RESUMEN
Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single-nitrogen-atom insertion reaction, and skeletal editing to construct N-heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen-atom into hydrocarbons to generate N-heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen-containing heterocycles, and the current mechanistic understanding of these processes.
RESUMEN
A reductive amidation of unactivated esters with nitroarenes, a key step in the telescopic synthesis of tetrahydropyrrolo[1,2-a]quinoxalinones and tetrahydropyrido[1,2-a]quinoxalinones, is reported. The process involves an intermolecular base-mediated SNAr reaction, followed by intramolecular reductive amidation employing sodium dithionite. The substrate scope coupled with the demonstration of the synthesis of pharmaceuticals is reported. The key features include nitro reduction at room temperature, easy purification without chromatography, amidation of unactivated esters without any externally added activating agent, and a telescopic process.
RESUMEN
A novel biomass-derived glucose-mediated one-pot multicomponent nitro-reductive cyclization method is presented for the direct synthesis of diverse pyrrole-fused heterocycles. The process involves two-component reactions of alkyl (NH)-pyrrole-2-carboxylates and 2-fluoronitroarenes, yielding pyrrolo[1,2-a]quinoxalin-4(5H)-ones, as well as three-component reactions utilizing (NH)-pyrroles, nitroarenes, and DMSO as carbon sources, resulting in various pyrrolo[1,2-a]quinoxaline derivatives. High yields were achieved with broad substrate scope and gram-scale synthesis capability, including pharmaceuticals featuring pyrroloquinoxaline scaffolds. The method's key innovation lies in enabling three or four reactions in a single-pot setup, previously unexplored in pyrrole chemistry. The simplicity of nitro group reduction by biomass-derived glucose ensures practical safety during scale-up, while mechanistic insights from control experiments reveal a new paradigm in pyrrole chemistry. The tandem process demonstrates low PMI values and high step and atom economies, aligning well with green chemistry principles.
RESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder associated with mitochondrial dysfunctions and oxidative stress. However, to date, therapeutics targeting these pathological events have not managed to translate from bench to bedside for clinical use. One of the major reasons for the lack of translational success has been the use of classical model systems that do not replicate the disease pathology and progression with the same degree of robustness. Therefore, we employed a more physiologically relevant model involving alpha-synuclein-preformed fibrils (PFF) exposure to SH-SY5Y cells and Sprague Dawley rats. We further explored the possible involvement of transient receptor potential canonical 5 (TRPC5) channels in PD-like pathology induced by these alpha-synuclein-preformed fibrils with emphasis on amelioration of oxidative stress and mitochondrial health. We observed that alpha-synuclein PFF exposure produced neurobehavioural deficits that were positively ameliorated after treatment with the TRPC5 inhibitor clemizole. Furthermore, Clemizole also reduced p-alpha-synuclein and diminished oxidative stress levels which resulted in overall improvements in mitochondrial biogenesis and functions. Finally, the results of the pharmacological modulation were further validated using siRNA-mediated knockdown of TRPC5 channels, which also decreased p-alpha-synuclein expression. Together, the results of this study could be superimposed in the future for exploring the beneficial effects of TRPC5 channel modulation for other neurodegenerative disorders and synucleopathies.
Asunto(s)
Mitocondrias , Estrés Oxidativo , Ratas Sprague-Dawley , Canales Catiónicos TRPC , alfa-Sinucleína , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Animales , Ratas , Estrés Oxidativo/efectos de los fármacos , Humanos , Canales Catiónicos TRPC/genética , Canales Catiónicos TRPC/antagonistas & inhibidores , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Línea Celular Tumoral , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/inducido químicamente , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológicoRESUMEN
An elegant synthesis of pyrrole-2-carboxylic acid anhydrides from pyrrole-2-carboxaldehydes using TBAI as a catalyst and tert-butyl hydroperoxide (TBHP) as an oxidant is described herein. Unlike the previous reports wherein pyrrole-2-carboxylic acids were invariably used, we report here for first time the oxidative self-coupling of N-benzyl pyrrole-2-carboxaldehydes for the synthesis of 1-benzyl-1H-pyrrole-2-carboxylic anhydrides. In addition, a one-pot synthesis of novel pyrrole-2-carboxamides from pyrrole-2-carboxaldehydes is also reported. The mechanistic investigation supports a previously unexplored oxidative self-coupling of a pyrrole acyl radical, leading to the synthesis of a carboxylic anhydride.
