Novel four-step synthesis of thioxo-quinazolino[3,4- A ]quinazolinone derivatives

Article abstract of DOI:10.1080/00397911.2013.800211

A novel synthesis of thioxo-quinazolino[3,4-a]quinazolinone framework was developed through a four-step reaction starting from isatoic anhydride. The resulting 2-aminobenzamides from the reaction of isatoic anhydride and different amines underwent coupling-cyclization reaction with 2-nitrobenzaldehydes, reduction of nitro group, and then cyclization reaction with carbon disulfide (CS2). All steps were carried out under easy and user-friendly conditions in a short time without using expensive catalysts or reagents. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.800211

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Novel Four-Step Synthesis of Thioxo-
quinazolino[3,4-a]quinazolinone
Derivatives
Behnaz Shafii a , Mina Saeedi a , Mohammad Mahdavi a , Alireza
Foroumadi a & Abbas Shafiee a
a Department of Medicinal Chemistry , Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences , Tehran , Iran
Accepted author version posted online: 27 Aug 2013.Published
online: 29 Oct 2013.
To cite this article: Behnaz Shafii , Mina Saeedi , Mohammad Mahdavi , Alireza Foroumadi & Abbas
Shafiee (2014) Novel Four-Step Synthesis of Thioxo-quinazolino[3,4-a]quinazolinone Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:2, 215-221, DOI: 10.1080/00397911.2013.800211
To link to this article: http://dx.doi.org/10.1080/00397911.2013.800211
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Synthetic Communications1, 44: 215–221, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.800211
NOVEL FOUR-STEP SYNTHESIS OF THIOXO-
QUINAZOLINO[3,4-a]QUINAZOLINONE DERIVATIVES
Behnaz Shafii, Mina Saeedi, Mohammad Mahdavi,
Alireza Foroumadi, and Abbas Shafiee
Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract A novel synthesis of thioxo-quinazolino[3,4-a]quinazolinone framework was
developed through a four-step reaction starting from isatoic anhydride. The resulting 2-
aminobenzamides from the reaction of isatoic anhydride and different amines underwent
coupling–cyclization reaction with 2-nitrobenzaldehydes, reduction of nitro group, and then
cyclization reaction with carbon disulfide (CS2). All steps were carried out under easy and
user-friendly conditions in a short time without using expensive catalysts or reagents.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Carbon disulfide (CS2); heterocycles; 2-nitrobenzaldehydes; thioxo-
quinazolino[3,4-a]quinazolinone
INTRODUCTION
The prominence of the quinazoline unit in various medicinal organic
compounds has been the subject of great interest because of its medicinal and
distinguished biological activities.[1] The quinazolinone and quinazolinthione
Received March 5, 2013.
Address correspondence to Abbas Shafiee, Department of Medicinal Chemistry, Faculty of
Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences,
Tehran 14176, Iran. E-mail: ashafiee@ams.ac.ir
215

216
B. SHAFII ET AL.
Figure 1. Structure of isolated 2-(4-hydroxybenzyl)quinazolin-4(3H)-one A and farinamycin B from
Cordyceps-colonizing fungus Isaria farinose and Streptomyces griseus, respectively.
(thioxo-quinazolinone) moieties are well known for their anticonvulsant,[2] antihyper-
tensive,[3] anti-inflammatory,[4] and phosphodiesterase inhibitor[5] properties. Recently,
Corbett et al. showed that fused quinazolines were HIV-1 non-nucleoside reverse tran-
scriptase inhibitors.[6] More to the point, the quinazolinone nucleus can be found in
natural products such as 2-(4-hydroxybenzyl)quinazolin-4(3H)-one (Fig. 1, A) obtained
from cultures of the Cordyceps-colonizing fungus Isaria farinosa[7] and farinamycin
(Figure 1, B), a quinazoline metabolite isolated from Streptomyces griseus.[8]
Unfortunately, the biological and medical activities of the quinazolinthiones have
not been fully investigated yet. Recently, Bahekar et al. investigated quinazolinthione
derivatives and found that they showed bronchodilator activity using in vitro and
in vivo methods (standard animal models).[9] In addition, El Azab et al. described
the synthesis of novel quinazolinone and quinazolinethione derivatives that showed
potential as antitumor agents.[10] A literature review revealed that quinazolinethione
has been center of attention not only for the biological properties but also they have
been suitable intermediates for the preparation of useful bioactive compounds.[11]
As part of our ongoing research program pertaining to the synthesis and design
of new heterocyclic compounds,[12–14] we have devised a novel synthetic scheme to
obtain fused thioxo-quinazolino[3,4-a]quinazolinones, and we realized that their
synthesis and biological activities were not fully understood. Thus, we tried to present
a suitable protocol for the synthesis of this class of heterocycles and thioxo-
quinazolino[3,4-a]quinazolinone derivatives (Scheme 1).
Scheme 1. Synthesis of fused thioxo-quinazolino[3,4-a]quinazolinones 6: (i) in water at room temperature
(2–3 h); (ii) 2-nitrobenzaldehyde or 3-methoxy-2-nitrobenzaldehyde, K2CO3=EtOH at reflux (2–4 h); (iii)
Zn, NH4Cl, MeOH, water at room temperature (1–2 h); (iv) CS2 (excess), KOH=EtOH at reflux (3–5 h).

