Kinetic Resolution of 2,2-Disubstituted Dihydroquinolines through Chiral Phosphoric Acid-Catalyzed C6-Selective Asymmetric Halogenations

Abstract

A novel kinetic resolution of 2,2-disubstituted dihydroquinolines was achieved by regioselective asymmetric halogenations enabled by chiral phosphoric acid catalysis. A series of dihydroquinolines bearing 2,2-disubstitutions were well-tolerated in these reactions, generating both the recovered dihydroquinolines and C-6-brominated products with high enantioselectivities, with s-factors up to 149. In addition, this kinetic resolution protocol is also applicable for 2,2-disubstituted tetrahydroquinoline and asymmetric iodonation reaction.

Ligand Design and Preparation, Photophysical Properties, and Device Performance of an Encapsulated-Type Pseudo-Tris(heteroleptic) Iridium(III) Emitter

“…The borylation of 4 , which afforded 2-(1-phenyl-1-(3-pinacolborylphenyl)­ethyl)­pyridine ( 5 ), was executed with pinB-Bpin in the presence of 4 equiv of potassium acetate, at 130 °C, using 5 mol% of complex Pd­(OMs)­{κ 2 - C,N -(C 6 H 4 -NH 2 )}­(XPhos) (XPhos-Pd-G3; OMs = methanesulfonate, XPhos = 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl) as catalyst precursor, and dimethylformamide as solvent. Buchwald’s XPhos-Pd-G3 complex had previously proved to be efficient for the direct borylation of a variety of aryl halides . Although a black solid was formed under these conditions, probably due to decomposition of the catalyst precursor to palladium(0), the Miyaura-borylation of the aryl halide took place in an efficient manner after 3 h. Thus, the borylated product 5 was isolated as a light-yellow oleaginous gum in 61% yield, with previous purification of the reaction crude by silica column chromatography.…”

Catalytic Kinetic Resolution and Desymmetrization of Amines

“…In 2021, our group reported the KR of 2,2-disubstituted hydroquinolines 131 through asymmetric C-H halogenations, which gave access to products with more synthetic utilities (Scheme 47). 77 Both dihydroquinolines and tetrahydroquinoline bearing ,-disubstitutions were kinetically resolved upon treatment with NBS enabled by CPA catalyst cat-48 at -78 °C, which afforded the recovered (R)-131 and the C6-brominated products 140 with high enantiomeric purity. In addition, a one-pot stepwise brominative KR and boronation reaction was performed on racemic 131e, which gave access to (R)-131c and the C-6 Bpin-substituted product 141e with good KR performance.…”

Kinetic Resolution of 2‐Aryldihydroquinolines Using Lithiation – Synthesis of Chiral 1,2‐ and 1,4‐Dihydroquinolines

“…Direct addition of an organometallic species to quinoline generally gives moderate enantioselectivity with sparteine as a chiral ligand, [14] although an asymmetric Heck reaction with a 1,4‐dihydroquinoline has been successful [15] . Recently, the synthesis of 1,2‐dihydroquinolines has been reported using kinetic resolution [16–20] . This strategy has involved the preferential reaction of one enantiomer of the 2‐substituted 1,2‐dihydroquinoline by reaction of the 3,4‐alkene using a borylation, oxidation, or arylation process (Scheme 1A,B), [16–18] or by electrophilic aromatic substitution (Scheme 1C) [19–20] .…”

“… [15] Recently, the synthesis of 1,2‐dihydroquinolines has been reported using kinetic resolution. [ 16 , 17 , 18 , 19 , 20 ] This strategy has involved the preferential reaction of one enantiomer of the 2‐substituted 1,2‐dihydroquinoline by reaction of the 3,4‐alkene using a borylation, oxidation, or arylation process (Scheme 1 A, B ),[ 16 , 17 , 18 ] or by electrophilic aromatic substitution (Scheme 1 C). [ 19 , 20 ] These methods have their limitations, for example in the lack of access to 4‐substituted derivatives.…”