Synthesis of 2-(5-Nitropyrid-2-yl)-3-(4-substitutedphenyl)amino-isoxazol-5(2H)-ones and Their Rearrangements to Imidazo[1,2-a]- pyridines and Indoles with Triethylamine

3-(4-Substitutedphenyl)aminoisoxazol-5(2H)-ones, substituted on nitrogen with a nitropyridine group, react with triethylamine to give imidazo[1,2-a]pyridines and indoles. With 4-bromophenyl and 4-methylphenyl group substituents only imidazopyridines are formed, but the 4-methoxyphenyl derivative gave a 3:1 mixture of the corresponding imidazo[1,2-a]pyridine and 2-pyridylaminoindole, respectively.


Introduction
We have recently reported [1] that the reaction of 2-aryl-3-phenylaminoisoxazolones 1, substituted on nitrogen with an isoquinoline or quinazoline group, react with triethylamine to give imidazo annelated compounds 2 and 3 respectively (Scheme 1). When the N-substituent is a nitropyridine, the 2-aminoindole structure 4 was assigned to the product. Evidence was presented that the reactions proceed by initial addition of the tertiary amine to C-4. In this paper we detail further research that suggests that both the proposed structure for 4, and the reaction pathway, require modification.

Scheme 1
These results are formally the same as those achieved by photolysis or pyrolysis of the corresponding N-substituted isoxazolones [2]. However, the reaction of 3 -subtituted isoxazolones with bases is not so well known, and the only examples appear to be those reported by Doleschall [3], who alkylated the anion of ethyl 2, 3-dimethyl-2,5-dihydro-5-oxoisoxazole-4-carboxylate ( 5) in order to obtain ?-alkylated acetoacetates.

Results and Discussion
The 2 -unsubstituted isoxazolones 8a-c were prepared by the general method of Worral [4]. Thus, the reaction of the sodium salt of diethyl malonate in ethanol with various aryl isothiocyanates gave the thiocarbamates 6a-c in high yield (Scheme 2). from strong H-bonding (see 7), resulting in H-bonded and free ester groups. Such H-bonding has also been deduced from a study of their infrared spectra [5] and acidity [6]. The reaction of these carbamates 6a-c with three equivalent of hydroxylamine gave the corresponding isoxazolones 8a-c in good yield (Scheme 3).

Scheme
Scheme 3  N-Substituted isoxazolones 9a and 9b reacted with triethylamine in refluxing ethanol to give the corresponding imidazo [1,2-a]pyridines 11a and 11b as the only products in 84% and 75% yield respectively, but the isoxazolone 9c gave the corresponding imidazo compound 11c as a major product (59%) with a significant amount of a second product (20%), whose spectral properties were more consistent with those expected for the indole 12. The imidazopyridine structures of 11a-c could clearly be deduced from the similarity of the coupling pattern for the protons in the 4 -substituted phenyl ring to that in the starting materials 9a-c, and the indole structure 12 had proton coupling similar to those of the nitropyridyl ring in 9c. The 1 H-NMR spectrum of compound 11a showed a doublet of doublets at δ 8.19 ppm with J 1 =9.7Hz and J 2 =1.3Hz due to H-7, which collapsed to a doublet with J=9.7Hz by irradiation of a broad doublet with J=1.3Hz at δ 9.87 ppm due to H-5. However, the 1 H-NMR spectra of compounds 11b, 11c and 13 showed H -7 to have meta coupling with H-5, but in none could the resonance for H-5 be clearly observed. The reason for the extreme broadening of this peak is unknown, though quadrupole coupling with N -4 is suspected. Finally, the rearrangement of the isoxazolone 10 with triethylamine in refluxing ethanol gave the corresponding imidazopyridine 13 in 81% yield. The reaction pathway resulting in the imidazopyridines, consistent with our earlier suggestion [1], is shown in Scheme 5.
While it is possible that the steric effect of the substituent at C-4 of the phenylamino group in the zwitterionic intermediate in Scheme 5 could affect the mode of cyclisation, the differences are more likely to have an electronic origin. We have found that the 4-methoxy derivative 9c reacts rapidly in refluxing e thanol (ca. 15 minutes, compared with 3 h for the corresponding reaction with triethylamine) to form a mixture of imidazopyridine and indole in a 2:1 ratio, respectively. Since the diethylamino group would be unlikely to retain a positive charge under the basic conditions, and thus would be unlikely to act as a leaving group, we feel that Scheme 5 is no longer tenable. An alternative, which is consistent with the electronic requirements of the reaction, is shown in Scheme 6.
These rearrangements, therefore, appear to be generally applicable to the synthesis of imidazo heterocycles and indoles, which are suitable synthetic intermediates for a series of polycyclic heterocycles with possible pharmaceutical applications [7][8].

Acknowledgements
We are grateful to Prof R.H Prager (Flinders University) for discussions leading to the conclusions shown in Scheme 6.

General
Freshly distilled solvents were used throughout, and anhydrous solvents were dried according to Perrin and Amarego [9]. 1 H-NMR and 13 C-NMR spectra were recorded, in deuteriochloroform, unless otherwise stated, at 500 and 125 MHz respectively, with a Bruker DRX-500 Avance spectrometer. Tetramethylsilane was used as an internal standard and all signals due to amino protons were removed by exchange with D 2 O. Infrared spectra were recorded on a Unicam Matsson 1000 Fourier-Transform Spectrometer. Mass spectra were recorded on a Varian Matt 311 spectrometer and relative abundance of fragments are quoted in parentheses after the m/z values. Melting points were determined on a Philip Harris C4954718 apparatus and are uncorrected. Micronalyses were preformed on a Carlo -Erba Analyzer 1104 at the University of Giessen, Germany.
The following thiocarbamates were made by the same procedure.