Preparation of fluoroadamantane acids and amines: Impact of bridgehead fluorine substitution on the solution- and solid-state properties of functionalized adamantanes

Functionalized adamantanes are utilized as medicinal therapeutics and a pra ctical route to novel bridgehead fluorinated adamantylamines and acids incl uding fully fluorinated 3,5,7-tri-fluoroadamantane-1-carboxylic acid 1 and 3,5,7-trifluoroadamantane-1-amine 2 is described. Potassium permanganate-me diated bridgehead hydroxylation followed by DAST fluorination was utilized to sequentially insert bridgehead fluorine atoms. C-13 NMR chemical shifts of mono-, di-, and trifluoroadamantylamines, acids and carbamates reveal lo ng-range fluorine-mediated electronic effects within the adamantane framewo rk, most notably by substrates bearing three bridgehead fluorine atoms. The impact of multiple bridgehead fluorine substitution on structure (X-ray cr ystallography) and on physicochemical parameters such as acidity (pK(a)) an d lipophilicity (log P) which are important for the design of medicinal the rapeutics is assessed.