DOI: 10.3109/14756366.2013.795562
Synthesis of new N,N0-bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides
215–218 ꢁC, ethanol, 32%), P4m (30 mmol, 4 h, 224–226 ꢁC, N,N0-bis[1-(4-hydroxyphenyl)-3-(piperidine-1-yl)propylidene]
3
ethanol, 33%), P5m (20 mmol, 9 h, 196–198 ꢁC, methanol-ether, hydrazine dihydrochlorides (P4). Yield: 64%. M.p. 219–221 ꢁC.
48%), P6m (30 mmol, 8 h, 152–155 ꢁC, ethanol-ether, 45%), P7m UV ꢀ
(20 mmol, 8 h, 173–177 ꢁC, methanol, 21%), P8m (20 mmol, 8 h, 12H), 3.30 (m, 8H), 3.50–3.53 (m, 8H), 6.87 (d, J ¼ 8.8 Hz, 4H),
205–207 ꢁC, methanol, 41%). As precursor Mannich bases were 7.94 (d, J ¼ 8.8 Hz); 13C NMR (MeOH-d4) d 21.43, 23.04, 32.21,
registered in literatures with their melting points42–45, NMR data 52.48, 53.57, 115.22, 127.92, 130.75, 163.20, 195.07. HRMS
of them was not reported here. In the case of P2m, the mol ratio 463.30 (Mþ).
1
MeOH
(log ") 281 (4.36) nm. H NMR (MeOH-d4) d 1.89 (m,
maks
of ketone, aldehyde and amine was 1:2:1. Acetic acid (99%,
30 ml) was used instead of ethanol. After refluxing 22 h, the
solvent was evoporated in vacuo and diethyl ether was added into
the residue and the mixture was cooled for one night at 4 ꢁC.
The precipitated compound was filtered, dried and crystallized
from methanol-diethyl ether.
N,N0-bis[1-(4-chlorophenyl)-3-(piperidine-1-yl)propylidene]
hydrazine dihydrochlorides (P5). Yield: 48%. M.p. 184–189 ꢁC.
1
(log ") 254 (4.32), 311 (4.06) nm. H NMR (MeOH-
MeOH
maks
UV ꢀ
d4) d 1.57–1.93 (m, 12H), 3.04–3.15 (m, 8H), 3.51–3.63 (m, 8H),
7.55 (d, J ¼ 7.7 Hz, 4H), 8.04 (d, J ¼ 8.8 Hz, 4H); 13C NMR
(MeOH-d4) d 21.41, 23.06, 32.93, 52.15, 53.64, 128.96, 129.78,
134.7, 139.99, 195.5. HRMS 499.24 (Mþ), 501.24 (M þ 2)þ.
General procedure for the synthesis of hydrazones, N,N0-bis[1-
aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides
(P1–P8)
N,N0-bis[1-(3-methoxyphenyl)-3-(piperidine-1-yl)propylidene]
hydrazine dihydrochlorides (P6). Yield: 88%. M.p. 187–192 ꢁC.
A solution of hydrazine hydrate (1 mol ratio) in ethanol was
added to a solution of mono Mannich base (2 mol ratio) in
ethanolic acetic acid (3% w/v). The mixture was stirred at room
temperature for 17–26 h. The precipitated compound was
filtered, dried and crystallized from suitable solvent to give
the corresponding hydrazone derivatives. The crystals formed
were filtered and dried at room temperature. Experimental data
of P-series hydrazone compounds, P1–P8 (Scheme 1) are shown
in Table 1.
1
(log ") 251 (3.94), 308 (3.67) nm. H NMR (MeOH-
MeOH
maks
UV ꢀ
d4) d 1.84 (m, 12H), 3.26 (m, 8H), 3.53–3.59 (m, 8H), 3.88 (s,
6H), 7.13 (dd, J ¼ 8.3, 2.6 Hz, 2H), 7.46 (t, J ¼ 8.1 Hz, 2H), 7.55
(t, J ¼ 2.2 Hz, 2H), 7.58 (td, J ¼ 7.7, 2.6 Hz); 13C NMR (MeOH-
d4) d 21.4, 23.03, 23.91, 53.19, 53.55, 54.96, 113.01, 116.38,
119.83, 130.1, 137.4, 160.44, 163.01; HRMS 491.34 (Mþ),
492.34 (M þ 1)þ.
N,N0-bis[1-(4-fluorophenyl)-3-(piperidine-1-yl)propylidene]
hydrazine dihydrochlorides (P7). Yield: 12%. M.p. 204–209 ꢁC.
N,N0-bis[1-phenyl-3-(piperidine-1-yl)propylidene]hydrazine dihy-
1
MeOH
maks
MeOH
maks
UV ꢀ
(log ") 306 (4.30) nm. H NMR (MeOH-d4) d 1.80–
drochlorides (P1). Yield: 57%. M.p. 185–189 ꢁC. UV ꢀ
(log ") 303 (4.22) nm. 1H NMR (MeOH-d4) d 1.80–1.95 (m,
12H), 2.97 (m, 8H), 3.54–3.63 (m, 8H), 7.51–7.56 (m, 8H), 8.03–
8.06 (m, 2H); 13C NMR (MeOH-d4) d 21.39, 23.05, 23.74, 53.15,
53.5, 127.39, 128.92, 131.09, 136.05, 163.27. HRMS: 431.32
(Mþ), 432.32 (M þ 1)þ.
1.86 (m, 12H), 2.99 (m, 8H), 3.52–3.60 (m, 8H), 7.27 (t,
J ¼ 8.8 Hz, 4H), 8.11 (d, J ¼ 8.8 Hz, 4H); 13C NMR (MeOH-d4) d
21.42, 23.05, 23.72, 53.18, 53.4, 115.91, 129.9, 132.37, 163.61,
166.11. HRMS 467.3 (Mþ), 468.3 (M þ 1)þ.
N,N0-bis[1-(4-bromophenyl)-3-(piperidine-1-yl)propylidene]
hydrazine dihydrochlorides (P8). Yield: 14%. M.p. 195–199 ꢁC.
N,N0-bis[1-(4-methylphenyl)-3-(piperidine-1-yl)propylidene]
1
(log ") 263 (4.13), 313 (4.30) nm. H NMR (MeOH-
MeOH
maks
UV ꢀ
hydrazine dihydrochlorides (P2). Yield: 9%. M.p. 207–210 ꢁC.
1
MeOH
maks
d4) d 1.84–2.01 (m, 12H), 3.03 (m, 8H), 3.50–3.61 (m, 8H), 7.72
(d, J ¼ 8.8 Hz, 4H), 7.96 (d, J ¼ 8.8 Hz, 4H); 13C NMR (MeOH-
d4) d 21.39, 23.04, 32.84, 52.12, 53.66, 128.67, 129.82, 132.03,
135.04, 195.71. HRMS 587.14 (Mþ), 589.14 (M þ 2)þ, 591.14
(M þ 4)þ.
UV ꢀ
(log ") 313 (4.28) nm. H NMR (MeOH-d4) d 1.85 (m,
12H), 2.41 (s, 6H), 2.99 (m, 8H), 3.52–3.63 (m, 8H), 7.35 (d,
J ¼ 7.7 Hz, 4H), 7.94 (t, J ¼ 8.4 Hz, 4H); 13C NMR (MeOH-d4) d
20.23, 21.41, 23.05, 23.61, 53.14, 53.67, 127.36, 129.53, 133.33,
141.77, 163.08. HRMS 459.35 (Mþ), 460.35 (M þ 1)þ.
Cytotoxic activity assay
N,N0-bis[1-(4-methoxyphenyl)-3-(piperidine-1-yl)propylidene]
hydrazine dihydrochlorides (P3). Yield: 72%. M.p. 214–217 ꢁC.
Hydrazone compounds, P1–P8 and 5-FU, which was used as
positive control compound, were tested against human hepatoma
(Huh7) and breast cancer (T47D) cells by NCI-60
SulforhodamineB Assay46,47 to identify the compounds with
growth-inhibitory activity. Briefly, T47D and Huh7 cells (5000 or
10 000) were inoculated into 96-well plates in 100 ml of standard
DMEM medium (Gibco-Invitrogen Corp., Grand Island, NY) 24 h
1
MeOH
maks
UV ꢀ
(log ") 276 (4.38) nm. H NMR (MeOH-d4) d 1.85–
1.92 (m, 12H), 3.30 (m, 8H), 3.49–3.58 (m, 8H), 3.88 (s, 6H),
7.04 (d, J ¼ 9.2 Hz, 4H), 8.03 (d, J ¼ 8.8 Hz, 4H); 13C NMR
(MeOH-d4) d 21.43, 23.04, 32.38, 52.41, 53.59, 54.95, 113.86,
129.02, 130.51, 164.62, 195.17. HRMS 491.34 (Mþ), 492.34
(M þ 1)þ.
Table 1. Experimental data of P series hydrazone compounds, P1–P8 (Scheme 1).
Compound
Formula
MW
Reaction time (h)
Crystallization solvent
Yield (%)
Melting point (ꢁC)
P1
P2
P3
P4
P5
P6
P7
P8
C28H40Cl2N4
502.26
530.29
562.28
534.25
570.19
562.28
538.24
658.08
17
23
18
18
18
26
26
20
Ethanol
Ethanol
Methanol
Ethanol
Ethanol
57
9
185–189*
208–210
214–217
219–221
186–189
190–192
204–209
195–199
C
C
C
C
C
C
C
30H44Cl2N4
30H44Cl2N4O2
28H40Cl2N4O2
28H38Cl4N4
30H44Cl2N4O2
28H38Cl2F2N4
28H38Br2Cl2N4
72
64
48
88
12
14
Chloroform
Chloroform/methanol
Ethyl acetate/methanol
*Reported melting point of P1 was 172.5–175 ꢁC52
.