Microwave-assisted synthesis of pyrazolyl bistriazines

Article abstract of DOI:10.1016/j.tet.2009.11.028

Reaction of 6-chloro-N,N′-bispyrazolyl-[1,3,5]triazine-2,4-diamines with 4-aminobenzylamine under microwave irradiation produces bistriazines in excellent yields. The use of a diamine bearing amino groups with different reactivities allowed the reaction t

Full text of DOI:10.1016/j.tet.2009.11.028

Tetrahedron 66 (2010) 121–127
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted synthesis of pyrazolyl bistriazines
´
´
´
´
Monica Moral, Amparo Ruiz, Andres Moreno, Angel Dıaz-Ortiz, Isabel Lopez-Solera,
*
*
´
´
Antonio de la Hoz , Ana Sanchez-Migallon
´
Facultad de Quımica, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain
a r t i c l e i n f o
a b s t r a c t
Reaction of 6-chloro-N,N0-bispyrazolyl-[1,3,5]triazine-2,4-diamines with 4-aminobenzylamine under
microwave irradiation produces bistriazines in excellent yields. The use of a diamine bearing amino
groups with different reactivities allowed the reaction to be carried out in two steps and selectively gave
monotriazines, bistriazines with identical substituents and differently substituted bistriazines. The
structures of these new compounds have been studied by NMR spectroscopy, mass spectrometry and in
one case by X-ray crystallogrphy. These new bistriazines have promising applications in supramolecular
chemistry based on hydrogen bonds and/or complexation with metals. The presence of a rigid linker can
be used for the efficient preparation of extended supramolecular polymers with interesting fluorescence
properties by complexation with cyanuric and barbituric acid derivatives.
Article history:
Received 23 September 2009
Received in revised form
2 November 2009
Accepted 5 November 2009
Available online 10 November 2009
Dedicated to Professor Luis Castedo
on celebrating his 70th birthday
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Microwaves
Bistriazines
Supramolecular
1. Introduction
subsequently used these compounds to prepare supramolecular
structures through the formation of intermolecular hydrogen
Supramolecular chemistry is one of the most important areas in
chemistry in the 21st Century.1 This field was defined by Lehn as the
‘Chemistry of molecular assemblies and of the intermolecular
bond’. The control of structures using supramolecular interactions
is an area of great interest in chemistry, biochemistry and crystal
engineering.
s-Triazine derivatives have important applications in the most
significant fields of Organic Chemistry, including Medicinal,2,3
Materials4–6 and Supramolecular Chemistry.7–11
The s-triazine ring is a remarkable system to produce supra-
molecular structures12 and the variety of interactions involving this
system has recently been reviewed.13
Aminotriazines have also been widely used because they easily
form hydrogen bonds7,9–11 and coordinate to transition metals.8
Microwave irradiation has been used with great success in
organic synthesis and a wide variety of reactions have been
improved under these conditions14dincluding modification of the
selectivity.15
bonds17 and coordination with metals.18
The use of microwave irradiation permitted the selective prep-
aration of di- and tri-substituted triazines and enabled the design of
a green procedure for their preparation.16
In this paper we describe the preparation of new bistriazines
with pyrazolyl substituents under microwave irradiation condi-
tions. These new polydentate ligands have numerous possibilities
in this field. The formation of supramolecular aggregates of
bistriazines with barbituric acid derivatives has been reported to
give rise to different structures such as 1þ1 complexes and folded
or extended supramolecular polymers. On using a flexible linker
the formation of 1þ1 complexes is favoured up to the point
where the number of atoms in the linker is 8. After this point an
extended supramolecular complex is formed and a folded su-
pramolecular polymer results when the number of atoms in the
linker reaches 11.10 In the present paper we describe the use of
a linker with an aromatic ring. The use of a rigid linker is
expected to favour the formation of extended supramolecular
polymers.
In recent years we have synthesized a series of pyrazolyl-
substituted triazines under microwave irradiation16 and we
2. Results and discussion
4-Aminobenzylamine was selected as the spacer because it
possesses two different amino groups, one aliphatic (more
nucleophilic) and other aromatic (less nucleophilic); as a conse-
quence, it should be possible to control the reaction and to obtain
* Corresponding authors. Tel.: þ34 926295411; fax: þ34 926295318 (A.d.l.H.);
tel.: þ34 926295300; fax: þ34 926295318 (A.S.-M.).
E-mail addresses: Antonio.Hoz@uclm.es (A. de la Hoz), Ana.Smigallon@uclm.es
´
´
(A. Sanchez-Migallon).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.028

122
M. Moral et al. / Tetrahedron 66 (2010) 121–127
selectively the mono- and di-substitution products. The starting
chlorotriazines 1 were previously described by our group and
prepared by reaction of cyanuric chloride with the corresponding
amine in THF using diisopropylethylamine as the base.16c
mmol) (Scheme 2). The use of an excess of 3b, again as a nucleo-
phile and a base, made the isolation of the dimeric triazine 4b
difficult as these compounds, 3 and 4, had the same Rf value in
chromatography studies; moreover, the major product was 5b
because elimination of the benzylamino group should be favoured
under basic conditions (Table 1, entry 1). Therefore, a hindered
amine, diisopropylethylamine (DIPEA), was assessed as a base but
5b was still the main product (Table 1, entry 2). Finally, the best
results were obtained on using DIPEA as the base and an excess of
the starting chlorotriazine 1b (Table 1, entry 3). However, even
under these conditions, formation of the aminotriazine 5 was
decreased but not completely avoided (Scheme 2).
Monosubstitution reactions were performed under microwave
irradiation at 270 W using toluene as the solvent and two equiva-
lents of 4-aminobenzylamine (Scheme 1). A high initial power was
used in order to reach the desired temperature in a short time.
Reactions were first tried in solvent-free conditions but only
moderate yields of triazines 3 were obtained (57–73%) and the
starting triazine 1 was not completely consumed (18–33%). We
believe that the reaction did not reach completion because the
reaction mixture was a highly heterogeneous slurry. As a result, it
was decided to use a small amount of toluene (1 mL/mmol) as
a solvent, which is transparent to microwaves (30¼2.408),19 in order
to obtain a homogeneous suspension. Under these conditions
excellent yields were obtained using 22 equiv of 4-aminobenzyl-
amine, which acts as both a nucleophile and a base to neutralize the
acid liberated in the reaction (Scheme 1). Pure products were
obtained simply by precipitation upon the addition of water.
Table 1
Reaction of 1b with 3b (DMSO, 1 mL/mmol, time, 10 min, temperature, 140 ꢀC, under
microwave irradiation, 270 W)
Entry
1b:3b:DIPEA
Yield 4b (%)
Yield 5b (%)
1
2
3
1:2:0
1:1:1
2:1:1
36
35
61
63
49
38
The use of small amounts of a solvent and the simplicity of the
isolation procedure (precipitation with water) makes this method
a green procedure for the preparation of this kind of compound.
Isolation of monomeric triazines 3 permitted the preparation of
asymmetrically substituted dimeric triazines. Under the same
conditions, shown in Scheme 2, excellent yields of dimeric triazines
4d and 4e were obtained (Table 2 and Scheme 3). It is remarkable
that in these reactions the formation of the aminotriazines 5b and
5c was not observed.
R
HN
R
NH
N
H2N
R
HN
R
NH
CH2
N
N
N
MW
Toluene
NH
+
N
N
Cl
NH2
1
2
NH2
3
Table 2
N
N
N
N
N
N
Synthesis of mono- and bistriazines 3 and 4
Temp (ꢀC)
Yield (%)
R=
Compound
Power (W)
Time (min)
3a
3b
3c
4aþ5a
270
270
270
50
45
15
20
10
80
80
80
84
98
96
64 (4a)
27 (5a)
61 (4b)
37 (5b)
86 (4c)
13 (5c)
98
a
b
c
140
Scheme 1.
4bþ5b
4cþ5c
50
50
10
10
140
140
Substitution through the aromatic amino group required
stronger conditions. In this respect, the use of toluene as the solvent
produced low yields (6%) in the reaction of 1b with 3b even when
heated under reflux. In order to attain a higher temperature the
polar solvent DMSO was used, again in a small amount (1 mL/
4d
4e
50
50
10
10
140
140
92
R
HN
R
NH
R
HN
R
NH
N
N
N
N
N
N
NH2
R
HN
R
NH
NH
NH
N
N
N
MW,DMSO
DIPEA
+
+
N
N
HN
R
N
NH
R
Cl
5
4
1
HN
NH2
3
N
N
NH
R
N
HN
R
N
N
N
N
N
N
R=
a
b
c
Scheme 2. Synthesis of symmetrically substituted bistriazines 4a–c.

M. Moral et al. / Tetrahedron 66 (2010) 121–127
123
7.7 for compounds 4. The aliphatic NH2 group of compounds 3
appears at 4 and is shifted downfield to 8–9 in compounds 4.
Comparison of the NMR spectra of 3 and 5 permits the assignment
of all signals in compounds 4 (Figs. 2 and 3).
N
N
N
d
d
N
N
N
N
N
N
HN
N
NH
HN
N
NH
7.26
7.45
7.71
8.50
N
N
7.25
7.44
N
NH
NH
7.68
N
N
N
N
N
N
N
N
7.84
7.85
8.50
HN
N
NH
H
HN
N
NH
H
HN
N
N
N
HN
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
4.48
4.63
7.73
7.34
HN
HN
4d
7.08
6.60
N
4e
N
N
N
H
7.68
7.86
NH2
HN
N
N
3c
8.22
N
N
Scheme 3. Structures of asymmetrically substituted bistriazines 4d–e.
N
N
HN
H
N
7.71
7.91
2.1. NMR spectroscopy
H2N
N
N
N
8.44
N
N
6.47
7.71
The NMR spectra of compounds 3–5 at room temperature show
a complex pattern with broad signals as a consequence of the
restricted rotation of the triazine–nitrogen bond. The free energy of
activation of aminotriazines has been determined by us16c,e and
others20 and lies in the range 50–80 KJ molꢁ1. In triazines 3–5, three
rotamers are expected for compounds 5, four for compounds 3 and
up to sixteen rotamers for compounds 4 due to the presence of two
triazine rings with four rotamers each (Fig. 1).
N
N
4e
HN
N
N
6.51
7.71
5b
Figure 2. NMR assignment of compound 4e from 3c and 5b.
The NMR spectra recorded at 135 ꢀC (308 K) show narrow
signals for all compounds and chemical shifts and coupling
constants can be assigned (Table S-1). Compounds 3–5 show
characteristic signals of pyrazole and substituted aryl groups.
Compounds 3 and 4 show the simplified AA0XX0 systems of the
p-phenylene group at 6.60 and 7.07 for compounds 3 and 7.3 and
2.2. Crystal structure of compound 3a
Compound 3a crystallizes from a THF/ethanol solution in the
monoclinic P21/n space group. Crystal data, bond lengths and
angles and the packing arrangement are collected in Tables S-2 and
S-3 and Figure S2, respectively.
H
N
H
N
H
N
N
N
N
N
N
H
N
H
N
N
H
N
H
N
N
N
N
N
N
N
N
H
H
H
N
N
N
N
H
H
3, 4
H
N
H
N
H
N
N
N
N
N
N
N
N
N
H
H
H
N
H
N
H
N
H
N
H
N
H
N
H
N
5
Figure 1. Expected rotamers for compounds 3–5.

124
M. Moral et al. / Tetrahedron 66 (2010) 121–127
An interesting supramolecular structure supported by weak
interactions is observed. Two intermolecular hydrogen bonds
(N11–H11a/N1 and N11–H11b/N8) support a supramolecular chain
in which the dihedral angle between two adjacent triazine rings is
84.5ꢀ (Fig. 5 and Table 3). Therefore N8 is implicated in a bifurcated
hydrogen bond with N4–H4 and N11–H11b (Table 3).
Table 3
Hydrogen bonds for compound 3a. Distances in Å
D–H/A
d(D–H) D(H..A) <DHA d(D..A)
Symmetry
N4–H4/N8
N6–H6/N10
0.98
0.98
2.169
2.074
2.286
2.442
131.6
133.1
155.5
149.4
2.814(3) x, y, z
2.735(3) x, y, z
1
1
N11–H11a/N1 0.98
11–H11b/N8 0.98
3.089(3) xꢁ ⁄2
,
,
⁄
ꢁy, 1
⁄
⁄
2 þz
2
1
1
N
3.212(3) xꢁ ⁄2
⁄
ꢁy, 1
2 þz
2
Each polymeric supramolecular chain interacts with two more
polymeric chains through weak and C–H/ interactions.
Information for these interactions is collected in Table 4 and Figures
6–8. The interactions are observed between triazine rings that
lie in completely parallel planes and have alternate N and C atoms;
p–
p
p
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
f1 (ppm)
Figure 3. NMR spectrum of 4e recorded at 135 ꢀC in DMSO-d6.
p–p
2
this corresponds to a [s–s] face-to-face geometry, where the
stacking interactions involve the heteroatoms and not the two
electron-poor ring centroids. This is expected to be the most stable
triazine–triazine stack as it has six stabilizing interactions between
electron rich N–atoms and electron deficient C–atoms and only one
centroid–centroid repulsive interaction (Fig. 6).13
The asymmetric unit shows only one rotamer for compound 3a,
with both aromatic rings in a trans conformation with respect to the
triazine N1 atom [torsion angles for N1–C1–N4–C11 and N1–C2–
N6–C21 are 178.0(2) and 175.4(2)ꢀ, respectively] (Fig. 4). All amino
groups are coplanar with the triazine ring [0.021(3), 0.009(3) and
0.042(3) Å out of the triazine plane for N4, N5 and N6, respectively].
The dihedral angles between planes C11–C16 and C21–C26 and the
triazine ring are 31.9(1) and 33.2(1)ꢀ, respectively.
Table 4
Weak intermolecular interactions
Interaction
Atoms involved
d(Å)
Dihedral(ꢀ)
Symmetry
Edge-to-face
Edge-to-face
p
p
/
/
p
p
D ring/F ring
E ring/F ring
A ring/A ring
4.916
4.692
3.594
2.952
75.5
72.1
0
1ꢁx, 1ꢁy, 1ꢁz
xþ1, y, z
p/
p
1ꢁx, ꢁy, 1ꢁz
1ꢁx, ꢁy, 1ꢁz
C–H/
p
H19/F ring
34.9
Figure 4. ORTEP diagram of 3a with 30% probability ellipsoids. Dashed lines represent
hydrogen bonds.
Figure 6.
p–p Interaction between two triazine rings.
Figure 5. Supramolecular chain arrangement of compound 3a in the crystal structure.

M. Moral et al. / Tetrahedron 66 (2010) 121–127
125
There are two
p
–
p
edge-to-face interactions. The phenylene
These compounds have potential applications in the preparation
of supramolecular structures through hydrogen bonding or
coordination with metals.
ring and the pyrazolylphenyl group are in an almost ideal ortho-
gonal arrangement, with a distance between centroids of 4.916 Å.
The second interaction observed between the phenylene ring and
the pyrazolyl group shows a distance between centroids of 4.693 Å
3. Experimental section
3.1. General
(Fig. 7).21 However, in both cases C–H/
p interactions between
H27/F ring and H33/D ring (d¼2.656 Å and 2.708 Å, respectively)
could also be present.22
Finally, one more C–H/
p
interaction is observed between
Melting points are uncorrected. NMR spectra were recorded on
a spectrometer operating at 499.772 MHz for 1H and 125.678 MHz
for 13C with TMS as the internal standard.
a C–H atom of a pyrazolyl group and the p-phenylene ring, with
a dihedral angle of 34.9ꢀ (Fig. 8).22
It should be remarked that all weak interactions are observed
between two adjacent triazine groups. These weak interactions
support the arrangement of the supramolecular chains. The first
Commercially available starting materials were used without
purification. 2,4-Bispyrazolyl-substituted-6-chlorotriazines 1 were
prepared according to previously described procedures.16c
The mass spectra were recorded using electron impact at 70 eV
and when the ionization technique was FAB the matrix m-nitro-
benzyl alcohol was used; determination of exact mass was carried
out with polyethylene glycol as the internal standard. Flash column
chromatography was performed on silica gel 60 (230–400 mesh).
Reactions under microwave irradiation were performed in
a CEM Discover microwave reactor. Temperature was measured
with an IR pyrometer.
chain shows C–H/
a second chain and C–H/
with a third chain (Fig. 7).12
p
interactions through F ring and H27 with
p
interactions through D ring and H33
,
In conclusion, microwave irradiation provides an efficient and
green procedure for the selective preparation of mono- and
bistriazines 3 and 4, respectively. The title compounds were
obtained in good to excellent yields in short reaction times and
with a simple isolation procedure. Compounds 3 and 4 show
restricted rotation of the triazine–amino bond and compound 3a
has an interesting supramolecular structure in the solid state.
3.2. General procedure for the synthesis of
4-aminobenzylaminotriazines
A
mixture of 4-aminobenzylamine (2) (2 mmol, 0.244 g),
the appropriate 2,4-bispyrazolyl-substituted-6-chlorotriazine
1
(1 mmol) and toluene (1 mL) was introduced into a Pyrex flask and
submitted to microwave irradiation at 270 W during the required
time (vide infra). The toluene was evaporated under vacuum. The
crude mixture was suspended in cold water and the solid was
filtered off and washed with water (3ꢂ10 mL). The resulting solid
was the pure triazine.
3.2.1. N-(4-Aminobenzyl)-N0,N00-bis-(2-pyrazol-1-yl-phenyl)-
[1,3,5]triazine-2,4,6-triamine 3a. From 6-chloro-N,N0-bis-(2-pyr-
azol-1-yl-phenyl)-[1,3,5]triazine-2,4-diamine 1a. The mixture was
submitted to microwave irradiation for 45 min. Yield 0.441 g (84%):
mp 187–188 ꢀC; IR (KBr) 3412, 3348, 1577, 1545 cmꢁ1
(DMSO, 100 ꢀC)
;
1H NMR
d
4.31 (d, J¼5.7 Hz, 2H), 4.75 (br s, 2H), 6.54 (s, 2H),
6.57 (d, J¼8.3 Hz, 2H), 7.02 (d, J¼8.3 Hz, 2H), 7.18 (t, J¼7.1 Hz, 2H),
7.28 (br s, 2H), 7.35 (t, J¼7.3 Hz, 2H), 7.49 (d, J¼8.3 Hz, 2H), 7.85 (d,
J¼1.5 Hz, 2H), 8.12 (d, J¼2.4 Hz, 2H), 8.36 (d, J¼7.3 Hz, 2H), 9.16 (br
Figure 7.
p–p edge-to-face interactions of p-phenylene with phenyl and pyrazolyl
groups.
s, 1H); 13C NMR (DMSO, 25 ꢀC)
d 43.3, 107.1, 107.1, 113.7, 113.8, 123.0,
123.3, 123.6, 123.7, 123.8, 124.0, 125.3, 126.9, 127.3, 127.4, 127.9,
128.2, 128.3, 128.9, 129.9, 130.1, 131.2, 131.3, 132.0, 132.2, 137.3,
140.9, 141.0, 147.0, 147.4, 163.9, 164.0, 165.6; MS (FAB) m/z 516.0
(MþHþ), 1031.0 (2 MþHþ); HRMS calcd for C28H25N11 m/z:
516.2373, found: 516.2367.
3.2.2. N-(4-Aminobenzyl)-N0,N00-bis-(4-pyrazol-1-yl-phenyl)-
[1,3,5]triazine-2,4,6-triamine 3b. From 6-chloro-N,N0-bis-(4-pyr-
azol-1-yl-phenyl)-[1,3,5]triazine-2,4-diamine 1b (1 mmol, 0.429 g).
The mixture was submitted to microwave irradiation for 15 min.
Yield 0.505 g (98%): mp 124–127 ꢀC; IR (KBr) 3263, 1620,
1579 cmꢁ1 1H NMR (CDCl3, 25 ꢀC)
; d 3.64 (br s, 2H), 4.49 (d,
J¼5.9 Hz, 2H), 5.60 (br s, 1H), 6.43 (s, 2H, H4), 6.61 (d, J¼8.5 Hz, 2H),
7.10 (d, J¼8.5 Hz, 2H), 7.28 (br s, 1H), 7.33 (br s, 1H), 7.5 (m, 8H), 7.69
(d, J¼1.5 Hz, 2H), 7.83 (s, 2H); 13C NMR (CDCl3, 25 ꢀC)
d 44.5, 107.3,
115.2, 119.7, 120.9, 121.1, 126.7, 128.4, 128.8, 135.5, 137.3, 140.8, 145.8,
164.1, 164.3, 165.9; MS (EI) m/z 515.2 (Mþ); HRMS calcd for
C28H25N11 m/z: 516.2373, found: 516.2358.
3.2.3. N-(4-Aminobenzyl)-N0,N00-bis-(1-phenyl-1H-pyrazol-4-yl)-
Figure 8. C–H/
p
Interaction between pyrazolyl and a p-phenylene group.
[1,3,5]triazine-2,4,6-triamine 3c. From 6-chloro-N,N0-bis-(1-phenyl-

126
M. Moral et al. / Tetrahedron 66 (2010) 121–127
1H-pyrazol-4-yl)-[1,3,5]triazine-2,4-diamine 1c. The mixture was
3.3.2.1. N,N0-bis{bis[4,6-(4-pyrazol-1-ylphenylamino)]-1,3,5-tri-
submitted to microwave irradiation for 20 min.ꢁY1ield 0.490 g (96%):
azin-2-yl}-4-aminobenzylamine 4b. Yield 0.135 g (61%): mp 175.1–
mp 200–201 ꢀC; IR (KBr) 3432, 1597, 1534 cm
;
1H NMR (DMSO,
176.4 ꢀC; IR (KBr) 3400, 3269, 1618, 1580 cmꢁ1 1H NMR (DMSO,
;
135 ꢀC)
d
4.48 (d, J¼3.9 Hz, 2H), 6.60 (d, J¼8.3 Hz, 2H), 6.96 (br s,1H),
25 ꢀC)
7.70 (s, 4H), 7.7–8.0 (m, 22H), 8.41 (d, J¼2.2 Hz, 4H), 9.2–9.5 (m,
4H); 13C NMR (DMSO, 25 ꢀC)
42.7, 107.4, 118.6, 120.3, 120.7, 127.2,
d
4.55 (d, J¼5.9 Hz, 2H), 6.51 (s, 4H), 7.33 (d, J¼8.4 Hz, 2H),
7.08 (d, J¼8.3 Hz, 2H), 7.26 (t, J¼7.3 Hz, 2H), 7.45 (dd, J¼7.3, 7.8 Hz,
4H), 7.71 (d, J¼7.8 Hz, 4H), 7.84 (s, 2H), 8.50 (s, 2H), 8.66 (br s, 2H);
d
13C NMR (DMSO, 25 ꢀC)
d
43.1, 113.8, 116.4, 116.8, 117.4, 117.6, 125.5,
127.4, 134.0, 134.3, 138.2, 138.4, 140.4, 163.9, 164.0, 165.78; MS (FAB)
m/z 909 (MþHþ), 1817 (2 MþHþ); HRMS calcd for C49H41N20 m/z:
909.3823; found: 909.3834.
125.5,126.9,127.2,128.3,129.4,129.5,133.1,139.7,139.9,147.4,163.1,
163.3, 163.6, 165.9; MS (FAB) m/z 516.1 (MþHþ), 1031.0 (2 MþHþ);
HRMS calcd for C28H25N11 m/z: 516.2373; found: 516.2365.
3.3.2.2. N,N0-Bis-(4-pyrazol-1-yl-phenyl)-[1,3,5]triazine-2,4,6-tri-
amine 5b. Yield 0.038 g (37%): mp >265 ꢀC; IR (KBr) 3173, 1619,
3.3. General procedure for the synthesis of bistriazines
1583 cmꢁ1; 1H NMR (DMSO, 25 ꢀC)
d
6.51 (t, J¼2.2 Hz, 2H), 6.66 (br
s, 2H), 7.71 (m, 6H), 7.91 (d, 4H, J¼8.3 Hz), 8.44 (d, 2H, J¼2.4 Hz),
13
A mixture of triazine 3 (0.25 mmol, 0.129 g), the appropriate 2,4-
9.23 (s, 2H); C NMR (DMSO, 25 ꢀC)
d 107.4, 118.7, 120.4, 127.4,
bispyrazolyl-substituted-6-chlorotriazine
1
(0.5 mmol, 0.214 g),
134.1, 138.6, 140.4, 164.4, 166.8; MS (FAB) m/z 411 (MþHþ), 821
(2 MþHþ); HRMS calcd for C21H18N10 m/z: 411.1794; found:
411.1806.
diisopropylethylamine (0.25 mmol, 0.031 g) and DMSO (1 mL) was
introduced into a Pyrex flask and submitted to microwave irradia-
tion at 50 W for 10 min. The crude mixture was suspended in cold
water and the solid was filtered off and washed with water
(5ꢂ10 mL). The solid was purified by column chromatography on
silica gel using hexane/ethyl acetate (1:1) gradient ethyl acetate as
the eluent.
3.3.3. N,N-Bis{bis[4,6-(1-phenylpyrazol-4-ylamino)]-1,3,5-triazin-2-
yl}-4-aminobenzyl amine 4c. From N-(4-aminobenzyl)-N0,N00-bis-(1-
phenylpyrazol-4-yl)-[1,3,5]triazine-2,4,6-triamine 3c (0.25 mmol,
0.129 g) and 6-chloro-N,N0-bis-(1-phenylpyrazol-4-yl)-[1,3,5]tri-
azine-2,4-diamine 1c (0.5 mmol, 0.214 g).
3.3.1. N,N-Bis{bis-[4,6-(2-pyrazol-1-ylphenylamino)]-1,3,5-triazin-2-
yl}-4-aminobenzylamine 4a. FromN-(4-aminobenzyl)-N0,N00-bis-(2-
pyrazol-1-yl-phenyl)-[1,3,5]triazine-2,4,6-triamine 3a (0.25 mmol,
0.129 g) and 6-chloro-N,N0-bis-(2-pyrazol-1-yl-phenyl)-[1,3,5]tri-
azine-2,4-diamine 1a (0.5 mmol, 0.214 g).
The solid was purified by column chromatography on silica gel
using hexane/ethyl acetate (1:1) gradient ethyl acetate as the elu-
ent. N,N-Bis{bis-[4,6-(2-pyrazol-1-ylphenylamino)]-1,3,5-triazin-
2-yl}-4-aminobenzylamine 4a, 0.147 g (64%), was eluted first
followed by 2-amino-4,6-bis(2-pyrazol-1-ylphenylamino)-1,3,5-
triazine 5a, 0.028 g (27%).
The solid was purified by column chromatography on silica gel
using hexane/ethyl acetate (1:1) gradient ethyl acetate as the elu-
ent. N,N-Bis{bis[4,6-(1-phenylpyrazol-4-ylamino)]-1,3,5-triazin-2-
yl}-4-aminobenzylamine 4c, 0.196 g (86%), was eluted first
followed by N0,N00-bis-(1-phenylpyrazol-4-yl)-[1,3,5]triazine-2,4,6-
triamine 5c, 0.013 g (13%).
3.3.3.1. N,N-Bis{bis[4,6-(1-phenylpyrazol-4-ylamino)]-1,3,5-tri-
azin-2-yl}-4-aminobenzylamine 4c. Yield 0.196 g (86%): mp 161.7–
163.4 ꢀC; IR (KBr) 3450, 3269, 1598, 1566 cmꢁ1 1H NMR (DMSO,
;
25 ꢀC)
(m, 4H), 9.2–9.6 (m, 6H); C NMR (DMSO, 25 ꢀC)
d 4.59 (br s, 2H), 7.1–7.6 (m, 14H), 7.6–7.9 (m, 14H), 8.6–8.9
13
d
116.8, 117.4,
3.3.1.1. N,N-Bis{bis-[4,6-(2-pyrazol-1-ylphenylamino)]-1,3,5-tri-
117.6, 117.7, 125.1, 125.4, 125.6, 125.7, 129.5, 133.2, 139.9, 163.2; MS
(FAB) m/z 909 (MþHþ), 1817 (2 MþHþ); HRMS calcd for C49H41N20
m/z: 909.3823; found: 909.3821.
azin-2-yl}-4-aminobenzylamine 4a. Yieꢁld1 0.147 g (64%): mp 142–
143.5 ꢀC; IR (KBr) 3263, 1575, 1505 cm
;
1H NMR (DMSO, 25 ꢀC)
d
4.35 (d, J¼5.86 Hz, 2H): 6.55 (m, 4H), 7.1–7.25 (m, 6H), 7.3–7.4 (m,
4H), 7.52 (m, 6H), 7.8–7.95 (m, 5H), 8.1–8.4 (m, 8H), 9.36 (s, 1H),
9.46 (s, 1H), 9.49 (s, 1H), 9.52 (s, 1H); 13C NMR (DMSO, 25 ꢀC)
43.2,
3.3.3.2. N0,N00-Bis-(1-phenylpyrazol-4-yl)-[1,3,5]triazine-2,4,6-tri-
d
amine 5c. Yield 0.013 g (13%): mp 240 ꢀC (decomposes); IR (KBr)
107.1,120.2,123.2,123.6, 123.8, 123.9,127.3,127.4,130.0, 131.3,131.3,
131.9, 132.1, 133.8, 138.1, 140.9, 163.9, 163.9, 164.0, 164.1, 165.7; MS
(FAB) m/z 909 (MþHþ), 1817 (2 MþHþ); HRMS calcd for C49H41N20
m/z: 909.3823; found: 909.3843.
3414, 3327, 1622, 1496 cmꢁ1 1H NMR (DMSO, 100 ꢀC)
; d 6.42 (br s,
2H), 7.27 (t, J¼7.1 Hz, 2H), 7.47 (t, J¼7.3 Hz, 4H), 7.78 (d, J¼7.3 Hz,
4H), 7.82 (s, 2H), 8.61 (br s, 2H), 8.84 (br s, 2H); 13C NMR (DMSO,
25 ꢀC)
d 116.9, 117.6, 125.4, 125.5, 129.4, 133.1, 139.9, 163.6, 167.1; MS
(FAB) m/z 411 (MþHþ); HRMS calcd for C21H18N10 m/z: 411.1794;
3.3.1.2. N,N0-Bis-(2-pyrazol-1-yl-phenyl)-[1,3,5]triazine-2,4,6-tri-
found: 411.1783.
amine 5a. Yield 0.028 g (27%): mp 163–165 ꢀC; IR (KBr) 3275, 1568,
1487, 1408 cmꢁ1; 1H NMR (DMSO, 135 ꢀC)
d
6.30–6.6 (m, 2H), 7–7.7
(m, 8H), 7.82 (m, 2H), 8.11 (s, 2H), 8.2–8.4 (m, 2H), 8.9–9.3 (m, 2H);
3.4. Synthesis of mixed bistriazines
13C NMR (DMSO, 25 ꢀC)
d 107.1,123.2,123.7,124.0,127.4,130.1,131.3,
131.3, 132.0, 140.9, 141.0, 164.3, 167.0; MS (FAB) m/z 411 (MþHþ);
3.4.1. N-[4,6-Bis(1-phenylpyrazol-4-ylamino)-1,3,5-triazin-2-yl]-N0-
[4,6-bis(4-pyrazol-1-ylphenylamino)-1,3,5-triazin-2-yl]-4-amino-
benzylamine 4d. From N-(4-aminobenzyl)-N0,N00-bis-(4-pyrazol-1-
ylphenyl)-[1,3,5]triazine-2,4,6-triamine 3b (0.25 mmol, 0.129 g)
and 6-chloro-N,N0-bis-(1-phenylpyrazol-4-yl)-[1,3,5]triazine-2,4-
diamine 1c (0.5 mmol, 0.214 g).
HRMS calcd for C21H18N10 m/z: 411.1794; found: 411.1804.
3.3.2. N,N0-Bis{bis[4,6-(4-pyrazol-1-ylphenylamino)]-1,3,5-triazin-2-
yl}-4-aminobenzyl amine 4b. From N-(4-aminobenzyl)-N0,N00-bis-(4-
pyrazol-1-yl-phenyl)-[1,3,5]triazine-2,4,6-triamine 3b (0.25 mmol,
0.129 g) and 6-chloro-N,N0-bis-(4-pyrazol-1-yl-phenyl)-[1,3,5]tri-
azine-2,4-diamine 1b (0.5 mmol, 0.214 g).
The solid was purified by column chromatography on silica gel
using hexane/ethyl acetate (1:1) gradient ethyl acetate as the eluent.
N,N0-Bis{bis[4,6-(4-pyrazol-1-ylphenylamino)]-1,3,5-triazin-2-yl}-4-
aminobenzylamine 4b, 0.135 g (61%), was eluted first followed by
N,N0-bis-(4-pyrazol-1-yl-phenyl)-[1,3,5]triazine-2,4,6-triamine 5b,
0.038 g (37%).
Yield 0.220 g (98%): mp 157–159 ꢀC; IR (KBr) 3398, 3272, 1574,
1495, 1405 cmꢁ1; 1H NMR (DMSO, 135 ꢀC)
d
4.59 (4d, J¼6.3 Hz, 2H),
6.47 (t, J¼2.2 Hz, 2H), 7.26 (t, J¼7.4 Hz, 2H), 7.34 (d, J¼8.3 Hz, 2H),
7.46 (t, J¼7.7 Hz, 4H), 7.66 (m, 4H), 7.67 (m, 2H), 7.71 (d, J¼8.3 Hz,
4H), 7.74 (d, J¼8.3 Hz, 2H), 7.85 (m, 2H), 7.86 (m, 4H), 7.87 (m, 2H),
8.53 (s, 2H), 8.68, 8.72, 8.78, 8.85 (br s, 6H); 13C NMR (DMSO, 25 ꢀC)
d
43.2, 107.3, 113.7, 117.1, 117.7, 118.6, 120.3, 125.1, 125.6, 127.1, 127.3,
128.0, 129.5, 134.0, 138.6, 139.9, 140.3, 140.4, 147.4, 164.0, 165.6,

M. Moral et al. / Tetrahedron 66 (2010) 121–127
127
165.8; MS (FAB) m/z 908.5 (Mþ), 909.5 (MþHþ); HRMS calcd for
C49H40N20 m/z: 908.3745; found: 908.3750.
4. (a) Yang, X.; Lowe, C. R. Tetrahedron Lett. 2003, 44, 1359–1362; (b) Wang, Q.-Q.;
Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X. Org. Lett. 2007, 9, 2847–2850.
