Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms.

Two limiting mechanisms are possible for oxidative addition of (hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and a nucleophilic displacement mechanism. Until now, there has been little understanding about when each mechanism is relevant. Prior investigations to distinguish between these pathways were limited to a few specific combinations of the substrate and ligand.

Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes.

We describe a detailed investigation into why bulky ligands-those that enable catalysis at "12 " Pd-tend to promote overfunctionalization during Pd-catalyzed cross-couplings of dihalogenated substrates. After one cross-coupling event takes place, PdL initially remains coordinated to the π system of the nascent product. Selectivity for mono- vs.

Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights.

This report describes a detailed study of Ni phosphine catalysts for the Suzuki-Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPhMe and PPh afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid.

Different Oxidative Addition Mechanisms for 12- and 14-Electron Palladium(0) Explain Ligand-Controlled Divergent Site Selectivity.

In cross-coupling reactions, dihaloheteroarenes are usually most reactive at C─halide bonds adjacent to a heteroatom. This selectivity has been previously rationalized. However, no mechanistic explanation exists for anomalous reports in which specific ligands effect inverted selectivity with dihalopyridines and -pyridazines.

Precision Deuteration Using Cu-Catalyzed Transfer Hydrodeuteration to Access Small Molecules Deuterated at the Benzylic Position.

A highly regio- and chemoselective Cu-catalyzed aryl alkyne transfer hydrodeuteration to access a diverse scope of aryl alkanes precisely deuterated at the benzylic position is described. The reaction benefits from a high degree of regiocontrol in the alkyne hydrocupration step, leading to the highest selectivities reported to date for an alkyne transfer hydrodeuteration reaction. Only trace isotopic impurities are formed under this protocol, and analysis of an isolated product by molecular rotational resonance spectroscopy confirms that high isotopic purity products can be generated from readily accessible aryl alkyne substrates.

Triflate-Selective Suzuki Cross-Coupling of Chloro- and Bromoaryl Triflates Under Ligand-Free Conditions.

In the absence of strong ancillary ligands such as phosphines or N-heterocyclic carbenes, palladium salts are selective for C-OTf cleavage in the room-temperature Suzuki couplings of chloroaryl triflates in acetonitrile. Similar "ligand-free" conditions in DMSO also promote triflate-selective Suzuki coupling of bromoaryl triflates. This triflate selectivity complements the typical preference for reaction of bromides in prior reports of Suzuki couplings using phosphine ligands.

The Road Less Traveled: Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dihalogenated -Heteroarenes.

The vast majority (≥90%) of literature reports agree on the regiochemical outcomes of Pd-catalyzed cross-coupling reactions for most classes of dihalogenated -heteroarenes. Despite a well-established mechanistic rationale for typical selectivity, several examples reveal that changes to the catalyst can switch site selectivity, leading to the unconventional product. In this Perspective, we survey these unusual cases in which divergent selectivity is controlled by ligands or catalyst speciation.

Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dichloroheteroarenes under Ligand-Controlled and Ligand-Free Systems.

Halides adjacent to nitrogen are conventionally more reactive in Pd-catalyzed cross-couplings of dihalogenated -heteroarenes. However, a very sterically hindered -heterocyclic carbene ligand is shown to promote room-temperature cross-coupling at C4 of 2,4-dichloropyridines with high selectivity (∼10:1). This work represents the first highly selective method with a broad scope for C4-coupling of these substrates where selectivity is clearly under ligand control.

Solvent coordination to palladium can invert the selectivity of oxidative addition.

Reaction solvent was previously shown to influence the selectivity of Pd/P Bu-catalyzed Suzuki-Miyaura cross-couplings of chloroaryl triflates. The role of solvents has been hypothesized to relate to their polarity, whereby polar solvents stabilize anionic transition states involving [Pd(P Bu)(X)] (X = anionic ligand) and nonpolar solvents do not. However, here we report detailed studies that reveal a more complicated mechanistic picture.

Combined Experimental and Computational Mechanistic Investigation of the Palladium-Catalyzed Decarboxylative Cross-Coupling of Sodium Benzoates with Chloroarenes.

Reported herein is a mechanistic investigation into the palladium-catalyzed decarboxylative cross-coupling of sodium benzoates and chloroarenes. The reaction was found to be first-order in Pd. A minimal substituent effect was observed with respect to chloroarene, and the reaction was zero-order with respect to chloroarene.

Chemodivergence between Electrophiles in Cross-Coupling Reactions.

Chemodivergent cross-couplings are those in which either one of two (or more) potentially reactive functional groups can be made to react based on choice of conditions. In particular, this review focuses on cross-couplings involving two different (pseudo)halides that can compete for the role of the electrophilic coupling partner. The discussion is primarily organized by pairs of electrophiles including chloride vs.

Solvent Effects on the Selectivity of Palladium-Catalyzed Suzuki-Miyaura Couplings.

The use of polar solvents MeCN or dimethylformamide (DMF) was previously shown to induce a selectivity switch in the Pd/P Bu-catalyzed Suzuki-Miyaura coupling of chloroaryl triflates. This phenomenon was attributed to the ability of polar solvents to stabilize anionic transition states for oxidative addition. However, we demonstrate that selectivity in this reaction does not trend with solvent dielectic constant.

Small Phosphine Ligands Enable Selective Oxidative Addition of Ar-O over Ar-Cl Bonds at Nickel(0).

Current methods for Suzuki-Miyaura couplings of nontriflate phenol derivatives are limited by their intolerance of halides including aryl chlorides. This is because Ni(0) and Pd(0) often undergo oxidative addition of organohalides at a similar or faster rate than most Ar-O bonds. DFT and stoichiometric oxidative addition studies demonstrate that small phosphines, in particular PMe, are unique in promoting preferential reaction of Ni(0) with aryl tosylates and other C-O bonds in the presence of aryl chlorides.

Gold Catalyzed Decarboxylative Cross-Coupling of Iodoarenes.

This report details a decarboxylative cross-coupling of (hetero)aryl carboxylates with iodoarenes in the presence of a gold catalyst (>25 examples, up to 96% yield). This reaction is site specific, which overcomes prior limitations associated with gold catalyzed oxidative coupling reactions. The reactivity of the (hetero)aryl carboxylate correlates qualitatively to the field effect parameter ().

N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki-Miyaura Cross Coupling.

Two N-heterocyclic carbene ligands provide orthogonal chemoselectivity during the Pd-catalyzed Suzuki-Miyaura (SM) cross-coupling of chloroaryl triflates. The use of SIPr [SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene] leads to selective cross-coupling at chloride, while the use of SIMes [SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] provides selective coupling at triflate. With most chloroaryl triflates and arylboronic acids, ligand-controlled selectivity is high (≥10:1).

Ligation state of nickel during C-O bond activation with monodentate phosphines.

The oxidative addition of phenolic electrophiles at Ni(0) in the presence of monodentate phosphine ligands was studied with both dispersion-free and dispersion-containing DFT methods. With the popular bulky ligand PCy3, consideration of dispersion has a striking effect on the predicted ligation state of nickel during oxidative addition of aryl sulfamates. Dispersioncontaining methods such as M06L indicate a clear preference for a bis-phosphine ligated transition state (TS), while dispersion free methods like B3LYP strongly favor a monophosphine ligated TS.

Nickel-Catalyzed Stille Cross Coupling of C-O Electrophiles.

Aryl sulfamates, tosylates, and mesylates undergo efficient Ni-catalyzed cross coupling with diverse organostannanes in the presence of relatively unhindered alkylphosphine ligands and KF. The coupling is valuable for difficult bond constructions, such as aryl- heteroaryl, aryl-alkenyl, and aryl-alkynyl, using non-triflate phenol derivatives. A combination of experimental and computational studies implicate an unusual mechanism for transmetalation involving an 8-centered cyclic transition state.

Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization.

The origin of the high reactivity and site selectivity of pyridine N-oxide substrates in O-pivaloyl hydroxamic acid-directed Rh(III)-catalyzed (4+2) annulation reactions with alkynes was investigated computationally. The reactions of the analogous pyridine derivatives were previously reported to be slower and to display poor site selectivity for functionalization of the C(2)-H vs the C(4)-H bonds of the pyridine ring. The N-oxide substrates are found to be more reactive overall because the directing group interacts more strongly with Rh.

A twist on facial selectivity of hydride reductions of cyclic ketones: twist-boat conformers in cyclohexanone, piperidone, and tropinone reactions.

The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted N-acylpiperidone, an N-acyltropinone, and tert-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin-Anh model.

Combining Transition Metal Catalysis with Radical Chemistry: Dramatic Acceleration of Palladium-Catalyzed C-H Arylation with Diaryliodonium Salts.

This paper describes a photoredox palladium/iridium-catalyzed C-H arylation with diaryliodonium reagents. Details of the reaction optimization, substrate scope, and mechanism are presented along with a comparison to a related method in which aryldiazonium salts are used in place of diaryliodonium reagents. The unprecedentedly mild reaction conditions (25 ºC in methanol), the requirement for light and a photocatalyst, the inhibitory effect of radical scavengers, and the observed chemoselectivity trends are all consistent with a radical-thermal reaction with diaryliodonium reagents that is believed to proceed an 'ionic' 2 pathway and requires a much higher reaction temperature (100 ºC).

Palladium-Catalyzed C-H Arylation Using Aryltrifluoroborates in Conjunction with a Mn Oxidant under Mild Conditions.

This paper describes the development of a mild Pd-catalyzed C-H arylation reaction using potassium aryltrifluoroborates in conjunction with Mn(OAc) as the oxidant. The scope of this transformation is explored with a variety of different aryltrifluoroborates and arylpyridine substrates. Preliminary mechanistic studies suggest that the reaction proceeds via a high-valent Pd mechanism with C-H activation occurring at or before the rate determining step.

Mild palladium-catalyzed C-H alkylation using potassium alkyltrifluoroborates in combination with MnF3.

A Pd-catalyzed method for ligand-directed C-H alkylation with organoboron reagents is described. The combination of potassium organotrifluoroborates, MnF3, and a Pd(II) catalyst effects pyridine and amide-directed C-H alkylation. These reactions proceed under mild conditions (25-40 °C in weakly acidic media), are effective for installing methyl and 1° alkyl groups, and do not require promoters such as benzoquinone.

Asymmetric chiral ligand-directed alkene dioxygenation.

A Pd-catalyzed asymmetric alkene 1,2-dioxygenation reaction is described. The diastereoselectivity of the reaction is controlled by tethering a chiral oxime ether directing group to the alkene substrate. The best selectivities are obtained with 8-substituted menthone-derived oxime ether auxiliaries.

Controlling site selectivity in palladium-catalyzed C-H bond functionalization.

Effective methodology to functionalize C-H bonds requires overcoming the key challenge of differentiating among the multitude of C-H bonds that are present in complex organic molecules. This Account focuses on our work over the past decade toward the development of site-selective Pd-catalyzed C-H functionalization reactions using the following approaches: substrate-based control over selectivity through the use of directing groups (approach 1), substrate control through the use of electronically activated substrates (approach 2), or catalyst-based control (approach 3). In our extensive exploration of the first approach, a number of selectivity trends have emerged for both sp(2) and sp(3) C-H functionalization reactions that hold true for a variety of transformations involving diverse directing groups.