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Electrostatically-directed Pd-catalysis in combination with C-H activation: site-selective coupling of remote chlorides with fluoroarenes and fluoroheteroarenes.

ABSTRACT: Systems incorporating catalyst-substrate non-covalent interactions are emerging as a versatile approach to address site-selectivity challenges in remote functionalization reactions. Given the achievements that have been made in this regard using metals such as iridium, manganese and rhodium, it is surprising that non-covalent catalyst direction has not been utilized in reactions incorporating palladium-catalyzed C-H activation steps, despite palladium being arguably the most versatile metal for C-H activation. Herein, we demonstrate that electrostatically directed, site-selective C-Cl oxidative addition is compatible with a subsequent C-H activation step, proceeding via a concerted metalation deprotonation-type mechanism. This results in site-selective cross-coupling of dichloroarenes with fluoroarenes and fluoroheteroarenes, with selectivity controlled by catalyst structure. This study demonstrates that Pd-catalyzed C-H activation can be used productively in combination with a non-covalently-directed mode of catalysis, with important implications in both fields.

SUBMITTER: Golding WA

PROVIDER: S-EPMC8157713 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Pd-catalyzed formal Mizoroki-Heck coupling of unactivated alkyl chlorides.

Project description:The use of alkyl chlorides in Pd-catalyzed Mizoroki-Heck coupling reactions remains an unsolved problem despite their significant potential for synthetic utility and applicability. The combination of the high thermodynamic barrier of alkyl chloride activation and kinetic propensity of alkylpalladium complexes to undergo undesired β-hydride elimination provides significant challenges. Herein, a variety of alkyl chlorides, even tertiary chlorides, are shown to efficiently participate in Mizoroki-Heck cross-coupling reactions with excellent functional group compatibility under mild reaction conditions via photoinduced Pd catalysis. The reaction is applied to late-stage functionalizations of diverse biologically significant scaffolds and iterative double Mizoroki-Heck annulations, affording high molecular complexity in a single step. Notably, studies on the kinetic isotope effects in combination with density functional theory (DFT)-computations completely exclude the involvement of a previously proposed β-hydride elimination in the catalytic cycle, revealing that the chlorine atom transfer process is the key catalytic turnover step. This distinctive single-electron transfer mediated reaction pathway resolves a longstanding challenge in traditional two-electron based Pd-catalyzed Mizoroki-Heck cross-coupling with alkyl electrophiles, wherein the β-hydride elimination is involved in the formation of both the desired product and undesired by-products.

| S-EPMC7881129 | biostudies-literature

sSPhos: A General Ligand for Enantioselective Arylative Phenol Dearomatization via Electrostatically-Directed Palladium Catalysis.

Project description:Arylative phenol dearomatization affords complex, cyclohexanone-based scaffolds from simple starting materials, and asymmetric versions allow access to valuable enantioenriched structures. However, bespoke chiral ligands must typically be identified for each new scaffold variation. We have addressed this limitation by applying the concept of electrostatically-directed palladium catalysis whereby the chiral sulfonated ligand sSPhos engages in electrostatic interactions with a phenolate substrate via its associated alkali metal cation. This approach allows access to highly enantioenriched spirocyclohexadienones, a process originally reported by Buchwald and co-workers in a predominantly racemic manner. In addition, sSPhos is proficient at forming two other distinct scaffolds, which had previously required fundamentally different chiral ligands, as well as a novel oxygen-linked scaffold. We envisage that the broad generality displayed by sSPhos will facilitate the expansion of this important reaction type and highlight the potential of this unusual design principle, which harnesses attractive electrostatic interactions.

| S-EPMC10690801 | biostudies-literature

Efficient Pd-Catalyzed Direct Coupling of Aryl Chlorides with Alkyllithium Reagents.

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| S-EPMC7692947 | biostudies-literature

Potent Reductants via Electron-Primed Photoredox Catalysis: Unlocking Aryl Chlorides for Radical Coupling.

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| S-EPMC7607533 | biostudies-literature

Chemo-selective Stille-type coupling of acyl-chlorides upon phosphine-borane Au(i) catalysis.

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| S-EPMC10988615 | biostudies-literature

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| S-EPMC4195375 | biostudies-literature

An Efficient System For the Pd-Catalyzed Cross-Coupling of Amides and Aryl Chlorides.

Project description:A catalyst based on a new biarylphosphine ligand (3) for the Pd-catalyzed cross-coupling reactions of amides and aryl chlorides is described. This system shows the highest turnover frequencies reported to date for these reactions, especially for aryl chloride substrates bearing an ortho substituent. An array of amides and aryl chlorides were successfully reacted in good to excellent yields.

| S-EPMC2927134 | biostudies-literature

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

Project description:Dienones are challenging building blocks in natural product synthesis due to their high reactivity and complex synthesis. Based on previous work and own initial results, a new stereospecific sequential hydrozirconation/Pd-catalyzed acylation of enynes with acyl chlorides towards conjugated (2E,4E)-dienones is reported. We investigated a number of substrates with different alkyl and aryl substituents in the one-pot reaction and showed that regardless of the substitution pattern, the reactions lead to the stereoselective formation (≥95% (2E,4E)) of the respective dienones under mild conditions. It was found that enynes with alkyl chains gave higher yields than the corresponding aryl-substituted analogues, whereas the variation of the acyl chlorides did not affect the reaction significantly. The synthetic application is demonstrated by formation of non-natural and natural dienone-containing terpenes such as β-ionone which was available in 4 steps and 6% overall yield.

| S-EPMC9940601 | biostudies-literature

Active site and remote contributions to catalysis in methylthioadenosine nucleosidases.

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| S-EPMC4485437 | biostudies-literature

Simple, Efficient Protocols for the Pd-Catalyzed Cross-Coupling Reaction of Aryl Chlorides and Dimethylamine.

Project description:Simple and efficient procedures for the Pd-catalyzed cross-coupling reaction of aryl chlorides and dimethylamine are described. At room temperature with a strong base, t-BuXPhos is employed as the supporting ligand; at 110 °C with a weak base, XPhos is employed as the supporting ligand. In each of these cases, commercially available solutions constitute the source of the dimethylamine, and recently disclosed precatalysts constitute the source of the ligand and Pd. This work further expands the utility of these precatalysts in reactions that benefit from an easily activated source of L(1)Pd(0).

| S-EPMC3148836 | biostudies-literature

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