Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent

Article abstract of DOI:10.1016/j.tet.2010.04.066

A useful and rapid access to 4-anilino-6-nitroquinazolines was investigated in a multi-gram scale via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with imines obtained by reaction of anthranilonitriles with formamide dimethylacetal. A novel short and efficient route to Azixa (EPi28495, MPC-6827), a microtubule destabilizing agent and apoptosis inducer, was performed with success demonstrating that well controlled parameters offer comfortable using of microwave technology with safe and environmental benefits.

Full text of DOI:10.1016/j.tet.2010.04.066

Tetrahedron 66 (2010) 4495e4502
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-accelerated Dimroth rearrangement for the synthesis of
4-anilino-6-nitroquinazolines. Application to an efficient synthesis of
a microtubule destabilizing agent
Alicia Foucourt a, Carole Dubouilh-Benard a, Elizabeth Chosson a, Cécile Corbière b,
,
Catherine Buquet b, Mauro Iannelli c, Bertrand Leblond d, Francis Marsais e, Thierry Besson a
*
a Université de Rouen, CNRS UMR 6014dC.O.B.R.A. & FR3038, I.R.C.O.F. rue Tesnière, F-76130 Mont Saint-Aignan, France
b Université de Rouen, EA 3829, UFR Médecine-Pharmacie, 22 Boulevard Gambetta, 76183 Rouen cedex 1, France
c Milestone S.r.l., Via Fatebenefratelli, 1/5, 24010 Sorisole (BG), Italy
d ExonHit Therapeutics, 65 Boulevard Masséna, F-75013, Paris, France
e INSA de Rouen, CNRS UMR 6014dC.O.B.R.A. & FR3038, I.R.C.O.F. rue Tesnière, F-76130 Mont Saint-Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A useful and rapid access to 4-anilino-6-nitroquinazolines was investigated in a multi-gram scale via
microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with imines
obtained by reaction of anthranilonitriles with formamide dimethylacetal. A novel short and efficient
route to AzixaÔ (EPi28495, MPC-6827), a microtubule destabilizing agent and apoptosis inducer, was
performed with success demonstrating that well controlled parameters offer comfortable using of
microwave technology with safe and environmental benefits.
Received 10 March 2010
Received in revised form 9 April 2010
Accepted 16 April 2010
Available online 21 April 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
4-Anilinoquinazolines
Microwave-assisted synthesis
Dimroth rearrangement
1. Introduction
type and the position of the substituents in their skeleton. Out of
the wide known substitution pattern, 4-aminoquinazolines and their
The use of adapted reactants and techniques offering operational,
economic and environmental benefits over conventional methods is
becoming crucial in the preparation and development of biologically
active molecules. Recently, the use of clean and more efficient
technologies, like microwaves, has become a major stimulus for both
industry and academia as it was found to be an effective heating
source applicable to a wide range of reactions.1,2 Novel commercial
microwave systems specific for synthesis offer improved opportu-
nities for reproducibility, rapid synthesis, fast reaction optimization
and potential discovery of new chemicals.3
Our research project consists in developing an easy access to
heterocyclic molecules with pharmaceutical interest and we are
particularly interested in finding a rapid preparation method of the
quinazoline skeleton.4 This ring is a building block for approximately
150 naturally occurring alkaloids. Their synthetic analogous possess
a variety of biological activities, including antimalarial,5 anticonvul-
sant,6 antibacterial,7 antidiabetic8 and anticancer.9 It is now assumed
that the biological activity of various quinazolines depends on the
N-anilino derivatives were found to be potent and selective ATP
competitive tyrosine kinase inhibitors for the treatment of EGFR-
associated cancer types (for example IressaÔdgefitinib and Tarce-
vaÔderlotinib, which are used for treatment of non-small-cell lung
cancer).10 More recently 6-thioureido-11 and 6-ureido-4-12 anilino-
quinazolines have been designed for antimalarial or anticancer
activity. In all of these studies 4-anilino-6-nitro-quinazolines are key
precursors allowing access to a wide range of N-substituted 4-ami-
noquinazolines. In our hands, the synthesis of such intermediates
proved to be quite difficult and complicated. Applying usual pro-
cesses,4 6-nitroquinazolin-4-ones were treated with thionyl chloride
or phosphoryl oxychloride to get the intermediates 4-chlororo-6-
nitroquinazolines, which are very unstable and decompose on stor-
age. To overcome this instability problem and in connection with our
work on the application of microwave irradiation in organic chem-
istry,13 we decided to focus our efforts on the access to 4-substituted
6-nitroquinazolines from 5-nitroanthranilonitrile, with the aim to
obtain efficient and adapted conditions with operational and envi-
ronmental benefits.
The developed microwave-assisted method was then applied to
the synthesis of AzixaÔ (EPi28495, MPC-6827),14 a 4-anilinoquina-
zoline derivative that acts as a microtubule disrupting agent, causing
* Corresponding author. Tel.: þ33 235 592 904/148 399; fax: þ33 235 148 423;
e-mail address: thierry.besson@univ-rouen.fr (T. Besson).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.066

4496
A. Foucourt et al. / Tetrahedron 66 (2010) 4495e4502
cell cycle arrest and apoptosis in cancer cells. AzixaÔ has also been
shown to be a vascular disrupting agent. Thus, AzixaÔ has a dual
mode of action; it induces apoptosis and reduces blood supply to the
tumour and is actually in phase II clinical studies in patients with
glioblastoma multiform and metastatic melanoma.15 This paper de-
scribes our most recent findings in this field and allows us to present
and discuss the mechanism of this chemical reaction.
amines, it was possible to generate a small library in a short time
(10 min). Different solvent conditions compared with the previous
reported thermal procedure were also used. This approach was
again recently used for the synthesis of intermediate
6-nitroquinazolines.19
Persuaded that 4-anilino-6-nitroquinazolines would be more
easily obtained from 5-nitroanthranilonitrile, our group decided to
re-investigate the microwave conditions of the initial reaction de-
scribed in 200117 with the aim to define a well established process
allowing high level of reproducibility and also scaling-up for fur-
ther developments. Our microwave experiments were performed
under pressurized conditions using the novel ‘hybrid’ microwave
platform MultiSYNTH (Milestone S.r.l. Italy) or at atmospheric
pressure using the multimode platform START SYNHTH (Milestone
s.r.l. Italy) equipped with an internal camera, which allows to ob-
serve general aspect of the mixture during the reaction (change of
colour, formation of crystals, etc.). Reaction conditions were opti-
mized varying applied power and temperature (measured by both,
fibre-optic contact thermometer and infrared pyrometer).
Our study started with the synthesis of the intermediate N-(2-
cyano-4-nitrophenyl)-N,N-dimethylimidoformamides (1 and 2).
