Crystal structure of [4-(2-meth­oxy­phen­yl)-3-methyl-1-phenyl-6-tri­fluoro­methyl-1H-pyrazolo­[3,4-b]pyridin-5-yl](thio­phen-2-yl)methanone

V Rajni Swamy; P Gunasekaran; R V Krishnakumar; N Srinivasan; P Müller

doi:10.1107/S1600536814017437

. 2014 Aug 6;70(Pt 9):o974–o975. doi: 10.1107/S1600536814017437

Crystal structure of [4-(2-methoxyphenyl)-3-methyl-1-phenyl-6-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-5-yl](thiophen-2-yl)methanone

V Rajni Swamy ^a, P Gunasekaran ^b, R V Krishnakumar ^a,^*, N Srinivasan ^a, P Müller ^c

PMCID: PMC4186079 PMID: 25309288

Abstract

The title compound, C₂₆H₁₈F₃N₃O₂S, a 2-methoxy-substituted derivative, is closely related to its 4-methyl- and 4-chloro-substituted analogues and yet displays no structural relationships with them. The thiophene ring is disorder free and the –CF₃ group exhibits disorder, respectively, in contrast and similar to that observed in the 4-methyl- and 4-chloro-substituted derivatives. The torsion angle which defines the twist of the thiophene ring is −69.6 (2)° (gauche) in the title compound, whereas it is anticlinal in the 4-methyl- and 4-chloro-substituted derivatives, with respective values of 99.9 (2) and 99.3 (2)°. The absence of disorder in the thiophene ring facilitates one of its ring C atoms to participate in the lone intermolecular C—H⋯O hydrogen bond present in the crystal, leading to a characteristic C(5) chain graph-set motif linking molecules related through glides along [010]. An intramoleculr C—H⋯N hydrogen bond also occurs.

Keywords: crystal structure; 1H-pyrazolo[3,4-b]pyridine; hydrogen bonding graph-set analysis

Related literature

For the biological activity of 1H-pyrazolo[3,4-b]pyridines, see: Hardy (1984 ▶); Chu & Lynch (1975 ▶); Ali (2009 ▶); Wilson et al. (2013 ▶); Souza et al. (2012 ▶). For applications of thiophene ring systems in solar cells, see: Hara et al. (2003 ▶). For related structures, see: Rajni Swamy et al. (2013 ▶). For the treatment of disorders in crystal structures, see: Müller (2009 ▶). For hydrogen-bond graph-set motifs, see: Bernstein et al. (1995 ▶).

Experimental

Crystal data

C₂₆H₁₈F₃N₃O₂S
M _r = 493.49
Monoclinic,
a = 18.9343 (11) Å
b = 11.6347 (6) Å
c = 20.9800 (12) Å
β = 92.511 (2)°
V = 4617.3 (4) Å³
Z = 8
Mo Kα radiation
μ = 0.19 mm⁻¹
T = 301 K
0.25 × 0.16 × 0.12 mm

Data collection

Bruker SMART APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2009 ▶) T _min = 0.949, T _max = 0.979
23854 measured reflections
5492 independent reflections
3784 reflections with I > 2σ(I)
R _int = 0.039

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.138
S = 1.02
5492 reflections
346 parameters
142 restraints
H-atom parameters constrained
Δρ_max = 0.33 e Å⁻³
Δρ_min = −0.47 e Å⁻³

Data collection: APEX2 (Bruker, 2009 ▶); cell refinement: SAINT (Bruker, 2009 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS2013 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXL2013.

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S1600536814017437/hg5397sup1.cif

e-70-0o974-sup1.cif^{(739.5KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814017437/hg5397Isup2.hkl

e-70-0o974-Isup2.hkl^{(301.2KB, hkl)}

Click here for additional data file.^{(8.8KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814017437/hg5397Isup3.cml

Click here for additional data file.^{(1.3MB, tif)}

. DOI: 10.1107/S1600536814017437/hg5397fig1.tif

Molecular structure of (I) showing the atom numbering scheme and displacement ellipsoids drawn at the 50% probability level. H atoms and atoms of minor disorder components have been omitted for clarity.

Click here for additional data file.^{(1.7MB, tif)}

. DOI: 10.1107/S1600536814017437/hg5397fig2.tif

Overlay of the molecular structures of (I) (blue), 4- methyl (red) and 4-chloro (green) analogues. H atoms and atoms of minor disordered components were not included in the least squares fit of the atomic positions.

Click here for additional data file.^{(1.5MB, tif)}

. DOI: 10.1107/S1600536814017437/hg5397fig3.tif

C—H⋯O hydrogen bond linking molecules through chains extending infinitely along [010]. Non-participating ring atoms and groups have been omitted for clarity.

CCDC reference: 1016829

Additional supporting information: crystallographic information; 3D view; checkCIF report

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C13—H13⋯N3	0.93	2.42	3.012 (2)	122
C11—H11⋯O1ⁱ	0.93	2.51	3.114 (3)	122

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors thank the Sophisticated Analytical Instrumentation Facility (SAIF), Indian Institute of Technology, Chennai, for the data collection and Professor S. Perumal for useful discussions.

supplementary crystallographic information

S1. Comment

Many polysubstituted derivatives of 1H-pyrazolo[3,4-b]pyridine have been synthesized as potentially biologically active materials (Hardy, 1984; Chu & Lynch, 1975) and established as antimicrobial agents against bacterial and fungal strain (Ali, 2009). Thiophenes are regarded as important building units for a variety of drugs. Recently, a new class of thiophene compounds that kill extensively drug resistant Mycobacterium tuberculosis have been reported (Wilson et al., 2013). An evaluation of the cytotoxic activities of some thiophene derivatives have indicated that they could be considered promising compounds for the discovery of new antitumor agents (Souza et al., 2012). Also, in the background of coumarin dyes being successfully used as organic dye photo-sensitizers for Dye-Sensitized-Solar-Cells (DSSC), the design of new coumarin dyes through the introduction of thiophene moieties have shown to remarkably improve the solar cell performance (Hara et al., 2003).

The title compound, C₂₆H₁₈F₃N₃O₂S, a 2-methoxy-substituted derivative, is closely related to its 4-methyl and 4-chloro analogues which have been earlier shown to obey the chloro-methyl exchange rule [Rajni Swamy et al., 2013] and yet displays no structural relationships. The title compound may be regarded as an example of a case where change in the nature and position of the substitution may affect intra and inter molecular interactions which in turn might alter the molecular geometry quite noticeably. Fig.1 shows the molecular structure of (I) showing the atom numbering scheme and displacement ellipsoids drawn at the 50% probability level.

The bond lengths and angles are comparable in all the three structures with deviations evident in the torsion angles related to the thiophene group which may be attributed to the absence of disorder in the ring, unlike in the methyl- and chloro- substituted derivatives. The torsion angle C3—C4—C7—C8 which defines the twist of the thiophene ring is –69.6 (2)° [gauche] in the title compound whereas it is anticlinal in 4-methyl and 4-chloro derivatives with respective values of 99.9 (2)° and 99.3 (2)° (Figure 2). Correspondingly, the orientation of the carbonyl O with respect to the carbon to which the CF₃ group is attached, defined by the torsion angle C5—C4—C7—O1 is –70.8 (3)° in the present compound and 98.6 (2)° and 98.8 (2)°, respectively for 4-chloro and 4-methyl analogues.

The intramolecular distances H13···N3 and H17···N2, on either sides of the phenyl ring, involving the N3 and N2 atoms of the pyrazolo-pyridine rings are 2.416 (1)Å and 2.436 (2) Å respectively. The increased values observed for these distances in 4-methyl and 4-chloro counterparts are 2.483 (1)Å and 2.513( 1)Å which is due to the participation of the phenyl ring (atom C15) in an intermolecular C—-H···.O hydrogen bond. The shortening of these distances in the present case is correlated to the non-participation of the phenyl ring in the hydrogen bond, which in turn has caused the associated phenyl and the fused pyrazolo-pyridine ring systems tend towards coplanarity. Thus, a C13—H13···N3 intramolecular hydrogen bond may well be regarded as present. The same argument is invalid for considering C17—H17···N2 as a hydrogen bond since its geometry is more of sterical consequence rather than a hydrogen bonded requirement.

The absence of disorder in the thiophene ring facilitates one of its ring C11 atom to participate in the lone intermolecular C—H···O hydrogen bond present in the crystal. As a consequene, the thiophene ring deviates significantly from being perpendicular to the central fused pyrazolo-pyridine ring. The C11—H11···O1 interaction gives rise to a characteristic C(5) chain graph-set motif [Bernstein et al.,1995] which links molecules related through glides extending along [010] (Figure 3). Thus, the scheme of non-covalent interactions is entirely different compared to the 4-methyl and 4-chloro analogues and the significant C—H···π interaction observed in them is absent in the present case.

S2. Refinement

The structure displays disorder of the CF₃ group. The disorder was refined with the help of similarity restraints on 1-2 and 1-3 distances and displacement parameters as well as rigid bond restraints (aka Hirshfeld restraints) for anisotropic displacement parameters (Müller, 2009). The first approach to the CF₃ disorder was to refine the CF₃ group as freely rotating about the C5—C25 bond. The thermal ellipsoids of the six fluorine atoms form a circular toroid as expected for a pure rotation about the C—C bond, elongated in a direction approximately perpendicular to the aromatic ring plane to which the CF₃ group binds. The occupancy ratio of the two components was refined freely and converged at 0.956 (3).

All hydrogen atoms except the nitrogen bound hydrogens, were included into the model at geometrically calculated positions (C—H target distance 0.96Å for methyl hydrogen atoms, 0.93Å for all others) and refined using a riding model. The torsion angle of the methyl groups were allowed to refine. The U_iso values of all hydrogen atoms were constrained to 1.2 times U_eq (1.5 times for methyl H atoms) of the respective atom to which the hydrogen atom binds.

S3. Synthesis and crystallization

A mixture of 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione (0.222g, 1 mmol), 2-methoxy benzaldehyde (0.136g, 1 mmol), 3- methyl-1-phenyl-1H-pyrazol-5-amine (0.173g, 1 mmol) in the presence of L-proline (20 mol%) in ethanol (15 ml) was stirred at 60^oC for 18 hrs. After completion of the reaction (TLC), the reaction mixture was extracted with ethyl acetate (2 x 40 ml) and the residue after removal of the solvent was chromatographed over silica gel (230–400 mesh) using petroleum ether-ethyl acetate mixture (4:1 v/v), which afforded pure product as a yellow solid; Yield 82%; mp 213 °C. Yellow coloured needles were obtained from a saturated solution of the solute in petroleum ether-ethyl acetate (4:1) mixture.