Biomimetic One-Pot Route to Acridine Epoxides

Abstract

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.

A Green and Versatile Route to Highly Functionalized Benzofuran Derivatives Using Biomimetic Oxygenation

“…Iron and manganese metaloporphyrins are known to be important models of CYP monooxygenases ,,,. These complexes are efficient catalysts for aromatic epoxidation reactions and studies of their reactions have led to important insights into the bioactivation of aromatics ,,. Notably, metaloporphyrin catalysis avoids the typical drawbacks of bio‐catalysis and allows the development of protocols for carrying out economically relevant reactions under eco‐sustainable conditions ,,.…”

Iron(III) Fluorinated Porphyrins: Greener Chemistry from Synthesis to Oxidative Catalysis Reactions

“…Using 0.3 mol % of catalyst, indene (1) is oxidized to indene oxide (2) with full conversion and 94% selectivity in a reaction time of 2 h (Figure S3). Epoxidation at the 1,2-position, preferential to the hydroxylation reaction, can be related to the alkene character present at this position [14,15]. The other products all show higher retention times than indene oxide, with their amounts increasing for higher reaction temperatures.…”

“…In the last few decades, studies of catalytic oxidations using metaloporphyrins as P450 models have led to new oxidation routes and new compounds that would otherwise be difficult to obtain, such as multi-epoxides of polycyclic aromatic hydrocarbons [14,15]. Furthermore, metaloporphyrin catalysis afforded novel synthetic methods for important chemicals with improved eco-compatibility [16,17], using green oxidants such as hydrogen peroxide [18,19] and mild conditions [20].…”

Biomimetic Oxidation of Benzofurans with Hydrogen Peroxide Catalyzed by Mn(III) Porphyrins

“…The 2,3-benzofuran is known to be toxic and is associated with mutagenesis and carcinogenesis. As for other polycyclic aromatic compounds, its toxicity is attributed to the formation of the reactive arene oxide in vivo during its metabolism [19], which then readily reacts with biomolecules, including DNA. On the other hand, a broad spectrum of clinically approved pharmaceuticals contain the benzofuran nucleus decorated with different functionalities [20,21].…”

“…The significantly different reactivity observed for iron and manganese porphyrins has been ascribed to the formation of different catalytic intermediates [10,29]. Some Mn(III) porphyrins have been used with success as models of CYPs in the oxidation of aromatic compounds, leading mainly to arene oxide products [19,30]. These systems required the presence of a co-catalyst for the activation of H 2 O 2 [31] and their action has been ascribed to the typical reactivity of a metalloporphyrin oxo-species [Mn(V)=O] intermediate [29].…”