The reaction of anthranilonitrile and triethylorthoformate revisited: Formation of dimeric and trimeric species

Article abstract of DOI:10.1016/j.tet.2010.09.013

The reaction of anthranilonitrile and triethylorthoformate was performed under different experimental conditions, leading to substituted quinazolines, triazachrysenes or quinazolinyl-aminophenyl quinazolines. A mechanistic proposal is presented to rationalize the formation of these compounds. The fluorescence properties of the highly conjugated triazachrysene structures were studied and the fluorescence quantum yield for compounds 5 and 13 was comparable to that of pyrene.

Full text of DOI:10.1016/j.tet.2010.09.013

Tetrahedron 66 (2010) 8681e8689
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The reaction of anthranilonitrile and triethylorthoformate revisited: formation
of dimeric and trimeric species
*
Elina Marinho, Rui Araújo, Fernanda Proença
Centro de Química, Universidade do Minho, Campos de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2010
Received in revised form 31 August 2010
Accepted 3 September 2010
Available online 15 September 2010
The reaction of anthranilonitrile and triethylorthoformate was performed under different experimental
conditions, leading to substituted quinazolines, triazachrysenes or quinazolinyl-aminophenyl quinazo-
lines. A mechanistic proposal is presented to rationalize the formation of these compounds. The fluo-
rescence properties of the highly conjugated triazachrysene structures were studied and the fluorescence
quantum yield for compounds 5 and 13 was comparable to that of pyrene.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Nitrogen heterocycles
2-Aminobenzonitrile
Cascade reaction
Diazachrysenes
Triazachrysenes
1. Introduction
properties are mainly reported in patented work.11 Compounds
with this core structure (e.g., ARC-111, Fig. 1) proved to be potent
The reaction of amines with orthoesters is a convenient and
widely used synthetic approach to prepare imidates.1 The formation
of a formimidate function from the reaction of anthranilonitrile with
triethylorthoformate was previously reported2 and the product was
generated by refluxing the amine in a large excess of orthoester. To
our knowledge, no evidence was provided for the formation of other
products in this reaction. The synthesis of imidates is usually fol-
lowed by their combination with nucleophiles, in particular with
amines to generate amidines, important units in biologically active
compounds.1,3 Nevertheless, the formation of a symmetrical ami-
dine from the reaction of 2-cyanophenylformimidate with anthra-
nilonitrile has not been reported. The same applies to the formation
of substituted triazachrysenes from this synthetic approach.
topoisomerase-targeting agents with exceptional cytotoxic activity
and have been studied as anticancer agents.12
N
N
R5
R4
O
O
MeO
MeO
R1
R2
N
N
O
R3
ARC-111
fagaronine (R1 R2 R4=OMe, R3=H, R5=OH)
nitidine (R1 R2=OMe, R3=H, R4 R5=OCH2O)
chelerythrine ( R1=H, R2 R3,=OMe, R4 R5=OCH2O)
sanguinarine (R1=H, R2 R3=OCH2O, R4 R5=OCH2O)
Azachrysenes are tetracyclic aromatic compounds containing
nitrogen in one of the ring positions.4 A number of natural products
with the benzophenanthridine core unit (Fig. 1) present a broad
spectrum of biological activity.5 These compounds have been im-
portant in particular for the drug industries, especially as antican-
cer,6 muscle relaxants,7 antimicrobial8 and anti-inflammatory
agents.9 Their unique structure makes them valuable intermediates
in the synthesis of azasteroids.10 Substituted diaza- and tri-
azachrysenes are less known and their synthesis and biological
Fig. 1. Biologically active compounds with the azachrysene and diazachrysene core unit.
As part of our research work on the synthesis of novel atypical
antipsychotic drugs,13 anthranilonitrile 1a was reacted with tri-
ethylorthoformate to prepare imidate 2a to be used as a precursor
of a variety of substituted amidines.
2. Results and discussion
The reaction of anthranilonitrile 1a with triethylorthoformate
(TEOF) was initially carried out in ethanol (1 mL/mmol 1a) and
using 3 mol equiv of the orthoester. The reaction was performed
* Corresponding author. Tel.: þ351 253 604379; fax: þ351 253 604382; e-mail
address: fproenca@quimica.uminho.pt (F. Proença).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.013

8682
E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
with nitric acid catalysis (16
m
L/mmol 1a) and warmed in a water
that shows the cyano and carbonyl stretching vibrations at 2235 and
bath at 40 ꢀC for 3 h. The tetracyclic compound 5a precipitated from
solution as the nitrate salt and was isolated as a yellow solid by
simple filtration (Table 1, entry 1). The use of sulfuric acid (Table 1,
entry 2) led to the formation of the same product, isolated in 47%
yield after 3.5 h at 40 ꢀC. In this case, the sulfate counterion was
alkylated, probably due to the presence of an excess of orthoester
and the product was isolated as the ethyl sulfate salt. The ethyl
sulfate anion is a stable counterion used for commercially available
ionic liquids and the NMR data registered for our compounds
agrees with the values reported in the literature for a number of
imidazolinium ethyl sulfate salts.14
1687 cmꢁ1, respectively. In the 1H NMR spectrum, the CeH signal is
a singlet at
d 8.45 ppm, confirming that the aromatic substituent in
the pyrimidone ring is now flexible and the ring current no longer
affects this chemical shift. Correlation studies fully confirm the po-
sition of the neighbouring carbon atoms.
Anthranilonitrile and TEOF were combined with different sol-
vents and acid catalysts. Table 2 summarizes the experimental
conditions selected to prepare the intermediate structures involved
in the synthetic pathway, as is represented in Scheme 1.
Table 2
Optimized experimental conditions for the acid-promoted reaction of an-
thranilonitrile (1) with TEOF
Table 1
Effect of the acid and of the solvent on the annulation of anthranilonitrile (1a) with
TEOF
H
R
NH2
CN
R
N
N
R
N
OEt
OEt
OEt
OEt
+
H
N
R
NH2
CN
R
N
N
OEt
OEt
OEt
N
R
H
+
CN
N
N
R
1a R= H,
2a R= H,
b R= Cl
b R= Cl
O
1a R= H
HX
NH
NC
HX
NH
6
5a R= H, X=SO4Et, NO3
b R= Cl, X=SO4Et, NO3
5a R= H, X=SO4Et, NO3
H
HN
N
R
N
N
N
Entry
1
Reactions conditionsa
Ethanol (1 mL/mmol 1a),
HNO3 (16
L/mmol 1a), 40 ꢀC, 3 h
Ethanol (1 mL/mmol 1a),
H2SO4 (13
L/mmol 1a), 40 ꢀC, 3.5 h
Ethanol (1 mL/mmol 1a),
CH3COOH (12
L/mmol 1a), 40 ꢀC, 11 days
CH3CN (1 mL/mmol 1a),
HNO3 (16
L/mmol 1a), 40 ꢀC, 2.5 h
Petroleum ether (1 mL/0.4 mmol 1a),
HNO3 (16
L/mmol 1a), 40 ꢀC, 3.5 h
H2O (1 mL/mmol 1a),
HNO3 (230 L/mmol 1a), rt, 1.5 days
Product (yield)
N
R
CN
5a, X¼NO3 (76%)
NC
3a
NH
HX
O
m
NC
NC
2
3
4
5
6
5a, X¼SO4Et (47%)
Complex mixtureb
5a, X¼NO3 (47%)
5a, X¼NO3 (41%)
6 (33%)
4a R= H, X=SO4Et
b R= Cl, X=SO4Et
6
m
m
Entry
Reactions conditions
Product (yield)
m
1
2
3
1aþTEOF (1 mL/1.8 mmol 1a), reflux 45 min
1bþTEOF (1 mL/mmol 1b), reflux 45 min
1bþTEOF (1:1), petroleum ether
2a (Quant)
2b (79%)
2b (88%)
m
(1 mL/0.3 mmol 1b), CH3COOH
m
(23 mL/mmol 1b), reflux 1 day
a
4
5
1aþTEOF (1:1), petroleum ether
3a (82%)
3a (45%)
Anthranilonitrile 1a and TEOF were combined in a 1:3 molar ratio.
By TLC.
b
(1 mL/0.6 mmol 1a), TFA
(3 mL/mmol 1a), rt, 18 h
1aþTEOF (1:3), petroleum ether
In the presence of acetic acid, the 2-aminobenzonitrile was only
(1 mL/0.7 mmol 1a),
completely consumed after 11 days at 40 ꢀC, leading to a complex
product mixture (Table 1, entry 3).
TFA (3
1aþTEOF (1:3), CH3CN (1 mL/1.7 mmol 1a),
H2SO4 (15 L/mmol 1a), rt, 1 h
1bþTEOF (1:3), CH3CN (1 mL/0.3 mmol 1b),
H2SO4 (26 L/mmol 1b), rt, 2 h
1aþTEOF (1:3), H2SO4 (7 L/mmol 1a), rt, 18 h
1bþTEOF (1:3), EtOH (1 mL/0.8 mmol 1b),
HNO3 (19
L/mmol 1b), 40 ꢀC, 3 days
1bþTEOF (1:1.2), CH3CN (1 mL/0.3 mmol 1b),
H2SO4 (20 L/mmol 1b), rt, 2.5 days
mL/mmol 1a), rt, 4.5 h
6
7
4a, X¼SO4Et (83%)
4b, X¼SO4Et (80%)
m
The structure of compound 5 was assigned mainly on the basis
of NMR spectroscopy. A broad singlet at
two protons, was assigned to the protonated imino substituent.
Besides the aromatic protons, a singlet at 10.06 ppm integrating
d 10.26 ppm, integrating for
m
8
9
m
5a, X¼SO4Et (83%)
5b, X¼NO3 (79%)
d
m
for one proton confirms that only 1 equiv of the orthoester was
incorporated in the product. This high chemical shift value was
considered a consequence of the anisotropic effect of the adjacent
aromatic ring in the fused heteroaromatic structure. Correlation
techniques (HMBC and HMQC) confirmed the position of the
neighbouring carbon atoms, and supported the proposed structure.
Nitric acid was selected as the most appropriate catalyst for this
reaction and other solvents were used, keeping a constant tem-
perature of 40 ꢀC. Acetonitrile and petroleum ether (boiling range
40e60) resulted in the formation of the same product 5a in a lower
isolated yield (Table 1, entries 4 and 5). In water, the reaction
evolves to the benzopyrimidone 6 suggesting that imine hydrolysis
from a possible intermediate prevents the formation of the
expected triazachrysene structure (Table 1, entry 6).
Substitutedbenzopyridinones were previously preparedfrom the
reaction of a range of substituted anthranilic acids with triethylor-
thoformate, in the presence of concentrated sulfuric acid and upon
reflux in DMF.15 The synthesis of benzopyrimidone 6 was reported
from the reaction of 1a with anhydrous formic acid16 or with N-for-
mylanthranilonitrile in the presence of thionyl chloride.17 The
structure of the product was confirmed by X-ray analysis17 and the
reported IR spectrum agrees with the data obtained for compound 6
10
11
5b, X¼SO4Et (71%)
6 (26%)
m
1aþTEOF (1:3), H2O (1 mL/0.7 mmol 1a),
H2SO4 (1 mL/3.5 mmol 1a), rt, 19 h
Imidate 2 could only be isolated when TEOF was used as solvent
and the mixture was refluxed for 45 min (Table 2, entry 1). The
product was quantitatively isolated as an oily material. This syn-
thetic approach was previously reported in the literature2 and, as
far as we know, is the only procedure that allows the isolation of
imidate 2. When a suspension of 1a and TEOF (1:1 molar ratio) in
petroleum ether and trifluoroacetic acid was stirred at room tem-
perature, compound 3a precipitated from solution as a yellow solid
and was isolated in 82% yield after 18 h (Table 2, entry 4). Increasing
the amount of TEOF (1:3 molar ratio) and decreasing the reaction
time to 4.5 h resulted in a decrease in the isolated yield of 3a to 45%
(Table 2, entry 5). The structure of this compound could only be
assigned on the basis of elemental analysis and IR spectroscopy as
in solution it rapidly evolves to the bicyclic structure 4a. The IR
spectrum clearly shows the stretching vibration of the NeH bond
(3353 cmꢁ1) and of the two cyano groups (2232 and 2219 cmꢁ1).

E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
8683
Table 3
X
X
H
H
N
Optimized experimental conditions for the acid-promoted synthesis of trimeric
compounds 7 and 8
R
R
R
NH2
CN
HC(OEt)3
HX
OEt
R
NH2
CN
R
N
N
N
R
N
OEt
OEt
OEt
CN
H
+
R
N
N
H2N
R
2
1
1a R= H,
R
NH
N
H
N
b R= Cl
X
NC
H
H
N
H2N
N
R
R
H
N
R
R
N
R
NH2
HN
7a R= H
NH
N
R
N
NC
8a R= H,
4
3
b R= Cl
Entry
1
Reactions conditions
Product (yield)
R
N
N
N
N
O
1aþTEOF (1:1), CH3COOH
7a (75%)
R
(13 mL/mmol 1a), rt, 5 days
N
R
2
3
1aþTEOF (1:1), petroleum ether
8a (90%)
8a (52%)
(1 mL/0.6 mmol 1a),
NC
. HX
CH3COOH (13 mL/mmol 1a), rt, 5 days
NH
5
6
1aþTEOF(1:1), petroleum ether
(1 mL/0.2 mmol 1a),
Scheme 1. Proposed mechanism for the reaction of 2-aminobenzonitrile 1 with TEOF
leading to compounds 5 and 6.
CH3COOH (13
1aþTEOF (1:1), ethanol (1 mL/mmol 1a),
CH3COOH (13
L/mmol 1a), 40 ꢀC, 11 days
1aþTEOF (1:1), acetonitrile (1 mL/mmol 1a),
CH3COOH (13
L/mmol 1a), 40 ꢀC, 11 days
1bþTEOF (1:2), EtOH (1 mL/0.2 mmol 1b),
CH3COOH (13 L/mmol 1b), reflux, 3 days
mL/mmol 1a), reflux, 30 min
4
5
6
7aþ8a, 1:2.4 (14%)
7aþ8a, 1:1 (11%)
8b (4%)
m
Compound 4a was isolated in 83% yield from an acetonitrile so-
lution of 1a and TEOF in the presence of sulfuric acid. The reaction
was complete after 1 h at room temperature (Table 2, entry 6).
The isolated yield of compound 5a was improved (83%) when
the amine and the orthoester were combined in the presence of
sulfuric acid, and the mixture was stirred at room temperature for
18 h (Table 2, entry 8).
This reaction sequence was studied for the 4-chloro-2-amino-
benzonitrile 1b resulting in the isolation of 2b, in the absence of
solventorin thepresence ofpetroleum etherand aceticacid(Table 2,
entries 2 and 3) and of 4b from sulfuric acid and acetonitrile (Table 2,
entry 7). The triazachryzene 5b was also prepared either from eth-
anol and nitric acid (Table 2, entry 9) or from acetonitrile and sulfuric
acid(Table 2, entry10). Theformationof the dimericspecies 5results
from a cascade reaction, initiated by the acid catalyzed nucleophilic
attack ofa second molecule of anthranilonitrile to imidate 2 (Scheme
1). Two consecutive intramolecular cyclization processes led to the
final structure 5, always isolated as a salt.
The formation of compound 6 may result from hydrolysis of the
imine function in compound 4, as was previously reported.16
Compound 7a was isolated when a 1:1 mixture of anthranilo-
nitrile 1a and TEOF was stirred at room temperature for 5 days, in
the presence of acetic acid (Table 3, entry 1).
The use of petroleum ether as solvent led to the formation of
compound 8a either after 5 days at room temperature (Table 3,
entry 2) or upon reflux for 30 min (Table 3, entry 3).
m
m
expected to extend the reaction sequence to generate the trimeric
species 8b. The low isolated yield of this compound and the recovery
of 2-amino-4-chlorobenzonitrile suggest that it is difficult to gener-
ate the imidate function under these experimental conditions.
The formation of a trimeric species can be associated with the
use of acetic acid as catalyst and not with the use of petroleum
ether as solvent. The reaction of anthranilonitrile 1a and TEOF was
performed in petroleum ether using nitric acid, sulfuric acid and
trifluoroacetic acid. With nitric acid, the dimer 5a was isolated in
41% yield after 3.5 h at 40 ꢀC (Table 1, entry 5). With trifluoroacetic
acid, compound 3 precipitated from solution and was isolated after
18 h at room temperature (Table 2, entry 4). With sulfuric acid,
a complex mixture was detected by TLC after 1 day at 40 ꢀC.
The reaction of anthranilonitrile 1a and TEOF in the presence of
acetic acid was also performed in ethanol and in acetonitrile. In both
cases, thehomogeneous reactionmixturewasstirredat40 ꢀCleading
to a solid suspension after 6 days. The solid was filtered after 11 days
at 40 ꢀC, when the starting material was no longer detected in solu-
tion. 1H NMR showed that the product was a mixture of compounds
7a and 8a in a 1:2.4 molar ratio (14% from ethanol, Table 3, entry 4)
and in a 1:1 molar ratio (11% from acetonitrile, Table 3, entry 5). The
mother liquor contains a complex mixture in both cases.
The formation of compound 7a, promoted by acetic acid, can be
rationalized if intramolecular cyclization in compound 3a is pre-
vented through a tight ionic interaction between the amidinium
and acetate ions (Scheme 2). The cyano group is now available for
nucleophilic attack by another molecule of anthranilonitrile leading
to 9. Intramolecular cyclization between the imino nitrogen and the
cyano group leads to intermediate 10A, where a new, more basic
aminopyrimidine unit is formed.
The acetate ion will now be preferentially stabilized through an
ionic interaction with this amidine moiety (intermediate 10B) en-
abling intramolecularcyclization togenerate7a. A non-polarsolvent
would favour the formation of a tight ionpair, ultimately responsible
for the major pathway. This could also explain the excellent yield of
the trimeric product obtained in petroleum ether. The formation of
8a is the result of Dimroth rearrangement of 7a, catalyzed by acid,
after prolonged stirring at room temperature or upon reflux.
Compound 8a was generated by Dimroth rearrangement of 7a,
as was confirmed by 1H NMR spectroscopy. In DMSO-d6 solution
and in the presence of TFA (5 mL), 7a (4 mg in 650 mL) gradually
evolved to 8a. After 10 days at room temperature, only traces of 7a
were detected in solution.
The reaction of 2-amino-4-chlorobenzonitrile(1b) with TEOF was
carried out in ethanol with acetic acid catalysis, under reflux condi-
tions (Table 3, entry 6). A clean but slow evolution to compound 8b
was confirmed by 1H NMR on the reaction mixture, recorded at
regular intervals. The solid suspension, filtered after 3 days, was
identified as the pure product 8b (4%). Only the reagents were
present in the mother liquor and 1H NMR confirmed the absence of
the dimeric species 5b. The pure starting material 1b was also iso-
lated in 80% yield. A similar experiment, where 1b and TEOF were
refluxed in petroleum ether, using acetic acid catalysis, led to the
formation of imidate 2b in 88% yield (Table 2, entry 3). The higher
boilingpointofethanolcombinedwithaprolongedrefluxperiodwas

8684
E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
H
presence of triethylamine. Products 12a and 12b were isolated in
82% yield (after 3 h) and 73% yield (after 18 h), respectively (Table 4,
entries 2e4).
H
N
CH3COO
NH2
CN
HC(OEt)3
OEt
CH3COOH
CN
Heating compound 5a in a small volume of DMSO for 10e15 min
(until most of the solvent is eliminated) resulted in its evolution to
compound 13. This product probably arises from hydrolysis
through moisture retained by the solvent, under the high temper-
ature conditions required for the reaction. Reducing the heating
time prevented complete evolution of the starting material 5a
(identified in the reaction mixture by 1H NMR) and performing the
reaction under reflux conditions for longer time periods (up to 3 h)
led mainly to decomposition products.
H2N
NC
1a
2a
CH3
CH3
O
CN
O
O
O
H2N
H
N
HN
H
N
H
N
CN
H
N
H
N
NC
H
H
CN
3a
CN
2.1. UV absorption and fluorescence measurements
9
The planar and highly conjugated structure of these dimeric
compounds suggested that they might be useful fluorophores and
the fluorescent properties of the nitrate salt of 5a and of com-
pounds 11, 12a and 13 were studied. The values recorded were
compared with those for pyrene, a well known and widely used
fluorescent probe.18 The absorption and fluorescence spectra were
recorded in a polar and a non-polar solvent (ethanol and chloro-
benzene) and the data are summarized in Table 5.
H3C
O
H
N
NH
H
O
O
O
HN
N
N
N
H
N
H
N
H
H
N
CH3
N
H
H
CN
CN
The nitrate salt of 5a was insoluble in chlorobenzene and the
only data available was recorded in ethanol.
10A
10B
N
N
Table 5
Absorption maxima (labs), molar extinction coefficients (3), excitation wavelength
NH2
(
lexcitation) and fluorescence quantum yield (4f) for compounds 5a, 11, 12a and 13 in
chlorobenzene (1.0ꢂ10ꢁ6 M) and in ethanol (1.0ꢂ10ꢁ6 M)
HN
N
N
N
Comp
5a HNO3 EtOH
C6H5Cl dc
EtOH 320 (1.16), 340 (1.01), 360 (0.95)
Solvent Absorption labs [nm] (
3 ]
) [104 Mꢁ1cmꢁ1 Fluoresc.a 4fb
H2N
N
Dimroth
N
323 (1.01), 337 (1.27), 353 (1.14)
337
dc
0.24
dc
0.02
N
NH
11
320
326
8a
7a
C6H5Cl 313 (0.94), 326 (0.97), 352 (0.75),
370 (0.60), 390 (0.24)
0.03
0.03
0.12
0.25
0.49
Scheme 2. Postulated mechanism for the reaction of 2-aminobenzonitrile 1 with TEOF
leading to compounds 7 and 8.
12a
EtOH
320 (0.95), 346 (0.89), 360 (0.81),
378 (0.38)
320
324
335
340
C6H5Cl 313 (0.57), 324 (0.58), 355 (0.40),
370 (0.30), 390 (0.11)
Compound 5a was reacted with phenylisocyanate and triethyl-
amine, at room temperature (Table 4, entry 1). The acylated product
11 was isolated in 88% yield after 2 h. The reaction with acetic an-
hydride was also performed at room temperature and in the
13
EtOH
320 (0.95), 335 (0.98), 354 (0.77),
373 (0.50)
C6H5Cl 325 (0.88), 340 (1.00), 358 (0.83),
377 (0.53)
Table 4
Pyr.
EtOH
C6H5Cl 305 (0.81), 318 (1.53), 333 (2.00)
334 (4.63)d
334
338
0.32d
0.39
Optimized experimental conditions for the reaction of dimer 5 with water, acetic
anhydride and phenylisocyanate
a
The measurements were performed under degassed conditions by bubbling of
O
Ar.
b
The fluorescence quantum yield values are relative to that of anthracene
N
N
NHPh
O
N
. HNO3
NH
N
(
4f¼0.27 in ethanol).19
c
N
N
The compound was insoluble in chlorobenzene.
Ref. 18.
N
N
d
H2O in
DMSO
R=H
PhNCO
NEt3
R
N
N
R
R=H
All compounds show a very similar absorption envelope, al-
13
5a R= H
b R= Cl
11
O
though compounds 5a and 13 present a more structured pattern,
resembling that of pyrene. For compound 13, the three well re-
solved absorption bands in the 300e350 nm region show a red shift
of approximately 20 nm relative to those of pyrene, probably as
N
N
CH3
Ac2O, NEt3
N
R
a result of the increase in p-electron density due to the presence of
R
N
nitrogen atoms in the aromatic core structure. In the UV spectrum
of compound 13, an extra absorption band is visible at 377 nm
(chlorobenzene) or at 373 nm (ethanol). In general, the electronic
absorption and fluorescence emission features of these compounds
show only marginal dependence on the solvent polarity.
The fluorescence quantum yield, an important parameter in
accessing the ability of these compounds to act as fluorescent
probes, varies from 0.02 to 0.49, with higher values recorded in
deoxygenated chlorobenzene rather than in ethanol. The low values
(below 0.12) measured for compounds 11 and 12a (Table 5) indicate
12a R= H
b R= Cl
Entry
Reactions conditions
Product (yield)
1
2
3
5aþPhNCO (1:1.2), NEt3 (265
m
L/mmol 5a), rt, 2 h
11 (88%)
12a (82%)
12a (88%)
5aþAc2O (1:8), NEt3 (60
m
L/mmol 5a), rt, 3 h
L/mmol 5a),
CH3CN (1 mL/0.13 mmol 5a), reflux, 3 h
5bþAc2O (1:8), NEt3 (400 L/mmol 5b), rt, 18 h
5a, DMSO (600 L/mmol 5a), heating to dryness
5aþAc2O (1:8), NEt3 (115
m
4
5
m
12b (73%)
13 (93%)
m

E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
8685
a significant involvement of non-radiative relaxation pathways that
may be associated with the conjugation of the -electrons with the
4.2. Spectroscopic measurements
p
exocyclic carbonyl double bond. Compounds 5a and 13 show high
fluorescence quantum yields (4f¼0.24e0.49) comparable with the
values reported for pyrene (4f¼0.32)18 or determined under iden-
tical conditions to those used in the characterization on the new
structures (4f¼0.39).
