Cu(I)-Catalyzed Alkynylation of Quinolones

Abstract

Herein we report the first alkynylation of quinolones with terminal alkynes under mild reaction conditions. The reaction is catalyzed by Cu(I) salts in the presence of a Lewis acid, which is essential for the reactivity of the system. The enantioselective version of this transformation has also been explored, and the methodology has been applied in the synthesis of the enantioenriched tetrahydroquinoline alkaloid cuspareine.

Enantioselective Copper-Catalyzed Alkynylation of Quinolones Using Chiral P,N Ligands

“…13 Benzyl (S)-5,7-Dimethyl-4-oxo-2-(m-tolylethynyl)-3,4-dihydroquinoline-1(2H)-carboxylate (3v). 17 Synthesized as per general procedure C using benzyl 5,7-dimethyl-4-oxoquinoline-1(4H)-carboxylate 1g and 3-methylphenylacetylene. The product was isolated as a…”

“…Surprisingly, the benzodioxole group was not well tolerated, and a significantly reduced yield of 15% and enantioselectivity of 28% ee were obtained for this product (3w). As had previously been noted by Harutyunyan, 17 substitution at the quinolone 8-position is not tolerated in the reaction and no conversion to product 3x was observed, which is likely due to steric factors. A protected 4(1H)pyridinone was also tested as a substrate but again no conversion to product 3y was observed.…”

“…15,16 In 2022 Harutyunyan applied a similar methodology to the alkynylation of quinolones, mainly developing the racemic reaction although they were able to synthesize a small number of products in good to moderate enantioselectivities using the Ph-BPE ligand. 17 were necessary to achieve good yields and enantioselectivities in this case (Scheme 1c). 18 While success has been achieved with metal complexes of diphosphine and diamine ligands, the phosphinamine (P,N) class of chiral ligands, which we and others have extensively investigated, offer a range of ligands possessing central, planar, and axial chiral elements whose copper complexes warrant further investigation in this alkynylation process.…”

Highly Enantioselective Catalytic Alkynylation of Quinolones: Substrate Scope, Mechanistic Studies, and Applications in the Syntheses of Chiral N-Heterocyclic Alkaloids and Diamines

“…Our discovery of highly enantioselective alkynylations of benzopyrylium triflates in the presence of a copper bis­(oxazoline) catalyst prompted our initiation of investigations into the facially selective alkynylation of quinolinium triflates. During our preparation of this article, Harutyunyan published a separate account on the addition of copper acetylides to quinolones, although there were only 3 enantioselective examples with modest stereocontrol (i.e., 54–86% ee) . Building from our previous studies, our initial efforts employed benzyl bis­(oxazoline) ligand-1 ( L1 ) in the reaction between 2,2,2-trichloroethoxycarbonyl (Troc)-protected quinolone 1 and phenyl acetylene 3 (Table ).…”

C(sp)–C(sp3) Bond Formation through Ligand- and Additive-Free CuO-Mediated Decarboxylative Direct Cross-Coupling of Coumarin-/Chromone-3-carboxylic Acids and Terminal Alkynes

“…Even though C­(sp)–C­(sp 2 ) bond formation has great success, the construction of direct C­(sp)–C­(sp 3 ) bonds is still limited. Recently, readily available and less-expensive copper salts or complexes have been given much attention in direct C­(sp)–C­(sp 3 ) coupling reactions …”