Reaction of 2-hydrazino-3-methylquinoxaline with aryl-1,3-diketones: A structural reinvestigation

Treatment of 2-hydrazino-3-methylquinoxaline (1) with phenyl-1,3-butanedione (2b) in THF affords regioisomeric 1-(3’-methylquinoxalin-2’-yl)-3(5)-methyl-5(3)-phenylpyrazoles (3b and 4b) as major products along with the formation of small amount of 1,4-dimethyl-1,2,4-triazolo[4,3-a ]quinoxaline (5) rather than the reported exclusive formation of 5 . Several other regioisomeric 1-(3’-methylquinoxalin-2’-yl)-3,5-disubstituted pyrazoles have similarly been synthesized using other aryl-and heteroaryl-1,3-diketones. The identity of the regioisomeric pyrazoles is based upon NMR ( 1 H & 13 C) spectral data and an unambiguous synthesis.


Introduction
The reaction of β-dicarbonyl compounds or synthetic equivalents with hydrazines is the most usual approach for the synthesis of pyrazoles 1 .Whereas there is no structural ambiguity concerning the structure of the products obtained in the cases of alkyl-or arylhydrazines, reaction of heterocyclylhydrazines with β-dicarbonyl compounds has been reported to yield isomeric products having different structures such as diazepines 2 or triazepines 3 .Structure of many of these compounds has been reinvestigated in our laboratory [4][5][6][7][8][9] and by Peet et al. 10 and it has been established that all such structures are in error and products are indeed pyrazole derivatives.
As a part of our comprehensive programme to establish the structure of products obtained by the reaction of heterocyclylhydrazines with β-diketones, we came across a report by Shiho and Tagami 11 describing the exclusive formation of 1,4-dimethyl-1,2,4-triazolo [4,3-a]quinoxaline by treating 2-hydrazino-3-methylquinoxaline with phenyl-1,3-butanedione.Such a triazole structure appeared questionable as in the same report these authors have reported the formation of expected pyrazoles while performing the reaction of 2-hydrazinoquinoxalines with a number of assignments find further support by an inspection of 13 C NMR spectral analysis.Analysis of 13 C NMR spectra of the isomeric products 5-and 3-isomer showed that carbon atoms C 3 , C 4 and C 5 in the 5-isomer (4b) resonated at δ 150.0, 102.53, 139.06 whereas in the 3-isomer, these carbon atoms resonated at δ 151.36, 106.57, 145.35, respectively.The intense signal located at 106 or 102 ppm is characteristic of the pyrazole 4-H.Furthermore, C 3 and C 5 of the pyrazole nucleus resonated at 151 (150) and 145 (139) ppm, respectively in agreement with the literature value. 1,13he solid obtained from the last fraction was identified as 1,4-dimethyl-s-triazolo [4,3a]quinoxaline (5) , mp 194-195 °C (lit. 11mp 196 °C).The structure of 5 was confirmed on the basis of mixed mp., co-TLC and 1 H NMR spectrum, which displayed two singlets of three protons intensity at δ 2.9 and δ 3.1 due to two CH 3 groups, one located on quinoxaline ring and other on triazole ring.

Scheme 2
To generalize the formation of these products in this reaction, phenyl-1,3-butanedione (2b) was replaced with substituted aryl and heteroaryldiketones 2c-h (Scheme 1).It was observed that in all these cases, there is formation of isomeric pyrazoles as major products along with smaller amount of the triazole 5. Ratio of the three products (3, 4 and 5) were calculated on the basis of 1 H NMR of the crude mixtures (Table 1).Distinction between the isomeric pairs was made using NMR ( 1 H & 13 C) spectroscopy.It is evident from the data given in Table 1 that 3methylpyrazole is the major isomer in all such cases.Mechanistically, predominance of 3-isomer appears more reasonable than 5-isomer as the carbonyl carbon attached to the methyl group is more reactive towards nucleophilic attack by the N of the hydrazines than the other carbonyl which is adjacent to the aryl ring. 14Careful inspection of the 13 C NMR spectra of 3 and 4 reveals that in each case 3-methyl isomer shows resonance signal for C-5 relatively downfield: ∆ δ 6.29, 5.49, 6.51, 5.32, 5.39, 4.32, for 3b, 4b; 3c, 4c; 3d, 4d; 3e, 4e; 3f, 4f; 3h, 4h, respectively.The comparative deshielding of C-5 in compounds 3 may be attributed to the presence of aryl/heteroaryl group at position-5.The complete assignment of the carbon atoms of compounds 3 and 4 are given in Table 2.
The formation of three products (3, 4 and 5) in these reactions can be explained on the basis of a plausible mechanism involving three intermediates (hydrazones-A & B and ketoimine-C) as outlined in Scheme-3.Intermediate C had been isolated and characterized by Zimmer and Amer 15 by super-cooling the reaction mixture of 1-hydrazinophthalazine with polycarbonyl compounds.
The following conclusions may be drawn as a result of the present study: (a) reaction of 2hydrazino-3-methylquinoxaline (1) with unsymmetrical aryl-and heteroaryldiketones always results in the formation of isomeric pyrazoles as the major products instead of the exclusive formation of a triazole as reported by Shiho and Tagami. 11(b) 3-methylpyrazole is the predominant isomer thus confirming that carbonyl carbon attached to the methyl group is more susceptible to nucleophilic attack than the carbonyl adjacent to aryl ring.(c) 1 H and 13 C NMR spectra are important tools for the characterization of isomeric 2'-pyrazolylquinoxalines... The IR spectra were recorded on a Buck Scientific IR M-500 spectrophotometer in KBr pellets (ν max in cm -1 ), 1 H and 13 C NMR spectra were recorded in CDCl 3 on a Bruker instrument at 300 MHz and 75 MHz, respectively; chemical shifts are expressed as δ values with units of ppm, downfield from TMS (δ 0.0) as an internal standard.Coupling constants (J) are given in Hertz (Hz).Elemental analysis were performed in the RSIC, Lucknow, India.All the compounds gave satisfactory elemental analyses.The reactions were monitored by the TLC carried out on precoated silica gel glass plates.Separations were accomplished by column chromatography using silica gel (100-200 mesh) and light petroleum (60-80 °C)-CHCl 3 as eluent.

Table 1 .
Analysis of crude reaction product based on 1 H NMR(Yield %) Under conditions employed by Shiho and Tagami 11 (heating for 20 min.at 130-160 °C).

Table 2 .
13C NMR data of compounds 3 and 4 General Procedures.Melting points were determined in open capillaries and are uncorrected.