Chromatography (FC) was carried out on a Biotage SP1 EXP
(4a, 4b, 5a, 5b) and 3-(4-benzyl-1-piperidyl)-1-(4-
phenylpiperazin-1-yl)propan-1-ones (6a, 6b, 7a, 7b)
1
13
(Biotage AB Uppsala, Sweden). H NMR and C NMR spectra
were measured in dimethylsulfoxide-d6 (DMSO-d ) with a Varian
Gemini 500 spectrometer (Varian Inc. Palo Alto, California USA);
chemical shifts are expressed in δ (ppm) and coupling constants
6
To a solution of 2-chloro-1-(4-phenylpiperazin-1-yl)ethanones
(2a-b) or 3-chloro-1-(4-phenylpiperazin-1-yl)propan-1-ones (3a-
b) (1.0 mmol) in DMF (1 mL) the appropriate amine derivative
(1.5 mmol) and K CO (0.5 mmol) were added. The reaction was
(J) in hertz. All exchangeable protons were confirmed by addition
2
3
of D O. R values were determined on TLC plates using a mixture
of DCM/MeOH (96/4) as eluent. None of the studied compounds
2
f
heated using microwave irradiation for 15 min at 100 °C and then
was quenched with water (5 mL) and a saturated solution of
NaHCO (5mL). The aqueous layer was extracted with EtOAc
3
(
(3x10 mL) and obtained organic phases were washed with brine,
filtered, concentrated and finally purified by flash chromatography
(
2
DCM/MeOH, 96:4) and crystallized with Et O and EtOH to
4
.1.1. General procedure to synthesize 2-chloro-1-
afford desired pure compounds 4a, 4b, 5a, 5b, 6a, 6b, 7a, and 7b.
For compounds 4a and 6a registered CAS numbers have been
already assigned; however, their synthetic procedure, chemical
properties and structural characterization are not available in
literature. Therefore, we synthesized all designed compounds 4a,
(
4-phenylpiperazin-1-yl)ethanones (2a, 2b) and 3-
chloro-1-(4-phenylpiperazin-1-yl)propan-1-ones
3a, 3b)
(
To a solution of phenylpiperazine (1a or 1b) (3 mmol) in dry
DCM (4 ml) the appropriate chloroacetyl chloride (3 mmol, 233.2
µl) or chloropropanoyl chloride (3 mmol, 286.4 µl) was added
slowly (0°C). Then, the reaction mixture was stirred at room
4
b, 5a, 5b, 6a, 6b, 7a, and 7b and their chemical characterization
is reported below.
temperature for 1 hr. A saturated solution of NaHCO
added to quench the reaction. The mixture was extracted with
DCM twice, dried over Na SO and the solvent was removed
under vacuum. The desired compounds 2a-b e 3a-b were obtained
as powder by treatment with EtOH and Et O. For these
intermediates registered CAS numbers have been already
assigned. For compound 3b the synthetic procedure, chemical
properties and structural characterization are not available in
literature.
3
(5 mL) was
4
.1.2.1. 2-(4-Benzyl-1-piperidyl)-1-(4-
2
4
phenylpiperazin-1-yl)ethanone (4a) CAS 946939-23-
7
2
1
Yield: 30%; white powder; M.p.: 95-96°C; R
(DMSO-d
Anal. for (C H N O): C 76.36, H 8.28, N 11.13. Found: C 76.48
f
= 0.34. H-NMR
6
): (δ) 1.14-3.67 (m, 2H, 21H), 6.77-7.25 (m, 10H, ArH).
2
4
31
3
H 8.07 N 11.44.
4
.1.2.2. 2-(4-Benzyl-1-piperidyl)-1-[4-(4-
hydroxyphenyl)piperazin-1-yl]ethanone (4b)
4
.1.1.1. 2-Chloro-1-(4-phenylpiperazin-1-
yl)ethanone (2a) CAS 1476139-8
1
Yield: 89%; white powder; M.p.: 183-184°C; R = 0.13. H-
f
NMR (DMSO-d ): (δ) 1.12-3.65 (m, 20H), 6.65 (d, J=8.7, 2H,
ArH), 6.79 (d, J=8.7, 2H, ArH), 7.12-7.27 (m, 5H, ArH), 8.83 (bs,
6
Yield: 50%; white powder; M.p.: 75-76°C. 1H-NMR (DMSO-
d
(
6
): (δ) 3.10-3.50 (m, 8H, CH
m, 5H, ArH). Anal. for (C12
Found: C 60.00, H 6.52, N 11.70.
2
), 4.42 (s, 2H, CH
2
-Cl), 6.69-7.25
1
3
1
4
1
6
H, OH). C-NMR (DMSO-d ): 31.81, 37.09, 41.31, 42.36,
H15ClN O): C 60.38, H 6.33, N 11.73.
2
5.32, 50.33, 50.99, 53.09, 61.43, 115.53, 118.40, 125.74, 128.13,
28.99, 140.36, 144.02, 151.35, 167.66. Anal. for C H N O : C
2
4
31
3
2
4
1
73.25, H 7.94, N 10.68. Found: C 73.26, H 7.93, N 10.69.
4
.1.2.3. 2-[4-[(4-Fluorophenyl)methyl]-1-
Yield: 30%; white powder; M.p.: 162-163°C. 1H-NMR
piperidyl]-1-(4-phenylpiperazin-1-yl)ethanone (5a)
(
6
1
6 2 2
DMSO-d ): (δ) 2.91-3.56 (m, 8H, CH ), 4.40 (s, 2H, CH -Cl),
.64 (d, J=8.2, 2H, ArH), 6.78-6.9 (d, J=8.2, 2H, ArH), 8.88 (bs,
1
Yield: 20%; pale yellow powder; M.p.: 95-97°C; R
NMR (DMSO-d
ArH). Anal. for (C H FN O): C 72.88, H 7.65, N 10.62. Found:
f
= 0.34. H-
6
): (δ) 1.12-3.67 (m, 21H), 6.79-7.22 (m, 9H,
H, OH). Anal. for (C H ClN O ): C 56.59, H 5.94, N 11.00.
1
2
15
2
2
2
4
30
3
Found: C 56.66, H 5.70, N 11.22.
C 72.69 H 7.44 N 10.84.
4
.1.1.3. 3-Chloro-1-(4-phenylpiperazin-1-
4
.1.2.4. 2-[4-[(4-Fluorophenyl)methyl]-1-
yl)propan-1-one (3a) CAS 2392-47-4
piperidyl]-1-[4-(4-hydroxyphenyl)piperazin-1-
yl]ethanone (5b)
1
Yield: 88%; white powder; M.p.: 84-85°C. H-NMR (DMSO-
): (δ) 2.84-2.91 (m, 2H, CH Cl), 3.33-3.12 (m, 8H CH ), 3.76-
.82 (m, 2H, CH -CO), 6.78-7.25 (m, 5H, ArH). Anal. for
d
3
6
2
2
Yield: 66%; pale yellow powder; M.p.: 184-185°C; R
H-NMR (DMSO-d ): (δ) 1.13-3.68 (m, 21H), 6.64 (d, J=8.7, 2H,
ArH), 6.81 (d, J=8.7, 2H, ArH), 7.07-7.20 (m, 4H, ArH), 8.89 (bs,
H, OH). Anal. for (C H FN O ): C 70.05, H 7.35, N 10.21.
f
= 0.13.
2
1
6
(C H ClN O): C 61.78, H 6.78, N 11.08. Found: C 61.89, H
13 17 2
.40, N 11.30.
6
1
2
4
30
3
2
4
1
.1.1.4. 3-Chloro-1-[4-(4-hydroxyphenyl)piperazin-
-yl]propan-1-one (3b) CAS 1183257-03-5
Found: C 70.16, H 7.24, N 10.29.
4
.1.2.5. 3-(4-Benzyl-1-piperidyl)-1-(4-
Yield: 97%; white powder; M.p.: 174-175°C. 1H-NMR
phenylpiperazin-1-yl)propan-1-one (6a) CAS
1
905697-95-1
(
DMSO-d
6
2
): (δ) 2.83-2.89 (m, 2H, CH Cl), 2.89-3.56 (m, 8H
CH
2
), 3.77-3.81 (m, 2H, CH -CO), 6.65 (d, J= 8.8, 2H, ArH), 6.80
2
1
f
Yield: 36%; white powder; M.p.: 67-68°C; R = 0.10. H-NMR
(d, J= 8.8, 2H, ArH), 8.89 (bs, 1H, OH). Anal. for (C H ClN O ):
13 17 2 2
(DMSO-d
6
): (δ) 1.08-3.56 (m, 23H), 6.76-7.27 (m, 10H, ArH).
C-NMR (DMSO-d ): 31.81, 37.09, 40.88, 44.80, 45.32, 50.33,
C 58.10, H 6.38, N 10.42. Found: C 58.32, H 6.50, N 10.20.
13
6
5
1
0.99, 53.09, 61.43, 115.82, 119.37, 125.73, 128.18, 128.98,
40.34, 144.02, 150.83, 169.76. Anal. for (C H N O): C 76.69,
4
1
.1.2. General procedure to synthesize 2-(4-benzyl-
-piperidyl)-1-(4-phenylpiperazin-1-yl)ethanones
25 33
3
H 8.49, N 10.73. Found: C 76.78, H 8.28, N 10.55.