Synthesis of 5-substituted 2-(4- or 3-methoxyphenyl)-4(1H)-quinolones

Article abstract of DOI:10.1016/j.tet.2003.09.094

5-Substituted 7-methoxy-2-(4- or 3-methoxyphenyl)-4(1H)-quinolones 8-17 have been synthesised in good yields from the corresponding 7-methoxy-2-(4- or 3-methoxyphenyl)-5-trifluoromethanesulfonate-4(1H)-quinolones 7 via palladium-mediated cross-coupling re

Full text of DOI:10.1016/j.tet.2003.09.094

Tetrahedron 59 (2003) 9627–9633
Synthesis of 5-substituted
2-(4- or 3-methoxyphenyl)-4(1H)-quinolones
a
Christophe Pain, Sylvain Celanire, Gerald Guillaumet and Benoıt Joseph
a
a
a,b
,
*
´
´
ˆ
a
´
´
´
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Universite d’Orleans, B.P. 6759, 45067 Orleans Cedex 2, France
´ ˆ
Laboratoire de Chimie Organique 1, UMR-CNRS 5622, Universite Claude Bernard-Lyon 1, CPE-Batiment 308,
b
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Received 19 June 2003; revised 5 September 2003; accepted 29 September 2003
Abstract—5-Substituted 7-methoxy-2-(4- or 3-methoxyphenyl)-4(1H)-quinolones 8–17 have been synthesised in good yields from the
corresponding 7-methoxy-2-(4- or 3-methoxyphenyl)-5-trifluoromethanesulfonate-4(1H)-quinolones 7 via palladium-mediated cross-
coupling reactions or aromatic nucleophilic substitution (SNAr) reactions.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
our knowledge, no example of 5-Csp2- or N-substituted
2-phenyl-4(1H)-quinolones has been mentioned in the
literature.
Substituted 2-phenyl-4-quinolones displayed potent anti-
tumor activity with effects similar to those observed with the
antimitotic natural products colchicine, podophyllotoxin
and combretastatin A-4.1 Most notably, 2-(2-fluorophenyl)-
6-(1-pyrrolidinyl)-4(1H)-quinolone I (Fig. 1) is a highly
effective inhibitor of tubulin polymerisation (IC50¼
0.46 mM) and inhibits the growth of tumor cell lines at
low concentrations.2 Three-dimensional structure-activity
relationship studies were also performed to predict novel
inhibitors of tubulin polymerisation.3 2-Phenyl-4-quino-
lones were also described as topoisomerase inhibitors,4
antiplatelet agents5 or inosine 50-monophosphate dehydro-
genase type II inhibitors (IMPDH) such as 7-methoxy-2-(4-
methoxyphenyl)-6-(5-oxazolyl)-4(1H)-quinolone II.6 To
In a previous patent,7 we reported the syntheses of 5-substi-
tuted 3-(4-methoxyphenyl)-4(1H)-quinolones via either
palladium-catalysed reactions or aromatic nucleophilic
substitution reactions. According to the same approach,
we have developed the syntheses of series of new 7-meth-
oxy-2-phenyl-4(1H)-quinolones III.
2. Results and discussion
These syntheses, first, require the preparation of 5,7-di-
methoxy-2-(4- or 3-methoxyphenyl)-4(1H)-quinolones 4.
Following the methodology described in the literature,8 the
4-quinolone nucleus was obtained in two steps. A mixture of
3,5-dimethoxyaniline 1 and ethyl 3-(4-methoxyphenyl)-3-
oxo-propanoate 2a9 or ethyl 3-(3-methoxyphenyl)-3-oxo-
propanoate 2b9 in ethanol was heated under reflux for 25 h
in the presence of p-toluenesulfonic acid (p-TsOH) to give
the enamino esters 3 in fair yields.10 The synthesis of
4-quinolones 4 were achieved by simply heating 3 in xylene
at 2508C in a sealed tube for 8 h. It should be noted that the
increasing of the reaction time led directly to the 5-hydroxy
derivative 5. As described in Ref. 7, the methyl ether in
5-position was selectively cleaved in the presence of HBr
48% to afford 5 in 85–90% yield (Scheme 1).
Figure 1.
Keywords: quinolones; Stille reaction; Suzuki reaction; SNAr; aminations.
*
Corresponding author. Address: Laboratoire de Chimie Organique 1,
´
ˆ
UMR-CNRS 5622, Universite Claude Bernard-Lyon 1, CPE-Batiment
308, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex,
France. Tel.: þ33-4-72-44-81-35; fax: þ33-4-72-43-12-14; e-mail:
benoit.joseph@univ-lyon1.fr
Methylation of 5 with iodomethane in basic medium
(K2CO3) in DMF at room temperature afforded 6 in good
yield. Contrary to classical 2-phenyl-4-quinolone alkylation
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.094

9628
C. Pain et al. / Tetrahedron 59 (2003) 9627–9633
Scheme 1.
reaction in DMF,1a,2,5,11 N-methyl compounds 6 were found
the major products (N-methyl/O-methyl ratio: 9:1). The
4-quinolone structure was established from 13C NMR
chemical shift of methyl group and 1H NMR chemical
shift of proton in 3-position. Finally, triflates 7 were
obtained by treatment of 6 with trifluoromethanesulfonic
anhydride (3 equiv.) in the presence of pyridine in
dichloromethane (Scheme 1).
Table 2.
Compound
R1
R2
NR3R4
Yield (%)
83
12b
H
OMe
13a
13b
14a
14b
15a
OMe
H
H
82
84
90
89
79
Scheme 2.
Table 1.
OMe
H
Compound
A
Yield (%)
OMe
H
8
9
CH2vCH–
90
76
OMe
H
10
11
84
86
OMe
15b
16a
16b
H
OMe
H
79
82
80
OMe
H
OMe
Scheme 3.

C. Pain et al. / Tetrahedron 59 (2003) 9627–9633
9629
2.1. Palladium-mediated cross-coupling reactions
(40–63 mm) using the indicated solvents (petroleum ether:
boiling range 40–608C). All reactions requiring anhydrous
conditions were conducted in flame-dried apparatus.
Stannane and boronic acids were purchased from Lancaster
or Sigma-Aldrich.
First family of compounds was obtained through Stille12 or
Suzuki reactions13 on triflate 7b. The latter were performed
in classical conditions with freshly prepared tetrakis-
(triphenylphosphine)palladium (6% mol) to led to the
desired derivatives 8–11 (Scheme 2, Table 1). Coupling
reaction between 7b and commercially available vinyl-
tributyltin (1.5 equiv.) afforded derivative 8 in good yield.
2-Thiophenyl, phenyl and 2-furanyl compounds 9–11 were
prepared by reaction of 7b with the corresponding boronic
acids (1.5 equiv.) (Table 1).
