Antimitotic activity of 5-hydroxy-7-methoxy-2-phenyl-4-quinolones

Article abstract of DOI:10.1021/jm049876x

We report the synthesis of 5-hydroxy-7-methoxy-2-phenyl-4-quinolones and their biological activity as antitumor agents. These molecules were initially evaluated for their ability to induce cell cycle arrest in the G2/M phase. Compounds that showed signifi

Full text of DOI:10.1021/jm049876x

4964
J . Med. Chem. 2004, 47, 4964-4970
An tim itotic Activity of 5-Hyd r oxy-7-m eth oxy-2-p h en yl-4-qu in olon es
Mohamed Hadjeri,† Eva-Laure Peiller,‡ Chantal Beney,† Nabajyoti Deka,† Martin A. Lawson,†
Charles Dumontet,‡ and Ahce`ne Boumendjel*,†
De´partement de Pharmacochimie Mole´culaire, UMR-CNRS 5063, Faculte´ de Pharmacie de Grenoble, Laboratoire de Chimie
Organique, 5 avenue de Verdun, 38240 Meylan, France, and Laboratoire de Cytologie Analytique, INSERM U590, Faculte´ de
Me´decine Rockefeller, Universite´ Claude Bernard Lyon I, 69008 Lyon, France
Received February 10, 2004
We report the synthesis of 5-hydroxy-7-methoxy-2-phenyl-4-quinolones and their biological
activity as antitumor agents. These molecules were initially evaluated for their ability to induce
cell cycle arrest in the G2/M phase. Compounds that showed significant G2/M cell cycle arrest
were tested for antiproliferative activity using both the MTT assay and the NCI in vitro 60
cell line human tumor screen. The 5-hydroxy-7-methoxy-2-phenyl-4-quinolone (3a ) and 2-(3-
fluorophenyl)-5-hydroxy-7-methoxy-4-quinolone (3f) were the most active in the cell cycle arrest
test whereas 3f was found to be the most active in the MTT assay. In terms of structural
requirements, we found that the presence of a 5-hydroxyl group, a 7-methoxy group, and an
unsubstituted N1 were essential for the antimitotic activity. In accordance with the literature,
a fluoro group at the 3′- or 2′-position and a methoxy or a chloro group at the 3′-position were
found to be highly advantageous for both the cell cycle arrest and the antiproliferative activities.
In tr od u ction
occurring flavonoids and confirms that nature has
evolved as an elegant solution to many complex biologi-
cal processes.14 There is an emerging consensus that the
biological potency of 5-hydroxyflavones might be due to
the ability of the 5-hydroxybenzofuran-4-one part to
behave as an ATP competitive inhibitor by mimicry of
the adenine moiety of ATP. The recent high-resolution
cocrystallization of flavonoids with two kinases supports
this mimicry phenomenon.15,16
Low molecular weight natural products and ana-
logues have been invaluable agents to induce arrest at
specific points in the cell cycle.1 Compounds such as
vincristine, vinblastine, and taxol, which cause mitotic
arrest, are of proven clinical utility.2 These agents act
by interfering with cytoskeletal dynamics, predomi-
nantly affecting the microtubules required for spindle
formation.3,4
The aim of the present study was to apply a similar
approach to potentiate the antimitotic activity of 2-phen-
yl-4-quinolones. We therefore chose to target 2-phenyl-
4-quinolones containing a hydroxyl at C-5 and a meth-
oxy group at C-7 and possessing variant substitution
patterns on the B ring. The C-3′ carbon was particularly
targeted since its substitution has been reported as
being the most critical for flavone and quinolone cyto-
toxicity.6,7,9,12 We synthesized and evaluated 5-hydroxy-
7-methoxy-2-phenyl-4-quinolones bearing N-substitu-
ents and determined the impact of these modifications
on antimitotic activity. We also determined the influence
of a spacer separating the B ring from the quinolone
moiety by introducing a phenyl group, a double bond,
or a methylene group as spacers. The phenyl and the
double bond are meant to space the B ring from the
quinolone moiety while maintaining the conjugation
pattern whereas the methylene group is a rather small
spacer, which breaks the conjugation between the
phenyl group and the quinolone moiety. The structures
of targeted compounds are shown in Figure 1.
In this context, 2-phenyl-4-quinolones have been the
subject of investigations as a new class of antitumor
agents during the past 10 years. Lee and co-workers at
the University of North Carolina have made a signifi-
cant contribution in this field and developed 2-phenyl-
4-quinolones with potent antitumor activity. These
latter compounds seem to exert their antitumor effect
through inhibition of tubulin polymerization involving
binding to the colchicine binding site of tubulin.5-9
Structure-activity studies led to the identification of
2-phenyl-4-quinolones possessing a pyrrolidine moeity
at the 6- or 7-position and a 6,7-methylenedioxy and a
fluoro or chloro substituent at the 3′-position as promis-
ing leads. Working on analogous compounds, Wiese and
Pageva have recently reported quantitative structure-
activity relationships in a variety of antimitotic 4-qui-
nolones.10
Our group has studied the biological activities of
flavones and their aza analogues.11 From our studies
and a review of the literature in different biological
areas, we note that the most active flavones are often
hydroxylated at the 5-position and hydroxylated or
methoxylated at the 7-position.12,13 Interestingly, this
substitution pattern is frequently found in naturally
Ch em istr y
The synthesis of compounds 3 and 4 is outlined in
Scheme 1.17 Briefly, condensation of 3,5-dimethoxy-
aniline with substituted benzoyl chlorides or benzoic
acids affords amide 1. Friedel-Crafts acylation with
acetyl chloride and using SnCl4 as a catalyst gave the
N-(2-acetyl-3,5-dimethoxyphenyl)benzamides 2 and a
* To whom correspondence should be addressed. Tel: 33-4 76 04
10 06. Fax: 33-4 76 04 10 07. E-mail: Ahcene.Boumendjel@ujf-
grenoble.fr.
† Laboratoire de Chimie Organique.
‡ Universite´ Claude Bernard Lyon I.
10.1021/jm049876x CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/26/2004

5-Hydroxy-7-methoxy-2-phenyl-4-quinolones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 20 4965
Sch em e 2a
F igu r e 1. Structures of targeted compounds.
Sch em e 1a
a
Reagents: (i) t-BuOK, t-BuOH, reflux. (ii) BBr3, CH2Cl2.
Resu lts a n d Discu ssion
To identify compounds with antimitotic activity, the
human leukemic K562 cell line, derived from a patient
with acute myeloid leukemia, was exposed to test
compounds continuously for 24 h at 5 µM concentration.
The cells were then stained with propidium iodide and
analyzed by flow cytometry. This test, which determines
the distribution of the total population in the different
phases of the cell cycle (G0/G1, S, and G2/M), indicates
whether the molecule induces cell cycle arrest, but it
does not evaluate the compound’s cytotoxicity. The latter
is measured by cell growth inhibition, which in this
study was performed secondarily on those molecules
that induced significant cell cycle arrest in the G2/M
phase.
