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Unexpected Intramolecular Phosphite‐Mediated Amide Coupling To Yield 3,5‐Dioxo‐1‐Piperazines
Author(s) -
Heim Philipp,
Twamley Brendan,
O'Brien John,
McDonald Aidan R.
Publication year - 2021
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202102576
Subject(s) - piperazine , acetamide , chemistry , amide , intramolecular force , nitrilotriacetic acid , carboxamide , medicinal chemistry , coupling reaction , ligand (biochemistry) , yield (engineering) , aniline , stereochemistry , organic chemistry , chelation , materials science , catalysis , biochemistry , receptor , metallurgy
The synthesis of tripodal carboxamide ligands using one‐pot phosphite coupling reactions with nitrilotriacetic acid (NTA) and 4‐substituted anilines is well established. Generation of such tripodal ligands using ortho ‐substituted anilines ( 2,6−R ArNH 2 , R=F, Me, i Pr) has proven to be challenging. The reaction between NTA and 2,6−R ArNH 2 using triphenylphosphite as a coupling reagent did not yield the desired tripodal carboxamide. Rather, the formation of 3,5‐dioxo‐1‐piperazine intramolecular coupling products N‐(2,6‐difluorophenyl)‐3,5‐dioxo‐1‐piperazine‐N‐(2,6‐difluorophenyl)acetamide ( 1 ), N‐(2,6‐dimethyphenyl)‐3,5‐dioxo‐1‐piperazine‐N‐(2,6‐dimethylphenyl)acetamide ( 2 ) and N‐(2,6‐diisopropylphenyl)‐3,5‐dioxo‐1‐piperazine‐N‐(2,6‐diisopropylphenyl)acetamide ( 3 ) was observed. All three compounds have been extensively characterized using nuclear magnetic resonance, Fourier‐transform infra‐red and mass spectrometry. X‐ray diffraction analysis yielded solid state structures of 2 and 3 . Substituents at the ortho position of aniline thus favours intramolecular cyclization over the formation of tripodal carboxamide ligands, preventing preparation of the desired bulky ligand.