Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536807021009/ci2379sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S1600536807021009/ci2379Isup2.hkl |
CCDC reference: 651374
Key indicators
- Single-crystal X-ray study
- T = 223 K
- Mean (C-C) = 0.002 Å
- R factor = 0.051
- wR factor = 0.126
- Data-to-parameter ratio = 16.2
checkCIF/PLATON results
No syntax errors found
Alert level C PLAT420_ALERT_2_C D-H Without Acceptor N6 - H6A ... ?
0 ALERT level A = In general: serious problem 0 ALERT level B = Potentially serious problem 1 ALERT level C = Check and explain 0 ALERT level G = General alerts; check 0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data 1 ALERT type 2 Indicator that the structure model may be wrong or deficient 0 ALERT type 3 Indicator that the structure quality may be low 0 ALERT type 4 Improvement, methodology, query or suggestion 0 ALERT type 5 Informative message, check
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).
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.
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.
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).
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.
C12H14N6 | Dx = 1.349 Mg m−3 |
Mr = 242.29 | Melting point: 567 K |
Orthorhombic, Pbca | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2ac 2ab | Cell parameters from 3419 reflections |
a = 9.9667 (6) Å | θ = 2.8–24.6° |
b = 12.6544 (8) Å | µ = 0.09 mm−1 |
c = 18.9142 (12) Å | T = 223 K |
V = 2385.5 (3) Å3 | Block, colourless |
Z = 8 | 0.38 × 0.38 × 0.22 mm |
F(000) = 1024 |
Bruker SMART APEX CCD area-detector diffractometer | 2732 independent reflections |
Radiation source: fine-focus sealed tube, Bruker SMART APEX CCD area-detector | 2345 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.032 |
φ and ω scans | θmax = 27.5°, θmin = 2.2° |
Absorption correction: multi-scan (SADABS; Sheldrick, 2001) | h = −12→12 |
Tmin = 0.923, Tmax = 0.981 | k = −16→16 |
15692 measured reflections | l = −24→20 |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.051 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.126 | H 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 parameters | Δρmax = 0.25 e Å−3 |
0 restraints | Δρmin = −0.24 e Å−3 |
C12H14N6 | V = 2385.5 (3) Å3 |
Mr = 242.29 | Z = 8 |
Orthorhombic, Pbca | Mo Kα radiation |
a = 9.9667 (6) Å | µ = 0.09 mm−1 |
b = 12.6544 (8) Å | T = 223 K |
c = 18.9142 (12) Å | 0.38 × 0.38 × 0.22 mm |
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 = 0.981 | Rint = 0.032 |
15692 measured reflections |
R[F2 > 2σ(F2)] = 0.051 | 0 restraints |
wR(F2) = 0.126 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.11 | Δρmax = 0.25 e Å−3 |
2732 reflections | Δρmin = −0.24 e Å−3 |
169 parameters |
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. |
x | y | z | Uiso*/Ueq | ||
N1 | 0.37457 (12) | 0.65120 (10) | 0.10869 (6) | 0.0291 (3) | |
N2 | 0.19963 (12) | 0.58806 (10) | 0.04415 (6) | 0.0296 (3) | |
N3 | 0.16605 (12) | 0.59905 (10) | 0.11387 (6) | 0.0279 (3) | |
N4 | 0.03331 (12) | 0.62047 (11) | 0.21265 (7) | 0.0311 (3) | |
H4N | −0.047 (2) | 0.6331 (15) | 0.2304 (10) | 0.045 (5)* | |
N5 | 0.26523 (12) | 0.65592 (11) | 0.22214 (6) | 0.0319 (3) | |
N6 | 0.12227 (13) | 0.69071 (11) | 0.31414 (6) | 0.0367 (3) | |
H6A | 0.1895 | 0.7154 | 0.3384 | 0.044* | |
H6B | 0.0422 | 0.6900 | 0.3325 | 0.044* | |
C1 | 0.54355 (16) | 0.64131 (12) | −0.01825 (9) | 0.0359 (4) | |
H1 | 0.5857 | 0.6534 | 0.0255 | 0.043* | |
C2 | 0.61893 (18) | 0.64144 (13) | −0.07971 (10) | 0.0424 (4) | |
H2 | 0.7118 | 0.6538 | −0.0776 | 0.051* | |
C3 | 0.5583 (2) | 0.62357 (14) | −0.14375 (10) | 0.0486 (5) | |
H3 | 0.6097 | 0.6230 | −0.1854 | 0.058* | |
C4 | 0.4215 (2) | 0.60640 (15) | −0.14692 (9) | 0.0517 (5) | |
H4 | 0.3799 | 0.5945 | −0.1908 | 0.062* | |
C5 | 0.34574 (18) | 0.60667 (14) | −0.08594 (9) | 0.0402 (4) | |
H5 | 0.2526 | 0.5954 | −0.0885 | 0.048* | |
C6 | 0.40643 (15) | 0.62352 (11) | −0.02072 (8) | 0.0293 (3) | |
C7 | 0.32580 (14) | 0.62084 (11) | 0.04426 (7) | 0.0270 (3) | |
C8 | 0.27040 (14) | 0.63578 (11) | 0.15129 (7) | 0.0269 (3) | |
C9 | 0.03860 (13) | 0.56495 (12) | 0.14464 (7) | 0.0278 (3) | |
C10 | 0.14201 (14) | 0.65383 (11) | 0.24861 (8) | 0.0277 (3) | |
C11 | 0.03960 (17) | 0.44561 (13) | 0.15463 (9) | 0.0384 (4) | |
H14A | 0.1180 | 0.4254 | 0.1818 | 0.058* | |
H14B | 0.0423 | 0.4113 | 0.1088 | 0.058* | |
H14C | −0.0409 | 0.4241 | 0.1796 | 0.058* | |
C12 | −0.07755 (15) | 0.59963 (13) | 0.09832 (8) | 0.0338 (3) | |
H13A | −0.1616 | 0.5817 | 0.1213 | 0.051* | |
H13B | −0.0722 | 0.5639 | 0.0530 | 0.051* | |
H13C | −0.0731 | 0.6754 | 0.0911 | 0.051* |
U11 | U22 | U33 | U12 | U13 | U23 | |
N1 | 0.0221 (6) | 0.0391 (7) | 0.0261 (6) | −0.0008 (5) | 0.0012 (5) | 0.0018 (5) |
N2 | 0.0286 (6) | 0.0368 (6) | 0.0234 (6) | −0.0032 (5) | 0.0038 (5) | −0.0005 (5) |
N3 | 0.0223 (6) | 0.0387 (7) | 0.0227 (6) | −0.0031 (5) | 0.0019 (4) | −0.0001 (5) |
N4 | 0.0202 (6) | 0.0463 (7) | 0.0267 (6) | −0.0017 (5) | 0.0031 (5) | −0.0044 (5) |
N5 | 0.0208 (6) | 0.0506 (7) | 0.0242 (6) | −0.0010 (5) | 0.0000 (5) | −0.0002 (5) |
N6 | 0.0234 (6) | 0.0573 (8) | 0.0295 (7) | −0.0030 (6) | 0.0016 (5) | −0.0084 (6) |
C1 | 0.0319 (8) | 0.0398 (8) | 0.0360 (8) | 0.0029 (6) | 0.0052 (6) | 0.0031 (7) |
C2 | 0.0379 (9) | 0.0404 (9) | 0.0489 (10) | 0.0031 (7) | 0.0167 (7) | 0.0055 (7) |
C3 | 0.0620 (12) | 0.0447 (10) | 0.0392 (10) | 0.0003 (8) | 0.0254 (9) | 0.0001 (7) |
C4 | 0.0702 (13) | 0.0566 (11) | 0.0282 (8) | −0.0132 (10) | 0.0088 (8) | −0.0067 (8) |
C5 | 0.0436 (10) | 0.0454 (9) | 0.0314 (8) | −0.0115 (7) | 0.0043 (7) | −0.0031 (7) |
C6 | 0.0319 (8) | 0.0276 (7) | 0.0284 (7) | −0.0007 (6) | 0.0058 (6) | 0.0014 (5) |
C7 | 0.0258 (7) | 0.0295 (7) | 0.0256 (7) | −0.0001 (5) | 0.0021 (5) | 0.0026 (5) |
C8 | 0.0209 (6) | 0.0337 (7) | 0.0260 (7) | −0.0002 (5) | −0.0011 (5) | 0.0024 (5) |
C9 | 0.0213 (7) | 0.0360 (7) | 0.0260 (7) | −0.0041 (5) | 0.0016 (5) | −0.0002 (6) |
C10 | 0.0229 (7) | 0.0343 (7) | 0.0260 (7) | 0.0011 (5) | −0.0001 (5) | 0.0013 (6) |
C11 | 0.0389 (9) | 0.0362 (8) | 0.0400 (9) | −0.0038 (6) | 0.0052 (7) | 0.0035 (7) |
C12 | 0.0254 (7) | 0.0423 (8) | 0.0337 (8) | −0.0028 (6) | −0.0033 (6) | −0.0008 (6) |
N1—C8 | 1.3286 (18) | C2—C3 | 1.373 (3) |
N1—C7 | 1.3670 (18) | C2—H2 | 0.94 |
N2—C7 | 1.3241 (19) | C3—C4 | 1.382 (3) |
N2—N3 | 1.3675 (16) | C3—H3 | 0.94 |
N3—C8 | 1.3410 (18) | C4—C5 | 1.379 (2) |
N3—C9 | 1.4624 (17) | C4—H4 | 0.94 |
N4—C10 | 1.3470 (18) | C5—C6 | 1.390 (2) |
N4—C9 | 1.4666 (18) | C5—H5 | 0.94 |
N4—H4N | 0.88 (2) | C6—C7 | 1.4690 (19) |
N5—C10 | 1.3266 (18) | C9—C12 | 1.517 (2) |
N5—C8 | 1.3652 (19) | C9—C11 | 1.522 (2) |
N6—C10 | 1.3389 (19) | C11—H14A | 0.97 |
N6—H6A | 0.87 | C11—H14B | 0.97 |
N6—H6B | 0.87 | C11—H14C | 0.97 |
C1—C2 | 1.384 (2) | C12—H13A | 0.97 |
C1—C6 | 1.386 (2) | C12—H13B | 0.97 |
C1—H1 | 0.94 | C12—H13C | 0.97 |
C8—N1—C7 | 102.79 (12) | C5—C6—C7 | 120.05 (14) |
C7—N2—N3 | 101.48 (11) | N2—C7—N1 | 115.29 (12) |
C8—N3—N2 | 110.75 (11) | N2—C7—C6 | 121.70 (13) |
C8—N3—C9 | 124.46 (12) | N1—C7—C6 | 123.01 (13) |
N2—N3—C9 | 124.49 (11) | N1—C8—N3 | 109.69 (13) |
C10—N4—C9 | 124.34 (12) | N1—C8—N5 | 126.68 (13) |
C10—N4—H4N | 118.6 (12) | N3—C8—N5 | 123.61 (13) |
C9—N4—H4N | 117.1 (12) | N3—C9—N4 | 103.82 (11) |
C10—N5—C8 | 113.69 (12) | N3—C9—C12 | 110.36 (12) |
C10—N6—H6A | 120.0 | N4—C9—C12 | 109.91 (12) |
C10—N6—H6B | 120.0 | N3—C9—C11 | 109.67 (12) |
H6A—N6—H6B | 120.0 | N4—C9—C11 | 111.51 (12) |
C2—C1—C6 | 120.48 (16) | C12—C9—C11 | 111.33 (13) |
C2—C1—H1 | 119.8 | N5—C10—N6 | 118.58 (13) |
C6—C1—H1 | 119.8 | N5—C10—N4 | 124.07 (13) |
C3—C2—C1 | 120.14 (17) | N6—C10—N4 | 117.30 (13) |
C3—C2—H2 | 119.9 | C9—C11—H14A | 109.5 |
C1—C2—H2 | 119.9 | C9—C11—H14B | 109.5 |
C2—C3—C4 | 119.90 (16) | H14A—C11—H14B | 109.5 |
C2—C3—H3 | 120.0 | C9—C11—H14C | 109.5 |
C4—C3—H3 | 120.0 | H14A—C11—H14C | 109.5 |
C5—C4—C3 | 120.24 (18) | H14B—C11—H14C | 109.5 |
C5—C4—H4 | 119.9 | C9—C12—H13A | 109.5 |
C3—C4—H4 | 119.9 | C9—C12—H13B | 109.5 |
C4—C5—C6 | 120.30 (17) | H13A—C12—H13B | 109.5 |
C4—C5—H5 | 119.9 | C9—C12—H13C | 109.5 |
C6—C5—H5 | 119.9 | H13A—C12—H13C | 109.5 |
C1—C6—C5 | 118.94 (14) | H13B—C12—H13C | 109.5 |
C1—C6—C7 | 121.00 (14) | ||
C7—N2—N3—C8 | −0.51 (15) | N2—N3—C8—N1 | 0.58 (16) |
C7—N2—N3—C9 | −174.53 (13) | C9—N3—C8—N1 | 174.60 (13) |
C6—C1—C2—C3 | −0.2 (2) | N2—N3—C8—N5 | 179.00 (13) |
C1—C2—C3—C4 | 0.6 (3) | C9—N3—C8—N5 | −7.0 (2) |
C2—C3—C4—C5 | −0.3 (3) | C10—N5—C8—N1 | 166.91 (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—N4 | 23.14 (18) |
C2—C1—C6—C7 | 178.63 (14) | N2—N3—C9—N4 | −163.64 (13) |
C4—C5—C6—C1 | 0.8 (2) | C8—N3—C9—C12 | 140.88 (14) |
C4—C5—C6—C7 | −178.32 (16) | N2—N3—C9—C12 | −45.91 (18) |
N3—N2—C7—N1 | 0.28 (16) | C8—N3—C9—C11 | −96.12 (16) |
N3—N2—C7—C6 | −179.93 (13) | N2—N3—C9—C11 | 77.09 (17) |
C8—N1—C7—N2 | 0.05 (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—C11 | 92.70 (17) |
C5—C6—C7—N2 | 9.7 (2) | C8—N5—C10—N6 | −168.20 (13) |
C1—C6—C7—N1 | 10.4 (2) | C8—N5—C10—N4 | 9.1 (2) |
C5—C6—C7—N1 | −170.48 (14) | C9—N4—C10—N5 | 11.3 (2) |
C7—N1—C8—N3 | −0.37 (15) | C9—N4—C10—N6 | −171.38 (14) |
C7—N1—C8—N5 | −178.73 (14) |
D—H···A | D—H | H···A | D···A | D—H···A |
N4—H4N···N5i | 0.88 (2) | 2.10 (2) | 2.9768 (17) | 176 (2) |
N6—H6B···N1i | 0.87 | 2.07 | 2.9113 (18) | 163 |
Symmetry code: (i) x−1/2, y, −z+1/2. |
Experimental details
Crystal data | |
Chemical formula | C12H14N6 |
Mr | 242.29 |
Crystal system, space group | Orthorhombic, Pbca |
Temperature (K) | 223 |
a, b, c (Å) | 9.9667 (6), 12.6544 (8), 18.9142 (12) |
V (Å3) | 2385.5 (3) |
Z | 8 |
Radiation type | Mo Kα |
µ (mm−1) | 0.09 |
Crystal size (mm) | 0.38 × 0.38 × 0.22 |
Data collection | |
Diffractometer | Bruker SMART APEX CCD area-detector |
Absorption correction | Multi-scan (SADABS; Sheldrick, 2001) |
Tmin, Tmax | 0.923, 0.981 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 15692, 2732, 2345 |
Rint | 0.032 |
(sin θ/λ)max (Å−1) | 0.649 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.051, 0.126, 1.11 |
No. of reflections | 2732 |
No. of parameters | 169 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.25, −0.24 |
Computer programs: SMART (Bruker, 2003), SAINT (Bruker, 2003), SAINT, SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), SHELXTL (Bruker, 2003), SHELXTL.
D—H···A | D—H | H···A | D···A | D—H···A |
N4—H4N···N5i | 0.88 (2) | 2.10 (2) | 2.9768 (17) | 176 (2) |
N6—H6B···N1i | 0.87 | 2.07 | 2.9113 (18) | 163 |
Symmetry code: (i) x−1/2, y, −z+1/2. |
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.