Catalytic Asymmetric Hydrogenation of 3-Substituted Benzisoxazoles

Abstract

A variety of 3-substituted benzisoxazoles were reduced with hydrogen using the chiral ruthenium catalyst, {RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl. The ruthenium-catalyzed hydrogenation proceeded in high yield in the presence of an acylating agent, affording -substituted o-hydroxybenzylamines with up to 57% ee. In the catalytic transformation, the N-O bond of the benzisoxazole substrate is reductively cleaved by the ruthenium complex under the hydrogenation conditions. The C-N double bond of the resulting imine is saturated stereoselectively through the PhTRAP-ruthenium catalysis. The hydrogenation produces chiral primary amines, which may work as catalytic poisons, however, the amino group of the hydrogenation product is rapidly acylated when the reaction is conducted in the presence of an appropriate acylating agent, such as Boc 2 O or Cbz-OSu.

The Isoxazole Ring and Its N‐Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics

“…[70] Scaffold hopping [50,71] has been found to be quite effective with the isoxazole core structure in enhancingt he potency of related lead structures or drugs. [73] Indeed, facile ring cleavage of isoxazole 1 [74] leads to chemically and biologically useful outcomes, for instance, diaryl amines, as perspective metal ion chelating ligands. [72] Alicyclich ydroxylation (onto an alicycle fused to it or bearing it as an arm) and/or ring NÀOc leavagea re commonm etabolic pathways.R ing opening( N ÀOs cission), asymmetric reduction in particular, provides access to optically active structures, core components in av ariety of medicines.…”

“…[72] Alicyclich ydroxylation (onto an alicycle fused to it or bearing it as an arm) and/or ring NÀOc leavagea re commonm etabolic pathways.R ing opening( N ÀOs cission), asymmetric reduction in particular, provides access to optically active structures, core components in av ariety of medicines. [73] Indeed, facile ring cleavage of isoxazole 1 [74] leads to chemically and biologically useful outcomes, for instance, diaryl amines, as perspective metal ion chelating ligands.…”

Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst

“…values in our previous study. [11] As with the benzisoxazoles, the isoxazole ring of 1a openedt oy ield achiral enaminone 3 in 39 %y ield (Scheme 2a). Enaminone 3 was further reduced with H 2 to give am ixture of products 3-6 when the reaction was carriedo ut in the presence of stoichiometric (Boc) 2 O( Scheme 2b;B oc = tert-butoxycarbonyl).…”

“…[11] Based on the resonance energy of the aromatic p system, [12] the dearomatization of isoxazoles is considered to be comparable in difficulty to the dearomatization of pyrroles and more difficult than the dearomatization of furans or oxazoles. Moreover,i soxazole reductioni sc ommonly accompanied by ar ingopeningr eaction [13] because the NÀOb ondi sa menable to cleavage with al ow-valence transition metal (Scheme 1).…”

Pd-catalyzed asymmetric hydrogenation of fluorinated aromatic pyrazol-5-ols via capture of active tautomers

“…The intrinsic problems are apparent: (i) the inherent stability resulting from aromaticity; (ii) the strong coordination effects endowed by the heteroatoms; (iii) the difficulty of controlling the stereoselectivity; (iv) the facile cleavage of the bond between the heteroatoms. 20 Therefore, the hydrogenation of this kind of electron-enriched aromatic pyrazol-5-ol with a free hydroxyl and two adjacent nitrogen-atoms is a great and significant challenge. Herein, we wish to report our initial findings on the development of a Pd-catalyzed asymmetric hydrogenation of fluorinated pyrazol-5-ols with excellent enantioselectivities, yields, and diastereoselectivities.…”