Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides

Abstract

Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantioselective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatility of bifunctional organocatalysts for the enantioselective construction of axially chiral compounds. Moderate to good enantioselectivities were afforded with a range of benzamide substrates. Mechanistic investigations were also carried out.

Keywords: axial chirality; benzamide; bifunctional organocatalyst; molecular conformation; multipoint recognition.

Figure 1

Brominating reagents.

Scheme 1

Optimization of the substituents of the amide group. Reactions were run using 1 (0.1 mmol), 3a (0.01 mmol), and 4a (0.3 mmol) in EtOAc (10 mL). Yields represent material isolated after silica gel column chromatography.

Scheme 2

Substrate scope. Reactions were run using 1 (0.1 mmol), 3a (0.01 mmol), and 4a (0.3 mmol) in EtOAc (10 mL). Yields represent material isolated after silica gel column chromatography.

Scheme 3

Reactions of substrates with substituted phenols.

Scheme 4

Reactions of monobrominated substrates.

Scheme 5

Rotational barriers of substrates and intermediates calculated at the B3YLP/6-31G(d) level of theory.

Scheme 6

Reaction of substrate with protected phenol.