Substituted quinolinones 27. Regioselective synthesis of pyrazolo-, oxazolo-, and triazepinoquinoline derivatives

Article abstract of DOI:10.1007/s10593-016-1813-y

Reactivity of 3-acetyl-4-(methylsulfanyl)quinolin-2(1H)-one towards 1,2- and/or 1,4-diazanucleophiles has been studied under different reaction conditions. Condensation of 3-acetyl-4-(methylsulfanyl)quinolin-2(1H)-one with hydrazine, phenylhydrazine, hydr

Full text of DOI:10.1007/s10593-016-1813-y

DOI 10.1007/s10593-016-1813-y
Chemistry of Heterocyclic Compounds 2015, 51(11/12) 1023–1029
Substituted quinolinones
2
7.* Regioselective synthesis of pyrazolo-, oxazolo-,
and triazepinoquinoline derivatives
1
1
1
1
Mohamed Abass , Hany M. Hassanin , Hassan A. Allimony , Heba Hassan *
1
Department of Chemistry, Faculty of Education, Ain Shams University,
Heliopolis 11757, Cairo, Egypt; e-mail: heba.hassan94@yahoo.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted July 19, 2015
Accepted after revision October 13, 2015
2
015, 51(11/12), 1023–1029
Me
Me
Me
S
O
O
O
S
N
N
Me
N
Me
O
N
N
H
O
H
(
X = O)
(X= O)
NH XH
2
EtOH, 
AcOH, 
EtOH, 
(X O)
DMF, 
or DMF, rt
AcOH, 
Me
XH
N
X
N
Me
S
S
N
Me
Me
(X O)
Me
DMF
AcOH
N
X
N
H
O


N
H
O
X = NH, NPh, O, NHC(O)NH,NHC(S)NH
Reactivity of 3-acetyl-4-(methylsulfanyl)quinolin-2(1H)-one towards 1,2- and/or 1,4-diazanucleophiles has been studied under different
reaction conditions. Condensation of 3-acetyl-4-(methylsulfanyl)quinolin-2(1H)-one with hydrazine, phenylhydrazine, hydroxylamine
hydrochloride, semicarbazide, and thiosemicarbazide was carried out in different media. The structure of the reaction products was
dependent not only on the reagent used, but also on the solvent and reaction temperature. Accordingly, the reaction regioselectively
produced in good yields pyrazolo[3,4-b]quinoline, pyrazolo[4,3-c]quinoline, oxazolo[5,4-b]quinoline, oxazolo[4,5-c]quinoline, isoxazolo-
[
4,5-c]quinoline, [1,2,4]triazepino[5,6-b]quinoline, and [1,2,4]triazepino[6,5-c]quinoline derivatives in addition to open-chain
condensates which, too, were transformed to the respective cyclic products. The structures of new products were established on basis of
their analytical and spectral data.
Keywords: quinolinone, Beckmann rearrangement, heterocyclic synthesis, nucleophilic condensation, regioselective cyclization.
1
3
Nitrogen-containing heterocycles are nearly indispens-
able structural units in the development of medicinal
compounds. Among the various heterocyclic compounds,
quinolinone derivatives including 2- and 4-quinolinones,
occur in many natural products, such as found in coal tar,
receptor modulators, CB2 receptor inverse antagonists,potent
14
CDK-5 inhibitors, steroid-5a reductase-type enzyme inhibi-
15
16
tors, and potential Rho-kinase inhibitors have been found.
The great importance of this class of heterocycles turned
our attention to the synthesis of a series of new heterocyclic
derivatives combining both known biologically active
heterocycles and quinoline in one molecular frame. Thus,
the present research work deals with the chemical reactivity
of 3-acetyl-4-(methylsulfanyl)quinolin-2(1H)-one and its
use in synthesis of novel fused heterocyclo[b or c]quinoline
derivatives where quinoline ring is fused with pyrazole,
isoxazole, oxazole, and triazepine rings. The starting
material used in this study, 3-acetyl-4-(methylsulfanyl)-
2
,3
oils, herbs, as well as in dyes.
-Quinolinones have long been targeted in synthetic
2
research due to their interesting biological and pharma-
4
,5
cological properties, which include antiparasitic and anti-
microbial,6 antioxidant and anti-inflammatory,8 anti-
,7
9
10,11
convulsive, antiviral (against hepatitis C and B),
anti-
tumor activity.12 Among 2-quinolinones also androgen
For Communication 26, see1.
17
*
quinolin-2(1H)-one (1), was prepared via thermal cycli-
0
009-3122/15/51(11/12)-1023©2015 Springer Science+Business Media New York 1023

Chemistry of Heterocyclic Compounds 2015, 51(11/12) 1023–1029
Scheme 1
zation of 2-[bis(methylsulfanyl)methylidene]-3-oxo-N-phenyl-
butanamide.
addition, the spectrum featured two singlet signals at 2.43
and 2.70 ppm standing for N=C–CH
3
and SCH protons,
3
Compound 1 possesses three active centers susceptible
respectively. 13C NMR spectrum of compound 3 indicated
to nucleophilic attack, viz. C-4 (with replacement of SCH
3
the absence of both acetyl group and 2-quinolinone
3
group), acetyl group carbon atom, and C-2 (quinolinone
carbon atom). Heterocyclization at either [b] or [c] face of
quinoline moiety can take place when compound 1 is
treated with certain dinucleophiles, such as hydrazines,
hydroxylamine hydrochloride, and semicarbazide deriva-
tives. Hence, compound 1 was reacted with high excess
carbonyl group, as well as the presence of two sp -carbons
SCH
3
and 3-CH represented by signals at 15.1 and
3
11.9 ppm, respectively.
Interestingly, when hydrazone 2 was refluxed in DMF
pyrazolo[4,3-c]quinolinone 4 was obtained in 84% yield.