After optimization of the microwave conditions by varying reaction
time, power input, temperature and pressure, we were able to
obtain the expected product 1 at 70 ꢀC in only 2 min of irradiation
at atmospheric pressure, in almost quantitative yields (90e94%
after purification) (Scheme 2). These yields were generally lower
when the reaction was performed using longer heating times (more
than 5 min) and in pressurized vials at higher temperatures
(>130 ꢀC). In this case large quantities of starting anthranilonitrile
were recovered in combination with degradation products that
were difficult to identify. This result suggested that hydrolysis of 1
can occurs more easily when effects of pressure and temperature
are combined. In order to avoid probable by-products generated by
this phenomenon, we decided to perform our experiments on the
second step of the synthesis at atmospheric pressure in a range of
temperature not exceeding 130 ꢀC. It is important to notice that our
2. Results and discussion
Due to the diverse range of the pharmacological activities of
quinazolines and their derivatives, there are numerous methods
available for their synthesis.4,13 One of the main route described for
4-anilino-6-nitroquinazolin-4-ones consists of reacting anilines with
4-chloro-6-nitroquinazolines obtained by chlorination with phos-
phorus oxychloride of the corresponding 6-nitroquinazolinone,
which, in turn, is prepared by heating 5-nitroanthranilate with
formamide (Niementowski reaction16). Nitration of the ring can also
be performed after formation of the nude quinazolin-4-one from
anthranilate. In our microwave-assisted experiments chlorination
step of the nitrated ring was fairly painstaking and required rela-
tively high temperatures. We often observed hydrolysis of a large
part of the 4-chloro-6-nitroquinazoline into the starting quinazolin-
4-one. Nitration of the 4-chloroquinazoline is also difficult and
yielded mainly to the 6-nitroquinazolin-4-one. Checking literature
data we observed that 4-chloro-6-nitroquinazoline is normally used
without purification for the condensation with aromatic amines,
confirming its instability.4,17
Looking for an efficient method allowing incorporation of the
4-anilino group during ring cyclisation, Tsou and co-workers17 have
reported the synthesis of a 6-nitro-4-(3-bromophenylamino)qui-
nazoline performed in only two steps via condensation of 3-bro-
moaniline with an intermediate N-(2-cyano-4-nitrophenyl)-N,
N-dimethylimidoformamide (1). This compound was obtained by
reaction between the commercial 5-nitroanthranilonitrile and
DMF-dimethylacetal (Scheme 1).
MeO
N
O2N
CN
N
HN
N
Br
O2N
CN
H2N
Br
MeO
O2N
N
N
NH2
100°C, 1.5h
AcOH, reflux, 1h
1
Scheme 1. Reaction described by Tsou and co-workers in 2001.17
Ar
CN
N
HN
N
CN
H
N
Ar-NH2
b
+
Ar
N
N
a
NH2
O
3a-c
2
4a-c
OMe
OMe
Ar :
OMe
OMe
a:
OMe
b:
c:
OMe
Scheme 2. Microwave-assisted synthesis of 4-anilinoquinazolines from anthranilonitriles. Reagents and conditions: (a) dimethylformamide dimethylacetal, 70 ꢀC (800 W), 2 min,
94%; (b) acetic acid, 118 ꢀC (600 W), 2 min, 93% (3a), 94% (3b) and 99% (3c).
Since 2001, this synthesis was very rarely used. In 2004, a pa-
per from Han and co-workers18 described a microwave approach
for the second step performed in a parallel format. Working at
160 ꢀC in pressurized vials and testing a number of aliphatic
atmospheric microwave-accelerated method allowed us to extend
the scale of this synthesis using up to 70 g of the starting imine.
Similar quantities of compound 2 were also prepared at 90 ꢀC in
only 15 min.

A. Foucourt et al. / Tetrahedron 66 (2010) 4495e4502
4497
Table 1
The second step of the synthesis consists in heating different an-
ilines with 1 or 2 in the presence of acetic acid. Applying methods
from the literature,17e19 we firstly studied condensation of 2 with 1.1
or 1.2 equiv of nucleophilic anilines substituted by one, two or three
methoxy groups. The evolution of all our experiments was followed
by GC/MS chromatography. After various trials to optimize reaction
time, temperature and power we were able to obtain, in 2 min, ex-
cellent yields (93e99%) of the expected 4-anilinoquinazolines
(3aec), which were often accompanied by small traces (1e2%) of the
acetylated anilines (4aec). These latest were easily eliminated by
washing the crystallized major product with diethyl ether (Scheme
2). This result suggested us that, in our microwave conditions, ace-
tic acid was able to react rapidly with aromatic amines to form the
corresponding acetamides. In order to confirm this hypothesis we
decided to observe evolution of the microwave heating of p-
methoxyaniline alone in solution with acetic acid. After 2 min of ir-
radiation the attempted acetamide was detected in a 28% yield and
this value increased with time. Intrigued by this result we also
compared our microwave experiments with traditional thermal
heating in pre-heated oil bath and we observed that this phenome-
non exists in the thermal processes but requires longer reaction time.
Then, we may confirm that previous works published in the literature
were not able to describe these by-products if the time used was
inferior to 1 h. Quantitative yield of 3a was obtained when 1 equiv of
p-anisidine reacted with 2 under the condition given above (Scheme
2). In order to complete our study, the same experiment was per-
formed with acetonitrile/acetic acid(7:3, v/v) assolvent.18 In thiscase,
product 3a was isolated in 91% yield after 25 min of heating at 100 ꢀC
(this value is the highest temperature that can be reached in these
conditions, at atmospheric pressure, whatever the value of the mi-
crowave power input). Comparing the two methods, we confirmed
that the use of acetic acid as the single solvent gave cleaner raw
mixtures easier to purify. Replacement of acetic acid by N-methyl-
pyrrolidone (NMP) and PTSA (1.1 equiv) was also experimented with
success (yield of 3a: 83%) but in a longer reaction time (25 min) and at
a higher temperature (160 ꢀC). Purification of the attempted product
was possible after several washing of the organic layer (ethyl acetate)
with water followed by column chromatography.
Taking into account these results we were able to optimize and
perform the synthesis of a short library of 6-nitroquinazolines
(5aek) substituted in position 4, in short time and good yields
(Scheme 3, Table 1). The reaction of 10 g of amidine 1 with
substituted anilines was followed by GC/MS (reaction times given
correspond to a complete disappearance of the starting compound
1) and yields are given after purification. It was also possible to
further extend the quantity of starting material up to 50 g. Here
again working at atmospheric pressure allowed scaling-up of the
reaction in very good conditions of quantities and time. It seems
obvious that the result of the reaction depends on the nucleo-
philicity of the aniline and also on its accessibility in connection
with the steric hindrance of the substituents. The presence of
electron-attracting groups on the benzene ring and voluminous
atoms or groups into the ortho-position of the aromatic amine
involved an increase in reaction times and lowered the yields (see
Table, products 5gem). Strong withdrawing groups, like nitro
group, can stop the cyclisation process, leaving the acetamide as
the main product. (e.g., 6 for p-NO2). It is important to note that
Starting aniline
Reaction time (min)a
3
Product
Yieldb (%)
5a
88
80
99
H2N
2
2
5b
5c
H2N
H2N
Me
OMe
OMe
H2N
H2N
2
2
5d
5e
97
89
OMe
OMe
OMe
OMe
5
7
5f
91
82
H2N
H2N
F
5g
CN
Cl
10
30
90
25
5h
5i
77
70
60
74
H2N
H2N
H2N
H2N
F
F
Br
Cl
Cl
F
5k
5l
F
CF3
H2N
210
30
5m
6
55
88
50
H2N
NO2
75
7a
N
H
45
7b
53
N
H
OMe
a
Time for the complete disappearance of 2 (followed by GC/MS chromatography).
After purification by crystallization and washing with diethyl ether.
b
Ar
HN
O2N
CN
N
O2N
CN
N
H2N Ar
O2N
N
Ar
or
N
N
R
AcOH, 118°C (MW)
N
6 (R = H)
7 (R = Me)
1
5
Scheme 3. Synthesis of 4-anilino-6-nitroquinazolines: for reaction times and yields see Table 1.

4498
A. Foucourt et al. / Tetrahedron 66 (2010) 4495e4502
the camera equipped with the microwave was a real enhancement
in the capabilities of the instrument; it allowed us to observe
changes in the aspect of the mixture. Then, we observed that the
reaction can be regarded as finished when crystals started to be
formed in the flask.
Interestingly, the formation of compounds 7, obtained when
N-methylanilines were condensed with 2, confirms the mechanism of
the reaction which was rarely described in the literature until now.20
We assume that the first attack of the aromatic amine takes place on
the carbon of the N,N-dimethylamidine and result into ejection of
dimethylamine. The intermediate aromatic amidine can then cyclise
into a quinazoline skeleton in which the endocyclic and exocyclic
nitrogen atoms switched place via a Dimroth rearrangement to afford
the attempted 4-anilinoquinazoline (Scheme 4). If a first attack of the
amine into the cyano group is possible in theory, it is more difficult in
reality despite a probable catalytic action of acetic acid.
metastatic brain tumours for which treatment are actually limited. It
is currently in phase II clinical studies in patients with glioblastoma
multiform and metastatic melanoma. The synthesis of this 4-anili-
noquinazoline substituted in position 2 by a methyl group was re-
cently described in three steps from 2-aminobenzoic acid methyl
ester and acetonitrile via an intermediate chloroimine, which was
condensed with N-methyl-4-methoxyaniline in anhydrous prop-
anol to give the final product with a total yield of 55%.13,14 Our
method starts from anthranilonitrile, which reacted with N,N-
dimethylacetamide dimethylacetal. Compared the previously syn-
thesized compounds (1 and 2) the synthesis of amidine 8 needed
more energy due to the steric hindrance of the methyl group. It was
obtained in good yield (90%) after 2 min of irradiation at 115 ꢀC.
Condensation of 4-methoxyaniline with 8 under the previous con-
ditions described for products 5 needed a longer reaction time of
30 min to afford the quinazoline 9 in an average yield of 56%, to-
gether with a significant amount of by-products. In this case heating
8 in a mixture of acetonitrile/acetic acid (7:3, v/v) gave a very good
yield (88%) of N-(4-methoxyphenylamino)-2-methylquinazoline
(9). This latter could be further N-alkylated to give AzixaÔ (10),
which was purified twice by column chromatography in a good
average yield of 55% from the starting anthranilonitrile (Scheme 5).
AzixaÔ [N-(4-methoxyphenylamino)-N,2-dimethylquinazoline]
(10) is a small-molecule inhibitor of microtubule formation and was
identified as a potent apoptosis inducer.13e15 Moreover, AzixaÔ is
not a substrate for Multiple Drug Resistance pumps and is able to
cross the bloodebrain barrier and accumulate in the brain.15 These
properties make AzixaÔ
a good candidate for primary and
NH
N
R
CN
N
R
R
Ar
H
N
N
Ar
N
N
N
1 or 2
H2O
H2N Ar
Ar
Ar
NH
N
HN
HN
R
Ar
R
(- H2O)
R
N
NH
N
N
OH
N
H
O
3 or 5
Scheme 4. Mechanism of the reaction involved in the synthesis of 4-anilinoquinazolines from anthranilonitrile.
OMe
OMe
N,N-dimethylacetamide
dimethyl acetal
CN
N
CN
H2N
CH3CN/AcOH
HN
N
N
115°C (MW), 2min
(90%)
N
NH2
118°C (MW), 30 min
8
9
(88%)
OMe
NaH, CH3I, DMF
OMe
N
H
0°C 1h then rt 1h
(70%)
Method A (22%)
or
N
H
Method B (71%)
OMe
OMe
N
N
N
N
N
NH
11
N
N
N
10 (Azixa)
N
(55%) in 3 steps via 8 and 9
(20%) in 2 steps via 8 (method A)
(63%) in 2 steps via 8 (method B)
Scheme 5. Synthesis of AzixaTM and suggested mechanism via attack on the carbonitrile function. Method A: AcOH, 140 ꢀC (MW), 6 h (22%); method B: AlCl3 (1.5 equiv), NMP,
200 ꢀC (MW), 2 h (63%).

A. Foucourt et al. / Tetrahedron 66 (2010) 4495e4502
4499
One of our research activity consist in studying reactions, which
need a high level of energy and to see if the intense heating available
via microwaves may generate unexpected compounds or help un-
derprivileged mechanisms.21 Thus, we decided to heat amidine 8
with N-methyl-4-methoxyaniline, in the presence of acetic acid.
Considering the mechanism described above, it was clear that nu-
cleophilic attack of the secondary amine could be restricted by steric
hindrance and we expected only formation of the cyano derivative
(11 in Scheme 5). Evolution of the reaction mixture was followed by
GC/MS. Disappearance of the starting compound (8) was observed
after 6 h (overall reaction time) of microwave heating in sealed vials.
In the same time the starting N-methyl-p-anisidine was mainly
transformed into its acetamide derivative. We also detected the
carboxylic acid resulting from hydrolysis of the cyano group of 8 and
we observed appearance of the starting anthranilonitrile due to its
hydrolysis. Addition of 1 equiv of N-methyl-p-anisidine after 4 h of
heating at 140 ꢀC allowed to obtained, after a novel heating period of
2 h, a 22% yield of a compound identified as AzixaÔ (10) by com-
parison of the physicochemical data (e.g., NMR, mass spectra, CG
profile, mp). This surprising result suggests that the secondary aro-
matic amine has finally attacked the cyano group present in ortho-
position of the amidine and that the intermediate compound (11)
cyclised into the expected product (Scheme 5). To confirm this result,
the same reaction was performed from 8 at 200 ꢀC in NMP in the
presence of 1.5 equiv of AlCl3 a Lewis acid, which accelerate attack of
the aromatic amine by activation of the carbonitrile function.22 After
2 h of irradiation in a sealed vial, a good yield (71%) of the attempted
N-(4-methoxyphenylamino)-N,2-dimethylquinazoline (10) was
obtained after purification. This efficient microwave-assisted syn-
thesis of AzixaÔ was then performed in only two steps and in a good
overall yield of 64%. This novel route provides many advantages over
the conventional process,14 it is more efficient, simple to purify and
can be easily extended to a multigram-scale preparation.
Liquids were applied as a film between KBr windows and solids
were dispersed in a KBr pellet. Absorption bands are given in cmꢂ1
.
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 two commercial mi-
crowave reactors especially designed for synthetic chemistry. The
‘hybrid’ microwave platform MultiSYNTHÔ (Milestone S.r.l. Italy) is
a novel dedicated microwave system for synthetic applications. It
allows a fast reaction optimization providing high energy density in a
single-mode like configuration and an efficient scale-up (maximum
working volume 300 mL) through parallel synthesis in a multi-mode
configuration. The instrument features a special shaking system that
ensures high homogeneity of the reaction mixtures. It is equipped
with an indirect pressure-control through pre-calibrated springs at
the bottom of the vessels shields and with both, contact-less infrared
pyrometer (IRT) and fibre-optic contact thermometer (FO) for accu-
rate temperature measurement. It is noteworthy that the IRT can be
calibrated directly on the temperature read by the FO to ensure the
highest accuracy and reproducibility.
START SYNTH (Milestone S.r.l. Italy) is a multimode cavity with
a microwave power delivery system ranging from 0 to 1200 W. Open
vessel experiments were carried out in a 250 mL round bottom flask
fitted with a reflux condenser. The temperature was monitored via
a fibre-optic contact thermometer protected in a Teflon coated ce-
ramic well inserted directly in the reaction mixture. 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, pressure and
power profiles were monitored in both cases through the EASY-
Control software provided by the manufacturer.
3. Conclusion
In conclusion, we describe a very useful and rapid method for the
synthesis of 4-anilino-6-nitroquinazolines via microwave assisted
condensation of the starting anilines with imines obtained by re-
action of anthranilonitriles with dimethylformamide dimethylacetal.
All these results were applied to perform a novel, short and efficient
route to AzixaÔ, a microtubule destabilizing agent, causing arrest of
cell division and apoptosis in cancer cells and currently in phase II
clinical studies. The information given in this paper is a further ex-
ample that microwave heating is a very powerful tool for chemists.
Well controlled parameters offer comfortable using of microwave
technology with safe and environmental benefits; moreover it al-
lows an easy scale-up to a multi-gram scale. These results are also in
accordance with our recent works in which we demonstrated that
the intense thermal effect of microwaves may generate un-
derprivileged mechanisms and unexpected products.21 During syn-
thesis of AzixaÔ, the high level of energy rapidly available under
microwaves allowed to bypass the main mechanism in favour of the
unusual alternative, allowing access to the expected products. The
strict control of the temperatures reached into the reactor is also
a benefit to the overall management of the reaction.
4.1.1. N0-(2-Cyanophenyl)-N,N-dimethylformamidine (1) (lit.17). A
suspension of anthranilonitrile (50.0 g, 0.42 mol) was suspended in
dimethylformamide dimethylacetal (125 mL, 1.05 mol, 2.5 equiv)
was irradiated at 90 ꢀC (power input: 600 W) for 15 min. The
resulting mixture was cooled to room temperature and purified by
column chromatography over silica gel using CH2Cl2/EtOAc (8:2, v/
v) as the eluent to give the desired compound 1 (68.0 g, 94% yield)
as a pale yellow solid; mp 66 ꢀC; IR (KBr) nmax/cmꢂ1 2912, 2215,
1979, 1628, 1588, 1557, 1474, 1447, 1415, 1366, 1280, 1254, 1222,
1172, 1118, 1098, 969, 942, 870, 846, 758, 736; 1H NMR (300 MHz,
DMSO-d6)
d
7.91 (s, 1H, NCHN), 7.59 (dd, 1H, J1¼1.5 Hz, J2¼7.5 Hz,
H-6), 7.49 (td, 1H, J1¼1.2 Hz, J2¼8.4 Hz, H-5), 7.14 (d, 1H, J¼8.4 Hz,
H-3), 7.02 (t, 1H, J¼7.5 Hz, H-4), 3.06 (s, 3H, NCH3), 2.98 (s, 3H,
NCH3); 13C NMR (75 MHz, DMSO-d6)
d 154.9, 154.5, 133.5, 132.8,
121.5, 118.8, 118.4, 105.9, 36.6, 33.9; HRMS calcd for C10H12N3
[MþH]þ 174.1031 found 174.1040.
4.1.2. N0-(2-Cyano-4-nitrophenyl)-N,N-dimethylformamidine (2)
(lit.17). A suspension of 5-nitroanthranilonitrile (70.0 g, 0.43 mol)
in dimethylformamide dimethylacetal (129 mL, 1.08 mol, 2.5 equiv)
was irradiated at 70 ꢀC (power input: 800 W) during 2 min. The
resulting mixture was cooled to room temperature and refrigerated
overnight. The orange precipitate formed was filtered, washed with
ethyl ether and dried to give 2 (87.9 g, 94% yield) as an orange solid;
mp 148e150 ꢀC dec; IR (KBr) nmax/cmꢂ1 2971, 2901, 2224, 1623,
1593, 1558, 1499, 1414, 1374, 1310, 1280, 1170, 1141, 1076, 922, 888,
4. Experimental section
4.1. General
All reactions were monitored by thin-layer chromatography
with silica gel 60 F254 pre-coated aluminium plates (0.25 mm).
Melting points of solid compounds were measured on a WME
Kofler hot-stage with a precision of ꢁ2 C and are uncorrected. IR
829, 776, 754, 726, 658; 1H NMR (300 MHz, DMSO-d6)
H-3), 8.24 (m, 2H, NCHN and H-5), 7.34 (d, 1H, J¼9 Hz, H-6), 3.16 (s,
d 8.42 (s,
ꢀ
€
spectra were recorded on a PerkineElmer IRFT 1650 spectrometer.

4500
A. Foucourt et al. / Tetrahedron 66 (2010) 4495e4502
3H, NCH3), 3.07 (s, 3H, NCH3); 13C NMR (75 MHz, DMSO-d6)
d
161.0,
(t, 1H, J¼7.5 Hz); 13C NMR (75 MHz, DMSO-d6)
d 158.7, 157.7, 153.0,
144.4, 138.4, 129.4, 128.5, 126.5, 125.3, 124.5, 122.9, 120.8, 114.3;
156.5, 139.9, 129.3, 128.5, 118.1, 116.8, 105.9, 40.4, 34.4; HRMS calcd
for C10H11N4O [MþH]þ 219.0882 found 219.0873.
HRMS calcd for C14H11N4O2 [MþH]þ 266.0811 found 266.0813.
4.2. Synthesis of the 4-arylaminoquinazolines (3aec)
4.3.2. N-(4-Methylphenyl)-6-nitro-quinazolin-4-amine (5b) (lit.12).
Yield: 79%; orange solid, mp 210 ꢀC; IR (KBr) nmax/cmꢂ1 3389, 3285,
3092, 3038, 1626, 1587, 1567, 1535, 1492, 1426, 1390, 1361, 1337,
1266, 1236, 1192, 1115, 1062, 975, 934, 900, 849, 810, 744, 677, 635,
A mixture of N0-(2-cyanophenyl)-N,N-dimethylformamidine 1
(0.5 g, 2.89 mmol) and appropriate aniline (1.0 equiv) in acetic acid
(3 mL) was irradiated at 118 ꢀC (power input: 600 W) for 2 min. On
completion, the reaction was cooled to ambient temperature. The
resulting mixture was cooled to room temperature and purified by
column chromatography over silica gel using CH2Cl2/EtOAc
(80e20) as the eluent to give the desired compounds 4aec.
618; 1H NMR (300 MHz, DMSO-d6)
d 10.4 (s, 1H, NH), 9.62 (d, 1H,
J¼2.3 Hz), 8.66 (s, 1H), 8.53 (dd, 1H, J1¼2.4 Hz, J2¼9.2 Hz), 7.89
(d, 1H, J¼9.2 Hz), 7.70 (d, 2H, J¼7.8 Hz), 7.23 (d, 2H, J¼7.8 Hz), 2.32
(s, 3H); 13C NMR (75 MHz, DMSO-d6)
d 158.8, 157.8, 153.1, 144.4,
135.8, 133.8, 129.4, 128.9, 126.6, 123.0, 120.9, 114.4; HRMS calcd for
C15H13N4O2 [MþH]þ 280.1003 found 280.1011.
4.2.1. N-(4-Methoxyphenyl)quinazolin-4-amine (3a). Yield: 93%;
yellow solid, mp 165 ꢀC; IR (KBr) nmax/cmꢂ1 3242, 3076, 2952, 2832,
1682, 1619, 1598, 1576, 1529, 1513, 1496, 1461, 1420, 1396, 1360,
1323, 1299, 1236, 1177, 1163, 1126, 1102, 1072, 1038, 974, 924, 857,
820, 778, 764, 753, 707, 683, 645, 629; 1H NMR (300 MHz, DMSO-
4.3.3. N-(4-Methoxyphenyl)-6-nitroquinazolin-4-amine (5c) (lit.12).
Yield: 99%; orange solid, mp 198e200 ꢀC; IR (KBr) nmax/cmꢂ1 3412,
3305, 3099, 1981, 1681, 1622, 1609, 1590, 1573, 1547, 1513, 1493,
1463, 1435, 1393, 1359, 1334, 1235, 1181, 1114, 1025, 943, 931, 899,
884, 847, 832, 808, 744, 679, 665, 625,624; 1H NMR (300 MHz,
d6)
(d, 2H, J¼8.7 Hz), 7.62 (t, 1H, J¼7.5 Hz), 6.98 (d, 2H, J¼8.7 Hz), 3.76
(s, 3H); 13C NMR (75 MHz, DMSO-d6)
157.9, 155.9, 154.7, 149.6,
d
9.74 (s, 1H, NH), 8.53 (d, 1H, J¼9 Hz), 7.82e7.74 (m, 2H), 7.71
DMSO-d6)
d
10.3 (s, 1H, NH), 9.56 (d, 1H, J¼2.1 Hz), 8.59 (s, 1H), 8.49
d
(dd, 1H, J1¼1.8 Hz, J2¼9.0 Hz), 7.85 (d, 1H, J¼9.3 Hz), 7.68 (d, 2H,
132.9, 131.9, 127.8, 126.1, 124.5, 122.9, 115.1, 113.7, 55.3; HRMS calcd
J¼8.7 Hz), 6.99 (d, 2H, J¼8.7 Hz), 3.77 (s, 3H); 13C NMR (75 MHz,
for C15H14N3O [MþH]þ 252.1137 found 252.1133.
DMSO-d6) d 172.1, 158.8, 157.9, 156.4, 153.1, 144.3, 131.2, 129.3, 126.4,
124.7, 120.8, 114.3, 113.7, 55.3; HRMS calcd for C15H13N4O3 [MþH]þ
4.2.2. N-(3,5-Dimethoxyphenyl)quinazolin-4-amine (3b). Yield:
94%; yellow solid, mp 142 ꢀC; IR (KBr) nmax/cmꢂ1 3380, 2945, 2836,
1699, 1609, 1573, 1529, 1501, 1476, 1457, 1427, 1388, 1356, 1234,
1205, 1155, 1078, 1052, 973, 932, 908, 855, 826, 800, 776, 680, 628,
296.0913 found 296.0920.
4.3.4. N-(3,5-Dimethoxyphenyl)-6-nitroquinazolin-4-amine (5d).
Yield: 97%; yellow solid, mp 220 ꢀC; IR (KBr) nmax/cmꢂ1 3372, 3079,
3005, 2939, 2841, 1694, 1621, 1586, 1531, 1494, 1462, 1409, 1385,
1362, 1327, 1289, 1225, 1202, 1154, 1111, 1072, 1051, 957, 932, 917,
900, 858, 846, 824, 810, 785, 746, 704, 676, 637, 620; 19F NMR
602; 1H NMR (300 MHz, DMSO-d6)
d 9.67 (s, 1H, NH), 8.65 (s, 1H),
8.58 (d, 1H, J¼8.1 Hz), 7.87e7.78 (m, 2H), 7.65 (t, 1H, J¼7.2 Hz), 7.25
(s, 2H), 6.30 (s, 1H), 3.77 (s, 6H); 13C NMR (75 MHz, DMSO-d6)
d
160.4, 157.8, 154.5, 149.7, 141.1, 132.9, 127.9, 126.2, 123.0, 115.4,
(282 MHz, DMSO-d6)
d6)
d
ꢂ138.3, ꢂ142.6; 1H NMR (300 MHz, DMSO-
100.5, 95.5, 55.2; HRMS calcd for C16H16N3O2 [MþH]þ 282.1243
d
10.2 (s,1H, NH), 9.60 (d,1H, J¼1.8 Hz), 8.71 (s,1H), 8.52 (dd,1H,
found 282.1242.
J1¼1.8 Hz, J2¼9.0 Hz), 7.89 (d, 1H, J¼9.3 Hz), 7.16 (m, 2H), 6.31 (m,
2H), 3.76 (s, 6H); 13C NMR (75 MHz, DMSO-d6)
d
160.3, 158.8, 157.6,
4.2.3. N-(3,4,5-Trimethoxyphenyl)quinazolin-4-amine (3c). >Yield:
99%; white solid, mp 186 ꢀC; IR (KBr) nmax/cmꢂ1 3210, 3100, 3004,
2937, 2840, 2371, 1977, 1693, 1658, 1594, 1539, 1509, 1453, 1419,
1382, 1342, 1236, 1127, 1083, 1001, 871, 842, 824, 773, 689, 673,
153.1, 144.6, 140.1, 129.6, 126.7, 120.8, 114.5, 101.0, 96.3, 55.3; HRMS
calcd for C16H15N4O4 [MþH]þ 326.1076 found 326.1070.
4.3.5. 6-Nitro-N-(3,4,5-trimethoxyphenyl)quinazolin-4-amine (5e).
Yield: 89%; red solid, mp 258 ꢀC; IR (KBr) nmax/cmꢂ1 3426, 3075,
2994, 2933, 2838, 1620, 1574, 1539, 1517, 1486, 1461, 1446, 1433,
1406, 1388, 1361, 1351, 1332, 1246, 1224, 1192, 1131, 1113, 1071, 998,
934, 911, 888, 853, 831, 809, 794, 785, 746, 678, 651, 633, 619, 604;
608; 1H NMR (300 MHz, DMSO-d6)
d 9.69 (s, 1H, NH), 8.61 (s, 1H),
8.55 (d, 1H, J¼8.1 Hz), 7.87e7.77 (m, 2H), 7.65 (t, 1H, J¼7.2 Hz), 7.32
(s, 2H), 3.80 (s, 6H), 3.67 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
157.8, 154.6, 152.6, 149.6, 135.3, 133.9, 133.0, 127.9, 126.3, 122.9,
115.2, 100.3, 60.2, 55.9; HRMS calcd for C17H18N3O3 [MþH]þ
1H NMR (300 MHz, DMSO-d6)
d 10.3 (s, 1H, NH), 9.58 (d, 1H,
312.1348 found 312.1368.
J¼1.8 Hz), 8.69 (s, 1H), 8.52 (dd, 1H, J1¼1.8 Hz, J2¼9.0 Hz), 7.89 (d,
1H, J¼9.3 Hz), 7.26 (m, 2H), 3.81 (s, 6H), 3.68 (s, 3H); 13C NMR
4.3. Synthesis of the 6-nitro-4-arylaminoquinazolines
(75 MHz, DMSO-d6) d 160.3, 158.6, 157.7, 153.0, 152.6, 144.4, 134.5,
(5aem)
134.4, 129.5, 126.5, 120.7, 114.4, 100.7, 60.2, 55.9; HRMS calcd for
C17H17N4O5 [MþH]þ 356.1188 found 356.1187.
A mixture of N0-(2-cyano-4-nitrophenyl)-N,N-dimethylforma-
midine 2 (1.0 g, 4.58 mmol) and appropriate aniline (1.0 equiv) in
acetic acid (5 mL) was irradiated at 118 ꢀC (power input: 600 W).
On completion (followed by TLC or GC/MS chromatography), the
reaction was cooled to ambient temperature. The separated solid
was filtered and washed with diethyl ether to obtain the expected
compounds 5aem, 6 and 7aeb. Some of the reaction mixtures
needed to be triturated in hexane/ethyl acetate (1:1, v/v) before
crystallization and washing.
4.3.6. N-(4-Fluorophenyl)-6-nitroquinazolin-4-amine (5f) (lit.12).
Yield: 91%; yellow solid, mp 252 ꢀC; IR (KBr) nmax/cmꢂ1 3369, 3106,
3011, 1732, 1621,1583,1513,1489, 1420,1389, 1361, 1335,1223,1194,
1157, 1115, 928, 895, 869, 858, 827, 807, 796, 768, 746, 682, 653, 633;
19F NMR (282 MHz, DMSO-d6)
d6)
d
ꢂ117.8; 1H NMR (300 MHz, DMSO-
d
10.48 (s, 1H, NH), 9.63 (d, 1H, J¼8.8 Hz), 8.69 (s,1H), 8.56 (dd,
1H, J1¼2.3 Hz, J2¼9.2 Hz), 7.93 (d, 1H, J¼8.8 Hz), 7.81e7.86 (m, 2H),
7.28 (t, 2H, J¼8.8 Hz); 13C NMR (75 MHz, DMSO-d6)
d 159.3, 158.1,
153.5, 144.9, 135.1, 129.9, 127.1, 125.4, 121.2, 115.8, 115.5, 114.7;
4.3.1. 6-Nitro-N-phenylquinazolin-4-amine (5a) (lit.12). Yield: 88%;
yellow solid, mp 239 ꢀC; IR (KBr) nmax/cmꢂ1 3281, 3026, 1947, 1629,
1610,1582, 1535,1493, 1448, 1417, 1389, 1336,1239, 1192, 1130, 1115,
932, 899, 853, 807, 755, 693, 633; 1H NMR (300 MHz, DMSO-d6)
HRMS calcd for C14H10N4O2F [MþH]þ 285.0786 found 285.0776.
