Synthesis and antiplatelet-activity evaluation of α-methylidene- γ- butyrolactones bearing 3,4-dihydroquinolin-2(1H)-one moieties

Article abstract of DOI:10.1002/(SICI)1522-2675(20000216)83:2<349::AID-HLCA349>3.0.CO;2-B

In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several α-methylidene-γ-butyrolactones bearing 3,4-dihydroquinolin-2(1H)-one moieties. O-Alkylation of 3,4-dihydro-8- hydroxyquinolin-2(1H)-one (1) with chloro

Full text of DOI:10.1002/(SICI)1522-2675(20000216)83:2<349::AID-HLCA349>3.0.CO;2-B

Helvetica Chimica Acta ± Vol. 83 (2000)
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Synthesis and Antiplatelet-Activity Evaluation of a-Methylidene-
g-butyrolactones Bearing 3,4-Dihydroquinolin-2(1H)-one Moieties
by Cherng-Chyi Tzeng*, I.-Li Chen, and Yeh-Long Chen
School of Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China
and Tai-Chi Wang
Department of Pharmacy, Tajen Institute of Technology, Pingtung, Taiwan, Republic of China
and Ya-Ling Chang and Che-Ming Teng
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 100, Taiwan, Republic of
China
In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several a-
methylidene-g-butyrolactones bearing 3,4-dihydroquinolin-2(1H)-one moieties. O-Alkylation of 3,4-dihydro-8-
hydroxyquinolin-2(1H)-one (1) with chloroacetone under basic conditions afforded 3,4-dihydro-8-(2-oxopro-
poxy)quinolin-2(1H)-one (2a) and tricyclic 2,3,6,7-tetrahydro-3-hydroxy-3-methyl-5H-pyrido[1,2,3-de][1,4]-
benzoxazin-5-one (3a) in a ratio of 1:2.84. Their Reformatsky-type condensation with ethyl 2-(bromomethyl)-
prop-2-enoate furnished 3,4-dihydro-8-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)methoxy]-
quinolin-2(1H)-one (4a), which shows antiplatelet activity, in 70% yield. Its 2'-Ph derivatives, and 6- and 7-
substituted analogs were also obtained from the corresponding 3,4-dihydroquinolin-2(1H)-ones via alkylation
and the Reformatsky-type condensation. Of these compounds, 3,4-dihydro-7-[(2,3,4,5-tetrahydro-4-methyl-
idene-5-oxo-2-phenylfuran-2-yl)methoxy]quinolin-2(1H)-one (10b) was the most active against arachidonic
acid (AA) induced platelet aggregation with an IC50 of 0.23 mm. For the inhibition of platelet-activating factor
(PAF) induced aggregation, 6-{[2-(4-fluorophenyl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]me-
thoxy}-3,4-dihydroquinolin-2(1H)-one (9c) was the most potent with an IC50 value of 1.83 mm.
Introduction. ± Recently, we have synthesized and evaluated the cardiovascular
activities of certain a-methylidene-g-butyrolactones bearing heterocycles such as
coumarins, flavones, xanthones, quinolines, and quinolin-2(1H)-ones [1 ± 3]. Among
these heterocycles, coumarins exhibited the most potent inhibitory activities on the
‡
high-K -medium, Ca2‡-induced vasoconstriction, and the norepinephrine-induced
phasic and tonic vasoconstrictions, while quinolin-2(1H)-ones proved to be the most
active against platelet aggregation [2][3]. One of the most potent antiplatelet agents, 6-
[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]quinolin-2(1H)-
one (CCT-62), has been proved to be an inhibitor of phosphodiesterases, and its
antiplatelet effect is mainly mediated by elevation of cyclic-AMP levels [4]. In the
continuation of our search for more potent antiplatelet agents, we report herein the
preparation, antiplatelet-activity evaluation, and structure-activity relationships of
several a-methylidene-g-butyrolactones bearing 3,4-dihydroquinolin-2(1H)-one moi-
eties, saturated analogs of CCT-62. The cardiovascular and neuroprotective activities of
certain quinolin-2(1H)-ones and 3,4-dihydroquinolin-2(1H)-ones substituted with
various side chains have been reported earlier [5 ± 9].

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Results and Discussion. ± The preparation of 3,4-dihydro-8-[(2,3,4,5-tetrahydro-2-
methyl-4-methylidene-5-oxofuran-2-yl)methoxy]quinolin-2(1H)-one (4a) and its 2'-Ph
derivatives is illustrated in Scheme 1. 3,4-Dihydro-8-hydroxyquinolin-2(1H)-one (1)
Scheme 1
was treated with chloroacetone under basic conditions to afford 3,4-dihydro-8-(2-
oxopropoxy)quinolin-2(1H)-one (2a) and 2,3,6,7-tetrahydro-3-hydroxy-3-methyl-5H-
pyrido[1,2,3-de][1,4]benzoxazin-5-one (3a) in a ratio of 1:2.84 (75% yield). Com-
pounds 2a and 3a are interconvertible: when the mixture was subjected to a
Reformatsky-type condensation, 4a was obtained in 70% yield. Accordingly, 1 was
reacted with 2-bromoacetophenone, 2-bromo-4'-fluoroacetophenone, and 2-bromo-4'-
phenylacetophenone, respectively, under the same reaction conditions to give 2b ± d
1
and 3b ± d in ratios of 1.32 :1 to 1.43 :1, based on the integration of CH2O H-NMR
signals. An electron-donating substituent (R ˆ 4-MeO C6H4) retarded ring cycliza-
tion, and only 2e was isolated, while an electron-withdrawing substituent (R ˆ 4-
NO2 C6H4) favored the formation of 3f. That alkylation of 1 occurred at HO C(8)
1
rather than at N(1) or C(2)ˆO was shown by the H,13C-HETCOR spectrum, which
reveals the correlation of CH2(1') protons (5.53 ppm, singlet) with C-atoms resonating
at 71.50 (1J) and 144.87 (3J), corresponding to C(1') and C(8). The structure of 3f was
1
confirmed by the H-NMR spectrum in which the CH2(2) protons are magnetically
nonequivalent, and two distinct doublets (J ˆ 11.4 Hz) at 3.80 and 3.99 ppm (AB type)
were observed. Furthermore, the 1H,13C-HETCOR spectrum revealed the correlation
of CH2(2) protons with C-atoms resonating at 74.35 (1J), 83.04 (2J), and 144.53 (3J)
ppm, corresponding to C(2), C(3), and C(11), respectively. Reformatsky-type
condensation of 2b ± d and 3b ± d afforded 3,4-dihydro-8-[(2,3,4,5-tetrahydro-4-meth-

Helvetica Chimica Acta ± Vol. 83 (2000)
351
ylidene-5-oxofuran-2-yl)methoxy]quinolin-2(1H)-ones 4b ± d, respectively, in 65 ± 68%
yield, indicating that 2b ± d and the corresponding tricyclic counterparts 3b ± d are
interconvertible. Accordingly, 4e and 4f were prepared from 2e and 3f, respectively, via
Reformatsky-type condensation. The 6- and 7-substituted analogs 9a ± h and 10a ± d
were also obtained from the corresponding 3,4-dihydroquinolin-2(1H)-ones 5 and 6
[10] via alkylation and Reformatsky-type condensation (Scheme 2).
Scheme 2
The antiplatelet activities of a-methylidene-g-butyrolactones with 3,4-dihydroqui-
nolin-2(1H)-one moieties were evaluated in washed rabbit platelets. Platelet aggrega-
tion was induced by thrombin (Thr, 0.1 U/ml), arachidonic acid (AA, 100 mm), collagen
(Col, 10 mg/ml), and platelet-activating factor (PAF, 2 nm). The final concentration of
compounds was 100 mg/ml, and the results are shown in Table 1.
Table 1. Effect of 3,4-Dihydroquinolin-2(1H)-ones on the Platelet Aggregation ([%]) Induced by Thrombin
(Thr), Arachidonic Acid (AA), Collagen (Col) and Platelet-Activating Factor (PAF) in Washed Rabbit
Plateletsa)
Compounds
Inducer
Thr (0.1 U/ml)
AA (100 mm)
Col (10 mg/ml)
PAF (2 nm)
Control
4a
90.5 Æ 0.8
69.7 Æ 3.5b
0
87.1 Æ 0.1
90.0 Æ 0.7
88.7 Æ 0.9
0b)
0
0
68.5 Æ 6.3b)
4bc)
4d
0
0
0
0
75.7 Æ 2.2b)
2.9 Æ 1.2b)
53.6 Æ 4.8b)
6.2 Æ 5.0b)
8.9 Æ 7.2b)
91.9 Æ 1.4
0
0
0
0
0
0
32.6 Æ 6.0b)
9a
9d
9e
10a
0
0
0
5.5 Æ 2.3b)
0
0
7.8 Æ 3.6b)
Aspirin
85.4 Æ 3.9
90.5 Æ 1.2
a) Platelets were preincubated with 3,4-dihydroquinolin-2(1H)-ones (100 mg/ml) or DMSO (0.5%, control) at
378 for 3 min, and the inducer was then added. Percentages of aggregation are presented as means Æ standard
errors of the mean (n ˆ 3 ± 7). b) Significantly different from control value at p < 0.001. c) Platelet aggregation
induced by the four inducers was completely inhibited by 4b, 4c, 4e, 4f, 9b, 9c, 9g, 9h, 10b ± d.
All of the tested compounds were found to completely inhibit platelet aggregation
induced by AA and Col. Compounds 4b, 4c, 4e, 4f, 9b ± c, 9g, 9h, and 10b ± d also
exhibited good inhibitory activity against Thr- and PAF-induced aggregation. The
inhibitory concentrations for 50% aggregation (IC50) induced by AA and PAF are
given in Table 2.

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Table 2. IC50 Values ([mm]) of 3,4-Dihydroquinolin-2(1H)-ones on the Platelet Aggregation Induced by AA and
PAF
a) 8-Substituted 3,4-dihydroquinolin-2(1H)-ones
4a
4b
4.39
21.7
4c
3.75
15.6
4d
7.73
4e
8.20
4f
3.40
8.63
AA
PAF
35.73
> 100
78.03
35.46
b) 6-Substituted 3,4-dihydroquinolin-2(1H)-ones
9a
1.64
13.29
9b
9c
9d
9e
9g
9h
AA
PAF
0.57
2.33
0.60
1.83
3.29
6.23
1.01
7.24
0.57
2.30
0.63
2.30
c) 7-Substituted 3,4-dihydroquinolin-2(1H)-ones
10a
2.31
51.37
10b
10c
10d
AA
PAF
0.23
6.13
0.28
3.54
1.91
11.44
Compound 4a, with a Me substituent at C(2') of the lactone moiety, was less active
against AA- and PAF-induced aggregation than its PhC(2')-lactone counterparts (4b ±
f). Compounds 4c and 4f, which possess electron-withdrawing substituents (Fand NO2,
resp.), were found to be more potent than that of onyl-Ph-substituted 4b, while 4d and
4e, which possess an electron-donating substituent (Ph and MeO, resp.), were even less
active. Comparison of the positional isomers showed that 6- and 7-substituted
derivatives 9a ± d and 10a ± d are more potent than the respective 8-substituted isomers
4a ± d in inhibiting both AA- and PAF-induced aggregations.
In summary, the lower inhibitory potency of 4d, 9d, and 10d implies that an
electron-donating aryl substituent at C(2') of the lactone moiety reduces the
antiplatelet activity of compounds of this type. For AA-induced platelet aggregation,
the inhibitory potency decreases in the order 7-substituted > 6-substituted > 8-sub-
stituted. For PAF-induced platelet aggregation, the inhibitory potency decreases in the
order 6-substituted > 7-substituted > 8-substituted. All of these a-methylidene-g-
butyrolactones bearing 3,4-dihydroquinolin-2(1H)-ones are more potent than their
respective unsaturated counterparts [3].
We gratefully acknowledge financial support from the National Science Council of the Republic of China.
Experimental Part
General. TLC: precoated (0.2 mm) silica gel 60 F254 plates from EM Laboratories, Inc.; detection by UV
light (254 nm). M.p.: Electrothermal IA-9000 micromelting-point apparatus; uncorrected. UV Spectra (lmax (log
e) in nm): Beckman UV-VIS spectrophotometer. 1H- and 13C-NMR spectra: Varian-Gemini-200 spectrometer, d
in ppm with Me4Si as an internal standard. Elemental analyses were carried out on a Heraeus CHN-O-Rapid
elemental analyzer, and results were within ‡ / 0.4% of calc. values.
3,4-Dihydro-8-(2-oxopropoxy)quinolin-2(1H)-one (2a) and 2,3,6,7-Tetrahydro-3-hydroxy-3-methyl-5H-
pyrido[1,2,3-de][1,4]benzoxazin-5-one (3a). 3,4-Dihydro-8-hydroxyquinolin-2(1H)-one (1, 1.63 g, 10 mmol),
K2CO3 (1.38 g, 10 mmol) and dry DMF (50 ml) were stirred at r.t. for 30 min. To this soln., chloroacetone
(0.92 g, 10 mmol) in dry DMF (10 ml) was added in one portion. The resulting mixture was stirred at r.t. for 24 h
(TLC monitoring) and then poured into ice-water (100 ml). The white solid thus obtained was collected and
purified by column chromatography (CC) (silica gel; hexane/AcOEt 1:1), affording a residual solid which was

Helvetica Chimica Acta ± Vol. 83 (2000)
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crystallized from CH2Cl2/Et2O 1:10: 2a and 3a (1:2.84; 1.64 g, 75%). 1H-NMR (DMSO): 4.79 (s, 2 H C(1') of
2a); 3.78, 3.91 (2d, J ˆ 11.2, AB type, 2 H C(2) of 3a). 13C-NMR (DMSO): 73.44 (C(1')); 169.60 (C(2)); 204.71
(C(2') of 2a); 73.51 (C(2)); 82.12 (C(3)); 169.53 (C(5) of 3a). Anal. calc. for C12H13NO3: C 65.74, H 5.98,
N 6.39; found: C 65.73, H 6.02, N 6.42.
