SYNTHESES OF [1,7-N-15(2)]- AND [1,7,NH2-N-15(3)]ADENOSINE AND 2'-DEOXYADENOSINE VIA AN N-1-ALKOXY-MEDIATED DIMROTH REARRANGEMENT

We have found that the N-1-methoxy derivatives of adenosine and 2'-deo xyadenosine undergo a Dimroth rearrangement in which the intermediate N,N-dimethylamino adducts are stable compounds. This mild and high-yie ld rearrangement allows efficient conversion of [7,NH2-N-15(2)]2'-deox yadenosine and [7,NH2-N-15(2)]adenosine into the triply labeled [1,7,N H2-N-15(3)] derivatives. The [7,NH2-N-15(2)]nucleoside is first oxidiz ed to the N-1-oxide with 3-chloroperoxybenzoic acid (MCPBA). Methylati on of the N-1-oxide with methyl iodide or dimethyl sulfate is followed by treatment with dimethylamine to afford the 6-amino-N-1-methoxy-2-( N,N-dimethylamino) derivative. Dimroth rearrangement of these surprisi ngly stable intermediates is accomplished by refluxing in the presence of a dimethylammonium hydrohalide salt to give the [1,7-N-15(2)]-6-N- methoxy nucleosides in high yield. Removal of the N-6-methoxy function to afford both [1,7-N-15(2)]deoxyadenosine and [1,7-N-15(2)]adenosine was accomplished readily with Raney nickel. No hydroxyl protection is required for these transformations. Introduction of the third label a t the N-6 was accomplished by conversion into the 6-(1,2,4-triazol-4-y l)purine nucleosides, followed by nucleophilic displacement of the 6-t riazole with [N-15]ammonia to afford the triply labeled title compound s.