Reaction of imidoformates with anthranilates: Facile, one-pot, three-component synthesis of 8H-quinazolino[4,3-b]quinazolin-8-ones

Article abstract of DOI:10.1002/jhet.1603

We report a facile, one-pot, three-component methodology for the synthesis of 8H-quinazolino[4,3-b]quinazolin-8-ones from commercially available 2-aminobenzonitriles, triethyl orthoformate, and anthranilic acids/esters/amides in good yields.

Full text of DOI:10.1002/jhet.1603

Month 2013
Reaction of Imidoformates with Anthranilates: Facile, One-Pot,
Three-Component Synthesis of 8H-Quinazolino[4,3-b]quinazolin-8-ones [1]
a
a
a
b
*
S. Venkateswarlu, M. Satyanarayana, P. Ravikiran, and V. Siddaiah
aDrug Discovery, Laila Impex Research Centre, No. 1, Phase III, Jawahar Autonagar, Vijayawada 520 007, India
bDepartment of Organic Chemistry, School of Chemistry, Andhra University, Visakhapatnam 530 003, India
*
E-mail: somepalli01@rediffmail.com
Received August 29, 2011
DOI 10.1002/jhet.1603
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
R3
R1
R2
CN
NH2
HC(OEt)3
AcOH,
N
N
+
R1
R2
NH2
R3
COOR
N
O
We report a facile, one-pot, three-component methodology for the synthesis of 8H-quinazolino[4,3-b]qui-
nazolin-8-ones from commercially available 2-aminobenzonitriles, triethyl orthoformate, and anthranilic
acids/esters/amides in good yields.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Over the past decade, the synthesis of heterocycles has
become the cornerstone of synthetic organic chemistry as
a result of a wide variety of applications of these hetero-
cycles in medicinal and pharmaceutical chemistry [2].
The exploration of heterocycles as privileged structures in
drug discovery is, beyond doubt, one of the major areas
in medicinal chemistry [3]. In these, quinazoline ring
system is a ubiquitous structural unit found in a number
of alkaloids and many biologically active compounds [4].
The quinazolinone moiety is an important pharmaco-
phore showing a number of pharmacological activities.
Among this class of molecules, 4-anilinoquinazolines
have been shown to possess EGFR (epidermal growth
factor receptor) tyrosine kinase inhibitory effects, use-
ful to inhibit tumor growth [5]. For example, Iressa
(1) and Tarceva (2; Fig. 1) are two selective EGFR-
TK inhibitors approved by the FDA in 2004 for locally
advanced or metastatic non-small cell lung cancer
(NSCLC) therapy and are currently under evaluation
in clinical trials for other tumors. The quinazoline-fused
nitrogen-heterocyclic unit, such as 8H-quinazolino[4,3-b]qui-
nazolin-8-ones, has received little attention [6–9] and its
biological activities are not evaluated. Multicomponent reac-
tions (MCRs) have manifested as a powerful tool for the rapid
introduction of molecular diversity. The design and develop-
ment of MCRs for the generation of heterocycles receive
growing interest [10].
Synthesis of the 8H-quinazolino[4,3-b]quinazolin-8-one
skeleton was rarely studied [6–9]. The known methods to
access these nitrogen heterocycles rely on multistep chemical
transformations. For example, two-step conversion of anthra-
nilic acid into 4-chloroquinazoline (3) via 4-(3H)-quinazoli-
none [11] followed by its reaction with either anthranilic
acid or its ester generates 8H-quinazolino[4,3-b]quinazolin-
8-one [6,7], whose efficiency has been increased by employ-
ing microwave irradiation technique [8]. Another method
involves the samarium iodide-promoted intramolecular
cascade radical cyclization of cyanamide radical precursor 4,
which was prepared in three steps from 2-iodoaniline [8]
(Scheme 1). Furthermore, these known methods involve a
series of reactions and the use of corrosive chemicals such
as thionyl chloride/phosphoryl chloride and costly reagents
such as samarium iodide.