Fluorescence quantum yields (4f) of pyrene and compounds 5a,
11, 12a and 13 were determined using anthracene as a standard
with a known 4f of 0.27 in ethanol.19 The fluorescence quantum
yields were calculated according to the following equation:
4fðsplÞ
[
4
fðstdÞ3½Astd=Asplꢃ3½Ispl=Istdꢃ3½nspl=nstdꢃ2
The normalized fluorescence and absorption spectra of com-
pounds 5a and 13 (Fig. 2) provide evidence for the structured ab-
sorption spectra of these compounds and the absence of significant
shifts in the fluorescence spectrum of 13 when the solvent is
changed from chlorobenzene to ethanol. The diagram also evi-
dences a loss of vibrational structure and a blue shift in the emis-
sion spectrum of the nitrate salt 5a compared with that of
compound 13 (22 nm).
In this equation, 4f(spl) and 4f(std) are quantum yields of a sample
and of the standard, respectively. Aspl, Ispl and nspl are the optical
density, the integrated emission intensity at the excitation wave-
length and the value of the refractive index of the sample, respec-
tively. Astd, Istd and nstd are those for the standard. Sample
solutions (3.0ꢂ10ꢁ6 M in ethanol and in chlorobenzene) were
degassed with argon before the measurements.
4.3. Procedure for the synthesis of ethyl (2-cyanophenyl)-
imidoformate (2a)
The colourless solution of the 2-aminobenzonitrile (0.21 g,
1.78 mmol) in triethylorthoformate (1 mL) was refluxed for
45 min., leading to a yellow solution. The solvent was concentrated
in the rotary evaporator and the resulting yellow oil was identified
as ethyl (2-cyanophenyl)imidoformate 2a: 1H NMR (300 MHz,
DMSO-d6)
d 8.09 (s, 1H, CH), 7.74 (dd, 1H, H-3, J1 1.5 Hz and J2
7.8 Hz), 7.61 (td, 1H, H-5, J1 1.5 Hz and J2 7.8 Hz), 7.26 (td, 1H, H-4, J1
0.9 Hz and J2 7.8 Hz), 7.21 (d, 1H, H-6, J 8.1 Hz), 4.30 (q, 2H, CH2, J
6.9 Hz,), 1.33 (t, 3H, CH3, J 6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d
158.13 (CH), 150.70 (C1), 134.16 (C5), 133.02 (C3), 124.64 (C4),
120.98 (C6), 117.41 (CN), 106.30 (C2), 62.76 (CH2), 13.90 (CH3); IR
(Nujol mull) 2226, 1640, 1594, 1571, 1485, 1447, 1391, 1372, 1305,
Fig. 2. Absorption and fluorescence spectra of 5a (
) in ethanol and 13 in ethanol
(
) and chlorobenzene ( ) at an excitation wavelength of 340 nm.
1293, 1271, 1257, 1203, 1161, 1101, 1038, 1011 cmꢁ1
.
3. Conclusion
4.4. Procedure for the synthesis of ethyl (5-chloro-
2-cyanophenyl)imidoformate (2b)
Anthranilonitrile and triethylorthoformate, two commercially
available reagents, were used as precursors of highly conjugated
triazachrysene structures. These novel compounds were prepared
under mild experimental conditions and were isolated in a high
purity form by simple filtration. The appropriate selection of sol-
vent, acid, reaction time and temperature, resulted in the formation
of different derivatives, including trimeric species. A mechanistic
proposal was presented to support these results. Compounds 5
were functionalized through the exocyclic imine nitrogen, upon
reaction with acetic anhydride and phenylisocyanate.
Method A: Triethylorthoformate (0.20 g, 1.36 mmol, 226 mL,
1 equiv) and acetic acid (23 mL) were added to a yellow suspension of
2-amino-4-chlorobenzonitrile (0.21 g, 1.36 mmol) in petroleum
ether (5 mL) and the mixture was refluxed. After 1 day, a yellow solid
was filtered and washed with petroleum ether and identified as ethyl
(5-chloro-2-cyanophenyl)imidoformate 2b (0.23 g,1.09 mmol, 88%).
Method B: The yellow suspension of the 2-aminobenzonitrile
(0.16 g, 1.04 mmol) in triethylorthoformate (1 mL) was refluxed for
45 min, leading to a yellow solution. After 2 h at room temperature
a yellow solid precipitatewas filtered and washed with n-hexane and
identified as ethyl (5-chloro-2-cyanophenyl)imidoformate 2b
(0.17 g, 0.82 mmol, 79%): mp 71e73 ꢀC; 1H NMR (300 MHz, DMSO-
4. Experimental section
4.1. General methods
d6)
d 8.16 (s, 1H, CH), 7.79 (d, 1H, H-3, J 8.1 Hz), 7.41 (d, 1H, H-6, J
1.8 Hz), 7.33 (dd, 1H, H-4, J1 1.8 Hz and J2 8.1 Hz), 4.30 (q, 2H, CH2, J
6.9 Hz), 1.33 (t, 3H, CH3, J 6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
All compounds were fully characterized by elemental analysis
and spectroscopic data. The NMR spectra were recorded on a Varian
Unity Plus (1H: 300 MHz, 13C: 75 MHz), or Bruker Avance IIþ 400
(1H: 400 MHz, 13C: 100 MHz) including the 1He13C correlation
spectra (HMQC and HMBC). Deuterated DMSO was used as solvent.
The peak patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; q, quartet and br, broad. The coupling con-
stants, J, are reported in hertz (Hz). IR spectra were recorded on an
FT-IR Bomem MB 104 using Nujol mulls and NaCl cells. The re-
actions were monitored by thin layer chromatography (TLC) using
silica gel 60 F254 (Merck). The melting points were determined on
a Stuart SMP3 melting point apparatus and are uncorrected. Ele-
mental analyses were performed on a LECO CHNS-932 instrument.
Petroleum ether with a boiling range 40e60 was used in all the
experiments.
d
159.26 (CH),152.07 (C1),138.63(C5),134.02(C3),124.66(C4),121.02
(C6),116.66(CN),105.45(C2), 63.08(CH2),13.85(CH3);IR(Nujolmull)
2228,1640,1589,1577,1561,1463,1404,1377,1287,1273,1263,1200,
1177, 1135, 1111, 1082, 1009 cmꢁ1. Anal. Calcd for C10H9N2OCl: C,
57.56; H, 4.36; N, 13.43. Found: C, 57.67; H, 4.49; N, 13.71.
4.5. Procedure for the synthesis of N,N0-bis(2-cyanophenyl)-
imidoformamide (3a)
Method A: Triethylorthoformate (0.27 g, 1.84 mmol, 1 equiv,
310 mL) and TFA (6 mL) were added to a solution of the 2-amino-
benzonitrile 1a (0.22 g, 1.84 mmol) in petroleum ether (3 mL), and
the reaction mixture was stirred at room temperature for 18 h. The
white precipitate was filtered and washed with diethyl ether. The

8686
E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
product was identified as N,N0-bis(2-cyanophenyl)imidoformamide
3a (0.19 g, 0.75 mmol, 82%).
4.8. Procedure for the synthesis of the ethyl sulfate salt of
13H-quinazolino[3,4-a]quinazolin-13-imine (5a)
Method B: Triethylorthoformate (0.98 g, 6.60 mmol, 3 equiv,
1100
mL) and TFA (6
mL) were added to a solution of the 2-amino-
Method A: Triethylorthoformate (0.91 g, 6.12 mmol, 3 equiv,
benzonitrile 1a (0.26 g, 2.20 mmol) in petroleum ether (3 mL), and
the reaction mixture was stirred at room temperature for 4.5 h.
The white precipitate was filtered and washed with diethyl ether.
The product was identified as N,N0-bis(2-cyanophenyl)imido-
formamide 3a (0.12 g, 0.49 mmol, 45%): mp 222e224 ꢀC; 1H and
13C NMR it is very unstable in solution; IR (Nujol mull) 3353, 2232,
2219, 1688, 1667, 1630, 1590, 1571, 1538, 1484, 1454, 1414, 1377,
1323, 1285, 1256, 1231, 1201, 1177, 1155, 1125, 1097, 1041 cmꢁ1. Anal.
Calcd for C15H10N4$1/3CF3COOH: C, 66.20; H, 3.64; N, 19.72. Found:
C, 65.90; H, 3.53; N, 19.74.
1020 mL) and sulfuric acid (26 mL) were added to a suspension of the
2-aminobenzonitrile (0.24 g, 2.04 mmol) in ethanol (2 mL) and the
reaction mixture was stirred at 40 ꢀC for 3.5 h. The pale yellow
precipitate was filtered and washed with diethyl ether. The product
was identified as the ethyl sulfate salt of 13H-quinazolino[3,4-a]-
quinazolin-13-imine 5a (0.18 g, 0.48 mmol, 47%).
Method B: Sulfuric acid (13
aminobenzonitrile (0.21 g, 1.75 mmol) and triethylorthoformate
(0.78 g, 5.25 mmol, 3 equiv, 875 L) and the reaction mixture was
mL) was added to a solution of 2-
m
stirred at room temperature for 18 h. The white precipitate was fil-
tered and washed with diethyl ether. The product was identified as
the ethyl sulfate salt of 13H-quinazolino[3,4-a]quinazolin-13-imine
5a (0.27 g, 0.73 mmol, 83%): mp 244e247 ꢀC; 1H NMR (300 MHz,
4.6. Procedure for the synthesis of the ethyl sulfate salt
of 3-(2-cyanophenyl)-quinazolin-4(3H)-imine (4a)
DMSO-d6) d 10.24 (br s, 2H, NH2),10.04 (s, 1H, CH), 8.97 (d,1H, H-4, J
8.7 Hz), 8.80 (d, 1H, H-11, J 7.8 Hz), 8.63 (d, 1H, H-1, J 8.1 Hz), 8.27 (t,
1H, H-3, J 8.4 Hz), 8.16 (td,1H, H-9, J11.2 Hz and J2 7.2 Hz), 8.06 (d,1H,
H-8, J 7.5 Hz), 8.00 (t,1H, H-2, J 7.5 Hz), 7.94 (t,1H, H-10, J 7.8 Hz), 3.74
(q, 2H, CH2, J 7.2 Hz), 1.09 (t, 3H, CH3, J 7.2 Hz); 13C NMR (75 MHz,
Acetonitrile (3 mL) and sulfuric acid (78
a yellow suspension of 2-aminobenzonitrile (0.60 g, 5.08 mmol) in
triethylorthoformate (2.23 g, 15.03 mmol, 2500 L, 3 equiv). The
mL) were added to
m
reaction mixture was stirred at room temperature and followed by
TLC. After 1 h the white precipitate was filtered and washed with
diethyl ether. The product was identified as the ethyl sulfate salt of
3-(2-cyanophenyl)quinazolin-4(3H)-imine 4a (0.75 g, 2.10 mmol,
DMSO-d6)
d 161.11 (C13), 150.60 (C11b), 144.67 (C7a), 138.90 (CH),
136.79 (C3), 136.70 (C3), 135.81 (C4a), 129.97 (C10), 129.88 (C2),
127.95 (C8), 126.51 (C11), 125.93 (C1), 119.57 (C11a), 117.23 (C4),
113.04 (C13a), 61.23 (CH2), 15.49 (CH3); IR (Nujol mull) 3375, 3297,
1676, 1624, 1598, 1573, 1532, 1501, 1467, 1412, 1378, 1357, 1340, 1317,
1253, 1245, 1216, 1198, 1164, 1146, 1121, 1073, 1062, 1051, 1040,
1020 cmꢁ1. Anal. Calcd for C15H10N4$HSO4C2H5$H2O: C, 52.29; H,
4.66; N, 14.35; S, 8.21. Found: C, 52.47; H, 4.60; N, 14.48; S, 8.07.
83%): mp 241e243 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d 10.68 (br s,
1H, NH), 8.69 (d, 1H, H-5, J 1.2 Hz), 8.31 (dd, 1H, H-30, J1 1.2 Hz and J2
8.0 Hz), 8.21 (td, 1H, H-7, J1 1.2 Hz and J2 7.2 Hz), 8.13 (td, 1H, H-50, J1
1.2 Hz and J2 7.2 Hz), 8.06 (dd, 1H, H-60, J1 1.2 Hz and J2 8.0 Hz), 8.04
(dd, 1H, H-8, J1 1.2 Hz and J2 8.4 Hz), 7.99e7.93 (m, 2H, H-6þH-40),
3.72 (q, 2H, CH2, J 7.2 Hz), 1.11 (t, 3H, CH3, J 7.2 Hz); 13C NMR
4.9. Procedure for the synthesis of the nitrate salt of 13H-
quinazolino[3,4-a]quinazolin-13-imine (5a)
(100 MHz, DMSO-d6)
d 155.91 (C4), 145.56 (C8a), 144.33 (CH),
137.90 (C7), 136.80 (C10), 136.17 (C50), 135.07 (C30), 132.53 (C40),
129.96 (C6), 129.92 (C60), 128.77 (C8), 125.66 (C5), 114.89 (CN),
113.82 (C4a), 111.33 (C20), 61.12 (CH2), 15.11 (CH3); IR (Nujol mull)
3203, 3043, 2227, 1690, 1629, 1602, 1583, 1491, 1482, 1465, 1376,
1298, 1268, 1204, 1193, 1107, 1062, 1020, 1010 cmꢁ1. Anal. Calcd for
C15H10N4$HSO4C2H5: C, 54.85; H, 4.30; N, 15.05; S, 8.60. Found: C,
54.95; H, 4.33; N, 15.00; S, 8.90.
Method A: Triethylorthoformate (0.89 g, 6.0 mmol, 3 equiv,
1000 mL) and nitric acid (31 mL) were added to a solution of the 2-
aminobenzonitrile (0.24 g, 2.0 mmol) in petroleum ether (5 mL)
and the reaction mixture was stirred at 40 ꢀC for 3.5 h. The yellow
precipitate was filtered and washed with diethyl ether. The product
was identified as the nitrate salt of 13H-quinazolino[3,4-a]quina-
zolin-13-imine 5a (0.13 g, 0.41 mmol, 41%).
4.7. Procedure for the synthesis of the ethyl sulfate salt of
7-chloro-3-(5-chloro-2-cyanophenyl)quinazolin-4(3H)-imine
(4b)
Method B: Triethylorthoformate (2.29 g, 15.48 mmol, 3 equiv,
2500 mL) and nitric acid (96 mL) were added to a solution of the 2-
aminobenzonitrile (0.61 g, 5.16 mmol) in ethanol (5 mL), and the
reaction mixture was stirred at 40 ꢀC for 3 h. The yellow precipitate
was filtered and washed with diethyl ether. The product was
identified as the nitrate salt of 13H-quinazolino[3,4-a]quinazolin-
13-imine 5a (0.61 g, 1.97 mmol, 76%).
Acetonitrile (5 mL) and sulfuric acid (26
yellow suspension of 2-amino-4-chlorobenzonitrile (0.20 g,
1.31 mmol) in triethylorthoformate (0.58 g, 3.93 mmol, 650 L,
mL) were added to
a
m
3 equiv). The reaction mixture was stirred at room temperature and
followed by TLC. After 2 h the yellow precipitate was filtered and
washed with diethyl ether. The product was identified as the ethyl
sulfate salt of 7-chloro-3-(5-chloro-2-cyanophenyl)quinazolin-4
(3H)-imine 4b (0.22 g, 0.52 mmol, 80%): mp 261e263 ꢀC; 1H NMR
Method C: Triethylorthoformate (0.93 g, 6.27 mmol, 3 equiv,
1045 mL) and nitric acid (31 mL) were added to a solution of the 2-
aminobenzonitrile (0.25 g, 2.09 mmol) in acetonitrile (2 mL) and
the reaction mixture was stirred at 40 ꢀC for 3 days. The yellow
precipitate was filtered and washed with diethyl ether. The product
was identified as the nitrate salt of 13H-quinazolino[3,4-a]quina-
zolin-13-imine 5a (0.15 g, 0.49 mmol, 47%): mp 262e264 ꢀC; 1H
(400 MHz, DMSO-d6) d 10.72 (br s, 1H, NH), 8.76 (s, 1H, CH), 8.70 (d,
1H, H-5, J 8.8 Hz), 8.36 (d, 1H, H-30, J 8.4 Hz), 8.25 (d, 1H, H-60, J
2.0 Hz), 8.17 (d, 1H, H-8, J 2.0 Hz), 8.11 (dd, 1H, H-40, J1 2.0 Hz and J2
8.4 Hz), 8.06 (dd, 1H, H-6, J1 2.0 Hz and J2 8.8 Hz), 3.71 (q, 2H, CH2, J
7.2 Hz), 1.09 (t, 3H, CH3, J 7.2 Hz); 13C NMR (100 MHz, DMSO-d6)
NMR (400 MHz, DMSO-d6) d 10.26 (br s, 2H, NH2), 10.05 (s, 1H, CH),
8.97 (d, 1H, H-4, J 8.4 Hz), 8.81 (dd, 1H, H-11, J1 1.2 Hz and J2 8.0 Hz),
8.63 (dd, 1H, H-1, J1 1.2 Hz and J2 8.0 Hz), 8.27 (td, 1H, H-3, J1 1.2 Hz
and J2 7.2 Hz), 8.16 (td, 1H, H-9, J1 1.2 Hz and J2 7.2 Hz), 8.07 (d, 1H,
H-8, J 8.4 Hz), 8.01 (t, 1H, H-2, J 7.6 Hz), 7.94 (td, 1H, H-10, J1 1.2 Hz
d
155.56 (C4), 146.50 (C8a), 145.32 (CH), 142.79 (C7), 140.17 (C50),
137.70 (C10), 136.42 (C30), 132.83 (C40), 130.50 (C60), 130.41 (C6),
128.01 (C8),127.71 (C5),114.23 (CN),112.88 (C4a),110.48 (C20), 61.13
(CH2), 15.10 (CH3); IR (Nujol mull) 3207, 3032, 2236, 1698, 1631,
1610, 1586, 1566, 1524, 1463, 1443, 1377, 1322, 1293, 1265, 1243,
1215, 1153, 1139, 1123, 1087, 1062, 1015 cmꢁ1. Anal. Calcd for
C15H8N4Cl2$HSO4C2H5: C, 46.26; H, 3.17; N, 12.70; S, 7.27. Found: C,
46.22; H, 3.28; N, 12.74; S, 6.89.
and J2 7.2 Hz); 13C NMR (100 MHz, DMSO-d6)
d 161.08 (C13), 150.59
(C11b), 144.65 (C7a), 138.89 (CH), 136.74 (C3), 136.66 (C9), 135.80
(C4a), 129.94 (C10), 129.85 (C2), 127.93 (C8), 126.48 (C11), 125.90
(C1), 119.56 (C11a), 117.20 (C4), 113.03 (C13a); IR (Nujol mull) 3278,
3051, 1675, 1623, 1598, 1569, 1535, 1500, 1469, 1412, 1378, 1339,
1310, 1254, 1173, 1141, 1120, 1076, 1037, 1029 cmꢁ1. Anal. Calcd for

E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
8687
C15H10N4$HNO3: C, 58.24; H, 3.59; N, 22.65. Found: C, 58.28; H,
3.47; N, 22.62.
1H, H-50, J 8.0 Hz), 7.80 (d, 1H, H-8, J 8.4 Hz), 7.76 (t, 1H, H-30, J
7.6 Hz), 7.65 (t, 1H, H-6, J 7.6 Hz); 13C NMR (100 MHz, DMSO-d6)
d
159.62 (CO), 147.61 (C8a), 146.41 (CH), 139.54 (C20), 135.25 (C7),
4.10. Procedure for the synthesis of the nitrate salt of 3,9-
dichloro-13H-quinazolino[3,4-a]quinazolin-13-imine (5b)
134.74 (C40), 133.54 (C60), 130.16 (C30), 129.66 (C50), 127.91 (C6),
127.57 (C8), 126.52 (C5), 121.43 (C4a), 115.79 (CN), 111.75 (C10); IR
(Nujol mull) 2235, 1687, 1609, 1597, 1561, 1494, 1465, 1456, 1396,
1377, 1320, 1307, 1291, 1277, 1252, 1187, 1121, 1024 cmꢁ1. Anal. Calcd
for C15H9N3O: C, 72.86; H, 3.68; N,17.00. Found: C, 72.79; H, 3.60; N,
17.16.
Triethylorthoformate (0.69 g, 4.68 mmol, 3 equiv, 780
mL) and
nitric acid (30 L) were added to a suspension of the 2-amino-4-
m
chlorobenzonitrile (0.24 g, 1.56 mmol) in ethanol (5 mL) and the
reaction mixture was stirred at 40 ꢀC for 3 days. The yellow pre-
cipitate was filtered and washed with diethyl ether. The product
was identified as the nitrate salt of 3,9-dichloro-13H-quinazolino
[3,4-a]quinazolin-13-imine 5b (0.23 g, 0.61 mmol, 79%): mp
4.13. Procedure for the synthesis of 2-[2-(4-iminoquinazolin-
3(4H)-yl)phenyl]quinazolin-4-amine (7a)
215e217 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 10.41 (br s, 2H, NH2),
Acetic acid (23
benzonitrile (0.21 g, 1.74 mmol) in triethylorthoformate (0.26 g,
1.74 mmol, 1 equiv, 290 L). The reaction mixture was stirred at
mL) was added to a solution of the 2-amino-
10.02 (s, 1H, CH), 9.17 (d, 1H, H-4, J 1.5 Hz), 8.74 (d, 1H, H-1, J 9.0 Hz),
8.63 (d, 1H, H-11, J 9.0 Hz), 8.23 (d, 1H, H-8, J 2.1 Hz), 8.16 (dd, 1H, H-
2, J1 1.5 Hz and J2 8.7 Hz), 8.03 (dd, 1H, H-10, J1 2.1 Hz and J2 8.7 Hz);
IR (Nujol mull) 3434, 3064, 1677, 1624, 1592, 1528, 1492, 1465, 1378,
1319, 1312, 1244, 1177, 1162, 1110, 1075, 1052, 1039 cmꢁ1. Anal. Calcd
for C15H8N4.HNO3.H2O: C, 45.47; H, 2.80; N, 17.68. Found: C, 45.59;
H, 2.90; N, 17.46.
m
room temperature and followed by TLC. After 5 days the yellow
precipitate was filtered and washed with a mixture of diethyl ether
and petroleum ether (1:1). The product was identified as 2-[2-(4-
iminoquinazolin-3(4H)-yl)phenyl]-quinazolin-4-amine 7a (0.16 g,
0.44 mmol, 75%): mp 228e230 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
8.35 (m, 1H, H-60), 8.12 (d, 1H, H-500, J 7.6 Hz), 8.06 (d, 1H, H-5, J
4.11. Procedure for the synthesis of the ethyl sulfate salt of
3,9-dichloro-13H-quinazolino[3,4-a]quinazolin-13-imine (5b)
7.6 Hz), 7.87 (s, 1H, CH), 7.68e7.66 (m, 2H, H-50þH-40), 7.60 (td, 1H,
H-7, J1 1.2 Hz and J2 8.0 Hz), 7.55e7.51 (m, 2H, H-30þH-700), 7.49 (dd,
1H, H-8, J1 0.8 Hz and J2 8.0 Hz), 7.35 (td, 1H, H-600, J1 1.2 Hz and J2
8.4 Hz), 7.31 (td, 1H, H-6, J1 1.2 Hz and J2 8.4 Hz), 6.99 (d, 1H, H-800, J
Triethylorthoformate (0.23 g, 1.58 mmol, 1.2 equiv, 265
mL) and
sulfuric acid (26 L) were added to a solution of the 2-amino-4-
m
8.0 Hz); 13C NMR (100 MHz, DMSO-d6)
d
161.80 (C400), 159.17 (C200),
chlorobenzonitrile (0.20 g, 1.32 mmol) in acetonitrile (5 mL). The
reaction mixture was stirred at room temperature and followed by
TLC. The yellow precipitate was filtered and washed with diethyl
ether after 2.5 days. The product was identified as the ethyl sulfate
salt of 3,9-dichloro-13H-quinazolino[3,4-a]quinazolin-13-imine 5b
(0.20 g, 0.47 mmol, 71%): mp 269e271 ꢀC; 1H NMR (300 MHz,
154.28 (C4), 149.69 (C8a0), 148.12 (CH), 145.16 (C8a), 137.00 (C20),
132.75 (C700), 132.20 (C7), 131.45 (C60), 130.73 (C40), 130.35 (C30),
129.26 (C50), 127.20 (C800), 126.68 (C8), 126.04 (C6), 125.52 (C600),
125.02 (C5), 123.32 (C500), 121.96 (C4a), 112.65 (C4a0); the signal for
C10 is not visible in the spectrum; IR (Nujol mull) 3305, 3133, 1667,
1633, 1604, 1567, 1547, 1505, 1459, 1377, 1366, 1339, 1299, 1256,
1242, 1184, 1164, 1112 cmꢁ1. Anal. Calcd for C22H16N6$0.2CH3COOH:
C, 71.49; H, 4.47; N, 22.34. Found: C, 71.77; H, 4.52; N, 22.24.
