Convenient Synthesis of Piperazine Substituted Quinolones

Article abstract of DOI:10.1002/jhet.2971

A series of 1-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonyl]-4-(substituted) piperazines 3a–c and methyl 2-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino] alkanoates 5a–d has been developed by the direct condensation of ethyl [4-hydroxy-2-oxo-1-phenyl-1,2-dihydro-3-quinoline] carboxylate 2 with N¹-monosubstituted piperazine hydrochlorides or amino acid ester hydrochloride in the presence of triethyl amine. The quinolone amino acid esters 5a–d were the key intermediate for the preparation of a series of 1-[2-((4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino)alkylcarbony]-4-substituted piperazine derivatives 8–11 (a-d) via azide coupling method with amino acid ester hydrochloride.

Full text of DOI:10.1002/jhet.2971

Month 2017
Convenient Synthesis of Piperazine Substituted Quinolones
a
Walid Fathalla
and Pavel Pazderab
*
aPhysics and Mathematics Engineering Department, Faculty of Engineering, Port-Said University, Port Said, Egypt
bCentre for Syntheses at Sustainable Conditions and Their Management, Chemistry Department, Masaryk University,
Brno, Czech Republic
*
E-mail: walid3369@yahoo.com
Received March 14, 2017
DOI 10.1002/jhet.2971
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A series of 1-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonyl]-4-(substituted) pipera-
zines 3a–c and methyl 2-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino]
alkanoates 5a–d has been developed by the direct condensation of ethyl [4-hydroxy-2-oxo-1-phenyl-
1,2-dihydro-3-quinoline] carboxylate 2 with N1-monosubstituted piperazine hydrochlorides or amino
acid ester hydrochloride in the presence of triethyl amine. The quinolone amino acid esters 5a–d were
the key intermediate for the preparation of
a series of 1-[2-((4-hydroxy-2-oxo-1-phenyl-1,2-
dihydroquinolin-3-yl)carbonylamino)alkylcarbony]-4-substituted piperazine derivatives 8–11 (a-d) via
azide coupling method with amino acid ester hydrochloride.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
Non-proteinogenic amino acids are major component in
a number of drugs including β-lactam antibiotics [18] and
glutamate antagonists [19]. These results motivated the
development of a series of quinolones directly attached to
biologically promising piperazine derivatives, or via
amino acid spacer.
Quinolone is
a
very important N-heteroaromatic
wide variety of
compounds known to possess
a
pharmacological activities [1]. Linomide (roquinimex),
immunomodulatory drug showed a wide variety of
effective applications in immunotherapy of tumors [2,3],
DISCUSSION
has
a
profound inhibitory influence in several
experimental autoimmune diseases, including acute and
chronic experimental allergic encephalomyelitis, and has
a potential for the treatment of multiple sclerosis [4].
We now report the preparation of 1-[(4-hydroxy-2-oxo-1-
phenyl-1,2-dihydroquinolin-3-yl)carbonyl]-4-(substituted)
piperazines
and
1-[2-((4-hydroxy-2-oxo-1-phenyl-
1,2-dihydroquinolin-3-yl)carbonylamino)alkycarbony]-4-
substituted piperazine derivatives. The quinoline ester
derivative 2 was prepared as reported [20] by the reaction
of isatoic anhydride derivative 1 with diethyl malonate in
the presence of NaH in DMF to afford the ester 2 in 74%
yield. Our efforts to attach piperazine residue to quinoline
ring system at position 3 were successful using the direct
condensation of the piperazine derivatives with the ester.
Thus, the reaction of ester 2 with N1-monosubstituted
piperazine hydrochlorides in the presence of triethyl
amine in toluene under reflux condition for 6 h gave
1-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydro-quinolin-3-yl)
carbonyl]-4-(substituted) piperazines 3a–c in good yield
(Scheme 1). N1-Monosubstituted piperazine hydrochlorides
used in this article were prepared by the direct reaction of
A large number of compounds conducted on piperazine
ring are well known as important marketed drugs and were
used in great variety of biological activities, such as
antidepressant (Amoxapine [5], Befuraline [6], Buspirone
[7], Flesinoxan [8], Ipsapirone [9]), antihistamine
(Meclozine [10], Cinnarizine [11], Hydroxyzine [12]),
antipsychotic (Perphenazine [13], Prochlorperazine
[14,15]), anticancer (Imatinib [16]), analgesic, and anti-
inflammatory (Antrafenine [17]).
© 2017 Wiley Periodicals, Inc.

W. Fathalla and P. Pazdera
Vol 000
Scheme 1. Synthesis of 1-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydro quinolin-3-yl)carbonyl]-4-(substituted) piperazine 3a–c and methyl 2-[(4-hydroxy-2-
oxo-1-phenylquinolin-3-yl)carbonylamino] alkanoates 5a–d.
piperazine-1-ium cation with alkyl halides or methyl acrylate
by Cu+, Cu2+, or Al3+ ions supported on weakly acidic cation-
exchanger resin [21,22]. Similarly, a series of amino acid
quinoline derivatives 5a–d was prepared by the reaction of
ester 2 with amino acid ester hydrochloride in the presence
of triethyl amine in toluene under reflux condition for 6 h
gave the amino acid derivatives 5a–d in high yield (65–
89%) (Scheme 1). Both piperazine carboxylate derivatives
3a–c and amino acid ester derivatives 5a–d are excellent
precursors for structure modification of quinoline ring
system with N1-monosubstituted piperazine via azide
coupling method. Azide coupling method is considered as
one of the important methods to couple amino acid
derivatives starting from hydrazides. It was also reported
that this method decreases the degree of racemization in the
amino acid coupling and amine nucleophiles [23,24].
(a-d). Thus, amino acid derivatives 5a–d was boiled with
hydrazine hydrate in ethyl alcohol to afford the
hydrazides 6a–d (Scheme 1), which subsequently
converted into azides 7a–d by treatment with NaNO2 and
HCl mixture. The in situ generated azide derivatives 7a–d
in ethyl acetate was used in a one-pot strategy without
purification nor isolation. The azides 7a–d solution in
ethyl acetate was reacted with N-methylpiperazine and 4-
substituted piperazine-1-ium chloride ester derivatives in
the presence of triethyl amine to afford 1-[2-((4-hydroxy-
2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino)
alkylcarbony]-4-substituted piperazine derivatives 8–11
(a–d) in good yield (Scheme 2, Table 1).
The structure assignment of piperazine derivatives 8–11
1
(a–d) is based on H and 13C NMR spectroscopy as well
1
as physicochemical analysis (Fig. 1). Thus, the H NMR
We first tried the hydrazinolysis of the piperazine
derivatives 3a–c, which represent the first step in the
azide coupling method. However, the reaction of ester 3b
(R=CH2COOCH3) with hydrazine hydrate in ethanol for
4 h and gave the hydrazide 4 with an over-all elimination
of the piperazine residue (Scheme 1).
