Microwave-assisted thermal decomposition of formamide: A tool for coupling a pyrimidine ring with an aromatic partner

Article abstract of DOI:10.1016/j.tet.2011.05.010

Rapid and efficient generation of CO and NH₃ in the reaction mixture via microwave-assisted thermal decomposition of formamide may represent a significant improvement over existing methods for coupling a pyrimidine ring with an aromatic partner. This work aims at alerting readers on the probability to observe interesting phenomena and reactions when this very powerful heating mode is associated with thermally unstable reagents.

Full text of DOI:10.1016/j.tet.2011.05.010

Tetrahedron 67 (2011) 4852e4857
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted thermal decomposition of formamide: a tool for coupling
a pyrimidine ring with an aromatic partner
*
Yvonnick Loidreau, Thierry Besson
ꢀ
ꢁ
Universite de Rouen, CNRS UMR 6014dC.O.B.R.A. & FR3038, I.R.C.O.F. rue Tesniere, 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:
Received 8 April 2011
Received in revised form 28 April 2011
Accepted 3 May 2011
Available online 17 May 2011
Rapid and efficient generation of CO and NH3 in the reaction mixture via microwave-assisted thermal
decomposition of formamide may represent a significant improvement over existing methods for cou-
pling a pyrimidine ring with an aromatic partner. This work aims at alerting readers on the probability to
observe interesting phenomena and reactions when this very powerful heating mode is associated with
thermally unstable reagents.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Microwave chemistry
Decomposition of formamide
Quinazolines
Dielectric properties
Niementowski reaction
1. Introduction
Among our recent projects, we decided to study the microwave
stability of various solvents and reactants in order to detect the pos-
Despite the area of microwave-assisted chemistry being twenty
five years old,1 the technique has only recently received wide-
spread global acceptance in the academic and industrial commu-
sible transformations of these molecules under microwaves and then,
to study the possibility to perform novel chemical reactions. This
strategyallowed ustorecentlyexploreefficient methodologies for the
preparation of various quinazolin-4(3H)-ones as building blocks for
the synthesis of derivatives of numerous bioactive molecules.4
Formamide is a quite reactive polar molecule, which is com-
monly used either as a nucleophilic or an electrophilic agent in the
synthesis of various heterocyclic rings, it possesses a high loss
nities. This is
a consequence of the recent availability of
commercial microwave systems specific for synthesis, which offer
improved opportunities for reproducibility, rapid synthesis, rapid
reaction optimization and the potential discovery of new chem-
istries.2 The beneficial effects of microwave dielectric heating for
performing organic reactions are well known (e.g., remarkable
reduction of reaction time, improved yields and cleaner reactions
than the one performed under conventional thermal heating).3
They are finding an increased role in process chemistry, espe-
cially in cases when usual methods require forcing conditions or
prolonged reaction times. In a large part of the examples pub-
lished, it was observed that the strong heating due to specific
molecules/microwaves interactions can be efficiently used for the
synthesis of various heterocyclic rings for which traditional
methods failed or are less attractive. In these cases, the use of
adapted reactants offers operational, economic and environmental
benefits over conventional methods and it allows to performed
chemistry in a ‘green approach’.
tangent value (tan
d
¼0.56)5 that guarantees a very efficient cou-
pling with microwaves. Taking into account all this data we re-
investigated under microwaves the Niementowski synthesis of
quinazolin-4(3H)-ones.6 This very popular ‘ancestral’ reaction in-
volves the thermal fusion of anthranilic acids with formamide. In
this work we described a significant rate enhancement and dem-
onstrated that the interesting dielectric properties of formamide
and its capacity to generate heat under microwaves are useful for
performing microwave-assisted chemistry. Nonetheless, in a recent
study, we also revealed that microwave-promoted rapid de-
composition of formamide under specific reaction conditions can
be a source of ammonia that generates unexpected products.7
Pursuing our investigations, we were able to control the thermal
decomposition of formamide under microwaves with a strict
monitoring of internal temperatures using fibre-optic contact
thermometers. A three-components fast (2 min) and safe synthesis
of some quinazolin-4-ones was described constituting the first
* Corresponding author. Tel.: þ33 (0) 235592904, þ33 (0) 235148399; fax: þ33
(0) 235148423; e-mail address: thierry.besson@univ-rouen.fr (T. Besson).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.010

Y. Loidreau, T. Besson / Tetrahedron 67 (2011) 4852e4857
4853
example where this reactant was used as a sole ammonia synthon
for the introduction of a nitrogen atom in a heterocyclic ring under
microwave irradiation (Scheme 1a).8
a strict control of temperature parameters is available via an in-
ternal fibre-optic probe associated with infrared pyrometer. Then,
the starting 2-nitrobenzonitrile was treated with 1 equiv of indium
chloride in formamide (40 equiv) and heated for 10e40 min at
various temperatures (150e200 ꢀC). Results obtained showed
a conversion of the starting material into the expected quinazolin-
4-one in similar ratio to those described by Negrete (around 90%,
GC analysis). Best yields were obtained when the reactions were
performed at 170 ꢀC for 40 min or at 200 ꢀC for 10 min (Scheme 2).
Scheme 2. Intramolecular reductive N-heterocyclization of 2-nitrobenzonitrile.