A preliminary screening on a set of representative
compounds ruled out any cell cycle blocking activity for
5,7-dihydroxy-2-phenyl-4-quinolones and 5-unsubsti-
tuted and 4′-substituted quinolones (results not shown).
The lead compound was 5-hydroxy-7-methoxy-4-qui-
nolone, which induced a strong G2/M (66%) arrest
comparable to that induced by taxol (71%) and a 2-fold
higher arrest than that induced by vinblastine, which
are both highly effective compounds used in the clinic.
Methylation of the 5-hydroxy group (5,7-dimethoxy-2-
phenyl-4-quinolones) or deletion of the 7-methoxy group
(3n ) led to a sensitive loss of activity (23 and 21%,
respectively).
We decided to substitute the B ring with small
substituents, especially at the 3′-position as this has
been proven to enhance the efficacy of this type of
compound. As shown in Table 1, in which various C-3′
substituents are compared, we can conclude that the
antimitotic potency follows this order: hydrogen )
fluorine > nitrogen atom > chlorine ) methoxy groups.
Because 3′- and 5′-positions are equivalent, we thought
that their simultaneous substitution with a F, Cl, or
OMe would enhance the activity. Unfortunately, as
shown in Table 1, the 3′,5′-difluoro analogue (3i) did not
possess any activity in the cell cycle assay. To confirm
that the C′-3 is the most suitable position for substitu-
tion, 2′-fluoro and 4′-fluoro derivatives were synthesized
and led to this order of potency: 3′-position > 2′ . 4′.
Substitution of C-3′ by a nitrogen (3u ) reduced the cell
cycle arrest from 70 to 45%, suggesting that a carbon
atom is the most suitable atom at this position.
Insertion of a methylene as a spacer between the
4-quinolone moiety and the B ring led to complete loss
a
Reagents: (i) X ) Cl:Et3N, THF. X ) OH:EDC, HOBT, THF.
(ii) Ac-Cl, SnCl4, 1,2-dichloroethane. (iii) t-BuOK, t-BuOH, reflux.
(iv) BBr3, CH2Cl2. (v) K2CO3, R-X, DMF.
little amount of its regioisomer N-(4-acetyl-3,5-dimeth-
oxy)benzamides 2′, which can be easily separated. Basic
cyclization affords 5,7-dimethoxyquinolones, which are
selectively demethylated with a solution of BBr3 in CH2-
Cl2 to afford 5-hydroxy-7-methoxy-4-quinolones 3. N-
Alkylquinolones 4 were obtained by alkylation of 5-hy-
droxyquinolones 3 as shown in Scheme 1.
Compounds with spacers can be prepared according
to Scheme 1 and replacing benzoic acid by phenylbenzoic
acid, phenylacetic acid, and cinnamic acid. In such
conditions, intermediates 5a -c (Scheme 2) were easily
obtained. When subjected to cyclization conditions (t-
BuOK/t-BuOH), derivatives 5a ,b were cyclized and
selectively demethylated to yield targeted quinolones
6a ,b. In the same cyclization conditions, we were not
able to convert 5c to the expected quinolone, and
instead, benzazocine 7 was isolated, certainly because
the cyclization takes place at the â-carbon of the double
bond and not at the carbonyl group. Attempts of other
cyclization conditions (NaH/THF, K2CO3/acetone) failed
to provide quinolone 6c. The structures of synthesized
compounds are summarized in Tables 1 and 2.

4966 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 20
Hadjeri et al.
Ta ble 1. Structures and Cell Cycle Arrest Activity of Synthesized Quinolones
substitution
physical properties
% cells in each phase
7
2′
3′
4′
formula
mp (°C)
G0/G1
S
G2/M
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
OMe
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
CF3
Cl
OCF3
OMe
F
I
Br
3′,5′-F
H
H
H
H
H
F
F
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
16H13NO3
257-259
219-221
250-252
214-215
123-125
272-274
264-266
a
152-154
257-259
216-218
a
219-221
157-159
172-174
a
191-193
a
7
41
33
32
28
9
26
38
35
35
41
30
50
37
40
36
37
45
48
52
33
53
54
51
48
69
31
18
30
47
66
20
32
32
31
60
6
12
18
10
41
8
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
6,7-OMe
5,6,7-OMe
H
17H12F3NO3
16H12ClNO3
17H12F3NO4
17H15NO4
16H12FNO3
16H12INO3
16H12BrNO3
16H11F2NO3
16H13NO3
44
51
42
54
23
47
47
26
17
26
28
30
26
22
24
11
33
47
16H12FNO3
17H15NO4
18H17NO4
5
15H11NO2
21
49
20
18
18
25
9
45
71
37
6
H
15H10FNO2
17H14FNO4
17H14FNO3
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
H
Et
F
F
CH2Cl
H
F
C17H14ClNO3
3s
3t
3u
C
C
C
18H17NO3
16H11F2NO3
15H12N2O3
230-232
269-271
199-201
nicotinyl
taxol
vinblastine
K562 (cells without antimitotic agent)
a
Amorphous.
Ta ble 2. N-Alkylquinolones and Quinolones with Spacers
substituent
physical properties
formula mp (°C)
>300
187-189
159-161
% cell in each phase
S
entry
R
X
R′
G0/G1
G2/M
5a
5b
8a
8b
8c
H
H
Me
Et
Et
C6H4-
-CH2-
H
H
H
H
F
C22H17NO3
C17H15NO3
46
41
46
43
53
45
50
50
46
28
9
9
4
11
19
C
C
C
17H15NO3
18H17NO3
18H16FNO3
Ta ble 3
compound
of activity (9%) suggesting the importance of an aryl-
C3-aryl, analogous to biaryl systems that occur in
natural products such as colchicine, podophyllotoxine,
and combretastatins.18,19 Replacing the methylene group
by a phenyl led to the same loss of activity, which may
indicate that steric hindrance is unfavorable.
IC50 (µM)a
mean GI50 (µM)b
3a
3e
3f
1.8
c
0.8
1.5
3
8.7
9.7
14.5
9.9
c
3k
vinblastine
Because the presence of a trimethoxyphenyl moiety
is important for the antitumor activity of several anti-
mitotics such as colchicine and podophylotoxins, we
hypothesized that substituting a methoxy at the 6-posi-
tion (compound 3l) would lead to active quinolones.
Unfortunately, we observed a complete loss of activity
(Table 1). Our results show that N-unsubstituted qui-
nolones are much more active than N-alkyl analogues
(Table 2).