3,4-Dihydro-8-(2-oxo-2-phenylethoxy)quinolin-2(1H)-one (2b) and 2,3,6,7-Tetrahydro-3-hydroxy-3-phen-
yl-5H-pyrido[1,2,3-de][1,4]benzoxazin-5-one (3b). A mixture of 2b and 3b (1.39 :1) was obtained from 1 and
2-bromoacetophenone, according to the procedure described above, in 74% yield. 1H-NMR (DMSO): 5.60
(s, 2H C(1') of 2b); 3.80, 3.96 (2d, J ˆ 11.6, AB type, 2 H C(2) of 3b). 13C-NMR (DMSO): 71.70 (C(1'));
169.54 (C(2)); 194.98 (C(2') of 2b); 74.82 (C(2)); 84.05 (C(3)); 168.74 (C(5) of 3b). Anal. calc. for C17H15NO3:
C 72.58, H 5.38, N 4.98; found: C 72.61, H5.37, N 4.97.
8-[2-(4-Fluorophenyl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (2c) and 3-(4-Fluorophenyl)-2,3,6,7-
tetrahydro-3-hydroxy-5H-pyrido[1,2,3-de][1,4]benzoxazin-5-one (3c). A mixture of 2c and 3c (1.43 :1) was
obtained from 1 and 2-bromo-4'-fluoroacetophenone, according to the procedure described above, in 80% yield.
1H-NMR (DMSO): 5.58 (s, 2 H C(1') of 2c); 3.80, 3.95 (2d, J ˆ 11.4, AB type, 2 H C(2) of 3c). 13C-NMR
(DMSO): 71.62 (C(1')); 169.56 (C(2)); 193.66 (C(2') of 2c); 74.75 (C(2)); 83.61 (C(3)); 168.66 (C(5) of 3c).
Anal. calc. for C17H14FNO3: C 68.22, H4.71, N 4.68; found: C 68.07, H 4.72, N 4.66.
8-[2-(1,1'-Biphenyl-4-yl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (2d) and 3-(1,1'-Biphenyl-4-yl)-
2,3,6,7-tetrahydro-3-hydroxy-5H-pyrido[1,2,3-de][1,4]benzoxazin-5-one (3d).
A mixture of 2d and 3d
(1.32 :1) was obtained from 1 and 2-bromo-4'-phenylacetophenone, according to the procedure described
above, in 84% yield. 1H-NMR (DMSO): 5.64 (s, 2H C(1') of 2d); 3.85, 4.00 (2d, J ˆ 11.2, AB type, 2 H C(2)
of 3d). 13C-NMR (DMSO): 71.72 (C(1')); 169.51 (C(2)); 194.53 (C(2') of 2d); 74.75 (C(2)); 83.89 (C(3)); 168.71
(C(5) of 3d). Anal. calc. for C23H19NO3 ´ H2O: C 73.58, H 5.64, N 3.73; found: C 73.33, H 5.72, N 3.74.
3,4-Dihydro-8-[2-(4-methoxyphenyl)-2-oxoethoxy]quinolin-2(1H)-one (2e). Compound 2e was obtained
from 1 and 2-bromo-4'-methoxyacetophenone, according to the procedure described above, in 77% yield. M.p.
169 ± 1708. 1H-NMR (DMSO): 2.45 ± 2.52 (m, 2 H C(3)); 2.85 ± 2.93 (m, 2 H C(4)); 3.86 (s, MeO); 5.53
(s, 2 H C(1')); 6.84 ± 8.04 (m, 7 arom. H); 8.95 (br. s, NH). 13C-NMR (DMSO): 24.84 (C(4)); 30.41 (C(3));
55.61 (MeO); 71.50 (C(1')); 112.06; 114.07; 120.56; 122.06; 124.68; 127.07; 127.49; 130.28; 144.87 (C(8)); 163.65;
169.51 (C(2)); 193.31 (C(2')). Anal. calc. for C18H17NO4: C 69.44, H 5.51, N4.50; found: C 69.11, H 5.48, N 4.48.
2,3,6,7-Tetrahydro-3-hydroxy-3-(4-nitrophenyl)-5H-pyrido[1,2,3-de][1,4]benzoxazin-5-one (3f). Com-
pound 3f was obtained from 1 and 2-bromo-4'-nitroacetophenone, according to the procedure described
above, in 74% yield. M.p. 183 ± 1848. 1H-NMR (DMSO): 2.50 ± 2.56 (m, 2 H C(6)); 2.56 ± 3.08 (m, 2 H C(7));
3.80, 3.99 (2d, J ˆ 11.4, AB type, 2 H C(2)); 6.91 ± 8.22 (m, 7 arom. H); 7.14 (s, OH). 13C-NMR (DMSO): 24.18
(C(7)); 31.86 (C(6)); 74.35 (C(2)); 83.04 (C(3)); 115.41; 121.38; 122.95; 123.24; 125.94; 126.30; 126.52; 144.53
(C(11)); 146.70; 149.44; 168.21 (C(5)). Anal. calc. for C17H14N2O5: C 62.58, H 4.32, N 8.58; found: C 62.40,
H 4.36, N 8.50.
3,4-Dihydro-6-(2-oxopropoxy)quinolin-2(1H)-one (7a). Compound 7a was obtained from 5a and
chloroacetone, according to the procedure described above, in 78% yield. M.p. 125 ± 1268. 1H-NMR (DMSO):
2.14 (s, Me); 2.36 ± 2.44 (m, 2 H C(3)); 2.79 ± 2.86 (m, 2 H C(4)); 4.72 (s, 2 H C(1')); 6.66 ± 6.79 (m, 3 ar-
om. H); 9.92 (br. s, NH). 13C-NMR (DMSO): 25.10 (C(4)); 26.27 (Me); 30.35 (C(3)); 72.50 (C(1')); 113.03;
114.10; 115.81; 124.97; 132.14; 153.02 (C(6)); 169.96 (C(2)); 204.57 (C(2')). Anal. calc. for C12H13NO3: C 65.74,
H 5.98, N 6.39; found: C 65.61, H 5.98, N 6.41.
3,4-Dihydro-6-(2-oxo-2-phenylethoxy)quinolin-2(1H)-one (7b). Compound 7b was obtained from 5b and
2-bromoacetophenone, according to the procedure described above, in 85% yield. M.p. 111 ± 1128. 1H-NMR
(DMSO): 2.37 ± 2.44 (m, 2 H C(3)); 2.79 ± 2.86 (m, 2 H C(4)); 5.49 (s, 2 H C(1')); 6.77 ± 8.04 (m, 8 ar-
om. H); 9.93 (br. s, NH). 13C-NMR (DMSO): 25.14 (C(4)); 30.39 (C(3)); 70.53 (C(1')); 113.27; 114.27; 115.83;
124.93; 127.94; 128.93; 132.14; 133.87; 134.50; 153.25 (C(6)); 169.99 (C(2)); 194.91 (C(2')). Anal. calc. for
C17H15NO3: C 72.58, H 5.38, N 4.98; found: C 72.44, H 5.42, N 4.98.
6-[2-(4-Fluorophenyl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (7c). Compound 7c was obtained
from 5c and 2-bromo-4'-fluoroacetophenone, according to the procedure described above, in 94% yield. M.p.