To confirm the absolute necessity to have a metal salt into the
mixture, the reaction was performed without InCl3. The lack of
attempted product confirmed that the metal salt is important into
the reduction process and not only in the formamide decomposition
as suggested in the reference paper. Pursuing our investigations we
decided to treat ortho-aminobenzonitrile in the conditions de-
scribed above. Our recent application of the Dimroth rearrangement
incites us to start also from the 5-nitroanthranilonitrile (1) and its N-
Scheme 1. Synthesis of quinazolinones from anthranilic acid (a) or 2-nitrobenzoic
acid (b).
The thermal decomposition of formamide has already been
described in the literature and mainly for preparing aromatic amide
derivatives.9 To our knowledge the first microwave-accelerated
decomposition of formamide has been described in 2003 by
a Swedish group in Uppsala University,10 where formamide was
used as combined ammonia (NH3) synthon and carbon monoxide
(CO) source in palladium-catalyzed aminocarbonylations of aryl
halides. Since this date, and in connection with microwave-assisted
methodologies, it has been recently exploited as both a surrogate
for carbon monoxide in the synthesis of pyrazolo[1,5-a] and [3,4-d]
pyrimidines11 and for ammonia in the synthesis of pyrimido[1,2-a]
pyrimidines.12
In 2008, Negrete and his group described the one-pot reductive
N-heterocyclization of various 2-nitrobenzoic acid derivatives with
formamide, in the presence of a molar equivalent amount of
indium(III) (chloride or acetate) or bismuth(III) acetate salts.13 They
observed that formamide decomposition was promoted by the
metal salts; the CO then produced allowed conversion of the aryl
nitro group to arylamine and the resultant anthranilic acid de-
rivative proceeded to Niementowski cyclocondensation to form
quinazolines (Scheme 1b). In the same study they claimed that
reduction of aryl nitro groups can be obtain by a long (5e10 h)
heating of nitrobenzene derivatives to InCl3 or In(OAc)3 in refluxing
N-methylformamide.
(2-cyano-4-nitrophenyl)-N,N-dimethylimidoformamides
de-
rivatives (2a and 2b) themselves prepared in good yields (96 and
60%, respectively, after purification) by treatment of the starting
molecule (1) with N,N-dimethylformamide dimethylacetal or N,N-
dimethylacetamide dimethylacetal, at 70 ꢀC in only 2 min of irra-
diation (800 W) at atmospheric pressure. Results given (Table 1)
show that in all cases, in the presence or not of InCl3, we never ob-
served the reduction of the nitro group present on the benzenic
moiety of the final product. The fact that the carbon in position 2 of
the quinazoline ring was present in the starting compound (e.g., for
imines 2a and 2b) led us to expect that the ‘CO’ part of formamide
can be, in these cases efficiently used for the reduction of the nitro
group. In fact, whatever were the conditions, all the experiments
Table 1
Synthesis of 6-nitroquinazoline-imine 3 from 1 or 2a
Considering our previous works on the synthesis of quinazolin-
4(3H)-ones bearing a nitro group,14 we decided to investigate the
possibility to generate NH3 and CO species in situ via microwave-
accelerated heating of formamide in order to perform a one-pot
procedure in which formation of the pyrimidine ring and simul-
taneous reduction of the starting nitro group can lead directly to
amino-substituted quinazolines from the corresponding nitro-
anthranilic acids and their derivatives. This paper describes a part
of our investigations in the use of formamide under microwaves
and it aims at alerting readers on the probability to observe in-
teresting phenomena and reactions when this very powerful
heating mode is associated with thermally unstable reagents.
S.M.b
Product
R
InCl3(Eq.)
T (ꢀC)
Time (min)
Yield (%)c
1
1
2a
2a
2b
2b
3a
3a
3a
3a
3b
3b
H
H
H
H
Me
Me
d
1
200
170
200
150
200
150
60
30
10
10
60
60
67
n.d.d
61
d
1
d
1
68
8e
n.d.d
a
2. Results and discussion
Reaction were performed in sealed vials on a 1.0 mmol scale from 1 or 2 with
equiv of InCl3 (or not) under microwave at
40 equiv of formamide and
1
400 W(MultiSYNTHÔ from Milestone S.r.l. Italy).
Our first approach consisted to study the method described by
Negrete and his group. In connection with our recent works on the
microwave-assisted decomposition of formamide we decided to
transfer this thermal process into a microwave reactor in which
b
S.M.: starting material.
Yield of isolated product.
n.d.¼not determined.
c
d
e
Conversion of unisolated product.

4854
Y. Loidreau, T. Besson / Tetrahedron 67 (2011) 4852e4857
performed from 5-nitroanthranilonitrile (1) or imine 2a gave the 6-
nitroquinazoline-imine (3a) in various yields (Table 1). The high
temperatures reached into these processes have generated NH3 into
the reaction mixture via rapid decomposition of formamide. The
ammonia synthon was then introduced into the final hetero-
aromatic part of the quinazoline skeleton as we previously de-
scribed. It should be noticed that compound 3b was never isolated
but only detected by GC/MS chromatography (Table 1).
Extending our investigations, we decided to reproduce some of
these experiments starting from the unfunctionalized anthranilo-
nitrile (4) or its N,N-dimethylimidoformamide derivatives (5a and
5b). The starting compounds were then heated at 200 ꢀC without
InCl3 or at 150e170 ꢀC in the presence of 1 equiv of the metal salt.
Here again indium trichloride helped the reaction by allowing
a short decrease in the optimal temperature and sometimes re-
duced the time of the reaction. In all cases the final product
obtained were the 4-aminoquinazoline derivatives (6a or 6b)
resulting from the condensation of formamide or its ammonia
synthon with the starting molecule (Table 2). The yields are similar
whatever conditions were used.
4,5-dimethoxyanthranilonitrile and formamide in the presence of
InCl3 gave a by-product identified as the N-(quinazolin-4-yl)form-
amide (10), which was isolated in a yield of 20% (see Table 2).
At this part of our work it is time to make some comments. The
accelerated decomposition of formamide into NH3 and CO in the
presence of InCl3 described in the paper of Negrete and his co-
workers is not easy to appreciate in our case and we assume that
the mechanism describing reduction of the nitro group, by the CO
liberated in the reaction mixture, is not as simple as described. We
may confirm that the metal salt is participating to the overall
process of the intramolecular reductive N-heterocyclization of 2-
nitrobenzonitrile and we can also suggest that the overall condi-
tions of these experiments are in favour of the quinazolin-4-one
derivatives certainly obtained after acidic hydrolysis of the in-
termediate quinazoline imines.
Considering our results we are not able to confirm if the addition
of InCl3 is really accelerating the thermal decomposition of form-
amide. We compared the results obtained with or without InCl3 in
the starting mixture and we can only say that InCl3 allows a small
decrease in reaction temperature without certifying that its pres-
ence helped in situ decomposition of formamide, taking in account
that we recently published that formamide can start to decompose
rapidly under microwaves at this temperature without any catalyst.
The use of N,N-dimethylimidoformamide derivatives of the
starting anthranilonitriles showed to be an attractive method,
which allows a striking reduction in reaction time (10 min instead
of 40 min) and good yields in the attempted products. The rapid
thermal decomposition of formamide at 200 ꢀC has generated NH3
synthon, which condensed rapidly with the amidines and cyclized
into the quinazoline ring. This reaction is similar to the process
leading to the Dimroth rearrangement in which anilines are con-
densed with N,N-dimethylimidoformamide derivatives to give 4-
anilinoquinazolines.
Table 2
Synthesis of 4-aminoquinazolines 6 or 9 from anthranilonitriles 4 or 7a
During our investigations we observed that the final com-
pounds synthesized from the unfunctionalized anthranilonitrile or
its electron rich analogue (4,5-diOMe) were quinazolin-4-amine
derivatives. Nevertheless, a stable tautomeric imine form was
obtained in the case of electron withdrawing substituent (e.g., NO2
group). Quinazolin-4-amine derivatives are quite rarely described
in literature15 compared to their 4-anilino analogues ,which con-
stitute an important part of medicinal chemistry, in particular for
their applications in the synthesis of tyrosine kinases inhibitors.
The quinazolin-4-amines were studied for various pathologies and
their synthesis was mainly patented.16 Traditional preparation of
quinazolin-4-amines involves the reaction of ammonia with
4-chloroquinazolines obtained by chlorination of the correspond-
ing quinazolin-4-ones. The routes described above constitute in-
teresting alternatives to this method and afford the expected
products in one or two steps. In order to extend the small library
prepared, we condensed various halogenated anthranilonitriles
with formamide at 200 ꢀC for 1 h under microwaves. The resulting
quinazolin-4-amines (11aec) were obtained in good yields
(75e90%) (Scheme 3).
S.M.b Product R1
R2 InCl3(Eq.) T (ꢀC) Time (min) Yield (%)c
4
4
6a
6a
6a
6a
6b
6b
9a
9a
9a
9a
9b
9b
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
d
1
200 60
170 30
200 10
150 10
200 50
150 35
200 60
170 30
200 10
1500 10
170 30
150 40
69
72
77
67
89
94
57
51
50
55
65
68
5a
5a
5b
5b
7
d
1
d
1
4,5-diOMe
4,5-diOMe
4,5-diOMe
4,5-diOMe
4,5-diOMe Me
4,5-diOMe Me
d
7
1
d
1
8a
8a
8b
8b
H
d
1
a
Reaction were performed in sealed vials on a 1.0 mmol scale from 4 or 7 with
equiv of InCl3 (or not) under microwave at
40 equiv of formamide and
1
400 W(MultiSYNTHiÔ from Milestone S.r.l. Italy).
b
S.M.: starting material.
Yield of isolated product.
c
In order to observe any probable effect of the substituents
present on the benzenic ring, we also study the possibility to start
from an electron rich anthranilonitrile derivative.
Then, 4,5-dimethoxyanthranilonitrile (7) and its N,N-dimethy-
limidoformamide analogue (8) were also heated in formamide in
the presence, or not, of InCl3. In all the experiments performed, the
yields of the 4-amino-6,7-dimethoxyquinazoline (9) obtained
were lower than those observed from the nitro substituted or
the unfunctionalized anthranilonitriles (1 and 4, respectively).
It should be noticed that at atmospheric pressure the reaction of
Scheme 3. Microwave-assisted Niementowski synthesis of quinazolin-4-amines
(11aec) from halogenated anthranilonitriles.

Y. Loidreau, T. Besson / Tetrahedron 67 (2011) 4852e4857
4855
Compared with our preceding studies of the Niementowski re-
action from anthranilic acid derivatives,8 we may notice here that
starting from the cyano analogues need more energy to cyclize. At
this temperature and in that time, we may assume that formamide
decomposed and gave NH3 and CO synthons. In this case, it may be
suggested that, after reaction of the aromatic amino group and CO,
the intermediate formamide derivative was attacked by the
residual NH3 and cyclized to afford the final quinazoline ring
(Scheme 3).
contact thermometer (FO) for accurate 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 ceramic 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 and power profiles were monitored in both cases
through the EASYControl software provided by the manufacturer.
3. Conclusion
In conclusion, we confirm that rapid and efficient generation of
ammonia in the reaction mixture via microwave-assisted thermal
decomposition of formamide may represent a significant im-
provement over existing methods for coupling a pyrimidine ring
with an aromatic partner. The procedure, which consists to start
from the N,N-dimethylimidoformamide derivatives is then really
a safe and comfortable process (150 ꢀC), which may avoid mis-
cellaneous drawbacks. Our work is alerting readers on the proba-
bility to observe various and interesting phenomena when this very
powerful heating mode is associated with thermally unstable re-
agents (e.g., formamides, dimethylsulfoxide), which can be the
source of various key reactants (carbon monoxide, amines, formyl
group and formate) in organic synthesis. Users of these classes of
compounds should be attentive to the fact that usual, but some-
times slow, thermal unexpected processes can be dramatically ac-
celerated under microwaves. Considering the recent work of
Cataldo and his co-workers on the synthesis of HCN polymers from
thermal decomposition of formamide,17 we also assume that the
conditions described in our studies (150 ꢀC, 170 ꢀC or 200 ꢀC) are
limiting the possible appearance of hydrogen cyanide, which is
known to be produced when thermal decomposition of formamide
is performed at 200e220 ꢀC during several hours. Further in-
vestigations extending the families of heterocyclic precursors are
underway.
4.2. General procedures for the syntheses of formimidamide
and acetimidamide derivatives
Benzonitriles were suspended in 2.5 equiv of N,N-dime-
thylformamide dimethylacetal or N,N-dimethylacetamide dime-
thylacetal and were irradiated at 1200 W under microwaves. The
resulting mixture was cooled to room temperature and refrigerated
overnight. The precipitate formed was filtered, washed with diethyl
ether and dried. Purification by column chromatography over silica
gel using CH2Cl2/PE (5:5, v/v) as the eluent gave the desired
compound.
4.2.1. (E)-N0-(2-Cyano-4-nitrophenyl)-N,N-dimethylformimidamide
(2a) (lit.14). Starting from 2-amino-5-nitrobenzonitrile 1 (50.0 g;
0.36 mol) and N,N-dimethylformamide dimethylacetal (102 mL;
0.77 mol), 2a was obtained after an irradiation at 70 ꢀC during 2 min
as a yellow solid (64.2 g; 96%); mp 149 ꢀC; IR (KBr) nmax(cmꢂ1):
2971, 2901, 2224, 1623, 1593, 1558, 1499, 1414, 1374, 1310, 1280,
1170, 1141, 1076, 922, 888, 829, 776, 754, 726, 658; 1H NMR
(300 MHz, DMSO-d6):
J1¼3 Hz, J2¼9 Hz, NCHN and H-5), 7.38 (d, 1H, J¼9 Hz, H-6), 3.16 (s,
3H, NCH3), 3.08 (s, 3H, NCH3); 13C NMR (75 MHz, DMSO-d6):
160.5
d
8.48 (d, 1H, J¼3 Hz, H-3), 8.27 (m, 2H,
d
4. Experimental section
4.1. General
(C-1), 156.7 (C-7), 140.0 (C-4), 129.5 (C-3), 128.6 (C-5), 118.4 (C-6),
116.8 (CN), 105.9 (C-2), 34.4 (N(CH3)2); HRMS calcd for C10H10N4O2
[MþH]þ 219.0882 found 219.0873.
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
4.2.2. (E)-N0-(2-Cyano-4-nitrophenyl)-N,N-dimethylacetimidamide
(2b). Starting from 2-amino-5-nitrobenzonitrile
1
(4.46 g;
27.4 mmol) and N,N-dimethylacetamide dimethylacetal (10 mL;
68.4 mmol), 2b was obtained after an irradiation at 90 ꢀC during
2 min as a yellow solid (3.56 g; 57%); mp 131 ꢀC; IR (neat)
nmax(cmꢂ1): 2938, 2227, 1584, 1549, 1504, 1395, 1329, 1298, 1169,
1132, 1076, 901, 842, 777, 768, 736, 656; 1H NMR (300 MHz, DMSO-
Kofler hot-stage with a precision of ꢁ2 ꢀC and are uncorrected. IR
€
spectra were recorded on a PerkineElmer IRFT 1650 spectrometer.
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 sealed vials or at
atmospheric pressure in two commercial microwave reactors es-
pecially designed for synthetic chemistry. The ‘hybrid’ microwave
platform MultiSYNTHÔ (Milestone S.r.l. Italy) is a dedicated mi-
crowave system for synthetic applications. 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
d6):
6.92 (d, 1H, J¼9 Hz, H-6), 3.10 (br s, 6H, N(CH3)2), 2.05 (s, 3H, CH3);
13C NMR (75 MHz, DMSO-d6):
160.4 (C-1), 159.8 (C-7), 139.7 (C-4),
129.3 (C-3), 128.5 (C-5), 122.8 (C-6), 116.8 (CN), 105.3 (C-2), 40.3
(N(CH3)2), 15.9 (C-8); HRMS calcd for C11H13N4O2 [MþH]þ 233.1039
found 233.1033.
