Investigation and Synthesis of Some Novel Spiro Heterocycles Related to Indoline Moiety

Reactions of indole-2,3-dione 1 with 2-mercaptobenzimidazole, o-phenylenediamine, 2aminophenol, 2-aminobenzothiazole, 2-aminobenzimida zole and 3-methyl-1-phenyl-2pyrazolin-5-one were carried out to give compounds spiroindolethiazetobenzimidazole 2, spirobenzimidazole(oxazole)indoline 3a,b, benzothiazol(imidazol) iminoindolinone 4a,b and methyloxoindolylidenepyrazolone 5 respectively. Compound 5 was reacted with 2aminophenol as well as o-phenylenediamine to give new spirooxazepine and di azepine derivatives 6a,b respectively. Reaction of 5 with nitrogen nucleophiles as well as carbon nucleophiles was investigated to furnish new spiro heterocycles 7-11. The reaction of 2-(2oxo-1,2-dihydroindol-3-ylidene)malononitrile compou nd 12 with 3-methyl-1-phenyl-2pyrazoline-5-one was carried out to give spiroindolopyranopyrazolo d erivative 13. Compounds 4a,b was reacted with thioglycolic acid to give thiazol idinone derivatives 14a,b. Epoxidation of 5 using monoperoxyphthalic acid magnesium salt hexah ydrate and hydrogen peroxide were executed to afford the novel dispiro (2-pyrazolin oxiraneindoline)dione compound 15. The chemical structures of the synthesized compou nds were well established by elemental and spectral ana lyses.


Introduction
Among the various heterocyclic systems, indole holds a prominent place because it is present as a core unit in a number of compounds possessing a broad spectrum of biological activates [1,2].It is well known that the spiro-oxindole heterocyclic framework is an important structural motif in biologically relevant compounds as natural products and pharmaceuticals, e.g., surugatoxin, horsfiline, spirotryprostatin A and B, elacomine, gelsemine, alstonisine and strychnofoline [3][4][5][6][7][8][9].

Experimental
The time required for completion of each reaction was monitored by TLC.Melting point was measured by (Gallen-Kamp) apparatus and was uncorrected.Elemental analysis was performed with elemental analysen systeme GmbH.Verio EI.IR spectra were recorded with Shimadzu 470 Infrared Spectrophotometer (KBr wafer technique). 1 H and 13 C NMR spectra were taken with a NMR LA 400 (Joel) (400 and 100 MHz respectively) with TMS as internal standard.Mass spectrometric analysis was recorded with Joel-JMS 600.

Synthesis of compounds 3a,b
A mixture of 1 (0.002 mol), o-phenylenediamine and/or o-aminophenol (0.002 mol) and triethylamine (1 mL) was refluxed in absolute ethanol (20 mL) for 6 h.The reaction mixture was cooled to room temperature and the resultant solid was filtered, and recrystallized from a mixture of ethanol: water (2:1).

Synthesis of compounds 6a,b
A mixture of chalcone 5 (0.01 mol), o-aminophenol and/or o-phenylenediamine (0.01 mol) and few drops of piperdine was refluxed in ethanol (50 mL) for 4 h, then glacial acetic acid (10 mL) was added to the reaction mixture then heating was continued for further 2 h.The reaction mixture was cooled to room temperature, left overnight and the resultant solid was filtered, dried and recrystallized from ethanol.

Synthesis of spiropyrazolo [3,4-c] pyrazole derivatives 8a -e
The chalcone 5 (0.001 mol) and an excess of the appropriate hydrazine (1 mmol) was refluxed for 2 h in ethanol (20 mL).The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure.The residual product recrystallized from ethanol.

Synthesis of spirothiazolidineindoline 14a,b
A mixture of 4a or 4b (0.01 mol), thioglycolic acid (0.01 mL) and 30 mL THF was heated under reflux for 4h in presence of anhydrous ZnCl 2 .The reaction mixture was cooled and filtered.The filtrate was evaporated under reduced pressure.The residual solid product was recrystallized from ethanol.

Results and Discussions
Refluxing of isatin with 2-mercaptobenzimidazole in ethanol and in presence of triethylamine as a basic catalyst furnished the new spiroindolethiazetobenzimidazole derivative 2, The chemical structure of thiazeto derivative 2 was established by elemental and spectral analyses.IR spectrum showed absorption band at 1720 cm -1 characteristic for one carbonyl group of isatin and at 3250 cm -1 for NH group. 1 H-NMR showed multiplet signals centered at 6.61-7.70characteristic for aromatic protons.Mass spectrum showed a molecular ion peak at m/z 279 with high intensity.Also, isatin was refluxed with ophenylenediamine as well as with 2-aminophenol in ethanol and in presence of TEA to give spirobenzimidazoleindoline 3a and benzoxazoleindoline 3b derivatives respectively.The structures of the latter compounds were elucidated using IR, 1 H-NMR and mass spectrometric analyses which were in full agreement with the suggested structures.Mass spectrum showed a molecular ion peak at 238 as a base peak.Condensation of compound 1 with 2-aminobenzothiazole or 2-aminobenzimidazole was carried out in ethanol and triethylamine as a basic catalyst to give the corresponding Schiff's bases 4a and 4b respectively.Isatin reacted with 3-methyl-1-phenyl-2-pyrazoline-5-one in ethanol and triethylamine to give the corresponding chalcone 5.The chemical structure of chalcone 5 was confirmed by TLC, IR, 1 H-NMR and mass spectra.IR spectrum showed two absorptions at 1720 cm -1 , characteristic for carbonyl group of indole moiety, 1680 cm -1 characteristic for carbonyl group of pyrazolone moiety. 1 H-NMR spectrum showed singlet signals at δ 2.30 and 10.35 ppm for CH 3 group of pyrazole, NH group of isatin respectively (Scheme 1).Compound 5 was subjected to extensive study through the reaction with nitrogen nucleophiles.Reaction of compound 5 with 2-aminophenol , o - phenylenediamine, gave the new spiro indole pyrazolo benzoxazepine 6a and spiro indole pyrazolo benzodiazepine 6b respectively.
The chemical structure of compound 6a was elucidated on the basis of elemental and spectral analyses.IR spectrum of 6a showed absorption bands at 3150 cm -1 for NH and at 1710 and 1605 cm -1 for CO group of indole and C=C of pyrazole respectively. 1H-NMR spectrum showed singlet signal at δ 2.30 for CH 3 of pyrazole moiety and singlet at 9.60, 10.35 characteristic for NH groups of oxazepine and indole respectively.Mass spectrum of 6a showed a molecular ion peak at 394.While reaction of chalcone 5 with urea, thiourea, hydrazine, phenylhydrazine, m-bromophenyl hydrazine, m-nitrophenyl hydrazine and p-methoxy phenylhydrazine in ethanol afforded spiro indole pyrazolopyrimidines 7a,b and spiropyrazolopyrazoles 8a-e respectively (Scheme 2).It was found that the percentage of yield of products 8a-e depended on the nucleophilicity of substituent on the pyrazole ring.Where, the weak nucleophilic group decreases the percentage of yield according to its intensity as in 8c and 8d while the strong nucleophilic group increases the percentage of yield.But in case of p-methyl phenylhydrazine as strong nucleophile which contain electron releasing (OCH 3 ) group, the yield doesn't increase (may be) due to steric interaction of OCH 3 group with the spiroindolopyrazole nucleus.

EtOH
The suggested mechanism for the formation of compounds 6a,b was described as 1, 2-Michael addition of nucleophilic OH or NH 2 group in o-aminophenol or o-phenylene diamine to the C=C bond of α,β-unsaturated carbonyl of pyrazolone followed by cyclization through nucleophilic addition of NH 2 to the carbonyl group of pyrazolone and elimination of water molecule to form the oxazepine (diazepine) compounds 6a,b as shown in the following scheme.Scheme 3. The suggested reaction mechanism for formation of spirooxazepine 6a and diazepine 6b.
On the other hand, 3-methyl-4-(2`-oxoindole-3-ylidene)-1-phenyl-pyrazol-5-one compound (5) reacted with acetylacetone as well as ethyl cyanoacetate as active methylene derivatives in ethanol and in presence of triethylamine to give the new acetylspiroindolepyranopyrazole 9 and amino spiroindolepyranopyrazole acetic acid ethyl ester 10 in quantitative yield.Compound 5 was treated with malononitrile in ethanol and in presence of triethylamine to give 3-indolone derivative 11 not the aminospiroindolepyranopyrazole carbonitrile derivative 13 which was clearly shown by IR spectroscopy.Further investigation was done through treatment of isatin with malononitrile to give the 3-dicyanomethylene derivative 12 which reacted with 3-methyl-1-phenyl-2-pyrazoline-5-one in ethanol and triethylamine to furnish the cyclic spiro derivative 13 in quantitative yield (Scheme 4).The structure of compound 13 was established by spectral analysis.IR spectrum showed absorption bands at 3350, 3300 and 3200 cm -1 for NH 2 , NH groups and absorption band at 2200 cm -1 for CN group. 1 H-NMR showed singlet signal at δ 4.75 for NH 2 group and singlet signal at δ 9.45 for NH group.Mass spectrum of compound 13 showed a molecular ion peak at 369 as a base peak.
Alternative route to synthesize spiro-indoline thiazolidinones 14a,b was carried out through the reaction of Schiff's bases 4a,b with thioglycolic acid (Scheme 5).IR spectrum of compound 14a showed two absorption bands at 1720 cm -1 characteristic for carbonyl group of indole moiety and 1680 cm -1 characteristic for carbonyl group of thiazolidine Epoxidation of compound 5 with hydrogen peroxide as well as monoperoxy phthalic acid magnesium salt hexahydrate gives the new epoxide derivative 15.Compound 15 which was synthesized by two routes are identical in all aspects (Scheme 6).The chemical structure of compound 15 was proved by elemental and spectral data.IR spectrum showed absorption bands at 1720 cm -1 characteristic for carbonyl group of indole moiety, 1680 cm -1 characteristic for pyrazole moiety and absorption band at 1110 for C-O of epoxide ring. 1 H-NMR spectrum showed multiplet signals at 6.65-7.75 for aromatic protons and singlet signal at 10.35 for NH group.Mass spectrum showed a molecular ion peak at 319.