Electrochemical N-Aroylation of Sulfoximines by Using Benzoyl Hydrazines with H2 Generation.

Developed here is a robust electrochemical cross-coupling reaction between aroyl hydrazine and NH-sulfoximine via concomitant cleavage and formation of C(sp2 )-N bonds with the evolution of H2 and N2 as innocuous by-products. This sustainable protocol avoids the use of toxic reagents and occurs at room temperature. The reaction proceeds via the generation of an aroyl and a sulfoximidoyl radical via anodic oxidation under constant current electrolysis (CCE), affording N-aroylated sulfoximine. The strategy is applied to late-stage sulfoximidation of L-menthol, (-)-borneol, D-glucose, vitamin-E derivatives, and marketed drugs such as probenecid, ibuprofen, flurbiprofen, ciprofibrate, and sulindac. In addition, the present methodology is mild, high functional group tolerance with broad substrate scope and scalable.

Photo-Induced Generation of Oxygenated Quaternary Centers via EnT Enabled Singlet O2 Addition to C3-Maleimidated Quinoxaline: A Reagent-Less Approach.

Demonstrated here is an external photo-sensitizer-free (auto-sensitized) singlet oxygen-enabled solvent-dependent tertiary hydroxylation and aryl-alkyl spiro-etherification of C3-maleimidated quinoxalines. Such "reagent-less" photo-oxygenation at Csp3-H and etherification involving Csp3-H/Csp2-H are unparalleled. Possibly, the highly π-conjugated N-H tautomer allows the substrate to get excited by irradiation, and subsequently, it attains the triplet state via ISC. This excited triplet-state sensitized molecule then transfers its energy to a triplet-state oxygen (3O2) generating reactive singlet oxygen (1O2) for hydroxylation and spirocyclization depending on the solvent used. In HFIP, the generated alkoxy radical accepts a proton via HAT giving hydroxylated product. In contrast, in an aprotic PhCl it underwent a radical addition at the ortho-position of the C2 aryl to provide spiro-ether. An unprecedented orthogonal spiro-etherification was observed via the displacement of o-substitutents for ortho (-OEt, -OMe, -F, -Cl, -Br) substituted substrates. The order of ipso substitution follows the trend -OMe>-OEt>-F>-H>-Cl>-Br. Both these oxygenation reactions can be carried out with nearly equal ease using direct sunlight without the requirement of any elaborate reaction setup. Demonstration of large-scale synthesis and a few interesting transformations have also been realized. Furthermore, several insightful control experiments and quantum chemical computations were performed to unravel the mechanism.

Electrochemical NH-Sulfoximidation with α-Keto Acids.

An electrochemical N-acylation of sulfoximine has been achieved via the coupling of α-keto acids and NH-sulfoximines. This process involves the sequential cleavage of C-C bond followed by C(sp2)-N bond formation, with the liberation of H2 and CO2 as the by-products. A library of N-aroylated sulfoximines is produced via the coupling of aroyl and sulfoximidoyl radicals by anodic oxidation under constant current electrolysis (CCE). The compatibility of the present protocol has been demonstrated by coupling of various bio-active compounds, such as NH-sulfoximine derived from (-)-borneol, L-menthol, D-glucose derivative, and some commercial drugs such as flurbiprofen, and ibuprofen. This late-stage functionalization highlights the importance of this sustainable protocol. Besides this, various control experiments and detection of H2 evolution have been performed to support the proposed mechanism.

Base-Promoted Synthesis of S-Arylisothiazolones via Intramolecular Dehydrative Cyclization of α-Keto-N-acylsulfoximines.

A base (Et3N)-promoted synthesis of 1,4-diarylisothiazolones from α-keto-N-acylsulfoximines has been achieved. The reaction proceeds via α-hydrogen abstraction from sulfoximine, followed by an intramolecular nucleophilic attack at the keto carbonyl to form a tert-hydroxy isothiazolone intermediate. The 1,4-substituted isothiazolone is obtained after dehydration via an E1cB path. This one-pot synthesis of isothiazolinones has a broad substrate scope, has a high atom economy, and provides products with good yields. The ΔELUMO-HOMO is calculated using Gaussian 16 at the B3LYP/6-31G(d,p) level of theory.

