Synthesis of 2-aryl-4-(4-β-D-allopyranosyloxyphenyl)4,6,7,8- tetrahydroquinolin-5(1H)-one derivatives under solvent-free conditions and study of sedative activity

Article abstract of DOI:10.1007/s10600-011-9781-z

Under solvent-free conditions, syntheses of 2-aryl-4-(4-β-D- allopyranosyloxyphenyl)-4,6,7,8tetrahydroquinolin-5(1H)-one derivatives were carried out from chalcone (2a-2e), cyclohexane-1,3-dione (3), and NH ₄OAc in excellent yield without using

Full text of DOI:10.1007/s10600-011-9781-z

Chemistry of Natural Compounds, Vol. 46, No. 6, 2011
SYNTHESIS OF 2-ARYL-4-(4-ꢀ-D-ALLOPYRANOSYLOXYPHENYL)-
4,6,7,8-TETRAHYDROQUINOLIN-5(1H)-ONE DERIVATIVES UNDER
SOLVENT-FREE CONDITIONS AND STUDY OF SEDATIVE ACTIVITY
1
2
2
2*
Congling Yang, Shiming Lv, Ying Li, and Shufan Yin
UDC 547.74+547.589
Under solvent-free conditions, syntheses of 2-aryl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-4,6,7,8-
tetrahydroquinolin-5(1H)-one derivatives were carried out from chalcone (2a–2e), cyclohexane-1,3-dione
(3), and NH OAc in excellent yield without using any catalysts. The structure of the new compounds were
4
1
characterized by H NMR, IR, and HR-MS spectroscopy. The preliminary bioassay tests of 4a–4j indicated
that compounds 4b, 4e, and 4f exhibited potent sedative and hypnotic activity.
Keywords: chalcone, 4,6,7,8-tetrahydroquinolin-5(1H)-one, solvent-free, sedative-hypnotic activity.
The natural compound helicid (1) [4-formylphenyl-ꢀ-D-allopyranoside, C H O ], extracted from the fruit of Helicia
13 16
7
nilagirica Beed [1], distributed widely in Yunnan Province of China, is a major active ingredient of Chinese herb medicine. It
has been reported that helicid possesses a variety of biological effects on the central nervous system such as sedative, hypnotic,
and anticonvulsant activity; moreover no obvious side effect has been reported [2]. However, the drug also shows some
disadvantage, including large dose and low bioavailability. Our work focuses on epigenetic modifications at the aldehyde
group of helicid in order to improve its pharmacological and therapeutic activity [3–6].
4-Substituted 1, 4-dihydroquinolines are analogues of NADH coenzymes that exhibit a wide range of biological and
pharmacological properties such as antihypertensive, anticonvulsant, etc. [7, 8]. Therefore, there has been intense research
activity in this area recently, leading to the development of many methods for the synthesis of hydroquinoline derivatives
[9, 10]. Nevertheless, these methods often involved harsh conditions, long reaction times, unsatisfactory yields, and amounts
of organic solvents, which are usually volatile, flammable, toxic, and thus environmentally hazardous. Keeping in view the
biological importance of the hydroquinoline and our ongoing endeavors in the development of environmental benign tactics,
we now choose a solid state approach without catalyst [11]. Herein, we reported the solvent-free synthesis of hydroquinoline
derivatives 4a–4j by the reaction of different chalcones 2a–2e from helicid with cyclohexane-1,3-dione (or 5,5-dimethyl-
cyclohexane-1,3-dione) 3 in the presence of ammonium acetate, as shown in Scheme 1. The sedative-hypnotic activities of the
target compounds were evaluated, and the result showed that derivatives 4b, 4e, 4h, and 4f showed good activities.
First, we examined the feasibility of the present procedure using E-(4-ꢀ-D-allopyranosyloxyphenyl)-1-phenyl-
propenone 2a as a model substrate. Compound 2a, ammonium acetate, and cyclohexane-1, 3-dione 3 were mixed together and
heated at 80ꢁC in the absence of solvent for 3 h. However, subsequent TLC analyses showed that the reaction resulted in a
complicated mixture with a mere 27% yield. As an alternative, we first heated the mixture of ammonium acetate and cyclohexane-
1, 3-dione 3.After half an hour, TLC analyses indicated that the reactants were consumed completely and an enamine intermediate
was formed. Then, after adding 2a, the mixture was heated constantly (monitored by TLC). Finally, when the reaction was
prolonged for 3 h, a wonderful conversion of the reactans took place, with the desired product 4a obtained in 84% yield. We did
some comparative experiments where the reaction was performed at different temperatures 75ꢁ, 80ꢁ, and 85ꢁ with 70%, 84%, and
73% yields, respectively; we found that 80ꢁ was the best choice. Then, we extended the one-pot three-component condensation
reaction to the other chalcones 2a–2e and to 5,5-dimethylcyclohexane-1,3-dione. The results are summarized in Table 1.
1) College of Chemical and Material Science, Sichuan Normal University, Chengdu 610066; 2) College of Chemistry,
Sichuan University, Chengdu 610064, China, e-mail: chuandayouji217@163.com. Published in Khimiya Prirodnykh
Soedinenii, No. 6, pp. 775–778, November–December, 2010. Original article submitted June 9, 2009.
910
0009-3130/11/4606-0910 02011 Springer Science+Business Media, Inc.

TABLE 1. The Sedative-hypnotic Activities of the Target Compounds Evaluated Using the Spontaneous Locomotor Activity
Test
Number of movements per minute (movements/min)
Compound
initial
after 30 min
after 60 min
after 90 min
A
B
1
215.83ꢂ32.37
211.83ꢂ26.48
223.00ꢂ26.09
216.00ꢂ28.10
228.50 31.63
4.17 3.64***
1.67 2.73**
1.50 2.26***
ꢂ
ꢂ
ꢂ
ꢂ
232.33 38.53
199.17 20.80
168.00 24.22
130.21 29.23
ꢂ
ꢂ
ꢂ
ꢂ
4a
4b
4c
4d
4e
4f
4g
4h
4i
227.83 38.37
212.33 81.28
101.00 22.29*
171.00 91.88
152.67 36.63
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
239.83 10.83
57.67 21.15**
86.67 19.35*
ꢂ
ꢂ
ꢂ
226.83ꢂ30.97
192.50ꢂ25.95
151.67ꢂ41.63
142.67ꢂ33.51
229.50 38.35
215.00 53.57
147.67 83.83
106.00 50.01*
ꢂ
ꢂ
ꢂ
ꢂ
230.00 52.28
132.00 52.89
174.50 11.55
91.00 30.02*
ꢂ
ꢂ
ꢂ
ꢂ
232.00 21.51
168.17 39.60
142.00 83.07
83.00 62.18*
ꢂ
ꢂ
ꢂ
ꢂ
207.33ꢂ58.88
172.33ꢂ94.56
158.83ꢂ93.17
140.83ꢂ117.64
231.17 21.41
159.17 80.16
107.83 79.51*
90.83 95.04*
ꢂ
ꢂ
ꢂ
ꢂ
231.67 21.15
174.17 45.45
151.50 69.20
118.17 39.43
ꢂ
ꢂ
ꢂ
ꢂ
4j
226.50 29.52
150.83 96.01
109.33 98.52
141.83 95.80
ꢂ
ꢂ
ꢂ
ꢂ
______
–1
–1
Dose of 1 and 4a–4j: 200 mg·kg . Dose of A: –; dose of B: 20 mg·kg .
Values are means ꢂ S.
*P < 0.05, **P < 0.01, ***P < 0.001 compared with A, A: saline, B: diazepam, 1: helicid.
OH
OH
CHO
O
C
O
HO
OH
NaOH
EtOH
O
CH CH
C
O
R
1
O
HO
OH
H C
3
R
1
+
O
OH
OH
OH
1
2a - e
HO
O
OH
O
O
R
2
HO
O
R
3
3
NH OAc
4
solvent-free
O
R
1
R
2
N
H
R
3
4a - j
2a: R = H; 2b: R = Me; 2c: R = F; 2d: R = Cl; 2e: R = Br; 4a, 4f: R = H; 4b, 4g: R = Me
1
1
1
1
1
1
1
4c, 4h: R = F; 4d, 4i: R = Cl; 4e, 4j: R = Br; 4a - 4e: R = R = H; 4f - 4j: R = R = Me
1
1
1
2
3
2
3
Scheme 1
Herein, ten novel helicid derivatives 4a–4j have been successfully synthesized under solvent-free conditions with good yields
(75–85%). It is remarkable that the electronic property of the aromatic ring of chalcones has some effects on the rate of the
condensation reaction. Substrates bearing electron-withdrawing groups on the aromatic ring require shorter reaction times
[4c–4e (3, 32, 3.5 h), 4h–4j (3.5, 4.0, 4.4 h)], while substrates bearing electron-donating groups afford the corresponding
products with satisfactory yields but requiring longer reaction times to complete the total reaction [4a, 4b, 4f, 4g (4, 4.5, 5, 5.6 h)].
