Synthesis and Characterization of New Heterocyclic Compounds Containing Thienylbenzo[h]Quinoline Moiety

Article abstract of DOI:10.1002/jhet.2451

In this paper the reaction of 2-(2′-thienylmethylene)-3,4-dihydronaphthalen-2(1H)-one (1) with cyanothioacetamide gave a mixture of 3-cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2(1H)-thione (2) and the related disulfide 3. Compound 2 was reacted with some halo compounds namely; ethyl chloroacetate, chloroacetamide, chloro(N-(p-chlorophenyl))acetamide, N¹-chloroacetylsulfanilamide, and 2-chloromethyl-1H-benzimidazole to produce a series of 2-(substituted)methylthio-3-cyano-5,6-dihydro-4-(2′-thienyl)benzo[h]quinolines 4a, 4b, 4c, 4d, 4e and 11. Upon heating the latter compounds with sodium ethoxide, they underwent intramolecular Thorpe–Zeigler cyclization to furnish the corresponding 2-(substituted)-3-amino-5,6-dihydro-4-(2′-thienyl)-benzo[h]thieno[2,3-b]quinolines 5a, 5b, 5c, 5d, 5e and 12. (3-Cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2-ylthio)acethydrazide (8) and the related isomer, 3-amino-5,6-dihydro-4-(2′-thienyl)thieno[2,3-b]benzo[h]quinoline-2-carbohydrazide (9), were also synthesized. Most of the aforementioned compounds were used as key intermediates for synthesizing other benzo[h]quinolines, benzo[h]thieno[2,3-b]quinolines as well as benzo[h]pyrimido[4′,5′:4,5] thieno[2,3-b]quinolines. The structure of all synthesized compounds was confirmed by spectroscopic measurements and analytical analyses.

Full text of DOI:10.1002/jhet.2451

Month 2015
Synthesis and Characterization of New Heterocyclic Compounds
Containing Thienylbenzo[h]Quinoline Moiety
a
b
b
*
Elham A. Al-Taifi, Mohamed S. Abbady, and Etify A. Bakhite
aDepatment of Chemistry, Faculty of Science, Sana’a Unversity, Sana’a, Yemen
bDepatment of Chemistry, Faculty of Science, Assiut Unversity, Assiut 71516, Egypt
*
E-mail: ebakhite@yahoo.com
Received October 17, 2014
DOI 10.1002/jhet.2451
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
In this paper the reaction of 2-(2′-thienylmethylene)-3,4-dihydronaphthalen-2(1H)-one (1) with
cyanothioacetamide gave
a mixture of 3-cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2(1H)-
thione (2) and the related disulfide 3. Compound 2 was reacted with some halo compounds namely;
ethyl chloroacetate, chloroacetamide, chloro(N-(p-chlorophenyl))acetamide, N1-chloroacetylsulfanilamide,
and 2-chloromethyl-1H-benzimidazole to produce a series of 2-(substituted)methylthio-3-cyano-5,6-dihydro-
4-(2′-thienyl)benzo[h]quinolines 4a–e and 11. Upon heating the latter compounds with sodium ethoxide, they
underwent intramolecular Thorpe–Zeigler cyclization to furnish the corresponding 2-(substituted)-3-amino-
5,6-dihydro-4-(2′-thienyl)-benzo[h]thieno[2,3-b]quinolines 5a–e and 12. (3-Cyano-5,6-dihydro-4-(2′-thienyl)-
benzo[h]quinolin-2-ylthio)acethydrazide (8) and the related isomer, 3-amino-5,6-dihydro-4-(2′-thienyl)thieno
[2,3-b]benzo[h]quinoline-2-carbohydrazide (9), were also synthesized. Most of the aforementioned compounds
were used as key intermediates for synthesizing other benzo[h]quinolines, benzo[h]thieno[2,3-b]quinolines as
well as benzo[h]pyrimido[4′,5′:4,5] thieno[2,3-b]quinolines. The structure of all synthesized compounds was
confirmed by spectroscopic measurements and analytical analyses.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
pyridothienopyrimidines [22–24], we report herein the syn-
thesis and characterization of the title compounds.
Thiophene moiety is present in a large number of bioac-
tive molecules having diverse biological activities such as
anti-inflammatory [1], anticonvulsant [2], antibacterial [3],
and antitumor activities [4]. Moreover, thiophene moiety
is a well known as isostere for benzene; for example, the re-
placement of benzene ring of the antidepressant drug,
Viloxazine (I, Fig. 1), by thiophene one led to a prolonga-
tion of half-life [5]. Also, the quinoline ring system is well
known as an important structural unit widely existing in al-
kaloids, therapeutics, and synthetic analogues with interest-
ing biological activities [6–8]. A large variety of quinoline
derivatives have been used as antimalarial, anti-inflammatory,
antiasthmatic, antibacterial, antihypertensive, and platelet-
derived growth factor receptor tyrosine kinase (PDGF-RTK)
inhibiting agents [9–11]. Fused pyrimidine derivatives have
been the subject of several chemical and biological studies
on account of their wide spectrum of biological activity,
particularly in cancer and virus research [12,13]. Among these
heterocycles, the thienopyrimidine class is also of interest be-
cause some derivatives, such as Tiprinsat (II, Fig. 1), have
been shown to be clinically effective antiallergics [14]. In ad-
dition, antianaphylatic [15,16], anti-inflammatory [17,18], an-
algesic and antipyretic [19,20], and antineoplastic activities
[21] have been described for these compounds. In view of
the above observations and as a continuation of our earlier
work on the synthesis of thieno[2,3-b]pyridines and
RESULTS AND DISCUSSION
The condensation of ∞-tetralone with thiophene-2-
carboxaldehyde produced a good yield of 2-(2′-thienyl-
methylene)-3,4-dihydronaphthalen-2(1H)-one (1). The re-
action of 1 with cyanothioacetamide, in the presence of
triethylamine as a basic catalyst, was carried out, and its
product was assigned as a mixture of 3-cyano-5,6-
dihydro-4-(2′-thienyl)-benzo[h]quinolin-2(1H)-thione (2)
and the related disulfide 3 (Scheme 1).