On the basis of the cell cycle results, we selected
compounds 3a ,e,f,k and tested them for their antipro-
liferative effect using MTT assays in comparison with
vinblastine, a potent antimitotic vinca alkaloid. As
shown in Table 3, all compounds are more potent than
a
Data obtained from MTT assay on K562 line. IC50, inhibitory
b
concentration 50% values. Data obtained from NCIs in vitro 60
cell line human tumor screen. GI50 values (growth inhibitory
b
concentration 50%) are the concentrations that reduced cell growth
by 50%. c Not available.
vinblastine and 2-(3′-fluorophenyl)-5-hydroxy-7-meth-
oxy-4-quinolone (3f) is the most active. However, po-
lymerization assays of purified tubulin in vitro and
immunocytochemistry of microtubules in cells exposed
to these compounds were negative, suggesting that
these compounds do not target microtubules (data not
shown). When tested in the NCI primary in vitro human
tumor cell screen for cytotoxicity, the compounds dis-

5-Hydroxy-7-methoxy-2-phenyl-4-quinolones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 20 4967
N-(2-Acetyl-3,5-dim eth oxyph en yl)ben zam ide (2a). Yield
played moderate overall cytotoxicities; colon cancer was
the most sensitive.20-22
1
60%; mp 120 °C. H NMR (CDCl3): δ 8.25 (d, 1H, J ) 2.0 Hz,
H6); 8.10 (dd, 2H, J 1 ) 1.3 Hz, J 2 ) 7.6 Hz, H2′, H6′); 7.55-
7.48 (m, 3H, H3′, H4′, H5′); 6.25 (d, 1H, J ) 2.0 Hz, H4); 3.92 (s,
3H, OCH3); 3,88 (s, 3H, OCH3); 2.65 (s, 3H, CH3CO). MS m/z
300 (M + 1)+. Anal. (C17H17NO4) C, H, N.
In conclusion, this study shows that 5-hydroxy-7-
methoxy-4-quinolones induce cell cycle arrest in G2/M
and possess a significant antimitotic activity on tumor
lines in vitro. These results reinforce previous studies
and describe new structural requirements, which will
be of use when conceiving new 2-phenyl-4-quinolone
anticancer agents. Further evaluation of the cytotoxic
activity, the antimitotic mechanism, and the in vivo
activity of these compounds is warranted.
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-3-t r iflu or om et h yl-
1
ben za m id e (2b). Yield 65%; mp 142 °C. H NMR (CDCl3): δ
8.35 (sl, 1H, NH); 8.20 (d, 1H, J ) 2.3 Hz, H6); 7.83-7.79 (m,
3H, H2′, H4′, H6′); 7.69-7.62 (m, 1H, H5′); 6.27 (d, 1H, J ) 2.3
Hz, H4); 3.94 (s, 3H, OCH3); 3.91 (s, 3H, OCH3); 2.65 (s, 3H,
CH3CO). MS m/z 367 (M)+. Anal. (C18H16F3NO4) C, H, F, N.
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-3-ch lor ob en za m -
id e (2c). Yield 65%; mp 95 °C. 1H NMR (CDCl3): δ 8.22 (d,
1H, J ) 2.3 Hz, H6); 7.95-7.72 (m, 3H, H2′, H4′, H6′); 7.57-
7.30 (m, 1H, H5′); 6.28 (d, 1H, J ) 2.3 Hz, H4); 3.95 (s, 3H,
OCH3); 3.85 (s, 3H, OCH3); 2.67 (s, 3H, CH3CO). MS m/z 333
(M+). Anal. (C17H16ClNO4) C, H, Cl, N.
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-3-t r iflu or om et h yl-
oxyb en za m id e (2d ). Yield 69%; mp 105 °C. 1H NMR
(CDCl3): δ 8.22 (d, 1H, J ) 2.4 Hz, H6); 7.98-7.93 (m, 2H,
H2′, H6′); 7.55 (t, 1H, J ) 8.1 Hz, H5′); 7.42-7.38 (m, 1H, H4′);
6.26 (d, 1H, J ) 2.4 Hz, H4); 3.95 (s, 3H, OCH3); 3.93 (s, 3H,
OCH3); 2.65 (s, 3H, CH3CO). MS m/z 383 (M+). Anal. (C18H16F3-
NO5) C, H, F, N.
Exp er im en ta l Section
F low Cytom etr ic An a lysis of Cell Cycle. For analysis
of DNA content and cell cycle distribution, cells were treated
with the test compound at 5 µM for 24 h. After drug exposure,
106 cells/mL were resuspended in 2 mL of propidium iodide
solution (50 mL/ml), incubated at 4 °C overnight, and then
analyzed by flow cytometry. Flow cytometry was performed
on a FACScalibur (Becton Dickinson, San J ose, CA). The cell
cycle distribution was calculated after exclusion of cell doublets
and aggregates on a FL2-area/FL2-width dot plot using Modfit
LT 2.0 software (Verity Software Inc, Topsham, ME).
MTT a n d GTT Cytotoxicity Assa ys. The cell viability was
determined in our laboratory on exponentially growing K562
cells using the MTT assay as previously described.23 Briefly,
asynchronously growing cells were transferred into 96 well
cultures plates (Costar, Corning Inc., NY) in 100 µL of medium
with a final cell concentration of 3 × 103 cells/well and
incubated in media for 24 h. The corresponding drug concen-
trations were then added to each plate. After 72 h of drug
exposure, 20 µL of MTT reagent (Sigma-Aldrich, 5 mg/mL) was
added to each well. The cell viability was expressed as the
percent of absorbance of treated wells relative to the untreated
control wells. The inhibitory concentration 50 (IC50) was
defined as the drug concentration resulting in 50% loss of cell
viability relative to untreated cells. The assays were performed
in triplicate in at least three separate experiments. Compounds
with significant antimitotic activity were analyzed at the
National Cancer Institute using a similar assay, providing
growth inhibitory 50% values (GI50 values) for 60 different cell
lines representative of most types of human cancers.
N-(2-Acetyl-3,5-d im eth oxyp h en yl)-3-m eth oxyben za m -
id e (2e). Yield 74%; mp 122°C. H NMR (acetone-d6): δ 8.20
(d, 1H, J ) 2.5 Hz, H6); 7.55-7.44 (m, 2H, H2′, H6′); 7.18-7.13
(m, 1H, H5′); 6.42 (d, 1H, J ) 2.4 Hz, H4); 6.26-6.24 (m, 1H,
H4′); 3.91 (s, 3H, OCH3); 3.90 (s, 3H, OCH3); 3.77 (s, 3H, OCH3);
2.59 (s, 3H, CH3CO). MS m/z 330 (M + 1)+. Anal. (C18H19NO5)
C, H, N.
1
N -(2-Ace t yl-3,5-d im e t h oxyp h e n yl)-3-flu or ob e n za m -
1
id e (2f). Yield 69%; mp 126 °C. H NMR (CDCl3): δ 8.23 (d,
1H, J ) 2.4 Hz, H6); 7.84-7.72 (m, 2H, H2′, H6′); 7.54-7.44
(m, 1H, H4′); 7.29-7.24 (m, 1H, H5′); 6.26 (d, 1H, J ) 2.4 Hz,
H4); 3.93 (s, 3H, OCH3); 3.91 (s, 3H, OCH3); 2.64 (s, 3H, CH3-
CO). MS m/z 317 (M+). Anal. (C17H16FNO4) C, H, F, N.
