One-pot diastereoselective synthesis of new spiro indenoquinoxaline derivatives containing cyclopropane ring

A one-pot procedure was introduced for the synthesis of some new spiro derivatives of indenoquinoxaline containing cyclopropane ring from chalcones. The chalcones 1a-e were reacted with hydrazine hydrate and then in situ with lead(IV) acetate (LTA) and two new diastereomers 2a-e and 3a-e were prepared. The compounds 2a-e diastereoselectively produced in higher yields than 3a-e .


Introduction
The cyclopropane ring is a main structural part in many synthetic and natural compounds that exhibits a wide range of biological activities from enzyme inhibition to antibiotic, herbicidal, antitumor, and antiviral properties. 1,2 ome derivatives of cyclopropane have shown potent HIV antiviral activities as non-nucleoside reverse transcriptase inhibitors. 3Due to diversity of cyclopropane containing compounds with biological activity, chemists have tried to find novel and facile methods for synthesis of these compounds. 4,5 denoquinoxaline derivatives are important classes of nitrogen containing heterocycles and they have applications in dyes and are useful intermediates in organic synthesis and have also been used as building blocks for the synthesis of organic semiconductors. 6More studies have discovered that these compounds exhibit diverse medical functions such as antimetabolism and antitubercular properties. 7any synthetic methods have been reported for the preparation of cyclopropanes such as intramolecular cyclization, addition of carbenes to olefins and Michael initiated ring closure (MIRC). 1,8 n this study along our pervious works on the synthesis of spiro indenoquinoxalines and other biologically active compounds, 9,10 we report a novel one-pot facile procedure for the synthesis of some spiro indenoquinoxaline-cyclopropane derivatives which directly prepared from chalcones of indenoquinoxaline.

Results and Discussion
Among the synthetic procedures for preparation of cyclopropane rings, the Michael initiated ring closure (MIRC) reaction of α,β-unsaturated carbonyl compounds (like chalcones) with dimethylsulfoxonium methylides or Corey-Chaykovsky reaction is the well-known method. 11,12n this reaction, the cyclopropane ring forms between C-2 and C-3 carbons of chalcones by addition of a new CH 2 group (Scheme 1).In the present work, we wish to report a novel one-pot procedure to synthesis the cyclopropane derivatives with connecting the C-1 and C-3 carbons of chalcones (Scheme 2).
The chalcones 1a-e were prepared by the reaction of indenoquinoxaline with acetophenones in a solvent free condition catalyzed by dimethylamine and then glacial acetic acid and HCl. 10,14hese chalcones reacted with hydrazine hydrate in toluene and then in situ with lead(IV) acetate (LTA or Pb(OAc) 4 ) to afford new spiro indenoquinoxaline-cyclopropane derivatives 2a-e and 3a-e (Scheme 3).The intermediate of this reaction is a spiro indenoquinoxaline-pyrazoline 4 which was not separated and reacted in situ with LTA to form new diastereomers 2a-e and 3a-e and then the overall yield of the reaction increased.A probable mechanism of the one-pot reaction is presented in scheme 4.This one-pot reaction was diastereoselective and diastereomers 2a-e were prepared in higher yields than their 3a-e isomers.For example, the diastereomeric ratios were determined by integration of separated signals in the 1 H NMR spectra of the mixture of compounds 2a and 3a in the reaction product (Figure 1).This ratio was 2a:3a=2.85:1.The ratios of other derivatives were 2b:3b=3:1, 2c:3c=3.35:1,2d:3d=1.04:1,2e:3e=3:1.For instant, the 1 H NMR spectrum of 2a indicated two doublets at δ 2.48 and 3.26 ppm (J = 0.014×500= 7 Hz) which belong to diastereotopic CH 2 protons of C-3' position of cyclopropane ring and a singlet at δ 2.10 ppm for hydrogens of CH 3 in acetate group.The multiplets at δ 7.19-8.39ppm showed the aromatic protons.The 1 H decoupled 13 C NMR spectrum of 2a exhibited spiro carbon at δ 38.69, C-2' carbon of cyclopropane ring at δ 72.17, carbon of CH 2 at δ 27.39, carbon of CH 3 at δ 21.29 and carbon of acetate group at δ 170.67 ppm.
In the 1 H NMR spectrum of compound 3a a doublet was appeared at δ 6.07 (J = 0.016×500= 8 Hz) ppm for the H-1 hydrogen atom of indenoquinoxaline ring.This hydrogen was shielded by the magnetic anisotropy effect of the phenyl ring attached to the position 2' of cyclopropane ring (Figure 2).

Conclusions
In summary, some novel spiro indenoquinoxalines containing the cyclopropane ring were synthesized from chalcones in a one-pot simple procedure and the products were obtained in good yields.These compounds can be active biological substances and worthy of attention for the medicinal chemists.

Experimental Section
General.The chemicals used in this work are the pure products which were purchased from Merck and Fluka companies.Melting points were measured on a Qallenkamp melting point apparatus in open capillary tubes and are uncorrected.IR spectra were taken from a Bruker Vector 22 FT-IR spectrometer. 1 H NMR was recorded on a Bruker DRX-400 Avance instrument and 13 C NMR (125 MHz) was run on a Bruker DRX-500 Avance instrument using CDCl 3 as the solvent and TMS as the internal standard.The purity of prepared spiro compounds was tested by the elemental analysis of C, H, and N elements using a Heraus CHN rapid analyzer.All prepared compounds were filtered and fractionally crystallized from ethanol/water.Indenoquinoxaline were prepared by the procedure described by Ruhemann. 13The chalcones of indenoquinoxaline were synthesized with method of Lindwall and Mclennan. 14neral procedure for preparation of chalcones of indenoquinoxaline.To a solid homogenous mixture of 10 mmol indenoquinoxaline and 10 mmol acetophenones, 10 drops of dimethylamine was added and the mixture stirred for 15-30 minutes and a colorless solid formed and then 20 ml glacial acetic acid and five drops of concentrated HCl was added to this precipitate and the mixture warmed in 80 ºC for 30 minutes and after dehydration, chalcones 1a-e were produced and washed with water (2×20ml) and then recrystallized from absolute ethanol. 10neral procedure for preparation of spiro indenoquinoxaline-cyclopropane derivatives 2 and 3.The chalcones 1a-e (10 mmol) were dissolved in 20 ml toluene and then 11 mmol hydrazine hydrate was added to this solution and the mixture was stirred and refluxed at 70-80 ºC for one hour.Then 11 mmol of solid LTA was added to the reaction mixture at 40-50 ºC and nitrogen extrusion began.The reaction was continued for 10-20 minutes and the spiro compounds 2a-e and 3a-e were prepared (Scheme 3).The products were filtered and fractionally crystallized from ethanol/water.

Figure 2 .
Figure 2. H-1 hydrogen shielded by anisotropic effect of the phenyl ring.