High yielding microwave-assisted synthesis of tri-substituted 1,3,5-triazines using Pd-catalyzed aryl and heteroarylamination

Article abstract of DOI:10.1016/j.tet.2012.03.041

A rapid and efficient Pd-catalyzed aryl and heteroarylamination under microwave irradiation has been developed for various tri-substituted triazines that can serve as versatile building blocks for both supramolecular and medicinal chemistry research. Particularly valuable features of this method included the short reaction time, good yield, and convenient operation.

Full text of DOI:10.1016/j.tet.2012.03.041

Tetrahedron 68 (2012) 3856e3860
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
High yielding microwave-assisted synthesis of tri-substituted 1,3,5-triazines using
Pd-catalyzed aryl and heteroarylamination
*
Pascal Dao, Christiane Garbay, Huixiong Chen
ꢀ
ꢀ
ꢁ
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601, UFR Biomedicale, Universite Paris Descartes, 45 rue des Saints-Peres,
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:
A rapid and efficient Pd-catalyzed aryl and heteroarylamination under microwave irradiation has been
developed for various tri-substituted triazines that can serve as versatile building blocks for both su-
pramolecular and medicinal chemistry research. Particularly valuable features of this method included
the short reaction time, good yield, and convenient operation.
Received 16 December 2011
Received in revised form 8 March 2012
Accepted 12 March 2012
Available online 17 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Microwave chemistry
Cross-coupling reactions
Triazines
Rotamers
1. Introduction
chloride, that is, 2,4,6-trichloro-1,3,5-triazine. Each chloride atom
of cyanuric chloride can be substituted by various nucleophiles in
Tri-substituted 1,3,5-triazines are one of the oldest classes of
organic compounds that continue to be used as important core
structure in many chemotherapeutic agents due to their interesting
pharmacological properties, including anticancer,1 anti-angiogen-
esis,2 anti-HIV,3 antimalarial,4 antibacterial,5 and antimicrobial
activity.6 These compounds have also been used as subunits in the
formation of supramolecular structure because they possess good
optical and electronic properties and are able to form multiple
hydrogen bonds.7,8 Despite numerous implications of these com-
pounds, synthetic methods for the preparation of analogues con-
taining different substituents at each carbon are limited.
Development of valuable methods for the preparation of many new
substituted compounds is still a challenge.
Previous synthetic methods for such compounds mainly relied
on two approaches. One involves the formation of triazinic ring by
the reaction of substituted biguanides with carboxylates,9 acid
chlorides,10 anhydrides11 or by cyclization of acylamidines with
amidines or guanidines.12 A recently published procedure involves
the treatment of isothiocyanates with N,N-diethylamidines through
the formation of intermediate amidinothioureas, which react with
carbamidines in the presence of mercury (II) chloride.13 The most
used alternative route to these compounds starts with cyanuric
the presence of a base and controlled by temperature to run in
a stepwise manner. An empirical rule, based upon observation, is
that mono-substitution of chlorine occurs below or at 0 ꢀC, di-
substitution at room temperature and tri-substitution above
60 ꢀC. Although widely used, this route has some deficiencies: most
notably, harsh conditions, and low reaction yields resulting from
the poor reactivity of its third chlorine atom toward nucleophiles.
We have previously reported an efficient and practical pro-
cedure to prepare novel 2-(arylmethyl)amino-4-arylamino-6-
alkyl-1,3,5-triazines under microwave (MW) irradiation.9 MW-
assisted organic synthesis is a high-speed methodology with
clear benefits: the higher degree of purity achieved due to short
residence time at high temperature and the significant rate-
enhancements that result in short reaction time, energy saving,
and better product yields. Thus, in recent years, MW irradiation has
been described for a wide spectrum of organic reactions including,
for instance, heterocyclic, organometallic, radio, photo, and com-
binatorial chemistries.14,15
As part of our ongoing research toward the design of new imi-
dazotriazine containing compounds, we wanted to synthesize tri-
substituted 1,3,5-triazines 2 (Scheme 1). Herein, we report our
optimized conditions, scope, and applications of microwave-
assisted Pd-catalyzed aryl and heteroarylamination of compounds
1 and 4, which provide facile access to these compounds and their
derivatives.
* Corresponding author. E-mail address: huixiong.chen@univ-paris5.fr (H. Chen).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.041

P. Dao et al. / Tetrahedron 68 (2012) 3856e3860
3857
Table 2
Optimization of the arylamination reaction on 2a1 in dioxane under MW irradiation
Entry Catalyst Ligand Base
Time (min) T (ꢀC) Conversion (%) Yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
BINAPc Cs2CO3 10
100 100
76
50
53
69
19
62
32
24
BINAPc t-BuONa 10
100
100
100
100
100
100
100
80
75
91
54
87
62
34
BINAPc DIEA
10
a
BINAPc Cs2CO3 10
Pd(Ph3P)2Cl2 BINAPc Cs2CO3 10
Pd(dppf)Cl2 BINAPc Cs2CO3 10
Pd(OAc)2
Pd(OAc)2
b
(tolyl)3P Cs2CO3 10
(t-Bu)3P Cs2CO3 10
a
b
c
Tris(dibenzylideneacetone)dipalladium(0).
[1,10-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).
racemic-2,20-Bis(diphenylphosphino)-1,10-binaphthyl.
Scheme 1. Reagents and conditions: (a) arylamine/THF/DIEA, ꢁ20 ꢀC; NH3/THF, rt; (b)
arylamine/dioxane/Pd(OAc)2/rac-BINAP/Cs2CO3/MW, 100 ꢀC, 10 min.
2. Results and discussion
afforded 2a1 in poor yield (entry 5). The use of palladium (II) ace-
tate/(tolyl)3P (entry 7) or palladium (II) acetate/(t-Bu)3P (entry 8) as
catalyst led to a significant decrease in turnover and yield (32% and
24%, respectively).
The scope of Pd-catalyzed arylamination method was explored
by applying the optimized reaction conditions to 1a and other less
nucleophilic anilines (Table 3, entries 1, 2). The results showed that
the reaction could be efficiently generalized. Under these condi-
tions, excellent conversion and good isolated yields were obtained.
We also applied the same conditions to various di-substituted tri-
azines 1b to 1e and 3,4,5-trimethoxyaniline (Table 3, entries 3e6).
The corresponding products 2bee were generated in good yields of
61e78%.
For this study, we chose 2,4,6-trichloro-1,3,5-triazine as starting
material. Substituted 1,3,5-triazine-2,4-diamines 1aed can be
prepared from corresponding amines in good to excellent yields in
a one-pot procedure. Then we first examined the reaction of di-
substituted triazine 1a with 3,4,5-trimethoxyaniline in the pres-
ence of DIEA in dioxane to furnish 2a1. As anticipated, reaction
times as long as 24 h were necessary under conventional thermal
heating conditions and the yield of the desired product was 21%.
In order to optimize the reaction yield, we began our in-
vestigation with a microwave-assisted procedure. We were de-
lighted to find a better yield under the MW conditions. The same
conversion of this reaction was achieved within 30 min, to give the
corresponding 2a1 in 42% yield (Table 1, entry 1). Next, the effect of
the solvent was examined and the results are summarized in Table
1. Optimal conditions for the preparation of 2a1 in 59% yield were
identified (entry 5), but this reaction is accompanied by a trans
esterification.
Table 3
Preparation of tri-substituted triazines 2
Table 1
Solvent influence under MW conditions on reaction rate and yield of 2a1
Entry
Solvent
Time (min)
T (ꢀC)
Conversion (%)
Yields (%)
Entry
2
R1
R2
R3
Time
T
Conversion Yield
(m n) (ꢀC) (%)
(%)
1
2
3
4
5
6
Dioxane
THF
Toluene
CH3CN
n-BuOH
DMF
30
30
30
30
30
30
100
100
110
90
120
150
65
40
75
36
90
90
42
13
36
12
59
32
1
2
3
4
5
6
2a2 2-CO2Me
2a3 2-CO2Me
2b 2-CO2Me
2c 3-CO2Me
2d 2-CONHMe
2e 2-NHSO2Me
H
H
4-Cl
3-NO2
10
10
100 100
100 100
100 93
100 95
100 92
100 92
67
67
75
78
61
62
CH3 3,4,5-(OMe)3 10
H
H
H
3,4,5-(OMe)3 10
3,4,5-(OMe)3 10
3,4,5-(OMe)3 10
Considering the remarkable progress made in the development
of palladium-catalyzed arylamination of aryl halides,16,17 we turned
our attention to a MW-assisted Buchwald-type coupling. To the
best of our knowledge, few approaches using palladium cross-
coupling are known for preparing tri-substituted 1,3,5-triazines.
For these reactions, the key to success was the optimum combined
choice of the solvent, base, and catalyst/ligand. We first tested
standard Buchwald amination conditions (Pd(OAc)2, rac-BINAP,
Cs2CO3) using dioxane as solvent, under MW conditions. As shown
in Table 2 (entry 1), the reaction proceeded rapidly to completion
within a few minutes. Thus, treatment of 1a under MW conditions
for 10 min gave 2a1 in 76% yield.
Attempts to increase the yield of 2a1 by varying the base failed.
Replacement of cesium carbonate with sodium tert-butoxylate or
DIEA as the base led to a decrease in the yields to 50% or 53%
(entries 2 and 3). Then, we focused our attention on the study of the
influence of the palladium catalyst or the ligand on the cross-
coupling arylamination. The replacement of Pd(OAc)2 by
Pd2(dba)3 (entry 4) afforded 2a1 in 69%. Similar results were ob-
served using Pd(dppf)Cl2 (entry 6). In contrast, Pd(Ph3P)2Cl2
Encouraged by these results, we decided to apply this procedure
to the arylation of N-4-substituted 1,3,5-triazine-2,4-diamine 4,
which were prepared by reaction of substituted biguanides with
esters under MW irradiation9 (Scheme 2), because this reaction
does not work under classical reaction conditions. Initially, at-
tempts to condense 6-methyl-N-morpholino-1,3,5-triazine-2,4-
diamine 4a with 1-bromo-2-nitrobenzene using the same
microwave-assisted
palladium
cross-coupling
procedure
(Pd(OAc)2, BINAP, Cs2CO3) were unsuccessful. Therefore, we fo-
cused on investigating this procedure with different combinations
of catalyst/ligand. When the reaction was performed with Pd(OAc)2
(4%), xantphos (4%), and Cs2CO3 (1.5 equiv) in dioxane at 150 ꢀC
using irradiation power of 150 W (entry 1, Table 4), we were very
pleased to find that the arylation of 4a proceeded efficiently and we
observed completion of reaction within 15 min with 82% isolated
yield. Similarly, 4a reacts with 4-iodotoluene to give the corre-
sponding compound 5a2 in 60% yield (entry 2, Table 4). Moreover,
high yields were also obtained in the reaction of 1-bromo-2-
nitrobenzene with compounds 4b1eb2 (entries 3, 4, Table 4).

3858
P. Dao et al. / Tetrahedron 68 (2012) 3856e3860
R2
N
NH2
R2
N
NH
NH2
NH
NH2
NH
R1
R3
a
b
c
HN
HN
HN
N
N
N
N
R1
4
R1
N
3
5a-b
4a: R1=morpholino, R2= CH3
3a: R1= morpholino
3b: R1=(3,4,5-trimethoxy)PhNH
4b1: R1=(3,4,5-trimethoxy)PhNH, R2=CF3
4b2: R1=(3,4,5-trimethoxy)PhNH, R2=CH3
Scheme 2. (a) RNH2/dioxane/MW, 90 ꢀC, 15 min; (b) R2CO2Et/MeONa/THF/MW, 70 ꢀC,
20 min; (c) 4-iodotoluene or 1-bromo-2-nitrobenzene/dioxane/Pd(OAc)2/xantphos/
Cs2CO3/MW, 150 ꢀC, 15e30 min.
Table 4
Preparation of tri-substituted triazines 5
Entry
5
R1
R2
R3
Time
T
Conversion Yield
(min) (ꢀC) (%)
(%)
1
2
3
4
5a1 N-morpholino
5a2 N-morpholino
5b1 [3,4,5-(OMe)3]PhNH CF3 2-NO2 15
5b2 [3,4,5-(OMe)3]PhNH CH3 2-NO2 15
CH3 2-NO2 15
CH3 4-CH3 30
150 100
150 85
150 100
150 100
82
60
74
80
Fig. 2. . Aromatic and NH regions of the solution-state 1H NMR spectrum of 1b.
Finally, the NMR spectra of 1a, 2a1, and 2b (Table S3eS5) at 213 K
(DMF-d7) showed the presence of two, four, and eight distin-
guishable rotamers, in an analogous way to the effects observed for
1b. As the temperature is increased, 2a1 and 2b present two and
four rotamers along the range of temperatures used (240e280 K for
2a1 and 240e260 K for 2b). At 280 K, the signals for 2b coalesced
again to show the presence of two rotamers. On heating further
temperature to 363 K for 2b and 300 K for 1a and 2a1, a rapid ro-
tation of all bonds was observed, giving signals for a unique
compound.
The structures of tri-substituted triazines were determined in
solution using NMR spectroscopy. Conformers resulting from the
restricted rotation about the amine-triazine bond for compounds
1b, 2b, and 5b1 were detected and identified in solution and at
room temperature (300 K). This effect of internal rotation can be
also observed for melamine derivatives in solution as well as in the
solid state.18 Theoretically, compounds I and II can exist in four and
sixteen possible rotamers arising from two possible conformations
about the triazine CeN bonds and the two orientations possible for
the aromatic rings, while compounds 1b and 2b present eight and
thirty-two possible rotamers. All the rotamers, which would in-
3. Conclusion
In conclusion, we have developed a two-step or three-step ap-
proach to tri-substituted triazines that can serve as versatile
building blocks for both supramolecular and medicinal chemistry
research. The advantageous features of this method, including
simple operation, good yielding, and short reaction times provide
an excellent opportunity for parallel synthesis. We have also shown
different rotamers resulting from the restricted rotation about the
amino triazine bond. Determining the molecular structure in so-
lution could allow insight into possible supramolecular interactions
and prediction of the crystal structure of a system.
terconvert by
a, b, g, d, and u rotations are equivalent for com-
pounds 1e5, so that there is a single distinguishable form, as shown
in Fig. 1. Each of the a, b, g, d, and u rotations would, if fast on the
NMR time-scale, result in averaging of some of the 1H and 13C
resonances for their structure.
4. Experimental section
4.1. General information
Fig. 1. Compounds 1e5 rotamer (except 3, 4a).
All reagents were purchased from SigmaeAldrich, Acros Or-
ganics and Alfa Aesar and used without further purification. Mi-
crowave irradiation was carried out with a BenchMate monomode
reactor (IR detector for temperature) from CEM corporation.
Melting points were determined on a Kofler apparatus as un-
corrected values. TLC was carried out on a Merck Kieselgel 60 PF254
and visualized with UV light. Column chromatography was per-
The NMR spectrum of 1b (Fig. 2, Table S1) at 363 K in DMF-d7
solution showed a single compound, consistent with fast rotation
about all the bonds. At 300 K in DMF-d7 solution,
slowed and all of signals except the OCH3 peak have split in two. A
similar behavior was observed in the DMSO-d6 solution. On low-
ering the temperature in DMF-d7 solution, the resonances broaden,
by 213 K the signals were split, and in particular, four signals were
observed for each of two NH groups (PhNH, CH3NH), suggesting
a rotation has
formed using Silica gel 60 (40e63 mm) purchased from Carlo Erba-
SDS. 1H NMR and 13C NMR spectra were measured on a Bruker
WMFT-250 MHz or AMX-500 MHz spectrometer in DMSO-d6 or
that
g
rotation is now slow. One signal of high intensity, one signal
CDCl3 or DMF-d7 with chemical shift (d) given in parts per million
of medium intensity and two signals of low intensity were
observed.
(ppm) relative to TMS as internal standard and recorded at the
temperature indicated (300ꢂ0.1 K except 1a, 1b, 2b, and 2a1) with

P. Dao et al. / Tetrahedron 68 (2012) 3856e3860
3859
a probe calibrate with methanol. MS (ESI) was determined by using
a Q-Tof1 spectrometer with Z-spray source. High-resolution mass
spectra (HRSM) were performed on Q-TOF Micro micromass posi-
tive ESI (CV¼30 V).
Pd(OAc)2 (7.2
m
mol), BINAP (7.2
m
mol) and Cs2CO3 (0.27 mmol,
1.5 equiv) and anhydrous dioxane (2 ml). The vessel was sealed and
purged with argon. The mixture was subjected to microwave irra-
diation for 10 min at 100 ꢀC using irradiation power of 100 W. On
cooling to room temperature, the mixture was concentrated, and
filtered. The crude product was purified by flash chromatography
(silica gel, 5% methanol/CH2Cl2) to afford the desired product.
4.2. General procedure for the synthesis of di-substituted
triazines 1
The solution of cyanuryl chloride (3 mmol,1 equiv) inTHF (20 ml)
was stirred, cooled to ꢁ15 ꢀC, and aniline (3 mmol, 1 equiv) in THF
(6 ml) and DIEA (3.6 mmol, 1.2 equiv) was added dropwise. The
mixture was stirred at this temperature for 0.5e1 h. Upon comple-
tion, monitored by TLC, NH3 (13 ml, 28% in water) was added. The
mixture was stirred under room temperature for 1 h. After the sol-
vent was removed under reduced pressure the resulting solid was
collected by filtration, dried, and crystallized or purified by silica gel
column chromatography to get the desired product.
4.3.1. Methyl 2-(4-amino-6-(3,4,5-trimethoxyphe-nylamino)-1,3,5-
triazin-2-ylamino)benzoate (2a1). 76%, white solid, mp 224 ꢀC; 1H
NMR (250 MHz, DMSO): d 3.65 (s, 3H, OMe), 3,79 (s, 6H, OMe), 3.91
(s, 3H, CH3); 6.95 (s, 2H, NH2), 7.06 (t, 1H, ArH), 7.22 (s, 2H, ArH),
7.60 (t, 1H, ArH), 8.0 (d, 1H, ArH), 8.98 (d, 1H, ArH), 9.20 (s, 1H, NH),
10.43 (s, 1H, NH). 13C NMR (500 MHz, DMSO):
d 167.0, 168.7, 166.2,
165.9, 154.5, 144.3, 138.0, 136.0, 134.5, 132.6, 122.5, 122.0, 116.0,
99.9, 62.0, 57.6, 54.2. MS (ESI) m/z 427.1 [Mþ1]þ. ESI-HRMS m/z
calcd for C20H23N6Oþ5 [MþH]þ 427.1730, found 427.1729.
4.2.1. Methyl 2-(4-amino-6-chloro-1,3,5-triazin-2-ylamino)benzoate
4.3.2. Methyl 2-(4-amino-6-(4-chlorophenylami-no)-1,3,5-triazin-2-
(1a). Yield 79%, white solid, mp 234 ꢀC; 1H NMR (250 MHz, DMSO):
ylamino)benzoate (2a2). Yield 67.2%, white solid, mp 146 ꢀC; 1H
d
3.85 (s, 3H, CH3), 7.19 (t, 1H, ArH), 7.63 (t, 1H, ArH), 7.70 (s, 2H,
NMR (250 MHz, DMSO): d 3.89 (s, 3H, CH3), 6.97 (s, 2H, NH2), 7.08 (t,
NH2), 7.95 (d, 1H, ArH), 8.42 (d, 1H, ArH), 10.51 (s, 1H, NH). 13C NMR
1H, ArH), 7.31 (d, 2H, ArH), 7.60 (t,1H, ArH), 7.82 (d, 2H, ArH), 8.0 (d,
(500 MHz, DMSO):
d 170.5, 169.6, 168.8, 165.9, 141.9, 135.7, 132.5,
1H, ArH); 8.91 (d, 2H, ArH), 9.47 (s, 1H, NH), 10.38 (s, 1H, NH). 13C
124.5, 123.4, 119.3, 54.3. MS (ESI) m/z 280.0 [Mþ1]þ. ESI-HRMS m/z
NMR (500 MHz, DMSO): d 168.0, 166.9, 164.3, 164.1, 142.4, 139.2,
calcd for C11H11ClN5Oþ2 [MþH]þ 280.0601, found 280.0612.
134.1, 130.7, 128.1, 125.5, 121.38, 120.8, 120.4, 114.5, 52.2. MS (ESI) m/
z 371.0 [Mþ1]þ. ESI-HRMS m/z calcd for C17H16ClN6Oþ2 [MþH]þ
371.1023, found 371.1015.
4.2.2. Methyl 2-(4-methylamino-6-chloro-1,3,5-triazin-2-ylamino)
benzoate (1b). Yield 83%, white solid, mp 248 ꢀC; 1H NMR
(250 MHz, DMF, 363 K):
(t, 1H, ArH), 7.79 (s, br, 2H, ArH, NH), 8.19 (d, 1H, ArH), 8.88 (d, 1H,
ArH), 10.71 (s, 1H, NH). 13C NMR (500 MHz, DMF, 363 K):
169.8,
d
3.17 (d, 3H, NCH3), 4.14 (s, 3H, OCH3), 7.33
4.3.3. Methyl 2-(4-amino-6-(3-nitrophenylamino)-1,3,5-triazin-2-
ylamino)benzoate (2a3). Yield 66.8%, pale yellow solid, mp 172 ꢀC;
d
1H NMR (250 MHz, DMSO):
d 3.90 (s, 3H, CH3), 7.08 (m, 3H, NH2,
168.7, 166.0, 142.9, 135.4, 132.7, 124.0, 122.9, 118.3, 53.6, 28.9. MS
(ESI) m/z 294.0 [Mþ1]þ. ESI-HRMS m/z calcd for C12H13ClN5O2þ
[MþH]þ 294.0758, found 294.0743.
ArH), 7.60 (m, 2H, ArH), 7.80 (d, 1H, ArH), 7.89 (d, 1H, ArH), 8.19 (d,
1H, ArH), 8.62 (s, 1H, ArH), 8.90 (d, 1H, ArH), 9.82 (s, 1H, NH), 10.44
(s, 1H, NH). 13C NMR (500 MHz, DMSO):
d 169.9, 168.8, 166.3, 166.1,
149.9, 143.9, 143.3, 136.0, 132.6, 131.5, 127.6, 122.8, 122.3, 118.0,
116.5, 115.7, 54.2. MS (ESI) m/z 382.1 [Mþ1]þ. ESI-HRMS m/z calcd
for C17H16N7Oþ4 [MþH]þ 382.1264, found 382.1251.
4.2.3. Methyl 3-(4-amino-6-chloro-1,3,5-triazin-2-ylamino)benzoate
(1c). Yield 82.3%, white solid, mp 256 ꢀC; 1H NMR (250 MHz,
DMSO):
d 3.87 (3H, s, CH3) 7.47 (1H, t, ArH), 7.65 (3H, m, ArH, NH2),
8.19 (2H, m, ArH), 10.17 (1H, s, NH). 13C NMR (500 MHz, DMSO):
4.3.4. Methyl 2-(4-methylamino-6-(3,4,5-trimethoxyphenylamino)-
d
170.4, 168.8, 168.0, 166.0, 141.3, 132.0, 130.8, 126.8, 125.4, 122.8,
1,3,5-triazin-2-ylamino)benzoate (2b). Yield 74.8%, white solid, mp
54.0. MS (ESI) m/z 280.1 [Mþ1]þ. ESI-HRMS m/z calcd for
209 ꢀC; 1H NMR (250 MHz, DMSO, 300 K):
d 2.92 (s, 3H, NMe), 3.67
C11H11ClN5Oþ2 [MþH]þ 280.0601, found 280.0615.
(s, 6H, OMe), 3.79 (s, 6H, OMe), 3.9 (s, 3H, CH3), 7.09 (t,1H, ArH), 7.16
(s, 2H, ArH), 7.45 (s, 1H, NH), 7.57 (t, 1H, ArH), 7.98 (d, 1H, ArH), 8.78
(d, 1H, ArH), 9.06 (s, 1H, NH), 10.29 (s, 1H, NH). 13C NMR (500 MHz,
4.2.4. 2-(4-Amino-6-chloro-1,3,5-triazin-2-ylam-ino)-N-methyl-
benzamide (1d). Yield 87%, white solid, mp 230 ꢀC; 1H NMR
DMSO, 363 K): d 169.8, 167.2, 166.4, 165.0, 155.0, 143.5, 137.3, 136.1,
(250 MHz, DMSO):
ArH), 7.70 (3H, m, ArH, NH2), 8.58 (1H, d, ArH), 8.77 (1H, s, NH),
11.18 (1H, s, NH). 13C NMR (500 MHz, DMSO):
170.7, 170.5, 168.8,
d
2.80 (3H, d, CH3), 7.13 (1H, t, ArH), 7.51 (1H, t,
135.6, 132.5, 123.2, 123.0, 117.8, 101.5, 62.1, 58.2, 54.0, 29.2. MS (ESI)
m/z 441.1 [Mþ1]þ. ESI-HRMS m/z calcd for C21H25N6Oþ5 [MþH]þ
441.1886, found 441.1879.
d
165.6, 140.6, 133.4, 129.9, 124.0, 123.1,122.9, 28.1. MS (ESI) m/z 278.9
[Mþ1]þ. ESI-HRMS m/z calcd for C11H12ClN6Oþ [MþH]þ 279.0761,
found 279.0752.
4.3.5. Methyl 3-(4-amino-6-(3,4,5-trimethoxyphenylamino)-1,3,5-
triazin-2-ylamino)benzoate (2c). Yield 78.4%, white solid, mp
152 ꢀC; 1H NMR (250 MHz, DMSO):
d 3.62 (3H, s, OCH3), 3.73 (6H, s,
4.2.5. N-(2-(4-Amino-6-chloro-1,3,5-triazin-2-ylamino)phenyl)
OCH3), 3.83 (3H, s, CH3), 6.68 (2H, s, NH2), 7.14 (2H, s, ArH), 7.40 (1H,
t, ArH), 7.52 (1H, d, ArH), 8.18 (1H, s, ArH), 8.27 (1H, d, ArH), 8.94
methanesulfonamide (1e). Yield 85%, white solid, mp 254 ꢀC; 1H
NMR (250 MHz, DMSO):
d
2.92 (3H, s, CH3), 7.14 (2H, m, ArH), 7.39
(1H, s, NH), 9.22 (1H, s, NH). 13C NMR (500 MHz, DMSO):
d 166.8,
(1H, t, ArH), 7.54 (2H, s, NH2), 7.74 (1H, t, ArH), 8.56 (1H, s, NH), 9.0
166.4, 164.5, 152.5, 140.8, 136.1, 132.5, 129.9, 128.7, 124.6, 122.2,
120.5, 98.1, 60.1, 55.8, 52.0. MS (ESI) m/z 427.1 [Mþ1]þ. ESI-HRMS
m/z calcd for C20H23N6Oþ5 [MþH]þ 427.1730, found 427.1723.
(1H, s, NH). 13C NMR (500 MHz, DMSO):
d 168.6, 166.9, 164.1, 139.7,
138.5, 129.1, 116.3, 114.5, 112.2. MS (ESI) m/z 315.1 [Mþ1]þ. ESI-
HRMS m/z calcd for C10H12ClN6O2Sþ [MþH]þ 315.0431, found
315.0426.
4.3.6. 2-(4-Amino-6-(3,4,5-trimethoxyphenylam-ino)-1,3,5-triazin-
2-ylamino)-N-methylbenzamide (2d). Yield 61.1%, white solid, mp
4.3. General procedure for the synthesis of tri-substituted
triazines 2
182 ꢀC; 1H NMR (250 MHz, DMSO):
d 2.80 (3H, d, CH3), 3.63 (3H, s,
OCH3), 3.78 (6H, s, OCH3), 6.82 (2H, s, NH2), 7.01 (1H, t, ArH), 7.19
(2H, s, ArH), 7.41 (1H, t, ArH), 7.62 (1H, d, ArH), 8.61 (1H, s, NH), 8.81
(1H, d, ArH), 9.10 (1H, s, NH), 10.80 (1H, s, NH). 13C NMR (500 MHz,
To a 10 ml microwave vessel were added the corresponding
compounds 1 (0.18 mmol, 1 equiv), arylamine (0.18 mmol, 1 equiv),
DMSO): d 169.1, 166.8, 164.3, 163.9, 152.5, 140.3, 136.2, 132.4, 131.3,

3860
P. Dao et al. / Tetrahedron 68 (2012) 3856e3860
127.9, 120.4, 120.1, 119.8, 97.8, 60.1, 55.7, 26.1. MS (ESI) m/z 426.0
[Mþ1]þ. ESI-HRMS m/z calcd for C20H24N7O4þ [MþH]þ 426.1890,
found 426.1885.
136.1, 135.5, 133.6, 128.5, 127.7, 127.0, 102.4, 62.1, 58.2, 26.7. MS (ESI)
m/z 413.1 [Mþ1]þ. ESI-HRMS m/z calcd for C19H21N6Oþ5 [MþH]þ
413.1573, found 413.1559.