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-3-iod ob en za m id e
1
(2g). Yield 72%; mp 122 °C. H NMR (CDCl3): δ 8.18 (d, 1H,
J ) 2.4 Hz, H6); 8.0-7.75 (m, 1H, H2′); 7.25-7.23 (m, 2H, H4′,
H6′); 6.87 (m, 1H, H5′); 6.24 (d, 1H, J ) 2.4 Hz, H4); 3.89 (s,
3H, OCH3); 3.79 (s, 3H, OCH3); 2.62 (s, 3H, CH3CO). MS m/z
425 (M+). Anal. (C17H16INO4) C, H, N.
Ch em istr y. 1H and 13C NMR spectra were recorded on a
1
Bruker AC-200 instrument (200 MHz for H, 50 MHz for 13C).
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-3-b r om ob en za m -
Chemical shifts are reported as δ values (ppm) relative to Me4-
Si as an internal standard. EI and DCI mass spectra were
recorded on a Fisons Trio 1000 instrument. Elemental analyses
were performed by the analytical department of CNRS (Ver-
naison, France). Thin-layer chromatography (TLC) was carried
out using E. Merck silica gel F-254 plates (thickness, 0.25 mm).
Flash chromatography was carried out using Merck silica gel
60, 200-400 mesh. All solvents were distilled prior to use.
Chemicals and reagents were obtained from either Aldrich or
ACROS companies and used according to the manufacturer’s
specifications.
N-(2-Acetyl-3,5-d im eth oxyp h en yl)ben za m id es (2). The
preparation from benzoyl chloride derivatives has already been
reported.17 From benzoic acid derivatives: Benzoic acid deriva-
tive was dissolved in THF (4 mmol/mL) and treated with EDC
(1.1 equiv) and then with HOBT (1.1 equiv). The mixture was
stirred at room temperature for 1.5 h, and then, 3,5-
dimethoxyaniline (1 equiv) was added. The solution was stirred
at room temperature overnight and then hydrolyzed, and the
precipitate was filtered off. The filtrate was diluted with ethyl
acetate and washed with water and then brine, dried, and
evaporated to yield pure benzamides 1. A solution of 1 was
prepared in 1,2-dichloroethane, cooled to 0 °C (ice bath), and
successively treated by dropwise adding of SnCl4 (2 equiv) and
acetyl chloride (1.1 equiv). After it was stirred for 1.5 h, the
solution was poured into crushed ice, extracted with AcOEt,
washed with brine, dried over Na2SO4, and concentrated. The
crude was purified by column chromatography eluted with
AcOEt:cyclohexane (1:1) to obtain 2 as a white solid.
1
id e (2h ). Yield 67%; mp 140 °C. H NMR (CDCl3): δ 8.21 (d,
1H, J ) 2.2 Hz, H6); 7.95 (dd, 1H, J 1 ) 1.0 Hz, J 2 ) 7.8 Hz,
H2′); 7.68-7.66 (m, 2H, H4′, H6′); 7.39 (t, 1H, J ) 7.8 Hz, H5′);
6.26 (d, 1H, J ) 2.2 Hz, H4); 3.93 (s, 3H, OCH3); 3.91 (s, 3H,
OCH3); 2.64 (s, 3H, CH3CO). MS m/z 378 (M+). Calcd (C17H16
-
BrNO4) C, H, N.
N-(2-Acetyl-3,5-d im eth oxyph en yl)-3,5-diflu or oben za m -
id e (2i). Yield 73%; mp 118 °C. 1H NMR (CDCl3): δ 8.17 (d,
1H, J ) 2.4 Hz, H6); 7.40-7.35 (m, 2H, H2′, H6′); 7.03-7.00
(m, 1H, H4′); 6.27 (d, 1H, J ) 2.4 Hz, H4); 3.91 (s, 3H, OCH3);
3.81 (s, 3H, OCH3); 2.65 (s, 3H, CH3CO). Anal. (C17H15F2NO4)
C, H, F, N.
N -(2-Ace t yl-3,5-d im e t h oxyp h e n yl)-4-flu or ob e n za m -
1
id e (2j). Yield 44%; mp 114 °C. H NMR (CDCl3): δ 8.23 (d,
1H, J ) 2.2 Hz, H6); 8.10-8.03 (m, 2H, H2′, H6′); 7.18 (t, 2H, J
) 8,7 Hz, H3′, H5′); 6.25 (d, 1H, J ) 2.3 Hz, H4); 3.93 (s, 3H,
OCH3); 3.91 (s, 3H, OCH3); 2.64 (s, 3H, CH3CO). MS m/z 318
(M + 1)+. Anal. (C17H16FNO4) C, H, F, N.
N -(2-Ace t yl-3,5-d im e t h oxyp h e n yl)-2-flu or ob e n za m -
1
id e (2k ). Yield 66%; mp 75 °C. H NMR (CDCl3): δ 8.39 (sl,
1H, N-H); 8.12 (d, 1H, J ) 2.1 Hz, H6); 7.98-7,96 (m, 1H,
H6′); 7.49-7.47 (m, 1H, H4′); 7.30-7.14 (m, 1H, H5′); 6.90-6.88
(m, 1H, H3′); 6.27 (d, 1H, J ) 2.1 Hz, H4); 3.89 (s, 3H, OCH3);
3.75 (s, 3H, OCH3); 2.57 (s, 3H, CH3CO). MS m/z 318 (M +
1)+. Anal. (C17H16FNO4) C, H, F, N.
N-(2-Acet yl-3,4,5-t r im et h oxyp h en yl)b en za m id e (2l).
1
Yield 15%. H NMR (CDCl3): δ 8.4 (s, 1H, H6); 8.03-7.98 (m,
2H, H2′, H6′); 7.52-7.48 (m, 3H, H3′, H4′, H5′); 3.98 (s, 3H,

4968 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 20
Hadjeri et al.
OCH3); 3.97 (s, 3H, OCH3); 3.84 (s, 3H, OCH3); 2.65 (s, 3H,
CH3CO). MS m/z 330 (M + 1)+. Anal. (C18H19NO5) C, H, N.
N-(2-Acetyl-3-m eth oxyp h en yl)ben za m id e (2n ). 1H NMR
(CDCl3): δ 8.08 (dd, 2H, J 1 ) 1.7 Hz, J 2 ) 7.9 Hz, H2′, H6′);
7.60-7.43 (m, 3H, H3′, H4′, H5′); 7.36-7.28 (m, 1H, H5′); 7.20-
7.08 (m, 1H, H6); 6.68 (dd, 1H, J 1 ) 2.3 Hz, J 2 ) 8.9 Hz, H4);
3.87 (s, 3H, OCH3); 2.65 (s, 3H, CH3CO). MS m/z 269 (M +).
