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Acta Crystallogr Sect E Struct Rep Online. 2010 July 1; 66(Pt 7): o1810.
Published online 2010 June 26. doi:  10.1107/S1600536810021847
PMCID: PMC3006786

N-[3-Chloro-4-(3-fluoro­benz­yloxy)phen­yl]-6-iodo­quinazolin-4-amine

Abstract

In the title mol­ecule, C21H14ClFIN3O, the bicyclic ring system has a twisted conformation; the two fused rings form a dihedral angle of 4.5 (1)°. The dihedral angles between the fused ring system and the benzene rings are 27.3 (6) and 5.3 (5)° while the dihedral angle between the benzene rings is 22.0 (5)°. In the crystal structure, weak inter­molecular N—H(...)N hydrogen bonds link the mol­ecules into chains propagating in [100]. A short inter­molecular distance of 3.806 (3) Å between the centroids of the fluorobenzene and iodobenzene rings suggests the existence of π–π stacking inter­actions.

Related literature

For a related structure, see: Calestani et al. (2001 [triangle]). The title compound is an important inter­mediate in the synthesis of the anti­cancer agent lapatinib, see: Kimberly et al. (2006 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o1810-scheme1.jpg

Experimental

Crystal data

  • C21H14ClFIN3O
  • M r = 505.70
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1810-efi1.jpg
  • a = 13.128 (3) Å
  • b = 7.6293 (15) Å
  • c = 18.898 (4) Å
  • V = 1892.8 (7) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 1.86 mm−1
  • T = 113 K
  • 0.20 × 0.18 × 0.06 mm

Data collection

  • Rigaku Saturn CCD area-detector diffractometer
  • Absorption correction: multi-scan (ABSCOR; Higashi, 1995 [triangle]) T min = 0.707, T max = 0.897
  • 11905 measured reflections
  • 3183 independent reflections
  • 2510 reflections with I > 2σ(I)
  • R int = 0.045

Refinement

  • R[F 2 > 2σ(F 2)] = 0.030
  • wR(F 2) = 0.067
  • S = 1.01
  • 3183 reflections
  • 258 parameters
  • 1 restraint
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 1.24 e Å−3
  • Δρmin = −0.70 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 1433 Friedel pairs
  • Flack parameter: −0.039 (19)

Data collection: RAPID-AUTO (Rigaku, 1998 [triangle]); cell refinement: RAPID-AUTO; data reduction: CrystalStructure (Rigaku/MSC, 2002 [triangle]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810021847/cv2724sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810021847/cv2724Isup2.hkl

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

Acknowledgments

The authors thank the State Key Laboratory of Elemento-organic Chemistry, Nankai University, for the X-ray data collection.

supplementary crystallographic information

Comment

The title compound (I) is an important intermediate in the preparation of anticancer agent lapatinib (Kimberly et al., 2006). Herein, the synthesis and the crystal structure of (I) are reported.

In (I) (Fig. 1), all bond lengths and angles are normal and comparable with those observed in the related compound (Calestani et al., 2001). The bicycle quinazoline system has a twisted conformation - two fused rings form a dihedral angle of 4.5 (1)°. In the crystal structure, weak intermolecular N—H···N hydrogen bonds (Table 1) link molecules into chains propagated in direction [100]. Short intermolecular distance of 3.806 (3) Å between the centroids of aromatic rings suggests an existence of π-π interactions.

Experimental

2-Chloro-4-(6-iodo-quinazolin-4-ylamino)-phenol (10 mmol) in acetone (5 ml) was added to a stirred mixture of anhydrous potassium carbonate (20 mmol) and 1-Chloromethyl-3-fluoro-benzene (10 mmol) in dry acetone (25 ml). It was stirred at room temperature for 6 h. Upon completion reaction mixture was diluted with water, extracted with dichloromethane and concentrated. Recrystallization from ethyl acetate afforded title compound in 89% yield as yellow crystal: 1H NMR (DMSO-d6): 9.82 (1H, s, NH), 8.94(1H, s, ArH), 8.60(1H, s, ArH), 8.08(1H, dd, ArH), 8.01(1H, d ArH), 7.72 (1H, dd ArH), 7.49(1H, d ArH), 7.43 (1H, dd ArH), 7.19 (3H, m ArH), 7.14 (1H, t ArH), 5.24(2H, s CH2).

Refinement

All H atoms were initially located in a difference Fourier map. C-bound H atoms were then constrained to an ideal geometry (C—H 0.93 Å), N-bound H atom was refined with N—H bond restraint of 0.83 (5) Å. All H-atoms were refined with Uiso(H) = 1.2Ueq(C,N).

Figures

Fig. 1.
The structure of C21H14ClFIN3O with atom-labelling scheme and ellipsoids drawn at the 50% probability level.

Crystal data

C21H14ClFIN3OF(000) = 992
Mr = 505.70Dx = 1.775 Mg m3
Orthorhombic, Pca21Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2c -2acCell parameters from 7022 reflections
a = 13.128 (3) Åθ = 1.1–27.9°
b = 7.6293 (15) ŵ = 1.86 mm1
c = 18.898 (4) ÅT = 113 K
V = 1892.8 (7) Å3Prism, colourless
Z = 40.20 × 0.18 × 0.06 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer3183 independent reflections
Radiation source: fine-focus sealed tube2510 reflections with I > 2σ(I)
graphiteRint = 0.045
Detector resolution: 14.63 pixels mm-1θmax = 25.0°, θmin = 3.1°
ω scanh = −15→15
Absorption correction: multi-scan (ABSCOR; Higashi, 1995)k = −8→9
Tmin = 0.707, Tmax = 0.897l = −21→22
11905 measured reflections

Refinement

Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.030w = 1/[σ2(Fo2) + (0.0292P)2] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.067(Δ/σ)max = 0.001
S = 1.00Δρmax = 1.24 e Å3
3183 reflectionsΔρmin = −0.70 e Å3
258 parametersExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
1 restraintExtinction coefficient: 0.0309 (8)
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), 1433 Friedel pairs
Secondary atom site location: difference Fourier mapFlack parameter: −0.039 (19)

Special details

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)

xyzUiso*/Ueq
I10.299873 (18)−0.00631 (3)0.50844 (4)0.01983 (11)
Cl10.28694 (8)1.26802 (14)0.25075 (8)0.0248 (3)
F10.0085 (3)1.7039 (4)0.0746 (2)0.0538 (10)
O10.0946 (2)1.1497 (4)0.19493 (17)0.0220 (8)
N10.2954 (3)0.6395 (5)0.3538 (2)0.0165 (9)
N20.4616 (3)0.7425 (5)0.3551 (2)0.0185 (10)
N30.6006 (3)0.5682 (5)0.3991 (2)0.0173 (9)
C10.0028 (5)1.4220 (8)0.1242 (3)0.0289 (14)
H10.07271.42590.13190.035*
C2−0.0476 (4)1.5583 (9)0.0935 (3)0.0288 (16)
C3−0.1501 (5)1.5661 (7)0.0807 (3)0.0336 (14)
H3−0.18041.66400.06030.040*
C4−0.2058 (4)1.4207 (7)0.0999 (3)0.0290 (13)
H4−0.27561.41880.09140.035*
C5−0.1602 (3)1.2779 (6)0.1315 (3)0.0225 (12)
H5−0.19951.18210.14490.027*
C6−0.0549 (4)1.2766 (6)0.1433 (3)0.0171 (12)
C7−0.0070 (3)1.1135 (6)0.1729 (3)0.0201 (11)
H7A−0.04661.07200.21290.024*
H7B−0.00661.02230.13710.024*
C80.1419 (4)1.0178 (5)0.2308 (3)0.0177 (11)
C90.1065 (4)0.8496 (6)0.2378 (3)0.0193 (11)
H90.04550.81770.21630.023*
C100.1605 (4)0.7262 (6)0.2767 (2)0.0210 (12)
H100.13590.61210.27970.025*
C110.2503 (3)0.7694 (6)0.3110 (2)0.0138 (10)
C120.2883 (4)0.9387 (7)0.3038 (3)0.0175 (11)
H120.34800.97090.32680.021*
C130.2365 (4)1.0605 (5)0.2618 (3)0.0168 (11)
C140.3949 (3)0.6194 (6)0.3725 (2)0.0158 (10)
C150.5600 (4)0.7107 (7)0.3715 (3)0.0202 (13)
H150.60520.80150.36200.024*
C160.5303 (4)0.4390 (8)0.4183 (3)0.0164 (13)
C170.5680 (4)0.2842 (6)0.4475 (3)0.0209 (12)
H170.63800.26790.45160.025*
C180.5028 (3)0.1559 (6)0.4703 (2)0.0179 (10)
H180.52820.05170.48870.022*
C190.3977 (3)0.1828 (5)0.4656 (2)0.0156 (10)
C200.3593 (3)0.3317 (5)0.4348 (3)0.0170 (11)
H200.28930.34680.43070.020*
C210.4254 (4)0.4606 (6)0.4094 (3)0.0158 (11)
H210.260 (5)0.555 (7)0.363 (4)0.05 (2)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
I10.01930 (17)0.01590 (15)0.02429 (18)−0.00277 (13)0.0006 (2)0.00282 (15)
Cl10.0276 (6)0.0170 (6)0.0299 (8)−0.0025 (5)−0.0030 (7)0.0048 (5)
F10.065 (2)0.034 (2)0.062 (3)−0.0141 (18)−0.011 (2)0.0118 (17)
O10.0168 (18)0.0207 (18)0.029 (2)0.0031 (15)−0.0055 (17)0.0074 (15)
N10.013 (2)0.014 (2)0.022 (3)−0.0002 (18)0.0021 (18)0.0039 (17)
N20.013 (2)0.021 (2)0.021 (3)0.0003 (17)0.0004 (17)0.0033 (18)
N30.014 (2)0.017 (2)0.021 (3)0.002 (2)0.002 (2)0.0030 (18)
C10.028 (3)0.025 (3)0.034 (4)0.002 (3)0.000 (3)0.001 (3)
C20.046 (5)0.022 (3)0.019 (4)−0.009 (3)−0.007 (3)0.001 (3)
C30.052 (4)0.027 (3)0.022 (3)0.024 (3)−0.013 (3)−0.006 (2)
C40.035 (3)0.033 (3)0.019 (3)0.010 (3)−0.004 (2)−0.005 (2)
C50.021 (3)0.027 (3)0.018 (3)0.004 (2)−0.005 (2)0.001 (2)
C60.024 (3)0.017 (3)0.010 (3)0.003 (2)−0.003 (2)0.004 (2)
C70.018 (3)0.021 (3)0.022 (3)−0.001 (2)−0.001 (2)0.003 (2)
C80.015 (3)0.022 (3)0.016 (3)0.008 (2)0.002 (2)0.005 (2)
C90.015 (2)0.022 (3)0.021 (3)−0.003 (2)−0.003 (2)−0.002 (2)
C100.030 (3)0.013 (2)0.021 (3)0.001 (2)0.002 (2)0.0024 (19)
C110.014 (2)0.016 (2)0.012 (3)0.004 (2)0.000 (2)0.0000 (18)
C120.012 (3)0.028 (3)0.013 (3)0.005 (2)0.001 (2)−0.002 (2)
C130.017 (3)0.0134 (19)0.020 (3)−0.004 (2)0.004 (2)0.001 (3)
C140.013 (2)0.017 (2)0.017 (3)0.002 (2)0.001 (2)−0.0035 (19)
C150.015 (3)0.019 (3)0.027 (4)−0.003 (2)0.005 (2)0.004 (2)
C160.018 (3)0.012 (3)0.019 (4)0.002 (2)0.007 (2)0.002 (2)
C170.019 (3)0.021 (3)0.022 (3)0.003 (2)0.000 (2)−0.001 (2)
C180.020 (3)0.015 (2)0.019 (3)0.005 (2)−0.001 (2)0.003 (2)
C190.017 (3)0.014 (2)0.016 (3)−0.004 (2)0.001 (2)0.0003 (19)
C200.015 (3)0.022 (3)0.015 (3)0.000 (2)−0.003 (2)−0.003 (2)
C210.013 (3)0.019 (3)0.016 (3)−0.003 (2)−0.001 (2)0.0007 (19)

Geometric parameters (Å, °)

I1—C192.094 (4)C7—H7A0.9700
Cl1—C131.729 (4)C7—H7B0.9700
F1—C21.380 (7)C8—C91.372 (6)
O1—C81.363 (5)C8—C131.411 (8)
O1—C71.425 (5)C9—C101.389 (6)
N1—C141.362 (5)C9—H90.9300
N1—C111.408 (6)C10—C111.386 (6)
N1—H210.81 (6)C10—H100.9300
N2—C141.326 (6)C11—C121.392 (7)
N2—C151.350 (6)C12—C131.398 (8)
N3—C151.318 (6)C12—H120.9300
N3—C161.399 (7)C14—C211.454 (7)
C1—C21.363 (9)C15—H150.9300
C1—C61.391 (7)C16—C171.395 (7)
C1—H10.9300C16—C211.397 (7)
C2—C31.368 (8)C17—C181.370 (6)
C3—C41.377 (9)C17—H170.9300
C3—H30.9300C18—C191.398 (6)
C4—C51.380 (7)C18—H180.9300
C4—H40.9300C19—C201.373 (6)
C5—C61.400 (6)C20—C211.396 (7)
C5—H50.9300C20—H200.9300
C6—C71.502 (6)
C8—O1—C7115.4 (4)C11—C10—C9121.4 (4)
C14—N1—C11129.1 (4)C11—C10—H10119.3
C14—N1—H21114 (5)C9—C10—H10119.3
C11—N1—H21116 (5)C10—C11—C12118.6 (4)
C14—N2—C15116.6 (4)C10—C11—N1117.3 (4)
C15—N3—C16114.6 (4)C12—C11—N1124.0 (4)
C2—C1—C6117.0 (6)C11—C12—C13119.9 (5)
C2—C1—H1121.5C11—C12—H12120.0
C6—C1—H1121.5C13—C12—H12120.0
C1—C2—C3125.9 (6)C12—C13—C8120.7 (4)
C1—C2—F1117.7 (5)C12—C13—Cl1119.4 (4)
C3—C2—F1116.4 (6)C8—C13—Cl1119.9 (4)
C2—C3—C4116.2 (6)N2—C14—N1119.3 (4)
C2—C3—H3121.9N2—C14—C21121.8 (4)
C4—C3—H3121.9N1—C14—C21118.9 (4)
C3—C4—C5121.3 (5)N3—C15—N2128.8 (5)
C3—C4—H4119.4N3—C15—H15115.6
C5—C4—H4119.4N2—C15—H15115.6
C4—C5—C6120.2 (5)C17—C16—C21119.8 (5)
C4—C5—H5119.9C17—C16—N3117.7 (5)
C6—C5—H5119.9C21—C16—N3122.4 (5)
C1—C6—C5119.4 (5)C18—C17—C16120.5 (5)
C1—C6—C7122.0 (5)C18—C17—H17119.8
C5—C6—C7118.5 (4)C16—C17—H17119.8
O1—C7—C6109.9 (4)C17—C18—C19119.5 (4)
O1—C7—H7A109.7C17—C18—H18120.2
C6—C7—H7A109.7C19—C18—H18120.2
O1—C7—H7B109.7C20—C19—C18120.7 (4)
C6—C7—H7B109.7C20—C19—I1120.6 (3)
H7A—C7—H7B108.2C18—C19—I1118.7 (3)
O1—C8—C9125.8 (5)C19—C20—C21120.1 (4)
O1—C8—C13115.9 (4)C19—C20—H20120.0
C9—C8—C13118.3 (4)C21—C20—H20120.0
C8—C9—C10120.8 (5)C20—C21—C16119.2 (5)
C8—C9—H9119.6C20—C21—C14125.4 (4)
C10—C9—H9119.6C16—C21—C14115.3 (5)
C6—C1—C2—C31.0 (10)O1—C8—C13—Cl1−1.9 (7)
C6—C1—C2—F1179.6 (5)C9—C8—C13—Cl1177.0 (4)
C1—C2—C3—C4−1.1 (10)C15—N2—C14—N1−176.3 (5)
F1—C2—C3—C4−179.8 (5)C15—N2—C14—C211.9 (7)
C2—C3—C4—C51.3 (8)C11—N1—C14—N26.6 (7)
C3—C4—C5—C6−1.4 (8)C11—N1—C14—C21−171.6 (5)
C2—C1—C6—C5−1.0 (8)C16—N3—C15—N2−5.0 (8)
C2—C1—C6—C7175.8 (5)C14—N2—C15—N34.3 (8)
C4—C5—C6—C11.2 (8)C15—N3—C16—C17179.7 (5)
C4—C5—C6—C7−175.6 (5)C15—N3—C16—C21−0.6 (8)
C8—O1—C7—C6172.2 (4)C21—C16—C17—C18−2.7 (8)
C1—C6—C7—O115.5 (7)N3—C16—C17—C18177.1 (5)
C5—C6—C7—O1−167.8 (4)C16—C17—C18—C19−1.6 (7)
C7—O1—C8—C910.2 (7)C17—C18—C19—C203.9 (7)
C7—O1—C8—C13−171.0 (4)C17—C18—C19—I1−175.0 (4)
O1—C8—C9—C10−178.9 (4)C18—C19—C20—C21−1.8 (7)
C13—C8—C9—C102.3 (8)I1—C19—C20—C21177.0 (4)
C8—C9—C10—C111.7 (7)C19—C20—C21—C16−2.5 (8)
C9—C10—C11—C12−2.5 (7)C19—C20—C21—C14176.7 (5)
C9—C10—C11—N1175.0 (4)C17—C16—C21—C204.7 (8)
C14—N1—C11—C10154.4 (5)N3—C16—C21—C20−175.1 (5)
C14—N1—C11—C12−28.3 (8)C17—C16—C21—C14−174.5 (5)
C10—C11—C12—C13−0.7 (7)N3—C16—C21—C145.7 (8)
N1—C11—C12—C13−178.0 (5)N2—C14—C21—C20174.4 (5)
C11—C12—C13—C84.7 (8)N1—C14—C21—C20−7.4 (8)
C11—C12—C13—Cl1−177.7 (4)N2—C14—C21—C16−6.4 (7)
O1—C8—C13—C12175.6 (5)N1—C14—C21—C16171.8 (5)
C9—C8—C13—C12−5.5 (8)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H21···N3i0.81 (6)2.39 (6)3.128 (6)151 (6)

Symmetry codes: (i) x−1/2, −y+1, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CV2724).

References

  • Calestani, G., Capella, L., Leardini, R., Minozzi, M., Nanni, D., Papa, R. & Zanardi, G. (2001). Tetrahedron, 57, 7221–7223.
  • Flack, H. D. (1983). Acta Cryst. A39, 876–881.
  • Higashi, T. (1995). ABSCOR Rigaku Corporation, Tokyo, Japan.
  • Kimberly, G. P., Zhang, Y. M., Malcolm, C., Cockerill, G. S., Dickerson, S., Cassandra, A. G., Guo, Y., Robert, A. M., David, W. R., Ann, L. W., Edgar, R. W. & Karen, E. L. (2006). Bioorg. Med. Chem. Lett.16, 4686–4691. [PubMed]
  • Rigaku (1998). RAPID-AUTO Rigaku Corporation, Tokyo, Japan.
  • Rigaku/MSC (2002). CrystalStructure Rigaku/MSC, The Woodlands, Texas, USA.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]

Articles from Acta Crystallographica Section E: Structure Reports Online are provided here courtesy of International Union of Crystallography