Quinolone analogs 13: Synthesis of novel 1,1′-(2-methylenepropane-1,3-diyl)di(4-quinolone-3-carboxylate) and related compounds

Article abstract of DOI:10.1002/jhet.1861

The reaction of the 4-hydroxyquinoline-3-carboxylate 6 with pentaerythritol tribromide gave the 1,1′-(2-methylenepropane-1,3-diyl)di(4-quinolone-3-carboxylate) 11, whose reaction with bromine afforded the 1,1′-(2-bromo-2-bromomethylpropane-1,3-diyl)di(4-quinolone-3-carboxylate) 12. Compound 12 was transformed into the (Z)-1,1′-(2-acetoxymethylpropene-1,3-diyl)di(4-quinolone-3-carboxylate) 13 or (E)-1,1′-[2-(imidazol-1-ylmethyl)propene-1,3-diyl]di(4-quinolone-3-carboxylate) 14. Hydrolysis of the dimer (Z)-13 or (E)-14 with potassium hydroxide provided the (E)-1,1′-(2-hydroxymethylpropene-1,3-diyl)di(4-quinolone-3-carboxylic acid) 15 or (Z)-1,1′-[2-(imidazol-1-ylmethyl)propene-1,3-diyl]di(4-quinolone-3-carboxylic acid) 16, respectively. The nuclear Overhauser effect (NOE) spectral data supported that those hydrolysis resulted in the geometrical conversion of (Z)-13 into (E)-15 or (E)-14 into (Z)-16.

Full text of DOI:10.1002/jhet.1861

0
1
720
Quinolone Analogs 13: Synthesis of Novel 1,1 -(2-Methylenepropane-1,3-
Vol 51
diyl)di(4-quinolone-3-carboxylate) and Related Compounds
a
a
a
b
c,d
d
Yoshihisa Kurasawa, * Kiminari Yoshida, Naoki Yamazaki, Eisuke Kaji, Kenji Sasaki, * Yoshito Zamami,
d
d
d
e
Takatoshi Fujii, Min Zhao, Hideyuki Ito, and Haruhiko Fukaya
a
School of Pharmacy, Iwakli Meisei University, Iino, Chuodai, Iwaki-shi, Fukushima 970-8551, Japan
b
School of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku, Tokyo 108-8641, Japan
Center for Faculty Development, Okayama University, Tsushimanaka, Okayama-shi, Okayama 700-8530, Japan
Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Tsushimanaka, Okayama-shi,
Okayama 700-8530, Japan
c
d
e
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi, Hachioji, Tokyo 192-0392, Japan
*
E-mail: kura77@iwakimu.ac.jp; sasaki-k@cc.okayama-u.ac.jp
Received May 17, 2012
DOI 10.1002/jhet.1861
Published online 16 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
0
The reaction of the 4-hydroxyquinoline-3-carboxylate 6 with pentaerythritol tribromide gave the 1,1 -(2-
0
methylenepropane-1,3-diyl)di(4-quinolone-3-carboxylate) 11, whose reaction with bromine afforded the 1,1 -
(
2-bromo-2-bromomethylpropane-1,3-diyl)di(4-quinolone-3-carboxylate) 12. Compound 12 was transformed
0
0
into the (Z)-1,1 -(2-acetoxymethylpropene-1,3-diyl)di(4-quinolone-3-carboxylate) 13 or (E)-1,1 -[2-(imidazol-
1
-ylmethyl)propene-1,3-diyl]di(4-quinolone-3-carboxylate) 14. Hydrolysis of the dimer (Z)-13 or (E)-14 with
0
potassium hydroxide provided the (E)-1,1 -(2-hydroxymethylpropene-1,3-diyl)di(4-quinolone-3-carboxylic
acid) 15 or (Z)-1,1 -[2-(imidazol-1-ylmethyl)propene-1,3-diyl]di(4-quinolone-3-carboxylic acid) 16, respec-
0
tively. The nuclear Overhauser effect (NOE) spectral data supported that those hydrolysis resulted in the geomet-
rical conversion of (Z)-13 into (E)-15 or (E)-14 into (Z)-16.
