4-Difluoro­methyl-1-(2,5-dimethoxy­phen­yl)-1H-1,2,3-triazole

Costa, M.S.; Boechat, N.; Ferreira, V.F.; Wardell, S.M.S.V.; Skakle, J.M.S.

doi:10.1107/S1600536806013924

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 62| Part 5| May 2006| Pages o2048-o2050

https://doi.org/10.1107/S1600536806013924

4-Difluoromethyl-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole

Marilia S. Costa,^a Nubia Boechat,^a Vitor F. Ferreira,^b Solange M. S. V. Wardell ^a and Janet M. S. Skakle ^c ^*

^aFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Departamento de Síntese Orgânica, Manguinhos, CEP 21041-250 Rio de Janeiro, RJ, Brazil, ^bUniversidade Federal Fluminense, Departamento de Química Orgânica, Instituto de Química, Outeiro de São João Baptista, CEP 24020-150 Niterói, RJ, Brazil, and ^cDepartment of Chemistry, College of Physical Sciences, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland
^*Correspondence e-mail: j.skakle@abdn.ac.uk

(Received 11 April 2006; accepted 18 April 2006; online 26 April 2006)

In the title compound, C₁₁H₁₁F₂N₃O₂, the aryl and triazole rings are both planar, but at an angle of 45.27 (4)° to each other.

Comment

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading cause of mortality worldwide. The World Health Organization estimates that about one-third of the world's population harbours latent infection of TB. Among such infected individuals, approximately eight million develop active TB, and almost two million of these die from this disease each year. 95% of new TB cases occur in developing countries. The current human immunodeficiency virus (AIDS) pandemic and resistance to the currently available drugs are proving major obstacles to the control of tuberculosis (Tewari et al., 2004 ; World Health Organization, 2005 ; Tripathi et al., 2005 ).

Chemotherapy of TB started in the 1940s. Various drugs have been used against TB, including para-aminosalicylic acid, isoniazid, pyrazinamide, cycloserine, ethionamide, rifampicin and ethambutol. However, six decades have passed without any significant development of new chemical treatments of tuberculosis. TB really can be classed as a neglected disease.

In pursuit of new drugs for TB, we have synthesized a new series of 1-aryl-4-difluoromethyl-1,2,3-triazole derivatives and evaluated their inhibitory activities against M. tuberculosis. All derivatives exhibited tuberculosis inhibitory activity at high concentrations (MIC > 6.5 g ml⁻¹); a full description of the biological tests will be reported elsewhere (Costa, Boechat, Rangel et al., 2006 ). The structure of the title compound, (I), which exhibited 74% of inhibition at a concentration of 80.0 µg ml⁻¹, is reported below.

C₁₁H₁₁F₂N₃O₂ (Fig. 1) crystallizes in the space group P2₁/c; the geometry of the structure was analysed with the aid of PLATON (Spek, 2003 ). Both the triazole and the aryl rings are planar and the methoxy groups are nearly coplanar with the aryl ring, with torsion angles C8—C7—O7—O71 = 4.7 (2)° and C9—C10—O10—C101 = 6.7 (2)°. The angle between the planes defined by the triazole and aryl rings is 45.27 (4)° (Fig. 2). Comparison with 1-(4-methylphenyl)-4-difluoromethyl-1H-1,2,3-triazole (Costa, Boechat, Ferreira et al., 2006 ) indicates that the presence of the methoxy groups, ortho and meta to the triazole, leads to this deviation from coplanarity.

Figure 1
The molecular structure of the title compound, showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are shown as circles of arbitrary radii.

Figure 2
The unit-cell contents, showing the relative orientation of the triazole and aryl groups. Ellipsoids are represented as in Fig. 1

. H atoms have been omitted.

Experimental

A solution of diazomalonaldehyde (5.0 mmol) in water (30 ml) was added dropwise to a stirred solution of 2,5-dimethoxyaniline hydrochloride (4.5 mmol) in water (5 ml). The reaction mixture was stirred for 24 h at room temperature; the solid was collected, washed with cold water and crystallized from aqueous ethanol. The title compound was obtained in 98% yield as a white solid (m.p. 351–352 K). ¹H NMR (500 MHz, CDCl₃/Me₄Si): δ 3.89 (s, 3H, 2OCH₃), 6.95 (t, 1H, CHF₂, J = 55.0 Hz), 7.04 (dd, 2H, J = 2.0 e 7.0 Hz, arom.), 7.63 (dd, 2H, J = 2.0 e 7.0 Hz, arom.), 8.14 (sl, 1H, triazole). ¹⁹F NMR (376.0 MHz, CDCl₃/CFCl₃): δ −112.2 (2F, CHF₂). Full spectroscopic data are given in the CIF. Analysis calculated for C₁₁H₁₁F₂N₃O₂: C 51.77, H 4.34, N 16.46%; found: C 51.78, H 4.36, N 16.49%.

Crystal data

C₁₁H₁₁F₂N₃O₂
M_r = 255.23
Monoclinic, P 2₁ /c
a = 13.4574 (6) Å
b = 11.4815 (5) Å
c = 7.3719 (2) Å
β = 105.247 (3)°
V = 1098.95 (7) Å³
Z = 4
D_x = 1.543 Mg m⁻³
Mo Kα radiation
μ = 0.13 mm⁻¹
T = 120 (2) K
Shard, colourless
0.14 × 0.12 × 0.05 mm

Data collection

Nonius KappaCCD diffractometer
φ and ω scans
Absorption correction: multi-scan (SADABS; Sheldrick, 2003 ) T_min = 0.822, T_max = 1.000
14882 measured reflections
2510 independent reflections
1975 reflections with I > 2σ(I)
R_int = 0.053
θ_max = 27.5°

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.042
wR(F²) = 0.110
S = 1.06
2510 reflections
167 parameters
H atoms treated by a mixture of independent and constrained refinement
w = 1/[σ²(F_o²) + (0.0488P)² + 0.501P] where P = (F_o² + 2F_c²)/3
(Δ/σ)_max < 0.001
Δρ_max = 0.26 e Å⁻³
Δρ_min = −0.24 e Å⁻³
Extinction correction: SHELXL97
Extinction coefficient: 0.021 (3)

All H atoms were located in difference maps and then treated as riding atoms with C—H distances of 0.95 (aryl), 1.00 (methine), 1.01 (triazole) and 0.98 Å (methyl), and with U_iso(H) values of 1.2U_eq(aryl) or 1.5U_eq(methyl); U_iso values for the triazole and methine H atoms were freely refined.

Data collection: COLLECT (Hooft, 1998 ); cell refinement: DENZO (Otwinowski & Minor, 1997 ) and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: OSCAIL (McArdle, 2003 ) and SHELXS97 (Sheldrick, 1997 ); program(s) used to refine structure: OSCAIL and SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ); software used to prepare material for publication: CIFTAB (Sheldrick, 1997).

Supporting information

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S1600536806013924/wn2023sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536806013924/wn2023Isup2.hkl

Computing details top

Data collection: COLLECT (Hooft, 1998); cell refinement: DENZO (Otwinowski & Minor, 1997) and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: OSCAIL (McArdle, 2003) and SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: OSCAIL and SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: CIFTAB (Sheldrick, 1997).

4-Difluoromethyl-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole top

Crystal data top

C₁₁H₁₁F₂N₃O₂	F(000) = 528
M_r = 255.23	D_x = 1.543 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 2600 reflections
a = 13.4574 (6) Å	θ = 2.9–27.5°
b = 11.4815 (5) Å	µ = 0.13 mm⁻¹
c = 7.3719 (2) Å	T = 120 K
β = 105.247 (3)°	Shard, colourless
V = 1098.95 (7) Å³	0.14 × 0.12 × 0.05 mm
Z = 4

Data collection top

Nonius KappaCCD diffractometer	2510 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1975 reflections with I > 2σ(I)
10 cm confocal mirrors monochromator	R_int = 0.053
Detector resolution: 9.091 pixels mm^-1	θ_max = 27.5°, θ_min = 3.1°
φ and ω scans	h = −17→17
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −14→14
T_min = 0.822, T_max = 1.000	l = −9→9
14882 measured reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F² > 2σ(F²)] = 0.042	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.110	w = 1/[σ²(F_o²) + (0.0488P)² + 0.501P] where P = (F_o² + 2F_c²)/3
S = 1.06	(Δ/σ)_max < 0.001
2510 reflections	Δρ_max = 0.26 e Å⁻³
167 parameters	Δρ_min = −0.24 e Å⁻³
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.021 (3)

Special details top

Experimental. IR (KBr) ν_max (cm^-1) 3169; 1027

¹³C NMR (125 MHz; CDCl₃/Me₄Si): δ 55.9 (3H, OCH₃); 56.5 (3H, OCH₃); 110.3 (t, CF₂H, J= 230.0 Hz); 113.6; 116.2; 124.4; 121.1; 127.3; 142.3 (t, J = 29.1 Hz) 144.7; 153.9;

EIMS (m/z): 255(M⁺; 60%); 227(M⁺-28; 8%); 226(M⁺-29; 5%); 212 (M⁺-43; 100%).

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

	x	y	z	U_iso*/U_eq
N1	0.24556 (10)	0.76731 (11)	0.21516 (18)	0.0190 (3)
N2	0.25076 (10)	0.87928 (11)	0.15679 (18)	0.0218 (3)
N3	0.15878 (10)	0.92462 (11)	0.13265 (19)	0.0231 (3)
C4	0.09560 (12)	0.84281 (14)	0.1761 (2)	0.0211 (3)
C41	−0.01440 (13)	0.86907 (14)	0.1624 (2)	0.0258 (4)
H41	−0.0524	0.8858	0.0291	0.035 (5)*
F41	−0.05715 (8)	0.77552 (9)	0.22864 (16)	0.0367 (3)
F42	−0.02215 (8)	0.96095 (10)	0.27463 (17)	0.0414 (3)
C5	0.14916 (12)	0.74227 (14)	0.2272 (2)	0.0213 (3)
H5	0.1350	0.6622	0.2711	0.028 (5)*
C6	0.33404 (12)	0.69383 (13)	0.2450 (2)	0.0193 (3)
C7	0.32268 (12)	0.58104 (14)	0.1701 (2)	0.0200 (3)
O7	0.22486 (9)	0.54727 (9)	0.08105 (16)	0.0247 (3)
C71	0.21121 (14)	0.42979 (14)	0.0163 (2)	0.0260 (4)
H71A	0.2503	0.4168	−0.0769	0.039*
H71B	0.1380	0.4152	−0.0415	0.039*
H71C	0.2360	0.3767	0.1227	0.039*
C8	0.41010 (12)	0.51322 (14)	0.1909 (2)	0.0221 (3)
H8	0.4042	0.4368	0.1399	0.027*
C9	0.50675 (13)	0.55602 (14)	0.2860 (2)	0.0226 (4)
H9	0.5663	0.5091	0.2981	0.027*
C10	0.51596 (12)	0.66705 (14)	0.3629 (2)	0.0206 (3)
O10	0.60716 (8)	0.71525 (10)	0.46465 (16)	0.0246 (3)
C101	0.69796 (12)	0.64907 (15)	0.4723 (2)	0.0246 (4)
H10A	0.6929	0.5732	0.5302	0.037*
H10B	0.7582	0.6911	0.5473	0.037*
H10C	0.7051	0.6375	0.3446	0.037*
C11	0.42913 (12)	0.73624 (14)	0.3421 (2)	0.0197 (3)
H11	0.4351	0.8124	0.3944	0.024*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0162 (7)	0.0173 (6)	0.0240 (7)	0.0003 (5)	0.0061 (5)	0.0001 (5)
N2	0.0218 (7)	0.0164 (7)	0.0273 (7)	0.0013 (5)	0.0068 (5)	0.0013 (5)
N3	0.0193 (7)	0.0210 (7)	0.0282 (7)	0.0032 (6)	0.0050 (5)	−0.0004 (5)
C4	0.0180 (8)	0.0217 (8)	0.0231 (8)	−0.0002 (6)	0.0044 (6)	−0.0023 (6)
C41	0.0208 (8)	0.0227 (8)	0.0333 (9)	−0.0003 (7)	0.0063 (7)	−0.0023 (7)
F41	0.0208 (5)	0.0346 (6)	0.0561 (7)	−0.0003 (4)	0.0124 (5)	0.0076 (5)
F42	0.0264 (6)	0.0381 (7)	0.0607 (8)	0.0041 (5)	0.0132 (5)	−0.0195 (5)
C5	0.0176 (8)	0.0214 (8)	0.0249 (8)	−0.0017 (6)	0.0058 (6)	−0.0004 (6)
C6	0.0185 (8)	0.0185 (8)	0.0224 (7)	0.0024 (6)	0.0080 (6)	0.0013 (6)
C7	0.0184 (8)	0.0201 (8)	0.0218 (7)	−0.0011 (6)	0.0057 (6)	0.0004 (6)
O7	0.0193 (6)	0.0192 (6)	0.0334 (6)	−0.0002 (5)	0.0031 (5)	−0.0056 (5)
C71	0.0284 (9)	0.0190 (8)	0.0295 (8)	−0.0025 (7)	0.0059 (7)	−0.0037 (6)
C8	0.0223 (8)	0.0183 (8)	0.0265 (8)	−0.0001 (6)	0.0076 (6)	−0.0013 (6)
C9	0.0208 (8)	0.0206 (8)	0.0275 (8)	0.0028 (6)	0.0082 (6)	0.0002 (6)
C10	0.0169 (8)	0.0210 (8)	0.0240 (8)	−0.0023 (6)	0.0054 (6)	0.0008 (6)
O10	0.0162 (6)	0.0223 (6)	0.0340 (6)	0.0004 (5)	0.0042 (5)	−0.0040 (5)
C101	0.0171 (8)	0.0246 (8)	0.0320 (9)	0.0028 (6)	0.0063 (6)	0.0020 (7)
C11	0.0200 (8)	0.0176 (8)	0.0229 (8)	0.0001 (6)	0.0080 (6)	−0.0001 (6)

Geometric parameters (Å, º) top

N1—C5	1.354 (2)	O7—C71	1.4266 (19)
N1—N2	1.3633 (18)	C71—H71A	0.9800
N1—C6	1.4284 (19)	C71—H71B	0.9800
N2—N3	1.3111 (19)	C71—H71C	0.9800
N3—C4	1.360 (2)	C8—C9	1.395 (2)
C4—C5	1.361 (2)	C8—H8	0.9500
C4—C41	1.488 (2)	C9—C10	1.387 (2)
C41—F42	1.3614 (19)	C9—H9	0.9500
C41—F41	1.3677 (19)	C10—O10	1.3752 (18)
C41—H41	1.0000	C10—C11	1.388 (2)
C5—H5	1.0095	O10—C101	1.4274 (19)
C6—C11	1.380 (2)	C101—H10A	0.9800
C6—C7	1.400 (2)	C101—H10B	0.9800
C7—O7	1.3637 (19)	C101—H10C	0.9800
C7—C8	1.385 (2)	C11—H11	0.9500

C5—N1—N2	110.52 (13)	O7—C71—H71B	109.5
C5—N1—C6	129.69 (13)	H71A—C71—H71B	109.5
N2—N1—C6	119.71 (12)	O7—C71—H71C	109.5
N3—N2—N1	106.99 (12)	H71A—C71—H71C	109.5
N2—N3—C4	108.67 (13)	H71B—C71—H71C	109.5
N3—C4—C5	109.43 (14)	C7—C8—C9	120.67 (15)
N3—C4—C41	121.09 (14)	C7—C8—H8	119.7
C5—C4—C41	129.48 (15)	C9—C8—H8	119.7
F42—C41—F41	106.56 (13)	C10—C9—C8	120.03 (15)
F42—C41—C4	110.47 (13)	C10—C9—H9	120.0
F41—C41—C4	108.72 (13)	C8—C9—H9	120.0
F42—C41—H41	110.3	O10—C10—C9	124.31 (14)
F41—C41—H41	110.3	O10—C10—C11	115.76 (14)
C4—C41—H41	110.3	C9—C10—C11	119.92 (15)
N1—C5—C4	104.39 (14)	C10—O10—C101	116.05 (12)
N1—C5—H5	118.6	O10—C101—H10A	109.5
C4—C5—H5	137.0	O10—C101—H10B	109.5
C11—C6—C7	121.39 (14)	H10A—C101—H10B	109.5
C11—C6—N1	119.55 (14)	O10—C101—H10C	109.5
C7—C6—N1	119.03 (14)	H10A—C101—H10C	109.5
O7—C7—C8	125.29 (14)	H10B—C101—H10C	109.5
O7—C7—C6	116.37 (13)	C6—C11—C10	119.61 (14)
C8—C7—C6	118.34 (14)	C6—C11—H11	120.2
C7—O7—C71	116.94 (12)	C10—C11—H11	120.2
O7—C71—H71A	109.5

C5—N1—N2—N3	0.16 (16)	C11—C6—C7—O7	178.38 (13)
C6—N1—N2—N3	177.20 (12)	N1—C6—C7—O7	−3.5 (2)
N1—N2—N3—C4	0.33 (16)	C11—C6—C7—C8	−1.8 (2)
N2—N3—C4—C5	−0.70 (18)	N1—C6—C7—C8	176.34 (13)
N2—N3—C4—C41	179.89 (13)	C8—C7—O7—C71	4.7 (2)
N3—C4—C41—F42	−58.4 (2)	C6—C7—O7—C71	−175.52 (13)
C5—C4—C41—F42	122.30 (18)	O7—C7—C8—C9	−179.53 (14)
N3—C4—C41—F41	−175.02 (13)	C6—C7—C8—C9	0.7 (2)
C5—C4—C41—F41	5.7 (2)	C7—C8—C9—C10	0.8 (2)
N2—N1—C5—C4	−0.56 (17)	C8—C9—C10—O10	177.57 (14)
C6—N1—C5—C4	−177.23 (14)	C8—C9—C10—C11	−1.2 (2)
N3—C4—C5—N1	0.76 (17)	C9—C10—O10—C101	6.7 (2)
C41—C4—C5—N1	−179.90 (15)	C11—C10—O10—C101	−174.54 (13)
C5—N1—C6—C11	−138.24 (17)	C7—C6—C11—C10	1.5 (2)
N2—N1—C6—C11	45.36 (19)	N1—C6—C11—C10	−176.70 (13)
C5—N1—C6—C7	43.6 (2)	O10—C10—C11—C6	−178.78 (13)
N2—N1—C6—C7	−132.84 (15)	C9—C10—C11—C6	0.1 (2)

Acknowledgements

We are indebted to the EPSRC for the use of both the Chemical Database Service at Daresbury, primarily for access to the Cambridge Structural Database (Fletcher et al., 1996 ), and the X-ray service at the University of Southampton for data collection.

References

Costa, M. S., Boechat, N., Ferreira, V. F., Wardell, S. M. S. V. & Skakle, J. M. S. (2006). Acta Cryst. E62, o1925–o1927. CSD CrossRef IUCr Journals Google Scholar
Costa, M. S., Boechat, N., Rangel, È. A., Ferreira, V. F., Junior, I. N., Lourenço, M. C. S. & Wardell, S. M. S. V. (2006). Eur. J. Med. Chem. In preparation. Google Scholar
Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565. CrossRef IUCr Journals Google Scholar
Fletcher, D. A., McMeeking, R. F. & Parkin, D. (1996). J. Chem. Inf. Comput. Sci. 36, 746–749. CrossRef CAS Web of Science Google Scholar
Hooft, R. W. W. (1998). COLLECT. Nonius BV, Delft, The Netherlands. Google Scholar
McArdle, P. (2003). OSCAIL for Windows. Version 10. Crystallography Centre, Chemistry Department, NUI Galway, Ireland. Google Scholar
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276. Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press. Google Scholar
Sheldrick, G. M. (1997). SHELXS97, SHELXL97 and CIFTAB. University of Göttingen, Germany. Google Scholar
Sheldrick, G. M. (2003). SADABS. Version 2.10. University of Göttingen, Germany. Google Scholar
Spek, A. L. (2003). J. Appl. Cryst. 36, 7–13. Web of Science CrossRef CAS IUCr Journals Google Scholar
Tewari, N., Tiwari, V. K., Tipathi, R. P., Chaturvedi, V., Srivastava, A., Srivastava, R., Shukla, P. K., Chaturvedi, A. K., Gaikwad, A., Sinha, S. & Srivastava, B. S. (2004). Bioorg. Med. Chem. Lett. 14, 329–332. Web of Science CrossRef PubMed CAS Google Scholar
Tripathi, R. P., Tewari, N., Dwivedi, N. & Tiwari, V. K. (2005). Med. Res. Rev. 25, 93–131. Web of Science CrossRef PubMed CAS Google Scholar
World Health Organization (2005). WHO Report 2005. Global Tuberculosis Control – Surveillance, Planning, Financing. WHO/HTM/TB/2005. https://www.who.int/tb. Google Scholar

© International Union of Crystallography. Prior permission is not required to reproduce short quotations, tables and figures from this article, provided the original authors and source are cited. For more information, click here.