Enantioselective organocatalyzed trihaloalkylation of activated phenols

ŠVESTKA, David, Jan OTEVŘEL and Pavel BOBÁĽ. Enantioselective organocatalyzed trihaloalkylation of activated phenols. In 22nd Tetrahedron Symposium: Catalysis for a Sustainable World. 2022.

Basic information

• Original name: Enantioselective organocatalyzed trihaloalkylation of activated phenols
• Authors: ŠVESTKA, David (203 Czech Republic, belonging to the institution), Jan OTEVŘEL (203 Czech Republic, belonging to the institution) and Pavel BOBÁĽ (703 Slovakia, belonging to the institution).
• Edition: 22nd Tetrahedron Symposium: Catalysis for a Sustainable World, 2022.

Other information

• Original language: English
• Type of outcome: Presentations at conferences
• Field of Study: 10401 Organic chemistry
• Country of publisher: Czech Republic
• Confidentiality degree: is not subject to a state or trade secret
• RIV identification code: RIV/00216224:14160/22:00126276
• Organization unit: Faculty of Pharmacy
• Keywords in English: Friedel-Crafts; Cinchona; phenol; trihaloacetaldehyde

Abstract

Trihaloacetaldehydes represent useful electrophiles in many asymmetric processes that can grant access to a large number of biologically active compounds containing CX3 groups. One of the possibilities to obtain aromatic trihaloethanols is the asymmetric organocatalyzed Friedel-Crafts reaction between phenol and trihaloacetaldehyde, which represented the subject of our current research. As such, we started with the extensive three-phase catalyst screening. Sesamol and chloral were used as substrates in the model reaction. Cinchona alkaloid-based amide derivatives showed the best enantioselectivity in the initial stage of catalyst testing. Improvement of the catalyst structure revealed 3,5-dinitrobenzamide of 9-aminoepicinchonidine as the lead catalytic molecule. Next, a series of optimizations were performed to establish the most suitable reaction conditions (catalyst load, solvent type, amount of chloral, temperature, and reaction time). Having the optimal parameters in hand, the reaction between electron-rich phenols and trihaloacetaldehydes or their hemiacetals conveniently provided enantioenriched adducts with good to excellent enantiomeric ratios (up to 99:1) within 12–24 h at 25 °C. The substrate scope included 27 derivatives containing –CF3, –CCl3, –CF2Cl, and –CF2Br groups, which suggests a reasonable generality of the developed process. Additionally, several stereoretentive downstream transformations of products were identified. This work constitutes the first organocatalyzed method for the synthesis of chiral non-racemic 2,2,2-trihalo-1-hydroxyalkylphenols.

Links

• MUNI/IGA/0916/2021, interní kód MU: Name: Asymmetric organocatalyzed hydroxymethylation of isoindolinones

Investor: Masaryk University