An alternative effort to attach monosubstituted
piperazine derivative to quinoline ring system could be
achieved from the corresponding amino acid derivatives
5a–d to give the target compounds 1-[2-((4-hydroxy-2-
oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino-
alkylcarbony]-4-substituted piperazine derivatives 8–11
spectrum of 8b (R=COOCH3) exhibits two interesting
singlet signals at δ 16.73 and 10.76 ppm corresponding to
OH and NH groups, respectively. The H NMR spectrum
1
of 8b exhibits an interesting doublet signal at δ 8.23 ppm
due an anisotropic shielding of the neighboring carbonyl
on an aromatic proton. All three chemical shifts mentioned
earlier are common for all amino acid derivatives 5a–d as
well as the piperazine derivatives 8–11 (a–d). The 1H
NMR spectrum of 8b also shows a doublet signal at δ
4.26 ppm typically associated with NHCH2 group. The 1H
NMR spectrum of 8b also reveals signals at δ 3.74–
3.50 ppm for 11 protons corresponding to four piperazine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Convenient Synthesis of Piperazine Substituted Quinolones
Scheme 2. Synthesis of 1-[2-((4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonyl-amino)alkylcarbony]-4-substituted piperazine derivatives
8–11 (a–d).
Table 1
Structures of 1-[2-((4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino)alkylcarbony]-4-substituted piperazine derivatives 8–11 (a–d).
8–11
8a
n
R1
R2
8–11
n
R1
R2
0
0
0
0
0
0
0
0
H
H
H
H
CH3
10a
10b
10c
0
0
0
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH3
8b
8c
8d
9a
9b
9c
9d
COOCH3
COOCH3
CH2COOCH3
CH2COOCH3
CH2CH2COOCH3
CH3
COOCH3
CH2COOCH3
CH2CH2COOCH3
CH3
CH3
CH3
CH3
11a
11b
11c
11d
1
1
1
1
H
H
H
H
CH3
COOCH3
CH2COOCH3
CH2CH2COOCH3
2-[(4-hydroxy-2-oxo-1-phenylquinolin-3-yl)carbonyl amino]
alkanoates 5a–d has been developed by the direct
condensation of ethyl [4-hydroxy-2-oxo-1-phenyl-
1,2-dihydro-3-quinoline] carboxylate
2
with N1-
monosubstituted piperazine hydrochlorides or amino acid
ester hydrochloride in the presence of triethyl amine. Azide
coupling method was successfully applied to attach
piperazine moiety to quinoline ring system via amino acid
spacer to afford 15 piperazine derivatives 8–11(a–d).
However this method failed to give results to attach amino
acid to quinoline ring system via piperazine spacer.
Figure 1. Selected 1H and 13C NMR spectral data of 1-[2-((4-hydroxy-2-
oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino)-acetyl]-4-
(methoxycarbonyl) piperazine (8b).
CH2 groups and OCH3 group. The 13C NMR spectrum of 8b
reveals quaternary carbon signals at δ 172.5, 166.1, 162.7,
and 155.7 ppm assigned to one C=O ester group and three
C=O amide groups, respectively. The 13C NMR spectrum
of 8b also reveals signals at δ 44.5, 43.6, 43.5, and
41.8 ppm associated with four piperazine CH2 groups. The
13C NMR spectrum of 8b also reveals signals at δ 52.9
and 41.1 ppm for OCH3 and NHCH2, respectively (Fig. 1).
EXPERIMENTAL
General procedures. Solvent were purified and dried
by standard procedures. The boiling range of the
petroleum ether used was 40–60°C. Thin layer
chromatography: silica gel 60 F254 plastic plates (E.
Merck, layer thickness 0.2 mm) detected by UV
absorption. Elemental analyses were performed on a
Flash EA-1112 instrument at the Microanalytical
laboratory, Faculty of Science, Suez Canal University,
Ismailia, Egypt. Melting points were determined on a
Buchi 510 melting-point apparatus and the values are
CONCLUSION
A series of 4-hydroxy-2-oxo-1-phenylquinolin-3-yl)
carbonyl]-4-(substituted) piperazines 3a–c and methyl
Journal of Heterocyclic Chemistry
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W. Fathalla and P. Pazdera
Vol 000
1
uncorrected. H and 13C NMR spectra were recorded at
spectrum, δ, ppm (J, Hz): 8.21 (1H, d, J = 8.0, ArH);
7.67–7.49 (3H, m, ArH); 7.31–7.21 (4H, m, ArH); 6.63
(1H, d, J = 8.0, ArH); 3.81–3.63 (7H, m, 2CH2, OCH3),
3.61 (2H, s, CH2), 2.79–2.71 (4H, m, 2CH2). 13C NMR
spectrum, δ, ppm: 170.1 (C=O ester); 169.0 (C–OH);
168.2 (C=O amide); 160.0 (C=O ester); 141.6 (C Ar);
137.6 (C Ar); 132.7 (CHAr); 130.2 (CHAr); 129.1
(CHAr); 128.9 (CHAr); 124.8 (CHAr); 122.2 (CHAr);
115.8 (CHAr); 115.4 (C Ar); 101.9 (C Ar); 58.8 (NCH2);
52.9 (CH2-piperazine); 52.7 (CH2Àpiperazine); 51.8
(OCH3); 47.2 (CH2Àpiperazine); 46.8 (CH2Àpiperazine).
Found, %: C, 65.39; H, 5.40; N, 9.86. For C23H23N3O5
300 and 75.5 MHz, respectively (Bruker AC 300) in
CDCl3 and DMSO solution with tetramethylsilane as an
internal standard. The NMR analyses were performed at
Organic Chemistry Department Masaryk University, Brno,
Czech Republic. The starting ester 2 and the reagents
N1-monosubstituted piperazine hydrochlorides described
in literature [20–22].
Ethyl [4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl]
carboxylate (2).
isatoic anhydride derivative in the presence of sodium
hydride in dry dimethylformamide led to compound 2
[20]. Yield 74%. White crystals, mp 188–189°C. 1H
NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz):
14.45 (1H, s, OH); 8.21 (1H, d, J = 8.0, ArH);
7.58–7.22 (7H, m, ArH); 6.61 (1H, d, J = 8.0, ArH);
4.28 (2H, q, J = 6.0, OCH2); 1.45 (3H, t, J = 6.0, CH3).
13C NMR spectrum (75.0 MHz, CDCl3), δ, ppm: 172.7
(C=O ester); 172.5 (C–OH); 159.7 (C=O amide); 142.3
(C Ar); 137.6 (C Ar); 133.9 (CHAr); 130.1 (CHAr);
129.3 (CHAr); 128.8 (CHAr); 125.3 (CHAr); 122.1
(CHAr); 115.9 (CHAr); 114.7 (C Ar); 98.1 (C Ar); 62.3
(OCH2); 14.3 (CH3). Found, %: C, 69.65; H, 4.81; N,
4.49. For C18H15NO4 (309.1). Calculated, %: C, 69.89;
H, 4.89; N, 4.53.
Condensation of diethyl malonate and
(421.2). Calculated, %: C, 65.55; H, 5.50; N, 9.97.
1-[(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonyl]-4-(3-methoxy-3-oxopropyl) piperazine (3c).
