Novel synthesis of angular thiazolo[5,4-f] and [4,5-h]quinazolines, preparation of their linear thiazolo[4,5-g] and [5,4-g]quinazoline analogs

Article abstract of DOI:10.1016/j.tet.2013.02.066

Synthesis of 9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carbonitrile (1) or 6-oxo-6,7-dihydrothiazolo[4,5-h]quinazoline-2-carbonitrile (2) was reinvestigated with the ambition of varying the position of the thiazole ring linked to the quinazolin-4-one

Full text of DOI:10.1016/j.tet.2013.02.066

Tetrahedron 69 (2013) 3182e3191
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel synthesis of angular thiazolo[5,4-f] and [4,5-h]quinazolines,
preparation of their linear thiazolo[4,5-g] and [5,4-g]quinazoline
analogs
a
,
b
c
a,b
ꢀ
ꢀ
ꢀ
ꢀ c
Damien Hedou , Remi Guillon , Charlotte Lecointe , Cedric Loge ,
Elizabeth Chosson a b, Thierry Besson a
Universite de Rouen, Place Emile Blondel, 76821, Mont-Saint-Aignan, France
Laboratoire C.O.B.R.A., CNRS UMR 6014 & FR3038, Batiment I.R.C.O.F. rue Tesniere, 76821 Mont Saint-Aignan, France
Universite de Nantes, Nantes Atlantique Universites, Laboratoire de Chimie Therapeutique, Cibles et Medicaments des Infections et du Cancer,
,
,b,
*
a
ꢀ
b
c
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
IICiMed UPRES EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, F-44035 Nantes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 January 2013
Received in revised form 15 February 2013
Accepted 19 February 2013
Available online 26 February 2013
Synthesis of 9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carbonitrile (1) or 6-oxo-6,7-dihydrothiazolo
[4,5-h]quinazoline-2-carbonitrile (2) was reinvestigated with the ambition of varying the position of the
thiazole ring linked to the quinazolin-4-one moiety, in order to synthesize two novel linear tricyclic 8-
oxo-7,8-dihydrothiazolo[4,5-g]quinazoline-2-carbonitrile (3) and 8-oxo-7,8-dihydrothiazolo[5,4-g]qui-
nazoline-2-carbonitrile (4). The routes described in this paper open the door to various substitutions and
transformations for an access to libraries of potent biologically active heterocyclic compounds.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted chemistry
Thiazolo[5,4-f]quinazoline
Thiazolo[4,5-h]quinazoline
Thiazolo[4,5-g]quinazoline
Thiazolo[5,4-g]quinazoline
1. Introduction
relationships as dual CDK1/GSK-3 kinases inhibitors were de-
scribed.2 The major drawback observed during this work was linked
Our research groups are mainly invested in the synthesis of C,N,S-
or C,N,O-containing heterocyclic precursors of bioactive molecules
able to modulate the activity of kinases in signal transduction.1e5 In
the course of our work, the multi-step synthesis of the 8H-thiazolo
[5,4-f]quinazolin-9-one (A) and its regio-isomer 7H-thiazolo[4,5-h]
quinazolin-6-one (B) was described for the first time 10 years ago
under microwave heating.6,7 The chemical highlight of this work was
the use of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt8),
a versatile reagent, which can be used in the design of novel het-
erocyclic skeletons and especially for the conception of nitrile-
bearing heteroarenes with broad applications in biological sci-
ences.8 Apart from this work, chemistry of both heterocyclic ring
systems (A and B in Fig.1) was explored and reactivity of the car-
bonitrile function present in position 2 of the thiazole ring was
studied, allowing easy synthesis of various amidine, imidazoline, and
imidate derivatives.2,3 Brief studies of their structureeactivity
to the instability of the carbonitrile group generated by the trans-
formation of imino-1,2,3-dithiazoles intermediates. At that time, it
was not possible to isolate 9-oxo-8,9-dihydrothiazolo[5,4-f]quina-
zoline-2-carbonitrile (1) or 6-oxo-6,7-dihydrothiazolo[4,5-h]quina-
zoline-2-carbonitrile (2) (Fig. 1) with both an unsubstituted
pyrimidin-4-one moiety and a thiazole ring itself substituted in
position 2 by the versatile carbonitrile group.
Because we thought that the synthesis of such intermediates
would grant access to many derivatives and thus the preparation of
a library of interesting molecules, we decided to reinvestigate the
synthesis of these thiazolo[5,4-f]quinazolin-4-one (1) and thiazolo
[4,5-h]quinazolin-4-one (2) and to explore the possibility of vary-
ing the position of the thiazole ring linked to the quinazolin-4-one
moiety in order to synthesize two novel linear tricyclic 8-oxo-7,8-
dihydrothiazolo[4,5-g]quinazoline-2-carbonitrile (3) and 8-oxo-
7,8-dihydrothiazolo[5,4-g]quinazoline-2-carbonitrile (4) (Fig. 1).
Here again we decided to examine the possibilities offered by the
thermal transformation of intermediate N-arylimino-1,2,3-
dithiazoles themselves obtained by condensation of Appel salt
with aromatic amines. This paper describes the results of our
* Corresponding author. Tel.: þ33 (0) 235522904; fax: þ33 (0) 235522962;
e-mail address: thierry.besson@univ-rouen.fr (T. Besson).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.066

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3183
Fig. 1. Target molecules of this study.
investigations. In an overall aspect, this work also aims at showing
the crucial utility of microwaves in organic reactions, especially in
heterocyclic syntheses where harsh thermal conditions are some-
times required.9
imine 9. The latter was condensed with 4,5-dichloro-1,2,3-
dithiazolium chloride (Appel salt) in dichloromethane at room
temperature. Addition of pyridine led to the desired imino-1,2,3-
dithiazoloquinazolinone 10. Product 11 was obtained by
microwave-assisted thermolysis consisting into a rapid heating of
the starting imine 10 (1 min at 160 ꢀC in a sealed tube) in the
presence of copper(I) iodide in pyridine. Access to ring A was per-
formed by heating the protected compound 11 in sulfuric acid,
involving deprotection of the nitrogen group and decyanation
(hydrolysisþdecarboxylation) of the thiazole moiety. Technology
used for heating, reaction times, and yields are given in Scheme 1.
This route (Scheme 1) was the result of various trials and
experiments,1e7 which demonstrated that: (a) in step b, protection
of the nitrogen atom in position 3 of the pyrimidine part was ab-
solutely necessary for a good access to the expected ring. The
method afforded a small amount of an O-benzylated derivative,
usually eliminated by chromatography; (b) no matter the method,
final deprotection of this nitrogen atom involved loss of the car-
bonitrile function in position 2 of the thiazole moiety, leading to the
unsubstituted 8H-thiazolo[5,4-f]quinazolin-9-one (A); (c) step g,
prior transformation of the cyano group into amidines, amides, or
imidates never allowed the successive debenzylation of the py-
rimidine ring.
2. Results and discussion
2.1. Synthesis of the angular 9-oxo-8,9-dihydrothiazolo[5,4-f]
quinazoline-2-carbonitrile (1) or 6-oxo-6,7-dihydrothiazolo
[4,5-h]quinazoline-2-carbonitrile (2)
The synthetic route previously described for rings A and B is
depicted in Scheme 1.6 The expected 9-oxo-thiazoloquinazoline-2-
carbonitrile derivatives (A or B in Fig. 1) were obtained in six steps
from commercially available 5-nitro- or 4-nitroanthranilic acid. For
example, in the case of A, 6-nitro-3H-quinazolin-4-one (6) was
synthesized by atmospheric microwave heating of 5-
nitroanthranilic acid (5) with 5 equiv of formamide (150 ꢀC).10 Se-
lective N-alkylation in position 3 of the quinazolin-4-one ring was
performed at atmospheric pressure by treatment of 6 with sodium
hydride and benzyl bromide as alkylating agent. Reduction of the 3-
substituted-6-nitroquinazolin-4-one (7) led to the 6-amino de-
rivative 8 by using ammonium formate for catalytic transfer hy-
drogenation in ethanol. Compound 8 was brominated in the
presence of bromine in acetic acid, to give the ortho brominated
In a recent exploration of the possibilities offered by such syn-
thesis to access to novel antifungal agents,11 it was discovered that
Scheme 1. Reagents and conditions: (a) formamide (5 equiv), 150 ꢀC (
m
W), 40 min, 87%; (b) benzyl bromide, NaH, DMF, 140 ꢀC (
m
W), 30 min, 95%; (c) HCO2NH4, Pd/C, EtOH, 85 ꢀ
W), 15 min, 40%.
