Abstract: ConspectusThe hydrogenation of alkenes is one of the most impactful reactions catalyzed by homogeneous transition metal complexes finding application in the pharmaceutical, agrochemical, and commodity chemical industries. For decades, catalyst technology has relied on precious metal catalysts supported by strong field ligands to enable highly predictable two-electron redox chemistry that constitutes key bond breaking and forming steps during turnover. Alternative catalysts based on earth abundant transition metals such as iron and cobalt not only offer potential environmental and economic advantages but also provide an opportunity to explore catalysis in a new chemical space. The kinetically and thermodynamically accessible oxidation and spin states may enable new mechanistic pathways, unique substrate scope, or altogether new reactivity. This Account describes my group’s efforts over the past decade to develop iron and cobalt catalysts for alkene hydrogenation. Particular emphasis is devoted to the inter...

Abstract: The direct functionalization of unactivated sp(3) C-H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp(3) C-H bonds in C-C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C-H bonds (that is, C-H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C-C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug's action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C-H arylation. This C-C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C-H bonds.

Abstract: Direct olefinic C–H functionalization represents the ideal way of introducing an alkenyl group into organic molecules. A well-known process is the Heck reaction, which involves alkene insertion and β-hydride elimination in the presence of a transition metal. However, the traditional Heck reaction mainly deals with the alkenylation of aryl or vinyl electrophiles. Recent developments have revealed that alkenylation can also be achieved through radical addition to alkenes and following single-electron-transfer (SET) oxidation/elimination. The radical alkenylation pathway allows alkenylation with a variety of carbon-centered radicals and even heteroatom-centered radicals. This tutorial review gives an overview of recent advances in this emerging field.

Abstract: An efficient palladium-catalyzed Heck-type reaction of fluoroalkyl halides, including perfluoroalkyl bromides, trifluoromethyl iodides, and difluoroalkyl bromides, has been developed. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, and provides a general and straightforward access to fluoroalkylated alkenes which are of interest in life and material sciences.

Abstract: Here we describe a dual catalyst system comprised of an iridium photocatalyst and weak phosphate base that is capable of both selectively homolyzing the N-H bonds of N-arylamides (bond dissociation free energies ∼ 100 kcal/mol) via concerted proton-coupled electron transfer (PCET) and mediating efficient carboamination reactions of the resulting amidyl radicals. This manner of PCET activation, which finds its basis in numerous biological redox processes, enables the formal homolysis of a stronger amide N-H bond in the presence of weaker allylic C-H bonds, a selectivity that is uncommon in conventional molecular H atom acceptors. Moreover, this transformation affords access to a broad range of structurally complex heterocycles from simple amide starting materials. The design, synthetic scope, and mechanistic evaluation of the PCET process are described.

Abstract: Tertiary carbon radicals have notable utility for uniting complex carbon fragments with concomitant formation of new quaternary carbons. This article explores the scope, limitations, and certain mechanistic aspects of Okada’s method for forming tertiary carbon radicals from N-(acyloxy)phthalimides by visible-light photocatalysis. Optimized conditions for generating tertiary radicals from N-(acyloxy)phthalimide derivatives of tertiary carboxylic acids by visible-light irradiation in the presence of 1 mol % of commercially available Ru(bpy)3(PF6)2, diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (8), and i-Pr2NEt and their coupling in dichloromethane at room temperature with alkene acceptors were developed. Four representative tertiary N-(acyloxy)phthalimides and 15 alkene radical acceptors were examined. Both reductive couplings with electron-deficient alkenes and radical substitution reactions with allylic and vinylic bromides and chlorides were examined with many such reactions occurring in go...

Abstract: A cooperative Cu/Pd-catalyzed asymmetric three-component reaction of styrenes, B2(pin)2, and allyl carbonates was reported. This reaction, in the presence of chiral CuOAc/SOP and achiral Pd(dppf)Cl2 catalysts, occurs smoothly with high enantioselectivities (up to 97% ee) . The allylboration products, which contain alkene (or diene) unite and alkylboron group, are easily functionalized. The utility of this protocol was demonstrated through the synthesis of an antipsychotic drug, (−)-preclamol.

Abstract: Alkenes are the most ubiquitous prochiral functional groups--those that can be converted from achiral to chiral in a single step--that are accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes (whereby two functional groups are added to the same double bond) are particularly important, as they can be used to produce highly complex molecular architectures. Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation, are well established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbon- and nitrogen-based functionalities stereoselectively across an alkene has not been reported. Here we describe the rhodium-catalysed carboamination of alkenes at the same (syn) face of a double bond, initiated by a carbon-hydrogen activation event that uses enoxyphthalimides as the source of both the carbon and the nitrogen functionalities. The reaction methodology allows for the intermolecular, stereospecific formation of one carbon-carbon and one carbon-nitrogen bond across an alkene, which is, to our knowledge, unprecedented. The reaction design involves the in situ generation of a bidentate directing group and the use of a new cyclopentadienyl ligand to control the reactivity of rhodium. The results provide a new way of synthesizing functionalized alkenes, and should lead to the convergent and stereoselective assembly of amine-containing acyclic molecules.

Abstract: Alkene hydrosilylation is typically performed with Pt catalysts, but inexpensive base-metal catalysts would be preferred. We report a Co catalyst for anti-Markovnikov alkene hydrosilylation that can be used without added solvent at low temperatures with low loadings, and can be generated in situ from an air-stable precursor that is simple to synthesize from low-cost, commercially available materials. In addition, a mixture of Co catalysts performs a tandem catalytic alkene isomerization/hydrosilylation reaction that converts multiple isomers of hexene to the same terminal product. This regioconvergent reaction uses isomerization as a benefit rather than a hindrance.

Abstract: Nickel(0) catalysts have proven to be powerful tools for multicomponent coupling reactions in our laboratories over the past 15 years. This interest was originally sparked by the ubiquity of allylic alcohol motifs in natural products, such as (-)-terpestacin, which we envisioned assembling by the coupling of two π components (alkyne and aldehyde) with concomitant reduction. Mechanistic investigations allowed us to elucidate several modes of controlling the regioselectivity and stereoselectivity in the oxidative cyclization, and these insights enabled us to leverage combinations of alkenes and phosphine ligands to direct regioselective outcomes. The initial success in developing the first intermolecular reductive alkyne-aldehyde coupling reaction launched a series of methodological investigations that rapidly expanded to include coupling reactions of alkynes with other electrophilic π components, such as imines and ketones, as well as electrophilic σ components, such as epoxides. Aziridines proved to be more challenging substrates for reductive coupling, but we were recently able to demonstrate that cross-coupling of aziridines and alkylzinc reagents is smoothly catalyzed by a zero-valent nickel/phenanthroline system. Moreover, the enantioselective alkyne-aldehyde coupling and the development of novel P-chiral ferrocenyl ligands enabled the total synthesis of (-)-terpestacin, amphidinolides T1 and T4, (-)-gloeosporone, and pumiliotoxins 209F and 251D. We subsequently determined that alkenes could be used in place of alkynes in several nickel-catalyzed reactions when a silyl triflate activating agent was added. We reason that such an additive functions largely to enhance the electrophilicity of the metal center by coordination to the electrophilic π component, such that less nucleophilic alkene π donors can undergo productive combination with nickel complexes. This activation manifold was further demonstrated to be effective for alkene-aldehyde couplings. In a related manner, electrophilic promoters were also successfully employed for allylic substitution reactions of allylic carbonates with simple alkenes and in the Mizoroki-Heck reaction of both benzyl and aryl electrophiles. In these instances, it is proposed that counterion exchange from a more strongly coordinating anion to the weakly or noncoordinating triflate counterion enables reaction at an electrophilic Ni(II) center rather than by coordination to one of the coupling components. Mechanistic insights also played an important role in the development of mixed N-heterocyclic carbene/phosphite ligand systems to overcome challenges in regioselective alkene-aldehyde coupling reactions. We hope that, taken together, the body of work summarized in this Account demonstrates the constructive interplay among total synthesis, methodological development, and mechanistic investigation that has driven our research program.