1
0.29 g, Yield 67%. White crystals, mp 205–206°C. H
NMR spectrum, δ, ppm (J, Hz): 8.23 (1H, d, J = 8.0,
ArH); 7.41–7.25 (7H, m, ArH); 6.65 (1H, d, J = 8.0,
ArH); 3.78–3.53 (7H, m, 2CH2, OCH3); 3.48–2.91 (8H,
m, 4CH2). 13C NMR spectrum, δ, ppm: 172.2 (C=O
ester); 169.2 (C–OH); 168.3 (C-amide); 160.0 (C=O
ester); 141.6 (C Ar); 137.6 (C Ar); 132.8 (CHAr); 130.2
(CHAr); 129.1 (CHAr); 129.0 (CHAr); 124.8 (CHAr);
122.3 (CHAr); 115.9 (CHAr); 115.4 (C Ar); 101.7 (C
Ar); 53.2 (NCH2); 53.0 (CH2Àpiperazine); 52.7 (CH2
piperazine); 51.8 (OCH3); 47.3 (CH2 piperazine); 46.6
(CH2 piperazine); 31.4 (CH2COOCH3). Found, %: C,
66.01; H, 5.68; N, 9.47. For C24H25N3O5 (435.2).
General procedure for preparation of 1-[(4-hydroxy-2-oxo-
1-phenyl-1,2-dihydro quinolin-3-yl)carbonyl]-4-(substituted)
piperazine (3a–c).
N1-monosubstituted piperazine
hydrochlorides (1.2 mmol) and ethyl 1,2-dihydro-4-
hydroxy-1-phenyl-2-oxo-3-quinolinecarboxylate 2 (0.31 g,
1.0 mmol) and triethyl amine (0.15 mL, 1.5 mmol) were
dissolved in 100 mL of dry toluene. The reaction mixture
was refluxed, and an amount of approximately 60 mL of
the volatiles was distilled off at atmospheric pressure for
6 h using a dean stark system. After cooling, the reaction
mixture was evaporated under reduced pressure and the
Calculated, %: C, 66.19; H, 5.79; N, 9.65.
[4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3yl]
carbohydrazide (4). To a solution of piperazine derivative
3b (0.42 g, 1.0 mmol) in ethyl alcohol (15 mL), hydrazine
hydrate 100% (0.1 mL, 2.0 mmol) was added. The reaction
mixture was refluxed for 4 h, cooled and the resultant
precipitate was filtered off, washed with ethanol and ether
then crystallized from aqueous ethanol to yield the
hydrazide 5.
resultant solid was crystalized from ethanol.
1-[(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonyl]-4-(methoxy-carbonyl) piperazine (3a).
1
0.18 g, Yield 62%. White crystals, mp 209–210°C. H
0.30 g,
Yield 74%. White crystals, mp 179–180°C. 1H NMR
spectrum, δ, ppm (J, Hz): 8.21 (1H, d, J = 8.0, ArH);
7.67–7.28 (7H, m, ArH); 6.66 (1H, d, J = 8.0, ArH);
3.76–3.54 (11H, m, 4CH2, OCH3). 13C NMR spectrum,
δ, ppm: 170.3 (C=O ester); 168.9 (C–OH); 159.9 (C=O
amide); 155.8 (C=O ester); 141.6 (C Ar); 137.5 (C Ar);
132.9 (CHAr); 130.2 (CHAr); 129.1 (CHAr); 129.0
(CHAr); 124.8 (CHAr); 122.3 (CHAr); 115.9 (CHAr);
115.3 (C Ar); 101.6 (C Ar); 52.8 (OCH3); 47.2
NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):
10.78 (1H, s, NH); 8.15 (1H, d, J = 8.0, ArH); 7.70–7.52
(5H, m, ArH); 7.38–7.18 (5H, m, ArH); 6.53 (1H, d,
J = 8.0, ArH); 4.86 (2H, bs, NH2). 13C NMR spectrum
(75.0 MHz, DMSO-d6), δ, ppm: 171.7 (C=O ester);
168.4 (C–OH); 161.2 (C=O amide); 141.0 (C Ar); 137.4
(C Ar); 134.2 (CHAr); 130.5 (CHAr); 129.6 (CHAr);
129.4 (CHAr); 124.8 (CHAr); 123.2 (CHAr); 116.3
(CHAr); 115.2 (C Ar). Found, %: C, 64.96; H, 4.38; N,
14.12. For C16H13N3O3 (295.1). Calculated, %: C, 65.08;
H, 4.44; N, 14.23.
(CH2Àpiperazine);
46.7
(CH2Àpiperazine);
43.7
(CH2Àpiperazine); 43.4 (CH2Àpiperazine). Found, %: C,
64.74; H, 5.12; N, 10.27. For C22H21N3O5 (407.2).
General procedure for preparation of methyl 2-[(4-
hydroxy-2-oxo-1-phenylquinolin-3-yl)carbonylamino]
Calculated, %: C, 64.86; H, 5.20; N, 10.31.
alkanoates (5a–d).
Amino acid ester hydrochlorides
1-[(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonyl]-4-(2-methoxy-2-oxoethyl) piperazine (3b). 0.35 g,
(1.2 mmol) and ethyl 1,2-dihydro-4-hydroxy-1-phenyl-2-
oxo-3-quinolinecarboxylate 2 (0.31 g, 1.0 mmol) and
Yield 84%. White crystals, mp 80–81°C. 1H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Convenient Synthesis of Piperazine Substituted Quinolones
triethyl amine (mL, 1.2 mmol) were dissolved in 100 mL
of dry toluene. The reaction mixture was refluxed, and an
amount of approximately 60 mL of the volatiles was
distilled off at atmospheric pressure for 6 h using a dean
stark system. After cooling, the reaction mixture was
evaporated under reduced pressure and the resultant solid
8.25 (1H, d, J = 8.0, ArH); 7.63–7.28 (7H, m, ArH); 6.65
(1H, d, J = 8.0, ArH); 3.66 (3H, s, OCH3); 3.42 (2H, q,
J = 6.0, CH2); 2.32 (2H, t, J = 6.0, CH2); 1.69–1.41 (6H,
m, 2CH3). 13C NMR spectrum, δ, ppm: 173.9 (C=O
ester); 173.0 (C–OH); 172.9 (C=O amide); 171.0 (C=O
amide); 163.1 (C=O amide); 140.8 (C Ar); 137.2 (C Ar);
133.2 (CHAr); 130.3 (CHAr); 129.1 (CHAr); 129.0
(CHAr); 125.2 (CHAr); 122.6 (CHAr); 116.2 (CHAr);
116.0 (C Ar); 96.7 (C Ar); 51.4 (OCH3); 38.9 (C-Leu);
33.9 (CH2-Leu); 29.0 (CH2-Leu); 26.5 (CH3); 24.6
(CH3). Found, %: C, 67.59; H, 5.84; N, 6.77. For
C23H24N2O5 (408.2). Calculated, %: C, 67.63; H, 5.92;
N, 6.86.
was crystallized from ethanol.
Methyl 2-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydro-quinolin-
3-yl)carbonylamino] acetate (5a).
0.31 g, Yield 88%.