The same compound 4 was directly produced in 70% yield
when compound 1 was treated with hydrazine hydrate in
boiling DMF (Scheme 1). A positive Lassaigne's test for
sulfur revealed that compound 4 did not contain sulfur,
which implies that the cyclization involved elimination of
methanethiol. The structure of compound 4 was confirmed
by comparison with the sample prepared according to
(
20 equiv) of hydrazine hydrate in DMF at room tempe-
rature to give hydrazone 2 in a good yield (Scheme 1).
IR spectrum of compound 2 showed that the product
comprises a quinolinone C=O group with the correspond-
–
1
ing absorption band at 1620 cm . In addition, the presence
of an amino group was revealed by its characteristic sym
–1
17
and asym vibrational bands at 3355 and 3243 cm along
literature procedure.
with the vibration band due to the N–H bond of quino-
Treatment of compound 1 with phenylhydrazine in
boiling ethanol afforded a pale-brown product that was
identified as phenylhydrazone 5 with (Z/E)-isomer ratio
65:35 (Scheme 1). IR spectrum of compound 5 exhibited
–1
1
linone at 3198 cm . H NMR spectrum of compound 2
showed signals due to both NH
2
and NH protons at 6.15
O.
and 10.80 ppm, both disappearing upon addition of D
2
–1
Also, the spectrum revealed the presence of two singlet
absorption bands at 3620 and 3188 cm , corresponding to
both H-bonded O–H, N–H functions of 2-quinolinol and
signals at 2.49 and 2.63 ppm due to N=C–CH
protons, respectively.
3
and SCH
3
1
hydrazone, respectively. H NMR spectrum of compound 5
Hydrazone 2 was subjected to different treatment
conditions in order to obtain cyclization products. Thus,
cyclocondensation of hydrazone 2 in refluxing acetic acid
or absolute ethanol yielded 3-methyl-4-(methylsulfanyl)-
pyrazolo[3,4-b]quinoline (3) which was also obtained
directly by the reaction of compound 1 with hydrazine
hydrate under the same conditions (Scheme 1). The
IR spectrum of compound 3 showed absence of both
carbonyl functions (at C-2 and that of the acetyl group).
presented four singlet signals at 8.50 (NH hydrazone,
(E)-form), 9.00 (NH hydrazone, (Z)-form), 11.04 (NH
quinolinone, (Z)-form) and 11.20 ppm (OH quinolinol,
(E)-form), besides two signals at 2.13 and 2.60 ppm due to
the corresponding chemical shifts of N=C–CH
3
and SCH
3
protons. Moreover, 13C NMR spectrum proved that the
structure of product 5 contains a carbonyl group with a
corresponding resonance at 174.5 ppm in addition to two
3
methyl groups with the resonances of sp -carbons at 16.1
1
H NMR spectrum displayed a singlet signal at 13.93 ppm
and 23.7 ppm.
that was attributed to an NH proton different from that of
Refluxing phenylhydrazone 5 in glacial acetic acid
afforded 1-phenylpyrazolo[3,4-b]quinoline 6 in 70% yield.
The same compound was directly obtained by the reaction
1
-NH of quinolinone system, which normally appears at
~
10.80 ppm and was absent from this spectrum. In
1
024

Chemistry of Heterocyclic Compounds 2015, 51(11/12) 1023–1029
Scheme 2
of compound 1 with phenylhydrazine in boiling glacial
acetic acid (Scheme 1). The structure of product 6 was
inferred from the sulfur test which confirmed the presence
of sulfur and the presence of the signal of SCH
3
protons in
1
its H NMR spectrum, indicating that SCH
3
group was not
1
involved in the cyclization reaction. H NMR spectrum of
product 6 exhibited signals at 2.84 and 2.88 ppm, assigned
to characteristic chemical shifts of N=C–CH
3
and SCH
3
13
protons. C NMR spectrum supported the conclusion about
the structure of product 6, since no signal in the chemical
shift range characteristic for carbonyl carbon was observed.
Refluxing phenylhydrazone 5, in DMF, for only 1 h led
to 1-phenylpyrazolo[4,3-c]quinolinone 7 in 79% yield. The
same product 7 was also obtained when compound 1 was
treated with phenylhydrazine in boiling DMF (Scheme 1).
Structure of compound 7 was established on the basis of
sulfur test, revealing the elimination of methanethiol,
which was noticed also during the course of reaction by the
characteristic odor, and, additionally, by a comparison with
the sample obtained according to literature method.18
It was reasonable to assume that extension of the above
study to investigate the reactivity of compound 1 with
hydroxylamine hydrochloride under different reaction
conditions may furnish new interesting fused heterocyclic
compounds. Thus, treatment of compound 1 with hydroxyl-
amine hydrochloride in boiling ethanol containing few
drops of trimethylamine led to oxime 8 (Scheme 2). The
structure of oxime 8 was verified by elemental analysis and
gave a different heterocyclic product isoxazolo[4,5-c]-
quinolinone 12. The same compound was obtained via
refluxing of acetylquinoline 1 with hydroxylamine hydro-
chloride in DMF (Scheme 2). It is interesting to compare
the analytical and spectral data of both isomers 11 and 12.
Both of them have the same empirical formula as revealed
by elemental analysis, indicating the loss of methanethiol
fragment during cyclization process. Nevertheless, both of
them are clearly different in their physical and spectral
properties. The structures of isomers 11 and 12 were
confirmed also by a comparison with the samples prepared
1
spectroscopic methods. H NMR spectrum displayed, in
addition to aromatic protons, four singlet signals at 1.98,
2
.62, 10.87, and 11.20 ppm assigned to the protons of
N=C–CH
3
, SCH , quinolinone NH, and oxime OH
3
13
groups, respectively. Also, C NMR revealed a distinctive
signal at 174.0 ppm that points to the presence of carbonyl
group at position 2 of quinolinone moiety. Oxime 8 was
subjected to cyclization processes under different condi-
tions in order to obtain a variety of tricylcic fused systems.
When oxime 8 was refluxed in glacial acetic acid oxazolo-
20,21
[
5,4-b]quinoline 9 was obtained in 53% yield. Compound 9
according to literature procedures.
was also obtained directly from compound 1 when reacted with
hydroxylamine hydrochloride in boiling glacial acetic acid.
Presence of sulfur in the cyclized product 9, as indicated
The Beckmann rearrangement19 may be a conceivable
explanation for the formation of products 9 and 11 in acidic
medium. Thus, protonation of oxime group at the oxygen
atom takes place first to give an oxonium cation A from
which the rearrangement proceeds (Scheme 3). The pathway
leads to the 3-acetamidoquinoline intermediate B which
regioselectively can be cyclized to give either product 9 or 11.
1,4-Dinucleophiles such as semicarbazide and its analog
thiosemicarbazide are known useful reagents in the
synthesis of 1,2,4-triazaheterocycles. Treatment of com-
pound 1 with semicarbazide hydrochloride or thiosemicarb-
azide in boiling ethanol afforded semicarbazone derivatives
13a,b, respectively (Scheme 4).
by a positive Lassaigne's sulur test and by the signal of
1
SCH
3
protons in its H NMR spectrum, led us to the
conclusion that cyclization in boiling acetic acid takes
place regioselectively at the face [b] and not face [c] of the
quinoline ring. The chemical shift value at 2.68 ppm
characteristic for 2-methyloxazole20,21 methyl group
protons confirmed that 2-methyloxazolo[5,4-b]quinoline 9
was formed instead of the usually expected 3-methyl-
isoxazolo[5,4-b]quinoline 10, for which the chemical shift
of methyl protons is expected at a more upfield region,
δ ~2.3 ppm 2 (Scheme 2).
0,21
The analytical and spectral data of the reaction products
confirmed that reaction under these conditions leads to the
open-chain semicarbazones. Thus, IR spectrum of semi-
carbazones 13a,b showed absorption bands at 3277 and
Boiling a solution of oxime 8 in absolute ethanol in the
presence of a few drops of hydrochloric acid gave oxazolo-
2
2
[
4,5-c]quinolin-4-one 11 (Scheme 2). The same compound
was directly obtained by treatment of compound 1 with
hydroxylamine hydrochloride in boiling ethanol without
any additives. Furthermore, refluxing oxime 8 in DMF
3217, 3143, and 1650–1654 cm–1 corresponding to NH
2
,
1
NH, and carbonyl groups, respectively. H NMR spectrum
of these products represented two singlet signals at 2.53–
1
025

Chemistry of Heterocyclic Compounds 2015, 51(11/12) 1023–1029
Scheme 3
2
.61 and 2.67–2.70 ppm due to N=C–CH
3
and SCH
3
Scheme 4
protons, in addition to a broad signal of the amino protons
at 4.48 ppm. Interestingly, it was again the case that when
this reaction was carried out in boiling glacial acetic acid
instead of ethanol the cyclization into [1,2,4]triazepino[5,6-b]-
quinolines 14a,b took place with the respective yields of 64
and 60%. The same products 14a,b were also obtained
when semicarbazones 13a,b were subjected to heating in
boiling glacial acetic acid for only 1 h (Scheme 4).
Analytical data of products 14a,b showed that in the course
of the conversion of open-chain semicarbazones 13a,b
dehydration took place to affect annulation at face [b] of
Me
S Me
N
NH
N
N
H
2
NH CXNHNH2
AcOH, , 1 h
X
AcOH, , 4 h
14a,b
Me
S
Me
H
N
NH CXNHNH2
2
NH2
1
N
EtOH, , 3 h
X
N
H
O
the quinoline ring. Moreover, a signal with a chemical shift
1
3a,b
DMF, , 1 h
1
2
.64–2.69 ppm, characteristic of SCH
3
protons in the H
X
NH CXNHNH2
2
NMR spectrum confirmed that SCH
3
group is still present
NH
DMF, , 4 h
HN
N
in the structure of both products 14a,b. On the other hand,
carrying out the reaction of compound 1 with semicarb-
azide hydrochloride or thiosemicarbazide in boiling DMF
furnished known 1,2,4-triazepino[6,5-c]quinolinones 15a,b
Me
N
H
O
1
7
in 78% yield in both cases. Once more, it was found that
1
5a,b
a X = O, b X = S
in refluxing DMF open-chain semicarbazones 13a,b led to
Experimental
the respective cyclized products 15a,b (Scheme 4). The
1
lack of proton signal of SCH
3
group in the H NMR spectra
IR spectra were recorded on a Perkin Elmer FT-IR 1650
1
proved that the cyclization process in DMF, a relatively
high-boiling neutral solvent, proceeded not by dehydration,
but involving the liberation of methanethiol. Furthermore,
compounds 15a,b with identical characteristics were
spectrophotometer using samples in KBr pellets. H and
13
C NMR spectra were recorded on Varian Mercury-300
(300 and 75 MHz, respectively) or Bruker Avance III
(400 and 100 MHz, respectively) spectrometers using
1
7
prepared according to a literature procedure.
In conclusion, the condensation reaction of 3-acetyl-
DMSO-d
6
or CDCl as solvent. The internal standard was
3
1
either TMS or solvent signal (for H nuclei, 7.22 ppm in
13
4
-(methylsulfanyl)quinolin-2(1H)-one with certain dinucleo-
philic reagents under different reaction conditions regio-
selectively leads to different open or cyclized quinoline deri-
vatives. This variability of products is attributed to the pre-
sence of three active reaction centers in the quinolinone moiety.
The key compound may be considered as a good synthon
for a wide scale of heterocyclized quinoline derivatives,
depending on the nature of reagent and reaction conditions.
