Novel symmetrical trans-bis-Schiff bases of N-substituted-4- piperidones: Synthesis, characterization, and preliminary antileukemia activity mensurations

Article abstract of DOI:10.1002/jhet.916

A series of novel symmetrical trans-bis-Schiff bases (11a, 11b, 11c, 11d, 11e, 11f, 11g, 11h, 11i, 11j, 11k, 11l, 11m) were designed and prepared as novel anticancer analogues, with the trans-configuration confirmed by X-ray diffraction. Preliminary inhibitory effects of these compounds on CML K562 cell growth were investigated, and the potential analogue 11e showed an excellent anti-leukemia activity (IC₅₀=6.35 μg/mL), which is higher than that of the clinical drug 5-fluorouracil (IC₅₀=8.48 μg/mL). Complete assignments had been achieved for the title compounds by spectroscopic techniques, and their structure-activity relationships have been studied.

Full text of DOI:10.1002/jhet.916

Month 2013
Novel Symmetrical trans‐Bis‐Schiff Bases of N‐Substituted‐4‐
piperidones: Synthesis, Characterization, and Preliminary
Antileukemia Activity Mensurations
a
b
b
b
*
Chuan‐Wen Sun, Hai‐Feng Wang, Jun Zhu, Ding‐Rong Yang,
Jiahua Xing,c and Jia Jinb
aDepartment of Biology, College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
bDepartment of Chemistry, College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
cBioassay Department, Branch of National Pesticide R&D South Center, Zhejiang Research Institute of Chemical
Industry, Hangzhou 310023, China
*
E-mail: willin112@163.com
Received January 1, 2011
DOI 10.1002/jhet.916
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel symmetrical trans‐bis‐Schiff bases (11a‐11m) were designed and prepared as novel
anticancer analogues, with the trans‐configuration confirmed by X‐ray diffraction. Preliminary inhibitory
effects of these compounds on CML K562 cell growth were investigated, and the potential analogue 11e
showed an excellent anti‐leukemia activity (IC50=6.35 μg/mL), which is higher than that of the clinical drug
5‐fluorouracil (IC50=8.48 μg/mL). Complete assignments had been achieved for the title compounds by
spectroscopic techniques, and their structure–activity relationships have been studied.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
antifungal [23–25], and herbicidal activities [26–28]. In
discovering biological schiff base molecules, a notable role is
played by heterocyclic structures, which were reported to pos-
sess the cytotoxic [29], anticonvulsant [30], antiproliferative
[31], anticancer, and antifungal activities [32]. Development
of a new chemotherapeutic Schiff bases is now attracting the
attention of medicinal chemists [33–36]. For example, Hwu
et al. have reported that photolytic cleavage of the nitrogen–
nitrogen single bond in benzaldehyde phenylhydrazones
produced aminyl (R2N·) and iminyl (R2C=N·) radicals. This
photochemical property was utilized in the development of
hydrazones as photoinduced DNA cleaving agents [37].
Arylcarbaldehyd‐4‐(1‐phenyl‐3‐ methylpyrazolo‐[3,4‐b]
pyridine) hydrazone derivatives were utilized as a new
pharmacophoric tool for the development of more efficacious
analgesics [38]. Moreover, due to the known therapeutic
properties of piperidines and due to the presence of a keto
function that facilitates the introduction of other substituents
on the piperidine ring. Piperidine derivatives are useful as
anti‐osteoporotic raloxifene [39], vasodilator minoxidil
[40,41], analgesic fentanyl 1 (Fig. 1) [42,43], anti‐Pakinsonian
Chronic myelogenous leukemia (CML) is a myeloprolifer-
ative disorder characterized by unregulated growth of myeloid
leukemia cells in the bone marrow and accumulation of these
cells in the blood, which is caused by clonal expansion of
pluripotent hematopoietic stem cells retaining their differen-
tiation potential [1]. It is usually a triphasic disease, having a
chronic, an accelerated, and a blast phase [2–4], during
which progressive resistance to therapy is acquired [5–10].
