A metal-free, biomimetic catalytic
protocol for the cyclization
of N-(2-hydroxyethyl)amides to the corresponding
2-oxazolines (4,5-dihydrooxazoles), promoted by the 1,3,5,2,4,6-triazatriphosphorine
(TAP)-derived organocatalyst tris(o-phenylenedioxy)cyclotriphosphazene
(TAP-1) has been developed. This approach requires less
precatalyst compared to the reported relevant systems, with respect
to the phosphorus atom (the maximum turnover number (TON) ∼
30), and exhibits a broader substrate scope and higher functional-group
tolerance, providing the functionalized 2-oxazolines with retention
of the configuration at the C(4) stereogenic center of the 2-oxazolines.
Widely accessible β-amino alcohols can be used in this approach,
and the cyclization of N-(2-hydroxyethyl)amides provides
the desired 2-oxazolines in up to 99% yield. The mechanism of the
reaction was studied by monitoring the reaction using spectral and
analytical methods, whereby an 18
O-labeling
experiment furnished valuable insights. The initial step involves
a stoichiometric reaction between the substrate and TAP-1, which leads to the in situ generation of the catalyst, a catechol
cyclic phosphate, as well as to a pyrocatechol phosphate and two possible
active intermediates. The dehydrative cyclization was also successfully
conducted on the gram scale.