Syntheses of [1,7-15N2]- and [1,7,NH2-15N3]Adenosine and 2‘-Deoxyadenosine via an N1-Alkoxy-Mediated Dimroth Rearrangement

We have found that the N 1 -methoxy derivatives of adenosine and 2‘-deoxyadenosine undergo a Dimroth rearrangement in which the intermediate N,N -dimethylamino adducts are stable compounds. This mild and high-yield rearrangement allows efficient conversion of [7, NH 2 - 15 N 2 ]-2‘-deoxyadenosine and [7, NH 2 - 15 N 2 ]adenosine into the triply labeled [1,7, NH 2 - 15 N 3 ] derivatives. The [7, NH 2 - 15 N 2 ]nucleoside is first oxidized to the N 1 -oxide with 3-chloroperoxybenzoic acid (MCPBA). Methylation 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 surprisingly stable intermediates is accomplished by refluxing in the presence of a dimethylammonium hydrohalide salt to give the [1,7- 15 N 2 ]-6- N -methoxy nucleosides in high yield. Removal of the N 6 -methoxy function to afford both [1,7- 15 N 2 ]deoxyadenosine and [1,7- 15 N 2 ]adenosine was accomplished readily with Raney nickel. No hydroxyl protection is required for these transformations. Introduction of the third label at the N 6 was accomplished by conversion into the 6-(1,2,4-triazol-4-yl)purine nucleosides, followed by nucleophilic displacement of the 6-triazole with [ 15 N]ammonia to afford the triply labeled title compounds.