Asymmetric Organocatalyzed Friedel-Crafts Reaction of
Trihaloacetaldehydes and Phenols

k 2021

Asymmetric Organocatalyzed Friedel-Crafts Reaction of Trihaloacetaldehydes and Phenols

ŠVESTKA, David, Jan OTEVŘEL and Pavel BOBÁĽ

Basic information

Original name

Asymmetric Organocatalyzed Friedel-Crafts Reaction of Trihaloacetaldehydes and 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

55th Advances in Organic, Bioorganic and Pharmaceutical Chemistry Liblice 2021, 2021

Other information

Language

English

Type of outcome

Prezentace na konferencích

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

Czech Republic

Confidentiality degree

není předmětem státního či obchodního tajemství

RIV identification code

RIV/00216224:14160/21:00123483

Organization unit

Faculty of Pharmacy

Keywords (in Czech)

enantioselektivní organokatalýza; chinovníkové alkaloidy; trihalogenmethylkarbinoly

Keywords in English

enantioselective organocatalysis; Cinchona alkaloids; trihalomethyl carbinols

Abstract

V originále

The trihalogenmethylalcohol moiety is constituent of many nonracemic biologically active compounds (e.g., efavirenz, acetofenate, muironolide A, sigillin A). Optically pure trihalogenmethyl carbinols could be also important building blocks for the preparation of new chiral molecules. One of the possibilities to obtain these aromatic trihalogenethanols is Friedel-Crafts reaction of phenol and trihalogenacetaldehyde. We started with three phase-screening of 40 organocatalysts, that were tested in model reaction of sesamol and chloral. Cinchona alkaloid-based amide derivatives showed the best enantioselectivity. Improvement of the catalyst structure resulted in the discovery of 3,5-dinitrobenzamide of 9-amino-epi-cinchonidine as the most convenient molecule. After that, the series of optimization reactions were performed to establish the most suitable conditions (catalyst load, solvent type, amount of chloral, temperature, and reaction time). The catalyst was utilized for the asymmetric Friedel-Crafts reaction of electron-rich phenols and trihalogenacetaldehydes or their hemiacetals. The substrate scope included more than 20 derivatives containing –CF3, –CCl3, –CF2Cl or –CF2Br groups. A high enantiomeric ratio (up to 97.5:2.5) of adducts was accomplished at 25 °C in 12–24 h. Several transformations of resulting molecules were provided without loss of enantiomeric excess. Our current work represents the first organocatalyzed method for the enantioselective synthesis of this type.

Links

MUNI/A/1510/2020, interní kód MU

Name: Vývoj asymetrické organokatalytické syntézy trihalogenmethylkarbinolů

Investor: Masaryk University

Citovat

ŠVESTKA, David, Jan OTEVŘEL and Pavel BOBÁĽ. Asymmetric Organocatalyzed Friedel-Crafts Reaction of Trihaloacetaldehydes and Phenols. In 55th Advances in Organic, Bioorganic and Pharmaceutical Chemistry Liblice 2021. 2021.

@proceedings{1816422,
   author = {Švestka, David and Otevřel, Jan and Bobáľ, Pavel},
   booktitle = {55th Advances in Organic, Bioorganic and Pharmaceutical Chemistry Liblice 2021},
   keywords = {enantioselective organocatalysis; Cinchona alkaloids; trihalomethyl carbinols},
   language = {eng},
   title = {Asymmetric Organocatalyzed Friedel-Crafts Reaction of Trihaloacetaldehydes and Phenols},
   year = {2021}
}

TY  - CONF
ID  - 1816422
AU  - Švestka, David - Otevřel, Jan - Bobáľ, Pavel
PY  - 2021
TI  - Asymmetric Organocatalyzed Friedel-Crafts Reaction of Trihaloacetaldehydes and Phenols
KW  - enantioselective organocatalysis
KW  - Cinchona alkaloids
KW  - trihalomethyl carbinols
N2  - The trihalogenmethylalcohol moiety is constituent of many nonracemic biologically active compounds (e.g., efavirenz, acetofenate, muironolide A, sigillin A). Optically pure trihalogenmethyl carbinols could be also important building blocks for the preparation of new chiral molecules. One of the possibilities to obtain these aromatic trihalogenethanols is Friedel-Crafts reaction of phenol and trihalogenacetaldehyde. We started with three phase-screening of 40 organocatalysts, that were tested in model reaction of sesamol and chloral. Cinchona alkaloid-based amide derivatives showed the best enantioselectivity. Improvement of the catalyst structure resulted in the discovery of 3,5-dinitrobenzamide of 9-amino-epi-cinchonidine as the most convenient molecule. After that, the series of optimization reactions were performed to establish the most suitable conditions (catalyst load, solvent type, amount of chloral, temperature, and reaction time). The catalyst was utilized for the asymmetric Friedel-Crafts reaction of electron-rich phenols and trihalogenacetaldehydes or their hemiacetals. The substrate scope included more than 20 derivatives containing –CF3, –CCl3, –CF2Cl or –CF2Br groups. A high enantiomeric ratio (up to 97.5:2.5) of adducts was accomplished at 25 °C in 12–24 h. Several transformations of resulting molecules were provided without loss of enantiomeric excess. Our current work represents the first organocatalyzed method for the enantioselective synthesis of this type.
ER  -

ŠVESTKA, David, Jan OTEVŘEL and Pavel BOBÁĽ. Asymmetric Organocatalyzed Friedel-Crafts Reaction of Trihaloacetaldehydes and Phenols. In \textit{55th Advances in Organic, Bioorganic and Pharmaceutical Chemistry Liblice 2021}. 2021.

Detailed Information on Publication Record