4-Hydroxy-1-phenylquinolin-2(1H)-one in One-pot Synthesis of Pyrimidoquinolines and Related Compounds under Microwave Irradiation and Conventional Conditions

Article abstract of DOI:10.1002/jhet.2286

Biginelli condensation reactions of 4-hydroxy-1-phenylquinolin-2(1H)-one, aryl aldehydes and urea, or thiourea, 5-amino-1H-1,2,4-triazole, or 2-amine-1H-benzimidazole (9) under microwave irradiation afforded the corresponding pyrimido[5,4-c]quinolin-5-one derivatives in high yields. One-pot synthesis of 2H-pyrano[3,2-c]quinolines is also reported.

Full text of DOI:10.1002/jhet.2286

March 2016
4-Hydroxy-1-phenylquinolin-2(1H)-one in One-pot Synthesis of
Pyrimidoquinolines and Related Compounds under Microwave Irradiation
and Conventional Conditions
383
a
b
a
b
a
*
*
Aboul-Fetouh E. Mourad, Amer A. Amer, Kamal M. El-Shaieb, Ali M. Ali, and Ashraf A. Aly
aDepartment of Chemistry, Faculty of Science, Minia University, El-Minia, Egypt
bDepartment of Chemistry, Faculty of Science, Sohag University, Sohag, Egypt
*
E-mail: mouradaboulf@yahoo.com; ashrafaly63@yahoo.com
Received March 21, 2014
DOI 10.1002/jhet.2286
Published online 6 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
Biginelli condensation reactions of 4-hydroxy-1-phenylquinolin-2(1H)-one, aryl aldehydes and urea, or
thiourea, 5-amino-1H-1,2,4-triazole, or 2-amine-1H-benzimidazole (9) under microwave irradiation afforded
the corresponding pyrimido[5,4-c]quinolin-5-one derivatives in high yields. One-pot synthesis of 2H-pyrano
[3,2-c]quinolines is also reported.
J. Heterocyclic Chem., 53, 383 (2016).
INTRODUCTION
chemical research and industry, the challenge for a sustain-
able environment calls for clean procedures to avoid harm-
ful organic solvents. It is well known that chemical
synthesis can be dramatically promoted using microwave
(MW) irradiation [10]. Not only can it reduce chemical
reaction times from hours to minutes but it can also reduce
side reactions, increase yields, and improve reproducibility
compared with conventional heating conditions [11]. For
Biginelli reaction, significant rate and yield enhancement
have been reported when the reaction was carried out under
MW irradiation [12].
In over 110 years of study of the Biginelli reaction, only
minor structural variations in all the three building blocks
have been reported [13,14]. However, to the best of our
knowledge, there has been no such major variation in the
active methylene building block; this could be a significant
and useful extension of the Biginelli reaction for the
synthesis of polyfunctionalized heterocycles.
The Biginelli reaction is one of the fundamental one-pot
three-component cyclocondensation strategies for the synthe-
sis of dihydropyrimidinone (DHPM) scaffolds. DHPMs have
attracted considerable interest, since appropriately functional-
ized DHPMs have been used as antihypertensive agents [1–5]
and potent calcium channel blockers [3,5], and they are
also shown to be useful for the development of anticancer
drugs [6,7].
Because of the importance of Biginelli reaction products,
the discovery and development of a better method with mild
conditions and with new catalysts have received attention.
Several improved procedures have been reported using
Lewis acids as well as protic acids as promoters [8].
However, some of the newer reported methods also suffer
from drawbacks such as low yields, cumbersome product
isolation procedures, expensive catalysts, and environmental
pollution [9]. As environmental consciousness increases in
© 2015 HeteroCorporation

384
A.-F. E. Mourad, A. A. Amer, K. M. El-Shaieb, A. M. Ali, and A. A. Aly
Vol 53
Table 1
Pyrimidoquinolines are classes of heterocycles that are of
Comparison of the reaction times and yields for Biginelli reaction under
conventional and microwave conditions.
considerable interest because of their diverse range of thera-
peutic and biological properties, including antioxidative ac-
tivity [15], nitric oxide production inhibitory activity [16],
and cytotoxicity against human tumor cell lines [17], angio-
tensin II receptor antagonist [18], glycine NMDA receptor
antagonists [19], endothelin receptor antagonist [20], anti-
platelet agents [21], and antitumor agents [22].
A recent communication from our laboratory has de-
scribed an MW-assisted synthesis of triazolo- and benzimi
dazoquinazolinones [23], and MW heterocyclization of
thioureidoethylthioureas as well as hydrazinecarboxamide
derivatives [24]. Because the aim of our research is con-
cerned on the synthesis of heterocyclic systems that might
have prospective biological and pharmaceutical activities,
we now report our studies on the synthesis of several novel
condensed heterocyclic systems derived from pyrimido-
quinolines applying the MW irradiation technique and using
an interesting binuclear active methylene building block, 4-
hydroxy-1-phenylquinolin-2(1H)-one.
MW irradiation
Conventional protocol
Yield
(%)
Time
(min)
Yield
(%)
Time
(h)
Compound
6a
6b
6c
6d
7a
7b
7c
7d
10a
10b
10c
10d
11a
11b
11c
11d
80
79
82
83
82
85
79
81
77
80
82
79
80
82
84
80
4
3
5
5
4
3
3
4
5
5
3
3
3
5
4
4
45
37
34
46
28
38
35
51
54
43
61
42
31
34
44
46
11
10.20
10
11
12
14
7
8
21
19
20
19
20
21
17
19
RESULTS AND DISCUSSION
(7–14 h) in moderate yields (Table 1). The structure of
these products is established on the basis of IR, H NMR,
1
The parent compound 4-hydroxy-1-phenylquinolin-
2(1H)-one (3) was prepared via the reaction of diphenyl-
amine (1) with diethylmalonate (2) under reflux conditions
in diphenylether [25]. A multicomponent reaction between
4-hydroxy-1-phenylquinolin-2(1H)-one (3), urea (5a), or
thiourea (5b) and aryl aldehydes, namely benzaldehyde,
p-chlorobenzaldehyde, p-methoxybenzaldehyde, and p-ni-
trobenzaldehyde 4a–d, has the same content as Biginelli
condensation. Equimolar amounts of aryl aldehydes, urea,
or thiourea together with quinolinone 3 were condensed
under MW conditions. Products of pyrimido[5,4-c]quino-
line-2,5(1H,3H)-diones 6a–d and 2-thioxo-2,3,4,6-tetra
hydropyrimido-[5,4-c]quinolin-5(1H)-ones 7a–d were ob-
tained (Scheme 1) within few minutes (3–5 min) of irradi-
ation. The optimized results are summarized in Table 1.
