organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

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

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[Riccaboni, M., Bianchi, I. & Petrillo, P. (2010). Drug Discov. Today, 15, 517-530.]). For the anti­tumor activity of 4-aniline-substituted 5-fluoro­pyrimidines, see: Lawrence et al. (2012[Lawrence, H. R., Martin, M. P., Luo, Y. & Pireddu, R. (2012). J. Med. Chem. 55, 7392-7416.]).

[Scheme 1]

Experimental

Crystal data
  • C12H11ClFN3

  • Mr = 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)

  • Rint = 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

  • Δρmax = 0.17 e Å−3

  • Δρmin = −0.21 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA 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[Enraf-Nonius (1994). CAD4. Enraf-Nonius, Delft, The Netherlands.]); cell refinement: CAD-4 Software (Enraf–Nonius, 1994[Enraf-Nonius (1994). CAD4. Enraf-Nonius, Delft, The Netherlands.]); data reduction: XCAD4 (Harms & Wocadlo, 1995[Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]); software used to prepare material for publication: SHELXL97.

Supporting information


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.

Refinement top

The amino H atom was found in a difference Fourier map and treated as riding with N—H = 0.86 Å, and with Uiso(H) = 1.2Ueq(N). The other H atoms were added at calculated positions and refined using a riding model, with C—H = 0.93 Å (or 0.96 Å for methyl H) and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(Cmethyl) .

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
[Figure 1] Fig. 1. The molecular structure of the title compound with 30% probability displacement ellipsoids.
[Figure 2] 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
C12H11ClFN3F(000) = 520
Mr = 251.69Dx = 1.399 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 1870 reflections
a = 12.0593 (7) Åθ = 3.0–29.1°
b = 8.3684 (4) ŵ = 0.31 mm1
c = 12.8611 (6) ÅT = 293 K
β = 113.021 (6)°Prismatic, colourless
V = 1194.54 (11) Å30.5 × 0.3 × 0.2 mm
Z = 4
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.014
Radiation source: fine-focus sealed tubeθmax = 25.1°, θmin = 3.0°
Graphite monochromatorh = 714
phi and ω scansk = 99
4692 measured reflectionsl = 1515
2125 independent reflections3 standard reflections every 60 min
1750 reflections with I > 2σ(I) intensity decay: none
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.034Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.096H-atom parameters constrained
S = 1.04 w = 1/[σ2(Fo2) + (0.0466P)2 + 0.2577P]
where P = (Fo2 + 2Fc2)/3
2125 reflections(Δ/σ)max = 0.002
156 parametersΔρmax = 0.17 e Å3
0 restraintsΔρmin = 0.21 e Å3
Crystal data top
C12H11ClFN3V = 1194.54 (11) Å3
Mr = 251.69Z = 4
Monoclinic, P21/cMo Kα radiation
a = 12.0593 (7) ŵ = 0.31 mm1
b = 8.3684 (4) ÅT = 293 K
c = 12.8611 (6) Å0.5 × 0.3 × 0.2 mm
β = 113.021 (6)°
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.014
4692 measured reflections3 standard reflections every 60 min
2125 independent reflections intensity decay: none
1750 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0340 restraints
wR(F2) = 0.096H-atom parameters constrained
S = 1.04Δρmax = 0.17 e Å3
2125 reflectionsΔρmin = 0.21 e Å3
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
xyzUiso*/Ueq
Cl10.75856 (5)0.06428 (7)1.24493 (4)0.0666 (2)
N20.57335 (12)0.12020 (18)1.15433 (11)0.0470 (4)
N30.70666 (11)0.09036 (16)1.05829 (11)0.0407 (3)
F10.46632 (9)0.35255 (15)0.89928 (9)0.0694 (3)
C10.66841 (15)0.0648 (2)1.14005 (14)0.0426 (4)
C40.63837 (14)0.1897 (2)0.97700 (13)0.0401 (4)
C30.53397 (14)0.2537 (2)0.98347 (14)0.0448 (4)
N10.66996 (12)0.22514 (18)0.89014 (11)0.0484 (4)
H10.62360.28820.83870.058*
C20.50232 (14)0.2189 (2)1.07122 (15)0.0460 (4)
C60.77521 (15)0.1655 (2)0.87727 (13)0.0445 (4)
C110.7589 (2)0.0547 (2)0.79274 (17)0.0627 (5)
H110.68210.01710.74910.075*
C50.39149 (18)0.2840 (3)1.08108 (19)0.0684 (6)
H5A0.35010.35281.01800.103*
H5B0.41360.34371.15000.103*
H5C0.33950.19741.08160.103*
C100.8577 (3)0.0005 (3)0.7736 (2)0.0862 (8)
H100.84820.07450.71740.103*
C80.98515 (19)0.1680 (4)0.9222 (2)0.0824 (8)
H81.06220.20520.96530.099*
C90.9696 (3)0.0584 (4)0.8384 (3)0.0925 (9)
H91.03610.02290.82540.111*
C70.88790 (16)0.2248 (2)0.94391 (16)0.0560 (5)
C120.9052 (2)0.3424 (3)1.03578 (19)0.0804 (7)
H12A0.85060.43021.00650.121*
H12B0.98660.38121.06450.121*
H12C0.88960.29161.09560.121*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0636 (3)0.0849 (4)0.0599 (3)0.0128 (3)0.0333 (3)0.0278 (3)
N20.0441 (8)0.0583 (9)0.0462 (8)0.0052 (7)0.0260 (7)0.0057 (7)
N30.0368 (7)0.0512 (8)0.0382 (7)0.0006 (6)0.0192 (6)0.0011 (6)
F10.0534 (6)0.0882 (8)0.0641 (7)0.0227 (6)0.0204 (5)0.0185 (6)
C10.0413 (9)0.0500 (10)0.0411 (9)0.0061 (8)0.0213 (7)0.0017 (7)
C40.0362 (8)0.0502 (10)0.0348 (8)0.0044 (7)0.0150 (7)0.0043 (7)
C30.0371 (9)0.0516 (10)0.0426 (9)0.0027 (8)0.0122 (7)0.0005 (8)
N10.0428 (8)0.0680 (10)0.0374 (7)0.0082 (7)0.0188 (6)0.0104 (7)
C20.0382 (9)0.0524 (10)0.0514 (10)0.0051 (8)0.0221 (8)0.0125 (8)
C60.0463 (9)0.0549 (10)0.0391 (8)0.0032 (8)0.0240 (7)0.0082 (8)
C110.0787 (14)0.0675 (13)0.0503 (11)0.0011 (11)0.0344 (10)0.0004 (9)
C50.0537 (11)0.0799 (14)0.0853 (15)0.0077 (10)0.0419 (11)0.0074 (12)
C100.133 (2)0.0771 (16)0.0817 (16)0.0254 (17)0.0782 (18)0.0111 (13)
C80.0516 (12)0.118 (2)0.0884 (16)0.0097 (13)0.0386 (12)0.0359 (16)
C90.095 (2)0.110 (2)0.109 (2)0.0400 (17)0.0793 (18)0.0411 (18)
C70.0487 (10)0.0710 (13)0.0524 (10)0.0027 (9)0.0240 (9)0.0115 (9)
C120.0692 (14)0.0959 (17)0.0673 (14)0.0293 (13)0.0171 (11)0.0094 (13)
Geometric parameters (Å, º) top
Cl1—C11.7384 (17)C11—H110.9300
N2—C11.314 (2)C5—H5A0.9600
N2—C21.357 (2)C5—H5B0.9600
N3—C11.321 (2)C5—H5C0.9600
N3—C41.337 (2)C10—C91.367 (4)
F1—C31.3533 (19)C10—H100.9300
C4—N11.347 (2)C8—C91.371 (4)
C4—C31.400 (2)C8—C71.391 (3)
C3—C21.357 (2)C8—H80.9300
N1—C61.433 (2)C9—H90.9300
N1—H10.8600C7—C121.488 (3)
C2—C51.494 (2)C12—H12A0.9600
C6—C111.383 (3)C12—H12B0.9600
C6—C71.385 (2)C12—H12C0.9600
C11—C101.384 (3)
C1—N2—C2114.88 (14)C2—C5—H5B109.5
C1—N3—C4115.01 (14)H5A—C5—H5B109.5
N2—C1—N3130.53 (16)C2—C5—H5C109.5
N2—C1—Cl1115.19 (12)H5A—C5—H5C109.5
N3—C1—Cl1114.28 (12)H5B—C5—H5C109.5
N3—C4—N1119.86 (14)C9—C10—C11119.3 (2)
N3—C4—C3118.98 (14)C9—C10—H10120.4
N1—C4—C3121.15 (15)C11—C10—H10120.4
F1—C3—C2121.27 (15)C9—C8—C7121.3 (2)
F1—C3—C4117.46 (14)C9—C8—H8119.3
C2—C3—C4121.27 (16)C7—C8—H8119.3
C4—N1—C6124.73 (14)C10—C9—C8121.0 (2)
C4—N1—H1117.6C10—C9—H9119.5
C6—N1—H1117.6C8—C9—H9119.5
N2—C2—C3119.31 (15)C6—C7—C8117.0 (2)
N2—C2—C5117.72 (16)C6—C7—C12121.83 (17)
C3—C2—C5122.97 (17)C8—C7—C12121.2 (2)
C11—C6—C7122.05 (17)C7—C12—H12A109.5
C11—C6—N1117.67 (16)C7—C12—H12B109.5
C7—C6—N1120.19 (16)H12A—C12—H12B109.5
C6—C11—C10119.4 (2)C7—C12—H12C109.5
C6—C11—H11120.3H12A—C12—H12C109.5
C10—C11—H11120.3H12B—C12—H12C109.5
C2—C5—H5A109.5
C2—N2—C1—N30.5 (3)F1—C3—C2—C50.8 (3)
C2—N2—C1—Cl1178.98 (11)C4—C3—C2—C5179.72 (17)
C4—N3—C1—N20.6 (3)C4—N1—C6—C11109.29 (19)
C4—N3—C1—Cl1179.90 (11)C4—N1—C6—C774.2 (2)
C1—N3—C4—N1179.34 (15)C7—C6—C11—C100.2 (3)
C1—N3—C4—C31.3 (2)N1—C6—C11—C10176.61 (17)
N3—C4—C3—F1179.39 (14)C6—C11—C10—C90.5 (3)
N1—C4—C3—F10.1 (2)C11—C10—C9—C80.6 (4)
N3—C4—C3—C21.1 (2)C7—C8—C9—C100.4 (4)
N1—C4—C3—C2179.61 (16)C11—C6—C7—C80.0 (3)
N3—C4—N1—C60.9 (3)N1—C6—C7—C8176.33 (16)
C3—C4—N1—C6179.75 (16)C11—C6—C7—C12179.19 (18)
C1—N2—C2—C30.8 (2)N1—C6—C7—C124.5 (3)
C1—N2—C2—C5178.99 (16)C9—C8—C7—C60.1 (3)
F1—C3—C2—N2179.44 (14)C9—C8—C7—C12179.3 (2)
C4—C3—C2—N20.1 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···N2i0.862.343.0768 (19)145
Symmetry code: (i) x, y+1/2, z1/2.

Experimental details

Crystal data
Chemical formulaC12H11ClFN3
Mr251.69
Crystal system, space groupMonoclinic, P21/c
Temperature (K)293
a, b, c (Å)12.0593 (7), 8.3684 (4), 12.8611 (6)
β (°) 113.021 (6)
V3)1194.54 (11)
Z4
Radiation typeMo Kα
µ (mm1)0.31
Crystal size (mm)0.5 × 0.3 × 0.2
Data collection
DiffractometerEnraf–Nonius CAD-4
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
4692, 2125, 1750
Rint0.014
(sin θ/λ)max1)0.597
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.034, 0.096, 1.04
No. of reflections2125
No. of parameters156
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)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···AD—HH···AD···AD—H···A
N1—H1···N2i0.862.343.0768 (19)145
Symmetry code: (i) x, y+1/2, z1/2.
 

Acknowledgements

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

References

First citationEnraf–Nonius (1994). CAD4. Enraf–Nonius, Delft, The Netherlands.
First citationFarrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.  Web of Science CrossRef CAS IUCr Journals
First citationHarms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.
First citationLawrence, H. R., Martin, M. P., Luo, Y. & Pireddu, R. (2012). J. Med. Chem. 55, 7392–7416.  Web of Science CrossRef CAS PubMed
First citationRiccaboni, M., Bianchi, I. & Petrillo, P. (2010). Drug Discov. Today, 15, 517–530.  Web of Science CrossRef CAS PubMed
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Follow Acta Cryst. E
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds