A DFT Study on the Conversion of Aryl Iodides to Alkyl Iodides: Reductive Elimination of R−I from Alkylpalladium Iodide Complexes with Accessible β‐Hydrogens

DFT calculations have been performed on the palladium‐catalyzed carboiodination reaction. The reaction involves oxidative addition, alkyne insertion, C?N bond cleavage, and reductive elimination. For the alkylpalladium iodide intermediate, LiOtBu stabilizes the intermediate in non‐polar solvents, thus promoting reductive elimination and preventing β‐hydride elimination. The C?N bond cleavage process was explored and the computations show that PPh₃ is not bound to the Pd center during this step. Experimentally, it was demonstrated that LiOtBu is not necessary for the oxidative addition, alkyne insertion, or C?N bond cleavage steps, lending support to the conclusions from the DFT calculations. The turnover‐limiting steps were found to be C?N bond cleavage and reductive elimination, whereas oxidative addition, alkyne insertion, and formation of the indole ring provide the driving force for the reaction.     

Scalable Rhodium(III)‐Catalyzed Aryl C−H Phosphorylation Enabled by Anodic Oxidation Induced Reductive Elimination

Transition metal catalyzed C?H phosphorylation remains an unsolved challenge. Reported methods are generally limited in scope and require stoichiometric silver salts as oxidants. Reported here is an electrochemically driven Rh^III‐catalyzed aryl C?H phosphorylation reaction that proceeds through H₂ evolution, obviating the need for stoichiometric metal oxidants. The method is compatible with a variety of aryl C?H and P?H coupling partners and particularly useful for synthesizing triarylphosphine oxides from diarylphosphine oxides, which are often difficult coupling partners for transition metal catalyzed C?H phosphorylation reactions. Experimental results suggest that the mechanism responsible for the C?P bond formation involves an oxidation‐induced reductive elimination process.     

Rhodium‐Catalyzed Intramolecular C−H Silylation by Silacyclobutanes

Silacyclobutane was discovered to be an efficient C?H bond silylation reagent. Under the catalysis of Rh^I/TMS‐segphos, silacyclobutane undergoes sequential C?Si/C?H bond activations, affording a series of π‐conjugated siloles in high yields and regioselectivities. The catalytic cycle was proposed to involve a rarely documented endocyclic β‐hydride elimination of five‐membered metallacycles, which after reductive elimination gave rise to a Si?Rh^I species that is capable of C?H activation.     

Site‐Selective C−S Bond Formation at C−Br over C−OTf and C−Cl Enabled by an Air‐Stable,Easily Recoverable,and Recyclable Palladium(I) Catalyst

This report widens the repertoire of emerging Pd^I catalysis to carbon–heteroatom, that is, C?S bond formation. While Pd⁰‐catalyzed protocols may suffer from the formation of poisonous sulfide‐bound off‐cycle intermediates and lack of selectivity, the mechanistically diverse Pd^I catalysis concept circumvents these challenges and allows for C?S bond formation (S–aryl and S–alkyl) of a wide range of aryl halides. Site‐selective thiolations of C?Br sites in the presence of C?Cl and C?OTf were achieved in a general and a priori predictable fashion. Computational, spectroscopic, X‐ray, and reactivity data support dinuclear Pd^I catalysis to be operative. Contrary to air‐sensitive Pd⁰, the active Pd^I species was easily recovered in the open atmosphere and subjected to multiple rounds of recycling.     

Highly Stereoselective Cobalt(III)‐Catalyzed Three‐Component C−H Bond Addition Cascade

A highly stereoselective three‐component C(sp²)?H bond addition across alkene and polarized π‐bonds is reported for which Co^III catalysis was shown to be much more effective than Rh^III. The reaction proceeds at ambient temperature with both aryl and alkyl enones employed as efficient coupling partners. Moreover, the reaction exhibits extremely broad scope with respect to the aldehyde input; electron rich and poor aromatic, alkenyl, and branched and unbranched alkyl aldehydes all couple in good yield and with high diastereoselectivity. Multiple directing groups participate in this transformation, including pyrazole, pyridine, and imine functional groups. Both aromatic and alkenyl C(sp²)?H bonds undergo the three‐component addition cascade, and the alkenyl addition product can readily be converted into diastereomerically pure five‐membered lactones. Additionally, the first asymmetric reactions with Co^III‐catalyzed C?H functionalization are demonstrated with three‐component C?H bond addition cascades employing N‐tert‐butanesulfinyl imines. These examples represent the first transition metal catalyzed C?H bond additions to N‐tert‐butanesulfinyl imines, which are versatile and extensively used intermediates for the asymmetric synthesis of amines.     

Computational Insight into Nickel‐Catalyzed Carbon–Carbon versus Carbon–Boron Coupling Reactions of Primary,Secondary, and Tertiary Alkyl Bromides

The nickel‐catalyzed alkyl–alkyl cross‐coupling (C?C bond formation) and borylation (C?B bond formation) of unactivated alkyl halides reported in the literature show completely opposite reactivity orders in the reactions of primary, secondary, and tertiary alkyl bromides. The proposed Ni^I/Ni^III catalytic cycles for these two types of bond‐formation reactions were studied computationally by means of DFT calculations at the B3LYP level. These calculations indicate that the rate‐determining step for alkyl–alkyl cross‐coupling is the reductive elimination step, whereas for borylation the rate is determined mainly by the atom‐transfer step. In borylation reactions, the boryl ligand involved has an empty p orbital, which strongly facilitates the reductive elimination step. The inability of unactivated tertiary alkyl halides to undergo alkyl–alkyl cross‐coupling is mainly due to the moderately high reductive elimination barrier.     

Rhenium(I)‐Catalyzed ortho‐C−H Addition to Bicyclic Alkenes

Hydroarylation of bicyclic alkenes has been developed using a low‐valent Re^I‐catalyzed, directing group‐assisted C?H bond activation strategy. The addition of sodium acetate significantly improves the reaction efficiency; moreover, bicyclic alkenes such as 7‐oxa and aza benzonorbornadienes worked efficiently under this reaction condition. Preliminary mechanistic studies suggest that, after the alkene insertion, the rhenacycle preferentially undergoes protonolysis rather than reductive elimination.     

Manganese(I)‐Catalyzed C−H Activation: The Key Role of a 7‐Membered Manganacycle in H‐Transfer and Reductive Elimination

Manganese‐catalyzed C?H bond activation chemistry is emerging as a powerful and complementary method for molecular functionalization. A highly reactive seven‐membered Mn^I intermediate is detected and characterized that is effective for H‐transfer or reductive elimination to deliver alkenylated or pyridinium products, respectively. The two pathways are determined at Mn^I by judicious choice of an electron‐deficient 2‐pyrone substrate containing a 2‐pyridyl directing group, which undergoes regioselective C?H bond activation, serving as a valuable system for probing the mechanistic features of Mn C?H bond activation chemistry.     

Carboxylate‐Assisted Oxidative Addition to Aminoalkyl PdII Complexes: C(sp3)−H Arylation of Alkylamines by Distinct PdII/PdIV Pathway

Reported is the discovery of an approach to functionalize secondary alkylamines using 2‐halobenzoic acids as aryl‐transfer reagents. These reagents promote an unusually mild carboxylate‐assisted oxidative addition to alkylamine‐derived palladacycles. In the presence of Ag^I salts, a decarboxylative C(sp³)?C(sp²) bond reductive elimination leads to γ‐aryl secondary alkylamines and renders the carboxylate motif a traceless directing group. Stoichiometric mechanistic studies were effectively translated to a Pd‐catalyzed γ‐C(sp³)?H arylation process for secondary alkylamines.     

Site‐Selective C−S Bond Formation at C−Br over C−OTf and C−Cl Enabled by an Air‐Stable,Easily Recoverable,and Recyclable Palladium(I) Catalyst

This report widens the repertoire of emerging Pd^I catalysis to carbon–heteroatom, that is, C−S bond formation. While Pd⁰‐catalyzed protocols may suffer from the formation of poisonous sulfide‐bound off‐cycle intermediates and lack of selectivity, the mechanistically diverse Pd^I catalysis concept circumvents these challenges and allows for C−S bond formation (S–aryl and S–alkyl) of a wide range of aryl halides. Site‐selective thiolations of C−Br sites in the presence of C−Cl and C−OTf were achieved in a general and a priori predictable fashion. Computational, spectroscopic, X‐ray, and reactivity data support dinuclear Pd^I catalysis to be operative. Contrary to air‐sensitive Pd⁰, the active Pd^I species was easily recovered in the open atmosphere and subjected to multiple rounds of recycling.     

Lewis Acid Assisted Nickel‐Catalyzed Cross‐Coupling of Aryl Methyl Ethers by C−O Bond‐Cleaving Alkylation: Prevention of Undesired β‐Hydride Elimination

In the presence of trialkylaluminum reagents, diverse aryl methyl ethers can be transformed into valuable products by C?O bond‐cleaving alkylation, for the first time without the limiting β‐hydride elimination. This new nickel‐catalyzed dealkoxylative alkylation method enables powerful orthogonal synthetic strategies for the transformation of a variety of naturally occurring and easily accessible anisole derivatives. The directing and/or activating properties of aromatic methoxy groups are utilized first, before they are replaced by alkyl chains in a subsequent coupling process.     

Ruthenium Catalyzed C−H Acylmethylation of N‐Arylphthalazine‐1,4‐diones with α‐Carbonyl Sulfoxonium Ylides: Highway to Diversely Functionalized Phthalazino‐fused Cinnolines

A direct ortho‐Csp²‐H acylmethylation of 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with α‐carbonyl sulfoxonium ylides is achieved through a Ru^II‐catalyzed C?H bond activation process. The protocol featured high functional group tolerance on the two substrates, including aryl‐, heteroaryl‐, and alkyl‐substituted α‐carbonyl sulfoxonium ylides. Thereafter, 2‐(ortho‐acylmethylaryl)‐2,3‐dihydrophthalazine‐1,4‐diones were used as potential starting materials for the expeditious synthesis of 6‐arylphthalazino[2,3‐a]cinnoline‐8,13‐diones and 5‐acyl‐5,6‐dihydrophthalazino[2,3‐a]cinnoline‐8,13‐diones under Lawesson's reagent and BF₃?OEt₂ mediated conditions, respectively. Of these, the BF₃?OEt₂‐mediated cyclization proceeded in DMSO as a solvent and a methylene source via dual C?C and C?N bond formations.     

Mechanistic Insights into the Ni‐Catalyzed Reductive Carboxylation of C−O Bonds in Aromatic Esters with CO2: Understanding Remarkable Ligand and Traceless‐Directing‐Group Effects

The mechanism of the Ni⁰‐catalyzed reductive carboxylation reaction of C(sp²)?O and C(sp³)?O bonds in aromatic esters with CO₂ to access valuable carboxylic acids was comprehensively studied by using DFT calculations. Computational results revealed that this transformation was composed of several key steps: C?O bond cleavage, reductive elimination, and/or CO₂ insertion. Of these steps, C?O bond cleavage was found to be rate‐determining, and it occurred through either oxidative addition to form a Ni^II intermediate, or a radical pathway that involved a bimetallic species to generate two Ni^I species through homolytic dissociation of the C?O bond. DFT calculations revealed that the oxidative addition step was preferred in the reductive carboxylation reactions of C(sp²)?O and C(sp³)?O bonds in substrates with extended π systems. In contrast, oxidative addition was highly disfavored when traceless directing groups were involved in the reductive coupling of substrates without extended π systems. In such cases, the presence of traceless directing groups allowed for docking of a second Ni⁰ catalyst, and the reactions proceed through a bimetallic radical pathway, rather than through concerted oxidative addition, to afford two Ni^I species both kinetically and thermodynamically. These theoretical mechanistic insights into the reductive carboxylation reactions of C?O bonds were also employed to investigate several experimentally observed phenomena, including ligand‐dependent reactivity and site‐selectivity.     

σ‐Noninnocence: Masked Phenyl‐Cation Transfer at Formal NiIV

Reductive elimination is an elementary organometallic reaction step involving a formal oxidation state change of ?2 at a transition‐metal center. For a series of formal high‐valent Ni^IV complexes, aryl–CF₃ bond‐forming reductive elimination was reported to occur readily (Bour et al. J. Am. Chem. Soc. 2015 , 137, 8034–8037). We report a computational analysis of this reaction and find that, unexpectedly, the formal Ni^IV centers are better described as approaching a +II oxidation state, originating from highly covalent metal–ligand bonds, a phenomenon attributable to σ‐noninnocence. A direct consequence is that the elimination of aryl–CF₃ products occurs in an essentially redox‐neutral fashion, as opposed to a reductive elimination. This is supported by an electron flow analysis which shows that an anionic CF₃ group is transferred to an electrophilic aryl group. The uncovered role of σ‐noninnocence in metal–ligand bonding, and of an essentially redox‐neutral elimination as an elementary organometallic reaction step, may constitute concepts of broad relevance to organometallic chemistry.     

Intramolecular Acetyl Transfer to Olefins by Catalytic C−C Bond Activation of Unstrained Ketones

A rhodium‐catalyzed intramolecular acetyl‐group transfer has been achieved through a “cut and sew” process. The challenge arises from the existence of different competitive pathways. Preliminary success has been achieved with unstrained enones that contain a biaryl linker. The use of an electron‐rich N‐heterocycilc carbene (NHC) ligand is effective to inhibit undesired β‐hydrogen elimination. Various 9,10‐dihydrophenanthrene derivatives can be prepared with excellent functional‐group compatibility. The ¹³C‐labelling study suggests that the reaction begins with cleavage of the unstrained C?C bond, followed by migratory insertion and reductive elimination.     

RhI‐Catalyzed Intramolecular Carbonylative C−H/C−I Coupling of 2‐Iodobiphenyls Using Furfural as a Carbonyl Source

Synthesis of fluoren‐9‐ones by a Rh‐catalyzed intramolecular C?H/C?I carbonylative coupling of 2‐iodobiphenyls using furfural as a carbonyl source is presented. The findings indicate that the rate‐determining step is not a C?H bond cleavage but, rather, the oxidative addition of the C?I bond to a Rh^I center.     

Transition‐metal‐free Chemoselective Oxidative C−C Coupling of the sp3 C−H Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3‐Aryl Oxindoles,and Benzofuro‐ and Indoloindoles

A transition‐metal (TM)‐free and halogen‐free NaOt Bu‐mediated oxidative cross‐coupling between the sp³ C−H bond of oxindoles and sp² C−H bond of nitroarenes has been developed to access 3‐aryl substituted and 3,3‐aryldisubstituted oxindoles in DMSO at room temperature in a short time. Interestingly, the sp³ C−H bond of oxindoles could also react with styrene under TM‐free conditions for the practical synthesis of quaternary 3,3‐disubstituted oxindoles. The synthesized 3‐oxindoles have also been further transformed into advanced heterocycles, that is, benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic experiments of the reaction suggests the formation of an anion intermediate from the sp³ C−H bond of oxindole by tert ‐butoxide base in DMSO. The addition of nitrobenzene to the in‐situ generated carbanion leads to the 3‐(nitrophenyl)oxindolyl carbanion in DMSO which is subsequently oxidized to 3‐(nitro‐aryl) oxindole by DMSO.     

M−C Bond Homolysis in Coinage‐Metal [M(CF3)4]− Derivatives

A comparative study of the homoleptic [M(CF₃)₄]^? complexes of all three coinage metals (M=Cu, Ag, Au) reveals that homolytic M?C bond cleavage is favoured in every case upon excitation in the gas phase (CID‐MS²). Homolysis also occurs in solution by photochemical excitation. Transfer of the photogenerated CF₃^. radicals to both aryl and alkyl carbon atoms was also confirmed. The observed behaviour was rationalized by considering the electronic structure of the involved species, which all show ligand‐field inversion. Moreover, the homolytic pathway constitutes experimental evidence for the marked covalent character of the M?C bond. The relative stability of these M?C bonds was evaluated by energy‐resolved mass spectrometry (ERMS) and follows the order Cu<Ag?Au. The qualitatively similar and rather uniform behaviour experimentally observed for all three coinage metals gives no ground to suggest variation in the metal oxidation state along the group.     

Cross‐Coupling of Organolithium with Ethers or Aryl Ammonium Salts by C−O or C−N Bond Cleavage

Various aryl‐, alkenyl‐, and/or alkyllithium species reacted smoothly with aryl and/or benzyl ethers with cleavage of the inert C?O bond to afford cross‐coupled products, catalyzed by commercially available [Ni(cod)₂] (cod=1,5‐cyclooctadiene) catalysts with N‐heterocyclic carbene (NHC) ligands. Furthermore, the coupling reaction between the aryllithium compounds and aryl ammonium salts proceeded under mild conditions with C?N bond cleavage in the presence of a [Pd(PPh₃)₂Cl₂] catalyst. These methods enable selective sequential functionalizations of arenes having both C?N and C?O bonds in one pot.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.