Good yields were obtained, and problems associated with
toxic solvent use were avoided. On the other hand, under-
going the same reaction under conventional heating in
DMF gave the same reaction products within several hours
13C NMR, MS spectral data, and elemental analyses.
The IR spectra of compounds 6a–d revealed the disap-
pearance of OH group and new absorption bands correspond-
ing to two NH groups in the range ν = 3398–3200 cmÀ1, in
addition to two bands at ν = 1670 and 1650 cmÀ1 assigned
1
to the existence of two carbonyl groups in 6a–d. The H
NMR spectra of compounds 6a–d showed a singlet band in
the range δ = 5.22–4.52 ppm, because of the aliphatic proton
attached to the sp3 carbon. The disappearance of the OH
1
signal in the H NMR spectrum at δ = 13.2 ppm of 3 and
the appearance of one NH broad signal in the range
δ = 12.45–10.98 ppm in compounds 6a–d and another one
in the range of δ = 11.61–9.40 ppm confirmed the formation
of dihydropyrimidoquinolinones.
1
Similarly, the structure of 7a–d was evidenced by IR, H
NMR, 13C NMR, MS spectral data, and elemental analyses.
IR spectra of 7a–d indicated only one carbonyl absorption in
the range 1660, 1685, and thione absorption in the range
1200–1210, in addition to two broad bands at ν = 3300–
3280 cmÀ1 for NH groups. The disappearance of the OH band
in the IR spectra is in agreement with the reaction sequence.
Scheme 1
1
The H NMR spectra of 7a–d showed, beside the expected
aromatic protons resonances, two broad singlets in the region
12.48–10.21 ppm consistent with the two NH protons. It
disclosed also one singlet at δ =5.63–4.67 ppm corresponding
to the aliphatic protons. Furthermore, the EI-MS spectrum of
7a showed exact molecular ion peak at m/z = 383. By analogy,
MW irradiation for equimolar amounts of compound 3, aryl al-
dehydes 4a–d, and 5-amino-1H-1,2,4-triazole (8) or 2-amino-
1H-benzimidazole (9) (Scheme 2) within few minutes afforded
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
4-Hydroxy-1-phenylquinolin-2(1H)-one in One-pot Synthesis of Pyrimidoquinolines
385
and Related Compounds under Microwave Irradiation and Conventional Conditions
Scheme 2
Scheme 3
absorption band of OH group and appearing of two absorption
bands between ν = 3445–3260 cmÀ1 for NH2 (see the Experi-
mental section). Additionally, strong absorption bands were
observed between ν = 2220 and 2196 cmÀ1 for CN group
and absorption bands between ν = 1660 and 1680 cmÀ1 for
CO group. The 1H NMR spectra of 13a–d are in agreement
with the IR spectral data that display, beside the aromatic pro-
tons and OH proton in case of 13c, the absence of OH signal
in 3 and appearance of NH2 signal as a singlet in the region
δ =3.44–3.31 ppm and a singlet for aliphatic proton in the
range δ =5.73–5.41 ppm. Moreover, the EI-MS spectrum of
13a shows the correct molecular ion peak at m/z = 391.
Treatment of compound 3 with (2-oxo-1,2-dihydro-3H-
indol-3-ylidene)malononitrile (14, prepared by reacting isatin
and malononitrile) in 1,4-dioxane at reflux temperature gave
the spiro compound 15 (Scheme 4). The IR spectrum of which
showed the absence of OH group and the existence of absorp-
tion bands for NH and NH2 bands between ν =3420 and
3320, strong absorption band for CN group at ν = 2210, and
another band for CO at ν = 1670, 1660 cmÀ1. Away from
11-aryl-9-phenyl-4,11-dihydro-1,2,3-triazolo[5′,1′:1,2]pyrimido
[5,4-c]-quinoline-10(9)ones 10a–d and 13-aryl-11-pheny
l-6,13-dihydrobenzimidazo[1′,2′:1,2]-pyrimido[5,4-c]qui
noline-12(11H)ones 11a–d, respectively in a good yields
(77–84%). Conventionally, the same reactants gave prod-
ucts 10a–d and 11a–d within approximately 17–21 h in
moderate yields (31–61%, Table 1).
Structure of 10a–d is substantiated from spectral
evidence and elemental analyses. For example, the IR
spectrum of 10a exhibited essential bands at ν = 3334 and
1670 cmÀ1 consistent with NH and CO groups. Further-
more, the IR spectrum did not reveal any OH groups,
which infers its participation of this group in the reaction.
1
Away from the aromatic protons, the H NMR spectrum
of 10a displayed a broad singlet at δ = 12.88 ppm (NH)
and another one at δ = 5.17 ppm due to the pyrimidine-
CH. The triazole-CH, however, appeared downfield at
δ = 9.05 ppm. Furthermore, the EI-MS spectrum of 10a
showed an exact molecular ion peak at m/z = 391
1
the aromatic protons, the H NMR spectrum of 15 discloses
two signals; one at δ =3.82ppm for NH2 group and the other
resonates at δ = 11.22 ppm for NH group. The existence of the
spiro carbon atom is confirmed by 13C NMR spectroscopy, in-
dicating its signal at δ = 77.8 ppm. A further evidence for the
chemical composition of 15 depends on MS spectrum by
giving a molecular ion peak at m/z = 432.
In conclusion, MW irradiation technique can be used
as a facile and very fast method for synthesis of several
pyrimidoquinolines. The reaction involves a three-component
condensation, and the products were obtained with high purity
and higher yields compared with the conventional methods.
