trans-4-(2-Amino-5-bromo-6-methyl­pyrimidin-4-ylamino)-1-methyl­cyclo­hexa­nol

Jacqui E Hoffman; Henry Cheng; Arnold L Rheingold; Antonio DiPasquale; Alex Yanovsky

doi:10.1107/S1600536809035533

. 2009 Sep 9;65(Pt 10):o2374. doi: 10.1107/S1600536809035533

trans-4-(2-Amino-5-bromo-6-methylpyrimidin-4-ylamino)-1-methylcyclohexanol

Jacqui E Hoffman ^a, Henry Cheng ^a, Arnold L Rheingold ^b, Antonio DiPasquale ^b, Alex Yanovsky ^a,^*

PMCID: PMC2970313 PMID: 21577839

Abstract

The title compound, C₁₂H₁₉BrN₄O, represents the minor component of the two products obtained in a series of transformations involving the Grignard reaction of tert-butoxycarbonyl-protected 4-aminocyclohexanone with MeMgBr, and subsequent interaction of the obtained amino-substituted cyclohexanol with 4-chloro-6-methylpyrimidin-2-amine followed by bromination with N-bromosuccinimide. The X-ray structure showed that this product represents a trans isomer with respect to the amino and hydroxy substituents in the cyclohexyl ring; the dihedral angle between the aminopyrimidine plane and the (noncrystallographic) mirror plane of the substituted cyclohexyl fragment is 33.6 (3)°. Only two of the four potentially ‘active’ H atoms participate in intermolecular N—H⋯O and O—H⋯N hydrogen bonds, linking the molecules into layers parallel to the (10 Inline graphic ) plane.

Related literature

For the structure of a similar N-pyrimidine derivative of aminocyclohexane, see Melguizo et al. (2003 ▶).

Experimental

Crystal data

C₁₂H₁₉BrN₄O
M _r = 315.22
Monoclinic,
a = 9.9514 (18) Å
b = 7.1879 (11) Å
c = 19.566 (4) Å
β = 91.053 (3)°
V = 1399.3 (4) Å³
Z = 4
Mo Kα radiation
μ = 2.93 mm⁻¹
T = 198 K
0.10 × 0.10 × 0.08 mm

Data collection

Siemens P4 with APEX CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2001 ▶) T _min = 0.758, T _max = 0.799
8853 measured reflections
3251 independent reflections
2500 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.041
wR(F ²) = 0.114
S = 1.05
3251 reflections
166 parameters
H-atom parameters constrained
Δρ_max = 0.83 e Å⁻³
Δρ_min = −0.77 e Å⁻³

Data collection: SMART (Bruker, 1997 ▶); cell refinement: SAINT (Bruker, 1997 ▶); data reduction: SAINT; program(s) used to solve structure: SIR2004 (Burla et al., 2005 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-32 (Farrugia, 1997 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809035533/bg2293sup1.cif

e-65-o2374-sup1.cif^{(16.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809035533/bg2293Isup2.hkl

e-65-o2374-Isup2.hkl^{(159.5KB, hkl)}

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

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—H3A⋯O1ⁱ	0.88	2.03	2.828 (3)	151
O1—H1⋯N1ⁱⁱ	0.84	2.02	2.803 (3)	155

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Symmetry codes: (i) Inline graphic ; (ii) .

supplementary crystallographic information

Comment

The Grignard reaction of tert-butoxycarbonyl(BOC)-protected 4-aminocyclohexanone, 4-C₄H₉OC(O)N(H)C₆H₉O, with MeMgBr produced the mixture of cis- and trans- 4-BOC-amino-1-methyl-cyclohexanols, which was subsequently reacted with 4-chloro-6-methylpyrimidin-2-amine and then brominated with N-bromosuccinimide. The isomeric mixture of the products was separated by means of flash chromatography and the corresponding X-ray structural study of the minor isomer showed that the title compound represents a trans-isomer with respect to the amino and hydroxy substituents in the cyclohexane ring (Fig. 1). The plane of the diaminopyrimidine C1/C2/C3/C4/N1/N2/N4 fragment forms a dihedral angle of 33.6 (3)° with the approximate mirror plane of the cyclohexyl fragment, namely the plane passing through N4/C6/C9/C12/O1. This conformation is significantly different from that observed in the related compound described in Melguizo et al., 2003, where the dihedral angle formed by the aminopyrimidine plane and the mirror plane of the cyclohexyl ring is just 13.6°.

There are four H atoms in the molecule, which are capable of H-bond formation. However, only two of them (H1 and H3A) participate in intermolecular H-bonds (Table 1), which link the molecules into layers parallel to the (1,0,-1) plane of the crystal (Fig. 2).

Experimental

Synthesis of tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate. To a cooled (0°C) solution of 4-N-boc-amino-cyclohexanone (4.79 g, 22.5 mmol) in tetrahydrofuran (190 ml) was added methylmagnesium bromide (3 M solution in diethyl ether, 22.5 ml, 67.2 mmol). The ice bath was removed and the reaction was stirred at room temperature for 6 h, and then quenched with saturated ammonia chloride and water. The reaction mixture was concentrated and residue was dissolved in ethyl acetate and washed with saturated ammonia chloride, dried (MgSO4), filtered, and concentrated again. The crude product was purified by flash chromatography eluting with hexanes/ethyl acetate (10–50%) then chloroform/methanol (10%) to afford tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate as a mixture of isomers (2.72 g, 53%).

Synthesis of 4-(2-amino-6-methylpyrimidin-4-ylamino)-1-methylcyclohexanol. To a cooled (0°C) solution of tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate (2.72 g, 11.9 mmol) in dichloromethane was added hydrochloric acid (2 M solution in diethyl ether, 10 eq). The ice bath was removed and the solution was stirred at room temperature for 6 hrs then concentrated to afford 4-amino-1-methylcyclohexanol hydrochloride, which was used without further purification. A solution of 2-amino-4-chloro-6-methylpyrimidine (2.20 g, 15.4 mmol), 4-amino-1-methylcyclohexanol hydrochloride, and diisopropylethyl amine (7.6 ml, 44 mmol) in dimethyl acetamide (52 ml) was heated to 160°C in a sealed tube overnight. The reaction mixture was concentrated, the solids were slurried in chloroform and the filtrate was concentrated again. The crude product was purified by flash choromatagraphy eluting with chloroform/7 N ammonia in methanol followed by SFC chromatography to afford 4-(2-amino-6-methylpyrimidin-4-ylamino)-1-methylcyclohexanol as a mixture of isomers (600 mg, 17% over 2 steps).

Synthesis of 4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino) -1-methylcyclohexanol. To a solution of 4-(2-amino-6-methylpyrimidin-4-ylamino)-1-methylcyclohexanol (600 mg, 2.54 mmol) in dichloromethane (20.0 ml) was added N-bromosuccinimide (452 mg, 2.54 mmol). After stirring for 2.5 hrs at room temperature, the solution was concentrated. The residue was dissolved in ethyl acetate (450 ml) and washed with 50% saturated sodium carbonate, brine, dried (MgSO4), filtered, and concentrated again. The crude product was purified by flash chromatography to afford major (407 mg, 51%) and minor (151 mg, 19%) isomers of 4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino)-1-methylcyclohexanol. Minor isomer (the title compound) was subjected to the X-ray study and proved to be the trans-isomer.

1H NMR spectra for major (cis) isomer: (400 MHz, DMSO-d6) δp.p.m. 1.11 (s, 3 H) 1.26 - 1.37 (m, 2 H) 1.52 - 1.61 (m, 4 H) 1.61 - 1.73 (m, 2 H) 2.17 (s, 3 H) 3.77 - 3.87 (m, 1 H) 4.06 (s, 1 H) 5.73 (d, J=8.34 Hz, 1 H) 6.08 (s, 2 H)

1H NMR spectra for minor (trans) isomer (the title compound): (400 MHz, DMSO-d6) δp.p.m. 1.16 (s, 3 H) 1.36 - 1.45 (m, 2 H) 1.45 - 1.56 (m, 4 H) 1.64 - 1.73 (m, 2 H) 2.17 (s, 3 H) 3.87 - 3.97 (m, 1 H) 4.28 (s, 1 H) 5.93 (d, J=8.59 Hz, 1 H) 6.11 (s, 2 H)