Solvent-free microwave-assisted synthesis of tetrahydrooxazolo[3,2-a ]pyrazolo[1,5-d ]pyrazin-5-ones

A series of novel oxazolo[3,2-a ]pyrazolo[1,5-d ]pyrazin-5-ones were synthesized by the reaction of ethyl 3-aryl-1-(2-oxo-2-arylethyl)-1 H -pyrazole-5-carboxylate derivatives and aminoethanol under microwave-assisted one-step and solvent-free conditions.


Introduction
Heterocyclic compounds are of significance since they play prominent roles in many fields of science including organic, bioorganic, agricultural, pharmaceutical, medicinal chemistry and materials science. 1,2Searching for new small molecules which can interact with biological systems as chemical-genetic probes or drug leads has created an ever-increasing demand for efficient synthetic sequences leading to diverse "drug-like" structures. 3][6][7] On the other hand, pyrazoles have occupied a unique position in the design and synthesis of novel biologically active agents and still continue to attract considerable attention due to their broad range of biological activities.[10][11][12][13][14]  Microwave-assisted organic synthesis (MAOS) has aroused a growing interest in chemists, since it was first reported in 1986. 15,16The use of this "non-conventional" synthetic method brings several advantages over conventional reactions, such as drastically reduced reaction times, higher yields and higher selectivity, lower quantities of byproducts and, consequently, easier work-up and purification of the products. 17,18MAOS is recommended as a "green" technology, since, using efficient and less hazardous energy sources, it can be applied in solvent-free conditions, and increasing "atom economy" by improving product selectivity and chemical yield. 19,20n the light of the above-mentioned facts and as an ongoing investigation on the development of new routes for the preparation of biologically active heterocyclic compounds, we herein describe the reaction of ethyl 3-aryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylate derivatives with aminoethanol under microwave (MW) irradiation and the formation of some novel 5Hoxazolo[3,2-a]pyrazolo [1,5-d]pyrazin-5-ones.To the best of our knowledge, the oxazolo[3,2a]pyrazolo [1,5-d]pyrazin-5-one heterocyclic system has not been reported previously.This method affords an easy and efficient way to prepare oxazolo [3,2-a]pyrazolo [1,5-d]pyrazin-5ones and permits us to introduce great molecular diversity, including substituent and skeleton diversity of oxazolo [3,2-a]pyrazolo [1,5-d]pyrazin-5-ones.
Following the same procedure, a series of reactions of 1a-i with aminoethanol were performed under microwave irradiation and the most satisfactory results for the synthesis of compounds 2a-i were obtained as shown in Scheme 2 and Table 1.The substituent groups have an effect on the reactions.When R 2 is chlorine, which is recognized to be an electronwithdrawing group, the nucleophilic addition on the carbonyl carbon more easily undergo because the positive charge is stronger, and the products are formed in higher yields.The mechanism is under investigation.The structure of compounds 2 were determined by IR, NMR and HRMS.Thus, for example 2i, obtained as white solid, gave a [M+H]-ion peak at m/z 392.1622 in the HRMS, in accord with the molecular formula C22H22N3O4.In the IR spectra, the lactam carbonyl group absorption bands and the ether group vibrations were observed at 1666 cm -1 and 1248 cm -1 , respectively.In the 1 H NMR spectrum of compound 2i in CDCl3, the methylene protons of the pyrazinone moiety resonated as a pair of doublets (J 12.1 Hz) in the ranges  = 4.55 and 4.82 ppm.A singlet signal appearing at  = 7.11 ppm is consistent with the proton at position 6, on the pyrazole ring.The C2-O1 and C19-O4 bond lengths suggest some double-bond character due to resonance delocalization of the O-atom lone pairs with the benzene ring.Two of the methoxy groups lie essentially in the plane of the attached benzene rings, with the C22-O4-C19-C20 and C1-O1-C2-C7 torsion angles being 179.87(23)° and -179.47(30)°,respectively.
The crystal packing of 2i is complex, despite the lack of any functional groups for classical hydrogen bonding.In the crystal lattice, the N1 atom of the pyrazole ring interacts with the H18 of benzene moiety through a pair of linear C18-H18•••N1 hydrogen bonds to form two kinds of ) 16 (

Experimental Section
General.Thin-layer chromatography was carried out with Merck silica gel (60 F254).Melting points were determined with an XD-4 digital micro melting point apparatus. 1H NMR spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer, using CDCl3 as solvent and TMS as internal standard. 13C NMR spectra were obtained on a Bruker Avance 400 (100 MHz) spectrometer with TMS as the internal standard and CDCl3 or DMSO-d6 as solvent.The chemical shifts () were measured in ppm with respect to the solvent (CDCl3: 1 H:  = 7.26 ppm, DMSO-d6: 1 H:  = 2.50 ppm).Coupling constants (J) are given in Hz.IR spectra were measured as KBr plates with an IR spectrophotometer Avtar 370 FT-IR (Termo Nicolet).Electrospray ionization mass spectrometry (ESI-MS) spectra were recorded with a LTQ Orbitrap Hybrid mass spectrograph.Microwave-assisted reactions were carried out in a Start Synth Microwave Synthesis Lab station.

General procedure for the synthesis of compounds 2, 3a, 4a
To an open glass vessel, ethyl 3-aryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylate 1 (1.0 mmol), obtained according to our previous reported method, 24 and aminoethanol (183 mg, 3.0 mmol) were added and were then irradiated constantly at 1200 W in the microwave cavity for the time given in Table 1.The reaction end was monitored by TLC.The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether = 1:2) to afford the products 2. Byproducts 3a and 4a have been also isolated.A crystal of 2i suitable for X-ray analysis was grown by slow evaporation from ethyl acetate solution.The diffraction measurement was carried out by graphite monochromated Mo K radiation with  = 0.71073 Å on a Bruker SMART CCD diffractometer.The structure was solved with direct methods using the SHELXS-97 program, and refined on F 2 by full-matrix least-squares with the SHELXL-97 package. 25All data were corrected by multi-scan method using SADABS program.Molecular graphics were designed by using ORTEP-3 and DIAMOND 3.2. 26PLATON program was also used for structure analysis. 27The crystal data and details concerning data collection and structural refinement are given in Table 4.

a
The end of reaction determined by TLC.b Isolated yield.CrystallographyCompound 2i crystallizes in the centrosymmetric space group C2/c.Two enantiomeric forms are present and the structure of the S form is shown in Figure2.The structure of compound 2i consists of two methoxy-substituted benzene rings and an oxazolo[3,2-a]pyrazolo[1,5-d]pyrazine frame in which a pyrazine ring fused with one pyrazole and an oxazole ring.All of the bond lengths and bond angles in the aromatic rings are in the normal range (Table2).

Figure 2 .
Figure 2. ORTEP view of compound 2i.Thermal ellipsoids for non-hydrogen atoms are drawn at the 30% probability level and hydrogen atoms are shown as cycles.

2 2 :
refers to the motif generated by pairs R form of the 2i molecules.

Figure 4 .
Figure 4. Packing diagram of compound 2i.Short contacts are showed as dashed lines.

Table 1 .
Yields and reaction time for 2a-i under solvent-free microwave conditions

Table 3 .
Hydrogen bonding geometry for structure 2i (Cg1 refers to the centroid of ring File CCDC 779359 contains the supplementary crystallographic data for compound 2i.These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033; or by e-mail: deposit@ccdc.cam.ac.uk).

Table 4 .
Summary of crystal data and structure refinement for compound 2i