Efficient Routes for the Synthesis of 1,4,7,10,13-Pentaazacyclohexadecane-14,16-dione

Abstract

The synthetic access to 1,4,7,10,13-pentaazacyclohexadecane-14,16-dione was significantly improved from an overall yield of 1% to 33%. The procedure involved the use of COCF₃ or DDE as highly selective protecting groups for primary amines and of Boc to protect the secondary amine functions. The reaction of a tris-Boc protected tetraethylenepentamine with malonic acid gave the macrocycle in a 44% yield, the same reaction with malonyl chloride, however, yielded only 3.6% of the desired product. Boc deprotection and removal of the trifluoroacetate salts gave access to the final product, 1,4,7,10,13-pentaazacyclohexadecane-14,16-dione, in an overall yield of 33%.

Key words

azamacrocycles - 1,4,7,10,13-pentaazacyclohexadec­ane-14,16-dione - protecting groups - cyclization - ligands

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1

Current address: The Open University, Milton Keynes, UK.

12

In ref. 6, compound 7 has been described as a solid. However, following the synthetic pathways in ref. 6, we have previously found that it is extremely difficult to completely remove all the hydrochlorides from tetraethylenepentamine. Therefore derivatives of 1,4,7,10,13-pentaazacyclohexadecane-14,16-dione are frequently isolated as their hydrochloride salts and purified. [4b]