 H), 2.41 (s, 3 H), 2.22 (dd, J = 17.1, 8.6 Hz, 1 H), 1.90 (dt,
J = 8.1, 5.0 Hz, 1 H), 1.58 – 1.46 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ 168.3, 136.3, 127.5, 122.00, 121.97, 119.3, 118.7, 113.1,
111.2, 53.2, 48.12, 45.7, 43.42, 38.8, 33.3, 28.4, 22.9; IR (NaCl,
film) 3252, 3053, 2926, 2856, 2799, 2361, 1624, 1498, 1456,
1344, 1302, 1264, 1233, 1158, 1102, 1011 cm-1; HRMS (ESI) m/z
calcd for C16H21N3O (M+Na)+ 294.1577; found 294.1574.
A
solution
of
tert-butyl
4-((3,5-
dichlorobenzyl)(methyl)amino)piperidine-1-carboxylate (52
mg, 0.14 mmol) and trifluoroacetic acid (160 mg, 1.4 mmol)
in CH2Cl2 (2.8 mL) was stirred at room temperature for 24
h, whereupon the solvent was removed by rotary evapora-
tion. The resulting solid was resuspended in 1 M HCl (20
mL) and washed with Et2O (20 mL). 3 M NaOH was added
to the aqueous layer until the solution became cloudy,
whereupon it was extracted with CH2Cl2 (3 x 20 mL), dried
(Na2SO4) and concentrated via rotary evaporation to give
29 mg (76%) of 27a as a yellow paste. 1H NMR (400 MHz) δ
7.22 (t, J = 0.6 Hz, 3 H), 3.52 (s, 2 H), 3.18 (d, J = 12.2 Hz, 2
H), 2.66 – 2.46 (m, 4 H), 2.19 (s, 3 H), 1.51 (qd, J = 12.1, 4.1
Hz, 3 H); 13C NMR (100 MHz) δ 144.1, 134.7, 126.9, 126.8, 61.1,
56.9, 46.1, 37.7, 29.0; IR (NaCl, film) 2941, 2851, 2791, 1589,
1568, 1449, 1432, 1384, 1353, 1273, 1208, 1045 cm-1; HRMS
(ESI) m/z calcd for C13H18Cl2N2 (M+H)+ 273.0920; found
273.0923.
1-(2-(1H-Indol-3-yl)ethyl)-4-((3,5-
dichlorobenzyl)(methyl)amino)piperidin-2-one (25a).
To a stirred solution of 24 (16 mg, 0.11 mmol) and 3,5-
dichlorobenzaldehyde (25 mg, 0.314 mmol) in 1,2-
dichloroethane (1.4 mL) was added sodium triacetoxyboro-
hydride (45 mg, 0.21 mmol). The reaction was stirred for 4
h, whereupon it was diluted with CH2Cl2 (50 mL) and
washed with sat. NaHCO3 (50 mL) and brine (50 mL). The
organic layer was dried (Na2SO4) and concentrated under
reduced pressure to afford crude 25a. The crude material
was purified via flash column chromatography, eluting
with hexanes:EtOAc:TEA (40:60:1) to furnish 17 mg (68%)
1-(4-((3,5-Dichlorobenzyl)(methyl)amino)piperidin-
1-yl)-2-(1H-indol-3-yl)ethan-1-one (28a). A solution 27a
(33 mg, 0.12 mmol), indole-3-acetic acid (32 mg, 0.18
mmol), EDCI·HCl (35 mg, 0.18 mmol), and iPr2NEt (0.8 mL,
0.48 mmol) in THF (1.2 mL) was stirred at rt for 2 h. The
reaction was then diluted with 1 M aq. NaOH (20 mL) and
extracted with CH2Cl2 (3 x 15 mL). The combined organic
extracts were dried (Na2SO4) and concentrated via rotary
evaporation. The crude material was purified by flash
1
of 25a as a yellow solid. H NMR (400 MHz) δ 8.10 (s, 1 H),
7.66 (d, J = 7.9 Hz, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.24 (s, 1 H),
7.31 – 7.25 (comp, 3 H), 7.18 (td, J = 8.1, 7.0 Hz, 1 H), 7.10 (td,
J = 7.9, 7.0 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 3.74 – 3.50
(comp, 4 H), 3.17 – 3.00 (comp, 4 H), 2.94 – 2.81 (m, 1 H),
2.65 (dd, J = 17.2, 5.2 Hz, 1 H), 2.51 – 2.41 (m, 1 H), 2.16 (s, 3
H), 2.05 – 1.91 (m, 1 H), 1.60 (qd, J = 11.5, 6.0 Hz, 1 H); 13C
NMR (100 MHz) δ 144.0, 137.0, 135.6, 128.2, 127.9, 127.4,
122.7, 122.5, 120.0, 119.4, 113.9, 111.8, 57.31, 57.29, 48.4, 46.9,
37.6, 35.0, 26.6, 23.7; IR (NaCl, film) 3624, 2509, 2929, 2855,
2793, 2242, 1623, 1569, 1499, 1456, 1433, 1345, 1303, 1231, 1209,
chromatography,
eluting
with
hexanes:EtOAc:Et3N
(40:60:1) to give 28a (40 mg, 78%) as a white solid. 1H NMR
(400 MHz) δ 8.17 (s, 1 H), 7.65 (dq, J = 7.9, 0.9 Hz, 1 H), 7.35
(dt, J = 8.1, 1.0 Hz, 1 H), 7.22 (t, J = 2.0 Hz, 1 H), 7.19 (ddd, J =
8.2, 7.0, 1.2 Hz, 1 H), 7.16 - 7.14 (m, 2 H), 7.13 (ddd, J = 8.0,
7.1, 1.1 Hz, 1 H), 7.09 (dd, J = 2.3, 1.1 Hz, 1 H), 4.74 (d, J = 13.7
Hz, 1 H), 4.05 – 3.93 (m, 1 H), 3.86 (dd, J = 4.4, 1.0 Hz, 2 H),
3.37 (s, 2 H), 2.93 (td, J = 12.9, 2.7 Hz, 1 H), 2.55 (td, J = 11.2,