Synthesis of novel trichloromethyl substituted azolo[1,3,5]triazines1

Article abstract of DOI:10.3987/COM-12-12542

The triazine ring bearing a trichloromethyl group was annelated to various aminoazoles using a new effective synthetic procedure. The method of preparation involved initial formation of trichloroacetamidines in the reaction of aminoazoles with trichloroacetonitrile followed by the triazine ring closure with triethyl orthoformate affording therefore the titled compounds.

Full text of DOI:10.3987/COM-12-12542

HETEROCYCLES, Vol. 85, No. 10, 2012
2515
HETEROCYCLES, Vol. 85, No. 10, 2012, pp. 2515 - 2522. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 9th July, 2012, Accepted, 8th August, 2012, Published online, 10th August, 2012
DOI: 10.3987/COM-12-12542
SYNTHESIS OF NOVEL TRICHLOROMETHYL SUBSTITUTED
AZOLO[1,3,5]TRIAZINES1
Dmitrii V. Kalinin,a Svetlana A. Kalinina,a and Anton V. Dolzhenko*b
a
Perm State Pharmaceutical Academy, 2 Polevaya Street, Perm 614990, Russian
Federation
b
School of Pharmacy, Curtin Health Innovation Research Institute, Curtin
University, GPO Box U1987 Perth, Western Australia 6845, Australia. E-mails:
A.Dolzhenko@curtin.edu.au; DolzhenkoAV@gmail.com
Abstract – The triazine ring bearing a trichloromethyl group was annelated to
various aminoazoles using a new effective synthetic procedure. The method of
preparation involved initial formation of trichloroacetamidines in the reaction of
aminoazoles with trichloroacetonitrile followed by the triazine ring closure with
triethyl orthoformate affording therefore the titled compounds.
Recently, chemistry and biological activity of azolo-fused 1,3,5-triazines have been extensively explored.2
Particular attention was addressed to the heterocycles possessing ring systems isosteric to the purine
scaffold, e.g. 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines)2b and pyrazolo[1,5-a][1,3,5]triazines
(5-aza-9-deazapurines).2c
Trichloromethyl substituted 1,3,5-triazines have been reported as potent polymerization photoinitiators3
and pesticides.4 1,3,5-Triazines, bearing a trichloromethyl group, also have great potential for synthetic
organic chemistry applications. Trichloromethyl group has been well recognized as versatile tool for
various chemical transformations.5 In heterocyclic compounds, this group usually is highly reactive making
them valuable synthons for diverse range of interesting molecules. Recently, we reported6 a method for
preparation of 5-amino-2-phenyl-7-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazine, which was the key
intermediate in the convenient synthesis of 7-amino-substituted 1,2,4-triazolo[1,5-a][1,3,5]triazines.
The present study aims to develop a practical method for preparation of 5-trichloromethyl-1,2,4-
triazolo[1,5-a][1,3,5]triazines and to assess applicability of this method for the synthesis of other
structurally related azolo-fused 1,3,5-triazines.

2516
HETEROCYCLES, Vol. 85, No. 10, 2012
The starting 5(3)-amino-1,3,5-triazoles (1) required for the preparation of targeted
5-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazines (3) were prepared according to previously reported
methods.7 The trichloromethyl group was introduced into the structure via the reaction of 1 with
trichloroacetonitrile, a versatile building block in heterocyclic chemistry.8 Previously, we successfully
applied this reagent for the construction of 1,3,5-triazines annelated to other heterocyclic rings.6,9 In the
present work, we established that upon heating in toluene, the reaction of 1 with trichloroacetonitrile
proceeded smoothly and regioselectively at the primary amino group of 1, affording therefore
trichloroacetamidines (2) (Scheme 1). The trichloromethyl activation of the cyano group abolished
necessity of any catalysis for this reaction.
HN N
HN N
N NH
N
R
NH
N
R
R
N
NH
CCl3
N
H
HN
2C
CCl3
CCl3
N
HN
H
2D
2B
N NH
N NH
N
N
Cl3CCN
N
N
R
R
N
R
R
N
H
NH2
N
toluene, reflux
N
N
CCl3
CCl3
HC(OEt)3
reflux
N
1A
3
H
2A
N N
N
R
HN N
CCl3
N
NH2
N
1-4: R = Ph (a), 3-MeOC6H4 (b), 4-ClC6H4 (c)
4
1B
Scheme 1
It has been established that for aryl substituted 1, 5-amino-tautomeric form (1A) is highly preferred over the
3-amino-form (1B).7 The G298 values of this equilibrium for 1a-c in DMSO solution were 5.2 kJ/mol,7 4.9
kJ/mol,10 and 7.5 kJ/mol,7 correspondingly. Trichloroacetamidines (2) were involved in both, annular
1
tautomersim (similarly to 1) and tautomeric exchange at the amidino group. H NMR spectroscopy data
(two broad signals at 8.95-8.99 and 9.41-9.45 ppm attributed to the NH2 protons) suggested that forms 2A
and 2D were preferred in the equilibrium when compared with alternative amidine forms 2B and 2C.
Tautomers 2A and 2D were stabilized by the intramolecular N-H…N hydrogen bonding with the N-4
triazole atom resulting in deshielding one of the NH2 protons. It seems that proton tautomeric exchange in
the triazole ring was too fast on the NMR time scale making forms 2A and 2D indistinguishable in the
spectra.

HETEROCYCLES, Vol. 85, No. 10, 2012
2517
Heating trichloroacetamidines (2) in triethyl orthoformate resulted in the 1,3,5-triazine ring closure thus
affording 2-aryl-5-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazines (3). The reaction was found to
proceed regioselectively to the N-1 triazole atom of 2; no formation of isomer 4 was observed. The
structure of 3 was confirmed by NMR spectroscopy. 2D NOESY experiments revealed no cross-peaks
between the methine proton singlet of the triazine ring at 10.34-10.36 ppm and signals of aromatic
substituent at the triazole ring, ruling out therefore alternative structure 4. The diagnostic signal of
trichloromethyl group appeared in 13C NMR spectra at ~ 95 ppm.
To further explore scope of the developed method in the synthesis of other trichloromethyl substituted
azolo-fused 1,3,5-triazines, the same sequence of the reactions with trichloroacetonitrile and triethyl
orthoformate was performed using 5(3)-amino-3(5)-phenylpyrazole (5) and 2-aminobenzimidazole (8)
(Schemes 2 and 3). It appears that product of the reaction between 5 and trichloroacetonitrile had a structure
similar to its triazole based analogues 2, but the absence of the nitrogen atom involved in the intramolecular
1
hydrogen bonding resulted in only one signal for both protons of the amidine group of 6 in H NMR
spectrum.
Treatment
of
6
with
triethyl
orthoformate
conveniently
provided
1
7-phenyl-2-trichloromethylpyrazolo[1,5-a][1,3,5]triazine (7). H NMR spectrum of this compound had a
characteristic unusual long range coupling between protons H-4 and H-8 at the triazine and pyrazole rings
(5J = 0.9 Hz).
NH2
CCl3
N NH
HC(OEt)3
reflux
N
Cl3CCN
N NH
N
N
Ph
Ph
NH2
Ph
N
toluene, reflux
N
CCl3
5
7
6
Scheme 2
The nucleophilic addition of 2-aminobenzimidazole (8) to the cyano group of trichloroacetonitrile
successfully furnished trichloroacetamidine (9) (Scheme 3).
H
N
NH
N
N
CCl3
N
HC(OEt)3
reflux
Cl3CCN
N
NH2
CCl3
toluene, reflux
N
N
H
N
H
N
9A
8
10
H2N
HN
CCl3
CCl3
N
N
N
NH
N
N
H
H
9B
9C
Scheme 3

2518
HETEROCYCLES, Vol. 85, No. 10, 2012
Three tautomeric forms are theoretically possible for 9 due to proton exchange within the amidine group
and between the amidine group and the benzimidazole ring. Interestingly, transfer of one proton of the
amidino group to the ring nitrogen atom generating tautomer 9A was observed in the DMSO solution. 1H
NMR spectrum of 9 had two downfield shifted signals at 10.40 and 12.40 ppm assignable to the
benzimidazole ring NH protons of the tautomeric form 9A. Substantially higher deshielding of one of these
protons can be explained by intramolecular hydrogen bonding and anisotropic effect of the imine-like =NH
moiety located in the plane of the heterocyclic ring. The cyclocondensation of 9 with triethyl orthoformate
led to the formation of 2-trichloromethyl-1,3,5-triazino[1,2-a]benzimidazole (10).
In
summary,
novel
trichloromethyl
substituted
1,2,4-triazolo[1,5-a][1,3,5]triazines
(3),
pyrazolo[1,5-a][1,3,5]triazine (7) and 1,3,5-triazino[1,2-a]benzimidazole (10) were successfully prepared
from corresponding aminoazoles. The developed method seemed to be practical and generally applicable to
variety of substrates. Reactivity of the prepared compounds towards various nucleophiles is currently under
extensive explorations.
EXPERIMENTAL
General Methods. Melting points (uncorrected) were determined on a Gallenkamp melting point
apparatus. 1H and 13C NMR spectra were recorded on a Bruker Avance III spectrometer (400 MHz), using
DMSO-d6 as a solvent and TMS as an internal reference. 5(3)-Amino-3(5)-aryl-1,2,4-triazoles (1) were
prepared according to previously reported method;7 5(3)-amino-3(5)-phenylpyrazole (5) was synthesized
using known method.11 Other reagents were purchased from Alfa Aesar.
N-[3(5)-Aryl-1,2,4-triazol-5(3)-yl]trichloroacetamidines (2)
A mixture of 5(3)-amino-3(5)-aryl-1,2,4-triazole (1, 10 mmol) with trichloroacetonitrile (3 mL, 30 mmol)
in toluene (15 mL) was heated under reflux for 12 h. Preparation of 2c required heating for 60 h with
addition of two more portions of trichloroacetonitrile (3 mL, 30 mmol) after 18 h and 40 h. After cooling,
the precipitate was filtered, washed with hexane and recrystallized from toluene.
N-[3(5)-Phenyl-1,2,4-triazol-5(3)-yl]trichloroacetamidine (2a)
Yield 59%; mp 164-166 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 7.43 (1H, t, J = 7.2 Hz, H-4’), 7.49
(2H, t, J = 7.2 Hz, C-3’ and C-5’), 8.05 (2H, d, J = 6.9 Hz, C-2’ and C-6’), 8.94 (1H, br. s, NH), 9.45 (1H, br.
s, NH), 13.95 (1H, br. s, H-1). Anal. Calcd for C10H8Cl3N5: C, 39.44; H, 2.65; N, 22.99. Found: C, 39.38; H,
2.69; N, 22.78.
N-[3(5)-(3-Methoxyphenyl)-1,2,4-triazol-5(3)-yl]trichloroacetamidine (2b)

HETEROCYCLES, Vol. 85, No. 10, 2012
2519
Yield 52%; mp 136-138 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 3.83 (3H, s, OMe), 7.01 (1H, dd,
J = 8.2, 1.8 Hz, C-4’), 7.40 (1H, t, J = 7.9 Hz, C-5’), 7.57 (1H, dd, J = 2.4, 1.4 Hz, C-2’), 7.63 (1H, dt, J =
7.6, 1.1 Hz, C-6’), 8.94 (1H, br. s, NH), 9.44 (1H, br. s, NH), 13.97 (1H, br. s, H-1). Anal. Calcd for
C11H10Cl3N5O: C, 39.49; H, 3.01; N, 20.93. Found: C, 39.40; H, 3.15; N, 20.82.
N-[3(5)-(4-Chlorophenyl)-1,2,4-triazol-5(3)-yl]trichloroacetamidine (2c)
Yield 59%; mp 193-195 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 7.55 (2H, t, J = 8.6 Hz, C-3’ and
C-5’), 8.06 (2H, d, J = 8.6 Hz, C-2’ and C-6’), 8.99 (1H, br. s, NH), 9.41 (1H, br. s, NH), 14.01 (1H, br. s,
H-1). Anal. Calcd for C10H7Cl4N5: C, 35.43; H, 2.08; N, 20.66. Found: C, 35.28; H, 2.00; N, 20.43.
2-Aryl-5-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazines (3)
Trichloroacetamidine (2, 2 mmol) was heated in triethyl orthoformate (10 mL) under reflux for 8 h. After
cooling, the precipitate was filtered, washed with hexane and recrystallized from toluene.
2-Phenyl-5-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazine (3a)
Yield 72%; mp 231-233 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 7.60-7.66 (3H, m, H-3’, H-4’, and
13
H-5’), 8.25-8.32 (2H, m, H-2’ and H-6’), 10.34 (1H, s, H-7). C NMR (100 MHz, DMSO-d6): δ 95.1
(CCl3), 127.4 (C-3’ and C-5’), 129.0 (C-4’), 129.3 (C-2’ and C-4’), 131.8 (C-1’), 150.7 (C-7), 155.9 (C-3a),
162.8 (C-5), 167.5 (C-2). Anal. Calcd for C11H6Cl3N5: C, 42.00; H, 1.92; N, 22.26. Found: C, 41.86; H,
2.00; N, 22.14.
2-(3-Methoxyphenyl)-5-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazine (3b)
Yield 76%; mp 219-221 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 3.88 (3H, s, OMe) 7.20 (1H, ddd,
J = 8.3, 2.7, 0.9 Hz, C-4’), 7.54 (1H, dd, J = 8.3, 7.7 Hz, C-5’), 7.78 (1H, dd, J = 2.6, 1.5 Hz, C-2’), 7.63 (1H,
ddd, J = 7.6, 1.6, 0.8 Hz, C-6’), 10.34 (1H, s, H-7). 13C NMR (100 MHz, DMSO-d6): δ 55.2 (OMe), 95.0
(CCl3), 112.0 (C-4’), 117.6 (C-2’), 119.6 (C-6’), 130.2 (C-1’), 130.4 (C-5’), 150.6 (C-7), 155.7 (C-3a),
159.6 (C-3’), 162.7 (C-5), 167.2 (C-2). Anal. Calcd for C12H8Cl3N5O: C, 41.83; H, 2.34; N, 20.32. Found:
C, 41.77; H, 2.44; N, 20.18.
2-(4-Chlorophenyl)-5-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazine (3c)
Yield 56%; mp 205-207 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 7.70 (2H, d, J = 8.7 Hz, C-3’ and
C-5’), 8.29 (2H, d, J = 8.7 Hz, C-2’ and C-6’), 10.36 (1H, s, H-7). 13C NMR (100 MHz, DMSO-d6): δ 95.0
(CCl3), 127.4 (C-1’), 129.1 (C-3’ and C-5’), 129.5 (C-2’ and C-6’), 136.6 (C-4’), 150.8 (C-7), 156.0 (C-3a),

2520
HETEROCYCLES, Vol. 85, No. 10, 2012
163.0 (C-5), 166.5 (C-2). Anal. Calcd for C11H5Cl4N5: C, 37.86; H, 1.44; N, 20.07. Found: C, 37.73; H,
1.51; N, 19.90.
N-[3(5)-Phenylpyrazol-5(3)-yl]trichloroacetamidine (6)
A mixture of 5(3)-amino-3(5)-phenylpyrazole (5, 10 mmol) with trichloroacetonitrile (3.0 mL, 30 mmol) in
toluene (10 mL) was heated under reflux for 2 h. After cooling, the precipitate was filtered, washed with
hexane and recrystallized from toluene to give 1.52 g of orange crystalline powder.
Yield 50%; mp 186-188 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 6.64 (1H, s, H-4), 7.36 (1H, t, J =
7.4 Hz, H-4’), 7.46 (2H, t, J = 7.6 Hz, C-3’ and C-5’), 7.78 (2H, d, J = 7.7 Hz, C-2’ and C-6’), 8.27 (2H, br.
s, NH2), 13.14 (1H, br. s, H-1). Anal. Calcd for C11H9Cl3N4: C, 43.52; H, 2.99; N, 18.46. Found: C, 43.58;
H, 3.08; N, 18.24.
7-Phenyl-2-trichloromethylpyrazolo[1,5-a][1,3,5]triazine (7)
Trichloroacetamidine (6, 0.61 g, 2 mmol) was heated in triethyl orthoformate (8 mL) under reflux for 6 h.
After cooling, the precipitate was filtered, washed with hexane and recrystallized from toluene to give 0.35
g of yellow powder.
Yield 56%; mp 234-236 C (toluene). 1H NMR (400 MHz, DMSO-d6): δ 7.51-7.60 (2H, m, H-3’, H-4’, and
H-5’), 7.64 (1H, d, J = 0.9 Hz, H-8), 8.13 (2H, dd, J = 8.1, 1.5 Hz, H-2’ and H-6’), 10.06 (1H, d, J = 0.9 Hz,
H-4). 13C NMR (100 MHz, DMSO-d6): δ 95.4 (CCl3), 95.7 (C-8), 126.7 (C-3’ and C-5’), 129.0 (C-2’ and
C-6’), 130.3 (C-4’), 130.9 (C-1’), 147.9 (C-7), 149.5 (C-4), 157.3 (C-8a), 159.5 (C-2). Anal. Calcd for
C12H7Cl3N4: C, 45.96; H, 2.25; N, 17.87. Found: C, 45.77; H, 2.36; N, 17.68.
N-(Benzimidazol-2-yl)trichloroacetamidine (9)
A mixture of 2-aminobenzimidazole (8, 1.34 g, 10 mmol) with trichloroacetonitrile (2.5 mL, 25 mmol) in
toluene (15 mL) was heated under reflux for 3 h. After cooling, the precipitate was filtered, washed with
hexane and recrystallized from toluene to give 1.58 g of pale cream crystalline powder.
Yield 57%; mp 196-198 C decomp. (toluene). 1H NMR (400 MHz, DMSO-d6): δ 7.10-7.20 (2H, m, H-5
and H-6), 7.34-7.56 (2H, m, H-4 and H-7), 9.02 (1H, s, NH), 10.40 (1H, br. s, NH), 12.40 (1H, br. s, NH).
Anal. Calcd for C9H7Cl3N4: C, 38.95; H, 2.54; N, 20.19. Found: C, 39.01; H, 2.65; N, 20.03.
2-Trichloromethyl-1,3,5-triazino[1,2-a]benzimidazole (10).
N-(Benzimidazol-2-yl)trichloroacetamidine (9, 0.56 g, 2 mmol) was heated in triethyl orthoformate (8 mL)
under reflux for 5 h. After cooling, the precipitate was filtered, washed with hexane and

HETEROCYCLES, Vol. 85, No. 10, 2012
2521
recrystallized from toluene to give 0.43 g of yellow crystalline powder.
Yield 75%; mp 284-286 C decomp. (toluene). 1H NMR (400 MHz, DMSO-d6): δ 7.61 (1H, ddd, J = 8.2,
7.2, 1.0 Hz, H-7), 7.69 (1H, ddd, J = 8.2, 7.2, 1.1 Hz, H-8), 7.98 (1H, ddd, J = 8.2, 1.4, 0.8 Hz, H-9), 8.44
(1H, ddd, J = 8.2, 1.2, 0.8 Hz, H-6), 10.40 (1H, s, H-4). 13C NMR (100 MHz, DMSO-d6): δ 95.6 (CCl3),
113.7 (C-6), 119.9 (C-9), 123.9 (C-7), 125.6 (C-5a), 127.9 (C-8), 144.3 (C-9a), 147.6 (C-10a), 151.5 (C-4),
162.1 (C-2). Anal. Calcd for C10H5Cl3N4: C, 41.77; H, 1.75; N, 19.49. Found: C, 41.82; H, 1.88; N, 19.43.
ACKNOWLEDGEMENTS
We acknowledge financial support of Russian Ministry of Education and Science.
REFERENCES AND NOTES
1. Part 21 in the series “Fused heterocyclic systems with s-triazine ring”, for part 20 see: A. V.
Dolzhenko, G. K. Tan, L. L. Koh, A. V. Dolzhenko, and W. K. Chui, Crystals, 2011, 1, 136.
2. For recent reviews see: (a) A. V. Dolzhenko, Heterocycles, 2011, 83, 695; (b) A. V. Dolzhenko, A. V.
Dolzhenko, and W. K. Chui, Heterocycles, 2006, 68, 1723; (c) A. V. Dolzhenko, A. V. Dolzhenko,
and W. K. Chui, Heterocycles, 2008, 75, 1575.
3. K. Kawamura and K. Kato, Polym. Adv. Technol., 2004, 15, 324.
4. S. Ohki, Y. Kasahara, Y. Sato, K. Wakabayashi, Y. Miyamoto, and J. W. Vonk, Pest. Sci., 1999, 55,
674.
5. For recent review see: F. G. Menezes, H. Gallardo, and C. Zucco, Quim. Nova, 2010, 33, 2233.
6. A. V. Dolzhenko, G. Pastorin, A. V. Dolzhenko, and W. K. Chui, Tetrahedron Lett., 2008, 49, 7180.
7. (a) A. V. Dolzhenko, G. Pastorin, A. V. Dolzhenko, and W. K. Chui, Tetrahedron Lett., 2009, 50,
2124; (b) A. V. Dolzhenko, A. V. Dolzhenko, and W. K. Chui, Heterocycles, 2007, 71, 429.
8. For reviews see: (a) G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., 1993, 1443; (b) S. M. Sherif and
A. W. Erian, Heterocycles, 1996, 43, 1083.
9. A. V. Dolzhenko, M. C. Foo, B. J. Tan, A. V. Dolzhenko, G. N. C. Chiu, and W. K. Chui, Heterocycles,
2009, 78, 1761.
10. 5(3)-Amino-3(5)-(3-methoxyphenyl)-1,2,4-triazole (1b); mp 174-176 C (water); 1H NMR (400 MHz,
DMSO-d6): δ 3.79 (3H, s, OMe), 5.38* and 6.14 (2H, two s, NH2), 6.91 (1H, dd, J = 8.1, 2.3 Hz, C-4’),
7.32 (1H, t, J = 7.9 Hz, C-5’), 7.46 (1H, dd, J = 2.3, 1.2 Hz, C-2’), 7.51 (1H, d, J = 7.6 Hz, C-6’), 12.11
13
and 13.26* (two s, 1H, NH); C NMR (100 MHz, DMSO-d6): δ 54.9 (OMe), 55.1* (OMe), 110.3
(C-4’), 110.6* (C-4’), 113.9 (C-2’), 115.3* (C-2’), 117.6 (C-6’), 129.4 (C-5’), 130.0* (C-5’), 133.7
(C-1’), 152.1* (C-3/5), 157.2 (C-3/5), 158.2 (C-3/5), 159.2 (C-3’), 159.4* (C-3’), 164.3* (C-3/5).

2522
HETEROCYCLES, Vol. 85, No. 10, 2012
* - signals of minor tautomeric form 1B; KT = 0.14. Anal. Calcd for C9H10N4O: C, 56.83; H, 5.30; N,
29.46. Found: C, 56.83; H, 5.30; N, 29.46.
11. M. C. Bagley, T. Davis, M. C. Dix, C. S. Widdowson, and D. Kipling, Org. Biomol. Chem., 2006, 4,
4158.