Synthesis of novel 2,3-substituted quinazolin-4-ones by condensation of alkyl or aromatic diamines with 5-(N-arylimino)-4-chloro-5H-1,2,3-dithiazoles

Article abstract of DOI:10.1016/j.tet.2006.11.028

The work described in this paper is a further example of the utility of Appel's salt in the conception of novel heterocyclic rings. We confirmed that primary alkyldiamines may react easily with the methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-anthrani

Full text of DOI:10.1016/j.tet.2006.11.028

Tetrahedron 63 (2007) 847–854
Synthesis of novel 2,3-substituted quinazolin-4-ones by
condensation of alkyl or aromatic diamines with
5-(N-arylimino)-4-chloro-5H-1,2,3-dithiazoles
*
ꢀ
Maria de Fatima Pereira, Valerie Thiery and Thierry Besson
ꢀ
Laboratoire de Biotechnologies et de Chimie Bio-organique, FRE CNRS 2766, UFR Sciences Fondamentales et Sciences pour
´
l’Ingenieur, Batiment Marie Curie, Universite de La Rochelle, F-17042 La Rochelle cedex 1, France
^
´
Received 3 October 2006; revised 6 November 2006; accepted 10 November 2006
Available online 28 November 2006
Dedicated in the memory of Professor Charles W. Rees
Abstract—The work described in this paper is a further example of the utility of Appel’s salt in the conception of novel heterocyclic rings. We
confirmed that primary alkyldiamines may react easily with the methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-anthranilates to afford qui-
nazolines, which are very interesting starting materials for the access to novel 2,3-condensed quinazolin-4-ones. On the other side, aromatic
amines allow the synthesis of polycyclic molecules, which are structurally close to the model natural products (e.g., rutaecarpine, luotonine,
tryptanthrine and vasicinone).
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of intermediate quinazolines (e.g., 5 in Scheme 1) and a final
nucleophilic attack of the primary amino group on the car-
bonitrile carbon to generate the cyclic amidines, whilst
nucleophilic substitution of the cyano group leads to the
five-membered derivatives (such a mechanism is confirmed
by the results obtained by Kim’s group, which studied the
reaction of ethanolamine and compound 2a).8 After estab-
lishment of the 3D structure of the amidines (3), we observed
that condensation of these key intermediates with anthranilic
acid led to various bis-quinazolines (6a–c) via a modified
Niementowski reaction.7
The quinazolin-4-one skeleton, when selectively functional-
ized, is a building block for the preparation of numerous
alkaloids and substances with pronounced biological proper-
ties, for example, anticancer, diuretic, antiinflammatory,
anticonvulsant and antihypertensive activities.1 As a part of
our ongoing research activity, we launched a research pro-
gramme dealing with the preparation and pharmacological
evaluation of some original quinazoline derivatives, which
possess a quinazolin-4-one moiety fused with another ring
system as described in various terrestrial natural alkaloids
among which rutaecarpine,2 luotonine A,3 tryptanthrine4
and vasicinone5 are the most studied (Fig. 1).
Exploring the best conditions for the synthesis of various
amidines, (e.g., 3) we recently isolated a third category of
products (7), which were identified as dimers of quinazo-
lin-4-ones. The isolated yields of these novel molecules
(7a–c) are low and very difficult to control, but their presence
confirms the existence of the intermediate compounds (5).
Thus, studying the chemistry of 4,5-dichloro-1,2,3-dithi-
azolium chloride (1) (Appel’s salt6) and its derivatives, we
recentlydiscovered that treatment of methyl N-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)-anthranilateswithethylenediamine
gave a rapid and easy access to novel 3,4-dihydro-2H-pyra-
zino[2,1-b]quinazolines (3a–d) mainly accompanied by
variable amounts of the known 2,3-dihydro-1H-imidazo-
[2,1-b]quinazolin-5-one derivatives (4a–d) (Scheme 1).7
The mechanism suggested for this reaction implied existence
Although a wide range of 2,3-condensed (3H)-quinazolin-4-
ones occur in different families of plants and microorgan-
isms, a few papers described the synthesis and the reactivity
of such ring systems.1 Novel derivatives like 3a–d can be
employed as intermediates in the synthesis of the expected
bioactive compounds. Consequently, one of our actual chal-
lenges is to study the chemical behaviour of the starting
imino-1,2,3-dithiazoles with alkanediamines and to vary the
length of the carbon chain between the two functions. Pursu-
ing our efforts, we also explored the possibility to condense
aromatic or semi-aromatic diamines with the imines. This
paper describes the scope and limitations for the access to
Keywords: 4,5-Dichloro-1,2,3-dithiazolium chloride (Appel’s salt); Quina-
zolin-4-ones; Alkanediamines; Imino-1,2,3-dithiazoles.
* Corresponding author at present address: UMR CNRS 6014, Laboratoire
ꢀ
ꢀ
de Chimie Pharmaceutique, UFR Medecine-Pharmacie, Universite de
Rouen, 22 Boulevard Gambetta, 76183 Rouen cedex 1, France. Tel.:
+33 235148399; fax: +33 235148592; e-mail: thierry.besson@
univ-rouen.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.028

848
M. de Fatima Pereira et al. / Tetrahedron 63 (2007) 847–854
O
N
O
N
O
N
O
N
N
N
N
N
N
O
OH
N
H
Rutaecarpine
Luotonine A
Tryptanthrine
Vasicinone
Figure 1.
NH2
R
CO2CH3
Cl
HN
N
O
N
Cl
O
N
S
R
N
+
S
1
-
Cl
6a-d (6-68%)
anthranilic acid
Cl
NH2
N
H
N
NH2
N
N
N
O
H2N
THF, r.t., 1-3h
N
S
R
R
R
+
S
N
N
CO2CH3
2a-d
O
4a-c (4-22%)
3a-d (58 -74%)
N
CN
CN
N
O
O
NH2
R
R
N
N
N
+
+
R
O
NC
7a-c (1-8%)
N
5
Scheme 1. Reaction of imino-1,2,3-dithiazoles (2a–d) with ethylene diamine and preparation of compounds 3, 4 and 7. Reagents and conditions: ethylene
diamine (1 equiv), tetrahydrofuran (THF), rt.
novel quinazolines via 5-(N-arylimino)-4-chloro-5H-1,2,3-
dithiazoles obtained by Appel’s salt chemistry.
2.2. Reaction with 1,3-propane- and 1,4-butanediamine
Extension of the carbon chain between the two amines was
explored using the methodology described for 1,2-ethane-
diamine.7 Reaction of 2a–d with 1 equiv of 1,3-propane-
diamine at room temperature was performed and afforded
good yields of only one family of cyclized and stable prod-
ucts (8a–c), which result from the substitution of the cyano
group by nucleophilic attack of the aliphatic amine of the in-
termediate quinazolin-4-ones. Here again, the dimethoxy
anthranilate derivative (2d) behaved differently than the
other compounds and gave only small amounts of a dimer
(8d) (Scheme 2 and Table 1).
2. Results and discussion
2.1. Synthesis of the starting imino-1,2,3-dithiazoles
Following the usual methods,9 treatment of methyl anthra-
nilates with 4,5-dichloro-1,2,3-dithiazolium chloride 1 in
dichloromethane at room temperature gave the corres-
ponding methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-
anthranilates (2a–d) in quantitative yields.
H
H
N
N
N
N
R
R
N
N
O
O
8a-c
MeO
9a-c
NH2-(CH2)3-NH2
NH2-(CH2)4-NH2
THF, reflux
R
and / or
2a-d
O
N
and / or
CN
THF, r.t.
MeO
N
N
CN
NC
N
N
N
O
N
N
O
NC
R
OMe
OMe
O
10a-b
8d
Scheme 2. Reaction of imino-1,2,3-dithiazoles (2a–d) with 1,3-propane- or 1,4-butanediamine. Reagents and conditions: diamine (1 equiv), THF, 3 h.

M. de Fatima Pereira et al. / Tetrahedron 63 (2007) 847–854
849
Table 1. Reaction of imino-esters (2a–d) with 1,3-propane- or 1,4-butane-
diamines
2.3.1. Reaction with o-phenylenediamine. As it was previ-
ously described in various preliminary studies, the less
nucleophilic aromatic amines have some difficulties in
reacting with the starting iminodithiazoles. In preliminary
experiments, heating of imine 2a and the aromatic diamine
in the presence of pyridine gave only traces of a cyclized
3-(2-aminophenyl)quinazolin-4-one-2-carbonitrile (11). Im-
provement was expected by changing the reaction para-
meters (times of heating, heating mode, atmospheric or
pressurized experiments) but the yields observed were quite
variable. Changing the solvent (THF instead of pyridine)
and stirring time (from 2 to 24 h) of the reaction mixture,
at room temperature, gave a 32% yield of the attempted
compound (11) accompanied by interesting amount (21%)
of another product, which was identified as the 2-aminoqui-
noxaline (12). Prolonged heating (24 h) of the starting
molecules afforded modest yield (18%) of the quinoxaline
(12), accompanied by quite an important amount (37%) of
cyanothioformamide (13a) (Scheme 3). It should be noticed
that, in this case, variable amounts of dithioxamide (14)
(<10%) were also detected, accompanied by traces (2%)
of the cyclized product (15).
Starting ester (R) Yield of 8 (%) Yield of 9 (%) Yield of 10 (%)
a (H)
56
86
81
7
4
4
45
—
3
7
—
—
b (5-Br)
c (4-Cl)
d (4,5-diOMe)
Pursuing our strategy, the iminodithiazole precursors (2a–d)
were heated in the presence of 1 equiv of 1,4-butanediamine.
In these cases, experiments at room temperature did not give
any results and a large part of the starting material was re-
trieved. The resulting products (9 and 10) were difficult to
isolate and the yields were quite low, showing the difficulty
for the intermediate quinazoline to cyclize and to fuse a
seven-membered ring with the quinazoline skeleton. Curi-
ously the chloro-derivative (2c) gave an interesting yield of
the attempted product (9c, 45%) with no traces of dimer. In
these reactions, the dimers can be considered as the major
products although low yields were obtained. Whatever
method was experimented, and in accordance with results
described above, no trace of products 9d and 10d was
detected from the methyl ester (2d).
The hypothesis that quinazolin-4-one (11) and quinoxaline
(12) derivatives may be the precursors of the tetracyclic
6-amino-5,7,12a-triaza-benzo[a]anthracen-12-one (15) was
confirmed by strong heating of these two partners separately
at 220 ꢀC for 10–30 min under microwave irradiation in
sealed tubes (Scheme 4). The synergic effect of microwaves
and pressure gave convenient yields of the final molecule
(15), 40% and 73% respectively from 11 and 12. In a prelim-
inary experiment we also observed that heating the starting
quinazoline 11 at 110 ꢀC in acidic conditions (HBr) gave
a 39% yield of the 6-amino-5,7,12a-triaza-benzo[a]anthra-
cen-12-one (15).
2.3. Condensation with arene- and semi-arene diamines
The second part of our work consisted of extending the fam-
ily of the amines studied to arene or semi-arene diamines.
We decided to investigate the reaction of the imino-1,2,3-di-
thiazoles (2) with o-phenylenediamine and o-aminophene-
thylamine. In these reactants the distance between the two
amine functions is similar to those observed with the ali-
phatic 1,2-ethane or 1,3-propanediamines. Compared with
the preceding examples, the expected cyclized products
will possess a tetracyclic skeleton.
H2N
H
N
H
N
N
CN
+
N
S
Cl
CO2CH3
13a (37%)
NH2
CO2CH3
N
H2N
H2N
N
S
12 (18%)
+
S
heating
CO2CH3
S
H
N
N
N
2a
CN
N
r.t.
S
+
CO2CH3
O
H2N
14 (<10%)
15 (2%)
CN
H
N
N
N
O
NH2
N
N
+
CO2CH3
11 (32%)
12 (21%)
Scheme 3. Conditions and yields: (a) THF, rt, 24 h (11: 32% and 12: 21%) or (b) THF, reflux, 24 h (12: 18%, 13a: 37%, 14: <10% and 15: 2%).
H2N
NH2
N
CN
H
N
N
N
N
NH2
N
N
N
MNP, MW,
220°C, 10 min
MNP, MW,
220°C, 30 min
CO2CH3
O
O
(40%)
(73%)
11
15
12
Scheme 4.

850
M. de Fatima Pereira et al. / Tetrahedron 63 (2007) 847–854
H2N
H2N
THF, reflux, 20h
H
N
H
N
Cl
CN
N
N
R
R
+
N
S
N
R
S
CO2CH3
S
CO2CH3
O
16a-c
13a-c
2a-c
CN
N
N
Br
NH2
O
17a-d
Scheme 5. Synthesis of the fused quinazolines (16a–c) from imino-1,2,3-dithiazoles (2a–c). Reagents and conditions: THF, reflux, 20 h. For yields see Table 2.
2.3.2. Reaction with o-aminophenethylamine. By compar-
ison with the preceding example, the diamine studied in
this paragraph possesses an aromatic amino group associ-
ated with an aliphatic amine. Keeping in mind the results
obtained above, we discovered that heating of imines 2a–c
and o-aminophenethylamine (2 equiv) in THF allowed
the synthesis of novel heterocyclic skeletons (16a–c) in
which two quinazoline rings are fused. The tetracyclic
products (16a–c) are certainly obtained via intermediate
N-substituted quinazolin-4-ones (17a–c in Scheme 5), gen-
erated after a first attack of the most nucleophilic aliphatic
amino group of the semi-arenediamine. This hypothesis was
confirmed when stirring 2b and o-aminophenethylamine at
room temperature for four days, gave a 30% yield of the
uncyclized quinazoline 17b, which cyclized into the corre-
sponding product 16b after heating in acidic conditions
(HBr). In all the experiments, a convenient amount (47–
68%) of the cyanothioformamides (13a–c) was obtained
(Scheme 5, Table 2). It should be noticed that prolonged
heating of 13b in the presence of o-aminophenethylamine,
using the conditions described above, yielded 16b and 17b
in modest yields (5%).
2.4. Discussion
Table 2. Reaction of imino-esters (2a–c) with o-aminophenethylamine
Considering the results obtained in this paper and those
previously published by our team7,9,10 and Kim’s group11
before, it is now possible to describe the most probable
mechanism of the reaction between alkane- or areneamines
and the starting imino-1,2,3-dithiazoles. We suggest that
Starting ester (R)
Yield of 13 (%)
Yield of 16 (%)
a (H)
b (5-Br)
c (4-Cl)
47
68
52
14
9
13
H2N
HN
R
(attack on CN)
H2N
N
NH2
CN
N
H
N
N
N
N
(cyclization)
R
N
O
CO2CH3
CO2CH3
12
15
NH2
N
N
attack on C-5
Cl
N
H2N
R
O
3
CN
R
N
O
H2N
R
N
N
H
N
S
N
N
S
CO2CH3
N
(attack on C-2
of the quinazoline)
n
5, 11, 17
2
O
n = 0(4), 1(8) or2 (9)
H2N
R
attack on S-2
H
N
N
O
S
H
N
H
N
CN
NH2
14
N
S
S
13
CO2CH3
16
CO2CH3
Scheme 6. Suggested mechanism of the action of various amines on the imino-1,2,3-dithiazoles.

M. de Fatima Pereira et al. / Tetrahedron 63 (2007) 847–854
851
´
performed on a Varian MAT 311 in the Centre Regional
´
de Mesures Physiques de l’Ouest (CRMPO, Universite de
Rennes).
most nucleophilic amines (e.g., alkaneamines or alkanedi-
amines) will attack firstly on C-5 of the dithiazole ring and
then give the intermediates quinazolin-4-ones (e.g., 6 in
Scheme 1) suggested in the first part of this work. The final
cyclization observed in the case of diamines may occur by
attack of the second amino group on C-2 of the quinazoline
(compounds 4, 7, 9 and 16) or on the carbonitrile group
(compounds 3 and 15) (Scheme 6).
Microwave heating was performed in a Smith-SynthesizerÔ
(Personal Chemistry, AB) single mode cavity, producing
controlled irradiation at 2450 MHz (a detailed description
of this microwave reactor with integrated robotics was
recently published.16 Reaction temperature and pressure
were determined using the built-in, on-line IR and pressure
sensors. Microwave assisted reactions were performed in
sealed Smith process vials (0.5–5 mL, total volume 10 mL)
under air with magnetic stirring. The software algorithm reg-
ulates the microwave output power so that the selected max-
imum temperature was maintained for the desired reaction/
irradiation time. After the irradiation period, the reaction
vessel was cooled rapidly to ambient temperature by com-
pressed air (gas-jet cooling). The minimal reaction times
were determined by performing sequential series of identical
reactions at constant temperature and with continuous heat-
ing, but with different irradiation times. Completion of the
reaction was estimated by TLC after each individual heating
period.
On the other hand, less nucleophilic amines (e.g., arene-
amines or diamines and also bulky amines in Kim’s work)
will attack on S-2 of the ring and lead to the intermediate cy-
anothioformamides (13), which can be transformed into the
cyanoamidines (6, 17) or into the unexpected thioxamides
(14), as we previously published in similar examples.1
A preliminary evaluation of the potential biological activity
of all the compounds described in this paper was realized
by Meijer’s group, in the Station Biologique de Roscoff,
France, on three protein kinases, CDK1/cyclin B, CDK5/
p25 and GSK-3a,b.13–15 Among all the molecules tested,
none exhibit a significant inhibitory activity against the
target kinases.
4.2. Reaction with alkanediamines, synthesis
of compounds 3–10
3. Conclusion
Spectral data for compounds 2a–d are consistent with struc-
tures published separately in Ref. 7.
The work described in this paper is a further example of the-
utility of Appel’s salt in the conception of novel heterocyclic
rings. We confirmed that methyl N-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-anthranilates are very interesting
starting materials for the access to novel N-substituted qui-
nazolin-4-one derivatives. Primary alkyldiamines may react
easily with the iminodithiazole rings to afford quinazolines,
which can have different behaviours as precursors of a large
family of 2,3-condensed quinazolines, whilst aromatic
amines allow the synthesis of polycyclic molecules, which
are structurally close to the model natural products (e.g.,
rutaecarpine, luotonine, tryptanthrine and vasicinone).
4.2.1. Reaction with 1,2-ethylene diamine, synthesis of
compounds 7a–c from esters 2a–c. A solution of ethylene
diamine (0.11 g, 1.71 mmol) in tetrahydrofuran (THF) (10 mL)
was added slowly to a solution of methyl N-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)-anthranilate (2a–c) (1.71 mmol)
in THF (10 mL). The mixture was stirred for 3 h at room
temperature under inert atmosphere (argon). After evapora-
tion of the solvent under reduced pressure, column chroma-
tography on silica gel with dichloromethane/methanol (9:1,
v/v) as solvent gave products 3, 4 and 7 as solids.
Spectral data for compounds 3 and 4 are consistent with
structures published in Ref. 7.
4. Experimental
4.1. Chemistry
4.2.1.1. Bis-3-methylene-4-oxo-3,4-dihydroquinazo-
line-2-carbonitrile (7a). White solid (6%); mp>260 ꢀC;
Commercial reagents were used as received without addi-
tional purification. Melting points were measured using a
Kofler melting point apparatus and are uncorrected (mp>
260 ꢀC means that the compound does not melt on Kofler
melting point apparatus). IR spectra were recorded on a
Perkin–Elmer Paragon 1000PC FT-IR instrument. 1H NMR
(400 MHz) and 13C NMR (100 MHz) were recorded with
a JEOL JNM LA400 spectrometer. Chemical shifts (d values)
are expressed in parts per million downfield from tetra-
methylsilane as an internal standard and coupling constants
(J) are expressed in hertz. Mass spectra were recorded on
Spectrometer simple quad platform LC micromass, electro-
spray. Thin-layer chromatography (TLC) was performed
on 0.2 mm precoated plates of silica gel 60F-264 (Merck).
Visualization was made with ultraviolet light. Column
chromatography was performed by using Merck silica gel
(70–230 mesh). High-resolution mass measurements were
1
IR (KBr) n 779, 1583, 1683, 2240, 2965 cmꢁ1; H NMR
(DMSO-d6) d 4.67 (s, 4H), 7.69 (td, J¼1.60 Hz and
J¼8.00 Hz, 2H), 7.82 (d, J¼8.00 Hz, 2H), 7.95 (td, J¼
1.60 Hz and J¼8.00 Hz, 2H), 8.08 (dd, J¼1.60 Hz and
J¼8.00 Hz, 2H); 13C NMR (DMSO-d6) d 44.67, 111.46,
121.86, 126.38, 128.00, 130.20, 131.78, 135.50, 145.60,
ꢂ
159.79; MS (m/z) 368; HRMS (EI) [M]+ (C20H12N6O2):
calcd 368.1022; found 368.1035.
4.2.1.2. Bis-6-bromo-3-methylene-4-oxo-3,4-dihydro-
quinazoline-2-carbonitrile (7b). White solid (1%); mp>
260 ꢀC; IR (KBr) n 841, 1382, 1467, 1581, 1688, 2244,
1
3088 cmꢁ1; H NMR (DMSO-d6) d 4.65 (s, 4H), 7.79 (d,
J¼8.80 Hz, H-8), 8.12 (dd, J¼2.80 Hz and J¼8.80 Hz,
H-7), 8.18 (d, J¼2.80 Hz, H-5); MS (m/z) 524; HRMS (EI)
[M]+ꢂ (C20H10N6O2Br2): calcd 523.9232; found 523.9219.

852
M. de Fatima Pereira et al. / Tetrahedron 63 (2007) 847–854
4.2.1.3. Bis-7-chloro-3-methylene-4-oxo-3,4-dihydro-
quinazoline-2-carbonitrile (7c). White solid (8%);
4.2.3. Reaction with 1,4-butanediamine, synthesis of
compounds 9a–c and 10a,b from esters 2a–c. A solution
of 1,4-butanediamine (1.71 mmol) in tetrahydrofuran (THF)
(10 mL) was added slowly to a solution of methyl N-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)-anthranilate (2a–d)
(1.71 mmol) in THF (10 mL). The mixture was stirred at
reflux for 3 h under inert atmosphere (argon). After cooling
and evaporation of the solvent under reduced pressure, col-
umn chromatography on silica gel with dichloromethane/
ethyl acetate (8:2, v/v) as eluent gave products 9a–d and
10a,b as solids.
mp>260 ꢀC; IR (KBr) n 781, 1580, 1706, 2248, 3015,
1
3107 cmꢁ1; H NMR (DMSO-d6) d 4.66 (s, 4H), 7.75 (dd,
J¼2.00 Hz and J¼8.00 Hz, H-6), 7.94 (d, J¼2.00 Hz, H-8),
8.09 (d, J¼8.00 Hz, H-5); 13C NMR (DMSO-d6) d 45.23,
111.68, 121.13, 127.69, 128.91, 130.99, 133.46, 140.84,
ꢂ
147.03, 159.84; MS (m/z) 436; HRMS (EI) [M]+
(C20H10N6O2Cl2): calcd 436.0242; found 436.0238.
4.2.2. Reaction with 1,3-propanediamine, synthesis of
compounds 8a–d from esters 2a–d. A solution of 1,3-pro-
panediamine (1.71 mmol) in tetrahydrofuran (THF) (10 mL)
was added slowly to a solution of methyl N-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)-anthranilate (2a–d) (1.71 mmol)
in THF (10 mL). The mixture was stirred for 3 h at room
temperature under inert atmosphere (argon). After evapora-
tion of the solvent under reduced pressure, column chroma-
tography on silica gel with dichloromethane/ethyl acetate
(8:2, v/v) as eluent gave products 8a–d as solids.
4.2.3.1. 7,8,9,10-Tetrahydro-6H-5,6,10a-triazacyclo-
hepta[b]naphthalen-11-one (9a). Yellow solid (4%);
1
mp¼125 ꢀC; IR (KBr) n 1492, 1690, 2862, 3238 cmꢁ1; H
NMR (CDCl3+D2O) d 1.82–1.97 (m, 4H), 3.28–3.38 (m,
2H), 4.32 (t, J¼6.00 Hz, 2H), 7.23–7.30 (m, 1H), 7.34 (d,
J¼8.00 Hz, 1H), 7.62 (td, J¼1.60 Hz and J¼8.00 Hz, 1H),
8.16 (dd, J¼1.60 Hz and J¼8.00 Hz, 1H); 13C NMR (CDCl3)
d 25.88, 27.12, 43.54, 45.83, 77.67, 118.22, 123.82, 124.61,
127.26, 134.45, 156.05, 163.36; MS (m/z) 215; HRMS (EI)
[M]+ꢂ (C12H13N3O): calcd 215.1057; found 215.1051.
4.2.2.1. 1,2,3,4-Tetrahydro-1,4a,9-triazaanthracen-
10-one (8a). Brown solid (56%); mp>260 ꢀC; IR (KBr) n
1
761, 1097, 1309, 1486, 1626, 1679, 3163 cmꢁ1; H NMR
4.2.3.2. 2-Bromo-7,8,9,10-tetrahydro-6H-5,6,10a-tri-
azacyclohepta[b]naphthalen-11-one (9b). White solid
(4%); mp¼162 ꢀC; IR (KBr) n 827, 1470, 1601, 1655, 2853,
(CDCl3+D2O) d 2.05–2.20 (m, 2H), 3.52 (t, J¼6.00 Hz,
2H), 4.12 (t, J¼6.00 Hz, 2H), 7.12 (t, J¼7.60 Hz, 1H),
7.20 (d, J¼8.00 Hz, 1H), 7.53–7.58 (m, 1H), 8.11 (dd,
J¼1.60 Hz and J¼8.00 Hz, 1H); 13C NMR (CDCl3)
d 20.65, 39.57, 39.79, 116.73, 122.04, 123.54, 127.06,
134.46, 149.47, 149.72, 162.24; MS (m/z) 201; HRMS (EI)
[M]+ꢂ (C11H11N3O): calcd 201.0902; found 201.0897.
1
2935, 3324 cmꢁ1; H NMR (CDCl3+D2O) d 1.85–1.95 (m,
4H), 3.28–3.38 (m, 2H), 4.31 (t, J¼5.60 Hz, 2H), 7.21 (d,
J¼8.80 Hz, H-4), 7.67 (dd, J¼1.60 Hz and J¼8.80 Hz,
H-3), 8.28 (d, J¼1.60 Hz, H-1); 13C NMR (CDCl3) d 25.72,
26.92, 43.74, 45.71, 116.51, 119.56, 126.58, 129.64, 137.44,
ꢂ
147.33, 156.23, 162.29; MS (m/z) 293; HRMS (EI) [M]+
4.2.2.2.
anthracen-10-one (8b). White solid (86%); mp>260 ꢀC;
IR (KBr) 732, 1483, 1623, 1690, 2884, 2972,
6-Bromo-1,2,3,4-tetrahydro-1,4a,9-triaza-
(C12H12N3OBr): calcd 293.0164; found 293.0169.
n
1
4.2.3.3. 3-Chloro-7,8,9,10-tetrahydro-6H-5,6,10a-tri-
azacyclohepta[b]naphthalen-11-one (9c). White solid
(45%); mp¼200 ꢀC; IR (KBr) n 784, 1602, 1684, 2944,
3180, 3224 cmꢁ1; 1H NMR (CDCl3+D2O) d 1.85–1.95 (m,
4H), 3.32 (t, J¼6.00 Hz, 2H), 4.30 (t, J¼6.00 Hz, 2H), 7.18
(dd, J¼2.00 Hz and J¼8.40 Hz, H-2), 7.32 (d, J¼2.00 Hz,
H-4), 8.07 (d, J¼8.40 Hz, H-1); 13C NMR (CDCl3) d 25.64,
26.80, 43.55, 45.59, 116.53, 124.10, 124.26, 128.69, 140.49,
3254 cmꢁ1; H NMR (CDCl3+D2O) d 2.05–2.15 (m, 2H),
3.49 (t, J¼5.80 Hz, 2H), 4.10 (t, J¼5.80 Hz, 2H), 7.09 (d,
J¼8.80 Hz, H-8), 7.59 (dd, J¼2.40 Hz and J¼8.80 Hz,
H-7), 8.21 (d, J¼2.40 Hz, H-5); 13C NMR (CDCl3)
d 20.44, 39.38, 39.93, 114.44, 118.01, 125.46, 129.38,
137.46, 148.38, 149.93, 161.15; MS (m/z) 279; HRMS (EI)
[M]+ꢂ (C11H10N3OBr): calcd 279.0007; found 279.0016.
ꢂ
149.26, 156.74, 162.77; MS (m/z) 249; HRMS (EI) [M]+
4.2.2.3.
7-Chloro-1,2,3,4-tetrahydro-1,4a,9-triaza-
(C12H12N3OCl): calcd 249.0669; found 249.0653.
anthracen-10-one (8c). White solid (81%); mp>260 ꢀC;
IR (KBr) n 684, 910, 1167, 1597, 1630, 1688, 2976,
4.2.3.4. Bis-3-ethylene-4-oxo-3,4-dihydroquinazoline-
2-carbonitrile (10a). White solid (3%); mp>260 ꢀC; IR
(KBr) n 775, 1267, 1582, 1694, 2240, 2945 cmꢁ1; 1H NMR
(CDCl3) d 2.00–2.15 (m, 4H), 4.40–4.50 (m, 4H), 7.66 (td,
J¼1.40 Hz and J¼7.60 Hz, 2H), 7.78–7.88 (m, 4H), 8.32
(dd, J¼1.40 Hz and J¼7.60 Hz, 2H,); 13C NMR (CDCl3)
d 26.35, 45.79, 111.49, 122.63, 127.14, 128.55, 130.16,
131.17, 135.20, 146.32, 159.95; MS (m/z) 396; HRMS (EI)
[M]+ꢂ (C22H16N6O2): calcd 396.1335; found 396.1351.
