Synthesis of Some Novel Heteroannulated Pyrano[3,2-c]quinoline-2,5(6H)-diones

Article abstract of DOI:10.1002/jhet.3205

6-Butyl-3-((dimethylamino)methylene)pyrano[3,2-c]quinolinone and 6-butyl pyrano[3,2-c]quinolone-3-carbonitrile were efficiently synthesized in good yield. These two new precursors were used to obtain some novel heteroannulated pyrano[3,2-c]quinolone derivatives from heterocyclization reactions with various binucleophiles. These heteroannulation reactions afforded novel heterocyclic systems fused to the pyranoquinolinone at face c, such as pyrazole, pyrimidine, pyridine, and pyrazolopyranone.

Full text of DOI:10.1002/jhet.3205

Month 2018
Synthesis of Some Novel Heteroannulated Pyrano[3,2-c]quinoline-
2,5(6H)-diones
*
Hany Mohamed Hassanin and Dalia Abdel-Kader
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Heliopolis, Cairo 11757, Egypt
*E-mail: hmm8807@hotmail.com
Received February 4, 2018
DOI 10.1002/jhet.3205
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
6-Butyl-3-((dimethylamino)methylene)pyrano[3,2-c]quinolinone and 6-butyl pyrano[3,2-c]quinolone-3-
carbonitrile were efficiently synthesized in good yield. These two new precursors were used to obtain some
novel heteroannulated pyrano[3,2-c]quinolone derivatives from heterocyclization reactions with various
binucleophiles. These heteroannulation reactions afforded novel heterocyclic systems fused to the
pyranoquinolinone at face c, such as pyrazole, pyrimidine, pyridine, and pyrazolopyranone.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
4-hydroxypyrano[3,2-c]quinoline-2,5(6H)-dione
(1)
(Fig. 1) [27]. The desired 3-((dimethylamino)methylene)
Pyrano[3,2-c]quinolinones consider great synthons
for many quinolinone derivatives [1–3]. Moreover, they
exist in naturally occurring alkaloids [4–6], which
are known to display different biological activities [7,8].
Heteroannulated pyranoquinolinones exhibit many
important medicinal properties such as antibacterial [9],
anticoagulant [10], antitumor [11], and antihypertensive
agents [12]. Despite the widespread of published work on
the synthesis of these types of compounds with various
substituents [13–19], there is a scarcity of literature reports
on the preparation of heteroannulated pyrano[3,2-c]
quinolone derivatives. Moreover, the combination of a
pyrazole, pyridine or pyrimidine nucleus with the pyran or
quinolinone moiety in one molecular framework is
reported to confer biological activity [20–25]. In
continuation of our research work directed on the
synthesis of heteroannulated pyrano[3,2-c]quinolinedione
derivatives [26], herein, we disclose the preparation
of synthetically valuable 6-butyl-3-((dimethylamino)
methylene)pyrano[3,2-c]quinolinone 2 and 3-cyanopyrano
[3,2-c]quinoline 12. A study of their chemical behavior
towards some binucleophiles was investigated. A new
series of pyranoquinolinones incorporating a pyrazole,
pyrimidine, pyridine, or pyrazolopyranone ring at face c
was obtained with the hope that these compounds turn out
to be biologically active.
pyrano[3,2-c]quinolinone derivative 2 was prepared in
good
pyranoquinolinone
yield
via
thermal
with
condensation
dimethylformamide
of
1
dimethylacetal (DMF-DMA). The structure of enamine 2
1
was confirmed on the basis of H NMR spectral data that
displays a singlet signal due to the olefinic proton at
1
8.16 ppm. Moreover, the H NMR spectrum reveals two
different N-methyl groups, one at 3.05 ppm and the other
at 3.14 ppm, attributed to Me2N group. These two methyl
groups are observed at 35.25 and 38.36 ppm in the 13C
NMR spectrum. In addition, the mass spectrum of
compound 2 displays a molecular ion peak at m/z 340
that is consistent with the formula weight (340.38).
The structure of enamine 2 contains several electron-
deficient centers, and it is expected to be quite reactive
towards nucleophilic reagents. Therefore, the reaction of
enamine 2 with 1,2-binucleophiles such as, hydrazine
hydrate and phenylhydrazine in ethanol at room
temperature was studied. It is thought that the reaction
takes place initially via Michael addition to the olefinic
carbon of compound 2 followed by elimination of
dimethylamine, leading to products 3a,b that were
present as interconverting hydrazine and hydrazone
1
tautomers (Fig. 2). The H NMR spectra of products 3a,b
suggest that they exist predominantly as the hydrazone
forms in deuterodimethyl sulfoxide solution. The 1H
NMR spectrum of compound 3a shows two deuterium-
exchangeable singlet signals at 5.64 ppm characteristic
for NH2 group and 13.38 ppm due to OH group; while
the corresponding signals NH and OH of compound 3b
are observed at 9.41 and 12.37 ppm, respectively. The
mass spectra of the compounds 3a,b display molecular
RESULTS AND DISCUSSION
A reaction of N-butylaniline with two equivalents of
diethyl malonate, under solvent-free conditions gave
© 2018 Wiley Periodicals, Inc.

H. M. Hassanin and D. Abdel-Kader
Vol 000
1648 cmꢀ1 attributed to the C═O groups of pyrone,
pyridine, and quinolone, respectively. The same
compound was obtained from the reaction of compound
2
with cyanoacetamide under the same reaction
conditions, thus confirming its structure as that of 8. The
proposed pathway for the formation of compound 8
involves initial nucleophilic addition of the active
malononitrile methylene group to the enamine carbon of
the side chain and subsequent loss of a molecule of
dimethylamine to give the corresponding malononitrile
intermediate 6. Intramolecular 6-exo-dig cyclization of
the intermediate 6, followed by rearrangement, leads to
the final product 8.
Figure 1. Synthesis of enamine 2.
ion peaks [M+] at m/z 327 and 403, respectively. The
hydrazones 3a,b underwent cyclization in acetic acid at
reflux to afford the pyrazolopyranoquinolinone
derivatives 4a,b, which are obtained directly by refluxing
enamine 2 with hydrazine hydrate or phenylhydrazine,
respectively, in boiling ethanol (Fig. 2). The 1H NMR
spectra of compounds 4a,b exhibit a new characteristic
singlet signal at 8.67 and 8.94 ppm, respectively,
assigned to pyrazole CH. Also, compound 4a reveals a
deuterium-exchangeable singlet signal at 9.94 ppm
ascribed to the NH of the pyrazole ring. The mass spectra
of pyrazoles 4a,b display molecular ion peaks [M+] at m/z
309 and 385, respectively.
The reactivity of compound 2 towards a variety of cyclic
active methylene compounds; various five- and six-
membered heterocycles was studied. Consequently,
compound 2 was treated with 3-methyl-2-pyrazolin-5-
one, in glacial acetic acid containing freshly fused
sodium acetate, to produce pyrazolopyranopyranone 9
(Fig. 4). 1H NMR spectrum of compound 9 shows a
peak, at 2.07 ppm due to the methyl group of pyrazole
ring, and a singlet signal at 9.20 ppm due to the pyran
proton. The mass spectrum of compound 9 reveals a
molecular ion peak [M+] at m/z 375 that is in agreement
with its formula weight (375.39). A pentaheterocyclic
system, pyrimidopyranopyranone, was obtained by
cyclocondensation of enamine 2 with barbituric acid and
thiobarbituric acid, under the same conditions affording
derivatives 10a and 10b of this ring system (Fig. 4). The
IR spectra of 10a and 10b show the presence of
Similarly, treatment of compound 2 with guanidine,
cyanoguanidine, and thiourea as 1,3-binucleophiles
produced the corresponding pyrimidopyranoquinolinones
1
5a–c (Fig. 3). The H NMR spectra of compounds 5a–c
show five aromatic protons, at 7.33–8.76 ppm. In the
mass spectra, the molecular ion peaks [M+] of these
compounds appear at m/z 336, 361, and 353, respectively.
