13H-Quinazolino[3,4-a]quinazolin-13-one: Synthesis and structural revision

Article abstract of DOI:10.1016/j.tetlet.2013.06.060

13H-Quinazolino[3,4-a]quinazolin-13-one has been synthesized from 2-aminobenzamide via 11b,12-dihydro-13H-quinazolino[3,4-a]quinazolin-13-one in four steps. However, the spectroscopic data did not match with those of literature data. Thus, the published s

Full text of DOI:10.1016/j.tetlet.2013.06.060

Tetrahedron Letters 54 (2013) 4512–4514
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Tetrahedron Letters
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13H-Quinazolino[3,4-a]quinazolin-13-one: synthesis and structural
revision q
⇑
Somepalli Venkateswarlu , Meka Satyanarayana, Pasupuleti Ravikiran, Anupoju Vijayakumar
Drug Discovery, Laila Impex Research Centre, No. 1, Phase III, Jawahar Autonagar, Vijayawada 520 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
13H-Quinazolino[3,4-a]quinazolin-13-one has been synthesized from 2-aminobenzamide via 11b,
12-dihydro-13H-quinazolino[3,4-a]quinazolin-13-one in four steps. However, the spectroscopic data
did not match with those of literature data. Thus, the published structure from the reaction of 2-amino-
benzonitrile and triethyl orthoformate is not 13H-quinazolino[3,4-a]quinazolin-13-one and has been
revised as 8H-quinazolino[4,3-b]quinazolin-8-one.
Received 24 April 2013
Revised 11 June 2013
Accepted 13 June 2013
Available online 20 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Nitrogen heterocycles
Quinazolines
Fused quinazolinoquinazolinones
Dehydrogenation
Structural revision
Quinazoline and its derivatives are a class of heteroaromatic
compoundsthat have drawn much attentionbecause of their biolog-
ical and pharmaceutical importance and their synthesis has been
extensively investigated.1,2 Among these, 4-(phenylamino)quinazo-
lines were found to be potent and selective ATP competitive tyrosine
kinase inhibitors for the treatment of EGFR-associated cancer types
(e.g., Iressa™-gefitinib and Tarceva™-erlotinib are being used for
the treatment of nonsmall cell lung cancer).3 8H-Quinazolino
[4,3-b]quinazolin-8-ones (1) and 13H-quinazolino[3,4-a]quinazo-
lin-13-ones (2) are two isomeric angularly fused quinazolinoqui-
nazolinones (Fig. 1). Although, a number of methods4–7 were
reported for the synthesis of 1, synthetic studies on the isomeric
compound 2 are rather limited.8–10 In view of the important biolog-
ical activities of the fused quinazolinones and in continuation of our
interest in this chemistry,11 we required an efficient synthesis of
13H-quinazolino[3,4-a]quinazolin-13-one (2).
Our initial efforts11b to make 2 by dehydrogenation of 11b,
12-dihydro-13H-quinazolino[3,4-a]quinazolin-13-one (3) failed
and instead gave a rearranged product 1. Among the several known
dehydrogenation reagents,12 DDQ was chosen for the aromatiza-
tion reaction. The requisite intermediate 3 was prepared starting
from 2-aminobenzamide in three steps (Scheme 2).
O
O
6
9
1
4
13
N
8
7
N
2
12
10
11
N 5
2
11
8
5
N
3
10
9
N
4
3
12
13
1
6
N
7
1
2
Figure 1. 8H-Quinazolino[4,3-b]quinazolin-8-one (1) and 13H-quinazolino[3,4-
a]quinazolin-13-one (2).
Only two methods were reported for the synthesis of 6-unsub-
stituted 13H-quinazolino[3,4-a]quinazolin-13-one (2).8,9 The first
Letter described the formation of compound 2 as a minor product
during the reaction of 2-[4-imino-2-thioxa-1,4-dihydro-3(2H)-
quinazolinyl]benzonitrile with Mn(OAc)3.8 A recent report9 has
described the synthesis of 2 in two steps starting from 2-amino-
benzonitrile via 13H-quinazolino[3,4-a]quinazolin-13-imine acid
salt (Scheme 1).