214 ± 2158. 1H-NMR (DMSO): 2.35 ± 2.43 (m, 2 H C(3)); 2.78 ± 2.85 (m, 2H C(4)); 5.46 (s, 2 H C(1'));
6.75 ± 8.12 (m, 7 arom. H); 9.91 (br. s, NH). 13C-NMR (DMSO): 25.12 (C(4)); 30.37 (C(3)); 70.47 (C(1'));
113.27; 114.26; 115.75; 115.81; 116.18; 124.93; 130.93; 131.12; 131.24; 131.29; 132.17; 153.19 (C(6)); 162.87;
167.89; 169.97 (C(2)); 193.57 (C(2')). Anal. calc. for C17H14FNO3: C 68.22, H 4.71, N 4.68; found: C 68.02,
H 4.72, N 4.71.
6-[2-(1,1'-Biphenyl-4-yl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (7d). Compound 7d was obtained
from 5d and 2-bromo-4'-phenylacetophenone, according to the procedure described above, in 87% yield. M.p.

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Helvetica Chimica Acta ± Vol. 83 (2000)
182 ± 1838. 1H-NMR (DMSO): 2.36 ± 2.43 (m, 2 H C(3)); 2.78 ± 2.86 (m, 2 H C(4)); 5.51 (s, 2 H C(1'));
6.77 ± 8.11 (m, 12 arom. H); 9.93 (br. s, NH). 13C-NMR (DMSO): 25.14 (C(4)); 30.38 (C(3)); 70.56 (C(1'));
113.27; 114.26; 115.83; 124.94; 127.07; 127.10; 128.60; 128.71; 129.22; 132.14; 133.29; 138.90; 145.19; 153.25
(C(6)); 169.98 (C(2)); 194.45 (C(2')). Anal. calc. for C23H19NO3: C 77.29, H 5.36, N 3.92; found: C 77.09, H 5.41,
N 3.90.
3,4-Dihydro-6-[2-(4-methoxyphenyl)-2-oxoethoxy]quinolin-2(1H)-one (7e). Compound 7e was obtained
from 5e and 2-bromo-4'-methoxyacetophenone, according to the procedure described above, in 96% yield. M.p.
179 ± 1808. 1H-NMR (DMSO): 2.38 ± 2.42 (m, 2 H C(3)); 2.80 ± 2.84 (m, 2 H C(4)); 3.86 (MeO); 5.40
(s, 2 H C(1')); 6.75 ± 8.01 (m, 7 arom. H); 9.91 (br. s, NH). 13C-NMR (DMSO): 25.11 (C(4)); 30.34 (C(3));
55.65 (MeO); 70.28 (C(1')); 113.21; 114.09; 114.23; 115.77; 124.87; 127.41; 130.28; 132.07; 153.29 (C(6)); 163.59;
169.91 (C(2)); 193.18 (C(2')). Anal. calc. for C18H17NO4: C 69.44, H 5.51, N 4.50; found: C 69.16, H 5.56, N 4.43.
6-[2-(4-Chlorophenyl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (7g). Compound 7g was obtained
from 5g and 2-bromo-4'-chloroacetophenone, according to the procedure described above, in 76% yield. M.p.
212 ± 2138. 1H-NMR (DMSO): 2.37 ± 2.44 (m, 2 H C(3)); 2.79 ± 2.86 (m, 2 H C(4)); 5.48 (s, 2 H C(1'));
6.77 ± 8.05 (m, 7 arom. H); 9.93 (br. s, NH). 13C-NMR (DMSO): 25.12 (C(4)); 30.38 (C(3)); 70.53 (C(1'));
113.27; 114.26; 115.82; 124.94; 129.03; 129.91; 132.19; 133.17; 138.74; 153.15 (C(6)); 169.98 (C(2)); 194.04
(C(2')). Anal. calc. for C17H14ClNO3: C 64.66, H 4.47, N 4.44; found: C 64.47, H 4.45, N 4.44.
6-[2-(4-Bromophenyl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (7h). Compound 7h was obtained
from 5h and 2-bromo-4'-bromoacetophenone, according to the procedure described above, in 75% yield. M.p.
198 ± 1998. 1H-NMR (DMSO): 2.36 ± 2.44 (m, 2 H C(3)); 2.79 ± 2.86 (m, 2 H C(4)); 5.47 (s, 2 H C(1'));
6.76 ± 7.97 (m, 7 arom. H); 9.92 (br. s, NH). 13C-NMR (DMSO): 25.13 (C(4)); 30.38 (C(3)); 70.51 (C(1'));
113.28; 114.27; 115.83; 124.96; 127.94; 130.00; 131.99; 132.20; 133.49; 153.15 (C(6)); 169.99 (C(2)); 194.27
(C(2')). Anal. calc. for C17H14BrNO3: C 56.68, H 3.92, N 3.89; found: C 56.48, H 3.92, N 3.87.
3,4-Dihydro-7-(2-oxopropoxy)quinolin-2(1H)-one (8a). Compound 8a was obtained from 6a and
chloroacetone, according to the procedure described above, in 72% yield. M.p. 136 ± 1378. 1H-NMR (DMSO):
2.14 (s, Me); 2.38 ± 2.45 (m, 2 H C(3)); 2.75 ± 2.82 (m, 2 H C(4)); 4.71 (s, 2 H C(1')); 6.40 ± 7.06 (m, 3 ar-
om. H); 9.97 (br. s, NH). 13C-NMR (DMSO): 23.97 (C(4)); 26.20 (Me); 30.67 (C(3)); 72.18 (C(1')); 101.92;
107.30; 116.15; 128.38; 139.21; 156.95 (C(7)); 170.31 (C(2)); 204.19 (C(2')). Anal. calc. for C12H13NO3: C 65.74,
H 5.98, N 6.39; found: C 65.74, H 6.03, N 6.36.
3,4-Dihydro-7-(2-oxo-2-phenylethoxy)quinolin-2(1H)-one (8b). Compound 8b was obtained from 6b and
2-bromoacetophenone, according to the procedure described above, in 84% yield. M.p. 181 ± 1828. 1H-NMR
(DMSO): 2.37 ± 2.45 (m, 2 H C(3)); 2.75 ± 2.82 (m, 2 H C(4)); 5.50 (s, 2 H C(1')); 6.45 ± 8.04 (m, 8 ar-
om. H); 9.96 (br. s, NH). 13C-NMR (DMSO): 23.97 (C(4)); 30.67 (C(3)); 70.18 (C(1')); 102.01; 107.48; 116.04;
127.81; 128.29; 128.82; 133.77; 134.37; 139.16; 157.14 (C(7)); 170.22 (C(2)); 194.61 (C(2')). Anal. calc. for
C17H15NO3 ´ 0.125 H2O: C 72.01, H 5.42, N 4.94; found: C 72.01, H 5.42, N 4.82.
7-[2-(4-Fluorophenyl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (8c). Compound 8c was obtained
from 6c and 2-bromo-4'-fluoroacetophenone, according to the procedure described above, in 78% yield. M.p.
190 ± 1918. 1H-NMR (DMSO): 2.38 ± 2.45 (m, 2 H C(3)); 2.75 ± 2.82 (m, 2 H C(4)); 5.48 (s, 2 H C(1'));
6.45 ± 8.14 (m, 7 arom. H); 9.96 (br. s, NH). 13C-NMR (DMSO): 24.01 (C(4)); 30.71 (C(3)); 70.16 (C(1'));
102.08; 107.52; 115.72; 116.15; 128.35; 130.87; 131.06; 131.14; 131.20; 139.19; 157.14 (C(7)); 162.84; 167.86;
170.32 (C(2)); 193.36 (C(2')). Anal. calc. for C17H14FNO3: C 68.22, H 4.71, N 4.68; found: C 68.08, H 4.76,
N 4.67.
7-[2-(1,1'-Biphenyl-4-yl)-2-oxoethoxy]-3,4-dihydroquinolin-2(1H)-one (8d). Compound 8d was obtained
from 6d and 2-bromo-4'-phenylacetophenone, according to the procedure described above, in 80% yield. M.p.
187 ± 1888. 1H-NMR (DMSO): 2.38 ± 2.45 (m, 2 H C(3)); 2.75 ± 2.83 (m, 2 H C(4)); 5.53 (s, 2 H C(1'));
6.47 ± 8.12 (m, 12 arom. H); 9.97 (br. s, NH). 13C-NMR (DMSO): 24.01 (C(4)); 30.70 (C(3)); 70.24 (C(1'));
102.04; 107.56; 116.09; 127.04; 128.35; 128.53; 128.61; 129.14; 133.18; 138.82; 139.19; 145.17; 157.19 (C(7));
170.30 (C(2)); 194.21 (C(2')). Anal. calc. for C23H19NO3 ´ 0.125 H2O: C 76.81, H 5.39, N 3.90; found: C 76.75,
H 5.43, N 3.89.
3,4-Dihydro-8-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)methoxy]quinolin-2(1H)-one
(4a). To a soln. of 2a and 3a (0.66 g, 3 mmol) in dry THF (60 ml), activated Zn powder (0.26 g, 3.9 mmol),
hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol) were added. The mixture was
refluxed under N2 for 6 h (TLC monitoring). After cooling, it was poured into ice-cold 5% HCl soln. (300 ml)
and extracted with CH2Cl2 (3 Â 60 ml). The combined CH2Cl2 extracts were washed with H2O, dried (Na2SO4),
and evaporated to give a residual solid which was purified by CC on silica gel using CH2Cl2/acetone 5 :1. The
proper fractions were combined and evaporated, furnishing a residual solid, which was crystallized from CH2Cl2

Helvetica Chimica Acta ± Vol. 83 (2000)
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to afford 4a (0.60 g, 70%). Colorless crystals. M.p. 178 ± 1798. UV (0.1n HCl/MeOH): 249 (3.99), 284 (3.63). UV
(MeOH): 249 (3.95), 285 (3.58). UV (0.1n NaOH/MeOH): 249 (3.98), 284 (3.63). 1H-NMR (CDCl3): 1.58
(s, Me); 2.59 ± 2.63 (m, 2 H C(3)); 2.81 (dt, J ˆ 17.2, 2.8, 1 H C(3')); 2.93 ± 2.97 (m, 2 H C(4)); 3.16 (dt, J ˆ
16.8, 2.4, 1 H C(3')); 3.95, 4.09 (2d, J ˆ 9.6, AB type, CH2O); 5.75 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.37 (t, J ˆ 2.4,
1 H, CH2ˆC(4')); 6.72 ± 6.94 (m, 3 arom. H); 7.55 (br. s, NH). 13C-NMR (CDCl3): 23.95 (Me); 25.36 (C(4));
30.53 (C(3)); 37.01 (C(3')); 73.66 (CH2O); 81.11 (C(2')); 109.93; 120.88; 122.48; 122.64; 124.48; 126.62; 135.27;
144.32 (C(8)); 169.16 (C(5')); 170.09 (C(2)). Anal. calc. for C16H17NO4: C 66.88, H 5.92, N 4.88; found: C 66.71,
H 6.05, N 4.88.
The same procedure was used to convert each of the compounds 2b ± f and 3b ± f to the follow-up products
4b ± f; 7a ± e and 7g to 9a ± e and 9g; and 8a ± d to 10a ± d, resp.
3,4-Dihydro-8-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]quinolin-2(1H)-one
(4b). Yield: 65%. M.p. 212 ± 2138. UV (0.1n HCl/MeOH): 249 (4.00), 284 (3.61). UV (MeOH): 249 (3.97), 285
1
(3.57). UV (0.1n NaOH/MeOH): 249 (4.00), 284 (3.63). H-NMR (CDCl3): 2.54 ± 2.62 (m, 2 H C(3)); 2.89 ±
2.97 (m, 2 H C(4)); 3.25 (dt, J ˆ 16.8, 3.0, 1 H C(3')); 3.64 (dt, J ˆ 16.8, 2.2, 1 H C(3')); 4.13, 4.27 (2d, J ˆ
10.2, AB type, CH2O); 5.82 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.44 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.64 ± 7.49
(m, 8 arom. H); 7.45 (br. s, NH). 13C-NMR (CDCl3): 25.35 (C(4)); 30.51 (C(3)); 37.61 (C(3')); 75.10 (CH2O);
84.07 (C(2')); 110.11; 120.96; 122.33; 122.53; 124.50; 124.93; 126.74; 128.73; 128.79; 128.90; 134.89; 139.65;
144.26 (C(8)); 168.78 (C(5')); 169.95 (C(2)). Anal. calc. for C21H19NO4: C 72.19, H 5.48, N 4.01; found: C 72.07,
H 5.62, N 4.02.
8-{[2-(4-Fluorophenyl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (4c). Yield: 66%. M.p. 168 ± 1698. UV (0.1n HCl/MeOH). 249 (4.00), 284 (3.61). UV (MeOH): 249
(4.00), 285 (3.59). UV (0.1n NaOH/MeOH). 249 (4.02), 285 (3.64). 1H-NMR (CDCl3): 2.57 ± 2.62
(m, 2 H C(3)); 2.91 ± 2.96 (m, 2 H C(4)); 3.22 (dt, J ˆ 16.8, 3.2, 1 H C(3')); 3.62 (dt, J ˆ 16.8, 2.4,
1 H C(3')); 4.10, 4.24 (2d, J ˆ 10.4, AB type, CH2O); 5.83 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.45 (t, J ˆ 2.8, 1 H,
CH2ˆC(4')); 6.66 ± 7.49 (m, 7 arom. H); 7.45 (br. s, NH). 13C-NMR (CDCl3): 25.37 (C(4)); 30.51 (C(3)); 37.66
(C(3')); 75.04 (CH2O); 83.65 (C(2')); 110.13; 115.83; 116.04; 121.09; 122.57; 122.63; 124.58; 126.76; 126.87;
126.96; 134.65; 135.53; 135.57; 144.18 (C(8)); 161.49; 163.96; 168.57 (C(5')); 169.97 (C(2)). Anal. calc. for
C21H18FNO4: C 68.65, H 4.94, N 3.81; found: C 68.58, H5.01, N 3.83.
8-{[2-(1,1'-Biphenyl-4-yl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (4d). Yield: 68%. M.p. 162 ± 1638. UV (0.1n HCl/MeOH). 251 (4.66). UV (MeOH): 250 (4.61). UV
(0.1n NaOH/MeOH): 250 (4.64). 1H-NMR (CDCl3): 2.57 ± 2.62 (m, 2 H C(3)); 2.91 ± 2.96 (m, 2 H C(4));
3.29 (dt, J ˆ 17.2, 2.8, 1 H C(3')); 3.66 (dt, J ˆ 16.8, 2.4, 1 H C(3')); 4.16, 4.31 (2d, J ˆ 10.0, AB type, CH2O);
5.84 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.46 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.68 ± 7.69 (m, 12 arom. H); 7.49 (br. s, NH).
