Stereoselective Oxidative Cyclization of N-Allyl Benzamides to Oxaz(ol)ines

This study presents an enantioselective oxidative cyclization of N-allyl carboxamides via a chiral triazole-substituted iodoarene catalyst. The method allows the synthesis of highly enantioenriched oxazolines and oxazines, with yields of up to 94% and enantioselectivities of up to 98% ee. Quaternary stereocenters can be constructed and, besides N-allyl amides, the corresponding thioamides and imideamides are well tolerated as substrates, giving rise to a plethora of chiral 5-membered N-heterocycles. By applying a multitude of further functionalizations, we finally demonstrate the high value of the observed chiral heterocycles as strategic intermediates for the synthesis of other enantioenriched target structures.

Figure 1. Examples of natural products containing a chiral C5-substituted oxazoline unit.

Scheme 2. General Mechanism for an Iodane-Mediated N-Oxidative Cyclization of NAAs

Racemic compounds:
N-Allylbenzamide derivatives 3 (1.00 mmol, 1.00 equiv.) was dissolved in MeCN (8.10 mL) and 2-iodoanisole (1.00 mmol, 1.00 equiv.) was added, followed by trifluoroacetic acid (1.50 mmol, 1.50 equiv.) and Selectfluor (1.00 mmol, 1.00 equiv.). The mixture was stirred for 18 hours at room temperature. Then aqueous NaOH solution (1.00 M, 3.00 ml) was added, and the mixture was stirred for 10 min. The phases were separated, and the aqueous layer was extracted with DCM (2x15 mL). The solvent was removed under reduced pressure. The product was purified by column chromatography.

Enantiomeric compounds:
N-Allylbenzamide derivatives 3 (0.40 mmol, 1.00 equiv.) was dissolved in MeCN (3.20 mL) and 1i (0.04 mmol, 0.10 equiv.) was added, followed by trifluoroacetic acid (0.60 mmol, 1.50 equiv.) and Selectfluor (0.40 mmol, 1.00 equiv.). The mixture was stirred for 18 hours at room temperature, then aqueous NaOH solution (1.00 M, 3.00 ml) was
added, and the mixture was stirred for 5 minutes, then extracted with CH2Cl2 (5.00 ml x 2). The solvent was removed under reduced pressure. The product was purified by colmn chromatography.

Scheme 4. Derivatization of Oxazoline 5a

https://doi.org/10.1021/acs.orglett.1c01607