d
8.52 (d, 1H, J¼3 Hz, H-3), 8.26 (dd, 1H, J1¼3 Hz, J2¼9 Hz, H-5),
d
4.2.3. (E)-N0-(2-Cyanophenyl)-N,N-dimethylformimidamide
(5a)
(lit.14). Starting from anthranilonitrile 4 (5.0 g; 42.3 mmol) and
N,N-dimethylformamide dimethylacetal (14 mL; 105.6 mmol), 5a
was obtained after an irradiation at 90 ꢀC during 15 min as a pale
yellow solid (5.7 g; 79%); 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
7.93 (s, 1H, NCHN), 7.58 (dd, 1H, J1¼1 Hz, J2¼7 Hz, H-3),
7.47 (td, 1H, J1¼1 Hz, J2¼9 Hz, H-5), 7.14 (d, 1H, J¼7 Hz, H-6), 7.00 (t,
1H, J¼9 Hz, H-4), 3.07 (s, 3H, NCH3), 2.99 (s, 3H, NCH3); 13C NMR
(75 MHz, DMSO-d6):
d 155.0 (C-7), 154.9 (C-1), 133.7 (C-5), 132.9

4856
Y. Loidreau, T. Besson / Tetrahedron 67 (2011) 4852e4857
(C-3),121.6 (C-4),119.0 (C-6), 118.6 (CN),105.8 (C-2), 34.0 (N(CH3)2);
HRMS calcd for C10H11N3 [MþH]þ 174.1031 found 174.1040.
36.66 mmol), 3a was obtained following Method A after an irra-
diation at 200 ꢀC during 60 min as a dark solid (117 mg; 67%); mp
336 ꢀC; IR (neat) nmax(cmꢂ1): 3084, 1952, 1681, 1618, 1587, 1510,
1482,1341,1320,1284,1260,1199,1094, 927, 904, 847, 806, 749, 742,
4.2.4. (E)-N0-(2-Cyanophenyl)-N,N-dimethylacetimidamide
(5b)
(lit.14). Starting from anthranilonitrile 4 (2.0 g; 16.9 mmol) and N,N-
dimethylacetamide dimethylacetal (6.2 mL; 42.3 mmol), 5b was
obtained after an irradiation at 115 ꢀC during 2 min as white nee-
dles (2.41 g; 78%); mp 68 ꢀC; IR (neat) nmax(cmꢂ1): 2931, 2214, 1575,
1550, 1442, 1413, 1395, 1363, 1314, 1290, 1218, 1191, 1168, 1022, 959,
636; 1H NMR (300 MHz, DMSO-d6):
d
9.33 (d, 1H, J¼2 Hz, H-7), 8.58
(br s, 1H, NH), 8.53 (s, 1H, H-2), 8.48 (dd, 1H, J1¼2 Hz, J2¼9 Hz, H-5),
8.25 (br s, 1H, NH), 7.81 (d, 1H, J¼9 Hz, H-8); 13C NMR (75 MHz,
DMSO-d6): d 162.8 (C-4), 158.6 (C-8a), 153.2 (C-6), 143.8 (C-2), 129.0
(C-7), 126.5 (C-8), 121.4 (C-5), 113.3 (C-4a); HRMS calcd for
875, 839, 182, 755, 722; 1H NMR (300 MHz, DMSO-d6):
d
7.61 (dd,
C8H7N4O2 [MþH]þ 191.0569 found 191.0564.
1H, J1¼1 Hz, J2¼7 Hz, H-3), 7.49 (td, 1H, J1¼1 Hz, J2¼8 Hz, H-5), 7.01
(td, 1H, J1¼1 Hz, J2¼7 Hz, H-4), 6.78 (dd, 1H, J1¼1 Hz, J2¼8 Hz, H-6),
3.02 (br s, 6H, N(CH3)2), 1.89 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-
4.3.2. 2-Methyl-6-nitroquinazolin-4-(3H)-imine (3b). Starting from
acetimidamide derivative 2b (0.29 g; 1.25 mmol) and formamide
(2.0 mL; 50.17 mmol), 3b was converted (8%) following Method B
after an irradiation at 200 ꢀC during 60 min but could not be
isolated.
d6):
d 157.9 (C-7), 155.4 (C-1), 133.5 (C-5), 132.7 (C-3), 123.0 (C-4),
121.0 (C-6), 118.4 (CN), 105.0 (C-2), 37.6 (N(CH3)2), 14.9 (C-8); HRMS
calcd for C11H14N3 [MþH]þ 187.1179 found 187.1178.
4.2.5. (E)-N0-(2-Cyano-4,5-dimethoxyphenyl)-N,N-dimethylformimi-
damide (8a). Starting from 4,5-dimethoxybenzonitrile 7 (4.0 g;
22.5 mmol) and N,N-dimethylformamide dimethylacetal (7.5 mL;
56.12 mmol), 8a was obtained after an irradiation at 90 ꢀC during
10 min as a pale yellow solid (3.98 g; 77%); mp 120 ꢀC; IR (neat)
nmax(cmꢂ1): 3011, 2916, 2813, 2215, 1623, 1602, 1560, 1495, 1419,
1378, 1248, 1213, 1198, 1121, 1099, 1033, 998, 888, 855, 830; 1H NMR
4.3.3. Quinazolin-4-amine (6a). Starting from formimidamide de-
rivative 5a (0.22 g; 1.25 mmol) and formamide (2.0 mL;
50.17 mmol), 6a was obtained following Method B after an irradi-
ation at 200 ꢀC during 10 min as a yellow solid (140 mg; 77%); mp
274 ꢀC; IR (neat) nmax(cmꢂ1): 3076, 2718, 1948, 1684, 1614, 1580,
1559, 1514, 1483, 1457, 1364, 1321, 1290, 1203, 1117, 1023, 921, 757,
736, 629; 1H NMR (300 MHz, DMSO-d6):
d 8.38 (s, 1H, H-2), 8.20 (d,
(300 MHz, DMSO-d6):
1H, H-6), 3.82 (s, 3H, OCH3), 3.72 (s, 3H, OCH3) 3.05 (s, 3H, NCH3),
2.96 (s, 3H, NCH3); 13C NMR (75 MHz, DMSO-d6):
154.5 (C-5),
d
7.92 (s, 1H, NCHN), 7.09 (s, 1H, H-3), 6.74 (s,
1H, J¼8 Hz, H-8), 7.77 (m, 3H, J1¼1 Hz, J2¼8 Hz, H-5 and NH2), 7.66
(d, 1H, J¼8 Hz, H-7), 7.48 (td, 1H, J1¼1 Hz, J2¼8 Hz, H-6); 13C NMR
d
(75 MHz, DMSO-d6): d 161.7 (C-4), 155.4 (C-2), 149.6 (C-8a), 132.7
153.3 (C-7), 150.6 (C-4), 143.9 (C-1), 119.1 (CN), 114.1 (C-3), 102.6 (C-
6), 95.8 (C-2), 55.9 (OCH3), 55.6 (OCH3), 33.9 (N(CH3)2); HRMS calcd
for C12H16N3O2 [MþH]þ 234.1243 found 234.1243.
(C-7), 127.3 (C-8), 125.3 (C-5), 123.5 (C-6), 114.3 (C-4a); HRMS calcd
for C8H8N3 [MþH]þ 146.0718 found 146.0714.
4.3.4. 2-Methylquinazolin-4-amine (6b) (lit.15b). Starting from ace-
timidamide derivative 5b (0.235 g; 1.25 mmol), formamide (2.0 mL;
50.17 mmol) and InCl3 (0.277 g; 1.25 mmol), 6b was obtained fol-
lowing Method B after an irradiation at 150 ꢀC during 35 min as
a pale yellow solid (0.187 g; 94%); mp 306 ꢀC; IR (neat) nmax(cmꢂ1):
2886, 1560, 1508, 1466, 1396, 1369, 1324, 1128, 1056, 986, 875, 744,
4.2.6. (E)-N0-(2-Cyano-4,5-dimethoxyphenyl)-N,N-dimethylacetimi-
damide (8b). Starting from 4,5-dimethoxybenzonitrile 7 (1.0 g;
5.6 mmol) and N,N-dimethylacetamide dimethylacetal (2.1 mL;
14.0 mmol), 8b was obtained after an irradiation at 80 ꢀC during
6 min. The crude product was previously purified directly by col-
umn chromatography and gave 8b (1.31 g; 95%) as an orange oil; IR
(neat) nmax(cmꢂ1): 2935, 2210, 1593, 1494, 1440, 1416, 1381, 1365,
1251, 1214, 1189, 1174, 1113, 1020, 1003, 948, 843, 765, 754; 1H NMR
640; 1H NMR (300 MHz, DMSO-d6):
d
8.17 (d, 1H, J¼8 Hz, H-8), 7.72
(m, 3H, J1¼1 Hz, J2¼8 Hz, H-5 and NH2), 7.67 (d, 1H, J¼8 Hz, H-7),
7.39 (td, 1H, J1¼1 Hz, J2¼8 Hz, H-6); 13C NMR (75 MHz, DMSO-d6):
(300 MHz, DMSO-d6):
3H, OCH3), 3.73 (s, 3H, OCH3) 3.00 (br s, 6H, N(CH3)2), 1.87 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO-d6):
158.1 (C-7), 153.1 (C-5), 151.4
d
7.10 (s, 1H, H-3), 6.36 (s, 1H, H-6), 3.77 (s,
d 163.6 (C-4), 162.9 (C-2), 150.1 (C-8a), 132.6 (C-7), 126.7 (C-8), 124.4
(C-5), 123.4 (C-6), 112.5 (C-4a), 25.8 (CH3); HRMS calcd for C9H10N3
d
[MþH]þ 160.0875 found 160.0863.
(C-4), 143.4 (C-1), 118.8 (CN), 113.8 (C-3), 106.5 (C-6), 94.6 (C-2),
55.9 (OCH3), 55.6 (OCH3), 37.5 (N(CH3)2), 15.0 (C-8); HRMS calcd for
C13H18N3O2 [MþH]þ 248.1399 found 248.1393.
4.3.5. 6,7-Dimethoxyquinazolin-4-amine (9a). Starting from 4,5-
dimethoxybenzonitrile 7 (0.227 g; 1.25 mmol) and formamide
(2.0 mL; 50.17 mmol), 9a was obtained following Method A after an
irradiation at 200 ꢀC during 60 min as a pale yellow solid (0.146 g;
57%); mp 202 ꢀC; IR (neat) nmax(cmꢂ1): 3335, 3082,1676,1585,1476,
1452, 1438, 1337, 1283, 1248, 1220, 1196, 1165, 1115, 1029, 990, 847,
4.3. General procedures for the syntheses of quinazolin4-
amines
All quinazolines could be obtained by two methods. Each de-
rivative was described once using the best method.