Iodine-Promoted Sulfoximidation of Cinnamic Acids via Oxidative C═C Bond Cleavage.

An iodine-promoted C═C bond cleavage with concomitant decarboxylation and cross-coupling between cinnamic acids and NH-sulfoximines has been developed. This reaction proceeds via selective C═C bond cleavage, followed by decarboxylation and oxidative sulfoximidation. This metal- and base-free protocol involves dioxygen as the source of oxygen, which is facilitated by tert-butyl hydroperoxide (TBHP) as the oxidant affording N-aroylated sulfoximines with good functional group tolerance and good yields.

Access to Chromenopyrrole via Tandem [3 + 2] Cycloaddition and Intramolecular C-O Coupling.

A mild and concise method for the synthesis of chromenopyrrole from 2'-hydroxychalcone is devised. The reaction proceeds via an initial [3 + 2] cycloaddition on the C═C bond of 2'-hydroxychalcone and 1,3-dipolarophile, generated in situ by the reaction of ethyl isocyanoacetate and AgOAc. This is then followed by an intramolecular C-O bond formation with the -OH group and C5-H of the in situ generated pyrrole, leading to chromenopyrroles.

Isothiocyanates: happy-go-lucky reagents in organic synthesis.

Owing to their unique structural features, isothiocyanates (ITCs) are a class of highly useful and inimitable reagents as the -NCS group serves both as electrophile and nucleophile in organic synthesis. ITCs share a rich legacy in organic, medicinal, and combinatorial chemistry. Compared to their oxygen equivalents, isocyanates, ITCs are easily available, less unpleasant, and somewhat less harmful to work with (mild conditions) which makes them happy-go-lucky reagents. Functionalized ITCs can finely tune the reactivity of the -NCS group and thus can be exploited in the late-stage functionalization processes. This review's primary aim is to outline ITC chemistry in the construction and derivatization of heterocycles through the lens of sustainability. For ease and brevity, the sections are divided based on reactive centers present in functionalized ITCs and modes of cyclisation. Scrutinizing their probable unexplored directions for future research studies is also addressed.

PIDA/I2-mediated photo-induced aerobic N-acylation of sulfoximines with methylarenes.

A visible-light-promoted, PIDA/I2-mediated acylation of NH-sulfoximines with methylarenes as an acyl source has been achieved. This transition metal and photosensitizer-free approach provides easy access to N-acylsulfoximines via oxidative coupling of sulfoximines with easily available methylarenes without using any peroxide source. Mechanistic investigations suggest the intermediacy of radicals and the importance of molecular oxygen.

Base-Induced Decarboxylative 1,1-Alkoxy Thiolation via Hydrothiolation of Vinylene Carbonate.

A base-mediated 1,1-difunctionalization of vinylene carbonate has been achieved using two different nucleophiles, namely, thiol and alcohol, with the assistance of air (O2). In alcoholic solvents, decarboxylation occurs at room temperature to provide a 1,1-difunctionalized product, where vinylene carbonate serves as an ethynol (C2) synthon in this three-component reaction. On the other hand, in acetonitrile, exclusive hydrothiolation occurs under the basic conditions at room temperature. This method offers a one-pot decarboxylative regioselective difunctionalization of vinylene carbonate at room temperature for the construction of α-alkoxy-ß-hydroxy sulfide.

Visible/solar-light-driven thiyl-radical-triggered synthesis of multi-substituted pyridines.

A light-triggered synthesis of thio-functionalized pyridines is demonstrated using γ-ketodinitriles, thiols, and eosin Y as the photocatalyst. The reaction proceeds via the selective attack on one of the cyano groups by an in situ generated thiyl radical. The reaction also proceeds with nearly equal efficiency using direct sunlight. Large-scale synthesis and a few useful synthetic transformations of the substituted pyridines are also performed.

Transformable Transient Directing Group-Assisted C(sp2)-H Activation: Synthesis and Late-Stage Functionalizations of o-Alkenylanilines.

The isocyanate group in aryl isocyanates serves as a transformable transient directing group in a Ru(II)-catalyzed ortho olefination leading to o-alkenylanilines. In alcoholic solvents, aryl isocyanates are transformed into carbamates, which initiate the insertion of acrylates via o-C-H activation. In particular, tAmOH serves the dual role of solvent-cum transient directing mediator. The o-alkenylanilines are converted into azacoumarins and subsequently into C-4 aryl-substituted azacoumarins using aryl iodides as coupling partners via Pd(II)-catalyzed C-H functionalizations.

Correction: Updates on hypervalent-iodine reagents: metal-free functionalisation of alkenes, alkynes and heterocycles.

Correction for 'Updates on hypervalent-iodine reagents: metal-free functionalisation of alkenes, alkynes and heterocycles' by Anjali Dahiya et al., Org. Biomol. Chem., 2022, DOI: 10.1039/d1ob02233d.

Updates on hypervalent-iodine reagents: metal-free functionalisation of alkenes, alkynes and heterocycles.

Hypervalent iodine (HVI) chemistry is a rapidly growing subdomain of contemporary organic chemistry because of its enormous synthetic applications. The high nucleofugality of the phenyliodonio group (-I+Ph) and its radical nature, serving as a single-electron oxidant makes HVI compounds highly valuable in organic synthesis. Due to the feasibility and benignity, reactions that rely solely on HVI reagents as promoters have received particular interest. Considering their great influence and synthetic potential, we contribute a brief synopsis on this field with a specific emphasis on metal-free functionalisations of alkenes, alkynes and heterocycles. The discussion is divided according to the type of substrate and reaction type and elaborated with mechanism and representative examples.

Metal-catalyzed reactions of organic nitriles and boronic acids to access diverse functionality.

The nitrile or cyano (-CN) group is one of the most appreciated and effective functional groups in organic synthesis, having a polar unsaturated C-N triple bond. Despite sufficient stability and being intrinsically inert, the nitrile group can be easily transformed into many other functional groups, such as amines, carboxylic acids, ketones, etc. which makes it a vital group in organic synthesis. On the other hand, despite several boronic acids having a low level of genotoxicity, they have found wide applicability in the field of organic synthesis, especially in transition metal-catalyzed cross-coupling reactions. Recently, transition-metal-catalyzed cascade additions or addition/cyclization processes of boronic acids to the nitrile group open up exciting and useful strategies to prepare a variety of functional molecules through the formation of C-C, C-N and CO bonds. Boronic acids can be added to the cyano functionality through catalytic carbometallation or through a radical cascade process to provide newer pathways for the rapid construction of various important acyclic ketones or amides, carbamidines, carbocycles and N,O-heterocycles. The present review focuses on various transition-metal-catalyzed additions of boronic acids via carbometallation or radical cascade processes using the cyano group as an acceptor.

The Rich Legacy and Bright Future of Transition-Metal Catalyzed Peroxide Based Radical Reactions.

This personal account is mainly focused on the author's involvement in the field of transition metal-catalyzed peroxide based radical reactions. Over the past decades, radical chemistry has flourished and become crucial in contemporary synthetic organic chemistry. Owing to the presence of a single electron in one orbital, radicals are very unstable and react very fast. To carry out desired transformations and to control the side reactions the stabilizations of these radicals is essential. Fortunately, the implementation of a suitable transition metal and peroxide combination into the radical reactions have proved beneficial. Transition metals not only stabilizes the radicals but also protects them from being quenched by undesired homo-coupling or fragmentation. Transition metal-catalyzed radical-radical reactions provide an innovative way for the construction and derivatization of carbocycles and heterocycles. The objective of this review is to give an overview of the construction and derivatization of heterocycles through the lens of radical chemistry, mainly focusing on research work done by our group.

Visible-Light-Mediated Difunctionalization of Alkynes: Synthesis of ß-Substituted Vinylsulfones Using O- and S-Centered Nucleophiles.