The 1H NMR spectrum of 11a shows, beside the expected
aromatic protons resonances, a broad singlet at δ = 10.90
ppm and another one at δ = 5.31 ppm consistent with the
NH and pyrimidine-CH protons, respectively. The structure
of 11a was further supported by IR spectrum, which showed
absorptions for NH and CO groups at ν = 3330 and
1676cmÀ1, respectively. Moreover, the EI-MS spectrum of
11a showed a molecular ion peak at m/z = 440 consistent
with the proposed structure. For comparison between the
conventional procedure and MW heating (Table 1), it is
worth mentioning that the MW irradiation procedure is con-
sidered as environment-friendly and produce better yields
compared with the conventional procedure for synthesis of poly-
cyclic dihydropyrimidines. Compound 3 reacted with arylidene
compounds, namely benzylidene-malononitrile, p-chlorobenz
ylidene-malononitrile, p-hydroxybenzylidenemalononitrile, and
p-nitrobenzylidenemalononitrile (12a–d) to give 2H-pyrano[3,
2-c]quinoline derivatives 13a–d (Scheme 3).
EXPERIMENTAL
Melting points were determined on a Koffler melting points ap-
paratus and are uncorrected. IR spectra were recorded on Perkin-
Scheme 4
The structure of products 13a–d is deduced from the fol-
lowing spectral evidence as well as elemental analyses. The
IR spectra of compounds 13a–d showed the absence of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

386
A.-F. E. Mourad, A. A. Amer, K. M. El-Shaieb, A. M. Ali, and A. A. Aly
Vol 53
1
Elmer 137 and Nicolet FT-IR 710 spectrophotometers. H NMR
and 13C NMR spectra were measured on Bruker WM 300
(300 MHz) and Bruker AC 200 (200 MHz) instruments with
TMS as internal standard (δ in ppm). Mass spectra were obtained
with a Finigan MAT 8430 instrument at 70 eV. Elemental analy-
ses were performed on a Perkin-Elmer CHN-2400C analyzer
1H, NH), 10.01 (s, 1H, NH), 8.23–9.72 (m, 12H, Ar–H), 5.22 (s,
1H, Aliph-CH);; 13C NMR, δ = 170.0, 155.5, 142.1, 114.3, 59.3 (C5,
C2, pyrimidine-C6, C4a, C4), 140.9, 139.8, 137.1, 136.4, 135.0,
132.9, 132.0, 130.9, 130.0, 128.8, 125.6, 120.7, 116.8, 115.4 (14
Ar–C); MS-EI (rel. inten., %) m/z = 412 (M+, 60) 388 (41), 356 (19),
312 (17), 266 (100), 248 (36), 223 (19), 189 (39), 156 (13), 121 (9),
107 (17), 91 (44); Anal. Calcd for C23H16N4O4 (412.40): C, 66.92;
H, 3.89; N, 13.58: found: C, 67.02; H, 3.99; N, 13.49.
model. MW irradiations were carried out in
OM9925E MW oven (2450 MHz, 800 W).
a Kenstar
Synthesis of 4-aryl-6-phenyl-4,6-dihydropyrimido[5,4-c]
quinoline-2,5(1H,3H)-diones 6a–d and 4-aryl-6-phenyl-2-thioxo-
2,3,4,6-tetrahydropyrimido[5,4-c]-quinolin-5(1H)-ones 7a–d
Method A: General procedure (conventional heating). A mixture
of aldehydes 4a–d (0.001 mol), (3) (0.01 mol), and urea (5a) or
thiourea (5b, 0.01mol) in DMF (30mL) was heated under reflux for
the time indicated in Table 1. On completion of the reaction (TLC
monitoring), the reaction mixture was allowed to cool to room
temperature. The solid precipitate was collected by filtration, dried,
and recrystallized from ethanol afforded the pure product.
Method B: General procedure (microwave heating). A mixture
of aldehyde (4a–d, 0.01 mol), 4-hydroxy-2(1H)-qunolinone (3)
(0.24g, 0.001mol), and urea (5a) or thiourea (5b, 0.001mol) was
mixed in 3mL DMF. The reaction mixture was irradiated in a MW
oven for 3–5 min. as indicated in Table 1. On cooling at room
temperature, the precipitated products were filtered and recrystallized
from ethanol.
4,6-Diphenyl-2-thioxo-2,3,4,6-tetrahydropyrimido[5,4-c]quinolin-
5(1H)-one (7a). M.p. 242–244°C; IR (KBr): νmax = 3300, 3280,
1685, 1665, 1200cmÀ1; 1H NMR (200 MHz, DMSO-d6)
δ = 12.23 (br, s, 1H, NH), 10.22 (br, s, 1H, NH), 8.32–6.76 (m,
13H, Ar–H), 4.78 (s, 1H, Aliph.-CH); 13C NMR, δ = 180.9, 166.7,
138.7, 113.6, 64.5 (C2, C5, pyrimidine-C6, C4a, C4), 137.9, 137.4,
136.4, 133.5, 132.3, 131.1, 130.4, 128.5, 128.1, 125.7, 123.3,
121.0, 119.7, 114.39 (14 Ar–C); MS-EI (rel. inten., %) m/z = 383
(M+, 46), 348 (61), 309 (16), 257 (100), 230 (45), 208 (37), 180
(19), 166 (47), 141 (12), 105 (44); Anal. Calcd for C23H17N3OS
(383.47): C, 71.97; H, 4.44; N, 10.95; found: C, 72.13; H, 4.50;
N, 10.90.
4-(4-Chlorophenyl)-6-phenyl-2-thioxo-2,3,4,6-tetrahydropyrimido
[5,4-c]quinolin-5(1H)-one (7b). M.p. 255–257°C; IR (KBr): νmax
=
3438, 3208, 3063, 2950 1680, 1665, 1205 cmÀ1 1H-NMR
;
(200 MHz, DMSO-d6) δ = 11.67 (br, s, 1H, NH), 10.93 (br, s, 1H,
NH), 8.98–7.21 (m, 12H, ArH), 4.79 (s, 1H, Aliph.-CH); 13C NMR,
δ = 180.5, 165.9, 138.8, 112.6, 63.8 (C2, C5, pyrimidine-C6, C4a, C4),
137.8, 137.0, 135.9, 134.3, 133.0, 132.2, 131.7, 130.8, 129.1, 128.0,
127.2, 125.5, 120.2, 115.4 (14 Ar–C); MS-EI (rel. inten., %)
m/z = 420 (M++2, 23), 418 (M+, 79), 356 (35), 304 (16), 278 (100),
241 (24), 203 (63), 175 (19), 150 (18), 111 (13), 96 (30); Anal. Calcd
for C23H16ClN3OS (417.99): C, 66.01; H, 3.83; N, 10.05; found: C,
66.13; H, 3.85; N, 10.00.
4,6-Diphenyl-4,6-dihydropyrimido[5,4-c]quinoline-2,5(1H,3H)-
dione (6a). M.p. 255–257°C; IR (KBr): νmax = 3300, 3200, 1670,
1
1666 cmÀ1; H NMR (300 MHz, DMSO-d6) δ = 11.72 (br, s, 1H,
NH), 9.40 (s, 1H, NH), 8.90–6.52 (m, 13H, Ar–H), 4.62 (s, 1H,
Aliph.-CH); 13C NMR, δ = 169.8, 155.3, 140.1, 112.5, 58.4 (C5,
C2, pyrimidine-C6, C4a, C4), 138.9, 137.2, 133.3, 132.4, 131.0,
131.7, 135.5, 128.8, 128.1, 126.7, 124.5, 122.6, 115.6, 114.9 (14
Ar–C); MS-EI (rel. inten., %) m/z = 367 (M+, 65), 296 (15), 334
(31), 197 (100), 169 (19), 149 (10), 107 (18), 94 (52); Anal. Calcd
for C23H17N3O2 (367.41): C, 75.12; H, 4.63; N, 11.43; found: C,
75.17; H, 4.52; N, 11.40.
4-(4-Methoxyphenyl)-6-phenyl-2-thioxo-2,3,4,6-tetrahydropyrimido-
[5,4-c]quinolin-5(1H)-one (7c). M.p. 248–250°C; IR (KBr): νmax
=
3360, 3308, 1676, 1660, 1210 cmÀ1; 1H NMR (300 MHz, DMSO-d6)
δ = 11.32 (br, s, 2H, 2NH), 10.21 (br, s, 1H, NH), 8.27–6.43 (m, 12H,
Ar–H), 4.67 (s, 1H, Aliph.-CH); 4.37 (s, 3H, OCH3); 13C NMR,
δ = 181.2, 166.6, 165.6, 139.4, 112.0, 62.5, 56.6 (C2, C5, C-OMe,
pyrimidine-C6, C4a, C4, OCH3), 138.0, 137.4, 137.0, 136.2, 132.0,
131.1, 130.4, 129.0, 128.3, 125.6, 120.7, 115.6, 114.7 (13 Ar–C); Anal.
Calcd for C24H19N3O2S (413.50): C, 69.65; H, 4.59; N, 10.16; found: C,
69.77; H, 4.69; N, 10.19.
4-(4-Chlorophenyl)-6-phenyl-4,6-dihydropyrimido[5,4-c]quino-
line-2,5-(1H,3H)-dione (6b). M.p. 258–260°C; IR (KBr): νmax
=
3350, 3220, 1670, 1655 cmÀ1 1H NMR (200 MHz, DMSO-d6)
;
δ = 12.45 (br, s, 1H, NH), 11.61 (s, 1H, NH), 8.34–6.60 (m, 12H,
Ar–H), 5.16 (s, 1H, Aliph.-CH); 13C NMR, δ = 171.4, 154.8, 140.9,
113.4, 59.2 (C5, C2, pyrimidine-C6, C4a, C4), 138.7, 137.7, 136.5,
135.6, 135.0, 132.0, 131.9, 130.0, 129.1, 128.2, 125.5, 124.7,
116.4, 114.5 (14 Ar–C); MS-EI (rel. inten., %) m/z =403 (M++2,
32), 401(M+, 48), 372 (19), 358 (100), 318 (11), 305 (35), 290 (44),
264 (32), 196 (28), 167 (24), 139 (10), 92 (11); Anal. Calcd for
C23H16ClN3O2 (401.84): C, 68.68; H, 3.98; N, 10.45; found: C,
68.83; H, 4.01; N, 10.44.
4-(4-Nitrophenyl)-6-phenyl-2-thioxo-2,3,4,6-tetrahydropyrimido
[5,4-c]quinolin-5(1H)-one (7d). M.p. 260–262°C; IR (KBr): νmax
=
3300, 3210, 1677, 1660, 1208 cmÀ1; 1H NMR (200 MHz, DMSO-d6)
δ = 12, 48 (br, s, 1H, NH), 11.39 (br, s, 1H, NH), 8.18–6.61 (m, 12H,
Ar–H), 5.63 (s, 1H, Aliph.-CH); 13C NMR, δ = 181.0, 167.3, 144.5,
139.0, 113.1, 65.8 (C2, C5, C-NO2, pyrimidine-C6, C4a, C4), 138.3,
138.0, 137.4, 136.0, 134.2, 131.5, 130.5, 129.8, 129.0, 128.8, 126.6,
122.0, 115.3 (13 Ar–C); MS-EI (rel. inten., %) m/z =428 (M+, 100),
317 (19), 277 (14), 183 (12), 155 (27), 145 (32), 131 (13), 119 (27),
109 (34), 105 (72); Anal. Calcd for C23H16N4O3S (428.46): C, 64.41;
H, 3.73; N, 13.07; found C, 64.44; H, 3.77; N, 13.07.