3150 cmꢁ1; H NMR (CDCl3+D2O) d 2.05–2.20 (m, 2H),
1
3.52 (t, J¼6.00 Hz, 2H), 4.10 (t, J¼6.00 Hz, 2H), 7.06 (dd,
J¼2.00 Hz and J¼8.20 Hz, H-6), 7.19 (d, J¼2.00 Hz,
H-8), 8.02 (d, J¼8.20 Hz, H-5); 13C NMR (CDCl3)
d 20.40, 39.42, 39.76, 115.04, 122.55, 122.76, 128.55,
140.50, 150.35, 150.52, 161.59; MS (m/z) 235; HRMS (EI)
[M]+ꢂ (C11H10N3OCl): calcd 235.0512; found 235.0503.
4.2.2.4. 1,3-Di[3-(2-cyano-6,7-dimethoxy 4-oxo-3,4-
dihydroquinazoline)]propane
(8d).
White
solid;
4.2.3.5. Bis-6-bromo-3-ethylene-4-oxo-3,4-dihydro-
quinazoline-2-carbonitrile (10b). White solid (7%);
mp>260 ꢀC; IR (KBr) n 676, 828, 1325, 1576, 1695,
mp>260 ꢀC; IR (KBr) n 872, 1280, 1500, 1691, 2238,
1
2928 cmꢁ1; H NMR (CDCl3) d 2.42–2.52 (m, 2H), 4.02
1
(br s, 12H, 4ꢃCH3), 4.47 (t, J¼7.00 Hz, 4H,), 7.16 (s,
2H), 7.60 (s, 2H); 13C NMR (CDCl3) d 27.27, 43.61,
55.97, 56.20, 105.30, 108.44, 112.00, 115.86, 130.11,
141.89, 150.85, 154.91, 158.65; MS (m/z) 502; HRMS
(EI) [M]+ꢂ (C25H22N6O6): calcd 502.1601; found 502.1612.
2246, 2944, 3085 cmꢁ1; H NMR (DMSO-d6) d 1.80–1.90
(m, 4H), 4.20–4.30 (m, 4H), 7.77 (d, J¼8.60 Hz, 2H), 8.09
(dd, J¼2.40 Hz and J¼8.60 Hz, 2H), 8.27 (d, J¼2.40 Hz,
ꢂ
2H); MS (m/z) 552; HRMS (EI) [M]+ (C22H14N6O2Br2):
calcd 551.9545; found 551.9525.

M. de Fatima Pereira et al. / Tetrahedron 63 (2007) 847–854
853
4.3. Reaction with o-phenylenediamine, synthesis
of compounds 11–15 from ester 2a
purified by column chromatography on silica gel with
dichloromethane/ethyl acetate (80:20, v/v) as eluent to fur-
nish 16a–c and cyanothioformamides 13a–c. The same pro-
cedure was realized from 2b at room temperature for four
days and afforded 17b in a modest yield (5%).
A solution of N-(4-chloro-5H-1,2,3-dithiazol-5-yliden)-
methyl-benzoate (2a) (0.35 g, 1.22 mmol) and o-phenylene-
diamine (0.26 g, 2.44 mmol) in tetrahydrofuran (20 mL)
was stirred at room temperature for 24 h. The solvent was
evaporated under reduced pressure and the residue was puri-
fied by column chromatography on silica gel with dichloro-
methane/ethyl acetate (9:1, v/v) as eluent to furnish 11
(32%) and 12 (21%). The same procedure was realized at
reflux for 24 h and gave, after purification, compounds 12
(18%), 13a (37%), 14 (<10%) and 15 (2%).
Spectral data for compounds 13a–c are consistent with struc-
tures published in Ref. 7.
4.4.1. 5,12-Dihydro-5,6,11a-triazanaphthacen-11-one
(16a). White solid (47%); mp>260 ꢀC; IR (KBr) n 755,
1
1483, 1556, 1681, 3228 cmꢁ1; H NMR (DMSO-d6+D2O)
d 5.12 (s, 2H), 6.99–7.00 (m, 2H), 7.10–7.25 (m, 2H),
7.25–7.35 (m, 2H), 7.63 (d, J¼7.60 Hz, 1H), 7.97 (d,
J¼7.60 Hz, 1H); 13C NMR (DMSO-d6) d 42.54, 113.84,
116.42, 117.72, 121.85, 122.58, 124.34, 126.38, 126.44,
128.37, 134.44, 135.63, 146.47, 149.00, 161.21; MS (m/z)
4.3.1. 3-(2-Aminophenyl)-4-oxo-3,4-dihydroquinazoline-
2-carbonitrile (11). Yellow solid (32%); mp>260 ꢀC; IR
(KBr) n 559, 1278, 1340, 1634, 1681, 2241, 3362,
ꢂ
1
3450 cmꢁ1; H NMR (CDCl3+D2O) d 6.96–7.00 (m, 2H),
249; HRMS (EI) [M]+ (C15H11N3O): calcd 249.09021;
7.18 (d, J¼8.00 Hz, 1H), 7.39 (t, J¼8.00 Hz, 1H), 7.68–
found 249.0880.
7.72 (m, 1H), 7.88–7.94 (m, 2H), 8.39 (d, J¼8.00 Hz, 1H);
ꢂ
MS (m/z) 262; HRMS (EI) [M]+ (C15H10N4O): calcd
262.0855; found 262.0844.
4.4.2. 9-Bromo-5,12-dihydro-5,6,11a-triazanaphthacen-
11-one (16b). White solid (68%); mp>260 ꢀC; IR (KBr) n
743, 1290, 1479, 1584, 1671, 3266 cmꢁ1
;
1H NMR
4.3.2. 2-(3-Aminoquinoxalin-2-ylamino)-benzoic acid
methyl ester (12). Yellow solid (18–21%); mp¼198 ꢀC;
IR (KBr) n 744, 1258, 1431, 1593, 1690, 2950, 3135,
(DMSO-d6+D2O) d 5.13 (s, 2H), 6.95–7.00 (m, 2H), 7.21
(t, J¼7.80 Hz, 1H), 7.25 (d, J¼8.80 Hz, H-7), 7.29 (d,
J¼8.00 Hz, 1H), 7.74 (dd, J¼2.40 Hz and J¼8.80 Hz,
H-8), 8.03 (d, J¼2.40 Hz, H-10); 13C NMR (DMSO-d6)
d 42.67, 113.83, 113.99, 116.22, 119.18, 122.01, 126.37,
126.70, 128.18, 128.33, 135.16, 137.05, 146.79, 148.07,
3405 cmꢁ1 1H NMR (DMSO-d6+D2O) d 3.80 (s, 3H),
;
7.15 (t, J¼7.60 Hz, 1H), 7.26–7.35 (m, 2H), 7.46–7.52 (m,
2H), 7.63–7.67 (m, 1H), 7.95–7.97 (m, 1H), 8.52 (d,
J¼8.40 Hz, 1H); 13C NMR (DMSO-d6) d 52.01, 117. 62,
121.61, 124.09, 124.51, 125.39, 125.56, 130.41, 135.64,
137.73, 141.34, 146.35, 167.60; MS (m/z) 294; HRMS
(EI) [M]+ꢂ (C16H14N4O2): calcd 294.1117; found 294.1104.
ꢂ
160.12; MS (m/z) 327; HRMS (EI) [M]+ (C15H10N3OBr):
calcd 327.0008; found 327.0350.
4.4.3. 8-Chloro-5,12-dihydro-5,6,11a-triazanaphthacen-
11-one (16c). White solid (52%); mp>260 ꢀC; IR (KBr) n
1
Spectral data for compounds 13a and 14 are consistent with
structures published in Refs. 10 and 12.
775, 866, 1265, 1475, 1584, 1671, 3271 cmꢁ1; H NMR
(DMSO-d6+D2O) d 5.12 (s, 2H), 6.95–7.00 (m, 2H), 7.17
(dd, J¼2.30 Hz and J¼8.60 Hz, H-9), 7.17–7.24 (m, 1H),
7.27–7.31 (m, 2H), 7.95 (d, J¼8.60 Hz, H-10); 13C NMR
(DMSO-d6) d 42.76, 114.20, 116.49, 116.57, 122.45,
122.89, 123.35, 126.54, 128.58, 135.25, 139.31, 147.54,
4.3.3. 6-Amino-5,7,12a-triaza-benzo[a]anthracen-12-one
(15). In a sealed vial, a solution of quinazolinone 11 or 12
(0.06 g, 0.30 mmol) in MNP (3 mL) was heated under mi-
crowave irradiation at 220 ꢀC during 30 min. After cooling,
the solution was diluted with ethyl acetate (10 mL) and
washed with water (3ꢃ10 mL). The organic layer was dried
(MgSO4) and concentrated under reduced pressure. The
crude residue was purified by chromatography on silica gel
with dichloromethane/ethyl acetate (9:1, v/v) as eluent to
give compound 15 as white solid (40% from 11 and 73%
from 12); mp>260 ꢀC; IR (KBr) n 760, 1290, 1562, 1658,
ꢂ
150.32, 160.87; MS (m/z) 283; HRMS (EI) [M]+
(C15H10N3OCl): calcd 283.0512; found 283.0504.
4.4.4. 3-(2-Aminobenzyl)-6-bromo-4-oxo-3,4-dihydro-
quinazoline-2-carbonitrile (17b). Yellow solid (5%);
mp¼212 ꢀC; IR (KBr) n 852, 1386, 1625, 1666, 2237,
1
3032, 3358, 3431 cmꢁ1; H NMR (CDCl3+D2O) d 5.43 (s,
2H), 6.68 (d, J¼8.00 Hz, 1H), 6.75–6.80 (m, 1H), 7.16 (m,
1H), 7.45–7.47 (m, 1H), 7.67 (d, J¼8.80 Hz, H-8), 7.93
(dd, J¼2.00 Hz and J¼8.80 Hz, H-7), 8.47 (d, J¼2.00 Hz,
H-5); 13C NMR (CDCl3) d 46.80, 112.14, 116.99, 118.16,
118.59, 123.58, 124.47, 129.98, 130.09, 130.42, 131.54,
131.78, 138.69, 145.04, 146.03, 159.94; MS (m/z) 354;
1
1700, 3098, 3446 cmꢁ1; H NMR (CDCl3+D2O) d 7.32
(td, J¼1.50 Hz and J¼7.80 Hz, 1H), 7.42–7.48 (m, 1H),
7.56 (dd, J¼1.50 Hz and J¼7.80 Hz, 1H), 7.60–7.67 (m,
1H), 7.80–7.91 (m, 2H), 8.50 (d, J¼7.80 Hz, 1H), 9.50 (d,
ꢂ
J¼8.80 Hz, 1H); MS (m/z) 262; HRMS (EI) [M]+
ꢂ
(C15H10N4O): calcd 262.0854; found 262.0836.
HRMS (EI) [M]+ (C16H11N4OBr): calcd 354.0116; found
354.0110.
4.4. Reaction with o-aminophenethylamine, synthesis of
compounds 16a–c and 17b from esters 2a–c
Acknowledgements
A solution of N-(4-chloro-5H-1,2,3-dithiazol-5-yliden)-
methyl-benzoate (2a–c) (1.19 mmol) and 2-aminophen-
ethylamine (0.29 g, 2.38 mmol) in tetrahydrofuran (20 mL)
was refluxed for 20 h in an oil bath. Upon cooling, the solvent
was evaporated under reduced pressure and the residue was
´
We thank the Comites de Charente (16) & Charente-Mari-
time (17) de la Ligue Nationale contre le Cancer for finan-
cial support and for a Ph.D. grant (M.-F.P.). This work is
also supported by the Canceropo^le Grand-Ouest programme

854
M. de Fatima Pereira et al. / Tetrahedron 63 (2007) 847–854
Rajagopal, S.; Sunil Kumar, K. B.; Seshagiri Rao, C.; Rao
Mamidi, N. V. S.; Deevi, D. S.; Ajaykumar, R.; Rajagopalan,
R. Bioorg. Med. Chem. Lett. 2002, 12, 2303–2307; (c)
Mitscher, L. A.; William, B. Med. Res. Rev. 1998, 18, 363–374.
5. (a) Mhaske, S.; Argade, N. P. J. Org. Chem. 2001, 66, 9038–
9040; (b) Kamal, A.; Ramana, K. V.; Rao, M. V. J. Org.
Chem. 2001, 66, 997–1001; (c) Jolivet-Fouchet, S.; Fabis, F.;
Bovy, P.; Ochsenbein, P.; Rault, S. Heterocycles 1999, 51,
1257–1273; (d) Al-Shamma, A.; Drake, S.; Flynn, D. L.;
Mitscher, L. A.; Park, Y. H.; Rao, G. S. R.; Simpson, A.;
Swayze, J. K.; Veysoglu, T.; Wu, S. T. J. Nat. Prod. 1981, 44,
745–747.
6. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985,
118, 1632–1643.
ꢀ
7. Pereira, M.-F.; Alexandre, F. R.; Thiery, V.; Besson, T.
Tetrahedron Lett. 2004, 45, 3097–3099.
8. For reviews on the chemistry of Appel’s salt derivatives see: (a)
Kim, K. Sulfur Rep. 1998, 21, 147–207; (b) Rees, C. W.
J. Heterocycl. Chem. 1992, 29, 639–651.
‘Modulators of apoptosis’. We also thank Biotage for multi-
form support on microwave experiments.
References and notes
1. For reviews on quinazolinones and quinazolines see: (a)
Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153–10202; (b) Witt, A.; Bergman,
J. Curr. Org. Chem. 2003, 7, 659–677; (c) Armarego,
W. L. F. Adv. Heterocycl. Chem. 1997, 24, 1–62.
2. (a) Chen, J.-J.; Huang, H.-Y.; Duh, C.-Y.; Chen, I.-S. J. Chin.
Chem. Soc. 2004, 51, 659–663; (b) Baruah, B.; Dasu, K.;
Vaitilingam, B.; Mamnoor, P.; Venkata, P. P.; Rajagopal, S.;
Yeleswarapu, K. R. Bioorg. Med. Chem. 2004, 12, 1991–
1994; (c) Zhang, Y.; Zhang, Q.-H.; Wu, L.-J.; Tashiro, S.-I.;
Onodera, S.; Ikejima, T. J. Asian Nat. Prod. Res. 2004, 6,
19–27; (d) Christopher, E.; Bedir, E.; Chuck, D.; Khan, I. A.;
Okunji, C. O.; Schuster, B. M.; Iwu, M. M. Helv. Chim. Acta
2003, 86, 2914–2918; (e) Chang, H. W.; Kim, S. I.; Jung, H.;
Jahng, Y. Heterocycles 2003, 60, 1359–1366; (f) Don, M.-J.;
Lewis, D. F. V.; Wang, S.-Y.; Tsai, M. W.; Ueng, Y.-F.
Bioorg. Med. Chem. Lett. 2003, 13, 2535–2538; (g) Yang,
L.-M.; Chen, C.-F.; Lee, K.-H. Bioorg. Med. Chem. Lett.
1995, 5, 465–468.
3. (a) Lee, E. S.; Park, J. G.; Kim, S. I.; Jahng, Y. Heterocycles
2006, 68, 1990–1998; (b) Ma, Z.; Hano, Y.; Nomura, T.;
Chen, Y. Bioorg. Med. Chem. Lett. 2004, 14, 1193–1196; (c)
Cagir, A.; Eisenhauer, B. M.; Gao, R.; Thomas, S. J.; Hecht,
S. M. Bioorg. Med. Chem. 2004, 12, 6287–6299; (d) Cagir,
A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M.;
Luotonin, A. J. Am. Chem. Soc. 2003, 125, 13628–13629; (e)
Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles
1997, 46, 541–546.
ꢀ
9. Pereira, M.-F.; Picot, L.; Guillon, J.; Leger, J.-M.; Jarry, C.;
Thiery, V.; Besson, T. Tetrahedron Lett. 2005, 46, 3445–3447.
ꢀ
10. (a) Cottenceau, G.; Besson, T.; Gautier, V.; Rees, C. W.; Pons,
A. M. Bioorg. Med. Chem. Lett. 1996, 6, 529–532; (b) Besson,
T.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1995, 1659–
1662; (c) Besson, T.; Emayan, K.; Rees, C. W. J. Chem. Soc.,
Chem. Commun. 1995, 1419–1420; (d) Besson, T.; Emayan,
K.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1995, 2097–
2102.
11. (a) Mohanta, P. K.; Kim, K. Heterocycles 2002, 57, 1471–1485;
(b) Mohanta, P. K.; Kim, K. Tetrahedron Lett. 2002, 43, 3993–
3996; (c) Lee, H.-S.; Chang, Y.-G.; Kim, K. J. Heterocycl.
Chem. 1998, 35, 659–668.
ꢀ
12. Besson, T.; Rees, C. W.; Thiery, V. Synthesis 1999, 1345–1348.
13. Primot, A.; Baratte, B.; Gompel, M.; Borgne, A.; Liabeuf, S.;
Romette, J. L.; Costantini, F.; Meijer, L. Protein Expr. Purif.
2000, 20, 394–404.
14. Borgne, A.; Meijer, L. J. Biol. Chem. 1996, 271, 27847–27854.
15. De Azevedo, W. F.; Leclerc, S.; Meijer, L.; Havlicek, L.;
Strnad, M.; Kim, S. H. Eur. J. Biochem. 1997, 243, 518–526.
16. Schanche, J. S. Mol. Divers. 2003, 7, 293–300.
4. (a) Bhattacharjee, A. K.; Hartell, M. G.; Nichols, D. A.; Hicks,
R. P.; Stanton, B.; van Hamont, J. E.; Milhous, W. K. Eur.
J. Med. Chem. 2004, 39, 59–67; (b) Sharma, V. M.; Prasanna,
P.; Adi Seshu, K. V.; Renuka, B.; Laxman Rao, C. V.; Sunil
Kumar, G.; Prasad Narasimhulu, C.; Aravind Babu, P.;
Puranik, R. C.; Subramanyam, D.; Venkateswarlu, A.;