DMSO-d6) d 10.46 (br s, 2H, NH2), 10.01 (s, 1H, CH), 9.16 (d, 1H, H-4, J
1.8 Hz), 8.64 (d, 1H, H-1, J 8.7 Hz), 8.73 (d, 1H, H-11, J 9.0 Hz), 8.20 (d,
1H, H-8, J 2.1 Hz), 8.13 (dd, 1H, H-2, J1 1.5 Hz and J2 9.0 Hz), 8.01 (dd,
1H, H-10, J1 2.1 Hz and J2 9.0 Hz), 3.71 (q, 2H, CH2, J 6.9 Hz), 1.08 (t,
3H, CH3, J 6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d
160.60 (C13),
4.14. Procedure for the synthesis of 2-[2-(quinazolin-4-
ylamino)phenyl]quinazolin-4-amine (8a)
150.49 (C11b), 145.45 (C7a), 142.03 (C3), 141.60 (C9), 140.28 (CH),
136.65 (C4a), 130.52 (C10), 130.36 (C2), 128.40 (C11), 127.90 (C1),
127.23 (C8), 118.83 (C13a), 118.34 (C11a), 117.44 (C4), 61.16 (CH2),
15.11 (CH3); IR (Nujol mull) 3265, 3067, 1679,1622, 1610, 1591, 1563,
1525, 1492, 1467, 1439, 1377, 1348, 1328, 1297, 1265, 1245, 1217,
1195, 1159, 1143, 1108, 1071, 1054, 1040, 1016 cmꢁ1. Anal. Calcd for
C15H8N4Cl2$0.5H2SO4$0.5HSO4C2H5: C, 44.96; H, 2.81; N, 13.11; S,
7.49. Found: C, 45.14; H, 2.94; N, 13.10; S, 7.42.
Method A: Triethylorthoformate (0.26 g, 1.73 mmol, 1 equiv,
288 mL) and acetic acid (23 mL) were added to a solution of the 2-
aminobenzonitrile (0.20 g, 1.73 mmol) in petroleum ether (10 mL).
The reaction mixture was refluxed for 30 min. The resulting yellow
precipitate was filtered and washed with ethanol. The product was
identified as 2-[2-(quinazolin-4-ylamino)phenyl]quinazolin-4-
amine 8a (0.11 g, 0.30 mmol, 52%).
4.12. Procedure for the synthesis of 2-(4-oxoquinazolin-3
Method B: Triethylorthoformate (0.27 g, 1.83 mmol, 1 equiv,
(4H)-yl)benzonitrile (6)
305 mL) and acetic acid (23 mL) were added to a solution of the 2-
aminobenzonitrile (0.22 g, 1.83 mmol) in petroleum ether (3 mL).
The reaction mixture was stirred at room temperature and followed
by TLC. After 5 days the yellow precipitate was filtered and washed
with diethyl ether. The product was identified as 2-[2-(quinazolin-
4-ylamino)phenyl]quinazolin-4-amine 8a (0.20 g, 0.55 mmol,
Method A: To a white suspension of the 2-aminobenzonitrile
(0.41 g, 3.47 mmol) in water (5 mL) were added triethylortho-
formate (1.54 g, 10.41 mmol, 3 equiv, 1750 mL) and sulfuric acid
(1 mL) and the reaction mixture was stirred at room temperature
for 19 h. The yellow precipitate was filtered and washed with
ethanol. The product was identified as 2-(4-oxoquinazolin-3(4H)-
yl)benzonitrile 6 (0.11 g, 0.44 mmol, 26%).
Method B: Triethylorthoformate (0.96 g, 6.48 mmol, 3 equiv,
1080 mL) and nitric acid (0.5 mL) were added to a suspension of the
90%): mp 251e253 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d 13.96 (s, 1H,
NH), 8.99 (d, 1H, H-30, J 7.6 Hz), 8.72 (s, 1H, CH), 8.62 (d, 1H, H-60, J1
1.2 Hz and J2 7.8 Hz), 8.53 (d, 1H, H-5, J 8.4 Hz), 8.31 (d, 1H, H-500, J
8.0 Hz), 8.16 (br s, 2H, NH2), 7.96e7.89 (m, 3H, H-600þH-7þH-700),
7.85 (d, 1H, H-8, J 7.2 Hz,), 7.80 (td, 1H, H-6, J1 1.2 Hz and J2 8.4 Hz),
7.57 (dd,1H, H-800, J11.6 Hz and J2 8.0 Hz), 7.53 (dd,1H, H-40, J11.6 Hz
and J2 8.4 Hz), 7.21 (td, 1H, H-50, J1 1.2 Hz and J2 8.4 Hz); 13C NMR
2-aminobenzonitrile (0.26 g, 2.16 mmol) in water (2 mL) and the
reaction mixture was stirred at 25 ꢀC for 1.5 days. The white pre-
cipitate was filtered and washed with ethanol. The product was
identified as 2-(4-oxoquinazolin-3(4H)-yl)benzonitrile 6 (0.09 g,
0.36 mmol, 33%): mp 200e203 ꢀC; 1H NMR (400 MHz, DMSO-d6)
(100 MHz, DMSO-d6) d
161.80 (C400),161.12 (C200),157.21 (C4),154.54
(CH), 149.68 (C8a), 148.37 (C8a0), 139.78 (C20), 133.91 (C700), 133.15
(C7), 130.78 (C60), 130.49 (C40), 128.18 (C8), 126.88 (C6), 126.07
(C600), 125.99 (C800), 124.65 (C10), 123.93 (C500), 122.31 (C5), 122.06
(C50), 121.39 (C30), 116.12 (C4a), 112.81 (C4a0); IR (Nujol mull) 3314,
d
8.45 (s, 1H, CH), 8.24 (d, 1H, H-5, J 8.4 Hz), 8.10 (d, 1H, H-60, J
7.6 Hz), 7.96 (t, 1H, H-40, J 1.2 Hz), 7.94 (t, 1H, H-7, J 1.2 Hz), 7.85 (d,

8688
E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
3407, 1656, 1632, 1601, 1575, 1542, 1499, 1463, 1436, 1412, 1376,
1356, 1330, 1320, 1286, 1277, 1242, 1159, 1112, 1075, 1029 cmꢁ1
Method B: Triethylamine (48
compound 5a (0.12 g, 0.40 mmol) in acetonitrile (3 mL) and acetic
anhydride (0.33 g, 3.20 mmol, 8 equiv, 300 L). The reaction mixture
mL) was added to a suspension of
.
m
was refluxed for 3 h. Yellow crystals were formed on cooling. The solid
was filtered and washed with ethanol to give N-[13H-quinazolino[3,4-
a]quinazolin-13-ylidene]acetamide 12a (0.10 g, 0.35 mmol, 88%): mp
4.15. Procedure for the synthesis of7-chloro-2-{4-chloro-2-[(7-
chloroquinazolin-4-yl)amino]phenyl}quinazolin-4-amine (8b)
224e227 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 9.46 (s,1H, CH), 8.48 (d,
Triethylorthoformate (0.48 g, 3.26 mmol, 2 equiv, 550
mL) and
1H, H-4, J 1.2 Hz), 8.45 (d, 1H, H-11, J 1.5 Hz), 8.17 (dd, 1H, H-1, J11.5 Hz
and J2 7.8 Hz), 7.93e7.82 (m, 1H, H-9þH-3), 7.77 (dd, 1H, H-8, J1 0.9 Hz
and J2 7.2 Hz), 7.71e7.61 (m, 1H, H-10þH-2), 2.28 (s, 3H, CH3); 13C NMR
acetic acid (23 L) were added to a yellow suspension of 2-amino-
m
4-chlorobenzonitrile (0.25 g, 1.63 mmol) in ethanol (7 mL). The
reaction mixture was refluxed for 3 days. The resulting yellow solid
was filtered and washed with diethyl ether to give the compound
7-chloro-2-{4-chloro-2-[(7-chloroquinazolin-4-yl)amino]phenyl}-
quinazolin-4-amine 8b (0.01 g; 0.02 mmol; 4%): mp >300 ꢀC; 1H
(75 MHz, DMSO-d6) d 186.97 (CO), 148.74 (C13), 147.15 (C11b), 144.06
(C7a), 139.39 (CH), 135.32 (C4a), 134.76 (C9), 133.21 (C3), 128.70 (C10),
128.33(C2),127.30(C8),126.70(C1),125.99(C11),120.42(C11a),118.72
(C13a),115.57 (C4), 26.25 (CH3); IR (Nujol mull) 1674,1631,1608,1591,
1567, 1538, 1477, 1465, 1415, 1377, 1350, 1311, 1293, 1280, 1241, 1223,
1179, 1145, 1118, 1086, 1036, 1018 cmꢁ1. Anal. Calcd for C17H12N4O: C,
70.81; H, 4.20; N, 19.44. Found: C, 70.57; H, 4.31; N, 19.24.
