Synthesis of tetrahydroindazol-4 ( 5 H ) one and 7-thione from reaction of functionalized cyclic enaminones with hydrazine

Functionalized enaminones; 3-N-(aryl)amino-1--oxo-cyclohex-2-ene-2-dithiocarboxylates cyclohex-2-en-1-ones and 3-N-(aryl)amino-2-(N-aryl)thioamido-cyclohex-2-en-1-ones were obtained upon reaction of 3-N(aryl)amino-5,5-dimethyl-1-oxo-cyclohex-2-enes with carbon disulfide in presence of sodium hydroxide in DMSO, followed by methylation with dimethyl sulfate or with phenyl and pbromophenyl isothiocyanates in toluene or under solvent-free condition, respectively. The cyclization of the dithioesters or the thioamides with hydrazine hydrate was accompanied by a displacement of the 3Narylamine moiety by a hydrazine group to give 6-hydrazino-4,4-dimethyl-1,3,4,5-tetrahydroindazole7-thione or 3-N-(aryl)amino-4,5,6,7-tetrahydro-1H-indazole-4(5H)one respectively. Structure of the indazole derivatives formed was further confirmed from their reaction with acetone or p-nitrobenzaldehyde. The new structures were confirmed using HNMR, CNMR, 2DNMR, DEPT experiments and mass spectra.

Therefore, ongoing interest in the chemistry of enaminones we investigate herein the versatility of some enaminone dithiocarboxylates and enaminone thioamides derived from dimedone as precursors for the synthesis of indazole derivatives.

Results and Discussion
Enaminones have two electron deficient centers at C-1 and C-3 while C-2 and amino functions are electron rich.They can thus react with both electrophiles and nucleophiles.Therefore, treatment of enaminones 1-6 29 with carbon disulfide in the presence of sodium hydroxide in dimethyl sulfoxide followed by methylation with dimethyl sulfate afforded the respective methyl 3-N-(aryl)amino-5,5dimethyl-1-oxo-cyclohex-2-ene-2-dithiocarboxylates 7-12, in 40-73 % yield 11 .The formation of the thioesters 7-12 rather than [3,1d]benzothiazine-2-thiones 13 was based on their spectral analyses.Thus, the mass spectrum of 11 showed a molecular ion peak at m/z 339.1 (M +. ) which in agreement with its molecular formula C16H18NOS2Cl.Furthermore, the 1 HNMR spectra of 9, 11 and 12 showed an exchangeable NH proton at the downfield region at δ 13.17-14.60ppm which excluded structure 13 and agreed with the assigned structure 7-12.
The disappearance of the vinylic C-H proton and the assignment of a characteristic singlet signal of S-Me protons at δ 3.36 ppm of 9 measured in DMSO-d6 and at δ 2.55, 2.57 ppm for 11 and 12, respectively measured in CDCl3, also confirmed the assigned structure.
Attempted synthesis of the thiohyrazide derivatives 17 by the reaction of the enamino dithiocarboxylates 7-12 with hydrazine hydrate did not take place, but surprisingly, the products from the different dithiocarboxylates 7-12 have been found to be the same yellow crystalline product.Thus, an indazole ring structure 16 was formed rather than the expected thiohydrazide derivative 17 as deduced from its spectral data.The mass spectrum showed a molecular ion peak at m/z 211.3 (M +• +1) which agreed with the molecular formula C9H14N4S (210.29).Furthermore, the 1 H NMR spectrum showed the presence of four exchangeable protons at δ 5.75 ppm (NH2), 12.14 and 12.70 ppm (2 NH) as well as the absence of signals characteristic for aromatic protons.The three singlets at δ 1.00, 2.40 and 2.68 ppm were assigned for two equivalent methyl protons and two methylene protons respectively.The spectral data agreed with the formation of 16 which could be explained to proceed through three different pathways.Hydrazine could react with the carbonyl group of 7-12 to form the hydrazone derivative 14 that upon intramolecular cyclocondensation by nucleophilic displacement of the thiomethyl group will form indazole ring structure 15 that upon further nucleophilic displacement of the arylamino group by hydrazine gave 16 through an additionelimination reaction (rout i).
Alternatively, nucleophilic displacement of the thiomethyl group could take place by hydrazine to form the thiohydrazide 17 that spontaneously intermolecularly cyclized with the elimination of arylamine to form 18 whose reaction with hydrazine hydrate gave 16 (rout ii).However, as a consequence of the enaminones, nature [30][31][32] the hydrazine would attack C-3 first with subsequent elimination of the arylamine moiety to form the intermediate 19 as in route iii.Intramolecular nucleophilic displacement of the thiomethyl group by NH2 of the hydrazine moiety would afford the indazole 18 which reacted with hydrazine to form 16. Accordingly, route iii represents the most convenient postulated mechanism for this reaction and in agreement with literature data [30][31][32] .The elimination of arylamine moiety explained the formation of the same product from each of 7-12.Structure of 16 was further confirmed from X-ray diffraction experiment of the hydrazone derivative 20 derived from the reaction of 16 with acetone that showed the structure of the product in full accord with 16.The acetone derivative 20 is identical with that reported earlier 33 .
Furthermore, the reaction of 16 with p-nitrobenzaldehyde in boiling ethanol gave a red crystalline hydrazone derivative 21.The 1 HNMR spectrum of 21 showed in addition to the signals characteristic for the two methyl groups and the methylene protons of C-3 and C-5, two doublets at δ 8.11 and 8.34 corresponding to the four aromatic protons.At the downfield region, only two exchangeable singlets at δ 12.59 and 14.62 ppm corresponding to two NH protons were assigned.Further support for the structure of compound 21 was verified from its 13 C NMR spectrum where the assignment of signals was supported by 1 H, 1 H COSY technique and 1 H, 13 C shift correlation.Thus, a signal corresponding to the two methyl groups appeared at δc 26.8 ppm which was correlated with their protons that resonated at δ 1.0 ppm whereas the C-4 was resonated at δc 33.1 ppm.Both of the methylene carbons, C-3 and C-5, were assigned based on their correlation with their protons that assigned at δ 2.49 and 3.05 ppm as well as from the DEPT experiment at δc 36.1 and 38.1 ppm.The azomethine carbon resonated at δc 152.6 ppm as confirmed from its correlation with its proton at δ 8.74 ppm.Both of C-6a and C-3a were assigned at δc 106.2 and 162.7 ppm, respectively, whereas, that of C-7 at δc 165.4 ppm.
The attempted reaction of enaminones 1, 2 and 4 with phenyl isothiocyanate 22 and pbromophenyl isothiocyanate 23 in toluene under reflux gave the thioamides, 24-29, respectively in low to moderate yield (33-54%) in addition to the recovery of the respective starting material.An improved yield was obtained when the reaction was carried out under solvent free conditions.Thus, heating of 1, 2 and 4 with 22, and 1 with 23 without solvent at 160 °C for one hour afforded the respective thioamides 24-27, respectively in 79-95 % yield as a sole product.The formation of thioamides 24-29 rather than the thiourea derivatives 30 was established from their 1 HNMR spectra.The disappearance of vinylic H-2 proton and the assignment of two D2O exchangeable NH protons at δ 14.17-14.74and 15.81-15.97ppm for compounds 25-29 whereas that of 24 were assigned at δ 16.71 ppm, confirmed the assigned structure.Both of the C-4 and C-6 protons of dimedone moiety were assigned as either singlet of four protons intensity at δ 2.48 and 2.47 ppm, for compounds 26 and 29, respectively or as two singlets of two protons intensity each at δ 2.45-2.49and 2.49-2.50ppm, for 24, 25, 27 and 28 respectively.Signals characteristic for the thiocarbonyl group was observed in the 13 CNMR spectrum of 25 and 27 at δc 189.85-189.87ppm whereas C-1 (C=O) was assigned at a higher frequency region at δc 196.26-196.37ppm.Both of C-2 and C-3 were resonated at δc 104.72-104.74 and 170.84-171.00ppm, respectively.At the lower frequency region C-4, C-5 and C-6 were assigned at δc 30.25-30.29,27.82 and 52.31-52.33ppm, respectively.Furthermore, the mass spectra of 25, 27 and 29 were in full accord with their assigned structural formula (experimental).Scheme 1. Postulated mechanism for the synthesis of indazole derivatives.

Scheme 2. Thioamides from enaminones
Treatment of different substrates 24-26 with hydrazine hydrate in ethanol under reflux for three hours afforded the same product 32.The formation of a single product can be explained only as a result of the removal of the arylamine moiety at C-3 to give one of two possible structures 32 or 33 respectively.Spectral analyses of the isolated products agreed with structure 32.The 1 HNMR showed only two D2O exchangeable NH protons at δ 7.96 ppm as sharp singlet and δ 8.78 ppm as broad one which ruled out structure 33.Furthermore, the removal of arylamine moiety was confirmed from the absence of 4-methyl group protons of 25 as well as its carbon in the 13 CNMR spectrum as well as the assignment of only five aryl protons at the aromatic area as two triplets and doublet at δ 6.99, 7.36 and 7.53 ppm, respectively.The 13 CNMR spectrum of 32 further supported the displacement of arylamine moiety and cyclization process.Only signals characteristic for one phenyl group carbons were observed at their appropriate position as well as the disappearance of the thione carbonyl carbon.Moreover, the mass spectrum of 32 obtained from 26 showed a molecular ion peak at m/z 254.31 (M +. -1) which in agreement with the assigned structure 32.Consequently, the formation of the indazole derivative 32 can be rationalized as a result of an addition-elimination reaction of hydrazine at C-3 with subsequent elimination of the arylamine moiety with the formation of the intermediate 31 that intramolecularly cyclized through an additionelimination reaction at the thione group C-3 forming the indazole 32 34 .Although we could not isolate compound 33, Jirkovshy 34 in a similar reaction using benzylamine instead of arylamine could isolate 33 which upon hydrolysis with HCl gave 32.
Furthermore compounds 27 and 28 were also subjected to the reaction with hydrazine hydrate to give also a single product 34.The 1 HNMR showed only four aromatic protons at δ 7.37-7.48which moreover confirmed the removal of arylamine moiety at C-3.Also, two D2O exchangeable NH protons were assigned at δ 7.92 and 8.87 ppm.The 13 CNMR spectra of 34 showed signals of C-3 at δc 150.07 ppm whereas C-7a and C-4a were assigned at δ 140.46 and 104.57ppm, respectively.Other signals are in their appropriate positions.
The formation of 32 rather than the hydrazine derivative 33 was elucidated from the recovery of 32 upon reaction with p-nitrobenzaldehyde.Under these circumstances we could prove that reaction of hydrazine hydrate with thioesters 7-12 or thioamides 24-27 proceed first by attack of hydrazine C-3 with subsequent elimination of arylamine followed by an intramolecular attack of the hydrazine NH2 to the thiocarbonyl group of thioester or thioamide with subsequent elimination of either methylmercaptan or hydrogen sulfide to form indazole ring structure.

Conclusion
The results considered in this work demonstrate the high synthetic utilities of enaminones as precursors for functionalized derivatives such as dithioesters and thioamides.Selective removal of the arylamino groups from these enaminone derivatives by hydrazine moiety with subsequent cyclization represents a unique method for the synthesis of indazole derivatives.

Experimental
Melting points were determined with a Mel-Temp apparatus and are uncorrected.TLC was performed on Baker-Flex silica gel 1B-F (1.5-5cm) and the spots were detected by UV absorption.IR spectra were recorded for all compounds in a matrix of KBr with Perkin-Elmer 1430 spectrometer. 1H NMR spectra were recorded on Jeol spectrometer (500 MHz), and Bruker AC (300 MHz) spectrometer and the 13 C NMR spectra were recorded on Joel spectrometer (125 MHz) and Bruker AC spectrometer (75 MHz).Chemical shifts () are given in ppm relative to the signal for TMS as an internal standard.Mass spectra were recorded using electron ionization (EI) on a Finnigan MAT 312 spectrometer or Jeol (JMS.600H)instrument.Microanalysis was performed in the unit of microanalysis at Faculty of Science, Cairo University and unit of microanalysis at Faculty of Chemistry, Konstanz University, Germany.

General Method.
To a well stirred cold solution of 1-6 (20 mmol) in DMSO (50 mL) and sodium hydroxide solution in water (20 mmol; 2 mL), carbon disulfide (30 mmol) was added in 30 minutes.The mixture was stirred for further 20 minutes below 10 ºC whereby dimethyl sulfate (20 mmol) was added dropwise during 20 min.The reaction mixture was left at room temperature for 1 hour with stirring, diluted with water (200 mL) and acidified with 10 % hydrochloric acid.The resulting precipitate was collected by filtration, dried and recrystallized from methanol to give 7-12.