Microwave-assisted regioselective N-alkylation of cyclic amidines

Article abstract of DOI:10.1016/j.tetlet.2007.08.100

A simple and efficient methodology for regioselective alkylation of exocyclic nitrogen of cyclic amidines was developed by microwave-assisted heating in the presence of amines. Novel N-alkylated 3,4-dihydropyrazino[2,1-b]quinazolin-6-ones were prepared in

Full text of DOI:10.1016/j.tetlet.2007.08.100

Tetrahedron Letters 48 (2007) 7657–7659
Microwave-assisted regioselective N-alkylation of cyclic amidines
*
´
´
Maria de Fatima Pereira, Valerie Thiery and Thierry Besson
Laboratoire de Biotechnologies et de Chimie Bio-organique, FRE CNRS 2766, UFR Sciences Fondamentales et
ˆ
´
Sciences pour l’Inge´nieur, Batiment Marie Curie, Universite de La Rochelle, F-17042 La Rochelle cedex 1, France
Received 27 June 2007; revised 1 August 2007; accepted 28 August 2007
Available online 31 August 2007
Abstract—A simple and efficient methodology for regioselective alkylation of exocyclic nitrogen of cyclic amidines was developed by
microwave-assisted heating in the presence of amines. Novel N-alkylated 3,4-dihydropyrazino[2,1-b]quinazolin-6-ones were pre-
pared in good yields. The reaction occurred via a transamination (addition–elimination) process involving a first attack of the amine
on the electrophilic carbon of the amidine function.
Ó 2007 Elsevier Ltd. All rights reserved.
The occurrence of the cyclic amidine function in various
natural and synthetic products has generated interest of
many research groups in medicinal chemistry because of
their useful biological properties.1–3 As a part of our
ongoing research program dealing with the preparation
and pharmacological evaluation of some original qui-
nazoline derivatives, we unambiguously established the
3D structure of novel 3,4-dihydropyrazino[2,1-b]quinaz-
olin-6-ones (1a–d in Scheme 1) and we confirmed their
amidine isomerization in the solid state by X-ray
crystallography.4,5
recent results of Bourguignon and his co-workers3 on
the synthesis of amidines trust us to publish this preli-
minary work in which we describe a rapid and simple
method for the preparation of N-alkylated cyclic ami-
dines via a mechanism of transamination. This work is
connected to our study on the development of environ-
mentally convenient microwave-assisted methods in
organic and medicinal chemistry.
The synthesis of 2,3-condensed (3H)-quinazolin-4-one
precursor 1a was performed from methyl N-(4-chloro-
5H-1,2,3-dithiazol-5-ylidene)-anthranilate itself obtained
by condensation of 4,5-dichloro-1,2,3-dithiazolium chlo-
ride (Appel’s salt7) and methyl anthranilate (Scheme 2).
Stirring of a solution of the intermediate imine and ethyl-
enediamine at room temperature in tetrahydrofuran, for
1 or 2 h, gave a 58% yield of 1-amino-3,4-dihydropyraz-
ino[2,1-b]quinazolin-6-one 1a (Scheme 2).
Recent biological screening of these novel molecules
suggested that it might possess significant antimicrobial
activity.6 Considering these results, we focused our ef-
forts on the synthesis of various N-substituted amidines
(e.g., 2 in Scheme 1) in which the substituent will be
present specifically on the exogenic nitrogen atom. The
R
NH
NH2
HN
N
N
O
N
NH
N
N
R
R
N
N
N
O
O
1a-d (58-74%)
R = a, CH3; b, Br; c, Cl; d, di-OMe.
2
Scheme 1.
Keywords: Cyclic amidines; Regioselective N-alkylation; Microwave heating.
*
´
´
Corresponding author at present address: UMR CNRS 6014, Laboratoire de Chimie Pharmaceutique, UFR Medecine-Pharmacie, Universite de
Rouen, 22 Boulevard Gambetta, 76183 Rouen cedex 1, France. Tel.: +33 0235148399; fax: +33 0235148423; e-mail: thierry.besson@univ-rouen.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.100