NMR (400 MHz, DMSO-d6)
d
13.95 (s, 1H, NH), 9.09 (d, 1H, H-30, J
2.0 Hz), 8.80 (s, 1H, CH), 8.60 (d, 1H, H-60, J 8.8 Hz), 8.46 (d, 1H, H-5, J
8.8 Hz), 8.33 (d, 1H, H-500, J 8.8 Hz), 8.33(br s, 2H, NH2), 7.94 (d, 1H,
H-8, J 2.0 Hz), 7.88 (d, 1H, H-800, J 2.0 Hz), 7.69 (dd, 1H, H-6, J1 2.0 Hz
and J2 8.8 Hz), 7.63 (dd, 1H, H-600, J1 2.0 Hz and J2 8.8 Hz), 7.29 (dd,
1H, H-50, J1 2.0 Hz and J2 8.8 Hz); 13C NMR (100 MHz, DMSO-d6)
4.18. Procedure for the synthesis of N-[3,9-dichloro-13H-
quinazolino[3,4-a]quinazolin-13-ylidene]acetamide (12b)
d
161.64 (C400), 161.26 (C200), 157.16 (C4), 155.65 (CH), 150.71 (C8a),
146.72 (C8a0), 140.85 (C20), 138.51 (C700), 137.8 (C7 or C40), 137.2 (C7
or C40), 132.42 (C60), (C40), 127.07 (C8), 127.07 (C6), 126.51 (C600),
126.05 (C500), 125.22 (C800), 124.86 (C5), 122.94 (C10), 122.26 (C50),
120.66 (C30), 111.56 (C4a0); IR (Nujol mull) 3434, 3321, 1637, 1604,
1567, 1536, 1491, 1461, 1401, 1377, 1341, 1317, 1261, 1238, 1162,
1083 cmꢁ1. Not enough sample was available for elemental analy-
sis. Removal of the solvent from the mother liquor led to the iso-
lation of 2-amino-4-chlorobenzonitrile (0.20 g; 1.31 mmol; 80%).
The structure of this compound was confirmed by comparison of
the 1H NMR spectrum with that of a commercial sample.
Triethylamine (40
(0.03 g, 0.09 mmol) in acetic anhydride (0.07 g, 0.72 mmol, 8 equiv,
68 L). The reaction mixture was stirred at room temperature and
mL) was added to a suspension of compound 5b
m
followed by TLC. After 18 h the pale yellow solid was filtered and
washed with diethyletherand a few dropsofacetonitrile. Theproduct
was identified as N-[3,9-dichloro-13H-quinazolino[3,4-a]quinazolin-
13-ylidene]acetamide 12b (0.02 g, 0.06 mmol, 73%): mp 268e270 ꢀC;
1H NMR (300 MHz, DMSO-d6)
d 9.39 (s, 1H, CH), 8.59 (d, 1H, H-4, J
1.5 Hz), 8.40(d,1H, H-1, J 9.0 Hz), 8.15 (d,1H, H-11, J 8.7 Hz), 7.82 (d,1H,
H-8, J 2.1 Hz), 7.71e7.65 (m, 2H, H-10þH-2), 2.40 (s, 3H, CH3); 13C NMR
(75 MHz, DMSO-d6) d 169.96 (CO),147.45 (C13),146.63 (C11b),144.78
4.16. Procedure for the synthesis of N-phenyl-N0-[13H-
quinazolino[3,4-a]quinazolin-13-ylidene]urea (11)
(C7a),140.46(CH),139.30(C9),137.92(C3),137.36(C13a),135.94(C4a),
128.75 (C10),128.37 (C2),128.27 (C1),127.68 (C11),126.26 (C8),119.03
(C11a),115.56(C4), 24.82(CH3); IR (Nujolmull) 1686,1634,1592,1540,
1485, 1467, 1430, 1377, 1354, 1338, 1317, 1286, 1264, 1236, 1214, 1147,
1112, 1081, 1052, 1015 cmꢁ1. Anal. Calcd for C17H12N4O.0.3H2O: C,
56.30; H, 2.92; N, 15.45. Found: C, 56.33; H, 2.99; N, 15.44.
Triethylamine (40
pound 5a (0.05 g, 0.16 mmol) and phenyl isocianate (0.02 g,
0.18 mmol,1.2 equiv, 20 L). The reaction mixture was stirred at room
mL) was added to a yellow suspension of com-
m
temperature. After 2 h the white solid was filtered and washed with
few drops of acetonitrile and water leading to the pure product. The
product was identified as N-phenyl-N0-[13H-quinazolino[3,4-a]qui-
nazolin-13-ylidene]urea 11 (0.05 g, 0.14 mmol, 88%): mp 210e212 ꢀC;
4.19. Procedure for the synthesis of 13H-quinazolino[3,4-a]
quinazolin-13-one (13)
1H NMR (300 MHz, DMSO-d6)
d 9.48 (s,1H, CH), 9.45 (s,1H, NH), 8.50
DMSO (90 mL) was addedto compound 5a (0.04 g, 0.14 mmol)and
(d, 1H, H-4, J 8.7 Hz), 8.36 (d, 1H, H-11, J 7.8 Hz), 8.31 (d, 1H, H-1, J
7.5 Hz), 7.91e7.85 (m, 2H, H-9þH-3), 7.77 (d, 1H, H-8, J 8.1 Hz),
7.71e7.60 (m, 4H, H-10þH-20þH-60þH-2), 7.29 (t, 2H, H-30þH-50, J
7.5 Hz), 6.98 (t, 1H, H-40, J 7.2 Hz); 13C NMR (100 MHz, DMSO-d6)
the reaction mixture was heated to dryness in a hot plate (ca.10 min).
The solid was filtered after the addition of water, leading to the pure
product that was identified as 13H-quinazolino[3,4-a]quinazolin-13-
one 13 (0.03 g, 0.13 mmol, 93%): mp 181e183 ꢀC; 1H NMR (300 MHz,
d
162.18 (CO), 151.57 (C13), 146.86 (C11b), 144.04 (C7a), 140.36 (C10),
DMSO-d6) d 9.28 (s,1H, CH), 8.72 (dd,1H, H-11, J11.2 Hz and J2 7.8 Hz),
139.40 (CH), 135.24 (C4a), 134.69 (C9), 133.22 (C3), 128.58 (C10),
128.61(C30 andC50),128.26(C2),127.26(C8),126.63(C1),125.81(C11),
121.98 (C40), 120.36 (C11a), 118.94 (C13a), 118.54 (C20 and C60), 115.49
(C4); IR (Nujol mull) 3301, 1660, 1624, 1603, 1591, 1569, 1547, 1521,
1486, 1473, 1465, 1441, 1377, 1353, 1309, 1290, 1276, 1238, 1217, 1183,
1172, 1147, 1121, 1090, 1077, 1037, 1001 cmꢁ1. Anal. Calcd for
C22H15N5O: C, 72.31;H, 4.15; N,19.17. Found: C, 72.17;H, 4.25; N,19.03.
8.32 (dd,1H, H-1, J11.2 Hz and J2 8.1 Hz), 7.95 (td,1H, H-3, J11.2 Hz and
J2 6.9 Hz), 7.89 (td,1H, H-9, J11.2 Hz and J2 6.9 Hz), 7.84 (dd,1H, H-8, J1
1.2 Hz and J2 8.1 Hz), 7.82 (dd,1H, H-4, J11.5 Hz and J2 8.1 Hz), 7.72 (td,
1H, H-10, J1 1.5 Hz and J2 6.9 Hz), 7.59 (td, 1H, H-2, J1 1.2 Hz and J2
8.1 Hz); 13C NMR (75 MHz, DMSO-d6)
d 157.75 (CO), 147.13 (C4a),
144.49 (C7a), 142.89 (C11b), 138.18 (CH), 135.97 (C3), 133.85 (C9),
128.90 (C10),127.73 (C8),127.37 (C4),127.00 (C1),126.50 (C2),125.41
(C11), 121.24 (C13a), 118.74 (C11a); IR (Nujol mull) 1703, 1625, 1602,
1588,1557,1530,1480,1463,1378,1339,1328,1301,1268,1246,1218,
1179, 1152, 1137, 1096, 1027 cmꢁ1. Anal. Calcd for C15H9N3O$0.7H2O:
C, 69.32; H, 4.04; N, 16.17. Found: C, 69.31; H, 3.80; N, 16.04.
4.17. Procedure for the synthesis of N-[13H-quinazolino[3,4-
a]quinazolin-13-ylidene]acetamide (12a)
Method A: Triethylamine (40
compound 5a (0.20 g, 0.65 mmol) in acetic anhydride (0.53 g,
5.20 mmol, 8 equiv, 490 L). The reaction mixture was stirred at
mL) was added to a suspension of
Acknowledgements
m
room temperature and followed by TLC. After 3 h the white solid
was filtered and washed with diethyl ether and a few drops of
acetonitrile. The product was identified as N-[13H-quinazolino[3,4-
a]quinazolin-13-ylidene]acetamide 12a (0.15 g, 0.53 mmol, 82%).
This work was supported by the University of Minho and by
Fundação para a Ciência e a Tecnologia through project (PCDT/QUI/
59356/2004) and a Ph.D. grant awarded to R.A. (SFRH/BD/38318/
2007).

E. Marinho et al. / Tetrahedron 66 (2010) 8681e8689
8689
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.013. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
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