THIOXO-QUINAZOLINO[3,4-a]QUINAZOLINONES
217
RESULTS AND DISCUSSION
We recently reported synthesis of diverse new heterocyclic compounds starting
from isatoic anhydride.[12,15] Because of the good results and easy procedure, we
were encouraged to design a novel strategy for the synthesis of quinazolino[3,4-a]
quinazolinones utilizing isatoic anhydride. For this purpose, we outlined a synthetic
route in four steps for the preparation of these compounds (Scheme 1).
The first step of our synthetic route included preparation of various 2-amino-
benzamide derivatives 3 from the reaction of isatoic anhydride 1 and various amines
2 in water at room temperature.[12,15] Clearly the reaction is conducted by the nucleo-
philic attack of amine on the isatoic anhydride with liberation of CO2.[16]
The second step of our synthetic scheme was preparing the 2,3-dihydro-2-
(2-nitrophenyl)-3-arylquinazolin-4(1H)-one derivatives 4. A literature survey shows
that there are various procedures for the one-pot, three-component synthesis of
quinazolin-4(1H)-ones starting from isatoic anhydride, amines, and aldehydes.[17]
We investigated some of these procedures and obtained the related products 4 in poor
yields. It seems that those methods did not work as efficiently as we expected for the
selected sterically hindered aldeydes in our study. Also some of them used complex or
expensive catalysts.[18] We observed that heating mixture of a stoichiometric amount
of 2-aminobenzamides 3, 2-nitobenzaldehyde derivatives, and potassium carbonate
(K2CO3) in EtOH led to the formation of compounds 4 in good yields.
In the third step, reduction of nitro group in compounds 4 gave 2-(2-
aminophenyl)-2,3-dihydro-3-arylquinazolin-4(1H)-ones 5. It should be noted that
the best reaction conditions for reduction of the NO2 group was obtained using
a mixture of Zn powder and ammonium chloride (NH4Cl) in MeOH=H2O, at room
temperature.
In the fourth step, the final products 6 were obtained easily by heating the
mixture of compounds 5 and an excess amount of carbon disulfide (CS2) in the
presence of potassium hydroxide (KOH).
The structure of all products was confirmed on the basis of their mass spectro-
1
scopic fragmentation pattern analysis and H and 13C NMR spectra. For instance,
for 12-benzyl-6-thioxo-11b,12-dihydro-6H-quinazolino[3,4-a]quinazolin-13(7H)-one
6a (Table 1, entry 1), the MS peak (m=z 371) associated with the molecular ion was
observed and was in accordance with calculated mass for C22H17N3OS. The MS shows
a strong peak (m=z 237) that is related to elimination of the benzyl and CS groups
and the formation of 2-(2-aminophenyl)quinazolin-4(1H)-one. Also a rather strong
peak was also observed (m=z 266) resulting from the loss of phenylmethanimine.
1H NMR spectrum of 6a consisted of two doublet signals at 4.06 and 4.81 for
the two protons of NCH2 and a singlet at 6.67 ppm for CH. The 13 protons associa-
ted with the aromatic rings were observed around 6.71–8.01 ppm. The singlet signal
at 11.61 corresponded to the NH group. As expected, the 13C spectrum exhibited 20
distinct resonances. Two signals at 44.0 and 68.6 are related to two aliphatic carbons.
Sixteen signals related to aromatic carbons were observed around 113.0–142.5. Two
=
=
signals at 162.9 and 175.4 ppm are related to C O and C S, respectively.
As can be seen in Table 1, we could synthesize various thioxo-quinazolino[3,4-
a]quinazolinone derivatives through the described method. It is worth mentioning
that all 2-aminobenzamides showed good reactivity toward 2-nitrobenzaldehydes