Reaction of enamine 2 with malononitrile as C-
nucleophile was carried out in boiling ethanol containing
small amount of anhydrous potassium carbonate giving
rise to pyridopyranoquinoline derivative 8 (Fig. 3). The
probable products were pyranopyranoquinolinone 7 or
pyridopyranoquinolinone 8. The IR spectrum of the
product exhibited absorption bands at 1725, 1676, and
1
absorption band due to NH bond at 3280–3105 cmꢀ1. H
NMR spectra show singlet signals due to the pyran CH
that appears at 8.95 ppm for compound 10a and
8.88 ppm for compound 10b. In addition, there is a
deuterium-exchangeable singlet signal at 13.38 ppm (NH)
for compound 10a and 13.53 ppm (NH) for compound
Figure 2. Reaction of enamine 2 with some hydrazines.
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Synthesis of Some Novel Heteroannulated Pyranoquinolinones
Figure 3. Synthesis of pyrimidopyranoquinolinones 5a–c and pyridopyranoquinoline 8.
Figure 4. Reaction of compound 2 with some cyclic active methylene compounds.
10b. The mass spectra of compounds 10a,b reveal the
correct molecular ion peaks [M+] at m/z 405 and 421,
respectively.
Continuing the synthesis of new heteoannulated
pyrano[3,2-c]quinolone derivatives, we planned to
prepare the carbonitrile 12 as a new precursor for
further functionalized heteroannulated pyranoquinolone
derivatives. To approach this target, the reaction of
12 was further confirmed from its mass spectrum, which
revealed a molecular ion peak at m/z 310.
Heterocyclization at face c of the pyran moiety can take
place when compound 12 is treated with binucleophiles.
Because the active cyano group at position-3 is
susceptible to nucleophilic addition and OH function at
position-4 participates in heterocyclization through
nucleophilic substitution. Hence, compound 12 was
reacted with hydrazine hydrate, phenyl hydrazine,
and hydroxylamine hydrochloride in boiling glacial
acetic acid to give pyrazolopyranones 13a,b and
isoxazolopyranone 13c, respectively (Fig. 6). Evidence
for the formation of the pyrazole derivatives 13a–c is
from their IR spectra where there is an absence of the OH
absorption band and the appearance of two characteristic
absorption bands at 3526–3368 cmꢀ1 that corresponds to
the amine functionality. Furthermore, the 1H NMR
compound
2 with hydroxylamine hydrochloride in
boiling ethanol was carried out yielding the oxime 11.
This compound underwent dehydration in boiling glacial
acetic acid to give the desired carbonitrile 12 (Fig. 5). Its
IR spectrum exhibits the characteristic vibrational
absorption band at 2200 cmꢀ1 due to (C≡N).
Furthermore, the 1H NMR spectrum of compound 12
displays a deuterium-exchangeable singlet signal at
12.38 ppm assignable to OH. The structure of compound
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H. M. Hassanin and D. Abdel-Kader
Vol 000
Figure 5. Preparation of carbonitrile 12.
Figure 6. Reaction of carbonitrile 12 with some 1,2-, 1,3-binucleophiles, and malononitrile.
spectra display a deuterium-exchangeable singlet signal in
the range of 6.98–7.20 ppm assigned to NH2. Mass spectra
show the correct molecular ion peaks at m/z 324, 400, and
325, respectively.
The carbonitrile 12, as a bifunctional electrophile,
represents a good building unit for the synthesis of a series
few drops of triethylamine, affording pyridopyranone
derivative 16 via the non-isolable intermediate 15
(Fig. 6). The IR spectrum exhibited absorption bands at
3473 and 3335 cmꢀ1 due to amino group and 2189 cmꢀ1
attributed to the nitrile function. Three carbonyl groups
are observed, at 1752 cmꢀ1 (α-pyrone), 1669 cmꢀ1
(pyridone), and 1636 cmꢀ1 (quinolone), respectively. The
1H NMR spectrum of compound 16 showed
exchangeable singlet signals attributed to NH2 and NH
proton at 7.72 and 13.15 ppm, respectively. In the 13C
NMR spectrum, there are three characteristic downfield
signals at 170.61, 164.49, and 158.89 ppm that attributed
the carbonyl carbon atoms of α-pyrone, pyridine, and
quinolone, respectively. Also, the structure of compound
16 was further confirmed from its mass spectrum that
revealed the molecular ion peak at m/z 376 that agreed
well with its suggested molecular formula.
Pyrano[3,2-c]quinolinones undergo ring opening at C-2
and ring reclosure at C-4 when reacted with
binucleophiles [2,31]. However, we introduce the more
highly reactive enamine or nitrile function at the 3-
position of pyranoquinolinone, use mild condition, and
avoid using a strong basic media, in order to direct the
binucleophiles to heterocyclization at face [c] with
retention of 2-pyranone nucleus. Notable in the IR
of
pyrimidopyrano[3,2-c]quinolinones,
via
its
cyclocondensation reactions with a variety of 1,3-
bifiunctional nucleophiles. Thus, condensation of
carbonitrile 12 with guanidine hydrochloride, acetamidine,
or thiourea in boiling DMF produced the suggested
pyrimidine derivatives 14a–c (Fig. 6). The 1H NMR
spectra of these compounds show an exchangeable signal
at 6.97–7.37 ppm characteristic for NH2 protons. Further
evidence is from their mass spectra that reveal the correct
molecular ion peaks [M+] at m/z 351, 350, and 368
respectively. The elemental analyses of the products are
in agreement with their proposed formulae. The
predominance of the amino tautomer of compounds 14a–c
(Fig. 6) is expected because there is a literature report that
supports that the amino form is more predominant than the
imino form [28].
Reaction of the carbonitriles with malononitrile was
previously studied [29,30]. Thus, compound 12 was
treated with malononitrile, in boiling ethanol containing
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis of Some Novel Heteroannulated Pyranoquinolinones
spectra of the desired compounds is the presence of a band
at 1720–1750 cmꢀ1 due to the carbonyl group of the 2-
pyranone moiety.
CH2CH3), 1.39–1.41 (m, 2H, CH2CH3), 1.57–1.62 (m,
2H, CH2CH2), 3.05 (s, 3H, NCH3), 3.14 (s, 3H, NCH3),
4.19 (t, 2H, J = 8.0 Hz, NCH2), 7.34 (t, 1H, J = 8.4 Hz,
H-9), 7.60 (d, 1H, J = 8.4 Hz, H-7), 7.70 (t, 1H,
J = 8.2 Hz, H-8), 8.04 (d, 1H, J = 8.4 Hz, H-10), 8.16
(s, 1H, CHolefinic). 13C NMR (125 MHz, DMSO-d6) δC:
13.81 (CH3), 20.16 (CH2), 29.52 (CH2), 35.25 (NCH3),
38.36 (NCH3), 42.60 (NCH2), 102.53, 107.34, 113.04,
114.93, 123.02, 124.24, 126.33, 133.89, 139.65, 141.10,
156.84, 158.89, 164.51. MS: m/z (relative intensity):
341 [M++ 1; 6], 340 [M+; 25], 312 (6), 311 (7), 297
(10), 296 (25), 284 (6), 283 (26), 268 (4), 254 (5), 253
(8), 241 (15), 240 (18), 215 (10), 213 (7), 212 (9), 201
(15), 187 (14), 172 (4), 161 (11), 159 (3), 158 (3), 133
(13), 132 (100), 119 (22), 104 (17), 77 (56). Anal. Calcd
for C19H20N2O4 (340.38): C, 67.05; H, 5.92; N, 8.23.
Found: C, 67.08; H, 5.89; N, 8.33%.
CONCLUSION
In the present work, the novel enamine 2 and
carbonitrile 12 were efficiently synthesized and
utilized as good precursors to obtain a series of novel
annulated heterocyclic systems containing the pyrano[3,2-
c]quinolinedione skeleton.
EXPERIMENTAL
Melting points were determined on a digital Stuart
SMP3 apparatus. IR spectra were measured on a Perkin-
Elmer 293 spectrophotometer (cmꢀ1), using KBr disks.
1H NMR (400 MHz) and 13C NMR (101 MHz)
measurements were performed using a Mercury-400BB,
and Varian-400 spectrometers, and chemical shifts were
expressed in δ (ppm) relative to tetramethylsilane (in
CDCl3 or DMSO-d6 as solvent) as the internal standard.
Mass spectra were obtained using the GC-2010 Shimadzu
gas chromatography mass spectrometer (70 eV).
Elemental microanalyses were performed on a Perkin–
Elmer CHN-2400II analyzer at the Chemical War
department, Ministry of Defense, Cairo, Egypt. Thin-layer
chromatography (TLC) was carried out on aluminum
sheets covered with silica gel 60 F254, 0.2 mm layer
(Merck). Column flash chromatography was performed
on Fluka analytical silica gel 60 0.063–0.2 mm (70–230
mesh ASTM) using UV light (254 and 366 nm) for
detection.
General procedure for formation of 3-(hydrazonomethylene)
pyrano quinolinediones (3a,b). A mixture of enamine 2
(3.40 g, 10 mmol) and hydrazine hydrate (0.50 mL,
10 mmol), or phenylhydrazine (1.1 mL, 10 mmol), in
ethanol (25 mL) was stirred at room temperature for 8 h.
After partial evaporation of the solvent, the solid
deposited after cooling was isolated by filtration, air
dried, and crystallized from the proper solvent to give
compounds 3a,b.
6-Butyl-4-hydroxy-3-(hydrazonomethylene)pyrano[3,2-c]
quinoline-2,5(6H)-dione (3a). Crystallized from EtOH to
give orange crystals, (2.65 g, 81%), mp 254–255°C. IR
(KBr, cmꢀ1) νmax: 3526, 3357 3234 (NH2 and OH),
3049 (CHarom), 2953, 2942, 2860 (CHaliph), 1709
(C═Oα-pyrone), 1679 (C═Oγ-pyrone), 1636 (C═Oquinolone),
1574 (C═C). 1H NMR (CDCl3, δ) δH: 0.97 (t, 3H,
J = 8.0 Hz, CH2CH3), 1.45–1.50 (m, 2H, CH2CH3),
1.71–1.75 (m, 2H, CH2CH2), 4.29 (t, 2H, J = 8.1 Hz,
NCH2), 5.64 (s, 2H, NH2), 7.33 (t, 1H, J = 8.0 Hz,
H-9), 7.46 (d, 1H, J = 8.0 Hz, H-7), 7.70 (t, 1H,
J = 8.0 Hz, H-8), 8.17 (d, 1H, J = 8.0 Hz, H-10), 8.94
(s, 1H, CHenamine), 13.38 (s, 1H, OH). 13C NMR
(125 MHz, DMSO-d6) δC: 14.12 (CH3), 19.93 (CH2),
29.91 (CH2), 42.07 (NCH2), 101.69, 114.0 0, 114.88,
116.37, 122.70, 124.37, 132.20, 136.08, 137.99, 145.92,
148.44, 158.98, 162.80. MS: m/z (relative intensity):
327 [M+; 3], 326 [M+ꢀ 1; 1], 310 (1), 309 (3), 298 (1),
285 (4), 284 (2), 270 (1), 254 (1), 253 (5), 240 (3), 239
(2), 215 (7), 201 (8), 187 (5), 161 (35), 132 (100), 119
(32), 105 (19), 104 (14), 91 (10), 77 (53). Anal. Calcd
for C17H17N3O4 (327.34): C, 62.38; H, 5.23; N, 12.84.
Found: C, 62.40; H, 5.28; N, 12.81%.
6-Butyl-3H-pyrano[3,2-c]quinoline-2,4,5(6H)-trione (1).
This compound was prepared according to the published
method [27], mp 227–229°C.
6-Butyl-3-((dimethylamino)methylene)-3H-pyrano[3,2-c]
quinoline-2,4,5(6H)-trione
(2).
A
mixture
of
pyranoquinolinone 1 (2.85 g, 10 mmol) and dimethyl
formamide dimethylacetal (4 mL, 30 mmol) was
refluxed for 4 h under free-solvent condition at 100°C.
The course of the reaction was monitored by TLC until
the starting material had completely disappeared. The
crude product was filtered off, purified by flash
chromatography and compound 2 was eluted with n-
hexane: EtOAc (4:6). After evaporation of the solvent,
compound 2 was obtained as yellow crystals (2.66 g,
78%) mp 190–192°C. TLC (silica gel, n-hexane: EtOAc
(4:6)): Rf 0.79. IR (KBr, cmꢀ1) νmax: 3042 (CHarom),
2971, 2936, 2860 (CHaliph), 1720 (C═Oα-pyrone), 1674
(C═Oγ-pyrone), 1627 (C═Oquinolone), 1592 (C═C). 1H
NMR (DMSO-d6) δH: 0.91 (t, 3H, J = 8.0 Hz,
6-Butyl-4-hydroxy-3-(N0-phenylhydrazonomethylene)pyrano
[3,2-c]quinoline-2,5(6H)-dione (3b).
Crystallized from
EtOH as yellow crystals, (3.12 g, 77%), mp 242–243°C.
IR (KBr, cmꢀ1) νmax: 3266 (NH), 3049 (CHarom),
2954, 2930, 2855 (CHaliph), 1752 (C═Oα-pyrone), 1677
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H. M. Hassanin and D. Abdel-Kader
Vol 000
(C═Oγ-pyrone), 1639 (C═Oquinolone), 1615 (C═N), 1573
(C═C). H NMR (DMSO-d6) δH: 1.02 (t, 3H, J = 8.0 Hz,
212–213°C. IR (KBr, cmꢀ1) νmax: 3082 (CHarom), 2957,
2929, 2868 (CHaliph), 1713 (C═Oα-pyrone), 1673
(C═Oquinolone), 1614 (C═N), 1570 (C═C). 1H NMR
(DMSO-d6) δH: 0.90 (t, 3H, J = 7.6 Hz, CH2CH3),
1.40–1.45 (m, 2H, CH2CH3), 1.61–1.65 (m, 2H,
CH2CH2), 4.31 (t, 2H, J = 8.0 Hz, NCH2), 7.11 (t, 1H,
J = 8.2 Hz, Ar─H), 7.29 (t, 1H, J = 8.2 Hz, Ar─H),
7.42 (t, 1H, J = 7.4 Hz, Ar─H), 7.50 (d, 1H, J = 8.4 Hz,
Ar─H), 7.72–7.78 (m, 2H, Ar─H), 7.86 (t, 1H,
J = 8.2 Hz, Ar─H), 8.05 (d, 1H, J = 8.2 Hz, Ar─H),
8.14 (d, 1H, J = 8.1 Hz, Ar─H), 8.94 (s, 1H, CHpyrazole).
13C NMR (100.62 MHz, DMSO-d6) δC: 14.01 (CH3),
20.06 (CH2), 29.71 (CH2), 42.34 (NCH2), 99.86,
102.64, 113.69, 115.16, 116.62, 118.70, 122.36, 123.03,
123.91, 124.62, 134.38, 134.80, 138.05, 157.32, 158.40,
160.08, 163.28, 163.41, 163.85. MS: m/z (relative
intensity): 385 [M+; 55], 384 [M+ꢀ 1; 88], 370 (63),
343 (65), 328 (75), 293 (100), 215 (63), 188 (60), 160
(55), 105 (58), 104 (97). Anal. Calcd for C23H19N3O3
(385.43): C, 71.68; H, 4.97; N, 10.90. Found: C, 71.70;
H, 4.99; N, 10.30%.
1
CH2CH3), 1.52–1.55 (m, 2H, CH2CH3), 1.77–1.83 (m,
2H, CH2CH2), 4.35 (t, 2H, J = 8.1 Hz, NCH2), 7.12–7.16
(m, 2H, Ar─H), 7.25 (s, 1H, CHenamine), 7.48–7.56 (m,
3H, Ar─H), 7.76 (t, 1H, J = 8.2 Hz, Ar─H), 7.94–8.23
(m, 2H, Ar─H), 8.33 (d, 1H, J = 7.2 Hz, Ar─H), 9.41 (s,
1H, NH), 12.37 (s, 1H, OH). 13C NMR (125 MHz,
DMSO-d6) δC: 13.77 (CH3), 20.18 (CH2), 29.58 (CH2),
42.50 (NCH2), 100.57, 113.70, 113.84, 115.11, 115.61,
115.83, 124.12, 124.81, 130.73, 133.62, 133.77, 137.89,
156.02, 157.82, 160.25, 161.89, 163.17, 163.39, 165.89.