NH
CN
ref. 8
N
O
N
CN
N
H
S
NCS
N
N
CN
NH.HX
2
ref. 9
+
HC(OEt)3
N
NH2
N
q
In memories of Professor A. Srikrishna (1955–2013), Department of Organic
N
Chemistry, Indian Institute of Science, Bangalore, India.
⇑
Corresponding author. Tel.: +91 866 2545689; fax: +91 866 2543484.
E-mail addresses: somepalli01@rediffmail.com, drvsomepalli@gmail.com (S.
X = NO3 or SO4Et
Scheme 1. Known methods to prepare 13H-quinazolino[3,4-a]quinazolin-13-one.
Venkateswarlu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.060

S. Venkateswarlu et al. / Tetrahedron Letters 54 (2013) 4512–4514
4513
The carbonyl absorption of 2 is at 1656 cmÀ1, whereas for 2
(published) it was reported at 1703 cmÀ1. In proton NMR, the H-
6 proton in 2 gave a singlet at d 9.67 and the same proton in 2 from
the published work resonated at d 9.28. The other chemical shifts
of published 2 are also inconsistent with the synthetic 2 (Table
2). Further, in carbon NMR, the carbonyl carbon in 2 resonated at
d 166.05 and the same carbon in published 2 resonated at d
157.75. The other carbon values (13C NMR) of published 2 are also
inconsistent with 2 (Table 2). Obviously, the structure published
for the product from the reaction of 2-aminobenzonitrile is not
13H-quinazolino[3,4-a]quinazolin-13-one (2). In light of this
observation, we carefully reanalyzed the spectroscopic data of
published structure 2 by Marinho et al. and found that the data
were well in agreement with an isomeric structure 1. The spectro-
scopic data of isomeric compound 1 are reported in CDCl3 from our
group15 as well as others,5,6 since the compound is freely soluble in
CDCl3. To compare unambiguously, the spectroscopic data of 1 are
recorded in DMSO-d6 and presented in Table 2. The carbonyl
absorption in IR for published 2 was reported at 1703 cmÀ1, which
is in good agreement with those of 1 (1705 cmÀ1). Further, the sin-
glet at d 9.28 in the 1H NMR data of published 2 agrees well with
the chemical shift of 1 (d 9.31). From Table 2, it is clearly evident
that the mp, IR, proton and carbon NMR data reported for pub-
lished 2 are in good agreement with those of 1. From the above
O
a
NH NH2
CONH2
NH2
3
(iii)
(i), (ii)
1
N
Path b
H
b
4
O
O
N
N
NH
N
(iv)
N
N
2
3
Scheme 2. Reagents and conditions: (i) 2-Nitrobenzaldehyde, water/AcOH, reflux,
5 h, 88% (ii) Fe/HCl, NH4Cl, MeOH, reflux, 0.5 h, 86% (iii) DMF–DMA, AcOH, toluene,
reflux, 2 h, 82% (iv) DDQ, dioxane, rt, 16 h, 85%.
Table 1
Dehydrogenation of 3 with DDQ
S. no.
Conditionsa
Yieldb (%)
1
2
1
2
3
4
5
Dioxane, rt, 16 h
Dioxane, 80 °C, 4 h
Dioxane, reflux, 2 h
THF, rt, 16 h
0
20
43
0
85
50
30
80
49
THF, reflux, 8 h
24
a
All the reactions were performed with 3 (0.5 mmol), DDQ (0.6 mmol) and sol-
vent (20 mL).
Table 2
b
Isolated yields.
Physical and spectroscopic data of 2, published 2 and revised 1
Data
2a
Published 2b
181–183
Revised 1c
190–192
Mp (°C)
IR (cmÀ1
1H NMR
>300
Thus 2-aminobenzamide was condensed with 2-nitrobenzalde-
hyde to give 2-(2-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one13
in 88% yield, which was reduced to 4 using iron powder/HCl in 86%
yield. Selective cyclization of 2-(2-aminophenyl)-2,3-dihydroqui-
nazolin-4(1H)-one (4) on to N1-nitrogen via path b with dimethyl-
formamide–dimethylacetal (DMF–DMA) in toluene/acetic acid at
refluxing temperature gave 3 in 82% yield (Scheme 2). Compound
3 was then treated with DDQ under various conditions and the re-
sults are summarized in Table 1. Dehydrogenation of 3 with
1.2 equiv of DDQ in dioxane at rt gave selectively 2 in 85% yield
(entry 1). However, the same reaction at 80 °C and at refluxing con-
ditions resulted in the formation of 1 and 2 in good yield (entries 2
and 3). As expected dehydrogenation of 3 with DDQ in THF at rt
gave selectively 2, while at refluxing temperature gave both 1
and 2 (entries 4 and 5). These results indicated that the dehydroge-
nation of 3 at lower temperature gave kinetic isomer 2, whereas at
higher temperature thermodynamically stable product 1 is formed.
This might be due to better stability of the system 1 (having com-
)
1656 (C@O)
1703 (C@O)
1705 (C@O)
9.67 (1H, s)
9.28 (1H, s)
9.31 (1H, s)
8.70 (1H, d, 7.6)
8.65 (1H, d, 8.8)
8.29 (1H, d, 7.6)
7.99 (2H, t, 7.4)
7.88 (1H, d, 8.0)
7.77 (1H, t, 7.2)
7.75 (1H, t, 7.2)
8.72 (1H, dd, 7.8, 1.2)
8.32 (1H, dd, 8.1, 1.2)
7.95 (1H, td, 6.9, 1.2)
7.89 (1H, td, 6.9, 1.2)
7.84 (1H, dd, 8.1, 1.2)
7.82 (1H, dd, 8.1, 1.5)
7.72 (1H, td, 6.9, 1.5)
7.59 (1H, td, 8.1, 1.2)
8.75 (1H, d, 7.6)
8.34 (1H, d, 8.0)
7.99 (1H, t, 7.6)
7.92 (1H, t, 7.6)
7.84–7.87 (2H, m)
7.75 (1H, t, 7.4)
7.62 (1H, t, 7.6)
13C NMR
166.05
150.71
143.94
139.28
136.84
134.92
133.94
128.77
128.21
127.68
127.37
126.39
120.46
120.35
115.81
157.75
147.13
144.49
142.89
138.18
135.97
133.85
128.90
127.73
127.37
127.00
126.50
125.41
121.24
118.74
158.73
147.15
144.49
142.91
138.13
135.93
133.81
128.87
127.72
127.37
126.97
126.47
125.41
121.25
118.75
plete
p-conjugation from the carbonyl group to the carbon-6,
which is absent in 2). All the structures have been deduced from
their spectroscopic data.14
Calestani et al. reported8 2 (mp 112–114 °C) with very limited
spectroscopic data while Marinho et al. reported9 the synthesis
of 2 (mp 181–183 °C) starting from o-aminobenzonitrile as shown
in Scheme 3. The differences reported for 2, prompted us to inves-
tigate further. The physical and spectroscopic data of 2 from our
synthesis and that reported are presented in Table 2.
1H NMR (400 MHz) and 13C NMR (100 MHz) in DMSO-d6, chemical shifts are
a
expressed in ppm and J values in parentheses are in Hz.
1H NMR (300 MHz) and 13C NMR (75 MHz) in DMSO-d6 are taken from Ref.9.
b
The compound was synthesized by a known method (Ref.15) and 1H NMR
c
(400 MHz) and 13C NMR (100 MHz) are recorded in DMSO-d6.
O
O
a: HC(OEt)3, H2SO4,
CN
N
N
N
40 oC, 3.5 h
N
N
NH2
b: DMSO, reflux,
1
N
10 min
2
Revised
Published
Scheme 3. Synthesis of 2 by Marinho et al.9 and structure of 1.

4514
S. Venkateswarlu et al. / Tetrahedron Letters 54 (2013) 4512–4514
6. Hu, Z.; Li, S.-d.; Hong, P.-z. ARKIVOC 2010, 9, 171–177.
observation it is safe to conclude that the structure of the product
from the reaction of 2-aminobenzonitrile with triethyl orthofor-
mate is 8H-quinazolino[4,3-b]quinazolin-8-one (1), a known fused
quinazolinoquinazoline.5,6
In summary, we have accomplished the synthesis of 13H-qui-
nazolino[3,4-a]quinazolin-13-one (2) from 2-aminobenzamide in
four steps with an overall yield of 53%. The physical (mp) and spec-
troscopic data (IR, 1H NMR and 13C NMR) did not match with those
published for 2. The reported data for 13H-quinazolino[3,4-a]qui-
nazolin-13-one from the reaction of 2-aminobenzonitrile and tri-
ethyl orthoformate have been reassigned to that of an isomeric
compound, 8H-quinazolino[4,3-b]quinazolin-8-one.