In summary, ten novel helicid derivatives were successfully synthesized, characterized, and tested for sedative-hypnotic
activity in our study (Table 1). These helicid derivatives can serve as lead compounds for designing new compounds possessing
potential sedative-hypnotic activity with high selectivity, low toxicity, and additional pharmaceutical effects. Further study is
now in progress.
911

EXPERIMENTAL
Materials. All reagents were purchased from commercial suppliers. Compounds 2a, 2b, 2d, and 2e were prepared
according to the literature method [3]. Helicid was purchased from Yunnan Chemical Company, China. The solvents used
were purified according to the standard methods. Melting points were determined on a Thomas-Hoover melting point apparatus
1
and were uncorrected. H NMR spectra were measured with a Bruker AV-400 MHz. IR spectra were measured with a
Perkin–Elmer 16PC-FT infrared spectrometer. HR-MS spectra were measured with a Bruker Daltonics ESI-Bio TOF-Q mass
spectroscope. Mice (Kunming strain) weighing 18–22 g were obtained from West China School of Pharmacy, Sichuan University
(Chengdu, China). All samples were dissolved in 0.05% CMC from different concentrations of solutions for later use.
E-(4-ꢀ-D-Allopyranosyloxyphenyl)-1-(4-fluorophenyl)-propenone (2c). Under ice bath, to a solution of helicid
(5 mmol) in 12 mL of 10% sodium hydroxide aqueous solution and 30 mL of anhydrous ethanol, 4-fluoroacetophenone
(5.5 mmol) was added dropwise (monitored by TLC). At completion, the reaction mixture was neutralized with diluted
hydrochloric acid (3 mol/L) and extracted with ethyl acetate. The extract was washed with brine, dried over Na SO , and
2
4
evaporated to leave a crude product, which was recrystallized from ethanol (95%) to give a yellow crystal product 2c in yield
86%, mp 108–110ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3400, 3072, 2900, 1655, 1598, 1509, 1426, 1333, 1180, 1084, 1030, 870, 824. H NMR (400 MHz,
DMSO-d , ꢄ, ppm, J/Hz): 3.45–3.95 (6H, m), 4.51–5.11 (4H, br, 4OH), 5.20 (1H, d, J = 8.0, H-1), 6.87 (2H, d, J = 8.6, ArH),
6
7.16 (2H, d, J = 8.6, ArH), 7.62 (2H, d, J = 7.2, ArH), 7.73 (1H, d, J = 16.0, CH=CH), 7.83 (1H, d, J = 16.0, CH=CHCO), 8.24
+
(2H, d, J = 7.2, ArH), HR-MS-ESI m/z calcd for C H O F [M + H] 405.1344, found 405.1362.
21 22
7
General Procedure for the Preparation of Compounds 4a–4j. Cyclohexane-1,3-dione (or 5,5-dimethylcyclohexane-
1,3-dione) 3 (1 mmol) and ammonium acetate (2.5 mmol) were mixed together and heated at 80ꢁC in a 10 mL open flask for
about 0.5 h. Then, 2 (1 mmol) was added and the mixture was exposed to continuous heating for a period of time sufficient to
complete the reaction (monitored by TLC). After cooling to room temperature, the solid was transferred to a small amount of
ethanol and then filtered. The obtained solid was washed three times with water to leave a crude product, which was purified
by chromatography (MeOH–CHCl , 1:6, v/v) over silica gel to furnish the pure product 4.
2
2-Phenyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4a). This compound was prepared
from 2a, cyclohexane-1,3-dione, and ammonium acetate; yield 84%, yellow powder, mp 145–146ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3399, 2951, 2926, 2887, 1666, 1590, 1485, 1389, 1227, 916, 847, 696. H NMR (400 MHz,
DMSO-d , ꢄ, ppm, J/Hz): 1.04–1.07 (2H, m, H-7), 2.09–2.20 (2H, m, H-8), 2.49–2.51 (2H, m, H-6) 3.43–3.90 (6H, m), 4.49–5.11
6
(4H, br, 4OH), 4.53 (1H, d, J = 5.6, H-4), 5.06 (1H, d, J = 5.6, H-3), 5.20 (1H, d, J = 8.0, H-1), 6.87 (2H, d, J = 8.0, ArH), 7.12
(2H, d, J = 8.0, ArH), 7.37–7.39 (3H, m, ArH), 7.48 (2H, d, J = 8.4, ArH), 8.67 (1H, s, NH).
–
HR-MS-ESI m/z calcd for C H NO [M – H] 478.1866, found 478.1858.
27 28
7
2-(4-Methylphenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4b). This compound
was prepared from 2b, cyclohexane-1,3-dione, and ammonium acetate; yield 85%, yellow powder, mp 139–140ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3387, 2953, 2926, 2887, 1660, 1597, 1485, 1391, 1232, 1036, 835, 696. H NMR (400 MHz,
DMSO-d , ꢄ, ppm, J/Hz): 1.03–1.23 (2H, m, H-7), 2.24 (3H, s, CH ), 2.31–2.40 (2H, m, H-8), 2.47–2.49 (2H, m, H-6), 3.35–3.91
6
3
(6H, m), 4.34–4.52 (4H, br, 4OH), 4.50 (1H, d, J = 5.6, H-4), 5.05 (1H, d, J = 5.6, H-3), 5.17 (1H, d, J = 8.0, H-1), 6.88 (2H,
d, J = 8.0, ArH), 7.11 (2H, d, J = 8.0, ArH), 7.20 (2H, d, J = 8.4, ArH), 7.38 (2H, d, J = 8.4, ArH), 8.62 (1H, s, NH).
+
HR-MS-ESI m/z calcd for C H NNaO [M + Na] 516.1998, found 516.1970.
28 31
7
2-(4-Fluorophenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4c). This compound
was prepared from 2c, cyclohexane-1,3-dione, and ammonium acetate; yield 75%, yellow powder, mp 130–132ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3332, 2958, 2926, 2887, 1660, 1595, 1486, 1391, 1229, 1037, 832, 615. H NMR (400 MHz,
DMSO-d , ꢄ, ppm, J/Hz): 1.03–1.07 (2H, m, H-7), 1.78–2.20 (2H, m, H-8), 2.45–2.50 (2H, m, H-6), 3.32–3.90 (6H, m), 4.63–5.10
6
(4H, br, 4OH), 4.70 (1H, d, J = 5.6, H-4), 5.06 (1H, d, J = 5.6, H-3), 5.17 (1H, d, J = 8.0, H-1), 6.89 (2H, d, J = 8.0, ArH), 7.11
(2H, d, J = 8.0, ArH), 7.30 (2H, d, J = 8.4, ArH), 7.52 (2H, d, J = 8.4, ArH), 8.69 (1H, s, NH).
+
HR-MS-ESI m/z calcd for C H FNNaO [M + Na] 520.1748, found 520.1669.
27 28
7
2-(4-Chlorophenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4d). This compound
was prepared from 2d, cyclohexane-1,3-dione, and ammonium acetate; yield 80%, yellow powder, mp 150–151ꢁ.
–1
1
IR (KBr, ꢃ, cm ): 3375, 2933, 2926, 2871, 1660, 1596, 1485, 1392, 1230, 1037, 835, 762. H NMR (400 MHz,
DMSO-d , ꢄ, ppm, J/Hz): 1.82–1.90 (2H, m, H-7), 2.44–2.50 (2H, m, H-8), 2.59–2.64 (2H, m, H-6), 3.35–3.90 (6H, m), 4.60–5.11
6
912

(4H, br, 4OH), 4.62 (1H, d, J = 5.6, H-4), 5.06 (1H, d, J = 5.6, H-3), 5.24 (1H, d, J = 8.0, H-1), 6.89 (2H, d, J = 8.0, ArH), 7.12
(2H, d, J = 8.0, ArH), 7.44 (2H, d, J = 8.4, ArH), 7.53 (2H, d, J = 8.4, ArH), 8.69 (1H, s, NH).
+
HR-MS-ESI m/z calcd for C H ClNNaO [M + Na] 536.1452, found 536.1450.
27 28
7
2-(4-Bromophenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4e). This compound
was prepared from 2e, cyclohexane-1,3-dione, and ammonium acetate; yield 81%, yellow powder, mp 152–154ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3361, 2953, 2926, 2887, 1654, 1594, 1485, 1444, 1391, 1078, 828, 619. H NMR (400 MHz,
DMSO-d , ꢄ, ppm, J/Hz): 1.03–1.07 (2H, m, H-7), 1.81–1.90 (2H, m, H-8), 2.50–2.65 (2H, m, H-6), 3.36–3.91 (6H, m), 4.52
6
(1H, d, J = 5.6, H-4), 4.59–5.12 (4H, br, 4OH), 5.04 (1H, d, J = 5.6, H-3), 5.25 (1H, d, J = 8.0, H-1), 6.88 (2H, d, J = 8.0, ArH),
7.11 (2H, d, J = 8.0, ArH), 7.45 (2H, d, J = 8.4, ArH), 7.57 (2H, d, J = 8.4, ArH), 8.71 (1H, s, NH).
+
HR-MS-ESI m/z calcd for C H BrNNaO [M + Na] 580.0947, found 580.0963.
27 28
7
7,7-Dimethyl-2-phenyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4f). This compound
was prepared from 2a, 5,5-dimethylcylohexane-1,3-dione, and ammonium acetate; yield 83%, yellow powder, mp 172–174ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3416, 2925, 2865, 1744, 1599, 1652, 1485, 1388, 1116, 1094, 835, 618. H NMR (400 MHz,
DMSO-d , ꢄ, ppm, J/Hz): 0.94 (3H, s, CH ), 1.03 (3H, s, CH ), 1.98 (1H, d, J = 16.0, H-8), 2.16 (1H, d, J = 16.0, H-8), 2.46
6
3
3
(2H, s, H-6), 3.34–3.90 (6H, m), 4.50 (1H, d, J = 5.6, H-4), 4.59–5.10 (4H, br, 4OH), 5.05 (1H, d, J = 5.6, H-3), 5.20 (1H, d,
J = 8.0, H-1), 6.89 (2H, d, J = 8.0, ArH), 7.13 (2H, d, J = 8.0, ArH), 7.35–7.40 (3H, m, ArH), 7.49 (2H, d, J = 8.4, ArH), 8.60
(1H, s, NH).
+
HR-MS-ESI m/z calcd for C H NNaO [M + Na] 530.2155, found 530.2021.
29 33
7
7,7-Dimethyl-2-(4-methylphenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4g).
This compound was prepared from 2b, 5,5-dimethyl-cylohexane-1,3-dione, and ammonium acetate; yield 84%, yellow powder,
mp 139–141ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3362, 2925, 2882, 1660, 1592, 1485, 1390, 1227, 1085, 830, 619. H NMR (400 MHz, DMSO-d ,
6
ꢄ, ppm, J/Hz): 0.93 (3H, s, CH ), 1.07 (3H, s, CH ), 1.99 (1H, d, J = 16.0, H-8), 2.14 (1H, d, J = 16.0, H-8), 2.24 (3H, s, CH ),
3
3
3
2.48 (2H, s, H-6), 3.42–3.47 (6H, m), 4.51 (1H, d, J = 5.6, H-4), 4.59–5.10 (4H, br, 4OH), 5.06 (1H, d, J = 5.6, H-3), 5.19 (1H,
d, J = 8.0, H-1), 6.89 (2H, d, J = 8.0, ArH), 7.12 (2H, d, J = 8.0, ArH), 7.38 (2H, d, J = 8.4, ArH), 7.50 (2H, d, J = 8.4, ArH),
8.61 (1H, s, NH).
+
HR-MS-ESI m/z calcd for C H NNaO [M + Na] 544.2311, found 544.2307.
30 35
7
7,7-Dimethyl-2-(4-fluorophenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4h). This
compound was prepared from 2c, 5,5-dimethyl-cyclohexane-1,3-dione, and ammonium acetate; yield 76%, yellow powder,
mp 163–165ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3352, 2925, 2882, 1661, 1595, 1485, 1390, 1228, 914, 839, 620. H NMR (400 MHz, DMSO-d ,
6
ꢄ, ppm, J/Hz): 0.96 (3H, s, CH ), 1.05 (3H, s, CH ), 1.92 (1H, d, J = 16.0, H-8), 2.15 (1H, d, J = 16.0, H-8), 2.48 (2H, s, H-6),
3
3
3.34–3.90 (6H, m), 4.49 (1H, d, J = 5.6, H-4), 4.58–5.09 (4H, br, 4OH), 5.03 (1H, d, J = 5.6, H-3), 5.16 (1H, d, J = 8.0, H-1),
6.90 (2H, d, J = 8.0, ArH), 7.12 (2H, d, J = 8.0, ArH), 7.22 (2H, d, J = 8.4, ArH), 7.52 (2H, d, J = 8.4, ArH), 8.60 (1H, s, NH).
–
HR-MS-ESI m/z calcd for C H FO [M – H] 524.2085, found 524.2101.
29 31
7
7,7-Dimethyl-2-(4-chlorophenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4i). This
compound was prepared from 2d, 5,5-dimethyl-cyclohexane-1,3-dione, and ammonium acetate; yield 79%, yellow powder,
mp 142–143ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3361, 2953, 2826, 1660, 1597, 1490, 1390, 1230, 1038, 838, 620. H NMR (400 MHz, DMSO-d ,
6
ꢄ, ppm, J/Hz): 0.93 (3H, s, CH ), 1.06 (3H, s, CH ), 2.00 (1H, d, J = 16.0, H-8), 2.16 (1H, d, J = 16.0, H-8), 2.49 (2H, s, H-6),
3
3
3.35–3.90 (6H, m), 4.47–5.02 (4H, br, 4OH), 4.55 (1H, d, J = 5.6, H-4), 5.05 (1H, d, J = 5.6, H-3), 5.23 (1H, d, J = 8.0, H-1),
6.88 (2H, d, J = 8.0, ArH), 7.11 (2H, d, J = 8.0, ArH), 7.44 (2H, d, J = 8.4, ArH), 7.52 (2H, d, J = 8.4, ArH), 8.62 (1H, s, NH).
–
HR-MS-ESI m/z calcd for C H ClNO [M – H] 540.1789, found 540.1790.
29 31
7
7,7-Dimethyl-2-(4-bromophenyl)-4-(4-ꢀ-D-allopyranosyloxyphenyl)-5-oxo-4,6,7,8-tetrahydroquinoline (4j). This
compound was prepared from 2e, 5,5-dimethyl-cyclohexane-1,3-dione, and ammonium acetate; yield 77%, yellow powder,
mp 163–165ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3353, 2927, 2871, 1670, 1589, 1485, 1393, 1228, 1035, 825, 618. H NMR (400 MHz, DMSO-d ,
6
ꢄ, ppm, J/Hz): 0.95 (3H, s, CH ), 1.06 (3H, s, CH ), 2.07 (1H, d, J = 16.0, H-8), 2.16 (1H, d, J = 16.0, H-8), 2.47 (2H, s, H-6),
3
3
3.35–3.90 (6H, m), 4.51 (1H, d, J = 5.6, H-4), 4.59–5.10 (4H, br, 4OH), 5.05 (1H, d, J = 5.6, H-3), 5.24 (1H, d, J = 8.0, H-1),
6.89 (2H, d, J = 8.0, ArH), 7.11 (2H, d, J = 8.0, ArH), 7.45 (2H, d, J = 8.4, ArH), 7.58 (2H, d, J = 8.4, ArH), 8.63 (1H, s, NH).
+
HR-MS-ESI m/z calcd for C H BrNNaO [M + Na] 608.1260, found 608.1258.
29 32
7
913

Mice (Kunming strain) weighing 18–22 g were obtained from West China School of Pharmacy, Sichuan University
(Chengdu China). Diazepam was purchased from Tianjin Pharmaceutical Co. Ltd. (China). All samples were dissolved in
0.05% CMC to form different concentrations of solutions for later use.
The sedative-hypnotic activities of the compounds were investigated by recording the number of spontaneous
locomotion in mice using an actophotometer [12, 13]. Seventy-two mice were randomized into 12 groups of 6 mice each (3
males and 3 females). When testing, the basal activity score was taken and then a solution of the drugs in 0.05% CMC and
saline was injected into the mouse stomach with a syringe in a volume of 0.2 mL/10 g body weight. Scores were recorded
before the drug and saline injection and at 15, 30, 60, and 90 min after the drug and saline injection. The data were expressed
as number of movements per minute, averaged over 7 min.
As shown in Table 2, the parent compound helicid (1) exhibited weak activity and compounds 4b, 4e, and 4f
demonstrated greater activity than helicid. It is interesting that compound 4b, which bears a p-methyl substituent, showed
potent sedative-hypnotic activity. These results confirm that the lipophilic property might play a vital role in determining their
activities. So, further modification of helicid to improve its lipophilic property will be worthwhile.
ACKNOWLEDGMENT
The authors thank the Analytical & Testing Center, Sichuan University, P. R. China for assistance in obtaining
analytical data, and Mr. Bao (Department of Pharmacy, Sichuan University) who performed the sedative-hypnotic tests.
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