Herein, we develop a practical protocol for the dearomative annulation of indoles with 2-aminoaryl disulfides under mild conditions for accessing three-dimensional (3D) indoline frameworks. The developed protocol shows remarkable tolerance toward different functional groups. Additionally, this method was applied for the late-stage modification of drugs and natural products. Mechanistic studies reveal that this reaction proceeds via the activation of aryl disulfide by NFSI, generating an electrophilic sulfur as a key intermediate.

The present study reports the divergent reaction of previously underexplored arylglyoxyl radicals generated in situ from arylglyoxals in the presence of tert-butyl hydroperoxide (TBHP) and a catalytic amount of iodine with various amines at two different temperatures leading to the synthesis of arylglyoxal amides at 120 °C and aromatic amides at 180 °C. The two radicals, arylglyoxyl radical and aroyl radical, generated via decarbonylation at higher temperature, could react with amines via radical polar crossover.

An unconventional oxidative denitrogenative radical N-cyanoacetylation strategy for amines has been described using cyanoacetohydrazide as a novel cyanoacetyl radical precursor. The method achieves high yields across diverse amines with excellent chemoselectivity and significant practical applicability, highlighting the generation and synthetic utilization of an unprecedented, otherwise difficult-to-generate aliphatic cyanoacetyl radical.

Traumatic brain injury (TBI) triggers complex secondary pathological mechanisms, including neuroinflammation, oxidative stress, and apoptosis, contributing to long-term cognitive and motor deficits. This study investigates the neuroprotective potential of Clemizole, a known TRPC5 inhibitor, in a weight-drop rat model of TBI. Target prediction analyses using Swiss Target Prediction and CTD databases identified 159 overlapping genes between Clemizole and TBI. Protein-protein interaction network and hub gene analyses highlighted key proteins, such as TNF-α, CASP3, MMP-9, and TRPC5, implicating them in TBI pathogenesis. KEGG pathway enrichment revealed Clemizole-targeted pathways, including PI3K-Akt, TNF signaling, and apoptosis. After TBI, behavioral assessments showed that Clemizole significantly improved neurological scores, grip strength, locomotor activity, and spatial learning deficits. Biochemical assays revealed that Clemizole dose-dependently reduced nitrite and MDA levels while restoring GSH, indicating attenuation of oxidative stress. H&E (hematoxylin and eosin) and cresyl violet staining confirmed reduced neuronal degeneration and preserved cortical integrity. Clemizole also downregulated inflammatory cytokines and glial markers (Iba-1 and GFAP), alongside restoring BBB integrity via upregulation of tight junction proteins and suppressing MMP-9 expression. Furthermore, Clemizole activated the PI3K-Akt signaling pathway, decreasing the expression of pro-apoptotic proteins (Bax, caspase-9 and caspase-3) and restoring Bcl-2 levels. Importantly, Clemizole decreased TRPC5 expression and attenuated CHOP-mediated ER stress, suggesting a mechanistic link between TRPC5 inhibition and PI3K-Akt-mediated neuroprotection. Collectively, these findings demonstrate that Clemizole confers multifaceted neuroprotection following TBI by targeting TRPC5-mediated calcium dysregulation, restoring PI3K-Akt signaling, and attenuating oxidative, inflammatory, and apoptotic cascades. This study identifies Clemizole as a promising therapeutic candidate for mitigating secondary brain injury and promoting functional recovery after TBI.

A sustainable, transition-metal-free approach for the oxidative esterification of aldehydes with N-hydroxysuccinimide has been developed using ammonium persulfate as the sole oxidant. The protocol affords N-hydroxyimide esters in quantitative yields under mild aqueous acetonitrile conditions, displaying broad substrate scope and high functional group tolerance. These esters serve as versatile intermediates and have been directly transformed, either telescopically or in one pot, into a wide range of pharmaceutically relevant amides. The synthetic utility was demonstrated by the preparation of marketed drugs, including moclobemide, procainamide, acecainide, and bezafibrate, with moclobemide further synthesized on a 100 g scale, highlighting the practicality and industrial relevance of the process. Mechanistic studies, supported by radical trapping and density functional theory calculations, provide unprecedented evidence for sulfate radical anion (SO4·-)-mediated hydrogen atom abstraction from aromatic aldehydes. The results suggest that the generation and subsequent radical-radical coupling of acyl and succinimide-N-oxyl radicals constitute the most favorable pathway, while alternative radical and cationic routes may also contribute under reaction conditions. This study not only advances an efficient and scalable amide synthesis but also broadens the mechanistic understanding of sulfate radical anion reactivity in aromatic systems.