C
(
m
W), 10 min, 92%; (d) Br2, AcOH, rt, 2 h; (e) Appel’s salt, pyridine, DCM, rt, 3 h, 82%; (f) CuI, pyridine, 115 ꢀC (
m
W), 15 min, 83%; (g) concd H2SO4, 130 ꢀC (
m

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3184
deprotection of the benzylated nitrogen by treatment of in-
termediate 10, with aluminum chloride (AlCl3) in toluene, was
possible without decomposition of the reactive and sometimes
instable imino-1,2,3-dithiazole ring present on the starting mole-
cule. Taking into account these results, we decided to reinvestigate
the synthesis of thiazolo[5,4-f]- (1) or thiazolo[4,5-h]quinazolinone
(2), associated to a recent work on the synthesis of 4-substituted
quinazolines12 via a microwave-assisted Dimroth rearrangement.13
The route described in Scheme 2 started from 5-nitroanthranilic
acid (5), which was treated with N,N-dimethylformamidedime-
thylacetal (DMFDMA) under microwave heating at 105 ꢀC for
15 min. The resulting N,N-dimethylformamidine 12 was in fact
a methyl ester due to the capacity of DMFDMA to alkylate nitrogen
or oxygen atoms as described in various papers.14 The methyl ester
12 was heated with benzylamine in the presence of acetic acid at
118 ꢀC for 20 min (time measured when the mixture has reached
the programmed temperature after a ramp period of 3 min under
a power at 400 W). Compound 7 was then obtained in two steps in
a good average yield of 92%. This result is comparable to the yield
obtained in the previous process (Scheme 1) but this novel access to
7 can be considered more efficient and easier in practice. The other
part of this synthesis was the same as described above until com-
pound 10 was obtained. The latter was heated at 85 ꢀC for 30 min
under microwaves with excess of AlCl3 (5.5 equiv) in toluene and
afforded deprotected quinazolinone 13 in a quantitative yield. Cy-
clization of 13 into the tricyclic thiazolo[5,4-f]quinazoline 1 was
accomplished in an excellent yield (97%), with microwave heating
(atmospheric pressure) in the presence of CuI in pyridine at 115 ꢀC
for 15 min. The resulting 9-oxo-8,9-dihydrothiazolo[5,4-f]quina-
zoline-2-carbonitrile (1) was obtained in seven steps in an overall
yield of 42%.
via the key N3-benzylated and brominated aminoquinazolin-4-one
intermediates (framed compounds in Scheme 4) themselves ob-
tained from the two anthranilic acid isomers.
2.2.1. Synthesis of key N3-benzylated and brominated aminoquinazolin-
4-ones. The synthesis of 6-amino-3-benzyl-7-bromoquinazolin-
4(3H)-one is depicted in Scheme 5; it was firstly studied from 5-
nitroanthranilic acid. Unfortunately, various conditions of bromina-
tion of the intermediates stayed infructuous or gave inseparable
mixtures containing the desired product. Failure to obtain the proper
precursors led us to investigate a new synthetic route from methyl 4-
bromoanthranilate (21), which was treated by DMFDMA in the usual
conditions. The resulting N,N-dimethylformamidine 22 was then
heated in acetic acid in the presence of benzylamine to afford the 3-
benzyl-7-bromoquinazolin-4(3H)-one (23) in an excellent yield
(99%). Unfortunately its nitration yielded polynitrated derivatives as
we presumed, especially on the benzyl group. Taking into account
these results, it was decided to cyclize the starting anthranilic methyl
ester 21 or the formamidine 22 into the unsubstituted 7-
bromoquinazolin-4-one (24) before performing nitration. The re-
action of 21 or 22 with formamide at 200 ꢀC gave the brominated
product 24 in quantitative yield. Nitration with a mixture of nitric and
sulfuric acid gave the 7-bromo-6-nitroquinazolin-4(3H)-one (25) in
a good yield (79%). N3-Benzylation of the pyrimidin-4-one part of the
molecule was realized as described in the preceding studies, by
treatment of the starting material with benzyl bromide in the pres-
ence of sodium hydride. Reduction of the resulting 3-benzyl-7-
bromo-6-nitroquinazolin-4(3H)-one (26) was successfully per-
formed by treatment with iron in the presence of acetic acid and
ethanol. The key 6-amino-3-benzyl-7-bromoquinazolin-4(3H)-one
(27) was obtained in four steps in average yield of 49%. It can be
Scheme 2. Reagents and conditions: (a) DMF/DMA, DMF, 105 ꢀC (
m
W), 15 min, 93%; (b) benzylamine, AcOH, 118 ꢀC (
m
W), 20 min, 99%; (c) HCO2NH4, Pd/C, EtOH, 85 ꢀC (
W), 15 min, 97%.
mW), 20 min,
quant.; (d) Br2, AcOH, rt, 2 h, quant.; (e) Appel salt, pyridine, DCM, rt, 3 h, 51%; (f) AlCl3, toluene, 85 ꢀC (
m
W), 30 min, 90%; (g) CuI, pyridine, 115 ꢀC (
m
Starting from 4-nitroanthranilic acid (14), the same route was
experimented for the synthesis of 6-oxo-6,7-dihydrothiazolo[4,5-
h]quinazoline-2-carbonitrile (2) in a good overall yield (20%). De-
tails of products obtained (15e20), experimental conditions,
heating method, times, and yields are given in Scheme 3.
noticed that the first step of this synthesis can be performed from
methyl 4-bromo-2-nitrobenzoate (28) as depicted in Scheme 5 via
a one-pot reductive N-heterocyclization of various 2-nitrobenzoic
acid or ester derivatives with formamide, in the presence of a mo-
lar equivalent amount of indium(III) chloride (InCl3).11,15
In contrast with 6-amino-3-benzyl-7-bromoquinazolin-4(3H)-
one (27), its 7-amino-3-benzyl-6-bromo isomer (33) was prepared
from 4-nitroanthranilic acid (14) as suggested in the retrosynthetic
Scheme 4. The simultaneous formations of the imino group and
esterification of the acid function were easily realized by with
DMFDMA. Regardless of the method used to selectively brominate
the intermediate methyl 2-([(dimethylamino)methylene]amino)-
4-nitrobenzoate (15), compound 31 was never isolated but rather
led to various unidentified compounds. Instead, partial hydrolysis
of 15 with aqueous hydrochloric acid (8%) gave the methyl 2-
amino-4-nitrobenzoate (29) in quantitative yield. It can be
2.2. Synthesis of 8-oxo-7,8-dihydrothiazolo[4,5-g]quinazo-
line-2-carbonitrile (3) and 8-oxo-7,8-dihydrothiazolo[5,4-g]
quinazoline-2-carbonitrile (4)
At this point of our work, we decided to investigate the possibility
to obtain two novel linear tricyclic 8-oxo-7,8-dihydrothiazolo[4,5-g]
quinazoline-2-carbonitrile (3) and 8-oxo-7,8-dihydrothiazolo[5,4-g]
quinazoline-2-carbonitrile (4) by using a similar route. The retro-
synthetic pathways depicted in Scheme 4 were inspired from the
work described above. It suggested to prepare the target molecules

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3185
Scheme 3. Reagents and conditions: (a) DMFDMA, DMF, 105 ꢀC (
m
W), 15 min, 92%; (b) BnNH2, AcOH, 118 ꢀC (
m
W), 20 min, 90%; (c) HCO2NH4, Pd/C, EtOH, 85 ꢀC (
W), 15 min, 75%.
m
W), 20 min, 75%;
(d) NBS, DMF, rt, 2 h, 84%; (e) Appel salt, pyridine, DCM, rt, 3 h, 70%; (f) AlCl3, toluene, 85 ꢀC (
m
W), 30 min, 73%; (g) CuI, pyridine, 115 ꢀC (
m
Scheme 4. Proposed retrosynthetic pathway for the synthesis of 3 and 4.
noticed that the two steps described for the synthesis of 29 can be
realized from 14 in an efficient one pot procedure (93% yield). The
following step consisted in a regioselective introduction of the
bromide atom on the desired position of the methyl anthranilate
30. The brominated derivative 30 was treated with DMFDMA and
the intermediate formamidine 31 was cyclized into the 3-benzyl-6-
bromo-7-nitroquinazolin-4(3H)-one (32). The fifth step involved
reduction of the nitro group in order to furnish the expected 7-
amino-3-benzyl-6-bromoquinazolin-4(3H)-one (33) in an overall
yield of 70% (Scheme 6).
Scheme 5. Reagents and conditions: (a) DMFDMA, DMF, 105 ꢀC (
m
W), 15 min, 96%; (b) benzylamine, AcOH, 118 ꢀC (
m
W), 25 min, 99%; (c) formamide (40 equiv), 200 ꢀC (
W) 30 min, 84%; (g) Fe, AcOH/EtOH, reflux, 1 h, 96%.
mW), 40 min,
quant.; (d) formamide, InCl3, 150 ꢀC ( W), 40 min, 81%; (e) HNO3, H2SO4, 100 ꢀC (
m
m
W), 1 h, 79%; (f) benzyl bromide, NaH, DMF, (m

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3186
Scheme 6. Reagents and conditions: (a) DMFDMA, DMF, 105 ꢀC (
m
W), 15 min, 92% (15), 96% (31); (b) HCl (8%), MeOH, 100 ꢀC (
m mW),
W), 15 min, quant.; (c) DMFDMA, DMF, 105 ꢀC (
15 min, then HCl (8%), 100 ꢀC ( W), 15 min, 93%; (d) NBS, DMF, rt, 6 h, 92%; (e) benzylamine, AcOH, 118 ꢀC (
m mW), 25 min, 92%; (f) Fe, AcOH/EtOH, reflux, 1 h, 92%.
Scheme 7. Reagents and conditions: (a) Appel salt, pyridine, DCM, rt, 2 h, 58% (34), 72% (35); (b) AlCl3, toluene, 75 ꢀC (
15 min, 86% (3), 80% (4); (d) HBr (48%), 115 ꢀC (
W), 30 min, 93% (38), 92% (39).
m mW),
W), 30 min, 90% (36), 72% (37); (c) CuI, pyridine, 115 ꢀC (
m
2.2.2. 8-Oxo-7,8-dihydrothiazolo[4,5-g]quinazoline-2-carbonitrile
(3) and 8-oxo-7,8-dihydrothiazolo[5,4-g]quinazoline-2-carbonitrile
(4) (Scheme 7). With the 6-(or 7-)amino-3-benzyl-7-(or 6-)bro-
moquinazolin-4(3H)-ones (27 and 33) in hands, the second part of
the synthetic route was realized according to our previous results.
The next step was the condensation of the starting amines with
Appel salt in usual conditions of temperature (rt) and time (2 h).
The two imino-1,2,3-dithiazoles 34 and 35 were treated with AlCl3
in toluene for 30 min to afford to the N3-free quinazolin-4-ones 36
and 37 in good yields (90% and 72%, respectively). Thermal cycli-
zation in the presence of copper(I) iodide in pyridine as solvent
gave the target 8-oxo-7,8-dihydrothiazolo[4,5-g]quinazoline-2-
carbonitrile (3) and 8-oxo-7,8-dihydrothiazolo[5,4-g]quinazoline-
2-carbonitrile (4) in good yields (86% and 80%, respectively). Hy-
drolysis and decarboxylation of the carbonitrile function led to the
unsubstituted rings 3816a and 3916b (93% and 92%, respectively).
transformations for an access to libraries of potent biologically ac-
tive heterocyclic compounds. The interest of the multi-step routes
described in this paper is also to allow further modulations of the
final compounds (1e4). The use of formamidine intermediates (e.g.,
12, 15, 22, and 31) offered some advantages although it may be
observed that each modification of the substituent in N3 of the
pyrimidine ring will generate three or four intermediates for which
synthetic and biological interests are not really established yet.
Despite this drawback, this work constitutes the only route to novel
tricyclic systems with potential pharmaceutical interest.
4. Experimental section
4.1. General
All reactions were monitored by thin-layer chromatography
with silica gel 60 F254 pre-coated aluminum plates (0.25 mm). Vi-
sualization was performed with a UV light.
3. Conclusion
Melting points of solid compounds were measured on a WME
Kofler hot-stage with a precision of ꢁ2 ꢀC and are uncorrected. IR
€
We performed the synthesis of various tricyclic heterocyclic
skeletons, varying the position of the thiazole ring linked to the
quinazolin-4-one moiety. The simultaneous presence of the re-
active cyano group and the pyrimidin-4-one part on the same
molecules (1e4) open the door to various substitutions and
spectra were recorded on a PerkineElmer Spectrum 100 Series FT-
IR spectrometer. Liquids and solids were applied on the Single
Reflection Attenuated Total Reflectance (ATR) Accessories. Ab-
sorption bands are given in cmꢂ1
.

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3187
1H, 13C, and 19F NMR spectra were recorded on a Brucker DXP
300 spectrometer at 300, 75, and 282 MHz, respectively. Abbrevi-
ations used for peak multiplicities are s: singlet, d: doublet, t:
triplet, q: quadruplet, and m: multiplet. Coupling constants J are in
hertz and chemical shifts are given in parts per million and cali-
brated with DMSO-d6 or D2O (residual solvent signals). Mass
spectra analysis was performed by the Mass Spectrometry Labo-
ratory of the University of Rouen. Mass spectra (EI) were recorded
with a Waters LCP 1er XR spectrometer.
Microwave experiments were conducted in a commercial mi-
crowave reactor especially designed for synthetic chemistry.
RotoSYNTHÔ (Milestone S.r.l. Italy) is a multi-mode cavity with
a microwave power delivery system ranging from 0 to 1200 W. The
temperatures of the reactions were mainly monitored via contact-
less infrared pyrometer, which was calibrated in control experi-
ments with a fibre-optic contact thermometer protected in TeflonÔ
coated ceramic well inserted directly in the reaction mixture. Re-
action time described correspond to the time measured when the
mixture has reached the programmed temperature, after a ramp
period of 3 min. Open vessel experiments were carried out in
a 100e250 mL roundbottom flask fittedwith a refluxcondenser. The
vessel contents were stirred by means of an adjustable rotating
magnetic plate located below the floor of the microwave cavity and
a Teflon-coated magnetic stir bar inside the vessel. Temperature and
power profiles were monitored in both cases through the EASY-
Control software provided by the manufacturer.
successively. After drying over MgSO4, evaporation of the solvent
gave a crude residue, which was purified by column chromatog-
raphy on silica gel using ethyl acetate/dichloromethane (5:5, v/v) as
eluent to furnish 7 (5.54 g, yield 99%) as a white powder: mp 166 ꢀC
(lit.5 164 ꢀC); spectra data for compounds 7 are consistent with
assigned structure, as previously described in Ref. 5.
4.2.3. 6-Amino-3-benzylquinazolin-4(3H)-one (8). A stirred mixture
of 7 (5.50 g,19.6 mmol), ammonium formate (6.17 g, 97.9 mmol), and
a catalytic amount of 10% palladium charcoal in ethanol (120 mL)
was heated at 85 ꢀC (300 W) for 20 min. The reaction mixture was
filtered through Celite and washed with hot ethanol. The solvent was
removed in vacuo to give the crude product, which was dissolved in
ethyl acetate, washed with water, dried over MgSO4, and concen-
trated under reduced pressure to provide the reduced compound 8
(4.92 g, quantitative yield) as a brown powder: mp 168 ꢀC (lit.5
174 ꢀC); spectra data for compound 8 are consistent with assigned
structures, as previously described in Ref. 5.
4.2.4. 6-Amino-3-benzyl-5-bromoquinazolin-4(3H)-one (9). A solu-
tion of bromine (920 mL, 17.9 mmol) in dichloromethane (20 mL)
was added dropwise, under an inert atmosphere, to a solution of 8
(5.0 g, 19.9 mmol) in acetic acid (200 mL). After stirring for 2 h at
room temperature, the reaction mixture was diluted with water
and the product was extracted with ethyl acetate. The combined
organic layers were washed with a saturated solution of NaHCO3,
water, and brine, successively. Evaporation of solvent gave the ex-
pected product 9 (6.57 g, quantitative yield) as brown powder: mp
190 ꢀC (lit.5 184 ꢀC); spectra data for compound 9 are consistent
with assigned structure, as previously described in Ref. 5.
Dichloromethane was distilled from CaH2 under argon. NBS was
recrystallized in water. Other reagents and solvents were used as
provided by chemical companies.
Appel salt was prepared according to literature procedure,8a by
addition of chloroacetonitrile (1 equiv) to a solution of sulfur
dichloride (5 equiv) in dichloromethane (50 mL). AdogenÔ (3e4
drops) was then added and the reaction was placed in a bowl of
cold water.17 The mixture was left for 18 h without stirring under
CaCl2 tube protection: the dark olive green solid was removed from
the wall of the flask, filtered off under a blanket of argon, washed
abundantly with dichloromethane, and dried under vacuum for
2e3 h (average yield: 85%): mp 172e174 ꢀC (dec) [172 ꢀC (dec)16]; IR
(Nujol) cmꢂ1 1707, 1358s, 1280s, 1253, 1083, 917, 828s, and 605.
4.2.5. 3-Benzyl-5-bromo-6-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)quinazolin-4(3H)-one (10). A suspension of 9 (4.0 g,
12.1 mmol) and 4,5-dichloro-1,2,3-dithiazolium chloride (Appel
salt) (3.78 g,18.5 mmol) in dichloromethane (120 mL) was stirred at
room temperature under an argon atmosphere. After 1 h of stirring
at room temperature, pyridine (2 equiv) was added and the mixture
was stirred again 2 h at room temperature. The resulting solution
was concentrated under reduced pressure. The crude residue was
purified by chromatography on silica gel with ethyl acetate/
dichloromethane (5:95 then 10:90, v/v) to give the expected
compound 10 (2.90 g, yield 51%) as a yellow powder: mp 210 ꢀC
(lit.5 198 ꢀC); spectra data for compound 10 are consistent with
assigned structure, as previously described in Ref. 5.