White crystals, mp 194–195°C.1H NMR spectrum, δ,
ppm (J, Hz): 16.67 (1H, s, OH); 10.55 (1H, bs, NH);
8.26 (1H, d, J = 9.0, ArH); 7.64–7.29 (7H, m, ArH); 6.69
(1H, d, J = 8.0, ArH); 4.20 (2H, d, J = 6.0, CH2); 3.78
(3H, s, OCH3). 13C NMR spectrum, δ, ppm: 172.6 (C=O
ester); 171.4 (C–OH); 169.4 (C=O amide); 162.9 (C=O
amide); 141.0 (C Ar); 137.1 (C Ar); 133.5 (CHAr); 130.3
(CHAr); 129.1 (CHAr); 129.0 (CHAr); 125.2 (CHAr);
122.7 (CHAr); 116.1 (CHAr); 115.8 (C Ar); 96.9 (C Ar);
52.4 (OCH3); 40.9 (CH2). Found, %: C, 64.57; H, 4.42;
N, 7.81. For C19H16N2O5 (352.1). Calculated, %: C,
General method for the preparation of 2-[2-(4-hydroxy-2-
oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino]
alkanehydrazides (6a–d). To a solution of methyl-2-[2-
(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carboxamido] alkanoate 5a–d (1.0 mmol) in absolute
ethyl alcohol (30 mL), hydrazine hydrate 100%
(0.24 mL, 5 mmol) was added. The reaction mixture was
refluxed for 4 h; afterwards, it was left overnight at room
temperature. The formed precipitate was filtered off,
washed with aqueous ethanol and ether, then crystallized
64.77; H, 4.58; N, 7.95.
Methyl 2-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-
yl)carbonylamino] propanoate (5b).
0.24 g, Yield 65%.
White crystals, mp 150–151°C. 1H NMR spectrum, δ,
ppm (J, Hz): 16.81 (1H, s, OH); 10.48 (1H, d, J = 6.0,
NH); 8.24 (1H, d, J = 8.0, ArH); 7.62–7.28 (7H, m,
ArH); 6.65 (1H, d, J = 8.0, ArH); 4.74–4.67 (1H, m,
CH); 3.76 (3H, s, OCH3); 1.51 (3H, d, J = 6.0, CH3). 13C
NMR spectrum, δ, ppm: 172.8 (C=O ester); 172.6 (C–
OH); 171.8 (C=O amide); 170.7 (C=O amide); 162.9
(C=O amide); 141.0 (C Ar); 137.1 (C Ar); 133.4 (CHAr);
130.3 (CHAr); 129.2 (CHAr); 129.1 (CHAr); 129.0
(CHAr); 125.2 (CHAr); 122.7 (CHAr); 116.1 (CHAr);
115.9 (C Ar); 96.8 (C Ar); 52.4 (OCH3); 48.0 (CH); 18.3
(CH3). Found, %: C, 65.54; H, 4.84; N, 7.48. For
C20H18N2O5 (366.1). Calculated, %: C, 65.57; H, 4.95;
from ethanol to yield the hydrazide.
2-[(4-Hydroxy-2-oxo-1-phenyl1,2-dihydroquinolin-3-yl)
carbonylamino] ethanhydrazide (6a). 0.27 g, Yield 78%.
White crystals, mp 270–271°C. 1H NMR spectrum, δ,
ppm (J, Hz): 10.38 (1H, bs, NH); 9.38 (1H, bs, NH);
8.13 (1H, d, J = 8.0, ArH); 7.65–7.60 (4H, m, ArH);
7.38–7.36 (3H, m, ArH); 6.57 (1H, d, J = 8.0, ArH);
4.48 (3H, bs, NH2); 4.15 (2H, d, J = 6.0, CH2). 13C
NMR spectrum, δ, ppm: 172.3 (C=O ester); 171.0 (C–
OH); 167.5 (C=O amide); 162.1 (C=O amide); 141.2
(C Ar); 137.5 (C Ar); 134.4 (CHAr); 130.5 (CHAr);
129.7 (CHAr); 129.4 (CHAr); 125.0 (CHAr); 123.1
(CHAr); 116.4 (CHAr); 115.4 (C Ar); 96.8 (C Ar);
41.2 (CH2). Found, %: C, 61.24; H, 4.48; N, 15.73.
For C18H16N4O4 (352.1). Calculated, %: C, 61.36; H,
N, 7.65.
Methyl 2-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-
yl)carbonylamino] 4-methylpentanoate (5c). 0.33 g, Yield
1
4.58; N, 15.90.
2-[(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino] propan-hydrazide (6b). 0.24 g, Yield 65%.
89%. White crystals, mp 190–191°C. H NMR spectrum,
δ, ppm (J, Hz): 16.20 (1H, s, OH); 10.31 (1H, bs, NH);
8.26 (1H, d, J = 8.0, ArH); 7.64–7.28 (7H, m, ArH); 6.66
(1H, d, J = 8.0, ArH); 3.77–3.69 (5H, m, CH2, OCH3);
2.67 (2H, t, J = 6.0, CH2). 13C NMR spectrum, δ, ppm:
172.9 (C=O ester); 171.8 (C–OH); 171.3 (C=O amide);
163.0 (C=O amide); 140.9 (C Ar); 137.2 (C Ar); 133.3
(CHAr); 130.3 (CHAr); 129.1 (CHAr); 129.0 (CHAr);
125.2 (CHAr); 122.6 (CHAr); 116.0 (CHAr); 96.8 (C
Ar); 51.8 (OCH3); 34.9 (CH2); 33.9 (CH2). Found, %: C,
65.40; H, 4.86; N, 7.59. For C20H18N2O5 (366.1).
White crystals, mp 230–231°C. 1H NMR spectrum, δ, ppm
(J, Hz): 10.44 (1H, bs, NH); 9.41 (1H, bs, NH); 8.12 (1H,
d, J = 8.0, ArH); 7.63–7.55 (4H, m, ArH); 7.35–7.28 (3H,
m, ArH); 6.51 (1H, d, J = 8.0, ArH); 5.25 (3H, bs, NH2);
4.53–4.46 (1H, m, CH); 1.31 (3H, d, J = 6.0, CH3). 13C
NMR spectrum, δ, ppm: 173.0 (C=O ester); 171.2 (C–
OH); 169.9 (C=O amide); 162.9 (C=O amide); 141.2 (C
Ar); 138.0 (C Ar); 133.6 (CHAr); 130.4 (CHAr); 129.9
(CHAr); 129.1 (CHAr); 125.2 (CHAr); 122.6 (CHAr);
116.0 (CHAr); 115.6 (C Ar); 97.3 (C Ar); 47.3 (CH);
19.4 (CH3). Found, %: C, 62.12; H, 4.87; N, 15.17. For
C19H18N4O4 (366.1). Calculated, %: C, 62.29; H, 4.95;
N, 15.29.
Calculated, %: C, 65.57; H, 4.95; N, 7.65.
Methyl 3-[(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-
yl)carbonylamino] propanoate (5d).
0.31 g, Yield 75%.
White crystals, mp 120–121°C. 1H NMR spectrum, δ,
ppm (J, Hz): 17.48 (1H, s, OH); 10.14 (1H, bs, NH);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Fathalla and P. Pazdera
Vol 000
2-[(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
spectrum, δ, ppm (J, Hz): 16.79 (1H, s, OH); 10.76 (1H,
bs, NH); 8.23 (1H, d, J = 8.0, ArH); 7.60–7.28 (7H, m,
ArH); 6.65 (1H, d, J = 8.0, ArH); 4.26 (2H, d, J = 6.0,
CH2), 3.69 (2H, t, J = 6.0, CH2); 3.51 (2H, t, J = 6.0,
CH2); 2.48 (4H, t, J = 6.0, 2CH2); 2.34 (3H, s, CH3).13C
NMR spectrum, δ, ppm: 174.5 (C=O ester); 172.4 (C–
OH); 170.9 (C=O amide); 165.7 (C=O amide); 162.7
(C=O amide); 141.1 (C Ar); 137.2 (C Ar); 133.3 (CHAr);
130.1 (CHAr); 129.2 (CHAr); 129.0 (CHAr); 125.1
(CHAr); 122.5 (CHAr); 116.1 (CHAr); 115.8 (C Ar);
97.1 (C Ar); 54.5 (CH2-piperazine); 54.2 (CH2-
piperazine); 45.6 (CH3); 44.2 (CH2-piperazine); 41.6
(CH2-piperazine); 41.0 (NHCH2). Found, C, 65.33; H,
5.46; N, 13.07. For C23H24N4O4 (420.2). Calculated, %:
carbonylamino]-4-methyl pentanhydrazide (6c).
0.31 g,
Yield 76%. White crystals, mp 170–171°C. 1H NMR
spectrum, δ, ppm (J, Hz): 10.15 (1H, bs, NH); 8.84 (1H,
bs, NH); 8.14 (1H, d, J = 8.0, ArH); 7.64–7.57 (4H, m,
ArH); 7.39–7.36 (3H, m, ArH); 6.57 (1H, d, J = 8.0,
ArH); 3.54 (2H, q, J = 6.0, CH2); 2.01 (2H, t, J = 6.0,
CH2); 1.54–1.25 (6H, m, 2CH3). 13C NMR spectrum, δ,
ppm: 172.6 (C=O ester); 171.9 (C–OH); 170.9 (C=O
amide); 163.1 (C=O amide); 141.1 (C Ar); 137.5 (C Ar);
134.4 (CHAr); 130.5 (CHAr); 129.7 (CHAr); 125.0
(CHAr); 123.1 (CHAr); 116.4 (CHAr); 96.8 (C Ar); 38.9
(C-Leu); 33.7 (CH2-Leu); 28.9 (CH2-Leu); 26.5 (CH3);
25.3 (CH3). Found, %: C, 64.57; H, 5.85; N, 13.61. For
C22H24N4O4 (408.2). Calculated, %: C, 64.69; H, 5.92;
C, 65.70; H, 5.75; N, 13.33.
N, 13.72.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-acetyl]-4-(methoxycarbonyl)
(8b).
piperazine
3-[(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino] propanhydrazide (6d). 0.31 g, Yield 84%.
0.36 g, Yield 78%. White crystals, mp 240–
1
White crystals, mp 245–246°C. 1H NMR spectrum, δ,
ppm (J, Hz): 10.24 (1H, bs, NH); 9.04 (1H, bs, NH);
8.14 (1H, d, J = 8.0, ArH); 7.66–7.57 (4H, m, ArH);
7.38–7.35 (3H, m, ArH); 6.56 (1H, d, J = 8.0, ArH); 3.57
(2H, q, J = 6.0, CH2); 2.36 (2H, t, J = 6.0, CH2). 13C
NMR spectrum, δ, ppm: 172.6 (C=O ester); 171.0 (C–
OH); 170.0 (C=O amide); 163.7 (C=O amide); 141.2 (C
Ar); 137.5 (C Ar); 134.4 (CHAr); 130.5 (CHAr); 129.7
(CHAr); 129.4 (CHAr); 125.0 (CHAr); 123.0 (CHAr);
116.2 (CHAr); 115.6 (CHAr); 96.5 (C Ar); 35.5 (CH2);
33.1 (CH2). Found, %: C, 62.11; H, 4.73; N, 15.06. For
C19H18N4O4 (366.1). Calculated, %: C, 62.29; H, 4.95;
241°C. H NMR spectrum, δ, ppm (J, Hz): 16.73 (1H, s,
OH); 10.76 (1H, bs, NH); 8.23 (1H, d, J = 8.0, ArH);
7.60–7.27 (7H, m, ArH); 6.65 (1H, d, J = 8.0, ArH); 4.26
(2H, d, J = 6.0, CH2), 3.74–3.50 (11H, m, 4CH2,
OCH3).13C NMR spectrum, δ, ppm: 172.5 (C=O ester);
170.0 (C–OH); 166.1 (C=O amide); 162.7 (C=O amide);
155.7 (C=O amide); 141.1 (C Ar); 137.2 (C Ar); 133.4
(CHAr); 130.1 (CHAr); 129.2 (CHAr); 129.1 (CHAr);
129.0 (CHAr); 125.2 (CHAr); 122.5 (CHAr); 116.1
(CHAr); 115.8 (C Ar); 97.0 (C Ar); 52.9 (OCH3); 44.5
(CH2-piperazine); 43.6 (CH2-piperazine); 43.5 (CH2-
piperazine); 41.8 (CH2-piperazine); 41.1 (NHCH2).
Found, C, 61.73; H, 5.01; N, 11.75. For C24H24N4O6
(464.2). Calculated, %: C, 62.06; H, 5.21; N, 12.06.
N, 15.29.
General procedure for the preparation of 1-[2-((4-hydroxy-
2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)carbonylamino)
alkylcarbony]-4-substituted piperazine derivatives 8–11 (a–
d). To a cold solution (À5°C) of quinoline hydrazides
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-acetyl]-4-(2-methoxy-2-oxoethyl)
(8c).