During the course of synthesis of novel analogues for
cancer, we were surprised to find that the reaction of imido-
formate [12] with methyl anthranilate produces 8H-quinazo-
lino[4,3-b]quinazolin-8-one (5) in moderate yield. The
structure of the product has been deduced from its spectro-
scopic data and finally confirmed by comparing with that
described in the literature [8,9]. To find the best conditions
for this new reaction, we have selected imidoformate
7a, which was prepared from 2-aminobenzonitrile (6a) and
triethyl orthoformate in presence of acetic acid. Then the
imidoformate 7a was treated with methyl anthranilate under
various conditions and the results were summarized in
Table 1. First, the reaction was examined under protic and
aprotic solvents; however, no reaction was observed (Table 1,
entries 1–3). We were pleased to observe that, with acetic acid
as solvent at RT, the reaction provided the highest yield
Because of our interest in bio-active heterocycles for
cancer, we are interested in the synthesis and evaluation
of fused quinazolines. Herein, we describe a facile, one-
pot, three-component synthesis of 8H-quinazolino[4,3-
b]quinazolin-8-ones.
© 2013 HeteroCorporation

S. Venkateswarlu, M. Satyanarayana, P. Ravikiran, and V. Siddaiah
Vol 000
F
Table 1
O
Optimizationa of 5 from imidoformate 7a.
N
HN
N
HN
N
Cl
O
O
O
H3CO
H3CO
N
N
H3CO
1
2
Figure 1. Chemical structures of Iressa (1) and Tarceva (2).
(65%) of 5a after 1 h (entry 4). When acetic acid was replaced
with trifluoroacetic acid or HCl, the reaction did not proceed
but the imidoformate 7a was completely decomposed (entries
6 and 11). It was also observed that the reaction proceeded
with 1 equivalent of acetic acid and toluene as a solvent in
55% yield (entry 8). The reaction did not proceed in
basic conditions such as K2CO3 and triethylamine (entries
14 and 15).
Encouraged by the aforementioned results, we
tried one-pot procedure to make 5 from readily avail-
able 2-aminobenzonitriles and anthranilic acid esters.
Thus, 2-aminobenzonitrile (6a) was treated with triethyl
orthoformate in toluene to produce imidoformate deriv-
ative 7a. Without purification, the imidoformate 7a was
treated with acetic acid and methyl anthranilate to pro-
duce 5a, in good yield (Scheme 2).
Entry
Solvent
Acid/
base
Temp. (ꢀC)/time (h)
Yieldb
(%)
1
2
3
4
5
6
7
8
Toluene
DMF
DMSO
─
─
─
CH3CN
Toluene AcOH
Toluene AcOH
DMF
DMF
─
─
─
Reflux/1
130–140/1
130–140/1
RT/1
Reflux/0.5
RT/16
Reflux/1
RT/2
Reflux/1
Reflux/5
RT/16
NR
NR
NR
65
64
NR
43
55
44
10
NR
5
AcOH
AcOH
TFA
AcOH
9
10
11
12
13
14
15
AcOH
HCl
AcOH
AcOH
K2CO3
DMSO
Ethanol
DMF
Reflux/3
Reflux/1
130–140/1
Reflux/2
10
NR
NR
Toluene TEA
aReaction conditions: imidoformate 7a (1.0 equiv), methyl anthranilate
(1.2 equiv), solvent, and/or acid/base.
bIsolated yield.
The generality of the methodology has been estab-
lished and generated substituted 8H-quinazolino[4,3-b]
quinazolin-8-ones 5a–5g, summarized in table 2. A
wide variety of substituents on the 2-aminobenzonitrile
and anthranilates were tolerated including methoxy,
methyl, and halogens. We also tried the same procedure
using various esters such as methyl anthranilate (entry
1) and ethyl anthranilate (entry 2) with same yields of
the product. All the products have been characterized
by their analytical and spectroscopic data. Further, the
purity of the compounds has been established by high
performance liquid chromatography (HPLC). Quite ex-
pectedly, the reaction was found to proceed not only
with esters (entries 1–8) but also with anthranilic acids
(entries 9–15) with equal efficiency.
