N. Scalacci et al. / European Journal of Medicinal Chemistry 127 (2017) 147e158
155
4
.1.10. General procedure for the synthesis of Boc-protected
4.1.11. General procedure for the synthesis of thioridazine
derivatives (12a-e)
thioridazine derivatives (S12a-e)
The appropriate 2-substituted phenothiazine (5a-c) or carba-
zole, indole, or benzimidazole (0.42 mmol, 1eq.) was added to
The appropriate Boc-protected compound (S12a-e) (0.24 mmol,
1 eq.) was added to a round bottom flask containing 5 mL HCl
saturated solution in EtOAc. The reaction mixture was allowed to
stir at room temperature for 24 h. The solvent was removed under
reduced pressure giving a white solid as product of the reaction.
10 mL of DMF in a double neck round bottomed flask. NaH
(
0
0.52 mmol, 12.5 mg, 1.2 eq.) was added to the stirring solution at
C, which then was allowed to reach r.t stirring for 20 min. Then,
ꢀ
t-butyl 2-(2-bromoethyl)piperidine-1-carboxylate (11) (0.52 mmol,
52 mg, 1.2eq.) and NaI (0.02 mmol, 3 mg, 0.1eq) were added to the
stirring solution. The reaction mixture was allowed to stir under N
atmosphere for 12 h at r.t. Then, the reaction mixture was quenched
with 20 mL of water and extracted twice with 20 mL of EtOAc. The
combined organic layers were washed with brine, dried over
2
The solid products 12a-e were washed several times with cold Et O.
1
2
4.1.11.1. 10-(2-(piperidin-2-yl)ethyl)-10H-phenothiazine
(12a).
1
Yield: 99% (73 mg). H NMR (400 MHz CDCl ) d 9.41 (br. s., 1H), 9.24
3
(br. s., 1H), 7.15e7.12 (m, 4H), 6.92e6.86 (m, 4H), 3.97e3.92 (m, 2H),
3.49e3.45 (m, 1H), 3.08e3.05 (m, 1H), 2.73e2.57 (m, 1H),
2.45e2.43 (m, 1H), 2.18e2.06 (m, 1H), 1.93e1.74 (m, 3H), 1.69e1.60
2 4
Na SO and concentrated under reduced pressure giving a yellow-
brown crude oil. The crude product was purified by chromatog-
13
3
(m, 2H), 1.44e1.34 (m, 1H) ppm. C NMR (100 MHz CDCl ) d 145.3,
raphy on silica gel, using hexane/EtOAc (4:1) as eluent.
127.7, 127.4, 125.4, 122.7, 115.6, 55.6, 46.8, 44.3, 33.7, 32.4, 25.9,
þ
2
4.5 ppm. LRMS m/z (ESþ) m/z: 311 [MþH] . HRMS (ESI) m/z calcd.
for C19
22
H N
2
S [M þH] 311.1576, found 311.1579.
4
.1.10.1. t-Butyl 2-(2-(10H-phenothiazin-10-yl)ethyl)piperidine-1-
1
3
carboxylate (S12a). Yield: 45% (77 mg). H NMR (400 MHz CDCl )
4
.1.11.2. Synthesis of 2-chloro-10-(2-(piperidin-2-yl)ethyl)-10H-
d
7.16e7.12 (m, 4H), 6.93e6.89 (m, 2H), 6.84 (d, J ¼ 8.0 Hz, 2H),
1
phenothiazine (12b). Yield: 94% (77 mg). H NMR (400 MHz CDCl
9.54 (br s, 1H), 9.34 (br s, 1H), 7.19 (t, J ¼ 8.0 Hz 1H), 7.13 (d,
J ¼ 8.0 Hz,1H), 7.04 (d, J ¼ 8.0 Hz,1H), 6.95e6.89 (m, 4H), 4.07e3.96
m, 2H), 3.31 (d, J ¼ 8.0 Hz, 1H), 3.12e3.04 (m, 1H), 2.77e2.68 (m,
H), 2.50e2.42 (m, 1H), 2.13e2.09 (m, 1H), 1.85e1.69 (m, 6H) ppm.
3
)
4
3
.45e4.35 (m, 1H), 4.08e3.96 (m, 1H), 3.92e3.74 (m, 2H),
.38e3.28 (m, 1H), 2.83e2.69 (m, 1H), 2.37e2.18 (m, 1H), 1.91e1.85
d
13
(
m, 1H), 1.67e1.49 (m, 5H), 1.40 (s, 9H) ppm. C NMR (100 MHz
(
CDCl 155.1, 145.3, 127.6, 127.3, 125.1, 122.5, 115.3, 79.4, 49.5, 38.7,
3
) d
1
3
3.6, 30.3, 28.7, 28.5, 25.5, 19.2 ppm. LRMS m/z (ESþ) m/z: 411
1
3
þ
C NMR (100 MHz CDCl3) d 146.6, 144.5, 133.3, 128.0, 127.6, 127.5,
[MþH]
1
25.1, 123.9, 123.1, 122.5, 115.9, 55.4, 46.7, 44.4, 33.5, 29.7, 25.8,
þ
24.4 ppm. LRMS m/z (ESþ) m/z: 345 [MþH] . HRMS (ESI) m/z calcd.
4
.1.10.2. t-Butyl 2-(2-(2-chloro-10H-phenothiazin-10-yl)ethyl)piper-
1
for C19
H21ClN
2
S [M þH] 345.1187, found 345.1194.
idine-1-carboxylate (S12b). Yield: 61% (111 mg). H NMR (400 MHz
CDCl
3
4
2
3
)
d
7.17e7.11 (m, 2H) 7.02 (d, J ¼ 8.0 Hz, 1H), 6.95e6.83 (m,
4
.1.11.3. Synthesis of 9-(2-(piperidin-2-yl)ethyl)-9H-carbazole (12c).
H), 6.78 (d, J ¼ 4.0 Hz, 1H), 4.44e4.39 (m, 1H), 4.38e4.35 (m, 1H),
.05e4.00 (m, 1H), 3.88e3.79 (m, 2H), 2.78 (t, J ¼ 12 Hz, 1H),
.22e2.16 (m, 1H), 1.90e1.81 (m, 1H), 1.68e1.45 (m, 5H), 1.42 (s, 9H)
1
Yield: 95% (63 mg). H NMR (400 MHz CDCl
br s, 1H), 8.02 (d, J ¼ 8.0, 2H), 7.46e7.37 (m, 4H), 7.17 (t, J ¼ 8.0, 2H),
4.51e4.43 (m, 1H), 4.31e4.25 (m, 1H), 3.38e3.36 (m, 1H), 3.02e2.90
3
) d 9.66 (br s, 1H), 9.41
(
13
3
ppm. C NMR (100 MHz CDCl ) d 155.2, 146.7, 144.6, 133.4, 128.1,
(
m, 1H), 2.70e2.67 (m, 1H), 2.49e2.48 (m, 1H), 2.18e2.12 (m, 1H),
1
2
27.5, 124.9, 123.0, 122.4, 115.7, 79.6, 48.8, 44.8, 39.1, 29.3, 28.5, 27.7,
13
5.6, 19.3 ppm. LRMS m/z (ESþ) m/z: 468 [MþNa]þ
1.88e1.61 (m, 6H) ppm.
3
C NMR (100 MHz CDCl ) d 140.0, 126.1,
1
22.9, 120.4, 119.3, 108.8, 55.5, 44.9, 39.5, 32.7, 30.0, 22.3, 22.0 ppm.
þ
LRMS m/z (ESþ) m/z: 279 [MþH] . HRMS (ESI) m/z calcd. for
4
.1.10.3. t-Butyl 2-(2-(9H-carbazol-9-yl)ethyl)piperidine-1-
19 22 2
C H N
[M þH] 279.1856, found 279.1855.
1
carboxylate (S12c). Yield: 61% (94 mg). H NMR (400 MHz
CD
H), 4.74 (m, 1H), 4.69e4.59 (m, 1H), 4.36e4.18 (m, 1H), 3.69e3.60
m, 2H), 3.10e3.07 (m, 1H), 2.73e2.53 (m, 1H), 2.22 (m, 1H),
3
OD)
d
8.37 (d, J ¼ 7.8 Hz, 2H), 7.87e7.64 (m, 4H), 7.60e7.35 (m,
4
.1.11.4. Synthesis of 1-(2-(piperidin-2-yl)ethyl)-1H-benzo[d]imid-
2
(
1
3
azole (12d). Yield: 90% (49 mg). H NMR (400 MHz CDCl ) d 10.17 (s
1
5
2
H), 9.68 (br s, 2H), 7.82 (t, J ¼ 8.0 Hz, 2H), 7.44e7.36 (m, 2H),
13
2
CD
.00e1.86 (m, 5H), 1.85e1.76 (m, 9H) ppm. C NMR (100 MHz
OD) 155.8, 140.6, 140.5, 125.9, 125.6, 123.4, 123.3, 120.4, 120.0,
.01e4.79 (m, 2H), 3.46e3.43 (m, 1H), 3.36e3.25 (m, 1H),
3
d
.98e2.94 (m, 1H), 2.85e2.71 (m, 1H), 2.50e2.36 (m, 1H) 1.90e1.75
1
1
19.1, 118.7, 110.8, 108.7, 80.1, 78.6, 40.2, 33.2, 28.5, 27.9, 27.8, 25.7,
13
(m, 6H) ppm. C NMR (100 MHz CDCl
3
)
d
140.9, 130.7, 126.9, 126.7,
9.1, 19.0 ppm. LRMS m/z (ESþ) m/z: 401 [MþNa]þ
115.6, 112.7, 54.1, 45.0, 43.7, 33.4, 28.7, 22.3, 20.9 ppm. LRMS m/z
þ
(
2
ESþ) m/z: 230 [MþH] . HRMS (ESI) m/z calcd. for C14
H
19
N
3
[M þH]
4
.1.10.4. t-Butyl 2-(2-(1H-benzo[d]imidazol-1-yl)ethyl)piperidine-1-
30.1652, found 230.1652.
1
3
carboxylate (S12d). Yield: 63% (87 mg). H NMR (400 MHz CDCl )
d
7.91 (s, 1H), 7.84e7.67 (m, 1H), 7.39e7.31 (m, 1H), 7.31e7.09 (m,
H), 4.49e4.19 (m, 1H), 4.10e3.90 (m, 2H), 2.81e2.65 (m, 1H),
.38e2.18 (m, 1H), 1.96e1.77 (m, 1H), 1.72e1.44 (m, 7H), 1.44e1.29
4
.1.11.5. 1-(2-(piperidin-2-yl)ethyl)-1H-indole (12e). Yield: 94%
2
1
(51 mg). H NMR (400 MHz CD
3
OD) d 7.42e7.34 (m, 1H), 7.24e7.19
2
(
(m, 1H), 7.10e7.01 (m, 2H), 6.90e6.80 (m, 2H), 4.12e4.01 (m, 2H),
m, 9H) ppm. 13C NMR (100 MHz CDCl
)
d
155.2, 144.0, 143.2, 133.7,
3
3
2
.39e3.24 (m, 1H), 2.95e2.89 (m, 2H), 2.82e2.73 (m, 1H),
1
1
22.9, 122.1, 120.6, 109.5, 79.9, 60.4, 42.4, 30.1, 28.9, 28.5, 25.5, 19.2,
.75e2.59 (m, 1H), 2.49e2.40 (m, 1H), 2.38e2.29 (m, 2H), 1.84e1.67
4.2 ppm. LRMS m/z (ESþ) m/z: 330 [MþH]þ
13
(m, 3H) ppm. C NMR (100 MHz (CD
3
)
2
SO)
d
135.8, 127.9, 121.8,
121.1, 119.6, 119.1, 109.7, 54.2, 45.2, 43.6, 33.3, 28.8, 22.1, 20.8 ppm.
þ
4
.1.10.5. t-Butyl 2-(2-(1H-indol-1-yl)ethyl)piperidine-1-carboxylate
LRMS m/z (ESþ) m/z: 229 [MþH] . HRMS (ESI) m/z calcd. for
1
(
S12e). Yield: 42% (58 mg). H NMR (400 MHz CDCl
J ¼ 8.0 Hz, 1H) 7.31 (d, J ¼ 8.0 Hz, 1H), 7.22e7.18 (m, 1H), 7.12e7.07
m, 2H), 6.48 (d, J ¼ 4.0 Hz, 1H), 4.38e4.33 (m, 1H), 4.15e4.03 (m,
H), 2.81 (t, J ¼ 8.0 Hz, 1H), 2.31e2.21 (m, 1H), 1.93e1.86 (m, 1H),
3
)
d
7.62 (d,
15 20 2
C H N
[M þH] 229.1626, found 229.1701.
(
3
1
d
4.1.12. General procedure for the synthesis of thioridazine
derivatives (13a-d)
Compounds (12a-d) (0.14 mmol, 1 eq.) were added to a round
bottom flask containing THF (5 mL) and formaldehyde aqueous
solution 37% w/v (0.28 mmol, 2 eq.). The solution was then allowed
13
.68e1.58 (m, 6H), 1.45 (s, 9H) ppm C NMR (100 MHz CDCl
3
)
155.2, 135.8, 128.8, 127.9, 121.5, 121.1, 119.4, 109.2, 101.2, 79.7, 43.8,
3
0.7, 29.0, 28.6, 25.6, 19.2 ppm. LRMS m/z (ESþ) m/z: 352 [MþNa]þ