218
B. SHAFII ET AL.
Table 1. Synthesis of fused thioxo-quinazolino[3,4-a]quinazolinone derivatives 6
Entry
R
X
Product 6
Yield (%)a
1
2
C6H5CH2-
C6H5CH2-
H
OMe
H
6a
6b
6c
6d
6e
6f
88
80
82
79
80
80
81
75
84
81
3
4-Me-C6H4CH2-
4-Me-C6H4CH2-
4-F-C6H4CH2-
4-F-C6H4CH2-
2-Cl-C6H4CH2-
Furfuryl
4
OMe
H
5
6
OMe
H
7
6g
6h
6i
8
H
9
10
CH2¼CHCH2-
CH3CH2CH2-
H
H
6j
aIsolated yields.
and all of corresponding products tolerated reduction reaction and also cyclization
reaction with CS2. It should be noted that different electron-donating and
electron-withdrawing substituents on either para or ortho positions of aromatic rings
did not show remarkable differences in the yield of products and reaction times.
In the case of products 6h, lower yield can be related to electron-withdrawing effect
of furfuryl, which decreased the nucleophilicity of NH2 group of furfurylamine
and also NH in 2-amino-N-((furan-2-yl)methyl)benzamide.
CONCLUSION
In summary, we have developed a novel and efficient four-step synthesis of
fused thioxo-quinazolino[3,4-a]quinazolinone derivatives starting from isatoic
anhydride as an available starting material, in moderate to good yields. All four steps
included easy and user friendly procedures which did not diminish yields of products
significantly. All steps were done without using expensive catalyst and reagents in
short time. Noticing that synthesis and biological evaluation of the title compounds
have not been investigated, we hope that the described strategy for the synthesis of
these potentially bioactive products can open a new horizon for organic and
medicinal chemists. These compounds may possess cytotoxic activities.
EXPERIMENTAL
Melting points were taken on a Kofler hot-stage apparatus and are uncorrected.
1H and 13C NMR spectra were recorded on a Bruker FT-500, using tetramethylsilane
(TMS) as an internal standard. The infrared (IR) spectra were obtained on a Nicolet
Magna FTIR 550 spectrophotometer (KBr disks). Mass spectra were recorded on an

THIOXO-QUINAZOLINO[3,4-a]QUINAZOLINONES
219
Agilent Technology (HP) mass spectrometer operating at an ionization potential of
70eV. Elemental analyses were carried out with a Perkin-Elmer model 240-C apparatus.
Synthesis of Thioxo-Quinazolino[3,4-a]quinazolinone
Derivatives 6: General Procedure
A
mixture of 2-(2-aminophenyl)-2,3-dihydro-3-arylquinazolin-4(1H)-one
derivatives 5 (2 mmol), carbon disulfide (CS2) (5 mmol), and potassium hydroxide
(KOH) (2 mmol) in EtOH (10 mL) was heated at reflux for 3–5 h. After completion
of the reaction (checked by thin-layer chromatography, TLC), the reaction mixture
was cooled down to room temperature and poured into ice-cold water, and the white
precipitates were filtered off and recrystallized from EtOH to give pure produts 6.
12-(4-Fluorobenzyl)-8-methoxy-6-thioxo-11b,12-dihydro-6H-
quinazolino[3,4-a]quinazolin-13(7H)-one (6f)
Yield: 0.33 g (80%); white crystal; mp 220–222ꢀC. IR (KBr): 3440, 3152, 3118,
1
3026, 1648, 1602, 1517, 1430, 1180 cmꢁ1. H NMR (500 MHz, DMSO-d6): d ¼ 3.80
(s, 3 H, OMe), 4.02 (d, J ¼ 15.9 Hz, 1 H, benzylic), 4.84 (d, J ¼ 15.9 Hz, 1 H, benzylic),
0
0
6.65 (s, 1 H, CH), 6.70–6.73 (m, 2 H, H9, H10), 6.92–6.96 (m, 3 H, H11, H3 , H5 ),
0
0
7.09–7.16 (m, 2 H, H2 , H6 ), 7.51 (t, J ¼ 8.0 Hz, 1 H, H2), 7.63 (dt, J ¼ 8.0, 1.1 Hz,
1 H), 7.68 (d, J ¼ 8.0 Hz, 1 H, H4), 8.00 (dd, J ¼ 8.0, 1.1 Hz, 1 H, H1), 10.00 (s, 1 H,
NH). 13C NMR (125 MHz, DMSO-d6): d ¼ 43.4, 56.2, 68.6, 113.1, 114.1, 114.6
(d, JC-F ¼ 21.2 Hz), 120.5, 124.1, 124.3, 126.0, 127.1, 127.3, 127.5, 127.9 (d, JC-F
¼
7.8 Hz), 130.9, 133.8, 142.6, 144.9, 160.9 (d, JC-F ¼ 240.7 Hz), 162.9, 175.6. MS: m=z
(%) ¼ 419 (35) [M]þ., 296 (100), 267 (49), 253 (40), 237 (31), 162 (23), 134 (12), 109
(66), 77 (18). Anal. calcd. for C23H18FN3O2S: C, 65.86; H, 4.33; N, 10.02. Found: C,
65.59; H, 4.55; N, 9.86.
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra are available. This
material can be found via the Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
This research was supported by grants from the research council of Tehran
University of Medical Sciences, Iran National Science Foundation (INSF), and Iran
National Elite Foundation (INEF).
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