Homogeneous Catalysis in N-formylation/N-methylation Utilizing Carbon Dioxide as the C1 Source.

The growing emphasis on sustainable chemistry has driven research into utilizing carbon dioxide (CO2) as a nontoxic, abundant, and cost-effective C1 building block. CO2 offers a promising avenue for direct conversion into valuable chemicals ranging from fuels to pharmaceuticals. This review focuses on the utilization of CO2 for reductive N-formylation/N-methylation reactions of various amines, providing advantages over conventional methods involving toxic CO and other methylating reagents. The approach employs readily available reductants such as silane, borane reagents, and hydrogen (H2). The discussion encompasses recent developments in transition metal and organocatalyst systems for these reactions, highlighting mechanistic interpretations and factors influencing product selectivity.

Highly Efficient Thiolate-Based Ionic Liquid Catalysts for Reduction of CO2: Selective N-Functionalization of Amines to Form N-Formamides and N-Methylamines.

Developing efficient catalysts to convert CO2 into value-added chemicals is valuable for reducing carbon emissions. Herein, a kind of novel thiolate-based ionic liquid with sulfur as the active site was designed and synthesized, which served as highly efficient catalyst for the reductive N-functionalization of CO2 by amines and hydrosilane. By adjusting the CO2 pressure, various N-formamides and N-methylamines were selectively obtained in high yields. Remarkably, at the catalyst loading of 0.1 mol %, the N-formylation reaction of N-methylaniline exhibited an impressive turnover frequency (TOF) up to 600 h-1, which could be attributed to the roles of the ionic liquids in activating hydrosilane and amine. In addition, control experiments and NMR monitoring experiments provided evidence that the reduction of CO2 by hydrosilane yielded formoxysilane intermediates that subsequently reacted with amines to form N-formylated products. Alternatively, the formoxysilane intermediates could further react with hydrosilane and amine to produce 4-electron-reduced aminal products. These aminal products served as crucial intermediates in the N-methylation reactions.

Aerobic Oxidative Synthesis of Formamides from Amines and Bioderived Formyl Surrogates.

Herein we present a new strategy for the oxidative synthesis of formamides from various types of amines and bioderived formyl sources (DHA, GLA and GLCA) and molecular oxygen (O2) as oxidant on g-C3N4 supported Cu catalysts. Combined characterization data from EPR, XAFS, XRD and XPS revealed the formation of single CuN4 sites on supported Cuphen/C3N4 catalysts. EPR spin trapping experiments disclosed ⋅OOH radicals as reactive oxygen species and ⋅NR1R2 radicals being responsible for the initial C-C bond cleavage. Control experiments and DFT calculations showed that the successive C-C bond cleavage in DHA proceeds via a reaction mechanism co-mediated by ⋅NR1R2 and ⋅OOH radicals based on the well-equilibrated CuII and CuI cycle. Our catalyst has much higher activity (TOF) than those based on noble metals.

Direct additive-free N-formylation and N-acylation of anilines and synthesis of urea derivatives using green, efficient, and reusable deep eutectic solvent ([ChCl][ZnCl2]2).

In the current report, we introduce a simple, mild efficient and green protocol for N-formylation and N-acetylation of anilines using formamide, formic acid, and acetic acid as inexpensive, nontoxic, and easily available starting materials just with heating along stirring in [ChCl][ZnCl2]2 as a durable, reusable deep eutectic solvent (DES), which acts as a dual catalyst and solvent system to produce a wide range of formanilides and acetanilides. Also, a variety of unsymmetrical urea derivatives were synthesized by the reaction of phenyl isocyanate with a range of amine compounds using this benign DES in high to excellent yields. [ChCl][ZnCl2]2 showed good recycling and reusability up to four runs without considerable loss of its catalytic activity.

CO2-Driven N-Formylation/N-Methylation of Amines Using C-Scorpionate Metal Complexes.

C-scorpionate metal complexes, specifically, [NiCl2(tpm)]·3H2O, [CoCl2(tpm)]·3H2O and [PdCl2(tpm)] [tpm = hydrotris(1H-pyrazol-1-yl)methane], were effective in the N-formylation and N-methylation of amines using carbon dioxide, as carbon source, in the presence of sodium borohydride. Various parameters were studied, including reaction time, temperature, solvent volume, presence of additives, and catalyst amount. These parameters were found to have a significant impact on the selectivity of the product. [NiCl2(tpm)]·3H2O exhibited good conversion at 80 °C, but its selectivity towards formamide decreased with prolonged reaction time. Increasing the amount of [NiCl2(tpm)]·3H2O, the selectivity changed. [PdCl2(tpm)] showed different selectivity compared to [NiCl2(tpm)]·3H2O, while [CoCl2(tpm)]·3H2O presented poor results. Monitoring the reaction course by 1H NMR revealed the presence of an intermediate species that influenced product formation. These results highlight the versatility and catalytic potential of C-scorpionate metal complexes in the N-formylation/N-methylation of amines in the catalytic system (NaBH4/MeCN/CO2).

Genetic analysis of translation initiation in bacteria: An initiator tRNA-centric view.

Translation of messenger RNA (mRNA) in bacteria occurs in the steps of initiation, elongation, termination, and ribosome recycling. The initiation step comprises multiple stages and uses a special transfer RNA (tRNA) called initiator tRNA (i-tRNA), which is first aminoacylated and then formylated using methionine and N10 -formyl-tetrahydrofolate (N10 -fTHF), respectively. Both methionine and N10 -fTHF are produced via one-carbon metabolism, linking translation initiation with active cellular metabolism. The fidelity of i-tRNA binding to the ribosomal peptidyl-site (P-site) is attributed to the structural features in its acceptor stem, and the highly conserved three consecutive G-C base pairs (3GC pairs) in the anticodon stem. The acceptor stem region is important in formylation of the amino acid attached to i-tRNA and in its initial binding to the P-site. And, the 3GC pairs are crucial in transiting the i-tRNA through various stages of initiation. We utilized the feature of 3GC pairs to investigate the nuanced layers of scrutiny that ensure fidelity of translation initiation through i-tRNA abundance and its interactions with the components of the translation apparatus. We discuss the importance of i-tRNA in the final stages of ribosome maturation, as also the roles of the Shine-Dalgarno sequence, ribosome heterogeneity, initiation factors, ribosome recycling factor, and coevolution of the translation apparatus in orchestrating a delicate balance between the fidelity of initiation and/or its leakiness to generate proteome plasticity in cells to confer growth fitness advantages in response to the dynamic nutritional states.

Pyrimido[5,4-c]quinolines: Synthesis from 3,4-Di-functionallized Quinoline, Reactivity and Biological Activities.

Quinoline and pyrimidine moieties are ubiquitous components in both natural and synthetic compounds, showcasing diverse applications. The fusion of these well-known structures into hybrid molecules has garnered attention due to their intriguing biological properties. Particularly in the field of medicinal chemistry, numerous studies in the last decade have focused on pyrimido[5,4-c]quinoline ring systems (PyQs5,4-c). This review elucidates the synthesis of PyQs5,4-c and their derivatives using 3,4-difunctionalized quinoline as a key starting material. The preparation of PyQs5,4-c involves a series of chemical transformations, including the Friedländer, Ullmann and Biginelli reaction, Vilsmeier-Haack formylation, Suzuki coupling, and a one-pot three-component reaction. These synthetic routes not only offer access to diverse PyQs5,4-c derivatives.

Direct Synthesis of N-formamides by Integrating Reductive Amination of Ketones and Aldehydes with CO2 Fixation in a Metal-Organic Framework.

Formamides are important feedstocks for the manufacture of many fine chemicals. State-of-the-art synthesis of formamides relies on the use of an excess amount of reagents, giving copious waste and thus poor atom-economy. Here, we report the first example of direct synthesis of N-formamides by coupling two challenging reactions, namely reductive amination of carbonyl compounds, particularly biomass-derived aldehydes and ketones, and fixation of CO2 in the presence of H2 over a metal-organic framework supported ruthenium catalyst, Ru/MFM-300(Cr). Highly selective production of N-formamides has been observed for a wide range of carbonyl compounds. Synchrotron X-ray powder diffraction reveals the presence of strong host-guest binding interactions via hydrogen bonding and parallel-displaced π⋅⋅⋅π interactions between the catalyst and adsorbed substrates facilitating the activation of substrates and promoting selectivity to formamides. The use of multifunctional porous catalysts to integrate CO2 utilisation in the synthesis of formamide products will have a significant impact in the sustainable synthesis of feedstock chemicals.

Borohydride Ionic Liquids as Reductants of CO2 in the Selective N-formylation of Amines.

Borohydride imidazolium ionic liquids, [IL]BH4, used for the first time as reductants in the N-formylation of various amines with CO2, provided an excellent yield of formamides. Under the same conditions, 5 bar CO2 and 80 °C, NaBH4 produced a mixture of N-formylated and N-methylated products in a ratio of 1 : 2. An alternative approach, based on the addition of halide imidazolium salts ([IL]Cl or [IL]Br) to the reactions of amine with NaBH4 and CO2, resulted in a significant increase of selectivity to formamide. However, no effect was noted for [IL]BF4 and [IL]PF6. Monitoring the reaction course in time using 1H NMR brought about new insight into the role of BH3 in the reduction of CO2 and the functionalization of amines. The formation of N-methylaniline - borane intermediate was evidenced.

Carbonylation as a Key Step in New Tandem Reactions - A Route to BODIPYs.

Herein, a highly efficient five-step reaction sequence to BODIPYs is presented. The key step is the combination of transition metal-catalyzed in-situ generation of aldehydes and their subsequent organocatalytic activation to yield dipyrromethanes, which are further converted to the corresponding BODIPY. Classic syntheses towards BODIPYs have relied on aldehydes or acid chlorides, which are often not commercially available and rather sensitive to handle. The presented approach starts from readily available and stable alkenes or aryl-bromides, which allows to extend the range of readily available BODIPYs that can be tailored for their specific use. The synthesis of 55 derivatives with overall yields of up to 78 % demonstrates the wide applicability and advantages of the presented method.

Rapid On-Resin N-Formylation of Peptides as One-Pot Reaction.

N-formylation is a common pre- and post-translational modification of the N-terminus or the lysine side chain of peptides and proteins that plays a role in the initiation of immune responses, gene expression, or epigenetics. Despite its high biological relevance, protocols for the chemical N-formylation of synthetic peptides are scarce. The few available methods are elaborate in their execution and the yields are highly sequence-dependent. We present a rapid, easy-to-use one-pot procedure that runs at room temperature and can be used to formylate protected peptides at both the N-terminus and the lysine side chain on the resin in near-quantitative yields. Only insensitive, storage-stable standard chemicals - formic acid, acetic anhydride, pyridine and DMF - are used. Formylation works for both short and long peptides of up to 34 amino acids and over the spectrum of canonical amino acids.

Meso-Formyl, Vinyl, and Ethynyl Porphyrins-Multipotent Synthons for Obtaining a Diverse Array of Functional Derivatives.

This review presents a strategy for obtaining various functional derivatives of tetrapyrrole compounds based on transformations of unsaturated carbon-oxygen and carbon-carbon bonds of the substituents at the meso position (meso-formyl, vinyl, and ethynyl porphyrins). First, synthetic approaches to the preparation of these precursors are described. Then diverse pathways for the transformations of the multipotent synthons are discussed, revealing a variety of products of such reactions. The structures, electronic, and optical properties of the compounds obtained by the methods under consideration are analyzed. In addition, there is an overview of the applications of the products obtained. Biomedical use of the compounds is among the most important. Finally, the advantages of using the reviewed synthetic strategy to obtain dyes with targeted properties are highlighted.

Graphitic Carbon Nitride as Photocatalyst for the Direct Formylation of Anilines.

The use of graphitic carbon nitride (g-CN) for the photocatalytic radical formylation of anilines, which represents a more sustainable and attractive alternative to the currently used approaches, is reported herein. Our operationally simple method occurs under mild conditions, employing air as an oxidant. In particular, the chemistry is driven by the ability of g-CN to reach an electronically excited state upon visible-light absorption, which has a suitable potential energy to trigger the formation of reactive α-amino radical species from anilines. Mechanistic investigations also proved the key role of the g-CN to form reactive superoxide radicals from O2 via single electron transfer. Importantly, this photocatalytic transformation provides a variety of functionalized formamides (15 examples, up to 89 % yield).

Moderately lipophilic 2-(Het)aryl-6-dithioacetals, 2-phenyl-1,4-benzodioxane-6-dithioacetals and 2-phenylbenzofuran-5-dithioacetals: Synthesis and primary evaluation as potential antidiabetic AMPK-activators.

Since the 1950's, AMP-kinase (AMPK) has been used as a promising target for the development of antidiabetic drugs against Type 2 diabetes mellitus (T2D). Indeed, the canonical antidiabetic drug metformin recruits, at least partially, AMPK activation for its therapeutic effect. Herein we present design and synthesis of 20 novel relatively polar cyclic and acyclic dithioacetals of 2-(Het)arylchroman-6-carbaldehydes, 2-phenyl-1,4-benzodioxane-6-carbaldehyde, and 2-phenylbenzofuran-5-carbaldehyde, which were developed as potential AMPK activators. Three of the synthesized dithioacetals demonstrated significant enhancement (≥70%) of glucose uptake in rat L6 myotubes. Noteworthy, one of the dithioacetals, namely 4-(6-(1,3-dithian-2-yl)chroman-2-yl)pyridine, exhibited high potency comparing to other molecules. It increased the rate of glucose uptake in rat L6 myotubes and augmented insulin secretion from rat INS-1E cells in pharmacological relevant concentrations (up to 2 µM). Both effects were mediated by activation of AMPK. In addition, the compound showed excellent pharmacokinetic profile in healthy mice, including maximal oral bioavailability. Such bifunctionality (increased glucose uptake and insulin secretion) can be used as a starting point for the development of a novel class of antidiabetic drugs with dual activity that is relevant for T2D treatment.

Recent Advances On Direct Formylation Reactions.

Aldehydes serve as the key functional group in organic synthesis and are valuable intermediates. The various advanced methods of direct formylation reactions have been reviewed in this article. Overcoming the drawbacks of the traditional methods of formylation, newer methods involving homo and heterogenous catalysts, one pot reactions, solvent free techniques are elaborated, which can be performed under mild conditions and using inexpensive resources.

Tailoring Active Cu2 O/Copper Interface Sites for N-Formylation of Aliphatic Primary Amines with CO2 /H2.

Heterogeneously catalyzed N-formylation of amines to formamide with CO2 /H2 is highly attractive for the valorization of CO2 . However, the relationship of the catalytic performance with the catalyst structure is still elusive. Herein, mixed valence catalysts containing Cu2 O/Cu interface sites were constructed for this transformation. Both aliphatic primary and secondary amines with diverse structures were efficiently converted into the desired formamides with good to excellent yields. Combined ex and in situ catalyst characterization revealed that the presence of Cu2 O/Cu interface sites was vital for the excellent catalytic activity. Density functional theory (DFT) calculations demonstrated that better catalytic activity of Cu2 O/Cu(111) than Cu(111) is attributed to the assistance of oxygen at the Cu2 O/Cu interface (Ointer ) in formation of Ointer -H moieties, which not only reduce the apparent barrier of HCOOH formation but also benefit the desorption of the desired N-formylated amine, leading to high activity and selectivity.

Electrochemically Enabled Direct C3-Formylation of Imidazopyridines with Me3 N as a Carbonyl Source.

A metal-free and oxidant-free electrochemically enabled strategy for C-3 formylation of imidazopyridines using trimethylamine as a one-carbon source has been established. This conversion has high functional group compatibility under mild conditions and ensures late-stage functionalization of pharmaceutical molecules. Furthermore, unexpected hexafluoroisopropoxylation products have been observed in some cases. Mechanistic studies using cyclic voltammetry and control experiments reveal the key intermediate of the formylation process.

Design, Synthesis of 3-(5-Substituted Phenyl-[1,3,4]oxadiazol-2-yl)-1H-indole and Its Microbial Activity.

Fischer indole synthesis of indole by using phenyl-hydrazine and acetaldehyde resulted 1H-Indole while phenyl-hydrazine reacted with malonaldehyde gives 1H-Indole-3-carbaldehyde. Also Vilsmeier-Haack formylation of 1H-Indole gives 1H-Indole-3-carbaldehyde. 1H-Indole-3-carbaldehyde were oxidized to form 1H-Indole-3-carboxylic acid. 1H-Indole reacted with excess of BuLi at -78 °C using dry ice also gives 1H-Indole-3-carboxylic acid. Obtained 1H-Indole-3-carboxylic acid was converted to ester and ester in to acid hydrazide. Finally 1H-Indole-3-carboxylic acid hydrazide reacted with substituted carboxylic acid gives microbial active indole substituted oxadiazoles. Synthesized compounds 9a-j showing promising in vitro anti microbial activities against S. aureus bacteria compared with Streptomycin. Compound 9a, 9f and 9g showing activities against E. coli compared with standards. Compound 9a and 9f are found potent active against B. subtilis compared with reference standard while compound 9a, 9c and 9j active against S. typhi.

In Situ-Generated CuI Catalytic System for Oxidative N-Formylation of N-Heterocycles and Acyclic Amines with Methanol.

The development of a sustainable and simple catalytic system for N-formylation of N-heterocycles with methanol by direct coupling remains a challenge, owing to many competing side reactions, given the sensitivity of N-heterocycles to many catalytic oxidation or dehydrogenation systems. This work concerns the development of an in situ-generated CuI catalytic system for oxidative N-formylation of N-heterocycles with methanol that is based on the case study of a more typical 1,2,3,4-tetrahydroquinoline as substrate. Aside from N-heterocycles, some acyclic amines are also transformed into the corresponding N-formamides in moderate yields. Furthermore, a probable reaction mechanism and reaction pathway are proposed and extension of work based on some findings leads to a demonstration that the formed ⋅O2 - and ⋅OOH radicals in the catalytic system is related to the formation of undesired tar-like products.

The Eschenmoser's Salt as a Formylation Agent for the Synthesis of Indolizinecarbaldehydes and Their Use for Colorimetric Nitrite Detection.

C-H bond formylation is the most immediate way to incorporate the versatile formyl group into (hetero)aromatics. However, the type of reagents and severe conditions involved in the classical formylation methods often curtail their application, especially in the presence of other functional groups. Herein, we present the Eschenmoser's salt, a commercially available (dimethylamino)methylating chemical, as a useful reagent for the C-H formylation of indolizines and other compounds. The method is straightforward and mild, furnishing indolizinecarbaldehydes in modest-to-good yields with exclusive and remote regioselectivity. Furthermore, these compounds can be easily transformed into push-pull dyes and are highly selective in the colorimetric detection of nitrite, a substance extensively employed as preservative in the food industry, the concentration of which is crucial to control to prevent harmful effects in living organisms. The assay is simple, allowing the naked-eye detection of nitrite in solution or on a cotton swab for a wide range of concentrations.