Indazole derivatives from substituted ylidene-N -phenylhydrazine- carbothioamides and benzo-as well as naphthoquinones

2-Substituted ylidene-N -phenylhydrazinecarbothioamides 1a - f reacted with 2,3-dicyano-5,6-dichloro-1,4-benzoquinone, 2,3,5,6-tetrachloro-1,4-benzoquinone, 2,3-dichloro-1,4-naphtho-quinone, 2,3-dicyano-1,4-naphthoquinone and 3,4,5,6-tetrachloro-1,2-benzoquinone to form substituted N -phenylindazolecarbothioamides, substituted benzindazolecarbothioamides and substituted benzophthalazinediones. Rationales for the role of benzo-and naphthoquinones in heterocyclization of compounds 1a - f are presented.


Introduction
Aldehyde thiosemicarbazones are appropriate substrates for the preparation of five-or sixmembered heterocyclic rings that contains three heteroatoms by reacting them with oxidizing agents or other cyclization reagents. 1-6Several oxidizing agents can be used for the cyclization of semi-and thiosemicarbazones and it has been investigated how the oxidant as well as the structure of the open chain molecules can affect regiochemistry and yield of the process. 1,7-92,3,5,6-Tetrachloro-1,4-benzoquinone (CHL-p, 10) and 2,3-dichloro-1,4-naphthoquinone (14) undergo nucleophilic substitution of one or two chlorine atoms by thioacetamide, 10-12  thiourea, 13,14 substituted thiourea, 15 thiocarbazones, 16 hydrazine-1,2-dicarbothioamides, 17  thiosemicarbazides, 18 and thiosemicarbazones. 4On the other hand, the synthesis of indazole derivatives from the reaction of diazoalkanes with some benzo-and naphthoquinones has been extensively investigated. 19-23Much less attention has been given to the synthesis of indazole derivatives during the reaction of thiosemicarbazides with benzoquinones, 4,18 therefore we undertook to prepare a series of indazole and benzindazole derivatives from the reaction of substituted ylidene-N-phenylhydrazinecarbothioamides 1a-f with different benzo-and naphthoquinones.
ARKAT USA, Inc.  or or Scheme 2. Products formed during the reaction of 1a-f with 10.
The 1 H-NMR spectrum of 11c revealed a broad singlet at 9.88 ppm for (Ph-NH) proton, singlet at 3.84 (OCH 3 ) and a multiplet at 7.05-7.69ppm, which is characteristic of phenyl protons.The 13 C-NMR spectrum showed the presence of two carbonyl groups at δ = 173.3and 174.6 ppm, 143.8 (C-5, C-6), 149.2 (C-3) and 181.3 ppm (C=S).The analytical data of compound 11c could also match for other isomers of products 12 and 13 (Scheme 2).The alternative structures 12 and 13 could also ruled out on the basis of 1 H-NMR, 13 C-NMR and fragment ions in the mass spectrum of 11c at m/z 457/461, 422, 386, 251, 195, 150, 135, 133 and 93.As shown in scheme 2, structure 11c fits best to all the spectroscopic data (see experimental section).
ARKAT USA, Inc.It has been described in the literature that 14 resembles 10 in most of its substitution reactions, especially with compounds containing nucleophilic nitrogen (amines, pyrazoles, imidazoles). 30-33From this point of view one might expect that thiosemicarbazones 1a,c,e,f should react with 14 similarly like 10. Mixing equimolar amounts of 1a,c,e,f and 14 in ethyl acetate for 72 hours led to the formation of substituted benzindazole-4,9-diones 15a-d as major products and substituted benzophthalazinediones 17a-d as minor products (Scheme 3).
The gross formula of 15a (C 24 H 15 N 3 O 2 S) represent a product from one molecule of 14 and one molecule of 1a with loss of 2HCl.The structure of 15a-d were supported by 1 H-NMR, 13 C-NMR, mass spectroscopy and elemental analyses (see experimental).
Another type of benzindazoles, namely 4-cyano-5-hydroxy-N-substituted-1-phenylbenzo-[e]indazole-3-carbothioamides 20a-d was obtained in 51-59% yield from the reaction of thiosemicarbazones 1a,c,e,f with 2,3-dicyano-1,4-naphthoquinone (Scheme 4).The benzindazoles 20a-d exhibited three IR absorption at 3460-3450 (OH), 3330-3315 (NH) and 2220-2210 cm -1 (CN), respectively.A sharp bands at 1575-1579 due to (NH-deformation and C-N stretching) and intense band in the range of 1360-1348 and 1010-995 cm -1 assigned to strongly coupled between C=S and C-N vibrations. 30-33The products 20a-d show two broad signals are for Ph-NH at 9.96-9.89ppm and the other at 9.76-9.71due to OH, besides the nature of R as well as phenyl protons.In the 13 C-NMR spectrum of 20a, C-4 and C-5 resonate at 76.5 and 156.2 ppm, respectively, and are in accordance with the observed trends in the δ values for the C-atoms in push-pull alkenes. 28-34Further peaks at 117.8 (CN), 148.1 (C-1) and 181.6 (C=S), besides the aromatic carbons support the assigned structure.The formation of 20a-d may be rationalized as follows (see Scheme 4).On the other hand, 3,4,5,6-tetrachloro-1,2-benzoquinone 22 reacted with an equimolar quantity of 1a,c,e,f to give indazole derivatives 24a-d and thiadiazole derivatives 5a,c,e,f (Scheme 5).As an example, the structural assignment of 24a was supported by the following spectral data: In its 13 C-NMR spectrum the characteristic resonance signal of the two carbonyl Catoms of o-chloranil 22, 24 is replaced by signals at 133.2 and 152.2 ppm which are characteristic to indazole-C-3a and C-4. 28In addition, indazole-C-7a was observed at 143.2.The IR spectrum showed two sharp bands at υ = 3460 and 3295 cm -1 due to hydroxyl and NH groups, further bands were observed (see experimental section). 1H-NMR spectrum of 24a showed two broad signals at 9.88 and 9.56 ppm due to NH attached to phenyl ring and hydroxyl group, respectively.The formation of 24a was further confirmed by mass spectrometry, at m/z = 447/453, the characteristic fragment ion patterns of substituted trichlororo compounds were observed. 29

