High‐Pressure Accelerated Enantioselective Addition of Indoles to Trifluoromethyl Ketones with a Low Loading of Chiral BINOL‐Derived Phosphoric Acid

Abstract

The effect of pressure (up to 10 kbar) on the Brønsted acid catalyzed enantioselective hydroxyalkylation of indoles with trifluoromethyl ketones was explored. The reaction was effectively accelerated at 9kbar with av ery low loading of a1 ,1'-bi-2naphthol (BINOL) -derived phosphoric acid (0.05-0.2 mol %o f TRIP) and provided the products with high enantioselectivity (84-98 % ee).Over the last decade, Brønsted acid catalysish as become av ery powerful strategy for the synthesis of enantiomerically enriched molecules. [1] In particular, chiral 3,3'-diaryl-BINOL-derived phosphoric acids (BINOL = 1,1'-bi-2naphthol), successfully introduced by Akiyama [2] and Te rada, [3] are some of the mostu seful and versatile catalysts of this type, as they enable numeroust ypes of asymmetric transformations. [4] However,t heir use in practical applications is limiteda saresult of the need for relatively high loadings (typically ! 5mol %) and the high molecular masses of the catalysts (typically ! 700 gmol À1 ), as well as their availability and cost. [4] Therefore, the development of methods allowing the use of expensive catalysts in very low amountsiso fh igh importance. [5] The aim of our study was to investigate the influence of hydrostatic pressure [6,7] on selected enantioselectiver eactions catalyzed by Brønsted acids, especially 3,3'-diaryl-BINOL-derived phosphoric acids. In recent years, we demonstratedasignificant effect of pressure (8-10 kbar;1kbar = 100 MPa) on difficult organocatalytic 1,4-conjugate addition reactions to congested b,b-disubstituted enones in the presence of chiral amines as catalysts to form products containing quaternary stereogenic centers in good yields with excellent enantioselectivities (up to 99 % ee). [8,9] Also, we found that high pressure remarkably accelerated the reactionb etween indoles andt rifluoroacetophenones in the presence of chiral bases (e.g.,2mol %c inchonidine) with up to 89 % ee. [10] Here, we focusedo ur attention on the enantioselective hydroxyalkylation of indoles [11] with trifluoromethyl ketones [12] in Supporting Information for this article can be foundu nder: https://doi.

Green Asymmetric Organocatalysis

“…Only 0.1 mol % of chiral phosphoric acid C110 successfully catalyzed the same reaction under high pressure (Scheme ) . Products 194 were afforded after 20 h in 93 % yields with up to 98 % ee .…”

Asymmetric Arylation of 2,2,2-Trifluoroacetophenones Catalyzed by Chiral Electrostatically-Enhanced Phosphoric Acids

“…In general, these reactions proceed in good yields and high enantioselectivities with suitable catalysts. For the specific case of Friedel–Crafts alkylations of indole derivatives with 2,2,2-trifluoromethyl aryl ketones, inorganic bases, cinchona alkaloids, guanidine, trifluoromethanesulfonic acid, and phosphoric acids were reported to be successful catalysts. Most of these studies, however, focused on either racemic products or bis-coupled adducts.…”

“…Most of these studies, however, focused on either racemic products or bis-coupled adducts. There are only a few reports on asymmetric alkylations, and these required either long reaction times (i.e., up to 96 h) or harsh reaction conditions (i.e., up to 9 kbar pressure) presumably because it is a challenge to trigger the alkylation and terminate it at the monoarylated stage. , More effective enantioselective catalysts, consequently, are still needed for this transformation.…”

Hyperbaric reactions in organic synthesis. Progress from 2006 to 2021

“…Primary or tertiary anilines (such as PhNMe 2 ) are outside the scope of the reaction. 130 When trying to develop the asymmetric synthesis of trifluoromethylated alcohols 227 bearing 3-indolyl and aryl substituents, Kwiatkowski and co-authors studied the enantioselective hydroxyalkylation of indoles 225 with aryl(trifluoromethyl) ketones 226, 131,132 and found that these reactions did not occur under catalyst-free conditions at atmospheric pressure. The conversion of the initial reagents under high pressure without a catalyst reached only 5-6%, but the application of 2-3 mol% of different chiral amines containing hydrogen-bonding donors (such as Cinchona alkaloid derivatives thiourea or squaramides) under hyperbaric conditions accelerated the reaction rate considerably (Scheme 74).…”