4.2. Synthesis of 9-oxo-8,9-dihydrothiazolo[5,4-f]quinazo-
line-2-carbonitrile (1)
4.2.1. (E)-Methyl 2-((dimethylamino)methyleneamino)-5-
nitrobenzoate (12). A stirred mixture of 5 (20.0 g, 110 mmol) and
DMFDMA (36.5 mL, 275 equiv) in DMF (110 mL) was heated at
105 ꢀC for 15 min (350 W). After cooling until room temperature,
the crude mixture was diluted with water and the aqueous layer
was extracted with ethyl acetate. The organic layers were combined
and washed with water and brine. After drying over MgSO4,
evaporation of solvent gave the expected product 12 (25.7 g, yield
93%) as a yellow powder: mp 82 ꢀC; IR nmax (cmꢂ1): 3098, 3076,
2949, 2905,1706,1623,1568,1497,1321,1106, 974, 837, 744, 699; 1H
4.2.6. 5-Bromo-6-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)qui-
nazolin-4(3H)-one (13). A mixture of 10 (2.27 g, 4.87 mmol) and
AlCl3 (3.57 g, 26.8 mmol) in toluene (50 mL) was heated at 85 ꢀC
(300 W) for 30 min. The resulting mixture was neutralized to pH 7
with a saturated solution of NaHCO3 and the product was extracted
with ethyl acetate. The organic layers werewashed with water, brine
and dried over MgSO4. Evaporation of the solvent provided a crude
product, which was purified bycolumn chromatographyon silica gel
with ethanol/dichloromethane (2:98 then 5:95, v/v) as eluent to
furnish the expected compound 13 (1.65 g, yield 90%) as an orange
powder: mp 258 ꢀC; IR nmax (cmꢂ1) 3457, 3063, 2909, 1666, 1621,
1590, 1568, 1492, 1442, 1377, 1377, 1294, 1239, 1171, 1109, 948, 863,
NMR (300 MHz, DMSO-d6)
d
8.31 (d, J¼2.7 Hz, 1H, HAr), 8.18 (dd,
J¼9.0, 2.7 Hz, 1H, HAr), 7.94 (s, 1H, NCH), 7.18 (d, J¼9.0 Hz, 1H, HAr),
3.79 (s, 3H, OCH3), 3.10 (s, 3H, NCH3), 2.97 (s, 3H, NCH3); 13C NMR
(75 MHz, DMSO-d6)
d 166.6, 157.4, 155.0, 140.0, 126.8, 125.5, 125.1,
120.7, 52.0, 34.1 (2C); HRMS calcd for C11H13N3O4 [MþH]þ
807; 1H NMR (300 MHz, DMSO-d6)
d 12.40 (br s, 1H, NH), 8.18 (s,1H,
252.0984 found 252.0974.
HAr), 7.77 (d, 1H, J¼8.7 Hz, HAr), 7.60 (d, 1H, J¼8.7 Hz, HAr); 13C NMR
(75 MHz, DMSO-d6)
d 163.2, 159.2, 150.3, 147.8, 145.9, 145.5, 128.9,
4.2.2. 3-Benzyl-6-nitroquinazolin-4-one (7). Benzylamine (3.26 mL,
1.5 equiv) was added dropwise to a solution of 12 (5.0 g, 19.9 mmol)
in acetic acid (40 mL). After 20 min of heating at 118 ꢀC (400 W), the
reaction mixture was diluted with water and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with a saturated solution of NaHCO3, water, and brine,
124.8, 121.6, 111.4; HRMS calcd for C10H579Br35ClN4OS2 [MþH]þ
374.8777 found 374.8761.
4.2.7. 9-Oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carbonitrile
(1). A suspension of 13 (1.46 g, 3.9 mmol) and copper(I) iodide (CuI,
1.49 g, 7.8 mmol) in pyridine (40 mL) was irradiated under

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3188
microwaves at 115 ꢀC (300 W) for 15 min. After cooling, the mixture
was diluted in ethyl acetate, washed with sodium thiosulfate so-
lution. The organic layer was dried over MgSO4, and the solvent was
removed in vacuo. The crude residue was purified by column
chromatography on silica gel with ethyl acetate/dichloromethane
(5:5, v/v) as eluent to furnish the thiazoloquinazolinone 1 (0.860 g,
yield 97%) as an orange powder: mp >265 ꢀC; IR nmax (cmꢂ1) 3160,
3048, 2855, 2232 (CN), 1659, 1608, 1590, 1460, 1382, 1354, 1303,
1274, 1225, 1164, 1110, 1013, 973, 897, 859, 832; 1H NMR (300 MHz,
mp 200 ꢀC (lit.5 202 ꢀC); spectra data for 19 are consistent with
assigned structure, as previously described in Ref. 5.
4.3.6. 8-Bromo-7-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)qui-
nazolin-4(3H)-one (20). According to the procedure described for
13 in Section (4.2.6.), reaction of 19 (1.45 g, 3.11 mmol) and AlCl3
(3.57 g, 26.8 mmol) in toluene (50 mL), at 85 ꢀC (300 W) for 30 min,
gave product 20 (0.853 g, yield 73%) as an orange powder: mp
>265 ꢀC; IR nmax (cmꢂ1) 3072 (NeH), 2906, 1688, 1588, 1418, 1380,
DMSO-d6)
d
8.22 (d, J¼9.0 Hz, 1H, HAr), 7.41 (s, 1H, HAr), 7.95 (d,
1241, 1155, 989, 916, 871; 1H NMR (300 MHz, DMSO-d6)
d 12.53 (br
J¼9.0 Hz, 1H, HAr); 13C NMR (75 MHz, DMSO-d6)
d
159.3, 149.9,
s, 1H, NH), 8.25 (d, J¼3.6 Hz, 1H, HAr), 8.19 (d, 3J¼8.4 Hz, 1H, HAr),
149.1, 146.9, 138.8, 131.1, 129.7, 127.6, 116.0, 113.4 (CN); HRMS calcd
7.30 (d, 3J¼8.4 Hz, 1H, HAr); 1H NMR (DMSO-d6þD2O, 300 MHz)
for C10H5N4OS [MþH]þ 229.0184 found 229.0170.
d
8.19 (d, J¼8.4 Hz, 1H, HAr), 8.16 (s, 1H, HAr2), 7.27 (d, J¼8.4 Hz, 1H,
HAr); 13C NMR (75 MHz, DMSO-d6)
d 163.4, 160.2, 156.0, 147.8, 146.7,
145.8, 127.7, 120.3, 118.1, 111.8; HRMS calcd for C10H579Br35ClN4OS2
[MþH]þ 374.8777 found 374.8786.
4.3. Synthesis of 6-oxo-6,7-dihydrothiazolo[4,5-h]quinazo-
line-2-carbonitrile (2)
4.3.7. 6-Oxo-6,7-dihydro[1,3]thiazolo[4,5-h]quinazoline-2-
carbonitrile (2). According to the procedure described for com-
pound 1 in Section (4.2.7.), reaction of 20 (0.50 g, 1.33 mmol) and
copper(I) iodide (CuI, 0.507 g, 2.7 mmol) in pyridine (20 mL), at
115 ꢀC (300 W) for 15 min, gave product 2 (0.224 g, yield 75%) as
a beige powder: mp >265 ꢀC; IR nmax (cmꢂ1) 3176, 3062, 2868, 2238
(CN), 1679, 1618, 1442, 1346, 1238, 923, 798; 1H NMR (300 MHz,
4.3.1. (E)-Methyl 2-[(dimethylamino)methyleneamino]-4-
nitrobenzoate (15). According to the procedure described for 12
in Section (4.2.1.), reaction of 4-nitroanthranilic acid 14 (10.0 g,
55 mmol) and DMFDMA (19 mL, 138 mmol) in DMF (60 mL), at
105 ꢀC (350 W) for 15 min, gave compound 15 (12.70 g, yield 92%)
as an orange solid: mp 75 ꢀC; IR nmax (cmꢂ1) 3103, 2955, 2911, 1706,
1634, 1513, 1343, 1282, 1101, 897, 826, 738; 1H NMR (300 MHz,
DMSO-d6)
d
12.83 (br s, 1H, NH), 8.40 (s, 1H, HAr), 8.32 (d, J¼9.0 Hz,
1H, HAr), 8.29 (d, J¼9.0 Hz, 1H, HAr); 13C NMR (75 MHz, DMSO-d6)
DMSO-d6)
d
7.93 (s, 1H, NCH), 7.82 (d, J¼2.4 Hz, 1H, HAr), 7.75 (dd,
d 160.0, 155.0, 148.3, 144.8, 140.2, 133.2, 125.5, 122.3, 120.7, 113.0;
J¼8.1, 2.4 Hz, 1H, HAr), 7.63 (d, J¼8.1 Hz, 1H, HAr), 3.79 (s, 3H, OCH3),
HRMS calcd for C10H3N4OS [MꢂH]ꢂ 227.0028 found 227.0023.
3.07 (s, 3H, NCH3), 2.92 (s, 3H, NCH3); 13C NMR (75 MHz, DMSO-d6)
d
167.6, 154.8, 151.8, 149.3, 132.4, 129.4, 115.1, 113.8, 52.0 (OCH3),
4.4. Synthesis of 8-oxo-7,8-dihydrothiazolo[4,5-g]quinazo-
line-2-carbonitrile (3)
34.1 (2C); HRMS calcd for C11H13N3O4 [MþH]þ 252.0984 found
252.0974.
4.4.1. (E)-Methyl
4-bromo-2-((dimethylamino)methyleneamino)-
4.3.2. 3-Benzyl-7-nitroquinazolin-4-one (16). According to the
procedure described for compound 7 in Section (4.2.2.), reaction of
15 (4.0 g, 15.9 mmol) and benzylamine (2.61 mL, 23.9 mmol) in
acetic acid (30 mL), at 118 ꢀC (400ꢀW) for 20 min, gave product 16
(4.02 g, yield 90%) as a pale yellow powder: mp 160 ꢀC (lit.5 160 ꢀC);
spectra data for 16 are consistent with assigned structure, as pre-
viously described in Ref. 5.
benzoate (22). According to the procedure described for 12 in
Section (4.2.1.), reaction of methyl 4-bromoanthranilate 21 (4.0 g,
17.4 mmol) and DMFDMA (3.8 mL, 43.5 mmol) in DMF (40 mL), at
105 ꢀC (350 W) for 15 min, gave product 22 (4.76 g, yield 96%) as
a dark purple oil: IR nmax (cmꢂ1) 3098, 3076, 2944, 1721, 1629, 1574,
1379, 1231, 1086, 911, 871, 772; 1H NMR (300 MHz, DMSO-d6)
d 7.71
(s, 1H, NCH), 7.41 (d, J¼8.1 Hz, 1H, HAr), 7.17 (d, J¼2.0 Hz, 1H, HAr),
7.13 (dd, J¼8.1, 2.0 Hz, 1H, HAr), 3.73 (s, 3H, OCH3), 3.02 (s, 3H,
4.3.3. 7-Amino-3-benzylquinazolin-4(3H)-one (17). According to
the procedure described for 8 in Section (4.2.3.), reaction of com-
pound 16 (3 g,10.7 mmol), ammonium formate (3.48 g, 53.5 mmol),
and a catalytic amount of 10% palladium charcoal in ethanol
(60 mL), at 85 ꢀC (300 W) for 20 min, gave product 17 (2.02 g, yield
75%) as a pale brown powder: mp 172 ꢀC (lit.5 175 ꢀC); spectra data
for 17 are consistent with assigned structure, as previously de-
scribed in Ref. 5.
NCH3), 2.89 (s, 3H, NCH3); 13C NMR (75 MHz, DMSO-d6)
d 167.6,
154.0, 152.9, 130.8, 125.0, 124.7, 123.5, 123.0, 51.6, 33.8 (2C); HRMS
calcd for C11H1479BrN2O2 [MþH]þ 285.0239 found 285.0236, for
C11H1481BrN2O2 [MþH]þ 287.0218 found 287.0220.
4.4.2. 3-Benzyl-7-bromoquinazolin-4-one (23). According to the
procedure described for compound 7 in Section (4.2.2.), reaction of
22 (3.80 g, 13.3 mmol) and benzylamine (2.18 mL, 20 mmol) in
acetic acid (60 mL), at 118 ꢀC (400 W) for 25 min, gave product 23
(4.15 g, yield 99%) as a white solid: mp 122 ꢀC; IR nmax (cmꢂ1) 3030,
2948, 1666, 1594, 1362, 1312, 1274, 811, 777, 694; 1H NMR
4.3.4. 7-Amino-3-benzyl-8-bromoquinazolin-4(3H)-one (18). N-Bro-
mosuccinimide (NBS, 1.56 g, 8.8 mmol) was added portion-wise to
a solution of 17 (2.20 g, 8.8 mmol) in DMF (80 mL). After 2 h of
stirring at room temperature, the reaction mixture was diluted with
water and extracted with ethyl acetate. The organic layers were
combined and washed with water and brine. Evaporation of the
solvent provided product 18 (2.40 g, yield 84%) as a white solid: mp
228 ꢀC (lit.5 224 ꢀC); spectra data for 18 are consistent with assigned
structure, as previously described in Ref. 5.
(300 MHz, DMSO-d6)
d
8.62 (s, 1H, HAr), 8.03 (d, J¼8.4 Hz, 1H, HAr),
7.85 (d, J¼2.4 Hz, 1H, HAr), 7.64 (dd, J¼8.4, 2.4 Hz, 1H, HAr),
7.39e7.25 (m, 5H, Ph), 5.19 (s, 2H, CH2Ph);13C NMR (75 MHz,
DMSO-d6) d 159.6, 149.3, 149.0, 136.5, 130.1, 129.5, 128.6 (2C), 128.1,
127.9, 127.7 (2C), 120.7, 49.0; HRMS calcd for C15H1279BrN2O2
[MþH]þ 315.0133 found 315.0133, for C15H1281BrN2O2 [MþH]þ
317.0113 found 315.0107.
4.3.5. 3-Benzyl-8-bromo-7-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)quinazolin-4(3H)-one (19). According to the procedure
described for 10 in Section (4.2.5.), reaction of compound 18 (1.50 g,
4.54 mmol) and 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt)
(1.42 g, 6.81 mmol) in dichloromethane (45 mL), at room tempera-
ture for 3 h, gave product 19 (1.48 g, yield 70%) as an orange powder:
4.4.3. 7-Bromoquinozolin-4-one (24). A mixture of 4-bromoanth-
ranilate (21, 1.25 g, 5.4 mmol) and formamide (8.60 mL, 40 equiv)
was heated at 200 ꢀC (350 W) for 35 min. After cooling, the reaction
mixture was diluted with water and the product was extracted with
ethyl acetate. The combined organic layers were washed with water
and brine. After drying over MgSO4, evaporation of the solvent gave

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3189
product 24 (1.21 g, quantitative yield) as a white powder: mp
260e258 ꢀC (lit.9 259e258 ꢀC); IR nmax (cmꢂ1) 3466 (NeH), 3050,
3.63 mmol) and 4,5-dichloro-1,2,3-dithiazolium chloride (Appel
salt) (1.14 g, 5.45 mmol) in dichloromethane (35 mL), at room
temperature for 2 h, gave product 34 (0.980 g, yield 58%) as an or-
ange powder: mp 214e216 ꢀC; IR nmax (cmꢂ1) 1677 (C]O), 1586,
1668 (C]O), 1609, 1239, 858; 1H NMR (300 MHz, DMSO-d6)
d 12.41
(br s, 1H, NH), 8.14 (s, 1H, HAr), 8.03 (d, J¼8.7 Hz, 1H, HAr), 7.89 (d,
J¼1.8 Hz, 1H, HAr), 7.69 (dd, J¼8.7, 1.8 Hz, 1H, HAr); 13C NMR (75 MHz,
1451,1366, 868; 1H NMR (300 MHz, DMSO-d6)
d
8.62 (s,1H, HAr), 8.16
(s, 1H, HAr), 8.00 (s, 1H, HAr), 7.41e7.29 (m, 5H, Ph), 5.21 (s, 2H,
CH2Ph); 13C NMR (75 MHz, DMSO-d6)
162.6, 159.5, 148.7, 148.2,
DMSO-d6)
d 160.3, 149.8, 156.8, 129.8, 129.3, 128.0 (2C), 121.6; HRMS
calcd for C8H679BrN2O [MþH]þ 224.9663 found 224.9665, for
d
C8H681BrN2O 226.9643 found 226.9651.
146.5, 146.2, 136.5, 132.1, 128.7 (2C), 127.2 (2C), 123.5, 122.2, 114.3,
49.1; HRMS calcd for C17H1079Br35ClN4OS2 [MþH]þ 464.9246 found
464.9254.
4.4.4. 7-Bromo-6-nitroquinozolin-4-one (25). HNO3 (550
mL,
2 equiv) was added dropwise to a solution of 24 (1.47 g, 6.53 mmol)
in H2SO4 (23 mL) maintained at 0 ꢀC. The reaction was heated at
100 ꢀC (400 W) for 1 h. After cooling, the resulting mixture was
quenched in ice water and pH was adjusted to 7 with NaOH (20%).
The product was extracted with ethyl acetate. The organic layers
were washed with water and brine, and then dried over MgSO4.
