Skeletal Editing by Hypervalent Iodine Mediated Nitrogen Insertion.

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.

Intramolecular Reductive Amidation of Unactivated Esters with Nitroarenes: A Telescoped Synthesis of Tetrahydropyrrolo/Pyrido[1,2-a]quinoxalinones.

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.

Dithionite-Mediated Tandem Nitro Reduction/Imine Formation/Intramolecular Cyclization for the Synthesis of Dihydro-benzothiadiazine-1,1-dioxides.

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.

Direct access to pyrrole anhydrides via oxidative self-coupling of pyrrole carboxaldehydes.

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.

Modular synthesis of pyrrole-fused heterocycles via glucose-mediated nitro-reductive cyclization.

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.

Growing Utilization of Radical Chemistry in the Synthesis of Pharmaceuticals.

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.

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.

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines.

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.

Sulfoxylate Anion Radical-Induced Aryl Radical Generation and Intramolecular Arylation for the Synthesis of Biarylsultams.

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-•), 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.

Diversity in Heterocycle Synthesis Using α-Iminocarboxylic Acids: Decarboxylation Dichotomy.

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.

pH-Controlled Intramolecular Decarboxylative Cyclization of Biarylacetic Acids: Implication on Umpolung Reactivity of Aroyl Radicals.

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.

Recent Advances in Functionalization of Pyrroles and their Translational Potential.

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.

Possible competitive modes of decarboxylation in the annulation reactions of ortho-substituted anilines and arylglyoxylates.

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.

Intramolecular Oxidative Arylations in 7-Azaindoles and Pyrroles: Revamping the Synthesis of Fused N-Heterocycle Tethered Fluorenes.

We revealed intramolecular oxidative arylations in 7-azaindoles and pyrroles that, for the first time, provided direct access to 7-azaindole- or pyrrole-fused isoindolines and tetrahydroisoquinolines. In addition, N-benzylation of 7-azaindoles or pyrroles with sterically hindered sec-benzyl alcohols by Mitsunobu reaction followed by intramolecular oxidative arylation allowed access to chiral congeners of fused isoindolines that have little precedence. A new opportunity in the design and synthesis of fluorene-based organic emitters is demonstrated in the preparation of novel fused N-heterocycle tethered fluorenes, including a chiral fluorene architecture.

Access to Imidazolidine-Fused Sulfamidates and Sulfamides Bearing a Quaternary Center via 1,3-Dipolar Cycloaddition of Nonstabilized Azomethine Ylides.

A 1,3-dipolar cycloaddition reaction of nonstabilized azomethine ylides and cyclic N-sulfonyl imines has been developed providing a workable access to imidazolidine-fused sulfamidates, sulfamides, and benzosultams bearing a quaternary center. Distinct from the available literature, this current work enables to make entry, for the first time, into the novel imidazolidine-fused sulfamidates and sulfamides. Furthermore, the selective imidazolidine ring opening accompanied by CH2 extrusion yielded tetra-substituted sulfamidates with an aminomethyl group. In addition, imidazolidine ring opening coupled with SO2 extrusion provided synthetically useful 1,2-diamines.

Design, Sustainable Synthesis, and Programmed Reactions of Templated N-Heteroaryl-Fused Vinyl Sultams.

A de novo design and synthesis of N-heteroaryl-fused vinyl sultams as templates for programming chemical reactions on vinyl sultam periphery or (hetero)aryl ring is described. The key features include rational designing and sustainable synthesis of the template, customized reactions of vinyl sultams at C═C bond or involving N-S bond cleavage, and reactions on the periphery of the heteroaryl ring for late-stage diversification. The simple, easy access to the template coupled with opportunities for the synthesis of diversely functionalized heterocyles from a single template constitutes a rare study in contemporary organic synthesis.

Intramolecular Acylation of Unactivated Pyridines or Arenes via Multiple C-H Functionalizations: Synthesis of All Four Azafluorenones and Fluorenones.

An unprecedented intramolecular acylation of unactivated pyridines via multiple C(sp3/sp2)-H functionalizations of a methyl, hydroxymethyl, or aldehyde group has been developed providing a general access to all four azafluorenones. The application of this protocol is further demonstrated to the synthesis of azafluorenone related fused nitrogen heterocycles and fluorenones. In addition, design and synthesis of a novel fluorene based organic emitter for potential use in organic light emitting devices (OLEDs) is also reported.

Geometry Driven Intramolecular Oxidative Cyclization of Enamides: An Umpolung Annulation of Primary Benzamides with Acrylates for the Synthesis of 3-Methyleneisoindolin-1-ones.

A palladium-catalyzed tandem oxidative annulation of primary benzamides with acrylates via intermolecular N-alkenylation followed by intramolecular C-alkenylation yielded a stereoselective synthesis of (E)-3-methyleneisoindolin-1-ones. The study unveils, for the first time, that only E-enamides could undergo intramolecular oxidative cyclization under the optimized conditions to give isoindolinones. The current strategy represents an umpolung strategy when compared to the literature approaches that use benzamides.

Intramolecular Minisci acylation under silver-free neutral conditions for the synthesis of azafluorenones and fluorenones.

Despite its synthetic potential, intramolecular acylation by the Minisci reaction remains unexplored. The development of a new intramolecular Minisci acylation under silver-free neutral conditions providing access to azafluorenones and fluorenones is described. Distinct from the current literature known approaches for Minisci acylation, the report described herein features a method that: (a) avoids the use of silver that is invariably used in Minisci acylation, (b) does not require any acidic conditions for the activation of pyridines, and

Implications of dynamic imine chemistry for the sustainable synthesis of nitrogen heterocycles via transimination followed by intramolecular cyclisation.

An exploration of a tandem approach to the sustainable synthesis of N-heterocycles from readily available N-aryl benzylamines or imines and ortho-substituted anilines is described, which demonstrates, for the first time, an important synthetic application of dynamic imine chemistry. The key features to the successful development of this protocol include the utilisation of N-aryl benzylamines as imine precursors in transimination, the occurrence of transimination in acetonitrile in the absence of any catalysts, an intramolecular nucleophilic addition occurring in the newly formed imine causing irreversible transimination, and the tandem event occurring under green conditions.