Approaches to primary tert-alkyl amines as building blocks

Abstract Primary tert -alkyl amines represent analogues of amantadine, a fragment commonly linked to pharmacophoric groups to enhance biological activity. The preparation of primary tert -alkyl amines is considered to be a difficult problem. Four synthetic procedures, which have been previously reported for the synthesis of amines with primary (RCH 2 NH 2 ) or secondary (RR'CHNH 2 ) alkyl and/or aryl groups, were tested for the synthesis of primary tert -alkyl amines (RR′R″CNH 2 ) in aliphatic series including adamantane adducts. These procedures included the formation and reduction of tert -alkyl azides, the Ritter reaction in standard and modified conditions, the addition of organometallic reagents to N - tert -butyl sulfinyl ketimines and one-pot reactions between nitriles and organometallic reagents in the presence of a Lewis acid, Τi(iPrO) 4 or CeCl 3. These synthetic routes are unexplored for primary tert -alkyl amines and their unexpected results should be included in organic chemistry literature. The reaction conditions and substrate limitations were studied for each procedure, with the first procedure being the more general and applicable also for compounds bearing bulky adducts.