A classical transformation involving benzylic oxidation is developed using a metal-free approach. Unlike the reported methods, this report unveils for the first time the synthesis of arylglyoxylic esters from arylacetic esters utilizing the TBN/NHS catalytic system. A variety of substrates in moderate to good yields (upto 85%) are synthesized to exhibit the practical applicability of the reaction. The synthesized products display great utility and value in terms of synthetic transformations including the synthesis of many useful scaffolds. Mechanistic studies reveal the formation of a benzylic functionalized nitro compound as active intermediate leading to the formation of desired product.

N-Substituted anilines and their derivatives are versatile building blocks for synthesizing pharmaceutical molecules, natural products, and functional materials. Given the significant role of biarylamine motifs in modern chemistry, the development of a mild and easily handleable protocol is highly desirable in contemporary organic synthesis. In this context, we develop a transition-metal-free C-N cross-coupling of carboxamides and sulfonamides, resulting in the synthesis of valuable biarylamines and alkylarylamines. This discovery represents an intermolecularly challenging Smiles rearrangement and introduces a method for synthesizing N-substituted anilines through the activation of carboxamides derived from carboxylic acids, a previously unexplored approach. The protocol showcases a broad substrate scope with various functional groups and scalability, providing access to key building blocks in medicinal chemistry and drug discovery. Furthermore, the developed protocol was successfully applied to 20 late-stage modifications of drugs and natural products containing primary amides derived from the corresponding acids.

Amines are generally prepared from their corresponding nitro compounds by reduction. The question is whether nitro compounds can be used directly in place of amines in any synthetic transformation. While in-situ reduction of nitro compound to amine could have a significant advantage, the challenge would be how to integrate the reduction coupled with a subsequent synthetic transformation without isolation of amine especially in the presence of one reducing agent. Sodium dithionite (Na2S2O4) is an inexpensive, green and one-electron reductant, which has recently gained recognition not only in the chemoselective reduction of nitro to the amino group, but also coupled with another synthetic transformation. To further expand the scope of this tandem reductive synthetic transformation, we report herein a Na2S2O4 mediated intramolecular tandem reductive cyclization of N-(2-nitroaryl)-2-oxo-2-arylacetamides to the synthesize 3-arylquinoxalin-2(1H)-ones. The substrates were prepared using our previously reported method from arylglyoxals and ortho-nitroanilines in the presence of TBHP and a catalytic amount of iodine. The reductive cyclization of N-(2-nitroaryl)-2-oxo-2-arylacetamides proceeds through a sequential chemoselective reduction of nitro group followed by condensation of the amino group, generated in-situ, with the ketone group attached to the aryl ring. The two reactions occur in a tandem fashion exclusively in the presence of Na2S2O4 producing only sodium bisulfite as the only inorganic waste in this reaction. The method is operationally simple, avoids purification by column chromatography, exhibits a wide substrate scope, and has the ability for late-stage modification of the synthesized molecules. Unlike the previous reports, the strategy is substantially different overcoming limitations in the prior arts.

N-substituted anilines and their derivatives are versatile building blocks for synthesizing pharmaceutical molecules, natural products, and functional materials. Given the significant role of biarylamine motifs in modern chemistry, the development of a mild and easily manageable protocol is highly desirable in contemporary organic synthesis. In this context, we develop a transition-metal-free C-N cross-coupling of carboxamides and sulfonamides, resulting in the synthesis of valuable biarylamines and alkylarylamines. This discovery represents an intermolecularly challenging Smiles rearrangement and introduces a novel method for synthesizing N-aryl/alkyl amines through the activation of carboxamides derived from carboxylic acids, a previously unexplored approach. The protocol showcases a broad substrate scope with various functional groups and scalability, providing access to key building blocks in medicinal chemistry and drug discovery. Furthermore, the developed protocol was successfully applied to 20 late-stage modifications of drugs and natural-product derivatives.

The development of a mild, green, and metal-free oxidative dearomatization process of substituted indoles into 3-hydroxyoxindole derivatives is highly desirable in modern organic chemistry. This emphasis stems from the significance of oxindole cores as an essential and prevalent reactive intermediate in the synthesis of natural products and pharmaceutically relevant molecules. Herein, we report the dual vicinal functionalization of 3-substituted indoles into 3-hydroxy-2-oxindole scaffolds using a sulfonium intermediate generated in situ by activating DMSO with alkyl bromides. Water acts as an oxygen source in this process, allowing the indoles to be 2,3-dioxygenated products. This reaction is a unique approach for generating 3-hydroxy-2-oxindoles and has a broad substrate scope. The transformation takes place in a single step at mild and ambient temperature, allowing access to a variety of 3-hydroxyoxindoles, including natural products, such as donaxaridine.

Herein, we report a general and mild approach to effectively synthesize N-substituted anilines under metal-free conditions using sulfonyl chlorides and amines. Notably, this approach has shown a wide array of functional group tolerance, operational simplicity, and scalability, making it a useful tool for accessing N,N-disubstituted anilines and functionalized products.

Quetiapine, a dibenzothiazepine derivative, is an antagonist of serotonin and dopamine. It was approved by the Food Drug and Administration for the treatment of schizophrenia in 1997 and has been used as a commonly prescribed second-generation atypical antipsychotic drug. Loxapine is a dibenzoxazepine tricyclic compound used as an antipsychotic, antagonising dopamine and serotonin receptors for the treatment of acute and chronic schizophrenia. However, the preparation of their Key Starting Materials (KSMs) in the reported synthesis routes suffers from several significant restrictions, such as multistep synthesis, harsh reaction conditions, high cost factors, and the use of reagents that are environmentally unfriendly. In this work, we aimed to explore a telescopic green process for the synthesis of dibenzo[b,f][1,4]thiazepin-11(10H)-one and 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one, the two KSMs required for the commercial production of quetiapine and loxapine. The process involves an intermolecular base-mediated SNAr reaction of 2-fluoro-1-nitrobenzene and methyl 2-mercaptobenzoate or methyl 2-hydroxybenzoate, followed by intramolecular reductive amidation employing sodium dithionite (Na2S2O4) as the sole reagent. The SNAr reaction was performed in the presence of K2CO3 in DMF at 90°C, followed by workup to give a crude product, which was treated with Na2S2O4 in DMSO without any prepurification to obtain the desired cyclized KSMs. Unlike the commonly used metal/acid reagent for the reduction of nitro compounds, the developed process avoids the use of any metal reagent or acidic conditions. The key features include a reduced number of steps, a telescopic process avoiding purification of the first step product, and reductive amidation of unactivated esters without any externally added activating agent.

The present invention discloses a unified strategy for N-acetylation/formylation directly from nitroarenes employing solvents DMAc/DMF as the source of acetyl/formyl groups, with sodium dithionite serving as the sole reagent. Unlike the conventional N-acetylation/formylation of anilines, the method uses precursor nitroarenes to form acetanilides/formanilides via in situ reduction to anilines. The regioselectivity, application to drug molecules, tandem process, and dual role of the reagent are the key features of the method.

Customized nano-biocatalysts of laccase have been made using nano-structured polyaniline viz. nano-fibers and nano-tubes, as immobilization supports and a simultaneous comparison between them has been made. Laccases are poly-phenol oxidases having tremendous utility concerning wider areas of application especially in the field of organic and drug syntheses. Considering importance of laccases in drug syntheses, an effort has been made to immobilize laccase on the nano-structured polyaniline by adsorption. Immobilization was assessed using percentage enzyme loading as well as immobilization efficiency. Further immobilization process was strengthened using statistical optimization (Response Surface Methodology) for the parameters affecting immobilization viz. pH, Stirring rate, Enzyme Support ratio. In comparison to free enzyme, better thermal stability was depicted with almost 3- and 4-fold increase in half-life for immobilized laccase on nanofibers and nanotubes, respectively, at 80 °C. The storage stability of the nano-biocatalysts was revealed by the retention >50 % of higher enzyme activity in comparison to free form, when stored at 4 °C for up to 60 days. Moreover, slow and gradual decline in activity was observed when the immobilized laccase preparations were re-utilized for ten consecutive cycles of guaiacol oxidation. Greater than 60 % retention of enzyme activity after consistent catalytic cycles renders the utilization of immobilization preparations in industrial biocatalysis. Manifestation of efficient nano-biocatalysts has portrayed superior enzyme kinetics in rendering efficient biotransformations of ortho-phenylenediamine analogues to subsequent Phenazines which are known to possess therapeutic properties ranging from anti-microbial to anti-proliferative and so on.

A nonconventional oxidative denitrogenative radical transacetylation method for the chemoselective N-acetylation of primary and secondary aryl/heteroaryl amines using acetohydrazide as a new source of acetyl radical has been discussed. This method, conducted under mild, transition-metal-free conditions in water, offers significant advantages over existing acetylation strategies, which largely rely on harsh reagents such as acetic anhydride, acetyl chloride, or enzyme catalysts. The process utilizes environmentally friendly reagents, namely, tert-butyl hydroperoxide (TBHP) and tert-butyl ammonium iodide (TBAI), to generate acetyl radicals through the oxidative cleavage of acetohydrazide, enabling efficient and selective N-acetylation of a wide variety of amines, including those bearing other sensitive functional groups. Control experiments with radical scavengers confirmed the in situ generation of the acetyl radical, providing strong evidence for the proposed mechanism. Importantly, this protocol demonstrates excellent scalability with successful application in the synthesis and late-stage functionalization of pharmaceutical compounds and advanced drug intermediates. The method not only expands the toolkit for amine functionalization but also offers a sustainable and scalable approach for industrial applications in drug discovery and development.

Among various types of solvents used in organic synthesis for organic transformations, halogenated solvents have been widely used in industries and laboratories. In many reports, it has been noticed that these halogenated solvents have been involved themselves and are utilized as surrogates for the organic reactions, and thus, the examples have been summarized in the present article, covering the commonly used solvents bearing chlorine, like chloroform, dichloromethane, and dichloroethane, which have been discussed in detail.

An effective approach for the synthesis of N-vinylaromatic sulfonamides using copper-catalyzed deoxygenative cross-coupling of epoxides and sulfonamides has been reported. This method allows for easy synthesis of a number of N-vinylsulfonamides under mild reaction conditions. This protocol is notable for its utilization of an affordable and easy-to-handle wide range of N-substituted sulfonamides, cheap and readily available copper catalysts, robust functional group tolerance, and good to excellent yields. The developed method was also applied to large-scale syntheses.

Metal-nitrenes are valuable reactive intermediates for synthesis and are widely used to construct biologically relevant scaffolds, complexes and functionalized molecules. The ring expansion of cyclic molecules via single-nitrogen-atom insertion via nitrene or metal-nitrenoid intermediates has emerged as a promising modern strategy for driving advantageous nitrogen-rich compound synthesis. In recent years, the catalytic insertion of a single nitrogen atom into carbocycles, leading to N-heterocycles, has become an important focus of modern synthetic approaches with applications in medicinal chemistry, materials science, and industry. Catalytic single-nitrogen-atom insertions have been increasing in prominence in modern organic synthesis due to their capability to construct high-value added nitrogen-containing heterocycles from simple feedstocks. In this review, we will discuss the rapidly growing field of skeletal editing via single-nitrogen-atom insertion using transition metal catalysis to access nitrogen-containing heterocycles, with a focus on nitrogen insertion across a wide spectrum of carbocycles.

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.