(E)-2-(2-Methyl­cyclo­hexyl­idene)hydrazinecarbothio­amide

Justin W Hicks; Alan J Lough; Alan A Wilson; Neil Vasdev

doi:10.1107/S1600536811042486

. 2011 Oct 22;67(Pt 11):o3005. doi: 10.1107/S1600536811042486

(E)-2-(2-Methylcyclohexylidene)hydrazinecarbothioamide

Justin W Hicks ^a, Alan J Lough ^b,^*, Alan A Wilson ^a, Neil Vasdev ^a

PMCID: PMC3247404 PMID: 22220022

Abstract

In the crystal of the title compound, C₈H₁₅N₃S, molecules are linked by N—H⋯S hydrogen bonds, forming chains along [1 Inline graphic 0]. An intramolecular N—H⋯N hydrogen bond is also present.

Related literature

The title compound, C₈H₁₅N₃S, is a key intermediate for the preparation of hydrazinyl-5-arylthiazole-based monoamine oxidase B (MAO-B) inhibitors. For the synthesis of hydrazinyl-5-arylthiazoles and their MAO-B inhibitory activity, see: Chimenti et al. (2008 ▶, 2010 ▶). For background on our interest in radiolabelled molecules targeting MAO-B, see: Vasdev et al. (2011a ▶,b ▶). For the preparation of ¹⁸F-labelled potassium cryptand fluoride, see: Vasdev et al. (2009 ▶).

Experimental

Crystal data

C₈H₁₅N₃S
M _r = 185.29
Triclinic,
a = 6.0261 (5) Å
b = 8.0655 (4) Å
c = 10.9129 (9) Å
α = 83.904 (5)°
β = 89.386 (4)°
γ = 68.416 (4)°
V = 490.19 (6) Å³
Z = 2
Mo Kα radiation
μ = 0.28 mm⁻¹
T = 150 K
0.20 × 0.14 × 0.04 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SORTAV; Blessing, 1995 ▶) T _min = 0.710, T _max = 1.060
5938 measured reflections
2184 independent reflections
1698 reflections with I > 2σ(I)
R _int = 0.077

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.122
S = 1.05
2184 reflections
122 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.26 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Data collection: COLLECT (Nonius, 2002 ▶); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997 ▶); data reduction: DENZO-SMN; program(s) used to solve structure: SIR92 (Altomare et al., 1994 ▶); program(s) used to refine structure: SHELXTL (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811042486/pv2460sup1.cif

e-67-o3005-sup1.cif^{(19.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811042486/pv2460Isup2.hkl

e-67-o3005-Isup2.hkl^{(107.4KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811042486/pv2460Isup3.cml

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
N2—H1N⋯S1ⁱ	0.88 (3)	2.61 (3)	3.4645 (19)	162 (2)
N3—H3N⋯S1ⁱⁱ	0.88 (2)	2.52 (2)	3.3954 (19)	170.9 (19)
N3—H2N⋯N1	0.81 (3)	2.28 (2)	2.601 (2)	104.6 (19)

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

Acknowledgments

Funding was provided by the Ontario Ministry for Research and Innovation (Early Researcher Award to Dr Neil Vasdev).

supplementary crystallographic information

Comment

(E)-2-(2-Methylcyclohexylidene)hydrazinecarbothioamide is an intermediate towards the preparation of hydrazinyl-5-arylthiazoles which are curerntly under exploration as a new class of inhibitors of the enzyme monoamine oxidase B (Chimenti et al. 2010). Our interest in this class of compounds is to prepare a radiotracer for imaging MAO-B in the central nervous system with positron emission tomography (PET). Chimenti et al. (2010) reported the synthesis of (E)-2-(2-(2-methylcyclohexylidene)hydrazinyl)-5-(4-nitrophenyl)thiazole, and (E)-2-(2-(2-methylcyclohexylidene)hydrazinyl)-5-(4-fluorophenyl)thiazole which demonstrated high affinity for MAO-B (K_i > 10 nM). We have attempted to use the 4-nitrophenyl thiazole derivative as a precursor for radiofluorination with the positron emitting isotope fluorine-18 (t_1/2 = 109.7 min) to prepare [¹⁸F]-(E)-2-(2-(2- methylcyclohexylidene)hydrazinyl)-5-(4-fluorophenyl)thiazole. Although initial attempts to achieve this goal have not been successful due to degradation of the precursor under basic conditions, we continue to investigate the application of thiazoles as an activating group for aromatic radiofluorination.

The molecular structure of the title compound is shown in Fig. 1. In the crystal, molecules are linked by N—H···S hydrogen bonds to form chains along [110] (see Fig. 2). An intramolecular N—H···N hydrogen bond is also present.

Experimental

Synthesis

The title compound, C₈H₁₅N₃S, was obtained by stirring equimolar amounts (10 mmol) of racemic 2-methylcyclohexanone and thiosemicarbazide with a catalytic amount of acetic acid (ca 350 µL) in 2-propanol (100 ml) for 16 h at room temperature. A white precipitate resulted and was collected by vacuum filtration and washed with cold 2-propanol (3 x 20 ml). This solid was then dissolved in chloroform (20 ml) and the insoluble unreacted thiosemicarbazide was removed by vacuum filtration. The solvent was removed from the filtrate by rotary evaporation and C₈H₁₅N₃S was obtained as a white solid in 98% yield. X-ray quality crystals were obtained by slow evaporation of a solution of the title compound in 1:1:2 chloroform/acetonitrile/acetone. m.p. = 420 - 421 K.

Attempted Radiosynthesis

Dry ¹⁸F-labeled potassium cryptand fluoride ([K₂₂₂][¹⁸F]; 760 µCi) was prepared as previously described (Vasdev et al., 2009). A solution of 2-(2-cyclohexylidenehydrazinyl)-4-(4-nitrophenyl)thiazole in anhydrous CH₃CN (9.5 mM, 1 ml) was added to the glass test tube and the solution turned a dark purple. The reaction was stirred at room temperature for 10 minutes, then an aliquot was quenched in HPLC buffer to monitor the progress of the reaction by analytical HPLC. As no reaction occurred, the mixture was then heated to 333 K and 363 K in an oil bath for 10 minutes, respectively, with still no reaction occurring. Analytical HPLC was performed using a perfluorophenyl column (Thermo Scientific Fluophase PFP, 150 x 10 mm, 5 µm) eluted with 70:30 CH₃OH:H₂O + 0.1 N ammonium formate using a flow of 5 ml min^-1. Authentic 2-(2-cyclohexylidenehydrazinyl)-4-(4-fluorophenyl)thiazole (t_R = 12.5 min) was used as a standard.

A second reaction under microwave heating (60 W) was also attempted using dimethylsulfoxide (DMSO) as the solvent. The reaction again turned dark purple with the addition of the precursor as a DMSO solution (9.5 mM, 1 ml) to the dry [K₂₂₂][¹⁸F] containing glass test tube. After heating to 393 K for 5 minutes with no reaction occurring, the temperature was increased to 453 K for 15 minutes. At this point, there was no precursor remaining intact, as determined by analytical HPLC. Proton NMR spectroscopy revealed that the hydrazinic proton is removed under basic conditions.