Conclusions
The reactions and products presented here provide insight into the spontaneous reactions between the electron donating ylidene-N-phenyhydrazinecarbothiamide derivatives 1a-f and suitable electron acceptors, here 2, 10, 14, 18 and 22.In a fairly complex and multisteps process two types of novel and interesting substituted indazoles (9, 11, 15, 20 and 24) as well as benzophthalazinediones 17 are formed from the interaction of electron rich 1a-f and different benzo-and naphthoquinones.The ring forming reactions of 1a-f with different quinones have ARKAT USA, Inc.
been observed: (i) Cyclization of 1a-f by intramolecular nucleophilic attack, may be activated by quinones.(ii) On the other hand, the nucleophilic substitution reactions between 1a-f and quinones followed by condensation.Thus, quinones may act either as a mediator or as a building block in heterocyclizations of thiosemicarbazones.

Experimental Section
General Procedures.The uncorrected melting points were determined using open glass capillaries in a Gallenkamp melting point apparatus.Elemental analyses have been determined by the Microanalytical Center, Cairo University, Egypt.The IR spectra were recorded with a Shimadzue 408 and on FT-IR 1650 (Perkin Elmer) instruments using potassium bromide pellets.500MHz 1 H and 125 MHz 13 C-NMR spectra were recorded on a Bruker DRX 500 spectrometer.Chemical shifts are expressed as δ [ppm] with reference to tetramethylsilane as an internal standard, br = broad, s = singlet, and m = multiplet. 13C assignments were made with the aid of DEPT 135/90 spectra.The mass spectra (70 eV, electron impact mode) were recorded on a Varian MAT 311 instrument.Preparative layer chromatography (plc) was made using 48 cm × 20 cm glass plates covered with slurry applied and air dried 1mm thick layer of Merck silica gel Pf 254 .Zones were detected by indicator fluorescence quenching upon 254 nm excitation, removed from plates and extracted with cold acetone.

Reaction of la-f with 2,3,5,6-tetrachloro-1,4-benzoquinone (10).
To a stirred solution of 246 mg (1.0 mmol) of 10 in 20 ml of dry ethyl acetate, la-f (1.0 mmol) in 20 ml of dry ethyl acetate was added dropwise which caused a spontaneous change of colour from yellow to green and finally to brown.The mixture was stirred for 48 hours.After concentration, the residue was subjected to plc using toluene/ethyl acetate (3:1).The fastest moving zone contained compounds 5a-f, while the slowest migrating zone contained compounds 11a-f.Extraction of these zones with acetone and recrystallization from a suitable solvent afforded the pure compounds.

Scheme 3 .
Scheme 3. Products formed during the reaction of 1a, c, e, f with 14.