7. (a) Roy, A. D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382–385; (b) Roy,
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Acknowledgments
We sincerely thank Sri G. Ganga Raju, Chairman, and Mr. G.
Rama Raju, Director, Laila Impex, for support and encouragement.
Supplementary data
Supplementary data (general experimental procedures, copies
of 1H, 13C NMR spectra of 1–3 and HPLC chromatogram of 1 and
2) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2013.06.060.
14. Procedure and spectroscopic data of 3: To
a suspension of 4 (717 mg,
3.0 mmol) in toluene (20 mL) were added successively DMF–DMA (0.8 mL,
6.0 mmol) and acetic acid (0.16 mL, 3.0 mmol) at rt and refluxed for 2 h. The
reaction mixture was allowed to rt and the precipitated product was filtered,
washed with toluene and dried. The crude product was recrystallized from
excess of chloroform–methanol to give 3 as a white solid (615 mg, 82% yield),
References and notes
mp 296–302 °C. IR (KBr)
mmax 3447, 3162, 1686, 1620, 1603, 1356, 1303, 1254,
1181, 746 cmÀ1 1H NMR (400 MHz, DMSO-d6) d 8.76 (1H, s, exchangeable
;
1. (a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Comprehensive Heterocyclic
Chemistry II; Pergamon: Oxford, 1996; (b) Joule, J. A.; Mills, K. Heterocyclic
Chemistry; Blackwell Science: Oxford, 2000.
with D2O), 7.98 (1H, d, J = 7.6 Hz), 7.78 (1H, s), 7.69 (1H, t, J = 7.8 Hz), 7.64 (1H,
d, J = 7.6 Hz), 7.36–7.41 (3H, m), 7.25 (1H, t, J = 7.4 Hz), 7.20 (1H, d, J = 8.0 Hz),
6.50 (1H, s); 13C NMR (100 MHz, DMSO-d6) d 162.0, 143.6, 140.8, 139.8, 133.5,
129.9, 128.1, 127.6, 125.8, 125.2, 125.1, 123.1, 118.5, 118.2, 62.0; LC–MS
(positive ion mode): m/z 250 (M+H)+; HRMS-(EI) (m/z): (M+H)+ calcd for
2. (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543–559; (b) Reddy, P. S.; Reddy, P. P.;
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C15H11N3OH 250.0980, found 250.0977.
Procedure and spectroscopic data of 2: To an ice cold suspension of 3 (125 mg,
0.50 mmol) in dioxane (20 mL) was added DDQ (136 mg, 0.60 mmol) and
stirred at rt for 16 h. The reaction mixture was filtered, washed with dioxane to
remove excess reagent. The residue was suspended in 0.1% aqueous sodium
bicarbonate (100 mL) and sonicated for 15 min. The solid was filtered, washed
with water (20 mL) and dried, which was further recrystallized from excess of
chloroform/methanol (1:1) to give the product as a pale yellow solid (105 mg,
85% yield), mp >300 °C. IR (KBr) mmax 1656, 1601, 1529, 1352, 1270, 1238, 1142,
1120, 1034, 910 cmÀ1 1H and 13C NMR: see Table 2; LC–MS (positive ion
;
mode): m/z 248 (M+H)+; HRMS-(EI) (m/z): (M+Na)+ calcd for C15H9N3ONa
270.0643, found 270.0645; HPLC: 99.9%.
Spectroscopic data of 1: mp 190–192 °C (lit.5 mp 194–196 °C). IR (KBr) mmax
1705, 1625, 1379, 1326, 1265, 1211, 1179, 1136, 902, 878, 777 cmÀ1 1H and
;
13C NMR: see Table 2; LC–MS (positive ion mode): m/z 248 (M+H)+; HPLC:
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99.8%.
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