Synthesis of 4-propionyl-3-( 4-substitutedphenylamino )-2-( 5-Nitropyridin-2-yl ) isoxazol-5 ( 2 H )-ones and their Rearrangements to Imidazo [ 1 , 2-a ] pyridines and Indoles with Triethylamine (

4-propionyl-3-(4-Substitutedphenylamino)isoxazol-5(2H)-ones, substituted on nitrogen with a 2-chloro-5-nitropyridine group, react with triethylamine (TEA) 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[1,2a]pyridine and 2-pyridylaminoindole, respectively.

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 .

RESULTS AND DISCUSSION
The 2-unsubstituted isoxazolones 10a-c were prepared by the general method of Worral 5 .Thus, the reaction of the sodium salt of ethyl-3oxopentanoate in ethanol with various aryl isothiocyanates gave the thiocarbamates 8a-c in high yield (Scheme 3).
The appearance of two different quartets for the ethoxy groups and two different carbonyl groups in the 1 H-NMR (500 MHz) and FT-IR spectra of carbamates 8a-c is due to their non equivalency arising 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 6 and acidity 7 .The reaction of these carbamates 8a-c with three equivalent of hydroxylamine gave the corresponding isoxazolones 10a-c in good yield (Scheme 4).

Scheme 3: Scheme 4:
Refluxing the isoxazolone 10b with one equivalent of 2-chloro-5-nitropyridine in butanol for 12 hours gave the butyl ester analogue 12 by acid catalysed transesterification (Scheme 5); reaction in the absence of solvent gave the ethyl esters 11.

Scheme 5:
N-Substituted isoxazolones 11a and 11b reacted with triethylamine in refluxing ethanol to give the corresponding imidazo[1,2-a]pyridines 13a and 13b as the only products in 84% and 75% yield respectively, but the isoxazolone 11c gave the corresponding imidazo compound 13c 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 14.The imidazopyridine structures of 13a-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 11a-c, and the indole structure 14 had proton coupling similar to those of the nitropyridyl ring in 11c.The 1 H-NMR spectrum of compound 13a showed a doublet of doublets at d 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 d 9.87 ppm due to H-5.However, the 1 H-NMR spectra of compounds 13b, 13c 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 12 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 7.

Scheme 6:
While it is possible that the steric effect of the substituent at C-4 of the phenylamino group in the zwitterionic intermediate in Scheme 7 could affect the mode of cyclisation, the differences are more likely to have an electronic origin.We have found that the 4-methoxy derivative 11c reacts rapidly in refluxing ethanol (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 triethylamino 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 7 is no longer tenable.An alternative, which is consistent with the electronic requirements of the reaction, is shown in Scheme 6.

Scheme 7:
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 8,9 .

General
Freshly distilled solvents were used throughout, and anhydrous solvents were dried according to Perrin and Amarego. 10
1  H-NMR and13  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.