High yielding microwave-assisted synthesis of 2-(arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-triazines

Article abstract of DOI:10.1016/j.tetlet.2010.04.042

An efficient and practical procedure was developed to prepare novel 2-(arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-triazines, starting from dicyandiamide and the corresponding arylamines under microwave irradiation and its scope is demonstrated with a number of examples. The valuable feature of this procedure included the short reaction times, high yields, and easy operation.

Full text of DOI:10.1016/j.tetlet.2010.04.042

Tetrahedron Letters 51 (2010) 3174–3176
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
High yielding microwave-assisted synthesis of 2-(arylmethyl)amino-4-
arylamino-6-alkyl-1,3,5-triazines
*
Huixiong Chen , Pascal Dao, Alice Laporte, Christiane Garbay
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, UFR Biomédicale, Université Paris Descartes, 45 rue des Saints Pères,
75270 Paris Cedex 06, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 February 2010
Revised 8 April 2010
Accepted 9 April 2010
Available online 14 April 2010
An efficient and practical procedure was developed to prepare novel 2-(arylmethyl)amino-4-arylamino-
6-alkyl-1,3,5-triazines, starting from dicyandiamide and the corresponding arylamines under microwave
irradiation and its scope is demonstrated with a number of examples. The valuable feature of this proce-
dure included the short reaction times, high yields, and easy operation.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-(Arylmethyl)amino-4-arylamino-6-alkyl-
1,3,5-triazines
Microwave synthesis
Cyclocondensation
N-4,6-Disubstituted 1,3,5-triazine-4,6-diamines analogues have
been often reported as important core structures in many chemo-
therapeutic agents, including anti-angiogenesis,1 depressants for
reticuloendothelial hyperfunction,2 herbicides,3 antimicrobials,4
antivirals,5 antitumors,6 antimalarials,7 estrogen receptor modula-
tors8 and cyclin-dependent kinase inhibitors.9 Previous synthetic
methods for such compounds mainly relied on two approaches.
One starts with cyanuric chloride, that is, 2,4,6-trichloro-1,3,5-tri-
azine. Each chloride atom of cyanuric chloride can be substituted
by various nucleophiles in the presence of a base. Therefore, a care-
ful control of the temperature during the substitution reactions
could allow the synthesis of 2,4,6-trisubstituted-triazines by
sequential and selective addition of amines, alcohols, thiols or
alkyls.10,11 However, alkyl replacement can be problematic due to
the highly reactive nature of the Grignard reagents. The second in-
volves the formation of triazinic ring, one of which is carried out by
the reaction of the amidines, prepared from the corresponding
acetonitrile by the procedure of Garigipati12 and the isourea part-
ners.13 A limitation of this method was that the latter are often
obtained in modest yields. The other ring formation involves the
condensation of substituted biguanides with acid chlorides,14
anhydrides15 or carboxylates.16 These reactions are often per-
formed in alcoholic solution in the presence of a strong base.
Unfortunately, these transformations have traditionally suffered
from long reaction times and modest yields.
non-polluting method of activation. The scope of applications is
very extended and successful, that concerns a wide spectrum of or-
ganic syntheses including, for instance, heterocyclic, organometal-
lic, radio, photo reactions, and combinatorial chemistries.17–19 The
main benefits of performing reactions under MW irradiation condi-
tions are the significant rate-enhancements that result in short
reaction time, energy saving, and the higher product yields by low-
ering decomposition of the reagents and/or products and by equil-
ibrating reaction, with displacement by vaporization of light
molecules.
In this Letter, we describe a three-step synthesis of 2-(aryl-
methyl)amino-4-arylamino-6-alkyl-1,3,5-triazines 3a–d (Scheme
1) using MW techniques. We have focused our efforts on the
application of MW irradiation in the cyclocondensation of substi-
tuted biguanides with esters, which is
synthesis.
a key step for this
Our study began with the synthesis of 3,4,5-trimethoxyphenyl-
biguanide hydrochloride 1a as precursors of 2-amino-4-(304050-
trimethoxyphenyl)amino-6-alkyl-1,3,5-triazines
2a–c,
from
dicyandiamide and 3,4,5-trimethoxyaniline in the presence of
hydrochloric acid. The preparation was performed in dioxane under
MW irradiation at 90 °C in 15 min.20 The hydrochloride salts of the
3,4,5-trimethoxyphenylbiguanide were crystallized from the reac-
tion mixture in good yields (89%) and in high purity, and they can
be deprotonated with methanolic sodium methoxide in nearly
quantitative yield. The other 1-arylbiguanide hydrochlorides 1b–c
can be also obtained from dicyandiamide and commercially avail-
able arylamine in the same way (86–87% yields).
In the recent decades, microwave (MW) irradiation has taken an
incontestable place in organic synthesis as a very effective and
The formation of N-4-substituted 1,3,5-triazine-2,4-diamine
analogues by condensation between biguanides and esters is well
* Corresponding author. Tel.: +33 0142864085; fax: +33 0142864082.
E-mail address: huixiong.chen@parisdescartes.fr (H. Chen).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.042

H. Chen et al. / Tetrahedron Letters 51 (2010) 3174–3176
3175
H
N
R3
R2
N
NH2
NH2
HN NH
HN NH
N
NH2
HN NH
c
a
b
N
N
N
N
HN
O
HN
O
O
N
O
R1
O
O
1a : R1 = 3,4,5-trimethoxy
1b : R1 = 4-Cl
2a : R2 = CH3
2b : R2 = CF3
2c : R2 = H
3a : R3 = 3-NO2
3b : R3 = 3-Br
3c : R3 = 2-Cl
3d : R3 = 4-CH3
1c : R1 = 4-morpholino
Scheme 1. Reagents and conditions: (a) arylamine/dioxane/MW, 90 °C, 15 min; (b) R2CO2Et/MeONa/THF/MW, 70 °C, 20 min; (c) ArCH2Br/tBuONa/dioxane/MW, 90 °C,
15 min.
known.16 We believed that we could also implement a MW strategy
to enhance the rate of these often slow reactions. In order to opti-
mize the reaction conditions, initially, the effect of heating modes
was studied. In our first experiment, condensation between 3,4,5-
trimethoxyphenylbiguanide hydrochloride 1a (1 equiv) and ethyl
acetate (3 equiv) in methanolic sodium methoxide (1.5 equiv)
was chosen as a prototype to furnish 2-amino-4-(30,40,50-trime-
thoxyphenyl)amino-6-methyl-1,3,5-triazine 2a.21 Reaction times
as long as 24 h were necessary under conventional thermal heating
conditions and the yield of the desired product was 50%. No amelio-
ration for the yields was observed under the same experimental
conditions when the reaction was carried out by using NaOtBu or
NaNH2 or KOH as a base, by which 2a was obtained in 44%, 22%
and 15% yield, respectively.
an SN1 process, the difference of yields for 3b–d, except 3a could
be quite consistent with the stability of arylmethyl cation
intermediates.
In conclusion, an efficient, convenient, and practical preparation
of novel 2-(arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-triazines,
starting from easily accessible dicyandiamide and arylamines in
three steps has been carried out under microwave irradiation in
high yields. These procedures can be classified as a green synthesis
due to short reaction times, reduction of the solvent volume, good
yields, and simple work-up procedure. Furthermore, the advantage
of this route of synthesis is its application to parallel synthesis that
permits an easy and rapid access to a large number of derivatives
for biological evaluation as potential chemotherapeutic agents.
Interestingly, a remarkable rate acceleration was observed in
methanolic sodium methoxide under the MW conditions. The reac-
tion was achieved within 20 min at the same temperature, to give
the corresponding 2a in 61% yield (Table 1). It demonstrated the
beneficial effect of microwaves as the energy source.
Acknowledgment
We thank Le Corre Laurent for the use of microwave reactor and
Mauro Hélène for the mass spectra recording.
Next, the effect of the solvent was examined and the results are
summarized in Table 1. With the exception of entry 1, the yield
was very high in most solvents, and the best recovery was recorded
in THF.22 This result could be related to the presence of ‘superheat-
ing effect’,23 because THF possesses a stronger effect than MeOH.
For this reason, THF couples better with MV irradiation, resulting
in a higher temperature increase. In a similar manner and using
THF as a solvent, 2b24 was obtained from 1a and ethyl trifluoroace-
tate in quantitative yield and 2c25 in 90% from 1a and ethyl formate.
At last, 2-(arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-tria-
zines 3a–d were prepared by a similar strategy, that is, treatment
of 2a with appropriate derived benzylbromides under MW irradi-
ation in the presence of tBuONa as a base and dioxane as a solvent.
The MW assisted direct conversion of 2a was carried out at 90 °C in
10–15 min to afford the expected products 3a,26 3b,27 3c,28 and
3d29 in 82%, 77%, 69%, and 81% yields, respectively.30 As these
nucleophilic substitution reactions were carried out probably in
References and notes
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Wisely, G. B.; Lambert, M. H. J. Med. Chem. 2002, 45, 5492–5505.
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12. Garigipati, R. S. Tetrahedron Lett. 1990, 31, 1969–1972.
13. Ludovici, D. W.; Kavash, R. W.; Kukla, M. J.; Ho, C. Y.; Ye, H.; De Corte, B. L.;
Andries, K.; Béthune, M. P.; Azijn, H.; Pauwels, R.; Moereels, H. E. L.; Heeres, J.;
Koymans, L. M. H.; Jonge, M. R.; Van Aken, K. J. A.; Daeyaert, F. F. D.; Lewi, P. J.;
Das, K.; Arnold, E.; Janssen, P. A. J. Bioorg. Med. Chem. Lett. 2001, 11, 2229–2234.
14. Shapiro, S. L.; Isaacs, E. S.; Parrino, V. A.; Freedman, L. J. Org. Chem. 1961, 26, 68–
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Beutel, B.; Katz, L.; Fesik, S. W. J. Med. Chem. 1999, 42, 3852–3859.
17. Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2002.
Table 1
Solvent influence under MW conditions on reaction rate and yield for the preparation
of triazine 2a
Entry
Solvent
Time (min)
Yielda (%)
HPLCb (%)
1
2
3
4
5
6
MeOH
20
20
20
20
20
5
61
97
99
99
100
95
99
98
98
99
99
98
n-BuOH
Dioxane
Acetonitrile
THF
DMF
18. Alen, J.; Robeyns, K.; De Borggraeve, W. M.; Van Meervelt, L.; Compernolle, F.
Tetrahedron 2008, 64, 8128–8133.
19. Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6, 314–320.
a
Isolated yield of pure compound.
Purity was determined by HPLC at 214 nm.
b

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H. Chen et al. / Tetrahedron Letters 51 (2010) 3174–3176
20. All MV reactions were performed in a BenchMate monomode reactor (IR
detector for temperature) from CEM corporation.
25. Compound 2c: 1H NMR (250 MHz, DMSO-d6) d: 3.62 (3H, s), 3.76 (6H, s), 7.12
(2H, s), 7.16 (2H, s), 8.14 (1H, s), 9.36 (1H, s). MS (ESI) m/z 278.1 (M+1).
26. Compound 3a: 1H NMR (250 MHz, DMSO-d6) d: 2.14 (3H, s), 3.64 (3H, s), 3.68
(6H, s), 5.29 (2H, s), 6.55 (2H, s), 6.92 (2H, s), 7.60 (1H, t, J = 8 Hz), 7.75 (1H, d,
J = 8 Hz), 8.15 (2H, m). MS (ESI) m/z 427.1 (M+1).
General procedure: A mixture of dicyandiamide (10.8 mmol, 1 equiv), arylamine
(10.8 mmol, 1 equiv), and concentrated HCl (10.8 mmol, 1 equiv) in dioxane
(20 ml) was introduced into a 50 mL round-bottomed flask equipped with a
condenser and a magnetic stirring bar. The flask was placed in the microwave
cavity and subjected to microwave irradiation for 15 min at 90 °C using
irradiation power of 150 W. After cooling to room temperature, the
arylbiguanide hydrochloride salt was precipitated. The solid was collected by
filtration, washed with dioxane.
27. Compound 3b: 1H NMR (250 MHz, DMSO-d6) d: 2.13 (3H, s), 3.65 (3H, s), 3.67
(6H, s), 5.16 (2H, s), 6.50 (2H, s), 6.89 (2H, s), 7.29 (2H, s), 7.45 (2H, s). MS (ESI)
m/z 460.1 (M+1).
28. Compound 3c: 1H NMR (250 MHz, DMSO-d6) d: 2.11 (3H, s), 3.63 (3H, s), 3.67
(6H, s), 5.24 (2H, s), 6.62 (2H, s), 6.88 (2H, s), 7.31 (2H, s), 7.43 (2H, s). MS (ESI)
m/z 416.1 (M+1).
21. Compound 2a: 1H NMR (250 MHz, DMSO-d6) d: 2.18 (3H, s), 3.61 (3H, s),
3.75 (6H, s), 6.92 (2H, s, br), 7.20 (2H, s), 9.29 (1H, s). MS (ESI) m/z
292.1 (M+1).
29. Compound 3d: 1H NMR (250 MHz, DMSO-d6) d: 2.12 (3H, s), 2.25 (3H, s), 3.64
(9H, s), 5.12 (2H, s), 6.48 (2H, s), 6.84 (2H, s), 7.10 (4H, m). MS (ESI) m/z 396.1
(M+1).
22. General procedure: A mixture of sodium methoxide (0.75 mmol, 1.5 equiv)
prepared from Na and methanol, arylbiguanide hydrochloride (0.5 mmol,
1 equiv), and ethyl acetate (1.5 mmol, 3 equiv) in dry THF (3 ml) was
introduced into a 50 mL round-bottomed flask equipped with a condenser
and a magnetic stirring bar. The flask was placed in the microwave cavity and
exposed to microwave irradiation for 20 min at 70 °C using irradiation power
of 100 W. On cooling to room temperature, the mixture was evaporated under
vacuum, and the residue was subjected to flash chromatography (silica gel, 5%
methanol/CH2Cl2) to afford the desired product as a white solid.
30. General procedure: A mixture of 2-amino-4-(30,40,50-trimethoxyphenyl)amino-
6-methyl-1,3,5-triazine 2a (0.17 mmol, 1 equiv), arylmethylbromide
(0.19 mmol, 1.1 equiv), and tBuONa (0.26 mmol, 1.5 equiv) in dioxane
(2.5 ml) was introduced into a 50 mL round-bottomed flask equipped with a
condenser and a magnetic stirring bar. The flask was placed in the microwave
cavity and exposed to microwave irradiation for 15 min at 90 °C using
irradiation power of 150 W. On cooling to room temperature, the mixture
was diluted with CH2Cl2, washed with water, and dried over anhydrous
Na2SO4. The solution was concentrated under vacuum, and the residue was
subjected to flash chromatography (silica gel, 5% methanol/CH2Cl2) to give the
desired product.
23. Bougrin, K.; Loupy, A.; Soufiaoui, M. J. Photochem. Photobiol. 2005, C6, 139–167.
24. Compound 2b: 1H NMR (250 MHz, DMSO-d6) d: 3.63 (3H, s), 3.77 (6H, s), 7.17
(2H, s), 7.88 (2H, s, br), 10.04 (1H, s). MS (ESI) m/z 346.1 (M+1).