Quinolone analogues 12: Synthesis and tautomers of 2-substituted 4-quinolones and related compounds

Article abstract of DOI:10.1002/jhet.922

The 4-quinolone-2-carboxylates 4a,b were converted into the 4-quinolone-2-carbohydrazides 5a,b, hydrazones 6,7,10, and related compounds 8,9,11. The 4-methoxyquinoline-2-carboxylate 12 was also transformed into the 4-methoxyquinoline-2-carbohydrazide 13, which was modified to the hydrazone 14 and related compound 15. The antimicrobial activities of compounds 6b and 14 are described together with the 4-oxo and 4-hydroxy tautomers of compounds 4-11 in deuteriodimethyl sulfoxide and deuteriotrifluoroacetic acid.

Full text of DOI:10.1002/jhet.922

November 2012
Quinolone Analogues 12: Synthesis and Tautomers of
2-Substituted 4-Quinolones and Related Compounds
1323
a
a
a
*
Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kotoji
Iwamoto,b Yoshihiko Hamamoto,b Eisuke Kaji,b Kenji Sasaki,c
and Yoshito Zamamic
aDepartment of Organic Chemistry, School of Pharmacy, Iwaki Meisei University, Iino, Chuodai, Iwaki, Fukushima
970-8551, Japan
bDepartment of Medicinal Chemistry, School of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku,
Tokyo 108-8641, Japan
cDepartment of Molecular Design for Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences,
Okayama University, Tsushimanaka, Kita-ku, Okayama-Shi, Okayama 700-8530, Japan
*
E-mail: kura77@iwakimu.ac.jp
Received November 24, 2010
DOI 10.1002/jhet.922
View this article online at wileyonlinelibrary.com.
The 4-quinolone-2-carboxylates 4a,b were converted into the 4-quinolone-2-carbohydrazides 5a,b,
hydrazones 6,7,10, and related compounds 8,9,11. The 4-methoxyquinoline-2-carboxylate 12 was also
transformed into the 4-methoxyquinoline-2-carbohydrazide 13, which was modified to the hydrazone 14
and related compound 15. The antimicrobial activities of compounds 6b and 14 are described together
with the 4-oxo and 4-hydroxy tautomers of compounds 4-11 in deuteriodimethyl sulfoxide and deuterio-
trifluoroacetic acid.
J. Heterocyclic Chem., 49, 1323 (2012).
INTRODUCTION
4-quinolones between the 4-oxo and 4-hydroxy forms in
some solvent system (Chart 2) [13,15], we have also
studied to specify the 4-oxo and 4-hydroxy tautomers of
our 2-substituted 4-quinolones 4–11 (Schemes 1,2) in
the deuteriodimethyl sulfoxide or deuteriotrifluoroacetic
acid solution using the 4-methoxyquinolines 12–15
(Scheme 3) as reference compounds. In this article, we re-
port the synthesis and in vitro antimicrobial activities of the
2-substituted 4-quinolones 4-11 and 4-methoxyquinolines
12–15 together with the tautomerism of compounds 4-11
between the 4-oxoquinoline and 4-hydroxyquinoline forms
in deuteriodimethyl sulfoxide or deuteriotrifluoroacetic
acid media.
In previous articles [1–8], we reported the synthesis
of the 1-methylpyridazino[3,4-b]quinoxalines 1a-h as
candidates of antibacterial quinolone analogues (Chart 1).
The 3-alkyl 1c-e, 3-H 1f, and 3-halogeno 1g,h derivatives
were found to have antifungal and/or antibacterial activi-
ties [3–6,9], whereas the 3-amino 1i,j and 3-heteroaryl
1k,l,m derivatives were clarified to possess no
antibacterial and antifungal activities [10]. Thereafter,
we converted the target ring system of the pyridazino
[3,4-b]quinoxalin-4-(1H)-one into the 4-quinolone in the
study to search for more potent antimicrobial agents.
In literatures, the 2-alkylthio-4-quinolones 2a [11] and
2-alkylthioquinolines 2b [11] (Chart 1) were known to
have antibacterial activities, especially to MRSA,
wherein the alkyl chains were composed of C10∼C15
carbons. The naturally occurring 4-quinolones 3a
[12,13], 3b [13,14] and quinoline 3c [13,14] (Chart 1)
were also reported to possess antibiotic (3a), antirheumatic
(3b,c), and antispasmodic (3b,c) activities. Thus, there
have been many useful compounds in the 2-substituted
4-quinolones and 4-hydroxyquinolines, and hence we
undertook the synthesis of some 2-substituted 4-quinolones
and 4-methoxyquinolines. Moreover, since there have
been a few papers on the tautomerism of the 2-substituted
RESULTS AND DISCUSSION
Synthesis of compounds 4–15. The 6-substituted 4-
quinolone-2-carboxylates 4a,b were synthesized by the
reaction of 4-fluoroaniline and 4-trifluoromethylaniline
with dimethyl acetylenedicarboxylate, according to a
known method [16] in a slight modification [17],
wherein intermediary adducts were not purified before
cyclization into compounds 4a,b under reflux in
diphenyl ether.
© 2012 HeteroCorporation

1324
Y. Kurasawa, K. Yoshida, N. Yamazaki, K. Iwamoto, Y. Hamamoto, E. Kaji, K. Sasaki,
and Y. Zamami
Vol 49
Scheme 1
Chart 1
The reaction of compounds 4a,b with hydrazine hydrate
gave the 2-carbohydrazides 5a,b, whose reaction with ketones
afforded the hydrazones 6a,b and 7a,b, respectively (Scheme 1).
The reaction of compound 5a with methyl isothiocyanate
furnished the thiosemicarbazide derivative 8.
The reaction of compound 5b with phenyl isocya-
nate gave the semicarbazide derivative 9, while the re-
action of compounds 5a,b with cyclohexane-1,3-dione
or hexane-2,5-dione afforded the hydrazones 10a,b or
N-(2,5-dimethylpyrrol-1-yl)carboxamides 11a,b, respectively
(Scheme 2).
The methylation of compound 4a with methyl iodide
and potassium carbonate effected the 4-O-methylation to
provide methyl 6-fluoro-4-methoxyquinoline-2-carboxyl-
ate 12 (Scheme 3), which was supported by the NOE mea-
surement between the 4-O-methyl and 3-H proton signals
(17%). The reaction of compound 12 with hydrazine hy-
drate formed the 2-carbohydrazide 13, whose reaction
with 1,1,1-trifluoroacetylacetone or methyl isothio-
cyanate afforded the hydrazone 14 or thiosemicarbazide
15, respectively.
In vitro evaluation of novel compounds as antimicrobials.
The in vitro antimicrobial activities were evaluated for our
2-substituted 4-quinolones. As the result, compound 14
showed weak antifungal activities against five kinds of fungi
(Candida albicans, Candida crusei, Aspergillus fumigatus,
Tricophyton rubrum, Tricophyton mentagrophytes), wherein
the minimum inhibitory concentrations were 8–16 ppm. On
the other hand, compounds 6b and 14 exhibited weak anti-
MRSA activities against five kinds of strains (Streptococcus
aureus ATCC 33591, 33592, 33593, 13301, 11632) at
concentrations of 16–32 ppm, respectively.
4-Oxoquinoline and 4-hydroxyquinoline tautomers assigned
by the 1H-NMR and 13C-NMR spectral data. The chemical
shifts of the 3-H protons in the 2-substituted
4-quinolones and 4-methoxyquinolines have been known to
vary depending on the kind of the 2-substituents and solvents
1
used for the measurement of H-NMR spectra. Namely,
the 3-H proton signals of the 2-alkyl-4-quinolone 3b and
2-alkyl-4-methoxyquinoline 3c (Chart 2) were reported
to appear at δ 6.27 and 6.63 in deuteriochloroform
[13], respectively, while the 3-H proton signals of the
4-quinolones 16a,b,c were observed at δ 5.89, 6.25, 6.24
in deuteriochloroform/deuteriomethanol preponderating
as the 4-oxo form and at δ 6.26, 6.20, 6.20 in
deuteriodimethylsulfoxide predominating as the 4-hydroxy
form [15] (Chart 2), respectively.
In our 4-quinolones 4-7, the 3-H proton signals in
deuteriodimethyl sulfoxide (δ 6.29–6.90) were observed
in higher magnetic fields than those in deuteriotrifluoroacetic
Chart 2
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November 2012 Quinolone Analogues 12: Synthesis and Tautomers of 2-Substituted 4-Quinolones and
Related Compounds
1325
Scheme 2
acid (δ 7.64–8.31) (Table 1). Moreover, the 3-H proton
signals of the 4-quinolones 4a, 5a, and 6a in deuteriotrifluor-
oacetic acid appeared in similar magnetic fields to those of the
corresponding 4-methoxyquinolines 12, 13, and 14 in deuter-
iotrifluoroacetic acid, respectively [δ (4a: 7.74, 12: 7.70),
(5a: 7.64, 13: 7.60), (6a: 8.20, 14: 8.19)] (Table 1). These
data support that the 4-quinolones 4-7 preponderate as the
4-hydroxy form (4-7)-(B-D)+ in deuteriotrifluoroacetic acid
(Chart 3). While, the 3-H proton signals of the 4-quinolones
4a, 5a, and 6a in deuteriodimethyl sulfoxide were observed
in higher magnetic fields than those of the corresponding
4-methoxyquinolines 12, 13, and 14 in deuteriodimethyl
sulfoxide, respectively [δ (4a: 6.59, 12: 7.51), (5a: 6.72, 13:
7.54), (6a: 6.29, 14: 7.00)] (Table 1). These data suggest that
the 4-quinolones 4-7 predominate as the 4-oxo form A in
deuteriodimethyl sulfoxide (Chart 3).
In a deuteriodimethyl sulfoxide solution of the thiosemi-
carbazide derivative 8, two kinds of 3-H proton signals
were observed at δ 6.76 (major) and 7.49 (minor) together
with paired NH proton signals [δ 10.88 (major)/10.57
(minor), 9.51 (major)/9.37 (minor), 8.22 (major)/7.79
(minor)], which would be due to the presence of the
4-oxo A and 4-hydroxy B tautomers in the ratio of approx-
imately 81% to 19% [18], respectively (Scheme 4). That
is, the 3-H proton signals of compound 8 at δ 6.76
(4-oxo form A) and 7.49 (4-hydroxy form B) in
deuteriodimethyl sulfoxide appeared in similar magnetic
fields to those of the 4-quinolones (4–7)-A (δ 6.29–6.90)
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1326
Y. Kurasawa, K. Yoshida, N. Yamazaki, K. Iwamoto, Y. Hamamoto, E. Kaji, K. Sasaki,
and Y. Zamami
Vol 49
Table 1
Chemical shifts (δ) of 3‐H for compounds 4–8 and 12–15.
Substituent
C2
4‐Quinolones
4‐Mcthoxyqninolincs
δ in
δ in CF3COOD
4‐hydroxy
δ in (CD3)2SO
4‐oxo form A
δ in
C6
F
CF3
F
CF3
F
CF3
F
CF3
F
Compound
form (B‐D)+
Compound
(CD3)2SO
CF3COOD
COOCH3
COOCH3
CONHNH2
4a
4b
5a
5b
6a
6b
7a
7b
8
6.59
6.70
6.72
7.74
7.67
7.64
7.67
8.20
8.31
8.01
7.98
7.86
12
13
14
7.51
7.70
7.54
7.60
a
CONHNH2
–
CONHN=C(CF3)CH2COCH3
CONHN=C(CF3)CH2COCH3
CONIHN=C(CH3)C4H9
CONHN=C(CH3)C4H9
CONHNHCSNHCH3
6.29
6.37
6.90
6.84
6.76b
7.49c
7.00
8.19
15
7.56
7.83
aInsoluble in (CD3)2SO.
bSignal due to the 4‐oxo form.
cSignal due to the 4‐hydroxy form.
and the corresponding 4-methoxyquinoline 15 (δ 7.56) in
deuteriodimethyl sulfoxide, respectively. The 3-H protion
signals of the 4-hydroxy tautomer 8-(B-D)+ (δ 7.86) and
the corresponding 4-methoxyquinoline 15-D+ (δ 7.83) in
deuteriotrifluoroacetic acid were observed in similar
magnetic fields. Furthermore, such a tautomerism was
observed in a deuteriodimethyl sulfoxide solution of the
4-quinolone 10a, which showed two kinds of 3-H proton
signals at δ 6.69 (4-oxo tautomer A, major) [(4-7)-A: δ
6.29 – 6.90] and 7.48 (4-hydroxy tautomer B, minor)
(12-15: δ 7.00 – 7.56) in the ratio of approximately 68%
to 32% [19], respectively, together with paired NH
proton signals [δ 11.03 (major)/10.74 (minor), 9.17
(major)/9.05 (minor)] (Tables 1 and 2, Scheme 4).
The 3-H proton signal of the 4-hydroxy tautomer
10a-(B-D)+ in deuteriotrifluoroacetic acid was observed
at δ 7.76 (Table 2), whose value was included in that
of the 4-hydroxy tautomers (4-8)-(B-D)+ (δ 7.64–8.31)
and the 4-methoxyquinolines (12-15)-D+ (δ 7.60–8.19) in
deuteriotrifluoroacetic acid (Tables 1 and 2).
On the other hand, the semicarbazide derivative 9 and
the 4-quinolones 10b,11a,b were predominant as the
4-oxo tautomer A in deuteriodimethyl sulfoxide.
The 13C-NMR spectral data [20] also supported the pres-
ence of the tautomers shown in Chart 3, as described below.
Tables 3 and 4 exhibit that the respective carbon chemical
shifts in deuteriotrifluoroacetic acid are similar values
between compounds 4a and 12, compounds 5a and 13,
and compounds 6a and 14. These data indicate that the
4-quinolones 4a, 5a, 6a, and 4-methoxyquinolines 12, 13,
14 would exist as the species (4a, 5a, 6a)-(B-D)+ and
(12, 13, 14)-D+ in deuteriotrifluoroacetic acid, respectively.
In addition, the N1-deuteronation of compounds 4a, 5a, 6a
and 12, 13, 14 was supported in comparison of the α-, β-,
and γ-carbon chemical shifts measured in deuteriodimethyl
sulfoxide with those measured in deuteriotrifluoroacetic acid.
Namely, after the N1-deuteronation of compounds 12, 13,
and 14 in deuteriotrifluoroacetic acid, the α-carbons
(2-C, 8a-C) and one of β-carbons (8-C) were shielded
eminently (6.6–11.9 ppm), and the γ-carbons (4-C, 7-C)
Table 2
Chemical shifts (δ) of 3‐H for compounds 9–11.
Substituent
C2
δ in (CD3)2SO
δ in CF3COOD
C6
Compound
4‐Oxo form A
4‐Hydroxy form B
4‐Hydroxy form (B‐D)+
CF3
F
CF3
F
CONHNHCONHC6H5
CONHR1
9
6.88
6.69
6.81
6.87
6.99
–
7.48
–
–
–
–
7.76
–
–
–
10a
10b
11a
11b
CONHR1
CONHR2
CF3
CONHR2
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November 2012 Quinolone Analogues 12: Synthesis and Tautomers of 2-Substituted 4-Quinolones and
Related Compounds
1327
Table 3
13C‐NMR spectral data for 4‐quinolones 4a, 5a, 6a measured in deuteriodimethyl sulfoxide and deuteriotrifluoroacetic acid.a
Carbon
4a (CD3)2SO
4a‐D+ CF3COOD
5a (CD3)2SO
5a‐D+ CF3COOD
6a (CD3)2SO
6a‐D+ CF3COOD
2‐C
3‐C
4‐C
4a‐C
5‐C
6‐C
7‐C
8‐C
144.0
109.1
176.5
127.1
108.6
158.9
121.7
122.6
137.3
162.6
55.5
–
140.5
105.8
171.3
123.0
108.1
162.8
127.8
123.3
136.5
160.7
55.0
–
142.8
105.8
175.7
126.9
108.9
161.2
121.8
124.3
138.5
158.2
–
139.6
103.5
171.4
122.9
108.0
160.2
127.9
123.4
136.5
164.0
–
143.6
108.2
176.0
124.5
108.8
158.7
121.3
121.8
136.5
160.6
–
91.5
122.8
47.6
156.7
15.3
143.1
108.3
170.4
122.6
108.0
162.8
127.6
123.3
135.9
157.2
–
94.0
123.2
45.7
163.4
14.2
8a‐C
2‐COR
2‐COOCH3
Hydrazone C
Hydrazone CF3
Hydrazone CH2COCH3
Hydrazone CH2COCH3
Hydrazone CH2COCH3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
aCarbon chemical shifts were assigned by HMQC and HMBC spectral data.
were deshielded remarkably (6.0–9.9 ppm) (Table 5)
[21,22]. The other β-carbon (3-C) of compounds 12, 13,
and 14 was not shielded significantly (1.0–3.9 ppm)
(Table 4) [21,22].
and oxo-enol forms of the cyclohexenol moiety. For example,
it is hard to specify the tautomeric structures showing the
paired N1-H (δ 12.28, 11.00) and CONH (δ 10.30, 9.51) pro-
ton signals of compound 5a in deuteriodimethyl sulfoxide
[23,24]. As the general characteristics ordinary observed, the
vinylic proton signal in the cyclohexenol moiety of compound
10a and the active methylene proton signals in the C2-side
chain of compound 14 disappeared because of the D-H
exchange in deuteriotrifluoroacetic acid.
Concerning the tautomerism due to the prototropy in the
C2-side chain moiety of our quinolones and quinolines, no
obvious data were obtained to estimate the ratios (%) of
some tautomeric pairs (Chart 4), since there was no
diagnostic C–H signal pair such as the C3-H proton of
the quinoline ring. Therefore, we refrained from the analy-
sis of the tautomerism attributable for the prototropy in the
C2-side chain moiety, which would include the oxo-
hydroxy forms of the carbohydrazide moiety (Chart 4),
thioxo-thiol forms of the thiosemicarbazide moiety (Chart 4),
EXPERIMENTAL
All melting points were determined on a Yazawa micro melt-
ing point BY-2 apparatus and are uncorrected. The IR spectra
Table 4
13C‐NMR spectral data for 4‐methoxyquinolines 12–14 measured in deuteriodimethyl sulfoxide and deuteriotrifluoroacetic acid.a
Carbon
12 (CD3)2SO
12‐D+ CF3COOD
13 (CD3)2SO
13‐D+ CF3COOD
14 (CD3)2SO
14‐D+ CF3COOD
2‐C
3‐C
4‐C
4a‐C
5‐C
6‐C
7‐C
8‐C
148.0
100.2
161.8
121.8
104.8
160.2
120.4
132.3
144.4
164.8
52.2
56.0
–
141.4
101.2
172.0
123.9
107.9
163.2
127.5
123.6
135.6
160.3
55.1
58.5
–
151.4
98.6
162.6
122.1
105.5
160.3
120.8
132.2
144.4
162.8
–
56.6
–
–
–
–
141.8
100.3
172.5
124.1
108.4
159.2
128.2
124.3
136.3
165.0
–
58.2
–
–
–
–
155.9
99.5
144.0
103.4
171.0
123.3
107.7
163.1
127.1
123.4
134.7
156.5
–
58.2
94.0
122.3
45.1
163.5
14.1
161.7
121.3
105.4
160.1
121.1
131.9
144.6
165.4
–
56.7
91.0
123.1
47.9
155.2
15.3
8a‐C
2‐COR
2‐COOCH3
4‐OCH3
Hydrazone C
Hydrazone CF3
Hydrazone CH2COCH3
Hydrazone CH2COCH3
Hydrazone CH2COCH3
–
–
–
–
–
–
–
–
–
–
aCarbon chemical shifts were assigned by HMQC and HMBC spectral data.
Journal of Heterocyclic Chemistry
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Y. Kurasawa, K. Yoshida, N. Yamazaki, K. Iwamoto, Y. Hamamoto, E. Kaji, K. Sasaki,
and Y. Zamami
Vol 49
Table 5
Selected 13C-NMR spectral data for 4‐methoxyquinolines 12–14 measured in deuteriodimethyl sulfoxide and deuteriotrifluoroacetic acid.
12
(CD3)2SO
12‐D+
CF3COOD
Difference
13
13‐D+
CF3COOD
Difference
in 6
14
14‐D+
CF3COOD
Difference
in δ
Carbon
in δ
(CD3)2SO
(CD3)2SO
2‐C
4‐C
7‐C
8‐C
8a‐C
148.0
161.8
120.4
132.3
144.4
141.4
172.0
127.5
123.6
135.6
6.6 (S)a
8.2 (D)a
7.1 (D)
8.7 (S)
8.8 (S)
151.4
162.6
120.8
132.2
144.4
141.8
172.5
128.2
124.3
136.3
9.6 (S)
9.9 (D)
7.4 (D)
7.9 (S)
8.1 (S)
155.9
161.7
121.1
131.9
144.6
144.0
171.0
127.1
123.4
134.7
11.9 (S)
9.3 (D)
6.0 (D)
8.5 (S)
9.9 (S)
a(S) and (D) mean shielding and deshielding, respectively, after deuteronation in deuteriotrifluoroacetic acid.
ether (40 mL). The diphenyl ether solution was refluxed for 1 h
to precipitate colorless needles 4a,b, which were triturated with
ethanol/hexane and collected by filtration. The crystals were
washed with ethanol several times to provide analytically pure
samples 4a (8.32 g, 42%) and 4b (9.42 g, 56%).
Compound 4a had mp 250–251°; IR: n 3100, 2960, 2920, 1740,
1610 cm−1; ms: m/z 222 (M+); NMR (deuteriodimethyl sulfoxide):
12.23 (s, 1H, NH), 7.98 (dd, J = 9.0, 4.5 Hz, 1H, 8-H), 7.68 (dd,
J = 9.0, 3.0 Hz, 1H, 5-H), 7.61 (ddd, J = 9.0, 8.0, 3.0 Hz, 1H, 7-H),
6.59 (s, 1H, 3-H), 3.93 (s, 3H, CH3). Anal. Calcd. for C11H8FNO3:
C, 59.73; H, 3.65; N, 6.33. Found: C, 59.65; H, 3.80; N, 6.44.
Chart 3
Compound 4b had mp 293–294°; IR: n 3250, 3220, 3170, 1740,
1610 cm−1; ms: m/z 272 (M+); NMR (deuteriodimethyl sulfoxide):
12.40 (s, 1H, NH), 8.28 (d, J = 2.0 Hz, 1H, 5-H), 8.08 (d, J = 9.0
Hz, 1H, 8-H), 7.98 (dd, J = 9.0, 2.0 Hz, 1H, 7-H), 6.70 (s, 1H,
3-H), 3.95 (s, 3H, CH3). Anal. Calcd. for C12H8F3NO3: C, 53.15;
H, 2.97; N, 5.16. Found: C, 53.08; H, 3.06; N, 5.33.
6-Fluoro-1,4-dihydro-4-oxoquinoline-2-carbohydrazide
5a and 1,4-Dihydro-4-oxo-6-trifluoromethylquinoline-2-
carbohydrazide 5b. General procedure. A suspension of the
appropriate 4-quinolone-2-carboxylates 4a,b (5.0 g) and hydrazine
hydrate (5-fold molar amount) in ethanol (100 mL) was refluxed for
5 h to precipitate colorless needles 5a,b, which were collected by
filtration and washed with ethanol to give analytically pure samples
5a (4.80 g, 96%) and 5b (4.50 g, 90%).
(potassium bromide) were recorded with a JASCO FT/IR-200
spectrometer. The NMR spectra were measured with a Varian
XL-400 spectrometer at 400 MHz. The chemical shifts are given
in the δ scale. The mass spectra (ms) (DIEI) were determined with
a JEOL JMS-01S spectrometer. Elemental analyses were per-
formed on a Perkin-Elmer 240B instrument.
Methyl 6-Fluoro-1,4-dihydro-4-oxoquinoline-2-carboxylate
4a and Methyl 1,4-Dihydro-4-oxo-6-trifluoromethylquinoline-
2-carboxylate 4b. General procedure.
A suspension of
the appropriate aniline derivatives (10.0 g) and dimethyl
acetylenedicarboxylate (1.5-fold molar amount) in ethanol
(100 mL) was refluxed for 2 h. Evaporation of the solvent in
vacuo gave an oily residue, which was dissolved in diphenyl
Scheme 4
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November 2012 Quinolone Analogues 12: Synthesis and Tautomers of 2-Substituted 4-Quinolones and
Related Compounds
1329
for 2 h. Evaporation of the solvent in vacuo gave crystals
7a,b, which were collected by filtration. Recrystallization from
N,N-dimethylformamide/ethanol provided colorless needles
7a (580 mg, 85%) and 7b (460 mg, 71%).
Compound 7a had mp 272–273°; IR: n 3310, 3250, 1670,
1610 cm−1; ms: m/z 303 (M+); NMR (deuteriodimethyl
sulfoxide): 12.10 (br, 1H, NH), 10.92 (s, 1H, CONH), 8.01 (dd,
J = 9.0, 4.5 Hz, 1H, 8-H), 7.74 (dd, J = 9.0, 3.0 Hz, 1H, 5-H),
7.64 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H, 7-H), 6.90 (br, 1H, 3-H),
2.31 (t, J = 7.5 Hz, 2H, CH2), 1.97 (s, 3H, CH3), 1.51 (tt, J = 7.5,
7.5 Hz, 2H, CH2), 1.31 (tq, J = 7.5, 7.5 Hz, 2H, CH2), 0.89
(t, J = 7.5 Hz, 3H, CH3). Anal. Calcd. for C16H18FN3O2: C,
63.35; H, 5.98; N, 13.85. Found: C, 63.09; H, 5.92; N, 13.75.
Chart 4
Compound 7b had mp 293–294°; IR: n 3310, 3250, 1670,
1640, 1605 cm−1; ms: m/z 353 (M+); NMR (deuteriodimethyl
sulfoxide): 12.29 (br, 1H, NH), 10.99 (s, 1H, CONH), 8.34
(d, J = 2.0 Hz, 1H, 5-H), 8.09 (d, J = 9.5 Hz, 1H, 8-H), 7.99
(dd, J = 9.5, 2.0 Hz, 1H, 7-H), 6.84 (br, 1H, 3-H), 2.32 (t, J = 7.0
Hz, 2H, CH2), 1.96 (s, 3H, CH3), 1.51 (tt, J = 7.0, 7.0 Hz, 2H,
CH2), 1.31 (tq, J = 7.0, 7.0 Hz, 2H, CH2), 0.88 (t, J = 7.0 Hz, 3H,
CH3). Anal. Calcd. for C17H18F3N3O2: C, 57.79; H, 5.13; N,
11.89. Found: C, 57.58; H, 5.12; N, 11.96.
Compound 5a had mp above 300°; IR: n 3375, 3160, 1695 cm−1;
ms: m/z 221 (M+); NMR (deuteriodimethyl sulfoxide): 12.28 (br),
11.00 (br) (1H, NH) [23], 10.30 (br), 9.51 (br) (1H, CONH) [23],
8.01 (dd, J = 9.0, 5.0 Hz, 1H, 8-H), 7.68 (dd, J = 9.0, 3.0 Hz,
1H, 5-H), 7.60 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H, 7-H), 6.72 (s,
1H, 3-H), 4.73 (br, 2H, NH2). Anal. Calcd. for C10H8FN3O2:
C, 54.30; H, 3.65; N, 19.00. Found: C, 54.13; H, 3.71; N, 19.01.
6-Fluoro-1,4-dihydro-(N′-methylthiocarbamoyl)-4-oxoquinoline-
2-carbohydrazide 8. A solution of compound 5a (0.50 g,
2.26 mmoles) and methyl isothiocyanate (215 mg, 2.94 mmoles) in
N,N-dimethylformamide (20 mL) was refluxed for 1 h. Evaporation
of the solvent in vacuo gave colorless crystals 8, which were
recrystallized from N,N-dimethylformamide/ethanol to afford
colorless powders 8 (220 mg, 33%); mp 245–246°; IR: n
3260, 3180, 1690, 1610 cm−1; ms: m/z 294 (M+); NMR
(deuteriodimethyl sulfoxide): 12.07 (s, 1H, NH), 10.88
(s), 10.57 (s) (1H, NH), 9.51 (s), 9.37 (s) (1H, NH), 8.22
(q), 7.79 (q) (J = 4.0 Hz, 1H, NH), 8.02 (dd, J = 9.0, 4.5
Hz, 1H, 8-H), 7.70 (dd, J = 9.0, 2.5 Hz, 1H, 5-H), 7.62
(ddd, J = 9.0, 9.0, 2.5 Hz, 1H, 7-H), 7.49 (s), 6.76 (s)
(1H, 3-H) [18], 2.86 (d, J = 4.0 Hz, 3H, CH3). Anal. Calcd. for
C12H11FN4O2S•1/2H2O: C, 47.52; H, 3.99; N, 18.47. Found: C,
47.37; H, 3.97; N, 18.34.
Compound 5b had mp above 300°; IR: n 3320, 3260, 3200,
3030, 1690, 1640 cm−1; ms: m/z 271 (M+); NMR (deuteriotri-
fluoroacetic acid): 8.49 (d, J = 2.0 Hz, 1H, 5-H), 8.04 (d,
J = 9.0 Hz, 1H, 8-H), 7.96 (dd, J = 9.0, 2.0 Hz, 1H, 7-H),
7.67 (s, 1H, 3-H); NH and OH proton signals disappeared be-
cause of D-H exchange. Anal. Calcd. for C11H8F3N3O2: C,
48.72; H, 2.97; N, 15.44. Found: C, 48.67; H, 3.00; N, 15.24.
6-Fluoro-1,4-dihydro-4-oxo-N′-(3-oxo-1-trifluoromethylbuty-
lidene)quinoline-2-carbohydrazide 6a and 1,4-dihydro-4-oxo-
N′-(3-oxo-1-trifluoromethylbutylidene)-6-trifluoromethylquino-
line-2-carbohydrazide 6b. General procedure. A solution of the
appropriate 4-quinolone-2-carbohydrazides 5a,b (0.50 g) and
1,1,1-trifluoropentane-2,4-dione (1.5-fold molar amount) in N,
N-dimethylformamide (20 mL) was refluxed for 2 h. Evaporation
of the solvent in vacuo gave an oily substance, which was
crystallized from ethanol/water to afford yellow needles 6a (540 mg,
76%) and 6b (480 mg, 64%).
1,4-Dihydro-4-oxo-(N′-phenylcarbamoyl)-6-trifluoromethyl-
quinoline-2-carbohydrazide 9. A solution of compound 5b
(0.50 g, 1.85 mmole) and phenyl isocyanate (286 mg, 2.41
mmoles) in N,N-dimethylformamide (20 mL) was refluxed
Compound 6a had mp 214-215°; IR: n 3220, 1675 cm−1; ms:
m/z 357 (M+); NMR (deuteriodimethyl sulfoxide): 12.32
(br, 1H, NH), 8.34 (br, 1H, CONH), 7.82 (dd, J = 9.0, 4.0 Hz,
1H, 8-H), 7.72 (dd, J = 9.0, 3.0 Hz, 1H, 5-H), 7.62 (ddd,
J = 9.0, 9.0, 3.0 Hz, 1H, 7-H), 6.29 (br, 1H, 3-H), 3.54 (d, J = 19.5
Hz, 1H, CH), 3.17 (d, J = 19.5 Hz, 1H, CH), 1.97 (s, 3H, CH3). Anal.
Calcd. for C15H11F4N3O3: C, 50.43; H, 3.10; N, 11.76. Found: C,
50.55; H, 3.23; N, 11.59.
Compound 6b had mp 228–229°; IR: n 3430, 3260, 3230,
3175, 1670, 1640, 1600 cm−1; ms: m/z 407 (M+); NMR (deuter-
iodimethyl sulfoxide): 12.51 (s, 1H, NH), 8.38 (s, 1H, CONH),
8.33 (d, J = 2.0 Hz, 1H, 5-H), 7.98 (dd, J = 9.0, 2.0 Hz, 1H, 7-H),
7.92 (d, J = 9.0 Hz, 1H, 8-H), 6.37 (s, 1H, 3-H), 3.56 (d, J = 19.5
Hz, 1H, CH), 3.18 (d, J = 19.5 Hz, 1H, CH), 1.98 (s, 3H, CH3). Anal.
Calcd. for C16H11F6N3O3: C, 47.19; H, 2.73; N, 10.32. Found:
C, 47.02; H, 2.78; N, 10.12.
for
1 hour. Evaporation of the solvent in vacuo gave
colorless crystals 9, which were recrystallized from N,
N-dimethylformamide/ethanol/hexane to provide colorless
powders 9 (150 mg, 20%); mp above 300°; IR: n 3260,
1690, 1620, 1605 cm−1; ms: m/z 390 (M+); NMR
(deuteriodimethyl sulfoxide): 12.28 (br, 1H, NH), 10.85 (s, 1H,
CONH), 8.95 (s, 1H, NH), 8.44 (s, 1H, NH), 8.33 (d, J = 2.0 Hz,
1H, 5-H), 8.13 (d, J = 9.0 Hz, 1H, 8-H), 8.00 (dd, J = 9.0, 2.0 Hz,
1H, 7-H), 7.46 (dd, J = 8.0, 1.0 Hz, 2H, phenyl 2-H, 6-H), 7.25
(dd, J = 8.0, 8.0 Hz, 2H, phenyl 3-H, 5-H), 6.96 (tt, J = 8.0, 1.0
Hz, 1H, phenyl 4-H), 6.88 (br, 1H, 3-H). Anal. Calcd. for
C18H13F3N4O3•1/2H2O: C, 54.14; H, 3.53; N, 14.27. Found: C,
54.04; H, 3.33; N, 14.26.
6-Fluoro-1,4-dihydro-N′-(3-hydroxy-2-cyclohexenylidene)-4-
oxoquinoline-2-carbohydrazide 10a and 1,4-dihydro-N′-(3-
hydroxy-2-cyclohexenylidene)-4-oxo-6-trifluoromethylquinoline-
2-carbohydrazide 10b. A solution of compound 5a,b (0.50 g)
and cyclohexane-1,3-dione (1.5-fold molar amount) in
N,N-dimethylformamide (20 mL) was refluxed for 1 h. Evaporation
6-Fluoro-1,4-dihydro-N′-(1-methylpentylidene)-4-oxoquino-
line-2-carbohydrazide 7a and 1,4-dihydro-N′-(1-methylpen-
tylidene)-4-oxo-6-trifluoromethylquinoline-2-carbohydrazide
7b. General procedure. A solution of the appropriate 4-quinolone-
2-carbohydrazides 5a,b (0.50 g) and 2-hexanone (1.5-fold
molar amount) in N,N-dimethylformamide (20 mL) was refluxed
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1330
Y. Kurasawa, K. Yoshida, N. Yamazaki, K. Iwamoto, Y. Hamamoto, E. Kaji, K. Sasaki,
and Y. Zamami
Vol 49
of the solvent in vacuo gave an oily product 10a,b, which was
crystallized from ethanol/water to afford yellow powders 10a
(550 mg, 77%) and 10b (500 mg, 70%), respectively.
(150 mL) was refluxed for 2 h to precipitate colorless needles 13,
which were collected by filtration and washed with ethanol to give
an analytically pure sample (3.65 g, 73%); mp 215–216°; IR:
ν 3310, 3260, 1680, 1620, 1600 cm−1; ms: m/z 235 (M+); NMR
(deuteriodimethyl sulfoxide): 9.95 (s, 1H, CONH), 8.06 (dd, J = 9.0,
5.0 Hz, 1H, 8-H), 7.76 (dd, J = 9.5, 3.0 Hz, 1H, 5-H), 7.72
(ddd, J = 9.0, 9.0, 3.0 Hz, 1H, 7-H), 7.54 (s, 1H, 3-H), 4.65
(br, 2H, NH2), 4.12 (s, 3H, 4-OCH3). Anal. Calcd. for C11H10FN3O2:
C, 56.17; H, 4.29; N, 17.86. Found: C, 55.89; H, 4.31; N, 17.80.
6-Fluoro-4-methoxy-N′-(3-oxo-1-trifluoromethylbutylidene)-
quinoline-2-carbohydrazide 14. A solution of compound 13
(0.50 g, 2.13 mmoles) and 1,1,1-trifluoropentane-2,4-dione (0.49 g,
3.20 mmoles) in N,N-dimethylformamide (20 mL) was refluxed
for 2 h. Evaporation of the solvent in vacuo afforded an oily
substance, which was crystallized from ethanol/water to provide
reddish orage needles 14 (420 mg, 53%); mp; 159-160°; IR: n
3100, 1600 cm−1; ms: m/z 371 (M+); NMR (deuteriodimethyl
sulfoxide): 8.24 (br, 1H, CONH), 8.04 (dd, J = 9.0, 5.5 Hz,
1H, 8-H), 7.78 (dd, J = 9.0, 3.0 Hz, 1H, 5-H), 7.69 (ddd, J = 9.0,
9.0, 3.0 Hz, 1H, 7-H), 7.02 (s, 1H, 3-H), 4.06 (s, 3H, 4-OCH3),
3.51 (d, J = 19.5 Hz, 1H, CH), 3.13 (d, J = 19.5 Hz, 1H, CH), 1.85
(s, 3H, CH3). Anal. Calcd. for C16H13F4N3O3: C, 51.76; H, 3.53;
N, 11.32. Found: C, 51.74; H, 3.56; N, 11.22.
6-Fluoro-4-methoxy-N′-(methylthiocarbamoyl)quinoline-
2-carbohydrazide 15. A solution of methyl isothiocyanate (2.34 g,
32.0 mmoles) in dioxane (20 mL) was added to a refluxing solution
of compound 13 (5.0 g, 21.3 mmoles) in dioxane (80 mL) to
precipitate colorless needles 15 while 1-h reflux. The colorless
needles were collected by filtration and washed with ethanol to
give an analytically pure sample (6.95 g, 99%); mp: 245-246°; IR:
ν 3360, 3180, 1700, 1690 cm−1; ms: m/z 294 (M+); NMR
(deuteriodimethyl sulfoxide): 10.70 (br, 1H, CONH), 8.10 (dd,
J = 9.0, 5.0 Hz, 1H, 8-H), 8.02 (q, J = 5.0 Hz, 1H, NH), 7.82 (dd,
J = 9.5, 3.0 Hz, 1H, 5-H), 7.76 (ddd, J = 9.5, 9.0, 3.0 Hz, 1H, 7-H),
7.56 (s, 1H, 3-H), 4.11 (s, 3H, 4-OCH3), 2.84 (d, J = 5.0 Hz, 3H,
CH3). Anal. Calcd. for C13H13FN4O2S: C, 50.64; H, 4.25; N,
18.17. Found: C, 50.51; H, 4.33; N, 18.22.
Compound 10a had mp: 234–235°; IR: n 3300, 3250, 1685,
1610 cm−1; ms: m/z 315 (M+); NMR (deuteriodimethyl sulfoxide):
12.13 (s, 1H, NH), 11.03 (s), 10.74 (s) (1H, CONH) [19], 9.17 (s),
9.05 (s) (1H, OH), 8.00 (dd, J = 8.0, 5.0 Hz, 1H, 8-H), 7.70 (dd,
J = 8.0 Hz, 1H, 5-H), 7.62 (dd, J = 8.0, 8.0 Hz, 1H, 7-H), 7.48 (s),
6.69 (s) (1H, 3-H), 4.97 (s, 1H, cyclohexene 2-H), 2.40 (t, J = 6.0 Hz,
2H, CH2), 2.13 (t, J = 6.0 Hz, 2H, CH2), 1.86 (tt, J = 6.0, 6.0 Hz,
2H, CH2). Anal. Calcd. for C16H14FN3O3•H2O: C, 57.65; H,
4.84; N, 12.61. Found: C, 57.78; H, 4.71; N, 12.57.
Compound 10b had mp 292-293°; IR: n 3440, 3200, 1680,
1640, 1600 cm−1; ms: m/z 365 (M+); NMR (deuteriodimethyl
sulfoxide): 12.28 (br, 1H, NH), 11.08 (br 1H, CONH), 9.18
(s, 1H, OH), 8.33 (d, J = 2.0 Hz, 1H, 5-H), 8.11 (d, J = 9.0 Hz,
1H, 8-H), 8.00 (dd, J = 9.0, 2.0 Hz, 1H, 7-H), 6.81 (br, 1H,
3-H), 4.99 (s, 1H, cyclohexene 2-H), 2.41 (t, J = 6.0 Hz, 2H,
CH2), 2.14 (t, J = 6.0 Hz, 2HCH2), 1.86 (tt, J = 6.0, 6.0 Hz, 2H,
CH2). Anal. Calcd. for C17H14F3N3O3•1/2H2O: C, 54.55; H,
4.04; N, 11.23. Found: C, 54.49; H, 3.76; N, 11.51.
6-Fluoro-1,4-dihydro-N′-(2,5-dimethylpyrrol-1-yl)-4-oxoquinoline-
2-carbohydrazide 11a and 1,4-Dihydro-N′-(2,5-dimethylpyrrol-
1-yl)-4-oxo-6-trifluoromethylquinoline-2-carbohydrazide
11b. A solution of compound 5a,b (0.50 g) and hexane-2,5-
dione (1.5-fold molar amount) in N,N-dimethylformamide
(20 mL) was refluxed for 1 h. Evaporation of the solvent in
vacuo gave crystals 11a,b, which were recrystallized from
N,N-dimethylformamide/ethanol/water to afford yellow needles
11a (620 mg, 84%) and 11b (610 mg, 95%), respectively.
Compound 11a had mp: 280–281° (decompose); IR: n 3250,
3210, 3000, 1690, 1610 cm−1; ms: m/z 299 (M+); NMR (deuteriodi-
methyl sulfoxide): 12.24 (br, 1H, NH), 11.76 (s, 1H, CONH), 8.04
(dd, J = 8.5, 4.5 Hz, 1H, 8-H), 7.76 (dd, J = 8.0 Hz, 1H, 5-H), 7.67
(dd, J = 8.5, 8.0 Hz, 1H, 7-H), 6.87 (br, 1H, 3-H), 5.72 (s, 2H, pyrrole
3-H, 4-H), 2.04 (s, 6H, pyrrole 2-CH3, 5-CH3). Anal. Calcd. for
C16H14FN3O2: C, 64.21; H, 4.71; N, 14.04. Found: C, 64.27; H,
4.82; N, 13.96.
Compound 11b had mp 292–293° (decompose); IR: n 3250,
1690, 1640, 1610 cm−1; ms: m/z 349 (M+); NMR
(deuteriodimethyl sulfoxide): 12.40 (br, 1H, NH), 11.85 (s 1H,
CONH), 8.36 (d, J = 2.0 Hz, 1H, 5-H), 8.13 (d, J = 8.0 Hz,
1H, 8-H), 8.02 (dd, J = 8.0, 2.0 Hz, 1H, 7-H), 6.99 (br, 1H,
3-H), 5.73 (s, 2H, pyrrole 3-H, 4-H), 2.05 (s, 6H, pyrrole
2-CH3, 5-CH3). Anal. Calcd. for C17H14F3N3O2•1/2H2O:
C, 56.98; H, 4.22; N, 11.73. Found: C, 57.16; H, 4.27; N, 11.56.
Methyl 6-Fluoro-4-methoxyquinoline-2-carboxylate 12. A
mixture of compound 4a (5.0 g, 22.6 mmoles), methyl iodide
(5mL) and potassium carbonate (5 g) in N,N-dimethylformamide
(100 mL) was heated at 120–140° for 3 h. After cooling to room
temperature, the solution was filtrated, and the filtrate was
evaporated in vacuo to give crystals 12. Recrystallization from
ethanol/water provided colorless needles 12 (4.30 g, 81%); mp
134–135°; IR: n 3050, 3010, 1720, 1600 cm−1; ms: m/z 236 (M+);
NMR (deuteriodimethyl sulfoxide): 8.13 (dd, J = 9.0, 5.5 Hz, 1H,
8-H), 7.75 (dd, J = 9.0, 3.0 Hz, 1H, 5-H), 7.72 (ddd, J = 9.0, 9.0,
3.0 Hz, 1H, 7-H), 7.51 (s, 1H, 3-H), 4.08 (s, 1H, 4-OCH3), 3.92 (s,
3H, COOCH3). Anal. Calcd. for C12H10FNO3: C, 61.28; H, 4.29;
N, 5.95. Found: C, 61.25; H, 4.39; N, 6.04.
REFERENCES AND NOTES
[1] Kurasawa, Y.; Tsuruoka, N.; 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.
S. Heterocycles 2002, 56, 291.
[5] Kurasawa, Y.; Takizawa, J.; Maesaki, Y.; Kawase, A.;
Okamoto, Y.; Kim, H. S. Heterocycles 2002, 58, 359.
[6] Kurasawa, Y.; Satoh, W.; Matsuzaki, I.; Maesaki, Y.;
Okamoto, Y.; Kim, H. S. J Heterocycl Chem 2003, 40, 837.
[7] Kurasawa, Y.; Kawase, A.; Takizawa, J.; Maesaki, Y.; Kaji,
E.; Okamoto, Y.; Kim, H. S. J Heterocycl Chem 2005, 42, 551.
[8] Kurasawa, Y.; Kaji, E.; Okamoto, Y.; Kim, H. S. J Heterocycl
Chem 2005, 42, 249.
[9] Kurasawa, Y.; Kim, H. S. J Heterocycl Chem, 2005, 42, 387.
[10] Kurasawa, Y.; unpublished results. References 7 and 8.
[11] Narita, K.; Izumi, Y.; Nishino, H.; Yoshida, T.; Takahashi, Y.;
Nagata, O.; Katoh, H. 121st Conference of the Pharmaceutical Society of
Japan, Sapporo, Japan, Abstract-3 No. 29 [PB] I-042 ( 2001).
[12] Wratten, S. J.; Wolfe, M. S.; Andersen, R. J.; Faulkner, D. J.
Antimicrob Agents Chemother 1977, 11, 411.
6-Fluoro-4-methoxyquinoline-2-carbohydrazide 13. A solution
of compound 12 (5.0 g) and hydrazine hydrate (5 mL) in ethanol
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012 Quinolone Analogues 12: Synthesis and Tautomers of 2-Substituted 4-Quinolones and
Related Compounds
1331
[13] Back, T. G.; Parvez, M.; Wulff, J. E. J Org Chem 2003, 68, 2223.
[14] Back T. G.; Wulff, J. E. J Chem Soc Chem Commun 2002, 1710.
[15] Wentrup, C.; Rao, V. V. R.; Frank, W.; Fulloon, B. E.;
Moloney, D. W. J.; Mosandl, T. J Org Chem 1999, 64, 3608.
[16] Erickson, E. H.; Lappi, L. R.; Rice, T. K.; Swingle, K. F.;
Winkle, M. V. J Med Chem 1978, 21, 984; the yields are not so high
(2 ∼ 50%), and this paper includes no nmr spectral data.
[17] In our experiment, the yields of compounds 4a and 4b were
42% and 47%, respectively.
[22] The shielding and deshielding data between 4-methoxyquinolines
12-14 and [(12–14)-D]+ were similar to those between 2,6-dichloroquinoxaline
and N4-deuterio-2,6-dichloroquinoxalinium ion reported in our previous
paper [21].
[18] Estimated from the integral curves of the 3-H proton signals at
δ 6.76 and 7.49.
[19] Estimated from the integral curves of the paired NH proton
signals at δ 11.03 and 10.74.
[23] Paired NH proton signals were observed in deuteriodimethyl
sulfoxide at δ 12.28 (br, minor)/11.00 (br, major) and 10.30 (br, major)/
9.51 (br, minor).
[20] All carbon chemical shifts were assigned by the HMQC and
HMBC spectral data.
[21] Kim, H. S.; Okamoto, Y.; Kurasawa, Y. J Heterocycl Chem
1997, 34, 1029.
[24] There have hardly been literatures dealing with the
specification and estimation of the oxo-hydroxy and thioxo-thiol
tautomers in open chain carbohydrazides and thiosemicarbazides,
respectively.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet