2,4,6-tris(azol-1-yl)-1,3,5-triazines: A new class of multidentate ligands

Article abstract of DOI:10.3987/com-01-9173

The synthesis of thirteen tris(azol-1-yl)-s-triazines (azole = pyrazoles, imidazoles, 1,2,4-triazole and benzimidazoles) is described. Particularly interesting are the compounds derived from C-adamantylazoles (4-adamantylpyrazole, 2-adamantylimidazole and

Full text of DOI:10.3987/com-01-9173

HETEROCYCLES, Vol. 55, No. 5, 2001, pp. 905 - 924, Received, 5thFebruary, 2001
2,4,6-TRIS(AZOL-1-YL)-1,3,5-TRIAZINES: A NEW CLASS OF
MULTIDENTATE LIGANDS
1
1
1
*
Viktor Milata, Rosa María Claramunt, Pilar Cabildo, María Dolores Santa
María,1 Pilar Cornago,1 Lourdes Infantes,2 Felix H. Cano,2 and Jose Elguero3
1Departamento de Química Orgánica y Biología, Facultad de Ciencias, UNED,
Senda del Rey 9, E-28040 Madrid, Spain
2 Departamento de Cristalografía, Instituto de Química-Física Rocasolano,
CSIC, Serrano 119, E-28006 Madrid, Spain
3Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006, Madrid,
Spain
Abstract- The synthesis of thirteen tris(azol-1-yl)-s-triazines (azole = pyrazoles,
imidazoles, 1,2,4-triazole and benzimidazoles) is described. Particularly interesting
are the compounds derived from C-adamantylazoles (4-adamantylpyrazole, 2-
adamantylimidazole and 2-adamantylbenzimidazole) because of their high
lipophilicity. The crystal and molecular structures of 2,4,6-tris(2-phenylimidazol-1-
yl)-1,3,5-triazine (6c) and 2,4,6-tris(2-phenylbenzimidazol-1-yl)-1,3,5-triazine
(8c) have been determined by X-Ray analysis. The molecular structure can be
described as a propeller taking into account the twists existing between the central
ring and the substituents. The crystal structure of both compounds show a distorted
hexagonal packing of chains. All trisazolyltriazines have been fully characterized by
15
13
15
1H-, 13C- and N-NMR spectroscopy. The C and N chemical shifts in CDCl3
and trifluoroacetic acid have been used to discuss the conformation and the site of
protonation.
INTRODUCTION
The 1,3,5-triazine systems tri-substituted by amines at positions 2, 4 and 6 are of considerable interest.
These compounds (1) the simplest representative being melamine (2), are easily obtained from 2,4,6-
trichloro-1,3,5-triazine (3) (trivial name: cyanuric chloride) by nucleophilic substitution.1
1
2
R
R
N
N
N
NH
Cl
2
N
N
N
N
N
N
N
2
1
R
R
N
R
N
N
R
N
N
N
H N
N
NH
Cl
N
Cl
2
2
1
2
1
2
3
4

Melamine has been used extensively by Whitesides to built up supramolecular crystal structures.2,3 Other
related derivatives have shown interesting properties in crystal structure engineering,4 and in dendrimers.5
There are some studies dealing with their affinity for flavin (electronic communication),6 as well as with
their important biological properties.7 Fujita has published a series of remarkable papers describing the
supramolecular organometallic structures derived from tris(4-pyridyl)-1,3,5-triazines.8
A particular sub-field is constituted by trisazolyl-s-triazines (4) where the substituents are 1-azolyl groups.
The bibliography on these compounds is scarce. We have described some 2,4,6-tris(pyrazol-1-yl)-1,3,5-
triazines (5a)9-11 and (5b)12 including their chemical properties and structural characterisation. Other authors
have described the use of 5c to prepare Re fluxional complexes13 as well as 1:1, 1:2 and 1:3 Eu(III)
complexes and to demonstrate that their luminescence is sensitive to the π-π stacking and H-bonding
interactions.14
3
4
R
R
N
5
R
N
N
N
5
5
N
N
R
R
N
4
4
R
R
N
N
3
3
R
R
5a R3 = R4 = R5 = H
5b R3 = R5 = H, R4 = CH3
5c R3 = R5 = CH3, R4 = H
Other azoles have been even less studied. Triazines bearing 1-benzimidazolyl substituents are described in
patents (fungicides and antitumor compounds).15,16 Those substituted with two 1-imidazolyl residues have
aromatase inhibitory activity (the same paper has reported mono-substituted 1-pyrazolyl and 1-v-triazolyl
derivatives).17
Chemistry
Starting from cyanuric chloride and NH-azoles, named 5aH-8eH, we have prepared the thirteen trisazolyl-
s-triazines corresponding to the radicals of Scheme 1 plus two known derivatives (5a) and (5c) (literature

yields about 70% for 5a and about 30% for 5c).9-13 The starting azoles are commercial compounds save the
three adamantyl derivatives (5dH, 6dH and 8dH). The yields are between moderate and good: 5a: 75, 5c:
29, 5d: 48, 6a: 55, 6b: 34, 6c: 62, 6d: 25, 7: 64, 8a: 82, 8b: 58, 8c: 57, 8d: 46, and 8e: 53 %.
Ad
N
N
N
N
N
N
N
N
N
C H
Ad
CH
6
5
3
N
N
N
N
N
N
8a
6d
7
5d
6a
6b
6c
α
CH
N
N
N
N
N
3
N
N
β
γ
CH
Ad
C H
CH
3
3
6
5
N
CH
3
δ
8d
8b
8c
8e
Ad
Scheme 1. The azol-1-yl substituents on 1,3,5-triazine ring. For the corresponding azoles, an H is added
For the preparation of the starting C-adamantylazoles (5dH, 6dH and 8dH) we have modified the methods
described in the literature. 4-Adamantylpyrazole (5dH) has been synthesized according to a known
procedure consisting in the adamantylation of pyrazole,18 but the isolation procedure has been modified
because the use of the method described for its isolation leads to considerable decomposition. Of the three
products present in reaction mixture, only the desired compound has an acidic proton. Therefore the
transformation into the corresponding sodium salt can be exploited for its separation after extraction of the
N-adamantylated species (1-adamantyl and 1,4-diadamantylpyrazole) with hexane. Chromatography of 2-
adamantylimidazole (6dH)19 appears to be the best method for its purification. 2-Adamantylbenzimidazole
(8dH) has been synthesized by ring closure of the appropriate benzenediamine in benzene with p-
toluenesulfonic acid as catalyst20 with better results than those obtained previously with polyphosphoric acid
ethyl ester (PPE).21 When anhydrous p-toluenesulfonic acid or an equimolar mixture of p-toluenesulfonic
acid and tosyl chloride is used, the N-tosyl derivative was formed. This compound can be hydrolysed in
alkaline media to desired product, which has been prepared as described in the experimental part.
The preparation of triazines requires activation of the appropriate N-H azole, because the leaving group
ability of the chlorine atoms in cyanuric chloride (3) is not sufficient, compared with similar compounds
like hexachloro-cyclotriphosphazene.22 The corresponding azoles were therefore converted into their
sodium salts using sodium hydride in tetrahydrofuran as solvent. In the case of 2-(1-adamantyl)imidazole
(6dH), the salt must be prepared at 0 °C because it decomposes, in other cases a reflux about 1 h is
recommended. By addition of 3 to an excess of azole, in a 1:3 molar ratio, only the tris-substituted products
are formed (the addition of 3 must be slow and afterwards the temperature could be elevated to reflux). In

all cases, only tri-substituted derivatives have been isolated, in agreement with other authors.23 It seems that
the successive azole groups activate the remaining chlorine atoms.
Most compounds here reported being "symmetric", only one isomer is possible. Only in the case of 1,2,4-
triazole (7H), there is the possibility of mixture of isomers 1H- and 4H-substituted. It is well know that
arylation of 1,2,4-triazole (7H) yields, in general, 1-aryl derivatives.24 Then, as expected, in the case of 7,
NMR spectra demonstrated that only substitution through the nitrogen atom in position 1 has occurred. In
the case of benzotriazole, a complex mixture of 1- and 2-benzotriazolyltriazines was obtained and the study
was not proceeded further.
Note that when the colour of the reaction mixture started to darken, the reaction must be stopped as soon as
possible. All the products bound very strongly to solvents and removing them requires heating to about
95 °C for 2 days (the samples after drying became colourless). Many of them, when heated, partially
sublime about 30 °C before the melting point. Recrystallisation from DMSO causes decomposition of the
products.
X-RAY STRUCTURE DETERMINATION
The molecular structure and the atom labelling scheme of 6c and 8c are depicted in Figure 1. The bond
distances and angles of the triazine rings, Table 1, are not significantly different from those of the 1,3,5-
triazine itself (CSD refcode: TRIAZIN).25 When the bond distances in the imidazole rings are compared
with the mean values retrieved from the Cambridge Structural Database, CSD,26 the single and double
bonds appear to be elongated and shortened respectively, which suggests a of the π-electronic system in the
ring. This is a consequence of the powerful electron-withdrawing effect of the 1,3,5-triazine ring,
comparable to a 2,4,6-trinitrophenyl group. The fusion bond (Ci2-Ci3) in the benzimidazoles of 8c is
obviously longer than the corresponding double bond in the imidazoles of 6c. The C-N distances between
the triazine and the azolyl substituents are elongated with respect to the tabulated value of 1.371(16) Å for
Car-N(sp2 planar) bond.26
N
N
N
N
N
N
N
N
N
The conformation of the molecules shows the imidazole and benzimidazole rings rotated out of the triazine
plane, -5.7(7)°in 6c and -15.0(7)° in the more crowded 8c (Table 1), which corresponds to a propeller-like

structure. Until now, none of the 2,4,6-tris(aromatic ring)-1,3,5-triazines retrieved from the CSD25
displayed the three substituents twisted in the same sense; the angles between triazine and aromatic ring are
less than 15°, except in NUNGUY where θ = 16-33°. The dihedral angles about the
imidazole(benzimidazole)/2-phenyl inter-ring bonds are different for each substituent showing that the
propeller lacks a C3v structure and, on average, 72° and 45° for 6c and 8c respectively (Table 1). The
hydrogen atoms Hi3 in 6c and Hi4 in 8c (i = 1, 2, 3), seem to promote the "tightening" of the molecules,
forming bifurcated hydrogen bond interactions Ci3/4-Hi3/4···Ni/π cloud(phenyl ring), Table 2.
In 6c the molecules related by a twofold screw axis at (3/4, 0, 1/4) and equivalent ones, are assembled into
chains, mainly by C-H···π cloud interactions, Table 2. These chains are then linked through π···π stackings,
forming the (1, 0, -1) sheets of the tertiary structure. Finally, the crystal is built up by the union of these
sheets through contacts involving the chlorine atoms of the solvent. In 8c there are dimers of
centrosymmetric molecules joined through several CH···π/N contacts. The tertiary structure is formed by
layers (001), within which it can be distinguished chains along the b axis, by CH···π interactions, or along
the a axis, by CH···N contacts; the 3D structure is formed through interactions involving the isopropanol
molecules. All together, the packing of both compounds can be described topologically as a distorted
hexagonal packing of chains,27 Figure 2. The chains in 6c and 8c present internal p1121 and p-1
crystallographic rod groups, respectively.28 Compound (6c) has two enantiomeric types of chains, C0 and
C-1, packing one around each other with necklace topology, C0(21):2[C0, C-1, C-1], C0 and one C-1 slid so
as to produce the glide plane n. Compound (8c) has all the chains equal and without sliding each other,
giving a packing C0(-1):6[C0]. There are no voids in the structures and the total packing coefficients are
0.66 and 0.65 for 6c and 8c.29
NMR SPECTROSCOPIC RESULTS
1
The assignment of the H and 13C chemical shifts of the tris(azolyl)triazines has been made by analogy with
13
other azole derivatives reported in the literature.30,31 For the tris(1-benzimidazolyl)triazines, the C NMR
values have been assigned by analogy with other benzimidazoles.30-32
From these data and through (1H-13C) HMQC and (1H-13C) HMBC correlations, the 1H chemical shifts of
compounds (8a, 8b, 8c and 8e) have been assigned simultaneously confirming the 13C chemical shifts. In
3
the case of compound (8d) the assignment of H4 and H7 is based on the value of J(1H-1H). For this
compound as well as for (8c) H7 present a coupling of 8.2 Hz while for H4 this coupling is only 7.9 Hz.
The 13C chemical shifts of the azole residues are affected only to a small extent by the nature of the
substituent, only in compound (8b) the general rule δC6 ≥ δC5 is reversed.
1
Table 3. H NMR chemical shifts (δ in ppm) and coupling constants (J in Hz) of tris(1-azolyl)triazines in
CDCl3
Compd
2(3)a
7.95
4
5
Coupling constants and other signals
3J(H4,H5)= 2.8, J(H4,H3)= 1.5, J(H3,H5)= 0.7
3
4
5a
6.59
8.79

5c
5d
6a
6b
2.32
7.87
8.69
2.94
6.09
----
2.80
8.44
7.92
7.86
4J(H4,Me5)= 0.8
Ad: 1.78(Hδ), 1.93(Hβ), 2.08(Hγ)
4
3
7.27
7.05
4J(H2,H4)= 0.8, J(H2,H5)= 1.3, J(H4,H5) ≅ 1.7
3J(H4,H5)= 1.8
6c
6d
7b
----
6.50
7.05
----
6.95
7.65
10.36
3J(H4,H5) ≅ 1.8
3J(H4,H5) ≅ 1.7
Ph: 7.51(5H)
----
Ad: 1.71(Hδ), 2.02(Hβ), 2.23(Hγ)
8.81
a Position 3 in pyrazoles (5) and in 1,2,4-triazole (7) and position 2 in imidazoles (6); b In TFA.
Table 4. 1H NMR chemical shifts (δ in ppm) and coupling constants (J in Hz) of tris(1-benzimidazolyl)-
triazines in CDCl3
Compd
8a
2
4
5
6
7
9.22
3.07
7.61
7.96
7.52
7.59
8.56
3J(H4,H5) = 7.6
4J(H5,H7) = 1.2 4J(H4,H6) = 1.2
3J(H6,H7) = 8.1
8b
7.78
7.39
7.33
8.29
3J(H4,H5) = 8.0
4J(H5,H7) = 1.2 4J(H4,H6) = 1.2
3J(H6,H7) = 8.1
8c
7.79
7.34 7.10
7.19
(H2,H6)
3J(H4,H5) = 7.9
4J(H5,H7) = 1.0 4J(H4,H6) = 1.0
3J(H6,H7) = 8.2
7.40
(H3-H5 and H4)
8d
8e
1.84(Hδ), 2.7 7.83
7.36
7.26
7.73
(Hβ and Hγ)
3J(H4,H5) = 7.9
4J(H5,H7) = 1.0 4J(H4,H6) = 1.0
3J(H6,H7) = 8.2
3.03
7.52
2.40 2.33
8.17
13
Table 5. C NMR chemical shifts (δ in ppm) and coupling constants (J in Hz) of tris(1-azolyl)triazines in
CDCl3
Compd C-Triazine
C-2 (Me-2) C-3 (Me-3) C-4
C-5 (Me-5) Others
5a
163.7
----
146.1
110.4
130.7
----
1J=188.7
1J=179.7
1J=195.9

3J=9.0
2J=6.1
2JH3=9.2
2JH5=9.2
2J=9.3
3J=3.9
5c
5d
164.3
163.4
----
----
153.3
111.9
144.4
2J=2J=5.9
14.0
1J=174.2
2J=2J=7.4
15.5
1J=127.9
1J=130.3
144.2
137.8
125.6
31.6 (Cα)
1J=185.0
3J=8.6
1J=192.9
3J=2.7
43.4 (Cβ) 1J=126.0
28.4 (Cγ) 1J=133.2
36.6 (Cδ) 1J=126.6
6a
162.7
136.7
----
132.4
116.5
----
1J=218.6
3J=9.9
3J=5.8
1J=193.1
1J=198.2
2J=3J=11.0 2J=17.2
6b
6c
163.4
162.7
147.5
----
----
129.2
118.2
----
19.0
1J=191.7
2J=19.2
1J=196.5
2J=16.5
1J=130.8
148.9
129.6
119.0
132.9 (1')
129.4 (2') J=162.5
128.3 (3') J=162.0
129.1 (4') J=161.0
1J=192.0
2J=9.3
1J=199.1
2J=16.7
1
1
1
6d
165.8
162.5
157.1
----
128.1
121.1
37.9 (Cα)
1J=191.6
2J=9.2
1J=194.0
2J=16.6
40.4 (Cβ) 1J=128.9
28.4 (Cγ) 1J=131.8
36.4 (Cδ) 1J=125.5
7a
----
150.6
----
145.9
----
1J=222.4
3J=10.6
1J=228.9
3J=5.5
a In TFA.
13
Table 6. C NMR chemical shifts (δ in ppm) and coupling constants (J in Hz)of tris(1-benzimidazolyl)-
triazines in CDCl3
Compd
C-Triazine C-2
Me, Ph, Ad
----
C-3a
C-4
C-5
8a
163.2
141.6
1J=218.4
143.1a
120.9
126.4
1J=164.3
3J=8.8
1J=162.3
3J=8.0

8 b ‰
164.2
152.2
19.0
143.0
119.8
125.1
2J=7.6
1J=130.8
3J=5.7
1J=162.8
1J=160.8
3J=9.0
3J=7.8
3J=7.8
125.0
8c
164.4
153.5
161.9
131.6, 3J=6.9 (C1')
128.5, J=159.8 J=6.9 (C3') J=6.0
143.0
120.2
1
3
3
1J=163.3
1J=159.5
1
129.2, J=162.0 (C2')
3J=9.4
3J=8.3
3J=7.8
124.5
1
3
130.2, J=161.5 J=7.5 (C4')
8d
167.0
164.0
38.7 (Cα)
40.9 (Cβ) 1J=131.4
142.1
3J=5.8
120.0
1J=162.4
1J=161.1
28.4 (Cγ) 1J=132.3
36.4 (Cδ) 1J=130.5
3J=9.7
3J=8.5
3J=7.8
8e
151.5
19.1
141.4
119.9
133.5
2J=7.6
1J=130.7
3J=6.1
1J=159.7
3J=4.7
3J=6.1
Compd
Me-5
----
C-6
Me-6
----
C-7
C-7a
8a
127.0
115.7
130.7a
1J=162.2
3J=7.9
1J=169.4
3J=8.4
8b
----
124.7
----
115.1
133.2
1J=161.2
3J=7.9
1J=167.4
3J=7.9
3J=6.9
3J=11.2
8c
8d
8e
----
----
125.2
----
----
114.3
133.8
3J=9.2
3J=9.2
1J=161.1
3J=7.6
1J=169.3
3J=8.3
124.5
112.6
134.7
3J=8.8
3J=8.8
1J=161.0
3J=7.8
1J=165.7
3J=8.5
20.1
133.8
20.4
115.8
131.5
1J=126.4
3J=4.8
3J=6.1
1J=126.6
3J=5.5
1J=164.5
3J=5.9
3J=6.9
13
1
a This compound is very insoluble and the signals of C-3a and C-7a in the C NMR H-coupled spectrum
are too small to measure the coupling constants.
The 15N NMR triazine signals for all compounds are highly shielded compared with those of triazine itself (-
98.5 ppm)33 or even with regard with 2,4,6-trichloro-1,3,5-triazine (-109.0 ppm, this work).

15
Table 7. N NMR chemical shifts (δ in ppm) referenced to external nitromethane
Compd
Solvent
N-Triazine
N-1
N-2
N-3(4)
5a
CDCl3
-173.5
-173.9
-176.4
-167.1a
-176.1
-172.1
-158.2
-167.8
-163.3
-141.2
-160.3
-157.0
-158.3
-150.5
-160.1
-160.2
-169.9
-162.4
-166.5a
-163.0
-192.6
-191.7a
-195.9
-197.2
-197.6
-154.1a
-207.8a
-209.2
-214.4
-209.8
-78.5
-173.9
-80.3
-81.6
-80.6
----
----
CF3CO2H
CDCl3
----
5b
5c
5d
6a
----
CDCl3
----
CDCl3
----
CDCl3
-109.6
-199.3a
-111.1
-104.7
-113.2
-157.0a
-211.7a
-123.7
-116.9
-124.8
CF3CO2H
CDCl3
----
6b
6c
6d
7
----
CDCl3
----
CDCl3
----
CF3CO2H
CF3CO2H
CDCl3
-100.8
----
8a
8b
8c
8e
----
CDCl3
----
CDCl3
----
a The assignment of these pairs of signals is only tentative.
From these 15N chemical shifts it is possible to estimate the torsion angles θ between the azolyl residues and
the triazine central ring. Using the torsion angles of the crystallographic study (6c 5.7° and 8c 15.0°) and
assuming that pyrazoles unsubstituted at position 5 5a, 5b and 5d should be planar and that there is a linear
relationship between δ15N in CDCl3 and θ it is possible to do it. The torsion angles should be: 5a 0° (H-5),
5b 0° (H-5), 5c 4.5° (Me-5), 5d 0° (H-5), 6a 1.4° (H-2 and H-5), 6b 3.9° (Me-2), 6c 5.7° (Ph-2), 6d
19.4°(Ad-2), 8a 8.7°(H-2, assuming a δ15N in CDCl3 of -159 ppm), 8b 9.5°(Me-2), 8c 15.0°(Ph-2) and
8d 23° (Ad-2, see below). These angles correspond to an equation:
δ15N = -(174.6±0.6) + (1.74±0.06) θ, n = 12, R2 = 0.987
The angles reflect the increase of steric effects in position 2 of imidazoles and benzimidazoles and position 5
of pyrazoles. In 13C NMR spectrum, we have to use the signals of the azolyl substituents. For instance, the
difference between the chemical shifts of carbons C-4 and C-5 in imidazoles decrease monotonously with
the increase of θ: 6a 15.9 ppm, 1.4°; 6b 11.0 ppm, 3.9°; 6c 10.6 ppm, 5.7°and 6d 7.0 ppm, 19.4°. The
contrary happens with the difference between the chemical shifts of carbons C-4 and C-7 in benzimidazoles:
8a 5.2 ppm, 8.7° (but the spectrum was recorded in TFA); 8b 4.7 ppm, 9.5°, 8c 5.9 ppm, 15.0° and 8d
7.4 ppm, 23°.

δ13C(imidazoles) = (14.1±1.6) - (0.40±0.16) θ, n = 4, R2 = 0.76 (compound 6a clearly deviates)
δ13C(benzimidazoles) = (3.1±0.3) + (0.19±0.02) θ, n =4, R2 = 0.97
The 15N chemical shifts in TFA of compounds (5a, 6a, 7 and 8a) (the last two rather insoluble in CDCl3)
prove that all these compounds are protonated in these conditions. Most of them are protonated exclusively
on the azole. The pyrazole derivative (5a) shows an almost negligible effect on the triazine signal and the
characteristic effects on N-1 and N-2.34 Although not identical to those measured in N-methylpyrazole, they
are quite close indicating that the three pyrazoles are protonated to some extent (a monoprotonation would
have produced a third of the effects). A salt of pyrazole (5a) has been studied by X-Ray crystallography
and the proton is on the pyrazole ring.35
The imidazole derivative (6a) shows both the characteristics effects on imidazole nitrogen atoms,34 but also
a significant effect (+13.9 ppm) on the triazine nitrogen. Protonation of pyridine produces a shift of + 89
ppm34 (other authors describe larger effects, up to 115 ppm)36 but the protonation of 1,3,5-triazine in TFA
should lead to a monocation which an average shift of about 30 ppm, thus, +14 ppm indicate a partial
protonation.37
In the case of the 1,2,4-triazolyl derivative (7) there is no information about the triazine because the
compound cannot be recorded in CDCl3. On the other hand, something curious happens to the azole
nitrogen chemical shifts. 1-Methyl-1,2,4-triazole protonates exclusively at N-4 with chemical shifts of -
164.3 ppm (N-1), - 81.2 ppm (N-2) and -208.5 ppm (N-4).34 In the case of 7, the observed chemical shifts
(Table 7) are only consistent with a mixture of cations (7aH+) and (7bH+). The stability of 7bH+ is
probably due to an intramolecular hydrogen bond with the triazine nitrogen:
H
H
N
N
N
N
N
N
N
N
N
N
N
N
H
CH
3
N
N
N
Id
Id
Id
Id
7aH+
7bH+
This work provides, for the first time, a comprehensive description of trisazolyl-s-triazines a promising
class of multidentate ligands with possible use for extracting heavy metals. The structure in the solid state
and in solution, the protonation site and the conformation of these compounds have been explored. The
sensitivity of some derivatives to hydrolysis is a possible limiting factor in the use of trisazolyl-s-triazines as
ligands and as drugs.

EXPERIMENTAL
The melting points were determined with a hot-stage microscope and are uncorrected. Column
chromatography was performed on silica gel Merck 60 (70-230 mesh), TLC on glass sheets of silica gel
SDS 60 F254 (layer thickness 2 mm), both using a mixture chloroform - methanol (10 : 1) as eluent. The Rf
values were measured and reaction were monitored on TLC aluminum sheets of silica gel Merck 60 F254
(layer thickness 0.2 mm) with the same eluent. MS spectra (electron impact 60-70 eV) were obtained with
1
Shimadzu QP-5000 and VG Autospec spectrometers. H NMR (at 400 MHz), 13C NMR (at 100 MHz) and
15N NMR (at 40.56 MHz) spectra were obtained using a Bruker DRX 400 instrument. Coupling constants
2
3
4
(J in Hz) are given with an accuracy of JCH ± 0.5 Hz, JCH, JCH ± 0.2 Hz). Chemical shifts (δ) in ppm
were measured using the signal of the solvent as an internal standard, in the case of TFA-d1, external
1
DMSO-d6 has been used. 15N NMR chemical shifts were obtained by the Inverse Gated H-Decoupling
Technique and are referenced to an external sample of nitromethane.
Starting materials.
Imidazole, 2-methylimidazole, pyrazole, 2-methylbenzimidazole (Fluka), 2-phenylimidazole (Acros), 3,5-
dimethylpyrazole (Janssen Chimica), 1,2,4-triazole, benzimidazole (EGA Chemie), 2,5,6-trimethyl-
benzimidazole (Aldrich), and 2-phenylbenzimidazole (Lancaster) are commercial products. 4-Adamantyl-
pyrazole (5dH) and 2-adamantylimidazole (6dH) have been prepared respectively according to Cabildo et
al.18 and to Pellicciari et al. 19 The method of isolation has been modified in the following way. The
combined dichloromethane extracts were dried over magnesium sulfate and evaporated to dryness and
combined with the dry precipitate from the reaction to obtain 1.9-2.4 g of a mixture. Of this raw reaction
mixture, 2.4 g were dissolved in 40 mL of dry THF and 0.315 g (12.5 mmol) of 95 % NaH was added.
When the effervescence ended, the mixture was stirred at room temperature for 30 min. After evaporation of
the solvent, the solid residue is extracted with 3 x 50 mL of hot hexane (after evaporation, 0.72 g of a
mixture of 1-adamantylpyrazole and 1,4-diadamantylpyrazole was obtained). To the dry solid residue is
added carefully 50 mL of water (to destroy the excess of NaH) and neutralised with 32% HCl, extracted
with CH2Cl2, washed with water, dried over magnesium sulfate and evaporated to dryness to give about
1.1 g of pure product (the method for isolation can be scaled up).
2-Adamantylbenzimidazole (8dH):20,21 To 1 g (0.0036 mmol) of N-(1-adamantylcarbonyl)benzene-1,2-
diamine in benzene (20 mL) was added 0.66 g (0.0035 mmol) of p-toluenesulfonic acid [monohydrate or a
mixture 0.33 g (0.0017 mmol) of monohydrate and 0.33 g (0.0017 mmol) of tosyl chloride] and the
mixture is heated to 120 °C for 48 h. When the monohydrate is used, the product crystallised after cooling,
in the case of using its mixture with tosyl chloride, the N-tosyl-2-(1-adamantyl)benzimidazole is formed.
The last compound can be hydrolysed in 10 % sodium hydroxide to afford the desired product.
General procedure for preparation of 5a-8e:
The appropriate N-H azole (30 mmol) is added, under stirring and in small portions, to 0.834 g (33 mmol,
95 %) of sodium hydride in dry THF (60 mL). When the effervescence is damped, the mixture is refluxed
for 1 h. Then is added drop-wise a solution of 1.844 g (10 mmol) of 2,4,6-trichloro-1,3,5-triazine (1)

dissolved in dry THF (20 mL) and reaction is monitored using TLC. After finishing the reaction, the
solvent is evaporated under vacuum to dryness and water is carefully added (50 mL). The product is
separated or appropriately purified. To remove the rests of solvents a vacuum drying (2 days at 95 °C) is
required.
Tris(pyrazolyl-1-yl)-1,3,5-triazine (5a), tris(imidazol-1-yl)-1,3,5-triazine (6a), tris(1,2,4-triazolyl-1-yl)-
1,3,5-triazine (7), tris(benzimidazolyl-1-yl)-1,3,5-triazine (8a) and tris(2-(1-adamantyl)benzimidazolyl-1-
yl)-1,3,5-triazine (8d) were purified according to the following procedure: The separated product is washed
with water to remove the unreacted azole and dried.
Tris(2-methylimidazol-1-yl)-1,3,5-triazine (6b), tris(2-phenylimidazol-1-yl)-1,3,5-triazine (6c), tris(2-
methyl-benzimidazolyl-1-yl)-1,3,5-triazine (8b), tris(2-phenylbenzimidazolyl-1-yl)-1,3,5-triazine (8c) and
tris(2,5,6-trimethylbenzimidazolyl-1-yl)-1,3,5-triazine (8e) were extracted with dichloromethane,
evaporated and chromatographed on column and finally dried under reduced pressure.
Table 8. Physico-chemical properties of compounds (5a – 8e)
No.
Formula
Mp (°C)
Yield (%)
Elemental analysis
(calculated/found)
Rf
CHCl3/CH3OH, 10:1
% C
% H
% N
M+· (rel. intensity)
5a
5c
5d
6a
6b
6c
6d
7
C12H9N9
C18H21N9
240-243
75.0
241-244
29.4
0.30
279 (95)
0.71
363 (65), 95 (100)
C42H51N9.CH2Cl2 187-191
48.2
67.35
67.19
51.61
51.77
56.07
55.88
70.99
71.07
70.26
70.03
38.30
38.01
6.97
7.07
3.25
3.21
4.71
4.89
4.17
4.22
7.72
7.59
2.14
2.30
16.44
16.25
45.14
45.07
39.23
38.93
24.84
25.01
17.56
17.33
59.56
59.43
0.63
681(44), 145(100)
C12H9N9
C15H15N9
C30H21N9
259-261
54.8
267-270
34.3
194-196
62.1
0.16; 0.51 (1:1)
279 (100)
0.72
321 (100)
0.47
507 (100)
0.60
682 (18)
C42H51N9.2H2O 256-258
25.3
C9H6N12
> 375
63.8
0.12; 0.53 (1:1)
282 (100)
8a
8b
8c
8d
8e
C24H15N9
364-366
81.9
67.12
65.74
65.89
66.15
76.70
76.72
77.95
78.02
3.52
3.73
4.96
4.74
4.14
4.19
6.90
6.83
29.35
29.50
24.84
24.60
19.17
19.31
15.15
15.27
0.73
429 (100)
C27H21N9.2 H2O 194-195
58.3
C42H27N9
0.48
471 (100)
0.66
657 (100)
149-151
56.7
301-305
46.2
274-276
53.4
C54H57N9
0.74
831 (100), 832 (64)
C33H33N9.H2O
69.09
69.10
6.15
6.09
21.97
21.79
0.53
555 (100)

Tris(3,5-dimethylpyrazolyl-1-yl)-1,3,5-triazine (5c) was purified by column chromatography.
Tris(4-(1-adamantyl)pyrazolyl-1-yl)-1,3,5-triazine (5d) was isolated according to procedure described for
6b, but to obtain analytical samples requires preparative thin layer chromatography on silica gel.
Tris(2-(1-adamantyl)imidazol-1-yl)-1,3,5-triazine (6d). Addition of the 2-(1-adamantyl)imidazole requires
cooling to 0 °C and stirring 2 hours at 0 °C, isolation of the product was carried out similarly to 5d.
X-Ray Crystallography
A summary of data collection and refinement process is given in Table 9. The crystal of 8c was sealed into
a glass capillary to prevent air decomposition. The structures were solved by direct methods, SIR92,38 and
they were refined with a full matrix least squares procedure on Fobs. In the case of 6c empirical absorption
corrections were applied.39 Except the hydrogen atoms of the isopropyl groups in 8c, all remaining
hydrogen atoms were located on the corresponding difference Fourier syntheses and most of them were
refined isotropically in the last cycles; some hydrogen atoms of the solvent molecules including the
hydrogen of the hydroxyl group in the C molecule of isopropanol were kept fixed. In both structures, no
disorder model for the solvents could be modelled in spite of the values of the thermal displacement
parameters for the chlorine atoms in 6c and for the isopropyl groups in 8c. The atomic scattering factors
were taken from the International Tables for X-Ray Crystallography40 and most of the calculations were
carried out with the XTAL,41 PESOS,42 and PARST43 programs running on an AXP 600 computer.
ACKNOWLEDGEMENTS
One of us (V. M.) greatly acknowledged the Ministry of Education and Culture of Spain for a sabbatical
grant (SAB 1998-0106). Thanks are also given to the Dirección General de Investigación of the Ministry of
Science and Technology (Project no. BQU-2000-0252) and to the Comunidad de Madrid (Project no.
07N/0001/1999) of Spain.
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