CDCl
3
and 2.50 ppm in DMSO-d
). Mass spectra (electron ionization, 70 eV)
6
; for C nuclei, 40.0 ppm
in DMSO-d
6
were obtained using a Shimadzu GC-2010 gas chromatograph-
mass spectrometer. Elemental microanalyses were performed
on a Perkin Elmer CHN-2400 analyzer. Melting points are
uncorrected and were determined in open capillary tubes by
digital Stuart-SMP3 melting point apparatus. Compound 1
was prepared according to the reported literature method.17
1
026

Chemistry of Heterocyclic Compounds 2015, 51(11/12) 1023–1029
3
-(1-Ethanehydrazonoyl)-4-(methylsulfanyl)quinolin-
(1H)-one (2). Hydrazine hydrate (99%, 10 ml, 200 mmol)
was added dropwise to a stirred solution of compound 1
2.33 g, 10 mmol) in DMF (70 ml). The reaction mixture
precipitated solid was collected by filtration, washed with
diethyl ether, and recrystallized from ethanol. Yield 2.30 g
2
–1
(70%), mp 216–218°C (decomp.). IR spectrum, ν, cm :
(
3620 (O–H), 3188 (N–H), 3069, 2965, 1620 (C=N), 1559,
1
was stirred at room temperature for 3 h, and the excess
solvent was evaporated at room temperature. The
precipitated solid was collected by filtration, washed with
ethanol, and dried to give compound 2. Yield 1.30 g (53%),
1528, 756, 752. H NMR spectrum (400 MHz, DMSO-d
6
),
); 2.60 (3H, s,
); 6.63–6.71 (1H, m, H Ar); 7.01–7.14 (4H, m, H Ar);
δ, ppm (J, Hz): 2.13 (3H, s, N=C–CH
SCH
3
3
7.32–7.35 (1H, m, H Ar); 7.62–7.73 (2H, m, H Ar); 8.08–
8.10 (1H, m, H Ar); 8.50 (0.35H, s, NH hydrazone,
(E)-form); 9.00 (0.65H, s, NH hydrazone, (Z)-form); 11.04
(br. s, NH quinolinone, (Z)-form) and 11.20 (1H in total,
–
1
mp 198–199°C (decomp.). IR spectrum, ν, cm : 3355,
3
1
243 (NH
2
), 3198, 3129 (N–H), 3064, 2963, 1620, 1603,
1
555, 1513, 1480, 1362, 1349, 759. H NMR spectrum
13
(
300 MHz, DMSO-d
6
), δ, ppm (J, Hz): 2.49 (3H, s,
); 2.63 (3H, s, SCH ); 6.15 (2H, s, NH
O); 7.28–7.38 (1H, m, H-6); 7.55–
br. s, OH quinolinol, (E)-form). C NMR spectrum (100
N=C–CH
3
3
2
,
MHz, DMSO-d ), δ, ppm: 174.5; 149.5; 146.7; 141.9;
6
exchangeable with D
2
132.1; 129.1; 128.8; 125.4; 123.8; 122.6; 119.0; 118.3;
7
.71 (2H, m, H-7,8), 8.07 (1H, d, J = 8.1, H-5); 10.80 (1H,
s, NH, exchangeable with D O). Mass spectrum, m/z (Irel, %):
47 [M] (1), 130 (12), 127 (32), 115 (21), 104 (14), 103
16), 102 (29), 97 (16), 91 (16), 89 (38), 88 (22), 83 (16),
113.1; 112.5; 23.7; 17.2; 16.1 (2C). Mass spectrum, m/z
+
2
(Irel, %): 323 [M] (39), 308 (13), 276 (37), 231 (15), 217
+
2
(
(13), 132 (15), 130 (13), 115 (21), 114 (14), 108 (9), 102
(14), 93 (100), 91 (61), 89 (19), 77 (56), 65 (57). Found, %:
7
7 (71), 76 (95), 70 (24), 63 (84), 57 (100). Found, %:
C 66.70; H 5.10; N 12.89. C18
C 66.85; H 5.30; N 12.99.
H
17
3
N OS. Calculated, %:
C 58.10; H 5.20; N 16.80. C12
C 58.28; H 5.30; N 16.99.
H
13
N OS. Calculated, %:
3
3-Methyl-4-(methylsulfanyl)-1-phenylpyrazolo[3,4-b]-
quinoline (6). I. A mixture of compound 1 (2.33 g,
10 mmol) and phenylhydrazine (1.1 ml, 10 mmol) in
glacial acetic acid (100 ml) was heated under reflux for 4 h,
then the reaction mixture was left to cool to room
temperature. The precipitated yellow crystalline material
was filtered off, washed with ethanol (30 ml), and
recrystallized from glacial acetic acid. Yield 1.60 g (60%),
3-Methyl-4-(methylsulfanyl)-1H-pyrazolo[3,4-b]quino-
line (3). I. A mixture of compound 1 (2.33 g, 10 mmol) and
hydrazine hydrate (1 ml, 200 mmol) was heated under
reflux in absolute ethanol (100 ml) for 3 h. The reaction
mixture was left to cool at room temperature. The
crystalline precipitate was filtered off, dried, and recrystal-
lized from ethanol. Yield 1.56 g (68%), mp 260–262°C.
–
1
–1
IR spectrum, ν, cm : 3213, 3132 (N–H), 3027, 2919, 1629
C=N), 1586, 1567, 1518, 1376, 1349, 1294, 763, 756.
