2-Chloro-5-fluoro-6-methyl-N-o-tolyl­pyrimidin-4-amine

Jiang, Y.; Wu, K.; Cui, D.; Zhou, W.

doi:10.1107/S160053681300812X

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 69| Part 5| May 2013| Page o626

https://doi.org/10.1107/S160053681300812X

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2-Chloro-5-fluoro-6-methyl-N-o-tolylpyrimidin-4-amine

Yufei Jiang,^a Kong Wu,^a Dongmei Cui ^a and Wei Zhou ^a ^*

^aCollege of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, People's Republic of China
^*Correspondence e-mail: zhouwei@zjut.edu.cn

(Received 12 March 2013; accepted 25 March 2013; online 5 April 2013)

In the title compound, C₁₂H₁₁ClFN₃, the benzene ring forms a dihedral angle of 72.43 (5)° with the pyrimidine ring. In the crystal, N—H⋯N hydrogen bonds link the molecules into a chain running along the c axis.

Related literature

For background to and applications of fluoro-pyrimidines, see: Riccaboni et al. (2010 ). For the antitumor activity of 4-aniline-substituted 5-fluoropyrimidines, see: Lawrence et al. (2012 ).

Experimental

Crystal data

C₁₂H₁₁ClFN₃
M_r = 251.69
Monoclinic, P 2₁ /c
a = 12.0593 (7) Å
b = 8.3684 (4) Å
c = 12.8611 (6) Å
β = 113.021 (6)°
V = 1194.54 (11) Å³
Z = 4
Mo Kα radiation
μ = 0.31 mm⁻¹
T = 293 K
0.5 × 0.3 × 0.2 mm

Data collection

Enraf–Nonius CAD-4 diffractometer
4692 measured reflections
2125 independent reflections
1750 reflections with I > 2σ(I)
R_int = 0.014
3 standard reflections every 60 min intensity decay: none

Refinement

R[F² > 2σ(F²)] = 0.034
wR(F²) = 0.096
S = 1.04
2125 reflections
156 parameters
H-atom parameters constrained
Δρ_max = 0.17 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯N2ⁱ	0.86	2.34	3.0768 (19)	145
Symmetry code: (i) $[x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

Data collection: CAD-4 Software (Enraf–Nonius, 1994 ); cell refinement: CAD-4 Software (Enraf–Nonius, 1994); data reduction: XCAD4 (Harms & Wocadlo, 1995 ); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012 ); software used to prepare material for publication: SHELXL97.

Supporting information

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S160053681300812X/is5256sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S160053681300812X/is5256Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S160053681300812X/is5256Isup3.cml

checkCIF report

Comment top

The fluoro-containning pyrimidine skeleton was found in many biologically active molecules (Riccaboni et al., 2010). Especially, the 4-anilines-substituted derivatives of 5-fluoropyrimidine were proved possessing obvious antitumor activity in recent years (Lawrence et al., 2012). Owing to our interest in this area, we have prepared a series of 5-fluoropyrimidine derivatives substituted with anilines. In a continuation of our SAR investigations, we present here the crystal structure of the title compound, (1).

In (1) (Fig. 1), the atoms N1/H1 and C6 are co-planar well with the pyrimidine ring [r.m.s. 0.007 (1) Å], indicating a good conjugate system between the atom N1 and pyrimidine. The plane of o-toluidine moiety is torsional toward the pyrimidine ring, showing a dihedral angle of 72.43 (5)°. The amino group is involved in the formation of intermolecular N—H···N hydrogen bond (Table 1). In the crystal (Fig. 2), the intermolecular N—H···N hydrogen bonds link the molecules into one-dimensional chains running along the c axis.

Related literature top

For background to and applications of fluoro-pyrimidines, see: Riccaboni et al. (2010). For the antitumor activity of 4-aniline-substituted 5-fluoropyrimidines, see: Lawrence et al. (2012).

Experimental top

In a tube-reactor was added a mixture of 2,4-dichloro-5-fluoro-6-methylpyrimidine (0.181 g, 1.0 mmol), o-toluidine (0.107 g, 1.0 mmol), KHCO₃ (0.1 g, 1.0 mmol) and 1.0 ml DMSO. The mixture was heated at 333 K until the TLC test showed that the reaction is complete. Then the mixture was diluted with 30 ml e thyl acetate, washed with 30 ml water for three times, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 8/1) to give a white solid (0.238 g, yield 94.5%, m.p. 430–432 K). Since the crystal product was not found to be suitable for X-ray diffraction studies, a few solids were dissolved in ethyl acetate, which was allowed to evaporate slowly to give colourless crystals of (1) suitable for X-ray diffraction studies.

Structure description top

For background to and applications of fluoro-pyrimidines, see: Riccaboni et al. (2010). For the antitumor activity of 4-aniline-substituted 5-fluoropyrimidines, see: Lawrence et al. (2012).

Computing details top

Data collection: CAD-4 Software (Enraf–Nonius, 1994); cell refinement: CAD-4 Software (Enraf–Nonius, 1994); data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures top

	Fig. 1. The molecular structure of the title compound with 30% probability displacement ellipsoids.
	Fig. 2. Packing diagram of the title compound, viewed normal to (010), showing hydrogen bonds (dashed lines). For clarity, H atoms not involved in the hydrogen bonds have been omitted.

2-Chloro-5-fluoro-6-methyl-N-o-tolylpyrimidin-4-amine top

Crystal data top

C₁₂H₁₁ClFN₃	F(000) = 520
M_r = 251.69	D_x = 1.399 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 1870 reflections
a = 12.0593 (7) Å	θ = 3.0–29.1°
b = 8.3684 (4) Å	µ = 0.31 mm⁻¹
c = 12.8611 (6) Å	T = 293 K
β = 113.021 (6)°	Prismatic, colourless
V = 1194.54 (11) Å³	0.5 × 0.3 × 0.2 mm
Z = 4

Data collection top

Enraf–Nonius CAD-4 diffractometer	R_int = 0.014
Radiation source: fine-focus sealed tube	θ_max = 25.1°, θ_min = 3.0°
Graphite monochromator	h = −7→14
phi and ω scans	k = −9→9
4692 measured reflections	l = −15→15
2125 independent reflections	3 standard reflections every 60 min
1750 reflections with I > 2σ(I)	intensity decay: none

Refinement top

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)] = 0.034	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.096	H-atom parameters constrained
S = 1.04	w = 1/[σ²(F_o²) + (0.0466P)² + 0.2577P] where P = (F_o² + 2F_c²)/3
2125 reflections	(Δ/σ)_max = 0.002
156 parameters	Δρ_max = 0.17 e Å⁻³
0 restraints	Δρ_min = −0.21 e Å⁻³

Crystal data top

C₁₂H₁₁ClFN₃	V = 1194.54 (11) Å³
M_r = 251.69	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 12.0593 (7) Å	µ = 0.31 mm⁻¹
b = 8.3684 (4) Å	T = 293 K
c = 12.8611 (6) Å	0.5 × 0.3 × 0.2 mm
β = 113.021 (6)°

Data collection top

Enraf–Nonius CAD-4 diffractometer	R_int = 0.014
4692 measured reflections	3 standard reflections every 60 min
2125 independent reflections	intensity decay: none
1750 reflections with I > 2σ(I)

Refinement top

R[F² > 2σ(F²)] = 0.034	0 restraints
wR(F²) = 0.096	H-atom parameters constrained
S = 1.04	Δρ_max = 0.17 e Å⁻³
2125 reflections	Δρ_min = −0.21 e Å⁻³
156 parameters

Special details top

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
Cl1	0.75856 (5)	−0.06428 (7)	1.24493 (4)	0.0666 (2)
N2	0.57335 (12)	0.12020 (18)	1.15433 (11)	0.0470 (4)
N3	0.70666 (11)	0.09036 (16)	1.05829 (11)	0.0407 (3)
F1	0.46632 (9)	0.35255 (15)	0.89928 (9)	0.0694 (3)
C1	0.66841 (15)	0.0648 (2)	1.14005 (14)	0.0426 (4)
C4	0.63837 (14)	0.1897 (2)	0.97700 (13)	0.0401 (4)
C3	0.53397 (14)	0.2537 (2)	0.98347 (14)	0.0448 (4)
N1	0.66996 (12)	0.22514 (18)	0.89014 (11)	0.0484 (4)
H1	0.6236	0.2882	0.8387	0.058*
C2	0.50232 (14)	0.2189 (2)	1.07122 (15)	0.0460 (4)
C6	0.77521 (15)	0.1655 (2)	0.87727 (13)	0.0445 (4)
C11	0.7589 (2)	0.0547 (2)	0.79274 (17)	0.0627 (5)
H11	0.6821	0.0171	0.7491	0.075*
C5	0.39149 (18)	0.2840 (3)	1.08108 (19)	0.0684 (6)
H5A	0.3501	0.3528	1.0180	0.103*
H5B	0.4136	0.3437	1.1500	0.103*
H5C	0.3395	0.1974	1.0816	0.103*
C10	0.8577 (3)	0.0005 (3)	0.7736 (2)	0.0862 (8)
H10	0.8482	−0.0745	0.7174	0.103*
C8	0.98515 (19)	0.1680 (4)	0.9222 (2)	0.0824 (8)
H8	1.0622	0.2052	0.9653	0.099*
C9	0.9696 (3)	0.0584 (4)	0.8384 (3)	0.0925 (9)
H9	1.0361	0.0229	0.8254	0.111*
C7	0.88790 (16)	0.2248 (2)	0.94391 (16)	0.0560 (5)
C12	0.9052 (2)	0.3424 (3)	1.03578 (19)	0.0804 (7)
H12A	0.8506	0.4302	1.0065	0.121*
H12B	0.9866	0.3812	1.0645	0.121*
H12C	0.8896	0.2916	1.0956	0.121*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0636 (3)	0.0849 (4)	0.0599 (3)	0.0128 (3)	0.0333 (3)	0.0278 (3)
N2	0.0441 (8)	0.0583 (9)	0.0462 (8)	−0.0052 (7)	0.0260 (7)	−0.0057 (7)
N3	0.0368 (7)	0.0512 (8)	0.0382 (7)	−0.0006 (6)	0.0192 (6)	0.0011 (6)
F1	0.0534 (6)	0.0882 (8)	0.0641 (7)	0.0227 (6)	0.0204 (5)	0.0185 (6)
C1	0.0413 (9)	0.0500 (10)	0.0411 (9)	−0.0061 (8)	0.0213 (7)	−0.0017 (7)
C4	0.0362 (8)	0.0502 (10)	0.0348 (8)	−0.0044 (7)	0.0150 (7)	−0.0043 (7)
C3	0.0371 (9)	0.0516 (10)	0.0426 (9)	0.0027 (8)	0.0122 (7)	−0.0005 (8)
N1	0.0428 (8)	0.0680 (10)	0.0374 (7)	0.0082 (7)	0.0188 (6)	0.0104 (7)
C2	0.0382 (9)	0.0524 (10)	0.0514 (10)	−0.0051 (8)	0.0221 (8)	−0.0125 (8)
C6	0.0463 (9)	0.0549 (10)	0.0391 (8)	0.0032 (8)	0.0240 (7)	0.0082 (8)
C11	0.0787 (14)	0.0675 (13)	0.0503 (11)	−0.0011 (11)	0.0344 (10)	0.0004 (9)
C5	0.0537 (11)	0.0799 (14)	0.0853 (15)	0.0077 (10)	0.0419 (11)	−0.0074 (12)
C10	0.133 (2)	0.0771 (16)	0.0817 (16)	0.0254 (17)	0.0782 (18)	0.0111 (13)
C8	0.0516 (12)	0.118 (2)	0.0884 (16)	0.0097 (13)	0.0386 (12)	0.0359 (16)
C9	0.095 (2)	0.110 (2)	0.109 (2)	0.0400 (17)	0.0793 (18)	0.0411 (18)
C7	0.0487 (10)	0.0710 (13)	0.0524 (10)	−0.0027 (9)	0.0240 (9)	0.0115 (9)
C12	0.0692 (14)	0.0959 (17)	0.0673 (14)	−0.0293 (13)	0.0171 (11)	−0.0094 (13)

Geometric parameters (Å, º) top

Cl1—C1	1.7384 (17)	C11—H11	0.9300
N2—C1	1.314 (2)	C5—H5A	0.9600
N2—C2	1.357 (2)	C5—H5B	0.9600
N3—C1	1.321 (2)	C5—H5C	0.9600
N3—C4	1.337 (2)	C10—C9	1.367 (4)
F1—C3	1.3533 (19)	C10—H10	0.9300
C4—N1	1.347 (2)	C8—C9	1.371 (4)
C4—C3	1.400 (2)	C8—C7	1.391 (3)
C3—C2	1.357 (2)	C8—H8	0.9300
N1—C6	1.433 (2)	C9—H9	0.9300
N1—H1	0.8600	C7—C12	1.488 (3)
C2—C5	1.494 (2)	C12—H12A	0.9600
C6—C11	1.383 (3)	C12—H12B	0.9600
C6—C7	1.385 (2)	C12—H12C	0.9600
C11—C10	1.384 (3)

C1—N2—C2	114.88 (14)	C2—C5—H5B	109.5
C1—N3—C4	115.01 (14)	H5A—C5—H5B	109.5
N2—C1—N3	130.53 (16)	C2—C5—H5C	109.5
N2—C1—Cl1	115.19 (12)	H5A—C5—H5C	109.5
N3—C1—Cl1	114.28 (12)	H5B—C5—H5C	109.5
N3—C4—N1	119.86 (14)	C9—C10—C11	119.3 (2)
N3—C4—C3	118.98 (14)	C9—C10—H10	120.4
N1—C4—C3	121.15 (15)	C11—C10—H10	120.4
F1—C3—C2	121.27 (15)	C9—C8—C7	121.3 (2)
F1—C3—C4	117.46 (14)	C9—C8—H8	119.3
C2—C3—C4	121.27 (16)	C7—C8—H8	119.3
C4—N1—C6	124.73 (14)	C10—C9—C8	121.0 (2)
C4—N1—H1	117.6	C10—C9—H9	119.5
C6—N1—H1	117.6	C8—C9—H9	119.5
N2—C2—C3	119.31 (15)	C6—C7—C8	117.0 (2)
N2—C2—C5	117.72 (16)	C6—C7—C12	121.83 (17)
C3—C2—C5	122.97 (17)	C8—C7—C12	121.2 (2)
C11—C6—C7	122.05 (17)	C7—C12—H12A	109.5
C11—C6—N1	117.67 (16)	C7—C12—H12B	109.5
C7—C6—N1	120.19 (16)	H12A—C12—H12B	109.5
C6—C11—C10	119.4 (2)	C7—C12—H12C	109.5
C6—C11—H11	120.3	H12A—C12—H12C	109.5
C10—C11—H11	120.3	H12B—C12—H12C	109.5
C2—C5—H5A	109.5

C2—N2—C1—N3	0.5 (3)	F1—C3—C2—C5	0.8 (3)
C2—N2—C1—Cl1	−178.98 (11)	C4—C3—C2—C5	−179.72 (17)
C4—N3—C1—N2	0.6 (3)	C4—N1—C6—C11	109.29 (19)
C4—N3—C1—Cl1	−179.90 (11)	C4—N1—C6—C7	−74.2 (2)
C1—N3—C4—N1	179.34 (15)	C7—C6—C11—C10	0.2 (3)
C1—N3—C4—C3	−1.3 (2)	N1—C6—C11—C10	176.61 (17)
N3—C4—C3—F1	−179.39 (14)	C6—C11—C10—C9	−0.5 (3)
N1—C4—C3—F1	−0.1 (2)	C11—C10—C9—C8	0.6 (4)
N3—C4—C3—C2	1.1 (2)	C7—C8—C9—C10	−0.4 (4)
N1—C4—C3—C2	−179.61 (16)	C11—C6—C7—C8	0.0 (3)
N3—C4—N1—C6	−0.9 (3)	N1—C6—C7—C8	−176.33 (16)
C3—C4—N1—C6	179.75 (16)	C11—C6—C7—C12	−179.19 (18)
C1—N2—C2—C3	−0.8 (2)	N1—C6—C7—C12	4.5 (3)
C1—N2—C2—C5	178.99 (16)	C9—C8—C7—C6	0.1 (3)
F1—C3—C2—N2	−179.44 (14)	C9—C8—C7—C12	179.3 (2)
C4—C3—C2—N2	0.1 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···N2ⁱ	0.86	2.34	3.0768 (19)	145

Symmetry code: (i) x, −y+1/2, z−1/2.

Experimental details

Crystal data
Chemical formula	C₁₂H₁₁ClFN₃
M_r	251.69
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	293
a, b, c (Å)	12.0593 (7), 8.3684 (4), 12.8611 (6)
β (°)	113.021 (6)
V (Å³)	1194.54 (11)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.31
Crystal size (mm)	0.5 × 0.3 × 0.2

Data collection
Diffractometer	Enraf–Nonius CAD-4
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	4692, 2125, 1750
R_int	0.014
(sin θ/λ)_max (Å⁻¹)	0.597

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.034, 0.096, 1.04
No. of reflections	2125
No. of parameters	156
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.17, −0.21

Computer programs: CAD-4 Software (Enraf–Nonius, 1994), XCAD4 (Harms & Wocadlo, 1995), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 2012).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···N2ⁱ	0.86	2.34	3.0768 (19)	145

Symmetry code: (i) x, −y+1/2, z−1/2.

Acknowledgements

We are acknowledge the support of Education Department Fund (Y201018689) of Zhejiang Province.

References

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