An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to Adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high
conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.