Recent advances in biocatalytic C-N bond-forming reactions.

Molecules containing C-N bonds are of paramount importance in a diverse array of organic-based materials, natural products, pharmaceutical compounds, and agricultural chemicals. Biocatalytic C-N bond-forming reactions represent powerful strategies for producing these valuable targets, and their significance in the field of synthetic chemistry has steadily increased over the past decade. In this review, we provide a concise overview of recent advancements in the development of C-N bond-forming enzymes, with a particular emphasis on the inherent chemistry involved in these enzymatic processes. Overall, these enzymatic systems have proven their potential in addressing long-standing challenges in traditional small-molecule catalysis.

Copper-catalyzed N-arylation of amines with aryliodonium ylides in water.

Copper sulfate catalyzed an efficient, inexpensive, and environment-friendly protocol that has been developed for N-arylation of amines with 1,3-cyclohexadione-derived aryliodonium ylides in water as a green solvent. Aromatic primary amines substituted with electron-donating as well as electron-withdrawing groups on the aryl ring reacted smoothly with iodonium ylides to give the corresponding diarylamines with good to excellent yields. Also, secondary amines underwent N-arylation to deliver tertiary amines with moderate yields.

SNH Amidation of 5-Nitroisoquinoline: Access to Nitro- and Nitroso Derivatives of Amides and Ureas on the Basis of Isoquinoline.

For the first time, amides and ureas based on both 5-nitroisoquinoline and 5-nitrosoisoquinoline were obtained by direct nucleophilic substitution of hydrogen in the 5-nitroisoquinoline molecule. In the case of urea and monosubstituted ureas, only 5-nitrosoisoquinoline-6-amine is formed under anhydrous conditions.

C-N Bond Formation by Consecutive Continuous-Flow Reductions towards A Medicinally Relevant Piperazine Derivative.

A new, continuous-flow consecutive reduction method was developed for the C-N bond formation in the synthesis of the key intermediate of the antipsychotic drug cariprazine. The two-step procedure consists of a DIBAL-H mediated selective ester reduction conducted in a novel, miniature alternating diameter reactor, followed by reductive amination using catalytic hydrogenation on 5% Pt/C. The connection of the optimized modules was accomplished using an at-line extraction to prevent precipitation of the aluminum salt byproducts.

Metal Nanoparticles as Sustainable Tools for C-N Bond Formation via C-H Activation.

The design of highly active metal nanoparticles to be employed as efficient heterogeneous catalysts is a key tool for the construction of complex organic molecules and the minimization of their environmental costs. The formation of novel C-N bonds via C-H activation is an effective atom-economical strategy to access high value materials in pharmaceuticals, polymers, and natural product production. In this contribution, the literature of the last ten years on the use of metal nanoparticles in the processes involving direct C-N bond formation will be discussed. Where possible, a discussion on the role and influence of the support used for the immobilization and/or the metal chosen is reported. Particular attention was given to the description of the experiments performed to elucidate the active mechanism.

PEt3-Mediated Deoxygenative C-N Coupling of Nitroarenes and Boronic Acids.

A method for the preparation of aryl- and heteroarylamine products by triethylphosphine-mediated deoxygenative coupling of nitroarenes and boronic acids is reported. This method provides access to an array of functionalized (hetero)arylamine products from readily available starting materials under the action of an inexpensive commercial reagent. The developed triethylphosphine-mediated transformation highlights the capability of organophosphorus compounds to carry out this useful deoxygenative transformation without the necessity of any transition metal additives.

Catalytic Conversion of Carbon Dioxide through C-N Bond Formation.

From the viewpoint of green chemistry and sustainable development, it is of great significance to synthesize chemicals from CO2 as C1 source through C-N bond formation. During the past several decade years, many studies on C-N bond formation reaction were involved, and many efforts have been made on the theory. Nevertheless, several great challenges such as thermodynamic limitation, low catalytic efficiency and selectivity, and high pressure etc. are still suffered. Herein, recent advances are highlighted on the development of catalytic methods for chemical fixation of CO2 to various chemicals through C-N bond formation. Meanwhile, the catalytic systems (metal and metal-free catalysis), strategies and catalytic mechanism are summarized and discussed in detail. Besides, this review also covers some novel synthetic strategies to urethanes based on amines and CO2. Finally, the regulatory strategies on functionalization of CO2 for N-methylation/N-formylation of amines with phenylsilane and heterogeneous catalysis N-methylation of amines with CO2 and H2 are emphasized.

Accelerated generation of (protonated) imines and quinoxalines by formation of C=N bonds in the microdroplets of a nebuliser.

Ions corresponding to protonated imines appear in the positive ion electrospray mass spectra of mixtures of the parent aromatic aldehyde and arylamine. The formation of these imine products occurs readily in the electrospray source nebuliser, even without the application of a spray potential. This accelerated formation of C=N bonds in the nebuliser has been extended to encompass the preparation of quinoxalines from a range of substituted phenylenediamines and benzils. The condensation may be induced either under conventional positive ion electrospray conditions (to give the protonated quinoxalines) or when the nebuliser is disconnected from the mass spectrometer (to give the neutral quinoxaline). Ions corresponding to intermediate adducts formed by condensation of the phenylenediamine component with the protonated benzil are observed in many cases when the condensation occurs in the mass spectrometer. This finding supports an interpretation based on nucleophilic addition in droplets generated by the nebuliser.

Aminations with Hypervalent Iodine.

Recent progress in the area of hypervalent iodine-mediated and catalyzed amination reaction of hydrocarbons is reviewed. These reactions comprise processes under both intra and intermolecular control and include the functionalization of aromatic C-H bonds as well as conversion of sp-, sp(2)-, and sp(3)-hybridized carbon atoms. These developments demonstrate that hypervalent iodine(III) methodology has reached a high level in amination chemistry. The individual reactions are discussed with a focus on mechanistic details and emphasis is made to the underlying hypervalent iodine reagents, for which structural information is available.

Palladium/Copper-Cocatalyzed Oxidative Amidobrominations of Alkenes.

In the presence of LiBr, a palladium/copper combination catalyzes dehydrogenative amidobrominations of acrylates with NH-sulfoximines, leading to N-vinylated products by dual NH/CH coupling, followed by oxidative enamide bromination. Mechanistically, the domino process is proposed to involve palladium(II) species as key intermediates. First synthetic applications of the products have been demonstrated.

Diastereoselective Oxidative C-N/C-O and C-N/C-N Bond Formation Tandems Initiated by Visible Light: Synthesis of Fused N-Arylindolines.

The synthesis of fused N-arylindolines using visible light photoredox catalysis has been developed. We previously described that photogenerated amine radical cations generate substituted indoles through an intermediate benzylic carbocation. Herein, we expand the application of this chemistry by trapping the benzylic carbocation with tethered heteronucleophiles. The reactivity of the photogenerated benzylic carbocation is explored and applied to a range of substrates with various electronic characters and ring constraints. The method described provides C2 and C3 fused indolines bearing a tetrasubstituted carbon stereocenter with greater than 99:1 diastereoselectivity in moderate to good yields.

A one-dimensional coordination polymer created via in situ ligand synthesis involving C-N bond formation.

The novel cadmium complex catena-poly[cadmium(II)-µ3-{2-[3-(pyridin-2-yl)-1H-pyrazol-1-yl]butanedioato}], [Cd(C12H9N3O4)]n, has been prepared by the conjugate addition reaction of 2-(1H-pyrazol-3-yl)pyridine to fumaric acid in the presence of Cd(OAc)2·3H2O (OAc is acetate) at 413 K. Single-crystal X-ray diffraction analysis reveals that the complex consists of one-dimensional ladders constructed from [Cd2(COO)2] dimeric subunits. A combination of hydrogen bonding and π-π stacking interactions extend the one-dimensional ladders into a three-dimensional supramolecular architecture.

Catalytic Mechanism of Nonglycosidic C-N Bond Formation by the Pseudoglycosyltransferase Enzyme VldE.

The pseudoglycosyltransferase (PsGT) enzyme VldE is a homologue of the retaining glycosyltransferase (GT) trehalose 6-phosphate synthase (OtsA) that catalyzes a coupling reaction between two pseudo-sugar units, GDP-valienol and validamine 7-phosphate, to give a product with α,α-N-pseudo-glycosidic linkage. Despite its biological importance and unique catalytic function, the molecular bases for its substrate specificity and reaction mechanism are still obscure. Here, we report a comparative mechanistic study of VldE and OtsA using various engineered chimeric proteins and point mutants of the enzymes, X-ray crystallography, docking studies, and kinetic isotope effects. We found that the distinct substrate specificities between VldE and OtsA are most likely due to topological differences within the hot spot amino acid regions of their N-terminal domains. We also found that the Asp158 and His182 residues, which are in the active site, play a significant role in the PsGT function of VldE. They do not seem to be directly involved in the catalysis but may be important for substrate recognition or contribute to the overall architecture of the active site pocket. Moreover, results of the kinetic isotope effect experiments suggest that VldE catalyzes a C-N bond formation between GDP-valienol and validamine 7-phosphate via an SNi-like mechanism. The study provides new insights into the substrate specificity and catalytic mechanism of a member of the growing family of PsGT enzymes, which may be used as a basis for developing new PsGTs from GTs.

Benzimidazol-2-ylidene ruthenium complexes for C-N bond formation through alcohol dehydrogenation.

A low temperature hydrogen borrowing approach to generate secondary amines using benzimidazole-based N-heterocyclic carbene (BNHC) ruthenium complexes is reported. A series of the piano-stool complexes of the type [(η6-p-cymene)(BNHC)RuCl2] (1a-g) were synthesized via one-pot reaction of the NHC salt precursor, Ag2O, and [RuCl2(p-cymene)]2 and characterized using conventional spectroscopic techniques. The geometry of two precursors, [(η6-p-cymene)(Me4BnMe2BNHCCH2OxMe)RuCl2] (1f) and [(η6-p-cymene)(Me5BnMe2BNHCCH2OxMe)RuCl2] (1g), was studied by single crystal X-ray diffraction. These catalysts were found to dehydrogenate alcohols efficiently at temperatures as low as 50 °C to allow Schiff-base condensation and subsequent imine hydrogenation to afford secondary amines. Notably, this ruthenium-based procedure enables the N-alkylation of aromatic and heteroaromatic primary amines with a wide range of primary alcohols in excellent yields of up to 98%. The present methodology is green and water is liberated as the sole byproduct.

Palladium-Mediated Hydroamination of DNA-Conjugated Aryl Alkenes.

C-N bond formation is one of the most commonly used reactions in medicinal chemistry. Herein, we report an efficient Pd-promoted hydroamination reaction between DNA-conjugated aryl alkenes and a wide scope of aliphatic amines. The described reactions are demonstrated in good to excellent conversions to furnish C (sp3)-N bonds on DNA. This DNA-compatible transformation has strong potentials for the application into DNA-encoded library synthesis.

Deciphering the Reaction Pathway of Mononuclear Iron Enzyme-Catalyzed N≡C Triple Bond Formation in Isocyanide Lipopeptide and Polyketide Biosynthesis.

Despite the diversity of reactions catalyzed by 2-oxoglutarate-dependent nonheme iron (Fe/2OG) enzymes identified in recent years, only a limited number of these enzymes have been investigated in mechanistic detail. In particular, several Fe/2OG-dependent enzymes capable of catalyzing isocyanide formation have been reported. While the glycine moiety has been identified as a biosynthon for the isocyanide group, how the actual conversion is effected remains obscure. To elucidate the catalytic mechanism, we characterized two previously unidentified (AecA and AmcA) along with two known (ScoE and SfaA) Fe/2OG-dependent enzymes that catalyze N≡C triple bond installation using synthesized substrate analogues and potential intermediates. Our results indicate that isocyanide formation likely entails a two-step sequence involving an imine intermediate that undergoes decarboxylation-assisted desaturation to yield the isocyanide product. Results obtained from the in vitro experiments are further supported by mutagenesis, the product-bound enzyme structure, and in silico analysis.

Carbon-nitrogen bond formation to construct novel polyketide-indole hybrids from the indole-3-carbinol exposed culture of Daldinia eschscholzii.

A plenty of cytochrome P450s have been annotated in the Daldinia eschosholzii genome. Inspired by the fact that some P450s have been reported to catalyze the carbon-nitrogen (C-N) bond formation, we were curious about whether hybrids through C-N bond formation could be generated in the indole-3-carbinol (I3C) exposed culture of D. eschscholzii. As expected, two skeletally undescribed polyketide-indole hybrids, designated as indolpolyketone A and B (1 and 2), were isolated and assigned to be constructed through C-N bond formation. Their structures were elucidated by 1D and 2D NMR spectra. The absolute configurations of 1 and 2 were determined by comparing the recorded and calculated electronic circular dichroism (ECD) spectra. Furthermore, the plausible biosynthetic pathways for 1 and 2 were proposed. Compounds 1 and 2 exhibited significant antiviral activity against H1N1 with IC50 values of 45.2 and 31.4 µM, respectively. In brief, compounds 1 and 2 were reported here for the first time and were the first example of polyketide-indole hybrids pieced together through C-N bond formation in the I3C-exposed culture of D. eschscholzii. Therefore, this study expands the knowledge about the chemical production of D. eschscholzii through precursor-directed biosynthesis (PDB).

Intramolecular C-N Bond Formation via Thermal Arene C-H Bond Activation Supported by Au(III) Complexes.

One of the main tactics to access C-N bonds from inactivated C-H functionalities is direct transition metal-supported aminations. Due to the often harsh reaction conditions, the current goal in the field is the search for more mild and sustainable transformations. Herein, we present the first solvent-free thermally induced C-N bond formation driven by Au(III) salts. The general structure of the products was confirmed by 1H, 13C, 15N NMR, TGA-DTA and ATR/FT-IR analysis. Additionally, all derivatives were tested as catalysts in a three-component coupling reaction between phenylacetylene, benzaldehyde and piperidine and as anticancer agents on HL-60 and MCF-7 cell lines.

Selective Functionalization of Aliphatic Amines via Myoglobin-catalyzed Carbene N-H Insertion.

Engineered myoglobins have recently gained attention for their ability to catalyze a variety of abiological carbene transfer reactions including the functionalization of amines via carbene insertion into N-H bonds. However, the scope of myoglobin and other hemoprotein-based biocatalysts in the context of this transformation has been largely limited to aniline derivatives as the amine substrates and ethyl diazoacetate as the carbene donor reagent. In this report, we describe the development of an engineered myoglobin-based catalyst useful for promoting carbene N-H insertion reactions across a broad range of substituted benzylamines and α-diazo acetates with high efficiency (82-99% conversion), elevated catalytic turnovers (up to 7,000), and excellent chemoselectivity for the desired single insertion product (up to 99%). The scope of this transformation could be extended to cyclic aliphatic amines. These studies expand the biocatalytic toolbox available for the selective formation of C-N bonds, which are ubiquitous in many natural and synthetic bioactive compounds.

Synthetic Approaches for C-N Bonds by TiO2 Photocatalysis.

Nitrogen-containing organic compounds possess the most important status in drug molecules and agricultural chemicals. More than 80% currently used drugs have at least a C-N bond. The green and mild methodology to prepare diverse C-N bonds to replace traditional harsh preparation protocols is always a hotspot in modern synthetic chemistry. TiO2-based nanomaterials, considered as environmentally benign, stable, and powerful photocatalysts, have recently been applied in some certain challenging organic synthesis including construction of useful C-N compounds under mild conditions that are impossible to complete by conventional catalysis. This mini review would present state-of-the-art paragon examples of TiO2 photocatalyzed C-N bond formations. The discussion would be divided into two main sections: (1) N-alkylation of amines and (2) C-N formation in heterocycle synthesis. Especially, the mechanism of TiO2 photocatalytic C-N bond formation through activating alcohol into C=O by photo-induced hole followed by C=NH-R formation and finally hydrogenating C=NH-R into C-N bonds by combination of photo-induced electron/H+ assisted with loaded-Pt would be covered in detail. We believe that the mini-review will bring new insights into TiO2 photocatalysis applied to construct challenging organic compounds through enabling photo-induced hole and electron in a concerted way on coupling two substrate molecules together with respect to their conventionally independent catalysis behavior.