Unexpected Formation of Bis ( hydrazinecarboximidamide ) via Ultrasound Promoted Rearrangement of Epoxy Ketone

An efficient synthesis of aromatic pyrazoles via cyclocondensation of epoxy chalcones with hydrazine is reported. When aminoguanidine hydrochloride is the dinucleophilic specie the reaction leads to a mixture of amidino pyrazole and a minor amount (15%) of an interesting coproduct identified as 2,2'-(1,3-diphenylpropane-1,2-diylidene)bis(hydrazinecarboximidamide) dihydrochloride by X-ray diffraction and NMR. A plausible mechanism for the co-product formation via rearrangement of the epoxy chalcone into 1,2-diketone followed by the condensation with aminoguanidine reaction is proposed.


INTRODUCTION
Pyrazole derivatives are important scaffolds due to their wide applicability in medicinal chemistry, agrochemistry and material chemistry [1,2].Therefore, numerous synthetic methods for the preparation of pyrazoles have been developed in the last years.Conventional synthetic approaches involve formation of C-N and C-C bonds via intermolecular [3+2] cycloadditions between 1,3-dipoles and dipolarophiles [3] or formation of two C-N bonds by the condensation between hydrazine derivatives and 1,3-dicarbonyl compounds or their 1,3-dielectrophilic equivalents [4].Although each method has its utilities and advantages, the reaction of α,β-unsaturated ketones I with hydrazines is the most useful approach for the preparation of 1,3,5-trissubstituted pyrazole derivatives due to the work up simplicity, availability of starting materials and great regioselectivity (Figure 1).However, the product of such reaction is an enantiomeric mixture of pyrazolines II.In order to obtain 1,3,5-trissubstituted pyrazoles from I, it is necessary an oxidation step to convert the pyrazolines II into the corresponding aromatic pyrazoles III [5].Another way of preparing aromatic pyrazoles starting from α,β-unsaturated ketones without loss of regiosselectivity requires the oxidation of the C=C double bond of chalcones I forming α,β-epoxy ketones IV followed by the condensation/dehydration steps [6].The course of these reactions may be defined by using acidic or basic catalysis.Generally, neutral conditions and basic catalysts lead to the formation of 3,5-diaryl-4-hydroxy-4,5-dihydro-1Hpyrazoles V [7] whereas the presence of acidic medium favors the dehydration of intermediates V leading to the pyrazoles III [8].
As a part of our ongoing research on the clean ultrasound-promoted synthesis and bioactivity of pyrazole derivatives [9][10][11][12] we explored the reactions between epoxy chalcones and hydrazines aiming the scope enlargement for more complex hydrazines as well as the development of cleaner synthetic methods.In this direction, we report here the catalyst-free preparation of a series of aromatic pyrazoles by the reaction between epoxy chalcones and hydrazines.We also describe the unprecedented formation of a bis(hydrazinecarboximidamide) from the reaction between epoxy chalcones and aminoguanidine hydrochloride as well as its structural determination by X ray diffraction and NMR.

Figure 1.
General routes for the synthesis of aromatic pyrazoles starting from chalcones.

General
Phenyl(3-aryloxiran-2-yl)methanones (epoxy chalcones) 1a-f were prepared by us following reported procedures [13].All the chemicals were used without purification as purchased from commercial suppliers.The sonicated reactions were carried out with a microtip probe connected to a 500 W Sonics Vibracell ultrasonic processor operating at 20 kHz at 20% of the maximum power output.Reaction progresses were monitored by thin layer chromatography (TLC) or gas chromatography (GC).Melting point values were determined in open capillary on an Instrutherm DF-3600 II apparatus and are uncorrected.Infrared spectra (IR) were acquired on a JASCO-4100 spectrophotometer as KBr pellets. 1 H and 13 C nuclear magnetic resonance (NMR) spectra were acquired on a Bruker Avance III HD instrument (300 MHz for 1 H and 75 MHz for 13 C) in 5 mm sample tubes at 298 K in dimethyl sulfoxide (DMSO-d6) using tetramethylsilane (TMS) as internal reference standard.Low-resolution mass spectra were obtained on a Varian 210 MS connected to a Varian 431 GC.The GC was equipped with a split-splitless injector, cross-linked to a Varian Factor Four™ capillary column (30 m × 0.25 mm), and helium was used as the carrier gas.A Bruker CCD X8 Kappa APEX II diffractometer outfitted with a graphite monochromator and Mo-Kα radiation (λ = 0.71073 Å) was used to collect X-ray data for structural analysis.CCDC 1536540 contains the supplementary for 4a.Additional Material containing the spectra and selected crystallographic data of the synthesized compounds is available free of charge at http://www.orbital.ufms.br/index.php/Chemistryas a PDF file.

General procedure for the ultrasoundpromoted synthesis of 5-aryl-3-phenyl-1Hpyrazoles (2a-f)
Hydrazine hydrate (0.1 g, 2 mmol) was added to a 50 mL vial containing a solution of phenyl(3aryloxiran-2-yl)methanone 1a-f (1 mmol) in ethanol (20 mL).The mixture was sonicated for 45 minutes and the resulting solution was cooled overnight in a refrigerator.The solid material which precipitated was filtered off, washed with cold water and dried in a desiccator to give the pure products 2a-f.The authenticity of compounds 2a-f was established by comparing their melting points with data reported in literature [6,[14][15][16] as well as by means of their IR and low-resolution mass spectra.

General procedure for the ultrasoundpromoted reaction between phenyl(3phenyloxiran-2-yl)methanone 1a and aminoguanidine hydrochloride
To a 50 mL vial containing a solution of the phenyl(3-phenyloxiran-2-yl)methanone 1a (0.11 g, 0.5 mmol) and aminoguanidine hydrochloride (0.16 g, 1.5 mmol) in ethanol (20 mL) was added HCl (2 mL).The reaction mixture was sonicated for 45 min.The solvent was removed under vacuum.Methanol was added to the resulting crude material and the insoluble solid was filtered off, washed with cold methanol and dried in a desiccator.Analysis of the NMR spectra and X-ray structure of the isolated material revealed that the obtained product possessed the structure of 2,2'-(1,3-diphenylpropane-1,2diylidene)bis(hydrazinecarboximidamide) dihydrochloride 4a.Methanol was evaporated from the filtered solution, the resulting solid was neutralized with 10% KOH and filtered.After washing with cold water the solid was dried in a desiccator.GC-MS analysis revealed two peaks with similar retention times and low-resolution mass spectra in accordance with the structure of the 3,5diphenyl-1H-pyrazole-1-carboximidamide 3a.The pyrazole was obtained in yield of 79%.

RESULTS AND DISCUSSION
The synthetic way has started with the preparation of a series of chalcones which were converted into the corresponding epoxy chalcones by oxidation of the olefinic portions, using the known H 2 O 2 /NaOH oxidative system, in the presence of ultrasonic irradiation [13].Next, we investigated the ultrasound-promoted reactions of epoxy chalcones with hydrazine monohydrate in order to verify the possibility of obtaining aromatic pyrazoles without acid catalysis or detection of the intermediates 4hydroxy-4,5-dihydro-1H-pyrazoles.Thus, epoxy chalcones 1a-f were dispersed in ethanol and treated with hydrazine monohydrate.The pyrazoles 2a-f were obtained in yields up to 89% after sonication during 40 minutes (Scheme 1).

Scheme 1
The molecular structures of compounds 2a-f were confirmed by comparing melting points with those reported in literature, IR spectroscopy and lowresolution mass spectrometry.Yields and melting points of the compounds 2a-f are shown in the Table 1.
Table 1.Yields and melting points of the 5-aryl-3phenyl-1H-pyrazoles (2a-f).We have also investigated the reaction of epoxy chalcone with aminoguanidine hydrochloride aiming the preparation of 1-amidino pyrazoles, employing the same methodology described above.

Compound
As the acid free condition was not effective for converting starting material in the desired product, we added increasing amounts of HCl.Reaction was carried on under ultrasonic conditions.The solvent was removed under vacuum when starting material was not detected by TLC anymore (typically 45 min).GC-MS analysis of the crude residue showed the presence of the desired pyrazole together with an additional peak.Fortunately, this component was separated from the pyrazole by selective solubilization in methanol followed by filtration.Analysis of the NMR spectra and X-ray structure of the isolated material revealed that the obtained product possessed the structure of 2,2'-(1,3diphenylpropane-1,2diylidene)bis(hydrazinecarboximidamide) dihydrochloride 4a (Scheme 2).Further treatment of the methanol solution gave the diphenyl-1H-pyrazole-1-carboximidamide 3a in 79% of yield.

Scheme 2
Due to the novelty of the result for such reactions we searched in the literature a rationalization for the unexpected formation of the bis(hydrazinecarboximidamide).The elucidation came to the light when we found that epoxy chalcones rearrange to 1,2-diketones in concentrated HCl [17].Indeed, the rearrangement of epoxy chalcones in the presence of acids usually gives mixture of 1,2-and 1,3-diketones by hydride or acyl migration, respectively.Therefore, we propose that the formation of compound 4a started with the rearrangement of the epoxy chalcone 1a to the 1,2-diketone I which undergo a double acid catalyzed condensation with two equivalents of aminoguanidine hydrochloride according to the mechanism shown in the Scheme 3.

Scheme 3 3.1 X-Ray structural determination
The molecular crystal structure of the compound 4a was solved using direct methods in the SHELXS program [18].The final structure was refined using SHELXL [18], in which anisotropic displacement parameters were applied to all nonhydrogen atoms.All hydrogen atoms were placed in ideal positions and refined as riding atoms with relative isotropic displacement parameters.Additional structural information is provided in Table 2.
The structure of the compound 4a is shown in Figure 2. It shows protonated amidino-nitrogen atoms resulting in a delocalized positive charge in C17 and C18, according to the symmetric bond lengths between C17-N7 = 1.318(2)Å, C17-N8 = 1.314(2)Å and C18-N3 = 1.315(2)Å, C18-N4 = 1.309(3).The charge-balance is achieved by two chloride anions.The Cl(3) has multiplicity equal to 1.0 while the Cl(1) electron-donating groups were equally synthesized in high yields under green conditions such as ultrasonic irradiation and use of ethanol as reaction medium, which is a bio-renewable product of low toxicity to human health and relatively non-hazardous to the environment.When reactions between epoxy chalcones and aminoguanidine hydrochloride were conducted in the presence of HCl, an interesting unreported co-product was obtained besides the expected amidino pyrazole.The proposed mechanism for the formation of the unexpected bis(hydrazinecarboximidamide) opened a way to explore the viability of using aminoguanidine as an organocatalyst for converting epoxy chalcones into 1,2-diketones.Moreover, the structure of the bis(hydrazinecarboximidamide) was fully elucidated by means of X-ray diffraction and NMR.