7658
M. F. Pereira et al. / Tetrahedron Letters 48 (2007) 7657–7659
Cl
NH2
Appel's salt
pyridine
NH2
H2N
NH2
N
N
O
N
N
S
S
N
CH2Cl2, r.t., 2h
Cl
CO2CH3
CO2CH3
THF, r.t., 1-3h
Cl
1a (58%)
N
+
S
= Appel's salt
S
-
Cl
Scheme 2. Synthesis of 1a from methyl anthranilate.
The second step of the synthesis is an alkylation of the
heterocyclic amidine present on the studied molecule.
The usual methods for alkylation of this 1,3-dinucleo-
phile usually afforded mixtures of both the N-endosub-
stituted and the N-exosubstituted products.8,9 For
example, microwave heating of 1a with methyl iodide
in THF in the presence of sodium hydride gave a mix-
ture of N-endo (6%) and N-exomethylated 3,4-dihydro-
pyrazino[2,1-b]quinazolin-6-one 2a (49%). Our method
consists in microwave heating10 of a mixture of 1a and
aliphatic amines in tetrahydrofuran (THF), in the pres-
ence of 1.1 equiv of para-toluenesulfonic acid (PTSA), in
a sealed tube. The expected N-alkylated 3,4-dihydro-
pyrazino[2,1-b]quinazolin-6-ones (2) were obtained in
good yields. The suggested mechanism of this reaction
is a transamination (addition–elimination) process in
which the primary amine will first attack the carbon of
the amidine function, and then, eliminate ammonia
(Scheme 3).
of 1a and propylamine was realized under similar condi-
tions (temperature, quantities and sealed tube). Only
58% of the attempted product (2b) were isolated after
30 h of experiment.
Applying the conditions described above to an aromatic
amine (e.g., aniline in Scheme 3) led to different results.
The low nucleophilicity of the amine can explain that
the synthesis of the expected product needed a more
intense heating (220 °C) of the starting reactants in the
presence of N-methylpyrrolidinone (NMP), a solvent
which is particularly well adapted for microwave experi-
ments (Scheme 3).
In conclusion, we developed a simple and efficient meth-
odology for regioselective alkylation of exocyclic nitro-
gen of cyclic amidines via a transamination process.
These results confirm that microwave-assisted heating
is helped by the capacity of reactants to heat under the
microwave field. This phenomenon was combined with
pressure to allow very short reaction times and clean
conditions for work-up (no by-products).
In order to confirm the utility of microwave-assisted
heating in this reaction, a traditional heating (oil bath)
CH3
HN
N
N
2a : 49%
N
ICH3, NaH
Microwaves
O
b : 95%
c : 60%
R
N
NH2
HN
N
R-NH2
N
N
N
Microwaves
N
d : 81%
e : 66%
O
O
R-NH2
1a
2b-f
+
NH3
H
N
O
N
N
f : 58%
g : 62%
N
Scheme 3. Reagents and conditions: THF, MW, reflux, 20 min (for 2a); PTSA (1.1 equiv), THF, MW, 150 °C, 5 min (for 2b–f); NMP, MW, 220 °C,
15 min (for 2f).

M. F. Pereira et al. / Tetrahedron Letters 48 (2007) 7657–7659
7659
of Appel’s salt derivatives see: (b) Kim, K. Sulfur Reports
1998, 21, 147–207.
Acknowledgments
8. Abarghaz, M.; Kerbal, A.; Bourguignon, J.-J. Tetrahedron
Lett. 1995, 36, 6463–6466.
9. Fossey, J.; Loupy, A.; Strezelecka, H. Tetrahedron 1981,
37, 1935–1941.
We thank the Comite´s de Charente (16) and Charente-
Maritime (17) de la Ligue Nationale contre le cancer for
financial support and for a PhD grant (M.-F.P.). This
ˆ
work is also supported by the Canceropole Grand-Ouest
10. Focused microwave irradiations were carried out with a
Smith-SynthetizerTM (personal chemistry, AB) focused
microwave reactor (300 W, 2450 MHz, monomode sys-
tem). The Smith-SynthetizerTM (personal chemistry, AB) is
a single mode cavity, producing controlled irradiation at
2450 MHz. Reaction temperature and pressure were
determined using the built-in, on-line IR, and pressure
sensors. Microwave-assisted reactions were performed in
sealed Smith process vials (0.5–5 mL, total volume 10 mL)
under air with magnetic stirring. The microwave output
power was regulated by the software algorithm so that the
selected maximum temperature was maintained for the
desired reaction/irradiation time. After the irradiation
period, the reaction vessel was cooled rapidly to ambient
temperature by compressed air (gas-jet cooling). The
minimal reaction times were determined by performing
sequential series of identical reactions at constant temper-
ature and with continuous heating, but with different
irradiation times. Completion of the reaction was esti-
mated by T.L.C. after each individual heating period.).
Technical description of this microwave reactor with
integrated robotics was recently published: Schanche, J.
S. Mol. Diversity 2003, 7, 293–300.
program ‘Modulators of apoptosis’. We also thank Bio-
tage for multiform support on microwave experiments.
References and notes
1. Simone, M.; Erba, E.; Damia, G.; Vikhanskaya, F.;
Di Francesco, A. M.; Riccardi, R.; Bailly, C.; Cuevas, C.;
Fernandez Souza-Faro, J. M.; D’Incalci, M. Eur. J.
Cancer 2005, 41, 2366–2377.
2. Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron Lett. 2004,
45, 7073–7075.
3. Hellal, M.; Bihel, F.; Mongeot, A.; Bourguigon, J.-J. Org.
Biomol. Chem. 2006, 4, 3142–3146.
´
4. Pereira, M.-F.; Alexandre, F. R.; Thiery, V.; Besson, T.
Tetrahedron Lett. 2004, 45, 3097–3099.
´
5. Pereira, M.-F.; Picot, L.; Guillon, J.; Leger, J.-M.; Jarry,
´
C.; Thiery, V.; Besson, T. Tetrahedron Lett. 2005, 46,
3445–3447.
´
6. Pereira, M.-F., PhD thesis, Universite de La Rochelle,
France, 2006.
7. (a) Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem.
Ber. 1985, 118, 1632–1643; For a review on the chemistry