Design and synthesis of 1-(6-(2-(2-arylethynyl)phenyl)hexyn-5-yl)piperidin- 2-ones as antitumor agents that induce apoptotic progress

Article abstract of DOI:10.1002/jccs.200800100

A series of 1-(6-(2-(2-arylethynyl)phenyl)hexyn-5-yl)piperidin-2-ones 2a-j were synthesized and their antitumor activities were evaluated. Of these compounds, 1-(6-(2-(2-(4-nitrophenyl)ethynyl)phenyl) hexyn-5-yl)piperidin-2-one (2j) showed the highest pot

Full text of DOI:10.1002/jccs.200800100

668
Journal of the Chinese Chemical Society, 2008, 55, 668-674
Design and Synthesis of
1-(6-(2-(2-Arylethynyl)phenyl)hexyn-5-yl)piperidin-2-ones as Antitumor
Agents that Induce Apoptotic Progress
I-Ling Lina (
Yu-Hsiang Lod (
Shinne-Ren Linb (
), I-Hsiang Chenb,#
(
), Chi-Fong Linc (
),
), Sheng-Huei Yangb (
),
) and Ming-Jung Wub,* (
)
aFaculty of Biomedical Laboratory Science, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
bFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
cDepartment of Biological Science and Technology, Chung Hwa College of Medical Technology,
Tainan, Taiwan, R.O.C.
dGraduate Institute of Pharmaceutical Science, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
A series of 1-(6-(2-(2-arylethynyl)phenyl)hexyn-5-yl)piperidin-2-ones 2a-j were synthesized and
their antitumor activities were evaluated. Of these compounds, 1-(6-(2-(2-(4-nitrophenyl)ethynyl)phen-
yl)hexyn-5-yl)piperidin-2-one (2j) showed the highest potency of growth inhibition activity, especially
against the RPMI-8226 (0.4 mM) and SR (0.02 mM) cell lines of human leukemia. Compound 2j also in-
duced significant apoptotic progress in the cell cycle assay with the K-562 cell line.
Keywords: Enediyne; Antitumor; Apoptosis.
INTRODUCTION
The development of new anticancer drugs have been
K-562 cell line in the cell cycle. It is almost seven times
higher than the control.5 Due to the high apoptotic property
of this compound, we anticipate that modification of the
structure by changing the phenyl lactam moiety of com-
pound 2 to the more flexible alkyl lactam would also show
focused on the design of small molecules that can interfere
with the cell cycle machinery to led to the antiproliferation
of cancer cells.1 To design drugs that can induce apoptosis
is another pathway to force cancer cells into programmed
cell death.2 In our earlier reports, we disclosed new acyclic
enediynes that showed potent cytotoxic activity against
various human tumor cell lines and significant G2/M phase
blockage activity in the cell cycle.3 Based on the structure
of the potent compound 1a, we designed and synthesized a
series of acyclic enediynes by replacing the 2-methoxy-
phenyl moiety with a flexible side chain and keeping the
heteroatom at the end of the aliphatic side chain, such as
6-(2-arylethynyl))phenyl-5-hexyn-1-ols. Of these com-
pounds, compound 1b where the aryl group is 2-trifluoro-
methylphenyl showed the highest potency of growth inhi-
bition activity against various human tumor cell lines, par-
ticularly against SR (0.4 mM) and MDA-MB-435 (0.8 mM)
cell lines.4 Recently, we found that compound 1c, 2-(6-tri-
fluromethylphenyl-3(Z)-hexen-1,5-diynyl)phenylpiperi-
din-2-one, showed significant apoptotic activity against a
H3CO
OH
F3C
NC
N
1a
1b
O
N
O
Ar
F3C
2
1c
# Contribution was equal to that of the first author.
* Corresponding author. Fax: +886-7-3125339; E-mail: mijuwu@kmu.edu.tw

Synthesis of Enediynes as Antitumor Agents
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 669
a good apoptotic property of cancer cell lines in the cell cy-
cle. Thus, compounds 2a-j were synthesized and their bio-
logical activities were evaluated.
ether, r.t., 72%; (d) 5, Pd(PPh3)4, CuI, nBuNH2, ether, r.t.,
95%; (e) Pd(PPh3)4, CuI, K2CO3, CH3OH, r.t., 26-88%.
