Nickel-Catalyzed Regio- and Enantioselective Migratory Hydrocyanation of Internal Alkenes: Expanding the Scope to α,ω-Diaryl Internal Alkenes.

Metal-hydride-catalyzed migratory functionalization of alkenes witnessed extensive development in the past few years. However, the asymmetric version of this reaction has remained largely underdeveloped owing to the difficulty in simultaneous control of both regio- and stereoselectivity. In addition, exploring the wider alkene substrate scope to enable more synthetically valuable applications represents another challenge in this field. In this context, a nickel-catalyzed asymmetric hydrocyanation of internal alkenes involving a chain-walking process is demonstrated. The reaction exhibits excellent regio- and enantioselectivity, proceeds under mild reaction conditions, and delivers benzylic nitriles in high yields. Even α,ω-diaryl internal alkenes, which are known to be one of the most challenging substrates of this type, could be successfully converted to the desired products with good regio- and stereoselectivity by modifying the electronic and steric effects. Theoretical calculations suggest that the η3-benzyl coordination mode and the aryl substituent (3,5-(OMe)2C6H3) on the diphosphite ligand are both key factors in regulating regio- and enantioselectivity.

Palladium-Catalyzed Alkyne Hydrocyanation toward Ligand-Controlled Stereodivergent Synthesis of (E)- and (Z)-Trisubstituted Acrylonitriles.

We herein describe a palladium-catalyzed hydrocyanation of propiolamides for the stereodivergent synthesis of trisubstituted acrylonitriles. This synthetic method tolerated various primary, secondary and tertiary propiolamides. The cautious selection of a suitable ligand is essential to the success of this stereodivergent process. Control experiments indicate the intermediacy of E-acrylonitriles, which lead to Z-acrylonitriles via isomerization. The density functional theory calculations suggests that the bidentate ligand L2 enables a feasible cyclometallation/isomerization pathway for the E to Z isomerization, while the monodentate ligand L1 inhibits the isomerization, leading to divergent stereoselectivity. The usefulness of this method can be demonstrated by the readily derivatization of products to give various E- and Z-trisubstituted alkenes. In addition, the E- and Z-acrylonitrile products have also been successfully employed in cycloaddition reactions.

Nickel-Catalyzed Asymmetric Hydroaryloxy- and Hydroalkoxycarbonylation of Cyclopropenes.

The asymmetric Reppe carbonylation reactions provide a straightforward access to α-chiral carbonyl compounds. The reported paradigms predominantly adopted precious palladium as the catalyst. Here we report a nickel-catalyzed asymmetric carbonylation of cyclopropenes with phenyl formate and CO/ROH, respectively. This asymmetrical synthetic protocol features high atom economy, good functional group tolerance, which rapidly constructs polysubstituted cyclopropanecarboxylic derivatives with excellent diastereo- and enantioselectivity. The synthetic utility is demonstrated by facile conversion of the chiral products into bioactive molecules such as (-)-Tranylcypromine and (-)-Lemborexant.

Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric-Ligand-Controlled Regiodivergence.

A regiodivergent nickel-catalyzed hydrocyanation of a broad range of internal alkenes involving a chain-walking process is reported. When appropriate diastereomeric biaryl diphosphite ligands are applied, the same starting materials can be converted to either linear or branched nitriles with good yields and high regioselectivities. DFT calculations suggested that the catalyst architecture determines the regioselectivity by modulating electronic and steric interactions. In addition, moderate enantioselectivities were observed when branched nitriles were produced.

Highly Regio- and Stereoselective Ni-Catalyzed Hydrocyanation of 1,3-Enynes.

A highly regio- and stereoselective hydrocyanation of 1,3-enynes was implemented by nickel/diphosphine catalysts. A wide range of highly regio- and stereoselective alkenyl nitriles were efficiently prepared. In this transformation, both the tethered alkene and the ligand play key roles in the reactivity and selectivity. The origin of regioselectivity was understood preliminarily by DFT studies.

Enantioselective Nickel-Catalyzed Migratory Hydrocyanation of Nonconjugated Dienes.

Metal-catalyzed chain-walking reactions have recently emerged as a powerful strategy to functionalize remote positions in organic molecules. However, a chain-walking protocol for nonconjugated dienes remains scarcely reported, and developments are currently ongoing. In this Communication, a nickel-catalyzed asymmetric hydrocyanation of nonconjugated dienes involving a chain-walking process is demonstrated. The reaction exhibits excellent regio- and chemoselectivity, and a wide range of substrates were tolerated, delivering the products in high yields and enantioselectivities. Deuterium-labeling experiments support the chain-walking process, which involves an iterative ß-H elimination and reinsertion processes. Gram-scale synthesis, regioconvergent experiments, and downstream transformations gave further insights into the high potential of this transformation.

Access to 1,3-Dinitriles by Enantioselective Auto-tandem Catalysis: Merging Allylic Cyanation with Asymmetric Hydrocyanation.

Enantioselective auto-tandem catalysis represents a challenging yet highlight attractive topic in the field of asymmetric catalysis. In this context, we describe a dual catalytic cycle that merges allylic cyanation and asymmetric hydrocyanation. The one-pot conversion of a broad array of allylic alcohols into their corresponding 1,3-dinitriles proceeds in good yield with high enantioselectivity. The products are densely functionalized and can be easily transformed to chiral diamines, dinitriles, diesters, and piperidines. Mechanistic studies clearly support a novel sequential cyanation/hydrocyanation pathway.

Efficient Palladium-Catalyzed Alkoxycarbonylation of Bulk Industrial Olefins Using Ferrocenyl Phosphine Ligands.

The development of ligands plays a key role and provides important innovations in homogeneous catalysis. In this context, we report a novel class of ferrocenyl phosphines for the alkoxycarbonylation of industrially important alkenes. A basic feature of our ligands is the combination of sterically hindered and amphoteric moieties on the P atoms, which leads to improved activity and productivity for alkoxycarbonylation reactions compared to the current industrial state-of-the-art ligand 1,2-bis((di-tert-butylphosphino)methyl)benzene). Advantageously, palladium catalysts with these novel ligands also enable such transformations without additional acid under milder reaction conditions. The practicability of the optimized ligand was demonstrated by preparation on >10 g scale and its use in palladium-catalyzed carbonylations on kilogram scale.

Unlocking Mizoroki-Heck-Type Reactions of Aryl Cyanides Using Transfer Hydrocyanation as a Turnover-Enabling Step.

A new transfer hydrofunctionalization strategy to turnover H-MII -X complexes has enabled both intra- and intermolecular Mizoroki-Heck (MH)-type reactions of aryl cyanides that are challenging to realize under traditional, basic conditions. Initially, a cascade carbonickelation/MH reaction of 2-cyanostyrenes was achieved using a key alkyne transfer hydrocyanation step. Mechanistic experiments supported the proposed catalytic cycle, including the turnover-enabling transfer hydrocyanation step. The reactivity was then extended to the intermolecular MH reaction of benzonitriles and styrenes.

Rh(I)-Catalyzed Hydroamidation of Olefins via Selective Activation of N-H Bonds in Aliphatic Amines.

Hydroamidation of olefins constitutes an ideal, atom-efficient method to prepare carboxylic amides from easily available olefins, CO, and amines. So far, aliphatic amines are not suitable for these transformations. Here, we present a ligand- and additive-free Rh(I) catalyst as solution to this problem. Various amides are obtained in good yields and excellent regioselectivities. Notably, chemoselective amidation of aliphatic amines takes place in the presence of aromatic amines and alcohols. Mechanistic studies reveal the presence of Rh-acyl species as crucial intermediates for the selectivity and rate-limiting step in the proposed Rh(I)-catalytic cycle.

Transition-metal-catalyzed carbonylation reactions of olefins and alkynes: a personal account.

Carbon monoxide was discovered and identified in the 18th century. Since the first applications in industry 80 years ago, academic and industrial laboratories have broadly explored CO's use in chemical reactions. Today organic chemists routinely employ CO in organic chemistry to synthesize all kinds of carbonyl compounds. Despite all these achievements and a century of carbonylation catalysis, many important research questions and challenges remain. Notably, apart from academic developments, industry applies carbonylation reactions with CO on bulk scale. In fact, today the largest applications of homogeneous catalysis (regarding scale) are carbonylation reactions, especially hydroformylations. In addition, the vast majority of acetic acid is produced via carbonylation of methanol (Monsanto or Cativa process). The carbonylation of olefins/alkynes with nucleophiles, such as alcohols and amines, represent another important type of such reactions. In this Account, we discuss our work on various carbonylations of unsaturated compounds and related reactions. Rhodium-catalyzed isomerization and hydroformylation reactions of internal olefins provide straightforward access to higher value aldehydes. Catalytic hydroaminomethylations offer an ideal way to synthesize substituted amines and even heterocycles directly. More recently, our group has also developed so-called alternative metal catalysts based on iridium, ruthenium, and iron. What about the future of carbonylation reactions? CO is already one of the most versatile C1 building blocks for organic synthesis and is widely used in industry. However, because of CO's high toxicity and gaseous nature, organic chemists are often reluctant to apply carbonylations more frequently. In addition, new regulations have recently made the transportation of carbon monoxide more difficult. Hence, researchers will need to develop and more frequently use practical and benign CO-generating reagents. Apart from formates, alcohols, and metal carbonyls, carbon dioxide also offers interesting options. Industrial chemists seek easy to prepare catalysts and patent-free ligands/complexes. In addition, non-noble metal complexes will interest both academic and industrial researchers. The novel Lucite process for methyl methacrylate is an important example of an improved catalyst. This reaction makes use of a specific palladium/bisphosphine catalyst, which led to the successful implementation of the technology. More active and productive catalysts for related carbonylations of less reactive olefins would allow for other large scale applications of this methodology. From an academic point of view, researchers continue to look for selective reactions with more functionalized olefins. Finally, because of the volatility of simple metal carbonyl complexes, carbonylation reactions today remain a domain of homogeneous catalysis. The invention of more stable and recyclable heterogeneous catalysts or metal-free carbonylations (radical carbonylations) will be difficult, but could offer interesting challenges for young chemists.

Selective palladium-catalyzed aminocarbonylation of 1,3-dienes: atom-efficient synthesis of ß,γ-unsaturated amides.

Carbonylation reactions constitute important methodologies for the synthesis of all kinds of carboxylic acid derivatives. The development of novel and efficient catalysts for these transformations is of interest for both academic and industrial research. Here, the first palladium-based catalyst system for the aminocarbonylation of 1,3-dienes is described. This atom-efficient transformation proceeds under additive-free conditions and provides straightforward access to a variety of ß,γ-unsaturated amides in good to excellent yields, often with high selectivities.

Sequential hydroformylation/diels-alder processes: one-pot synthesis of polysubstituted cyclohexenes, cyclohexadienes, and phthalates from alkynes.

A novel, one-pot hydroformylation/Diels-Alder sequence for the synthesis of multisubstituted cyclohexenes, cyclohexadienes, and phthalates has been developed. Various alkynes were efficiently converted into the corresponding products in good yields and with excellent diastereoselectivity through palladium-catalyzed hydroformylation followed by an AAD-type reaction (AAD: Amides-Aldehydes-Dienophiles). In view of the availability of the substrates, the atom-efficiency of the overall process, and the convenient introduction of substituents in the cyclohexene ring, this method complements current methods for the preparation of polysubstituted cyclohexane derivatives.

Domino hydroformylation/aldol condensation/hydrogenation catalysis: highly selective synthesis of ketones from olefins.

A general and highly chemo- and regioselective synthesis of ketones from olefins by domino hydroformylation/aldol condensation/hydrogenation reaction has been developed. A variety of olefins are efficiently converted into various ketones in good to excellent yields and regioselectivities in the presence of a specific rhodium phosphine/base-acid catalyst system.

Domino-hydroformylation/aldol condensation catalysis: highly selective synthesis of α,ß-unsaturated aldehydes from olefins.

A general and highly chemo-, regio-, and stereoselective synthesis of α,ß-unsaturated aldehydes by a domino hydroformylation/aldol condensation reaction has been developed. A variety of olefins and aromatic aldehydes were efficiently converted into various substituted α,ß-unsaturated aldehydes in good to excellent yields in the presence of a rhodium phosphine/acid-base catalyst system. In view of the easy availability of the substrates, the high atom-efficiency, the excellent selectivity, and the mild conditions, this method is expected to complement current methodologies for the preparation of α,ß-unsaturated aldehydes.

Palladium-catalyzed alkoxycarbonylation of conjugated dienes under acid-free conditions: atom-economic synthesis of ß,γ-unsaturated esters.

Carbonylation reactions constitute important methodologies for the synthesis of all kinds of carboxylic acid derivatives. The development of novel and better catalysts for these transformations is of interest for both academic and industrial research. Here, a benign palladium-based catalyst system for the alkoxycarbonylation of conjugated dienes under acid-free conditions has been developed. This atom-efficient transformation provides straightforward access to a variety of ß,γ-unsaturated esters in good to excellent yields and often with high selectivities. As an industrially relevant example the (formal) synthesis of dimethyl adipate and ε-caprolactam from 1,3-butadiene is demonstrated.

Enantioselective Synthesis of Axially and Centrally Chiral Styrenes via Nickel-Catalyzed Desymmetric Hydrocyanation of Biaryl Dienes.

Herein, a highly regio-, enantio-, and diastereoselective nickel-catalyzed desymmetric hydrocyanation of biaryl dienes for the simultaneous construction of axial and central chiralities is presented, which offers a convenient approach to a variety of tirenes containing the union of an axially chiral biaryl and a centrally α-chiral nitrile under mild conditions using a commercially available catalyst. The synthetic utility is highlighted by the development of a novel axially chiral phosphine ligand and biphenyl-based chiral diene ligand and their potential applications in the field of asymmetric catalytic reactions.

3-Methylpyridine: Synthesis and Applications.

3-Methylpyridine holds a pivotal role in organic chemistry as it constitutes a fundamental structure in numerous biologically active compounds. Its significance is underscored by its involvement in synthesizing vitamin B3 and developing pyridine insecticides, garnering considerable attention. Consequently, chemists have dedicated efforts to devising efficient and environmentally friendly methods for its preparation. This review systematically reviews several synthetic routes to 3-methylpyridine, alongside recent advancements, while summarizing its application progress in various organic transformations.

Nickel-Catalyzed Cyanation of Allylic Alcohols: High Degree of Chiral Inversion in Aqueous Reaction Media.

Nickel-catalyzed aqueous cyanation of allylic alcohols is herein described. This catalytic protocol provided environmentally friendly and operationally simple access to a variety of allylic nitriles in good yields. For chiral allylic alcohols, the reaction gave chiral allylic nitriles with a high degree of chiral inversion. The accelerated release of cyanide in H2O was crucial for the success of this reaction.

Palladium-Catalyzed Hydrocyanation of Ynoates: En Route to the Stereodivergent Synthesis of ß-Cyanated α,ß-Unsaturated Esters via Ligand Controlled Regio- and Stereoselectivity.

A Pd-catalyzed highly regio- and stereoselective hydrocyanation was developed, providing a novel approach to the stereodivergent synthesis of ß-cyano-substituted acrylates in good yields with a wide substrate scope. The judicious selection of ligands was crucial for elegant control over the stereodivergence. Furthermore, the success of the E-hydrocyanation hinges on the right matching of Pd and L1, which not only ensured the catalytic activity but also prevented the formation of α-cyanation products.