N-Benzyl-2-chloro­quinazolin-4-amine

Tarek Mohamed; Abdeljalil Assoud; Praveen P N Rao

doi:10.1107/S1600536814006746

. 2014 Apr 16;70(Pt 5):o554. doi: 10.1107/S1600536814006746

N-Benzyl-2-chloroquinazolin-4-amine

Tarek Mohamed ^a,^b, Abdeljalil Assoud ^a, Praveen P N Rao ^b,^*

PMCID: PMC4011242 PMID: 24860362

Abstract

The asymmetric unit of the title compound, C₁₅H₁₂ClN₃, contains two independent molecules. The quinazoline ring system in each is essentially planar, with maximum deviations of 0.025 (16) and 0.0171 (16) Å. The dihedral angles between quinazoline ring systems and the phenyl rings are 88.25 (8) and 85.28 (16)° in the two independent molecules. In the crystal, alternating independent molecules are linked by N—H⋯N hydrogen bonds, forming chains along [001].

Related literature

For the biological activity of some quinazoline and related derivatives, see: Deng & Mani (2006 ▶); Lee et al. (1995 ▶); Lopez et al. (2011 ▶); Mohamed et al. (2011 ▶); Wynne et al. (2009 ▶); Yoshida & Taguchi (1992 ▶); Zhang et al. (2009 ▶); Zhou et al. (2011 ▶).

Experimental

Crystal data

C₁₅H₁₂ClN₃
M _r = 269.73
Triclinic,
a = 9.4018 (1) Å
b = 13.0108 (1) Å
c = 13.3035 (1) Å
α = 113.968 (1)°
β = 105.377 (1)°
γ = 100.213 (1)°
V = 1356.69 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.27 mm⁻¹
T = 296 K
0.35 × 0.26 × 0.10 mm

Data collection

Bruker Kappa APEXII diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.911, T _max = 0.974
22349 measured reflections
6531 independent reflections
5274 reflections with I > 2σ(I)
R _int = 0.024
3 standard reflections every 15 min intensity decay: none

Refinement

R[F ² > 2σ(F ²)] = 0.039
wR(F ²) = 0.086
S = 1.13
6531 reflections
344 parameters
H-atom parameters constrained
Δρ_max = 0.33 e Å⁻³
Δρ_min = −0.49 e Å⁻³

Data collection: APEX2 (Bruker, 2008 ▶); cell refinement: SAINT (Bruker, 2008 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008 ▶); molecular graphics: DIAMOND (Brandenburg, 1999 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S1600536814006746/lh5690sup1.cif

e-70-0o554-sup1.cif^{(834.6KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814006746/lh5690Isup2.hkl

e-70-0o554-Isup2.hkl^{(319.6KB, hkl)}

Click here for additional data file.^{(4.8KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814006746/lh5690Isup3.cml

CCDC reference: 993912

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3A—H3AA⋯N1B ⁱ	0.86	2.21	2.9954 (17)	152
N3B—H3BA⋯N1A	0.86	2.18	2.9482 (16)	149

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors would like to thank Faculty of Science, Office of Research, and the School of Pharmacy at the University of Waterloo and Ontario Mental Health Foundation (TM) for financial support of this research project.

supplementary crystallographic information

1. Introduction

Quinazolines represent an important class of nitrogen containing heterocycles that are present in a number of therapeutically useful small molecules such as tyrosine kinase inhibitors (Zhang et al., 2009; Lopez et al., 2011) and adrenergic antagonists (Zhou et al., 2011). In our study, we have used 2,4-dichloroquinazolines to explore the selectivity of nucleophilic displacement of halogens (Mohamed et al., 2011). It is known that the monocyclic compound 2,4-dichloropyrimidine, generally favours C-4 substitution selectively or as the major regioisomer during simple S_NAr reactions with amine nucleophiles (Deng et al., 2006). A similar effect is seen with the bicyclic 2,4-dichloroquinazoline (Yoshida et al., 1992). Reaction of 2,4-dichloroquinazoline with benzylamine provided selective substitution at C-4 position. The chemical structure was confirmed by determining the crystal structure of N-benzyl-2-chloroquinazoline-4-amine (I).

2. Experimental

The title compound was prepared by slowly adding 0.75 mL of benzylamine (6.53mmol) to a mixture of 2,4-dichloroquinazoline (1g, 5.02 mmol) in 20 mL of methanol on ice-bath while stirring. The solution was allowed to stir on ice for 5 minutes before drop wise addition of DIPEA (1.75 mL, 10.04 mmol). The reaction was allowed to stir on the ice-bath for an additional 5 minutes and then refluxed at 348–353K for 3 hours. After cooling to 298 K, the solvent was evaporated in vacuo and the residue was re-dissolved in EtOAc, washed with saturated NaHCO₃ and NaCl solution (2 x 15 mL) respectively. Aqueous layer (pH 7.5-8.0) was washed with EtOAc (1 x 15 mL) and the combined organic layer was dried over anhydrous MgSO₄, then filtered. The organic layer was evaporated in vacuo and the resulting yellowish solid was further purified by silica gel column chromatography using EtOAc:MeOH (5:1) as eluent to afford the desired product as a white solid (1.02 g, 75% yield). Mp: 442–444K. ¹H-NMR (300MHz, DMSO-d₆) d 9.24 (t, 6.0Hz 1H), d 8.27 (d, J = 6.0, 1H), d 7.75 (t, J = 9.0Hz, 1H), d 7.59 (d, J = 6.0, 1H), d 7.49 (t, J = 9.0Hz, 1H), d 7.20-7.34 (m, 5H), d 4.72 (d, J = 6.0, 2H). ESI-MS m/z: 270 [M+1]⁺ (Lee et al., 1995; Wynne et al., 2009). Crystal growth was carried out by dissolving 5mg of the product in 20mL of ethanol at room temperature and heating the solution to 353K to form a concentrated solution with a reduced volume of 10mL. The hot solution was transferred to a scintillation vial, capped and stored at 275-279K undisturbed for four days at which needle-like crystals were obtained which were suitable for X-ray diffraction.

2.1. Refinement

All H-atoms were positioned in geometrically idealized positions and refined using a riding model with C—H = 0.93–1.00 Å and N—H = 0.86 Å and isotropic displacement parameters of U_iso(H) = 1.2U_eq(C).

3. Results and discussion

The asymmetric unit of (I) is shown in Fig. 1. The quinazoline ring system [N1/N2/C1–8] in each independent molecule is essentially planar with maximum deviations of 0.025 (16) and 0.0171 (16) Å for C4A and C4B, repectively. The dihedral angles between quinazoline ring systems and the phenyl rings [C10–C15 ] are 88.25 (8)° and 85.28 (16) ° for molecules A and B, respectively. In the crystal, alternating independent molecules are linked by N—H···N hydrogen bonds forming chains along [001] (Fig .2).