4.3.7. N-(2-(4-Amino-6-(3,4,5-trimethoxyphenylam-ino)-1,3,5-
4.5. General procedure for the synthesis of N-4-substituted
1,3,5-triazine-2,4-diamine 4
triazin-2-ylamino)phenyl)methanesulfonamide (2e). Yield 61.5%,
white solid, mp 134 ꢀC; 1H NMR (250 MHz, DMSO):
d 3.01 (3H, d,
CH3), 3.62 (3H, s, OCH3), 3.74 (6H, s, OCH3), 6.57 (2H, s, NH2), 6.84
(1H, d, ArH), 7.14 (2H, s, ArH), 7.20 (1H, t, ArH), 7.46 (1H, t, ArH), 7.69
(1H, d, ArH), 8.83 (1H, s, NH), 9.07 (1H, s, NH), 9.58 (1H, s, NH). 13C
A mixture of sodium methoxide (0.75 mmol, 1.5 equiv) prepared
from Na and methanol, arylbiguanide hydrochloride (0.5 mmol,
1 equiv) and ester (1.5 mmol, 3 equiv) in dry THF (3 ml) was in-
troduced into a 50 ml round-bottomed flask equipped with a con-
denser 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.
NMR (500 MHz, DMSO):
d 176.3, 163.3, 164.0, 152.5, 135.9, 135.6,
133.1, 132.8, 130.7, 127.4, 125.9, 125.4, 98.1, 60.1, 55.7, 39.5. MS (ESI)
m/z 462.1 [Mþ1]þ. ESI-HRMS m/z calcd for C19H24N7O5Sþ [MþH]þ
462.1560, found 462.1567.
4.4. General procedure for the synthesis of tri-substituted
triazines 5
To a 10 ml microwave vessel were added the corresponding
compounds 4 (0.18 mmol, 1 equiv), 1-bromo-2-nitrobenzene or 4-
4.5.1. 6-Methyl-N-morpholino-1,3,5-triazine-2,4-diamine
(4a). Yield 88%, white solid, mp 192 ꢀC; 1H NMR (250 MHz, DMSO):
iodotoluene (0.18 mmol, 1 equiv), Pd(OAc)2 (7.2
mmol), xantphos
d
2.13 (3H, s, CH3), 3.6 (4H, t, 2ꢃ CH2), 3.67 (4H, t, 2ꢃ CH2), 6.75 (2H,
s, NH2). 13C NMR (500 MHz, DMSO):
d 176.3, 168.6, 166.5, 68.0, 45.0,
(7.2 mol) and Cs2CO3 (0.27 mmol, 1.5 equiv) and anhydrous di-
m
27.0. MS (ESI) m/z 196.1 [Mþ1]þ. ESI-HRMS m/z calcd for
oxane (2 ml). The vessel was sealed and purged with argon. The
mixture was subjected to microwave irradiation for 15e30 min at
150 ꢀC using irradiation power of 150 W. On cooling to room
temperature, the mixture was concentrated, and filtered. The crude
product was purified by flash chromatography (silica gel, 5%
methanol/CH2Cl2) to afford the desired product.
C8H14N5Oþ [MþH]þ 196.1198, found 196.1185.
Acknowledgements
We thank Le Corre Laurent for the use of microwave reactor,
ꢀ ꢁ
Bertho Gildas for the use of NMR spectrometer and Mauro Helene
for the mass spectra recording.
4.4.1. 4-Methyl-6-morpholino-N-(2-nitrophenyl)-1,3,5-triazin-2-
amine (5a1). Yield 82.2%, yellow solid, mp 156 ꢀC; 1H NMR
(250 MHz, CDCl3):
t, 2ꢃ CH2), 7.12 (1H, t, ArH), 7.62 (1H, t, ArH), 8.22 (1H, d, ArH), 8.86
(1H, d, ArH), 10.02 (1H, s, NH). 13C NMR (500 MHz, DMSO):
177.7,
166.1, 165.5, 138.2, 137.5, 136.4, 127.4, 123.9, 123.1, 68.2, 45.2, 27.1.
MS (ESI) m/z 317.1 [Mþ1]þ. ESI-HRMS m/z calcd for C14H17N6O3þ
[MþH]þ 317.1362, found 317.1347.
d
2.42 (3H, s, CH3), 3.80 (4H, t, 2ꢃ CH2), 3.90 (4H,
Supplementary data
d
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.041.
References and notes
4.4.2. 4-Methyl-6-morpholino-N-p-tolyl-1,3,5-triazin-2-amine
1. Brzozowski, Z.; Saczewski, F.; Gdaniec, M. Eur. J. Med. Chem. 2000, 35,
1053e1056.
(5a2). Yield 60.2%, white solid, mp 199 ꢀC; 1H NMR (250 MHz,
2. Ono, M.; Kawahara, N.; Goto, D.; Wakabayashi, Y.; Ushiro, S.; Yoshida, S.; Izumi,
H.; Kuwano, M.; Sato, Y. Cancer Res. 1996, 56, 1512e1516.
3. Daeyaert, F. F. D.; De Corte, B.; De Jonge, M. R.; Heeres, J.; Ho, C. Y.; Janssen, P. A.
J.; Kavash, R.W.; Koymans, L. M.H.; Kukla, M.J.; Ludovici, D.W. PCT Int. Appl..
(1999), WO 9950256 A1 19991007.
DMSO):
d
2.24 (3H, s, CH3), 2.26 (3H, s, CH3), 3.66 (4H, t, 2ꢃ CH2),
3.75 (4H, t, 2ꢃ CH2), 7.1 (2H, d, ArH), 7.58 (2H, d, ArH), 9.49 (1H, s,
NH). 13C NMR (500 MHz, DMSO):
d 176.5, 166.3, 165.6, 139.0, 132.9,
130.8, 121.9, 67.8, 45.2, 27.1, 22.3. MS (ESI) m/z 286.1 [Mþ1]þ. ESI-
4. Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett.
2005, 15, 531e533.
HRMS m/z calcd for C15H20N5Oþ [MþH]þ 286.1668, found 286.1659.
5. Solankee, A.; Kapadia, K.; Solankee, S.; Patel, G. J. Indian Chem. Soc. 2009, 868,
837e840.
4.4.3. N-(2-Nitrophenyl)-6-(trifluoromethyl)-N-(3,4,5-
trimethoxyphenyl)-1,3,5-triazine-2,4-diamine (5b1). Yield 74.1%,
ꢀ
6. Solankee, A.; Kapadia, K.; Ana, C.; Sokovic, M.; Doytchinova, I.; Geronikaki, A.
Eur. J. Med. Chem. 2010, 452, 510e518.
7. Zhong, H.; Xu, E.; Zeng, D.; Du, J.; Sun, J.; Ren, S.; Jiang, B.; Fang, Q. Org. Lett.
2008, 10, 709e712.
yellow solid, mp 184 ꢀC; 1H NMR (250 MHz, DMSO, 363 K):
d 3.69
(9H, s, OCH3), 7.0 (2H, s, ArH), 7.43 (1H, t, ArH), 7.72 (1H, t, ArH), 7.94
8. Sherrington, D. C.; Taskinen, K. A. Chem. Soc. Rev. 2001, 30, 83e93.
9. Chen, H.; Dao, P.; Laporte, A.; Garbay, C. Tetrahedron Lett. 2010, 51, 3174e3176.
10. Shapiro, S. L.; Isaacs, E. S.; Parrino, V. A.; Freedman, L. J. Org. Chem. 1961, 26,
68e74.
11. Alkalay, D.; Volk, J.; Barlett, M. F. J. Pharm. Sci. 1976, 65, 525e529.
12. Chen, C.; Dagnino, R.; McCarthy, J. R. J. Org. Chem. 1995, 60, 8428e8430.
13. Kaila, J. C.; Baraiya, A. B.; Pandya, A. N.; Jalani, H. B.; Sudarsanam, V.; Vasu, K. K.
Tetrahedron Lett. 2010, 51, 1486e1489.
(1H, d, ArH), 8.05 (1H, d, ArH), 9.95 (2H, s, NH). 13C NMR (500 MHz,
DMSO, 363 K):
d 166.7, 165.9, 165.2, 154.7, 144.6, 137.3, 136.0, 135.7,
133.8, 128.8, 127.6, 127.0, 121.8, 119.6, 102.5, 62.1, 58.2. MS (ESI) m/z
467.1 [Mþ1]þ. ESI-HRMS m/z calcd for C19H18F3N6Oþ5 [MþH]þ
467.1291, found 467.1277.
14. Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199e9223.
15. Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6, 314e320.
16. Negishi, E. Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley
Interscience: 2002.
17. Alen, J.; Robeyns, K.; De Borggraeve, W. M.; Meervelt, L. V.; Compernolle, F.
Tetrahedron 2008, 64, 8128e8133.
4.4.4. 6-Methyl-N-(2-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)-
1,3,5-triazine-2,4-diamine (5b2). Yield 80.1%, yellow solid, mp
214 ꢀC; 1H NMR (250 MHz, DMSO):
d 2.27 (3H, s, CH3), 3.62 (3H, s,
OCH3), 3.66 (6H, s, OCH3), 7.06 (2H, s, ArH), 7.35 (1H, t, ArH), 7.72
(1H, t, ArH), 8.02 (2H, m, ArH), 9.66 (1H, s, NH), 9.94 (1H, s, NH). 13C
18. Diaz-Ortiz, A.; Elguero, J.; Foces-Foces, C.; Hoz, A.; Moreno, A.; Moreno, S.;
Sanchez-Migallon, A.; Valiente, G. Org. Biomol. Chem. 2003, 1, 4451e4457.
NMR (500 MHz, DMSO):
d 177.7, 166.5, 165.8, 154.7, 144.3, 137.2,