Synthesis of Tris[2‐(dimethylamino)ethyl]amine with Regiospecific Deuterium Labels

Simple synthetic routes to regioselectively deuterated tris[2-(dimethylamino)ethyl]amine (Me6TREN) variants are described. Imine formation with formaldehyde-d2 from tris(2-aminoethyl)amine (TREN) and subsequent reductions with NaBD4 afforded N[CH2CH2N(CD3)2]3 or d18-Me6TREN in 79 % yield. A trisubstitution protocol from 2-bromo-N,N-dimethylacetamide and ammonium carbonate and subsequent reduction of the N(CH2CONMe2)3 intermediate by lithium aluminum deuteride has afforded N[CH2CD2N(CH3)2]3 or (d6-arm)-Me6TREN in three steps and 52 % overall yield. A similar protocol from 2-bromo-N,N-dimethyl-d2-acetamide, obtained in two steps from d4-acetic acid, with reduction of the N(CD2CONMe2)3 intermediate by lithium aluminum hydride has afforded N[CD2CH2N(CH3)2]3 or (d6-cap)-Me6TREN in four steps and 13 % overall yield from CD3COOD.