4-(4-Methoxyphenyl)-6-phenyl-4,6-dihydropyrimido[5,4-c]quin-
oline-2,5(1H,3H)-dione (6c). M.p. 250–252°C; IR (KBr): νmax
=
3398, 3208, 1670, 1650 cmÀ1; H NMR (300 MHz, DMSO-d6)
δ = 10.98 (br, s, 1H, NH), 10.11 (s, 1H, NH), 8.21–6.55 (m, 12H,
Ar–H), 4.52 (s, 1H, Aliph.-CH); 4.09 (OCH3); 13C NMR,
δ = 168.7, 166.5, 155.6, 141.0, 113.1, 56.2, 54.9 (C5, C-OMe, C2,
pyrimidine-C6, C4a, OMe, C4), 138.4, 136.8, 136.0, 135.2, 134.1,
132.2, 130.8, 129.7, 128.0, 126.4, 124.9, 123.5, 115.4 (13 Ar–C);
Anal. Calcd for C24H19N3O3 (397.43): C, 72.46; H, 4.82; N,
10.75; found: C, 72.17; H, 4.52; N, 11.00.
1
Synthesis of 9-aryl-11-phenyl-4,11-dihydro-1,2,4-triazolo[5′,1′:1,2]-
pyrimido[5,4-c]quinolin-10(9H)-ones (10a–d) and 13-aryl-11-phenyl-
6,13-dihydrobenzimidazo[1′,2′:1,2]-pyrimido[5,4-c]quinoline-12(11H)
ones (11a–d)
Method A: General procedure (conventional heating). A solution
of aldehydes 4a–d (0.001 mol), 4-hydroxy-1-phenylquinolin-2(1H)-
one (3) (0.01 mol), and 5-amino-1H-1,2,4-triazole (8) or 2-amine-1H-
benzimidazol (9) (0.01 mol) in DMF (30 mL) was refluxed for the
4-(4-Nitrophenyl)-6-phenyl-4,6-dihydropyrimido[5,4-c]quinoline-
2,5(1H,3H)-dione (6d). M.p. 265°C; IR (KBr): νmax = 3383, 3223,
1
1660, 1650 cmÀ1; H NMR (200 MHz, DMSO-d6) δ = 12.41 (br, s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
4-Hydroxy-1-phenylquinolin-2(1H)-one in One-pot Synthesis of Pyrimidoquinolines
387
and Related Compounds under Microwave Irradiation and Conventional Conditions
time indicated in Table 1. On completion of the reaction (TLC
monitoring), the reaction mixture was allowed to cool to room
temperature. The solid precipitate was collected by filtration, dried,
and recrystallized from 1,4-dioxane to afford the pure product.
137.0, 134.5, 134.0, 133.4, 131.7, 131.0, 130.2, 129.0, 128.1, 127.6,
127.0, 126.0, 124.5, 123.3, 121.5, 120.0, 119.4, 117.8 (20 Ar–C, C6a);
Anal. Calcd for C29H20N4O (440.50): C, 79.11; H, 4.39; N, 13.05; found:
C, 79.16; H, 4.46; N, 13.01.
Method B: General procedure (microwave heating).
A
13-(4-Chlorophenyl)-11-phenyl-6,13-dihydrobenzimidazo[1′,2′:1,2]-
pyrimido[5,4-c]-quinoline-12(11H)-one (11b). M.p. 330–333°C; IR
mixture of aldehydes 4a–d (0.01 mol), 4-hydroxy-1-phenylquinolin-
2(1H)-one (3) (0.24 g, 0.001 mol) and 5-amino-1H-1,2,3-triazole (8)
or 2-amine-1H-benzimidazol (9) (0.001 mol) was mixed in 4 mL
DMF. The reaction mixture was irradiated in an MW oven for 3–
5 min. as indicated in Table 1. On cooling at room temperature, the
precipitated products were filtered and recrystallized from 1,4-dioxane.
11,9-Diphenyl-4,11-dihydro-1,2,3-triazolo[5′,1′:1,2]pyrimido[5,4-c]
quinoline-10(9H)one (10a). M.p. 202–203°C; IR (KBr): νmax = 3334,
1670, cmÀ1; 1H NMR (200 MHz, DMSO-d6) δ = 12.88 (s, 1H, NH),
9.05 (s, 1H, triazole-CH, 7.89–6.43 (m, 14H, Ar–H), 5.17 (s, 1H,
Aliph.-CH); 13C NMR, δ = 189.6, 160.8, 149.2, 144.5, 114.4, 71.9
(C10, C3a, C2, C4a, C10a, CH11), 139.8, 134.9, 128.9, 128.1, 127.6,
126.0, 133.2, 125.9, 125.0, 124.3, 123.0, 122.0, 117.2, 116.7 (14 Ar–
C); MS-EI (rel. inten., %) m/z =391 (M+, 100), 371 (41), 312 (38),
266 (53), 231 (24), 209 (44), 188 (18), 155 (67), 140 (22), 106 (31),
88 (19); Anal. Calcd for C24H17N5O (391.43): C, 73.57; H, 4.59; N,
17.83; found: C, 73.64; H, 4.38; N, 17.89.
1
(KBr): νmax = 3380, 1680, cmÀ1; H NMR (200 MHz, DMSO-d6)
δ = 11.33 (br, s, 1H, NH), 8.69–6.78 (m, 17H, Ar–H), 5.31 (s, 1H,
Aliph.-CH); 13C NMR, δ = 168.8, 162.3, 111.9, 65.8 (C12, C5a,
C12a, C13), 140.8, 140.0, 139.5, 139.0, 137.1, 136.2, 134.8, 132.0,
130.4, 129.5, 129.0, 128.4, 128.0, 127.2, 126.3, 125.0, 124.4,
120.0, 119.3, 117.5, 116.0 (21 Ar–C); MS-EI (rel. inten., %)
m/z = 477 (M++2, 21), 475 (M+, 67), 409 (31), 377 (100), 345
(39), 281 (18), 256 (30), 221 (35), 189 (19), 166 (40), 130 (14),
104 (21), 92 (9); Anal. Calcd for C29H19ClN4O (474.95): C,
73.27; H, 4.03; N, 11.79; found: C, 73.42; H, 3.93; N, 11.55.
13-(4-Methoxyrophenyl)-11-phenyl-6,13-dihydrobenzimidazo
[1′,2′:1,2]-pyrimido[5,4-c]- quinoline-12(11H)one (11c). M.p.
