Synthesis and rearrangement of 3-amino-2-benzyl[1,2,4]triazolo[4,3-a] pyrimidinium salts

Full text of DOI:10.1007/s10593-012-1153-5

Chemistry of Heterocyclic Compounds, Vol. 48, No. 9, December, 2012 (Russian Original Vol. 48, No. 9, September, 2012)
SYNTHESIS AND REARRANGEMENT OF 3-AMINO-
2-BENZYL[1,2,4]TRIAZOLO[4,3-a]PYRIMIDINIUM SALTS
A. V. Astakhov1 and V. M. Chernyshev1*
Keywords: [1,2,4]triazolo[4,3-a]pyrimidines, [1,2,4]triazolo[1,5-a]pyrimidines, debenzylation, Dimroth
rearrangement.
It has previously been shown that the reaction of 1-phenyl[1,2,4]triazole-3,5-diamine perchlorate with
1,3-diketones or 1,1,3,3-tetraethoxypropane yields 2-amino-1-phenyl[1,2,4]triazolo[1,5-a]pyrimidinium perchlorates
[1]. According to the authors [1], these compounds are the products of a Dimroth rearrangement of the initially
formed [4,3-a]-isomers, which could not be separated.
We have shown that brief heating of 1-benzyl[1,2,4]triazole-3,5-diamine (1) with the 1,3-diketones 2a,b or
1,1,3,3-tetramethoxypropane (2c) in ethanol in the presence of HCl gives the 2-R-3-amino[1,2,4]triazolo-
[4,3-a]pyrimidinium chlorides 3a-c, i.e. condensation proceeds similarly to the reaction of 1-substituted
[1,2,4]triazole-3,5-diamines with -ketoesters [2].
R2
5
NH2
N
N
1
NH2
R1
R2
R
3
Ph
Ph
EtOH, HCl
EtOH
N
N
N+
+
R1
R
7
, 30 min
, 48 h
2
8a N
1
N
Cl
H2N
2a–c
8
3a–c
R2
7
1
N
R1
R2
N
6
NH2
+
PhCH2Cl
2
N
5
3a
N
3
4a–c
2 a,b R = Ac, c R = CH(OMe)2; 2–4 a,c R1 = H; b R1 = Cl; 3, 4 a,b R2 = Me, c R2 = H
The structure of compounds 3a-c was confirmed using spectroscopic methods including the NOESY
spectra of compounds 3a,c in which correlated peaks were observed for the protons of the amino group with the
signals for both the CH2Ph group and the substituent at the position 5. The chemical shift values for the C-3 and
C-8a atoms in compounds 3a-c (signal assignments were made with the help of the HSQC and HMBC spectra)
were close to analogous signals in the spectra of the mesoionic 2-R-3-amino[1,2,4]triazolo[4,3-a]pyrimidin-
5-ones [2, 3].
_______
*To whom correspondence should be addressed, e-mail: chern13@yandex.ru.
1South Russian State Technical University, 132 Prosveshcheniya St., Novocherkassk 346428, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1519-1521, September, 2012.
Original article submitted June 4, 2012.
0009-3122/12/4809-1417©2012 Springer Science+Business Media New York
1417

Prolonged refluxing of salts 3a-c in ethanol solutions gives the 2-amino[1,2,4]triazolo[1,5-a]pyrimidines
4a-c. Hence, in contrast to the mesoionic triazolopyrimidin-5-ones (which rearrange to 1-R-3-amino-
[1,2,4]triazolo[4,3-a]pyrimidin-5-ones [2]), compounds 3a-c undergo a Dimroth rearrangement with loss of the
benzyl group under mild conditions. Using gas chromato-mass spectrometry it was established that the benzyl
group is lost as benzyl chloride, which undergoes gradual solvolysis.
The properties of compounds 4a-c are identical to those reported in the literature [4-6], and their
structure was additionally confirmed by a counter synthesis from [1,2,4]triazole-3,5-diamine and compounds
2a-c using a known method [4].
The results presented here and previously published data show that the primary route of
cyclocondensation of 1-substituted [1,2,4]triazole-3,5-diamines with a variety of 1,3-carbonyl compounds is
apparently the same and yields 2-substituted 3-amino[1,2,4]triazolo[4,3-a]pyrimidines. However, the route of
subsequent recyclizations of these compounds depends markedly on their structural features.
1H and 13C NMR spectra were recorded on a Bruker Avance 600 instrument (600 and 150 MHz,
respectively) using DMSO-d6 with TMS as internal standard. Mass spectra (EI, 70 eV) were registered on a
Finnigan MAT Incos 50 spectrometer with direct introduction of the sample into the ion source. Gas chromato-
mass spectrometry experiments were performed on an Agilent 7890A chromatograph fitted with an Agilent
5975C (EI, 70 eV) mass selective detector and HP-5MS capillary column. Elemental analysis was carried out on
a Perkin Elmer 2400 analyzer. Melting points were determined in sealed capillaries on a PTP apparatus.
Preparation of Compounds 3a-c (General Method). 36% HCl (390 mg, 3.71 mmol) in EtOH (1 ml)
was added to a solution of compound 1 (539 mg, 2.85 mmol) and compound 2a-c (3.71 mmol) in EtOH (2 ml).
The mixture was refluxed for 30 min, cooled to 0-5°C, and the precipitate formed was filtered off and
crystallized from MeCN.
3-Amino-2-benzyl-5,7-dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-2-ium Chloride (3a). Yield 297 mg
(36%). Colorless prisms, mp 215-217°C. 1H NMR spectrum, , ppm: 2.45 (3H, s, CH3); 2.83 (3H, s, CH3); 5.64
13
(2H, s, CH2); 6.82 (1H, s, H-6); 7.34-7.45 (5H, m, H Ph); 8.82 (2Н, s, NH2). C NMR spectrum, , ppm: 18.2
(5-CH3); 25.0 (7-CH3); 51.1 (CH2); 111.8 (C-6); 128.2, 128.4, 128.6, 134.4 (C Ph); 144.3 (C-3); 146.2 (C-5);
147.9 (C-8a); 169.9 (C-7). Mass spectrum, m/z (Irel, %): 254 [M-Cl]+ (6), 253 [M-HCl]+ (36), 162 (11), 107
(100), 91 (58), 67 (55), 65 (32), 36 (30). Found, %: C 58.31; H 5.41; N 23.89. C14H16ClN5. Calculated, %:
C 58.03; H 5.57; N 24.17.
3-Amino-2-benzyl-6-chloro-5,7-dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-2-ium Chloride (3b). Yield
1
286 mg (31%). Colorless prisms, mp 211-214°C. H NMR spectrum, , ppm: 2.56 (3H, s, CH3); 2.99 (3H, s,
CH3); 5.74 (2H, s, CH2); 7.32-7.47 (5H, m, H Ph); 9.24 (2Н, s, NH2). 13C NMR spectrum, , ppm: 15.9 (5-CH3);
24.8 (7-CH3); 51.3 (CH2); 118.2 (C-6); 128.2, 128.3, 128.5, 134.0 (C Ph); 143.2 (C-5); 144.4 (C-3); 145.5
(C-8a); 166.9 (C-7). Mass spectrum, m/z (Irel, %): 289 [M-Cl]+ (6), 287 [M-HCl]+ (18), 141 (50), 91 (100), 67
(40), 36 (30). Found, %: C 52.08; H 4.53; N 21.47. C14H15Cl2N5. Calculated, %: C 51.86; H 4.66; N 21.60.
3-Amino-2-benzyl[1,2,4]triazolo[4,3-a]pyrimidin-2-ium Chloride (3c). Yield 330 mg (44%).
1
Colorless prisms, mp 206-207°C. H NMR spectrum, , ppm: 5.59 (2H, s, CH2); 7.14-7.16 (1H, m, H-6);
7.33-7.46 (5H, m, H Ph); 8.78-8.79 (1H, m, H-7); 9.28-9.29 (1H, m, H-5); 10.03 (2Н, s, NH2). 13C NMR
spectrum, , ppm: 51.2 (CH2); 110.2 (C-6); 128.2, 128.3, 128.5 (C Ph); 133.7 (C-5); 134.0 (C Ph); 143.7 (C-3);
146.4 (C-8a); 160.4 (C-7). Mass spectrum, m/z (Irel, %): 226 [M-Cl]+ (1), 225 [M-HCl]+ (20), 91 (100), 79 (38),
65 (37), 53 (28), 36 (23). Found, %: C 55.32; H 4.53; N 26.49. C12H12ClN5. Calculated, %: C 55.07; H 4.62;
N 26.76.
Preparation of Compounds 4a-c (General Method). A solution of compound 3a-c (1.15 mmol) in
EtOH (3 ml) was refluxed for 48 h, cooled, and the precipitate formed was filtered off and crystallized.
5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (4a). Yield 244 mg (84%); mp 354-357°C
(DMF–EtOH) (mp 355-357°C [4]). The material did not give a depression in melting point when mixed with a
1
sample obtained by method [4]. H NMR spectrum, , ppm: 2.45 (3H, s, CH3); 2.52 (3H, s, CH3); 6.22 (2H, s,
1418

13
NH2); 6.80 (1H, s, H-6). C NMR spectrum, , ppm: 16.6 (CH3); 24.1 (CH3); 108.1 (C-6); 144.6 (C-7); 161.0
(C-3a); 166.9 (C-2,5). Mass spectrum, m/z (Irel, %): 163 [M]+ (100), 124 (17), 108 (11), 67 (10), 39 (14).
6-Chloro-5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (4b). Yield 180 mg (79%); mp 328°C
(decomp., DMF–EtOH). The material did not give a depression in melting point when mixed with a sample
obtained by condensation of [1,2,4]triazole-3,5-diamine with compound 2b in AcOH by using method [4].
1H NMR spectrum, , ppm: 2.54 (3H, s, CH3); 2.70 (3H, s, CH3); 6.31 (2H, s, NH2). Mass spectrum, m/z (Irel,
%): 197 [M]+ (100), 142 (10), 124 (12), 65 (9). Found, %: C 42.21; H 3.91; N 35.19. C7H8ClN5. Calculated, %:
C 42.54; H 4.08; N 35.44.
[1,2,4]Triazolo[1,5-a]pyrimidin-2-amine (4c). Yield 70 mg (45%); mp 205-206°C (EtOH) (mp
1
202-203°C (BuOH) [5]). The UV and H NMR spectra were identical with those reported in [5, 6]. Mass
spectrum, m/z (Irel, %): 135 [M]+ (100), 95 (6), 80 (7), 68 (5), 53 (22), 39 (10).
This work was carried out with the financial support Ministry of Education and Science of the Russian
Federation under the Federal Target Program "Scientific and Scientific-pedagogical Personnel of the Innovative
Russia" (contract P1297, project NK-656P).
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