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.

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.

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.

Molybdenum-Catalyzed Asymmetric Hydrogenation of Fused Arenes and Heteroarenes.

The synthesis of enantioenriched molybdenum precatalysts for the asymmetric hydrogenation of substituted quinolines and naphthalenes is described. Three classes of pincer ligands with chiral substituents were evaluated as supporting ligands in the molybdenum-catalyzed hydrogenation reactions, where oxazoline imino(pyridine) chelates were identified as optimal. A series of 2,6-disubstituted quinolines was hydrogenated to enantioenriched decahydroquinolines with high diastereo- and enantioselectivities. For quinoline derivatives, selective hydrogenation of both the carbocycle and heterocycle was observed depending on the ring substitution. Spectroscopic and mechanistic studies established molybdenum η6-arene complexes as the catalyst resting state and that partial hydrogenation arises from dissociation of the substrate from the coordination sphere of molybdenum prior to complete reduction. A stereochemical model is proposed based on the relative energies of the respective coordination of the prochiral faces of the arene determined by steric interactions between the substrate and the chiral ligand, rather than through precoordination by a heteroatom.

Development of Cobalt Catalysts for the meta-Selective C(sp2)-H Borylation of Fluorinated Arenes.

Cobalt precatalysts for the meta-selective borylation of fluorinated arenes are described. Initial screening and stoichiometric reactivity studies culminated in the preparation of a cobalt alkyl precatalyst supported by the sterically protected terpyridine (5,5″-Me2ArTpy = 4'-(4-N,N'-dimethylaminophenyl)-5,5″-dimethyl-2,2':6',2″-terpyridine). Under the optimized conditions, borylation with this precatalyst afforded up to 16 turnovers and near-exclusive meta regioselectivity with a range of substituted fluoroarenes in cyclopentyl methyl ether solvent at room temperature. Deuterium kinetic isotope effects of 2.9(2) at 23 °C support a turnover-limiting and selectivity-determining C(sp2)-H activation step, and stoichiometric C-H activation experiments provided insights into the identity of the C-H activating intermediate in catalysis. Analysis of the relevant Co-C and C-H bond thermodynamics support that the thermodynamics of C-H activation favor ortho-to-fluorine selectivity, providing additional, indirect support for kinetic control of C-H activation as the origin of meta selectivity.

Visible-Light-Driven, Iridium-Catalyzed Hydrogen Atom Transfer: Mechanistic Studies, Identification of Intermediates, and Catalyst Improvements.

The harvesting of visible light is a powerful strategy for the synthesis of weak chemical bonds involving hydrogen that are below the thermodynamic threshold for spontaneous H2 evolution. Piano-stool iridium hydride complexes are effective for the blue-light-driven hydrogenation of organic substrates and contra-thermodynamic dearomative isomerization. In this work, a combination of spectroscopic measurements, isotopic labeling, structure-reactivity relationships, and computational studies has been used to explore the mechanism of these stoichiometric and catalytic reactions. Photophysical measurements on the iridium hydride catalysts demonstrated the generation of long-lived excited states with principally metal-to-ligand charge transfer (MLCT) character. Transient absorption spectroscopic studies with a representative substrate, anthracene revealed a diffusion-controlled dynamic quenching of the MLCT state. The triplet state of anthracene was detected immediately after the quenching events, suggesting that triplet-triplet energy transfer initiated the photocatalytic process. The key role of triplet anthracene on the post-energy transfer step was further demonstrated by employing photocatalytic hydrogenation with a triplet photosensitizer and a HAT agent, hydroquinone. DFT calculations support a concerted hydrogen atom transfer mechanism in lieu of stepwise electron/proton or proton/electron transfer pathways. Kinetic monitoring of the deactivation channel established an inverse kinetic isotope effect, supporting reversible C(sp2)-H reductive coupling followed by rate-limiting ligand dissociation. Mechanistic insights enabled design of a piano-stool iridium hydride catalyst with a rationally modified supporting ligand that exhibited improved photostability under blue light irradiation. The complex also provided improved catalytic performance toward photoinduced hydrogenation with H2 and contra-thermodynamic isomerization.

Effect of Pincer Methylation on the Selectivity and Activity in (PNP)Cobalt-Catalyzed C(sp2)-H Borylation.

Cobalt complexes supported by a tetramethylated PNP pincer ligand (Me4 iPrPNP = 2,6-(iPr2PCMe2)2(C5H3N)) have been synthesized and structurally characterized. Examples include cobalt(I)-choride, -methyl, -aryl and -benzofuranyl derivatives. The performance of these compounds was evaluated in the catalytic borylation of fluorinated arenes using B2Pin2 as the boron source. While P-C bond cleavage, a known deactivation pathway in [(PNP)Co]-catalyzed borylation was suppressed, the overall activity and selectivity of the borylation of fluoroarenes was reduced as compared to the previously reported [(PNP)Co] catalyst lacking isopropylene spacers. Stoichiometric reactions support an increased barrier for oxidative addition to cobalt(I), a result of the increased steric profile and decreased conformational flexibility of the pincer resulting from methylation distal to the active site. With a more activated substrate such as benzofuran, catalytic borylation with cobalt(I) precatalysts and HBPin was observed. Monitoring the progress of the reaction by NMR spectroscopy revealed the presence of cobalt(III) intermediates during the course of the borylation, supporting a cobalt(I)-(III) redox cycle.

Catalyst Design Principles Enabling Intermolecular Alkene-Diene [2+2] Cycloaddition and Depolymerization Reactions.

Aryl-substituted pyridine(diimine) iron complexes promote the catalytic [2 + 2] cycloadditions of alkenes and dienes to form vinylcyclobutanes as well as the oligomerization of butadiene to generate divinyl(oligocyclobutane), a microstructure of poly(butadiene) that is chemically recyclable. A systematic study on a series of iron butadiene complexes as well as their ruthenium congeners has provided insights into the essential features of the catalyst that promotes these cycloaddition reactions. Structural and computational studies on iron butadiene complexes identified that the structural rigidity of the tridentate pincer enables rare s-trans diene coordination. This geometry, in turn, promotes dissociation of one of the alkene arms of the diene, opening a coordination site for the incoming substrate to engage in oxidative cyclization. Studies on ruthenium congeners established that this step occurs without redox involvement of the pyridine(diimine) chelate. Cyclobutane formation occurs from a metallacyclic intermediate by reversible C(sp3)-C(sp3) reductive coupling. A series of labeling experiments with pyridine(diimine) iron and ruthenium complexes support the favorability of accessing the +3 oxidation state to trigger C(sp3)-C(sp3) reductive elimination, involving spin crossover from S = 0 to S = 1. The high density of states of iron and the redox-active pyridine(diimine) ligand facilitate this reactivity under thermal conditions. For the ruthenium congener, the pyridine(diimine) remains redox innocent and irradiation with blue light was required to promote the analogous reactivity. These structure-activity relationships highlight important design principles for the development of next generation catalysts for these cycloaddition reactions as well as the promotion of chemical recycling of cycloaddition polymers.

A Tutorial on Selectivity Determination in C(sp2)-H Oxidative Addition of Arenes by Transition Metal Complexes.

A Tutorial on factors that determine the selectivity in C(sp2)-H activation and functionalization reactions involving two-electron oxidative addition processes with transition metals is presented. The interplay of the thermodynamics of C(sp2)-H oxidative addition and kinetic influences upon regioselectivity are presented alongside pedagogically valuable experimental and computational results from the literature. Mechanisms and energetics of chelate-assisted C(sp2)-H oxidative addition are examined, as are concepts related to chemoselectivity in the oxidative addition of C(sp2)-H or C(sp2)-X (X = F, Cl, Br, I) bonds with aryl halide substrates.

Mechanistic Origins of Regioselectivity in Cobalt-Catalyzed C(sp2)-H Borylation of Benzoate Esters and Arylboronate Esters.

Synthetic and mechanistic investigations into the C(sp2)-H borylation of various electronically diverse arenes catalyzed by bis(phosphine)pyridine (iPrPNP) cobalt complexes are reported. Borylation of various benzoate esters and arylboronate esters gave remarkably high selectivities for the position para to the functional group; in both cases, this regioselectivity was found to override the ortho to fluorine regioselectivity previously reported for (iPrPNP)Co borylation catalysts which arises from thermodynamic control of C(sp2)-H oxidative addition. Mechanistic studies support two distinct pathways that result in para-to-ester and para-to-boronate ester regioselectivity by thermodynamic and kinetic control, respectively, of C(sp2)-H oxidative addition. Borylation of a particularly electron-deficient fluorinated arylboronate ester resulted in acceleration of C(sp2)-H oxidative addition and concomitant inversion of regioselectivity, demonstrating that subtle changes in the relative rates of individual steps of the catalytic cycle can enable unique and switchable site selectivities.

C(sp2)-H Borylation of Heterocycles by Well-Defined Bis(silylene)pyridine Cobalt(III) Precatalysts: Pincer Modification, C(sp2)-H Activation and Catalytically Relevant Intermediates.

Well-defined bis(silylene)pyridine cobalt(III) precatalysts for C(sp2)-H borylation have been synthesized and applied to the investigation of the mechanism of the catalytic borylation of furans and pyridines. Specifically, [( Ar SiNSi)CoH3]·NaHBEt3 ( Ar SiNSi = 2,6-[EtNSi(NtBu)2CAr]2C5H3N, Ar = C6H5 (1-H 3 ·NaHBEt 3 ), 4-MeC6H4 (2-H 3 ·NaHBEt 3 )) and trans-[( Ar SiNSi)Co(H)2BPin] (Ar = C6H5 (1-(H) 2 BPin), 4-MeC6H4 (2-(H) 2 BPin), Pin = pinacolato) were prepared and employed as single component precatalysts for the C(sp2)-H borylation of 2-methylfuran, benzofuran and 2,6-lutidine. The cobalt(III) precursors, 2-H 3 ·NaHBEt 3 and 2-(H) 2 BPin also promoted C(sp2)-H activation of benzofuran, yielding [(ArSiNSi)CoH(Bf)2] (Ar = 4-MeC6H4, 2-H(Bf) 2 , Bf = 2-benzofuranyl). Monitoring the catalytic borylation of 2-methylfuran and 2,6-lutidine by 1H NMR spectroscopy established the trans-dihydride cobalt(III) boryl as the catalyst resting state at low substrate conversion. At higher conversion two distinct pincer modification pathways were identified, depending on the substrate and the boron source.

Synthesis and Reactivity of Organometallic Intermediates Relevant to Cobalt-Catalyzed Hydroformylation.

Intermediates relevant to cobalt-catalyzed alkene hydroformylation have been isolated and evaluated in fundamental organometallic transformations relevant to aldehyde formation. The 18-electron (R,R)-(iPr DuPhos)Co(CO)2 H has been structurally characterized, and it promotes exclusive hydrogenation of styrene in the presence of 50 bar of H2 /CO gas (1:1) at 100 °C. Deuterium-labeling studies established reversible 2,1-insertion of styrene into the Co-D bond of (R,R)-(iPr DuPhos)Co(CO)2 D. Whereas rapid ß-hydrogen elimination from cobalt alkyls occurred under an N2 atmosphere, alkylation of (R,R)-(iPr DuPhos)Co(CO)2 Cl in the presence of CO enabled the interception of (R,R)-(iPr DuPhos)Co(CO)2 C(O)CH2 CH2 Ph, which upon hydrogenolysis under 4 atm H2 produced the corresponding aldehyde and cobalt hydride, demonstrating the feasibility of elementary steps in hydroformylation. Both the hydride and chloride derivatives, (X=H- , Cl- ), underwent exchange with free 13 CO. Under reduced pressure, (R,R)-(iPr DuPhos)Co(CO)2 Cl underwent CO dissociation to form (R,R)-(iPr DuPhos)Co(CO)Cl.

A Boron Activating Effect Enables Cobalt-Catalyzed Asymmetric Hydrogenation of Sterically Hindered Alkenes.

Unsymmetric 1,1-diboryl alkenes bearing one -[BPin] (BPin = pinacolatoboryl) and one -[BDan] (BDan = 1,8-diaminonaphthalatoboryl) substituent each were hydrogenated in high yield and enantioselectivity using C1-symmetric pyridine(diimine) (PDI) cobalt complexes. High activities and stereoselectivities were observed with an array of 2-alkyl-, 2-aryl-, and 2-boryl-substituted 1,1-diboryl alkenes, giving rise to enantioenriched diborylalkane building blocks. Systematic study of substrate substituent effects identified competing steric and electronic demands in the key activating role of the boron substituents, whereby sterically unencumbered boronates such as -[BDan], -[BCat] (BCat = catecholatoboryl), and -[Beg] (Beg = ethylene glycolatoboryl) promote the hydrogenation of trisubstituted alkenes by enabling irreversible α-boron-directed insertion pathways to achieve otherwise challenging hydrogenations of trisubstituted alkenes. Deuterium-labeling studies with 1,1-diboryl alkenes support an insertion pathway generating a chiral intermediate with two different boron substituents and cobalt bound to the same carbon.

Synthesis, Structure, and Hydrogenolysis of Pyridine Dicarbene Iron Dialkyl Complexes.

Two methods for the synthesis of bis(imidazol-2-ylidene)pyridine iron dialkyl complexes, (CNC)Fe(CH2SiMe3)2, have been developed. The first route consists of addition of two equivalents of LiCH2SiMe3 to the iron dihalide complex, (CNC)FeBr2, while the second relies on addition of the free CNC ligand to readily-prepared (py)2Fe(CH2SiMe3)2 (py = pyridine). With aryl-substituted CNC ligands, octahedral complexes of the type ( Ar CNC)Fe(CH2SiMe3)2(N2) ( Ar CNC = bis(arylimidazol-2-ylidene)pyridine) were isolated, where the dinitrogen ligand occupies the site trans to the pyridine of the CNC-chelate. In contrast, the alkyl-substituted variant, (tBuACNC)Fe(CH2SiMe3)2 (tBuACNC = 2,6-(tBu-imidazol-2-ylidene)2pyridine) was isolated as the five-coordinate compound lacking dinitrogen. Exposure of the ( Ar CNC)Fe(CH2SiMe3)2(N2) derivatives to an H2 atmosphere resulted in formation of the corresponding iron hydride complexes ( Ar CNC)FeH4. These compounds catalyzed hydrogen isotope exchange between the deuterated benzene solvent and H2, generating isotopologues and isotopomers of ( Ar CNC)Fe(H n )(D4-n ) (n = 0-4). When (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2) (3,5-Me2 MesCNC = 2,6-(2,4,6-Me3-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) was treated successively with H2 and then N2, the corresponding reduced dinitrogen complex (3,5-Me2 MesCNC)Fe(N2)2 was isolated. The same product was also obtained following addition of pinacolborane to (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2).

Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic Control of C(sp2)-H Oxidative Addition Results in ortho-to-Fluorine Selectivity.

The mechanism of C(sp2)-H borylation of fluorinated arenes with B2Pin2 (Pin = pinacolato) catalyzed by bis(phosphino)pyridine (iPrPNP) cobalt complexes was studied to understand the origins of the uniquely high ortho-to-fluorine regioselectivity observed in these reactions. Variable time normalization analysis (VTNA) of reaction time courses and deuterium kinetic isotope effect measurements established a kinetic regime wherein C(sp2)-H oxidative addition is fast and reversible. Monitoring the reaction by in situ NMR spectroscopy revealed the intermediacy of a cobalt(I)-aryl complex that was generated with the same high ortho-to-fluorine regioselectivity associated with the overall catalytic transformation. Deuterium labeling experiments and stoichiometric studies established C(sp2)-H oxidative addition of the fluorinated arene as the selectivity-determining step of the reaction. This step favors the formation of ortho-fluoroaryl cobalt intermediates due to the ortho fluorine effect, a phenomenon whereby ortho fluorine substituents stabilize transition metal-carbon bonds. Computational studies provided evidence that the cobalt-carbon bonds of the relevant intermediates in (iPrPNP)Co-catalyzed borylation are strengthened with increasing ortho fluorine substitution. The atypical kinetic regime involving fast and reversible C(sp2)-H oxidative addition in combination with the thermodynamic preference for forming cobalt-aryl bonds adjacent to fluorinated sites are the origin of the high regioselectivity in the catalytic borylation reaction.