BIOLOGICAL ASSAY RESULT
CHEMISTRY
The synthesis of compounds 2a-j is outlined in Scheme
I. Treatment of 5-hexyn-1-ol (3) with methane sulfonyl
chloride afforded compound 4 in 94% yield. Mesylate 4
was then reacted with d-valerolactam in DMF using NaH
as a base and gave compound 5 in 52% yield. On the other
hand, 1,2-diiodobenzene (6) was coupled with trimethyl-
silylacetylene under Sonogashira coupling reaction condi-
tions6 to give compound 7 in 72% yield. Under similar re-
action conditions, compound 7 was coupled with com-
pound 5 to produce compound 8 in 95% yield. Finally, pal-
ladium-catalyzed coupling reaction of 8 with various aryl
iodides 9a-j in the presence of K2CO3 in MeOH gave the
desired products 2a-j in 26 to 88% yields, respectively.
Reagents and conditions: (a) Et3N, CH2Cl2, 92%;
(b) NaH, DMF; then 4, 52% (c) Pd(PPh3)4, CuI, nBuNH2,
(a) Cytotoxicity Activities
Compounds 2a-j were submitted to the National Can-
cer Institute for testing against a panel of approximately
sixty tumor cell lines. Details of this test system have been
published by others.7 Compounds 2a-i were found to be in-
active against these tumor cell lines. However, compounds
2h and 2j are found to be active against most cancer cell
lines including leukemia, colon cancer, CNS cancer, mela-
noma, ovarian cancer, prostate cancer and breast cancer
with GI50 values ranging from nanomolar to micromolar
scales. Compared to the growth inhibition activity of 2h
and 2j, compound 2j is more active than 2i. The GI50 values
of compound 2j are in almost single-digit micromolar lev-
els against these cancer cell lines. High selectivity of 2j
against two leukemia cell lines, RPMI-8226 (0.4 mM) and
Scheme I
O
HN
OH
a
OMs
N
H
H
H
O
N
b
4 (92%)
3
5 (52%)
TMS
I
I
c
d
O
+
TMS
H
I
TMS
8 (95%)
7 (72%)
6
N
ArI
e
O
Ar
9a Ar = 2-anisyl
9b Ar = 2-pyridinyl
9c Ar = 2-thienyl
9d Ar = 2-thieanisyl
9e Ar = 2-pyrazinyl
9f Ar = 2-nitrophenyl
9g Ar = 2-fluorophenyl
9h Ar = 3-pyridinyl
9i Ar = 4-anisyl
2a (30%)
2b (86%)
2c (29%)
2d (26%)
2e (70%)
2f (88%)
2g (70%)
2h (71%)
2i (30%)
2j (60%)
9j Ar = 4-nitrophenyl

670 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Lin et al.