mp 158–160°C. IR spectrum, ν, cm : 3069, 2974, 1617
1
(
(C=N), 1597, 1562, 776, 749. H NMR spectrum (400
1
H NMR spectrum (300 MHz, DMSO-d
.43 (3H, s, (N=C–CH ); 2.70 (3H, s, SCH
6
), δ, ppm (J, Hz):
MHz, CDCl
2.88 (3H, s, SCH
J = 7.8, H-8); 7.55–7.61 (6H, m, H-7, H Ph); 8.04 (1H, d,
3
), δ, ppm (J, Hz): 2.84 (3H, s, N=C–CH );
3
2
3
3
); 7.55 (1H, t,
3
); 7.15–7.24 (1H, m, H-6); 7.43 (1H, d,
J = 6.6, H-6); 7.67 (1H, t, J = 8.4, H-7); 7.94 (1H, d,
J = 8.1, H-8); 8.28 (1H, d, J = 7.8, H-5); 13.93 (1H, s, NH,
1
3
J = 8.0, H-5). C NMR spectrum (100 MHz, DMSO-d ),
6
1
3
exchangeable with D
DMSO-d
28.3; 125.7; 122.4; 114.9; 114.3; 15.1; 11.9. Mass
2
O). C NMR spectrum (100 MHz,
δ, ppm: 155.2; 145.9; 143.6; 140.6; 139.8; 130.3 (3C);
6
), δ, ppm: 155.1; 144.9; 143.2; 141.2; 129.4;
129.6; 128.8; 127.7 (2C), 125.4; 121.7; 115.6; 114.8; 15.0;
+
1
12.1. Mass spectrum, m/z (Irel, %): 305 [M] (100), 304
+
spectrum, m/z (Irel, %): 229 [M] (97), 228 (31), 214 (13),
(28), 259 (15), 258 (22), 190 (17), 169 (24), 154 (13), 128
(12), 114 (13), 108 (22), 102 (13), 93 (10), 89 (12), 77 (89).
1
1
7
96 (23), 183 (78), 169 (23), 167 (19), 154 (62), 140 (24),
29 (54), 128 (36), 127 (51), 115 (45), 114 (100), 102 (95),
Found, %: C 70.60; H 4.70; N 13.67. C18
ed, %: C 70.79; H 4.95; N 13.76.
H
15
3
N S. Calculat-
7 (52). Found, %: C 62.80; H 4.80; N 18.30. C12
H
11
N S.
3
Calculated, %: C 62.86; H 4.84; N 18.32.
II. A solution of compound 5 (3.23 g, 10 mmol) in
glacial acetic acid (50 ml) was heated under reflux for 1 h.
The reaction mixture was left to cool to give a yellow
crystalline precipitate which was filtered and washed with
ethanol and diethyl ether to give a product identical with
that obtained by method I. Yield 2.24 g (70%).
3-Methyl-1-phenyl-1,5-dihydropyrazolo[4,3-c]quinolin-
4-one (7). A solution of compound 5 (3.23 g, 10 mmol) in
DMF (50 ml) was heated under reflux for 1 h. The reaction
mixture was left to cool and the crystalline precipitate was
filtered off, dried, and recrystallized from glacial acetic
acid. Yield 2.21 g (79%).
3-(N-Hydroxyethanimidoyl)-4-(methylsulfanyl)quinolin-
2(1H)-one (8). A mixture of compound 1 (2.33 g, 10.0 mmol),
hydroxylamine hydrochloride (0.7 g, 10 mmol), and tri-
ethylamine 0.5 (1.0 mml, 10 mmol) in absolute ethanol
(100 ml) was heated under reflux for 3 h. The solid that
obtained, after cooling to room temperature, was filtered
II. A solution of compound 2 (2.50 g, 10 mmol) in
glacial acetic acid (25 ml) or absolute ethanol (50 ml) was
heated under reflux for 1 h. The reaction mixture was left
to cool at room temperature. The crystalline precipitate was
filtered off, dried, and recrystallized from absolute ethanol.
For the reaction carried out in ethanol, yield 1.04 g (45%),
for the reaction carried out in acetic acid, yield 1.72 g (75%).
3
-Methyl-1,5-dihydropyrazolo[4,3-c]quinolin-4-one (4).
A solution of compound 2 (2.50 g, 10 mmol) in DMF
(
25 ml) was heated under reflux for 1 h. The reaction
mixture was left to cool to room temperature. The crystalline
precipitate was filtered off and dried. Yield 1.67 g (84%).
(Z,E)-4-(Methylsulfanyl)-3-[1-(phenylhydrazinylidene)-
ethyl]quinolin-2(1H)-one (5). A mixture of compound 1
2.33 g, 10 mmol) and phenylhydrazine (1.1 ml, 10 mmol)
in absolute ethanol (100 ml) was heated under reflux for
h. Then the reaction mixture was left to cool, and the
(
3
1
027

Chemistry of Heterocyclic Compounds 2015, 51(11/12) 1023–1029
off, dried, and recrystallized from ethanol. Yield 1.9 g
mixture was left to cool and the crystalline precipitate was
filtered off, dried, and crystallized from glacial acetic acid.
Yield 1.24 g (62%).
–
1
(
75%), mp 198–199°C. IR spectrum, ν, cm : 3446 (O–H),
3
243 (N–H), 3061, 2957, 1625 (C=O, C=N), 1606, 1560,
1
1
496, 1473, 758. H NMR spectrum (300 MHz, DMSO-d
6
),
2-{1-[4-(Methylsulfanyl)-2-oxo-1,2-dihydroquinolin-
3-yl]ethylidene}hydrazinecarboxamide (13a). Semicarb-
azide hydrochloride (1.11 g, 10.0 mmol) was added to a
solution of compound 1 (2.33 g, 10.0 mmol) in ethanol
(50 ml), and the reaction mixture was heated under reflux
for 3 h. Upon cooling to room temperature, a solid
precipitate formed was filtered off and recrystallized from
δ, ppm (J, Hz): 1.98 (3H, s, N=C–CH
SCH ); 7.32 (1H, t, J = 7.2, H-6); 7.65–7.69 (2H, m,
3
); 2.62 (3H, s,
3
H-7,8); 8.03 (1H, d, J = 7.8, H-5); 10.87 (1H, s, NH,
exchangeable. with D O); 11.20 (1H, s, OH, exchangeable
O). C NMR spectrum (100 MHz, DMSO-d ),
2
1
3
with D
2
6
δ, ppm: 174.0; 152.8; 149.3; 140.7; 132.3; 125.5; 124.6;
1
23.9; 120.0; 118.3; 16.1; 15.2. Mass spectrum, m/z
absolute ethanol. Yield 1.98 g (68%), mp 221–223°C.
+
–1
(I
rel, %): 248 [M] (33), 233 (15), 217 (47), 216 (100), 215 (16),
IR spectrum, ν, cm : 3277, 3217 (NH
2
), 3143 (N–H),
2
02 (41), 188 (13), 185 (14), 172 (11), 170 (13), 158 (18), 155
3058, 2927, 1650 (C=O), 1620 (C=N), 1609, 1567, 1532,
1
(
15), 142 (29), 132 (16), 130 (31), 128 (22), 120 (16), 115 (36),
1489, 1380, 1297, 758. H NMR spectrum (300 MHz,
89 (40), 76 (43). Found, %: C 57.80; H 4.70; N 11.10.
DMSO-d
(3H, s, SCH
6
), δ, ppm (J, Hz): 2.61 (3H, s, N=C–CH
3
); 2.70
O);
C
12
H
12
N
2
O
2
S. Calculated, %: C 58.05; H 4.87; N 11.28.
3
); 4.48 (2H, s, NH
2
, exchangeable with D
2
2
-Methyl-4-(methylsulfanyl)[1,3]oxazolo[5,4-b]quino-
7.39 (1H, t, J = 7.5, H-6); 7.70 (1H, t, J = 7.7, H-7); 7.78
(1H, d, J = 8.4, H-8), 8.13 (1H, d, J = 7.8, H-5), 8.62 (1H,
line (9). I. Hydroxylamine hydrochloride (0.7 g, 10 mmol)
was added to a solution of compound 1 (2.33 g,
s, NNH, exchangeable with D
2
O); 10.86 (1H, s, 1-NH,
13
10.0 mmol) in glacial acetic acid (100 ml), and the reaction
exchangeable with D
2
O). C NMR spectrum (75 MHz,
mixture was heated under reflux for 3 h. The crystalline
precipitate, which formed upon cooling, was filtered off,
dried, and recrystallized from acetic acid. Yield 1.70 g
DMSO-d ), δ, ppm: 198.7; 178.9; 156.0; 139.5; 132.3;
6
131.8; 125.0; 124.3; 123.4; 119.6; 118.3; 31.5; 14.9.
Mass spectrum, m/z (Irel, %): 234 (12), 233 (16), 218
–
1
+
(
73%), mp 110–112°C. IR spectrum, ν, cm : 3069, 2927,
[M–N
2
CONH
2
]
(100), 215 (12), 200 (14), 172 (26).
1
1
632 (C=N), 1590, 1557, 1525, 1297, 761. H NMR
spectrum (300 MHz, DMSO-d ), δ, ppm (J, Hz): 2.68 (3H,
s, N=C–CH ); 2.73 (3H, s, SCH ); 7.61 (1H, t, J = 6.9,
H-6); 7.83 (1H, t, J = 7.2, H-7); 7.97 (1H, d, J = 8.4, H-8);
Found, %: C 53.60; H 4.60; N 19.10. C13
Calculated, %: C 53.78; H 4.86; N 19.30.
H
14
N
4
O S.
2
6
3
3
2-{1-[4-(Methylsulfanyl)-2-oxo-1,2-dihydroquinolin-
3-yl]ethylidene}hydrazinecarbothioamide (13b) was
obtained analogously from compound 1 (2.33 g, 10.0 mmol)
and thiosemicarbazide (0.92 g, 10.1 mmol). Yield 2.00 g
13
8
.21 (1H, d, J = 8.4, H-5). C NMR spectrum (75 MHz,
DMSO-d ), δ, ppm: 169.3; 161.7; 130.7; 127.8; 126.5;
23.9; 122.1; 121.4; 120.7; 120.6; 34.0; 23.0. Mass
6
–1
1
(65%), mp 202–204°C. IR spectrum, ν, cm : 3277, 3217
(NH ), 3143 (N–H), 3070, 2930, 1654 (C=O), 1619 (C=N),
1566, 1540, 1489, 1340, 758. H NMR spectrum (300
MHz, DMSO-d ), δ, ppm (J, Hz): 2.53 (3H, s,
N=C–CH ); 2.67 (3H, s, SCH ); 4.50 (2H, s, NH
exchangeable with D O); 7.30–7.45 (1H, m, H-6); 7.65–
7.85 (2H, m, H-7,8); 8.02–8.23 (1H, m, H-5); 10.30 (1H, s,
NNH, exchangeable with D O); 10.86 (1H, s, 1-NH,
O). C NMR spectrum (100 MHz,
+
spectrum, m/z (Irel, %): 230 [M] (100), 229 (28), 202 (53),
2
1
1
1
8
97 (39), 184 (24), 173 (10), 169 (16), 155 (14), 141 (13),
30 (38), 129 (28), 120 (11), 115 (46), 114 (85), 102 (74),
8 (44), 76 (65). Found, %: C 62.40; H 4.20; N 12.00.
6
3
3
2
,
C
12
H
10
N
2
OS. Calculated, %: C 62.59; H 4.38; N 12.16.
2
II. A solution of compound 8 (2.48 g, 10.0 mmol) in
glacial acetic acid (50 ml) was heated under reflux for 3 h.
The reaction mixture was left to cool and the crystalline
precipitate was filtered off and dried. Yield 1.30 g (53%).
2
13
exchangeable with D
2
DMSO-d ), δ, ppm: 199.2; 179.0; 175.0; 156.7; 150.0;
6
2-Methyl[1,3]oxazolo[4,5-c]quinolin-4(5H)-one (11).
140.0; 132.9; 125.6; 124.9; 120.1; 118.8; 32.0; 16.2. Mass
+
I. Compound 1 (2.33 g, 10.0 mmol) and hydroxylamine
hydrochloride (0.70 g, 10 mmol) were heated under reflux
in absolute ethanol (70 ml) for 3 h. The reaction mixture
was left to cool. The solid precipitate was collected by
filtration and dried. Yield 1.40 g (64%).
II. A mixture of compound 8 (2.48 g, 10.0 mmol) and
concd. hydrochloric acid (1 ml) in ethanol (50 ml) was
heated under reflux for 2 h. The reaction mixture was left to
cool and the crystalline precipitate was filtered, dried, and
recrystallized from glacial acetic acid. Yield 1.50 g (75%).
spectrum, m/z (Irel, %): 306 [M] (3), 305 (10), 218
+
[M–N
2
CSNH
2
] (100), 216 (11), 215 (13), 199 (33), 190
(13), 172 (48), 145 (17), 130 (17), 128 (11), 117 (25), 116
(22), 115 (20), 102 (22), 91 (37), 89 (42), 77 (46). Found,
%: C 50.70; H 4.50; N 18.20. C13
C 50.96; H 4.61; N 18.28.
H
14
N
4
OS . Calculated, %:
2
5-Methyl-6-(methylsulfanyl)-1,3-dihydro-2H-[1,2,4]-
triazepino[5,6-b]quinolin-2-one (14a). I. Semicarbazide
hydrochloride (1.11 g, 10.0 mmol) was added to a solution
of compound 1 (2.33 g, 10.0 mmol) in glacial acetic acid
(50 ml), and the reaction mixture was heated under reflux
for 4 h. Upon cooling to room temperature, a solid
precipitate formed was filtered off and recrystallized
from absolute ethanol. Yield (64%), mp 299–301°C.
3
-Methyl[1,2]oxazolo[4,5-c]quinolin-4(5H)-one (12).
I. A mixture of compound 1 (2.33 g, 10.0 mmol) and
hydroxylamine hydrochloride (0.7 g, 10 mmol) in DMF
100 ml) was heated under reflux for 1 h. The brown solid
(
–1
obtained after cooling was filtered, dried, and recrystallized
from ethanol to give compound 12. Yield 1.06 g (53 %).
II. A solution of compound 8 (2.48 g, 10.0 mmol) in
DMF (50 ml) was heated under reflux for 4 h. The reaction
IR spectrum, ν, cm : 3248, 3135 (N–H), 3061, 2985, 1647
(C=O), 1620 (C=N triazepine), 1603, 1560, 1510, 1474,
1
1344, 758. H NMR spectrum (300 MHz, DMSO-d
6
),
δ, ppm (J, Hz): 2.48 (3H, s, N=C–CH
3
); 2.64 (3H, s,
1
028

Chemistry of Heterocyclic Compounds 2015, 51(11/12) 1023–1029
SCH
3
); 7.37 (1H, t, J = 7.8, H-9); 7.65 (1H, t, J = 8.1, H-8);
Supporting material to this article containing 1H,
C NMR, and mass spectra of the synthesized compounds
1
3
7
.79 (1H, d, J = 8.4, H-7); 8.11 (1H, d, J = 8.1, H-10); 8.50
(
1H, s, NH, exchangeable with D
2
O), 10.86 (1H, s, NH,
is available online at http://link.springer.com/journal/10593.
exchangeable with D
2
O). Found, %: C 57.20; H 4.40;
References
N 20.50. C13
N 20.57.
H
12
N OS. Calculated, %: C 57.34; H 4.44;
4
1. Abass, M.; Hassan, H.; Mohamed, E. A.; Zalat, R. S.; Magdi, M.;
II. A solution of compound 13a (1.45 g, 5.00 mmol) in
glacial acetic acid (30 ml) was heated under reflux for 1 h.
The reaction mixture was left to cool, and the crystalline
product was filtered off and dried. Yield 1.01 g (75%).
El-Shenawy, A. A. Global Vet. 2015, 15, 215.
2
. Padoley, K. V.; Mudliar, S. N.; Pandey, R. A. Bioresour.
Technol. 2008, 99, 4029.
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. Mundt, M.; Hollender J. J. Chromatogr. A 2005, 1065,
2
11.
5
-Methyl-6-(methylsulfanyl)-1,3-dihydro-2H-[1,2,4]tri-
4
5
. Abass, M. Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 735.
. El-Shennawy, A. M.; Mohamed, A. H.; Abass, M. Medscape
Gen. Med. 2007, 9(1), 15.
azepino[5,6-b]quinoline-2-thione (14b). I. Thiosemicarb-
azide (0.92 g, 10.0 mmol) was added to a solution of
compound 1 (2.33 g, 10.0 mmol) in glacial acetic acid
6
. Bolakatti, G.; Katagi, M. S.; Mamledesai, S. N.; Sujatha, M. L.;
Dabadi, P.; Miskin , N. RGUHS J. Pharm. Sci. 2012, 2, 60.
(
50 ml), and the reaction mixture was heated under reflux
for 4 h. Upon cooling to room temperature, a solid pre-
cipitate formed was filtered off and recrystallized from
absolute ethanol. Yield 1.88 g (60%), mp 130–133°C.
7. Aubry, A.; Veziris, N.; Cambau, E.; Truffot-Pernot, C.;
Jarlier, V.; Fisher, L. M. Antimicrob. Agents Chemother.
2006, 50, 104.
–
1
8
. Ukrainets, V.; Andreeva, K. V.; Gorokhova, O. V.;
IR spectrum, ν, cm : 3316, 3200 (N–H), 3026, 2961, 1622
1
Kravchenko, V. N. Chem. Heterocycl. Compd. 2013, 48,
(
C=N triazepine), 1592, 1498, 1472, 723. H NMR
spectrum (300 MHz, DMSO-d ), δ, ppm (J, Hz): 2.14 (3H,
s, N=C–CH ); 2.69 (3H, s, SCH ); 7.40 (1H, t, J = 8.1,
H-9); 7.65–7.78 (2H, m, H-7,8); 8.07 (1H, d, J = 7.8,
1
809. [Khim. Geterotsikl. Soedin. 2012, 1932.]
6
9
. Rowely, M.; Leeson, P. D.; Stevenson, G. I.; Moseley, A. M.;
Stansfield, I.; Sanderson, I.; Robinson, I.; Baker, R.; Kemp, J. A.;
Marshall, G. R.; Foster, A. C.; Grimwood, S.; Tricklebank, M. D.;
Saywell, K. L. J. Med. Chem. 1993, 36, 3386.
3
3
H-10); 9.66 (1H, s, NH, exchangeable with D
2
O); 11.97
O). C NMR spectrum
), δ, ppm: 178.6; 172.5; 149.5; 147.9;
46.6; 141.3; 132.4; 125.4; 124.0; 118.4; 116.8; 23.8; 16.2.
13
(
1H, s, NH, exchangeable with D
100 MHz, DMSO-d
2
1
0. Tedesco, R.; Shaw, A. N.; Bambal, R.; Chai, D.; Concha, N. O.;
Darcy, M. G.; Dhanak, D.; Fitch, D. M.; Gates, A.;
Gerhardt, W. G.; Halegoua, D. L.; Han, C.; Hofmann, G. A.;
Johnston, V. K.; Kaura, A. C.; Liu, N.; Keenan, R. M.;
Lin-Goerke, J.; Sarisky, R. T.; Wiggall, K. J.; Zimmerman,
M. N.; Duffy, K. J. J. Med. Chem. 2006, 49, 971.
(
6
1
+
Mass spectrum, m/z (Irel, %): 288 [M] (1), 242 (12), 218
(
(
(
30), 199 (31), 170 (10), 145 (12), 120 (11), 115 (30), 114
26), 94 (25), 91 (39), 89 (20), 77 (44), 69 (15), 63 (17), 60
48), 59 (100). Found, %: C 54.00; H 4.10; N 19.20%.
1
1
1. Cheng, P.; Zhang, Q.; Ma, Y.-B.; Jiang, Z.-Y.; Zhang, X.-M.;
Zhang, F.-X.; Chen, J.-J. Bioorg. Med. Chem. Lett. 2008, 18,
C
13
H
12
N
4
S
2
. Calculated, %: C 54.14; H 4.19; N 19.43.
3
787.
II. A solution of compound 13b (1.53 g, 5.00 mmol) in
2. Arsenyan, P.; Vasiljeva, J.; Shestakova, I.; Domracheva, I.;
glacial acetic acid (30 ml) was heated under reflux for 1 h.
The reaction mixture was left to cool, and the crystalline
product was filtered off and dried. Yield 1.09 g (75%).
Preparation of [1,2,4]triazepino[6,5-c]quinolines 15a,b
Belyakov, S. Chem. Heterocycl. Compd. 2014, 49, 1674.
[
Khim. Geterotsikl. Soedin. 2013, 1804.]
13. Martinborough, E.; Shen, Y.; Oeveren, A. V.; Long, Y. O.;
Lau, T. L. S.; Marschke, K. B.; Chang, W. Y.; López, F. J.;
Vajda, E. G.; Rix, P. J.; Viveros, O. H.; Negro-Vilar, A.; Zhi, L.
J. Med. Chem. 2007, 50, 5049.
(
(
General method). I. A solution of either compound 13a
1.45 g, 5 mmol) or 13b (1.53 g, 5 mmol) in DMF (30 ml)
1
4. Zhong, W.; Liu, H.; Kaller, M.; Henley, C.; Magal, E.;
Nguyen, T.; Osslund, T. D.; Powers, D.; Wang, H. L.;
Xiaoling, X.; Norman, M. H. Bioorg. Med. Chem. Lett. 2007,
was heated under reflux for 1 h. The reaction mixture was left
to cool and the crystalline product was filtered off and dried.
II. To a solution of compound 1 (2.33 g, 10 mmol) in
DMF (50 ml), semicarbazide hydrochloride (1.11 g, 10.0
mmol) or thiosemicarbazide (0.92 g, 10.1 mmol) was
added, and the reaction mixture was heated under reflux for
1
7, 5384.
1
1
5. Baston, E.; Palusczak, A.; Hartmann, R. W. Eur. J. Med.
Chem. 2000, 35, 931.
6. Letellier, M. A.; Guillard, J.; Caignard, D. H.; Ferry, G.;
Boutin, J. A.; Viaud-Massuard, M. C. Eur. J. Med. Chem.
2008, 43, 1730.
4
h. After cooling to room temperature, the solid precipitate
was filtered and recrystallized from ethanol to give
compounds 15a and 15b, respectively.
17. Hassan, M. M.; Othman, E. S.; Abass, M., Res. Chem.
Intermed. 2013, 39, 1209.
5-Methyl-3,7-dihydro-1H-[1,2,4]triazepino[6,5-c]
1
1
8. Stadlbauer, W.; Hojas, G. J. Heterocycl. Chem. 2004, 41, 681.
9. Hwang, B. H.; Choi, E. B.; Lee, H. K.; Yang, H. C.; Chung, B. Y.;
Pak, C. S. Synthesis 2008, 3569.
quinoline-2,6-dione (15a). This compound was obtained
from semicarbazide hydrochloride, mp > 300°C (mp
17
>
300°C ). Yield 1.88 g (78%, method I and II).
2
2
2
0. Zhang, X.; Huang, R.; Marrot, J.; Coeffard, V.; Xiong, Y.
Tetrahedron 2015, 71, 700.
5-Methyl-2-thioxo-1,2,3,7-tetrahydro-6H-[1,2,4]tri-
azepino[6,5-c]quinolin-6-one (15b). This compound was
1. Dou, G.; Xu, P.; Li, Q.; Xi, Y.; Huang, Z.; Shi, D. Molecules
obtained from thiosemicarbazide, recrystallized from
2
013, 18, 13645.
17
absolute ethanol, mp > 300°C (mp > 300°C ). Yield 2.06 g
2. Kappe, T.; Algner, R.; Jobstl, M.; Hohengassner, P.;
(
80%, method I), 2.00 g (78%, method II).
Stadlbauer, W. Heterocycl. Commun. 1995, 3, 341.
1
029