An inimitable illustration of a green-light-induced, regioselective difunctionalization of terminal alkynes has been disclosed using sodium arylsulfinates and carboxylic acids in the presence of eosin Y as the photocatalyst. The present methodology is further demonstrated by employing NH4SCN as an S-centered nucleophile instead of carboxylic acid. The mechanistic investigation reveals a radical-induced iodosulfonylation followed by a base-mediated nucleophilic substitution. The mechanism is supported by various studies, viz., radical-trapping experiment, fluorescence quenching, and CV studies. In this protocol, (Z)-ß-substituted vinylsulfones are obtained, exclusively covering a broad range of alkynes and nucleophiles, which are often unaddressed. The present strategy can tolerate structurally discrete substrates with steric bulk and different electronic properties, which provides a straightforward and practical pathway for the synthesis of highly functionalized (Z)-ß-substituted vinylsulfones. Herein, C-O and C-S bonds are assembled simultaneously with the concomitant introduction of important functional groups, viz., ester, thiocyanate, and sulfone.

Cu(II)-Promoted Cascade Synthesis of Fused Imidazo-Pyridine-Carbonitriles.

A Cu(II)-promoted synthesis of an aza-fused N-heterocycle having a benz-imidazopyridine scaffold is developed via an addition-cyclization reaction followed by an Ullmann-type C-N coupling between o-iodoanilines and γ-ketodinitriles. This protocol features a broad substrate scope, giving products in 32-84% yields. The compounds show excellent photoluminescence properties having two absorption maxima in the region between 270-280 and 338-350 nm and emission maxima in the range of 502-533 nm. The HOMO-LUMO energy gap of 3.49-3.57 eV was determined using Gaussian 09 at the B3LYP/6-31G (d, p) basis set level. We also demonstrated a few postsynthetic modifications.

Copper(I)-Mediated Cascade Annulation via Dual C-H/C-H Activation: Access to Benzo[a]carbazolic AEEgens.

A Cu(I)-mediated cascade cyclization/annulation of unprotected o-alkynylanilines with maleimides in one pot is developed. The protocol offers sequential formation of one C-N and two C-C bonds to deliver fused benzo[a]carbazoles having free NH skeletons. The annulated products display fluorescence emission in the range of 485-502 nm with a large Stokes shift and fluorescence lifetime of ∼17 ns. The annulated 3aa displays AEE behavior in the ethanol/hexane system and possesses marigold-flower-like morphology at the aggregated state. Cell viability assays enumerate biocompatible AEEgens, while their high intracellular fluorescence depicts cell imaging applicability.

An expedient route to tricyanovinylindoles and indolylmaleimides from o-alkynylanilines utilising DMSO as a one-carbon synthon.

A Pd(ii)/Cu(ii) catalysed domino synthesis of tricyanovinylindoles has been achieved using DMSO as a one-carbon synthon. The reaction proceeds via the construction of 2-aryl-3-formyl indole followed by sequential addition of malononitrile and a CN resulting in two C-C, one C[double bond, length as m-dash]C and one C-N bonds in the final product. Furthermore, post-synthetic modification results in the unprecedented formation of 4-cyano-3-indolylmaleimides. Photophysical studies of selected compounds show emission in the visible range.

Visible-Light-Accelerated Pd-Catalyzed Cascade Addition/Cyclization of Arylboronic Acids to γ- and ß-Ketodinitriles for the Construction of 3-Cyanopyridines and 3-Cyanopyrrole Analogues.

The one-pot synthetic strategies for 2,4,6-triarylnicotinonitriles and 2,5-diaryl-1H-pyrrole-3-carbonitriles have been accomplished via a Pd-catalyzed coupling of arylboronic acid with 2-(3-oxo-1,3-diarylpropyl)malononitrile and 2-(2-oxo-2-arylethyl)malononitrile, respectively, under mild reaction conditions, followed by intramolecular cyclization of an intermediate formed after the regeneration of the catalyst under acidic reaction conditions. The cascade reactions proceed in 1,2-dichloroethane solvent under visible-light irradiation, and the active catalyst is generated in situ in the presence of catalytic amounts of Pd(OAc)2 and 2,2'-bipyridine. The active Pd catalyst undergoes photoexcitation by the virtue of metal-to-ligand charge transfer (MLCT), and subsequent redox trans-metalation occurs with arylboronic acid, thus obviating the necessity of any exogenous photosensitizer. The targeted products, composed of a new C-C, a C-N, a C═N, and two new C═C bonds, were isolated in good yields.