835, 785, 721, 667, 630; 1H NMR (300 MHz, DMSO-d6):
H-2), 7.56 (s, 1H, H-8), 7.40 (br s, 2H, NH2), 7.05 (s, 1H, H-5), 3.89 (s,
3H, OCH3), 3.86 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6):
160.4
d 8.25 (s, 1H,
Method A: Benzonitriles were suspended in formamide
(40 equiv) and InCl3 (1 equiv), or not, in a sealed vial and were ir-
radiated at 400 W under microwaves. The residue was cooled to
room temperature, filtrated, washed with water and dried.
Method B: Formimidamide or acetimidamide intermediates
were suspended in formamide (40 equiv) and InCl3 (1 equiv), or
not, in a sealed vial and were irradiated at 400 W under micro-
waves. The residue was cooled to room temperature, filtrated,
washed with water and dried.
d
(C-4), 153.9 (C-7), 153.8 (C-2), 148.1 (C-6), 146.8 (C-8a), 107.9 (C-4a),
106.7 (C-8), 102.6 (C-5), 55.9 (OCH3), 55.6 (OCH3); HRMS calcd for
C10H12N3O2 [MþH]þ 206.0930 found 206.0928.
4.3.6. 2-Methyl-6,7-dimethoxyquinazolin-4-amine
(9b). Starting
from acetimidamide 8b (0.31 g; 1.25 mmol), formamide (2.0 mL;
50.17 mmol) and InCl3 (0.277 mg; 1.25 mmol), 9b was obtained
following Method B after an irradiation at 150 ꢀC during 40 min as
a yellow solid (0.186 g; 68%); mp >350 ꢀC; IR (neat) nmax(cmꢂ1):
3117, 2163, 1683, 1574, 1500, 1438, 1386, 1289, 1215, 1099, 774; 1H
In the two methods, purification by column chromatography
over silica gel using a gradient of CH2Cl2/EtOAc (from 100/0 to 0/
100, v/v) as the eluent gave the desired compounds.
NMR (300 MHz, DMSO-d6):
7.00 (s, 1H, H-5), 3.86 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 2.36 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO-d6):
161.7 (C-4), 160.5 (C-7), 153.9
(C-2), 147.5 (C-6), 147.1 (C-8a), 106.5 (C-4a), 105.9 (C-8), 102.6 (C-5),
d 7.52 (s, 1H, H-8), 7.30 (br s, 2H, NH2),
4.3.1. 6-Nitroquinazolin-4-(3H)-imine (3a). Starting from 2-amino-
5-nitrobenzonitrile 1 (0.2 g; 0.92 mmol) and formamide (1.46 mL;
d

Y. Loidreau, T. Besson / Tetrahedron 67 (2011) 4852e4857
4857
56.0 (OCH3), 55.5 (OCH3), 25.6 (CH3); HRMS calcd for C11H14N3O2
[MþH]þ 220.1086 found 220.1077.
828, 777, 740, 640, 630; 1H NMR (300 MHz, DMSO-d6):
d
8.40 (s, 1H,
H-2), 8.25 (d, 1H, J¼9 Hz, H-8), 7.94 (br s, 2H, NH2), 7.70 (d, 1H,
J¼2 Hz, H-5), 7.54 (dd, 1H, J1¼2 Hz, J2¼9 Hz, H-6); 13C NMR
4.3.7. N-(6,7-Dimethoxyquinazolin-4-yl)formamide (10). Starting
from 4,5-dimethoxybenzonitrile 7 (0.227 g; 1.25 mmol) and
formamide (2.0 mL; 50.17 mmol), 10 was a by-product obtained
following Method A, after an irradiation at 170 ꢀC during 10 min as
a brown solid (0.058 g; 20%); mp 265 ꢀC; IR (neat) nmax(cmꢂ1):
3240, 2917,1921,1698,1480,1423,1377,1358,1257,1227,1214,1198,
1191, 1139, 1047, 987, 850, 838, 772, 741, 693, 628; 1H NMR
(75 MHz, DMSO-d6): d 161.6 (C-4), 156.6 (C-2), 150.6 (C-9), 137.3 (C-
7), 126.1 (C-8), 125.8 (C-6), 125.8 (C-5), 112.9 (C-10); HRMS calcd for
C8H7ClN3 [MþH]þ 180.0329 found 180.0310.
Acknowledgements
ꢀ
This work was supported by a grant from the Region Haute-
(300 MHz, DMSO-d6):
d
11.37 (d, 1H, J¼9 Hz, NHCO), 9.68 (d, 1H,
Normandie (YL) and the ISCE-CHEM program. We acknowledge
Milestone S.r.l. (Italy) for the provision of the microwave reactors
and financial and technical support.
J¼9 Hz, NCOH), 8.66 (s, 1H, H-2), 7.82 (s, 1H, H-8), 7.28 (s, 1H, H-5),
3.96 (s, 3H, OCH3), 3.92 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6):
d
163.3 (C-4), 155.4 (NCO), 154.2 (C-7), 152.1 (C-2), 149.7 (C-6), 148.2
(C-8a), 108.7 (C-4a), 106.8 (C-8), 101.4 (C-5), 56.2 (OCH3), 56.0
(OCH3); HRMS calcd for C11H12N3O3 [MþH]þ 234.0879 found
234.0871.
References and notes
1. Giguere, R. L.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986, 41,
4945e4948 This paper is considered as the first paper reporting the interest of
microwave heating in organic synthesis.
2. For the most cited book see:Microwaves in Organic Synthesis, 2nd ed.; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, 2006.
3. For recent reviews see: (a) Kappe, C. O.; Dallinger, D. Mol. Diversity 2009, 13,
71e193; (b) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325e3355; (c)
For a recent paper on the thermal effect of microwaves see: Obermayer, D.;
Guttmann, B.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 8321e8324.
4. Besson, T.; Chosson, E. Comb. Chem. High Troughput Screening 2007, 10, 903e917.
5. For more details see: Gabriel, C.; Gabriel, S.; Grant, E. J.; Halstead, B. S.; Mingos,
D. M. P. Chem. Soc. Rev. 1998, 27, 213e223 Lost dissipation factor (tan d) ex-
presses the capacity of a molecule or a material to transform electromagnetic
energy into thermal energy. A high susceptibility to microwaves is character-
ized by a high value of tan d.
6. Alexandre, F.-R.; Berecibar, A.; Besson, T. Tetrahedron Lett. 2002, 43, 3911e3913.
7. Kostakis, I. K.; Elomri, H.; Seguin, E.; Iannelli, M.; Besson, T. Tetrahedron Lett.
2007, 48, 6609e6613.
4.3.8. 6-Bromoquinazolin-4-amine (12a). Starting from 2-amino-5-
bromobenzonitrile 11a (0.15 g; 0.76 mmol) and formamide
(1.20 mL; 30.50 mmol), 12a was obtained following Method A after
an irradiation at 200 ꢀC during 60 min as a pale orange solid
(0.152 g; 90%); mp >350 ꢀC; IR (neat) nmax(cmꢂ1): 3306, 3109, 2173,
1916, 1668, 157, 1549, 1497, 1472, 1355, 1318, 1287, 1265, 1123, 1026,
918, 866, 844, 828, 622; 1H NMR (300 MHz, DMSO-d6):
d 8.51 (d,1H,
J¼2 Hz, H-5), 8.41 (s, 1H, H-2), 7.88 (br dd, 3H, J1¼2 Hz, J2¼9 Hz, H-7
and NH2), 7.61 (d, 1H, J¼9 Hz, H-8); 13C NMR (75 MHz, DMSO-d6):
d
160.7 (C-4),155.6 (C-2),148.0 (C-8a),136.2 (C-7),129.3 (C-8),125.9
(C-5), 117.9 (C-6), 115.3 (C-4a); HRMS calcd for C8H7BrN3 [MþH]þ
223.9823 found 223.9828.
8. Nouira, I.; Kostakis, I. K.; Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T.
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4.3.9. 6-Fluoroquinazolin-4-amine (12b). Starting from 2-amino-5-
fluorobenzonitrile 11b (0.171 g; 1.25 mmol) and formamide
(2.0 mL; 50.17 mmol), 12b was obtained following Method A after
an irradiation at 200 ꢀC during 60 min as a pale yellow solid
(0.165 g; 80%); mp 329 ꢀC; IR (neat) nmax(cmꢂ1): 3277, 3090, 2238,
1942, 1675, 1583, 1565, 1513, 1488, 1437, 1368, 1327, 1276, 1256,
1213, 1038, 906, 872, 861, 831, 760, 713; 1H NMR (300 MHz, DMSO-
9. (a) Back, R. A.; Boden, J. C. Trans. Faraday Soc. 1971, 67, 88e96; (b) Kametani, T.;
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Three years later the same group published an alternative microwave-assisted
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d6):
d
8.38 (s, 1H, H-2), 8.05 (dd, 1H, J1¼3 Hz, J2¼10 Hz, H-7), 7.80 (br
s, 2H, NH2), 7.72 (m, 2H, J1¼3 Hz, J2¼10 Hz, H-8 and H-5); 13C NMR
(75 MHz, DMSO-d6):
d 161.5e161.4 (C-6), 157.2 (C-4), 154.9 (C-2),
11. Daniels, N. R.; Kim, K.; Lebois, E. P.; Muchalski, A.; Hughes, M.; Linsley, C. W.
Tetrahedron Lett. 2008, 49, 305e310.
12. Grosjean, S.; Triki, S.; Meslin, J. C.; Julienne, D.; Deniaud, D. Tetrahedron 2010,
66, 9912e9924.
146.7 (C-8a), 130.2e130.1 (C-8), 122.3e122.0 (C-7), 114.7e114.6 (C-
4a), 107.8e107.5 (C-5); HRMS calcd for C8H7FN3 [MþH]þ 164.0624
found 164.0615.
13. Kundu, S. K.; Mahindaratne, P. D.; Quintero, M. V.; Bao, A.; Negrete, G. R. AR-
KIVOC 2008, i, 33e42.
14. Foucourt, A.; Dubouilh-Benard, C.; Chosson, E.; Corbiere, C.; Buquet, C.; Iannelli,
ꢁ
4.3.10. 7-Chloroquinazolin-4-amine (12c). Starting from 2-amino-
4-chlorobenzonitrile 11c (0.192 g; 1.25 mmol) and formamide
(2.0 mL; 50.17 mmol), 12c was obtained following Method A after
an irradiation at 200 ꢀC during 60 min as a yellow solid (0.170 g;
75%); mp 322 ꢀC; IR (neat) nmax(cmꢂ1): 3078,1950,1682,1574,1559,
1468, 1447, 1376, 1352, 1321, 1281, 1257, 1164, 1074, 924, 883, 867,
M.; Leblond, B.; Marsais, F.; Besson, T. Tetrahedron 2010, 66, 4495e4502.
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M. P.; Martinez, M. M. Tetrahedron Lett. 2000, 41, 2215e2217.
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2009, 46, 1039e1048.