Abstract: ConspectusThe development of catalytic enantioselective transformations has been the focus of many research groups over the past half century and is of paramount importance to the pharmaceutical and agrochemical industries. Since the award of the Nobel Prize in 2001, the field of enantioselective transition metal catalysis has soared to new heights, with the development of more efficient catalysts and new catalytic transformations at increasing frequency. Furthermore, catalytic reactions that allow higher levels of redox- and step-economy are being developed. Thus, alternatives to asymmetric alkene dihydroxylation and the enantioselective reduction of α,β-unsaturated ketones can invoke more strategic C–C bond forming reactions, such as asymmetric aldol reactions of an aldehyde with α-hydroxyketone donors or enantioselective alkynylation of an aldehyde, respectively. To facilitate catalytic enantioselective addition reactions, including the aforementioned aldol and alkynylation reactions, our lab has devel...

Abstract: Cycloadditions, such as the [4+2] Diels-Alder reaction to form six-membered rings, are among the most powerful and widely used methods in synthetic chemistry. The analogous [2+2] alkene cycloaddition to synthesize cyclobutanes is kinetically accessible by photochemical methods, but the substrate scope and functional group tolerance are limited. Here, we report iron-catalyzed intermolecular [2+2] cycloaddition of unactivated alkenes and cross cycloaddition of alkenes and dienes as regio- and stereoselective routes to cyclobutanes. Through rational ligand design, development of this base metal-catalyzed method expands the chemical space accessible from abundant hydrocarbon feedstocks.

Abstract: Conventional approaches to Pd-catalyzed alkene 1,2-carboamination rely upon the combination of a nucleophilic nitrogen-based component and an internal C-based or external oxidant. In this study, we outline an umpolung approach, which is triggered by oxidative initiation at an electrophilic N-based component and employs “standard” organometallic nucleophiles to introduce the new carbon-based fragment. Specifically, oxidative addition of a Pd(0)-catalyst into the N–O bond of O-pentafluorobenzoyl oxime esters generates imino-Pd(II) intermediates, which undergo 5-exo cyclization with sterically diverse alkenes. The resultant alkyl-Pd(II) intermediates are intercepted by organometallic nucleophiles or alcohols, under carbonylative or noncarbonylative conditions, to provide 1,2-carboamination products. This approach provides, for the first time, a unified strategy for achieving alkene 1,2-amino-acylation, -carboxylation, -arylation, -vinylation, and -alkynylation. For carbonylative processes, orchestrated proto...

Abstract: A novel copper-catalyzed regiodivergent alkylboration of alkenes with bis(pinacolato)diboron and alkyl halides has been developed. The regioselectivity of the alkylboration was controlled by subtle differences in the ligand structure. The reaction thus enables the practical, regiodivergent synthesis of two different alkyl boronic esters with complex structures from a single alkene.

Abstract: Chemoselective C(sp(3))-C(sp(2)) coupling reactions under mild reaction conditions are useful for synthesizing alkyl-substituted alkenes having sensitive functional groups. Reported here is a visible-light-induced chemoselective alkenylation through a deboronation/decarboxylation sequence under neutral aqueous reaction conditions at room temperature. This reaction represents the first hypervalent-iodine-enabled radical decarboxylative alkenylation reaction, and a novel benziodoxole-vinyl carboxylic acid reaction intermediate was isolated. This C(sp(3))-C(sp(2)) coupling reaction leads to aryl-and acyl-substituted alkenes containing various sensitive functional groups. The excellent chemoselectivity, stable reactants, and neutral aqueous reaction conditions of the reaction suggest future biomolecule applications.

Abstract: An elegant approach for fast polymer postfunctionalization and step-growth polymerization (via addition reaction) under aerobic condition was developed from visible light photocatalytic thiol–ene “click” reaction, employing Ru(bpy)3Cl2 as photoredox catalyst and p-toluidine as redox mediator. The nature of the photoredox catalysts, thiol substrates, and solvents were extensively investigated for this reaction with two types of alkene polymers: polybutadiene and poly(allyl methacrylate)s. The use of N-methyl-2-pyrrolidone as the solvent and p-toluidine as redox mediator remarkably improved the reaction rates and limited the formation of side products. Finally, this highly efficient thiol–ene reaction was employed for the synthesis of polymers by step-growth addition polymerization.

Abstract: A regio- and stereoselective synthesis of trifluoromethylated alkenes bearing four different substituents has been developed. Stereocontrolled sulfonyloxytrifluoromethylation of unsymmetric internal alkynes with an electrophilic CF3 reagent, namely the triflate salt of the Yagupol’skii–Umemoto reagent, in the presence of an Ir photoredox catalyst under visible-light irradiation afforded trifluoromethylalkenyl triflates with well-predictable stereochemistry resulting from anti addition of the trifluoromethyl and triflate groups. Subsequent palladium-catalyzed cross-couplings led to tetrasubstituted trifluoromethylated alkenes in a highly stereoselective manner. The present method is the first example of a facile one-pot synthesis of tetrasubstituted trifluoromethylated alkenes from simple alkynes.

Abstract: A method for the diastereoselective carboboration of 1,2-disubstituted styrenes with aryl/vinyl bromides and (Bpin)2 is reported. High diastereoselectivities and yields are observed for the formation of either diastereomer of the product from a single alkene isomer. These reactions provide access to a diverse range of structures from simple starting materials.

Abstract: We report a new synthetic strategy for the fabrication of several supported nickel phosphides (Ni12P5, Ni2P, and NiP2) with particle size ranging from 5 to 15 nm via a two-step procedure: preparation of supported Ni particles from layered double hydroxide precursors, followed by a further reaction with a certain amount of red phosphorus. The selective hydrogenation of phenylacetylene over these metal phosphides was evaluated, and the as-prepared Ni2P/Al2O3 catalyst shows a much higher selectivity to styrene (up to 88.2%) than Ni12P5/Al2O3 (48.0%), NiP2/Al2O3 (65.9%), and Ni/Al2O3 (0.7%) catalysts. EXAFS and in situ IR measurements reveal that the incorporation of P increases the bond length of Ni–Ni, which imposes a key influence on the adsorption state of alkene intermediates: as the Ni–Ni bond length extends to 0.264 nm, the alkene intermediate undergoes di-π(C═C) adsorption, facilitating its desorption and the resulting enhanced selectivity. Moreover, electron transfer occurs from Ni to P, as confirmed...

Abstract: A method for the catalytic enantioselective diarylation of alkenes is presented. The method allowed for the synthesis of highly enantioenriched 2,3-dihydrobenzofurans and indolines containing molecules from readily available substrates. Furthermore, this method allowed for the enantioselective synthesis of quaternary carbons. Based on mechanism studies, the process likely functions by enantioselective insertion of an alkene into an Ar-CuBenzP* complex to generate a Csp(3)-Cu complex. Capture of this intermediate with an ArX led to formation of the desired product.

Abstract: A novel and efficient palladium-catalyzed hydroaminocarbonylation of alkenes with aminals has been developed under mild reaction conditions, and allows the synthesis of a wide range of N-alkyl linear amides in good yields with high regioselectivity. On the basis of this method, a cooperative catalytic system operating by the synergistic combination of palladium, paraformaldehyde, and acid was established for promoting the hydroaminocarbonylation of alkenes with both aromatic and aliphatic amines, which do not react well under conventional palladium-catalyzed hydroaminocarbonylation.

Abstract: A dual catalytic approach enlisting gold and iron synergy is described. This method offers readily access to substituted heterocycle aldehydes via oxygen radical addition to vinyl–gold intermediates under Fe catalyst assistance. This system shows good functional group compatibility for the generation of substituted oxazole, indole, and benzofuran aldehydes. Mechanistic evidence greatly supports selective radical addition to an activated vinyl–Au double bond over alkene. This unique discovery offers a new avenue with great potential to further extend the synthetic power and versatility of gold catalysis.

Abstract: Stable CO linkages are generally unreactive in cross-coupling reactions which mostly employ more electrophilic halides or activated esters (triflates, tosylates). Acetates are cheap and easily accessible electrophiles but have not been used in cross-couplings because the strong CO bond and high propensity to engage in unwanted acetylation and deprotonation. Reported herein is a selective iron-catalyzed cross-coupling of diverse alkenyl acetates, and it operates under mild reaction conditions (0 °C, 2 h) with a ligand-free catalyst (1–2 mol %).

Abstract: Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development over the past several years. To gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were performed on the CuH-catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and nonlinear effect studies are consistent with a monomeric active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple setup (ligated copper(II) precatalyst, open to air) and short reaction times (<30 min). This improved protocol is amenable to a diverse range of alkene and alkyne substrate classes.

Abstract: Insights into the mechanism of the unusual trans-hydrogenation of internal alkynes catalyzed by {Cp*Ru} complexes were gained by para-hydrogen (p-H2) induced polarization (PHIP) transfer NMR spectroscopy. It was found that the productive trans-reduction competes with a pathway in which both H atoms of H2 are delivered to a single alkyne C atom of the substrate while the second alkyne C atom is converted into a metal carbene. This “geminal hydrogenation” mode seems unprecedented; it was independently confirmed by the isolation and structural characterization of a ruthenium carbene complex stabilized by secondary inter-ligand interactions. A detailed DFT study shows that the trans alkene and the carbene complex originate from a common metallacyclopropene intermediate. Furthermore, the computational analysis and the PHIP NMR data concur in that the metal carbene is the major gateway to olefin isomerization and over-reduction, which frequently interfere with regular alkyne trans-hydrogenation.

Abstract: Polymethylbenzene (polyMB) and alkene cycles are considered as two main routes forming light olefins in the process of methanol to olefins (MTO); however, the contribution that each cycle makes to MTO is still unclear. In this work, density functional theory considering dispersive interactions (DFT-D) was used to elucidate the catalytic roles that the polyMB and the alkene cycles may play in forming ethene and propene from methanol in MTO over H-ZSM-5. The results demonstrated that ethene and propene can be produced in nearly the same probability via the polyMB cycle, as they have a very close free energy height as well as a similar free energy barrier for the rate-determining steps. Via the alkene cycle, however, propene is the dominant product, because the methylation and cracking steps to get propene have a much lower free energy barrier in comparison with those to form ethene. As a result, ethene is predominantly formed via the polyMB cycle, whereas propene is produced via both the polyMB and the alke...

Abstract: An unprecedented phosphine-catalyzed remote β-CH functionalization of amine derivatives triggered by trifluoromethylation of an alkene with Togni's reagent was disclosed. This reaction proceeded through the highly selective and concomitant activation of an unactivated alkene and the β-C sp 3H bond of an amine derivative, providing bistrifluoromethylated enamides in excellent yields with good regio-, chemo-, and stereoselectivity. Furthermore, the newly developed one-pot protocol provides a facile and step-economical access to valuable trisubstituted 5-(trifluoromethyl)oxazoles. Mechanistic studies showed that this reaction may initiate with a novel phosphine-catalyzed radical trifluoromethylation of unactivated alkene via a phosphorus radical cation.

Abstract: Formation of highly oxidized, multifunctional products in the ozonolysis of three endocyclic alkenes, 1- methylcyclohexene, 4-methylcyclohexene, and α-pinene, was investigated using a chemical ionization atmospheric pressure interface time-of-flight (CI-APi-TOF) mass spectrometer with a nitrate ion (NO3–) based ionization scheme. The experiments were performed in borosilicate glass flow tube reactors at room temperature (T = 293 ± 3 K) and at ambient pressure. An ensemble of oxidized monomer and dimer products was detected, with elemental compositions obtained from the high-resolution mass spectra. The monomer product distributions have O/C ratios from 0.8 to 1.6 and can be explained with an autocatalytic oxidation mechanism (=autoxidation) where the oxygen-centered peroxy radical (RO2) intermediates internally rearrange by intramolecular hydrogen shift reactions, enabling more oxygen molecules to attach to the carbon backbone. Dimer distributions are proposed to form by homogeneous peroxy radical recombi...