A State-of-the-Art Heterogeneous Catalyst for Efficient and General Nitrile Hydrogenation.

Cobalt-doped hybrid materials consisting of metal oxides and carbon derived from chitin were prepared, characterized and tested for industrially relevant nitrile hydrogenations. The optimal catalyst supported onto MgO showed, after pyrolysis at 700 °C, magnesium oxide nanocubes decorated with carbon-enveloped Co nanoparticles. This special structure allows for the selective hydrogenation of diverse and demanding nitriles to the corresponding primary amines under mild conditions (e.g. 70 °C, 20 bar H2 ). The advantage of this novel catalytic material is showcased for industrially important substrates, including adipodinitrile, picolinonitrile, and fatty acid nitriles. Notably, the developed system outperformed all other tested commercial catalysts, for example, Raney Nickel and even noble-metal-based systems in these transformations.

Asymmetric Hydrogenation of Unfunctionalized Tetrasubstituted Acyclic Olefins.

Asymmetric hydrogenation has evolved as one of the most powerful tools to construct stereocenters. However, the asymmetric hydrogenation of unfunctionalized tetrasubstituted acyclic olefins remains the pinnacle of asymmetric synthesis and an unsolved challenge. We report herein the discovery of an iridium catalyst for the first, generally applicable, highly enantio- and diastereoselective hydrogenation of such olefins and the mechanistic insights of the reaction. The power of this chemistry is demonstrated by the successful hydrogenation of a wide variety of electronically and sterically diverse olefins in excellent yield and high enantio- and diastereoselectivity.

Manganese(I)-Catalyzed Enantioselective Hydrogenation of Ketones Using a Defined Chiral PNP Pincer Ligand.

A new chiral manganese PNP pincer complex is described. The asymmetric hydrogenation of several prochiral ketones with molecular hydrogen in the presence of this complex proceeds under mild conditions (30-40 °C, 4 h, 30 bar H2 ). Besides high catalytic activity for aromatic substrates, aliphatic ketones are hydrogenated with remarkable selectivity (e.r. up to 92:8). DFT calculations support an outer sphere hydrogenation mechanism as well as the experimentally determined stereochemistry.

A Biomass-Derived Non-Noble Cobalt Catalyst for Selective Hydrodehalogenation of Alkyl and (Hetero)Aryl Halides.

Hydrodehalogenation is a straightforward approach for detoxifications of harmful anthropogenic organohalide-based pollutants, as well as removal of halide protecting groups used in multistep syntheses. A novel sustainable catalytic material was prepared from biowaste (chitosan) in combination with an earth-abundant cobalt salt. The heterogeneous catalyst was fully characterized by transmission electron microscope, X-ray diffraction, and X-ray photoelectron spectroscopy measurements, and successfully applied to hydrodehalogenation of alkyl and (hetero)aryl halides with broad scope (>40 examples) and excellent chemoselectivity using molecular hydrogen as a reductant. The general usefulness of this method is demonstrated by successful detoxification of non-degradable pesticides and fire retardants. Moreover, the potential of the catalyst as a deprotection tool is demonstrated in a multistep synthesis of (±)-peronatin B (alkaloid).

Sterically Congested 2,6-Disubstituted Anilines from Direct C-N Bond Formation at an Iodine(III) Center.

2,6-Disubstituted anilines are readily prepared from the direct reaction between amides and diaryliodonium salts. As demonstrated for 24 different examples, the reaction is of unusually broad scope with respect to the sterically congested arene and the nitrogen source, occurs without the requirement for any additional promoter, and proceeds through a direct reductive elimination at the iodine(III) center. The efficiency of the coupling procedure is further demonstrated within the short synthesis of a chemerin binding inhibitor.

Synthesis and Characterization of Iron-Nitrogen-Doped Graphene/Core-Shell Catalysts: Efficient Oxidative Dehydrogenation of N-Heterocycles.

An important goal for nanocatalysis is the development of flexible and efficient methods for preparing active and stable core-shell catalysts. In this respect, we present the synthesis and characterization of iron oxides surrounded by nitrogen-doped-graphene shells immobilized on carbon support (labeled FeOx@NGr-C). Active catalytic materials are obtained in a simple, scalable and two-step method via pyrolysis of iron acetate and phenanthroline and subsequent selective leaching. The optimized FeOx@NGr-C catalyst showed high activity in oxidative dehydrogenations of several N-heterocycles. The utility of this benign methodology is demonstrated by the synthesis of pharmaceutically relevant quinolines. In addition, mechanistic studies prove that the reaction progresses via superoxide radical anions (·O2(-)).

Efficient Synthesis of Differentiated syn-1,2-Diol Derivatives by Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of α-Alkoxy-Substituted ß-Ketoesters.

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α-alkoxy-ß-ketoesters in the presence of well-defined, commercially available, chiral catalyst Ru(II) -(N-p-toluenesulfonyl-1,2-diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α-alkoxy-ß-hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99 %). Additionally, after extensive screening of the reaction conditions, the use of Ru(II) - and Rh(III) -tethered precatalysts extended this process to more-challenging substrates that bore alkenyl-, alkynyl-, and alkyl substituents to provide the corresponding syn α-alkoxy-ß-hydroxyesters with excellent enantiocontrol (up to 99 % ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoate, which is an important pharmacophore in a number of peroxisome proliferator-activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type-II diabetes.

Room-temperature Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to maleimides and enones in the presence of CF3-substituted MeOBIPHEP analogues.

A Rh-based catalytic system implying electron-poor MeOBIPHEP analogues has been developed for the 1,4-addition of boronic acids to maleimides and enones under mild conditions at room temperature and led to succinimide derivatives and arylated cyclic ketones in good to excellent yields and ee. We uncovered the crucial role of the electronic and steric properties of diphosphine ligand and observed a strong boronic acid/ligand dependency in the case of maleimide derivatives and substrate/ligand matching in the case of cyclic enones.

A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones.

By applying N-doped carbon modified iron-based catalysts, the controlled hydrogenation of N-heteroarenes, especially (iso)quinolones, is achieved. Crucial for activity is the catalyst preparation by pyrolysis of a carbon-impregnated composite, obtained from iron(ii) acetate and N-aryliminopyridines. As demonstrated by TEM, XRD, XPS and Raman spectroscopy, the synthesized material is composed of Fe(0), Fe3C and FeN x in a N-doped carbon matrix. The decent catalytic activity of this robust and easily recyclable Fe-material allowed for the selective hydrogenation of various (iso)quinoline derivatives, even in the presence of reducible functional groups, such as nitriles, halogens, esters and amides. For a proof-of-concept, this nanostructured catalyst was implemented in the multistep synthesis of natural products and pharmaceutical lead compounds as well as modification of photoluminescent materials. As such this methodology constitutes the first heterogeneous iron-catalyzed hydrogenation of substituted (iso)quinolones with synthetic importance.

Correction: A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones.

[This corrects the article DOI: 10.1039/C8SC02744G.].

Biomass-Derived Catalysts for Selective Hydrogenation of Nitroarenes.

Development of catalytically active materials from biowaste represents an important aspect of sustainable chemical research. Three heterogeneous materials were synthesized from inexpensive biomass-based chitosan and abundant Co(OAc)2 using complexation followed by pyrolysis at various temperatures. These materials were applied in the catalytic hydrogenation of nitroarenes using molecular hydrogen. A variety of diversely functionalized nitroarenes including some pharmaceutically active compounds were converted into aromatic amines in high yields, with high selectivity, and with excellent functional group tolerance. This green protocol has also been implemented for the synthesis of a biologically important TRPC3 inhibitor.

Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib.

A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (1) is reported. The bicyclic pyrimidine 2 starting material was prepared via a nitrilase biocatalytic resolution, halogen-metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce α-aryl-ß-amino acid 3 in high yield and enantioselectivity. The API was assembled in a convergent manner through a late-stage amidation/deprotection/monohydrochloride salt formation sequence.

Efficient route to atropisomeric ligands--application to the synthesis of MeOBIPHEP analogues.

A highly efficient Pd-catalyzed P-C coupling reaction of easily accessible atropisomeric bisphosphane is described in the presence of various electron-poor aromatic iodides. The reactions are conducted in the presence of a Pd(II)/dppf catalyst in acetonitrile at 80 °C. The reaction conditions are compatible with several electron-withdrawing groups such as esters, cyano, chloro, and trifluoromethyl groups and lead to atropisomeric MeOBIPHEP derivatives in good to excellent yields and high enantiomeric purities.

Highly diastereo- and enantioselective synthesis of monodifferentiated syn-1,2-diol derivatives through asymmetric transfer hydrogenation via dynamic kinetic resolution.

The first enantio- and diastereoselective approach to alpha-alkoxy-substituted syn-beta-hydroxyesters through highly efficient catalytic asymmetric transfer hydrogenation via dynamic kinetic resolution reactions from the corresponding racemic beta-ketoesters is described. In this atom-economical process, two contiguous stereogenic centers are generated simultaneously with an excellent diastereoselectivity (up to 99/1) and enantioselectivity (up to 99%), allowing a rapid access to a wide variety of aromatic and heteroaromatic monodifferentiated syn-1,2-diols.

Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives.

A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C4 of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.