Anal. (C16H15NO3) C, H, N.
was added t-BuOK (5 equiv). The reaction mixture was then
refluxed for 20 h and then cooled to room temperature before
it was poured into a saturated solution of NH4Cl. The solution
was extracted with AcOEt, dried over Na2SO4, and evaporated
and subjected to selective demethylation. A solution of 5,7-
dimethoxyquinolone in anhydrous CH2Cl2 (5 mL/mmol) was
cooled to 0 °C (ice bath) and treated with a solution of BBr3 (1
M solution in CH2l2, 1.5 equiv). The mixture was stirred for
24 h at room temperature and then poured into iced water.
After extraction with CH2Cl2, washing with H2O, drying, and
CH2Cl2 evaporation, the crude was purified by column chro-
matography using a gradient of cyclohexane:AcOEt (1:1 to 3:7)
to yield quinolones 3 and 5 as yellow solids.
N-(2-Acetyl-3-m eth oxyph en yl)-3-flu or oben za m id e (2o).
Yield 22%; mp 155 °C. 1H NMR (CDCl3): δ 7.90-7.76 (m, 3H,
H6, H5, H6′); 7.52-7.49 (m, 2H, H5′, H2′); 7.31-7.23 (m, 1H,
H4′); 6.68 (dd, 1H, J 1 ) 2.6 Hz, J 2 ) 8.9 Hz, H4); 3.94 (s, 3H,
OCH3); 2.66 (s, 3H, CH3CO). MS m/z 287 (M+). Anal. (C16H14
-
5-Hyd r oxy-7-m eth oxy-2-p h en yl-4-qu in olon e (3a ). Yield
80%. 1H NMR (acetone-d6): δ 13,35 (s, 1H, OH); 7.85-7.80 (m,
2H, H2′, H6′); 7.59-7.56 (m, 3H, H3′, H4′, H5′); 6.61 (d, 1H, J )
2.1 Hz, H8); 6.27 (s, 1H, H3); 6.18 (d, 1H, J ) 2.2 Hz, H6); 3.84
(s, 3H, OCH3). MS m/z 268 (M + 1)+. Anal. (C16H13NO3) C, H,
N.
FNO3) C, H, F, N.
N-(2-Acetyl-3,5-d im eth oxyp h en yl)-(3-flu or o-4-m eth ox-
yben z)a m id e (2p ). Yield 35%. 1H NMR (CDCl3): δ 8.21 (d,
1H, J ) 2.4 Hz, H6); 7.85-7.76 (m, 1H, H6′); 7.10-7.00 (m,
2H, H2′, H5′); 6.24 (d, 1H, J ) 2.4 Hz, H4); 3.89 (s, 3H, OCH3);
3.86 (s, 3H, OCH3); 3.82 (s, 3H, OCH3); 2.65 (s, 3H, CH3CO).
MS m/z 347 (M+). Anal. (C18H18FNO5) C, H, F, N.
5-H yd r oxy-7-m et h oxy-2-(3-t r iflu or om et h ylp h en yl)-4-
1
qu in olon e (3b). Yield 75%. H NMR (CD3OD): δ 7.96-7.66
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-3-flu or o-4-m et h yl-
ben za m id e (2q). Yield 28%; mp 132 °C. H NMR (CDCl3): δ
1
(m, 4H, H2′, H4′, H5′, H6′); 6.52 (d, 1H, J ) 2.1 Hz, H8); 6.30 (s,
1H, H3); 6.27 (d, 1H, J ) 1.9 Hz, H6); 3.92 (s, 3H, OCH3). MS
m/z 335 (M+). Anal. (C17H12F3NO3) C, H, F, N.
8.49 (d, 1H, J ) 2.4 Hz, H6); 8.01-7.95 (m, 1H, H6′); 7.63-
7.46 (m, 2H, H2′, H5′); 6.52 (d, 1H, J ) 2.4 Hz, H4); 4.03 (s, 3H,
OCH3); 4.01 (s, 3H, OCH3); 2.65 (s, 3H, CH3CO); 2.62 (s, 3H,
Ph-CH3). MS m/z 331 (M+). Anal. (C18H18FNO4) C, H, F, N.
N-(2-Acetyl-3,5-dim eth oxyph en yl)-3-ch lor om eth ylben z-
a m id e (2r ). Yield 65%; mp 96 °C. 1H NMR (CDCl3): δ 8.24
(d, 1H, J ) 2.4 Hz, H6); 8.08-7.97 (m, 2H, H2′, H6′); 7.61-7.48
(m, 2H, H4′, H5′); 6.26 (d, 1H, J ) 2.4 Hz, H4); 4.68 (s, 2H,
CH2Cl); 3.93 (s, 3H, OCH3); 3.90 (s, 3H, OCH3); 2.64 (s, 3H,
CH3CO). MS m/z 347 (M+). Anal. (C18H18ClNO4) C, H, N.
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-4-et h ylb en za m id e
2-(3-Ch lor op h en yl)-5-h yd r oxy-7-m eth oxy-4-qu in olon e
(3c). Yield 65%. 1H NMR (CDCl3): δ 7.58-7.45 (m, 2H, H2′,
H6′); 7.38-7.31 (m, 2H, H4′, H5′); 6.89 (d, 1H, J ) 2 Hz, H8);
6.67 (s, 1H, H3); 6.45 (d, 1H, J ) 2 Hz, H6); 3.79 (s, 3H, OCH3).
MS m/z 301 (M+). Anal. (C16H12ClNO3) C, H, Cl, N.
5-Hyd r oxy-7-m eth oxy-2-(3-tr iflu or om eth yloxyp h en yl)-
1
4-qu in olon e (3d ). Yield 70%. H NMR (acetone-d6): δ 7,89-
7,68 (m, 3H, H2′, H4′, H6′); 7.56-7.52 (m, 1H, H5′); 6.60 (d, 1H,
J ) 1.2 Hz, H8); 6.32 (s, 1H, H3); 6.19 (d, 1H, J ) 1.2 Hz, H6);
3.84 (s, 3H, OCH3). MS m/z 351 (M+). Anal. (C17H12F3NO4) C,
H, F, N.
1
(2s). Yield 32%; mp 115 °C. H NMR (CDCl3): δ 8.24 (d, 1H,
J ) 2.2 Hz, H6); 7.94 (d, 2H, J ) 7.9 Hz, H2′, H6′); 7.32 (d, 2H,
J ) 7.9 Hz, H3′, H5′); 6.21 (d, 1H, J ) 2.2 Hz, H4); 3.90 (s, 3H,
OCH3); 3.87 (s, 3H, OCH3); 2.70 (q, 2H, J ) 7.6 Hz, CH2CH3);
2.61 (s, 3H, CH3CO); 1.25 (t, 3H, J ) 7.6 Hz, CH3CH2). MS
m/z 327 (M+). Anal. (C19H21NO4) C, H, N.