3.1.1. Ethyl 3-(3,5-dimethoxyanilino)-3-(4-methoxy-
phenyl)-2-propenoate (3a). A mixture of 3,5-dimethoxy-
aniline 1 (2.07 g, 13.51 mmol), ethyl 3-(4-methoxyphenyl)-
3-oxo-propanoate 2a (1.00 g, 4.48 mmol) and p-toluene-
sulfonic acid (200 mg) in anhydrous ethanol (20 mL) was
heated at reflux for 24 h. After cooling, the solvent was
evaporated. The residue was diluted with dichloromethane,
the organic phase was washed with water, then dried over
MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (eluent toluene) to
give 3a (916 mg, 57%) as an oil; IR (film) n 3356 (NH),
1638 (CO) cm21; 1H NMR (250 MHz, CDCl3) d 1.30 (t, 3H,
J¼7.0 Hz, CH3), 3.56 (s, 6H, OCH3), 3.79 (s, 3H, OCH3),
4.20 (q, 2H, J¼7.0 Hz, CH2), 4.96 (s, 1H, vCH), 5.84
(d, 2H, J¼2.0 Hz, H-2, H-6), 6.004 (t, 1H, J¼2.0 Hz, H-4),
6.82 (d, 2H, J¼8.8 Hz, H-30, H-5 ), 7.31 (d, 2H, J¼8.8 Hz,
H-20, H-60), 10.20 (broad s, 1H, NH); 13C NMR
(62.90 MHz, CDCl3) d 14.5 (CH3), 55.1 (2CH3), 55.3
(CH3), 59.3 (CH2), 91.0 (CH), 95.5 (CH), 100.3 (2CH),
113.8 (2CH), 128.4 (C), 129.5 (2CH), 142.4 (C), 158.6 (C),
160.6 (2C), 170.1 (CO). Anal. calcd for C20H23NO5: C,
67.21; H, 6.49; N, 3.92. Found: C, 66.99; H, 6.65; N, 4.10;
MS m/z 358 (Mþ1)þ.
2.2. Aromatic nucleophilic substitution
Similarly, amination reaction of 7a–b with various amines
was carried out in a sealed tube to afford 12–16 (Scheme 3).
Optimal condition reactions were obtained with 5 equiv. of
amine in 1,4-dioxane for t h depending of the amine used
(see Section 3). The solution was heated in a range of
100–1208C. Thus, several amines such as pyrrolidine,
piperidine, N-methylpiperazine, N,N-dimethylaminoethyl-
amine and 4-methoxybenzylamine were introduced at the
5-position in good yields (Table 2).
Finally, the cleavage of the nitrogen-protecting group was
performed on 16a–b in the presence of trifluoroacetic acid
at 658C for 1 h to afford 17a–b in fair yield (Scheme 4).
3.1.2. Ethyl 3-(3,5-dimethoxyanilino)-3-(3-methoxy-
phenyl)-2-propenoate (3b). The same procedure applied
to 2b gave 3b in 58% yield. Oil; IR (film) n 3267 (NH), 1659
1
(CO) cm21; H NMR (250 MHz, CDCl3) d 1.32 (t, 3H,
J¼7.0 Hz, CH3), 3.56 (s, 6H, OCH3), 3.72 (s, 3H, OCH3),
4.21 (q, 2H, J¼7.0 Hz, CH2), 5.00 (s, 1H, vCH), 5.83
(d, 2H, J¼2.1 Hz, H-2, 0H-6),06.04 (t, 1H, J¼2.1 Hz, H-4),
6.92 (m, 3H, H-20, H-4 , H-6 ), 7.19 (m, 1H, H-50), 10.24
(broad s, 1H, NH); 13C NMR (62.90 MHz, CDCl3) d 14.7
(CH3), 55.3 (2CH3), 55.5 (CH3), 59.5 (CH2), 91.6 (CH),
95.9 (CH), 100.3 (2CH), 113.4 (CH), 115.6 (CH), 120.7
(CH), 128.4 (CH), 129.7 (C), 137.7 (C), 142.2 (C), 158.6
(C), 160.8 (2C), 170.1 (CO). Anal. calcd for C20H23NO5: C,
67.21; H, 6.49; N, 3.92. Found: C, 67.55; H, 6.57; N, 3.77;
MS m/z 358 (Mþ1)þ.
Scheme 4.
To conclude, we have described versatile syntheses of
5-substituted 2-(4-or 3-methoxyphenyl)-4-quinolones 8–17
from triflates 7 through palladium-mediated cross-coupling
reactions or aromatic nucleophilic substitution (SNAr)
reactions.
3.1.3. 5,7-Dimethoxy-2-(4-methoxyphenyl)-1,4-dihydro-
4-quinolinone (4a). A mixture of 3a (300 mg, 0.84 mmol)
in xylene (8 mL) in a high-pressure reactor was heated at
240–2508C for 8 h. During the cooling, the final product 4a
precipitates in the medium. Filtration afforded 112 mg
of desired compound 4a as white solid. The filtrate was
evaporated in vacuo. The residue was purified by column
chromatography (eluent CH2Cl2/MeOH 98:2) to give 50 mg
(62% overall yield) of 4a. Mp 225–2268C (xylene); IR
(KBr) n 3275 (NH), 1638 (CO) cm21; 1H NMR (250 MHz,
CDCl3) d 3.61 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.70
(s, 3H, OCH3), 6.17 (d, 1H, J¼2.0 Hz, H-6 or H-8), 6.42 (s,
1H, H-3), 6.76 (d, 2H, J¼8.8 Hz, H-30, H-50), 7.110(d, 1H,
J¼2.0 Hz, H-6 or H-8), 7.77 (d, 2H, J¼8.8 Hz, H-2 , H-60),
11.70 (broad s, 1H, NH); 13C NMR (62.90 MHz, CDCl3) d
55.2 (OCH3), 55.3 (OCH3), 55.4 (OCH3), 93.2 (CH), 95.3
(CH), 108.1 (CH), 110.3 (C), 114.1 (2CH), 126.3 (C), 128.7
3. Experimental
3.1. General experimental procedures
Melting points were determined using a Bu¨chi capillary
instrument and are uncorrected. The infrared spectra of
compounds were recorded on a Perkin–Elmer FTIR
paragon 1000 spectrometer. NMR spectra were recorded
at 300 K in CDCl3 on a Bruker Avance DPX 250. Chemical
shifts are expressed in parts per million relative to
tetramethylsilane (TMS). Mass spectra were recorded on
Perkin–Elmer SCIEX API 300 using ionspray method-
ology. Thin-layer chromatography (TLC) was run on
precoated silica gel plates (Merck 60F254) and the spots
visualised using an ultraviolet lamp. Flash chromatography
was carried out on column using flash silica gel 60 Merck

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C. Pain et al. / Tetrahedron 59 (2003) 9627–9633
(2CH), 146.0 (C), 149.9 (C), 160.2 (C), 161.1 (C), 162.5
(C), 177.4 (CO). Anal. calcd for C18H17NO4: C, 69.44; H,
5.50; N, 4.50. Found: C, 69.13; H, 5.40; N, 4.25; MS m/z
312 (Mþ1)þ.
5a (310 mg, 1.04 mmol) in DMF (10 mL) was added
K2CO3 (288 mg, 2.08 mmol) then iodomethane (0.13 mL,
2.09 mmol). The final mixture was stirred at room
temperature for 4 h. After evaporation of solvent, the
residue was diluted with CH2Cl2, the organic phase was
washed with water, then dried over MgSO4, and concen-
trated in vacuo. The solid obtained was recrystallised from
methanol to afford 6a (227 mg, 70%). Mp 176–1778C
(MeOH); IR (KBr) n 1642 (CO) cm21; 1H NMR (250 MHz,
CDCl3) d 3.51 (s, 3H, NCH3), 3.88 (s, 3H, OCH3), 3.89 (s,
3H, OCH3), 6.10 (s, 1H, H-3), 6.29 (d, 1H, J¼2.0 Hz, H-6 or
H-8), 6.39 (d, 0 1H, J¼2.0 Hz, H-6 or H-8), 7.01 (d, 2H,
J¼8.8 Hz, H-3 , H-50), 7.32 (d, 2H, J¼8.8 Hz, H-20, H-60),
15.02 (sharp s, 1H, OH); 13C NMR (62.90 MHz, CDCl3) d
38.0 (NCH3), 55.6 (OCH3), 55.7 (OCH3), 90.6 (CH), 96.3
(CH), 108.9 (C), 110.6 (CH), 114.4 (2CH), 127.8 (C), 130.1
(2CH), 144.1 (C), 155.3 (C), 160.8 (C), 164.5 (C), 164.7
(C), 180.9 (CO). Anal. calcd for C18H17NO4: C, 69.44; H,
5.50; N, 4.50. Found: C, 69.27; H, 5.67; N, 4.47; MS m/z
312 (Mþ1)þ.
3.1.4. 5,7-Dimethoxy-2-(3-methoxyphenyl)-1,4-dihydro-
4-quinolinone (4b). The same procedure was carried out
with 3b to afford 4b in 60% yield. Mp 221–2228C (MeOH);
;
IR (KBr) n 3277 (NH), 1637 (CO) cm21 1H NMR
(250 MHz, DMSO-d6) d 3.78 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 6.12 (s, 1H, H-3), 6.33 (d, 1H,
J¼2.0 Hz, H-6 or H-8), 6.81 (d, 1H, J¼2.0 Hz, H-6 or H-8),
7.10 (broad d, 1H, J¼7.8 Hz, H-40), 7.33–7.35 (m, 2H, H-20,
H-60), 7.45 (t, 1H, J¼7.8 Hz, H-50), 11.12 (broad s, 1H, NH);
13C NMR (62.90 MHz, DMSO-d6) d 55.3 (OCH3), 55.4
(OCH3), 55.6 (OCH3), 92.0 (CH), 94.5 (CH), 109.4 (CH),
110.5 (C), 112.3 (CH), 115.9 (CH), 119.2 (CH), 130.1 (CH),
135.1 (C), 144.7 (C), 147.1 (C), 159.5 (C), 160.8 (C), 162.0
(C), 176.5 (CO). Anal. calcd for C18H17NO4: C, 69.44; H,
5.50; N, 4.50. Found: C, 69.77; H, 5.65; N, 4.61; MS m/z
312 (Mþ1)þ.
3.1.8. 5-Hydroxy-7-methoxy-2-(3-methoxyphenyl)-1-
methyl-1,4-dihydro-4-quinolinone (6b). The same pro-
cedure afforded 6b in 90% yield. Mp 210–2118C (MeOH);
IR (KBr) n 1654 (CO) cm21; 1H NMR (250 MHz, CDCl3) d
3.48 (s, 3H, NCH3), 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
6.10 (s, 1H, H-3), 6.31 (d, 1H, J¼2.0 Hz, H-6 or H-8), 6.41
(d, 1H, J¼2.0 Hz, H-6 or H-8), 6.91 (d, 1H, J¼1.8 Hz,
H-20), 6.95 (d, 1H, J¼7.7 Hz, H-60), 7.04 (dd, 1H, J¼1.8,
7.7 Hz, H-40), 7.41 (t, 1H, J¼7.7 Hz, H-50), 15.02 (sharp s,
1H, OH); 13C NMR (62.90 MHz, CDCl3) d 37.9 (NCH3),
55.6 (OCH3), 55.7 (OCH3), 90.7 (CH), 96.4 (CH), 109.0
(C), 110.4 (CH), 114.3 (CH), 115.4 (CH), 120.8 (CH), 130.2
(CH), 136.8 (C), 144.1 (C), 155.1 (C), 159.9 (C), 164.7 (C),
164.8 (C), 181.0 (CO). Anal. calcd for C18H17NO4: C,
69.44; H, 5.50; N, 4.50. Found: C, 69.77; H, 5.55; N, 4.36;
MS m/z 312 (Mþ1)þ.
3.1.5. 5-Hydroxy-7-methoxy-2-(4-methoxyphenyl)-1,4-
dihydro-4-quinolinone (5a). Compound 4a (360 mg,
1.15 mmol), HBr 48% in water (0.50 mL) in DMF
(10 mL) was stirred at 908C for 2.5 h. After cooling, the
solution was poured on ice. The precipitate was filtered
and washed with water. The solid obtained was dried over
P2O5 in vacuo to give 5a (292 mg, 85%). Mp.2708C
(EtOAc/petroleum ether); IR (KBr) n 3307 (OH), 3260
1
(NH), 1657 (CO) cm21; H NMR (250 MHz, DMSO-d6) d
3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.17 (d, 1H,
J¼2.0 Hz, H-6 or H-8), 6.27 (s, 1H, H-3), 6.66 (d, 1H,
J¼2.0 Hz, H-6 or H-8), 7.13 (d, 02H, J¼8.8 Hz, H-30, H-50),
7.82 (d, 2H, J¼8.8 Hz, H-20, H-6 ), 11.80 (broad s, 1H, NH),
14.77 (sharp s, 1H, OH); 13C NMR (62.90 MHz, DMSO-d6)
d 55.4 (OCH3), 55.5 (OCH3), 90.4 (CH), 96.3 (CH), 104.4
(CH), 107.3 (C), 114.4 (2CH), 125.4 (C), 129.0 (2CH),
142.5 (C), 150.7 (C), 161.3 (C), 162.3 (C), 163.5 (C), 181.1
(CO). Anal. calcd for C17H15NO4: C, 68.68; H, 5.09; N,
4.71. Found: C, 68.95; H, 5.25; N, 4.62; MS m/z 298
(Mþ1)þ.
3.1.9. 7-Methoxy-2-(4-methoxyphenyl)-1-methyl-5-tri-
fluoromethanesufonate-1,4-dihydro-4-quinolinone (7a).
To a solution of compound 6a (590 mg, 1.90 mmol) and
pyridine (0.46 mL, 5.64 mmol) in anhydrous dichloro-
methane (15 mL) at 08C, was added a solution of
trifluoromethanesulfonic anhydride (0.95 mL, 5.62 mmol)
in anhydrous dichloromethane (5 mL). The mixture was
stirred for 2 h at room temperature, then water was added
and the mixture was extracted. The organic layer was
washed with saturated aqueous NaHCO3 solution, dried
over MgSO4 and evaporated in vacuo. The crude residue
was purified by column chromatography (eluent CH2Cl2/
MeOH 98:2) to afford 7a (563 mg, 67%). Mp 183–1858C
(MeOH); IR (KBr) n 1619 (CO) cm21; 1H NMR (250 MHz,
CDCl3) d 3.76 (s, 3H, NCH3), 3.81 (s, 3H, OCH3), 3.94 (s,
3H, OCH3), 6.13 (s, 1H, H-3), 6.71 (d, 1H, J¼2.0 Hz, H-6 or
H-8), 6.88 (d, 0 1H, J¼2.0 Hz, H-6 or H-8), 6.99 0(d, 2H,
J¼8.8 Hz, H-3 , H-50), 7.30 (d, 2H, J¼8.8 Hz, H-2 , H-60);
13C NMR (62.90 MHz, CDCl3) d 38.4 (NCH3), 55.6
(OCH3), 56.1 (OCH3), 99.7 (CH), 106.2 (CH), 114.4
(2CHþC), 114.5 (CH), 118.9 (q, J¼321 Hz, CF3), 127.6
(C), 130.1 (2CH), 145.4 (C), 149.6 (C), 154.2 (C), 160.8
(C), 161.8 (C), 175.5. (CO). Anal. calcd for C19H16F3NO6S:
C, 51.47; H, 3.64; N, 3.16. Found: C, 51.11; H, 3.54; N,
3.10; MS m/z 444 (Mþ1)þ.
3.1.6. 5-Hydroxy-7-methoxy-2-(3-methoxyphenyl)-1,4-
dihydro-4-quinolinone (5b). Following the procedure
used for the preparation of 5a, compound 5b was obtained
from 4b in 90% yield. Mp 245–2468C (MeOH); IR (KBr) n
3373 (OH), 3271 (NH), 1635 (CO) cm21
;
1H NMR
(250 MHz, DMSO-d6) d 3.82 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 6.19 (d, 1H, J¼2.0 Hz, H-6 or H-8), 6.34 (s, 1H,
H-3), 6.68 (d, 1H, J¼2.0 Hz, H-6 or H-8), 7.10 (broad d, 1H,
J¼7.9 Hz, H-40), 7.37 (broad s, 1H, H-20), 7.38 (d, 1H,
J¼7.9 Hz, H-60), 7.50 (t, 1H, J¼7.9 Hz, H-50), 11.88 (broad
s, 1H, NH), 14.67 (sharp s, 1H, OH); 13C NMR (62.90 MHz,
DMSO-d6) d 55.4 (OCH3), 55.5 (OCH3), 90.5 (CH), 96.5
(CH), 105.4 (CH), 107.5 (C), 112.8 (CH), 116.5 (CH), 119.6
(CH), 130.2 (CH), 134.8 (C), 142.5 (C), 150.8 (C), 159.5
(C), 162.3 (C), 163.6 (C), 181.3 (CO). Anal. calcd for
C17H15NO4: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.43; H,
4.88; N, 4.89; MS m/z 298 (Mþ1)þ.
3.1.7. 5-Hydroxy-7-methoxy-2-(4-methoxyphenyl)-1-
methyl-1,4-dihydro-4-quinolinone (6a). To a solution of

C. Pain et al. / Tetrahedron 59 (2003) 9627–9633
9631
3.1.10. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-tri-
fluoromethanesufonate-1,4-dihydro-4-quinolinone (7b).
Following the procedure used for the preparation of 7a,
compound 7b was obtained from 6b in 74% yield. Mp 153–
eluent: CH2Cl2/EtOAc 9:1; yield: 76%. Mp 205–2068C
(EtOAc); IR (KBr) n 1616 (CO) cm21; 1H NMR (250 MHz,
CDCl3) d 3.57 (s, 3H, NCH3), 3.85 (s, 3H, OCH3), 3.95 (s,
3H, OCH3), 6.14 (s, 1H, H-3), 6.93–7.04 (m, 7H, H-6, H-8,
H-20, H-40, H-60, 2HThien), 7.32 (dd, 1H, J¼1.7, 4.5 Hz,
HThien), 7.40 (t, 1H, J¼8.0 Hz, H-50); 13C NMR
(62.90 MHz, CDCl3) d 38.3 (NCH3), 55.6 (OCH3), 55.8
(OCH3), 100.2 (CH), 113.9 (CH), 114.4 (CH), 115.1 (CH),
116.3 (CH), 121.0 (CH), 125.1 (CHþC), 125.9 (CH), 126.3
(CH), 130.0 (CH), 137.1 (C), 138.0 (C), 144.1 (C), 145.3
(C), 153.2 (C), 159.8 (C), 161.0 (C), 176.9 (CO). Anal.
calcd for C22H19NO3S: C, 70.01; H, 5.07; N, 3.71. Found:
C, 69.85; H, 5.21; N, 3.88; MS m/z 378 (Mþ1)þ.
1548C (MeOH); IR (KBr) n 3070 (OH), 1621 (CO) cm21
;
1H NMR (250 MHz, CDCl3) d 3.54 (s, 3H, NCH3), 3.85 (s,
3H, OCH3), 3.95 (s, 3H, OCH3), 6.13 (s, 1H, H-3), 6.70 (d,
1H, J¼1.8 Hz, H-6 or H-8), 6.90 (d, 1H, J¼0 1.8 Hz, H-6 or
H-8), 6.92–7.06 (m, 3H, H-20, H-40, H-6 ), 7.39 (t, 1H,
J¼7.9 Hz, H-50); 13C NMR (62.90 MHz, CDCl3) d 38.3
(NCH3), 55.5 (OCH3), 56.1 (OCH3), 99.5 (CH), 106.4 (CH),
114.0 (CH), 114.2 (CHþC), 115.4 (CH), 119.0 (q, J¼
321 Hz, CF3), 120.7 (CH), 130.1 (CH), 136.4 (C), 145.2 (C),
149.4 (C), 154.0 (C), 159.8 (C), 161.8 (C), 175.4 (CO).
Anal. calcd for C19H16F3NO6S: C, 51.47; H, 3.64; N, 3.16.
Found: C, 51.77; H, 3.81; N, 2.97; MS m/z 444 (Mþ1)þ.
3.2.2. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-
phenyl-1,4-dihydro-4-quinolinone (10). Chromatography
eluent CH2Cl2/EtOAc 8:2; yield: 84%. Mp 206–2078C
(EtOAc); IR (KBr) n 1615 (CO) cm21; 1H NMR (250 MHz,
CDCl3) d 3.54 (s, 3H, NCH3), 3.83 (s, 3H, OCH3), 3.91 (s,
3H, OCH3), 6.07 (s, 1H, H-3), 6.78 (d, 1H, J¼2.3 Hz, H-6 or
H-8), 6.90 (d, 1H, 0J¼2.3 Hz, H-6 or H-8), 6.93–7.02 (m,
3.1.11. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-
vinyl-1,4-dihydro-4-quinolinone (8). To a suspension of
freshly prepared tetrakis(triphenylphosphine)palladium
(16 mg, 0.01 mmol) and LiCl (28 mg, 0.70 mmol) in
anhydrous DMF (2 mL) was added a solution of 7b
(104 mg, 0.23 mmol) and tributylvinyltin (0.1 mL,
0.34 mmol) in anhydrous DMF under argon. The final
solution was stirred at 908C for 1.5 h. The solvent was then
removed in vacuo and the crude residue was purified by
column chromatography (eluent CH2Cl2) to give 8 (68 mg,
90%) as a solid. Mp 176–1778C (EtOAc); IR (KBr) n 1611
3H, H-20, H-40, H-6 ), 7.28–7.41 (m, 6H, H-50, 5HPhen); 13
C
NMR (62.90 MHz, CDCl3) d 38.0 (CH3), 55.5 (CH3), 55.7
(CH3), 99.1 (CH), 113.9 (CH), 114.3 (CH), 114.8 (CH),
114.9 (CH), 118.7 (C), 120.9 (C), 126.5 (CH), 127.3 (2CH),
128.2 (2CH), 129.9 (CH), 137.2 (C), 143.3 (C), 145.2 (C),
146.0 (C), 153.1 (C), 159.7 (C), 161.1 (C), 177.3 (CO).
Anal. calcd for C24H21NO3: C, 77.61; H, 5.70; N, 3.77.
Found: C, 77.34; H, 5.67; N, 3.90; MS m/z 372 (Mþ1)þ.
1
(CO) cm21; H NMR (250 MHz, CDCl3) d 3.52 (s, 3H,
NCH3), 3.85 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 5.35 (dd,
1H, J¼1.8, 10.8 Hz, CH2v), 5.52 (dd, 1H, J¼1.8, 17.3 Hz,
CH2v), 6.18 (s, 1H, H-3), 6.82 (d, 1H, J¼2.2 Hz, H-6 or
H-8), 6.92–7.03 (m, 4H, H-6 or H-8, H-20, H-40, H-60), 7.39
(t, 1H, J¼7.9 Hz, H-50), 8.21 (dd, 1H, J¼10.8, 17.3 Hz,
vCH); 13C NMR (62.90 MHz, CDCl3) d 38.2 (NCH3), 55.6
(OCH3), 55.7 (OCH3), 99.1 (CH), 111.0 (CH), 114.1 (CH),
114.3 (CH), 115.1 (CH), 115.2 (CH2), 118.9 (CH), 121.0
(CH), 130.0 (CH), 137.2 (C), 139.4 (C), 143.8 (C), 145.2
(C), 153.1 (C), 159.8 (C), 161.8 (C), 179.1 (CO). Anal.
calcd for C20H19N3O: C, 74.75; H, 5.96; N, 4.36. Found: C,
74.90; H, 6.18; N, 4.56; MS m/z 322 (Mþ1)þ.
3.2.3. 5-(2-Furanyl)-7-methoxy-2-(3-methoxyphenyl)-1-
methyl-1,4-dihydro-4-quinolinone (11). Chromatography
eluent CH2Cl2/EtOAc 7:3; yield: 86%. Mp 181–1828C
(EtOAc); IR (KBr) n 1618 (CO) cm21; 1H NMR (250 MHz,
CDCl3) d 3.55 (s, 3H, NCH3), 3.86 (s, 3H, OCH3), 3.96 (s,
3H, OCH3), 6.17 (s, 1H, H-3), 6.51 (dd, 1H, J¼1.8, 3.1 Hz,
HFuran), 6.55 (d, 1H, J¼2.3 Hz, H-6 or H-8), 6.93–7.05 (m,
5H, H-6 or H-8, H-20, H-40, H-60, HFuran), 7.40 (t, 1H,
J¼8.0 Hz, H-50), 7.54 (broad s, 1H, HFuran); 13C NMR
(62.90 MHz, CDCl3) d 38.1 (CH3), 55.6 (CH3), 55.8 (CH3),
100.3 (CH), 108.2 (CH), 111.0 (CH), 114.0 (CH), 114.4
(CH), 114.7 (CH), 115.1 (CH), 119.3 (CH), 121.0 (CH),
130.0 (CH), 133.7 (C), 137.2 (C), 142.1 (C), 145.3 (C),
153.1 (C), 154.2 (C), 159.8 (C), 161.4 (C), 177.0 (CO).
Anal. calcd for C22H19NO4: C, 73.12; H, 5.30; N, 3.88.
Found: C, 72.81; H, 5.47; N, 3.73; MS m/z 362 (Mþ1)þ.
3.2. General procedure for Suzuki reaction
To a stirred solution of 7b (100 mg, 0.22 mmol) in
anhydrous 1,4-dioxane (5 mL) was added freshly prepared
tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol).
The solution was stirred for 30 min at room temperature.
Boronic acid (2-thiophenylboronic acid for 9, phenyl-
boronic acid for 10 and 2-furanylboronic acid for 11,
0.33 mmol) diluted in ethanol (2 mL) was then added,
followed immediately by saturated aqueous NaHCO3
solution (2 mL). The heterogeneous solution was stirred at
reflux for 3 h. Palladium catalyst was removed by filtration.
Brine solution was then added, the two layers were
separated and the aqueous phase was extracted with ethyl
acetate (3£5 mL). The combined organic extracts were
dried over MgSO4 and evaporated in vacuo. The crude
residue was purified by column chromatography to give the
desired compound.
3.3. General procedure of nucleophilic aromatic
substitution
A mixture of triflate 7 (200 mg, 0.45 mmol) and amine
(2.20 mmol) in anhydrous 1,4-dioxane (4 mL) was heated at
100–1208C for t h. After cooling, the solvent was
evaporated. The crude residue was purified by column
chromatography to afford the desired compounds.
3.3.1. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-pyrro-
lidino-1,4-dihydro-4-quinolinone (12b). Amine: pyrro-
lidine; t¼12 h; chromatography eluent: petroleum ether/
EtOAc 1:9; yield 83%. Mp 155–1568C (EtOAc); IR (KBr) n
1617 (CO) cm21; 1H NMR (250 MHz, CDCl3) d 1.95–2.00
(m, 4H, CH2), 3.42–3.47 (m, 4H, CH2), 3.45 (s, 3H, NCH3),
3.85 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.10 (s, 1H, H-3),
3.2.1. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-(2-
thienyl)-1,4-dihydro-4-quinolinone (9). Chromatography

9632
C. Pain et al. / Tetrahedron 59 (2003) 9627–9633
6.28 (d, 1H, J¼1.8 Hz, H-6 or H-8), 6.34 (br0oad s, 1H, H-6
or H-8), 6.94–7.03 (m, 3H, H-20, H-40, H-6 ), 7.38 (t, 1H,
J¼7.8 Hz, H-50); 13C NMR (62.90 MHz, CDCl3) d 25.8
(2CH2), 38.1 (CH3), 52.7 (2CH2), 55.6 (2CH3), 89.5 (CH),
94.8 (CH), 111.3 (CH), 113.1 (CH), 114.2 (CH), 115.1
(CH), 121.0 (CH), 129.9 (C), 137.4 (C), 146.6 (C), 151.2
(C), 151.8 (C), 159.8 (C), 162.7 (C), 177.3 (CO). Anal.
calcd for C22H24N2O3: C, 72.51; H, 6.64; N, 7.69. Found: C,
72.68; H, 6.77; N, 7.80; MS m/z 365 (Mþ1)þ.
3.3.5. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-
(1-methylpiperazino)-1,4-dihydro-4-quinolinone (14b).
Amine: N-methylpiperazine; t¼6 h; chromatography eluent:
CH2Cl2/MeOH 98:2; yield: 89%. Mp 196–1978C (EtOAc/
1
petroleum ether); IR (KBr) n 1623 (CO) cm21; H NMR
(250 MHz, CDCl3) d 2.40 (s, 3H, NCH3), 2.75–2.80 (m,
4H, CH2), 3.15–3.25 (m, 4H, CH2), 3.49 (s, 3H, NCH3),
3.85 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.11 (s, 1H, H-3),
6.46 (s, 2H, H-6, H-8), 06.92 (d, 1H, J¼1.9 Hz, H-20), 06.95–
7.02 (m, 2H, H-40, H-6 ), 7.38 (t, 1H, J¼7.8 Hz, H-5 ); 13C
NMR (62.90 MHz, CDCl3) d 38.5 (CH3), 46.2 (CH3), 52.9
(2CH2), 55.3 (2CH2), 55.4 (CH3), 55.5 (CH3), 92.4 (CH),
100.2 (CH), 114.3 (CH), 114.5 (CH), 114.6 (C), 115.4 (CH),
121.0 (CH), 129.9 (CH), 137.3 (C), 147.3 (C), 151.7 (C),
155.3 (C), 159.8 (C), 162.5 (C), 177.1 (CO). Anal. calcd for
C23H27N3O3: C, 70.21; H, 6.92; N, 10.68. Found: C, 70.34;
H, 7.06; N, 10.79; MS m/z 394 (Mþ1)þ.
3.3.2. 7-Methoxy-2-(4-methoxyphenyl)-1-methyl-5-
piperidino-1,4-dihydro-4-quinolinone (13a). Amine:
piperidine; t¼6 h; chromatography eluent: petroleum
ether/EtOAc 1:9; yield: 82%. Mp 190–1918C (EtOAc/
1
petroleum ether); IR (KBr) n 1633 (CO) cm21; H NMR
(250 MHz, CDCl3) d 1.50–1.65 (m, 2H, CH2), 1.70–1.95
(m, 4H, CH2), 2.90–3.20 (m, 4H, CH2), 3.48 (s, 3H, NCH3),
3.85 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.08 (s, 1H, H-3),
6.42 (d, 1H, J¼2.0 Hz, H-6 or H-8), 6.500 (d, 1H, J¼2.0 Hz,
H-6 or H-8), 6.97 (d, 2H, J¼8.8 Hz, H-3 , H-50), 7.31 (d, 2H,
J¼8.8 Hz, H-20, H-60); 13C NMR (62.90 MHz, CDCl3) d
24.5 (CH2), 26.2 (2CH2), 38.5 (CH3), 54.7 (2CH2), 55.4
(CH3), 55.5 (CH3), 92.4 (CH), 100.2 (CH), 114.2 (2CHþC),
114.4 (CH), 128.4 (C), 130.1 (2CH), 147.3 (C), 151.7 (C),
156.0 (C), 160.4 (C), 162.5 (C), 177.3 (CO). Anal. calcd for
C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C, 72.67;
H, 6.85; N, 7.37; MS m/z 379 (Mþ1)þ.
3.3.6. 7-Methoxy-2-(4-methoxyphenyl)-1-methyl-5-
(dimethylaminoethylamino)-1,4-dihydro-4-quinolinone
(15a). Amine: N,N-dimethylaminoethylamine; t¼48 h;
chromatography eluent: CH2Cl2/MeOH 95:5; yield: 79%.
Mp 130–1318C (EtOAc/petroleum ether); IR (KBr) n 1626
1
(CO) cm21; H NMR (250 MHz, CDCl3) d 2.33 (s, 6H,
CH3), 2.66 (t, 2H, J¼7.0 Hz, CH2), 3.31 (broad q, J¼
7.0 Hz, CH2), 3.42 (s, 3H, NCH3), 3.87 (s, 3H, OCH3), 3.88
(s, 3H, OCH3), 5.94 (d, 1H, J¼2.2 Hz, H-6 or H-8), 5.97 (d,
1H, J¼2.2 Hz,0H-6 or H-8), 6.02 (s, 1H, H-3), 6.980 (d, 2H,
J¼8.8 Hz, H-3 , H-50), 7.30 (d, 2H, J¼8.8 Hz, H-2 , H-60),
10.48 (broad t, 1H, J¼7.0 Hz, NH); 13C NMR (62.90 MHz,
CDCl3) d 38.1 (CH3), 41.3 (CH2), 45.8 (2CH3), 55.2 (CH3),
55.5 (CH3), 58.0 (CH2), 86.2 (CH), 88.4 (CH), 107.7 (C),
112.9 (CH), 114.2 (2CH), 128.4 (C), 130.0 (2CH), 146.4
(C), 152.5 (C), 153.4 (C), 160.4 (C), 164.0 (C), 180.2 (CO).
Anal. calcd for C22H27N3O3: C, 69.27; H, 7.13; N, 11.02.
Found: C, 69.54; H, 6.94; N, 10.88; MS m/z 382 (Mþ1)þ.
3.3.3. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-
piperidino-1,4-dihydro-4-quinolinone (13b). Amine:
piperidine; t¼6 h; chromatography eluent: petroleum
ether/EtOAc 1:9; yield: 84%. Mp 171–1728C (EtOAc); IR
1
(KBr) n 1621 (CO) cm21; H NMR (250 MHz, CDCl3) d
1.60–1.90 (m, 2H, CH2), 1.90–2.00 (m, 4H, CH2), 3.10–
3.40 (m, 4H, CH2), 3.50 (s, 3H, NCH3), 3.85 (s, 3H, OCH3),
3.93 (s, 3H, OCH3), 6.13 (s, 1H, H-3), 6.47 (broad s, 1H,
H-6 or H-8),06.93 (d, 1H, J¼1.8 Hz, H-6 or H-8), 6.94–7.05
(m, 3H, H-2 , H-40, H-60), 7.40 (t, 1H, J¼7.8 Hz, H-50); 13
C
3.3.7. 7-Methoxy-2-(3-methoxyphenyl)-1-methyl-5-
(dimethylaminoethylamino)-1,4-dihydro-4-quinolinone
(15b). Amine: N,N-dimethylaminoethylamine; t¼60 h;
chromatography eluent: CH2Cl2/MeOH 95:5; yield: 79%.
Mp 121–1228C (EtOAc); IR (KBr) n 1628 (CO) cm21; 1H
NMR (250 MHz, CDCl3) d 2.34 (s, 6H, NCH3), 2.67 (t, 2H,
J¼7.0 Hz, CH2), 3.32 (broad q, 2H, J¼7.0 Hz, CH2), 3.41
(s, 3H, NCH3), 3.84 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.95
(d, 1H, J¼2.2 Hz, H-6 or H-8), 5.98 (d, 1H, J¼2.2 Hz, H-6
or H-8), 6.04 (s, 1H, H-3), 6.90–7.02 (m, 3H, H-20, H-40,
H-60), 7.38 (t, 1H, J¼7.8 Hz, H-50), 10.50 (broad t, 1H,
J¼7.0 Hz, NH); 13C NMR (62.90 MHz, CDCl3) d 38.1
(CH3), 41.3 (CH2), 45.8 (2CH3), 55.3 (CH3), 55.5 (CH3),
58.0 (CH2), 86.2 (CH), 88.5 (CH), 107.8 (C), 112.7 (CH),
114.3 (CH), 115.0 (CH), 121.0 (CH), 129.9 (CH), 137.4 (C),
146.3 (C), 152.5 (C), 153.5 (C), 159.8 (C), 164.1 (C), 180.2
(CO). Anal. calcd for C22H27N3O3: C, 69.27; H, 7.13; N,
11.02. Found: C, 68.94; H, 6.97; N, 10.93; MS m/z 382
(Mþ1)þ.
NMR (62.90 MHz, CDCl3) d 23.5 (CH2), 25.9 (2CH2), 38.7
(CH3), 55.0 (2CH2), 55.6 (2CH3), 89.5 (CH), 94.8 (CH),
111.3 (CH), 113.4 (CH), 114.3 (CH), 115.4 (CH), 120.9
(CH), 130.1 (C), 136.8 (C), 146.6 (C), 151.2 (C), 153.2 (C),
159.9 (C), 163.1 (C), 177.5 (CO). Anal. calcd for
C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C, 73.12;
H, 7.05; N, 7.33; MS m/z 379 (Mþ1)þ.
3.3.4. 7-Methoxy-2-(4-methoxyphenyl)-1-methyl-5-
(1-methylpiperazino)-1,4-dihydro-4-quinolinone (14a).
Amine: N-methylpiperazine; t¼6 h; chromatography eluent:
CH2Cl2/MeOH 98:2; yield: 90%. Mp 188–1898C (EtOAc/
1
petroleum ether); IR (KBr) n 1618 (CO) cm21; H NMR
(250 MHz, CDCl3) d 2.36 (s, 3H, NCH3), 2.70–2.80 (m,
4H, CH2), 3.10–3.20 (m, 4H, CH2), 3.46 (s, 3H, NCH3),
3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.05 (s, 1H, H-3),
6.41 (s, 2H, H-6, H-8), 6.95 (d, 2H, J¼8.8 Hz, H-30, H-50),
7.29 (d, 2H, J¼8.8 Hz, H-20, H-60); 13C NMR (62.90 MHz,
CDCl3) d 38.5 (CH3), 46.1 (CH3), 52.9 (2CH2), 55.3
(2CH2), 55.4 (CH3), 55.5 (CH3), 92.4 (CH), 100.1 (CH),
114.1 (2CH), 114.5 (CþCH), 128.2 (C), 130.1 (2CH),
147.4 (C), 151.7 (C), 155.1 (C), 160.4 (C), 162.4 (C), 177.0
(CO). Anal. calcd for C23H27N3O3: C, 70.21; H, 6.92; N,
10.68. Found: C, 69.98; H, 6.78; N, 10.52; MS m/z 394
(Mþ1)þ.
3.3.8. 7-Methoxy-5-(4-methoxybenzylamino)-2-(4-meth-
´
oxyphenyl)-1-methyl-1,4-dihydro-4-quinolinone (16a).
Amine: 4-methoxybenzylamine; t¼16 h; chromatography
eluent: CH2Cl2/EtOAc 9:1; yield: 82%. Mp 148–1508C
(EtOAc/petroleum ether); IR (KBr) n 1623 (CO) cm21; 1H
NMR (250 MHz, CDCl3) d 3.43 (s, 3H, NCH3), 3.79 (s, 6H,

C. Pain et al. / Tetrahedron 59 (2003) 9627–9633
9633
OCH3), 3.87 (s, 3H, OCH3), 4.40 (d, 2H, J¼5.5 Hz, CH2),
5.89 (d, 1H, J¼2.0 Hz, H-6 or H-8), 5.99 (d, 1H, J¼2.0 Hz,
H-6 or H-8), 6.05 (s, 1H, H-3), 6.86 (d, 2H, J¼8.8 Hz,
2HPhen), 6.98 (d, 2H, J¼8.8 Hz, H-30, H-50), 7.29–7.35 (m,
4H, H-20, H-60, 2HPhen), 10.88 (t, 1H, J¼5.5 Hz, NH); 13C
NMR (62.90 MHz, CDCl3) d 38.1 (CH3), 46.6 (CH2), 55.2
(CH3), 55.4 (CH3), 55.5 (CH3), 86.6 (CH), 89.4 (CH), 107.9
(C), 112.9 (CH), 114.1 (2CH), 114.2 (2CH), 128.4 (2CH),
130.1 (2CH), 131.0 (C), 146.4 (C), 152.6 (C), 153.4 (C),
158.7 (C), 160.5 (C), 163.9 (C), 180.3 (CO). Anal. calcd for
C26H26N2O4: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.33;
H, 5.90; N, 6.55; MS m/z 431 (Mþ1)þ.
3H, OCH3), 3.85 (s, 3H, OCH3), 6.00 (d, 1H, J¼2.0 Hz, H-6
or H-8), 6.03 (s 1H, H-3), 6.06 (d, 01H, J¼2.0 Hz, H-6 or
H-8), 6.90–7.07 (m, 5H, H-20, H-4 , H-60þNH2), 7.38 (t,
1H, J¼7.9 Hz, H-50); 13C NMR (62.90 MHz, CDCl3) d 38.0
(CH3), 55.4 (CH3), 55.6 (CH3), 88.5 (CH), 93.7 (CH), 108.2
(C), 112.5 (CH), 114.2 (CH), 115.1 (CH), 121.0 (CH), 130.0
(CH), 137.4 (C), 146.1 (C), 153.1 (C), 153.2 (C), 159.8 (C),
163.5 (C), 180.5 (CO). Anal. calcd for C18H18N2O3: C,
69.66; H, 5.85; N, 9.03. Found: C, 70.02; H, 5.92; N, 8.97;
MS m/z 311 (Mþ1)þ.
3.3.9. 7-Methoxy-5-(4-methoxybenzylamino)-2-(3-meth-
oxyphenyl)-1-methyl-1,4-dihydro-4-quinolinone (16b).
