Search

The selective activation of sp3 carbon–hydrogen bonds in the presence of multiple C–H bonds is challenging and remains of supreme importance in chemical research. Late-stage modification of complex molecules via sp3 C–H activation is of high prevalence in organic synthesis. Herein, we describe the activation of a C(sp3)–H bond in the α-position to an amine via a carbanion intermediate. In the presence of several α-amine sites, only one specific position is selectively activated. Applying this protocol, the proposed carbanion intermediate was effectively trapped with different electrophiles such as deuterium (D+), tritium (T+), or carbonyl compounds compiling over 50 examples. Further, this methodology was used to install deuterium or tritium in different drug-derivatives (>10 drugs) at a selected position in a late-stage functionalization. In addition, the protocol is suitable for a gram-scale synthesis, and a detailed mechanistic investigation has been carried out to support our hypothesis.

Visible light excitation of iodine(III)-BF

Polymeric graphitic carbon nitride materials have attracted significant interest in recent years and found applications in diverse light-to-energy conversions such as artificial photosynthesis, CO2 reduction or degradation of organic pollutants. However, their utilization in synthetic photocatalysis especially in the direct functionalization of C(sp3)−H bonds remains underexplored. Herein, we report mesoporous graphitic carbon nitride (mpg-CN) as a heterogeneous organic semiconductor photocatalyst for direct arylation of sp3 C−H bonds via a combination of hydrogen atom transfer and nickel catalysis. Our protocol has a broad synthetic scope (>70 examples including late-stage modification of densely functionalized bio-active molecules), is operationally simple, and shows high chemo- and regioselectivity. Facile separation and recycling of the mpg-CN catalyst in combination with its low preparation cost, innate photochemical stability and low toxicity are beneficial features overcoming typical shortcomings of homogeneous photocatalysis. Additionally, mechanistic investigations indicate that an unprecedented energy transfer process (EnT) from the organic semiconductor to the nickel complex is operating.

The metal‐free activation of C(sp3)−H bonds to value‐added products is of paramount importance in organic synthesis. We report the use of the commercially available organic dye 2,4,6‐triphenylpyrylium tetrafluoroborate (TPP) for the conversion of methylarenes to the corresponding aryl nitriles via a photocatalytic process. Applying this methodology, a variety of cyanobenzenes have been synthesized in good to excellent yield under metal‐ and cyanide‐free conditions. We demonstrate the scope of the method with over 50 examples including late‐stage functionalization of drug molecules (celecoxib) and complex structures such as l‐menthol, amino acids, and cholesterol derivatives. Furthermore, the presented synthetic protocol is applicable for gram‐scale reactions. In addition to methylarenes, selected examples for the cyanation of aldehydes, alcohols and oximes are demonstrated as well. Detailed mechanistic investigations have been carried out using time‐resolved luminescence quenching studies, control experiments, and NMR spectroscopy as well as kinetic studies, all supporting the proposed catalytic cycle., C(sp3)−H bonds have been converted to cyano derivatives under metal‐ and cyanide‐free condition in the presence of visible light and an organic dye. Potential applications of this method in the late‐stage transformation of complex drug molecules, steroid derivatives, and gram‐scale reactions have been described.

Herein, we report the synthesis of specific silica‐supported Co/Co3O4 core–shell based nanoparticles prepared by template synthesis of cobalt‐pyromellitic acid on silica and subsequent pyrolysis. The optimal catalyst material allows for general and selective hydrogenation of pyridines, quinolines, and other heteroarenes including acridine, phenanthroline, naphthyridine, quinoxaline, imidazo[1,2‐a]pyridine, and indole under comparably mild reaction conditions. In addition, recycling of these Co nanoparticles and their ability for dehydrogenation catalysis are showcased., One fits all: Co/Co3O4 core–shell nanoparticles prepared by pyrolysis of a Co‐pyromellitic acid template on silica served as stable and reusable catalysts for the selective hydrogenation of pyridines, quinolines, and other heteroarenes.

The selective activation of sp3 carbon-hydrogen bonds in presence of multiple C¬-H bonds is challenging and remains of supreme importance in chemical research. Herein, we describe the activation of a C(sp3) H bond in α position to an amine via a carbanion intermediate. In the presence of several α amine sites, only one specific position is selectively activated. Applying this protocol, the proposed carbanion intermediate was effectively trapped with different electrophiles such as deuterium (D+), tritium (T+), or carbonyl compounds compiling over 50 examples. Further, this methodology was used to install deuterium or tritium in different drug derivatives (> 10 drugs) at a selected position in a late-stage functionalization. In addition, the protocol is suitable for a gram-scale synthesis and a detailed mechanistic investigation has been carried out to support our hypothesis.

The effective utilization of levulinic acid, a renewable feedstock derived from sugar biomass, is of central importance for the preparation of value-added chemicals as well as catalytic materials. ...

A metal‐free generation of carbanion nucleophiles is of prime importance in organic synthesis. Herein we report a photocatalytic approach to the Corey–Seebach reaction. The presented method operates under mild redox‐neutral and base‐free conditions giving the desired product with high functional group tolerance. The reaction is enabled by the combination of photo‐ and hydrogen atom transfer (HAT) catalysis. This catalytic merger allows a C−H to carbanion activation by the abstraction of a hydrogen atom followed by radical reduction. The generated nucleophilic intermediate is then capable of adding to carbonyl electrophiles. The obtained dithiane can be easily converted to the valuable α‐hydroxy carbonyl in a subsequent step. The proposed reaction mechanism is supported by emission quenching, radical–radical homocoupling and deuterium labeling studies as well as by calculated redox‐potentials and bond strengths., Picture perfect: A photocatalytic approach for the Corey–Seebach reaction is presented. This base‐ and metal‐free reaction exploits the combination of photo‐ and HAT‐catalysis furnishing the desired product under mild conditions with a high functional group tolerance. The reactive intermediate is generated by hydrogen atom abstraction followed by radical reduction rendering a carbanion nucleophile capable of adding to aldehydes and ketones.

Reductive aminations constitute an important class of reactions widely applied in research laboratories and industries for the synthesis of amines as well as pharmaceuticals, agrochemicals and biomolecules. In particular, catalytic reductive aminations using molecular hydrogen are highly valued and essential for the cost-effective and sustainable production of different kinds of amines and their functionalization. These reactions couple easily accessible carbonyl compounds (aldehydes or ketones) with ammonia, amines or nitro compounds in the presence of suitable catalysts and hydrogen that enable the preparation of linear and branched primary, secondary and tertiary amines including N-methylamines and molecules used in life science applications. In general, amines represent valuable fine and bulk chemicals, which serve as key precursors and central intermediates for the synthesis of advanced chemicals, life science molecules, dyes and polymers. Noteworthily, amine functionalities are present in a large number of pharmaceuticals, agrochemicals and biomolecules, and play vital roles in the function of these active compounds. In general, reductive aminations are challenging processes, especially for the syntheses of primary amines, which often are non-selective and suffer from over-alkylation and reduction of carbonyl compounds to the corresponding alcohols. Hence, the development of suitable catalysts to perform these reactions in a highly efficient and selective manner is crucial and continues to be important and attracts scientific interest. In this regard, both homogeneous and heterogeneous catalysts have successfully been developed for these reactions to access various amines. There is a need for a comprehensive review on catalytic reductive aminations to discuss the potential catalysts used and applicability of this methodology in the preparation of different kinds of amines, which are of commercial, industrial and medicinal importance. Consequently, in this review we discuss catalytic reductive aminations using molecular hydrogen and their applications in the synthesis of functionalized and structurally diverse benzylic, heterocyclic and aliphatic primary, secondary and tertiary amines as well as N-methylamines and more complex drug targets. In addition, mechanisms of reductive aminations including selective formation of desired amine products as well as possible side reactions are emphasized. This review aims at the scientific communities working in the fields of organic synthesis, catalysis, and medicinal and biological chemistry.

The development of base metal catalysts for industrially relevant amination and hydrogenation reactions by applying abundant and atom economical reagents continues to be important for the cost-effective and sustainable synthesis of amines which represent highly essential chemicals. In particular, the synthesis of primary amines is of central importance because these compounds serve as key precursors and central intermediates to produce value-added fine and bulk chemicals as well as pharmaceuticals, agrochemicals and materials. Here we report a Ni-triphos complex as the first Ni-based homogeneous catalyst for both reductive amination of carbonyl compounds with ammonia and hydrogenation of nitroarenes to prepare all kinds of primary amines. Remarkably, this Ni-complex enabled the synthesis of functionalized and structurally diverse benzylic, heterocyclic and aliphatic linear and branched primary amines as well as aromatic primary amines starting from inexpensive and easily accessible carbonyl compounds (aldehydes and ketones) and nitroarenes using ammonia and molecular hydrogen. This Ni-catalyzed reductive amination methodology has been applied for the amination of more complex pharmaceuticals and steroid derivatives. Detailed DFT computations have been performed for the Ni-triphos based reductive amination reaction, and they revealed that the overall reaction has an inner-sphere mechanism with H2 metathesis as the rate-determining step., A Ni-triphos based homogeneous catalyst enabled the synthesis of all kinds of primary amines by reductive amination of carbonyl compounds with ammonia and hydrogenation of nitroarenes.

Reductive aminations are an essential class of reactions widely applied for the preparation of different kinds of amines, as well as a number of pharmaceuticals and industrially relevant compounds. In such reactions, carbonyl compounds (aldehydes, ketones) react with ammonia or amines in the presence of a reducing agent and form corresponding amines. Common catalysts used for reductive aminations, especially for the synthesis of primary amines, are based on precious metals or Raney nickel. However, their drawbacks and limited applicability inspired us to look for alternative catalysts. The development of base-metal nanostructured catalysts is highly preferable and is crucial to the advancement of sustainable and cost-effective reductive amination processes. In this protocol, we describe the preparation of carbon-supported cobalt-based nanoparticles as efficient and practical catalysts for synthesis of different kinds of amines by reductive aminations. Template synthesis of a cobalt-triethylenediamine-terephthalic acid metal-organic framework on carbon and subsequent pyrolysis to remove the organic template resulted in the formation of supported single cobalt atoms and nanoparticles. Applying these catalysts, we have synthesized structurally diverse benzylic, aliphatic and heterocyclic primary, secondary and tertiary amines, including pharmaceutically relevant products, starting from inexpensive and easily accessible carbonyl compounds with ammonia, nitro compounds or amines and molecular hydrogen. To prepare this cobalt-based catalyst takes 26 h, and the reported catalytic reductive amination reactions can be carried out within 18-28 h.

The development of earth abundant 3d metal-based catalysts continues to be an important goal of chemical research. In particular, the design of base metal complexes for reductive amination to produce primary amines remains as challenging. Here, we report the combination of cobalt and linear-triphos (bis(2-diphenylphosphinoethyl)phenylphosphine) as the molecularly-defined non-noble metal catalyst for the synthesis of linear and branched benzylic, heterocyclic and aliphatic primary amines from carbonyl compounds, gaseous ammonia and hydrogen in good to excellent yields. Noteworthy, this cobalt catalyst exhibits high selectivity and as a result the -NH2 moiety is introduced in functionalized and structurally diverse molecules. An inner-sphere mechanism on the basis of the mono-cationic [triphos-CoH]+ complex as active catalyst is proposed and supported with density functional theory computation on the doublet state potential free energy surface and H2 metathesis is found as the rate-determining step., Despite their higher abundance, 3d metal-based catalysts are less investigated than their precious metal counterparts. Here, the authors report a cobalt-triphos complex as molecularly-defined non-noble metal catalyst for the reductive amination of carbonyl compounds with gaseous ammonia and hydrogen.

Here we report Ni-nanoparticles as reusable catalysts for reductive N-alkylation of amides. These Ni-nanoparticles based catalysts have been prepared by the template synthesis of tartaric acid and 2-methyl imidazole ligated Ni-complex on SiO2 and subsequent pyrolysis under argon. Applying optimal Ni-nanostructured catalyst, N-alkylation of aromatic and heterocyclic primary amides with different aldehydes in presence of molecular hydrogen was performed to access structurally diverse N-alkylated amides in good to excellent yields. In addition, the applicability of this N-alkylation protocol has been demonstrated for the selective functionalization of primary amide group in Levetiracetam drug.

Here, we report the use of monosaccharides for the preparation of novel nickel nanoparticles (NP), which constitute selective hydrogenation catalysts. For example, immobilization of fructose and Ni(OAc)2 on silica and subsequent pyrolysis under inert atmosphere produced graphitic shells encapsulated Ni-NP with uniform size and distribution. Interestingly, fructose acts as structure controlling compound to generate specific graphitic layers and the formation of monodisperse NP. The resulting stable and reusable catalysts allow for stereo- and chemoselective semihydrogenation of functionalized and structurally diverse alkynes in high yields and selectivity. �� 2019 The Author(s)

A convenient protocol for stereodivergent hydrogenation of alkynes to E- and Z-alkenes by using nickel catalysts was developed. Simple Ni(NO3)2.6 H2O as a catalyst precursor formed active nanoparticles, which were effective for the semihydrogenation of several alkynes with high selectivity for the Z-alkene (Z/E>99:1). Upon addition of specific multidentate ligands (triphos, tetraphos), the resulting molecular catalysts were highly selective for the E-alkene products (E/Z>99:1). Mechanistic studies revealed that the Z-alkene-selective catalyst was heterogeneous whereas the E-alkene-selective catalyst was homogeneous. In the latter case, the alkyne was first hydrogenated to a Z-alkene, which was subsequently isomerized to the E-alkene. This proposal was supported by density functional theory calculations. This synthetic methodology was shown to be generally applicable in >40 examples and scalable to multigram-scale experiments.

The production of primary benzylic and aliphatic amines, which represent essential feedstocks and key intermediates for valuable chemicals, life science molecules and materials, is of central importance. Here, we report the synthesis of this class of amines starting from carbonyl compounds and ammonia by Ru-catalyzed reductive amination using H2. Key to success for this synthesis is the use of a simple RuCl2(PPh3)3 catalyst that empowers the synthesis of >90 various linear and branched benzylic, heterocyclic, and aliphatic amines under industrially viable and scalable conditions. Applying this catalyst, −NH2 moiety has been introduced in functionalized and structurally diverse compounds, steroid derivatives and pharmaceuticals. Noteworthy, the synthetic utility of this Ru-catalyzed amination protocol has been demonstrated by upscaling the reactions up to 10 gram-scale syntheses. Furthermore, in situ NMR studies were performed for the identification of active catalytic species. Based on these studies a mechanism for Ru-catalyzed reductive amination is proposed., Synthesis of primary amines via operationally simple, inexpensive and environmentally friendly methodologies has high impact in industrial settings. Here, the authors show a reductive amination process involving a ruthenium catalyst, aldehydes/ketones, ammonia, and hydrogen that displays a remarkable scope of primary amine products.

The sustainable introduction of nitrogen moieties in the form of nitrile or amide groups in functionalized molecules is of fundamental interest because nitrogen-containing motifs are found in a large number of life science molecules, natural products and materials. Hence, the synthesis and functionalization of nitriles and amides from easily available starting materials using cost-effective catalysts and green reagents is highly desired. In this regard, herein we report the nanoscale iron oxide-catalyzed environmentally benign synthesis of nitriles and primary amides from aldehydes and aqueous ammonia in the presence of 1 bar O2 or air. Under mild reaction conditions, this iron-catalyzed aerobic oxidation process proceeds to synthesise functionalized and structurally diverse aromatic, aliphatic and heterocyclic nitriles. Additionally, applying this iron-based protocol, primary amides have also been prepared in a water medium.

Pyrolysis of cobalt-terephthalic acid MOF template on carbon produces highly active and selective cobalt nanoparticles-based hydrogenation catalysts., The development of efficient and selective nanostructured catalysts for industrially relevant hydrogenation reactions continues to be an actual goal of chemical research. In particular, the hydrogenation of nitriles and nitroarenes is of importance for the production of primary amines, which constitute essential feedstocks and key intermediates for advanced chemicals, life science molecules and materials. Herein, we report the preparation of graphene shell encapsulated Co3O4- and Co-nanoparticles supported on carbon by the template synthesis of cobalt-terephthalic acid MOF on carbon and subsequent pyrolysis. The resulting nanoparticles create stable and reusable catalysts for selective hydrogenation of functionalized and structurally diverse aromatic, heterocyclic and aliphatic nitriles, and as well as nitro compounds to primary amines (>65 examples). The synthetic and practical utility of this novel non-noble metal-based hydrogenation protocol is demonstrated by upscaling several reactions to multigram-scale and recycling of the catalyst.

A MOF sets the stage to make amines Reductive amination is a common method that chemists use to make carbon-nitrogen bonds. The reaction, which often requires precious metal catalysts, couples ammonia or other amines with carbonyl compounds and then with hydrogen. Jagadeesh et al. report a class of nonprecious cobalt nanoparticles that catalyze this reaction across a very broad range of substrates, including complex molecules of pharmaceutical interest (see the Perspective by Chen and Xu). The cobalt was first embedded in a metal-organic framework (MOF), which, upon heating, transformed into a graphitic shell. The catalyst could be conveniently separated from products and recycled up to six times. Science , this issue p. 326 ; see also p. 304

N-methyl and -alkylamines represent important fine and bulk chemicals, which are extensively used in both academic research and industrial production. Notably, these structural motifs are found in a large number of life science molecules and play vital role in regulating their activities. Therefore, the development of convenient and cost-effective methods for the synthesis and functionalization of amines using earth abundant metal-based catalysts is of scientific interest. In this regard, herein we report an expedient reductive amination process for selective synthesis of N-methylated and -alkylated amines using nitrogen doped graphene activated nanoscale Co3O4-based catalysts. Starting from inexpensive and easily accessible nitroarenes or amines and aqueous formaldehyde or aldehydes in presence of formic acid, this cost-efficient reductive amination protocol allows for the synthesis of various N-methyl and N-alkylamines, amino acid derivatives and existing drug molecules.

The preparation of nickel nanoparticles as efficient reductive amination catalysts by pyrolysis of in situ generated Ni-tartaric acid complex on silica is presented. The resulting stable and reusable Ni-nanocatalyst enables the synthesis of functionalized and structurally diverse primary benzylic, heterocyclic and aliphatic amines starting from inexpensive and readily available carbonyl compounds and ammonia in presence of molecular hydrogen. Applying this Ni-based amination protocol, -NH2 moiety can be introduced in structurally complex compounds, for example, steroid derivatives and pharmaceuticals.