RESUMEN
A one-pot, tandem reductive annulation of 2-nitrobenzenesulfonamides with aldehydes to the synthesis of substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides in the presence of sodium dithionite (Na2S2O4) is reported under mild conditions. The method involves in situ reduction of the nitro group followed by condensation with aldehydes to form an imine, which upon subsequent intramolecular cyclization forms the product under one-pot conditions. The protocol features use of inexpensive Na2S2O4 as the exclusive reagent, appreciable functional group tolerance, broad substrate scope, high product yields, and scalability.
RESUMEN
Our current unhealthy lifestyle and the exponential surge in the population getting affected by a variety of diseases have made pharmaceuticals or drugs an imperative part of life, making the development of innovative strategies for drug discovery or the introduction of refined, cost-effective and modern technologies for the synthesis of clinically used drugs, a need of the hour. Ever since their discovery, free radicals and radical cations or anions as reactive intermediates have captivated the chemists, resulting in an exceptional utilization of these moieties throughout the field of chemical synthesis, owing to their unprecedented and widespread reactivity. Sticking with the idea of not judging the book by its cover, despite the conventional thought process of radicals being unstable and difficult to control entities, scientists and academicians around the globe have done an appreciable amount of work utilizing both persistent as well as transient radicals for a variety of organic transformations, exemplifying them with the synthesis of significant biologically active pharmaceutical ingredients. This review truly accounts for the organic radical transformations including radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling with metal-complexes and radical cations coupling with nucleophiles, that offers fascinating and unconventional approaches towards the construction of intricate structural frameworks of marketed APIs with high atom- and step-economy; complementing the otherwise employed traditional methods. This tutorial review presents a comprehensive package of diverse methods utilized for radical generation, featuring their reactivity to form critical bonds in pharmaceutical total synthesis or in building key starting materials or intermediates of their synthetic journey, acknowledging their excellence, downsides and underlying mechanisms, which are otherwise poorly highlighted in the literature. Despite great achievements over the past few decades in this area, many challenges and obstacles are yet to be unraveled to shorten the distance between the academics and the industry, which are all discussed in summary and outlook.
Asunto(s)
Complejos de Coordinación , Radicales Libres/química , Ciclización , Cationes , Preparaciones FarmacéuticasRESUMEN
A non-traditional approach for the synthesis of pyrrole carboxamides from pyrrole carboxaldehyde and formamides or amines with catalytic amounts of nBu4NI and TBHP as oxidants is reported herein. The method is operationally simple providing straightforward access to primary, secondary, and tertiary pyrrole carboxamides in good to excellent yields utilizing inexpensive reagents under mild conditions. Unlike traditional amidations that involve ionic reactions, a mechanistic study of our current method unveils the involvement of 2- or 3-pyrrole acyl radicals that are otherwise rarely postulated. The applicability of the current method is further demonstrated in the synthesis of a drug-like compound, i.e., an optically pure carboetomidate amide.
RESUMEN
A mild, operationally convenient, and practical method for the synthesis of synthetically useful N-arylsulfonylimines from N-(arylsulfonyl)benzylamines using K2S2O8 in the presence of pyridine as a base is reported herein. In addition, a "one-pot" tandem synthesis of pharmaceutically relevant N-heterocycles by the reaction of N-arylsulfonylimines, generated in situ with ortho-substituted anilines is also reported. The key features of the protocol include the use of a green oxidant, a short reaction time (30 min), chromatography-free isolation, scalability, and economical, delivering N-arylsulfonylimines in excellent yields of up to 96%. While the oxidation of N-aryl(benzyl)amines to N-arylimines using K2S2O8 is reported to be problematic, the oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines using K2S2O8 has been achieved for the first time. The dual role of the sulfate radical anion (SO4·-), including hydrogen atom abstraction (HAT) and single electron transfer (SET), is proposed to be involved in the plausible reaction mechanism.
RESUMEN
AIMS: Transient receptor potential canonical 5 (TRPC5) channels are redox-sensitive cation-permeable channels involved in temperature and mechanical sensation. Increased expression and over-activation of these channels has been implicated in several central nervous system disorders such as epilepsy, depression, traumatic brain injury, anxiety, Huntington's disease and stroke. TRPC5 channel activation causes increased calcium influx which in turn activates numerous downstream signalling pathways involved in the pathophysiology of neurological disorders. Therefore, we hypothesized that pharmacological blockade and knockdown of TRPC5 channels could attenuate the behavioural deficits and molecular changes seen in CNS disease models such as MPTP/MPP+ induced Parkinson's disease (PD). MATERIALS AND METHODS: In the present study, PD was induced after bilateral intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the Sprague Dawley rats. Additionally, SH-SY5Y neurons were exposed to 1-methyl-4-phenylpyridinium (MPP+) to further determine the role of TRPC5 channels in PD. KEY FINDINGS: We used clemizole hydrochloride, a potent TRPC5 channel blocker, to reverse the behavioural deficits, molecular changes and biochemical parameters in MPTP/MPP+-induced PD. Furthermore, knockdown of TRPC5 expression using siRNA also closely phenocopies these effects. We further observed restoration of tyrosine hydroxylase levels and improved mitochondrial health following clemizole treatment and TRPC5 knockdown. These changes were accompanied by diminished calcium influx, reduced levels of reactive oxygen species and decreased apoptotic signalling in the PD models. SIGNIFICANCE: These findings collectively suggest that increased expression of TRPC5 channels is a potential risk factor for PD and opens a new therapeutic window for the development of pharmacological agents targeting neurodegeneration and PD.
Asunto(s)
Neuroblastoma , Enfermedad de Parkinson , Canales de Potencial de Receptor Transitorio , Animales , Humanos , Ratas , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , 1-Metil-4-fenilpiridinio , Calcio/metabolismo , Neuronas Dopaminérgicas , Neuroblastoma/metabolismo , Oxidación-Reducción , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Ratas Sprague-Dawley , Canales Catiónicos TRPC/genética , Canales Catiónicos TRPC/metabolismoRESUMEN
Unlike conventional amide synthesis, a decarboxylative amidation of aryl/heteroarylacetic acids by reaction with NHS and tert-butyl nitrite has been reported to afford both aliphatic and (hetero)aromatic amides in satisfactory yields. Mechanistic studies revealed a previously unexplored pathway for the formation of an activated ester through the generation and subsequent reactions of traceless α-functionalized benzylic radicals, which upon subsequent one-pot reaction with amines form the amides. A gram-scale synthesis of Moclobemide indicates the practical applicability.
RESUMEN
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.
RESUMEN
A simple approach for the intramolecular aroylation of electron-rich arenes under mild conditions has been developed. A pH-controlled polarity umpolung strategy can be used to synthesize different fluorenones, which are important building blocks for biological applications. Unlike previous acylation reactions involving nucleophilic aroyl radicals, this approach likely relies on in situ generated electrophilic aroyl radicals. Detailed mechanistic and computational investigations provide detailed insights into the reaction mechanism and support the hypothesis of a pH-mediated umpolung.
Asunto(s)
Ciclización , Acilación , Concentración de Iones de HidrógenoRESUMEN
Aryl radical generation from the corresponding aryl halides using an electron donor and subsequent intramolecular cyclization with arenes could be an important advancement in contemporary biaryl synthesis. A green and practically useful synthetic protocol to access diverse six- and seven-membered biarylsultams especially with a free NH group including demonstration of a gram-scale synthesis is reported herein. The sulfoxylate anion radical (SO2-â¢), generated in situ from the reagents rongalite or sodium dithionite (Na2S2O4), was found to be the key single electron transfer agent forming aryl radicals from aryl halides, which upon intramolecular arylation gives biarylsultams with good to excellent yields. The approach features generation of aryl radicals that remained underexplored, use of a cheap and readily available industrial reagents, and transition metal-free, mild, and green reaction conditions.
RESUMEN
Despite the structural similarity with imines, α-iminocarboxylic acids have seldom been used in heterocycles synthesis. The reactions of ortho-substituted anilines and arylglyoxylic acids in DMSO at 40 °C gave various benzo-fused five- to six-membered N-heterocycles in good to excellent yields. The reaction proceeds via intramolecular Michael addition of α-iminocarboxylic acids, generated in situ, with an ortho-substituted nucleophile, yielding an isolable unprecedented tetrahedral carboxylic acids, which upon decarboxylation without any aid of additional reagents forms the N-heterocycles. DMSO is crucial in this reaction, perhaps because of improved solubility and the ease of decarboxylation of these tetrahedral carboxylic acids. However, a copper-catalyzed reaction of ortho-substituted anilines and 2-bromoarylglyoxylic acids gave a dibenzo-fused seven-membered N-heterocycle under a basic reaction condition. Unlike intramolecular cyclization with α-iminocarboxylic acids in the first case, α-iminocarboxylic acid undergoes a competitive decarboxylation under the copper-catalyzed conditions, which upon subsequent heteroarylation form the heterocycles. Taken together, the study described herein represents two different modes of decarboxylation observed with α-iminocarboxylic acids, leading to the synthesis of divergent heterocycles and pharmaceuticals, which remained unexplored previously.
Asunto(s)
Cobre , Dimetilsulfóxido , Compuestos de Anilina , Ácidos Carboxílicos/química , Cobre/química , DescarboxilaciónRESUMEN
While persulfate activation at room temperature using glucose has primarily been focused on kinetic studies of the sulfate radical anion, the utilization of this protocol in organic synthesis is rarely demonstrated. We reinvestigated selected K2S2O8-mediated known organic reactions that invariably require higher temperatures and an organic solvent. A diverse, mild functionalization and synthesis of heterocycles using the inexpensive oxidant K2S2O8 in water at room temperature is reported, demonstrating the sustainability and broad scope of the method. Unlike traditional methods used for persulfate activation, the current method uses naturally abundant glucose as a K2S2O8 activator, avoiding the use of higher temperature, UV light, transition metals or bases.
RESUMEN
Light activatable porphyrinic photosensitizers (PSs) are essential components of anticancer and antimicrobial therapy and diagnostic imaging. However, their biological applications are quite challenging due to the lack of hydrophilicity and biocompatibility. To overcome such drawbacks, photosensitizers can be doped into a biocompatible polymer such as gelatin and further can be used for biomedical applications. Herein, first, a novel A4 type porphyrin PS [5,10,15,20-tetrakis(4-pyridylamidephenyl)porphyrin; TPyAPP] was synthesized via a rational route with good yield. Further, this porphyrin was encapsulated into the gelatin nanoparticles (GNPs) to develop hydrophilic phototherapeutic nanoagents (PTNAs, A4por-GNPs). Notably, the synthesis of such porphyrin-doped GNPs avoids the use of any toxic chemicals or solvents. The nanoprobes have also shown good fluorescence quantum yield demonstrating their applicability in bioimaging. Further, the mechanistic aspects of the anticancer and antimicrobial efficacy of the developed A4por-GNPs were evaluated via singlet oxygen generation studies. Overall, our results indicated porphyrin-doped biodegradable polymeric nanoparticles act as effective phototherapeutic agents against a broad range of cancer cell lines and microbes upon activation by the low-cost LED light.
Asunto(s)
Luz , Nanocápsulas/administración & dosificación , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Materiales Biocompatibles , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Fluorescencia , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Teoría Cuántica , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Among the known aromatic nitrogen heterocycles, pyrrole represents a privileged aromatic heterocycle ranging its occurrence in the key component of "pigments of life" to biologically active natural products to active pharmaceuticals. Pyrrole being an electron-rich heteroaromatic compound, its predominant functionalization is legendary to aromatic electrophilic substitution reactions. Although a few excellent reviews on the functionalization of pyrroles including the reports by Baltazzi in 1963, Casiraghi and Rassu in 1995, and Banwell in 2006 are available, they are fragmentary and over fifteen years old, and do not cover the modern aspects of catalysis. A review covering a comprehensive package of direct functionalization on pyrroles via catalytic and non-catalytic methods including their translational potential is described. Subsequent to statutory yet concise introduction, the classical functionalization on pyrroles using Lewis acids largely following an ionic mechanism is discussed. The subsequent discussion follows the various metal-catalyzed C-H functionalization on pyrroles, which are otherwise difficult to implement by Lewis acids. A major emphasize is given on the radical based pyrrole functionalization under metal-free oxidative conditions, which is otherwise poorly highlighted in the literature. Towards the end, the current development of pyrrole functionalization under photocatalyzed and electrochemical conditions is appended. Only a selected examples of substrates and important mechanisms are discussed for different methods highlighting their scopes and limitations. The aromatic nucleophillic substitution on pyrroles (being an electron-rich heterocycle) happened to be the subject of recent investigations, which has also been covered accentuating their underlying conceptual development. Despite great achievements over the past several years in these areas, many challenges and problems are yet to be solved, which are all discussed in summary and outlook.
RESUMEN
Annulation reactions of ortho-substituted anilines and arylglyoxylates in the presence of K2S2O8 at 80 °C under metal-free neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles. While arylglyoxylic acids are known to undergo decarboxylation to form an acyl radical in the presence of K2S2O8 and used in the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-rich ortho-substituted anilines to form nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the reactions, the mechanism of the formation of heterocycles involving reactions of an acyl radical or aryl iminocarboxylic acids has been postulated. Given the subtle understanding of the mechanisms of annulation reactions of 2-substituted anilines and arylglyoxylates in the presence of K2S2O8, an extensive mechanistic investigation was undertaken. In the current study, the various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based on the available analytical data. The protocol uses a single, inexpensive reagent K2S2O8, which offers not only transition-metal-free conditions but also serves as the reagent for the key decarboxylation step. Taken together, this study complements the current development of the annulation reactions of 2-substituted anilines and arylglyoxylates in terms of synthesis and mechanistic understanding.
RESUMEN
The 7-azaindole building block has attracted considerable interest in the field of drug discovery in the current portfolio. Because of their powerful medicinal properties, the development of synthetic, elegant techniques for the functionalization of 7-azaindoles continues to be an active area of research. Advances in metal-catalyzed chemistry have recently supported the successful development of a number of novel and effective methods for functionalization of the 7-azaindole template. This review reports state-of-the-art functionalization chemistry of 7-azaindoles with an aspiration to highlight the global ring functionalization of 7-azaindoles that are potential as pharmacophores for various therapeutic targets. Other relevant reviews focused on 7-azaindole synthesis, properties and applications have also been reported. However, none of these reviews have been dedicated to the results achieved in the field of metal-catalyzed cross-coupling/C-H bond functionalized reactions. So we wish to discuss and summarize the advances made since 2011 in this field toward 7-azaindole functionalization.