328–330°C; IR (KBr):
ν ;
max = 3224, 1673 cmÀ1 1H NMR
(300 MHz, CDCl3) δ = 10.88 (br, s, 1H, NH), 8.29–6.74 (m, 17H,
Ar–H), 5.01 (s, 1H, Aliph.-CH), 4.1 (OCH3); 13C NMR, δ =167.7,
160.4, 157.9, 111.2, 64.3, 56.0 (C12, C5a, C-OMe, C12a, C13, OCH3),
141.0, 140.5, 139.7, 138.2, 136.9, 136.0, 134.o, 131.4, 130.0, 129.1,
128.8, 126.1, 125.0, 123.3, 121.0, 120.7, 119.2, 118.4, 117.6, 116.5
(19 Ar–C, C6a); MS-EI (rel. inten., %) m/z =471 (M+, 100), 410
(33), 290 (16), 262 (14), 250 (16), 237 (28), 220 (12), 196 (12), 180
(7), 168 (13), 92 (6); Anal. Calcd for C30H22N4O2 (471.54): C,
76.35,; H, 4.67; N, 11.88; found: C, 76.50; H, 4.69; N, 11.77.
11-(4-Chlorophenyl)-9-phenyl-4,11-dihydro-1,2,3-triazolo[5′,1′:1,2]-
pyrimido[5,4-c]quinoline-10(9H)one (10b). M.p. 214–216°C; IR (KBr):
ν
max = 3380, 1678, cmÀ1; 1H NMR (200 MHz, DMSO-d6) δ = 13.34 (s,
1H, NH), 9.19 (s, 1H, triazoile-CH), 8.72–6.46 (m, 13H, Ar–H), 5.42 (s,
1H, Aliph.-CH); 13C NMR, δ = 190.4, 160.7, 150.1, 144.6, 115.2, 74.4
(C10, C3a, C2, C4a, C10a, CH11), 142.1, 137.5, 137.0, 134.2, 133.5,
130.7, 129.4, 128.1, 127.6, 126.0, 124.8, 122.4, 118.7, 117.0 (14 Ar–
C); Anal. Calcd for C24H16ClN5O (425.88): C, 67.63; H, 3.76; N,
16.43; found C, 67.66; H, 3.74; N, 16.36.
13-(4-Nitrophenyl)-11-phenyl-6,13-dihydrobenzimidazo[1′,2′:1,2]-
pyrimido[5,4-c]-quinoline-12(11H)one (11d). M.p. 316–318°C; IR
(KBr): νmax = 3350, 1666, cmÀ1; 1H NMR (300 MHz, DMSO-d6)
δ = 11.49 (br, s, 1H, NH), 8.04–6.91 (m, 17H, Ar–H), 5.69 (s, 1H,
Aliph.-CH); 13C NMR, δ = 169.9, 161.7, 150.2, 112.3, 66.4 (C12, C5a,
C-NO2, C12a, C13), 142.8, 141.6, 140.2, 139.8, 138.5, 137.4, 137.0,
136.0, 135.1, 134.3, 132.0, 130.7, 130.0, 129.1, 125.5, 123.4, 121.0,
119.7, 117.8. 115.8 (20 Ar–C); MS-EI (rel. inten., %) m/z = 485 (M+,
100), 290 (33), 262 (20), 195 (34), 167 (32), 114 (7), 92 (9); Anal. Calcd
for C29H19N5O3 (485.50): C, 71.68; H, 3.91; N, 14.41; found: C, 71.77;
H, 4.01; N, 14.48.
11-(4-Methoxyphenyl)-9-phenyl-4,11-dihydro-1,2,3-triazolo[5′,1′:1,2]
pyrimido[5,4-c]quinoline-10(9H)one (10c). M.p. 209–210°C; IR (KBr):
1
ν
max = 3234, 1678, cmÀ1; H NMR (300 MHz, DMSO-d6) δ = 12.45
(br, s, 1H, NH), 9.17 (s, 1H, triazole-CH), 8.69–6.49 (m, 14H, Ar–H),
5.21 (s, 1H, Aliph.-CH), 3.88 (s, 3H, OCH3); 13C NMR, δ = 186.2,
160.1, 151.4, 142.9, 114.8, 73.8, 56.3 (C10, C3a, C2, C4a, C10a, CH11,
OMe), 140.8, 155.6, 133.0, 131.7, 130.6, 130.0, 129.1, 128.0, 126.8,
126.0, 125.0, 121.1, 117.2, 116.4 (14 Ar–C); MS-EI (rel. inten., %) m/
z= 421 (M+, 100), 364 (52), 258 (41), 309 (16), 235 (29), 219 (32), 193
(41), 178 (36), 163 (10), 149 (18), 134 (22), 128 (34), 113 (15), 107
(34), 95 (19); Anal. Calcd for C25H19N5O2 (422.46): C, 71.01; H, 4.50;
N, 16.57; found: C, 71.22; H, 4.49; N, 16.44.
Synthesis of 2-amino-4-aryl-phenyl-5-oxo-5,6-dihydro-2H-pyrano
[3,2-c]quinoline-3-carbo-nitriles (13a–d)
General procedure. A mixture of 4-hydroxy-1-phenylquinolin-
2(1H)-one (3, 0.001 mol), aryledine compounds, namely benzyli
denemalononitrile p-chlorobenzylidene malononitrile, p-hydroxyben
zylidene-malononitrile, and p-nitrobenzylidene malononitrile
(0.1 mol), in pyridine as solvent (10 mL) was refluxed for an
appropriate time. The reaction mixture was then poured into
crushed ice with stirring, filtered, and recrystallized from 1,4-
dioxane to afford pure product.
