The synthesis of potential DNA intercalaters. 1. Heterocycles from the reaction of aryl bis-isothiocyanates

1,3-Bis(isoxazol-3-ylamino)benzenes, substituted on isoxazole-nitrogen with a pyrimidine group, react with triethylamine in ethanol under reflux to afford the


Introduction
Prager and co-workers have reported 1 that 2-aryl-3-arylaminoisoxazol-5(2H)-ones undergo solvolysis in the presence of potassium carbonate to form either imidazopyridines or indoles, and have suggested the reaction proceeds via the formation of 1,3-dipoles that undergo intramolecular cyclisation.

Scheme 1
We have recently extended this work by noting 3,4 that the reaction of 3-(4-substitutedphenyl)aminoisoxazol-5(2H)-ones (3) and (4) with triethylamine leads to the formation of indoles (5), or imidazobenzothiazoles (6) respectively, and carbon dioxide, an outcome that is formally the same as that achieved by photolysis or pyrolsis 5

Scheme 2
In this paper we report the synthesis of new 1,3-bis(isoxazol-3-ylamino)benzenes and their isoxazolyl-N-substituted derivatives, and the rearrangement of the latter in the presence of triethylamine in ethanol under reflux to produce the indolylaminoimidazopyrimidine derivatives (Scheme 3).The reaction is formally a hybrid of the two reaction pathways noted previously, and provides suitable synthetic intermediates for a series of new heterocycles that could be expected to have pharmaceutical applications. 6,7=H,Me Scheme 3

Results and Discussion
The isoxazolones 8a,b were prepared by reaction of the corresponding thiocarbamates 7a,b with hydroxylamine by the general method of Worrall 8 (Scheme 3).
N-arylation of 8a,b with two equivalent of 2-chloroprymidine gave the desired N-substituted compounds 9a,b (Scheme 3).While the formation of 9a,b appear trivial, the reaction generally proceeded best in the absence of solvent, by heating the required reagent under nitrogen at 130˚ C for 30 min.
The rearrangement of bis pyrimidylisoxazolones 9a,b proceeded in refluxing ethanol for 3-12h in the presence of triethylamine or potassium carbonate(Scheme 3).
The mechanism of the rearrangement is consistent with the previous suggestions 1,9 for the formation of indoles and imidazopyrimidines from isoxazolones under basic conditions.We were unable to find any evidence for the formation of the bis indole (12), a plausible alternative product from the presumed penultimate intermediate (11) (Scheme 4).Presumably, subtle electron distribution within (11) dictates the direction of the final ring forming reaction.

R=H,Me
Scheme 4

Conclusion
The base catalysed rearrangements of 3-arylaminoisoxazolones substituted on N-2 with a diazine group appears to be generally applicable to the synthesis of indolaminoimidazopyrimidines, a class of molecule that has not been previously prepared and because of their multiple H bonding and acceptor sites, could be expected to intercalate with DNA. 6,7.They would also serve as intermediates for new planar polycyclic heterocycles.