Investigation of regioselectivity on the reaction of 5-bromo-2,4-dichloro-6-methylpyrimidine with ammonia

Abdolhassan Doulah; Hossein Eshtiagh-Hosseini; Masoud Mirzaei; Mohsen Nikpour; Ali Fazlara; Ali R. Salimi

doi:10.1016/j.arabjc.2010.12.026

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Original article

7 (

); 1000-1002

doi:

10.1016/j.arabjc.2010.12.026

Investigation of regioselectivity on the reaction of 5-bromo-2,4-dichloro-6-methylpyrimidine with ammonia

Abdolhassan Doulah^{^a,*}, Hossein Eshtiagh-Hosseini^{^b}, Masoud Mirzaei^{^b}, Mohsen Nikpour^{^c}, Ali Fazlara^{^d}, Ali R. Salimi^{^b}

a Department of Nursing, Faculty of Nursing and Midwifery, Ahvaz Branch, Islamic Azad University, Ahvaz 6134968875, Iran

b Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, P.O. Box 917791436, Mashhad, Iran

c Department of Chemistry, School of Sciences, Ahvaz Branch, Islamic Azad University, Ahvaz 6134968875, Iran

d Department of Biology, Shahid Chamran University of Ahvaz, Ahvaz, Iran

*Corresponding author. Tel./fax: +98 6113329193 doulahh@yahoo.com (Abdolhassan Doulah)

Received: 2010-11-27, Accepted: 2010-12-27, Published: 2011-12-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Available online 30 December 2010

Peer review under responsibility of King Saud University.

Abstract

Regioselective displacement reaction of ammonia with 5-bromo-2,4-dichloro-6-methylpyrimidine was studied by X-ray crystallography analysis and showed the formation of 5-bromo-2-chloro-6-methylpyrimidin-4-amine as a main product. Reaction of the latter compound with secondary amines in boiling ethanol afforded 4-amino-5-bromo-2-substituted aminopyrimidines. The synthesized compound in this paper crystallized in the monoclinic crystal system space group P2₁/n. In the title cocrystal, 5-bromo-2-chloro-6-methylpyrimidin-4-amine·3H₂O, the asymmetric unit contains one crystallographically independent 5-bromo-2-chloro-6-methylpyrimidin-4-amine and three crystallization of water molecules. The typical intramolecular O−H⋯N as well as O−H⋯O hydrogen bond is observed in the crystalline network of the title compound. It is interesting to point out that the crystal structure is further stabilized by O−H⋯O hydrogen bonds created by (H₂O)_∞ clusters.

Keywords

5-Bromo-2,4-dichloro-6-methylpyrimidine

5-Bromo-2-chloro-6-methylpyrimidin-4-amine

X-ray crystallography

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1 Introduction

Over the recent years, pyrimidines and fused pyrimidines were being on the scope of pharmaceutical research due to their variety applications. These compounds have been described as anticancer (Petrie et al., 1985), antiviral (Nasr and Gineinah, 2002), antitumor (Baraldi et al., 2002) and antiinflammatorial agents (Sondhi et al., 2001). In recent years, our research group has reported the synthesis and 15-lipoxygenase inhibitory of pyrimido[4,5-b][1,4]benzothiazine derivatives (Bakavoli et al., 2007, 2008). In a previous research we have reported the synthesis of new thiazolo[4,5-d] pyrimidine derivatives by sequential treatment of 5-bromo-2,4-dichloro-6-methylpyrimidine with ammonia, secondary amines and isothiocyanates (Bakavoli et al., 2006) as shown in Scheme 1 with no experimental evidence for regioselective displacement of the 4-chlorine atom with ammonia. In this research we show this regioselectivity by X-ray crystallography analysis of the product and report the synthesis of some new useful 4-amino-5-bromo-2-substituted aminopyrimidines.

Preparation of thiazolo[4,5-d] pyrimidines.

2 Experimental

The melting points were recorded on an Electrothermal type 9100 melting point apparatus. The IR spectra were obtained on a 4300 Shimadzu Spectrometer. The ¹H NMR (100 MHz) spectra were recorded on a Bruker AC 100 spectrometer. The mass spectra were scanned on a Varian Mat CH-7 instrument at 70 eV. Elemental analysis was obtained on a Thermo Finnigan Flash EA microanalyzer. Synthesis of 5-bromo-2,4-dichloro-6-methylpyrimidine 1 and its treatment with ammonia carried out according to our published method (Bakavoli et al., 2006).

2.1

2.1 General procedure for the reaction of 5-bromo-2-chloro-6-methylpyrimidin-4-amine (1) with amines

5-Bromo-2-chloro-6-methylpyrimidin-4-amine (1) (2.22 g, 10 mmol) in ethanol (25 mL) was heated under reflux with either 1-methylpiperazin (2.0 g), 1-phenylpiperazin (2 g) or piperidine (2 g) for 4 h. Then water (20 mL) was added and the solution kept overnight, the precipitate was filtered off and washed with warm water and dried at 80 °C to give 2a–c, respectively as shown in Scheme 2.

2.1.1

2.1.1 5-Bromo-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine (2a)

This compound was obtained as a creamy powder in 60% yield, mp 113–116 °C; IR: 3320 and 3460 cm⁻¹ (NH₂); ¹H NMR: (CDCl₃): δ 2.28 (m, 7H, 2(CH₂N)-CH₃), 2.47 (s, 3H, CH₃), 3.49 (t, 4H, 2(CH₂N-Pyr), 5.2 (s, 2H, NH₂); ms: m/z 285 (90%), 287 (90%). Anal. Calcd. for C₁₀H₁₆BrN₅: C, 41.97; H, 5.64; N, 24.47. Found: C, 42.12; H, 5.76; N, 24.31.

2.1.2

2.1.2 5-Bromo-6-methyl-2-(4-phenylpiperazin-1-yl)pyrimidin-4-amine (2b)

This compound was obtained as a creamy powder in 80% yield, mp 125–127 °C; IR: 3310 and 3440 cm⁻¹ (NH₂); ¹H NMR: (CDCl₃): δ 2.32 (t, 4H, 2(CH₂N)), 2.51 (s, 3H, CH₃), 3.55 (t, 4H, 2(CH₂N-Pyr)), 5.2 (s, 2H, NH₂), 7.2–7.5 (m, 5H, aromatic); ms: m/z, 347 (85%), 349 (85%). Anal. Calcd. for C₁₅H₁₈BrN₅: C, 51.73; H, 5.21; N, 20.11. Found: C, 51.95; H, 5.40; N, 20.31.

2.1.3

2.1.3 5-Bromo-6-methyl-2-(piperidin-1-yl)pyrimidin-4-amine (2c)

This compound was obtained as a creamy powder in 80% yield, mp 125–127 °C; IR: 3310 and 3440 cm⁻¹ (NH₂); ¹H NMR: (CDCl₃): δ 1.2–1.7 (m, 6H, 3CH₂), 2.51 (s, 3H, CH₃), 3.41 (t, 4H, 2(CH₂N-Pyr)), 5.2 (s, 2H, NH₂), ms: m/z, 270 (80%), 272 (80%). Anal. Calcd. for C₁₀H₁₅BrN₄: C, 44.29; H, 5.58; N, 20.66. Found: C, 44.24; H, 5.73; N, 20.39.

2.2

2.2 X-ray crystallography

Crystal data and structure refinement for 5-bromo-2-chloro-6-methylpyrimidin-4-amine·3H₂O were given in Table 1. Data were collected using a colorless prism crystal mounted on a Bruker APEX II CCD area detector diffractometer equipped with graphite monochromated Mo Kα radiation (λ = 0.71073 Å). The final unit cell was determined from 12,645 reflections in the range of 2.3° < θ < 30.5°. The diffraction data were collected at 100(2) K with the ω-scan technique. The structure was solved by direct methods and refined by full-matrix least squares based on F² with weight w = 1/[σ²( $F_{o}^{2}$ )+(0.0506P)² + 0.0000P] where P = ( $F_{o}^{2}$ + 2 $F_{c}^{2}$ )/3 using the shelxtl-97 software (Sheldrick, 1997). The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in geometrically calculated positions and thereafter allowed to ride on their parent atoms.

Table 1 Crystal data and structure refinement for 5-bromo-2-chloro-6-methylpyrimidin-4-amine·3H₂O.

Empirical formula	C₅H₁₁BrClN₃O₃
Fw	276.52
Crystal system	monoclinic
Crystal size (mm³)	0.21 × 0.25 × 0.34
Space group	P2₁/n
a (Å)	9.7470(11)
b (Å)	4.9353(6)
c (Å)	21.154(2)
β (°)	92.553(2)
Index range	−13 ⩽ h ⩽ 13
	−7 ⩽ k ⩽ 6
	−30 ⩽ l ⩽ 30
V (Å³)	1016.6(3)
Z	4
D_calcd (Mg/m³)	1.806
μ (mm⁻¹)	4.288
θ range (°)	2.3–30.5
F(0 0 0)	552
Goodness-of-fit (GOF) on F²	1.042
Final R indices [I > 2σ(I)]	R₁ = 0.0271, wR₂ = 0.0664
Largest diff. peak and hole (e Å⁻³)	0.77 and −0.44

X-ray crystallographic files in CIF format for the structure determination of the title compound has been deposited with the Cambridge Crystallographic Data Center. The CCDC reference number is 795507. Copy of this information may be obtained, free of charge, from The Director, CCDC, 12 Union Road, Cambridge, CB2 IEZ, UK (Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).

3 Results and discussion

The synthetic compound in this research crystallized in the monoclinic crystal system space group P2₁/n. In the title cocrystal, 5-bromo-2-chloro-6-methylpyrimidin-4-amine·3H₂O, the asymmetric unit contains one crystallo-graphically independent 5-bromo-2-chloro-6-methylpyrimidin-4-amine and three crystallization of water molecules (Fig. 1). The 5-bromo-2-chloro-6-methylpyrimidin-4-amine molecules interact with each other through N−H⋯N hydrogen bonds, forming a cyclic hydrogen-bonded motif $R_{2}^{2}$ (8) (Lynch and Jones, 2004). The pyrimidine molecules also connect them via water molecules. The typical intramolecular O−H⋯N as well as O−H⋯O hydrogen bond is observed in the crystalline network of the title compound. It is interesting to point out that the crystal structure is further stabilized by O−H⋯O hydrogen bonds created by (H₂O)_∞ clusters (Fig. 2). In fact, the presence of water molecules is important in establishing hydrogen bonds contributions to the total lattice energy, and is significant in the stability of the hydrated crystal structure (Aghabozorg et al., 2010). Water is of fundamental importance for human life and plays an important role in many biological and chemical systems. It possesses polar hydrogen bonds (hereafter P-HB) which are responsible for a striking set of anomalous physical and chemical properties. Water molecules have two hydrogen atoms and two lone pairs enabling them not only to participate in four hydrogen bonds in a tetrahedral arrangement but also frequently show 3-coordinate configurations. However, unlike covalent bonds, the P-HB geometry is much more flexible, Krygowski et al. (1998) describe the role of water molecules as a ‘gluing factor’ in organic crystals because of their readiness to deform from ideal P-HB geometry (Krygowski et al., 1998). P-HBs resulted in formation of diverse structures of water/water contacts directly as called water cluster, that is, (H₂O)_n clusters.

Ortep view of 5-bromo-2-chloro-6-methylpyrimidin-4-amine. Elipsoid are drawn in 50% probability.

(H2O)∞ clusters presents in the crystal of 5-bromo-2-chloro-6-methylpyrimidin-4-amine.

4 Conclusion

In conclusion X-ray crystallography of the product of amination of 5-bromo-2,4-dichloro-6-methylpyrimidine in ethanole evidenced the substitutional preference of 4 position in comparison with 2 position.

Acknowledgment

The financial support of this research by Ahvaz Branch, Islamic Azad University is gratefully acknowledged.

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