MS: m/z (relative intensity): 404 [M++ 1; 10], 403 [M+;
38], 402 [M+ꢀ 1; 1], 347 (1), 310 (1), 297 (23), 296
(100), 285 (1), 268 (3), 254 (2), 241 (41), 240 (30), 228
(1), 226 (1), 212 (18), 185 (5), 158 (2), 156 (37), 146 (9),
141 (11), 140 (10), 132 (19), 118 (1), 114 (7), 104 (5), 92
(10), 77 (69). Anal. Calcd for C23H21N3O4 (403.44): C,
68.47; H, 5.25; N, 10.42. Found: C, 68.50; H, 5.21; N,
10.40%.
General procedures for preparation of pyrazolo[30,40:4,5]
Procedure b: A solution of hydrazone 3a (3.27 g,
10 mmol) or 3b (4.03 g, 10 mmol) in glacial acetic acid
(50 mL) was heated under reflux for 6 h. The reaction
mixture was concentrated in vacuum and the obtained
solid was filtered and recrystallized from the proper
solvent to give compounds 4a (2.51 g, 81%) and 4b
(3.03 g, 79%).
pyrano[3,2-c]quinolineones (4a,b).
Procedure a: A
mixture of enamine 2 (3.40 g, 10 mmol) and hydrazine
hydrate (0.50 mL, 10 mmol), or phenylhydrazine
(1.1 mL, 10 mmol), in absolute ethanol (25 mL) was
refluxed for 8 h. The solid deposited during heating was
separated by filtration, air dried, and crystallized from the
proper solvent to give compounds 4a and 4b, respectively.
5-Butyl-3H-pyrazolo[30,40:4,5]pyrano[3,2-c]quinoline-4,11
General procedure for formation of pyrimido[40,50:4,5]
(5H)-dione (4a). Crystallized from DMF/H2O afforded
pyrano[3,2-c]quinolinones (5a–c). A mixture of enamine
compound 4a as brown crystals (2.45 g, 79%), mp
200–201°C. IR (KBr, cmꢀ1) νmax: 3292 (NH), 3035
(CHarom), 2958, 2932, 2876 (CHaliph), 1728
(C═Oα-pyrone), 1679 (C═Oquinoline), 1613 (C═N), 1576
(C═C). 1H NMR (DMSO-d6) δH: 0.89 (t, 3H,
J = 8.1 Hz, CH2CH3), 1.35–1.40 (m, 2H, CH2CH3),
1.46–1.52 (m, 2H, CH2CH2), 4.16 (t, 2H, J = 8.1 Hz,
NCH2), 7.34 (t, 1H, J = 8.0 Hz, H-8), 7.57 (d, 1H,
J = 8.0 Hz, H-6), 7.73 (t, 1H, J = 8.0 Hz, H-7), 8.07 (d,
1H, J = 8.0 Hz, H-9), 8.67 (s, 1H, CHpyrazole), 9.94 (s,
1H, NH). 13C NMR (125 MHz, DMSO-d6) δC: 14.10
(CH3), 19.90 (CH2), 29.62 (CH2), 42.24 (NCH2), 99.70,
102.46, 113.51, 116.6, 123.86, 124.66, 134.44, 137.90,
139.27, 157.21, 160.08, 163.14, 163.83. MS: m/z
(relative intensity): 309 [M+; 2], 308 [M+ꢀ 1; 3], 295
(1), 268 (14), 253 (4), 240 (43), 239 (12), 228 (13), 226
(6), 215 (56), 201 (94), 188 (14), 187 (34), 172 (19),
160 (3), 159 (19), 132 (100), 119 (30), 104 (22), 105
(16), 90 (15), 77 (64). Anal. Calcd for C17H15N3O3
(309.33): C, 66.01; H, 4.89; N, 13.58. Found: C, 66.00;
H, 4.91; N, 13.60%.
2 (3.40 g, 10 mmol) and 1,3-binucleophiles, viz.
guanidine hydrochloride (0.95 g, 10 mmol),
cyanoguanidine (0.84 gm, 10 mmol), thiourea (0.76 gm,
10 mmol) in DMF (50 mL) was refluxed for 8 h. The
solid precipitated during heating was collected by
filtration, air dried, and crystallized from the proper
solvent to give compounds 5a, 5b, and 5c, respectively.
3-Amino-6-butyl-4H-pyrimido[40,50:4,5]pyrano[3,2-c]quinoline-
5,12(6H)-dione (5a).
Was crystallized from AcOH to
afford compound 5a as brown crystals, (2.92 g, 87%),
mp 176–177°C. IR (KBr, cmꢀ1) νmax: 3483, 3395
(NH2), 2955, 2929, 2867 (CHaliph), 1727 (C═Oα-pyrone),
1669 (C═Oquinolone), 1621 (C═N), 1585 (C═C). 1H
NMR (DMSO-d6) δH: 0.91 (t, 3H, J = 8.0 Hz,
CH2CH3), 1.41–1.46 (m, 2H, CH2CH3), 1.68–1.73 (m,
2H, CH2CH2), 4.29 (t, 2H, J = 8.0 Hz, NCH2), 7.13 (s,
2H, NH2), 7.52 (t, 1H, J = 8.2 Hz, H-9), 7.66–7.87 (m,
2H, H-7 and H-8), 8.17 (d, 1H, J = 8.1 Hz, H-10), 8.53
(s, 1H, Hpyrimidine). 13C NMR (125 MHz, DMSO-d6) δC:
14.02 (CH3), 19.92 (CH2), 29.71 (CH2), 42.34 (NCH2),
99.87, 102.63, 113.71, 113.84, 116.65, 123.94, 124.63,
134.39, 138.08, 151.26, 157.34, 160.08, 163.30, 163.84.
MS: m/z (relative intensity): 337 [M++ 1; 7], 336 [M+;
50], 308 (22), 273 (13), 265 (17), 217 (100), 195 (41),
5-Butyl-3-phenyl-3H-pyrazolo[30,40:4,5]pyrano[3,2-c]quinoline-
4,11(5H)-dione (4b). Crystallized from DMF affording
compound 4b as yellow crystals, (2.96 g, 77%), mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Some Novel Heteroannulated Pyranoquinolinones
178 (28), 149 (25), 109 (13), 105 (25), 71 (27). Anal.
Calcd for C18H16N4O3 (336.35): C, 64.28; H, 4.79; N,
16.66. Found: C, 64.08; H, 4.71; N, 16.55%.
N-(6-Butyl-5,12-dioxo-5H-pyrimido[40,50:4,5]pyrano[3,2-c]
quinolin-3-yl)cyanamide (5b). Crystallized from AcOH to
(3.00 g, 83%), mp 271–272°C. IR (KBr, cmꢀ1) νmax
:
3223 (NH), 3083 (CHarom), 2959, 2932, 2871 (CHaliph),
2211 (C≡N), 1725 (C═Opyrone), 1676 (C═Opyridone),
1648 (C═Oquinoline), 1617 (C═N), 1572 (C═C). 1H
NMR (DMSO-d6) δH: 0.93 (t, 3H, J = 8.0 Hz,
CH2CH3), 1.42–1.50 (m, 2H, CH2CH3), 1.64–1.67 (m,
2H, CH2CH2), 4.33 (t, 2H, J = 8.0 Hz, NCH2), 7.54 (t,
1H, J = 7.8 Hz, H-9), 7.87–7.92 (m, 2H, H-7, and H-8),
8.16 (d, 1H, J = 7.8 Hz, H-10), 8.77 (s, 1H, CHpyridone),
13.50 (s, 1H, NH). MS: m/z (relative intensity): 362
[M++ 1; 2], 361 [M+; 6], 336 (1), 332 (1), 319 (2), 308
(2), 305(4), 282 (2), 277 (7), 268 (6), 240 (25), 226 (4),
215 (33), 201 (51), 188 (11), 187 (16), 172 (13), 160
(2), 159 (16), 145 (44), 132 (92), 119 (36), 117 (35),
115 (11), 104 (33), 91 (14), 90 (23), 77 (100), 76 (26).
Anal. Calcd for C20H15N3O4 (361.36): C, 66.48; H,
4.18; N, 11.63. Found: C, 66.50; H, 4.19; N, 11.60%.
Procedure b: A solution of enamine 2 (3.40 g,
10 mmol), in DMF (50 mL), was refluxed for 4 h with
cyanoacetamide (0.84 g, 10 mmol). The solid deposited
after cooling was collected by filtration and crystallized
from DMF giving compound 8 as white crystals, (3.21 g,
89%), mp 273–275°C.
give compound 5b as brown crystals, (3.00 g, 83%), mp
186–187°C. IR (KBr, cmꢀ1) νmax: 3304 (NH), 3053
(CHarom), 2959, 2926, 2878 (CHaliph), 2008 (CN), 1715
(C═Oα-pyrone), 1677 (C═Oquinolone), 1611(C═N), 1573
(C═C). 1H NMR (DMSO-d6) δH: 0.94 (t, 3H,
J = 8.0 Hz, CH2CH3), 1.42–1.47 (m, 2H, CH2CH3),
1.67–1.73 (m, 2H, CH2CH2), 4.33 (t, 2H, J = 7.6 Hz,
NCH2), 6.48 (s, 1H, NH), 7.33 (t, 1H, J = 8.2 Hz, H-9),
7.53 (d, 1H, J = 8.2 Hz, H-7), 7.82 (t, 1H, J = 8.2 Hz,
H-8), 8.14 (d, 1H, J = 8.2 Hz, H-10), 8.76 (s, 1H,
CHpyrimidine). 13C NMR (101 MHz, DMSO-d6) δC: 14.10
(CH3), 19.90 (CH2), 29.82 (CH2), 42.24 (NCH2), 88.62
(C≡N), 99.70, 102.46, 112.78, 113.51, 116.65, 123.86,
124.66, 134.44, 137.90, 157.21, 160.08, 163.14, 163.83,
173.18. MS: m/z (relative intensity): 361 [M+; 3], 336
(12), 320 (6), 319 (3), 294 (7), 280 (17), 268 (21), 253
(18), 240 (64), 228 (14), 215 (58), 201 (95), 200 (8),
187 (10), 184 (9), 172 (9), 158 (12), 145 (15), 132
(100), 104 (45), 90 (51), 76 (41). Anal. Calcd for
C19H15N5O3 (361.36): C, 63.15; H, 4.18; N, 19.38.
Found: C, 63.20; H, 4.16; N, 19.33%.
13-Butyl-8-methyl-6H-pyrazolo[4″,3″:50,60]pyrano[20,30:4,5]
pyrano[3,2-c]quinoline-6,12(13H)-dione (9). To a solution
of enamine 2 (3.40 g, 10 mmol) in glacial acetic acid
containing freshly fused sodium acetate, 3-methyl-2-
pyrazolin-5-one (0.98 g, 10 mmol) was added. Then, the
reaction mixture was refluxed for 4 h. The crystals
deposited were filtered and air dried. Crystallization from
DMF afforded compound 9 as yellow crystals, (3.00 g,
80%), mp 193–194°C. IR (KBr, cmꢀ1) νmax: 3072
(CHarom), 2958, 2925, 2869 (CHaliph), 1718 (C═Opyrone),
1670 (C═Oquinolinone), 1614 (C═N), 1570 (C═C). 1H
NMR (DMSO-d6) δH: 0.98 (t, 3H, J = 8.1 Hz, CH2CH3),
1.45–1.51 (m, 2H, CH2CH3), 1.76–1.79 (m, 2H,
CH2CH2), 2.07 (s, 3H, CH3), 4.45 (t, 2H, J = 8.1 Hz,
NCH2), 7.37 (t, 1H, J = 8.0 Hz, H-3), 7.65–7.68 (m, 2H,
H-1 and H-2), 8.21 (d, 1H, J = 8.1 Hz, H-4), 9.20 (s,
1H, CHpyran). MS: m/z (relative intensity): 376 [M++ 1;
18], 375 [M+; 69], 360 (1), 319 (2), 284 (4), 283 (9),
268 (2), 241 (3), 240 (2), 239 (3), 217 (15), 216 (100),
201 (3), 189 (17), 188 (36), 187 (9), 172 (5), 161 (13),
158 (3), 133 (8), 132 (26), 120 (41), 119 (15), 105 (11),
104 (14), 77 (61). Anal. Calcd for C21H17N3O4
(375.39): C, 67.19; H, 4.56; N, 11.19. Found: C, 67.22;
H, 4.60; N, 11.20%.
6-Butyl-3-thioxo-5H-pyrimido[40,50:4,5]pyrano[3,2-c]quinoline-
5,12(6H)-dione (5c).
Formed brown crystals (2.90 g,
82%), mp 211–212°C, and crystallized from DMF. IR
(KBr, cmꢀ1) νmax: 3166 (NH), 3080 (CHarom), 2954,
2928, 2866 (CHaliph), 1724 (C═Oα-pyrone), 1659
(C═Oquinolone), 1623 (C═N), 1600 (C═C). 1H NMR
(DMSO-d6) δH: 0.99 (t, 3H, J = 8.1 Hz, CH2CH3),
1.47–1.54 (m, 2H, CH2CH3), 1.72–1.76 (m, 2H,
CH2CH2), 4.30 (t, 2H, J = 7.8 Hz, NCH2), 7.39–7.41
(m, 2H, H-9 and H-7), 7.69 (t, 1H, J = 8.2 Hz, H-8),
8.24 (d, 1H, J = 8.1 Hz, H-10), 8.35 (s, 1H,
CHpyrimidine), 13.36 (s, 1H, NH). 13C NMR (101 MHz,
DMSO-d6) δC: 14.13 (CH3), 21.21 (CH2), 29.59 (CH2),
41.90 (NCH2), 100.17, 112.93, 116.15, 123.60, 123.83,
125.89, 128.60, 130.33, 134.16, 138.42, 145.54, 156.36,
163.33, 165.98. MS: m/z (relative intensity): 354 [M++
1; 4], 353 [M+; 8], 310 (25), 270 (28), 267 (11), 239
(27), 170 (48), 160 (12), 132 (100), 105 (14), 77 (95).
Anal. Calcd for C18H15N3O3S (353.40): C, 61.18; H,
4.28; N, 11.89; S, 9.07. Found: C, 61.20; H, 4.23; N,
11.90; S, 9.05%.
General procedure for formation of pyrimido[5″,4″:50,
6-Butyl-3,5,12-trioxo-3H-pyrido[20,30:4,5]pyrano[3,2-c]quinoline-
60]pyrano[20,30:4,5]pyrano [3,2-c]quinolinones (10a,b).
2-carbonitrile (8).
Procedure a: Enamine 2 (3.40 g,
Compound 2 (3.40 g, 10 mmol) was heated under reflux
with barbituric acid (1.28 g, 10 mmol) or thiobarbituric
acid (1.44 g, 10 mmol), in glacial acetic acid containing
freshly fused sodium acetate for 4 h. The course of the
reaction was monitored by TLC until the starting
10 mmol) was heated under reflux for 4 h with
malononitrile (0.66 g, 10 mmol) in ethanol containing a
small amount of potassium carbonate. The solid
deposited was then filtered and air dried. Crystallization
from DMF afforded compound 8 as white crystals,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. Hassanin and D. Abdel-Kader
Vol 000
material had completely disappeared. The solid obtained
after cooling was filtered and crystallized from the
proper solvent to give compounds 10a,b.
1590 (C═C). 1H NMR (DMSO-d6) δH: 0.91 (t, 3H,
J = 8.0 Hz, CH2CH3), 1.37–1.40 (m, 2H, CH2CH3),
1.55–1.57 (m, 2H, CH2CH2), 4.20 (t, 2H, J = 8.0 Hz,
NCH2), 7.41 (t, 1H, J = 7.6 Hz, H-9), 7.73 (d, 1H,
J = 8.1 Hz, H-7), 7.96 (t, 1H, J = 7.6 Hz, H-8), 8.12 (d,
1H, J = 7.8 Hz, H-10), 9.63 (s, 1H, N═CH), 10.20 (s,
1H, OH), 11.58 (s, 1H, OH). 13C NMR (125 MHz,
DMSO-d6) δC: 14.12 (CH3), 19.94 (CH2), 29.65 (CH2),
42.08 (NCH2), 100.45, 116.15, 116.40, 123.84, 124.10,
124.50, 128.86, 134.93, 138.45, 149.05, 159.36, 163.04,
179.99. MS: m/z (relative intensity): 329 [M++ 1; 2], 328
[M+; 11], 311 (4), 310 (20), 302 (18), 295 (5), 286 (10),
271 (19), 253 (12), 242 (24), 240 (7), 215 (55), 189 (37),
186 (23), 172 (10), 171 (30), 132 (41), 90 (5), 77 (100).
Anal. Calcd for C17H16N2O5 (328.33): C, 62.19; H, 4.91;
14-Butyl-6H,8H-pyrimido[5″,4″:50,60]pyrano[20,30:4,5]pyrano
[3,2-c]quinoline-6,8,10,13(14H)-tetraone (10a).
This
compound obtained as yellow crystals by crystallization
from DMF, (3.50 g, 86%), mp 266–267°C. IR (KBr,
cmꢀ1
)
νmax
:
3162 (NH), 3072 (CHarom), 2955,
2929, 2860 (CHaliph), 1716 (C═Opyrone), 1666
(2C═Opyrimidone), 1644 (C═Oquinoline), 1614 (C═N),
1569 (C═C). 1H NMR (CDCl3) δH: 0.98 (t, 3H,
J = 8.0 Hz, CH2CH3), 1.47–1.52 (m, 2H, CH2CH3),
1.70–1.75 (m, 2H, CH2CH2), 4.31 (t, 2H, J = 8.0 Hz,
NCH2), 7.33 (t, 1H, J = 8.2 Hz, H-2), 7.57 (d, 1H,
J = 8.2 Hz, H-1), 8.07 (t, 1H, J = 8.2 Hz, H-3), 8.23 (d,
1H, J = 8.2 Hz, H-4), 8.95 (s, 1H, CHpyran), 13.38 (s,
1H, NH). MS: m/z (relative intensity): 405 [M+; 100],
387 (15), 319 (5), 283 (17), 282 (25), 228 (6), 156
(12), 105 (18). Anal. Calcd for C21H15N3O6 (405.37):
C, 62.22; H, 3.73; N, 10.37. Found: C, 62.34; H, 3.70;
N, 10.31%.
N, 8.53. Found: C, 62.23; H, 4.94; N, 8.54%.
6-Butyl-4-hydroxy-2,5-dioxo-2H-pyrano[3,2-c]quinoline-3
(6H)-carbonitrile (12). A mixture of oxime 11 (3.28 g,
10 mmol) in glacial acetic acid (25 mL) was refluxed for
4 h. The solid so obtained after cooling was filtered and
crystallized from ethanol to give compound 12 as pale
yellow crystals (2.55 g, 82%), mp 214–215°C. IR (KBr,
cmꢀ1) νmax: 3415 (OH), 3043 (CHarom), 2959, 2924,
2872 (CHaliph), 2200 (C≡N), 1720 (C═Oα-pyrone), 1674
(C═Oquinolone), 1605 (C═N), 1580 (C═C). 1H NMR
(DMSO-d6) δH: 1.01 (t, 3H, J = 8.0 Hz, CH2CH3), 1.49–
1.52 (m, 2H, CH2CH3), 1.75–1.77 (m, 2H, CH2CH2),
4.33 (t, 2H, J = 8.0 Hz, NCH2), 7.44–7.46 (m, 2H, H-9
and H-7), 7.65 (t, 1H, J = 8.2 Hz, H-8), 8.23 (d, 1H,
J = 8.1 Hz, H-10), 12.38 (s, 1H, OH). 13C NMR
(125 MHz, DMSO-d6) δC: 14.09 (CH3), 19.89 (CH2),
29.58 (CH2), 42.36 (NCH2), 94.99 (C≡N), 105.45,
116.52, 116.74, 123.69, 124.90, 125.73, 127.23, 135.73,
146.17, 156.49, 162.97, 164.16. MS: m/z (relative
intensity): 311 [M++ 1; 11], 310 [M+; 31], 293 (23), 285
(16), 284 (47), 268 (36), 256 (16), 254 (48), 242 (41),
241 (17), 240 (39), 229 (17), 228 (74), 215 (44), 212 (2),
201 (88), 188 (97), 187 (34), 172 (16), 159 (11), 132
(100), 119 (30), 116 (12), 104 (26), 90 (16), 77 (68).
Anal. Calcd for C17H14N2O4 (310.31): C, 65.80; H, 4.55;
N, 9.03. Found: C, 65.77; H, 4.52; N, 9.04%.
14-Butyl-10-thioxo-6H,8H-pyrimido[5″,4″:50,60]pyrano[20,30
:4,5]pyrano[3,2-c]quinoline-6,8,13(14H)-trione (10b).
This
compound produced yellow crystals (3.00 g, 71%), mp
174–175°C, and crystallized from DMF. IR (KBr, cmꢀ1
max: 3280, 3105 (NH), 3049 (CHarom), 2954, 2864
)
ν
(CHaliph), 1715 (C═Opyrone), 1672 (C═Opyrimidone), 1639
(C═Oquinoline), 1582 (C═C). 1H NMR (DMSO-d6) δH:
1.01 (t, 3H, J = 8.0 Hz, CH2CH3), 1.49–1.54 (m, 2H,
CH2CH3), 1.75–1.81 (m, 2H, CH2CH2), 4.33 (t, 2H,
J = 8.0 Hz, NCH2), 7.37–7.80 (m, 2H, H-2 and H-1),
7.96 (t, 1H, J = 8.0 Hz, H-3), 8.20 (d, 1H, J = 8.0 Hz, H-
4), 8.88 (s, 1H, Hpyran), 13.53 (s, 1H, NH). 13C NMR
(125 MHz, DMSO-d6) δC: 13.84 (CH3), 20.25 (CH2),
29.68 (CH2), 43.48 (NCH2), 104.35, 114.15, 114.36,
116.21, 118.13, 122.29, 122.56, 124.54, 125.36, 132.35,
138.78, 148.78, 165.27, 166.47, 183.70, 188.13, 191.19.
MS: m/z (relative intensity): 422 [M++ 1; 3], 421 [M+; 9],
405 (14), 377 (6), 365 (3), 320 (11), 285 (7), 268 (12),
267 (69), 257 (100), 216 (11), 212 (58), 202 (21), 188
(4), 187 (12), 186 (24), 172 (19), 161 (9), 118 (8), 104
(10), 91(24), 77 (43). Anal. Calcd for C21H15N3O5S
(421.43): C, 59.85; H, 3.59; N, 9.97; S, 7.61. Found: C,
59.86; H, 3.60; N, 9.99; S, 7.55%.
General procedure for formation of amino(pyrazolo- and
isoxazolo-) [30,40:4,5]pyrano[3,2-c]quinolinones (13a–c).
A
mixture of compound 12 (3.10 g, 10 mmol) and 1,2-
binucleophiles, viz. hydrazine hydrate (0.50 mL,
10 mmol), phenyl hydrazine (1.0 mL, 10 mmol),
hydroxylamine hydrochloride (0.70 g, 10 mmol) in
glacial acetic acid (50 mL) was heated under reflux for
4 h. After cooling to room temperature, the precipitate so
formed was filtered off and crystallized from the proper
6-Butyl-4-hydroxy-2,5-dioxo-2H-pyrano[3,2-c]quinoline-3
(6H)-carbaldehyde oxime (11). To a solution of enamine 2
(3.40 g, 10 mmol) in ethanol (25 mL), hydroxylamine
hydrochloride (0.70 g, 10 mmol), was added. Then, the
reaction mixture was refluxed for 8 h. The solid formed
during heating was filtered off and crystallized from
EtOH/H2O to give compound 11 as yellow crystals
solvent to give compounds 13a–c.
(2.76 g, 84%), mp 214–215°C. IR (KBr, cmꢀ1) νmax
:
1-Amino-5-butyl-3H-pyrazolo[30,40:4,5]pyrano[3,2-c]quinoline-
4,11(5H)-dione (13a). Crystallized from AcOH to give
3322 (OH), 3088 (CHarom), 2957, 2931, 2869 (CHaliph),
compound 13a as yellow crystals (2.75 g, 85%), mp
1725 (C═Oα-pyrone), 1690 (C═Oquinolone), 1627 (C═N).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Some Novel Heteroannulated Pyranoquinolinones
188–189°C. IR (KBr, cmꢀ1) νmax: 3526, 3368 (NH2),
3228, 3170 (NH), 3018 (CHarom), 2965, 2872, 2837
(CHaliph), 1726 (C═Oα-pyrone), 1679 (C═Oquinolone), 1568
(C═C). 1H NMR (DMSO-d6) δH: 0.90 (t, 3H,
J = 8.0 Hz, CH2CH3), 1.36–1.39 (m, 2H, CH2CH3),
1.55–1.57 (m, 2H, CH2CH2), 4.19 (t, 2H, J = 8.0 Hz,
NCH2), 7.19 (s, 2H, NH2), 7.35 (t, 1H, J = 8.4 Hz, H-
8), 7.67 (d, 1H, J = 8.2 Hz, H-6), 7.96 (t, 1H,
J = 8.4 Hz, H-7), 8.11 (d, 1H, J = 8.4 Hz, H-9), 10.24
(s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) δC: 13.73
(CH3), 20.12 (CH2), 29.55 (CH2), 42.42 (NCH2),
100.09, 101.65, 113.69, 115.17, 124.21, 124.81, 134.07,
137.99, 156.99, 159.79, 162.70, 162.89, 169.11. MS: m/
z (relative intensity): 324 [M+; 1], 308 (1), 296 (1), 295
(2), 284 (1), 283 (1), 282 (1), 269 (2), 268 (1), 267 (1),
256 (2), 252 (1), 228 (2), 215 (100), 201 (4), 160 (11),
159 (95), 158 (12), 132 (15), 131 (53), 119 (4), 116
(10), 105 (26), 104 (35), 77 (55). Anal. Calcd for
C17H16N4O3 (324.34): C, 62.95; H, 4.97; N, 17.27.
Found: C, 62.92; H, 5.00; N, 17.30%.
2H, NH2), 7.46 (t, 1H, J = 8.1 Hz, H-8), 7.67 (d, 1H,
J = 7.4 Hz, H-6), 7.78 (t, 1H, J = 8.1 Hz, H-7), 8.24 (d,
1H, J = 8.1 Hz, H-9). 13C NMR (100.6 MHz, DMSO-d6)
δC: 14.03 (CH3), 19.92 (CH2), 29.70 (CH2), 42.35
(NCH2), 99.87, 102.63, 113.72, 115.88, 116.67, 123.95,
124.64, 134.41, 138.09, 157.35, 160.08, 163.31, 163.85.
MS: m/z (relative intensity): 326 [M++ 1; 42], 325 [M+;
100], 299 (22), 283 (2), 282 (99), 280 (17), 255 (19), 254
(10), 228 (9), 99 (15). Anal. Calcd for C17H15N3O4
(325.33): C, 62.76; H, 4.65; N, 12.92. Found: C, 62.75;
H, 4.55; N, 12.90%.
General
procedure
for
formation
of
aminopyrimidopyrano[3,2-c]quinolinone (14a–c). A mixture
of compound 12 (3.10 g, 10 mmol) and guanidine
hydrochloride (0.95 g, 10 mmol), acetamidine
hydrochloride (0.95 g, 10 mmol), or thiourea (0.76 g,
10 mmol) in DMF (50 mL) was refluxed for 4 h. The
solid obtained after cooling was filtered and crystallized
from the proper solvent to afford compounds 14a–c.
1,3-Diamino-6-butyl-5H-pyrimido[40,50:4,5]pyrano[3,2-c]
quinoline-5,12(6H)-dione (14a). Crystallized from DMF
1-Amino-5-butyl-3-phenylpyrazolo[30,40:4,5]pyrano[3,2-c]
quinoline-4,11(5H)-dione (13b).
Crystallization from
to give 14a as yellow crystals (2.39 g, 68%), mp
190–191°C. IR (KBr, cmꢀ1) νmax: 3526, 3380 (NH2),
3200, 3175 (NH), 3006 (CHarom), 2959, 2918, 2848
(CHaliph), 1722 (C═Oα-pyrone), 1666 (C═Oquinolone), 1613
DMF gave compound 13b as white crystals (3.12 g,
78%), mp 211–212°C. IR (KBr, cmꢀ1) νmax: 3487, 3398
(NH2), 3049 (CHarom), 2961, 2925, 2869 (CHaliph), 1709
(C═Oα-pyrone), 1679 (C═Oquinolone), 1606 (C═N), 1560
(C═C). 1H NMR (DMSO-d6) δH: 0.92 (t, 3H,
J = 8.1 Hz, CH2CH3), 1.41–1.44 (m, 2H, CH2CH3),
1.63–1.65 (m, 2H, CH2CH2), 4.33 (t, 2H, J = 8.1 Hz,
NCH2), 6.98 (s, 2H, NH2), 7.45 (t, 1H, J = 7.4 Hz,
Ar─H), 7.56 (d, 1H, J = 8.3 Hz, Ar─H), 7.75–7.77 (m,
2H, Ar─H), 7.84–7.88 (m, 2H, Ar─H), 8.05 (d, 1H,
J = 8.1 Hz, Ar─H), 8.15 (t,1H, J = 8.4 Hz, Ar─H), 8.24
(d, 1H, J = 8.1 Hz, Ar─H). 13C NMR (125 MHz,
DMSO-d6) δC: 13.75 (CH3), 20.17 (CH2), 29.56 (CH2),
42.49 (NCH2), 100.47, 113.81, 114.12, 115.11, 115.84,
124.13, 124.51, 124.84, 127.67, 132.56, 133.83, 137.93,
154.94, 156.20, 157.60, 161.48, 161.55, 163.17, 164.08.
MS: m/z (relative intensity): 401 [M++ 1; 3], 400 [M+;
10], 371(18), 372 (66), 344 (24), 343 (100), 328 (5),
315 (48), 300 (7), 268 (2), 241 (4), 240 (5), 216 (44),
204(6), 189 (85), 188 (58), 187 (10), 172 (8), 161 (77),
159 (4), 133 (24), 132 (80), 104 (24), 77 (65). Anal.
Calcd for C23H20N4O3 (400.44): C, 68.99; H, 5.03; N,
13.99. Found: C, 68.80; H, 5.11; N, 13.95%.
1
(C═N), 1572 (C═C). H NMR (DMSO-d6) δH: 0.92 (t,
3H, J = 8.0 Hz, CH2CH3), 1.41–1.43 (m, 2H, CH2CH3),
1.63–1.65 (m, 2H, CH2CH2), 4.31 (t, 2H, J = 8.0 Hz,
NCH2), 6.97 (s, 2H, NH2), 7.45 (t, 1H, J = 8.0 Hz, H-
9), 7.74 (d, 1H, J = 8.0 Hz, H-7), 8.05 (t, 1H,
J = 8.0 Hz, H-8), 8.10 (d, 1H, J = 8.0 Hz, H-10), 9.37
(s, 2H, NH2). MS: m/z (relative intensity): 352 [M++ 1;
2], 351 [M+; 4], 381 (23), 254 (52), 226 (48), 159 (40),
135 (39), 132 (100), 103 (58), 91 (87). Anal. Calcd for
C18H17N5O3 (351.37): C, 61.53; H, 4.88; N, 19.93.
Found: C, 61.51; H, 4.85; N, 19.63%.
1-Amino-6-butyl-3-methyl-5H-pyrimido[40,50:4,5]pyrano[3,
2-c]quinoline-5,12(6H)-dione (14b).
This compound
formed yellow crystals (2.66 g, 76%), mp > 300°C and
crystallized from AcOH. IR (KBr, cmꢀ1) νmax: 3523,
3358 (NH2), 3043 (CHarom), 2958, 2932, 2872 (CHaliph),
1705 (C═Oα-pyrone), 1682 (C═Oquinolone), 1613(C═N),
1570 (C═C). 1H NMR (DMSO-d6) δH: 1.00 (t, 3H,
J = 8.0 Hz, CH2CH3), 1.52–1.55 (m, 2H, CH2CH3),
1.76–1.78 (m, 2H, CH2CH2), 2.70 (s, 3H, CH3), 4.36 (t,
2H, J = 8.0 Hz, NCH2), 7.37 (bs, 2H, NH2), 7.46–7.49
(m, 2H, H-9 and H-7), 7.71 (t, 1H, J = 8.2 Hz, H-8),
8.30 (d, 1H, J = 8.1 Hz, H-10). 13C NMR (125 MHz,
DMSO-d6) δC: 13.80 (CH2CH3), 14.43 (CH3), 20.27
(CH2), 29.57 (CH2), 42.52 (NCH2), 100.82, 113.51,
114.89, 122.91, 123.16, 124.67, 124.94, 133.47, 138.77,
154.53, 156.15, 156.96, 157.13, 164.72. MS: m/z
(relative intensity): 351 [M++ 1; 62], 350 [M+; 93], 322
(82), 279 (60), 278 (75), 268 (75), 263 (55), 250 (100),
1-Amino-5-butyl-4H-isoxazolo[50,40:4,5]pyrano[3,2-c]quinoline-
4,11(5H)-dione (13c).