Thus, 2-aminobenzonitrile (6a) was treated with triethyl
orthoformate followed by anthranilamide at RT to produce
5a, in 60% yield. However, using the same procedure with
anthranilonitrile instead of anthranilates did not give the
product 5.
A tentative mechanism via Dimroth rearrangement is
given in Scheme 3. The first step involved the forma-
tion of imidoformate derivative 7 from 2-aminobenzoni-
trile and triethyl orthoformate in presence of acetic acid,
which was then added to methyl anthranilate (8) to give
9. Hydrolysis of the pyrimidine ring of 9 with subse-
quent rotation of 180ꢀ and ring closure gives 4-anilino-
quinazoline derivative 10 [13] and further undergoes
The procedure was also applicable to anthranilamide in-
stead of anthranilates and gave same yield of the products.
Scheme 1. Known methods to prepare 5.
11
12
10
Cl
N
9
N
1
N
I
8
N7
N
2
3
SmI2
O
COR
5
N
6
CN
4
3
5
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
One-Pot Synthesis of 8H-Quinazolino[4,3-b]quinazolin-8-ones
Scheme 2. One-pot synthesis of 8H-quinazolino[4,3-b]quinazolin-8-
ones (5).
CONCLUSIONS
In conclusion, we have demonstrated the reaction of
imidoformates with methyl anthranilate in presence of
acetic acid for the formation of 8H-quinazolino[4,3-b]
quinazolin-8-ones. To the best of our knowledge, this is
the first report for the formation of these nitrogen
heterocycles from imidoformates. This reaction opens the
possibility of new synthetic routes to various heterocyclic
compounds. Subsequently, the reaction has been utilized
as a facile, three-component, one-pot synthesis of 8H-
quinazolino[4,3-b]quinazolin-8-ones starting from readily
available 2-aminobenzonitriles, triethyl orthoformate, and
anthranilic acids/esters/amides. The generality of the meth-
odology has been established and has several advantages,
including simple conditions, easy workup, high yields, and
commercially available starting materials and reagents.
Further investigation into the mechanism and pharmacologi-
cal activities of these nitrogen heterocycles is underway and
will be reported in due course.
R1
R2
CN
R1
R2
CN
N
HC(OEt)3
NH2
AcOH,Δ
OEt
R3
6
7
NH2
COOR
N
R1
R2
R3
N
O
8
N
AcOH, Δ
5
5a: R1=R2=R3=H
5b: R1=R2=OCH3; R3=H
5c: R1=R2=H; R3=CH3
5d: R1=R3=H; R2=Cl
EXPERIMENTAL
Reagents and all solvents were analytically pure grade and
were used without further purification (Sigma-Aldrich, Banga-
lore, India). Anhydrous conditions were not required for this
reaction. Melting points were recorded on a Mel-Temp melt-
ing point apparatus (Electrothermal, Iowa, USA), in open cap-
illaries and were uncorrected. IR spectra were recorded on a
Perkin-Elmer BX1 FTIR spectrophotometer (CT, USA). 1H
NMR (400 MHz), 13C NMR-DEPT (100 MHz) spectra were
recorded on a Bruker AMX 400 MHz NMR spectrometer
(Switzerland). The chemical shifts (d ppm) and coupling con-
stants (Hz) are reported in the standard fashion with reference
to either internal tetramethylsilane (for 1H) or the central line
(77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the
nature of the carbons (C, CH, CH2 or CH3) was determined
by recording the DEPT-135 spectra. Mass spectra were
recorded on Agilent 1100 LC/MSD (USA). High resolution
mass spectra were recorded on Micromass Q-TOF micro mass
spectrometer using electro-spray ionization mode. HPLC was
recorded by a Shimadzu SIL-20A instrument (Tokyo, Japan)
under the following conditions: column, Phenomenex Luma
C18; flow rate, 1 mL/min; detection at 280–360 nm and mo-
bile phase, 0.1% phosphoric acid: acetonitrile.