Evaporation of the solvent provided a crude residue, which was
purified by column chromatography on silica gel with ethanol/
dichloromethane (1:99, v/v) as eluent to furnish the expected
compound 25 (1.34 g, yield 79%) as a white powder: mp >265 ꢀC; IR
nmax (cmꢂ1) 3504 (NeH), 3082, 1695 (C]O), 1656, 1605, 1518, 1332,
4.4.8. 7-Bromo-6-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)qui-
nazolin-4(3H)-one (36). According to the procedure described for
13 in Section (4.2.6.), reaction of 34 (1.50 g, 3.22 mmol) and AlCl3
(2.36 g, 17.7 mmol) in toluene (30 mL), at 85 ꢀC (300 W) for 30 min,
gave product 36 (1.35 g, yield 90%) as an orange powder: mp
>265 ꢀC; IR nmax (cmꢂ1) 3451 (NeH), 3030, 1671 (C]O), 1596, 1447,
1273, 861.4; 1H NMR (300 MHz, DMSO-d6)
8.14 (s, 1H, HAr), 8.12 (s, 1H, HAr), 7.98 (s, 1H, HAr); 13C NMR (75 MHz,
d 12.51 (br s, 1H, NH),
DMSO-d6) d 162.4, 160.1, 147.7, 147.1, 146.6, 146.2, 132.0, 123.5, 123.1,
114.0; HRMS calcd for C10H579Br35ClN4OS2 [MþH]þ 374.8777
1249, 810; 1H NMR (300 MHz, DMSO-d6)
d
12.82 (br s, 1H, NH), 8.65
found 374.8786.
(s, 1H, HAr), 8.32 (s, 1H, HAr), 8.20 (s, 1H, HAr); 13C NMR (75 MHz,
DMSO-d6)
d
159.5, 151.3, 149.5, 146.6, 133.2, 123.8, 122.1, 118.9;
4.4.9. 8-Oxo-7,8-dihydrothiazolo[4,5-g]quinazoline-2-carbonitrile
(3). According to the procedure described for compound 1 in Sec-
tion (4.2.7.), reaction of 36 (1.20 g, 3.30 mmol) and copper(I) iodide
(CuI, 1.26 g, 6.6 mmol) in pyridine (40 mL), at 115 ꢀC (300 W) for
15 min, gave product 3 (0.670 g, yield 86%) as a beige powder: mp
>265 ꢀC; IR nmax (cmꢂ1) 3468, 3054, 2227 (v CN), 1676 (v C]O),
HRMS calcd for C8H379BrN3O3 [MꢂH]ꢂ 267.9358 found 267.9355,
for C8H381BrN3O3 [MꢂH]ꢂ 269.9337 found 269.9327.
4.4.5. 3-Benzyl-7-bromo-6-nitroquinazolin-4-one (26). NaH (60%
dispersion) (0.40 g, 10.18 mmol) was added portion-wise to a stir-
red solution of 25 (2.50 g, 9.25 mmol) in DMF (25 mL). Then, benzyl
bromide (1.2 mL, 10.18 mmol) was added dropwise. The solution
was heated at 80 ꢀC (400 W) for 10 min. After cooling, the reaction
mixture was diluted with water and extracted with ethyl acetate.
The combined organic layers were washed with water and brine.
The solvent was evaporated and the product purified by column
chromatography on silica gel with ethyl acetate/dichloromethane
(5:5, v/v) as eluent to provide 26 (2.80 g, 84%) as a white powder:
mp 170e168 ꢀC; IR nmax (cmꢂ1) 3082, 1679, 1602, 1532, 1350, 1216,
1619, 1468, 1278; 1H NMR (300 MHz, DMSO-d6)
NH), 8.91 (s, 1H, HAr), 8.69 (s, 1H, HAr), 8.22 (s, 1H, HAr); 13C NMR
d 12.48 (br s, 1H,
(75 MHz, DMSO-d6)
d 160.7 (C]O), 149.4, 147.0, 146.3, 140.9, 139.4,
122.8, 122.0, 121.4, 113.1 (CN); HRMS calcd for C10H3N4OS [MꢂH]ꢂ
227.0028 found 227.0039.
4.4.10. Thiazolo[4,5-g]quinazolin-8(7H)-one (38). A mixture of 3
(0.250 g, 1.10 mmol) and HBr (48% in water, 5 mL) was heated at
115 ꢀC (450 W) for 30 min. After cooling, the reaction mixture was
diluted with water, neutralized with a saturated solution of NaHCO3
and the aqueous layer was extracted with ethyl acetate. The com-
bined organic layers were washed with a saturated solution of
NaHCO3 followed with water and brine. Evaporation of solvent gave
the expected product 38 (0.255 g, yield 93%) as a beige powder: mp
>265 ꢀC; IR nmax (cmꢂ1) 3455, 3038, 1670, 1615, 1445, 1278, 845; 1H
813; 1H NMR (300 MHz, DMSO-d6)
HAr), 8.22 (s, 1H, HAr), 7.41e7.30 (m, 5H, Ph), 5.22 (s, 2H, CH2Ph); 13
NMR (75 MHz, DMSO-d6) 159.0, 151.9, 150.5, 147.2, 136.1, 133.3,
d 8.80 (s, 1H, HAr), 8.67 (s, 1H,
C
d
128.6 (2C), 127.8, 127.7 (2C), 124.1, 121.2, 119.0, 49.4; HRMS calcd for
C15H1179BrN3O3 [MþH]þ 359.9984 found 359.9983.
4.4.6. 6-Amino-3-benzyl-7-bromoquinazolin-4(3H)-one
(27). A
NMR (300 MHz, DMSO-d6)
d 12.34 (br s, 1H, NH), 9.55 (s, 1H, HAr),
stirred mixture of 26 (1.0 g, 2.8 mmol) and iron powder (0.775 g,
13.9 mmol) in ethanol (7.5 mL) and acetic acid (7.5 mL) was refluxed
for 30 min. The reaction mixture was diluted with water, neutral-
ized with a saturated solution of NaHCO3 and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with a saturated solution of NaHCO3 followed with water
and brine. Evaporation of solvent gave the crude residue, which
was purified by column chromatography on silica gel with ethyl
acetate/dichloromethane (0%e100%) as eluent to furnish 27
(0.892 g, yield 96%) as a white powder: mp 168e166 ꢀC; IR nmax
(cmꢂ1) 3453 (NH2), 3332, 3020, 1669, 1621, 1595, 1483, 1213, 836;
8.74 (s,1H, HAr), 8.54 (s,1H, HAr), 8.14 (s,1H, HAr); 13C NMR (75 MHz,
DMSO-d6) d 161.1, 158.8, 151.4, 145.2, 145.0, 130.5, 121.3, 120.8, 119.6,
108.0; HRMS calcd for C9H6N3OS [MþH]þ 204.0232 found
204.0220.
4.5. Synthesis of 8-oxo-7,8-dihydrothiazolo[5,4-g]quinazo-
line-2-carbonitrile (4)
4.5.1. Methyl 2-amino-4-nitrobenzoate (29). A stirred mixture of 4-
nitroanthranilic acid 14 (10.0 g, 54.9 mmol) and DMFDMA (19.1 mL,
143 mmol) in DMF (55 mL) was heated at 105 ꢀC (350 W) for
15 min. The resulting mixture was acidified to pH 2 with HCl (8% in
water) (80 mL) and heated at 100 ꢀC (450 W) for 10 min. After
cooling at room temperature, the crude mixture was neutralized
with a saturated solution of NaHCO3 and extracted with ethyl ac-
etate. The organic layers were combined and washed with water
and brine. After drying over MgSO4, evaporation of solvent gave 29
1H NMR (300 MHz, DMSO-d6)
7.47 (s, 1H, HAr), 7.33e7.30 (m, 5H, Ph), 5.89 (br s, 2H, NH2), 5.15 (s,
2H, CH2Ph); 13C NMR (75 MHz, DMSO-d6)
156.7, 145.4, 144.4,
d 8.28 (s, 1H, HAr), 7.78 (s, 1H, HAr),
d
139.0, 137.0, 130.6, 128.6 (2C), 127.6, 127.5 (2C),þ122.3, 116.0, 108.1,
48.6; HRMS calcd for C15H1379BrN3O [MþH] 330.0242 found
330.0239, for C15H1381BrN3O [MþH]þ 332.0222 found 332.0222.
