Metal-catalyzed Hydrogenation Research Articles

Mild Photochemical Reduction of Alkenes and Heterocycles via Thiol-Mediated Formate Activation.

The reduction of alkenes to their respective alkanes is one of the most important transformations in organic chemistry, given the abundance of natural and commercial olefins. Metal-catalyzed hydrogenation is the most common way to reduce alkenes; however, the use of H2 gas in combination with the precious metals required for these conditions can be impractical, dangerous, and expensive. More complex substrates often require extremely high pressures of H2, further emphasizing the safety concerns associated with these hydrogenation reactions. Here we report a safe, cheap, and practical photochemical alkene reduction using a readily available organophotocatalyst, catalytic thiol, and formate. These conditions reduce a variety of di-, tri-, and tetra-substituted alkenes in good yield as well as dearomatize pharmaceutically relevant heterocycles to generate sp3-rich isosteres of benzofurans and indoles. These formal-hydrogenation conditions tolerate a broad range of functionalities that would otherwise be sensitive to typical hydrogenations and are likely to be important for industry applications.

Cyclization via Metal-Catalyzed Hydrogen Atom Transfer/Radical-Polar Crossover

AbstractCatalytic transformations of alkenes via the metal-hydride hydrogen atom transfer (MHAT) mechanism have notably advanced synthetic organic chemistry. This Account focuses on MHAT/radical-polar crossover (MHAT/RPC) conditions, offering a novel perspective on generating electrophilic intermediates and facilitating various intramolecular reactions. On using cobalt hydrides, the MHAT mechanism displays exceptional chemoselectivity and functional group tolerance, making it invaluable for the construction of complex biologically relevant molecules under mild conditions. Recent developments have enhanced regioselectivity and expanded the scope of MHAT-type reactions, enabling the formation of cyclic molecules via hydroalkoxylation, hydroacyloxylation, and hydroamination. Notably, the addition of an oxidant to traditional MHAT systems enables the synthesis of rare cationic alkylcobalt(IV) complexes, bridging radical mechanisms to ionic reaction systems. This Account culminates with examples of natural product syntheses and an exploration of asymmetric intramolecular hydroalkoxylations, highlighting the ongoing challenges and opportunities for future research to achieve higher enantioselectivity. This comprehensive study revisits the historical evolution of the MHAT mechanism and provides a groundwork for further innovations on the synthesis of structurally diverse and complex natural products.1 Introduction2 Intramolecular Hydroalkoxylation and Hydroacyloxylation Reactions3 Intramolecular Hydroamination Reactions4 Intramolecular Hydroarylation Reactions5 Deprotective Cyclization6 Asymmetric Intramolecular Hydroalkoxylation7 Conclusion

Fe/Thiol Cooperative Hydrogen Atom Transfer Olefin Hydrogenation: Mechanistic Insights That Inform Enantioselective Catalysis.

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis of complex molecules, but traditional metal catalysts have difficulty with enantioselective reduction of electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling the mild reduction of these challenging olefins with selectivity that is complementary to traditional hydrogenations with H2. Further, mHAT presents an opportunity for asymmetric induction through cooperative hydrogen atom transfer (cHAT) using chiral thiols. Here, we report insights from a mechanistic study of an iron-catalyzed achiral cHAT reaction and leverage these insights to deliver stereocontrol from chiral thiols. Kinetic analysis and variation of silane structure point to the transfer of hydride from silane to iron as the likely rate-limiting step. The data indicate that the selectivity-determining step is quenching of the alkyl radical by thiol, which becomes a more potent H atom donor when coordinated to iron(II). The resulting iron(III)-thiolate complex is in equilibrium with other iron species, including FeII(acac)2, which is shown to be the predominant off-cycle species. The enantiodetermining nature of the thiol trapping step enables enantioselective net hydrogenation of olefins through cHAT using a commercially available glucose-derived thiol catalyst with up to 80:20 enantiomeric ratio. To the best of our knowledge, this is the first demonstration of asymmetric hydrogenation via iron-catalyzed mHAT. These findings advance our understanding of cooperative radical catalysis and act as a proof of principle for the development of enantioselective iron-catalyzed mHAT reactions.

Asymmetric and Chemoselective Iridium Catalyzed Hydrogenation of Conjugated Unsaturated Oxime Ethers.

Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P-iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π-bond was observed under the applied reaction conditions (20 bar H2, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α-carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed.

