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

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• 作者：Bassim H. Abdulwahaab ; Benjamin P. Burke ; Juozas Domarkas ; Jon D. Silversides ; Timothy J. Prior ; Stephen J. Archibald
• 刊名：Journal of Organic Chemistry
• 出版年：2016
• 出版时间：February 5, 2016
• 年：2016
• 卷：81
• 期：3
• 页码：890-898
• 全文大小：478K
• ISSN：1520-6904

文摘

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.