J. Heterocyclic Chem., 51, 1720 (2014).
INTRODUCTION
Recently, we undertook the structural modification of
ordinary new quinolones (Chart 1), whose basic moiety at
the 7-position was shifted to the N1-side chain, leading to
the synthesis of the 1-(pyridin-4-ylalkenyl)-4-quinolone-3-
carboxylates 4 [18]. As the result, one of compounds 4
In previous papers [1–9], we reported the synthesis and
biological activities of the 1-alkyl-4-oxopyridazino[3,4-b]qui-
noxalines 1 as candidates of antibacterial quinolone analogs
(
Chart 1), some of which showed good antibacterial,
1
2
(
X═H, R ═R ═C H ) was found to possess antimalarial
2
5
antifungal, and/or algicidal activities [3–6]. To search for
biologically active compounds, we have then changed the tar-
get ring system from 4-oxopyridazino[3,4-b]quinoxaline to 4-
oxoquinoline such as quinolone antibacterials. Concerning the
antibacterial quinolones and new quinolones, many research
groups and pharmaceutical companies have developed the ex-
cellent antibacterial agents by the modification of the substitu-
ents at the N1, C7, and/or C8 positions of the quinolone
skeleton. Nowadays, typical new quinolones such as levoflox-
acin [10], enoxacin [11], ciprofloxacin [12,13], sparfloxacin
activity, whose potency was regarded as an effective level,
whereas the 7-chloro derivatives of compounds 4 (X═Cl)
did not exhibit the antimalarial activity. The subsequent shift
of the N1-pyridyl moiety to the C3-side chain produced one
more class of the antimalarial 4-quinolones 5 [19].
In continuation of the aforementioned works, we further
tried the transformation of the N1-moiety in the structural
modification of 4-quinolones. Namely, we attempted the
conversion of the 4-hydroxyquinoline-3-carboxylate 6 into
the 4-quinolone-3-carboxylate 7 (Scheme 1) using pentaer-
ythritol tribromide so as to provide various quinolone
analogs 8 possessing two kinds of bases A and B in the
[
14], and some others have clinically been used all over the
world. Because quinolone antibacterials are known to interact
with the DNA gyrase, various activities have been expected
for quinolone derivatives. For example, the 4-quinolone-3-
carboxamides 2 [15] and 3 [16] were reported to exhibit anti-
viral activities. The recent review on 4-quinolones involving
new quinolones introduces the synthesis and modification
together with the antibacterial and antitumor activities [17].
0
N1-moiety. However, the 1,1 -(2-methylenepropane-1,3-
diyl)di(4-quinolone-3-carboxylate) 11 was unexpectedly
obtained instead of compound 7 as shown in Scheme 2.
0
This paper describes the synthesis of novel 1,1 -(2-methyle-
nepropane-1,3-diyl)di(4-quinolone-3-carboxylate) 11 and
©
2014 HeteroCorporation

0
November 2014
Quinolone Analogs 13: Synthesis of Novel 1,1 -(2-Methylenepropane-1,3-diyl)di(4-
1721
quinolone-3-carboxylate) and Related Compounds
Chart 1
0
its transformation into the dibromo, imidazolyl, acetoxy, and
with sodium acetate or imidazole produced the (Z)-1,1 -(2-
hydroxy derivatives 12–16.
acetoxymethylpropene-1,3-diyl)di(4-quinolone-3-carboxylate)
0
13 or (E)-1,1 -[2-(imidazol-1-ylmethyl)propene-1,3-diyl]di(4-
RESULTS AND DISCUSSION
quinolone-3-carboxylate) 14, respectively. The hydrolysis of
the dimer 13 or 14 with potassium hydroxide provided the
0
Synthesis of the 1,1 -(2-methylenepropane-1,3-diyl)di(4-
0
(
E)-1,1 -(2-hydroxymethylpropene-1,3-diyl)di(4-quinolone-3-
quinolone-3-carboxylate) 11 and related dimers 12–16. The
reaction of the 4-hydroxyquinoline-3-carboxylate 6 with
pentaerythritol tribromide in the presence of potassium
carbonate gave the 1,1 -(2-methylenepropane-1,3-diyl)di(4-
quinolone-3-carboxylate) 11, presumably via intermediates 7,
0
carboxylic acid) 15 or (Z)-1,1 -[2-(imidazol-1-ylmethyl)
propene-1,3-diyl]di(4-quinolone-3-carboxylic
acid)
16,
0
respectively.
0
The structure of novel 1,1 -(2-methylenepropane-1,3-
diyl)di(4-quinolone-3-carboxylate) 11 and the dimers
9
, and 10 (Scheme 2). The electron withdrawing 4-quinolone
12–16 in Scheme 2 was assigned by the analytical and spectral
ring [20] would activate the bromomethyl carbon of an
intermediate 7, whose facile reaction with the second 4-
quinolone-3-carboxylate 6 formed an intermediate 9. The
presence of two 4-quinolone rings in an intermediate 9 might
further activate the bromomethyl carbon [20] to form an
oxetane intermediate 10 [21], whose ring cleavage was
postulated to afford the dimer 11 with elimination of
formaldehyde [22]. The reaction of the dimer 11 with
data. Most of dimers were hygroscopic and found to absorb
moisture gradually while the microanalyses were carried
out. Accordingly, the hydrate numbers in the molecular
formulae were not constant for all compounds.