4.3.7. 3-(6-Nitroquinazolin-4-ylamino)benzonitrile (5g). Yield: 82%;
pale yellow solid, mp>260 ꢀC; IR (KBr) nmax/cmꢂ1 3349, 3273, 3089,
2228,1755,1724,1627,1581,1542, 1495, 1474,1443,1411,1388,1361,
1338, 1251, 1146, 1113, 947, 925, 900, 857, 803, 745, 679, 631; 1H
d
10.4 (s, 1H, NH), 9.62 (d, 1H, J¼2.1 Hz), 8.67 (s, 1H), 8.52 (dd, 1H,
J1¼2.1 Hz, J2¼9.3 Hz), 7.89e7.81 (m, 3H), 7.45 (t, 2H, J¼7.5 Hz), 7.21

A. Foucourt et al. / Tetrahedron 66 (2010) 4495e4502
4501
NMR (300 MHz, DMSO-d6)
d
10.1 (s, 1H, NH), 9.36 (d, 1H, J¼2.4 Hz),
923, 890, 850, 830, 810, 748; 1H NMR (300 MHz, DMSO-d6)
d
8.60
8.84 (s, 1H), 8.63 (dd, 1H, J1¼2.4 Hz, J2¼9.0 Hz), 8.53 (s, 1H), 8.22
(d, 1H, J¼2.7 Hz), 8.53 (s, 1H), 8.32 (dd, 1H, J1¼2.7 Hz, J2¼9.0 Hz),
7.69 (d, 1H, J¼9.0 Hz), 7.45 (d, 2H, J¼8.7 Hz), 7.10 (d, 2H, J¼9.0 Hz);
HRMS calcd for C14H10N5O4 [MþH]þ 311.0701 found 311.0711.
(m, 1H), 8.04 (d, 1H, J¼9.3 Hz), 7.67e7.56 (m, 2H); 13C NMR
(75 MHz, DMSO-d6)
d 159.7, 158.2, 154.2, 146.2, 140.8, 130.9, 130.7,
128.4, 127.5, 127.3, 125.9, 120.9, 119.3, 115.6, 113.3; HRMS calcd for
C15H10N5O2 [MþH]þ 292.0834 found 292.0833.
4.3.14. N0-(2-Cyano-4-nitrophenyl)-N-methyl-N-phenylformamidine
(7a). Yield: 49%; orange solid, mp 186 ꢀC; IR (KBr) nmax/cmꢂ1 3055,
2233, 1623, 1588, 1564, 1511, 1490, 1418, 1330, 1310, 1263, 1229, 1171,
1125, 1077, 1031, 985, 922, 908, 835, 760, 750, 729, 692, 665; 1H NMR
4.3.8. N-(3-Chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine (5h)
(lit.19a). Yield: 84%; yellow solid; mp>260 ꢀC; IR (KBr) nmax/cmꢂ1
1736, 1624, 1585, 1572, 1536, 1510, 1495, 1485, 1423, 1364, 1340, 1263,
1216, 1115, 854, 808, 778, 746; 19F NMR (282 MHz, DMSO-d6)
(300 MHz, DMSO-d6)
d
8.62 (d,1H, J¼2.1 Hz), 8.58 (s,1H), 8.34 (dd,1H,
J1¼2.1 Hz, J2¼9.0 Hz), 7.65 (d,1H, J¼9.0 Hz), 7.53e7.43 (m, 4H), 7.30 (t,
d
ꢂ121.6; 1H NMR (300 MHz, DMSO-d6)
d
10.3 (s,1H, NH), 9.47 (d,1H,
1H, J¼7.2 Hz), 3.56 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d 159.6,
J¼2.1 Hz), 8.66 (s, 1H), 8.46 (dd, 1H, J¼6.6 Hz, J¼2.1 Hz), 8.09 (dd, 1H,
J¼9.0 Hz, J¼2.1 Hz), 7.82 (d, 1H, J¼9.0 Hz), 7.78 (m, 1H), 7.4 (t, 1H,
154.6, 143.6, 141.5, 129.5, 129.2, 128.7, 125.6, 120.9, 120.2, 116.6, 106.8,
34.3; HRMS calcd for C15H13N4O2 [MþH]þ 280.1048 found 280.1039.
J¼9.0 Hz); 13C NMR (75 MHz, DMSO-d6)
d 158.4, 157.4, 152.8, 144.5,
135.8, 129.5, 126.6, 124.1, 122.9, 120.6, 119.0, 118.8, 116.8, 116.5, 114.3;
4.3.15. N0-(2-cyano-4-nitrophenyl)-N-(4-methoxyphenyl)-N-methyl-
HRMS calcd for C14H9N4O2FCl [MþH]þ 319.0398 found 319.0382.
formamidine (7b). Yield: 53%; orange solid, mp 132 ꢀC; IR (KBr) nmax
/
cmꢂ1 3008, 2939, 2837, 2228,1620,1589,1561,1496,1442,1417,1333,
1292,1261,1247,1228,1187,1171,1128,1074,1029, 991, 969, 920, 905,
4.3.9. N-(4-Bromo-2-fluorophenyl)-6-nitroquinazolin-4-amine (5i).
Yield: 70%; yellow solid, mp 212 ꢀC; IR (KBr) nmax/cmꢂ1 3385, 3030,
2359, 1621, 1585, 1568, 1525, 1494, 1480, 1413, 1387, 1362, 1345,
1316, 1229, 1185, 1129, 1112, 1079, 1056, 979, 931, 899, 874, 844, 807,
842, 828, 809, 786, 752, 735,653;1HNMR (300 MHz, DMSO-d6)
d8.54
(d, 1H, J¼2.7 Hz), 8.49 (s,1H), 8.30 (dd,1H, J1¼2.7 Hz, J2¼9.0 Hz), 7.60
(d, 1H, J¼9.0 Hz), 7.44 (d, 2H, J¼8.7 Hz), 7.02 (d, 2H, J¼9.0 Hz), 3.77 (s,
800, 781, 745, 677, 634; 19F NMR (282 MHz, DMSO-d6)
d
ꢂ115.0; 1H
3H), 3.51 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d 159.7, 157.4, 154.7,
NMR (300 MHz, DMSO-d6)
d
10.6 (s, 1H, NH), 9.49 (d, 1H, J¼1.5 Hz),
141.2, 136.9, 129.2, 128.7, 122.9, 119.9, 116.7, 114.6, 106.7, 55.5, 34.9;
8.58 (s, 1H), 8.53 (dd, 1H, J1¼1.2 Hz, J2¼9.0 Hz), 7.91 (d, 1H,
HRMS calcd for C16H15N4O3 [MþH]þ 310.1155 found 310.1159.