11-(4-Nitrophenyl)-9-phenyl-4,11-dihydro-1,2,3-triazolo[5′,1′:1,2]-
pyrimido[5,4-c]quinoline-10(9H)one (10d). M.p. 218–220°C; IR
(KBr): νmax = 3334, 1670, cmÀ1 1H NMR (200 MHz, DMSO-d6)
;
δ = 13.59 (br, s, 1H, NH), 9.22(s, 1H, triazole-CH), 8.11–6.55 (m,
14H, Ar–H), 5.78 (s, 1H, Aliph.-CH); 13C NMR, δ = 192.2, 161.8,
152.0, 145.3, 115.0, 75.4 (C10, C3a, C2, C4a, C10a, CH11), 143.5,
142.6, 134.2, 133.0, 132.2, 131.0, 130.5, 129.5, 127.3, 126.0, 125.4,
123.0, 118.9, 116.6 (14 Ar–C); MS-EI (rel. inten., %) m/z =463 (M+,
100), 435 (33), 402 (19), 399 (30), 311 (52), 281 (66), 251 (18), 204
(34), 176 (70), 144 (35), 121 (11), 106 (19), 87 (55); Anal. Calcd for
C24H16N6O3 (436.43): C, 65.99; H, 3.66; N, 19.25; found: C,
65.77 H; 3.67 N; 19.21.
2-Amino-4,6-diphenyl-5-oxo-5,6-dihydro-2H-pyrano[3,2-c]quino-
line-3-carbonitrile (13a). Yield 65%; M.P. 350–353°C; IR (KBr):
ν
max = 3340, 3320, 2210, 1675 cmÀ1 1H NMR (200 MHz,
;
DMSO-d6) δ =8.10–6.44 (m, 14H, ArH), 5.41 (s, 1H, Aliph.-CH),
3.31 (s, 2H, NH2); 13C NMR, δ = 171.5, 149.9, 148.8, 109.1, 76.9
(C5, quinolone-C–O, C4, C4a, C2), 140.5, 137.9, 137.0, 135.1, 130.0,
129.2, 127.5, 127.0, 126.5, 126.2, 125.7, 122.o, 120.4, 117.4, 116.8,
114.7 (14 Ar–C, CN, C3); MS-EI (rel. inten., %) m/z = 391 (M+, 46),
376 (19), 334 (100), 275 (51), 243 (31), 202 (19), 156 (71), 131 (41),
106 (31), 88 (11); Anal. Calcd for C25H17N3O2 (391.44): C, 76.64;
H, 4.34; N, 10.73; found: C, 76.60; H, 4.58; N, 10.59.
11,13-Diphenyl-6,13-dihydrobenzimidazo[1′,2′:1,2]-pyrimido[5,4-c]-
quinoline-12(11H)one (11a). M.p. 318–320°C; IR (KBr): νmax = 3330,
1676, cmÀ1; 1H NMR (200 MHz, DMSO-d6) δ = 10.90 (br, s, 1H, NH),
8.14–6.53 (m, 18H, Ar–H), 5.31 (s, 1H, Aliph.-CH); 13C NMR,
δ = 168.5, 161.5, 110.8, 65.7 (C12, C5a, C12a, C13), 141.9, 141.0, 139.5,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

388
A.-F. E. Mourad, A. A. Amer, K. M. El-Shaieb, A. M. Ali, and A. A. Aly
Vol 53
Acknowledgments. The authors are thankful to Prof. H. Hopf,
Institute of Organic Chemistry, Braunschweig University,
Germany for measurements of NMR and MS spectra.
2-Amino-4-(4-chlorophenyl)-5-oxo-6-phenyl-5,6-dihydro-2H-
pyrano[3,2-c]quinoline-3-carbonitrile (13b). Yield 55%; M.P.
355–357°C; IR (KBr): νmax = 3300, 3265, 2196, 1670cmÀ1; H
NMR (200 MHz, DMSO-d6) δ = 8.22–6.68 (m, 13H, ArH), 5.73
(s, 1H, Aliph.-CH), 3.42 (s, 2H, NH2); 13C NMR, δ = 171.9,
149.5, 148.2, 110.5, 75.8 (C5, quinolone-C–O, C4, C4a, C2),
142.2, 138.1, 137.3, 134.8, 130.4, 130.0, 127.8, 127.0, 126.8,
126.0, 125.2, 123.1, 121.5, 116.8, 117.2, 115.0 (14 Ar–C, CN,
C3); MS-EI (rel. Inten., %) m/z = 427 (M++2, 22), 425 (M+, 43),
403 (22), 401 (43), 358 (100), 318 (12), 305 (24), 290 (42), 264
(44), 196 (28), 167 (55), 111 (25), 97 (33); Anal. Calcd for
C25H16ClN3O2 (425.88): C, 70.44; H, 3.75; N, 9.86; found: C,
70.65; H, 3.58; N, 10.21.
1
REFERENCES AND NOTES
[1] Biginelli, P. Gazz Chim Ital 1893, 23, 360.
[2] Kappe, C. O.; Fabian, W. M. F. Tetrahedron 1997, 53, 2803.
[3] Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.;
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dron 2000, 56, 1859.
[8] (a) Kappe, C. O.; Falsone, S. F. Synlett 1998, 718; (b)
Ranu, B. C.; Hajra, A.; Jana, U. J Org Chem 2000, 65, 6270; (c)
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Tetrahedron Lett 1999, 40, 3465.
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63, 3454; (b) Yadav, J. S.; Subba, B. V.; Reddy, K. B. J Chem Soc, Perkin
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Chem 2000, 65, 3864.
[10] (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, A. J.; Brosse, C. D.; Mai, S.; Truneh, A.; Faulkner, D. J.;
Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.;
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In Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Weinheim, 2005.
[11] Kappe, C. O. Angew Chem Int Ed 2004, 43, 6250.
[12] (a) Kidwai, M.; Saxena, S.; Mohan, R. J Chem Soc, Perkin Trans
2002, 1, 1845; (b) Mirza-Aghayan, M.; Bolourtchian, M.; Hosseini, M. Synth
Commun 2004, 34, 3335; (c) Wang, X.; Quan, Z.; Wang, F.; Wang, X.;
Zang, Z.; Li, Z. Synth Commun 2006, 36, 451.
[13] Kappe, C. O. Acc Chem Res 2000, 33, 879.
[14] Dallinger, D.; Stadler, A.; Kappe, C. O. Pure Appl Chem 2004,
76, 1017.
2-Amino-4-(4-hydroxyphenyl)-5-oxo-6-phenyl-5,6-dihydro-2H-
pyrano[3,2-c]quinoline-3-carbonitrile (13c).
