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Acta Cryst. (2007). E63, o2796    [ doi:10.1107/S1600536807021009 ]

7,7-Dimethyl-2-phenyl-6,7-dihydro-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine

A. V. Dolzhenko, G. K. Tan, L. L. Koh, A. V. Dolzhenko and W. K. Chui

Abstract top

The title compound, C12H14N6, was synthesized via cyclocondensation of 5-guanidino-3-phenyl-1,2,4-triazole with acetone. Only one tautomeric form with the NH H atom vicinal to the methyl groups was observed in the crystal structure. The triazine ring adopts a flattened half-boat conformation. The dihedral angle between the triazole and phenyl rings is 9.99 (5)°. The crystal packing is stabilized by intermolecular N-H...N hydrogen bonds which link the molecules into a chain along the a axis.

Comment top

4,6-Diamino-1,2-dihydro-1,3,5-triazines, such as antimalarial drug cycloguanil and WR 99210 (Fig. 1) are known to be potent inhibitors of dihydrofolate reductase (DHFR). Our laboratory has been working on the fused s-triazines as DHFR inhibitors in the search for potential antibacterial, antiparasitic and anticancer agents (Dolzhenko et al., 2005, Dolzhenko & Chui, 2006). The 5-aza-analogues of purine heterocyclic system, viz. 1,2,4-triazolo[1,5-a][1,3,5]triazines has been shown to possess a wide range of biological activities (Dolzhenko, Dolzhenko & Chui, 2006), therefore we became interested in using this nucleus as a skeleton for the construction of potential DHFR inhibitors (Dolzhenko et al., 2007).

5-Amino-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazine (I) which shares some structural similarity with the gem-dimethyl substituted antifolate triazines (Fig. 1) was synthesized and its structural investigation was carried out in order to facilitate further molecular modeling and docking studies. Theoretically, four tautomeric forms are possible for the synthesized compound due to annular tautomerism (Fig. 2). However, only one form namely 5-amino-7,7-dimethyl-2-phenyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]\ triazine (Fig. 3) was observed in the crystal.

The triazine ring of the fused heterocyclic core adopts a half-boat conformation, with atoms C9 and N5 at the bow and stern. The angle between the flagpole and bowsprit methyl groups is 111.33 (13)°. The mean planes of the triazole (N1/C7/N2—N3/C8) and phenyl (C1—C6) rings make a dihedral angle of 9.99 (5)°. The N4—C10, N5—C10 and N6—C10 bond distances are similar that suggests guanidine-like electron delocalization in the N4—N6/C10 fragment of the molecule. The crystal packing is stabilized by intermolecular N—H···N hydrogen-bonds (Table 1) which link the molecules into a chain along the a axis.

Related literature top

The 1,2,4-triazolo[1,5-a][1,3,5]triazine (5-azapurine) heterocyclic system has been reviewed by Dolzhenko et al. (2006). For related literature, see also: Dolzhenko et al. (2005); Dolzhenko & Chui (2006); Dolzhenko et al. (2007).

Experimental top

5-Guanidino-3-phenyl-1,2,4-triazole (0.50 g, 2.5 mmol) was heated under reflux in acetone (8 ml) containing piperidine (0.05 ml, 0.5 mmol) for 18 h. After cooling, the precipitated solid was filtered, washed with acetone and recrystallized from ethanol (m.p. 567 K).

Refinement top

Atom H4N was located in a difference map and refined isotropically. The remaining H atoms were placed in calculated positions (N—H = 0.87 Å and C—H = 0.94 or 0.97 Å), and included in the final cycles of refinement using a riding model, with Uiso(H) = 1.2Ueq(C, N) or 1.5Ueq(methyl C). A rotating group model was used for the methyl groups.

Computing details top

Data collection: SMART (Bruker, 2003); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 2003); software used to prepare material for publication: SHELXTL.

Figures top
[Figure 1] Fig. 1. The structures of the antifolate 1,3,5-triazines.
[Figure 2] Fig. 2. The annular tautomerism in (I).
[Figure 3] Fig. 3. The molecular structure of (I), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
7,7-Dimethyl-2-phenyl-6,7-dihydro-1,2,4-triazolo[1,5-a][1,3,5]triazin- 5-amine top
Crystal data top
C12H14N6Dx = 1.349 Mg m−3
Mr = 242.29Melting point: 567 K
Orthorhombic, PbcaMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2abCell parameters from 3419 reflections
a = 9.9667 (6) Åθ = 2.8–24.6°
b = 12.6544 (8) ŵ = 0.09 mm−1
c = 18.9142 (12) ÅT = 223 K
V = 2385.5 (3) Å3Block, colourless
Z = 80.38 × 0.38 × 0.22 mm
F(000) = 1024
Data collection top
Bruker SMART APEX CCD area-detector
diffractometer		2732 independent reflections
Radiation source: fine-focus sealed tube, Bruker SMART APEX CCD area-detector2345 reflections with I > 2σ(I)
graphiteRint = 0.032
φ and ω scansθmax = 27.5°, θmin = 2.2°
Absorption correction: multi-scan
(SADABS; Sheldrick, 2001)		h = −12→12
Tmin = 0.923, Tmax = 0.981k = −16→16
15692 measured reflectionsl = −24→20
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.051Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.126H atoms treated by a mixture of independent and constrained refinement
S = 1.11 w = 1/[σ2(Fo2) + (0.0592P)2 + 0.7044P]
where P = (Fo2 + 2Fc2)/3
2732 reflections(Δ/σ)max = 0.001
169 parametersΔρmax = 0.25 e Å−3
0 restraintsΔρmin = −0.23 e Å−3
Crystal data top
C12H14N6V = 2385.5 (3) Å3
Mr = 242.29Z = 8
Orthorhombic, PbcaMo Kα radiation
a = 9.9667 (6) ŵ = 0.09 mm−1
b = 12.6544 (8) ÅT = 223 K
c = 18.9142 (12) Å0.38 × 0.38 × 0.22 mm
Data collection top
Bruker SMART APEX CCD area-detector
diffractometer		2732 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 2001)		2345 reflections with I > 2σ(I)
Tmin = 0.923, Tmax = 0.981Rint = 0.032
15692 measured reflectionsθmax = 27.5°
Refinement top
R[F2 > 2σ(F2)] = 0.051H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.126Δρmax = 0.25 e Å−3
S = 1.11Δρmin = −0.23 e Å−3
2732 reflectionsAbsolute structure: ?
169 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.37457 (12)0.65120 (10)0.10869 (6)0.0291 (3)
N20.19963 (12)0.58806 (10)0.04415 (6)0.0296 (3)
N30.16605 (12)0.59905 (10)0.11387 (6)0.0279 (3)
N40.03331 (12)0.62047 (11)0.21265 (7)0.0311 (3)
H4N−0.047 (2)0.6331 (15)0.2304 (10)0.045 (5)*
N50.26523 (12)0.65592 (11)0.22214 (6)0.0319 (3)
N60.12227 (13)0.69071 (11)0.31414 (6)0.0367 (3)
H6A0.18950.71540.33840.044*
H6B0.04220.69000.33250.044*
C10.54355 (16)0.64131 (12)−0.01825 (9)0.0359 (4)
H10.58570.65340.02550.043*
C20.61893 (18)0.64144 (13)−0.07971 (10)0.0424 (4)
H20.71180.6538−0.07760.051*
C30.5583 (2)0.62357 (14)−0.14375 (10)0.0486 (5)
H30.60970.6230−0.18540.058*
C40.4215 (2)0.60640 (15)−0.14692 (9)0.0517 (5)
H40.37990.5945−0.19080.062*
C50.34574 (18)0.60667 (14)−0.08594 (9)0.0402 (4)
H50.25260.5954−0.08850.048*
C60.40643 (15)0.62352 (11)−0.02072 (8)0.0293 (3)
C70.32580 (14)0.62084 (11)0.04426 (7)0.0270 (3)
C80.27040 (14)0.63578 (11)0.15129 (7)0.0269 (3)
C90.03860 (13)0.56495 (12)0.14464 (7)0.0278 (3)
C100.14201 (14)0.65383 (11)0.24861 (8)0.0277 (3)
C110.03960 (17)0.44561 (13)0.15463 (9)0.0384 (4)
H14A0.11800.42540.18180.058*
H14B0.04230.41130.10880.058*
H14C−0.04090.42410.17960.058*
C12−0.07755 (15)0.59963 (13)0.09832 (8)0.0338 (3)
H13A−0.16160.58170.12130.051*
H13B−0.07220.56390.05300.051*
H13C−0.07310.67540.09110.051*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0221 (6)0.0391 (7)0.0261 (6)−0.0008 (5)0.0012 (5)0.0018 (5)
N20.0286 (6)0.0368 (6)0.0234 (6)−0.0032 (5)0.0038 (5)−0.0005 (5)
N30.0223 (6)0.0387 (7)0.0227 (6)−0.0031 (5)0.0019 (4)−0.0001 (5)
N40.0202 (6)0.0463 (7)0.0267 (6)−0.0017 (5)0.0031 (5)−0.0044 (5)
N50.0208 (6)0.0506 (7)0.0242 (6)−0.0010 (5)0.0000 (5)−0.0002 (5)
N60.0234 (6)0.0573 (8)0.0295 (7)−0.0030 (6)0.0016 (5)−0.0084 (6)
C10.0319 (8)0.0398 (8)0.0360 (8)0.0029 (6)0.0052 (6)0.0031 (7)
C20.0379 (9)0.0404 (9)0.0489 (10)0.0031 (7)0.0167 (7)0.0055 (7)
C30.0620 (12)0.0447 (10)0.0392 (10)0.0003 (8)0.0254 (9)0.0001 (7)
C40.0702 (13)0.0566 (11)0.0282 (8)−0.0132 (10)0.0088 (8)−0.0067 (8)
C50.0436 (10)0.0454 (9)0.0314 (8)−0.0115 (7)0.0043 (7)−0.0031 (7)
C60.0319 (8)0.0276 (7)0.0284 (7)−0.0007 (6)0.0058 (6)0.0014 (5)
C70.0258 (7)0.0295 (7)0.0256 (7)−0.0001 (5)0.0021 (5)0.0026 (5)
C80.0209 (6)0.0337 (7)0.0260 (7)−0.0002 (5)−0.0011 (5)0.0024 (5)
C90.0213 (7)0.0360 (7)0.0260 (7)−0.0041 (5)0.0016 (5)−0.0002 (6)
C100.0229 (7)0.0343 (7)0.0260 (7)0.0011 (5)−0.0001 (5)0.0013 (6)
C110.0389 (9)0.0362 (8)0.0400 (9)−0.0038 (6)0.0052 (7)0.0035 (7)
C120.0254 (7)0.0423 (8)0.0337 (8)−0.0028 (6)−0.0033 (6)−0.0008 (6)
Geometric parameters (Å, °) top
N1—C81.3286 (18)C2—C31.373 (3)
N1—C71.3670 (18)C2—H20.94
N2—C71.3241 (19)C3—C41.382 (3)
N2—N31.3675 (16)C3—H30.94
N3—C81.3410 (18)C4—C51.379 (2)
N3—C91.4624 (17)C4—H40.94
N4—C101.3470 (18)C5—C61.390 (2)
N4—C91.4666 (18)C5—H50.94
N4—H4N0.88 (2)C6—C71.4690 (19)
N5—C101.3266 (18)C9—C121.517 (2)
N5—C81.3652 (19)C9—C111.522 (2)
N6—C101.3389 (19)C11—H14A0.97
N6—H6A0.87C11—H14B0.97
N6—H6B0.87C11—H14C0.97
C1—C21.384 (2)C12—H13A0.97
C1—C61.386 (2)C12—H13B0.97
C1—H10.94C12—H13C0.97
C8—N1—C7102.79 (12)C5—C6—C7120.05 (14)
C7—N2—N3101.48 (11)N2—C7—N1115.29 (12)
C8—N3—N2110.75 (11)N2—C7—C6121.70 (13)
C8—N3—C9124.46 (12)N1—C7—C6123.01 (13)
N2—N3—C9124.49 (11)N1—C8—N3109.69 (13)
C10—N4—C9124.34 (12)N1—C8—N5126.68 (13)
C10—N4—H4N118.6 (12)N3—C8—N5123.61 (13)
C9—N4—H4N117.1 (12)N3—C9—N4103.82 (11)
C10—N5—C8113.69 (12)N3—C9—C12110.36 (12)
C10—N6—H6A120.0N4—C9—C12109.91 (12)
C10—N6—H6B120.0N3—C9—C11109.67 (12)
H6A—N6—H6B120.0N4—C9—C11111.51 (12)
C2—C1—C6120.48 (16)C12—C9—C11111.33 (13)
C2—C1—H1119.8N5—C10—N6118.58 (13)
C6—C1—H1119.8N5—C10—N4124.07 (13)
C3—C2—C1120.14 (17)N6—C10—N4117.30 (13)
C3—C2—H2119.9C9—C11—H14A109.5
C1—C2—H2119.9C9—C11—H14B109.5
C2—C3—C4119.90 (16)H14A—C11—H14B109.5
C2—C3—H3120.0C9—C11—H14C109.5
C4—C3—H3120.0H14A—C11—H14C109.5
C5—C4—C3120.24 (18)H14B—C11—H14C109.5
C5—C4—H4119.9C9—C12—H13A109.5
C3—C4—H4119.9C9—C12—H13B109.5
C4—C5—C6120.30 (17)H13A—C12—H13B109.5
C4—C5—H5119.9C9—C12—H13C109.5
C6—C5—H5119.9H13A—C12—H13C109.5
C1—C6—C5118.94 (14)H13B—C12—H13C109.5
C1—C6—C7121.00 (14)
C7—N2—N3—C8−0.51 (15)N2—N3—C8—N10.58 (16)
C7—N2—N3—C9−174.53 (13)C9—N3—C8—N1174.60 (13)
C6—C1—C2—C3−0.2 (2)N2—N3—C8—N5179.00 (13)
C1—C2—C3—C40.6 (3)C9—N3—C8—N5−7.0 (2)
C2—C3—C4—C5−0.3 (3)C10—N5—C8—N1166.91 (14)
C3—C4—C5—C6−0.4 (3)C10—N5—C8—N3−11.2 (2)
C2—C1—C6—C5−0.5 (2)C8—N3—C9—N423.14 (18)
C2—C1—C6—C7178.63 (14)N2—N3—C9—N4−163.64 (13)
C4—C5—C6—C10.8 (2)C8—N3—C9—C12140.88 (14)
C4—C5—C6—C7−178.32 (16)N2—N3—C9—C12−45.91 (18)
N3—N2—C7—N10.28 (16)C8—N3—C9—C11−96.12 (16)
N3—N2—C7—C6−179.93 (13)N2—N3—C9—C1177.09 (17)
C8—N1—C7—N20.05 (16)C10—N4—C9—N3−25.30 (18)
C8—N1—C7—C6−179.74 (13)C10—N4—C9—C12−143.35 (14)
C1—C6—C7—N2−169.39 (14)C10—N4—C9—C1192.70 (17)
C5—C6—C7—N29.7 (2)C8—N5—C10—N6−168.20 (13)
C1—C6—C7—N110.4 (2)C8—N5—C10—N49.1 (2)
C5—C6—C7—N1−170.48 (14)C9—N4—C10—N511.3 (2)
C7—N1—C8—N3−0.37 (15)C9—N4—C10—N6−171.38 (14)
C7—N1—C8—N5−178.73 (14)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N4—H4N···N5i0.88 (2)2.10 (2)2.9768 (17)176 (2)
N6—H6B···N1i0.872.072.9113 (18)163
Symmetry codes: (i) x−1/2, y, −z+1/2.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N4—H4N···N5i0.88 (2)2.10 (2)2.9768 (17)176 (2)
N6—H6B···N1i0.872.072.9113 (18)163
Symmetry codes: (i) x−1/2, y, −z+1/2.
Acknowledgements top

This work is supported by the Academic Research Fund from the National University of Singapore.

references
References top

Bruker (2003). SMART (Version 5.631), SAINT (Version 6.63), SHELXTL (Version 6.14) and SADABS (Version 2.03). Bruker AXS GmbH, Karlsruhe, Germany.

Dolzhenko, A. V. & Chui, W. K. (2006). J. Heterocycl. Chem. 43, 95–100.

Dolzhenko, A. V., Chui, W. K., Dolzhenko, A. V. & Chan, L. W. (2005). J. Fluorine Chem. 126, 759–763.

Dolzhenko, A. V., Dolzhenko, A. V. & Chui, W. K. (2006). Heterocycles, 68, 1723–1759.

Dolzhenko, A. V., Dolzhenko, A. V. & Chui, W. K. (2007). Heterocycles, 71, 429–436.

Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.

Sheldrick, G. M. (2001). SADABS. Version 2.03. University of Göttingen, Germany.