One-pot rapid and efficient synthesis of new spiro derivatives of 11 H -indeno[1,2-b ]quinoxalin-11-one, 6 H -indeno[1,2-b ]pyrido [3,2-e ]pyrazin-6-one and isatin-based 2-pyrazolines

Some new spiro derivatives ( 5a-h , 9a-c and 13a-c ) of 11 H -indeno[1,2-b ]quinoxalin-11-ones 1a-b and 6 H -indeno[1,2-b ]pyrido[3,2-e ]pyrazin-6-one 6 and isatin 10 were synthesized by two different pathways. The chalcones 4a-h , 8a-c and 12a-c were prepared by the reaction of acetophenone and its four derivatives with 1a-b , 6 and 10 via base-catalyzed condensation followed by addition of acid. In the first procedure, the chalcones were isolated and reacted with hydrazine hydrate to give products. In the second procedure, the chalcones were in situ reacted with hydrazine hydrate without isolation to give spiro compounds in improved yields


Results and Discussion
Many of 2-pyrazoline derivatives have been synthesized in last century, [70][71][72] but these synthesized spiro derivatives have not been reported yet.Therefore, our aim was to prepare some new spiro compounds with spiro 2-pyrazoline ring at C-11 carbon of indenoquinoxalines 1a-b, C-6 carbon of indenopyridopyrazine 6 and C-3 carbon of isatin 10, by the reaction of chalcones with hydrazines in one-pot rapid and efficient procedure.
The chalcones 4a-h, 8a-c and 12a-c were prepared by the reaction of acetophenones with indenoquinoxalines 1a-b, indenopyridopyrazine 6 or isatin 10 in a solvent free condition under the influence of dimethylamine and then warming compounds 3a-h, 7a-c and 11a-c in glacial acetic acid and HCl.Then the resulted chalcones were separated and allowed to react with hydrazine hydrate under refluxing in ethanol to afford spiro indenoquinoxaline-pyrazolines 5a-h ARKAT (Scheme 1), spiro indenopyridopyrazine-pyrazolines 9a-c (Scheme 2) and spiro isatinpyrazolines 13a-c (Scheme 3) in good yields.

Scheme 3
In most methods chalcones were synthesized in base or acid catalyzed manner and the resulted chalcones were reacted with hydrazines after separation and purification. 44, 46-50, 54, 61, 76- 77In this work these spiro compounds also were made by one-pot procedure without isolation of the intermediate chalcones, and the reaction yield increased (Scheme 4).In the case of isatin the reaction rate was increased because the C=O group in 2 position of isatin increases the reactivity of carbon in 3 position by electron-withdrawing effect.The s-trans conformation of hydrazones H 1 , H 2 and H 3 involve a van der Waals repulsion between the rings of Ar and indenoquinoxaline (Scheme 5) and therefore the s-cis conformer must be the predominant conformer. 78

Scheme 5
All prepared spiro compounds were purified by filtration and recrystallization of crude products from ethanol/water (70/30) solution.
The structures of compounds 5a-h, 9a-c and 13a-c were deduced from their elemental analyses and their IR, 1 H-, 13 C-NMR and Mass spectroscopic measurements.All compounds have shown an excellent agreement between calculated and experimentally obtained data for CHN analysis.For example the 1 H-NMR spectrum of 5a exhibited two doublets or AB quartet (δ 3.66 and 4.04) readily recognized to arise from two diastereotopic CH 2 protons of C-4 carbon of 2pyrazoline ring along with multiplets (δ 7.43-8.17)for the aromatic protons.The singlet at 6.35 is related to NH.The 1 H decoupled 13 C-NMR spectrum of 5a showed 21 distinct resonances in agreement with the proposed structure.Spiro carbon is resonated at δ 71.93 ppm and C=N carbon at 162.81 ppm.
In summary, the reaction described herein provides a simple and direct entry into a number interesting novel spiro indenoquinoxaline or isatin-based pyrazoline derivatives that may be of value in medicinal chemistry.

Experimental Section
General Procedures.Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected.IR spectra were recorded as KBr pellets on Bomem FT-IR MB100 and Thermo Nicolet model Nexus 870 spectrometers.¹H-NMR and ¹³C-NMR spectra were determined on a Bruker DRX-300 Avance instrument in CDCl 3 using TMS as internal standard.Mass spectra were recorded on a Finnegan Mat magnetic sector model 8430 operating at an ionization potential of 70 eV, range 30-700 and 1 sec scanning.The purity of obtained spiro compounds was tested by the CHN analysis.Indenoquinoxalines 1a-b were synthesized by the procedure of Ruhemann 73 and 6 by the method of Israel and co-workers 74 .The chalcones were synthesized on the basis of Lindwall and Mclennan method. 75piro indenoquinoxaline-pyrazolines (5a-h).To a solid homogenous mixture of 10 mmol indenoquinoxalines 1a-b and 10 mmol acetophenones 2, 10 drops of dimethylamine was added and the mixture stirred for 15-30 minutes and a colorless solid formed (3a-h).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 4a-h were produced.These chalcones were allowed to react with hydrazine hydrate by two pathways.At first the chalcones were separated and after filtration washed with water (2×20ml) to remove acids and dimethylammonium acetate and then recrystallized from absolute ethanol.Then these chalcones were refluxed with 11 mmol hydrazine hydrate in 20 ml absolute ethanol for 1 hour to give corresponding spiro derivatives 5a-h (Scheme 1).In second way or one-pot procedure the chalcones didn't separate and 11 mmol of hydrazine hydrate was added to the acidic solution of chalcone and reaction continued in 70-80 ºC for 1 hour and spiro compounds were formed in highly yields (Scheme 4).