The pathway of the latter reaction was depicted in
Scheme 2. Thus, it involves initial formation of Michael
addition product A which underwent enolization, dehydra-
tion followed by spontaneous dehydrogenation to give
compound 2. The disulfide 3 may be produced by aerobi-
cally oxidation of the thiol 2.
3-Cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2
(1H)-thione (2) was used as a starting material in this
investigation. Thus, its reaction with some halo compounds
namely, ethyl chloroacetate, chloroacetamide, chloro(N-(p-
chlorophenyl))acetamide, N1-chloroacetylsulfanil-amide,
and 2-chloromethyl-1H-benzimidazole gave the corre-
sponding 2-(substituted)methylthio-3-cyano-5,6-dihydro-
4-(2′-thienyl)-benzo[h]quinolines 4a–e in high yields.
© 2015 HeteroCorporation

E. A. Al-Taifi, M. S. Abbady, and E. A. Bakhite
Vol 000
the 3-amino-5,6-dihydro-4-(2′-thienyl)-benzo[h]thieno [2,
3-b]quinoline-2-carbohydrazide (9) was obtained. Reaction
of acid hydrazide 8 with phenyl iso-thiocyanate by refluxing
in ethanol gave the thiosemicarbazide derivative 10 in excel-
lent yield. Condensation of 8 with p-anisaldehyde led to the
formation of arylidene derivative 11 which was readily
cyclized into benzo[h]thieno[2,3-b]quinoline 12 by heating
in ehanolic sodium ethoxide. The latter compound (12)
was also obtained via direct condensation of the carbo-
hydrazide 9 with equimolar quantity of p-anisaldehyde in
boiling ethanol. Cyclocondensation of compound 12 into
benzopyrimidothienoquinoline 13 was achieved by heating
with triethyl orthoformate in the presence of acetic anhydride
(Scheme 4).
The o-aminocarbohydrazide 9 was also served as a facile
point to departure to other benzopyrimidothienoquinoline de-
rivatives. Thus, its condensation with formic acid at reflux tem-
perature produced the 3-formylaminopyrimidinone derivative
14. In the same manner, refluxing of compound 9 in glacial
acetic acid for long time furnished the monoacetyl derivative
Figure 1. The chemical structure of Viloxazine (I) and Tiprinast (II).
Upon heating the latter compounds (4a–e) with sodium
ethoxide in ethanol, they underwent intramolecular
Thorpe-Ziegler cyclization giving the related functionally
substituted 3-aminothieno[2,3-b]benzo[h]quinolines 5a–e.
The reactivity of compounds 5b,c or 5e was checked via
their reaction with triethyl orthoformate wherein the
benzopyrimidothienoquinoline 6b,c and benzopyridothien
opyrimidobenzimidazole 7 were obtained (Scheme 3).
Refluxing of the ester 4a with hydrazine hydrate in eth-
anol led to the formation of (3-cyano-5,6-dihydro-4-(2′-
thienyl)-benzo[h]quinolin-2-ylthio)acethydrazide (8). When
the above reaction was carried out under neat conditions,
Scheme 1. Synthesis of compounds 2 and 3.
Scheme 2. The pathway of the formation of compounds 2 and 3.
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Synthesis of New Heterocyclobenzo[h]Quinolines
Scheme 3. Synthesis of compounds 4a–e, 5a–e, 6b,c, and 7.
Scheme 4. Synthesis of compounds 8–13.
15. The related biacetylaminopyrimidinone 16 was prepared by
reaction of 9 or 15 with acetic anhydride at boiling temperature.
Heating compound 9 with triethyl orthoformate in DMF led to
the formation of 10-ethoxymethyleneamino-11-oxo-5,6,10,11-
tetrahydro-7-(2′-thienyl)-benzo[h ]pyrimid [4′,5′:4,5]thieno
[2,3-b] quinoline (17) (Scheme 5).
Heating o-aminocarboxamide 5b with acetic anhydride led
to the formation of 9-metylpyrimidothienobenzoquinoline 18.
Reaction of 5b with phenyl isothiocyanate by heating in
pyridine produced the thione derivative 19 which underwent
S-ethylation upon treatment with ethyl iodide in ethanolic so-
dium hydroxide solution producing the compound 20.
Journal of Heterocyclic Chemistry
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E. A. Al-Taifi, M. S. Abbady, and E. A. Bakhite
Vol 000
Scheme 5. Synthesis of compounds 14–17.
Scheme 6. Synthesis of compounds 18–21.
Condensation of compound 5b with p-anisaldehyde in ethanol
containing drops of concentrated HCl furnished 5,6,8,9,10,11-
hexahydro-9-(p-methoxyphenyl)-11-oxo-7-(2′-thienyl)-
benzo[h]pyrimido[4′,5′:4,5] thieno[2,3-b]quinoline (21)
in excellent yield (Scheme 6).
3-amino-4-(2′-thienyl)-benzo[h]thieno[2,3-b]quinolines 5a–e,
9, and 12 in good yields. Also, we used o-aminocarboxamides
5b,c,e and o-aminocarbohydrazide 9 and as precursors for
synthesizing novel benzo[h]pyrimido[4′,5′:4,5]thieno[2,3-b]
quinolines 6b,c, 7, and 13–21.
The structural formulas of all compounds prepared were
confirmed by elemental and spectral analyses (Experimen-
tal section).
EXPERIMENTAL
Melting points were measured with Gallan-Kamp
melting-point apparatus and are uncorrected. IR spectra
were recorded on a Shimadzu 470 IR-spectrophotometer
CONCLUSION
1
In the present study we have successfully synthesized a
series of 2-substituted methylthio-4-(2′-thienyl)-benzo[h]
quinolines 4a–e, 8, and 11, and the related 2-substituted
(KBr; νmax in cm-1). H-NMR spectra were taken on a
Varian EM-390, 90-MHz spectrometer using TMS as in-
ternal standard. Chemical shifts are given in δ, ppm and
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Synthesis of New Heterocyclobenzo[h]Quinolines
coupling constant (J) are given in Hz. Mass spectra were
recorded on a JEOL JMS-600 spectrometer. Elemental
analyses (C, H, N, and S) were performed on an Elemental
Analyses system GmbH VARIO EL V2.3 1998 CHNS
Mode. The reactions were monitored by TLC. ∞-Tetralone,
thiophene-2-carboxaldehyde, and cyanothioacetamide
were purchased from Sigma Chemicals Co.
2-(2′-Thienylmethylene)-3,4-dihydronaphthalene-2(1H)-one
(1). To a mixture of ∞-tetralone (2.66mL, 20mmol) and
thiophene-2-carboxaldehyde (1.9mL, 20mmol) in ethanol
(25mL), 0.5mL of aqueous NaOH 10% was added. The
reaction mixture was stirred at room temperature for 3h
whereby a precipitate formed. It was collected and
recrystallized from aqueous ethanol as pale yellow crystals
of 1, yield: 4.22g (88%); m.p.: 92–93°C. IR: 1680 (C¼O).
1H NMR (CDCl3): δ 8.4 (d, J=9Hz, 1H, thienyl-H), 7.0–
7.7 (m, 7H: two thienyl–H, CH¼C and Ar-H’s), 2.8–3.0
(m, 4H, CH2―CH2). EI-MS: m/z (fragment, %)=241
(M++1, 23); 240 (M+, 100); 239 (M+ꢀ1, 44); 212 (M-CO,
33). Anal. Calcd. for C15H12OS (240.32): C, 74.97; H,
heated under reflux for 1 h. The precipitate that formed on
cooling was collected and recrystallized from the proper
solvent.
Ethyl (3-cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2-
ylthio)acetate (4a). Obtained by using ethyl chloroacetate in
the above general procedure as colorless needles (EtOH),
yield: 1.62g (80%); m.p.: 180–181°C. IR: 2219 (C≡N);
1
1724 (C¼O). H NMR (CDCl3): δ 8.4 (d, J=8.5Hz, 1H,
thienyl–H), 7.1–7.7 (m, 6H: two thienyl–H and Ar-H’s), 4.4
(s, 2H, SCH2), 4.0–4.3 (q, J=9, 2H, OCH2), 2.7–2.9 (m,
4H, CH2―CH2), 0.9–1.1 (t, J=9Hz, 3H, CH3). EI-MS: m/z
(fragment, %)=406 (M+, 24); 361 (M+-OC2H5, 100). Anal.
Calcd. for C22H18N2O2S2 (406.52): C, 65.00; H, 4.46; N,
6.89; S, 15.77%. Found: C, 65.23; H, 4.44; N, 6.90; S,
15.92%.
(3-Cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2-
ylthio)acetamide (4b). Obtained by using chloroacetamide
in the above general procedure as buff crystals (EtOH),
yield: 1.6g, (85%); m.p.: 220–222°C. IR: 3446, 3250
1
(NH2), 2220 (C≡N), 1686 (C¼O). H NMR (CDCl3): δ
8.2 (d, J=9Hz, 1H, thienyl–H), 7.1–7.7 (m, 6H: two
thienyl–H and Ar-H′s), 6.7 (br. s, 2H, CONH2), 4.0 (s,
2H, SCH2), 2.6–2.8 (m, 4H, CH2—CH2). Anal. Calcd.
for C20H15N3OS2 (377.48): C, 63.64; H, 4.01; N, 11.13;
S, 16.99%. Found: C, 63.33; H, 4.07; N, 10.90; S,
5.03; S, 13.34%. Found: C, 74.70; H, 5.12; S, 13.00%.
General procedure for the reaction of compound 1 with
cyanothioacetamide; synthesis of compounds 2 and 3.
To a
mixture of chalcone 1 (4.48 g, 20mol) and cyanothioacetamide
(2.0 g, 20 mmol) in ethanol (40 mL), 2.0 mL of triethylamine
was added. The resulting mixture was heated under reflux for
5h, acidified with acetic acid, and then allowed to cool. The
precipitated solid was collected by filtration and recrystallized
from ethanol as orange needles. It was identified as 3-cyano-
5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2(1H)-thione (2);
yield: 2.88 g (45%); m.p.: 238–239 °C. IR: 3200 (NH), 2217
16.72%.
3-Cyano-5,6-dihydro-2-(N-(p-chlorophenyl))carbamoylmethylthio-
4-(2′-thienyl)benzo[h] quinoline (4c). Obtained by using chloro(N-
(p-chlorophenyl))acetamide in the above general procedure
as buff needles (EtOH), yield: 2.22g (91%); m.p.: 224–
1
226°C. IR: 3272 (NH), 2207 (C≡N); 1659 (C¼O). H
NMR (DMSO-d6): δ 9.0 (s, 1H, NH), 8.4 (d, J=9, 1H,
thienyl–H), 7.1–7.8 (m, 10H: two thienyl–H and Ar-H’s),
4.2 (s, 2H, SCH2), 2.7–3.0 (m, 4H, CH2—CH2). Anal.
Calcd. for C26H18ClN3OS2 (488.02): C, 63.99; H, 3.72; N,
8.61; S, 13.14%. Found: C, 64.31; H, 3.87; N, 8.50; S,
1
(C≡N), 1604(C¼N). H NMR (DMSO-d6): δ 11.1(s, 1H,
NH), 8.2 (d, J= 9 Hz, 1H, thienyl–H), 7.7 (d, J=9 Hz, 1H,
thienyl–H), 7.0–7.4 (m, 5H: thienyl–H and Ar-H’s), 2.6–2.8
(m, 4H, CH2―CH2). EI-MS: m/z (fragment, %) = 320.4 (M+,
100%). Anal. Calcd. for C18H12N2S2 (320.4): C, 67.47; H,
3.77; N, 8.74; S, 20.01%. Found: C, 67.13; H, 3.82; N, 8.56;
S, 19.83%.
12.82%.
3-Cyano-5,6-dihydro-2-(N-(p-sulfonamidophenyl))carbamoyl
methylthio-4-(2′-thienyl)-benzo[h]quinoline (4d). Obtained by
using N1-chloroacetylsulfanilamide in the above general
procedure as beige needles (dioxane), yield: 2.36g (89%);
m.p.: 311–312°C. IR: 3337, 3250 (NH2, NH), 2215
(C≡N), 1667 (C¼O). 1290, 1145 (SO2) 1H NMR
(DMSO-d6): δ 9.3 (s, 1H, NH), 8.4 (d, J=9, 1H, thienyl–
H), 7.1–7.8 (m, 12H: SO2NH2, two thienyl–H and Ar-H’s),
4.1 (s, 2H, SCH2), 2.6–2.8 (m, 4H, CH2—CH2). Anal.
Calcd. for C26H20N4O3S3 (532.65): C, 58.63; H, 3.78; N,
10.52; S, 18.06%. Found: C, 58.42; H, 3.98; N, 10.50; S,
The mother liquor of the above crude product was di-
luted with water (30 mL) to give a pale buff precipitate
which on crystallization from aqueous ethanol was
assigned as di(3-cyano-5,6-dihydro-4-(2′-thienyl)-benzo
[h]quinolin-2-yl)disulfide (3); yield: 0.32g (5%), m.p.:
1
187–188°C. IR: 2220 (C ≡ N). H NMR (CDCl3): δ 8.3
(m, 2H: two thienyl–H), 7.1–7.8 (m, 12H: four thienyl–H
and Ar-H’s), 2.8–3.0 (m, 8H, two CH2―CH2). EI-MS:
m/z (fragment, %) = 639 (M+, 100%). Anal. Calcd. for
C36H22N4S4 (638.84): C, 67.68; H, 3.47; N, 8.77; S,
18.00%.
2-(1′H-Benzimidazol-2′-yl)methylthio-3-cyano-5,6-dihydro-4-
(2′-thienyl)-benzo[h] quinoline (4e). Obtained by using 2-
20.07%. Found: C, 67.46; H, 3.55; N, 8.62; S, 20.30%.
General procedure for the reaction of cyano-5,6-dihydro-4-
(2′-thienyl)-benzo[h]quinolin-2(1H)-thione (2) with halo
compounds; synthesis of compounds 4a–e. To a suspension of
compound 2 (1.6g, 5 mmol) and sodium acetate trihydrate
(07g, 5 mmol) in ethanol (30 mL), the appropriate halo
compound (5 mmol) was added. The resulting mixture was
chloromethyl-1H-benzimidazole in the above general
procedure as pale yellow needles (EtOH), yield: 1.8g
(80%); m.p.: 187–188°C. IR: 3200–3000 (NH), 2200
(C≡N). 1H NMR (DMSO-d6): δ 8.3 (d, J=9, 1H, thienyl–
H), 7.2–7.8 (m, 11H: two thienyl–H, NH and Ar-H’s), 4.8
(s, 2H, SCH2), 2.8–30 (m, 4H, CH2—CH2). Anal. Calcd.
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E. A. Al-Taifi, M. S. Abbady, and E. A. Bakhite
Vol 000
for C26H18N4S2 (450.58): C, 69.31; H, 4.03; N, 12.43; S,
(m, 4H, CH2—CH2). Anal. Calcd. for C26H18N4S2
14.23%. Found: C, 69.00; H, 4.05; N, 12.29; S, 14.50%.
General procedure for cyclization of compounds 4a-e;
synthesis of 2-Substituted 3-amino-5,6-dihydro-4-(2′-thienyl)-
(450.58): C, 69.31; H, 4.03; N, 12.43; S, 14.23%. Found:
C, 69.13; H, 3.92; N, 12.18; S, 14.39%.
General procedure for the reaction of compounds 5b,c, 5e,
and 12 with triethyl orthoformate; synthesis of compounds
6b,c, 7, and 13, respectively. A mixture of compound 5b,
5c, 5e, or 12 (5 mmol) and triethyl orthoformate (5 mL)
in acetic anhydride (10 mL) was heated under reflux for
4 h. The precipitate that formed while hot was collected
by filtration, washed with ethanol, and recrystallized
from acetic acid as pale yellow crystals of 6b,c, 7, or 13,
thieno[2,3-b]benzo[h]quinoline 5a–e.
A
suspension of
compound 4a–e (5mmol) in sodium ethoxide solution
(0.2g of sodium in 30mL absolute ethanol) was heated at
reflux for 5min. The product that formed after cooling was
collected and recrystallized from an ethanol–chloroform
mixture as canary yellow needles.
Ethyl 3-amino-5,6-dihydro-4-(2′-thienyl)-thieno[2,3-b]benzo
[h]quinoline-2-carboxylate (5a). Obtained by cyclization of
respectively.
4a, yield: 1.78g (88%); m.p.: 242–243°C. IR: 3477, 3349
4-Oxo-5,6,10,11-tetrahydro-7-(2′-thienyl)-pyrimido[4′,5′:4,5]th
ieno[2,3-b]benzo[h] quinoline (6b). Prepared from compound
1
(NH2), 1667 (C¼O). H NMR (CDCl3): δ 8.4 (d, J=9Hz,
1H, thienyl–H), 7.7 (d, J=9Hz, 1H, thienyl–H), 7.0–7.5
(m, 5H: thienyl–H and Ar-H’s), 5.7 (s, 2H, NH2); 4.1–4.5 (q,
J=9 Hz, 2H, OCH2); 2.6–2.9 (m, 4H, CH2—CH2), 1.2–1.5
(t, J=9Hz, 3H, CH3). EI-MS: m/z (fragment, %)= 406.09
(M+, 23); 335.03 (M+-CO2C2H5, 100). Anal. Calcd. for
C22H18N2O2S2 (406.52): C, 65.00; H, 4.46; N, 6.89; S,
5b, yield: 1.66g (86%); m.p.: >360°C. IR: 3200 (NH),
1655 (C¼O). 1H NMR (CF3CO2D): δ 8.6 (s, 1H,
pyrimidine–H), 8.4 (d, J=9Hz, 1H, thienyl–H), 7.1–7.8
(m, 6H: two thienyl–H and Ar-H’s), 2.8–3.0 (m, 4H, CH2
—CH2). EI-MS: m/z (fragment, %)=387.35 (M+, 22);
386.49 (M+-H, 100). Anal. Calcd. for C21H13N3OS2
(387.47): C, 65.10; H, 3.38; N, 10.84; S, 16.55%. Found:
C, 64.94; H, 3.28; N, 10.91; S, 16.40%.
10-(p-Chlorophenyl)-4-oxo-5,6,10,11-tetrahydro-7-(2′-thienyl)-
pyrimido[4′,5′:4,5]thieno [2,3-b]benzo[h]quinoline (6c). Prepared
from compound 5c, yield: 2.01g (81%); m.p.: 315–317°C.
IR: 1677 (C¼O). 1H NMR (CF3CO2D): δ 8.5 (s, 1H,
pyrimidine–H), 8.3 (d, J, 8.5Hz, 1H, thienyl–H), 7.1–8.0
(m, 10H: two thienyl–H and Ar-H’s), 2.7–2.9 (m, 4H,
CH2—CH2). Anal. Calcd. for C27H16ClN3OS2 (498.02):
C, 65.12; H, 3.24; N, 8.44; S, 12.88%. Found: C, 65.16;
15.77%. Found: C, 65.18; H, 4.51; N, 6.66; S, 16.02%.
3-Amino-5,6-dihydro-4-(2′-thienyl)-thieno[2,3-b]benzo[h]qui
noline-2-carboxamide (5b). Obtained by cyclization of 4b,
yield: 1.24g (79%); m.p.: 254–255°C. IR: 3475, 3326,
1
3126 (2NH2), 1646 (C¼O). H NMR (CDCl3): δ 8.3 (d,
J =8 Hz, 1H, thienyl–H), 7.1–7.7 (m, 8H: CONH2, two
thienyl–H and Ar-H’s), 5.7 (s, 2H, NH2), 2.6–2.8 (m, 4H,
CH2—CH2). Anal. Calcd. for C20H15N3OS2 (377.48): C,
63.64; H, 4.01; N, 11.13; S, 16.99%. Found: C, 63.90; H,
4.20; N, 11.17; S, 17.12%.
3-Amino-2-(N-(p-chlorophenyl))carbamoyl-5,6-dihydro-4-(2′-
thienyl)-thieno[2,3-b]benzo[h] quinoline (5c). Obtained by
H, 3.04; N, 8.36; S, 12.69%.
10,11-Dihydro-9-(2′-thienyl)-benzo[h]benzimidazolo[1″,2″:1′,6′]
pyrimido[4′,5′:4,5]thieno [2,3-b]quinoline (7). Prepared from
cyclization of 4c, yield: 2.22g (91%); m.p.: 231–232°C.
1
IR: 3472, 3400, 3250 (NH, NH2), 1654 (C¼O). H NMR
compound 5e, yield: 1.81g (79%); m.p.: >360°C. IR: 1626
(DMSO-d6): δ 9.2 (s, 1H, CONH), 8.4 (d, J=9Hz, 1H,
thienyl–H), 7.0–7.8 (m, 10H: two thienyl–H and Ar-H’s),
5.9 (s, 2H, NH2), 2.8–3.1 (m, 4H, CH2—CH2). Anal.
Calcd. for C26H18ClN3OS2 (488.02): C, 63.99; H, 3.72;
N, 8.61; S, 13.14%. Found: C, 64.11; H, 3.76; N, 8.68;
1
(C¼N). H NMR (CF3CO2D): δ 8.9 (s, 1H, pyrimidine–
H), 8.3 (d, J= 9 Hz, 1H, thienyl–H), 7.1–8.1 (m, 10H: two
thienyl–H and Ar-H’s), 2.8–3.0 (m, 4H, CH2—CH2).
EI-MS: m/z (fragment, %)= 460.39 (M+, 42); 134 (100).
Anal. Calcd. for C27H16N4S2 (460.57): C, 70.41; H, 3.50; N,
12.16; S, 13.92%. Found: C, 70.03; H, 3.18; N, 12.09; S,
S, 12.90%.
3-Amino-2-5,6-dihydro-(N-(p-sulfonamidophenyl))carbamoyl-
4-(2′-thienyl)-thieno[2,3-b] benzo[h]quinoline (5d). Obtained
13.77%.
10-(p-Methoxybenzylideneamino)-5,6,10,11-tetrahydro-4-
oxo-7-(2′-thienyl)-pyrimido[4′,5′: 4,5]thieno[2,3-b]benzo[h]
quinoline (13). Prepared from compound 12, yield:
by cyclization of 4d, yield: 2.50g (94%); m.p.: 229–230°C.
IR: 3472, 3350 (NH2, NH), 2217 (C≡N), 1625 (C¼O),
1
1290, 1140 (SO2). H NMR (DMSO-d6): δ 9.3 (s, 1H,
2.16 g (%); m.p.: 315–317°C. IR: 1670 (C¼O). 1H
NMR (CF3CO2D): δ 9.5 (s, 1H, pyrimidine–H), 9.0
(s, 1H, N¼H), 8.3 (d, J=8.5Hz, 1H, thienyl–H), 6.8–7.8
(m, 10H: two thienyl–H and Ar-H’s), 2.7–2.9 (m, 4H,
CH2—CH2). Anal. Calcd. for C29H20N4O2S2 (520.62):
C, 66.90; H, 3.87; N, 10.76; S, 12.32%. Found: C,
66.61; H, 3.96; N, 10.57; S, 12.24%.
NH), 8.3 (d, J=9Hz, 1H, thienyl–H), 7.0–7.7 (m, 12H:
SO2NH2, two thienyl–H and Ar-H’s), 5.8 (s, 2H, NH2),
2.7–2.9 (m, 4H, CH2—CH2). Anal. Calcd. for
C26H20N4O3S3 (532.65): C, 58.63; H, 3.78; N, 10.52; S,
18.06%. Found: C, 58.29; H, 3.81; N, 10.32; S, 17.79%.
3-Amino-2-(1′H-2-benzimidazolyl)-5,6-dihydro-4-(2′-thienyl)-
thieno[2,3-b]benzo[h] quinoline (5e). Obtained by cyclization
(3-Cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-2-
ylthio)acethydrazide (8). To a suspension of ester 4a
(4.0g, 10 mmol) in ethanol (40mL), hydrazine hydrate
99% (1.0 mL, 20mmol) was added. The resulting mixture
was heated under reflux for 2h and then allowed to cool.
of 4e, yield: 1.85g (82%); m.p.: 218–220°C. IR: 3424,
1
3326, 3222 (NH, NH2), 1648 (C¼N). H NMR (CDCl3):
δ 8.4 (d, 1H, J = 9Hz, thienyl–H), 7.2–7.9 (m, 11H: two
thienyl–H, NH and Ar-H’s), 5.5 (s, 2H, NH2), 2.8–3.0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of New Heterocyclobenzo[h]Quinolines
N′-(p-Methoxybenzylidene)-3-amino-5,6-dihydro-4-(2′-
thienyl)-benzo[h]thieno[2,3-b]quin-oline-2-carbohydrazide (12).
The solid product was collected and recrystallized from
ethanol as colorless plates of 8, yield: 3.53g (90%); m.p.:
242–243°C. IR: 3350, 3276 (NHNH2), 2215 (C≡N), 1647
(C¼O). 1H NMR (CDCl3): δ 9.6 (s, 1H, NH), 8.5 (d,
J=8.5Hz, 1H, thienyl–H), 7.9 (d, J=8.5, 1H, thienyl–H),
7.3–7.6 (m, 5H: thienyl–H and Ar-H’s), 4.4 (br. s, 2H, NH2),
4.1 (s, 2H, SCH2), 2.8 (br. s, 4H, CH2—CH2). Anal.
Calcd. for C20H16N4OS2 (392.49): C, 61.20; H, 4.11; N,
14.27; S, 16.34%. Found: C, 61.52; H, 4.33; N, 13.94; S,
Method A.
A suspension of compound 11 (0.51g,
1 mmol) in sodium ethoxide solution (10 mg of sodium in
20mL absolute ethanol) was heated at reflux for 10min.
The solid that formed after cooling was collected and
recrystallized from DMF to give canary yellow needles of
12, yield: 0.45 g (88%); m.p.: 288–290°C. IR: 3464,
3311 (NH2), 3200 (NH), 1621 (C¼O). 1H NMR
(DMSO-D6): δ 10.0 (s, 1H, NH), 8.6 (d, J= 8.5Hz, 1H,
thienyl–H), 7.9 (d, J =8.5, 1H, thienyl–H), 7.0–7.6 (m,
10H: thienyl–H, N¼CH and Ar-H’s), 5.7 (s, 2H, NH2),
3.8 (s, 3H, OCH3), 2.8 (m, 4H, CH2—CH2). Anal.
Calcd. for C28H22N4O2S2 (510.63): C, 65.68; H, 4.34;
15.94%.
3-Amino-5,6-dihydro-4-(2′-thienyl)-benzo[h]thieno[2,3-b]
quinoline-2-carbohydrazide (9). A suspension of ester 4a
(4.0 g, 10 mmol) in hydrazine hydrate 99% (5 mL,
100 mmol) was added was heated under reflux for 2 h
and then allowed to cool. The reaction mixture was
triturated with ethanol (20mL) whereby a solid product
precipitated. It was collected and recrystallized from an
ethanol–chloroform mixture as yellow needles of 9, yield:
3.50g (89%); m.p.: 281–282°C. IR: 3451, 3307, 3200
(NH2, NH), 1627 (C¼O). EI-MS: m/z (fragment, %)
=392.24 (M+, 68); 361.20 (M+-NHNH2, 100). Anal.
Calcd. for C20H16N4OS2 (392.49): C, 61.20; H, 4.11; N,
14.27; S, 16.34%. Found: C, 61.03; H, 4.25; N, 14.00;
N, 10.97; S, 12.56%. Found: C, 65.72; H, 4.00; N,
10.88; S, 12.19%.
Method B. A mixture of compound 9 (0.78 g, 2 mmol)
and p-anisaldehyde (0.25mL, 2 mmol) in ethanol (30 mL)
was heated under reflux for 2 h and then left to cool. The
solid that formed on crystallization gave compound 12
which is identical to the above product in all aspects,
yield: 0.9 g (91%).
3-Formyamino-13-(2′-thienyl)-3,4,11,12-tetrahydro-4-
oxo-benzo[h]pyrimido[4′,5′:4,5] thieno[2,3-b]quinoline
(14). A solution of compound 9 (0.78 g, 2 mmol) in
S, 16.00%.
1-(3-Cyano-5,6-dihydro-4-(2′-thienyl)-benzo[h]quinolin-
formic acid 85% (20 mL) was heated at reflux for
3 h. The solid that formed after cooling was
collected and crystallized from ethanol as white
needles of 14, yield: 0.65g (75%); m. p.: 285–286°C. IR:
2-ylthio)acetyl-4-phenyl-3-thiosemicarbazide
(10).
A
mixture of 8 (1.18g, 3mmol) and phenyl isothiocyanate
(0.4mL, 3mmol) in ethanol (30mL) was heated under
reflux for 1h. The precipitate that formed while hot was
collected by filtration and recrystallized from dioxane as
white crystals of 10, yield: 1.5g (95%); m.p.: 230–231°C.
IR: 3400, 3369, 3289 (3NH), 2224 (C≡N), 1681 (C¼O).
1H NMR (CDCl3): δ 11.0 (s, 1H, NH), 9.6 (s, 1H, NH),
9.1 (s, 1H, NH), 8.4 (d, J=8.0Hz, 1H, thienyl–H), 7.8 (d,
J=8.5, 1H, thienyl–H), 7.1–7.7 (m, 10H: thienyl–H and
Ar-H’s), 4.1 (s, 2H, SCH2), 2.7 (br s, 4H, CH2―CH2).
EI-MS: m/z (fragment, %)=527.9 (M+, 11); 320.17
(M+-CH2CONHNHCSHPh, 37); 135 (PhNCS+, 98); 77
(Ph+, 100). Anal. Calcd. for C27H21N5OS3 (527.68): C,
61.46; H, 4.01; N, 13.27; S, 18.23%. Found: C, 61.30; H,
1
3350 (NH), 1720 (CHO), 1660 (C¼O, pyrimidinone). H
NMR (DMSO-d6): δ 8.6 (s, 1H, pyrimidine–H), 8.3 (d,
J=9Hz, 1H, thienyl–H), 8.1 (s, 1H, NH), 7.1–7.8 (m,
7H: two thienyl–H, CHO and Ar-H’s), 2.8–3.0 (m, 4H,
CH2—CH2). Anal. Calcd. for C22H14N4O2S2 (430.50): C,
61.38; H, 3.28; N, 13.01; S, 14.89%. Found: C, 61.19;
H, 3.25; N, 13.33; S, 14.60%.
10-Acetylamino-9-methyl-5,6,10,11-tetrahydro-11-oxo7-
(2′-thienyl)-benzo[h]pyrimido [4′,5′:4,5]thieno[2,3-b]quinoline
(15). A solution of compound 9 (0.78g, 2mmol) in glacial
acetic acid (15mL) was heated at reflux for 5h. The solid
that formed while hot was collected and crystallized from
DMF as white crystals of 15, yield: 0.9g (90%); m.p.:
298–9°C. IR: 3316 (NH), 1708 (C¼O, acetyl), 1660
(C¼O, pyrimidinone). 1H NMR (CF3CO2D): δ 7.4–8.3 (m,
7H: three thienyl–H and Ar-H’s), 3.0–3.2 (br. s, 4H, CH2
—CH2), 2.8 (s, 3H, CH3CO), 2.3 (s, 3H, CH3 at C-9).
Anal. Calcd. for C24H18N4O2S2 (458.55): C, 62.86; H,
3.96; N, 12.22; S, 13.98%. Found: C, 62.80; H, 4.09; N,
12.01; S, 13.69%.
10-Diacetylamino-9-methyl-5,6,10,11-tetrahydro-11-oxo-
7-(2′-thienyl)-benzo[h]pyrimido [4′,5′:4,5]thieno[2,3-b]quinoline
(16). A solution of compound 9 or 15 (2mmol) in acetic
anhydride (15mL) was heated at reflux for 4h. The solid
that formed on cooling was collected and recrystallized
from ethanol in the form of white crystals of 16, yield:
(82–87%); m. p.: 264–5°C. IR: 1745 (C¼O, biacetyl),
3.92; N, 13.09; S, 18.03%.
N′-(p-Methoxybenzylidene-(3-cyano-5,6-dihydro-4-(2′-
thienyl)-benzo[h]quinolin-2-ylthio))
acetylhydrazide
(11). A mixture of 8 (0.78 g, 2 mmol) and p-
anisaldehyde (0.25mL, 2mmol) in ethanol (25mL) was
refluxed for 2h. The precipitated solid was collected by
filtration and recrystallized from ethanol as white fine
needles of 11, yield: 0.9g (88%); m.p.: 299–300°C. IR:
3212 (NH), 2216 (C≡N), 1659 (C¼O). 1H NMR (CDCl3):
δ 10.3 (s, 1H, NH), 8.4 (d, J=8.0Hz, 1H, thienyl–H), 7.8
(d, J=8.5, 1H, thienyl–H), 7.1–7.6 (m, 10H: thienyl–H,
N¼CH and Ar-H’s), 4.2 (s, 2H, SCH2), 3.9 (s, 3H, OCH3),
2.7 (m, 4H, CH2—CH2). Anal. Calcd. for C28H22N4O2S2
(510.63): C, 65.68; H, 4.34; N, 10.97; S, 12.56%. Found:
C, 65.31; H, 4.22; N, 11.11; S, 12.39%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. A. Al-Taifi, M. S. Abbady, and E. A. Bakhite
Vol 000
1
1690 (C¼O, pyrimidinone). H NMR (CF3CO2D): δ 8.3
of white plates, yield: 0.84g (81%); m.p.: 285–6°C. IR:
1
(d, J=9Hz, 1H, thienyl–H), 7.4–7.9 (m, 6H: two
thienyl–H and Ar-H’s), 3.0–3.2 (m, 4H, CH2—CH2), 2.6
(s 6H, two CH3CO), 2.4 (s, 3H, CH3). Anal. Calcd. for
C26H20N4O3S2 (500.59): C, 62.38; H, 4.03; N, 11.19; S,
12.81%. Found: C, 62.80; H, 4.09; N, 11.01; S, 12.69%.
10-Ethoxymethyleneamino-11-oxo-5,6,10,11-tetrahydro-
7-(2′-thienyl)-benzo[h]pyrimido [4′,5′:4,5]thieno[2,3-b]quinoline
(17). A mixture of 9 (0.78g, 2mmol) and triethyl
1671 (C¼O). H NMR (DMSO-d6): δ 8.4 (d, J=8.5Hz,
1H, thienyl–H), 7.1–7.7 (m, 11H: two thienyl–H and Ar-
H’s), 3.1–3.4 (q, J=8Hz, 2H, SCH2), 1.3–1.5 (t, J=8Hz,
3H, CH3), 2.8–3.0 (m, 4H, CH2—CH2). EI-MS: m/z
(fragment, %)=524.67 (M++1, 23); 523.67 (M+, 34);
522.74 (M+ꢀ1, 100). Anal. Calcd. for C29H21N3OS3
(523.69): C, 66.51; H, 4.04; N, 8.02; S, 18.37%. Found: C,
66.72; H, 3.80; N, 8.31; S, 18.68%.
orthoformate (3mL) in DMF (10mL) was heated under
reflux for 4h. The precipitate that formed after cooling was
collected and recrystallized from DMF as pale yellow
crystals of 17; yield: 0.7g (77%); m.p.: 291–293°C. IR:
1660 (C¼O), 1610 (C¼N). 1H NMR (CF3CO2D): δ 9.3 (s,
1H, pyrimidine–H), 8.4 (d, J=8.5Hz, 1H, thienyl–H), 8.2
(s, 1H, N¼CH), 7.1–7.8 (m, 6H: two thienyl–H and Ar-
H’s), 4.2–4.6 (q, J=9Hz, 2H, OCH2), 2.7–3.0 (m, 4H,
CH2—CH2), 1.3–1.6 (t, J=9Hz, CH3). EI-MS: m/z
(fragment, %)=459.29 (M++1, 78); 458.11 (M+, 96); 386
(M+-N¼CHOEt, 100). Anal. Calcd. for C24H18N4O2S2
(458.55): C, 62.86; H, 3.96; N, 12.22; S, 13.98%. Found:
5,6,8,9,10,11-Hexahydro-9-(p-methoxyphenyl)-11-oxo-7-
(2′-thienyl)-benzo[h]pyrimido [4′,5′:4,5]thieno[2,3-b]quinoline
(21). To a mixture of compound 5b (1.13g, 3mmol) and
p-anisaldehyde (0.37mL, 3mmol) in ethanol (20mL), a
few drops of conc. HCl were added. The reaction mixture
was heated under reflux for 3h. The product that formed
while hot was collected and recrystallized from DMF as
yellow crystals of compound 21, yield: 1.35 g (91%); m.
p.: >360°C. IR: 3395, 3200 (2NH), 1646 (C¼O). 1H
NMR (CF3CO2D): δ 8.4 (d, J = 9 Hz, 1H, thienyl–H),
7.0–7.9 (m, 10H: two thienyl–H and Ar-H’s), 2.8–3.0
(m, 4H, CH2—CH2), 6.0 (s, 1H, CH at C-9), 3.9 (s, 3H,
OCH3). EI-MS: m/z (fragment, %) = 496 (M+, 21); 388
(M+-MeOC6H4, 42); 134 (MeOC6H4CN, 100). Anal.
Calcd. for C28H21N3O2S2 (495.61): C, 67.86; H, 4.27; N,
8.48; S, 12.94%. Found: C, 67.93; H, 4.12; N, 8.53; S,
13.27%.
C, 62.67; H, 4.00; N, 12.35; S, 13.75%.
9-Methyl-11-oxo-5,6,10,11-tetrahydro-7-(2′-thienyl)-benzo
[h]pyrimido[4′,5′:4,5]thieno[2,3-b]quinoline (18). A suspension of
compound 5b (1.13g, 3 mmol) in acetic anhydride (20mL)
was heated under reflux for 5 h and then left to cool. The
formed solid was collected and recrystallized from DMF to
give pale yellow crystals of 18, yield: 0.66g (82%); m.p.:
>360°C. IR: 3200 (NH), 1653 (C¼O). 1H NMR
(CF3CO2D): δ 8.3 (d, J=9 Hz, 1H, thienyl–H), 7.1–7.7 (m,
6H: two thienyl–H and Ar-H’s), 2.8–3.0 (m, 4H, CH2—
CH2), 2.2 (s, 3H, CH3). EI-MS: m/z (fragment, %)= 401.19
(M+, 20); 486.36 (M+-Me, 100). Anal. Calcd. for
C22H15N3OS2 (401.50): C, 65.81; H, 3.77; N, 10.47; S,
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15.97%. Found: C, 65.64; H, 3.42; N, 10.31; S, 15.68%.
5,6,8,9,10,11-Hexahydro-11-oxo-10-phenyl-9-thioxo-7-
(2′-thienyl)-benzo[h]pyrimido[4′,5′: 4,5]thieno[2,3-b]quinoline
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thienyl–H), 7.1–7.8 (m, 11H: two thienyl–H and Ar-H’s),
2.8–3.0 (m, 4H, CH2—CH2). Anal. Calcd. for
C27H17N3OS3 (495.63): C, 65.43; H, 3.46; N, 8.48; S,
19.41%. Found: C, 65.35; H, 3.44; N, 8.38; S, 19.07%.
9-Ethylthio-5,6,10,11-tetrahydro-11-oxo-10-phenyl-7-(2′-
thienyl)-benzo[h]pyrimido[4′,5′: 4,5]thieno[2,3-b]quinoline
(20). To a solution of compound 19 (0.99 g, 2 mmol) in
ethanol sodium hydroxide solution 5% (10mL), ethyl
iodide (0.17mL, 2mmol) was added. The reaction mixture
was stirred at room temperature for 1h whereby a white
crystalline solid precipitated. It was collected by filtration
and recrystallized from n-propanol to give 20 in the form
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of New Heterocyclobenzo[h]Quinolines
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet