CN Bond Formation Research Articles

Asymmetric C-H and N-H Functionalization of Indoles Involving Central Chirality via Chiral Phosphoric Acid Catalysis

Abstract: The C-H and N-H functionalization of indoles is an interesting area of research that has a useful impact on organic synthesis due to the availability of chiral indole scaffolds in the discovery of drugs, synthetic bioactive compounds, and natural products. The chiral phosphoric acid catalysts (CPAs) have proven to be a powerful and versatile class of enantioselective organocatalysts. Many asymmetric syntheses of organic compounds have been carried out with these catalysts in C-C and CN bond formation reactions, and great progress has been reported. By 2011, several reviews were published covering some important topics and recent achievements in this field. Therefore, in this review, the most recent advances, research breakthroughs with key examples involving mechanisms of CPA-catalyzed C-H and N-H functionalization of indoles to form central chirality via Friedel Crafts, Michael type, and rearrangement reactions were reviewed and reported.

Mechanism of hydride abstraction in the electrocyclic phototransformation of heterostilbene

A new mechanism of hydride abstraction in the course of a photochemical electrocyclic reaction of heterostilbene in aqueous solution is reported. The study of electrocyclic transformations of heterostilbenes containing different types of heterocyclic residues revealed that the herein estimated mechanism of hydride abstraction is common for heterostilbene photochemical electrocyclization through the formation of new CN bond.

Rhodium-catalyzed formal [4 + 3] annulation reaction of N-methoxybenzamides with gem‑difluorocyclopropenes: A combination of experimental and theoretical studies

A rhodium-catalyzed [4 + 3] cycloaddition reaction between N-methoxybenzamides and gem‑difluorocyclopropenes is described. The reaction offers a mild and efficient approach towards the synthesis of fluorinated 2H-azepin-2-ones with broad substrate scope. A consecutive HOAc-assisted CN bond formation and fluorine elimination are involved as key steps for success as illustrated by detailed DFT studies.

Development of a time–temperature indicator based on Maillard reaction for visually monitoring the freshness of mackerel

Due to the highly cost-effective and maneuverable property, Maillard reaction-based time–temperature indicators (TTIs) are considered ideal devices for temperature track and quality indication. The objective of this study was to develop a cold-sensitive TTI based on the Maillard reaction reflecting the freshness of chilled seafood. Firstly, the color evolution trends of a series of Maillard reaction-based TTIs were investigated and the xylose-lysine group represented obvious color change. Fourier transform infrared (FTIR) spectroscopy revealed the color change was associated with the formation of CN bond in melanoidin. Simultaneously, the relationships of the color change of TTI with time and temperature were established. The activation energy value (Ea) of TTI was close to that of mackerel. There existed a good relevance (R2 = 0.98) between the color change of TTI and the total volatile basic nitrogen content of mackerel, suggesting this novel TTI might have the potential to monitor the freshness of mackerel.

On the formation of CN bonds in Titan's atmosphere-a unified reaction valley approach study.

In this work, we investigated the formation of protonated hydrogen cyanide HCNH+ and methylene amine cation CH[Formula: see text] (both identified in Titan's upper atmosphere) from three different pathways which stem from the interaction between CH4 and N+(3P). As a mechanistic tool, we used the Unified Reaction Valley Approach (URVA) complemented with the Local Mode Analysis (LMA) assessing the strength of the CN bonds formed in these reactions. Our URVA studies could provide a comprehensive overview on bond formation/cleavage processes relevant to the specific mechanism of eight reactions R1- R8 that occur across the three pathways. In addition, we could explain the formation of CH[Formula: see text] and the appearance of HCNH+ and CHNH[Formula: see text] along these paths. Although only smaller molecules are involved in these reactions including isomerization, hydrogen atom abstraction, and hydrogen molecule capture, we found a number of interesting features, such as roaming in reaction R3 or the primary interaction of H2 with the carbon atom in HCNH+ in reaction R8 followed by migration of one of the H2 hydrogen atoms to the nitrogen which is more cost effective than breaking the HH bond first; a feature often found in catalysis. In all cases, charge transfer between carbon and nitrogen could be identified as a driving force for the CN bond formation. As revealed by LMA, the CN bonds formed in reactions R1-R8 cover a broad bond strength range from very weak to very strong, with the CN bond in protonated hydrogen cyanide HCNH+ identified as the strongest of all molecules investigated in this work. Our study demonstrates the large potential of both URVA and LMA to shed new light into these extraterrestrial reactions to help better understand prebiotic processes as well as develop guidelines for future investigations involving areas of complex interstellar chemistry. In particular, the formation of CN bonds as a precursor to the extraterrestrial formation of amino acids will be the focus of future investigations. Formation of CN bonds in Titan's atmosphere visualized via the reaction path curvature.

Iodine-mediated direct α-amination of dimethyl methylmalonate using non-protected amines

In this study, direct CN bond formation was achieved via the reaction of a dimethyl methylmalonate with various amines in the presence of molecular iodine to produce α-aminocarbonyl compounds. This versatile methodology of the α-amination of a carbonyl-containing compound involves the in situ iodination of the dimethyl methylmalonate, thus promoting the formation of its enolate isomer, which then facilitates its nucleophilic substitution reaction with an amine. This strategy is highly practical and can be used in industry due to its requirement of only readily available reagents without any pre-preparation of the amines and other substrates.

Chitosan/biological benzoxazine composites: Effect of benzoxazine structure on the properties of composites

In this study, two bio-based benzoxazines, PH-f and SA-f, were synthesized and used to prepare benzoxazine/chitosan (CS) composites of PH-f/CS and SA-f/CS and their corresponding curing products poly(PH-f)/CS and poly(SA-f)/CS. Differential scanning calorimeter (DSC) and Fourier-transform infrared spectroscopy (FTIR) spectra show that, compared with poly(PH-f)/CS, the formation of imine-linkages (C=N) between SA-f and CS accelerates the benzoxazine ring-opening reaction and lowers the curing temperature of SA-f/CS. Although poly(PH-f)/CS and poly(SA-f)/CS have lower thermal stability than corresponding pure polybenzoxazine, it is still high and their LOI values are >35, indicative of good flame retardancy. Due to the formation of CN bonds between SA-f and CS, the poly(SA-f)/CS composite has more regular surfaces and a more uniform pore distribution than poly(PH-f)/CS, with a specific area of 1.135 m2/g and porosity of 97.5%. The unique pore structure of the poly(SA-f)/CS composite gives it high adsorption capacity (reaching 95% for rhodamine B within 48 h), suggesting that it is a promising adsorption material.

Solvent-dependent metal-free chemoselective synthesis of benzimidazoles and 1,3,5-triarylbenzenes from 2-amino anilines and aryl alkyl ketones catalyzed by I2

A solvent-dependent I2-catalyzed chemoselective reaction was developed for the synthesis of benzimidazoles and 1,3,5-triarylbenzenes via the annulation of 2-amino anilines and aryl alkyl ketones or the cyclization of aryl alkyl ketones, respectively. With 1,4-dioxane as the solvent, sequential CN bond formation followed by C(CO)-C(CH3) bond cleavage leads to the formation of benzimidazoles in a highly selective manner while aldol-type self-condensation of aryl alkyl ketones predominates using PhNO2 or PhCl as the solvent to afford 1,3,5-triarylbenzenes.

Copper-catalyzed regioselective 2-amination of o-haloanilides with aqueous ammonia

An efficient Cu(II)-vasicine catalytic system has been developed for intramolecular CN bond formation. In this way, regioselective 2-amination of o-haloanilides with aqueous ammonia in EtOH has been achieved. This strategy provides several advantages, such as good regioselectivity, high yields and functional group tolerance.

C–CN bond formation: an overview of diverse strategies

Nitrile or cyano compounds are an important part of structural motifs in dyes, agrochemicals, medicinal compounds, and electronic materials. Also, aryl nitrile is an important intermediate in the preparation of numerous compounds via transformations such as hydrolysis, hydration, reduction, cycloadditions, and nucleophilic additions. Such methods are beneficial for introducing sensitive functional groups in various positions in the multi-step synthesis of natural products and medicinal compounds. In the past decades, various cyanation methods have been reported in the vast arena of chemistry, which have made several building blocks accessible. Previously reported cyanation reviews, letters, and perspectives are written in parts. Thus, today a comprehensive review that will be able to guide readers through the vast pool of C-CN bond forming reactions via different approaches is obligatory. The present feature article depicts the various areas of cyanation methodologies that are based on the metal catalyst used, directed, non-directed, electrochemical, photochemical, asymmetric, and radical based approaches. This feature article will serve as a comprehensive tool to navigate the C-CN (cyanation) reactions across the vast area in synthetic chemistry.

Advancements in multifunctional manganese complexes for catalytic hydrogen transfer reactions.

Catalytic hydrogen transfer reactions have enormous academic and industrial applications for the production of diverse molecular scaffolds. Over the past few decades, precious late transition-metal catalysts were employed for these reactions. The early transition metals have recently gained much attention due to their lower cost, less toxicity, and overall sustainability. In this regard, manganese, which is the third most abundant transition metal in the Earth's crust, has emerged as a viable alternative. However, the key to the success of such manganese-based complexes lies in the multifunctional ligand design and choice of appropriate ancillary ligands, which helps them mimic and, even in some cases, supersede noble metals' activities. The metal-ligand bifunctionality, achieved via deprotonation of the acidic C-H or N-H bonds, is one of the powerful strategies employed for this purpose. Alongside, the ligand hemilability in which a weakly chelating group tunes in between the coordinated and uncoordinated stages could effectively stabilize the reactive intermediates, thereby facilitating substrate activation and catalysis. Redox non-innocent ligands acting as an electron sink, thereby helping the metal center in steps gaining or losing electrons, and non-classical metal-ligand cooperativity has also played a significant role in the ligand design for manganese catalysis. The strategies were not only employed for the chemoselective hydrogenation of different reducible functionalities but also for the C-X (X = C/N) coupling reactions via HT and downstream cascade processes. This article features multifunctional ligand-based manganese complexes, highlighting the importance of ligand design and choice of ancillary ligands for achieving the desired catalytic activity and selectivity for HT reactions. We have also discussed the detailed reaction pathways for metal complexes involving bifunctionality, hemilability, redox activity, and indirect metal-ligand cooperativity. The synthetic utilization of those complexes in different organic transformations has also been detailed.

Synthesis of Drugs and Biorelevant N-heterocycles Employing Recent Advances in C-N Bond Formation

C-N bond formation is a particularly important step in the generation of many biologically relevant heterocyclic molecules. Several methods have been reported for this purpose over the past few decades. Well-known named reactions like Ullmann-Goldberg coupling, Buchwald-Hartwig coupling and Chan-Lam coupling are associated with the C-N bond formation reactions. Several reviews covering this topic have already been published. However, no comprehensive review covering the synthesis of drugs/ lead compounds using the C-N bond formation reactions was reported. In this review, we cover many modern methods of the C-N bond formation reactions, with special emphasis on metal-free and green chemistry methods. We also report specific strategies adopted for the synthesis of drugs, which involve the C-N bond formation reactions. Examples include anti-cancer, antidepressant, anti-inflammatory, anti-atherosclerotic, anti-histaminic, antibiotics, antibacterial, anti-rheumatic, antiepileptic and anti-diabetic agents. Many recently developed lead compounds generated using the C-N bond formation reactions are also covered in this review. Examples include MAP kinase inhibitors, TRKs inhibitors, Polo-like Kinase inhibitors and MPS1 inhibitors.

FeCl3 catalyzed intermolecular reaction between enol ethers and anilines: Access to 2,3-substituted indoles through aryl group migration

An intermolecular FeCl3 catalyzed reaction between anilines and enol ethers is described. A variety of enol ethers and aromatic amines undergo a CC bond formation followed by cyclization via CN bond formation to afford the 2,3-disubstituted indoles, involving an unexpected aryl group migration. In this methodology, anilines act as bis-nucleophiles, wherein the initial attack occurs at the α-position of enol ether from the ortho position of aniline followed by the subsequent reaction of the amine moiety of aniline at the β-position, leading to the indole framework. This method is simple, obviates the use of expensive/hazardous transition-metal catalysts, and offers a wide range of substrate scope.

Recent advances on N-heterocyclic carbene transition metal complexes for dehydrogenative catalysis using alcohols

N-heterocyclic carbenes (NHCs) are green and versatile ligands for the development of transition metal (TM) catalysts. Presented is a brief overview of recent advances on NHC-TM complexes for dehydrogenative catalysis using alcohols. Various NHC-TM complexes, mostly based on noble metals Ir, Ru, and Os, as well as some non-noble metals like Cu, Mo, and Mn, are described. These NHC-TM complexes have been applied to acceptorless alcohol dehydrogenation (AAD) to aldehydes or ketones, and dehydrogenative coupling of alcohols for CO bond, CC bond, CN or CN bond formation. In comparison, the NHC-based Ru and Ir systems are relatively widely studied, the development of NHC-based non-noble metals catalysts is still in its infant for sustainable dehydrogenative catalysis using alcohols.

Synthesis of Drugs and Biorelevant N-heterocycles Employing Recent Advances in C-N Bond Formation

C-N bond formation is a particularly important step in the generation of many biologically relevant heterocyclic molecules. Several methods have been reported for this purpose over the past few decades. Well-known named reactions like Ullmann-Goldberg coupling, Buchwald-Hartwig coupling and Chan-Lam coupling are associated with the C-N bond formation reactions. Several reviews covering this topic have already been published. However, no comprehensive review covering the synthesis of drugs/ lead compounds using the C-N bond formation reactions was reported. In this review, we cover many modern methods of the C-N bond formation reactions, with special emphasis on metal-free and green chemistry methods. We also report specific strategies adopted for the synthesis of drugs, which involve the C-N bond formation reactions. Examples include anti-cancer, antidepressant, anti-inflammatory, anti-atherosclerotic, anti-histaminic, antibiotics, antibacterial, anti-rheumatic, antiepileptic and anti-diabetic agents. Many recently developed lead compounds generated using the C-N bond formation reactions are also covered in this review. Examples include MAP kinase inhibitors, TRKs inhibitors, Polo-like Kinase inhibitors and MPS1 inhibitors.

An unprecedented cobalt-catalyzed selective aroylation of primary amines with aroyl peroxides

A novel and facile cobalt-catalyzed selective aroylation of primary amines with aroyl peroxides was developed for the synthesis of aryl amides. It was unprecedented that CN bond formation product was selectively generated without the common NO bond formation product. Aroyl peroxides act as the sole aroylation reagent without additional base or oxidant. The reactions proceeded under mild conditions and showed broad substrates scope with a series of primary amines and aroyl peroxides.

CuCl2-catalyzed N[sbnd]O bond cleavage of oxime esters: Approach to imidazoheterocycles and furo[3,2-c]chromenyl fused imidazoles

An articulate approach to a diverse set of imidazoheterocycles in good to high yields via a copper-catalyzed aza-annulation of several oxime esters with a group of 2-amino-azaarenes was developed. The above cyclization reaction probably proceeds via a single electron transfer process which embodies a new technique for creating two new CN bonds for imidazole ring synthesis. Gratifyingly, the implementation of this chemistry could be further stretched to the synthesis of a novel class of fused imidazoles bearing a furo[3,2-c]chromene moiety via a sequential CN bond formation, followed by C(sp2)-H functionalization/5-endo-dig-oxacyclization (CC and CO bonds) of in situ produced fused imidazoles with cyclic enynones in the presence of copper(II) as a π-electrophilic Lewis acid catalyst.

Computational study on the mechanism of CBT-Cys click reaction

Mechanism of CBT-Cys click reaction was studied by density functional theory calculations. Calculations show that the CS bond formation followed by amino nitrogen attack pathway is the most favorable mechanism. This mechanism includes CS bond formation, CN bond formation, CN bond cleavage, and several facile proton transfer steps. The rate-determining step is the CN bond cleavage step. Except for the CS bond formation step, all the steps occur with the assistance of phosphoric acid. The promotion of phosphoric acid on the reaction results from its strong proton-donating ability, low ring strain of the cluster structural transition states, and stabilizing effect of the hydrogen bonds in the transition states. The calculated results of the reactivities of β-mercaptoethanol, N-terminal homocysteine residues and N-terminal serine residues towards 2-cyanobenzothiazole are all consistent with the experimental observations.

Boosting multiple photo-assisted and temperature controlled reactions with a single redox-switchable catalyst: Solvents as internal substrates and reducing agent

An alternative and economically viable process for the synthesis of β-aryl enals, enones and the aryl amines has been developed by partial oxidation of ethanol, isopropanol and N, N-dimethyl formamide (DMF). The formation of β-aryl enals, enones and the aryl amines was catalyzed by a mixed metal oxides layer of cobalt and chromium supported on halloysite nanotubes, designated as CoCr2O4-HNT. The CC and CN bond formation reactions were found to be influenced by temperature and the nature of base. The condensation of aldehyde with in situ generated acetaldehyde by ethanol oxidation forming β-aryl enals occurred selectively at 120 °C. The partial oxidation of isopropanol to acetone and its condensation with aldehydes forming β-aryl enones occurred at room temperature. Increase in temperature caused the liberation of hydrogen gas from isopropanol and allowed the reversible reduction of aldehydes to alcohols. Increase in temperature in isopropanol and increase in base concentration in ethanol causes the selective reduction of aldehydes to alcohols. Besides being active for the Claisen-Schmidt type of reactions and the aryl halides amination process, the synthesized catalyst was also found to be highly active for the photocatalytic oxidation of benzyl alcohols in absence of any external oxidizing agent. The positive holes (h+) generated at the Co(II) site as evident from EPR analysis was considered to be responsible for high photocatalytic activity of the material reducing the recombination rate of holes and electrons (e−). Density Functional Theory calculations were performed to understand the mechanism of ethanol oxidation to acetaldehyde.

Cu(OAc)2 and acids promoted the oxidative cleavage of α-aminocarbonyl compounds with amines: efficient and selective synthesis of 2-t-amino-2-imino-carbonyl and 2-amino-2-oxocarbonyl

A novel and efficient method for the synthesis of 2-t-amino-2-imino-carbonyl (C) and 2-amino-2-oxocarbonyl (D) compounds has been discovered through a copper-promoted oxidating amidation reactions between α-amino -carbonyl compounds and amines. Promoted by the crucial copper species, perfect selectivity and good to excellent yields could be achieved. This transformation is achieved through CN bond oxidative cleavage and formation a novel CN bond. This reaction system has a broad reaction scope, providing a facile pathway for the α-functionalization of α-amino ketones.