Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 87, Issue 1, Pages 243-257Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.1c02318
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Funding
- JSPS [19H02713]
- MEXT [18H04247]
- National Institutes of Natural Sciences (NINS) [01112104]
- Grants-in-Aid for Scientific Research [19H02713, 18H04247] Funding Source: KAKEN
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A metal-free, biomimetic catalytic protocol has been developed for the cyclization of N-(2-hydroxyethyl)amides to 2-oxazolines, achieving high substrate scope and functional-group tolerance with high product yields.
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) similar to 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 beta-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 O-18-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.
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