5. (a) Lai, L.-L.; Wang, L.-Y.; Lee, C.-H.; Lin, Y.-C.; Cheng, K.-L. Org. Lett. 2006, 8,
1541–1544; (b) Steffensen, M. B.; Simanek, E. E. Org. Lett. 2003, 5, 2359–2361;
(c) Lim, J.; Simanek, E. E. Org. Lett. 2008, 10, 201–204; (d) Chouai, A.; Simanek,
E. E. J. Org. Chem. 2008, 73, 2357–2366.
6. (a) Lee, C. J.; Lee, S. J.; Chang, J. Y. Tetrahedron Lett. 2002, 43, 3863–3866; (b)
Cristiano, R.; Gallardo, H.; Bortoluzzi, A. J.; Bechtold, I. H.; Campos, C. E. M.;
Longo, R. L. Chem. Commun. 2008, 5134–5136; (c) Lehmann, M. Chem.d Eur. J.
2009, 15, 3638–3651.
3.4.2. N-[4,6-Bis(4-pyrazol-1-ylphenylamino)-1,3,5-triazin-2-yl]-N0-
[4,6-bis(1-phenylpyrazol-4-ylamino)-1,3,5-triazin-2-yl]-4-amino-
benzylamine 4e. From N-(4-aminobenzyl)-N0,N00-bis-(1-phenyl-1H-
pyrazol-4-yl)-[1,3,5]triazine-2,4,6-triamine 3c (0.25 mmol, 0.129 g)
and 6-chloro-N,N0-bis-(4-pyrazol-1-yl-phenyl)-[1,3,5]triazine-2,4-
diamine 1b (0.5 mmol, 0.214 g).
7. Malek, N.; Maris, T.; Simard, M.; Wuest, J. D. J. Am. Chem. Soc. 2005, 127,
5910–5916.
8. Telfer, S. G.; Wuest, J. D. Chem. Commun. 2007, 3166–6168.
Yield 0.210 g (92%): mp 181.5–183.3 ꢀC; IR (KBr) 3398, 3277, 1576,
1492 cmꢁ1; 1H NMR (DMSO, 135 ꢀC)
d
4.62 (d, J¼6.3 Hz, 2H), 6.47 (t,
´
9. Barbera, J.; Puig, L.; Romero, P.; Serrano, J. L.; Sierra, T. J. Am. Chem. Soc. 2006,
128, 4487–4492.
J¼2.1 Hz, 2H), 7.25 (t, J¼7.3 Hz, 2H), 7.34 (d, J¼8.5 Hz, 2H), 7.44 (t,
10. Yagai, S.; Kinoshita, T.; Higashi, M.; Kishikawa, K.; Nakanishi, T.; Karatsu, T.;
Kitamura, A. J. Am. Chem. Soc. 2007, 129, 13277–13287.
J¼7.4 Hz, 4H), 7.68 (m,10H), 7.73 (d, J¼8.5, 2H), 8.22 (d, J¼2.0 Hz, 2H),
8.50 (s, 2H), 8.71, 8.75, 8.87 (br s, 6H); 13C NMR (DMSO, 25 ꢀC)
d 43.6,
11. (a) Paraschiv, V.; Crego-Calama, M.; Fokkens, R. H.; Padberg, C. J.; Timmerman,
P.; Reinhoudt, D. N. J. Org. Chem. 2001, 66, 8297–8301; (b) Prins, L. J.;
Neuteboom, E. E.; Paraschiv, V.; Crego-Calama, M.; Timmerman, P.; Reinhoudt,
D. N. J. Org. Chem. 2002, 67, 4808–4820; (c) Prins, L. J.; Hulst, R.; Timmerman, P.;
Reinhoudt, D. N. Chem.d Eur. J. 2002, 8, 2288–2301; (d) Paraschiv, V.; Crego-
Calama, M.; Ishi-i, T.; Padberg, C. J.; Timmerman, P.; Reinhoudt, D. N. J. Am.
Chem. Soc. 2002, 124, 7638–7639; (e) McClenaghan, N. D.; Absalon, C.; Bassani,
D. M. J. Am. Chem. Soc. 2003, 125, 13004–13005.
107.4, 116.8, 117.4, 117.6, 118.6, 120.2, 120.8, 125.6, 127.3, 129.5, 133.2,
134.3, 138.2, 139.9, 140.4, 163.9; MS (FAB) m/z 908.4 (Mþ), 909.4
(MþHþ); HRMS calcd for C49H40
N20 m/z: 908.3745; found: 908.3757.
Acknowledgements
12. For a recent review on supramolecular interactions see: Schneider, H.-J. Angew.
Chem., Int. Ed. 2009, 48, 3924–3977 and references therein.
Financial support from the DGICYT of Spain through project
13. Mooibroek, T. J.; Gamez, P. Inorg. Chim. Acta 2007, 360, 381–404.
14. (a) Microwaves in Organic Synthesis, 2nd ed.; Loupy, A., Ed.; Wiley: Weinheim,
2006; (b) Microwave-Assisted Organic Synthesis; Lidstro¨m, P., Tierney, J. P., Eds.;
Blackwell Scientific: London, 2004; (c) Kappe, C. O.; Stadler, A. Microwaves in
Organic and Medicinal Chemistry; Wiley-VCH: Weinheim, 2005.
´
CTQ2007-60037/BQU and from the Consejerıa de Ciencia y Tecno-
´
logıa JCCM through projects PBI-06-0020 and PCI-08-0040 is
gratefully acknowledged.
´
15. Dıaz-Ortiz, A.; de la Hoz, A.; Moreno, A. In Selectivity under the Action of
Microwave Irradiation in Microwaves in Organic Synthesis, 2nd ed.; Loupy, A., Ed.;
Wiley: Weinheim, 2006.
Supplementary Data
´
´
´
16. (a) Elguero, J.; Dıaz-Ortiz, A.; Moreno, A.; de la Hoz, A.; Martınez, L. J.; Sanchez-
1H and 13C NMR spectra and assignments, crystal data and
structure of compound 3a. Supplementary data associated with
this article can be found in online version at doi:10.1016/
j.tet.2009.11.028.
Migallo´ n, A. Tetrahedron 2001, 57, 753–757; (b) Dı´az-Ortiz, A.; de la Hoz, A.;
´
´
Moreno, A.; Sanchez-Migallon, A.; Valiente, G. Green Chem. 2002, 4, 339–343;
(c) Dı´az-Ortiz, A.; Elguero, J.; Foces-Foces, C.; de la Hoz, A.; Moreno, A.; Moreno,
S.; Sa´nchez-Migallo´n, A.; Valiente, G. Org. Biomol. Chem. 2003, 1, 4451–4457; (d)
Dı´az-Ortiz, A.; Elguero, J.; Foces-Foces, C.; de la Hoz, A.; Moreno, A.; Mateo, M.
C.; Sa´nchez-Migallo´ n, A.; Valiente, G. New J. Chem. 2004, 28, 952–958; (e) Dı´az-
´
´
Ortiz, A.; Elguero, J.; de la Hoz, A.; Jimenez, A.; Moreno, A.; Moreno, S.; Sanchez-
References and notes
Migallo´ n, A. QSAR Comb. Sci. 2005, 24, 649–659.
´
´
17. Manzano, B. R.; Jalon, F. A.; Soriano, M. L.; Rodrıguez, A. M.; de la Hoz, A.;
Sa´nchez-Migallo´ n, A. Cryst. Growth Des. 2008, 8, 1585–1594.
1. (a) Steed, W. W.; Atwood, J. L. Supramolecular Chemistry, 2nd ed.; John Wiley &
Sons Ltd: West Sussex, 2009; (b) Lehn, J. M. Supramolecular Chemistry: Concepts
and Perspectives; Wiley: Weinheim, 1995.
18. Manzano, B. R.; Jalo´ n, F. A.; Soriano, M. L.; Carrio´n, M. C.; Carranza, P.; Mereiter,
´
´
´
K.; Rodrıguez, A. M.; de la Hoz, A.; Sanchez-Migallon, A. Inorg. Chem. 2008, 47,
8957–8971.
2. (a) Scharn, D.; Wenschuh, H.; Reineke, U.; Schneider-Mergener, J.; Germeroth, L.
J. Comb. Chem.2000, 2, 361–369; (b) Moon, H.-S.; Jacobson, E. M.; Khersonsky, S. M.;
Luzung, M. R.; Walsh, D. P.; Xiong, W.; Lee, J. W.; Parikh, P. B.; Lam, J. C.; Kang, T.-W.;
Rosania, G. R.; Schier, A. F.; Chang, Y.-T. J. Am. Chem. Soc. 2002,124,11608–11609; (c)
Khersonsky, S. M.; Jung, D.-W.; Kang, T.-W.; Walsh, D. P.; Moon, H.-S.; Jo, H.;
Jacobson, E. M.; Shetty, V.; Neubert, T. A.; Chang, Y.-T. J. Am. Chem. Soc. 2003, 125,
11804–11805; (d) Uttamchandani, M.; Walsh, D. P.; Khersonsky, S. M.; Huang, X.;
Yao, S. Q.; Chang, Y.-T. J. Comb. Chem. 2004, 6, 862–868.
19. (a) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem.
Soc. Rev. 1998, 27, 213–223; (b) Wohlfarth, Ch. Landolt-Bo¨rnstein IV/17: Static
Dielectric Constants of Pure Liquids and Binary Liquid Mixtures; Springer: Berlin,
Heidelberg, 2008; pp 392–394.
20. (a) Ghiviriga, I.; Oniciu, D. C. Chem. Commun. 2002, 2718–2719; (b) Fazekas, M.;
´
Pintea, M.; Lameiras, P.; Lesur, A.; Berghian, C.; Silaghi-Dumitrescu, I.; Ple, N.;
Darabantu, M. Eur. J. Org. Chem. 2008, 2473–2494; (c) Pintea, M.; Fazekas, M.;
´
Lameiras, P.; Cadis, I.; Berghian, C.; Silaghi-Dumitrescu, I.; Popa, F.; Bele, C.; Ple,
N.; Darabantu, M. Tetrahedron 2008, 64, 8851–8870.
3. (a) Coley, H. M.; Brooks, N.; Phillips, D. H.; Hewer, A.; Jenkins, T. C.; Jarman, M.;
Judson, I. R. Biochem. Pharm. 1995, 49, 1203–1212; (b) Brzozowski, Z.; Saçzewski,
F.; Gdaniec, M. Eur. J. Med. Chem. 2000, 35, 1053–1064; (c) Brzozowski, Z.;
Saçzewski, F. Eur. J. Med. Chem. 2002, 37, 709–720; (d) Azev, Y.; Slepukhina, I.;
Gabel, D. Appl. Radiat. Isot. 2004, 61, 1107–1110; (e) Saçzewski, F.; Bulakowska, A.
Eur. J. Med. Chem. 2006, 41, 611–615; (f) Januszko, A.; Kaszynski, P.; Drzewinski, W.
J. Mater. Chem. 2006,16, 452–461; (g) Lee, C.-H.; Jin, G. F.; Yoon, J. H.; Jung, Y. J.; Lee,
J.-D.; Cho, S.; Nakamura, H.; Kang, S. O. Tetrahedron Lett. 2008, 49, 159–164; (h)
Bork, J. T.; Lee, J. W.; Khersonsky, S. M.; Moon, H.-S.; Chang, Y.-T. Org. Lett. 2003, 5,
117–120.
21. (a) Hunter, C. A.; Sanders, J. M. K. J. Am. Chem. Soc. 1990, 112, 5525–5534; (b)
Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc., Perkin Trans. 2
2001, 651–659; (c) Yuan, L.; Sumpter, B. G.; Abboud, K. A.; Castellano, R. K. New
J. Chem. 2008, 32, 1924–1934.
22. (a) Nishio, M.; Hirota, M. Tetrahedron 1989, 45, 7201–7245; (b) Steiner, T.;
Starikov, E. B.; Amado, A. M.; Teixeira-Dias, J. J. C. J. Chem. Soc., Perkin Trans. 2
1995, 1321–1326; (c) Steiner, T.; Starikov, E. B.; Tamm, M. J. Chem. Soc., Perkin
Trans. 2 1996, 67–71.