13C-NMR (CDCl3): 25.37 (C(4)); 30.53 (C(3)); 37.62 (C(3')); 75.07 (CH2O); 84.03 (C(2')); 110.18; 121.01;
122.46; 122.56; 124.54; 125.45; 126.79; 127.10; 127.59; 127.72; 128.88; 134.85; 138.55; 140.08; 141.76; 144.29
(C(8)); 168.77 (C(5')); 169.97 (C(2)). Anal. calc. for C27H23NO4: C 76.22, H 5.45, N 3.29; found: C 75.84, H 5.60,
N 3.30.
3,4-Dihydro-8-{[2,3,4,5-tetrahydro-2-(4-methoxyphenyl)-4-methylidene-5-oxofuran-2-yl]methoxy}quinolin-
2(1H)-one (4e). Yield: 70%. M.p. 148 ± 1498. UV (0.1n HCl/MeOH): 249 (4.08), 280 (3.77). UV (MeOH): 249
(4.09), 280 (3.76): UV (0.1n NaOH/MeOH): 249 (4.09), 280 (3.78). 1H-NMR (CDCl3): 2.54 ± 2.63
(m, 2 H C(3)); 2.90 ± 2.98 (m, 2 H C(4)); 3.23 (dt, J ˆ 16.9, 3.1, 1H C(3')); 3.59 (dt, J ˆ 16.8, 2.2,
1 H C(3')); 3.83 (s, MeO); 4.08, 4.24 (2d, AB type, J ˆ 10.2, CH2O); 5.81 (t, J ˆ 2.7, 1 H, CH2ˆC(4')); 6.43
(t, J ˆ 2.5, 1 H, CH2ˆC(4')); 6.64 ± 7.44 (m, 7 arom. H); 7.36 (br. s, NH). 13C-NMR (CDCl3): 25.36 (C(4)); 30.53
(C(3)); 37.61 (C(3')); 55.36 (MeO); 75.13 (CH2O); 83.96 (C(2')); 110.12; 112.28; 114.25; 120.93; 122.24; 122.53;
124.48; 126.30; 126.75; 131.60; 135.07; 144.29 (C(8)); 159.80; 168.87 (C(5')); 169.95 (C(2)). Anal. calc. for
C22H21NO5: C 69.64, H 5.58, N 3.69; found: C 69.49, H 5.68, N 3.69.
3,4-Dihydro-8-{[2,3,4,5-tetrahydro-4-methylidene-2-(4-nitrophenyl)-5-oxofuran-2-yl]methoxy}quinolin-
2(1H)-one (4f). Yield: 66%. M.p. 192 ± 1938. UV (0.1n HCl/MeOH): 252 (4.14). UV (MeOH): 252 (4.14). UV
(0.1n NaOH/MeOH): 252 (4.14). 1H-NMR (CDCl3): 2.55 ± 2.63 (m, 2 H C(3)); 2.91 ± 2.98 (m, 2 H C(4));
3.23 (dt, J ˆ 16.8, 3.0, 1 H C(3')); 3.70 (dt, J ˆ 16.9, 2.2, 1 H C(3')); 4.18, 4.29 (2d, J ˆ 10.2, AB type, CH2O);
5.88 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.48 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.65 ± 8.34 (m, 7 arom. H); 7.44 (br. s, NH).
13C-NMR (CDCl3): 25.34 (C(4)); 30.46 (C(3)); 37.52 (C(3')); 74.60 (CH2O); 83.37 (C(2')); 110.20; 121.38;
122.63; 123.46; 124.16; 124.72; 126.23; 126.76; 133.71; 143.97 (C(8)); 146.54; 148.06; 168.05 (C(5')); 169.98
(C(2)). Anal. calc. for C21H18N2O6: C 63.96, H 4.60, N 7.10; found: C 63.78, H 4.67, N 7.07.
3,4-Dihydro-6-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)methoxy]quinolin-2(1H)-one
(9a). Yield: 81%. M.p. 135 ± 1368. UV (0.1n HCl/MeOH): 255 (4.18). UV (MeOH): 255 (4.20). UV (0.1n

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Helvetica Chimica Acta ± Vol. 83 (2000)
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NaOH/MeOH): 255 (4.21). H-NMR (CDCl3): 1.54 (s, Me); 2.56 ± 2.64 (m, 2 H C(3)); 2.73 (dt, J ˆ 16.1, 2.8,
1 H C(3')); 2.88 ± 2.96 (m, 2 H C(4)); 3.17 (dt, J ˆ 17.0, 2.6, 1H C(3')); 3.88, 3.96 (2d, J ˆ 9.7, AB type,
CH2O); 5.66 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.27 (t, J ˆ 2.9, 1 H, CH2ˆC(4')); 6.69 ± 6.71 (m, 3 arom. H); 8.32
(br. s, NH). 13C-NMR (CDCl3): 24.07 (Me); 25.55 (C(4)); 30.49 (C(3)); 36.61 (C(3')); 73.42 (CH2O); 81.41
(C(2')); 113.23; 114.75; 116.24; 121.95; 125.05; 131.54; 135.35; 154.20 (C(6)); 169.58 (C(5')); 171.64 (C(2)). Anal.
calc. for C16H17NO4; C 66.88, H 5.92, N 4.88; found: C 66.87, H 5.97, N 4.87.
3,4-Dihydro-6-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]quinolin-2(1H)-one
(9b). Yield: 90%. M.p. 113 ± 1148. UV (0.1n HCl/MeOH): 255 (4.21). UV (MeOH): 256 (4.22). UV (0.1n
NaOH/MeOH): 255 (4.22). 1H-NMR (CDCl3): 2.54 ± 2.62 (m, 2 H C(3)); 2.85 ± 2.93 (m, 2 H C(4)); 3.19
(dt, J ˆ 17.0, 2.9, 1 H C(3')); 3.65 (dt, J ˆ 16.8, 2.6, 1 H C(3')); 4.06, 4.13 (2d, J ˆ 10.2, AB type, CH2O); 5.68
(t, J ˆ 2.5, 1 H, CH2ˆC(4')); 6.29 (t, J ˆ 2.8, 1H, CH2ˆC(4')); 6.60 ± 7.47 (m, 8 arom. H); 8.91 (br. s, NH).
13C-NMR (CDCl3): 25.52 (C(4)); 30.46 (C(3)); 37.25 (C(3')); 74.87 (CH2O); 84.22 (C(2')); 113.35; 114.89;
116.17; 121.53; 125.01; 128.47; 128.72; 131.57; 134.91; 140.28; 154.12 (C(6)); 169.29 (C(5')); 171.56 (C(2)). Anal.
calc. for C21H19NO4: C 72.19, H 5.48, N 4.01; found: C 72.01, H 5.58, N 3.97.
6-{[2-(4-Fluorophenyl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (9c). Yield: 81%. M.p. 130 ± 1318. UV (0.1n HCl/MeOH): 255 (4.27). UV (MeOH): 255 (4.25). UV
(0.1n NaOH/MeOH): 255 (4.27). 1H-NMR (CDCl3): 2.55 ± 2.62 (m, 2 H C(3)); 2.86 ± 2.93 (m, 2 H C(4));
3.15 (dt, J ˆ 16.8, 2.9, 1 H C(3')); 3.63 (dt, J ˆ 16.9, 2.4, 1 H C(3')); 4.03, 4.10 (2d, J ˆ 10.2, AB type, CH2O);
5.69 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.30 (t, J ˆ 2.7, 1 H, CH2ˆC(4')); 6.60 ± 7.49 (m, 7 arom. H); 8.72 (br. s, NH).
13C-NMR (CDCl3): 25.56 (C(4)); 30.48 (C(3)); 37.35 (C(3')); 74.82 (CH2O); 83.81 (C(2')); 113.38; 114.93;
115.50; 115.93; 116.19; 121.93; 125.14; 126.91; 127.08; 131.67; 134.66; 136.15; 136.21; 154.04 (C(6)); 160.14;
165.07; 169.10 (C(5')); 171.49 (C(2)). Anal. calc. for C21H18FNO4: C 68.65, H4.94, N 3.81; found: C 68.39, H 5.04,
N 3.78.
6-{[(2-(1,1'-Biphenyl-4-yl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (9d). Yield: 90%. M.p. 206 ± 2078. UV (0.1n HCl/MeOH): 254 (4.35). UV (MeOH): 254 (4.36). UV
(0.1n NaOH/MeOH): 254 (4.36). 1H-NMR (CDCl3): 2.54 ± 2.62 (m, 2 H C(3)); 2.86 ± 2.93 (m, 2 H C(4));
3.22 (dt, J ˆ 16.9, 2.9, 1 H C(3')); 3.67 (dt, J ˆ 16.8, 2.4, 1 H C(3')); 4.10, 4.17 (2d, J ˆ 10.2, AB type, CH2O);
5.69 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.31 (t, J ˆ 2.7, 1 H, CH2ˆC(4')); 6.63 ± 7.67 (m, 12 arom. H); 8.71 (br. s, NH).
13C-NMR (CDCl3): 25.56 (C(4)); 30.49 (C(3)); 37.27 (C(3')); 74.84 (CH2O); 84.17 (C(2')); 113.42; 114.94;
116.17; 121.68; 125.11; 125.54; 127.07; 127.43; 127.68; 128.87; 131.61; 134.88; 139.21; 140.16; 141.49; 154.15 (C(6));
169.28 (C(5')); 171.46 (C(2)). Anal. calc. for C27H23NO4: C 76.22, H 5.45, N 3.29; found: C 75.98, H 5.49, N 3.29.
3,4-Dihydro-6-{[2,3,4,5-tetrahydro-2-(4-methoxyphenyl)-4-methylidene-5-oxofuran-2-yl]methoxy}quinolin-
2(1H)-one (9e). Yield: 74%. M.p. 128 ± 1298. UV (0.1n HCl/MeOH): 255 (4.22). UV (MeOH): 256 (4.23). UV
(0.1n NaOH/MeOH): 255 (4.22). 1H-NMR (CDCl3): 2.54 ± 2.62 (m, 2 H C(3)); 2.86 ± 2.93 (m, 2 H C(4));
3.16 (dt, J ˆ 16.9, 2.9, 1 H C(3')); 3.61 (dt, J ˆ 16.9, 2.4, 1 H C(3')); 3.82 (s, MeO); 4.02, 4.10 (2d, J ˆ 10.2, AB
type, CH2O); 5.67 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.28 (t, J ˆ 2.7, 1 H, CH2ˆC(4')); 6.61 ± 7.41 (m, 7 arom. H); 8.60
(br. s, NH). 13C-NMR (CDCl3): 25.54 (C(4)); 30.48 (C(3)); 37.22 (C(3')); 55.32 (MeO); 74.90 (CH2O); 84.11
(C(2')); 113.36; 114.06; 114.91; 116.09; 121.43; 125.07; 126.35; 131.51; 132.26; 135.09; 154.15 (C(6)); 159.61;
169.36 (C(5')); 171.36 (C(2)). Anal. calc. for C22H21NO5: C 69.64, H 5.58, N 3.69; found: C 69.35, H 5.66, N3.65.
6-{[2-(4-Chlorophenyl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (9g). Yield: 85%. M.p. 169 ± 1708. UV (0.1n HCl/MeOH): 256 (4.28). UV (MeOH): 255 (4.31). UV
(0.1n NaOH/MeOH): 255 (4.29). 1H-NMR (CDCl3): 2.54 ± 2.62 (m, 2 H C(3)); 2.86 ± 2.93 (m, 2 H C(4));
3.14 (dt, J ˆ 16.9, 2.9, 1 H C(3')); 3.63 (dt, J ˆ 16.8, 2.4, 1 H C(3')); 4.03, 4.10 (2d, J ˆ 10.1, AB type, CH2O);
5.70 (t, J ˆ 2.5, 1 H, CH2ˆC(4')); 6.30 (t, J ˆ 2.9, 1 H, CH2ˆC(4')); 6.60 ± 7.41 (m, 7 arom. H); 8.65 (br. s, NH).
13C-NMR (CDCl3): 25.56 (C(4)); 30.48 (C(3)); 37.26 (C(3')); 74.65 (CH2O); 83.71 (C(2')); 113.37; 114.93;
116.16; 122.07; 122.15; 126.55; 128.94; 131.70; 134.46; 134.55; 138.85; 153.99 (C(6)); 168.99 (C(5')); 171.42
(C(2)). Anal. calc. for C21H18ClNO4: C 65.71, H 4.72, N 3.65; found: C 65.46, H 4.77, N 3.63.
6-{[2-(4-Bromophenyl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (9h). Yield: 91%. M.p. 167 ± 1688. UV (0.1n HCl/MeOH): 255 (4.15). UV (MeOH): 255 (4.15). UV
(0.1n NaOH/MeOH): 255 (4.15). 1H-NMR (CDCl3): 2.57 ± 2.60 (m, 2H C(3)); 2.87 ± 2.91 (m, 2 H C(4)); 3.14
(dt, J ˆ 16.8, 2.8, 1 H C(3')); 3.62 (dt, J ˆ 16.8, 2.4, 1 H C(3')); 4.04, 4.09 (2d, J ˆ 10.0, AB type, CH2O); 5.70
(t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.30 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.61 ± 7.57 (m, 7 arom. H); 8.84 (br. s, NH).
13C-NMR (CDCl3): 25.53 (C(4)); 30.46 (C(3)); 37.20 (C(3')); 74.57 (CH2O); 83.72 (C(2')); 113.36; 114.90;
116.19; 122.08; 122.66; 125.12; 126.84; 131.71; 131.88; 134.41; 139.37; 153.97 (C(6)); 168.95 (C(5')); 171.49
(C(2)). Anal. calc. for C21H18BrNO4: C 58.89, H 4.24, N 3.27; found: C 58.70, H 4.21, N 3.25.

Helvetica Chimica Acta ± Vol. 83 (2000)
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3,4-Dihydro-7-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)methoxy]quinolin-2(1H)-one
(10a). Yield: 77%. M.p. 138 ± 1398. UV (0.1n HCl/MeOH): 251 (4.09). UV (MeOH): 251 (4.06). UV (0.1n
NaOH/MeOH): 251 (4.09). 1H-NMR (CDCl3): 1.54 (s, Me); 2.58 ± 2.65 (m, 2H C(3)); 2.73 (dt, J ˆ 17.2, 2.9,
1H C(3')); 2.86 ± 2.93 (m, 2 H C(4)); 3.16 (dt, J ˆ 17.1, 2.6, 1 H C(3')); 3.89, 3.97 (2d, J ˆ 9.6, AB type,
CH2O); 5.66 (t, J ˆ 2.5, 1 H, CH2ˆC(4')); 6.27 (t, J ˆ 2.7, 1 H, CH2ˆC(4')); 6.36 ± 7.06 (m, 3 arom. H); 8.88
(br. s, NH). 13C-NMR (CDCl3): 24.12 (Me); 24.53 (C(4)); 30.93 (C(3)); 36.62 (C(3')); 73.00 (CH2O); 81.37
(C(2')); 102.46; 108.69; 116.64; 122.13; 128.67; 135.23; 138.29; 157.84 (C(7)); 169.54 (C(5')); 172.11 (C(2)). Anal.
calc. for C16H17NO4: C 66.88, H 5.92, N 4.88; found: C 66.81, H 6.01, N4.91.
3,4-Dihydro-7-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]quinolin-2(1H)-one
(10b). Yield: 84%. M.p. 70 ± 718. UV (0.1n HCl/MeOH): 251 (4.01). UV (MeOH): 251 (3.96); UV (0.1n NaOH/
MeOH): 251 (4.05). 1H-NMR (CDCl3): 2.55 ± 2.63 (m, 2 H C(3)); 2.84 ± 2.91 (m, 2 H C(4)); 3.18 (dt, J ˆ 17.0,
2.9, 1H C(3')); 3.64 (dt, J ˆ 16.9, 2.4, 1 H C(3')); 4.07, 4.15 (2d, J ˆ 10.2, AB type, CH2O); 5.67 (t, J ˆ 2.5, 1 H,
CH2ˆC(4')); 6.29 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.43 ± 7.50 (m, 8 arom. H); 8.39 (br. s, NH). 13C-NMR (CDCl3):
24.53 (C(4)); 30.91 (C(3)); 37.26 (C(3')); 74.46 (CH2O); 84.16 (C(2')); 102.53; 108.84; 116.80; 121.69; 125.04;
128.50; 128.70; 128.74; 134.81; 138.20; 140.25; 157.76 (C(7)); 169.25 (C(5')); 171.77 (C(2)). Anal. calc. for
C21H19NO4: C 72.19, H 5.48, N 4.01; found: C 72.05, H 5.49, N 4.00.
7-{[2-(4-Fluorophenyl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (10c). Yield: 80%. M.p. 117 ± 1188. UV (0.1n HCl/MeOH): 251 (3.96). UV (MeOH): 252 (3.92). UV
(0.1n NaOH/MeOH): 252 (3.98). 1H-NMR (CDCl3): 2.57 ± 2.61 (m,2 H C(3)); 2.85 ± 2.89 (m, 2 H C(4)); 3.15
(dt, J ˆ 17.2, 2.8, 1 H C(3')); 3.62 (dt, J ˆ 16.8, 2.8, 1 H C(3')); 4.05, 4.11 (2d, J ˆ 10.4, AB type, CH2O); 5.69
(t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.30 (t, J ˆ 2.8, 1 H, CH2ˆC(4')); 6.32 ± 7.47 (m, 7 arom. H); 8.77 (br. s, NH).
13C-NMR (CDCl3): 24.50 (C(4)); 30.86 (C(3)); 37.31 (C(3')); 74.34 (CH2O); 83.75 (C(2')); 102.56; 108.88;
115.57; 115.78; 116.18; 116.87; 122.06; 126.96; 127.04; 128.69; 134.52; 136.11; 136.14; 138.25; 157.65 (C(7));
161.35; 163.81; 169.06 (C(5')); 172.02 (C(2)). Anal. calc. for C21H18FNO4 ´ H2O: C 65.45, H 5.23, N 3.64; found:
C 65.75, H 5.26, N 3.65.
7-{[2-(1,1'-Biphenyl-4-yl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-
2(1H)-one (10d). Yield: 83%. M.p. 101 ± 1028. UV (0.1n HCl/MeOH): 251 (4.47). UV (MeOH): 251 (4.49). UV
(0.1n NaOH/MeOH): 252 (4.40). 1H-NMR (CDCl3): 2.55 ± 2.58 (m,2H C(3)); 2.84 ± 2.88 (m, 2 H C(4)); 3.22
(dt, J ˆ 16.8, 2.9, 1 H C(3')); 3.66 (dt, J ˆ 16.8, 2.5, 1 H C(3')); 4.11, 4.19 (2d, J ˆ 10.2, AB type, CH2O); 5.69
(t, J ˆ 2.6, 1 H, CH2ˆC(4')); 6.31 (t, J ˆ 2.4, 1 H, CH2ˆC(4')); 6.32 ± 7.67 (m, 12 arom. H); 8.46 (br. s, NH).
13C-NMR (CDCl3): 24.56 (C(4)); 30.92 (C(3)); 37.27 (C(3')); 74.39 (CH2O); 84.12 (C(2')); 102.56; 108.86;
116.83; 121.85; 125.56; 127.09; 127.43; 127.67; 128.72; 128.87; 134.77; 138.24; 139.17; 140.17; 141.50; 157.77
(C(7)); 169.25 (C(5')); 171.81 (C(2)). Anal. calc. for C27H23NO4: C76.22, H 5.45, N 3.29; found: C 76.25, H 5.47,
N 3.28.
Antiplatelet-Activity Evaluation. Reagents: Collagen (type I, bovine Achilles tendon), obtained from Sigma
Chem. Co., was homogenized in 25 mm AcOH and stored (1 mg/ml) at 708. Platelet-activating factor (PAF)
was purchased from Calbiochem-Behring Co. and dissolved in CHCl3. Arachidonic acid (AA), EDTA, and
bovine serum albumin were purchased from Sigma Chem. Co.
Platelet Aggregation. Blood was collected from the rabbit marginal ear vein, anticoagulated with EDTA
(6 mm) and centrifuged for 10 min at 90 Â g at r.t. A platelet suspension was prepared from this EDTA-
anticoagulated, platelet-rich plasma according to the washing procedures described in [11]. Platelet numbers
were counted with a Coulter counter (model ZM) and adjusted to 4.5 Â 108 platelets/ml. The platelet pellets
were finally suspended in Tyrodeꢀs soln. of the following composition (mm): NaCl (136.8), KCl (2.8), NaHCO3
(11.9), MgCl2 (2.1), NaH2PO4 (0.33), CaCl2 (1.0), and glucose (11.2), containing bovine serum albumin
(0.35%). The platelet suspension was stirred at 1200 rpm, and the aggregation was measured at 378 by the
turbidimetric method as described by OꢀBrien [12] with a Chrono-Log Lumi-aggregometer. To eliminate the
effect of the solvent on the aggregation, the final concentration of DMSO was fixed at 0.5%. Percentage of
aggregation was calculated from the absorbance of platelet suspension as 0% aggregation and the absorbance of
Tyrodeꢀs solution as 100% aggregation. The inhibitory concentration for 50% aggregation (IC50) was calculated
with CA Cricket Graph III for five or six dose-effect levels.
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Received August 25, 1999