Table 1. The in vitro testing results of full panel screen of compounds 2h and 2ja
GI50
GI50
Panel/Cell line
Panel/Cell line
Melanoma
2h
2j
2h
2j
Leukemia
CCRF-CEM
HL-60(TB)
K-562
30.90
16.20
14.70
73.10
04.64
NT
2.87
1.75
3.60
2.76
0.40
0.02
LOX IMVI
MALME-3M
M14
08.55
21.70
14.30
NT
2.79
37.200
5.16
MOLT-4
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
3.65
RPMI-8226
SR
38.70
14.30
17.70
07.05
10.500
1.75
Non-Small Cell Lung Cancer
A549/ATCC
EKVX
2.89
18.40
23.50
15.20
19.20
12.90
17.10
> 100.0
19.60
19.00
3.03
5.77
5.26 Ovarian Cancer
HOP-62
8.01
4.39
5.03
4.23
22.70
2.00
IGROV1
14.70
22.60
13.40
17.70
21.60
16.40
8.21
10.900
4.38
HOP-92
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon Cancer
COLO 205
HCT-116
HCT-15
5.25
2.81
1.57
12.30 Renal Cancer
786-0
13.00
42.80
09.64
35.50
NT
8.41
4.01
06.88
04.67
03.96
11.90
20.40
39.90
2.75
4.18
1.50
3.74
3.78
5.18
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
3.44
2.93
HT29
1.68
KM12
14.10
49.80
05.97
17.100
1.72
SW-620
CNS Cancer
SF-268
19.500
27.00
31.80
13.00
04.05
07.05
11.70 Breast Cancer
SF-539
3.13
6.57
2.21
3.79
MCF7
30.40
17.50
12.00
28.50
28.90
18.60
05.66
10.20
1.38
3.35
SNB-19
NCI/ADR-RES
MDA-MB-231/ATCC
HS578T
SNB-75
12.800
5.05
U251
Prostate Cancer
DU-145
MDA-MB-435
BT-549
1.68
43.20
17.50
16.600
3.52
T-47D
MDA-MB-468
4.58
a Data obtained from the NCI’s in vitro human tumor cell screen. GI50 = the concentration produces 50%
reduction in cell growth.
SR (0.02 mM) cell lines, was observed. (Table 1) It was also
noted that the LC50 values (data not shown) of compounds
2h and 2j against these cancer cell lines are 10 to 100 times
higher than the GI50 values. This result indicates that com-
pounds 2h and 2j exhibit very good growth inhibition ac-
tivity but poor cytotoxicity toward these human cancer cell
lines. This phenomenon is meaningful to the development
of new drugs with low cytotoxicity for the medical therapy
of human cancer diseases.
bition activity of enediynes 2a-j, we examined the cell cy-
cle phase distribution by treating the K-562 cell line of leu-
kemia with these compounds at the concentration of 50 mM
for 72 h, and the cell cycle profile was analyzed by flow
cytometry. The percentages of cell cycle and apoptosis are
shown in Figs. 1(A) and 1(B). According to Fig. 1(A),
there is a slight increase of the G0/G1 phase percentage by
these compounds compared to the control. However the
most significant phenomenon is the increase of the percent-
age of apoptosis from 5% of the control to 15.39% and
11.19% caused by compounds 2i and 2j, respectively (Fig.
1(B)).
(b) Cell Cycle Assay
In further investigation of the mechanism of the inhi-

Synthesis of Enediynes as Antitumor Agents
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 671
CONCLUSION
from blood as described previously.8 Cells were maintained
in RPMI 1640 medium supplemented with 10% fetal calf
serum, 2 mM glutamine, and antibiotics (100 units/mL pen-
icillin and 100 m/mL streptomycin) at 37 °C in a humidified
atmosphere of 5% CO2.
We have found new acyclic enediynes that showed
potency in growth inhibition activity against various hu-
man cancer cells. In this study, several points were achieved.
i) The structure-activity relationship of these synthetic
enediynes showed that the phenyl ring at the terminus
alkyne bearing either electron-donating or withdrawing
group exhibits distinct cytotoxic activities against various
human cancer cell lines. ii) The most potent compound is 2j
with the average GI50 values from 10-8 to 10-5 M and high
selectivity against the RPMI-8226 (0.4 mM) and SR (0.02
mM) cell lines. iii) Compounds 2i and 2j can induce an
apoptotic phenomenon against the K-562 cell line in the
cell cycle. The results will be helpful for further elucidation
of undiscovered biological properties of these novel anti-
tumor enediynes.
Cell Cycle Analysis
Flow cytometry was used to measure cell cycle pro-
file and apoptosis. For cell cycle analysis, K-562 cells
treated with compounds 2a-j (50 mM) for 24 h were har-
vested by centrifugation. After being washed with PBS, the
cells were fixed with ice-cold 70% ethanol for 30 min,
washed with PBS, and then treated with 1 mL of 1 mg/mL
of RNase A solution at 37 °C for 30 min. Cells were har-
vested by centrifugation at 1000 rpm for 5 min and further
stained with 250 mL of DNA staining solution (10 mg of
propidium iodide [PI], 0.1 mg of trisodium citrate, and 0.03
mL of Triton X-100 were dissolved in 100 mL H2O) at
room temperature for 30 min in the dark. After loading 500
mL of PBS, the DNA contents of 10,000 events were mea-
sured by FACScan (Elite ESP, Beckman Coulter, Brea, CA)
and the cell cycle profile was analyzed from the DNA con-
tent histograms with WinCycle software. When cells were
EXPERIMENTAL SECTION
Cell Culture
Human leukemia K-562 cells were obtained from the
American Type Culture Collection (ATCC, Manassas, VA),
and human purified lymphocyte preparation was obtained
Fig. 1. The percentage of cell cycle and apoptosis by compounds 2a-j. (A) Cell cycle percentage of K-562 cells treated with
compound 2a-j (50 mM) for 72 h. (B) Apoptosis percentage of K-562 cells treated with compound 2a-j (50 mM). The
proportions of apoptotic cells are: control (5.00%), 2a (8.65%), 2b (8.27%), 2c (6.40%), 2d (8.10%), 2e (4.80%), 2f
(7.80%), 2g (8.66%), 2h (7.84%), 2i (15.39%) and 2j (11.19%).

672 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Lin et al.
in apoptosis the contained DNA was digested by endonu-
clease then the sub G1 pick appears. The percentages in sub
G1 were analyzed by gating on cell cycle dot blots using
Windows Multiple Document Interface software (WinMDI).
1-(Hex-5-ynyl)piperidin-2-one (5)
General procedure for the coupling of 8 and 9 to
compounds 2a-j
To a degassed solution of 2-(6-trimethylsilyl-3(Z)-
hexen-1,5-diynyl)aniline 8 (12 mmol) containing CuI (3.2
mmol) and K2CO3 (30 mmol) in MeOH (15 mL) was added
a degassed solution of aryl iodides (9a-9j) (12 mmol) con-
taining Pd(PPh3)4 (0.8 mmol) in MeOH (20 mL). The re-
sulting reaction mixture was stirred for 6 h, removal of
methanol in vacuo was performed, and then it was quenched
with saturated aqueous NH4Cl solution. The aqueous layer
was extracted with EtOAc (50 mL) and the combined or-
ganic extracts were washed with saturated aqueous Na2CO3
solution (40 mL) and dried over anhydrous MgSO4. After
filtration and removal of solvent in vacuo, the residue was
purified by column chromatography on silica gel to yield
the desired products.
To a stirred suspension of NaH (0.43 g, 18 mmol) in
DMF (10 mL) was added a solution of d-valerolactam (1.18
g, 12 mmol) in DMF (20 mL). The resulting reaction mix-
ture was stirred for 30 min before adding a solution of com-
pound 4 (2.12 g, 12 mmol) in DMF (20 mL). The mixture
was stirred at room temperature for an additional 4 h and
quenched with saturated aqueous NaCl solution. The aque-
ous layer was extracted with EtOAc (50 mL) and dried over
anhydrous MgSO4. After filtration and removal of solvent
in vacuo, the residue was purified by column chromatogra-
phy on silica gel (hexane/EA= 2:1 as eluent) to give 5 (1.16
1
g, 6.24 mmol, 52%) as brown oil. H NMR (CDCl3, 400
1-(6-(2-(2-(2-Methoxyphenyl)ethynyl)phenyl)hex-5-
ynyl)piperidin-2-one (2a)
MHz): d 3.37 (t, 2H, J = 7.3 Hz), 3.27 (t, 2H, J = 4.8 Hz),
2.37 (t, 2H, J = 6.4 Hz), 2.23 (t, 2H, J = 7.0 Hz), 1.94 (s,
1H), 1.76-1.68 (m, 4H), 1.67-1.62 (m, 2H), 1.55-1.50 (m,
2H). 13C NMR (CDCl3, 100 MHz): d 169.7, 84.1, 68.5,
47.7, 46.4, 32.2, 26.0, 25.6, 23.2, 21.3, 18.1. HRMS (EI)
calcd for C11H17NO 179.1310, found 179.1309.
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 30% of colorless
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 7.69-7.64 (m, 1H), 7.55-7.22 (m, 5H), 6.96-
6.90 (m, 2H), 3.91 (s, 3H), 3.35 (t, 2H, J = 7.1 Hz), 3.20 (t,
2H, J = 5.9 Hz), 2.54 (t, 2H, J = 7.0 Hz), 2.34 (t, 2H, J = 5.3
Hz), 1.77-1.61 (m, 8H). 13C NMR (CDCl3, 100 MHz): d
169.6, 159.9, 133.7, 132.1 (2C), 131.8 (2C), 129.8, 128.5
(2C), 120.5, 112.6, 110.8, 94.1, 92.5, 89.2, 79.9, 55.9, 47.6,
46.4, 32.2, 26.1, 25.9, 23.1, 21.3, 19.4. HRMS (EI) calcd
for C26H27NO2 385.2042, found 385.2043.
1-(6-(2-(2-(Trimethylsilyl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (8)
To a degassed solution of 5 (2.15 g, 12 mmol) con-
taining CuI (0.61 g, 3.2 mmol) and nBuNH2 (1.74 g, 30
mmol) in ether (20 mL) was added a degassed solution of
compound 7 (3.61 g, 12 mmol) containing Pd(PPh3)4 (0.93
g, 0.8 mmol) in ether (25 mL). The resulting reaction mix-
ture was stirred for 4 h and then quenched with saturated
aqueous NH4Cl solution. The aqueous layer was extracted
with EtOAc (50 mL) and the combined organic extracts
were washed with saturated aqueous Na2CO3 solution (40
mL) and dried over anhydrous MgSO4. After filtration and
removal of solvent in vacuo, the residue was purified by
column chromatography on silica gel (hexane/EA = 2:1 as
eluent) to give compound 8 (3.99 g, 11.4 mmol, 95%) as
brown oil. 1H-NMR (CDCl3, 400 MHz): d 7.40 (dd, 1H, J =
7.6, 1.1 Hz), 7.37 (d, 1H, J = 6.8 Hz), 7.26-7.17 (m, 2H),
3.35 (t, 2H, J = 7.1 Hz), 3.23 (t, 2H, J = 5.9 Hz), 2.54 (t, 2H,
J = 7.0 Hz), 2.34 (t, 2H, J = 5.3 Hz), 1.76-1.69 (m, 6H),
1.66-1.60 (m, 2H), 0.22 (s, 9H). 13C NMR (CDCl3, 100
MHz): d 169.5, 131.9, 131.6, 128.0, 127.0, 126.6, 125.2,
103.7, 97.7, 94.0, 79.4, 47.6, 46.3, 32.2, 26.1, 25.8, 23.1,
21.2, 19.2, 0.1 (3C). HRMS (EI) calcd for C22H29NOSi
351.2018, found 351.2015.
1-(6-(2-(2-(Pyridin-2-yl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (2b)
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 86% of colorless
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 8.60 (td, 1H, J = 4.2, 0.7 Hz), 7.68 (td, 1H, J =
7.7, 1.8 Hz), 7.56-7.50 (m, 2H), 7.42-7.40 (m, 1H), 7.23-
7.20 (m, 3H), 3.35 (t, 2H, J = 7.1 Hz), 3.20 (t, 2H, J = 5.9
Hz), 2.54 (t, 2H, J = 7.0 Hz), 2.34 (t, 2H, J = 5.3 Hz),
1.77-1.61 (m, 8H). 13C NMR (CDCl3, 100 MHz): d 169.5,
149.9, 143.4, 136.1, 132.2, 131.8, 128.5, 127.3, 127.2,
126.8, 124.5, 122.7, 94.6, 91.7, 88.2, 79.5, 47.5, 46.2, 32.2,
26.0, 25.8, 23.1, 21.2, 19.3. HRMS (EI) calcd for C24H24N2O
356.1889, found 356.1888.
1-(6-(2-(2-(Thiophen-2-yl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (2c)
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 29% of colorless

Synthesis of Enediynes as Antitumor Agents
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 673
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 7.68-7.40 (m, 2H), 7.40-7.22 (m, 4H), 7.02-
7.00 (m, 1H), 3.35 (t, 2H, J = 7.1 Hz), 3.20 (t, 2H, J = 5.9
Hz), 2.54 (t, 2H, J = 7.0 Hz), 2.34 (t, 2H, J = 5.3 Hz),
1.77-1.61 (m, 8H). 13C NMR (CDCl3, 100 MHz): d 169.6,
132.0, 131.9 (2C), 128.1 (2C), 127.4 (2C), 126.2, 125.2,
123.3, 94.5, 92.2, 85.9, 79.6, 47.6, 46.3, 32.2, 26.1, 25.8,
23.1, 21.2, 19.3. HRMS (EI) calcd for C23H23NOS
361.1500, found 361.1503.
(CDCl3, 100 MHz): d 169.6, 134.8, 132.8, 132.4, 132.0,
128.8, 128.6, 127.3, 126.7, 124.6, 124.5, 118.7, 96.1, 94.9,
87.7, 79.3, 47.6, 46.4, 32.2, 29.6, 26.2, 25.8, 23.1, 21.2,
19.4. HRMS (EI) calcd for C25H24N2O3 400.1787, found
400.1783.
1-(6-(2-(2-(2-Fluorophenyl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (2g)
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 70% of colorless
1
oil according to general procedure. H NMR (CDCl3, 400
1-(6-(2-(2-(2-(Methylthio)phenyl)ethynyl)phenyl)hex-5-
ynyl)piperidin-2-one (2d)
MHz): d 7.68-7.63 (m, 2H), 7.56-7.41 (m, 4H), 7.34-7.07
(m, 2H), 3.35 (t, 2H, J = 7.1 Hz), 3.20 (t, 2H, J = 5.9 Hz),
2.54 (t, 2H, J = 7.0 Hz), 2.34 (t, 2H, J = 5.3 Hz), 1.77-1.61
(m, 8H). 13C NMR (CDCl3, 100 MHz): d 169.6, 163.8,
133.5, 131.9 (2C), 130.0, 128.5 (2C), 127.2, 126.5, 123.9
(2C), 115.6, 94.6, 93.4, 79.4, 47.6, 46.4, 32.2, 29.6, 26.1,
25.8, 23.1, 21.2, 19.3. HRMS (EI) calcd for C25H24FNO
373.1842, found 373.1841.
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 26% of colorless
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 7.68-7.40 (m, 2H), 7.40-7.22 (m, 4H), 7.02-
7.00 (m, 1H), 3.35 (t, 2H, J = 7.1 Hz), 3.20 (t, 2H, J = 5.9
Hz), 2.54 (t, 2H, J = 7.0 Hz), 2.34 (t, 2H, J = 5.3 Hz), 1.77-
1.61 (m, 8H). 13C NMR (CDCl3, 100 MHz): d 169.6, 132.0,
131.9 (2C), 128.1 (2C), 127.4 (2C), 126.2, 125.2, 123.3,
94.5, 92.2, 85.9, 79.6, 47.6, 46.3, 32.2, 26.1, 25.8, 23.1,
21.2, 19.3. HRMS (EI) calcd for C23H23NOS 361.1500,
found 361.1503.
1-(6-(2-(2-(Pyridin-3-yl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (2h)
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 71% of colorless
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 8.75 (s, 1H), 8.52 (s, 1H), 7.79 (t, 1H, J = 1.8
Hz), 7.50-7.48 (m, 1H), 7.43-7.40 (m, 1H), 7.30-7.23 (m,
3H), 3.35 (t, 2H, J = 7.1 Hz), 3.20 (t, 2H, J = 5.9 Hz), 2.54
(t, 2H, J = 7.0 Hz), 2.34 (t, 2H, J = 5.3 Hz), 1.77-1.61 (m,
8H). 13C NMR (CDCl3, 100 MHz): d 169.5, 152.1, 148.5,
138.4 (2C), 131.9, 131.7, 128.4, 127.3, 126.5, 124.6, 94.6,
91.7, 89.1, 79.4, 47.6, 46.3, 32.2, 29.6, 26.1, 25.9, 23.1,
21.3, 19.3. HRMS (EI) calcd for C24H24N2O 356.1889,
found 356.1891.
1-(6-(2-(2-(Pyrazin-2-yl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (2e)
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 70% of colorless
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 8.71 (d, 1H, J = 1.5 Hz), 8.56-8.54 (m, 1H),
8.44 (d, 1H, J = 2.4 Hz), 7.55-7.52 (m, 1H), 7.41 (dd, 1H, J
= 7.7, 1.3 Hz), 7.30-7.21 (m, 2H), 3.35 (t, 2H, J = 7.1 Hz),
3.20 (t, 2H, J = 5.9 Hz), 2.54 (t, 2H, J = 7.0 Hz), 2.34 (t, 2H,
J = 5.3 Hz), 1.77-1.61 (m, 8H). 13C NMR (CDCl3, 100
MHz): d 169.5, 147.7, 144.4, 142.6, 132.2, 131.9, 129.1,
127.3, 127.0, 123.6, 95.1, 92.2, 88.8, 79.2, 47.5, 46.2, 32.1,
29.5, 26.1, 25.7, 23.1, 21.2, 19.3. HRMS (EI) calcd for
C23H23N3O 357.1841, found 357.1843.
1-(6-(2-(2-(4-Methoxyphenyl)ethynyl)phenyl)hex-5-
ynyl)piperidin-2-one (2i)
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 30% of colorless
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 7.51-7.48 (m, 3H), 7.43-7.40 (m, 1H), 7.26-
7.22 (m, 2H), 6.88 (d, 2H, J = 6.8 Hz), 3.83 (s, 3H), d 3.35
(t, 2H, J = 7.1 Hz), 3.20 (t, 2H, J = 5.9 Hz), 2.54 (t, 2H, J =
7.0 Hz), 2.34 (t, 2H, J = 5.3 Hz), 1.77-1.61 (m, 8H); 13C
NMR (CDCl3, 100 MHz): d 169.6, 159.8, 133.3 (2C),
131.9 (2C), 128.1 (2C), 125.9 (2C), 115.0, 113.9 (2C),
100.1, 92.9 (2C), 78.7, 55.9, 47.5, 46.3, 32.2, 26.1, 25.9,
23.1, 21.3, 19.4. HRMS calcd for C26H27NO2, Mr = 385.2042
found 385.2045.
1-(6-(2-(2-(2-Nitrophenyl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (2f)
The compound was purified by column chromatogra-
phy, eluting with hexane/EA (2:1) to give 88% of colorless
oil according to the general procedure. 1H NMR (CDCl3,
400 MHz): d 8.05 (dd, 1H, J = 8.3, 0.6 Hz), 7.72 (dd, 1H, J
= 7.7, 1.3 Hz), 7.63-7.59 (m, 1H), 7.55 (dd, 1H, J = 7.2, 1.5
Hz), 7.45-7.41 (m, 2H), 7.30-7.23 (m, 2H), 3.35 (t, 2H, J =
7.1 Hz), 3.20 (t, 2H, J = 5.9 Hz), 2.54 (t, 2H, J = 7.0 Hz),
2.34 (t, 2H, J = 5.3 Hz), 1.77-1.61 (m, 8H). 13C NMR

674 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Lin et al.
1-(6-(2-(2-(4-Nitrophenyl)ethynyl)phenyl)hex-5-ynyl)-
piperidin-2-one (2j)
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The compound was purified by column chromatogra-
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according to the general procedure. 1H NMR (CDCl3, 400
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(m, 2H), 7.31-7.24 (m, 2H), 3.35 (t, 2H, J = 7.1 Hz), 3.20 (t,
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ACKNOWLEDGEMENT
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We thank the National Science Council of the Repub-
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Received December 13, 2007.