Unraveling selectivity in non-noble metal-catalyzed hydrogenation of 5-hydroxymethylfurfural (HMF) through mechanistic insights

The development of heterogeneous catalysts for converting abundant biomass feedstocks to higher value products is one of the most challenges these days. 2,5-dihydroxymethylfuran (DHMF) and 2,5-dihydroxymethyltetrahydrofuran (DHMTHF), synthesized from HMF hydrogenation, serve as crucial precursors in various applications. Non-noble metal catalysts are particularly attractive for this reaction, given their affordability and impressive catalytic efficiency. This work unveils the origin of the unique selectivity over Ni and Cu through mechanistic investigation using density functional theory (DFT), thermodynamic and kinetic analyses. The results emphasize that temperature and solvent play a crucial role in altering the energetic stabilities of intermediates, thereby influencing the energetic span (δG), turnover frequency (TOF), and selectivity of the reaction. The theoretical results align well with experimental observations. At 373.15 K, the highest TOF values over Ni and Cu are predicted in the HMF-to-DHMTHF path (1.79 × 103h−1) and the HMF-to-DHMF path (4.01 × 105h−1), respectively, in gas phase—under low dielectric constant ε condition. In contrast, the highest TOF value for Ni is observed in the HMF-to-DHMF path under implicit water condition (ε = 78.4) at 298.15 K. Competitive DHMF desorption and further hydrogenation influence the reaction’s selectivity. These insightful fundamental findings reveal key descriptors essential for designing new heterogeneous catalysts or enhancing existing ones, with the aim of potentially impacting biomass upgrading and other hydrogenation reactions.

Electrochemical Nickel-Catalyzed Hydrogenation.

Olefin hydrogenation is one of the most important transformations in organic synthesis. Electrochemical transition metal-catalyzed hydrogenation is an attractive approach to replace the dangerous hydrogen gas with electrons and protons. However, this reaction poses major challenges due to rapid hydrogen evolution reaction (HER) of metal-hydride species that outcompetes alkene hydrogenation step, and facile deposition of the metal catalyst at the electrode that stalls reaction. Here we report an economical and efficient strategy to achieve high selectivity for hydrogenation reactivity over the well-established HER. Using an inexpensive and bench-stable nickel salt as the catalyst, this mild reaction features outstanding substrate generality and functional group compatibility, and distinct chemoselectivity. In addition, hydrodebromination of alkyl and aryl bromides could be realized using the same reaction system with a different ligand, and high chemoselectivity between hydrogenation and hydrodebromination could be achieved through ligand selection. The practicability of our method has been demonstrated by the success of large-scale synthesis using catalytic amount of electrolyte and a minimal amount of solvent. Cyclic voltammetry and kinetic studies were performed, which support a NiII/0 catalytic cycle and the pre-coordination of the substrate to the nickel center.

Illuminating cobalt co-catalysis

Recently, the Lin/Liang and Ohmiya/Nagao groups independently reported their dual-photoredox cobalt-based catalytic methods for alkene hydrohalogenation via metal-catalyzed hydrogen atom transfer (mHAT) and halogen atom transfer (XAT). Besides their immense synthetic merits, these metallaphotoredox approaches reveal detailed mechanistic insights into mHAT- and XAT-mediated processes, providing valuable guidelines for future alkene hydrofunctionalization reaction design.

Recent advances in the metal-catalyzed asymmetric alkene hydrogenation of cyclic conjugated carbonyl compounds

This review summarizes the recent advances (2016–2023) in the stereoselective metal-catalyzed hydrogenation of cyclic α,β-unsaturated ketones, lactams and lactones since considerable developments were made. Where possible the application of these methodologies in synthesis is outlined.

Investigating cyclization selectivity by ligand tuning based on MHAT/RPC mechanism

In this study, we investigated the metal-catalyzed hydrogen atom transfer (MHAT)/radical polar crossover (RPC) reaction, focusing on the influence of ligands on the cyclization selectivity by employing substrates containing two nucleophiles along with an alkene. We provide new insights into the importance of ligand optimization in the MHAT/RPC mechanism, particularly in hydroarylation reactions.

Synthesis of five-, six-, and seven-membered cyclic isoureas via MHAT/RPC promoted cycloisomerization

This study demonstrates a novel method for synthesizing rare heterocyclic compounds, namely, cyclic isoureas using alkenoic ureas via cobalt-catalyzed metal-catalyzed hydrogen atom transfer/radical polar crossover (MHAT/RPC). This method successfully produces five-membered rings along with the rare six- and seven-membered cyclic isoureas. Density functional theory (DFT) calculations were performed to elucidate the reaction mechanism focusing on cyclization.

Rh-catalyzed hydrogenation of the carbon–carbon double bond in carbostyril derivatives using [Rh(cod)2]BF4 and Et3SiH under mild conditions

Metal-catalyzed hydrogenation is often conducted in organic synthesis. Although H2 is frequently used as a reducing agent, Et3SiH is also used for the saturation of carbon–carbon double bonds. Carbostyril and 3,4-dihydrocarbostyril are utilized as a useful molecular skeleton for pharmaceutical agents and physiologically active substances. Thus, effective synthetic methods to obtain them in mild conditions should be developed. Recently, we discovered Rh-catalyzed hydrogenation of the carbon–carbon double bond of carbostyril derivatives in the presence of Et3SiH using [Rh(cod)2]BF4 at room temperature under normal pressure, to afford the 3,4-dihydrocarbostyril derivatives. Therefore, in this article we introduce the results.

Homogeneous Metal-Catalyzed Hydrogenation of CO2 Derivatives: Towards Indirect Conversion of CO2 to Methanol

The increase in anthropogenic CO2 concentrations and associated environmental issues have demanded the development of technologies for CO2 utilization. Among various potential solutions to decrease CO2 emissions and achieve carbon neutrality, the recycling of post-combustion CO2 into value-added chemicals and fuels is considered one of the most economically attractive processes. In this regard, due to its large global demand and versatile applications in the chemical and energy sectors, methanol serves as the most appealing target for the chemical utilization of CO2. However, direct hydrogenation of CO2 to MeOH has proved challenging due to selectivity issues and high energy input, mainly dependent on CO2-emitting fossil energy sources. To address these challenges, an alternative indirect CO2-to-MeOH methodology has been proposed, which involves the hydrogenation of CO2 via the intermediate formation of well-known CO2 derivatives, such as formates, carbonates, formamides, carbamates, and urea derivatives. Homogeneous transition metal catalysts have been at the center of this research avenue, potentially allowing for more selective and low-temperature alternative routes from CO2 to MeOH. This review aims to highlight the advances and challenges in homogeneous transition metal-catalyzed hydrogenation of major CO2 derivatives to MeOH. Special attention is paid to the mechanisms of such transformations.

Site-selective Hydrogenation/Deuteration of Benzylic Olefins Enabled by Electroreduction Using Water.

We describe an operationally simple and user-friendly protocol that allows the site-selective hydrogenation and deuteration of di-, tri- and tetrasubstituted benzylic olefins by electroreduction while other groups prone to hydrogenation are present. The radical anionic intermediates react with the most inexpensive hydrogen/deuterium source H2 O/D2 O. Our method overcomes many limitations that arise from previously reported electroreductive hydrogenations. The applicability of this reaction is demonstrated by a broad substrate scope (>50 examples) that focuses on functional group tolerance and sites that are affected by metal-catalyzed hydrogenation (alkenes, alkynes, protecting groups).

Role of Ion-Exchange Resins in Hydrogenation Reactions

The role of ion-exchange resins (IERs) as catalysts or catalysts supports, in hydrogenation reactions is revised and their potential application is presented. Both gel-type and macroreticular, basic or acid, IERs have been used for manifold metal-catalyzed hydrogenation processes in gas and liquid phase, including hydrogenation of alkenes, alkynes, carbonyls, arenes, nitroaromatics, and more. When available, qualitative relationships between the morphology and structure of resins and their performance as solid supports for metal catalysts are observed. Noble metals, such as Pt, Au, and Pd, and non-noble metals, such as Fe and Cu, have been introduced into IERs polymeric backbones by simple ion-exchange of a metal salt precursor with the resin, or by a combination of ion-exchange and other protocols, to obtain mono- and bimetallic catalysts supported on IERs. High yields towards target product, as well as the recyclability of metal-doped IERs, have been reported in the literature, with low metal leaching, which makes them highly interesting solid catalysts for a wide array of industrial applications. Multistep reaction processes, involving hydrogenation and hydration/cyclization/aldol condensation/etc., constitute promising applications due to the one-pot synthesis approach and relatively low temperatures required, which adds environmental interest in terms of process integration and optimization.

HAT lessons help hydrogen hop, skip, and jump

Nagib and Rajanbabu share a clever approach to remote desaturation triggered by metal-catalysed hydrogen atom transfer (mHAT) to an alkene, followed by intramolecular 1,6-HAT, and terminated via mHAT. This method both realizes a valuable synthetic transformation and provides multiple lessons for the design of HAT-mediated reactions.

Markovnikov alcohols via epoxide hydroboration by molecular alkali metal catalysts

SummarySynthesis of branched “Markovnikov” alcohols is crucial to various chemical industries. The catalytic reduction of substituted epoxides under mild conditions is a highly attractive method for preparing such alcohols. Classical methods based on heterogeneous or homogeneous transition metal-catalyzed hydrogenation, hydroboration, or hydrosilylation usually suffer from poor selectivity, reverse regioselectivity, limited functional group compatibility, high cost, and/or low availability of the catalysts. Here we report the discovery of highly regioselective hydroboration of nonsymmetrical epoxides catalyzed by ligated archetypal reductants in organic chemistry ‒ alkali metal triethylborohydrides. The chemoselectivity and turnover efficiencies of the present catalytic approach are excellent. Thus, terminal and internal epoxides with ene, yne, aryl, and halo groups were selectively and quantitatively reduced under a substrate-to-catalyst ratio (S/C) of up to 1000. Mechanistic investigations point to a mechanism reminiscent of frustrated Lewis pair action on substrates in which a nucleophile and Lewis acid act cooperatively on the substrate.

Catalytic Conversion of 5-Hydroxymethylfurfural to High-Value Derivatives by Selective Activation of C-O, C=O, and C=C Bonds.

With increasing concern for reducing CO2 emission and alleviating fossil resource dependence, catalytic transformation of 5-hydroxymethylfurfural (HMF), a vital platform compound derived from C6 sugars, holds great promise for producing value-added chemicals. Among several well-established catalytic systems, hydrogenation and oxidation processes have been efficiently adopted for upgrading HMF. This Review covers recent advances in the development of thermocatalytic conversion of HMF into value-added chemicals. The advances of metal-catalyzed hydrogenation, hydrogenolysis, ring-opening, decarbonylation, and oxidation involving selective activation of C-O, C=O, and C=C groups are described. The roles played by nature of metals, supports, additives, synergy of metal-acid sites, and metal-support interaction are also discussed at the molecular level. Finally, an outlook is provided to highlight major challenges associated with this huge research area.

Scalable Total Synthesis of (-)-Triptonide: Serendipitous Discovery of a Visible-Light-Promoted Olefin Coupling Initiated by Metal-Catalyzed Hydrogen Atom Transfer (MHAT).

An efficient and scalable total synthesis of (-)-triptonide is accomplished based on a metal-catalyzed hydrogen atom transfer (MHAT)-initiated radical cyclization. During the optimization of the key step, we discovered that blue LEDs significantly promoted the efficiency of reaction initiated by Co(TPP)-catalyzed MHAT. Further exploration and optimization of this catalytic system led to development of a dehydrogenative MHAT-initiated Giese reaction.

Interrupted Pyridine Hydrogenation: Asymmetric Synthesis of δ-Lactams.

Metal‐catalyzed hydrogenation is an effective method to transform readily available arenes into saturated motifs, however, current hydrogenation strategies are limited to the formation of C−H and N−H bonds. The stepwise addition of hydrogen yields reactive unsaturated intermediates that are rapidly reduced. In contrast, the interruption of complete hydrogenation by further functionalization of unsaturated intermediates offers great potential for increasing chemical complexity in a single reaction step. Overcoming the tenet of full reduction in arene hydrogenation has been seldom demonstrated. In this work we report the synthesis of sought‐after, enantioenriched δ‐lactams from oxazolidinone‐substituted pyridines and water by an interrupted hydrogenation mechanism.

Asymmetric Total Synthesis of Dankasterones A and B and Periconiastone A Through Radical Cyclization.

We describe herein the assembly of the cis-decalin framework through radical cyclization initiated by metal-catalyzed hydrogen atom transfer (MHAT), further applied it in the asymmetric synthesis of dankasterones A and B and periconiastone A. Position-selective C-H oxygenation allowed for installation of the necessary functionality. A radical rearrangement was adopted to create 13(14→8)abeo-8-ergostane skeleton. Interconversion of dankasterone B and periconiastone A was realized through biomimetic intramolecular aldol and retro-aldol reactions. The MHAT-based approach, serves as a new dissection means, is complementary to the conventional ways to establish cis-decalin framework.