Biomimetic One-Pot Route to Acridine Epoxides

• Published in: Journal of organic chemistry 2015-01, Vol.80 (1), p.281-289
• Main Authors: Linhares, Margarida, Rebelo, Susana L. H, Biernacki, Krzysztof, Magalhães, Alexandre L, Freire, Cristina
• Format: Article
• Language: English
• Subjects: Acridines - chemistry; Biomimetic Materials - chemistry; Catalysis; Epoxy Compounds - chemical synthesis; Epoxy Compounds - chemistry; Manganese - chemistry; Metalloporphyrins - chemistry; Molecular Structure; Quantum Theory
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo5023525

The first direct epoxidation of acridine on the edge positions is reported. The reaction proceeds under mild conditions using a biomimetic catalytic system based on a Mn(III) porphyrin. The successive oxyfunctionalization to mono-, di-, and tetraepoxy derivatives is accomplished using hydrogen peroxide as a green oxidant at room temperature. Computed optimized geometries showed only slight shifts to the base planarity upon dearomatization by epoxidation, which is an important feature for DNA intercalation and bioactivity. NMR studies and comparison with theoretical values allowed the assignment of the stereochemistry of the anti- and syn-diepoxy and -tetraepoxy derivatives as well as compounds resulting from epoxide ring opening, exemplified by epoxydiol. The diepoxide is formed in an anti:syn ratio of ∼4, and the attack by nucleophiles, exemplified by ethylaniline, occurs selectively and with full conversion, using a microwave process with acetonitrile reflux for 10 min. Finally, studies of the electrostatic potential allowed the mechanisms of the formation of 4-hydroxyacridine and the regioselective reaction of diepoxyacridine with nucleophiles to be rationalized.