Amine: 4-methoxybenzylamine; t¼16 h; chromatography
eluent: CH2Cl2/EtOAc 9:1; yield: 80%. Mp 181–1828C
(EtOAc); IR (KBr) n 1630 (CO) cm21; 1H NMR (250 MHz,
CDCl3) d 3.41 (s, 3H, NCH3), 3.79 (s, 6H, OCH3), 3.85 (s,
3H, OCH3), 4.40 (d, 2H, J¼5.5 Hz, CH2), 5.89 (d, 1H,
J¼2.0 Hz, H-6 or H-8), 5.99 (d, 1H, J¼2.0 Hz, H-6 or H-8),
6.06 (s, 1H, H-3), 6.86 (d, 2H, J¼8.8 Hz, 2HPhen), 6.90–
7.02 (m, 3H, H-20, H-40, H-60), 7.33 (d, 2H, J¼8.8 Hz,
2HPhen), 7.38 (t, 1H, J¼8.0 Hz, H-50), 10.88 (t, 1H, J¼
5.5 Hz, NH); 13C NMR (62.90 MHz, CDCl3) d 38.1 (CH3),
46.6 (CH2), 55.2 (CH3), 55.4 (CH3), 55.5 (CH3), 86.5 (CH),
89.5 (CH), 108.0 (C), 112.7 (CH), 114.1 (2CH), 114.3 (CH),
115.0 (CH), 121.0 (CH), 128.4 (2CH), 130.0 (CH), 130.9
(C), 137.4 (C), 146.2 (C), 152.5 (C), 153.4 (C), 158.7 (C),
159.8 (C), 163.9 (C), 180.3 (CO). Anal. calcd for
C26H26N2O4C, 72.54; H, 6.09; N, 6.51. Found: C, 72.81;
H, 5.99; N, 6.61; MS m/z 431 (Mþ1)þ.
References
1. (a) Kuo, S.-C.; Lee, H.-Z.; Juang, J.-P.; Lin, Y.-T.; Wu, T.-S.;
Chang, J.-J.; Lednicer, D.; Paull, K. D.; Lin, C. M.; Hamel, E.;
Lee, K.-H. J. Med. Chem. 1993, 36, 1146. (b) Li, L.; Wang,
H.-K.; Kuo, S.-C.; Wu, T.-S.; Lednicer, D.; Lin, C. M.; Hamel,
E.; Lee, K.-H. J. Med. Chem. 1994, 37, 1126. (c) Li, L.; Wang,
H.-K.; Kuo, S.-C.; Wu, T.-S.; Mauger, A.; Lin, C. M.; Hamel,
E.; Lee, K.-H. J. Med. Chem. 1994, 37, 3400.
2. Xia, Y.; Yang, Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger,
A.; Wu, J.-H.; Lee, K.-H. J. Med. Chem. 2001, 44, 3932.
3. (a) Weigt, M.; Wiese, M. Quant. Struct.-Act. Relat. 2000, 19,
142. (b) Zhang, S.-H.; Feng, J.; Kuo, S.-C.; Brossi, A.; Hamel,
E.; Tropsha, A.; Lee, K.-H. J. Med. Chem. 2000, 43, 167.
4. Sui, Z.; Nguyen, V. N.; Altom, J.; Fernandez, J.; Hilliard, J. J.;
Bernstein, J. I.; Barrett, J. F.; Ohemeng, K. A. Eur. J. Med.
Chem. 1999, 34, 381.
5. Ko, T.-C.; Hour, M.-J.; Lien, J.-C.; Teng, C.-M.; Lee, K.-H.;
Kuo, S.-C.; Huang, L. J. Bioorg. Med. Chem. Lett. 2001, 11,
279.
3.3.10. 5-Amino-7-methoxy-2-(4-methoxyphenyl)-1-
methyl-1,4-dihydro-4-quinolinone (17a). A solution of
16a (100 mg, 0.23 mmol) in trifluoroacetic acid (3 mL) was
stirred at 658C for 1 h. Acid was removed under reduced
pressure. The residue was diluted in ethyl acetate, washed
with 10% NaOH solution. The organic phase was dried over
MgSO4 and evaporated in vacuo. The solid obtained was
recrystallised from ethyl acetate to give 17a (46 mg, 65%)
as a solid. Mp 198–2008C (EtOAc); IR (KBr) n 3377 broad
6. Watterson, S. H.; Carlsen, M.; Murali Dhar, T. G.; Shen, Z.;
Pitts, W. J.; Guo, J.; Gu, H. H.; Norris, D.; Chorba, J.; Chen,
P.; Cheney, D.; Witmer, M.; Fleener, C. A.; Rouleau, K.;
Townsend, R.; Hollenbaugh, D. L.; Iwanowicz, E. J. Bioorg.
Med. Chem. Lett. 2003, 13, 543.
7. (a) Joseph, B.; Darro, F.; Guillaumet, G.; Kiss, R.; Frydman,
A. PCT Appl. Int. WO 0112607, 2001; Chem. Abstr. 2001,
´
134, 193348. (b) Joseph, B.; Behard, A.; Lesur, B.;
Guillaumet, G. Synlett 2003, 1542.
1
s (NH2), 1624 (CO) cm21; H NMR (250 MHz, CDCl3) d
8. Shingo, S.; Hironobu, K.; Shigeru, M.; Toshihiro, K.; Jun-Ichi,
O.; Masanobu, S. J. Heterocycl. Chem. 1999, 36, 1345.
9. Balaji, B. S.; Chanda, B. M. Tetrahedron 1998, 54, 13237.
10. (a) Toda, J.; Fuse, T.; Kishikawa, E.; Ando, N.; Negishi, R.;
Horiguchi, Y.; Sano, T. Heterocycles 1994, 38, 2091. (b) Chen,
K.; Kuo, S.-C.; Hsieh, M.-C.; Mauger, A.; Lin, C. M.; Hamel,
E.; Lee, K.-H. J. Med. Chem. 1997, 40, 2266.
3.41 (s, 3H, NCH3), 3.85 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
5.99 (d, 1H, J¼2.2 Hz, H-6 or H-8), 6.01 (s, 1H, H-3), 6.06
(d, 1H, J¼2.2 Hz, H-6 or H-8), 6.97 (d, 2H, J¼8.8 Hz, H-300,
H-50), 7.11 (broad s, 2H, NH2), 7.31 (d, 2H, J¼8.8 Hz, H-2 ,
H-60); 13C NMR (62.90 MHz, CDCl3) d 38.1 (CH3), 55.4
(CH3), 55.5 (CH3), 88.5 (CH), 93.6 (CH), 108.2 (C), 112.7
(CH), 114.2 (2CH), 128.5 (C), 130.1 (2CH), 146.2 (C),
153.2 (2C), 160.5 (C), 163.4 (C), 180.5 (CO). Anal. calcd
for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C,
69.87; H, 5.66; N, 8.88; MS m/z 311 (Mþ1)þ.
11. (a) Eyrolles, L.; Kawachi, E.; Kagechika, H.; Hashimoto, Y.;
Shudo, K. Chem. Pharm. Bull. 1994, 42, 2575. (b) Hadjeri, M.;
Mariotte, A.-M.; Boudmendjel, A. Chem. Pharm. Bull. 2001,
49, 1352.
12. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(b) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React.
1997, 50, 1.
3.3.11. 5-Amino-7-methoxy-2-(3-methoxyphenyl)-1-
methyl-1,4-dihydro-4-quinolinone (17b). Following the
procedure used for the preparation of 17a, compound 17b
was obtained from 16b in 54% yield. Mp 182–1838C
13. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513. (b) Miyaura, M.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (c) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(EtOAc); IR (KBr) n 3432, 3362 (NH2), 1627 (CO) cm21
;
1H NMR (250 MHz, CDCl3) d 3.40 (s, 3H, NCH3), 3.84 (s,