5e: R1=R2=OCH3; R3=Br
5f: R1=R2=OCH3; R3=Cl
5g: R1=R2=OCH3; R3=CH3
Table 2
One-pot synthesis of 5.
Entry
6
8
Product
Yielda
(%)
R1
R2
R
R3
1
2
3
4
5
6
7
8
H
H
H
H
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
CH3
H
Br
Cl
CH3
H
H
CH3
H
Br
Cl
CH3
5a
5a
5b
5c
5d
5e
5f
5g
5a
5b
5c
5d
5e
5f
65
64
64
69
65
66
62
64
53
55
58
55
56
52
54
OCH3
H
OCH3
H
Cl
OCH3
OCH3
OCH3
H
OCH3
H
H
OCH3
OCH3
OCH3
H
OCH3
H
Ethyl (2-cyanophenyl)imidoformate (7a). To a solution of
2-aminobenzenecarbonitrile (500 mg, 4.23 mmol) in toluene
(15 mL) was added sequentially triethyl orthoformate (1.35 g,
9.15 mmol) and acetic acid (0.15 g, 2.5 mmol) at RT. The
reaction mixture was stirred at 100–110ꢀC for 3 h, and while
stirring, ethanol was collected using the Dean–Stark apparatus.
Toluene was evaporated under vacuum, and the residue was
chromatographed over silica gel column using hexane-EtOAc
(98:2) as eluent to give the product as a pale yellow color oil
(730 mg, 99%) (literature [12a] oil). IR (neat) nmax 2984, 2226,
9
10
11
12
13
14
15
H
H
H
H
H
H
H
Cl
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
5g
aIsolated yields.
1
1643, 1595, 1264, 1199, 1098, 1008, 895, 832, 765 cmÀ1; H
intramolecular lactamization to give 5. Attempts to iso-
late any of the intermediates by carrying out the reac-
tion at low temperatures were unsuccessful.
NMR (400 MHz, CDCl3): d 7.75 (1H, s), 7.60 (1H, dd, J = 7.8,
1.4 Hz), 7.50 (1H, td, J = 7.8, 1.5 Hz), 7.17 (1H, td, J = 7.6,
0.8 Hz), 6.98 (1H, br d, J = 8.0 Hz), 4.42 (2H, q, J = 7.0 Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Venkateswarlu, M. Satyanarayana, P. Ravikiran, and V. Siddaiah
Vol 000
Scheme 3. Proposed mechanism for the formation of 5.
R3
ROOC
R3
NH
R1
R2
CN
N
H2N
OEt
R1
R2
N
R1
R2
8
N
HN
R3
COOR
N
N
7
COOR
H2O
9
ROOC
HN
R3
R3
R3
NH2
HN
N
R1
R2
R1
R2
R1
R2
-ROH
N
NH
OH
-H2O
COOR
N
5
COOR
OH
N
N
10
1.41 (3H, t, J = 7.0 Hz); LC-MS (positive ion mode): m/z 175
127.8, 127.1, 126.6, 125.8, 124.7, 120.6, 117.5, 20.3; LC-MS
(M + H)+.
(positive ion mode): m/z 262 (M + H)+; HPLC: 99.68%.
3-Chloro-8H-quinazolino[4,3-b]quinazolin-8-one (5d).
Pale
General procedure for the one–pot synthesis of 5. To a
solution of 2-aminobenzenecarbonitrile (5 mmol) in toluene
(15 mL) was added sequentially triethyl orthoformate (10 mmol)
and acetic acid (2.5 mmol) at RT. The reaction mixture was
stirred at 100–105ꢀC for 3 h, and while stirring, ethanol was
collected using the Dean–Stark apparatus. Toluene was
evaporated under vacuum. A solution of methyl anthranilate
(6 mmol) in acetic acid (12 mL) was added to the
aforementioned residue and the mixture was stirred at RT for
1 h and refluxed for 1 h. The mixture was poured into ice cold
water, neutralized with ammonia, and stirred for 10 min. The
precipitated solid was filtered, washed with water, dried, and
further purified by column chromatography.
