Sulfomethylation of di-, tri-, and Polyazamacrocycles: A New Route to Entry of Mixed-Side-Chain Macrocyclic Chelates

The sulfomethylation of piperazine and the polyazamacrocycles, [9]aneN3, [12]aneN3, [12]aneN4, and [18]aneN6 with formaldehyde bisulfite in aqueous medium at various pH values is described. The number of methanesulfonate groups introduced into these structures was found to be largely determined by pH. At neutral pH, disubstituted products of [9]aneN3, [12]aneN3, [12]aneN4 are formed and, in the latter case, the trans-1, 7-bis(methanesulfonate) isomer was predominant. Similarly, a single, symmetrical trisubstituted product was formed with [ 18] aneN6 at neutral pH. Monomethanesulfonated products of these same polyaza compounds were formed at more acidic pH's. These sulfomethylated products were used as an entry into a series of mono- and diacetate, phosphonate, and phosphinate derivatives of [9]aneN3, [12]aneN3, and [12]aneN4. The sulfonate groups may be converted to acetates without isolation of intermediates by using cyanide to displace the sulfonate(s) followed by acidic hydrolysis. The aminomethanesulfonates may also be oxidatively hydrolyzed by using aqueous triiodide as a prelude to the preparation of aminomethanephosphonates or aminomethanephosphinates.