(Phenoxyimine)nickel-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling: Evidence for a Recovering Radical Chain Mechanism.

Phenoxyimine (FI)-nickel(II)(2-tolyl)(DMAP) compounds were synthesized and evaluated as precatalysts for the C(sp2)-C(sp3) Suzuki-Miyaura cross coupling of (hetero)arylboronic acids with alkyl bromides. With 5 mol % of the optimal (MeOMeFI)Ni(Aryl)(DMAP) precatalyst, the scope of the cross-coupling reaction was established and included a variety of (hetero)arylboronic acids and alkyl bromides (>50 examples, 33-97% yield). A ß-hydride elimination-reductive elimination sequence from reaction with potassium isopropoxide base, yielding a potassium (FI)nickel(0)ate, was identified as a catalyst activation pathway that is responsible for halogen atom abstraction from the alkyl bromide. A combination of NMR and EPR spectroscopies identified (FI)nickel(II)-aryl complexes as the resting state during catalysis with no evidence for long-lived organic radical or odd-electron nickel intermediates. These data establish that the radical chain is short-lived and undergoes facile termination and also support a "recovering radical chain" process whereby the (FI)nickel(II)-aryl compound continually (re)initiates the radical chain. Kinetic studies established that the rate of C(sp2)-C(sp3) product formation was proportional to the concentration of the (FI)nickel(II)-aryl resting state that captures the alkyl radical for chain propagation. The proposed mechanism involves two key and concurrently operating catalytic cycles; the first involving a nickel(I/II/III) radical propagation cycle consisting of radical capture at (FI)nickel(II)-aryl, C(sp2)-C(sp3) reductive elimination, bromine atom abstraction from C(sp3)-Br, and transmetalation; and the second involving an off-cycle catalyst recovery process by slow (FI)nickel(II)-aryl → (FI)nickel(0)ate conversion for nickel(I) regeneration.

Ligand Field Sensitive Spin Acceleration in the Iron-Catalyzed [2 + 2] Cycloaddition of Unactivated Alkenes and Dienes.

Redox-active pyridine(diimine) (PDI) iron catalysts promote the reversible [2 + 2] cycloaddition of alkenes and dienes to cyclobutane derivatives that have applications ranging from fuels to chemically recyclable polymers. Metallacycles were identified as key intermediates, and spin crossover from the singlet to the triplet surface was calculated to facilitate the reductive coupling step responsible for the formation of the four-membered ring. In this work, a series of sterically and electronically differentiated PDI ligands was studied for the [2 + 2] cycloaddition of ethylene and butadiene to vinylcyclobutane. Kinetic studies revealed that the fastest and slowest turnover were observed with equally electron-deficient supporting ligands that either feature phenyl-substituted imine carbon atoms (MeBPDI) or a pyrazine core (MePZDI). While the oxidative cyclization was comparatively slow for both catalysts, the rate of reductive coupling─determined by stoichiometric 13C2H4 labeling studies─correlated with the turnover frequencies. Two-state density functional theory studies and the distinct electronic structures of related (iPrBPDI) and (iPrPZDI) iron methyl complexes revealed significantly different ligand field strengths due to either diminished ligand σ-donation (MeBPDI) or promoted metal π-backbonding (MePZDI). Spin acceleration, leading to fast reductive coupling and catalytic turnover, was promoted in the case of the weaker ligand field and depends on both the nature and position of the electron-withdrawing group. This study provides strong evidence for the role of two-state reactivity in C(sp3)-C(sp3) bond formation and insights on how ligand design either promotes or inhibits spin acceleration in earth-abundant metal catalysis.

Asymmetric Hydrogenation of Indazole-Containing Enamides Relevant to the Synthesis of Zavegepant Using Neutral and Cationic Cobalt Precatalysts.

The cobalt-catalyzed asymmetric hydrogenation of indazole-containing enamides relevant to the synthesis of the calcitonin gene-related peptide (CGRP) receptor antagonist, zavegepant (1), approved for the treatment of migraines, is described. Both neutral bis(phosphine)cobalt(II) and cationic bis(phosphine)cobalt(I) complexes served as efficient precatalysts for the enamide hydrogenation reactions, providing excellent yield and enantioselectivities (up to >99.9%) for a range of related substrates, though key reactivity differences were observed. Hydrogenation of indazole-containing enamide, methyl (Z)-2-acetamido-3-(7-methyl-1H-indazol-5-yl)acrylate, was performed on a 20 g scale.

Kinetic and thermodynamic control of C(sp2)-H activation enables site-selective borylation.

Catalysts that distinguish between electronically distinct carbon-hydrogen (C-H) bonds without relying on steric effects or directing groups are challenging to design. In this work, cobalt precatalysts supported by N-alkyl-imidazole-substituted pyridine dicarbene (ACNC) pincer ligands are described that enable undirected, remote borylation of fluoroaromatics and expansion of scope to include electron-rich arenes, pyridines, and tri- and difluoromethoxylated arenes, thereby addressing one of the major limitations of first-row transition metal C-H functionalization catalysts. Mechanistic studies established a kinetic preference for C-H bond activation at the meta-position despite cobalt-aryl complexes resulting from ortho C-H activation being thermodynamically preferred. Switchable site selectivity in C-H borylation as a function of the boron reagent was thereby preliminarily demonstrated using a single precatalyst.

Iridium-Catalyzed Hydrogenation of a Phenoxy Radical to the Phenol: Overcoming Catalyst Deactivation with Visible Light Irradiation.

Piano-stool iridium hydride complexes bearing phenylpyridine ligands are effective precatalysts for promoting the formation of element-hydrogen bonds using H2 as the stoichiometric H-atom source. Irradiation with blue light resulted in a profound enhancement of catalyst turnover for the iridium-catalyzed hydrogenation of the aryloxyl radical 2,4,6-tBu3-C6H2O• to the corresponding phenol. Monitoring the progress of the reaction revealed the formation of an iridium 3,3-dimethyl-2,3-dihydrobenzofuranyl compound arising from two C-H activation events following the proton-coupled electron transfer (PCET) step. Under thermal conditions, this compound was inactive for catalytic aryloxide hydrogenation, representing a deactivation pathway. Irradiation with blue light under H2 released the free heterocycle and regenerated the piano-stool iridium hydride precatalyst, establishing a pathway for catalyst recovery and overall enhanced turnover.

Phenoxythiazoline (FTz)-Cobalt(II) Precatalysts Enable C(sp2 )-C(sp3 ) Bond-Formation for Key Intermediates in the Synthesis of Toll-like Receptor 7/8 Antagonists.

Evaluation of the relative rates of the cobalt-catalyzed C(sp2 )-C(sp3 ) Suzuki-Miyaura cross-coupling between the neopentylglycol ester of 4-fluorophenylboronic acid and N-Boc-4-bromopiperidine established that smaller N-alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air-stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe⋅B(Oi Pr)3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise resulted in demetallation of the FI chelate. A first-order dependence on the cobalt precatalyst and a saturation regime in nucleophile were observed, supporting turnover-limiting transmetalation and the origin of the observed trends in N-imine substitution.

Arene Insertion with Pincer-Supported Molybdenum-Hydrides: Determination of Site Selectivity, Relative Rates, and Arene Complex Formation.

The synthesis of phosphino(oxazoline)pyridine-supported molybdenum(0) cycloocta-1,5-diene complexes is described. Exposure of these complexes to dihydrogen in the presence of an arene resulted in insertion of the substrate into the molybdenum hydride bond and afforded the corresponding molybdenum cyclohexadienyl hydrides. For mono- and disubstituted arenes, the site selectivity for insertion of the most substituted bond increases with increasing size of the substituent from methyl to ethyl, iso-propyl, and tert-butyl. In contrast, 1,3,5-trisubstituted arenes underwent insertion with exclusive site selectivity. Relative rates of insertion were determined by competition experiments and established faster insertions for electron-rich arenes. Introduction of electron-withdrawing trifluoromethyl groups on the arene resulted in decreased relative rates of insertion and an increased rate for H2 reductive elimination, favoring formation of the corresponding molybdenum η6-arene complex. Studies on the reductive elimination of the cyclohexadienyl ligand with the hydride enabled the synthesis of an enantioenriched cyclohexa-1,3-diene. This study provides new insights into the ligand requirements for catalytic arene hydrogenation and a new strategy for selective arene reduction.

CS-Symmetric Pyridine(diimine) Iron Methyl Complexes for Catalytic [2+2] Cycloaddition and Hydrovinylation: Metallacycle Geometry Determines Selectivity.

A series of CS-symmetric (aryl,alkyl)-substituted pyridine(dimine) iron methyl (CyARPDI)FeCH3 complexes have been prepared, characterized, and evaluated as precatalysts for the [2+2]-cycloaddition of butadiene and ethylene. Mixtures of vinylcyclobutane and (Z)-hexa-1,4-diene were observed in each case. By comparison, C2v-symmetric, arylated (PDI) iron catalysts are exclusively selective for reversible [2+2]-cycloaddition to yield vinylcyclobutane. The alteration in the chemoselectivity of the catalytic reaction was investigated through a combination of precatalyst stability studies, identification of catalytic resting state(s), and 2H and 13C isotopic labeling experiments. While replacement of an aryl-imine substituent with an N-alkyl group decreases the stability of the formally iron(0) dinitrogen and butadiene complexes, two diamagnetic metallacycles were identified as catalyst resting states. Deuterium labeling and NOESY/EXSY NMR experiments support 1,4-hexadiene arising from catalytic hydrovinylation involving reversible oxidative cyclization leading to accessible cis-metallacycle. Cyclobutane formation proceeds by irreversible C(sp3)-C(sp3) bond-forming reductive elimination from a trans-metallacycle. These studies provide key mechanistic understanding into the high selectivity of bis(arylated) pyridine(diimine) iron catalysts for [2+2]-cycloaddition, unique, thus far, to this class of iron catalysts.

Mechanistic Investigations of Phenoxyimine-Cobalt(II)-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling.

The mechanism of phenoxyimine (FI)-cobalt-catalyzed C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling was studied using a combination of kinetic measurements and catalytic and stoichiometric experiments. A series of dimeric (FI)cobalt(II) bromide complexes, [(4-CF3PhFI)CoBr]2, [(4-OMePhFI)CoBr]2, and [(2,6-diiPrPhFI)CoBr]2, were isolated and characterized by 1H and 19F NMR spectroscopies, solution and solid-state magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, X-ray crystallography, and diffusion-ordered NMR spectroscopy (DOSY). One complex, [(4-CF3PhFI)CoBr]2, was explored as a single-component precatalyst for C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling. Addition of potassium methoxide to [(4-CF3PhFI)CoBr]2 generated the corresponding (FI)cobalt(II) methoxide complex as determined by 1H and 19F NMR and EPR spectroscopies. These spectroscopic signatures were used to identify this compound as the resting state during catalytic C(sp2)-C(sp3) coupling. Variable time normalization analysis (VTNA) of in situ catalytic 19F NMR spectroscopic data was used to establish an experimental rate law that was first-order in a (FI)cobalt(II) precatalyst, zeroth-order in the alkyl halide, and first-order in an activated potassium methoxide-aryl boronate complex. These findings are consistent with turnover-limiting transmetalation that occurs prior to activation of the alkyl bromide electrophile. The involvement of boronate intermediates in transmetalation was corroborated by Hammett studies of electronically differentiated aryl boronic esters. Together, a cobalt(II)/cobalt(III) catalytic cycle was proposed that proceeds through a "boronate"-type mechanism.

Exploring the Effect of Pincer Rigidity on Oxidative Addition Reactions with Cobalt(I) Complexes.

Cobalt complexes containing the 2,6-diaminopyridine-substituted PNP pincer (iPrPNMeNP = 2,6-(iPr2PNMe)2(C5H3N)) were synthesized. A combination of solid-state structures and investigation of the cobalt(I)/(II) redox potential established a relatively rigid and electron-donating chelating ligand as compared to iPrPNP (iPrPNP = 2,6-(iPr2PCH2)2(C5H3N)). Based on a buried volume analysis, the two pincer ligands are sterically indistinguishable. Nearly planar, diamagnetic, four-coordinate complexes were observed independent of the field strength (chloride, alkyl, aryl) of the fourth ligand completing the coordination sphere of the metal. Computational studies supported a higher barrier for C-H oxidative addition, largely a result of the increased rigidity of the pincer. The increased oxidative addition barrier resulted in stabilization of (iPrPNMeNP)Co(I) complexes, enabling the characterization of the cobalt boryl and the cobalt hydride dimer by X-ray crystallography. Moreover, (iPrPNMeNP)CoMe served as an efficient precatalyst for alkene hydroboration likely because of the reduced propensity to undergo oxidative addition, demonstrating that reactivity and catalytic performance can be tuned by rigidity of pincer ligands.

Bimolecular Reductive Elimination of Ethane from Pyridine(diimine) Iron Methyl Complexes: Mechanism, Electronic Structure, and Entry into [2+2] Cycloaddition Catalysis.

The application of bimolecular reductive elimination to the activation of iron catalysts for alkene-diene cycloaddition is described. Key to this approach was the synthesis, characterization, electronic structure determination, and ultimately solution stability of a family of pyridine(diimine) iron methyl complexes with diverse steric properties and electronic ground states. Both the aryl-substituted, (MePDI)FeCH3 and (EtPDI)FeCH3 (RPDI = 2,6-(2,6-R2-C6H3N═CMe)2C5H3N), and the alkyl-substituted examples, (CyAPDI)FeCH3 (CyAPDI = 2,6-(C6H11N═CMe)2C5H3N), have molecular structures significantly distorted from planarity and S = 3/2 ground states. The related N-arylated derivative bearing 2,6-di-isopropyl aryl substituents, (iPrPDI)FeCH3, has an idealized planar geometry and exhibits spin crossover behavior from S = 1/2 to S = 3/2 states. At 23 °C under an N2 atmosphere, both (MePDI)FeCH3 and (EtPDI)FeCH3 underwent reductive elimination of ethane to form the iron dinitrogen precatalysts, [(MePDI)Fe(N2)]2(µ-N2) and [(EtPDI)Fe(N2)]2(µ-N2), respectively, while (iPrPDI)FeCH3 proved inert to C-C bond formation. By contrast, addition of butadiene to all three iron methyl complexes induced ethane formation and generated the corresponding iron butadiene complexes, (RPDI)Fe(η4-C4H6) (R = Me, Et, iPr), known precatalysts for the [2+2] cycloaddition of olefins and dienes. Kinetic, crossover experiments, and structural studies were combined with magnetic measurements and Mössbauer spectroscopy to elucidate the electronic and steric features of the iron complexes that enable this unusual reductive elimination and precatalyst activation pathway. Transmetalation of methyl groups between iron centers was fast at ambient temperature and independent of steric environment or spin state, while the intermediate dimer underwent the sterically controlled rate-determining reaction with either N2 or butadiene to access a catalytically active iron compound.

Identification of Cyclohexadienyl Hydrides as Intermediates in Molybdenum-Catalyzed Arene Hydrogenation.

Treatment of phosphino(imino)pyridine (PIP) molybdenum cyclooctadiene (COD) complexes [(PIP)Mo(COD)] with dihydrogen in the presence of benzene selectively furnished the molybdenum cyclohexadienyl hydrides [(PIP)MoH(η5 -C6 H7 )], which are precatalysts for the hydrogenation of benzene to cyclohexane. [(PIP)MoH(η5 -C6 H7 )] arises from a rarely observed insertion of benzene into a molybdenum-hydride bond, a key step in the molybdenum-catalyzed homogeneous hydrogenation of arenes. The reaction with toluene afforded a single isomer of the corresponding molybdenum cyclohexadienyl hydride while para-xylene predominantly formed the molybdenum η6 -arene complex with the insertion product being a minor component. Addition of carbon monoxide to a cyclohexane-d12 solution of [(PIP)MoH(η5 -C6 H7 )] liberated cyclohexadiene, providing experimental support for a higher kinetic barrier for the subsequent steps en route to cycloalkanes.

Catalytic N-H Bond Formation Promoted by a Ruthenium Hydride Complex Bearing a Redox-Active Pyrimidine-Imine Ligand.

The synthesis of a piano-stool ruthenium hydride, [(η5-C5Me5)Ru(PmIm)H] (PmIm = (N-(1,3,5-trimethylphenyl)-1-(pyrimidin-2-yl)ethan-1-imine), for the dual purpose of catalytic dihydrogen activation and subsequent hydrogen atom transfer for the formation of weak chemical bonds is described. The introduction of a neutral, potentially redox-active PmIm supporting ligand was designed to eliminate the possibility of deleterious C(sp2)-H reductive coupling and elimination that has been identified as a deactivation pathway with related rhodium and iridium catalysts. Treatment of [(η5-C5Me5)RuCl2]n with one equivalent PmIm ligand in the presence of zinc and sodium methoxide resulted in the isolation of the diruthenium complex, [(η5-C5Me5)Ru(PmIm)]2, arising from the C-C bond formation between two PmIm chelates. Addition of H2 to the ruthenium dimer under both thermal and blue light irradiation conditions furnished the targeted hydride, [(η5-C5Me5)Ru(PmIm)H], which has a relatively weak DFT-calculated Ru-H bond dissociation free energy (BDFE) of 47.9 kcal/mol. Addition of TEMPO to [(η5-C5Me5)Ru(PmIm)H] generated the 17-electron metalloradical, [(η5-C5Me5)Ru(PmIm)], which was characterized by EPR spectroscopy. The C-C bond forming process was reversible as the irradiation of [(η5-C5Me5)Ru(PmIm)]2 generated [(η5-C5Me5)Ru(PmIm)H] and a piano-stool ruthenium complex containing an enamide ligand derived from H-atom abstraction from the PmIm chelate. Equilibration studies were used to establish an experimental estimate of the effective Ru-H BDFE, and a value of 50.8 kcal/mol was obtained, in agreement with the observed loss of H2 and the DFT-computed value. The ruthenium hydride was an effective catalyst for the thermal catalytic hydrogenation of TEMPO, acridine, and a cobalt-imido complex and for the selective reduction of azobenzene to diphenylhydrazine, highlighting the role of this complex in catalytic weak bond formation using H2 as the stoichiometric reductant.

C-H Activation by Isolable Cationic Bis(phosphine) Cobalt(III) Metallacycles.

Five- and six-coordinate cationic bis(phosphine) cobalt(III) metallacycle complexes were synthesized with the general structures, [(depe)Co(cycloneophyl)(L)(L')][BArF4] (depe = 1,2-bis(diethylphosphino)ethane; cycloneophyl = [κ-C:C-(CH2C(Me)2)C6H4]; L/L' = pyridine, pivalonitrile, or the vacant site, BAr4F = B[(3,5-(CF3)2)C6H3]4). Each of these compounds promoted facile directed C(sp2)-H activation with exclusive selectivity for ortho-alkylated products, consistent with the selectivity of reported cobalt-catalyzed arene-alkene-alkyne coupling reactions. The direct observation of C-H activation by cobalt(III) metallacycles provided experimental support for the intermediacy of these compounds in this class of catalytic C-H functionalization reaction. Deuterium labeling and kinetic studies provided insight into the nature of C-H bond cleavage and C-C bond reductive elimination from isolable cobalt(III) precursors.

Alcohol Synthesis by Cobalt-Catalyzed Visible-Light-Driven Reductive Hydroformylation.

A cobalt-catalyzed reductive hydroformylation of terminal and 1,1-disubstituted alkenes is described. One-carbon homologated alcohols were synthesized directly from CO and H2, affording anti-Markovnikov products (34-87% yield) with exclusive regiocontrol (linear/branch >99:1) for minimally functionalized alkenes. Irradiation of the air-stable cobalt hydride, (dcype)Co(CO)2H (dcype = dicyclohexylphosphinoethane) with blue light generated the active catalyst that mediates alkene hydroformylation and subsequent aldehyde hydrogenation. Mechanistic origins of absolute regiocontrol were investigated by in situ monitoring of the tandem catalytic reaction using multinuclear NMR spectroscopy with syngas mixtures.

C(sp2)-H Activation with Bis(silylene)pyridine Cobalt(III) Complexes: Catalytic Hydrogen Isotope Exchange of Sterically-Hindered C-H Bonds.

The bis(silylene)pyridine cobalt(III) dihydride boryl, trans-[ ptol SiNSi]Co(H)2BPin (ptolSiNSi = 2,6-[EtNSi(NtBu)2CAr]2 C5H3N, where Ar = C6H5CH3, and Pin =pinacolato) has been used as a precatalyst for the hydrogen isotope exchange (HIE) of arenes and heteroarenes using benzene-d 6 as the deuterium source. Use of D2 as the source of the isotope produced modest levels of deuterium incorporation and stoichiometric studies established modification of the pincer ligand through irreversible addition of H2 across the silylene leading to catalyst deactivation. High levels of deuterium incorporation were observed with benzene-d 6 as the isotope source and enabled low (0.5 - 5 mol%) loadings of the cobalt precursor. The resulting high activity for C-H activation enabled deuterium incorporation at sterically encumbered sites previously inaccessible with first-row metal HIE catalysts. The cobalt-catalyzed method was also compatible with aryl halides, demonstrating a kinetic preference for chemoselective C(sp2)-H activation over C(sp2)-X (X = Cl, Br) bonds. Monitoring the catalytic reaction by NMR spectroscopy established cobalt(III) resting states at both low and high conversions of substrate and the overall performance was inhibited by the addition of HBPin. Studies on precatalyst activation with cis-[ ptol SiNSi]Co(Bf)2H and cis-[ ptol SiNSi]Co(H)2Bf (where Bf = 2-benzofuranyl), support the intermediacy of bis(hydride)aryl cobalt intermediates as opposed to bis(aryl)hydride cobalt complexes in the catalytic HIE method. Mechanistic insights resulted in an improved protocol using [ ptol SiNSi]Co(H)3 NaBHEt3 as the precatalyst, ultimately translating onto higher levels of isotopic incorporation.

Cobalt-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling Enabled by Well-Defined Precatalysts with L,X-Type Ligands.

Cobalt(II) halides in combination with phenoxy-imine (FI) ligands generated efficient precatalysts in situ for the C(sp2)-C(sp3) Suzuki-Miyaura cross coupling between alkyl bromides and neopentylglycol (hetero)arylboronic esters. The protocol enabled efficient C-C bond formation with a host of nucleophiles and electrophiles (36 examples, 34-95%) with precatalyst loadings of 5 mol%. Studies with alkyl halide electrophiles that function as radical clocks support the intermediacy of alkyl radicals during the course of the catalytic reaction. The improved performance of the FI-cobalt catalyst was correlated with decreased lifetimes of cage-escaped radicals as compared to diamine-type ligands. Studies of the phenoxy(imine)-cobalt coordination chemistry validate the L,X interaction leading to the discovery of an optimal, well defined, air-stable mono-FI cobalt(II) precatalyst structure.