NMR spectral data. The dimers 11 and 12 were found
to have a symmetrical structure from the NMR spectral data.
In the dimer 11, the methylene proton signal (4H, d 5.16)
was observed in a lower magnetic field than the vinilic
proton signal (2H, d 4.64), which was confirmed by the
0
bromine provided the 1,1 -(2-bromo-2-bromomethylpropane-
,3-diyl)di(4-quinolone-3-carboxylate) 12, whose reaction
1
Scheme 1
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Y. Kurasawa, K. Yoshida, N. Yamazaki, E. Kaji, K. Sasaki, Y. Zamami,
T. Fujii, M. Zhao, H. Ito, and H. Fukaya
Vol 51
Scheme 2
nuclear Overhauser effect (NOE) spectral data (Table 1,
Chart 2). The vinylic protons suspicious of shielding (d
and NOE (Table 1) exhibited the geometry of the dimers
13–16 as 13 (Z-form), 14 (E-form), 15 (E-form), and 16
(Z-form). The crucial NOE data are as follows: the dimer
13 [from d 5.91 (radiation) to d 7.28 (NOE); from d 4.53
(radiation) to d 9.02, 7.70 (NOE)]; the dimer 14 [from d 8.31
(radiation) to d 7.48, 4.82 (NOE); from d 4.82 (radiation) to
d 8.31 (NOE)]; the dimer 15 [from d 7.15 (radiation) to d
4.25 (NOE); from d 4.25 (radiation) to d 7.15 (NOE)]; the
dimer 16 [from d 5.33 (radiation) to d 7.26 (NOE)].
Table 2 shows the carbon chemical shifts of our typi-
cal quinolone dimers 11, 13, and 14 assigned by the
heteronuclear multiple bond connectivity (HMBC) and
heteronuclear multiple quantum coherence (HMQC)
spectral data.
4
.64) would exist in the position above the quinolone
ring to result in the anisotropy effect. The dimer 11
includes the 1-allyl-4-quinolone moiety, and the dimers
1
4–16 involve both the 1-allyl-4-quinolone and 1-vinyl-4-
quinolone moieties (Chart 3). On the basis of the 2-H (d
.65) and 8-H (d 7.86) proton signals of the dimer 11
8
having the 1-allyl-4-quinolone moiety, the 2-H and 8-H
proton signals of the dimers 14–16 were aasigned as
follows; 2-H (d 8.67–8.59) and 8-H (d 7.88–7.78) in the
1
-allyl-4-quinolone moiety; 2-H (d 8.55–8.32) and 8-H
d 7.72–7.30) in the 1-vinyl-4-quinolone moiety [23].
Namely, the 2-H and 8-H proton signals of the
-allyl-4-quinolone moiety were observed in lower
magnetic fields than those of the 1-vinyl-4-quinolone
moiety. The data of the chemical shifts (Charts 2 and 3)
(
1
Interpretation for the isomerization of the (E)-isomer and
(Z)-isomer into (Z)-isomer and (E)-isomer.
In the
transformation of the dibromodimer 12 into the dimer (Z)-
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Quinolone Analogs 13: Synthesis of Novel 1,1 -(2-Methylenepropane-1,3-diyl)di(4-
1723
quinolone-3-carboxylate) and Related Compounds
Table 1
NOE correlation of compounds 11, (Z)-13, (E)-14, (E)-15, and (Z)-16.
Compound
Radiation (d)
NOE (d) (%)
1
1
8,65
5.16 (1.1)
8.65 (0.73), 7.86 (2.2)
9.46 (5.7), 8.34 (6.1), 7.28 (2.2), 4.53 (0.69)
5
.16
a
a
a
a
(
Z)-13
E)-14
5.91
.53
8.31
a
a
4
9.02 (1.9), 7.70 (0.61), 5.91 (0.39)
a a a
(
7.48 (0.23), 7.02 (0.29), 4.82 (0.16)
4.82 (0.37)
7
6
6
5
4
.48
.80
.79
.18
.82
7.02 (0.94)
7.30 (0.30)
7.88 (0.57), 7.48 (0.41), 7.02 (1.2)
a
a
a
a
a
8.31 (0.70), 7.48 (1.7), 7.02 (1.2)
(
E)-15
Z)-16
8.59
5.47 (3.4)
7.15 (1.4)
8.36 (1.8), 7.52 (3.5), 4.25 (1.4)
8
7
5
5
4
7.98
5
5
.36
.15
.65
.47
.25
a
4.25 (2.0)
8.59 (1.8), 7.84 (8.7), 4.25 (1.5)
a
7.15 (4.9), 5.65 (1.5), 5.47 (0.77)
(
7.78 (1.5)
.54
.33
8.60 (0.84), 7.78 (3.2)
9.37 (1.7), 7.98 (2.2), 7.26 (0.90), 5.54 (0.23)
a
a
Bold letter values in radiation and NOE columns mean the crucial NOE to support the (E) or (Z) isomer.
Chart 2. Selected NMR spectral data for compounds 11, (Z)-13, (E)-14, (E)-15, and (Z)-16.
1
3 or (E)-14, the antiperiplanar position of two quinolone
(Scheme 3). The allyl bromide residue of an intermediate
17 then underwent substitution with acetate or imidazole to
give the dimer (Z)-13 or (E)-14, respectively.
rings would be favored for the elimination of hydrogen
bromide leading to the formation of an intermediate 17
Journal of Heterocyclic Chemistry
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Y. Kurasawa, K. Yoshida, N. Yamazaki, E. Kaji, K. Sasaki, Y. Zamami,
T. Fujii, M. Zhao, H. Ito, and H. Fukaya
Vol 51
Chart 3. Chemical shifts of 2-H and 8-H protons for compounds 11, (E)-14 (E)-15, and (Z)-16.
Concerning the (E)/(Z) isomerization in the respective
conversion of the dimer (Z)-13 or (E)-14 into the dimer
E)-15 or (Z)-16, there would be some attracting interaction
such as stacking (arene–arene or arene–p interaction) be-
tween two quinolone rings of anion intermediates (Scheme 3)
which was converted into the dibromodimer 12 (Scheme 2).
The reaction of the dibromodimer 12 with sodium acetate
or imidazole effected the b-elimination of hydrogen
bromide to afford the dimer (Z)-13 or (E)-14, respectively,
maintaining two quinolone rings in the trans position
(Scheme 3). Subsequent treatment of the dimer (Z)-13 or
(E)-14 with potassium hydroxide resulted in the geometry
conversion into the dimer (E)-15 or (Z)-16, respectively,
sustaining two quinolone rings in the cis position.
These results suggest the formation of an anion
intermediate 18 and then spontaneous stacking between
two quinolone rings.
(
[24,25]. Successive treatment of anion intermediates 18 with
hydrochloric acid afforded the dimer (E)-15 or (Z)-16.
Antimalarial screening data. The dimers 11–16 were
evaluated for the in vitro antimalarial activity, and the IC50
was 54–100 mM to Plasmodium falciparum. These values
were regarded as not effective level.
CONCLUSION
EXPERIMENTAL
The reaction of the 4-hydroxyquinoline-3-carboxylate 6
with pentaerythritol tribromide gave the 1,1 -dimer 11,
All melting points were determined on a Yazawa (Tokyo) micro
melting point BY-2 apparatus and are uncorrected. The IR spectra
0
Table 2
Carbon chemical shifts for compounds 11, 13, and 14.
Compound 13
Compound 14
1
- Allyl-4-
1- Vinyl-4-
quinolone moiety
1- Allyl-4-
quinolone moiety
1- Vinyl-4-quinolone
moiety
Carbon
Compound 11
quinolone moiety
2
3
4
1
5
6
7
8
8
-C
-C
-C
72
-C
-C
-C
-C
a-C
149.9
109.7
172.0
129.9
110.8
159.3
120.9
120.7
136.0
164.5
150.6
110.3
172.4
130.3
111.3
160.5
121.3
120.8
136.2
164.7
148.3
110.1
172.1
129.2
111.0
158.9
121.1
120.7
136.1
164.3
150.6
110.5
172.4
130.4
111.3
160.5
121.1
120.6
136.1
164.6
148.1
110.2
172.4
129.3
111.0
158.8
121.0
120.6
136.0
164.3
Ester
C═O
Ester
CH
Ester
CH
Others
59.9
14.3
60.3
14.5
60.1
14.4
60.2
14.5
60.1
14.4
2
3
139.1 [N1 (═C═)] 112.4 [N1
169.8 (Acetyl C═O) 134.2 ([N1 (═C═)]
129.6 (N1-CH═) 58.9 (N1-CH ) 54.1
Acetoxy CH ) 20.3 (Acetyl CH
137.9 (Imidazole 2-C) 135.6 [N1 (═C═)]
129.0 (Imidazole 4-C) 128.3 (Imidazole 5-C)
(
═CH
2
)] 54.7 (N1-CH
2
)
2
(
2
3
)
119.7 (N1-C═) 54.2 (N1-CH
2
) 43.3
(
Imidazolyl CH
2
)
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Quinolone Analogs 13: Synthesis of Novel 1,1 -(2-Methylenepropane-1,3-diyl)di(4-
1725
quinolone-3-carboxylate) and Related Compounds
Scheme 3. Postulated mechanism for the conversion of compounds (Z)-13, (E)-14 into (E)-15, (Z)-16.
(
2
potassium bromide) were recorded with a JASCO (Tokyo) FT/IR-
(5.0 g, 9.6 mmol) in acetic acid (100 mL), and the mixture was heated
at 100 C with stirring for 1 h to give a clear solution. After the
ꢀ
00 spectrophotometer. The NMR spectra were measured with a Var-
1
13
ian (Vernon Hills, IL) XL-400 (400 MHz for H and 100 MHz for C)
solution was cooled to room temperature, water (200 mL) was added
to the solution to precipitate crystals 12, which were collected by
filtration and washed with saturated sodium bicarbonate solution and
sodium thiosulfate solution (5.79 g, 92%). Recrystallization from
1
13
and Varian INOVA 600 (600 MHz for H and 151 MHz for C) spec-
trometers. The chemical shifts are given in the d scale. The mass spec-
tra (MS) were determined with a JEOL JMS-01S spectrometer.
Elemental analyses were performed on a Perkin-Elmer (Waltham,
MA) 240B instrument.
ꢀ
ꢁ1
ethanol provided colorless needles; mp 212–213 C; IR: n cm
+
+
+
1720, 1620; MS: m/z 680 (M ), 682 (M + 2), 684 (M +4); NMR
(deuteriodimethyl sulfoxide): 8.82 (s, 2H, 2-H), 8.35 (dd, J=9.0,
4.0 Hz, 2H, 8-H), 7.86 (dd, J= 9.0, 3.0 Hz, 2H, 5-H), 7.71 (ddd,
J=9.0, 9.0, 3.0Hz, 2H, 7-H), 5.18 (d, J= 16.0 Hz, 2H, methylene
CH ), 5.06 (d, J= 16.0 Hz, 2H, methylene CH), 4.19 (q, J=7.0Hz,
Ethyl 6-Fluoro-4-hydroxyquinoline-3-carboxylate (6).
This
sample was synthesized by a method reported in literatures
[
(
26,27], wherein diethyl (4-fluoroanilino)methylenemalonate
obtained from the reaction of 4-fluoroaniline with diethyl
ethoxymethylenemalonate) was refluxed in diphenyl ether.
Diethyl 1,1 -(2-Methylenepropane-1,3-diyl)di(6-fluoro-1,4-
4H, ester CH ), 1.23 (t, J= 7.0 Hz, 6H, ester
2
), 4.08 (s, 2H, BrCH
2
0
CH ). Anal. Calcd. for C28H24Br F N O : C, 49.29; H, 3.55; N,
3
2 2 2 6
dihydro-4-oxoquinoline-3-carboxylate) (11).
compound (5.0g, 21.3mmol), pentaerythritol tribromide
10.36g, 31.9 mmol), and potassium carbonate (4.4 g, 31.9 mmol)
A mixture of
4.11. Found: C, 49.18; H, 3.85; N, 4.21.
0
6
Diethyl (Z)-1,1 -(2-Acetoxymethylpropene-1,3-diyl)di(6-fluoro-
(
1,4-dihydro-4-oxoquinoline-3-carboxylate) (13).
A solution of
ꢀ
in N,N-dimethylformamide (100mL) was heated at 120–140 C
with stirring for 1 h. The reaction mixture was filtered, and the
filtrate was evaporated in vacuo to give colorless crystals 11.
Recrystallization from N,N-dimethylformamide/ethanol/water
afforded colorless needles as monohydrate (5.17 g, 87%); mp
compound 12 (5.0 g, 7.33 mmol) and anhydrous sodium acetate
ꢀ
(1.50 g, 18.3 mmol) in acetic acid (100 mL) was heated at 120 C
with stirring for 1 h and then refluxed with stirring for 2 h.
Evaporation of the solvent in vacuo gave an oily substance, which
was crystallized from ethanol/water to afford colorless needles 13
ꢁ1
+
ꢀ
ꢁ
1
ꢀ
1
(
4
57–158 C; IR: n cm 1720, 1620; MS: m/z 522 (M ); NMR
deuteriodimethyl sulfoxide): 8.65 (s, 2H, 2-H), 7.86 (dd, J = 9.0,
.5 Hz, 2H, 8-H), 7.85 (dd, J = 9.0, 3.0 Hz, 2H, 5-H), 7.66 (ddd,
(3.92 g, 92%); mp 223–225 C; IR: n cm 3440, 1740, 1690, 1620;
+
MS: m/z 580 (M ); NMR (deuteriotrifluoroacetic acid): 2-H [9.46 (s,
1H), 9.02 (s, 1H)], 8-H [8.34 (dd, J=9.0, 4.0Hz, 1H), 7.70 (dd,
J= 9.0, 4.0 Hz, 1H)], 5-H [8.20 (dd, J= 8.0, 3.0 Hz, 1H), 8.10 (dd,
J= 8.0, 2.5 Hz, 1H)], 7-H [7.96 (ddd, J=9.0, 9.0, 3.0Hz, 1H), 7.71
J = 9.0, 8.0, 3.0Hz, 2H, 7-H), 5.16 (s, 4H, CH ), 4.64 (s, 2H,
2
vinylic H), 4.21 (q, J = 7.0Hz, 4H, ester CH ), 1.26 (t, J = 7.0Hz,
2
6
H, ester CH
3
). Anal. Calcd. for C28
H
24
F
2
N
2
O
6
•
H
2
O: C, 62.22;
(ddd, J= 9.0, 9.0, 2.5 Hz, 1H)], 7.28 (s, 1H, vinylic H), 5.91 (s, 2H, CH
4.53 (s, 2H, acetoxy CH ), ester CH [4.49 (q, J= 7.0 Hz, 2H), 4.45 (q,
J= 7.0 Hz, 2H)], 1.86 (s, 3H, acetyl CH ), ester CH [1.31 (t, J=7.0Hz,
3H), 1.26 (t, J= 7.0 Hz, 3H)]. Anal. Calcd. for C30 2.5H O: C,
57.60; H, 4.99; N, 4.48. Found: C, 57.95; H, 4.66; N, 4.65.
2
),
H, 4.85; N, 5.18. Found: C, 62.26; H, 4.60; N, 5.09.
2
2
0
Diethyl 1,1 -(2-Bromo-2-bromomethylpropane-1,3-diyl)di(6-
3
3
fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate) (12). Bromine
H
26
F
2
N
2
O
8
•
2
(2.0 mL, 39.0 mmol) was added to a suspension of compound 11
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Y. Kurasawa, K. Yoshida, N. Yamazaki, E. Kaji, K. Sasaki, Y. Zamami,
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Vol 51
0
Diethyl (E)-1,1 -[2-(Imidazol-1-ylmethyl)propene-1,3-diyl]di-
6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate) (14).
solution of compound 12 (3.0 g, 4.40 mmol) and imidazole
3
.0 Hz, 1H)], 7.26 (s, 1H, vinylic H), 5.54 (s, 2H, CH ), 5.33 (s,
2
(
A
2H, CH ). The COOH proton signals were not observed
2
presumably due to the presence of moisture in a solution. Anal.
Calcd. for C27 3H O: C, 55.29; H, 4.12; N, 9.55.
Found: C, 55.21; H, 3.73; N, 9.51.
(
1.50 g, 22.0 mmol) in N,N-dimethylformamide (30mL) was
18 2 4 6
H F N O •
2
ꢀ
heated at 120–140 C with stirring for 5 h. Evaporation of the
solvent in vacuo gave an oily residue, which was crystallized from
ethanol/water afforded pale yellow needles 14 (1.89 g, 71%); mp
52–253 C; IR: n cm 3440,1720, 1620; MS: m/z 588 (M );
NMR (deuteriodimethyl sulfoxide): 2-H [8.67 (s, 1H), 8.31
s, 1H)], 8-H [7.88 (dd, J =9.0, 4.5 Hz, 1H), 7.30 (dd, J = 9.0,
.5 Hz, 1H)], 5-H [7.86 (dd, J = 9.0, 3.0 Hz, 1H), 7.79 (dd, J = 9.0,
.0 Hz, 1H)], 7-H [7.75 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H), 7.65
ddd, J = 9.0, 9.0, 3.0 Hz, 1H)], imidazole 2-H [7.48 (s, 1H)],
ꢀ
ꢁ1
+
2
REFERENCES AND NOTES
(
4
3
[1] Kurasawa, Y.; Tsuruoka, A.; Rikiishi, N.; Fujiwara, N.;
Okamoto, Y.; Kim, H. S. J Heterocycl Chem 2000, 37, 791.
[
2] Kurasawa, Y.; Sakurai, K.; Kajiwara, S.; Harada, K.;
Okamoto, Y.; Kim, H. S. J Heterocycl Chem 2000, 37, 1257.
3] Kurasawa, Y.; Ohshima, S.; Kishimoto, Y.; Ogura, M.;
Okamoto, Y.; Kim, H. S. Heterocycles 2001, 54, 359.
4] Kurasawa, Y.; Matsuzaki, I.; Satoh, W.; Okamoto, Y.; Kim, H.
(
[
vinylic H [7.02 (s, 1H)], imidazole 4-H, 5-H [6.81 (s, 1H), 6.80
[5.18 (s, 2H), 4.82 (s, 2H)], ester CH
J = 7.0 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H)], ester CH
(
s, 1H)], CH
2
2
[4.22 (q,
[1.27 (t,
[
3
S. Heterocycles 2002, 56, 291.
J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H)]. Anal. Calcd. for
C H F N O 5/6H O: C, 61.69; H, 4.62; N, 9.28. Found: C,
[5] Kurasawa, Y.; Takizawa, J.; Maesaki, Y.; Kawase, A.;
Okamoto, Y.; Kim, H. S. Heterocycles 2002, 58, 359.
•
3
1
26
2
4
6
2
[
6] Kurasawa, Y.; Satoh, W.; Matsuzaki, I.; Maesaki, Y.;
Okamoto, Y.; Kim, H. S. J Heterocycl Chem 2003, 40, 837.
7] Kurasawa, Y.; Kaji, E.; Okamoto, Y.; Kim, H. S. J Heterocycl
Chem 2005, 42, 249.
6
1.97; H, 4.45; N, 8.93.
0
(E)-1,1 -(2-Hydroxymethylpropene-1,3-diyl)di(6-fluoro-1,4-
[
dihydro-4-oxoquinoline-3-carboxylic acid) (15).
A solution
of potassium hydroxide (1.66 g, 29.6 mmol) in water (20 mL)
was added to a boiling suspension of compound 13 (5.0 g,
[8] Kurasawa, Y.; Kawase, A.; Takizawa, J.; Maesaki, Y.; Kaji,
E.; Okamoto, Y.; Kim, H. S. J Heterocycl Chem 2005, 42, 551.
[9] Kurasawa, Y.; Nakamura, M.; Ashida, H.; Masuda, M.; Kaji,
E.; Okamoto, Y.; Kim, H. S. J Heterocycl Chem 2007, 44, 1231.
8
.62 mmol) in ethanol (200 mL)/water (30 mL) to give a clear
solution. The solution was refluxed with stirring for 2 h to
precipitate colorless crystals of potassium salt. After cooling to
room temperature, the colorless crystals were collected by
filtration. The crystals were dissolved in water (20 mL), and 1 N
hydrochloric acid (30 mL) was added to the solution to
precipitate compound 15, which were collected by filtration and
washed with water to give an analytically pure sample (3.62 g,
[
10] Hayakawa, I.; Hiramitsu, T.; Tanaka, Y. Chem Pharm Bull
984, 32, 4907.
11] Matsumoto, J.; Miyamoto, T.; Minamida, A.; Nishimura, Y.;
Egawa, H. J Med Chem 1984, 27, 292.
12] Wise, R.; Andrews, J. M.; Edwards, L. J Antimicrob Agents
1
[
[
Chemother 1983, 23, 559.
[13] Grohe, K.; Heizer, H. Justus Liebigs Ann Chem 1987, 29.
ꢀ
ꢁ1
[14] Miyamoto, M.; Matsumoto, J.; Chiba, K.; Egawa, H.;
8
7%); mp 285 C (decomposed); IR: n cm 1730, 1620; MS:
+
Shibamori, K.; Minamida, A.; Nishimura, Y.; Okada, H.; Kataoka, M.;
Fujita, M.; Hirose, T.; Nakano, J. J Med Chem 1990, 33, 1645.
m/z 482 (M ); NMR (deuteriodimethyl sulfoxide): COOH [14.35
(
[
s, 1H), 14.31 (s, 1H)], 2-H [8.59 (s, 1H), 8.36 (s, 1H)], 8-H
7.84 (dd, J = 9.0, 4.0 Hz, 1H), 7.52 (dd, J = 9.0, 4.5 Hz, 1H)], 5-
[15] Wentland, M. P.; Perni, R. B.; Dorff, P. H.; Brundage, R. P.;
Castaldi, M. J.; Bailey, T. R.; Carabateas, P. M.; Bacon, E. R.; Young,
D. C.; Woods, M. G.; Rosi, D.; Drozd, M. L.; Kullnig, R. K.; Dutko, F.
J. J Med Chem 1993, 36, 1580.
H [7.78 (dd, J = 9.0, 3.0 Hz, 1H), 7.69 (dd, J = 9.0, 3.0 Hz, 1H)],
7
3
-H [7.67 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H), 7.58 (ddd, J = 9.0, 9.0,
.0 Hz, 1H)], 7.15 (s, 1H, vinylic H) , 5.65 (t, J = 3.5 Hz, 1H,
[16] Drug Data Report, 2001, 23 (7), PNU-183792, 292422.
[17] Boteva, A. A.; Krasnykh, O. P. Chem Heterocycl Com 2009,
OH), 5.47 (s, 2H, CH ), 4.25 (d, J = 3.5 Hz, 2H, CH ). Anal.
2
2
45, 757, and references cited therein.
Calcd. for C24
H
F
16 2
N
2
O
7
: C, 59.76; H, 3.34; N, 5.87. Found: C,
[18] Kurasawa, Y.; Yoshida, K.; Yamazaki, N.; Kaji, E.; Sasaki, K.;
5
9.78; H, 3.40; N, 5.85.
Hiwasa, Y.; Tsukamoto, A.; Ito H. J Heterocycl Chem 2010, 47, 657.
[19] Kurasawa, Y.; Yoshida, K.; Yamazaki, N.; Kaji, E.; Sasaki, K.;
Zamami, Y.; Sakai, Y.; Fujii, T.; Ito, H. J Heterocycl Chem 2012, 49, 288.
0
(Z)-1,1 -[2-(Imidazol-1-ylmethyl)propene-1,3-diyl]di(6-fluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid) (16). A solution
[20] The bromomethyl carbon of intermediates 7 and 9 may be-
of potassium hydroxide (250 mg, 4.46 mmol) in water (5 mL) was
added to a boiling suspension of compound 14 (800 mg,
come more electron deficient than that of pentaerythritol tribromide pre-
sumably due to the influence of the electron withdrawing 4-quinolone
ring, which would be rationalized by the fairly deshielded N1-methylene
protons [d 5.91 – 5.16 (dimers 11 – 16)].
1.32 mmol) in ethanol (50 mL)/water (5 mL), and the solution was
refluxed with stirring for 2 h to precipitate colorless crystals of
potassium salt. After cooling to room temperature, the colorless
crystals were collected by filtration. The crystals were dissolved in
water (10 mL), and 1 N hydrochloric acid (6 mL) was added to the
solution to precipitate compound 16, which was collected by
filtration and washed with water (460 mg, 66%). Recrystallization
[21] Xianming, H.; Kellogg, R. M. Synthesis 1995, 533.
[22] Imai, T.; Nishida, S. Can J Chem 1981, 59, 2503.
[23] The NMR spectra of the dimers 11, 14, 15, and 16 were
measured in deuteriodimethyl sulfoxide, while the NMR spectra of the
dimer 13 was measured in deuteriotrifluoroacetic acid. Accordingly, the
chemical shifts due to the 2-H and 8-H protons of the dimer 13 were not
compared with those of the dimers 11, 14, 15, and 16. However, the
NOE spectral data of the dimer 13 in deuteriotrifluoroacetic acid
supported that this compound is the (Z)-form.
ꢀ
from ethanol/water gave colorless needles; mp 262–263 C; IR: n
ꢁ
1
+
cm 3420, 3060, 1760, 1640; MS: m/z 532 (M ); high resolution
MS: Calcd. for C27 : 533.127, found: 533.127; NMR
deuteriodimethyl sulfoxide): 9.37 (dd, J = 1.5, 1.5 Hz, 1H,
imidazole 2-H), 2-H [8.60 (s, 1H), 8.55 (s, 1H)], 7.98 (dd, J=2.0,
18 2 4 6
H F N O
[
24] Kakehi, A.; Ito, S.; Suga, H.; Miwa, T.; Mori, T.; Fujii, T.;
Tanaka, N.; Kobayashi, T. Chem Pharm Bull 2003, 51, 75.
25] Kakehi, A.; Suga, H.; Kaneko, Y.; Fujii, T.; Tanaka, N. Chem
Pharm Bull 2005, 53, 1430.
(
[
1.5 Hz, imidazole 5-H), 7.78 (dd, J = 2.0, 1.5 Hz, imidazole 4-H),
8-H [7.78 (dd, J= 8.5, 4.5 Hz, 1H), 7.72 (dd, J= 8.5, 4.5 Hz, 1H)],
5-H [7.77 (dd, J= 8.5, 3.0 Hz, 1H), 7.60 (dd, J= 8.5, 3.0 Hz, 1H)],
7-H [7.62 (ddd, J=8.5, 8.5, 3.0Hz, 1H), 7.60 (ddd, J= 8.5, 8.5,
[26] Matsumoto, J.; Minami, S. J Med Chem 1968, 11, 160.
[27] Sheu, J.-H.; Chen, Y.-L.; Fang, K.-C.; Wang, T.-C.; Pen, C.-F.;
Tzeng, C.-C. J Heterocycl Chem 1998, 35, 955.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet