Synthesis of New Imidazo[4,5-e][1,3]thiazolo-[3,2-b][1,2,4]triazine Derivatives

Article abstract of DOI:10.1007/s10593-013-1349-3

Previously unknown (Z)-6-aryl(hetaryl)methylidene derivatives of imidazo[4,5-e][1,3]thiazolo[3,2-b]-[1,2,4]triazine-2,7-diones were synthesized by aldol-crotonic condensation of imidazo[4,5-e]-[1,3]thiazolo[3,2-b][1,2,4] triazine-2,7-diones with aromatic

Full text of DOI:10.1007/s10593-013-1349-3

Chemistry of Heterocyclic Compounds, Vol. 49, No. 7, October, 2013 (Russian Original Vol. 49, No. 7, July, 2013)
SYNTHESIS OF NEW IMIDAZO[4,5-e][1,3]THIAZOLO-
[3,2-b][1,2,4]TRIAZINE DERIVATIVES
G. A. Gazieva1*, S. A. Serkov1, N. V. Sigai1, N. N. Kostikova1,
Yu. V. Nelyubina2, E. A. Shishkova1, and A. N. Kravchenko1
Previously unknown (Z)-6-aryl(hetaryl)methylidene derivatives of imidazo[4,5-e][1,3]thiazolo[3,2-b]-
[1,2,4]triazine-2,7-diones were synthesized by aldol-crotonic condensation of imidazo[4,5-e]-
[1,3]thiazolo[3,2-b][1,2,4]triazine-2,7-diones with aromatic or heteroaromatic aldehydes, or by three-
component condensation of imidazo[4,5-e][1,2,4]triazine-3-thione, bromoacetic acid, and aldehyde.
Keywords: aromatic and heteroaromatic aldehydes, imidazo[4,5-e][1,3]thiazolo[3,2-b][1,2,4]triazine-
2,7-diones, perhydroimidazo[4,5-e][1,2,4]triazine-3-thione, aldol-crotonic condensation, one-pot
condensation.
1,3-Thiazolidines are a new class of antimicrobial compounds which are effective against a wide
spectrum of gram-positive microorganisms [1, 2]. 1,3-Thiazolidin-4-one derivatives possess fungicidal [3],
antiproliferative [4, 5], and antivirus activity [6]. Thiazolidines, annelated with other nitrogen-containing
heterocycles, also exibit various pharmacological effects. The anthelmintic and immunomodulating medication
levamisole was obtained based on imidazo[2,1-b]thiazole [7, 8]. Thiazolo[3,2-b] or thiazolo[2,3-c]-
[1,2,4]triazines show antidepressant [9], anti-HIV and anticancer activity[10, 11]. Among biologically active
thiazolidines there are a considerable group of their arylmethylidene derivatives [5, 12-14].
Me
Me
O
Me
O
Ph
H
N
Ph
H
N
Ph H
N
N
O
R
N
N
Br
CO2H
NH
N
N
3a–i
O
O
O
NaOAc
AcOH
NaOAc
AcOH

N
S
N
S
N
S
R
N
H
N
N
Ph
2
Ph
1
Ph
Me
Me
Me

4a–i
Br
CO H
2
, 3a–c,e,g–i, NaOAc, AcOH, 
3, 4 a R = Ph, b R = 4-BrC6H4, c R = 4-O2NC6H4, d R = 4-MeC6H4, e R = 2,3-Cl2C6H3,
f R = 3,4-(MeO)2C6H3, g R = 1,3-benzodioxol-4-yl, h R = furan-2-yl, i R = thiophen-2-yl
_______
*To whom correspondence should be addressed, e-mail: gaz@ioc.ac.ru.
1N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., Moscow
119991, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilova St., Moscow 119991, Russia; e-mail:
unelya@xrlab.ineos.ac.ru.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1176-1180, July, 2013. Original
article submitted March 21, 2013.
0009-3122/13/4907-1097©2013 Springer Science+Business Media New York
1097

In the present work we have synthesized new 6-aryl(hetaryl)methylidene derivatives of imidazo[4,5-e]-
[1,3]thiazolo[3,2-b][1,2,4]triazine-2,7-dione 1 by condensation with the corresponding aldehydes.
The starting material imidazothiazolotriazine 1 was synthesized by alkylation of imidazo[4,5-e]-
[1,2,4]triazinethione 2 with bromoacetic acid in acetic acid in the presence of sodium acetate [15, 16].
The reaction of imidazothiazolotriazine 1 with aromatic or heteroaromatic aldehydes 3a-i was carried
out in glacial acetic acid in the presence of excess sodium acetate. Aryl(hetaryl)methylidene derivatives 4a-i
were obtained in 47-68% yields.
1
The composition and structures of compounds 4a-i were confirmed by elemental analysis data and H
13
1
and C NMR spectra. The H NMR spectra of derivatives 4a-i contain singlets of the imidazolidine unit NMe
group protons at 2.62-2.65 ppm, two doublets and a multiplet of the protons of the phenyl groups at the bridging
carbon atoms C-3a and C-9a in the region 6.73-6.86 and 7.04-7.19 ppm, respectively. Singlets of the NH group
protons are present in the region 7.59-7.74 ppm. Signals of the methyne protons at the double bond are found in
downfield at 7.84-8.19 ppm as a result of the descreening effect of the carbonyl group, which indicates
formation of the Z-isomers of the 6-aryl(hetaryl)methylidene derivatives 4a-i [14, 17-19].
The structure of compound 4h was confirmed by X-ray structural analysis (Fig. 1), the results of which
show that the geometric parameters of the molecule fall within the range of values characteristic for this class of
compounds [20]. In particular the conformations of the imidazolidine and triazine rings are "envelope" (with
atom C(1) deviation from the plane by 0.49(1) Ǻ) and "twist" (with atoms N(3) and C(3) deviation from the
plane by 0.31(1) and 0.27(1) Ǻ, respectively). All nitrogen atoms, except N(3), have planar surroundings with
the sum of the valence angles within the range 350.0(1)-359.9(1)°. The corresponding value for the N(3) atom is
321.4(1)°. The thiazole ring is planar within limits 0.03(1) Ǻ. It remains to note that the thiazole and furan rings
are virtually coplanar: the angle between their least square planes equals 14.9(1)°.
In the crystal, molecule 4h formed centrosymmetric dimers with the help of the hydrogen bond N(3)–
H(3N)···O(2) (N···O 3.048(2) Ǻ, N–H–O 159(1)°) which then form a three-dimensional skeleton on account of
the multiplicity of weaker interactions C–H···O, C–H···S, CH···π, and H···H.
Since imidazothiazolotriazine 1 and its 6-substituted derivatives 4a-i are formed under practically the
same conditions, we have investigated the three-component condensation of imidazotriazinethione 2, bromo-
acetic acid, and the aldehydes 3a-c,e,g-i. The yields of the corresponding 6-aryl(hetaryl)methylidene derivatives
4a-c,e,g-i (35-56%) are comparable to the two-step variant, taking into account the two steps, but the one-pot
synthesis is simpler and more economical.
Thus the synthesis of new 6-aryl(hetaryl)methylidene derivatives of imidazo[4,5-e][1,3]thiazolo[3,2-b]-
[1,2,4]triazine-2,7-dione either by consecutive condensation of imidazo[4,5-e][1,2,4]triazine-3-thione with
bromoacetic acid and the corresponding aldehydes or by a three-component reaction.
Fig. 1. Molecular structure of compound 4h with atoms represented with thermal vibration ellipsoids of 50%
probability. Hydrogen atoms, with the exception of this in the NH group, are not shown.
1098

EXPERIMENTAL
1H and 13C NMR spectra of DMSO-d6 solutions were recorded with a Bruker AM-300 spectrometer
(300 and 75 MHz, respectively) with TMS as internal standard. Elemental analyses were carried out with a
Perkin-Elmer 2400 CHN analyzer and a Euro EA Elemental Analyzer. Melting points were determined with a
Sanyo Gallenkamp apparatus.
5,7-Dimethyl-3-thioxo-4a,7a-diphenyloctahydro-6H-imidazo[4,5-e][1,2,4]triazin-6-one 2 was synthesized in
75% yield by described method [21].
Preparation of Compounds 4a-i. The corresponding aldehyde 3a-i (2 mmol) was added to a
suspension of imidazothiazolotriazine 1 (0.79 g, 2 mmol) and anhydrous NaOAc (0.33 g, 4 mmol) in glacial
AcOH (15 ml), and the mixture was refluxed with stirring for 8 h (compounds 4a-g,i) or 6 h (compound 4h).
The precipitate of compound 4 which separated after cooling the reaction mixture was filtered off, washed with
water and hexane, and recrystallized from aqueous DMF.
(Z)-6-Benzylidene-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e][1,3]thiazolo[3,2-b]-
1
[1,2,4]triazine-2,7(1H,6H)-dione (4a). Yield 0.65 g (68%), white powder, mp 287-289°С. Н NMR spectrum,
δ, ppm (J, Hz): 2.63 (3Н, s, NCH3); 2.64 (3Н, s, NCH3); 6.76 (2H, d, J = 7.2, Н Ph); 6.84 (2H, d, J = 7.3, Н Ph);
7.05-7.17 (6Н, m, Н Ph); 7.51-7.71 (6Н, m, Н Ph, NH); 7.92 (1Н, s, СН). 13С NMR spectrum, δ, ppm: 25.2
(NCH3); 26.0 (NCH3); 79.9 and 82.1 (С-3а,9а); 119.1; 126.1; 127.3; 127.7; 127.9; 128.0; 128.2; 129.3; 129.9;
130.2; 131.4; 133.2; 133.9; 134.8; 147.6 (C=N); 159.1 (C=O); 160.1 (C=O). Found, %: C 67.37; H 4.83;
N 14.52; S 6.60. C27H23N5O2S. Calculated, %: C 67.34; H 4.81; N 14.54; S 6.66.
(Z)-6-(4-Bromobenzylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e][1,3]-
thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4b). Yield 0.63 g (56%), white powder, mp 283-285°С.
1Н NMR spectrum, δ, ppm (J, Hz): 2.62 (6Н, s, 2NCH3); 6.75 (2H, d, J = 7.2, Н Ph); 6.83 (2H, d, J = 7.4,
Н Ph); 7.04-7.17 (6Н, m, Н Ph); 7.63 (2H, d, J = 8.3, Н Ar); 7.65 (1Н, s, NH); 7.76 (2H, d, J = 8.3, Н Ar); 7.89
(1Н, s, СН). 13С NMR spectrum, δ, ppm: 25.2 (NCH3); 25.9 (NCH3); 79.9 and 82.1 (С-3а,9а); 120.1; 123.6;
126.1; 127.3; 127.7; 127.9; 128.0; 128.2; 130.1; 131.7; 132.3; 132.5; 133.9; 134.8; 147.3 (C=N); 159.0 (C=O);
160.1 (C=O). Found, %: C 57.87; H 3.93; Br 14.22; N 12.52; S 5.68. C27H22BrN5O2S. Calculated, %: C 57.86;
H 3.96; Br 14.26; N 12.50; S 5.72.
(Z)-1,3-Dimethyl-6-(4-nitrobenzylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e][1,3]-
thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4c). Yield 0.61 g (58%), yellowish powder, mp 290-292°С.
1Н NMR spectrum, δ, ppm (J, Hz): 2.64 (6Н, s, 2NCH3); 6.75 (2H, d, J = 7.3, H Ph); 6.85 (2H, d, J = 7.0,
H Ph); 7.09-7.18 (6Н, m, H Ph); 7.74 (1Н, s, NH); 7.96 (2H, d, J = 7.3, H Ar); 8.04 (1Н, s, СН); 8.38 (2H, d,
13
J = 7.3, H Ar). С NMR spectrum, δ, ppm: 25.2 (NCH3); 26.0 (NCH3); 79.9 and 82.2 (С-3а,9а); 123.7; 124.3;
126.1; 127.3; 127.6; 127.9; 128.0; 128.2; 128.8; 130.8; 133.8; 134.7; 139.5; 147.0; 147.3 (C=N); 159.0 (C=O);
159.8 (C=O). Found, %: C 61.54; H 4.19; N 15.93; S 6.01. C27H22N6O4S. Calculated, %: C 61.59; H 4.21;
N 15.96; S 6.09.
(Z)-1,3-Dimethyl-6-(4-methylbenzylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e][1,3]-
thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4d). Yield 0.42 g (42%), white powder, mp 272-274°С.
1Н NMR spectrum, δ, ppm (J, Hz): 2.40 (3Н, s, CH3); 2.63 (6Н, s, 2NCH3); 6.76 (2H, d, J = 6.6, H Ph); 6.84 (2H,
d, J = 6.7, H Ph); 7.08-7.18 (6Н, m, H Ph); 7.40 (2H, d, J = 7.5, H Ar); 7.59 (2H, d, J = 7.5, H Ar); 7.62 (1Н, s,
NH); 7.88 (1Н, s, СН). 13С NMR spectrum, δ, ppm: 21.0 (CH3); 25.2 (NCH3); 25.9 (NCH3); 79.8 and 82.0
(С-3а,9а); 117.8; 126.1; 127.1; 127.3; 127.6; 127.8; 127.9; 128.1; 129.9; 130.4; 131.3; 133.9; 134.9; 140.4; 147.6
(C=N); 159.0 (C=O); 160.4 (C=O). Found, %: C 67.82; H 5.03; N 14.15; S 6.42. C28H25N5O2S. Calculated, %: C
67.86; H 5.08; N 14.13; S 6.47.
(Z)-6-(2,3-Dichlorobenzylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e][1,3]-
thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4e). Yield 0.67 g (61%), beige powder, mp 293-296°С.
1Н NMR spectrum, δ, ppm (J, Hz): 2.63 (3Н, s, NCH3); 2.65 (3Н, s, NCH3); 6.76 (2H, d, J = 7.2, H Ph); 6.84
(2H, d, J = 7.3, H Ph); 7.04-7.19 (6Н, m, H Ph); 7.55-7.60 (2Н, m, H Ar, NH); 7.70 (1Н, d, J = 7.6, H Ar); 7.76
1099

(1H, d, J = 7.8, H Ar); 8.00 (1Н, s, СН). 13С NMR spectrum, δ, ppm: 25.2 (NCH3); 25.9 (NCH3); 79.8 and 82.1
(С-3а,9а); 124.5; 126.1; 126.5; 127.3; 127.5; 127.6; 127.8; 127.9; 128.0; 128.2; 128.9; 131.7; 133.0; 133.7;
133.8; 134.7; 147.0 (C=N); 159.0 (C=O); 159.5 (C=O). Found, %: C 58.90; H 3.88; Cl 12.83; N 12.70; S 5.77.
C27H21Cl2N5O2S. Calculated, %: C 58.91; H 3.85; Cl 12.88; N 12.72; S 5.83.
(Z)-6-(3,4-Dimethoxybenzylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]-
[1,3]thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4f). Yield 0.52 g (48%), white powder, mp 258-262°С.
1Н NMR spectrum, δ, ppm (J, Hz): 2.62 (6Н, s, 2NCH3); 3.85 (6Н, s, 2OCH3); 6.75 (2H, d, J = 6.7, H Ph); 6.83 (2H,
d, J = 6.7, H Ph); 7.07-7.17 (7Н, m, H Ph, Н Ar); 7.27 (2H, br. s, H Ar); 7.60 (1Н, s, NH); 7.87 (1Н, s, СН).
13С NMR spectrum, δ, ppm: 25.1 (NCH3); 25.9 (NCH3); 55.5 (OCH3); 55.6 (OCH3); 79.8 and 82.0 (С-3а,9а);
112.1; 112.9; 116.0; 123.7; 125.9; 126.0; 127.2; 127.6; 127.7; 127.9; 128.1; 131.6; 133.9; 134.9; 147.7 (C=N);
148.9; 150.6; 159.0 (C=O); 160.4 (C=O). Found, %: C 64.35; H 5.04; N 12.95; S 5.87. C29H27N5O4S. Calculated,
%: C 64.31; H 5.02; N 12.93; S 5.92.
(Z)-6-(1,3-Benzodioxol-4-ylmethylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimid-
azo[4,5-e][1,3]thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4g). Yield 0.56 g (53%), white powder, mp
290-293°С. 1Н NMR spectrum, δ, ppm (J, Hz): 2.65 (6Н, s, 2NCH3); 6.15 (2Н, s, OCH2O); 6.75 (2H, d, J = 6.9,
H Ph); 6.82 (2H, d, J = 7.0, H Ph); 7.04-7.25 (9Н, m, H Ph, Н Ar); 7.59 (1Н, s, NH); 7.84 (1Н, s, СН).
13С NMR spectrum, δ, ppm: 25.2 (NCH3); 25.9 (NCH3); 79.9 and 82.1 (С-3а,9а); 101.9; 109.1; 116.6; 125.6;
126.1; 127.1; 127.3; 127.4; 127.7; 127.8; 127.9; 128.2; 131.4; 134.0; 134.9; 147.6 (C=N); 148.2; 149.1; 159.1
(C=O); 160.4 (C=O). Found, %: C 64.03; H 4.40; N 13.35; S 6.04. C28H23N5O4S. Calculated, %: C 63.99;
H 4.41; N 13.33; S 6.10.
(Z)-6-(Furan-2-ylmethylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e][1,3]-
thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4h). Yield 0.45 g (48%), beige powder, mp 280-283°С.
1Н NMR spectrum, δ, ppm (J, Hz): 2.62 (6Н, s, 2NCH3); 6.73-6.83 (5H, m, H Ph, Н Fu); 7.07-7.16 (7Н, m,
H Ph, Н Fu); 7.59 (1Н, s, NH); 7.74 (1H, br. s, H Fu); 8.08 (1Н, s, СН). 13С NMR spectrum, δ, ppm: 25.2
(NCH3); 25.9 (NCH3); 79.8 and 81.8 (С-3а,9а); 113.4; 116.2; 117.8; 118.0; 126.1; 127.3; 127.7; 127.8; 127.9;
128.1; 134.0; 135.0; 147.1 (C=N); 148.1; 149.5; 159.1 (C=O); 160.2 (C=O). Found, %: C 63.71; H 4.46;
N 14.82; S 6.76. C25H21N5O3S. Calculated, %: C 63.68; H 4.49; N 14.85; S 6.80.
(Z)-1,3-Dimethyl-3a,9a-diphenyl-6-(thiophen-2-ylmethylidene)-3,3a,9,9a-tetrahydroimidazo[4,5-e]-
[1,3]thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-dione (4i). Yield 0.43 g (44%), beige powder, mp 278-282°С.
1Н NMR spectrum, δ, ppm (J, Hz): 2.62 (6Н, s, NCH3); 6.75 (2H, d, J = 7.2, H Ph); 6.83 (2H, d, J = 7.2, H Ph);
7.05-7.19 (6Н, m, H Ph); 7.33 (1Н, dd, J = 3.2, J = 4.8, H Th); 7.61 (1Н, s, NH); 7.72 (1H, d, J = 3.2, H Th); 8.04
13
(1H, d, J = 4.8, H Th); 8.19 (1Н, s, СН). С NMR spectrum, δ, ppm: 25.2 (NCH3); 25.9 (NCH3); 79.8 and 82.1
(С-3а,9а); 116.5; 124.6; 126.0; 127.3; 127.6; 127.8; 127.9; 128.1; 128.8; 132.5; 133.9; 134.0; 134.8; 137.2; 147.3
(C=N); 159.0 (C=O); 160.1 (C=O). Found, %: C 61.61; H 4.32; N 14.33; S 13.11. C25H21N5O2S2. Calculated, %:
C 61.58; H 4.34; N 14.36; S 13.15.
Three-component Condensation of Imidazotriazinethione, Bromoacetic Acid, and Acetaldehyde 3.
The corresponding aldehyde 3a-c,e,g-i (2 mmol) was added to a suspension of imidazotriazinethione 2 (0.71 g,
2 mmol), bromoacetic acid (0.28 g, 2 mmol), and anhydrous NaOAc (0.33 g, 4 mmol) in glacial AcOH (15 ml),
and the mixture was refluxed with stirring for 8 h (compounds 4a-c,e,g,i) or 6 h (compound 4h). The precipitate
of compound 4 which separated after cooling the reaction mixture was filtered off and recrystallized from
aqueous DMF. Compound 4a – yield 0.49 g (51%). Compound 4b – yield 0.48 g (43%). Compound 4c – yield
0.59 g (56%). Compound 4e – yield 0.54 g (49%). Compound 4g – yield 0.41 g (39%). Compound 4h – yield
0.36 g (38%). Compound 4i – yield 0.32 g (33%).
X-ray Structural Investigation of Compound 4h. Crystals of compound 4h (C25H21N5O3S, M 471.53)
monoclinic, space group P21/n. At 100 K, a 16.355(2), b 9.1566(12), c 17.050(2) Ǻ; β 116.840(2)°; V 2278.3(5)
Ǻ3; Z 4; dcalc 1.375 g·cm-3; μ 1.81 cm-1; F(000) 984. Intensities of 27025 reflections were measured on a Bruker
APEX2 DUO diffractometer (λ(MoKα) 0.71072 Ǻ, ω-scanning, 2θ < 58°), and 6062 independent reflections
(Rint 0.0747) were used in further calculations. The structure was solved by direct methods and refined by least
1100

squares analysis to F2 in the anisotropic-isotropic approximation. The hydrogen atoms of the NH group were
located from a difference Fourier electron density synthesis, the positions of the remaining hydrogen atoms
were calculated geometrically. The positions of all hydrogen atoms were refined isotropically using the "rider"
model. The final values of the probability factors for compound 4h: wR2 0.1605 and GOOF 0.999 for all
independent reflections (R1 0.0524 calculated to F for 4288 observed reflections with I > 2σ(I)). All calculations
were carried out with the SHELXTL PLUS 5.0 suite of programs. The complete crystallographic information on
compound 4h has been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 929690).
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