4,4-Dimethyl-3,4-dihydro­pyrido[2′,3′:3,4]pyrazolo­[1,5-a][1,3,5]triazin-2-amine ethanol monosolvate

Anton V Dolzhenko; Geok Kheng Tan; Anna V Dolzhenko; Lip Lin Koh; Wai Keung Chui

doi:10.1107/S160053681005097X

. 2010 Dec 11;67(Pt 1):o83–o84. doi: 10.1107/S160053681005097X

4,4-Dimethyl-3,4-dihydropyrido[2′,3′:3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amine ethanol monosolvate¹

Anton V Dolzhenko ^a,^*,^‡, Geok Kheng Tan ^b, Anna V Dolzhenko ^c, Lip Lin Koh ^b, Wai Keung Chui ^d

PMCID: PMC3050164 PMID: 21522794

Abstract

In the title compound, C₁₀H₁₂N₆·C₂H₅OH, the planarity of the heterocyclic system is slightly distorted at the triazine ring (r.m.s. deviation = 0.1191 Å), which adopts a conformation best described as intermediate between a flattened twisted boat and a half-boat with the tertiary Csp ³ atom at the bow. In the crystal, molecules form centrosymmetric dimers connected by N⋯H—O and O⋯H—N hydrogen bonds between the amino group H atom, the ethanol solvent molecule and the triazine N atom, making an R ₄ ⁴(12) graph-set motif. The other H atom of the amino group and the H atom on the endocyclic N atom form N⋯H—N hydrogen bonds with the N atoms of the pyrazole and pyridine rings, respectively, linking the molecules into C(7)C(7) chains with the R ₂ ²(8) binary graph-set motif running along [010].

Related literature

For a review on the synthesis and biological activity of pyrazolo[1,5-a]triazines, see: Dolzhenko et al. (2008 ▶). For the synthesis, crystal structure studies and biological activity of related fused gem-dimethyl-substituted amino-1,3,5-triazines, see: Dolzhenko et al. (2007a ▶,b ▶, 2009 ▶), Toyoda et al. (1997 ▶). For graph-set analysis of hydrogen bonding, see: Bernstein et al. (1995 ▶). For a related structure, see: Sachdeva et al. (2010 ▶).

Experimental

Crystal data

C₁₀H₁₂N₆·C₂H₆O
M _r = 262.32
Monoclinic,
a = 12.1250 (19) Å
b = 13.913 (2) Å
c = 16.598 (3) Å
β = 101.683 (4)°
V = 2742.0 (7) Å³
Z = 8
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 100 K
0.60 × 0.38 × 0.10 mm

Data collection

Bruker SMART APEX CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2001 ▶) T _min = 0.950, T _max = 0.991
9471 measured reflections
3129 independent reflections
2657 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.050
wR(F ²) = 0.133
S = 1.06
3129 reflections
209 parameters
38 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.37 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Data collection: SMART (Bruker, 2001 ▶); cell refinement: SAINT (Bruker, 2001 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053681005097X/hg2760sup1.cif

e-67-00o83-sup1.cif^{(20.3KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053681005097X/hg2760Isup2.hkl

e-67-00o83-Isup2.hkl^{(153.6KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N5—H5⋯N1ⁱ	0.86 (2)	2.16 (2)	3.0077 (18)	169.5 (18)
N6—H6B⋯N2ⁱ	0.90 (2)	2.08 (2)	2.9754 (18)	171.5 (18)
N6—H6A⋯O1Sⁱⁱ	0.85 (2)	2.03 (2)	2.8540 (18)	163.2 (18)
O1S—H1S⋯N4	0.87 (2)	1.93 (2)	2.7943 (17)	170 (2)

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

This work was supported by the School of Pharmacy, Curtin University of Technology, and the National Medical Research Council, Singapore (NMRC/NIG/0019/2008).

supplementary crystallographic information

Comment

The pyrazolo[1,5-a]triazine heterocyclic system has been recognized as a template for the construction of new potential therapeutic agents (Dolzhenko et al., 2008). However data on pyrido[2',3':3,4]pyrazolo[1,5-a][1,3,5]triazines are limited and no details on their structure are available. Herein, we report molecular and crystal structure of 4,4-dimethyl-3,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amine, which crystallizes with a ethanol molecule to give the title compound, C₁₀H₁₂N₆.C₂H₅OH (Fig. 1 & 2). This molecule has a close structural resemblance with some known dihydrofolate reductase inhibitors such as antimalarial drug cycloguanil and its fused analogue (Toyoda et al., 1997) (Fig. 3). Due to annular tautomerism, four tautomeric forms are theoretically possible for the compound (Fig. 4). Similarly to the previously reported (Dolzhenko et al., 2007b) related fused gem-dimethyl substituted amino-1,3,5-triazine, the compound exists in the crystal as a tautomer with the labile hydrogen atom located at the triazine nitrogen atom adjacent to the sp³ hybridized carbon atom.

The heterocyclic system is nearly planar (with r.m.s. deviation of 0.1191 Å) with a distortion at the triazine ring. The triazine ring adopts the conformation best described as an intermediate between a flatten twist boat and a half-boat with atoms C-8 and N-4 at the bow and the stern. The angle between the geminal flagpole and bowsprit methyl groups is 112.40 (14)°. The N4—C7, N5—C7 and N6—C7 bond distances are similar suggesting guanidine-like electron delocalization in the N4—N6/C7 fragment of the molecule.

In the crystal, the molecules form centrosymmetric dimers connected by the N···HO and O···HN hydrogen bonds between the amino group N6—H6A, ethanol molecule and the triazine N4 atom making a R₄⁴(12) graph-set motif (Bernstein et al., 1995). Another hydrogen atom of the amino group N6—H6B and the hydrogen atom at the endocyclic N5 atom act as hydrogen donors forming N···HN contacts with the pyrazole and pyridine N2 and N1 atoms, respectively. They arrange molecules into the running along a [010] axis C(7)C(7) chains with the R₂²(8) binary graph-set motif.

Experimental

4,4-Dimethyl-3,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amine was prepared by the cyclocondensation of pyrazolo[3,4-b]pyridin-3-guanidine with acetone similarly to the previously described methods (Dolzhenko et al., 2007a; Dolzhenko et al., 2009). 1H-Pyrazolo[3,4-b]pyridin-3-guanidine (0.88 g, 5.0 mmol) and piperidine (0.30 ml, 3.0 mmol) were heated in acetone (30 ml) under reflux for 10 h. After cooling, the product was filtered and washed with acetone. Yield: 0.89 g (82%). The crystals suitable for crystallographic analysis were grown by recrystallization from ethanol. m.p. 559 K.