Yield 71%; M.P.
320–322°C; IR (KBr): νmax = 3445, 3260, 2220, 1680cmÀ1
;
1H
NMR (300 MHz, DMSO-d6) δ = 13.31 (br, s, 1H, OH), 8.33–6.70
(m, 13H, ArH), 5.69 (s, 1H, Aliph.-CH), 3.44 (br. s, 2H, NH2);
13C NMR, δ = 173.0, 150.8, 150.2, 149.6, 113.2, 78.2 (C5, C–OH,
quinolone-C–O, C4, C4a, C2), 143.0, 139.7, 138.2, 135.0, 131.1,
130.0, 128.4, 127.6, 127.1, 126.2, 123.0, 122.2, 117.9, 116.5,
114.7 (14 Ar–C, CN, C3); Anal. Calcd for C25H17N3O3 (407.44):
C, 73.63; H, 4.17; N, 10.30; found: C, 73.71; H, 4.11; N, 10.48.
2-Amino-4-(4-nitrophenyl)-5-oxo-6-phenyl-5,6-dihydro-2H-
pyrano[3,2-c]quinoline-3-carbonitrile (13d).
Yield 63%; M.P.
340–343°C; IR (KBr): νmax = 3398, 3358, 3270, 1670cmÀ1; H
NMR (300 MHz, DMSO-d6) δ = 7.98–6.62 (m, 13H, ArH), 5.64
(s, 1H, Aliph.-CH), 3.41 (br. S, 2H, NH2); 13C NMR, δ = 170.2,
159.9, 148.9, 147.6, 110.0, 75.9, 56.3 (C5, C-OMe, quinolone-C–
O, C4, C4a, C2, OCH3), 140.7, 137.7, 137.1, 134.6, 132.0, 130.4,
129.1, 127.2, 125.9, 123.4, 122.0, 116.7, 115.0, 113.8, 113.0 (13
Ar–C, CN, C3); MS-EI (rel. inten., %) m/z = 436 (M+, 51), 388
(23), 339 (46), 317 (100), 291 (35), 260 (19), 231 (25), 208 (18),
178 (33), 151 (21), 131 (13), 106 (17), 81 (41); Anal. Calcd for
C25H16N4O4 (436.43): C, 68.74; H, 3.66; N, 12.83; found C,
68.66; H, 3.38; N, 12.49.
1
[15] Chung, H. S.; Woo, W. S. J Nat Prod 2001, 64, 1579.
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[17] He, J.; Lion, U.; Sattler, I.; Gollmick, F. A.; Grabley, S.; Cai, J.;
Meiners, M.; Schunke, H.; Schaumann, K.; Dechert, U.; Krohn, M. J Nat
Prod 2005, 68, 1397.
Synthesis of spiro compound 15. A mixture of 4-hydroxy-
1-phenylquinolin-2-(1H)-one (3, 0.237 g, 0.001 mmol) and 2-
oxo-1,2-dihydro-3H-indol-3-ylidene)malononitrile (14, 0.195 g,
0.001 mol) in 1,4-dioxane (30 mL) was heated under reflux in
the presence of few drops of piperidine for 1 h. On completion
of reaction (TLC monitoring), the reaction mixture was allowed
to cool to room temperature. The solid precipitate was collected
by filtration, dried, and recrystallized from 1,4-dioxane to afford
the spiro compound 15.
[18] Beier, N.; Labitzke, E.; Mederski, W.W. K. R.; Radunz, H.-E.;
Schneider, B. Heterocycles 1994, 39, 117.
[19] Hicks, C. A.; Ward, M. A.; Ragumoorthy, N.; Ambler, S. J.;
Dell, C. P.; Dobson, D.; O’Neill, M. J Brain Res 1999, 65, 819.
[20] Mederski, W. W. K. R.; Osswald, M.; Dorsch, D.;
Christadler, M.; Schmitges, C. J.; Wilm, C. Bioorg Med Chem Lett
1997, 7, 1883.
[21] Chen, K.; Kuo, S. C.; Hsieh, M. C.; Mauger, A.; Lin, C. M.;
Hamel, E.; Lee, K. H. J Med Chem 1997, 40, 2266.
[22] Huang, L. J.; Hsieh, M. C.; Teng, C. M.; Lee, K. H.; Kuo, S. C.
Bioorg Med Chem 1998, 6, 1657.
[23] Mourad, A. E.; Aly, A. A.; Farag, H. H.; Radwan, M. F.;
Beshr, E. A. Beilstein J Org Chem 2007, 3, 11.
[24] Hassan, A. A.; Mourad, A. E.; El-Shaieb, K. M.; Abou-Zied,
A. H.; Doepp, D. Heteroatom Chem 2003, 14, 535.
[25] Roschger, P.; Fiala, W.; Stdlbauer, W. J Heterocycl Chem
1992, 29, 225.
Yield, 42%, m.p. 328°C; IR (KBr): νmax = 3420, 3320, 2210,
1
1670, 1660 cmÀ1; H NMR (300 MHz, CDCl3) δ = 11.22 (br, s,
1H, NH), 8.41–6.75 (m, 13H, ArH), 3.82 (br, s, 2H, NH2); 13C
NMR, δ = 170.2 (quinolone-CO), 162.3 indolone-CO), 158.0
(C–NH2), 146.8 (pyrano-C–CO), 110.3 (quinolone-C–CO), 80.2
(C–CN), 77.8 (spiro-C), 141.9, 140.0, 138.6, 135.2, 133.0, 128.7,
128.4, 128.0, 127.3, 126.4, 124.8, 123.7, 122.0, 120.8, 117.3, 114.5,
114.0 (16 Ar–C, CN); MS-EI (rel. inten., %) m/z =432 (M+, 19),
381 (18), 338 (11), 327 (100), 305 (38), 277 (78), 221 (44), 195
(14), 167 (22), 129 (34), 93 (39); Anal. Calcd for C26H16N4O3
(432.44): C, 72.22; H, 3.70; N, 12.96; found: C, 72.56; H, 3.68; N,
13.10,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet