Acta Cryst. (2009). E65, o2374 [ doi:10.1107/S1600536809035533 ]
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-HN hydrogen bonds, linking the molecules into layers parallel to the (10
) plane.
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)
All H atoms were placed in geometrically calculated positions (O—H 0.84 Å, N—H 0.88 Å, C—H 0.98 Å, 0.99 Å, 1.00 Å for methyl, methylene and methyne H atoms respectively) and included in the refinement in riding motion approximation. The Uiso(H) were set to 1.2Ueq of the carrying atom for methylene, methyne and amine groups, and 1.5Ueq for methyl and hydroxyl H atoms.
Data collection: SMART (Bruker, 1997); cell refinement: SAINT (Bruker, 1997); data reduction: SAINT (Bruker, 1997); 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).
![[Figure 1]](./bg2293fig1thm.gif)
| Fig. 1. Molecular structure of the title compound showing 50% probability displacement ellipsoids and atom numbering scheme; H atoms are drawn as circles with arbitrary small radius. |
![[Figure 2]](./bg2293fig2thm.gif)
| Fig. 2. Packing diagram for the title compound viewed approximately along the b axis. H-Bonds are shown as dashed lines; H atoms bound to carbon atoms are omitted. |
| C12H19BrN4O | F(000) = 648 |
| Mr = 315.22 | Dx = 1.496 Mg m−3 |
| Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
| Hall symbol: -P 2yn | Cell parameters from 2554 reflections |
| a = 9.9514 (18) Å | θ = 2.3–26.0° |
| b = 7.1879 (11) Å | µ = 2.93 mm−1 |
| c = 19.566 (4) Å | T = 198 K |
| β = 91.053 (3)° | Prism, colorless |
| V = 1399.3 (4) Å3 | 0.10 × 0.10 × 0.08 mm |
| Z = 4 |
| Siemens P4 with APEX CCD area-detector diffractometer | 3251 independent reflections |
| Radiation source: fine-focus sealed tube | 2500 reflections with I > 2σ(I) |
| graphite | Rint = 0.030 |
| φ and ω scans | θmax = 28.3°, θmin = 2.1° |
| Absorption correction: multi-scan (SADABS; Bruker, 2001) | h = −13→13 |
| Tmin = 0.758, Tmax = 0.799 | k = −9→3 |
| 8853 measured reflections | l = −25→25 |
| Refinement on F2 | Primary atom site location: structure-invariant direct methods |
| Least-squares matrix: full | Secondary atom site location: difference Fourier map |
| R[F2 > 2σ(F2)] = 0.041 | Hydrogen site location: inferred from neighbouring sites |
| wR(F2) = 0.114 | H-atom parameters constrained |
| S = 1.05 | w = 1/[σ2(Fo2) + (0.0567P)2 + 0.5508P] where P = (Fo2 + 2Fc2)/3 |
| 3251 reflections | (Δ/σ)max < 0.001 |
| 166 parameters | Δρmax = 0.83 e Å−3 |
| 0 restraints | Δρmin = −0.77 e Å−3 |
| C12H19BrN4O | V = 1399.3 (4) Å3 |