New evidence suggests that CML blasts arise from leukemic
progenitors (rather than leukemic stem cells) that have restored
self‐renewal capacities [11,12]. Recent study also showed that
CML cell line K562 was considerably more resistant to
apoptosis than a number of other human hematopoietic cell
lines. Therefore, the development of novel and effective
anticancer drugs against CML is a high priority.
Schiff bases are an important class of organic compounds,
some of which show significant biological activities [13–16].
Many studies have reported the biological activities of Schiff
bases, including their anticancer [17–19], antibacterial [20–24],
© 2013 HeteroCorporation

C.-W. Sun, H.-F. Wang, J. Zhu, D.-R. Yang, J. Xing, and J. Jin
Vol 000
Figure 1. Structures of the compounds.
agent biperiden [44,45] and also as high antiproliferative
RESULTS AND DISCUSSION
A five‐step synthetic strategy
activity which was shown by the parent molecule 2 and 3
(Fig. 1) towards leukemia and colon cancer cell lines [46,47].
On the basis of above observations and obeying the prin-
ciple of active‐factor‐addition, the development of novel
bis‐Schiff bases of piperidones as potential anticancer
agents is very attractive. Continuing our interest in nitrogen
piperidine derivatives 4 (Fig. 1) endowed with anti‐leuke-
mia activity [48,49], we designed and synthesized a novel
series of highly functionalized piperidone azines 5 (Fig. 1)
and evaluated the effects of these compounds on CML
K562 cell growth.
Synthesis of compounds.
was adopted for the synthesis of symmetrical trans‐N‐
substituted‐4‐piperidone azines 11a–m. The general schematic
representation describing the routes of syntheses is
furnished in Scheme 1. N,N‐Bis[2‐(methoxycarbonyl)
ethyl] substitutedamines 8a–m was obtained by the
Michael addition of substitutedamine, methyl acrylate,
and acetic acid in 1:4:1 ratio, respectively. The N,N‐bis
[2‐(methoxycarbonyl)ethyl] substitutedamines 8a–m
afforded N‐substituted‐4‐piperidones 10a–m upon reflux
Scheme 1. Synthesis of novel symmetrical trans‐N‐substituted‐4‐piperidone azines 11a–m. Reagents and conditions: (a) acetic acid, absolute methanol,
refluxing; (b) sodium/ absolute methanol, toluene, refluxing; (c) 25% HCl, refluxing; (d) 35% sodium hydroxide, r.t; (e) 85% hydrazine hydrate, acetic
acid, absolute ethanol, refluxing.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Novel Symmetrical trans-Bis-Schiff Bases of N-Substituted-4-piperidones: Synthesis,
Characterization, and Preliminary Antileukemia Activity Mensurations
with sodium methoxide in the presence of absolute toluene
and the followed mixture was extracted with 25% HCl,
then directly refluxed. Azines 11a–m was obtained by
treatment of the N‐substituted‐4‐piperidones 10a–m with
hydrazine hydrate in the presence of acetic acid in
absolute ethanol in good yield 45–67.4%. For the
formation of the azines, taking 11b for example,
according to Sayer mechanistic model [50], various pH
value of buffers such as Tris 10 mM/EDTA 1 mM at pH
7.4 and acetic acid 100 mM at pH 4.6, other buffers
were hydrochloric (HCl 200 mM + KCl 200 mM, pH
1–2), citratephosphate (citric acid 50 mM + Na2HPO4
100 mM, pH 2.6–7), acetic (acetic acid 100 mM +
NaOH, pH 3.6–5), carbonate (K2CO3 50 mM + HCl,
pH 8–9.6), and phosphate (Na2HPO4 50 mM + Na3PO4
50 mM, pH 10–12) under 70°C temperature were
examined. Of these buffers, acetic acid at pH 4.6 was
found to be the proficient condition for getting the
excellent yields 67.4% of the azine 11b. All the
synthesized N‐substituted‐4‐piperidone azines 11a–m
are freely soluble in absolute toluene but insoluble in
polar aprotic solvent acetonitrile and partially soluble in
polar protic solvents such as ethanol, methanol at room
temperature. The structures of azine derivatives were
determined by IR, 1HNMR, mass spectroscopy and