J¼9.3 Hz), 7.69 (d, 1H, J¼9.9 Hz), 7.54e7.46 (m, 2H); 13C NMR
(75 MHz, DMSO-d6)
d
159.1, 158.2, 157.3, 154.9, 152.6, 144.5, 129.5,
4.4. Synthesis of N-(4-methoxyphenyl)-N,2-
dimethylquinazolin-4-amine (10) (AzixaÔ)
129.2, 127.7, 127.6, 126.8, 125.9, 120.9, 119.7, 119.4, 118.7, 118.5, 114.3;
HRMS calcd for C14H9N4O2FBr [MþH]þ 362.9893 found 362.9897.
4.4.1. N0-(2-cyanophenyl)-N,N-dimethylacetamidine (8). A suspen-
sion of anthranilonitrile (2.0 g,16.9 mmol) in N,N-dimethylacetamide
dimethylacetal (5.6 g,42.3 mmol, 2.5 equiv) was irradiated at 115 ꢀC
(power input: 1000 W) for 2 min. The resulting mixture wascooled to
room temperature and refrigerated overnight. The white precipitate
that formed was filtered, washed with petroleum ether and dried to
4.3.10. N-(2,3-Dichlorophenyl)-6-nitroquinazolin-4-amine (5k).
Yield: 60%; yellow solid, mp 182 ꢀC; IR (KBr) nmax/cmꢂ1 3408, 3087,
1682, 1622, 1585, 1537, 1488, 1450, 1431, 1415, 1389, 1362, 1337, 1297,
1196, 1121, 1063, 1042, 967, 945, 898, 884, 853, 809, 785, 743, 702,
692, 673, 633, 607; 1H NMR (300 MHz, DMSO-d6)
d 10.9 (s, 1H, NH),
9.46 (d,1H, J¼2.1 Hz), 8.54 (dd,1H, J1¼2.7 Hz, J2¼9.3 Hz), 8.48 (s,1H),
give 8 (2.8 g, 88% yield), as white needles; mp 68 ꢀC; IR (KBr) nmax
/
7.88 (d, 1H, J¼9.3 Hz), 7.58e7.55 (m,1H), 7.47e7.39 (m, 2H); 13C NMR
cmꢂ1 2932, 2215, 1971, 1913, 1747, 1588, 1553, 1463, 1443, 1401, 1364,
1315,1220,1192, 1168, 1100,1060, 1023, 960, 875, 839, 783, 756, 721;
(75 MHz, DMSO-d6)
d 151.9, 144.4, 132.2, 128.2, 127.3, 126.6, 120.8;
HRMS calcd for C14H9Cl2N4O2 [MþH]þ 334.0029 found 334.0013.
1H NMR (300 MHz, DMSO-d6)
d
7.61 (d, 1H, J¼7.5 Hz), 7.50 (t, 1H,
J¼7.5 Hz), 7.01 (t,1H, J¼7.8 Hz), 6.79 (d,1H, J¼8.1 Hz), 3.00 (s, 6H),1.88
4.3.11. N-(2,3-Difluorophenyl)-6-nitroquinazolin-4-amine (5l).
Yield: 74%; yellow solid, mp 220 ꢀC; IR (KBr) nmax/cmꢂ1 3365, 3095,
3012, 2358, 1694, 1624, 1584, 1568, 1525, 1513, 1497, 1474, 1410,
1382, 1363, 1338, 1282, 1251, 1232, 1197, 1160, 1131, 1118, 1073, 1060,
1011, 923, 898, 858, 833, 811, 803, 771, 746, 723, 702, 683, 650, 631;
(s, 3H); HRMS calcd for C11H14N3 [MþH]þ 187.1179 found 187.1178.
4.4.2. N-(4-Methoxyphenyl)-2-methylquinazolin-4-amine (9)
(lit.14b). p-Anisidine (0.18 g, 1.46 mmol, 1.1 equiv) was added to
a suspension of N0-(2-cyanophenyl)-N,N-dimethylacetamidine 8
(0.25 g, 1.33 mmol) in AcOH/ACN (3:7, v/v). The resulting mixture
was irradiated at 118 ꢀC (power input: 600 W) for 60 min and
cooled to room temperature. Purification by column chromatog-
raphy over silica gel using CH2Cl2/EtOAc (1:1, v/v) as the eluent gave
the desired compound 9 (0.31 g, 88% yield), as a white solid; mp
170 ꢀC; IR (KBr) nmax/cmꢂ1 3053, 2958, 2837, 1619, 1598, 1573, 1513,
1464, 1422, 1386, 1354, 1293, 1238, 1182, 1170, 1132, 1104, 1032,
1001, 883, 825, 794, 770, 738, 681, 644, 628; 1H NMR (300 MHz,
1H NMR (300 MHz, DMSO-d6)
d 10.7 (s, 1H, NH), 9.51 (d, 1H,
J¼1.8 Hz), 8.61 (s, 1H), 8.56 (dd, 1H, J1¼1.8 Hz, J2¼9.0 Hz), 7.93
(d, 1H, J¼9.0 Hz), 7.35e7.26 (m, 3H); 13C NMR (75 MHz, DMSO-d6)
d
158.9, 157.3, 152.5, 152.1, 151.9, 148.9, 148.7, 146.7, 146.5, 144.5,
143.4, 143.2, 129.1, 128.7, 128.6, 126.8, 124.4, 124.3, 124.2, 124.1,
123.1, 123.0, 121.0, 114.8, 114.6, 114.5; HRMS calcd for C14H9F2N4O2
[MþH]þ 302.0609 found 302.0603.
4.3.12. 6-Nitro-N-(2-(trifluoromethyl)phenyl)quinazolin-4-amine
(5m). Yield: 55%; yellow solid, mp 178 ꢀC; IR (KBr) nmax/cmꢂ1 3361,
3240, 3083, 1623, 1586, 1573, 1519, 1488, 1458, 1413, 1387, 1363,
1338, 1316, 1236, 1196, 1166, 1115, 1064, 1053, 1035, 933, 901, 865,
851, 812, 796, 767, 747, 737, 684, 663, 648, 633; 19F NMR (282 MHz,
DMSO-d6)
d
9.58 (s, 1H, NH), 8.48 (d, 1H, J¼8.1 Hz), 7.78e7.75 (m,
3H), 7.67 (d, 1H, J¼8.1 Hz), 7.54 (t, 1H, J¼7.5 Hz), 6.98 (d, 2H,
J¼8.7 Hz), 3.77 (s, 3H), 2.47 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
163.0, 157.7, 155.6, 150.2, 132.7, 132.3, 127.2, 125.1, 123.9, 122.8,
113.6, 113.2, 55.2, 26.3; HRMS calcd for C16H16N3O [MþH]þ
DMSO-d6)
d
ꢂ59.50; 1H NMR (300 MHz, DMSO-d6)
d
10.6 (s, 1H,
266.1352 found 266.1308.
NH), 9.62 (s, 1H), 8.55 (s, 1H), 8.49 (dd, 1H, J1¼1.7 Hz, J2¼9.1 Hz),
7.97 (d, 1H, J¼8.9 Hz), 7.83e7.54 (m, 4H); HRMS calcd C15H10F3N4O2
[MþH]þ 334.0734 found 334.0725.
4.4.3. N-(4-Methoxyphenyl)-N,2-dimethylquinazolin-4-amine (10)
(AzixaÔ) (lit.14b).
4.4.3.1. From N-(4-methoxyphenyl)-2-methylquinazolin-4-amine
9. A suspension of N-(4-methoxyphenyl)-2-methylquinazolin-4-
amine 9 (0.1 g, 0.38 mmol) in DMF (10 mL) was cooled to 0 ꢀC. Then
NaH (60% in mineral oil, 0.029 g, 0.76 mmol, 2.0 equiv) and CH3I
4.3.13. N0-(2-Cyano-4-nitrophenyl)-N-(4-nitrophenyl)formamidine
(6). Yield: 88%; orange solid, mp>260 ꢀC; IR (KBr) nmax/cmꢂ1 3084,
2225, 1627, 1572, 1504, 1418, 1376, 1331, 1282, 1246, 1173, 1112, 1079,

4502
A. Foucourt et al. / Tetrahedron 66 (2010) 4495e4502
2. For reviews see: (a) Larhed, M.; Allberg, A. Drug Discov. Today 2001, 6, 406e416;
(b) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325e3355; (c) Kappe, C. O.;
Dallinger, D. Mol. Divers. 2009, 13, 71e193.
3. Complete descriptions of some of these instruments were published (a) For
CEM Ferguson, J. D. Mol. Diversity 2003, 7, 281e286; (b) For Milestone Favretto,
L. Mol. Diversity 2003, 7, 287e291; (c) For Biotage Schanche, J.-S. Mol. Diversity
2003, 7, 293e300.
4. For reviews on quinazolines see (a) Armarego, W. L. F. Adv. Heterocycl. Chem.
1997, 24, 1e62; (b) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659e677; (c)
Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61,
10153e10202.
(1.4 mL, 9.12 mmol, 24.0 equiv) were added. The reaction mixture
wasstirred at0 ꢀC for 1 h and warmed to room temperature (1 h). The
reaction was quenched by adding 0.5 mL of water and diluted with
ethyl acetate. The organic phase was washed with water and satu-
rated NaCl, dried over anhydrous MgSO4, filtered and concentrated
under vacuum. The crude product was purified by chromatography
on silica gel with EtOAc as the eluent to afford 10 (0.074 g, 70%) as
a pale yellow solid.
5. Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, M.-A.; Kim, H.-S.; Wataya, Y.;
Miura, M.; Takeshita, M.; Oshima, Y. J. Med. Chem. 1999, 42, 3163e3166.
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Seymoyr, P. A.; Guanowsky, V.; Guhan, S.; Guinn, M. R.; Critchett, D.; Lazzaro, J.;
Ganong, A. H.; DeVries, K. M.; Staigers, T. L.; Chenard, B. L. Bioorg. Med. Chem.
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Settimo, F.; Martinelli, A. J. Med. Chem. 2009, 52, 964e975.
4.4.3.2. From N0-(2-cyanophenyl)-N,N-dimethylacetamidine 8 in
acetic acid. N-Methyl-p-anisidine (0.20 g, 1.46 mmol, 1.1 equiv) was
added to a suspension of N0-(2-cyanophenyl)-N,N-dimethylaceta-
midine 8 (0.25 g, 1.33 mmol) in AcOH (1.5 mL). The resulting mix-
ture was irradiated at 140 ꢀC (power input: 200 W) in a sealed tube
for 4 h. (evolution of the reaction was estimed by GC/MS chroma-
tography). N-Methyl-p-anisidine (0.20 g, 1.46 mmol, 1.1 equiv) was
added to the reaction and the resulting mixture was irradiated
again at 140 ꢀC for 2 h. The reaction was cooled to ambient tem-
perature and then solvent was evaporated under reduced pressure.
The residue was purified by column chromatography over silica gel
using CH2Cl2/EtOAc (20e80) as the eluent to give the desired
compounds 10 (0.082 g, 22%) as a pale yellow solid.
11. Mishra, A.; Srivastava, S. K.; Tripathi, R.; Puri, S. K.; Batra, S. Eur. J. Med. Chem.
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S. K.; Batra, S. Bioorg. Med. Chem. 2009, 17, 222e234.
4.4.3.3. From N0-(2-cyanophenyl)-N,N-dimethylacetamidine 8 in
NMP in the presence of AlCl3. To a suspension of N0-(2-cyano-
phenyl)-N,N-dimethylacetamidine 8 (0.25 g, 1.33 mmol) in NMP
(1.5 mL) was added N-methyl-p-anisidine (0.27 g, 1.99 mmol,
1.5 equiv) and anhydrous aluminium chloride (0.26 g, 1.99 mmol,
1.5 equiv). The resulting mixture was irradiated at 200 ꢀC (power
input: 200 W) for 2 h and cooled to room temperature. The reaction
mixture was diluted with ethyl acetate. The organic phase was
washed with water and saturated NaCl, dried over anhydrous
MgSO4, filtered and concentrated under vacuum. The crude product
was purified by chromatography on silica gel with EtOAc as the
eluent to afford 10 as a pale yellow solid (0.26 g, 71%); mp
13. For a recent review on the microwave-assisted synthesis of quinazolines see:
Besson, T.; Chosson, E. Comb. Chem. High Troughp. Screening 2007, 10, 903e917.
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Nilakantan, R.; Shen, R.; Discafani, C.; DeBlanc, R.; Davis, R.; Koehn, R. E.;
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2719e2734.
86e90 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
8.53 (d, 1H, J¼8.1 Hz),
7.57 (td, 1H, J1¼0.9 Hz, J2¼6.9 Hz), 7.20 (d, 2H, J¼8.7 Hz), 7.05 (td,
1H, J1¼0.9 Hz, J2¼6.9 Hz), 6.99e6.94 (m, 3H), 3.77 (s, 3H), 3.48 (s,
18. Yoon, D. S.; Han, H.; Stark, T. M.; Haber, J. C.; Gregg, B. T.; Stankovich, S. B. Org.
Lett. 2004, 6, 4775e4778.
3H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d 162.3, 161.0, 157.6,
19. (a) Albuschat, R.; Lowe, W.; Weber, M.; Luger, P.; Jendrossek, V. Eur. J. Med.
Chem. 2004, 39, 1001e1011; (b) Domarkas, J.; Dudouit, F.; Williams, C.; Qiyu, Q.;
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(c) Rachid, Z.; MacPhee, M.; Williams, C.; Torodova, M.; Jean-Claude, B. J. Bioorg.
Med. Chem. Lett. 2009, 19, 5505e5509.
151.7, 141.0, 131.9, 127.5, 127.2, 125.7, 124.1, 115.3, 114.2, 55.4, 42.4,
26.2; HRMS calcd for C17H18N3O [MþH]þ 280.3360 found 280.3357.
20. (a) Chandregowda, V. C.; Rao, C. G.; Reddy, G. C. Org. Process Res. Dev. 2007, 11,
813e816; (b) This paper was ready to be sent to journal editor when we dis-
covered the following paper which describes synthesis of furo- and thieno
Acknowledgements
A.F. thanks Ministère de la Recherche et des Technologies for
a PhD grant. T.B. thanks Milestone s.r.l. Italy for multiform support
and ExonHit Therapeutics for financial support.
pyrimidin-4-amines under microwaves via
a Dimroth rearrangement. The
mechanism described in our paper is similar to the hypothesis given in: Han, Y.;
Ebinger, K.; Vandevier, L. E.; Maloney, J. W.; Nirschl, D. S.; Weller, H. N. Tetra-
hedron Lett. 2010, 51, 629e632.
21. (a) Mésangeau, C.; Yous, S.; Pérès, B.; Lesieur, D.; Besson, T. Tetrahedron Lett.
2005, 46, 2465e2468; (b) Nouira, I.; Kostakis, I. K.; Dubouilh, C.; Chosson, E.;
Iannelli, M.; Besson, T. Tetrahedron Lett. 2008, 49, 7033e7036; (c) Lamazzi, C.;
Dreau, A.; Bufferne, C.; Flouzat, C.; Patrick Carlier, P.; ter Halle, R.; Besson, T.
Tetrahedron Lett. 2009, 50, 5402e5405.
References and notes
1. For a book see: Microwaves in Organic Synthesis; Loupy, A., Ed.; Whiley-VCH
Gmbh & Co. KGaA: Weinhein, 2006.
22. Szczepankiewicz, W.; Suwinski, J.; Bujok, R. Tetrahedron 2000, 56, 9343e9349.