ACS Chemical Neuroscience
Research Article
residue was purified by column chromatography (PE/DCM/Tol/
EtOH/NH3 (33% aq sol) = 15:5.5:3:1.5:1) affording 3bB as a yellow
viscous oil. Yield = 41%. 1H NMR (400 MHz, CDCl3-d): δ 7.81−7.74
(m, 1H), 7.28−7.10 (m, 5H), 7.10−7.07 (m, 1H), 7.02−6.92 (m,
2H), 6.84−6.77 (m, 1H), 4.01 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.51
(t, J = 6.6 Hz, 2H), 2.96 (t, J = 6.4 Hz, 2H), 2.52 (t, J = 6.3 Hz, 2H),
2.11 (p, J = 6.4 Hz, 2H), 1.90−1.80 (m, 2H), 1.78−1.71 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 156.11, 149.17, 145.40, 144.18, 130.22,
128.99, 128.18, 127.73, 127.71, 127.69, 125.25, 124.83, 123.45,
121.24, 120.25, 119.44, 117.87, 115.92, 112.06, 112.02, 109.99,
101.15, 55.40, 45.57, 44.46, 33.57, 28.25, 24.67, 22.94, 22.73. HRMS
(ESI+): [M]+ = calculated for C30H29F3N3OS+ (m/z), 536.197 79;
found, 536.197 75. LC-MS purity > 98%.
N-[4-(2-Chloro-10H-phenothiazin-10-yl)butyl]-1,2,3,4-tetrahy-
droacridin-9-amine (2cA). The resulting residue was purified by
column chromatography (EA/DCM = 1:1) affording 2cA as a yellow
viscous oil. Yield = 50%. 1H NMR (400 MHz, CDCl3-d): δ 7.90−7.76
(m, 2H), 7.57−7.47 (m, 1H), 7.30−7.22 (m, 1H), 7.15−7.06 (m,
2H), 7.03−6.97 (m, 1H), 6.96−6.83 (m, 2H), 6.82−6.74 (m, 2H),
3.84 (t, J = 6.3 Hz, 2H), 3.45 (t, J = 6.9 Hz, 2H), 3.02 (t, J = 6.1 Hz,
2H), 2.55 (t, J = 6.0 Hz, 2H), 1.92−1.80 (m, 6H), 1.79−1.69 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 158.39, 150.31, 147.38, 146.41,
144.37, 133.21, 128.72, 128.22, 128.03, 127.64, 127.40, 125.25,
123.61, 123.06, 122.60, 122.43, 120.11, 115.95, 115.87, 115.84,
109.99, 48.76, 46.82, 34.01, 28.92, 24.72, 24.04, 23.02, 22.73. HRMS
(ESI+): [M]+ = calculated for C29H29ClN3S+ (m/z), 486.176 52;
found, 486.176 33. LC-MS purity > 98%.
6-Chloro-N-{3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]-
propyl}-1,2,3,4-tetrahydroacridin-9-amine (3bC). The resulting
residue was purified by column chromatography (EA/DCM = 1:1)
N-[4-(2-Chloro-10H-phenothiazin-10-yl)butyl]-7-methoxy-
1,2,3,4-tetrahydroacridin-9-amine (2cB). The resulting residue was
purified by column chromatography (PE/DCM/Tol/EtOH/NH3
(33% aq sol) = 15:5.5:3:1.5:0.15) affording 2cB as a yellow viscous
1
affording 3bC as a yellow viscous oil. Yield = 63%. H NMR (400
MHz, CDCl3-d): δ 7.82−7.79 (m, 1H), 7.70−7.63 (m, 1H), 7.23−
7.08 (m, 5H), 7.01−6.92 (m, 2H), 6.83−6.77 (m, 1H), 4.00 (t, J =
6.1 Hz, 2H), 3.91 (bs, 1H), 3.54 (t, J = 6.5 Hz, 2H), 2.94 (t, J = 6.4
Hz, 2H), 2.48 (t, J = 6.3 Hz, 2H), 2.09 (p, J = 6.4 Hz, 2H), 1.89−1.79
(m, 2H), 1.78−1.70 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
159.66, 150.13, 147.89, 145.39, 144.10, 133.88, 130.99, 129.83,
129.51, 127.78, 127.73, 127.63, 125.03, 124.45, 123.90, 123.54,
119.53, 119.49, 118.56, 116.72, 115.99, 112.10, 112.07, 45.79, 44.12,
33.92, 28.06, 24.57, 22.80, 22.55. HRMS (ESI+): [M]+ = calculated
for C29H26ClF3N3S+ (m/z), 540.148 26; found, 540.148 25. LC-MS >
98%.
1
oil. Yield = 50%. H NMR (400 MHz, CDCl3-d): δ 7.83−7.76 (m,
1H), 7.23−7.17 (m, 1H), 7.15−7.08 (m, 3H), 7.02−6.96 (m, 1H),
6.95−6.88 (m, 1H), 6.88−6.84 (m, 1H), 6.81−6.76 (m, 2H), 3.88−
3.76 (m, 5H), 3.38 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.59
(t, J = 5.9 Hz, 2H), 1.93−1.79 (m, 6H), 1.80−1.69 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 156.11, 155.90, 149.46, 146.41, 144.38,
143.28, 133.19, 130.19, 128.01, 127.62, 127.39, 125.24, 123.99,
123.05, 122.42, 121.18, 120.30, 117.39, 115.84, 115.81, 101.46, 55.40,
48.52, 46.87, 33.70, 28.92, 24.66, 24.22, 23.03, 22.78. HRMS (ESI+):
[M]+ = calculated for C30H31ClN3OS+ (m/z), 516.187 09; found,
516.187 01. LC-MS purity > 97%.
N-[4-(10H-Phenothiazin-10-yl)butyl]-1,2,3,4-tetrahydroacridin-
9-amine (1cA). The resulting residue was purified by column
chromatography (PE/DCM/Tol/EtOH/NH3 (33% aq sol) =
15:5.5:3:1.5:0.15) affording 1cA as a dark yellow viscous oil. Yield
= 74%. 1H NMR (400 MHz, CDCl3-d): δ 7.92−7.85 (m, 1H), 7.85−
7.80 (m, 1H), 7.56−7.46 (m, 1H), 7.29−7.20 (m, 1H), 7.18−7.07
(m, 4H), 6.95−6.86 (m, 2H), 6.84−6.76 (m, 2H), 3.86 (t, J = 6.4 Hz,
2H), 3.45 (t, J = 6.9 Hz, 2H), 3.02 (t, J = 6.2 Hz, 2H), 2.54 (t, J = 6.1
Hz, 2H), 1.92−1.79 (m, 6H), 1.79−1.70 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 158.44, 150.36, 147.46, 145.11, 128.76, 128.17,
127.57, 127.22, 125.48, 123.56, 122.66, 122.59, 120.14, 115.92,
115.53, 48.81, 46.67, 34.05, 29.00, 24.71, 24.16, 23.04, 22.75. HRMS
(ESI+): [M]+ = calculated for C29H30N3S+ (m/z), 452.215 50; found,
452.215 27. LC-MS purity > 98%.
6-Chloro-N-[4-(2-chloro-10H-phenothiazin-10-yl)butyl]-1,2,3,4-
tetrahydroacridin-9-amine (2cC). The resulting residue was purified
by column chromatography (EA/DCM = 1:1) affording 2cC as a
1
yellow viscous oil. Yield = 47%. H NMR (400 MHz, CDCl3-d): δ
7.86−7.81 (m, 1H), 7.76−7.71 (m, 1H), 7.18−7.08 (m, 3H), 7.02−
6.96 (m, 1H), 6.95−6.89 (m, 1H), 6.89−6.84 (m, 1H), 6.81−6.74
(m, 2H), 3.84 (t, J = 6.2 Hz, 2H), 3.45 (t, J = 6.9 Hz, 2H), 2.98 (t, J =
6.0 Hz, 2H), 2.49 (t, J = 6.0 Hz, 2H), 1.92−1.78 (m, 6H), 1.78−1.68
(m, 2H). 13C NMR (100 MHz, CDCl3): δ 159.40, 150.38, 147.95,
146.34, 144.34, 133.92, 133.21, 128.05, 127.66, 127.48, 127.40,
125.32, 124.32, 124.20, 124.08, 123.10, 122.47, 118.23, 115.89,
115.84, 115.76, 48.80, 46.70, 33.93, 28.88, 24.48, 23.90, 22.88, 22.56.
HRMS (ESI+): [M]+ = calculated for C29H28Cl2N3S+ (m/z),
520.137 55; found, 520.137 33. LC-MS purity > 97%.
7-Methoxy-N-[4-(10H-phenothiazin-10-yl)butyl]-1,2,3,4-tetrahy-
droacridin-9-amine (1cB). The resulting residue was purified by
column chromatography (PE/DCM/Tol/EtOH/NH3 (33% aq sol) =
15:5.5:3:1.5:0.15) affording 1cB as a dark yellow viscous oil. Yield =
N-{4-[2-(Trifluoromethyl)-10H-phenothiazin-10-yl]butyl}-1,2,3,4-
tetrahydroacridin-9-amine (3cA). The resulting residue was purified
by column chromatography (PE/DCM/Tol/EtOH/NH3 (33% aq
sol)= 15:5.5:3:1.5:0.1) affording 3cA as a yellow viscous oil. Yield =
1
1
57%. H NMR (400 MHz, CDCl3-d): δ 7.83−7.77 (m, 1H), 7.23−
63%. H NMR (400 MHz, CDCl3-d): δ 7.89−7.80 (m, 2H), 7.55−
7.18 (m, 1H), 7.15−7.07 (m, 5H), 6.93−6.86 (m, 2H), 6.83−6.77
(m, 2H), 3.87 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.38 (t, J = 7.0 Hz,
2H), 3.00 (t, J = 6.1 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.94−1.80 (m,
6H), 1.79−1.70 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 156.15,
155.87, 149.50, 145.11, 143.38, 130.27, 127.55, 127.19, 125.47,
122.58, 121.20, 120.27, 117.40, 115.49, 101.47, 55.39, 48.58, 46.72,
7.47 (m, 1H), 7.29−7.22 (m, 1H), 7.22−7.16 (m, 1H), 7.17−7.10
(m, 3H), 7.01−6.98 (m, 1H), 6.98−6.91 (m, 1H), 6.84−6.79 (m,
1H), 3.91 (t, J = 6.4 Hz, 2H), 3.84 (bs, 1H), 3.52−3.41 (m, 2H), 3.02
(t, J = 6.1 Hz, 2H), 2.57 (t, J = 6.1 Hz, 2H), 1.95−1.71 (m, 8H). 13C
NMR (100 MHz, CDCl3): δ 158.50, 150.23, 147.49, 145.65, 144.17,
128.84, 128.18, 127.71, 127.62, 124.57, 123.61, 123.28, 122.53,
120.19, 119.25, 119.21, 116.08, 115.93, 111.95, 111.91, 48.79, 46.90,
33.78, 29.00, 24.64, 24.35, 23.05, 22.80. HRMS (ESI+): [M]+
=
calculated for C30H32N3OS+ (m/z), 482.226 06; found, 482.225 83.
LC-MS purity > 99%.
34.07, 28.93, 24.74, 24.05, 23.01, 22.74. HRMS (ESI+): [M]+
=
calculated for C30H29F3N3S+ (m/z), 520.202 88; found, 520.202 64.
LC-MS purity > 98%.
6-Chloro-N-[4-(10H-phenothiazin-10-yl)butyl]-1,2,3,4-tetrahy-
droacridin-9-amine (1cC). The resulting residue was purified by
column chromatography (EA/DCM = 1:1) affording 1cC as a yellow
7-Methoxy-N-{4-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]-
butyl}-1,2,3,4-tetrahydroacridin-9-amine (3cB). The resulting resi-
due was purified by column chromatography (PE/DCM/Tol/EtOH/
NH3 (33% aq sol) = 15:5.5:3:1.5:1) affording 3cB as a yellow viscous
1
sticky foam. Yield = 61%. H NMR (400 MHz, CDCl3-d): δ 7.86−
7.81 (m, 1H), 7.76−7.70 (m, 1H), 7.17−7.06 (m, 5H), 6.93−6.86
(m, 2H), 6.82−6.76 (m, 2H), 3.87 (t, J = 6.3 Hz, 2H), 3.44 (t, J = 6.9
Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.47 (t, J = 6.0 Hz, 2H), 1.90−1.78
(m, 6H), 1.78−1.69 (m, 2H). 13C NMR (100 MHz, cdcl3): δ 159.46,
150.42, 148.06, 145.08, 133.84, 127.60, 127.53, 127.21, 125.58,
124.39, 124.14, 122.64, 118.27, 115.74, 115.55, 48.85, 46.55, 34.00,
28.97, 24.46, 24.02, 22.90, 22.59. HRMS (ESI+): [M]+ = calculated
for C29H29ClN3S+ (m/z), 486.176 52; found, 486.176 36. LC-MS
purity > 97%.
1
oil. Yield = 53%. H NMR (400 MHz, CDCl3-d): δ 7.84−7.78 (m,
1H), 7.23−7.07 (m, 6H), 7.01−6.97 (m, 1H), 6.97−6.90 (m, 1H),
6.84−6.78 (m, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.38 (t, J =
7.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 1.94−
1.80 (m, 6H), 1.79−1.71 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
156.11, 155.93, 149.50, 145.63, 144.18, 143.19, 130.46, 130.09,
129.73, 129.41, 127.69, 127.61, 124.54, 123.28, 121.19, 120.33,
119.23, 119.20, 117.41, 115.91, 111.92, 111.88, 101.45, 55.36, 48.51,
1710
ACS Chem. Neurosci. 2021, 12, 1698−1715