yellow color solid, mp 234–236ꢀC; IR (KBr) nmax 3428, 1704,
1624, 1470, 1380, 1317, 1261, 1243, 1202, 1150, 1068, 844, 770
1
cmÀ1; H NMR (400 MHz, CDCl3): d 9.43 (1H, s), 8.75 (1H, d,
J= 8.4 Hz), 8.43 (1H, dd, J= 8.0, 0.8 Hz), 7.87–7.92 (1H, m),
7.83–7.85 (2H, m), 7.60 (1H, dd, J = 8.6, 1.8 Hz), 7.52–7.57
(1H, m); 13C NMR (100 MHz, CDCl3): d 159.0, 147.6, 144.1,
143.9, 139.9, 139.0, 136.0, 129.4, 127.9, 127.8, 127.7, 127.3,
126.8, 120.1, 118.8; LC-MS (positive ion mode): m/z 282, 284
(M + H)+; HRMS-(EI) (m/z) (M+ H)+ calcd. for C15H8ClN3O
282.0434, found 282.0434; HPLC: 99.49%.
10-Bromo-2,3-dimethoxy-8H-quinazolino[4,3-b]quinazolin-8-one
(5e).
1705, 1625, 1501, 1465, 1307, 1275, 1218, 1110, 1030, 986,
848 cmÀ1 1H NMR (400MHz, CDCl3): d 9.32 (1H, s), 8.42
Pale yellow color solid, mp 264–266ꢀC; IR (KBr) nmax
8H-Quinazolino[4,3-b]quinazolin-8-one (5a).
Pale yellow
color solid, mp 190–192ꢀC (literature [9] mp 194–196ꢀC); IR
(KBr) nmax 1704, 1625, 1460, 1377, 1326, 1262, 1245, 1140, 1023,
;
(1H, d, J = 2.0 Hz), 7.98 (1H, s), 7.85 (1H, dd, J = 8.6, 2.2 Hz),
7.60 (1H, d, J = 8.8Hz), 7.18 (1H, s), 4.10 (3H, s), 4.03 (3H, s);
13C NMR (100MHz, CDCl3): d 158.2, 154.6, 150.5, 146.9,
144.5, 139.4, 138.8, 136.3, 129.8, 129.1, 119.3, 119.0, 114.6,
109.0, 105.3, 56.5, 56.4; LC-MS (positive ion mode): m/z 386,
388 (M+ H)+; HRMS-(EI) (m/z) (M+ H)+ calcd. for
C17H12BrN3O3 386.0140, found 386.0144; HPLC: 98.65%.
10-Chloro-2,3-dimethoxy-8H-quinazolino[4,3-b]quinazolin-8-
one (5f). Pale yellow color solid, mp 272–274ꢀC; IR (KBr) nmax
3428, 1695, 1625, 1572, 1394, 1276, 1219, 1118, 1030, 986, 839
1
876, 773 cmÀ1; H NMR (400 MHz, CDCl3): d 9.37 (1H, s), 8.75
(1H, d, J= 8.0 Hz), 8.37 (1H, d, J=8.0Hz), 7.74–7.86 (4H, m),
7.60 (1H, t, J= 7.2 Hz), 7.49 (1H, t, J=7.2Hz); 13C NMR
(100 MHz, CDCl3): d 159.1, 147.6, 144.4, 143.1, 137.7, 135.8,
133.6, 128.8, 128.1, 127.7, 127.5, 126.5, 125.9, 121.4, 118.7; LC-
MS (positive ion mode): m/z 248 (M + H)+; HPLC: 99.44%.
2,3-Dimethoxy-8H-quinazolino[4,3-b]quinazolin-8-one (5b). Off-
white color solid, mp 290–292ꢀC (literature [8] mp
>260ꢀC); IR (KBr) nmax 3431, 1690, 1628, 1602, 1555,
1
cmÀ1; H NMR (400MHz, CDCl3): d 9.34 (1H, s), 8.28 (1H, d,
1286, 1240, 1213, 1148, 1111, 1019, 979, 861, 770 cmÀ1
;
1H NMR (400 MHz, CDCl3): d 9.40 (1H, s), 8.41 (1H, d,
J = 8.0 Hz), 8.15 (1H, s), 7.81–7.88 (2H, m), 7.48 (1H, t,
J = 7.2 Hz), 7.26 (1H, d, J = 7.6 Hz), 4.12 (3H, s), 4.04
(3H, s); 13C NMR (100 MHz, CDCl3): d 159.3, 154.4,
150.4, 148.1, 144.2, 139.3, 136.6, 135.7, 127.5, 127.3,
125.8, 118.1, 114.8, 109.0, 105.4, 56.5, 56.3; LC-MS
(positive ion mode): m/z 308 (M + H)+; HPLC: 99.57%.
10-Methyl-8H-quinazolino[4,3-b]quinazolin-8-one (5c). Pale
yellow color solid, mp 212–214ꢀC (literature [8] mp 211ꢀC); IR
(KBr) nmax 1712, 1626, 1585, 1489, 1421, 1375, 1328, 1288, 1267,
J = 1.6 Hz), 8.02 (1H, s), 7.68–7.75 (2H, m), 7.20 (1H, s), 4.11
(3H, s), 4.03 (3H, s); 13C NMR (100 MHz, CDCl3): d 158.3,
154.6, 150.5, 146.6, 144.4, 139.3, 136.3, 136.1, 131.5, 128.9,
126.6, 118.9, 114.6, 109.0, 105.3, 56.5, 56.4; LC-MS (positive
ion mode): m/z 342, 344 (M + H)+; HRMS-(EI) (m/z) (M +Na)+
calcd. for C17H12ClN3O3Na 364.0465, found 364.0470; HPLC:
99.51%.
2,3-Dimethoxy-10-methyl-8H-quinazolino[4,3-b]quinazolin-8-
one (5g). Pale yellow color solid, mp 306–308ꢀC (decomp); IR
(KBr) nmax 1699, 1627, 1607, 1289, 1281, 1248, 1218, 1044, 875
1
cmÀ1; H NMR (400MHz, CDCl3): d 9.42 (1H, s), 8.21 (1H, br
1253, 1215, 1149, 1080, 941, 908, 842, 831 cmÀ1 1H NMR
;
s), 8.17 (1H, s), 7.76 (1H, d, J = 8.4Hz), 7.69 (1H, dd, J = 8.2,
1.4 Hz), 7.27 (1H, s), 4.13 (3H, s), 4.05 (3H, s), 2.54 (3H, s); 13C
NMR (100 MHz, CDCl3): d 159.4, 154.2, 150.4, 146.2, 143.7,
(400 MHz, CDCl3): d 9.37 (1H, s), 8.74 (1H, d, J= 8.0 Hz), 8.15
(1H, s), 7.58–7.80 (5H, m), 2.50 (3H, s); 13C NMR (100 MHz,
CDCl3): d 158.1, 144.6, 142.7, 142.0, 136.8, 136.4, 135.8, 132.3,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
One-Pot Synthesis of 8H-Quinazolino[4,3-b]quinazolin-8-ones
[8] Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.; Besson,
T. Tetrahedron 2003, 59, 1413.
139.1, 137.4, 136.8, 136.1, 127.2, 126.8, 117.9, 115.0, 109.1,
105.4, 56.5, 56.4, 21.3; LC-MS (positive ion mode): m/z 322
(M + H)+; HRMS-(EI) (m/z) (M + Na)+ calcd. for C18H15N3O3Na
344.1011, found 344.1012; HPLC: 99.80%.
[9] Hu, Z.; Li, S.-d.; Hong, P.-z. Arkivoc 2010, 9, 171.
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Acknowledgments. We sincerely thank Sri G. Ganga Raju,
Chairman, and Mr. G. Rama Raju, Director, of Laila Impex for
support and encouragement. We are also thankful to Prof. A.
Srikrishna, Department of Organic Chemistry, Indian Institute
of Science, Bangalore, India, for helpful discussions.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet