1,3-Dipolar cycloaddition approach to the construction of new bis-heterocycles from thymine as potential non-nucleoside reverse transcriptase inhibitors

In the search for new anti-HIV agents, a synthetic route to novel acyclic (flexible) and tricyclic bis-heterocycles has been explored involving in the key steps the [3 + 2] cycloaddition reaction of the N-3 thymine-substituted enamines 34, 36 and 39 with the nitrile oxide 11, and the ring closure of the isoxazole amide derivatives 49 and 51 to the diazepine 10a, and the diazocine 10b. A number of competing reactions were also encountered during the construction of compounds 10. These include a fragmentation process wherein the 1-azadienes 38 and 46 are formed, and base-promoted rearrangement of the isoxazole ring in intermediates 50 and 59 to give the bicyclic thymine derivative 53 and the tricyclic succinimide derivative 60, respectively. Radical cyclisation of the guanidine amide 52 to isoxazole 57 on reaction with isoamyl nitrite in warm DMF was also observed.