piperidine rings do not show perfect chair conformation,
the endocyclic torsion angles varying between 43.116
(178)° and 53.846(169) ° which deviated from the criterion
region 56.5(4) to 56.7(4), respectively [51]. Moreover, for
steric reasons and bulky rongsform trans conformation
around the N(2)–N(3) bond, torsion angles C11–C10–N2–
N3 [−179.36(16) °] and C14–C13–N3–N2 [176.76(16) °]
close to 180°, which is different from the torsion angles
C17–C13–N3–N2 [0.4(3)°] and C9–C10–N2–N3 [0.1(3)°]
near to coplanarity. The axial C N bonds do not experience
a repulsion with the axial nitrogen lone pair as provided by
the opening of the following bond angles : N(1)C(12)C(11)
[111.64(16)°], N(1)C(8)C(9) [112.90(17)°], N(4)C(15)C
(114) [111.31(17)°] and N(4)C(16)C(17) [112.47(16)°]. In
addition, the nitrogen lone pair could cause a slight change
of C(8)–C(9), C(11)–C(12), C(13)–C(14) and C(13) –C(17)
as provided by the comparison of bond distances (means
1.484(3) to 1.500(3) Å) with typical C C single bond distance
1.53 Å. Similarly, as the existence of chair conformation, the
both conjugated C N bonds distance(1.271(3) Å) is shorter
than the normal value of 1.34 Å. The C(7)–N(1) and C
(18)–N(4) bond distances mean 1.472(3) and 1.458 (3) Å,
however, are different from the C N bond distance 1.50 Å
[52,53]. The crystal structures of 11b are stabilized by
C H…π bonds, without any intermolecular hydrogen bonds
(Fig. 3). The representative single‐crystal structural char-
acterization of the compound 11b should be valuable for
elementary analysis.
Single‐crystal structural characterization of compound 11b
by X‐ray. The spatial structure of compound 11b was
further investigation.
Preliminary anti‐leukemia activity. The growth inhibition
determined by using X‐ray diffraction analysis. The single
crystals were grown from ethanol at room temperature. The
molecular view of 11b is shown in Figure 2. The X‐ray
analysis showed the two C N bonds are trans with respect
to N N bond, which revealed unambiguous proof of the
interesting point that since the azines contain two double
bonds of imino group on 11b, a free roatation of the
imino double bond is restricted and formation of either
geometrical trans or cis isomer is expected as HNMR
provide a symmetrical set of singals.
The molecule of 11b is nonplanar, which consists of four
fragments, namely two piperidine rings [N(1)/C(8)–C(13)]
and [N(1)/C(13)–(17)], two benzene rings [C(1)–C(6)] and
[C(19)–C(24)]. Because the two conjugated C N bonds, the
activities of the title compounds and 5–fluorouracil (5–FU)
against K562 cell were determined by the MTT assay
according to the standard bioactivity test procedures of
the Zooblast‐molecular BiologyLaboratory of Shanghai
Normal University of China [54]. The data obtained by
MTT assay showed that compounds 11a–m had inhibitory
effects on the growth of K562 cells in dosage‐dependent
manners. As indicated in Figure 4, most of our designed
compounds exhibited significant inhibition activities against
K562 cells and had > 80% inhibition at 100 μg/mL, which
is higher than those of the anti‐tumor drug of clinical
practice 5‐FU at the same concentration. Analogues
11e, 11l, and 11m afforded the best in vitro activity,
1
Figure 2. Molecular structure of compound 11b (Number CCDC 739158).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

C.-W. Sun, H.-F. Wang, J. Zhu, D.-R. Yang, J. Xing, and J. Jin
Vol 000
Figure 3. Packing diagram of compound 11b viewed down the b axis.
Figure 4. Inhibition of K562 cells treated with compounds 11a–m. Cells were treated with the compounds at concentrations of 1, 10, and 100 μg/mL for
48 h. The cell viability was determined by MTT assay.
even at 1 μg/mL. Compounds 11a–m exhibited a
varying antileukemia IC50 values, ranging between
6.35 μg/mL and 29.17 μg/mL.
(11i–m) showed excellent inhibitory activities, IC50 < 20
μg/mL. Excepted for 11e, the inhibition activities of all
the corresponding analogues decreased in the order
heterocyclic methyl (11i–m) > phenylethyl (11h) >
phenylmethyl (11b‐d) > cyclohexyl (11a). In addition,
compounds 11g and 11f, with a methyl group at the
methenyl demonstrated higher activities than 11b. The
observations herein corroborate our point of view that a
Structure–activity relationships. As indicated in Table 1,
compound 11e was the most potent compound in this
series, having an IC50 value of 6.35 μg/mL in inhibiting
the K562 cell growth, which is higher than that of the
clinical drug 5‐fluorouracil (IC50=8.48 μg/mL). This
compound was almost fourfold more potent than 11a,
11b, and 11c, and the IC50 of other compounds varied
drastically, depending upon the size, types, and characters
of the 1‐position substitution on piperidine rings. The
introduction of 3‐pyridylmethyl, 2‐furanylmethyl, 6‐chloro‐
3‐pyridylmethyl, 2‐thienylmethyl and 2‐tetrahydrofuranyl
methyl at the 1‐position of piperidine rings in azines
3,4‐methylenedioxybenzyl or
a heterocyclic methyl
introduced at 1–position of piperidine rings may increase
the inhibition activity of piperidone azine analogues.
In summary, this article has described a facile approach to
prepare novel N‐ substitutedpiperidin‐4‐one azines deriva-
tives (11a–m) via a series of Michael addition, Dieckmann
condensation, hydrolysis decarhoxylation, and condensation
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Novel Symmetrical trans-Bis-Schiff Bases of N-Substituted-4-piperidones: Synthesis,
Characterization, and Preliminary Antileukemia Activity Mensurations
Table 1
investigation. Preliminary bioassay against the K562 cell
showed all the tested compounds exhibited good anticancer
activities at 100 μg/mL, and analogue 11e was found to
be the most effective molecule in inhibiting K562 cell
growth, with its IC50 of 6.35 μg/mL, which is better than
that of the anti‐tumor drug of clinical practice (5‐FU).
Studies on the inhibition mechanisms of compound 11e
against CML cell line are ongoing and will be reported
in due course. The structure–activity relationships described
in this study will be highly useful for the development of new
cancer inhibitors with high potency and selectivity.
Growth inhibitory properties IC50 (μg/mL) for the compounds 11a–m and
5‐FU at 48 h.
Compd
R1
R2
n
0
IC50(μg/mL)
11a
29.17
11b
11c
11d
11e
H
H
H
H
1
1
1
1
27.76
26.70
24.24
6.35
EXPERIMENTAL
All the chemical reagents purchased were of analytical grade
and used without further purification, except for the toluene,
which was dried by refluxing in the presence of sodium and
distilled prior to use. RPMI 1640 was obtained from Gibco BRL
(Grand Island, NY, USA) and Bovine calf serum was supplied
by Beijing DingGuo Biotechnology Co., China. Thin‐layer
chromatography (TLC) was carried out on silica gel 60 F254
plates Merck KGaA). 1HNMR spectra were recorded on a
Bruker Avance 400 (400 MHz) spectrometer, using CDCl3 or
DMSO as solvents and tetramethylsilane (TMS) as internal standard.
Melting points were determined by an RK1 microscopic melting
apparatus uncorrected. Elemental analysis was performed with a
Perkin‐Elmer 2400 instrument. IR spectra were obtained on a
Nicolet 5DX FT‐IR spectrophotometer in the region 4000‐400
cm−1 using KBr discs. MS spectra were recorded on a Trace
DSQ mass spectrograph. X‐ray diffraction data were recorded
on a Bruker Smart CCD diffractometer.
General procedure for the synthesis of 11a–m. To a stirred
solution of derivatives 10a–m [55] 1 mM and acetic acid 0.01
mM in 10 mL of ethanol, there was added a half amount of the
appropriate hydrazine hydrate. The reaction mixture was
maintained under reflux for 2–16 h, until TLC indicated the end
of reaction. After this time, the reaction mixture stood over
night and the solid formed was collected by filtration and
washed with ethanol and recrystallized from ethanol to afford
crystals. As a result of this process the compounds 11a–m were
prepared in yield of 45–67.4%.
11fa
11gb
11h
11i
CH3
CH3
H
1
1
1
1
25.94
23.78
20.32
12.37
H
11j
H
H
H
H
1
1
1
1
10.65
18.83
15.42
17.11
8.48
11k
11l
N‐Cyclohexyl‐4‐piperidone azine (11a). Yellow solid, yield
57.3%, m.p. 116–118°C; IR (KBr, cm−1) ν: 1632 (C N), 1117
(C N); 1HNMR (CDCl3, 400 MHz) δ: 1.09‐1.32 (m, 8H,
cyclohexyl), 1.80 (t, J = 2.8Hz, 1H, cyclohexyl), 1.96 (d, J = 8.4Hz,
1H, cyclohexyl), 2.38 (t, J = 5.6Hz, 2H, CH2, piperidine), 2.43
(d, J = 4.2Hz, 2H, CH2, piperidine), 2.49 (d, J = 4.2Hz, 2H, CH2,
piperidine), 2.53 (t, J = 5.6Hz, 2H, CH2, piperidine); MS (EI, 70 eV)
m/z (%): 358.4 (M+, 6.52), 179.3 (100), 83.3 (34.3). Anal. calcd
for C22H38N4: C 73.69, H 10.68, N 15.63%; found C 73.78, H
11m
5‐FU
10.73, N 15.45%.
a( )‐.
b(R)‐.
N‐Benzyl‐4‐piperidone azine (11b). Yellow solid, yield
67.4%, m.p. 134–135°C; IR (KBr, cm−1) ν: 1643 (C N), 1601,
1496, 1453 (C C), 1115 (C N); HNMR (CDCl3, 400 MHz) δ:
1
2.43 (t, J = 5.6Hz, 2H, CH2, piperidine), 2.46 (d, J = 4.2Hz,
2H, CH2, piperidine), 2.51 (d, J = 4.2Hz, 2H, CH2, piperidine),
2.60 (t, J = 5.6Hz, 2H, CH2, piperidine),3.56 (s, 2H, N‐CH2Ph),
7.25‐7.36 (m, 5H, Ph‐H); MS (EI, 70 eV) m/z (%): 374.5 (M+, 8.24),
187.4 (100), 91.3 (41.70). Anal. calcd for C24H30N4: C 76.97, H
8.07, N 14.96%; found C 76.84, H 8.12, N 14.88%.
reactions. These compounds were characterized by IR,
1HNMR, mass spectroscopy, and elementary analysis. The
structural characterization of the compound 11b was also
studied by X‐ray, which may be valuable for further
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

C.-W. Sun, H.-F. Wang, J. Zhu, D.-R. Yang, J. Xing, and J. Jin
Vol 000
N‐(4‐Methylbenzyl)‐4‐piperidone azine (11c). Yellow solid,
yield 61.2%, m.p. 147−149°C; IR (KBr, cm−1) ν: 1641 (C N),
1609, 1511, 1455 (C C), 1116 (C N); 1HNMR (CDCl3, 400
MHz) δ: 2.36 (s, 3H, CH3), 2.41 (t, J = 5.6Hz, 2H, CH2,
piperidine), 2.56 (d, J = 4.2Hz, 2H, CH2, piperidine), 2.59 (d, J
= 4.2Hz, 2H, CH2, piperidine), 2.63 (t, J = 5.6Hz, 2H, CH2,
piperidine), 3.55 (d, J = 2.2Hz, 2H, N‐CH2Ph), 7.15 (d, J =
8.0Hz, 2H, Ph‐H), 7.24 (d, J = 8.0Hz, 2H, Ph‐H); MS (EI, 70
eV) m/z (%): 402.3 (M+, 7.84), 201.4 (100), 105.3 (41.23).
Anal. calcd for C26H34N4: C 77.57, H 8.51, N 13.92%; found C
77.61, H 8.37, N 13.83%.
201.4 (100), 126.3 (38.62). Anal. calcd for C26H34N4: C
77.57, H 8.51, N 13.92%; found C 77.66, H 8.43, N 13.77%.
N‐(3‐Pyridylmethyl)‐4‐piperidone azine (11i). Yellow solid,
yield 45%, m.p. 143–144°C; IR (KBr, cm−1) ν: 1627 (C N),
1607, 1501, 1457 (C C), 1115 (C N); 1HNMR (CDCl3, 400
MHz) δ: 2.52 (t, J = 5.6 Hz, 2H, CH2, piperidine), 2.55 (d,
J = 5.2Hz, 2H, CH2, piperidine), 2.60 (d, J = 5.2Hz, 2H,
CH2, piperidine), 2.66 (t, J = 5.6 Hz, 2H, CH2, piperidine),
4.63 (d, 2H, CH2‐Pyri), 7.12(d, J = 7.6 Hz, 1H, Pyri‐H), 7.23‐
7.27(m, 1H, Pyri‐H), 7.36(d, J = 8.0Hz, 1H, Pyri‐H), 8.56‐8.58
(dd, J1 = J2 = 2.4 Hz, 1H, Pyri‐H); MS (EI, 70 eV) m/z (%):
376.4 (M+, 8.87), 188.3 (100), 92.4 (43.17). Anal. calcd for
C22H28N6: C 70.18, H 7.50, N 22.32%; found C 70.23, H
7.32, N 22.21%.
N‐(4‐Methoxybenzyl)‐4‐piperidone azine (11d). Yellow solid,
yield 52.3%, m.p. 151–153°C; IR (KBr, cm−1) ν: 1646 (C N),
1
1611, 1510, 1452 (C C), 1112 (C N); HNMR ([D6]DMSO, 400
N‐(6‐Chloro‐3‐pyridylmethyl)‐4‐piperidone azine (11j).
MHz) δ: 2.31 (t, J = 5.6Hz, 2H, CH2, piperidine), 2.39 (d, 4H,
J = 4.2Hz, CH2, piperidine), 2.44 (d, J = 4.2Hz, 2H, CH2,
piperidine), 2.49 (t, J = 5.6Hz, 2H, CH2, piperidine), 3.73(s,
3H, O‐CH3), 6.87 (d, J = 8.8Hz, 2H, Ph‐H), 7.21 (d, J = 8.8Hz,
2H, Ph‐H); MS (EI, 70 eV) m/z (%): 434.4 (M+, 8.17), 217.4
(100), 121.3 (35.43). Anal. calcd for C26H34N4O2: C 71.86, H
7.89, N 12.89%; found C 71.75, H 7.98, N 12.71%.
Yellow solid, yield 49.2%, m.p. 156–157°C; IR (KBr, cm−1
)
ν: 1633 (C N), 1612, 1486, 1453(C C), 1112 (C N); 1HNMR
(CDCl3, 400 MHz) δ: 2.46 (t, 5.6Hz, 2H, CH2,
J
=
piperidine), 2.52 (d, J = 4.8Hz, 2H, CH2, piperidine), 2.59
(d, J = 4.8Hz, 2H, CH2, piperidine), 2.77 (t, J = 5.6Hz, 2H,
CH2, piperidine), 4.64 (s, 2H, CH2‐Pyri), 7.37 (d, J = 8.0Hz,
1H, Pyri‐H), 7.82‐7.84 (dd, J1 = 2.4 Hz, J2 = 2.8, 1H, Pyri‐H),
8.33 (d, J = 2.4 Hz, 1H, Pyri‐H); MS (EI, 70 eV) m/z (%): 445.3
(M+, 7.84), 222.4 (100), 126.3 (38.62). Anal. calcd for
C22H26Cl2N4: C 59.33, H 5.88, N 18.87%; found C 59.42, H
5.71, N 18.89%.
N‐(3,4‐Methylenedioxybenzyl)‐4‐piperidone azine (11e).
Yellow solid, yield 50.8%, m.p. 171–173°C; IR (KBr, cm−1
)
ν: 1640 (C N), 1608, 1495, 1456(C C), 1120 (C N); 1HNMR
(CDCl3, 400 MHz) δ: 2.47 (t, 5.6Hz, 2H, CH2,
J
=
piperidine), 2.52 (d, J = 4.8Hz, 2H, CH2, piperidine), 2.57 (d,
J = 4.8Hz, 2H, CH2, piperidine), 2.60 (t, J = 5.6Hz, 2H,
CH2, piperidine), 3.46 (d, J = 4.8Hz, 2H, N‐CH2Ph), 5.95
(d, J = 5.2Hz, 2H, O‐CH2‐O), 6.75(d, J = 4.4Hz, 2H, Ph‐
H), 6.88(d, J = 5.2Hz, 1H, Ph‐H); MS (EI, 70 eV) m/z
(%): 462.5 (M+, 7.88), 231.4 (100), 135.3 (25.63). Anal.
calcd for C26H30N4O4: C 67.51, H 6.54, N 12.11%; found
C 67.27, H 6.65, N 12.28%.
( )‐N‐(1‐Phenylethyl)‐4‐piperidone azine (11f). Yellow solid,
yield 38.1%, m.p. 153–154°C; IR (KBr, cm−1) ν: 1643 (C N),
1610, 1496, 1451 (C C), 1115 (C N); 1HNMR (CDCl3, 400
MHz) δ: 1.27 (s, 3H, CH3), 2.44 (t, J = 6.0 Hz, 2H, CH2,
piperidine), 2.54 (d, J = 4.8 Hz, 2H, CH2, piperidine), 2.62 (d, J
= 4.8 Hz, 2H, CH2, piperidine), 2.77 (t, J = 5.6 Hz, 2H, CH2,
piperidine), 4.05 (s, 1H, Ph‐CH), 7.29‐7.36 (m, 5H, Ph‐H); MS
(EI, 70 eV) m/z (%): 401.5 (M+, 8.16), 201.2 (100), 106.3
(41.32). Anal. calcd for C26H34N4: C 71.86, H 7.89, N 12.89%;
found C 71.98, H 7.81, N 12.77%.
(R)‐N‐(1‐Phenylethyl)‐4‐piperidone azine (11g). Yellow
solid, yield 63%, m.p. 137–140°C; IR (KBr, cm−1) ν: 1635
(C N), 1611, 1498, 1457 (C C), 1109 (C N); 1HNMR (CDCl3,
400 MHz) δ: 1.40 (d, J = 2.8Hz, 3H, CH3), 2.43 (t, J = 5.6Hz,
2H, CH2, piperidine), 2.49 (d, J = 6.8Hz, 2H, CH2, piperidine),
2.54 (d, J = 3.2Hz, 2H, CH2, piperidine), 2.63 (t, J =5 .6Hz,
2H, CH2, piperidine), 3.51‐3.56 (dd, J = 6.4 Hz, 1H, Ph‐CH),
7.24‐7.36 (m, 5H, Ph‐H); MS (EI, 70 eV) m/z (%): 402.3 (M+,
11.93), 201.4 (100), 105.3 (39.87). Anal. calcd for C26H34N4: C
71.86, H 7.89, N 12.89%; found C 71.83, H 7.75, N 12.96%;
[Á] =+25.18° (C = 0.01 g/mL , CHCl3)
N‐(2‐Tetrahydrofurfuryl)‐4‐piperidone azine (11k). Yellow
solid, yield 39.6%, m.p. 138–139°C; IR (KBr, cm−1) ν: 1634
(C N), 1607, 1499, 1452 (C C), 1108 (C N); 1HNMR (CDCl3,
400 MHz) δ: 2.03‐2.16 (m, 2H, CH2‐THF), 2.44 (t, J = 5.6Hz,
2H, CH2, piperidine), 2.48 (d, J = 4.0Hz, 2H, CH2, piperidine),
2.56 (d, J = 4.4Hz, 2H, CH2, piperidine), 2.63 (t, J = 5.6Hz,
2H, CH2, piperidine), 3.87 (s, 2H, CH2‐THF); MS (EI, 70 eV)
m/z (%): 362.5 (M+, 6.57), 181.4 (100), 85.3 (28.97). Anal.
calcd for C20H34N4O2: C 66.26, H 9.45, N 15.46%; found C
66.45, H 9.52, N 15.38%.
N‐(2‐Furfuryl)‐4‐piperidone azine (11l). Yellow solid, yield
45.5%, m.p. 155–157°C; IR (KBr, cm−1) ν: 1627 (C N), 1615,
1
1500, 1461 (C C), 1114 (C N); HNMR (CDCl3, 400 MHz) δ:
2.51 (t, J = 5.6 Hz, 2H, CH2, piperidine), 2.57 (d, J = 4.2 Hz,
2H, CH2, piperidine), 2.61 (d, J = 4.2 Hz, 2H, CH2, piperidine),
2.67 (t, J = 5.6Hz, 2H, CH2, piperidine), 3.61 (s, 2H, CH2‐furan),
6.22 (d, J = 3.2 Hz, 1H, furan‐H), 6.33‐6.35 (m, 1H, furan‐H),
7.40‐7.41(dd, J1 = J2 = 0.8 Hz, 1H, furan‐H); MS (EI, 70 eV)
m/z (%): 354.4 (M+, 9.37), 177.4 (100), 81.3 (34.18). Anal.
calcd for C20H26N4O2: C 67.77, H 7.39, N 15.81%; found C
67.65, H 7.52, N 15.69%.
N‐(2‐Thienylmethyl)‐4‐piperidone azine (11m). Yellow solid,
yield 47.8%, m.p. 168–169°C; IR (KBr, cm−1) ν: 1636 (C N),
1611, 1493, 1449 (C C), 1117 (C N); 1HNMR (CDCl3, 400 MHz)
δ: 2.49 (t, J = 5.6 Hz, 2H, CH2, piperidine), 2.58‐2.61 (m, 4H,
CH2, piperidine), 2.68 (t, J = 5.6 Hz, 2H, CH2, piperidine),
3.78 (d, J = 0.8 Hz, 2H, thio‐CH2), 6.92‐6.98 (m, 2H, thio‐H),
6.92‐6.98(dd, J1 = 1.6 Hz, J2 = 1.2 Hz, 1H, thio‐H); MS (EI,
70 eV) m/z (%): 386.3 (M+, 12.13), 193.2 (100), 97.3 (28.84).
Anal. calcd for C20H26N4S2: C 62.14, H 6.78, N 14.49%;
found C 62.23, H 6.69, N 14.52%.
N‐Phenethyl‐4‐piperidone azine (11h). Yellow solid, yield
58.3%, m.p. 103–105°C; IR (KBr, cm−1) ν: 1635 (C N), 1609,
1
1496, 1455 (C C), 1116 (C N); HNMR (CDCl3, 400 MHz) δ:
Cell culture. K562 cells were cultured in RPMI 1640 medium
at 37 with 5% CO2, and 95% air, supplemented with 10% (v/v)
bovine calf serum and 80 U/mL gentamicin. The cells were
seeded onto 96‐well plates or other appropriate dishes containing
the medium at the density of 6250/cm2.
2.53 (t, J = 5.6Hz, 2H, CH2, piperidine), 2.64‐2.66 (m, 4H, CH2,
Ph‐CH2), 2.67‐2.69 (m, 2H, CH2, piperidine), 2.74 (t, J = 5.6Hz,
2H, CH2, piperidine), 2.83‐2.87 (m, 2H, N‐CH2), 7.20‐7.33
(m, 5H, Ph‐H); MS (EI, 70 eV) m/z (%): 402.5 (M+, 8.73),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Novel Symmetrical trans-Bis-Schiff Bases of N-Substituted-4-piperidones: Synthesis,
Characterization, and Preliminary Antileukemia Activity Mensurations
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Acknowledgments. This work was supported by Innovation
Program of Shanghai Municipal Education Commission
(09YZ157 and ssd08013) and Leading Academic Discipline
Project of Shanghai Normal University (DZL808 and SK200836).
We are also grateful for the support from National Science
foundation of China (21042010).
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