piperazine
0.31 g, Yield 65%. White crystals, mp 180–
1
6a–d (1.0 mmol) in AcOH (6 mL), 1 N HCl (3 mL), and
water (25 mL) was added a solution of NaNO2 (0.1 g,
1.5 mmol) in cold water (3 mL). After stirring at À5°C
for 15 min to afford a yellowish syrup, the reaction
mixture was extracted with cold ethyl acetate (30 mL),
washed with cold 3% NaHCO3, H2O, and finally dried
(Na2SO4) to give the in situ generated ethyl acetate
solution of azide 7a–d. A prepared cold solution of N-
methyl piperazine and N1-monosubstituted piperazine
hydrochlorides (1.0 mmol) in ethyl acetate (20 mL) and
triethyl amine (0.1 mL, 1.0 mmol) was added to the azide
solution 7a–d. The mixture was kept at À5°C for 24 h,
then at 25°C for another 24 h, followed by washing with
3% solution of NaHCO3 and dried (Na2SO4). The
solution was evaporated to dryness, and the residue was
181°C. H NMR spectrum, δ, ppm (J, Hz): 16.75 (1H, s,
OH); 10.76 (1H, bs, NH); 8.20 (1H, d, J = 8.0, ArH);
7.58–7.28 (7H, m, ArH); 6.64 (1H, d, J = 8.0, ArH); 4.25
(2H, d, J = 6.0, CH2), 3.77–3.52 (7H, m, 2CH2, OCH3);
3.26 (2H, s, CH2); 2.59 (4H, t, J = 6.0, 2CH2).13C NMR
spectrum, δ, ppm: 172.5 (C=O ester); 170.9 (C–OH);
170.4 (C=O amide); 165.6 (C=O amide); 162.7 (C=O
amide); 141.1 (C Ar); 137.2 (C Ar); 133.4 (CHAr); 130.1
(CHAr); 129.2 (CHAr); 129.0 (CHAr); 125.1 (CHAr);
122.5 (CHAr); 116.0 (CHAr); 115.8 (C Ar); 97.0 (C Ar);
58.9 (NCH2); 52.6 (CH2 piperazine); 52.4 (CH2
piperazine); 51.7 (OCH3); 44.5 (CH2 piperazine); 41.5
(CH2 piperazine); 41.0 (NHCH2). Found, %: C, 62.58; H,
5.32; N, 11.49. For C25H26N4O6 (478.2). Calculated, C,
62.75; H, 5.48; N, 11.71.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-acetyl]-4-(3-methoxy-3-oxopropyl) piperazine
recrystallized from petroleum ether/ ethyl acetate to give
8–11 (a–d).
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
(8d).
0.30 g, Yield 61%. White crystals, mp 165–
1
166°C. H NMR spectrum, δ, ppm (J, Hz): 16.80 (1H, s,
OH); 10.75 (1H, bs, NH); 8.23 (1H, d, J = 8.0, ArH);
carbonylamino)-acetyl]-4-methylpiperazine (8a).
0.19 g,
Yield 45%. White crystals, mp 210–211°C. 1H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Convenient Synthesis of Piperazine Substituted Quinolones
7.59–7.25 (7H, m, ArH); 6.65 (1H, d, J = 8.0, ArH); 4.24
(2H, d, J = 6.0, CH2), 3.76–3.46 (7H, m, 2CH2, OCH3);
2.73 (2H, t, J = 6.0, CH2); 2–54-2.47 (6H, m, 3CH2).13C
NMR spectrum, δ, ppm: 172.6 (C=O ester); 172.4 (C–
OH); 170.9 (C=O amide); 165.6 (C=O amide); 162.7
(C=O amide); 141.1 (C Ar); 137.2 (C Ar); 133.3 (CHAr);
130.1 (CHAr); 129.2 (CHAr); 129.0 (CHAr); 125.1
(CHAr); 122.5 (CHAr); 116.1 (CHAr); 115.8 (C Ar);
97.1 (C Ar); 53.3 (NCH2); 52.8 (CH2 piperazine); 52.4
(CH2 piperazine); 51.7 (OCH3); 44.6 (CH2 piperazine);
41.9 (CH2 piperazine); 41.0 (NHCH2); 32.0
(CH2COOMe). Found, %: C, 63.26; H, 5.64; N, 11.23.
For C26H28N4O6 (492.2). Calculated, %: C, 63.40; H,
J = 8.0, ArH); 7.58–7.25 (7H, m, ArH); 6.62 (1H, d,
J = 8.0, ArH); 5.08–4.98 (1H, m, CH); 3.79–3.60 (7H,
m, 2CH2, OCH3); 3.25 (2H, s, CH2); 2.64–2.54 (4H, m,
2CH2); 1.42 (3H, t, J = 6.0, CH3).13C NMR spectrum, δ,
ppm: 172.6 (C=O ester); 170.3 (C–OH); 170.1 (C=O
amide); 169.8 (C=O amide); 162.6 (C=O amide); 141.1
(C Ar); 137.2 (C Ar); 133.3 (CHAr); 130.2 (CHAr);
129.3 (CHAr); 129.1 (CHAr); 129.0 (CHAr); 125.1
(CHAr); 122.5 (CHAr); 116.0 (CHAr); 115.8 (C Ar);
96.9 (C Ar); 58.9 (CH2); 52.8 (CH2 piperazine); 52.5
(CH2 piperazine); 51.7 (OCH3); 45.3 (CH2 piperazine);
45.0 (CH); 42.0 (CH2 piperazine); 18.4 (CH3). Found, %:
C, 63.17; H, 5.48; N, 11.11. For C26H28N4O6 (492.2).
5.73; N, 11.38.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-2-methylacetyl]-4-methylpiperazine (9a).
Calculated, %: C, 63.40; H, 5.73; N, 11.38.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-2-methylacetyl]-4-(3-methoxy-3-oxopropyl)
piperazine (9d). 0.20 g, Yield 39%. White crystals, mp
1
0.18 g, Yield 41%. White crystals, mp 190–191°C. H
1
150–151°C. H NMR spectrum, δ, ppm (J, Hz): 16.92
NMR spectrum, δ, ppm (J, Hz): 16.9 (1H, s, OH); 10.59
(1H, d, J = 6.0, NH); 8.32 (1H, d, J = 8.0, ArH); 7.63–
7.28 (7H, m, ArH); 6.64 (1H, d, J = 8.0, ArH); 5.14–4.96
(1H, m, CH); 3.85–3.52 (4H, m, 2CH2); 2.58–2.49 (4H,
m, 2CH2); 2.45 (3H, s, CH3); 1.48 (3H, t, J = 6.0,
CH3).13C NMR spectrum, δ, ppm: 172.7 (C=O ester);
170.1 (C–OH); 169.9 (C=O amide); 162.7 (C=O amide);
141.1 (C Ar); 137.2 (C Ar); 133.3 (CHAr); 130.2
(CHAr); 129.3 (CHAr); 129.1 (CHAr); 125.1 (CHAr);
122.5 (CHAr); 116.1 (CHAr); 115.9 (C Ar); 96.9 (C Ar);
54.9 (CH2 piperazine); 54.5 (CH2 piperazine); 45.8 (CH);
45.2 (NCH3); 44.0 (CH2 piperazine); 42.2 (CH2
piperazine); 18.4 (CH3). Found, %: C, 66.14; H, 5.82; N,
12.64. For C24H26N4O4 (434.2). Calculated, %: C, 66.34;
(1H, s, OH); 10.66 (1H, d, J = 6.0, NH); 8.17 (1H, d,
J = 8.0, ArH); 7.57–7.25 (7H, m, ArH); 6.51 (1H, d,
J = 8.0, ArH); 5.05–4.96 (1H, m, CH); 3.66–3.55 (7H,
m, 2CH2, OCH3); 2.71 (2H, t, J = 6.0, CH2); 2.52–2.47
(6H, m, 3CH2); 1.40 (3H, t, J = 6.0, CH3).13C NMR
spectrum, δ, ppm: 172.6 (C=O ester); 172.6 (C–OH);
170.1 (C=O amide); 169.8 (C=O amide); 162.6 (C=O
amide); 141.0 (C Ar); 137.2 (C Ar); 133.3 (CHAr); 130.2
(CHAr); 129.3 (CHAr); 129.1 (CHAr); 129.0 (CHAr);
125.0 (CHAr); 122.5 (CHAr); 116.0 (CHAr); 115.8 (C
Ar); 96.8 (C Ar); 53.3 (NCH2); 52.9 (CH2 piperazine);
52.4 (CH2 piperazine); 51.7 (OCH3); 45.3 (CH2
piperazine); 45.1 (CH); 42.0 (CH2 piperazine); 31.9
(CH2COOCH3); 18.4 (CH3). Found, %: C, 63.78; H,
5.83; N, 10.77. For C27H30N4O6 (506.2). Calculated, %:
H, 6.03; N, 12.89.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-2-methylacetyl]-4-(methoxycarbonyl)
piperazine (9b). 0.24 g, Yield 51%. White crystals, mp
C, 64.02; H, 5.97; N, 11.06.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)4-methylpentylcarbonyl]-4-methylpiperazine
(10a). 0.18 g, Yield 37%. White crystals, mp 105–106°C.
1
220–221°C. H NMR spectrum, δ, ppm (J, Hz): 16.82
(1H, s, OH); 10.67 (1H, d, J = 6.0, NH); 8.24 (1H, d,
J = 8.0, ArH); 7.62–7.28 (7H, m, ArH); 6.65 (1H, d,
J = 8.0, ArH); 5.10–5.01 (1H, m, CH); 3.80–3.46 (11H,
m, 4CH2, OCH3); 1.45 (3H, t, J = 6.0, CH3).13C NMR
spectrum, δ, ppm: 172.7 (C=O ester); 170.3 (C–OH);
170.2 (C=O amide); 162.7 (C=O amide); 155.8 (C=O
amide); 141.1 (C Ar); 137.1 (C Ar); 133.4 (CHAr); 130.1
(CHAr); 129.3 (CHAr); 129.1 (CHAr); 129.0 (CHAr);
125.1 (CHAr); 122.6 (CHAr); 116.1 (CHAr); 115.8 (C
Ar); 96.8 (C Ar); 52.8 (OCH3); 45.4 (CH2 piperazine);
45.2 (CH); 43.9 (CH2 piperazine); 43.6 (CH2 piperazine);
42.0 (CH2 piperazine), 18.3 (CH3). Found, %: C, 62.67;
H, 5.26; N, 11.52. For C25H26N4O6 (478.2). Calculated,
1H NMR spectrum, δ, ppm (J, Hz): 17.42 (1H, s, OH);
10.06 (1H, bs, NH); 8.14 (1H, d, J = 8.0, ArH); 7.55–
7.21 (7H, m, ArH); 6.57 (1H, d, J = 8.0, ArH); 3.44–3.33
(6H, m, 3CH2); 2.37–2.23 (9H, m, 2CH2, CH3, CH2-
Leu); 1.59–1.26 (6H, m, 2CH3).13C NMR spectrum, δ,
ppm: 174.3 (C=O ester); 172.9 (C–OH); 171.2 (C=O
amide); 170.9 (C=O amide); 162.9 (C=O amide); 140.7
(C Ar); 137.2 (C Ar); 133.2 (CHAr); 130.2 (CHAr);
129.0 (CHAr); 125.0 (CHAr); 122.5 (CHAr); 116.1
(CHAr); 116.0 (C Ar); 96.5 (C Ar); 54.8 (CH2
piperazine); 54.4 (CH2 piperazine); 45.6 (CH2
piperazine); 45.0 (NCH3); 41.0 (CH2 piperazine); 38.9
(CH2); 32.9 (CH2); 29.1 (CH2); 26.8 (CH3); 24.8 (CH3).
Found, %: C, 67.86; H, 6.53; N, 11.64. For C27H32N4O4
%: C, 62.75; H, 5.48; N, 11.71.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-2-methylacetyl]4-(2-methoxy-2-oxoethyl)
piperazine (9c). 0.29 g, Yield 59%. White crystals, mp
(476.2). Calculated, %: C, 68.05; H, 6.77; N, 11.76.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)4-methylpentylcarbonyl]-4-(methoxycarbonyl)
piperazine (10b). 0.27 g,Yield 52%. White crystals, mp
1
155–156°C. H NMR spectrum, δ, ppm (J, Hz): 16.92
(1H, s, OH); 10.98 (1H, d, J = 6.0, NH); 8.20 (1H, d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Fathalla and P. Pazdera
Vol 000
130–131°C 1H NMR spectrum, δ, ppm (J, Hz): 17.38 (1H,
s, OH); 10.12 (1H, bs, NH); 8.23 (1H, d, J = 8.0, ArH);
7.61–7.26 (7H, m, ArH); 6.63 (1H, d, J = 8.0, ArH);
3.71–3.40 (11H, m, 4CH2, OCH3); 3.10 (2H, q, J = 6.0,
CH2); 2.30 (2H, t, J = 6.0, CH2); 1.59–1.26 (6H, m,
2CH3).13C NMR spectrum, δ, ppm: 173.0 (C=O ester);
171.6 (C–OH); 171.0 (C=O amide); 163.1 (C=O amide);
156.0 (C=O amide); 140.8 (C Ar); 137.2 (C Ar); 133.2
(CHAr); 130.3 (CHAr); 129.2 (CHAr); 129.0 (CHAr);
125.2 (CHAr); 122.6 (CHAr); 116.2 (CHAr); 116.0 (C
Ar); 96.6 (C Ar); 52.8 (OCH3); 45.8 (CH2 piperazine);
45.3 (CH2 piperazine); 43.6 (CH2 piperazine); 41.3 (CH2
piperazine); 38.9 (CH2); 33.0 (CH2); 29.1 (CH2); 26.8
(CH3); 24.3 (CH3). Found, %: C, 64.44; H, 6.03; N,
10.54. For C28H32N4O6 (520.2). Calculated, %: C, 64.60;
H, 6.20; N, 10.76.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)-ethylcarbonyl]- 4-(methoxycarbonyl) piperazine
(11b). 0.39 g, Yield 81%. White crystals, mp 200–201°C.
1H NMR spectrum, δ, ppm (J, Hz): 17.22 (1H, s, OH);
10.31 (1H, bs, NH); 8.25 (1H, d, J = 8.0, ArH);
7.62–7.26 (7H, m, ArH); 6.65 (1H, d, J = 8.0, ArH);
3.78–3.71 (5H, m, CH2, OCH3); 3.60 (2H, t, J = 6.0,
CH2); 3.51–3.38 (6H, m, 3CH2); 2.67 (2H, t,
J = 6.0, CH2).13C NMR spectrum, δ, ppm: 171.9
(C=O ester); 171.2 (C–OH); 169.3 (C=O amide);
155.8 (C=O amide); 140.9 (C Ar); 137.2 (C Ar);
133.3 (CHAr); 130.3 (CHAr); 129.1 (CHAr); 129.0
(CHAr); 125.2 (CHAr); 122.6 (CHAr); 116.1 (CHAr);
116.0 (C Ar); 96.8 (C Ar); 52.8 (OCH3); 45.1
(CH2 piperazine); 43.7 (CH2 piperazine); 43.3 (CH2
piperazine); 41.3 (CH2 piperazine); 35.3 (CH2), 32.9
(CH2). Found, %: C, 62.61; H, 5.36; N, 11.59.
For C25H26N4O6 (478.2). Calculated, %: C, 62.75; H,
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)4-methylpentylcarbonyl]-4-(2-methoxy-2-
5.48; N, 11.71.
oxoethyl) piperazine (10c).
0.22 g, Yield 41%. White
1
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)ethyl-carbonyl]-4-(2-methoxy-2-oxoethyl)
piperazine (11c). 0.39 g, Yield 78%. White crystals, mp
crystals, mp 170–171°C. H NMR spectrum, δ, ppm (J,
Hz): 16.75 (1H, s, OH); 10.76 (1H, bs, NH); 8.20 (1H, d,
J = 8.0, ArH); 7.58–7.28 (7H, m, ArH); 6.64 (1H, d,
J = 8.0, ArH); 4.25 (2H, d, J = 6.0, CH2), 3.71–3.23 (7H,
m, 2CH2, OCH3); 3.23 (2H, s, CH2); 2.55–2.27 (4H, t,
J = 6.0, 2CH2); 1.63–1.40 (6H, m, 2CH3) .13C NMR
spectrum, δ, ppm: 174.2 (C=O ester); 173.0 (C–OH);
171.4 (C=O amide); 171.0 (C=O amide); 162.4 (C=O
amide); 155.8 (C=O amide); 140.8 (C Ar); 137.2 (C Ar);
133.2 (CHAr); 130.3 (CHAr); 129.1 (CHAr); 129.0
(CHAr); 125.1 (CHAr); 122.6 (CHAr); 116.0 (CHAr);
116.0 (C Ar); 96.8 (C Ar); 58.9 (CH2); 52.9 (CH2
piperazine); 52.6 (CH2 piperazine); 51.7 (OCH3); 45.3
(CH2 piperazine); 41.1 (CH2 piperazine); 38.9 (CH2);
33.0 (CH2); 29.1 (CH2); 26.8 (CH3); 24.8 (CH3). Found,
%: C, 64.83; H, 6.28; N, 10.31. For C29H34N4O6 (534.3).
Calculated, C, 65.15; H, 6.41; N, 10.48.
1
120–121°C. H NMR spectrum, δ, ppm (J, Hz): 17.29
(1H, s, OH); 10.18 (1H, bs, NH); 8.23 (1H, d, J = 8.0,
ArH); 7.64–7.26 (7H, m, ArH); 6.65 (1H, d, J = 8.0,
ArH); 3.68–3.21 (9H, m, 2CH2, NHCH2, OCH3); 3.12
(4H, t, J = 6.0, 2CH2); 2.68 (2H, t, J = 6.0, CH2).13C
NMR spectrum, δ, ppm: 173.2 (C=O ester); 172.7 (C–
OH); 170.5 (C=O amide); 169.2 (C=O amide); 162.4
(C=O amide); 140.3 (C Ar); 137.2 (C Ar); 133.3 (CHAr);
130.3 (CHAr); 129.0 (CHAr); 125.1 (CHAr); 122.9
(CHAr); 116.1 (CHAr); 115.9 (C Ar); 96.8 (C Ar); 58.6
(CH2 piperazine); 53.1 (CH2 piperazine); 51.4 (OCH3);
44.6 (CH2 piperazine); 41.8 (CH2 piperazine); 35.5
(CH2), 32.2 (CH2). Found, %: C, 63.26; H, 5.54; N,
11.21. For C26H28N4O6 (492.2). Calculated, %: C, 63.40;
H, 5.73; N, 11.38.
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
1-[2-((4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)
carbonylamino)ethyl-carbonyl]-4-(3-methoxy-3-oxopropyl)
piperazine (11d). 0.24 g, Yield 48%. White crystals, mp
carbonylamino)ethyl-carbonyl]-4-methylpiperazine (11a).
1
0.26 g, Yield 60%. White crystals, mp 165–166°C. H
1
95–96°C. 1H NMR spectrum, δ, ppm (J, Hz): 17.23
(1H, s, OH); 10.26 (1H, bs, NH); 8.21 (1H, d, J = 8.0,
ArH); 7.60–7.25 (7H, m, ArH); 6.63 (1H, d, J = 8.0,
ArH); 3.69–3.43 (9H, m, 3CH2, OCH3); 2.76–2.42
(10H, m, 5CH2).13C NMR spectrum, δ, ppm: 172.8
(C=O ester); 172.6 (C–OH); 171.2 (C=O amide); 168.9
(C=O amide); 162.9 (C=O amide); 141.0 (C Ar); 137.2
(C Ar); 133.2 (CHAr); 130.2 (CHAr); 129.1 (CHAr);
125.1 (CHAr); 122.6 (CHAr); 116.0 (CHAr); 116.0 (C
Ar); 96.7 (C Ar); 53.4 (CH2); 52.9 (CH2 piperazine);
52.4 (CH2 piperazine); 51.6 (OCH3); 45.3 (CH2
piperazine); 41.5 (CH2 piperazine); 35.3 (CH2); 32.76
(CH2); 32.04 (CH2). Found, %: C, 63.78; H, 5.81; N,
10.84. For C27H30N4O6 (506.2). Calculated, %: C,
64.02; H, 5.97; N, 11.06.
NMR spectrum, δ, ppm (J, Hz): H NMR spectrum, δ,
ppm (J, Hz): 17.35 (1H, s, OH); 10.17 (1H, bs, NH);
8.26 (1H, d, J = 8.0, ArH); 7.62–7.28 (7H, m, ArH); 6.66
(1H, d, J = 8.0, ArH); 3.78–3.64 (4H, m, 2CH2); 3.48
(2H, t, J = 6.0, CH2); 2.66 (2H, t, J = 6.0, CH2); 2.45–
2.31 (7H, m, 2CH2, CH3).13C NMR spectrum, δ, ppm:
172.9 (C=O ester); 171.3 (C–OH); 169.0 (C=O amide);
162.9 (C=O amide); 140.9 (C Ar); 137.2 (C Ar); 133.3
(CHAr); 130.3 (CHAr); 129.1 (CHAr); 129.0 (CHAr);
125.2 (CHAr); 122.9 (CHAr); 116.0 (CHAr); 115.9 (C
Ar); 96.8 (C Ar); 54.9 (CH2 piperazine); 54.5 (CH2
piperazine); 45.9 (CH2 piperazine); 45.2 (NCH3); 41.6
(CH2 piperazine); 35.4 (CH2); 32.8 (CH2). Found, %: C,
66.24; H, 5.97; N, 12.74. For C24H26N4O4 (434.2).
Calculated, %: C, 66.34; H, 6.03; N, 12.89.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Convenient Synthesis of Piperazine Substituted Quinolones
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Acknowledgments. We would like to Thank Department of
Organic Chemistry Faculty of Science Masaryk University,
Brno, Czech Republic, and Ministry of High Education, Egypt,
for funding this research proposal. We would like to thank Dr.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet