Chemo-, Regio-, and Stereoselective Assembly of Polysubstituted Furan-2(5H)-ones Enabled by Rh(III)-Catalyzed Domino C–H Alkenylation/Directing Group Migration/Lactonization: A Combined Experimental and Computational Study

Abstract

Exploring multistep cascade reactions triggered by C−H activation are recognized as appealing, yet challenging. Herein, we disclose a Rh(III)-catalyzed domino C−H coupling of N-carbamoyl indoles and 4-hydroxy-2-alkynoates for the streamlined assembly of highly functionalized furan-2(5H)-ones in which the carbamoyl-directing group (DG) is given a dual role of an auxiliary group and a migrating acylating reagent via the cleavage of stable C−N bonds at room temperature. More importantly, the obtained furan-2(5H)-one skeleton could be further functionalized under air in situ via C5−H hydroxylation by simply switching the solvent or additive, providing fully substituted furan-2(5H)-ones with the installation of an alcohol-based C 5 quaternary carbon center. Detailed experimental studies and density functional theory calculations reveal that a Rh(III)-mediated tandem C−H activation/alkyne insertion/DG migration/lactonization accounts for the developed transformation to achieve high functionalities with the observed exclusive selectivity. The potential biological application of the obtained furan-2(5H)-ones as a class of potent PPARγ ligands further highlights the synthetic utility of the developed methodology. This protocol is endowed with several salient features including efficient multistep cascade triggered by C−H activation, excellent chemo-, regio-, and stereoselectivity, high bondforming efficiency (e.g., two C−C and two C−O bonds), solvent-or additive-controlled product selectivity, good functional-group compatibility, and mild redox-neutral conditions.

Rhodium-catalyzed cascade C–H activation/annulation/1,6-acyl migration: direct construction of free N–H indoles under mild conditions

“…Based on previous reports 20–22 and our preliminary observations, the mechanism of C–H activation/annulation/acyl migration was proposed (Scheme 6). The activated species A coordinates the amide carbonyl group of 1 via C–H activation to give the six-membered rhodacycle B .…”

“…Then, acyl transfer provides the O -acylated intermediate F through N–C (acyl) bond cleavage. 20,21 Alternatively, at this stage, acyl transfer via metal-free conditions cannot be excluded. Finally, reductive elimination gives the final product 3 , while copper oxidation regenerates the active Rh species A for the next catalytic cycle.…”

DFT studies on rhodium(iii)-catalyzed synthesis of indanones from N-methoxybenzamides via C–H activation reaction

“…We studied first the catalytic cycle process (black path in Scheme 2). According to Wu group's studies, 51 Afterwards, there are two competing reaction pathways to give the 4a product at different alkali concentrations. When the alkali concentration is low, the KOAc will not be involved in the reaction.…”

Regio‐ and Stereoselective Synthesis of Tetrasubstituted Alkenes via Ruthenium(II)‐Catalyzed C–H Alkenylation/Directing Group Migration

“…Moreover, despite the remarkable advantages such as excellent stereoselectivity and high atom‐economy, this method still shows some minor drawbacks such as the usage of excessive additives and the requirement of chromatography for the purification of products. Considering the low cost and outstanding catalytic performance of Ru catalysts in C−H activation, [14] and together with our interests in TM‐catalyzed C−H functionalization [11d–g,12,15] and indole compound synthesis, [16] herein we report an efficient Ru(II)‐catalyzed C−H alkenylation/DG migration cascade between N ‐carbamoyl indoles and alkynes for the regio‐ and stereoselective assembly of tetrasubstituted alkenes carrying the privileged indole substituent (Scheme 2c). Notably, the carbamoyl DG [17] is endowed with a dual role of auxiliary group and internal acylation reagent via C−N bond cleavage, which migrates onto the alkene moiety of the products to deliver tetrasubstituted α,β‐unsaturated amides.…”