5-Hydr oxy-7-m eth oxy-2-(3-m eth oxyph en yl)-4-qu in olon e
1
(3e). Yield 35%. H NMR (CD3OD): δ 7.49-7.31 (m, 3H, H2′,
H5′, H6′); 7,14-7.10 (m, 1H, H4′); 6.57 (d, 1H, J ) 2.2 Hz, H8);
6.29 (s, 1H, H3); 6.19 (d, 1H, J ) 2.2 Hz, H6); 3.86 (s, 3H,
OCH3); 3.81 (s, 3H, OCH3). Anal. (C17H15NO4 ) C, H, N.
2-(3-F lu or op h en yl)-5-h yd r oxy-7-m eth oxy-4-qu in olon e
(3f). Yield 71%. 1H NMR (DMSO-d6): δ 11.89 (sl, 1H, OH);
7.73-7.60 (m, 2H, H2′, H6′); 7.46-7.43 (m, 2H, H4′, H5′); 6.64
(d, 1H, J ) 1.3 Hz, H8); 6.35 (s, 1H, H3); 6.20 (d, 1H, J ) 1.2
Hz, H6); 3,81 (s, 3H, OCH3). MS m/z 286 (M + 1)+. Anal.
(C16H12FNO3) C, H, F, N.
N-(2-Acetyl-3,5-d im eth oxyp h en yl)-3,4-diflu or oben za m -
id e (2t). Yield 77%; mp 98 °C. 1H NMR (CDCl3): δ 8.17 (d,
1H, J ) 2.4 Hz, H6); 7.89-7.77 (m, 2H, H2′, H6′); 7.35-7.31
(m, 1H, H5′); 6.25 (d, 1H, J ) 2.4 Hz, H4); 3.91 (s, 3H, OCH3);
3.90 (s, 3H, OCH3); 2.64 (s, 3H, CH3CO). MS m/z 335 (M+).
Anal. (C17H15F2NO4) C, H, F, N.
N-(2-Acetyl-3,5-d im eth oxyp h en yl)n icotin a m id e (2u ).
Yield 48%; mp 136 °C. H NMR (CDCl3): δ 9.29 (d, 1H, J )
1
5-Hyd r oxy-2-(3-iod op h en yl)- 7-m et h oxy-4-q u in olon e
(3g). Yield 52%. 1H NMR (DMSO-d6): δ 8.18-8.16 (m, 1H,
H2′); 7.93 (dd, 1H, J 1 ) 1,7 Hz, J 2 ) 8 Hz, H6′); 7.83 (dd, 1H,
J 1 ) 1.7 Hz, J 2) 7.6 Hz, H4′); 7.36 (t, 1H, J ) 7.7 Hz, H5′);
6.61 (d, 1H, J ) 2.1 Hz, H8); 6.17 (d, 1H, J ) 2.1 Hz, H6); 3.81
(s, 3H, OCH3). MS m/z 394 (M + 1)+. Anal. (C16H12INO3).
Calcd: C, 48.88; H, 3.08; I, 32.28; N, 3.56. Found: C, 48.51;
H, 3.10; I, 31.24; N, 3.53.
2-(3-Br om op h en yl)-5-h yd r oxy-7-m eth oxy-4-qu in olon e
(3h ). Yield 52%. 1H NMR (DMSO-d6): δ 8.05 (sl, 1H, NH);
7.82-7.75 (m, 2H, H2′, H6′); 7.60-7.51 (m, 2H, H4′, H5′); 6.51
(d, 1H, J ) 2.1 Hz, H8); 6.31 (s, 1H, H3); 6.23 (d, 1H, J ) 2.1
Hz, H6); 4.05 (s, 3H, OCH3). MS m/z 346 (M + 2)+. Anal.
(C16H12BrNO3). Calcd: C, 55.51; H, 3.49; Br, 23.08; N, 4.05.
Found: C, 55.35; H, 3.42; Br, 22.14; N, 4.00.
2-(3,5-Difluorophenyl)-5-hydroxy-7-methoxy-4-quinolone
(3i). Yield 55%. 1H NMR (CDCl3): δ 7.82 (s, 1H, H3); 7.59-
7.54 (m, 2H, H2′, H6′); 7.42 (d, 1H, J ) 2.3 Hz, H8); 7.24-7.19
(m, 1H, H4′); 6.80 (d, 1H, J ) 2.2 Hz, H6); 4.31 (s, 3H, OCH3).
MS m/z 303 (M+). Anal. (C16H11F2NO3) C, H, F, N.
2-(4-F lu or op h en yl)-5-h yd r oxy-7-m eth oxy-4-qu in olon e
(3j). Yield 55%. 1H NMR (CDCl3): δ 7,58-7,56 (m, 2H, H2′,
H6′); 7,25 (d, 1H, J ) 2,2 Hz, H8); 7,11 (t, 2H, J ) 8,2 Hz, H3′,
H5′); 6,37 (s, 1H, H3); 6,19 (d, 1H, J ) 2,2 Hz, H6); 3,76 (s, 3H,
OCH3). MS m/z 286 (M + 1)+. Anal. (C16H12FNO3) C, H, F, N.
2-(2-F lu or op h en yl)-5-h yd r oxy-7-m eth oxy-4-qu in olon e
(3k ). Yield 47%. 1H NMR (DMSO): δ 12.59 (sl, 1H, O-H); 12.0
(sl, 1H, N-H); 7,71-7,60 (m, 2H, H4′, H6′); 7.47-7.38 (m, 2H,
1.6 Hz, H2′); 8.78 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.9 Hz, H4′); 8.31
(ddd, 1H, J 1 ) 1.6 Hz, J 2 ) 2.3 Hz, J 3 ) 8.0 Hz, H6′); 8.21 (d,
1H, J ) 2.4 Hz, H6); 7.47 (dd, 1H, J 1 ) 4.8 Hz, J 2 ) 7.8 Hz,
H5′); 6.27 (d, 1H, J ) 2.4 Hz, H4); 3.93 (s, 3H, OCH3); 3.91 (s,
3H, OCH3); 2.64 (s, 3H, CH3CO). MS m/z 301 (M + 1)+. Anal.
(C16H16N2O4) Calcd C, H, N.
N-(2-Acet yl-3,5-d im et h oxyp h en yl)-4-p h en ylb en za m -
id e (4a ). Yield 37%; mp 165 °C. H NMR (CDCl3): δ 8.29 (d,
1H, J ) 2.4 Hz, H6); 8.15-8.11 (m, 2H, H2′, H6′); 7.76-7.63
(m, 4H, H3′, H5′, H2′′, H6′′); 7.51-7,39 (m, 3H, H3′′, H4′′, H5′′);
6.26 (d, 1H, J ) 2.4 Hz, H4); 3.94 (s, 3H, OCH3); 3.91 (s, 3H,
OCH3); 2.65 (s, 3H, CH3CO). MS m/z 376 (M + 1)+. Anal.
(C23H21NO4) C, H, N.
1
N-(2-Acet yl-3,5-d im et h oxyp h en yl)b en zyla m id e (4b ).
1
Yield 45%. H NMR (CDCl3): δ 7.98 (d, 1H, J ) 2.4 Hz, H6);
7.38-7.30 (m, 5H, H2′, H3′, H4′, H5′, H6′); 6.18 (d, 1H, J ) 2.4
Hz, H4); 3,84 (s, 3H, OCH3); 3.83 (s, 3H, OCH3); 3.55 (s, 2H,
CH2); 2.54 (s, 3H, CH3CO). Anal. (C18H19NO4) C, H, N.
N-(2-Acetyl-3,5-dim eth oxyph en yl)-tr a n s-cin n am ide (4c).
1
Yield 31%; mp 117 °C. H NMR (CDCl3): δ 8.45 (sl, 1H, NH);
8.19 (d, 1H, J ) 2.4 Hz, H6); 7.73 (d, 1H, J ) 15.6 Hz, Hâ);
7.60-7.55 (m, 2H, H2′, H6′); 7.40-7.37 (m, 3H, H3′, H4′, H5′);
6.59 (d, 1H, J ) 15.6 Hz, HR); 6.22 (d, 1H, J ) 2.4 Hz, H4);
3.91 (s, 3H, OCH3); 3.89 (s, 3H, OCH3); 2.62 (s, 3H, CH3CO).
MS m/z 326 (M + 1)+. Anal. (C20H21NO4) C, H, N.
5-Hyd r oxy-7-m eth oxy-4-qu in olon es (3). To a stirred
solution of 2 in t-BuOH (5 mL/mmol) under N2 atmosphere

5-Hydroxy-7-methoxy-2-phenyl-4-quinolones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 20 4969
H3′, H5′); 6.51 (d, 1H, J ) 2.3 Hz, H8); 6.20 (d, 1H, J ) 2.2 Hz,
H6); 6.12 (s, 1H, H3); 3.79 (s, 3H, OCH3). MS m/z 286 (M +
1)+. Anal. (C16H12FNO3) C, H, F, N.
H4′, H5′); 7.41-7,38 (m, 2H, H2′, H6′); 6.42 (d, 1H, J ) 2.1 Hz,
H8); 6.32 (d, 1H, J ) 2.1 Hz, H6); 6.13 (s, 1H, H3); 3.90 (s, 3H,
OCH3); 3.49 (s, 3H, NCH3). Anal. (C17H15NO3) C, H, N.
6,7-Dim et h oxy-5-h yd r oxy-2-p h en yl-4-q u in olon e (3l).
Yield 15%. 1H NMR (DMSO-d6): δ 8.04-8.01 (m, 2H, H2′, H6′);
7.55-7.51 (m, 3H, H3′, H4′, H5′); 7.10 (s, 1H, H3); 7.01 (s, 1H,
H8); 3.95 (s, 3H, OCH3); 3.72 (s, 3H, OCH3). MS m/z 298 (M +
1)+. Anal. (C17H15NO4) C, H, N.
1-Eth yl-5-h ydr oxy-7-m eth oxy-2-ph en yl-4-qu in olon e (4b).
Yield 21%. 1H NMR (CDCl3): δ 7.52-7.48 (m, 3H, H3′, H4′,
H5′); 7.40-7.35 (m, 2H, H2′, H6′); 6.41 (d, 1H, J ) 2.1 Hz, H8);
6.35 (d, 1H, J ) 2.1 Hz, H6); 6.06 (s, 1H, H3); 3.94 (q, 2H, J )
7.1 Hz, N-CH2); 3,89 (s, 3H, OCH3); 1.26 (t, 3H, J ) 7.1 Hz,
CH3CH2). MS m/z 295 (M+). Anal. (C18H17NO3) C, H, N.
1-Eth yl-2-(3-flu or op h en yl)-5-h yd r oxy-7-m eth oxy-4-qu i-
n olon e (4c). Yield 22%. 1H NMR (CDCl3): δ 7.55-7.34 (m,
1H, H6′); 7.22-7.14 (m, 3H, H2′, H4′, H5′); 6.41 (d, 1H, J ) 1.9
Hz, H8); 6.35 (d, 1H, J ) 1.7 Hz, H6); 6.04 (s, 1H, H3); 3.94 (q,
2H, J ) 7.1 Hz, NCH2); 3.89 (s, 3H, OCH3); 1.27 (t, 3H, J )
7.1 Hz, CH3CH2). MS m/z 313 (M+). Anal. (C18H16FNO3) C, H,
F, N.
2-P h en yl-5,6,7-tr im eth oxy-4-qu in olon e (3m ). Yield 49%.
1H NMR (CDCl3): δ 8.06-8.01 (m, 2H, H2′, H6′); 7.49-7.45 (m,
3H, H3′, H4′, H5′); 7.30 (s, 1H, H3); 7.11 (s, 1H, H8); 4.19 (s, 3H,
OCH3); 4.01 (s, 3H, OCH3); 3.96 (s, 3H, OCH3). MS m/z 312
(M + 1)+. Anal. (C18H17NO4) C, H, N.
5-Hyd r oxy-2-P h en yl-4-qu in olon e (3n ). Yield 80%. 1H
NMR (CD3OD): δ 8.29 (d, 1H, J ) 9.1 Hz, H8); 7.94-7.89 (m,
2H, H2′, H6′); 7.71-7.66 (m, 3H, H3′, H4′, H5′); 7.41 (dd, 1H, J 1
) 2.3 Hz, J 2 ) 9 Hz, H7); 7.33-7.27 (dd, 1H, J 1 ) 2.2 Hz, J 2
)
2-(1,4-Biph en yl)-5-h ydr oxy-7-m eth oxy-4-qu in olon e (6a).
9.1 Hz, H6); 7.15 (s, 1H, H3). MS m/z 238 (M + 1)+. Anal.
(C15H11NO2) C, H, N.
Yield 25%. 1H NMR (CDCl3): δ 7.74-7.72 (m, 2H, H2′, H6′);
7.63-7.59 (m, 2H, H2′′, H6′′); 7.53-7.41 (m, 5H, H3′, H5′, H3′′
,
2-(3-F lu or op h en yl)-5-h yd r oxy-2-p h en yl-4-q u in olon e
(3o). Yield 70%. 1H NMR (CD3OD): δ 8.28 (d, 1H, J ) 9.1 Hz,
H8); 7.74-7,68 (m, 3H, H2′, H4′, H6′); 7.51-7.44 (m, 1H, H5′);
H
4′′, H5′′); 6.41 (s, 1H, H3); 6.34 (d, 1H, J ) 2.5 Hz, H8); 6.27
(d, 1H, J ) 2.5 Hz, H6); 3.87 (s, 3H, OCH3). MS m/z 344 (M +
1)+. Anal. (C22H17NO3) C, H, N.
7.40 (dd, 1H, J 1 ) 2.1 Hz, J 2 ) H7); 7.33-7.28 (dd, 1H, J 1
)
2-Ben zyl-5-h yd r oxy-7-m eth oxy-4-qu in olon e (6b). Yield
2.2 Hz, J 2 ) 9.1 Hz, H6); 7.14 (s, 1H, H3). MS m/z 256 (M +
1
35%. H NMR (CD3OD): δ 7.40-7.16 (m, 6H, H2′-6′, H3); 6.36
1)+. Anal. (C15H10FNO2) C, H, F, N.
(d, 1H, J ) 2.2 Hz, H8); 6.29 (d, 1H, J ) 2.2 Hz, H6); 3.84 (s,
3H, OCH3); 2.39 (s, 2H, CH2). MS m/z 282 (M + 1)+. Anal.
(C17H15NO3) C, H, N.
2-(3-F lu or o-4-m et h oxyp h en yl)-5-h yd r oxy-7-m et h oxy-
4-qu in olon e (3p ). Yield 15%. 1H NMR (CD3OD): δ 8.54 (d,
1H, J ) 2.1 Hz, H6′); 7.61-7.56 (m, 2H, H2′, H5′); 6.63 (d, 1H,
J ) 3.1 Hz, H8); 6.30 (s, 1H, H3); 6.24 (d, 1H, J ) 3.1 Hz, H6);
3.85 (s, 3H, OCH3); 3.81 (s, 3H, OCH3). MS m/z 316 (M + 1)+.
Anal. (C17H14FNO4) C, H, F, N.
2-(3-F lu or o-4-m et h ylp h en yl)-5-h yd r oxy-7-m et h oxy-4-
qu in olon e (3q). Yield 70%. 1H NMR (DMSO-d6): δ 11.81 (sl,
1H, OH); 7.69-7,45 (m, 3H, H2′, H5′, H6′); 6.64 (d, 1H, J ) 1.8
Hz, H8); 6.34 (s, 1H, H3); 6.19 (d, 1H, J ) 1.8 Hz, H6); 3.81 (s,
3H, OCH3); 2.32 (s, 3H, CH3). MS m/z 300 (M + 1)+. Anal.
(C17H14FNO3) C, H, F, N.
7,9-Dim eth oxy-4-p h en ylben za zocin -3,6-d ion e (7). Yield
10%. 1H NMR (DMSO-d6): δ 9.75 (sl, 1H, NH); 7.29-7.20 (m,
5H, H2′, H3′, H4′, H5′, H6′); 6.58 (d, 1H, J ) 1.7 Hz, H10); 6.28
(d, 1H, J ) 1.7 Hz, H8); 3.79 (s, 3H, OCH3); 3.78 (s, 3H, OCH3);
3.0-2.86 (m, 2H, COCH2CHPh); 2.68 (dd, 2H, J 1 ) 3.7 Hz, J 2
) 9.1 Hz, NHCOCH2CHPh); 2.28 (bd, 1H, J ) 11.8 Hz, CH-
Ph). MS m/z 326 (M + 1)+. Anal. (C19H19NO4) C, H, N.
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
of target compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
2-(3-Ch lor om eth ylp h en yl)-5-h yd r oxy-7-m eth oxy-4-qu i-
1
n olon e (3r ). Yield 21%. H NMR (CD3OD): δ 7.81-7.53 (m,
4H, H2′, H4′, H5′, H6′); 6.96 (d, 1H, J ) 2.2 Hz, H8); 6.60 (s, 1H,
H3); 6.25 (d, 1H, J ) 2.2 Hz, H6); 4.67 (s, 2H, CH2Cl); 3.86 (s,
3H, OCH3). Anal. (C17H14ClNO3) C, H, Cl, N.
2-(4-E t h ylp h en yl)-5-h yd r oxy-7-m et h oxy-4-q u in olon e
(3s). Yield 26%. 1H NMR (CD3OD): δ 7.66 (d, 2H, J ) 8.2 Hz,
H2′, H6′); 7.40 (d, 2H, J ) 8.1 Hz, H3′, H5′); 6.58 (d, 1H, J ) 2.2
Hz, H8); 6.30 (s,1H, H3); 6.23 (d, 1H, J ) 2,1 Hz, H6); 3.86 (s,
3H, OCH3); 2,72 (q, 2H, J ) 7,6 Hz, CH2CH3); 1.27 (t, 3H, J )
7,6 Hz, CH3CH2). MS m/z 296 (M + 1)+ . Anal. (C18H17NO3) C,
H, N.
2-(3,4-Difluorophenyl)-5-hydroxy-7-methoxy-4-quinolone
(3t). Yield 73%. 1H NMR (DMSO-d6): δ 11.89 (sl, 1H, OH);
8.04-7.95 (m, 1H, H6′); 7.71-7.63 (m, 2H, H2′, H5′); 6.63 (d,
1H, J ) 2,0 Hz, H8); 6,35 (s, 1H, H3); 6.20 (d, 1H, J ) 2,1 Hz,
H6); 3.81 (s, 3H, OMe). MS m/z 303 (M+). Anal. (C16H11F2NO3)
C, H, F, N.
5-Hyd r oxy-7-m eth oxy-2-(3-n icotin yl)-4-qu in olon e (3u ).
Yield 35%. 1H NMR (DMSO-d6): δ 12.0 (sl, 1H, OH); 9.0 (d,
1H, J ) 1.5 Hz, H2′); 8.76 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.6 Hz,
H4′); 8.23 (ddd, 1H, J 1 ) J 2 ) 1.7 Hz, J 3 ) 8.1 Hz, H6′); 7.61
(dd, 1H, J 1 ) 4.8 Hz, J 2 ) 7.8 Hz, H5′); 6.61 (d, 1H, J ) 2.6 Hz,
H8); 6.38 (s, 1H, H3); 6.22 (d, 1H, J ) 2.6 Hz, H6); 3.82 (s, 3H,
OCH3). MS m/z 269 (M + 1)+. Anal. (C15H12N2O3) C, H, N.
N-Alk yl-5-h yd r oxy-7-m eth oxy-4-qu in olon es (4). To a
stirred solution of quinolone 3 in anhydrous DMF (5 mL/mmol)
were successively added the alkyl halide (1.5 equiv) and K2-
CO3 (3 equiv). The reaction mixture was stirred at room
temperature for 2 h and then heated at 80 °C for 3 h. After it
was heated, the reaction mixture was poured into water,
extracted with EtOAC, and concentrated. Purification by
chromatography column eluted with cyclohexane:AcOEt (9:1)
or by preparative TLC (cyclohexane: AcOEt 7:3) afforded
N-alkylquinolones 7 as white solids.
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