| Mr = 315.22 | Z = 4 |
| Monoclinic, P21/n | Mo Kα radiation |
| a = 9.9514 (18) Å | µ = 2.93 mm−1 |
| b = 7.1879 (11) Å | T = 198 K |
| c = 19.566 (4) Å | 0.10 × 0.10 × 0.08 mm |
| β = 91.053 (3)° |
| Siemens P4 with APEX CCD area-detector diffractometer | 3251 independent reflections |
| Absorption correction: multi-scan (SADABS; Bruker, 2001) | 2500 reflections with I > 2σ(I) |
| Tmin = 0.758, Tmax = 0.799 | Rint = 0.030 |
| 8853 measured reflections | θmax = 28.3° |
| R[F2 > 2σ(F2)] = 0.041 | H-atom parameters constrained |
| wR(F2) = 0.114 | Δρmax = 0.83 e Å−3 |
| S = 1.05 | Δρmin = −0.77 e Å−3 |
| 3251 reflections | Absolute structure: ? |
| 166 parameters | Flack parameter: ? |
| 0 restraints | Rogers parameter: ? |
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. |
| x | y | z | Uiso*/Ueq | ||
| C1 | 0.5559 (2) | 0.1796 (4) | 0.70305 (12) | 0.0340 (5) | |
| C2 | 0.4564 (2) | 0.4484 (3) | 0.74028 (12) | 0.0345 (5) | |
| C3 | 0.3689 (2) | 0.4380 (4) | 0.68582 (12) | 0.0343 (5) | |
| C4 | 0.3783 (2) | 0.2877 (3) | 0.64026 (11) | 0.0308 (5) | |
| C5 | 0.4551 (4) | 0.6010 (4) | 0.79203 (16) | 0.0553 (8) | |
| H5A | 0.5224 | 0.5753 | 0.8280 | 0.083* | |
| H5B | 0.3659 | 0.6084 | 0.8123 | 0.083* | |
| H5C | 0.4760 | 0.7195 | 0.7698 | 0.083* | |
| C6 | 0.3088 (3) | 0.1409 (3) | 0.53025 (12) | 0.0360 (5) | |
| H6 | 0.3451 | 0.0203 | 0.5480 | 0.043* | |
| C7 | 0.4063 (2) | 0.2217 (4) | 0.47943 (12) | 0.0371 (6) | |
| H7A | 0.4223 | 0.1297 | 0.4428 | 0.045* | |
| H7B | 0.4934 | 0.2472 | 0.5029 | 0.045* | |
| C8 | 0.3519 (3) | 0.4009 (4) | 0.44790 (13) | 0.0387 (6) | |
| H8A | 0.4163 | 0.4467 | 0.4138 | 0.046* | |
| H8B | 0.3452 | 0.4964 | 0.4841 | 0.046* | |
| C9 | 0.2144 (3) | 0.3769 (3) | 0.41323 (12) | 0.0337 (5) | |
| C10 | 0.1169 (2) | 0.2822 (4) | 0.46142 (13) | 0.0359 (5) | |
| H10A | 0.0340 | 0.2493 | 0.4354 | 0.043* | |
| H10B | 0.0919 | 0.3715 | 0.4976 | 0.043* | |
| C11 | 0.1739 (3) | 0.1065 (3) | 0.49515 (14) | 0.0400 (6) | |
| H11A | 0.1095 | 0.0603 | 0.5292 | 0.048* | |
| H11B | 0.1842 | 0.0088 | 0.4600 | 0.048* | |
| C12 | 0.1583 (3) | 0.5624 (4) | 0.38954 (16) | 0.0529 (7) | |
| H12A | 0.2230 | 0.6233 | 0.3597 | 0.079* | |
| H12B | 0.1421 | 0.6415 | 0.4293 | 0.079* | |
| H12C | 0.0737 | 0.5423 | 0.3643 | 0.079* | |
| N1 | 0.5510 (2) | 0.3157 (3) | 0.75037 (10) | 0.0354 (5) | |
| N2 | 0.4744 (2) | 0.1602 (3) | 0.64825 (10) | 0.0334 (4) | |
| N3 | 0.6521 (2) | 0.0517 (4) | 0.71160 (12) | 0.0510 (6) | |
| H3A | 0.6596 | −0.0397 | 0.6820 | 0.061* | |
| H3B | 0.7081 | 0.0588 | 0.7469 | 0.061* | |
| N4 | 0.2904 (2) | 0.2682 (3) | 0.58727 (10) | 0.0355 (5) | |
| H4 | 0.2173 | 0.3370 | 0.5872 | 0.043* | |
| O1 | 0.23817 (18) | 0.2603 (3) | 0.35549 (9) | 0.0420 (4) | |
| H1 | 0.1654 | 0.2413 | 0.3342 | 0.063* | |
| Br1 | 0.23506 (4) | 0.62118 (5) | 0.671478 (18) | 0.06510 (16) |
| U11 | U22 | U33 | U12 | U13 | U23 | |
| C1 | 0.0334 (12) | 0.0391 (13) | 0.0292 (12) | 0.0023 (10) | −0.0052 (10) | −0.0036 (10) |
| C2 | 0.0362 (13) | 0.0361 (12) | 0.0311 (12) | −0.0024 (10) | 0.0010 (10) | −0.0052 (10) |
| C3 | 0.0341 (13) | 0.0357 (12) | 0.0330 (12) | 0.0048 (10) | −0.0012 (10) | −0.0026 (10) |
| C4 | 0.0305 (12) | 0.0357 (13) | 0.0261 (11) | −0.0010 (9) | −0.0015 (9) | 0.0012 (9) |
| C5 | 0.0625 (19) | 0.0506 (17) | 0.0523 (18) | 0.0074 (14) | −0.0080 (15) | −0.0204 (14) |
| C6 | 0.0397 (14) | 0.0341 (13) | 0.0336 (13) | 0.0029 (10) | −0.0131 (10) | −0.0028 (10) |
| C7 | 0.0305 (12) | 0.0488 (15) | 0.0318 (12) | 0.0033 (10) | −0.0085 (10) | −0.0130 (11) |
| C8 | 0.0392 (14) | 0.0455 (14) | 0.0315 (12) | −0.0098 (11) | 0.0002 (10) | −0.0048 (11) |
| C9 | 0.0378 (13) | 0.0344 (12) | 0.0289 (12) | 0.0038 (10) | −0.0043 (10) | −0.0023 (10) |
| C10 | 0.0308 (12) | 0.0419 (14) | 0.0346 (12) | 0.0000 (10) | −0.0085 (10) | 0.0023 (11) |
| C11 | 0.0418 (14) | 0.0376 (14) | 0.0402 (14) | −0.0080 (11) | −0.0122 (11) | 0.0056 (11) |
| C12 | 0.070 (2) | 0.0410 (15) | 0.0473 (17) | 0.0115 (14) | 0.0002 (15) | 0.0079 (13) |
| N1 | 0.0342 (11) | 0.0412 (11) | 0.0306 (10) | 0.0010 (9) | −0.0056 (8) | −0.0077 (9) |
| N2 | 0.0359 (11) | 0.0374 (11) | 0.0267 (10) | 0.0035 (8) | −0.0071 (8) | −0.0059 (8) |
| N3 | 0.0541 (14) | 0.0575 (14) | 0.0405 (12) | 0.0239 (12) | −0.0226 (11) | −0.0177 (11) |
| N4 | 0.0321 (10) | 0.0446 (12) | 0.0297 (10) | 0.0073 (9) | −0.0075 (8) | −0.0030 (9) |
| O1 | 0.0410 (10) | 0.0525 (11) | 0.0319 (9) | 0.0119 (8) | −0.0100 (7) | −0.0119 (8) |
| Br1 | 0.0679 (3) | 0.0608 (2) | 0.0659 (3) | 0.03307 (16) | −0.01891 (17) | −0.01908 (15) |
| C1—N3 | 1.335 (3) | C7—H7B | 0.9900 |
| C1—N2 | 1.340 (3) | C8—C9 | 1.526 (3) |
| C1—N1 | 1.349 (3) | C8—H8A | 0.9900 |
| C2—N1 | 1.352 (3) | C8—H8B | 0.9900 |
| C2—C3 | 1.366 (3) | C9—O1 | 1.430 (3) |
| C2—C5 | 1.493 (4) | C9—C12 | 1.514 (4) |
| C3—C4 | 1.405 (3) | C9—C10 | 1.525 (3) |
| C3—Br1 | 1.891 (2) | C10—C11 | 1.529 (3) |
| C4—N2 | 1.331 (3) | C10—H10A | 0.9900 |
| C4—N4 | 1.351 (3) | C10—H10B | 0.9900 |
| C5—H5A | 0.9800 | C11—H11A | 0.9900 |
| C5—H5B | 0.9800 | C11—H11B | 0.9900 |
| C5—H5C | 0.9800 | C12—H12A | 0.9800 |
| C6—N4 | 1.457 (3) | C12—H12B | 0.9800 |
| C6—C11 | 1.517 (3) | C12—H12C | 0.9800 |
| C6—C7 | 1.518 (4) | N3—H3A | 0.8800 |
| C6—H6 | 1.0000 | N3—H3B | 0.8800 |
| C7—C8 | 1.523 (4) | N4—H4 | 0.8800 |
| C7—H7A | 0.9900 | O1—H1 | 0.8400 |
| N3—C1—N2 | 116.8 (2) | H8A—C8—H8B | 107.8 |
| N3—C1—N1 | 116.6 (2) | O1—C9—C12 | 109.9 (2) |
| N2—C1—N1 | 126.6 (2) | O1—C9—C10 | 110.1 (2) |
| N1—C2—C3 | 120.5 (2) | C12—C9—C10 | 110.3 (2) |
| N1—C2—C5 | 115.7 (2) | O1—C9—C8 | 104.89 (19) |
| C3—C2—C5 | 123.8 (2) | C12—C9—C8 | 111.0 (2) |
| C2—C3—C4 | 119.2 (2) | C10—C9—C8 | 110.5 (2) |
| C2—C3—Br1 | 121.01 (19) | C9—C10—C11 | 113.6 (2) |
| C4—C3—Br1 | 119.76 (17) | C9—C10—H10A | 108.8 |
| N2—C4—N4 | 118.2 (2) | C11—C10—H10A | 108.8 |
| N2—C4—C3 | 120.7 (2) | C9—C10—H10B | 108.8 |
| N4—C4—C3 | 121.1 (2) | C11—C10—H10B | 108.8 |
| C2—C5—H5A | 109.5 | H10A—C10—H10B | 107.7 |
| C2—C5—H5B | 109.5 | C6—C11—C10 | 112.2 (2) |
| H5A—C5—H5B | 109.5 | C6—C11—H11A | 109.2 |
| C2—C5—H5C | 109.5 | C10—C11—H11A | 109.2 |
| H5A—C5—H5C | 109.5 | C6—C11—H11B | 109.2 |
| H5B—C5—H5C | 109.5 | C10—C11—H11B | 109.2 |
| N4—C6—C11 | 109.1 (2) | H11A—C11—H11B | 107.9 |
| N4—C6—C7 | 110.6 (2) | C9—C12—H12A | 109.5 |
| C11—C6—C7 | 109.7 (2) | C9—C12—H12B | 109.5 |
| N4—C6—H6 | 109.1 | H12A—C12—H12B | 109.5 |
| C11—C6—H6 | 109.1 | C9—C12—H12C | 109.5 |
| C7—C6—H6 | 109.1 | H12A—C12—H12C | 109.5 |
| C6—C7—C8 | 111.2 (2) | H12B—C12—H12C | 109.5 |
| C6—C7—H7A | 109.4 | C1—N1—C2 | 116.5 (2) |
| C8—C7—H7A | 109.4 | C4—N2—C1 | 116.4 (2) |
| C6—C7—H7B | 109.4 | C1—N3—H3A | 120.0 |
| C8—C7—H7B | 109.4 | C1—N3—H3B | 120.0 |
| H7A—C7—H7B | 108.0 | H3A—N3—H3B | 120.0 |
| C7—C8—C9 | 113.2 (2) | C4—N4—C6 | 124.3 (2) |
| C7—C8—H8A | 108.9 | C4—N4—H4 | 117.8 |
| C9—C8—H8A | 108.9 | C6—N4—H4 | 117.8 |
| C7—C8—H8B | 108.9 | C9—O1—H1 | 109.5 |
| C9—C8—H8B | 108.9 |
| 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 |
| Symmetry codes: (i) −x+1, −y, −z+1; (ii) x−1/2, −y+1/2, z−1/2. |
| 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 |
| Symmetry codes: (i) −x+1, −y, −z+1; (ii) x−1/2, −y+1/2, z−1/2. |
Bruker (1997). SMART and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.
Bruker (2001). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.
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Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837–838.
Melguizo, M., Quesada, A., Low, J. N. & Glidewell, C. (2003). Acta Cryst. B59, 263–276.
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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).