(10.0 g, yield 93%) as an yellow powder: mp 158 ꢀC; IR nmax (cmꢂ1
3493, 3377, 2957, 1699, 1583, 1344, 1245, 1082, 866, 819, 726; 1H
NMR (300 MHz, DMSO-d6)
7.91 (dd, J¼8.7, 1.2 Hz, 1H, HAr), 7.67
(dd, J¼2.4, 1.2 Hz, 1H, HAr), 7.25 (ddd, J¼8.7, 2.4, 1.2 Hz, 1H, HAr), 7.14
)
4.4.7. 3-Benzyl-7-bromo-6-(4-chloro-5H-1,2,3-dithiazol-5-ylidene-
amino)quinazolin-4(3H)-one (34). According to the procedure de-
scribed for 10 in Section (4.2.5.), reaction of compound 27 (1.20 g,
d

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D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3190
(br s, 2H, NH2), 3.84 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6)
orange powder: mp 176 ꢀC; IR nmax (cmꢂ1) 3027, 1650, 1576, 1442,
1396, 1354, 1249, 1157, 945, 896; 1H NMR (300 MHz, DMSO-d6)
d
166.6, 151.5, 150.8, 132.6, 113.1, 110.8, 108.1, 52.0; HRMS calcd for
C8H8N2O4 [MþH]þ 197.0562 found 197.0561.
d
8.64 (s, 1H, HAr), 8.42 (s, 1H, HAr), 7.51 (s, 1H, HAr), 7.40e7.30 (m,
5H, Ph), 5.20 (s, 2H, CH2Ph); 13C NMR (75 MHz, DMSO-d6)
d
163.4,
4.5.2. Methyl 2-amino-5-bromo-4-nitrobenzoate (30). NBS (3.81 g,
21.4 mmol) was added portion-wise to a solution of 29 (4.0 g,
20.4 mmol) in DMF (200 mL). After stirring for 6 h at room tem-
perature, the reaction mixture was diluted with water and the
product was extracted with ethyl acetate. The combined organic
layers were washed with water and brine, and then dried over
MgSO4. Evaporation of the solvent provided a crude product, which
was purified by column on silica, with dichloromethane/petroleum
ether (gradient from 0:10 to 6:4, v/v) as solvent to give 30 (5.10 g,
yield 92%) as an orange powder: mp 142 ꢀC; IR nmax (cmꢂ1) 3491,
3387, 2960, 1702, 1629, 1571, 1521, 1436, 1251, 1097, 835, 793; 1H
158.6, 155.1, 149.2, 149.0, 146.1, 136.6, 131.0, 128.6 (2C), 127.7 (2C),
120.0, 115.8, 113.8, 49.0; HRMS calcd for C17H1079Br35ClN4OS2
[MþH]þ 464.9246 found 464.9237.
4.5.7. 6-Bromo-7-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)qui-
nazolin-4(3H)-one (37). According to the procedure described for
13 in Section (4.2.6.), reaction of 35 (0.90 g, 1.93 mmol) and AlCl3
(0.42 g, 10.6 mmol) in toluene (20 mL), at 85 ꢀC (300 W) for 30 min,
gave product 37 (0.660 g, yield 72%) as a yellow powder: mp 262 ꢀC;
IR nmax (cmꢂ1) 3162, 2997, 1682, 1571, 1442, 1310, 1138, 909, 806,
758; 1H NMR (300 MHz, DMSO-d6)
d 12.43 (br s, 1H, NH), 8.38 (s,
NMR (300 MHz, DMSO-d6)
d
8.01 (s, 1H, HAr), 7.38 (s, 1H, HAr), 7.21
1H, HAr), 8.15 (d, J¼3.6 Hz, 1H, HAr), 7.48 (s, 1H, HAr); 13C NMR
(br s, 2H, NH2), 3.84 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6)
(75 MHz, DMSO-d6)
d 163.4, 159.2, 155.0, 149.7, 146.6, 146.1, 130.7,
d
165.5, 152.5, 150.6, 136.2, 112.8, 112.5, 94.0, 52.2; HRMS calcd for
121.0, 115.8, 113.2; HRMS calcd for C10H579Br35ClN4OS2 [MþH]þ
C8H779BrN2O4
[MꢂH]ꢂ 272.9511 found 272.9500, for
374.8777 found 374.8761.
C8H781BrN2O4 [MꢂH]ꢂ 274.9490 found 274.9489.
4.5.8. 8-Oxo-7,8-dihydro[1,3]thiazolo[5,4-g]quinazoline-2-
carbonitrile (4). According to the procedure described for com-
pound 1 in Section (4.2.7.), reaction of 37 (0.60 g, 1.6 mmol) and
copper(I) iodide (CuI, 0.609 g, 3.2 mmol) in pyridine (20 mL), at
115 ꢀC (300 W) for 15 min, gave product 4 (0.292 g, yield 80%) as
a beige powder: mp >265 ꢀC; IR nmax (cmꢂ1) 3147, 3049, 2922, 2245
(CN), 1671, 1608, 1439, 1400, 1319, 1263, 910, 896, 794; 1H NMR
4.5.3. (E)-Methyl 5-bromo-2-((dimethylamino)methyleneamino)-4-
nitrobenzoate (31). According to the procedure described for 12
in Section (4.2.1.), reaction of 30 (1.50 g, 5.45 mmol) and DMFDMA
(1.8 mL, 13.6 mmol) in DMF (12 mL), at 105 ꢀC (350 W) for 15 min,
gave product 31 (1.73 g, yield 96%) as an orange oil: IR nmax (cmꢂ1
)
3262, 3111, 1697, 1584, 1542, 1497, 1249, 1222, 1139, 1098, 913, 823,
781; 1H NMR (300 MHz, DMSO-d6)
7.91 (s, 1H, NCH), 7.85 (s, 1H,
HAr), 7.68 (s, 1H, HAr), 3.78 (s, 3H, OCH3), 3.05 (s, 3H, NCH3), 2.91 (s,
3H, NCH3); 13C NMR (75 MHz, DMSO-d6)
166.1, 155.1, 151.3, 151.2,
d
(300 MHz, DMSO-d6)
d
12.44 (br s, 1H, NH), 9.20 (s, 1H, HAr), 8.51 (s,
160.3,
1H, HAr), 8.19 (s, 1H, HAr); 13C NMR (75 MHz, DMSO-d6)
d
d
155.0, 147.2, 145.8, 142.4, 133.4, 122.8, 122.4, 121.9, 113.1; HRMS
133.6, 130.8, 115.8, 102.0, 52.1, 33.9 (2C); HRMS calcd for
C11H1379BrN3O4 [MþH]þ 330.0089 found 330.0075, for
C11H1381BrN3O4 [MþH]þ 332.0069 found 332.0050.
calcd for C10H5N4OS [MþH]þ 229.0184 found 229.0184.
4.5.9. Thiazolo[5,4-g]quinazolin-8(7H)-one (39). According to the
procedure described for 38 in Section (4.4.10.), heating of 4 (0.20 g,
0.87 mmol) and HBr (48% in water, 5 mL), at 115 ꢀC (450 W) for
30 min, gave product 39 (0.162 g, yield 92%) as a white powder: mp
>265 ꢀC; IR nmax (cmꢂ1) 3185, 3057, 2915, 2851, 1674, 1603, 1440,
4.5.4. 3-Benzyl-6-bromo-7-nitroquinazolin-4-one (32). According
to the procedure described for compound 7 in Section (4.2.2.), re-
action of 31 (1.25 g, 3.79 mmol) and benzylamine (6.20 mL,
5.69 mmol) in acetic acid (8 mL), at 118 ꢀC (400 W) for 25 min, gave
product 32 (1.26 g, yield 92%) as a white powder: mp 176e178 ꢀC; IR
nmax (cmꢂ1) 3079, 3030, 3002, 1674, 1605, 1531, 1353, 1319, 1228,
1330, 1267, 919, 848, 791; 1H NMR (300 MHz, DMSO-d6)
d
12.30 (br
s, 1H, NH), 9.68 (s, 1H, HAr), 9.01 (s, 1H, HAr), 8.32 (s, 1H, HAr), 8.14 (s,
1H, HAr); 13C NMR (75 MHz, DMSO-d6)
d 161.9, 160.6, 157.0, 146.4,
949, 799; 1H NMR (300 MHz, DMSO-d6)
1H, HAr), 8.39 (s,1H, HAr), 7.38e7.31 (m, 5H, Ph), 5.22 (s, 2H, CH2Ph);
13C NMR (75 MHz, DMSO-d6)
158.3, 153.3, 150.6, 147.6, 136.1, 132.1,
d
8.77 (s, 1H, HAr), 8.49 (s,
145.0, 132.5, 121.1, 120.5, 120.1; HRMS calcd for C9H6N3OS [MþH]þ
204.0232 found 204.0231.
d
128.6 (2C), 127.8, 127.7 (2C), 124.9, 123.8, 109.5, 49.4; HRMS calcd
for C15H1179BrN3O3 [MþH]þ 359.9984 found 359.9997, for
C15H1181BrN3O3 [MþH]þ 361.9963 found 361.9980.
Acknowledgements
This work was supported by Ph.D. grants (D.H. and R.G.) from
ꢁ
ꢀ
the Ministere de l’Enseignement Superieur et de la Recherche
(MESR). D.H., E.C., and T.B. thank the Labex SYNORG (ANR-11-LABX-
0029) and AI-Chem Channel programs for financial support and
acknowledge Milestone S.r.l. (Italy) for provision of the microwave
reactors and technical support.
4.5.5. 7-Amino-3-benzyl-6-bromoquinazolin-4(3H)-one (33). Acco-
rding to the procedure described for compound 27 in Section (4.4.6.),
a stirred mixture of 32 (1.15 g, 3.20 mmol) and iron powder (0.894 g,
16.0 mmol) in ethanol (8.5 mL) and acetic acid (8.5 mL) was refluxed
for 30 min. Product 33 (0.972 g, yield 92%) was obtained as a white
powder: mp 210 ꢀC; IR nmax (cmꢂ1) 3460, 3321, 1657, 1601, 1581, 1480,
References and notes
1272, 1234, 954, 864, 694; 1H NMR (300 MHz, DMSO-d6)
HAr), 8.05 (s, 1H, HAr), 7.33e7.30 (m, 5H, Ph), 6.89 (s, 1H, HAr), 6.32 (br
s, 2H, NH2), 5.11 (s, 2H, CH2Ph); 13C NMR (75 MHz, DMSO-d6)
158.7,
d 8.39 (s, 1H,
1. Loidreau, Y.; Marchand, P.; Dubouilh-Benard, C.; Nourrisson, M.-R.; Duflos, M.;
d
€
Lozach, O.; Loaec, N.; Meijer, L.; Besson, T. Eur. J. Med. Chem. 2012, 58, 171e183.
ꢀ
ꢀ
2. Loge, C.; Testard, A.; Thiery, V.; Lozach, O.; Blairvacq, M.; Robert, J.-M.; Meijer,
151.1, 148.8, 148.3, 137.1, 129.9, 128.6 (2C), 127.5 (2C), 111.7, 108.6, 108.1,
48.4; HRMS calcd for C15H1379BrN3O [MþH]þ 330.0242 found
330.0241, for C15H1381BrN3O [MþH]þ 332.0222 found 332.0225.
L.; Besson, T. Eur. J. Med. Chem. 2008, 43, 1469e1477.
ꢀ
ꢀ
3. Testard, A.; Loge, C.; Leger, B.; Robert, J.-M.; Lozach, O.; Blairvacq, M.; Meijer, L.;
ꢀ
Thiery, V.; Besson, T. Bioorg. Med. Chem. Lett. 2006, 16, pp 3419e3423.
ꢁ
4. Beauchard, A.; Ferandin, Y.; Frere, S.; Lozach, O.; Blairvacq, M.; Meijer, M.;
ꢀ
Thiery, V.; Besson, T. Bioorg. Med. Chem. 2006, 14, 6434e6443.
4.5.6. 3-Benzyl-6-bromo-7-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)quinazolin-4(3H)-one (35). According to the pro-
cedure described for 10 in Section (4.2.5.), reaction of compound 33
(1.0 g, 3.03 mmol) and 4,5-dichloro-1,2,3-dithiazolium chloride
(Appel salt) (0.948 g, 4.55 mmol) in dichloromethane (30 mL), at
room temperature for 2 h, gave product 35 (1.02 g, yield 72%) as an
5. Testard, A.; Picot, L.; Lozach, O.; Blairvac, M.; Meijer, L.; Murillo, L.; Piot, J.-M.;
ꢀ
Thiery, V.; Besson, T. J. Enzyme Inhib. Med. Chem. 2005, 20, 557e568.
6. Alexandre, F. R.; Berecibar, A.; Wrigglesworth, R.; Besson, T. Tetrahedron Lett.
2003, 44, 4455e4458.
7. Besson, T.; Guillard, J.; Rees, C. W. Tetrahedron Lett. 2000, 41, 1027e1030.
8. (a) Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985, 118, 1632e1643;
(b) For recent review see Foucourt, A.; Chosson, E.; Besson, T. In Targets in

ꢀ
D. Hedou et al. / Tetrahedron 69 (2013) 3182e3191
3191
Heterocyclic Systems e Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.;
Italian Society of Chemistry: Roma, 2010; Vol. 14, pp 315e350.
Claude, B. J. J. Med. Chem. 2006, 49, 3544e3552; (c) Yoon, D. S.; Han, H.; Stark,
T. M.; Haber, J. C.; Gregg, B. T.; Stankovich, S. B. Org. Lett. 2004, 6, 4775e4778;
(d) Tsou, H. R.; Mamuya, N.; Johnson, B. D.; Reich, M. F.; Gruber, B. C.; Ye, F.;
Nilakantan, R.; Shen, R.; Discafani, C.; DeBlanc, R.; Davis, R.; Koehn, F. E.;
Greenberger, L. M.; Wang, Y. F.; Wissner, A. J. Med. Chem. 2001, 44, 2719e2734.
14. Formamide acetals have been used in the synthesis of esters from acids ethers
or thioethers from phenols and heterocyclic thiols or intracyclic amines in
indoles, and benzimidazoles. For a complete review see Abdulla, R. F.; Brink-
meyer, R. S. Tetrahedron 1979, 35, 1675e1735.
9. For reviews on the interest of microwaves in heterocyclic chemistry see: (a)
Kappe, C. O.; Dallinger, D. Mol. Diversity 2009, 13, 71e193; (b) Caddick, S.; Fitz-
maurice, R. Tetrahedron 2009, 65, 3325e3355; (c) Besson, T.; Chosson, E. Comb.
Chem. High Throughput Screening 2007, 10, 903e917; (d) Alexandre, F. R.; Domon,
ꢁ
ꢀ
L.; Frere, S.; Testard, A.; Thiery, V.; Besson, T. Mol. Diversity 2003, 7, 273e280.
10. For recent examples see: (a) Loidreau, Y.; Besson, T. Tetrahedron 2011, 67,
4852e4857; (b) Grosjean, S.; Triki, S.; Meslin, J. C.; Julienne, D.; Deniaud, D.
Tetrahedron 2010, 66, 9912e9924; (c) Nouira, I.; Kostakis, I. K.; Dubouilh, C.;
Chosson, E.; Iannelli, M.; Besson, T. Tetrahedron Lett. 2008, 49, 7033e7036; (d)
Kostakis, I. K.; Elomri, H.; Seguin, E.; Iannelli, M.; Besson, T. Tetrahedron Lett.
2007, 48, 6609e6613 In this reaction, formamide played the dual role of solvent
and reactant. Its temperature-dependent ability to generate ammonia synthon
and its intrinsic properties of heating under microwave irradiation (its loss
15. Kundu, S. K.; Mahindaratne, P. D.; Quintero, M. V.; Bao, A.; Negrete, G. R. AR-
KIVOC 2008, i, 33e42.
16. Compound 38 and 39 were described as intermediates for the synthesis of
thiazolo[4,5-g] or [5,4-g]quinazolin-8(7H)-ones substituted in position 8 of the
tricyclic structure by aromatic amines: (a) The 1H NMR (DMSO-d6) of 38 was
the only data available in: U.S. Patent 5679683, 1997; Chem. Abstr. 1997, 127,
358871; (b) Data given in this paper for 39 are in accordance with those
published in: Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J.; Showalter, H. D. H.;
Sun, L.; Nelson, J.; McMichael, A.; Kraker, A. J.; Fry, D. W.; Denny, W. A. J. Med.
Chem. 1996, 39, 918e928.
dissipation factor, tan
process.
d, is greater than 0.5) were combined in a comfortable
11. (a) Guillon, R. Ph.D. Thesis, University of Nantes, 2010. (b) Guillon, R.; Pagniez,
ꢀ
F.; Hedou, D.; Picot, C.; Tonnerre, A.; Duflos, M.; Chosson, E.; Besson, T.; Loge, C.;
Le Pape, P. ACS Med Chem Lett 2013, 4, 288e292.
12. Foucourt, A.; Dubouilh-Benard, C.; Chosson, E.; Corbiere, C.; Buquet, C.; Iannelli,
17. The first synthesis of 4,5-dichloro-1,2,3-dithiazolium chloride 1 was described
in 1985 by Appel.8a It was improved by C. W. Rees and co-workers who de-
scribed the use of a phase transfer catalyst, AdogenÒ, used here as a source of
chloride. Its addition improves the quality, but not the yield of the salt: (a)
English, R. F.; Rakitin, O. A.; Rees, C. W.; Vlasova, O. G. J. Chem. Soc., Perkin Trans.
1 1997, 201e205; (b) Besson, T.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1995,
1659e1662.
ꢁ
M.; Leblond, B.; Marsais, F.; Besson, T. Tetrahedron 2010, 66, 4495e4502.
13. For various examples of the use of Dimroth transposition for the synthesis of
bioactive quinazolines see: (a) Rachid, Z.; MacPhee, M.; Williams, C.; Torodova,
M.; Jean-Claude, B. J. Bioorg. Med. Chem. Lett. 2009, 19, 5505e5509; (b) Do-
markas, J.; Dudouit, F.; Williams, C.; Qiyu, Q.; Banerjee, R.; Brahimi, F.; Jean-