Recrystallized from DMF
affording 13c as yellow crystals (2.79 g, 86%), mp
245–246°C. IR (KBr, cmꢀ1) νmax: 3492, 3394 (NH2),
3045 (CHarom), 2961, 2925, 2869 (CHaliph), 1709 (C═Oα-
pyrone), 1679 (C═Oquinolone), 1606 (C═N), 1560 (C═C).
1H NMR (DMSO-d6) δH: 1.01 (t, 3H, J = 8.0 Hz,
CH2CH3), 1.47–1.49 (m, 2H, CH2CH3), 1.78–1.81 (m,
2H, CH2CH2), 4.33 (t, 2H, J = 8.0 Hz, NCH2), 7.20 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. Hassanin and D. Abdel-Kader
Vol 000
REFERENCES AND NOTES
237 (72), 211 (63), 183 (50), 160 (57), 159 (57), 158 (77),
132 (63), 118 (59), 104 (50), 91 (80), 77 (57). Anal. Calcd
for C19H18N4O3 (350.38): C, 65.13; H, 5.18; N, 15.99.
[1] Abass, M.; Mostafa, B. B. Bioorg Med Chem 2005, 13, 6133.
[2] Hassanin, H. M. ARKIVOC 2012, vi, 384.
Found: C, 65.12; H, 5.20; N, 15.96%.
[3] Hassanin, H. M.; Abdel-Kader, D. Heterocycles 2013, 87, 369.
[4] Campbell, W. E.; Davidowitz, B.; Jackson, G. E. Phytochem-
istry 1990, 29, 1303.
1-Amino-6-butyl-3-thioxo-3H,5H-pyrimido[40,50:4,5]pyrano
[3,2-c]quinoline-5,12(6H)-dione (14c).
Crystallized from
[5] Wu, S.-J.; Chen, I.-S. Phytochemistry 1993, 34, 1659.
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DMF to afford 14c as yellow crystals, (2.70 g, 73%),
mp > 300°C. IR (KBr, cmꢀ1) νmax: 3490, 3342 (NH2),
3156 (NH), 2957, 2928, 2850 (CHaliph), 1748 (C═Oα-
pyrone), 1679 (C═Oquinolone), 1617 (C═N), 1576 (C═C).
1H NMR (DMSO-d6) δH: 0.93 (t, 3H, J = 8.0 Hz,
CH2CH3), 1.44–1.46 (m, 2H, CH2CH3), 1.65–1.67 (m,
2H, CH2CH2), 4.32 (t, 2H, J = 8.0 Hz, NCH2), 7.00 (s,
2H, NH2), 7.52 (t, 1H, J = 8.0 Hz, H-9), 7.76–7.78 (m,
2H, H-7 and H-8), 8.22 (d, 1H, J = 8.1 Hz, H-10), 12.28
(s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) δC: 14.02
(CH2CH3), 19.92 (CH2), 29.71 (CH2), 42.34 (NCH2),
99.89, 102.63, 113.71, 116.65, 123.94, 127.63, 134.39,
135.58, 138.08, 157.34, 160.08, 163.30, 163.83, 169.02.
MS: m/z (relative intensity): 369 [M++ 1; 3], 368 [M+; 9],
352 [M+ꢀ NH2; 2], 236 (11), 279 (10), 147 (13), 124
(14), 113 (11), 95 (37), 57 (100). Anal. Calcd for
C18H16N4O3S (368.42): C, 58.68; H, 4.38; N, 15.21; S,
8.70. Found: C, 58.70; H, 4.33; N, 15.22; S, 8.72%.
1-Amino-6-butyl-3,5,12-trioxo-3H-pyrido[20,30:4,5]pyrano[3,
[18] Nadaraj, V.; Selvi, S. T.; Bai, H. P.; Mohan, S.; Thangadurai, T. D.
Med Chem Res 2012, 21, 2902.
2-c]quinoline-2(6H)-carbonitrile (16).
A
solution of
carbonitrile 12 (3.10 g, 10 mmol) in ethanol (25 mL)
containing few drops of triethyl amine was treated with
malononitrile (0.66 g, 10 mmol) under reflux conditions
for 4 h. The solid so obtained after cooling was filtered
and crystallized from DMF to give compound 16 as pale
brown crystals, (3.23 g, 86%), mp 169–170°C. IR (KBr,
cmꢀ1) νmax: 3473, 3335 (NH2), 3167 (NH), 2958, 2930,
2871 (CHaliph), 2189 (CN), 1752 (C═Oα-pyrone), 1669
(C═Opyridone), 1636 (C═Oquinolone), 1612 (C═N), 1572
[19] Gunasekaran, P.; Prasanna, P.; Perumal, S.; Almansour, A. I.
Tetrahedron Lett 2013, 54, 3248.
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Yang, G.-Z.; Fu, L.-W. Eur J Med Chem 2012, 47, 206.
[22] Jimenez, H. N.; Liu, K. G.; Hong, S.-P.; Reitman, M. S.;
Uberti, M. A.; Bacolod, M. D.; Cajina, M.; Nattini, M.; Sabio, M.; Doller,
D. Bioorg Med Chem Lett 2012, 22, 3235.
[23] Parmar, N. J.; Barad, H. A.; Pansuriya, B. R.; Teraiya, S. B.;
Gupta, V. K.; Kant, R. Bioorg Med Chem Lett 2012, 22, 3816.
[24] Thumar, N. J.; Patel, M. P. Med Chem Res 2012, 21, 1751.
[25] Tomassoli, I.; Herlem, G.; Picaud, F.; Benchekroun, M.;
Bautista-Aguilera, O. M.; Luzet, V.; Jimeno, M.-L.; Gharbi, T.;
Refouvelet, B.; Ismaili, L. Monatsh Chem 2016, 147, 1069.
[26] Ibrahim, M. A.; Hassanin, H. M. ARKIVOC 2013, iv, 217.
[27] Kappe, T.; Aigner, R.; Hohengassner, P.; Stadlbauer, W. J Prakt
Chem 1994, 336, 596.
1
(C═C). H NMR (DMSO-d6) δH: 0.92 (t, 3H, J = 8.0 Hz,
CH2CH3), 1.37–1.40 (m, 2H, CH2CH3), 1.61–1.63 (m,
2H, CH2CH2), 4.33 (t, 2H, J = 8.0 Hz, NCH2), 7.32 (t,
1H, J = 8.1 Hz, H-9), 7.43 (d, 1H, J = 8.1 Hz, H-7), 7.56
(t, 1H, J = 8.1 Hz, H-8), 7.72 (s, 2H, NH2), 8.03 (d, 1H,
J = 8.1 Hz, H-10), 13.15 (s, 1H, NH). 13C NMR
(125 MHz, DMSO-d6) δC: 13.82 (CH3), 20.18 (CH2),
29.52 (CH2), 42.61 (NCH2), 89.38, 107.37, 113.09,
114.92, 122.74, 123.00, 124.29, 125.02, 133.84, 139.68,
141.12, 147.63, 156.86, 158.89, 164.49, 170.61. MS: m/z
(relative intensity): 377 [M++ 1; 5], 376 [M+; 32], 350
[M+ꢀ CN; 15] (4), 334 (31), 269 (40), 188 (15), 160 (2),
158 (13), 132 (100), 119 (5), 91 (11), 77 (30). Anal.
Calcd for C20H16N4O4 (376.37): C, 63.83; H, 4.28; N,
14.89. Found: C, 63.85; H, 4.30; N, 14.90%.
[28] Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12, 51.
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Singh, J. New J Chem 2015, 39, 4556.
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37, 607.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet