A Facile Synthesis of 2-Oxazolines via Dehydrative Cyclization Promoted by Triflic Acid

Abstract

2-oxazolines are common moieties in numerous natural products, pharmaceuticals, and functional copolymers. Current methods for synthesizing 2-oxazolines mainly rely on stoichiometric dehydration agents or catalytic dehydration promoted by specific catalysts. These conditions either generate stoichiometric amounts of waste or require forcing azeotropic reflux conditions. As such, a practical and robust method that promotes dehydrative cyclization while generating no byproducts would be attractive to oxazoline production. Herein, we report a triflic acid (TfOH)-promoted dehydrative cyclization of N-(2-hydroxyethyl)amides for synthesizing 2-oxazolines. This reaction tolerates various functional groups and generates water as the only byproduct. This method affords oxazoline with inversion of α-hydroxyl stereochemistry, suggesting that alcohol is activated as a leaving group under these conditions. Furthermore, the one-pot synthesis protocol of 2-oxazolines directly from carboxylic acids and amino alcohols is also provided.

Solvent Effect on Base-Free Synthesis 4-Substituted 2-Oxazolines via Intramolecular Cyclodemesylation

“…29 The most common cyclization reagents include N,N-dialkylaminosulfur trifluorides 24,30 (Deoxo-Fluor and DAST), PPh 3 /DIPEA/CCl 4 , 31 DIC-Cu(OTf) 2 , 32 and Burgess reagent. 33,34 Recently, phosphorus-based organocatalysis (TAP-1), 35 I 2 /TBHP/K 2 CO 3 , 36 PhI(OAc) 2 /BF 3 •Et 2 O, 37,38 and a triflic acid (TfOH) 39 promoted oxidative cyclizations for 2oxazoline synthesis with high efficiency were also reported.…”

Total Synthesis of Cyanobactin Natural Product Balgacyclamide B

“…[13] Finally, in 2005, Ishihara and co-workers reported a new methodology where retention of configuration at the threonine β-carbon to form the oxazoline was accessed after exposing the β-hydroxy amides under harsh conditions using molybdenum oxides as a catalyst in toluene. [14] These previous methodologies have been used to access multiple NPs, for example, fimsbactin A and B, [15] mycobactin J, [16] (R)-D-ornithine derivative BE-70016, [17] pseudobactin, [18] lissoclinamide, [19] leupyrrin B1, [20] madurastatin C1, [21] bistratamide D, [5] among others.…”

Direct Regioselective Reductive Allylation of Imines: Application to Synthesis of Oxazines with Halogenated Reagent

“…Heterocyclic nitrogen ligands play a crucial role in the advance of transition metal catalysis . Compared to the well-developed oxazoline ligands, oxazine ligands with a six member ring have been found to exhibit specific catalytic activities in the transition metal catalysis . In addition, oxazines are prevalent scaffolds in pharmaceuticals and biologically active molecules, such as 1,3-disubstituted-1 H -naphtho­[1,2- e ]­[1,3]­oxazines (Antimicrobal activity) and Etifoxine (anxiolytic and anticonvulsant drug) (Figure A) .…”