Synthesis of imidazo[1,2-a] pyridines by rearrangement of 2-pyridyl-3-arylaminoisoxazol-5-(2 H )-ones

2-Pyridyl-3-arylaminoisoxazol-5(2H)-ones, substituted on N with a nitropyridine group 12a-12e reacted with triethylamine in ethanol under reflux to give imidazo[1,2-a]pyridines 13a-13e and carbon dioxide. An analogous synthesis failed to yield ethyl 3-(2-ethoxycarbonylphenyl) amino-5-oxo-2,5-dihydroisoxazole-4-carboxylate; the reaction of diethyl (2-ethoxycarbonylphenyl)thiocarbamoylmalonate with hydroxylamine gave the novel isoxazolo[3,2-b]quinazoline 14 by intramolecular acylation of the isoxazolone intermediate 14a .


Introduction
The reaction of 3-substituted isoxazolones with bases is not well known, and the only examples appear to be those reported by Doleschall 1 , who alkylated the anion of ethyl 2,3-dimethyl-2,5dihydro-5-oxo-isoxazole-4-carboxylate 1 in order to obtain γ-alkylated acetoacetates.
We have recently reported 2 that the reaction of 2-aryl-3-arylaminoisoxazolones 2 with triethylamine leads to the formation of indoles 3 and carbon dioxide, an outcome that is formally the same as that achieved by photolysis. 3The evidence for the indole structure, rather than that of an isomer, rested on the number of aryl proton signals visible in the 1 H-NMR spectrum.
We have recently reported 2 that the reaction of 2-aryl-3-phenylaminoisoxazolones 2 substituted on nitrogen with an isoquinoline or quinazoline group, react with triethylamine to give imidazo annelated compounds 4 and 5, respectively.When the N-substituent is a nitropyridine the 2-aminoindole structure 6 was assigned to the product.We have also reported 4 that arylaminoisoxazol-5(2H)-one 7, substituted on nitrogen with a benzothiazole group 8, reacts with triethylamine in ethanol under reflux conditions to provide a convenient synthesis of ethyl 2-arylaminoimidazo[2,1-b]benzothiazole-3-carboxylates 9. Prager and co-workers have reported 5 that 2-aryl-3-aminoisoxazol-5(2H)-ones undergo solvolysis to form 1,3-dipoles that undergo intermolecular cyclisation to form either imidazopyridines or indoles in the presence of potassium carbonate.The mode of cyclisation is controlled by the electronegativity of the aryl substituent.

Results and Discussion
The required isoxazolones 12a-12e were synthesised by N-arylation of the 2H-isoxazolones 11a-11e which in turn were made by a modification of the procedure of Worrall. 6,7Thus, the reaction of the sodium salt of diethyl malonate in ethanol with aryl isothiocyanates gave the thiocarbamates 10a-10e in good yield, and these were converted to the corresponding isoxazolones 11a-11e by reaction with hydroxylamine (Scheme 1).

Scheme 1
N-Arylation of 11a-11e with 2-chloro-5-nitropyridine then gave the desired starting materials 12a-12e (Scheme I).While the formations of 12a-12e appear trivial, the reaction generally proceeded best in the absence of solvent, by heating the required reagent under nitrogen at 130 ˚C for an hour.

Scheme 2
Compound 12c reacted more slowly, but gave the corresponding imidazopyridine in 72% yield.It has been reported 5 that the rearrangement of 12c in the presence of potassium carbonate in ethanol, returned mainly starting materials.
With a number of imidazopyridine structures in hand, the structures of all imidazopyridines were confirmed by 1 HNMR, 13 CNMR, FT-IR, MASS spectra and microanalyses.
All compounds 13a-13e showed H-7 to have meta coupling with H-5, but the resonance for H-5 could not be clearly observed in compounds 13a-13e.The reason for the extreme broadening of this peak is unknown, though quadrupole coupling with N-4 is implicated.It has been reported previously 8 that the X-ray structure of (13, Ar = Ph ) did not show any unusual interactions.The reaction pathway resulting in the imidazopyridines is consistent with our earlier suggestion (Scheme 3).

Scheme 3
Therefore, these base induced rearrangements appear to be generally applicable to the synthesis of imidazopyridines, which are suitable synthetic intermediates for a series of polycyclic heterocycles.

Conclusions
The rearrangement of the 2-pyridyl-3-arylaminoisoxazolones substituted on nitrogen with nitropyridine (12a-12e) in the presence of triethylamine provides imidazo heterocycles (13a-13e) which are suitable synthetic intermediates for a series of new planar polycyclic heterocycles that could be expected to have pharmaceutical applications. 9,10In addition, the formation of the isoxazolo [3,2-b]quinazoline 14 opens up intriguing possibilities of carbenoid derived products of novel structure.

Experimental Section
General Procedures.Freshly distilled solvents were used throughout, and anhydrous solvents were dried according to Perrin and Armarego. 11 1H (400MHz) and 13 C (75MHz) NMR measurements were recorded on a Brucker 400 spectrometer in deuteriochloroform with tetramethylsilane as internal standard, unless otherwise stated.Infrared spectra were recorded on a Thermonicolet (Nexus670) FT-infrared spectrometer, using sodium chloride cells, measured as Nujol mulls or films.Mass spectra were recorded on a Varian Matt 311 spectrometer and relative abundance of fragments is quoted in parentheses after the m/z values.Melting points were determined on a Philip Harris C4954718 apparatus and are uncorrected.Microanalyses were performed on a Carlo-Erba Analyzer 1104 at the University of Giessen, Germany.