Functionalization of Heteroarenes via Palladium/Norbornene-Catalyzed Double C–H Activation

ConspectusElectron-rich five-membered heteroarenes, such as pyrroles, furans, indoles, and thiophenes, are prevalent in small-molecule drugs and other functional organic compounds. Consequently, methods that enable rapid and modular construction of densely substituted heteroaromatic frameworks are of high importance. From the synthetic efficiency standpoint, direct introduction of two or more functional groups into heteroarene cores would greatly increase complexity, facilitate structural diversification, and streamline preparation of target compounds. Direct C–H functionalization has emerged as one of the most step-economical strategies for synthesis of complex aromatic compounds. Despite that substantial progress has been achieved in site-selective functionalization of C–H bond at a single position, the regio- and site-selective installation of two distinct carbon substituents at adjacent positions remains a formidable challenge. On the other hand, palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a powerful platform for vicinal difunctionalization of arenes. The classical Pd/NBE reactions use aryl halides as substrates, which are initiated by Pd(0)-mediated oxidative addition. Recently, the Pd(II)-initiated variants triggered by C–H palladation offer unique advantages of employing less functionalized substrates and accommodating milder operational conditions. However, application of the Pd/NBE catalysis to the double C–H functionalization of electron-rich five-membered heteroarenes has not been a trivial task, due to competing heteroatom coordination, substrate sensitivity under oxidative conditions, and undesired side reactions such as ipso protonation. In this Account, we provide a concise summary of our systematic efforts in developing the Pd/NBE-catalyzed vicinal difunctionalization of diverse heteroarenes via double C–H activation in the past six years. Depending on the general catalytic mechanism, these reactions can be classified into “oxidative” and “redox-neutral” difunctionalization reactions. We will focus on describing the reaction scope, the proposed mechanism, the product selectivity, and current limitations of these reactions. In particular, we will discuss the design and use of structurally modified NBEs that enable these transformations, as well as the mechanistic insights into their roles in controlling reactivity and selectivity. The major topics covered include: (1) oxidative C2,C3-difunctionalization of thiophenes and furans, which are enabled by C2-amide-substituted NBEs; (2) oxidative C2,C3-difunctionalization of indoles, enabled by C1-substituted NBEs; (3) oxidative C2,C3-difunctionalization of pyrroles and its application to the total synthesis of leuconoxine-type alkaloids; and (4) redox-neutral C2,C3-difunctionalization of pyrroles, thiophenes, and furans. It is anticipated that this Account could offer a clear overview on the state of art in the field of the Pd/NBE-catalyzed difunctionalization of heteroarenes. Additionally, the scope and limitations outlined here would provide guidance to readers for choosing suitable conditions when using these reactions. Moreover, the mechanistic insights gained in these studies may have valuable implications for developing more general difunctionalization reactions via double C–H activation.

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Catalytic redox-neutral decarboxylative aromatization via transfer dehydrogenation | ChemRxiv

Arenes are fundamental structural motifs in organic molecules; therefore, methods for introducing aromatic rings are of broad importance. Traditional approaches that install arenes early followed by postfunctionalization often struggle to achieve diverse ...

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Transition Metal‐Free Heteroarene Insertion Into C─C Bonds of Benzocyclobutenones

A transition metal-free insertion of five-membered heteroarenes into the C─C bonds of benzocyclobutenones has been achieved under mild and operationally simple conditions. This method provides an eff...

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Asymmetric Synthesis of Tertiary Alkyl Boronates via Ligand-Controlled Enantioconvergent Homologation

Tertiary alkyl boronates are highly versatile synthetic intermediates; however, their asymmetric preparation remains challenging and exhibits limitations. Here we report a distinct ligand-controlled strategy for the synthesis of chiral tertiary alkyl boronates via enantioconvergent homologation with racemic tertiary α-thio lithium carbenoids. The enantioselectivity in this process is controlled by chiral hydrobenzoin-derived diether ligands. Both aryl and alkyl boronates give high yield and excellent enantioselectivity (up to >99:1 e.r.), showing good functional group tolerance. Mechanistic studies support an unusual pathway involving ligand-mediated dynamic thermodynamic resolution of racemic carbenoids, followed by rapid ate-complex formation and an indium-mediated stereospecific 1,2-migration. The utility of this strategy is demonstrated in the asymmetric construction of various fully substituted stereocenters and concise modular syntheses of precursors for muscarinic M3 receptor antagonists.

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Medicinal chemistry campaigns routinely require access to series of saturated nitrogen heterocycle (SNH)–based analogs that place nitrogen at different positions to probe structure-activity relationsh...

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Catalytic C-Demethylation of Phenols and Anilines Enabled by a Removable Mono-Directing Group

The activation of unstrained nonpolar C–C bonds, such as C(aryl)–C(alkyl) bonds, remains challenging to achieve. Existing catalytic strategies predominantly rely on bidentate chelating directing groups (DGs) or special substrates. Herein, we report a Ru-catalyzed activation of C(aryl)–C(methyl) bonds enabled by a removable mono-DG. By employing a bulky phosphinite or aminophosphine-DG that can be easily installed and removed later, a methyl group at the ortho position of phenols and anilines can be smoothly deleted under the hydrogenolysis condition. This reaction exhibits a broad substrate scope and excellent functional group tolerance. Mechanistic studies suggest that a Ru–hydride species generated in situ is responsible for the C(aryl)–C(methyl) bond activation, with methane identified as a byproduct.

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These shape-shifting rings create customizable cores

1,2-oxaborines can shift into 11 different ring shapes to make modifying molecular cores easy

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Core diversification using 1,2-oxaborines as a versatile molecular platform

Nature Chemistry - In drug discovery, the preparation of analogues with diverse core structures often requires laborious efforts. Now it has been shown that 1,2-oxaborines, which are synthesized...

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“Cut-and-Sew” Reactions of β-Lactams via C–C Bond Activation

Transition metal-catalyzed “cut-and-sew” reactions offer an efficient approach to construct bridged and fused scaffolds; however, the substrates have been primarily restricted to cyclic ketones and ac...

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Site-selective Ru-catalysed saturation of unactivated arenes via directed 6π activation

Nature Catalysis - Directing group strategies for selective dearomatization of unactivated aromatic π-systems have remained elusive. Now a homogeneous ruthenium catalyst, aided by a removable...

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Advances in vicinal dicarbo-C–H-functionalization of five-membered heteroarenes via palladium/norbornene cooperative catalysis

Direct introduction of two carbon substituents to less functionalized aromatic cores has been an attractive objective for late-stage modification and …

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N‐methylbicyclo[2.2.1]hept‐2‐ene‐2‐carboxamide

[2394994-09-1] C9H13NO (MW 151.21) InChI = 1S/C9H13NO/c1-10-9(11)8-5-6-2-3-7(8)4-6/h5-7H,2-4H2,1H3,(H,10,11) InChIKey = BYXAMVZFVXOYIF-UHFFFAOYSA-N (reagent used as a co-catalyst...

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Enantioconvergent carbenoid insertion into carbon–boron bonds

Nature Synthesis - An enantioconvergent approach for direct asymmetric insertion of racemic carbon-, oxygen-, nitrogen-, sulfur- and silicon-substituted carbenoids into carbon–boron bonds is...

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Toward Iridium-Catalyzed Asymmetric Branched-Selective α-Alkylation of Aldehydes with Unactivated Alkenes Enabled by a Pyrazole Mediator

Aldehyde α-alkylation remains a challenging transformation. On the other hand, given the wide availability of alkenes, it has been an attractive objective to use unactivated alkenes as alkylating agen...

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Carbonyl-to-sulfur swap enabled by sequential double carbon-carbon bond activation

In drug development, replacement of a skeletal carbon with a sulfur atom can result in analogs of bioactive compounds with improved properties. Currently, the sulfur analogs are almost exclusively pre...

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Downsizing lactams via Rh-catalyzed C–C activation

Ring-contraction reactions are valuable transformations to access harder-to-synthesize smaller-sized rings from more-available larger-sized precursors…

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Alkyl Fluoride Synthesis via Cu-Mediated Deacetylative Fluorination

Given the increasing demand for diverse alkyl fluorides for various applications, it would be beneficial to enrich the fluorination toolbox by including more kinds of common functional groups, such as ketones, as fluoride surrogates. Here we report a Cu-mediated deacylative fluorination approach that can convert a wide range of methyl ketones to the corresponding alkyl fluorides. The reaction is enabled by a ketone activation reagent and a nucleophilic fluoride source. It features broad functional group tolerance, capability for the late-stage fluorination, fluoro-annulation, synthesis of α,α-dideuterated fluorides, and degree-controlled synthesis of mono-, di-, and trifluoro alkanes from a single ketone starting material. The computational studies suggest interesting Cu(III)-mediated C–F bond forming pathways via either fluorine atom transfer or an SN2 process.

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Atom-by-Atom Iterative Synthetic Logic: Laying the Foundation for Programmable Automated Construction of Small Organic Molecules

Fully automated preparation of diverse small organic molecules remains a formidable challenge due to the inherent constraints of conventional synthetic philosophies. The existing automation approaches require access to either almost unlimited kinds of chemical reagents or custom-made building blocks (BBs). Herein we propose atom-by-atom iterative synthesis (AIS) as a new synthetic logic to tackle this challenge. By viewing complex organic molecules as assemblies of single-carbon- or heteroatom-based units, AIS aims to construct molecular skeletons through iterative coupling of simple atomic-scale BBs by a unified type of reaction─boron homologations. Compared with conventional approaches, the AIS strategy uses only a few types of chemical reactions and a small set of BBs, making it more suitable for automation and artificial intelligence-assisted synthetic route design. To date, enormous progresses have been made on the synthetic chemistry that serves for the purpose of AIS, such as introducing heteroatoms and sp2-carbons, forming ring structures, developing thermostable carbenoid reagents, and achieving stereochemical controls. On the other hand, substantial challenges and limitations remain to be overcome for realizing fully automated construction of diverse molecules. This Outlook article describes the AIS concept, recent progress, current limitations, and future opportunities in this field.

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