3-(2-Fluoro-phen-yl)-6-(phenoxy-meth-yl)-1,2,4-triazolo[3,4-b][1,3,4]thia-diazole.

The crystal structure of the title compound, C(16)H(11)FN(4)OS, was synthesized in the course of our studies on 1,2,4-triazolo[3,4-b][1,3,4]thia-diazo-les as inhibitors of p38 mitogen-activated protein kinase (MAPK). The three-dimensional data obtained were used to generate a three-dimensional pharmacophore model for in silico database screening. The dihedral angles between the central heterocylic system and the fluoro-phenyl and phenyl rings are 20.21 (3) and 5.43 (1)°, respectively; the dihedral angle between the two benzene rings is 15.80 (4)°.

Related literature

Protein kinases (PK) are favoured targets for the development of new drugs (Hopkins & Groon, 2002 ▶) because the reversible protein-phospho­rylation by PK is an important control mechanism in the signal pathways of a cell (Laufer et al., 2005 ▶). The [1,2,4]triazolo[3,4-b][1,3,4]thia­diazole nucleus is associated with diverse biological activities (Malhotra et al., 2003 ▶). For the preparation of the title compound, see: Invidiata et al. (1997 ▶); Malhotra et al. (2003 ▶).

Experimental

Crystal data

C16H11FN4OS

M = 326.35

Monoclinic,

a = 10.8551 (6) Å

b = 12.1899 (3) Å

c = 11.6667 (6) Å

β = 110.857 (5)°

V = 1442.61 (11) Å3

Z = 4

Cu Kα radiation

μ = 2.19 mm−1

T = 193 (2) K

0.58 × 0.51 × 0.26 mm

Data collection

Enraf–Nonius CAD-4 diffractometer

Absorption correction: ψ scan (CORINC; Dräger & Gattow, 1971 ▶) T min = 0.61, T max = 0.99 (expected range = 0.348–0.565)

2883 measured reflections

2736 independent reflections

2583 reflections with I > 2σ(I)

R int = 0.037

3 standard reflections frequency: 60 min intensity decay: 4%

Refinement

R[F 2 > 2σ(F 2)] = 0.048

wR(F 2) = 0.135

S = 1.06

2736 reflections

209 parameters

H-atom parameters constrained

Δρmax = 0.43 e Å−3

Δρmin = −0.43 e Å−3

Data collection: CAD-4 Software (Enraf–Nonius, 1989 ▶); cell refinement: CAD-4 Software; data reduction: CORINC (Dräger & Gattow, 1971 ▶); program(s) used to solve structure: SIR92 (Altomare et al., 1994 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2003 ▶); software used to prepare material for publication: SHELXL97.

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808003917/bt2678sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808003917/bt2678Isup2.hkl

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

C16H11FN4OS	F000 = 672
Mr = 326.35	Dx = 1.503 Mg m−3
Monoclinic, P21/n	Cu Kα radiation λ = 1.54178 Å
Hall symbol: -P 2yn	Cell parameters from 25 reflections
a = 10.8551 (6) Å	θ = 65–70º
b = 12.1899 (3) Å	µ = 2.19 mm−1
c = 11.6667 (6) Å	T = 193 (2) K
β = 110.857 (5)º	Plate, light brown
V = 1442.61 (11) Å3	0.58 × 0.51 × 0.26 mm
Z = 4

Enraf–Nonius CAD-4 diffractometer	Rint = 0.037
Monochromator: graphite	θmax = 69.9º
T = 193(2) K	θmin = 4.8º
ω/2θ scans	h = 0→13
Absorption correction: ψ scan(CORINC; Dräger & Gattow, 1971)	k = 0→14
Tmin = 0.61, Tmax = 0.99	l = −14→13
2883 measured reflections	3 standard reflections
2736 independent reflections	every 60 min
2583 reflections with I > 2s(I)	intensity decay: 4%

Refinement on F2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F2 > 2σ(F2)] = 0.048	w = 1/[σ2(Fo2) + (0.0847P)2 + 0.6884P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.135	(Δ/σ)max < 0.001
S = 1.06	Δρmax = 0.43 e Å−3
2736 reflections	Δρmin = −0.43 e Å−3
209 parameters	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0071 (8)
Secondary atom site location: difference Fourier map

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.

	x	y	z	Uiso*/Ueq
N1	0.65749 (15)	0.29912 (12)	0.27951 (14)	0.0311 (4)
C2	0.62295 (17)	0.25592 (16)	0.17147 (17)	0.0324 (4)
S3	0.63057 (5)	0.11269 (4)	0.16086 (4)	0.0375 (2)
C4	0.68622 (19)	0.11015 (15)	0.31907 (19)	0.0358 (4)
N5	0.72177 (18)	0.03789 (14)	0.40767 (17)	0.0445 (4)
N6	0.75709 (18)	0.09854 (14)	0.51539 (17)	0.0426 (4)
C7	0.74119 (17)	0.20439 (15)	0.48900 (18)	0.0331 (4)
N8	0.69477 (14)	0.21442 (12)	0.36353 (14)	0.0306 (4)
C9	0.58296 (19)	0.32345 (16)	0.05735 (17)	0.0358 (4)
H9A	0.5190	0.3806	0.0593	0.043*
H9B	0.6607	0.3596	0.0484	0.043*
O10	0.52441 (15)	0.24906 (12)	−0.04087 (12)	0.0433 (4)
C11	0.50482 (17)	0.28429 (16)	−0.15846 (17)	0.0326 (4)
C12	0.45545 (19)	0.20490 (17)	−0.24815 (18)	0.0376 (4)
H12	0.4366	0.1333	−0.2266	0.045*
C13	0.4337 (2)	0.23046 (19)	−0.36915 (19)	0.0436 (5)
H13	0.4012	0.1759	−0.4308	0.052*
C14	0.4591 (2)	0.3350 (2)	−0.40103 (19)	0.0451 (5)
H14	0.4442	0.3524	−0.4843	0.054*
C15	0.5060 (2)	0.41365 (19)	−0.3114 (2)	0.0439 (5)
H15	0.5220	0.4858	−0.3336	0.053*
C16	0.5303 (2)	0.38932 (16)	−0.1887 (2)	0.0378 (5)
H16	0.5637	0.4437	−0.1271	0.045*
C17	0.77445 (17)	0.29576 (16)	0.57653 (17)	0.0323 (4)
C18	0.76314 (19)	0.40498 (16)	0.53692 (18)	0.0345 (4)
H18	0.7312	0.4204	0.4515	0.041*
C19	0.79764 (19)	0.49076 (17)	0.61989 (18)	0.0390 (4)
H19	0.7895	0.5642	0.5909	0.047*
C20	0.8439 (2)	0.47064 (19)	0.74481 (19)	0.0426 (5)
H20	0.8664	0.5297	0.8016	0.051*
C21	0.8569 (2)	0.3633 (2)	0.78588 (19)	0.0451 (5)
H21	0.8895	0.3480	0.8713	0.054*
C22	0.8224 (2)	0.27895 (18)	0.70268 (19)	0.0399 (5)
F23	0.83678 (15)	0.17577 (12)	0.74746 (12)	0.0608 (4)

	U11	U22	U33	U12	U13	U23
N1	0.0311 (7)	0.0273 (8)	0.0325 (8)	0.0000 (6)	0.0082 (6)	0.0011 (6)
C2	0.0281 (8)	0.0299 (9)	0.0381 (10)	−0.0027 (7)	0.0105 (7)	−0.0040 (7)
S3	0.0402 (3)	0.0294 (3)	0.0430 (3)	−0.00168 (17)	0.0147 (2)	−0.00653 (18)
C4	0.0330 (10)	0.0276 (10)	0.0457 (11)	−0.0003 (7)	0.0126 (8)	−0.0033 (8)
N5	0.0482 (10)	0.0293 (9)	0.0522 (10)	0.0041 (7)	0.0134 (8)	0.0039 (7)
N6	0.0453 (10)	0.0317 (9)	0.0464 (10)	0.0027 (7)	0.0111 (8)	0.0066 (7)
C7	0.0283 (8)	0.0320 (10)	0.0375 (10)	0.0007 (7)	0.0099 (7)	0.0059 (7)
N8	0.0279 (7)	0.0244 (7)	0.0375 (8)	0.0009 (6)	0.0092 (6)	0.0011 (6)
C9	0.0390 (10)	0.0318 (10)	0.0325 (10)	−0.0051 (7)	0.0075 (8)	−0.0044 (7)
O10	0.0606 (9)	0.0355 (8)	0.0316 (7)	−0.0147 (6)	0.0137 (6)	−0.0050 (6)
C11	0.0304 (9)	0.0348 (10)	0.0322 (9)	0.0007 (7)	0.0107 (7)	−0.0011 (7)
C12	0.0398 (10)	0.0348 (10)	0.0375 (10)	−0.0024 (8)	0.0129 (8)	−0.0026 (8)
C13	0.0416 (10)	0.0532 (13)	0.0341 (10)	0.0000 (9)	0.0112 (8)	−0.0062 (9)
C14	0.0370 (10)	0.0612 (14)	0.0369 (11)	0.0034 (10)	0.0129 (8)	0.0081 (10)
C15	0.0377 (10)	0.0433 (11)	0.0495 (12)	0.0011 (9)	0.0141 (9)	0.0132 (9)
C16	0.0358 (10)	0.0340 (11)	0.0425 (11)	−0.0018 (7)	0.0125 (8)	−0.0018 (8)
C17	0.0262 (8)	0.0365 (10)	0.0334 (9)	0.0009 (7)	0.0097 (7)	0.0038 (7)
C18	0.0345 (9)	0.0356 (10)	0.0314 (9)	0.0036 (8)	0.0094 (7)	0.0030 (7)
C19	0.0412 (10)	0.0364 (10)	0.0378 (10)	0.0054 (8)	0.0119 (8)	0.0006 (8)
C20	0.0404 (10)	0.0500 (13)	0.0377 (10)	0.0005 (9)	0.0144 (8)	−0.0083 (9)
C21	0.0468 (11)	0.0600 (14)	0.0293 (10)	−0.0021 (10)	0.0144 (8)	0.0045 (9)
C22	0.0384 (10)	0.0428 (11)	0.0384 (10)	−0.0014 (8)	0.0136 (8)	0.0110 (9)
F23	0.0822 (10)	0.0482 (8)	0.0443 (7)	−0.0076 (7)	0.0128 (7)	0.0186 (6)

N1—C2	1.292 (2)	C13—C14	1.382 (3)
N1—N8	1.381 (2)	C13—H13	0.9500
C2—C9	1.492 (3)	C14—C15	1.376 (3)
C2—S3	1.7544 (19)	C14—H14	0.9500
S3—C4	1.726 (2)	C15—C16	1.392 (3)
C4—N5	1.307 (3)	C15—H15	0.9500
C4—N8	1.363 (2)	C16—H16	0.9500
N5—N6	1.389 (3)	C17—C22	1.391 (3)
N6—C7	1.324 (2)	C17—C18	1.400 (3)
C7—N8	1.373 (2)	C18—C19	1.383 (3)
C7—C17	1.467 (3)	C18—H18	0.9500
C9—O10	1.422 (2)	C19—C20	1.384 (3)
C9—H9A	0.9900	C19—H19	0.9500
C9—H9B	0.9900	C20—C21	1.384 (3)
O10—C11	1.380 (2)	C20—H20	0.9500
C11—C16	1.382 (3)	C21—C22	1.371 (3)
C11—C12	1.385 (3)	C21—H21	0.9500
C12—C13	1.381 (3)	C22—F23	1.349 (2)
C12—H12	0.9500
C2—N1—N8	107.31 (15)	C12—C13—H13	119.8
N1—C2—C9	122.45 (17)	C14—C13—H13	119.8
N1—C2—S3	118.02 (15)	C15—C14—C13	119.5 (2)
C9—C2—S3	119.48 (13)	C15—C14—H14	120.2
C4—S3—C2	87.12 (9)	C13—C14—H14	120.2
N5—C4—N8	111.49 (18)	C14—C15—C16	121.1 (2)
N5—C4—S3	138.59 (15)	C14—C15—H15	119.4
N8—C4—S3	109.92 (14)	C16—C15—H15	119.4
C4—N5—N6	105.39 (16)	C11—C16—C15	118.55 (19)
C7—N6—N5	109.71 (16)	C11—C16—H16	120.7
N6—C7—N8	107.62 (17)	C15—C16—H16	120.7
N6—C7—C17	126.80 (18)	C22—C17—C18	116.43 (19)
N8—C7—C17	125.48 (17)	C22—C17—C7	122.11 (18)
C4—N8—C7	105.78 (16)	C18—C17—C7	121.42 (17)
C4—N8—N1	117.63 (15)	C19—C18—C17	121.19 (18)
C7—N8—N1	136.59 (15)	C19—C18—H18	119.4
O10—C9—C2	105.77 (15)	C17—C18—H18	119.4
O10—C9—H9A	110.6	C18—C19—C20	120.62 (19)
C2—C9—H9A	110.6	C18—C19—H19	119.7
O10—C9—H9B	110.6	C20—C19—H19	119.7
C2—C9—H9B	110.6	C21—C20—C19	119.1 (2)
H9A—C9—H9B	108.7	C21—C20—H20	120.4
C11—O10—C9	117.99 (15)	C19—C20—H20	120.4
O10—C11—C16	124.62 (17)	C22—C21—C20	119.70 (19)
O10—C11—C12	114.51 (17)	C22—C21—H21	120.2
C16—C11—C12	120.87 (18)	C20—C21—H21	120.2
C13—C12—C11	119.58 (19)	F23—C22—C21	117.38 (19)
C13—C12—H12	120.2	F23—C22—C17	119.7 (2)
C11—C12—H12	120.2	C21—C22—C17	122.9 (2)
C12—C13—C14	120.3 (2)
N8—N1—C2—C9	−176.82 (15)	C9—O10—C11—C12	175.96 (17)
N8—N1—C2—S3	0.50 (19)	O10—C11—C12—C13	−179.06 (17)
N1—C2—S3—C4	0.04 (15)	C16—C11—C12—C13	1.2 (3)
C9—C2—S3—C4	177.45 (15)	C11—C12—C13—C14	−1.0 (3)
C2—S3—C4—N5	179.1 (2)	C12—C13—C14—C15	−0.1 (3)
C2—S3—C4—N8	−0.59 (14)	C13—C14—C15—C16	1.0 (3)
N8—C4—N5—N6	−0.9 (2)	O10—C11—C16—C15	179.97 (18)
S3—C4—N5—N6	179.41 (19)	C12—C11—C16—C15	−0.4 (3)
C4—N5—N6—C7	0.4 (2)	C14—C15—C16—C11	−0.8 (3)
N5—N6—C7—N8	0.2 (2)	N6—C7—C17—C22	−3.4 (3)
N5—N6—C7—C17	−176.25 (17)	N8—C7—C17—C22	−179.30 (17)
N5—C4—N8—C7	1.0 (2)	N6—C7—C17—C18	174.60 (19)
S3—C4—N8—C7	−179.19 (12)	N8—C7—C17—C18	−1.2 (3)
N5—C4—N8—N1	−178.73 (15)	C22—C17—C18—C19	−0.3 (3)
S3—C4—N8—N1	1.1 (2)	C7—C17—C18—C19	−178.43 (17)
N6—C7—N8—C4	−0.7 (2)	C17—C18—C19—C20	−0.3 (3)
C17—C7—N8—C4	175.79 (17)	C18—C19—C20—C21	0.9 (3)
N6—C7—N8—N1	178.96 (18)	C19—C20—C21—C22	−0.8 (3)
C17—C7—N8—N1	−4.5 (3)	C20—C21—C22—F23	−179.92 (18)
C2—N1—N8—C4	−1.0 (2)	C20—C21—C22—C17	0.2 (3)
C2—N1—N8—C7	179.34 (19)	C18—C17—C22—F23	−179.53 (17)
N1—C2—C9—O10	−167.07 (16)	C7—C17—C22—F23	−1.4 (3)
S3—C2—C9—O10	15.6 (2)	C18—C17—C22—C21	0.3 (3)
C2—C9—O10—C11	−165.85 (15)	C7—C17—C22—C21	178.45 (19)
C9—O10—C11—C16	−4.3 (3)