New method for synthesis of the hetero-cyclic system - 1,2,3,4-tetrahydro- imidazo[5,1-f][1,2,4]triazin-7-amine

Full text of DOI:10.1007/s10593-014-1512-5

Chemistry of Heterocyclic Compounds, Vol. 50, No. 4, July, 2014 (Russian Original Vol. 50, No. 4, April, 2014)
NEW METHOD FOR SYNTHESIS OF THE HETERO-
CYCLIC SYSTEM – 1,2,3,4-TETRAHYDRO-
IMIDAZO[5,1-f][1,2,4]TRIAZIN-7-AMINE
D. Yu. Vandyshev1, Kh. S. Shikhaliev1*, A. Yu. Potapov1,
S. I. Firgang2, and M. Yu. Krysin1
Keywords: 1,2-diaminoimidazoles, formaldehyde, imidazotetrazepines, primary amines, 1,2,3,4-tetra-
hydroimidazo[5,1-f][1,2,4]triazin-7-amines.
Imidazotriazines are used as dyes, luminophores, and corrosion inhibitors [1, 2]. Earlier these
compounds were obtained on the basis of diaminopyridinium salts, and this was not economically feasible. We
decided to study an alternative method for the preparation of imidazotriazines starting from 1,2-diamino-
imidazoles.
In the course of the investigations we found that 1,2,3,4-tetrahydroimidazo[5,1-f][1,2,4]triazin-7-amines
4a-e are formed during the reaction of 1,2-diaminoimidazoles 1a-c, obtained by the reaction between benz-
aldehyde guanylhydrazones and halo ketones [1], with formaldehyde and primary amines 2a,b.
R1
R
2
H
N
R
N
4
N
N
p-TsOH
+ 2 CH2O + R1NH2
N
4a
5
2-PrOH
h
Ph
NH2
N
1a–c
2a,b
Ph
R1
NH2
7
N
R
N
4a–e
N
N
Ph
N
H
N
3
1a, 4a,d R = 4-MeC6H4;
1b, 4b,e R = 2-MeOC6H4; 1c, 4c R = Ph;
2a, 4a,b R1 = PhCH2; 2b, 4c–e R1 = MeO(CH2)2
_______
*To whom correspondence should be addressed, e-mail: chocd261@chem.vsu.ru.
1Voronezh State University, 1 Universitetskaya Sq., Voronezh 394006, Russia.
2N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., Moscow
119991, Russia; e-mail: galina_stashina@chemical-block.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 638-640, April, 2014. Original
article submitted February 24, 2014.
0009-3122/14/5004-0587©2014 Springer Science+Business Media New York
587

It was supposed that as in the case of 2-aminobenzimidazole, where the reaction took place through the
exo- and endocyclic nitrogen atoms [3], the reaction should take place preferentially at the two amino groups
1
with the formation of the imidazotetrazepine ring 3. Analysis of the H NMR spectra of the products of this
multicomponent reaction showed that the two-proton singlet of the NH2 group remains, the characteristic signal
for the proton of the amino group in the hydrazine fragment NHR and the signal for the proton of the imidazole
ring are absent, but broadened signals for the CH2 group of the triazine ring appear at 3.56-3.95 and 4.10-
4.45 ppm. The 13C NMR spectra of compounds 4a-e contain characteristic signals for the carbon atom of the
imidazole ring C–NH2 at 144.7 ppm and for the bridgehead carbon atom of the imidazotriazine ring (C-4a) at
113.5 ppm. The signals for the carbon atoms of the methylene groups in the triazine ring resonate in the more
1
upfield region at 49.9-50.6 and 66.5-70.6 ppm. On the basis of the data from H NMR spectroscopy and mass
spectrometry the obtained compounds were assigned the structure of 1-R-3-R1-5-phenyl-1,2,3,4-tetrahydro-
imidazo[5,1-f][1,2,4]triazin-7-amines 4a-e, and it was concluded that the aminomethylation reaction takes place
at the amino group of the hydrazine fragment and at the carbon atom of the imidazole ring, as also in the case of
3-aminopyrazoles [4]. The relatively low yields of the reaction products (44-65%) can be explained by the side
formation of aminoformaldehyde resins.
Thus, a new three-component method has been developed for the preparation of tetrahydroimidazole
systems based on the reaction of 1,2-diaminoimidazoles with primary amines and formaldehyde.
1H and 13C NMR spectra were recorded on a Bruker DRX-500 spectrometer (500 and 126 MHz,
respectively) in DMSO-d6 with TMS as internal standard. Mass spectra were recorded on an LKB-9000
spectrometer with EI ionization. Elemental analysis was performed on a Carlo Erba NA 1500 instrument.
Melting points were determined on a Stuart SMP30 apparatus.
5-Phenyl-1,2,3,4-tetrahydroimidazo[5,1-f][1,2,4]triazin-7-amines 4a-e (General Method).
A
mixture of the diaminoimidazole 1a-c [1] (5 mmol), 40% aqueous solution of formaldehyde (10 mmol), the
amine 2a,b (5 mmol), and 2-PrOH (5 ml) was refluxed for 2 h in the presence of p-TsOH·H2O (50 mg). The
precipitate was filtered off and recrystallized from 2-PrOH. The obtained imidazotriazines were light-yellow
powdered substances.
3-Benzyl-1-(4-methylbenzyl)-5-phenyl-1,2,3,4-tetrahydroimidazo[5,1-f][1,2,4]triazin-7-amine (4a).
1
Yield 50%, mp 204-205°C. H NMR spectrum, δ, ppm (J, Hz): 2.25 (3Н, s, СН3); 3.50 (2H, s, NСН2Ar); 3.68
(2Н, br. s, 4-СН2); 3.95-4.31 (4Н, m, 2-СН2, NСН2Ph); 5.49 (2Н, s, NH2); 7.00 (2H, d, J = 7.9, H Ar);
7.05-7.12 (3Н, m, H Ar); 7.29-7.47 (9Н, m, H Ar). 13С NMR spectrum, δ, ppm: 21.1 (СН3); 50.1 (4-СН2); 56.9
(СН2Ph); 58.3 (СН2Ar); 66.9 (2-CH2); 113.6 (C-4а); 123.7, 125.1, 126.5, 127.7, 128.7, 128.8, 129.1, 129.6,
130.3, 133.1, 136.0, 137.0 (C Ar); 138.1 (C-5); 144.7 (C-7). Mass spectrum, m/z (Irel, %): 410 [M+Н]+ (100).
Found, %: С 76.18; Н 6.63; N 17.06. C26H27N5. Calculated, %: С 76.25; Н 6.65; N 17.10.
3-Benzyl-1-(2-methoxybenzyl)-5-phenyl-1,2,3,4-tetrahydroimidazo[5,1-f][1,2,4]triazin-7-amine
(4b). Yield 65%, mp 210-212°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.56 (2H, s, NСН2Ar); 3.81 (2Н, s, ОСН3);
3.90 (2H, br. s, 4-СН2); 4.30-4.45 (4Н, m, 2-СН2, NСН2Ph); 5.59 (2Н, s, NH2); 6.24 (1H, dd, J = 6.1, J = 7.4, H
Ar); 6.59 (1Н, t, J = 7.3, J = 7.4, H Ar); 7.00 (2H, d, J = 8.2, H Ar); 7.09-7.12 (3Н, m, H Ar); 7.23-7.27 (3Н, m,
H Ar); 7.32 (1Н, dd, J = 7.6, J = 7.9, H Ar); 7.37-7.49 (3Н, m, H Ar). 13С NMR spectrum, δ, ppm: 50.6 (4-СН2);
52.8 (СН2Ph); 55.7 (OСН3); 58.2 (СН2Ar); 66.5 (2-СН2); 111.4 (С-3 Ar); 113.5 (C-4а); 120.6, 123.7, 124.7,
125.0, 126.2, 127.8, 128.7, 128.9, 129.9, 130.0, 132.0, 136.1 (C Ar); 138.2 (C-5); 144.7 (C-7); 158.1 (С-2 Ar).
Mass spectrum, m/z (Irel, %): 426 [M+Н]+ (100). Found, %: С 73.30; Н 6.38; N 16.44. C26H27N5О. Calculated,
%: С 73.39; Н 6.40; N 16.46.
1-Benzyl-3-(2-methoxyethyl)-5-phenyl-1,2,3,4-tetrahydroimidazo[5,1-f][1,2,4]triazin-7-amine (4c).
1
Yield 44%, mp 180-181°C. H NMR spectrum, δ, ppm (J, Hz): 2.68-2.72 (2Н, m, NСН2СН2); 3.19 (3Н, s,
ОСН3); 3.32-3.34 (2Н, m, СН2СН2О); 3.49 (2Н, s, NСН2Ph); 3.60 (2H, br. s, 4-СН2); 4.25 (2H, br. s, 2-СН2);
5.50 (2Н, s, NH2); 7.11 (1H, dt, J = 7.4, J = 7.3, H Ph); 7.31-7.42 (5H, m, H Ph); 7.50 (2H, dd, J = 8.3, J = 8.2,
13
H Ph); 7.56 (2H, d, J = 7.0, H Ph). С NMR spectrum, δ, ppm: 49.9 (4-СН2); 53.6 (NСН2СН2); 57.1 (OСН3);
58.3 (СН2Ph); 67.9 (CH2СН2O); 70.5 (2-СН2); 113.6 (C-4а); 124.8, 125.1, 126.5, 128.2, 128.7, 130.4, 136.1
588

(C Ar); 136.5 (C-5); 144.7 (C-7). Mass spectrum, m/z (Irel, %): 363 [M]+ (100). Found, %: С 69.31; Н 6.91;
N 19.24. C21H25N5О. Calculated, %: С 69.40; Н 6.93; N 19.27.
3-(2-Methoxyethyl)-1-(4-methylbenzyl)-5-phenyl-1,2,3,4-tetrahydroimidazo[5,1-f][1,2,4]triazin-
1
7-amine (4d). Yield 48%, mp 183-185°C. H NMR spectrum, δ, ppm (J, Hz): 2.32 (3Н, s, ArСН3); 2.63-2.71
(2Н, m, NСН2СН2); 3.21 (3Н, s, ОСН3); 3.38 (2Н, s, СН2СН2О); 3.49-3.65 (2H, m, NСН2Ar); 3.56 (2Н, br. s,
4-СН2); 4.10 (2Н, br. s, 2-СН2); 5.50 (2Н, s, NH2); 7.11 (1H, dd, J = 7.4, J = 7.3, H Ar); 7.20 (2H, d, J = 7.8,
H Ar); 7.32 (2H, dd, J = 7.6, J = 7.9, H Ar); 7.44 (2H, d, J = 7.9, H Ar); 7.50 (2H, d, J = 7.4, H Ar). 13С NMR
spectrum, δ, ppm: 21.2 (ArСН3); 49.9 (4-СН2); 53.7 (NСН2СН2); 56.8 (OСН3); 58.3 (СН2Ar); 67.9
(CH2СН2O); 70.5 (2-СН2); 113.5 (C-4а); 124.8, 125.0, 126.5, 128.7, 129.3, 130.4, 133.4, 136.1 (C Ar); 137.3
(C-5); 144.7 (C-7). Mass spectrum, m/z (Irel, %): 374.49 [M+Н]+ (100). Found, %: С 69.89; Н 7.20; N 18.52.
C22H27N5О. Calculated, %: С 70.00; Н 7.21; N 18.55.
1-(2-Methoxybenzyl)-3-(2-methoxyethyl)-5-phenyl-1,2,3,4-tetrahydroimidazo[5,1-f](1,2,4)triazin-
1
7-amine (4e). Yield 52%, mp 189-192°C. H NMR spectrum, δ, ppm (J, Hz): 2.73-2.79 (2Н, m, NСН2СН2);
3.33 (3Н, s, CH2CH2ОСН3); 3.58 (2H, т, J = 5.0, J = 5.0, СН2СН2О); 3.70 (2Н, br. s, 4-СН2); 3.85 (2H, s,
ArОСН3); 4.25-4.48 (4Н, m, 2-СН2, NСН2Ar); 5.55 (2Н, s, NH2); 7.00 (1H, dd, J = 7.4, J = 7.3, H Ar);
7.07-7.13 (2Н, m, H Ar); 7.30-7.39 (4H, m, H Ar); 7.51 (2Н, d, J = 7.7, H Ar). 13С NMR spectrum , δ, ppm:
50.0 (4-СН2); 52.6 (NСН2СН2); 53.7 (ArOСН3); 55.8 (CH2CH2OCH3); 58.4 (СН2Ar); 67.9 (CH2СН2O); 70.6
(2-СН2); 111.6 (С-3 Ar); 113.5 (C-4а); 120.8, 124.1, 124.7, 125.0, 126.2, 128.7, 130.1, 132.3 (C Ar); 136.1
(C-5); 144.7 (C-7); 158.3 (С-2 Ar). Mass spectrum, m/z (Irel, %): 394 [M+Н]+ (100). Found, %: С 67.10; Н 6.90;
N 17.76. C22H27N5О2. Calculated, %: С 67.15; Н 6.92; N 17.80.
The work was carried out with support from the Ministry of Education and Science of the Russian
Federation (state contract 02.G25.31.0007).
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