Mono- and Bis-Alkylation of Glyoxal-Bridged Tetraazamacrocycles Using Mechanochemistry

Glyoxal-bridged
bisaminal tetraazamacrocyclic derivatives of 1,4,7,10-tetraazacyclododecane
(cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) can be N-functionalized
to incorporate coordinating groups or for conjugation to biomolecules.
Herein, we present an improved N-functionalization methodology using
mechanochemistry which reduces reaction times in comparison with conventional
synthetic routes. A range of six alkyl halides were reacted with cyclen
and cyclam bisaminal derivatives in various ratios to form mono- and
bis-functionalized quaternary ammonium salts. Cross-bridged cyclam,
a key intermediate for CB-TE2A, a commonly used chelator in positron
emission tomography medical imaging with 64Cu, has been
synthesized using nonconventional synthetic methodologies (grinding
and microwave heating) with intermediates characterized by 2D NMR
and single crystal XRD. The overall synthesis time of CB-TE2A from
cyclam could be shortened to 5 days from the 35 days required for
the conventional synthesis.