(R)-4-[2-(Methyl­sulfanyl)pyrimidin-4-yl]-1-(tetra­hydro­furan-3-yl)-1H-pyrazol-5-amine

Zhengyu Liu; Kevin K-C Liu; Jeff Elleraas; Arnold L Rheingold; Antonio DiPasquale; Alex Yanovsky

doi:10.1107/S160053680900734X

. 2009 Mar 6;65(Pt 4):o697. doi: 10.1107/S160053680900734X

(R)-4-[2-(Methylsulfanyl)pyrimidin-4-yl]-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-amine

Zhengyu Liu ^a, Kevin K-C Liu ^a, Jeff Elleraas ^a, Arnold L Rheingold ^b, Antonio DiPasquale ^b, Alex Yanovsky ^a,^*

PMCID: PMC2968870 PMID: 21582437

Abstract

The title compound, C₁₂H₁₅N₅OS, was obtained by reaction of 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile with (tetrahydrofuran-3-yl)hydrazine dihydrochloride, and the racemic product was subsequently separated by chiral chromatography (first peak; [α]_D ²⁰ = +51.3°). The chiral center at the substituted atom of the tetrahydrofuranyl group has an R-configuration. The pyrimidine and pyrazolyl rings are almost coplanar, their mean planes forming a dihedral angle of 6.4 (1)°. One of the H atoms of the amino group participates in an intramolecular hydrogen bond with the pyrimidine N atom in position 3. The second H atom is involved in an intermolecular hydrogen bond, which links the molecules into an infinite chain.

Related literature

For the structure of a related compound with a methyl-substituted amino group, see: Liu et al. (2009 ▶). graphic file with name e-65-0o697-scheme1.jpg

Experimental

Crystal data

C₁₂H₁₅N₅OS
M _r = 277.35
Orthorhombic,
a = 15.479 (2) Å
b = 7.1217 (10) Å
c = 11.7802 (17) Å
V = 1298.6 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.25 mm⁻¹
T = 208 K
0.20 × 0.20 × 0.20 mm

Data collection

Bruker D8 APEXII CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2001 ▶) T _min = 0.844, T _max = 0.952
6570 measured reflections
3025 independent reflections
2844 reflections with I > 2σ(I)
R _int = 0.043

Refinement

R[F ² > 2σ(F ²)] = 0.041
wR(F ²) = 0.115
S = 1.07
3025 reflections
174 parameters
H-atom parameters constrained
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.35 e Å⁻³
Absolute structure: Flack (1983 ▶), 1180 Friedel pairs
Flack parameter: −0.05 (8)

Data collection: APEX2 (Bruker, 2004 ▶); cell refinement: SAINT (Bruker, 2004 ▶); 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/S160053680900734X/tk2382sup1.cif

e-65-0o697-sup1.cif^{(16.9KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053680900734X/tk2382Isup2.hkl

e-65-0o697-Isup2.hkl^{(148.5KB, 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⋯N4ⁱ	0.87	2.19	2.9731 (19)	150
N3—H3B⋯N5	0.87	2.28	2.8616 (19)	124

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Symmetry code: (i) Inline graphic .

supplementary crystallographic information

Comment

The title compound was obtained by reaction of 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile with (tetrahydrofuran-3-yl)hydrazine dihydrochloride. The racemic product was then separated with the help of chiral chromatography; the title compound, (I), was collected as the earlier fraction, when eluted with methanol using the Chiralpak column (99% ee; [α]_D²⁰ = +51.3°).

The present X-ray study unambiguously established the R configuration of the chiral center at the C3 atom (Fig. 1).

The pyrimidine and pyrazolyl rings lie approximately in one plane; the dihedral angle formed by their mean planes is equal to 6.4 (1)°. The orientation of the tetrahydrofurane ring can be characterized by the dihedral angle 99.6 (1)° formed by the pyrazolyl plane with the C2—C3—C4 plane.

The molecular geometry of (I) is similar to that of related compound with a methyl substituent at the amino group (Liu et al., 2009). However, the crystal packing is substantially different as (I) has one additional H atom capable of H-bond formation. Indeed, while the H3A atom forms an intramolecular H-bond with the N5 atom of the pyrimidine ring similar to that observed in methyl-substituted structure, the H3B atom is involved in intermolecular H-bonding, which links molecules into infinite chains running along the a axis (Fig. 2; Table 2).

Experimental

To a suspension of 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile (13.5 g, 70.0 mmol) in AcOH (100 ml) was added (tetrahydrofuran-3-yl)hydrazine dihydrochloride (12.3 g,70.0 mmol), and the resulting orange mixture was heated at 80°C under nitrogen for 3 h. Acetic acid was removed and the orange solid residue was partitioned between aqueous Na₂CO₃ (200 ml) and EtOAc (400 ml). The mixture was refluxed for 30 min. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude product as a brown gum (16.82 g, 87%). The brown gum (8.32 g) was purified by flash chromatography using 30–70% EtOAc in hexane to afford a yellow solid (5.96 g).

The part of the product thus obtained (4.85 g) was subjected to chiral chromatography on Chiralpak AS—H 21.2 x 250 mm column with 35% MeOH in CO₂ at 140 bar as eluent (flow = 55 ml/min; UV detection at 260 nm). Two fractions corresponding to each of the enantiomers (Peak1 and Peak2) were collected and evaporated to dryness; the specific rotation [α]_D²⁰ was measured in CH₂Cl₂ solution and yielded the values of +51.3° and -52.1°, respectively. The enantiomer collected as Peak 1 was recrystallized from EtOAc/hexane to yield colorless single crystals.