Murarka, Sandip

Recent years have witnessed a significant advancement in the field of radical oxidative coupling of ketones towards the synthesis of highly useful synthetic building blocks, such as 1,4-dicarbonyl compounds, and biologically important heterocyclic and carbocyclic compounds. Besides oxidative homo- and cross-coupling of enolates, other powerful methods involving direct C(sp 3)-H functionalizations of ketones have emerged towards the synthesis of 1,4-dicarbonyl compounds. Moreover, direct α-C-H functionalization of ketones has also allowed an efficient access to carbocycles and heterocycles. This review summarizes all these developments made since 2008 in the field of metal-catalyzed/promoted radical-mediated functionalization of ketones at the α-position. 1 Introduction 2 Synthesis of 1,4-Dicarbonyl Compounds 3 Synthesis of Heterocyclic Scaffolds 4 Synthesis of Carbocyclic Scaffolds 5 Conclusion.

Recent years have witnessed a resurgence of novel, efficient and practical protocols for radical-mediated cross-coupling reactions involving N-(acyloxy)phthalimides (NHPI esters) as redox-active esters. After the initial discovery of the redox-active properties of NHPI esters, exciting examples of SET-based cross-coupling reactions under thermal or photolytic conditions leading to diverse C–X (X=C, B, Si, Se, S) bonds have been published. The operational simplicity and broad applicability exhibited in redox-active NHPI ester-based cross-couplings bode well for their widespread adoption. The review presented herein covers all the recent developments in the field of redox-active ester (RAE)-based cross-couplings since the initial discovery. Depending on the conditions employed the reactions have been categorized into photoinduced and non-photoinduced cross-couplings with representative examples and insightful mechanistic discussions. (Figure presented.).

We present an electrochemical alkylation of azauracils using N-(acyloxy)phthalimides (NHPI esters) as readily available alkyl radical progenitors under metal- and additive-free conditions. Several azauracils are shown to undergo alkylation with an array of NHPI esters (1°, 2°, 3°, and sterically congested), providing the desired products in good to excellent yields. This operationally simple method is robust, scalable, and suitable for both batch and flow setups.

Methods enabling direct C−H alkylation of heterocycles are of fundamental importance in the late-stage modification of natural products, bioactive molecules, and medicinally relevant compounds. However, there is a scarcity of a general strategy for the direct C−H alkylation of a variety of heterocycles using commercially available alkyl surrogates. We report an operationally simple palladium-catalyzed direct C−H alkylation of heterocycles using alkyl halides under the visible light irradiation with good scalability and functional group tolerance. Our studies suggest that the photoinduced alkylation proceeds through a cascade of events comprising, site-selective alkyl radical addition, base-assisted deprotonation, and oxidation. A combination of experiments and computations was employed for the generalization of this strategy, which was successfully translated towards the modification of natural products and pharmaceuticals. © 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.

We present an organophotoredox-catalyzed direct Csp3-H alkylation of 3,4-dihydroquinoxalin-2-ones employing N-(acyloxy)pthalimides to provide corresponding products in good yields. A broad spectrum of NHPI esters (1°, 2°, 3°, and sterically encumbered) participates in the photoinduced alkylation of a variety of 3,4-dihydroquinoxalin-2-ones. In general, mild conditions, broad scope with good functional group tolerance, and scalability are the salient features of this direct alkylation process.

There is a scarcity of general strategies for the site-selective α-Csp3-H arylation of glycine derivatives to synthesize nonproteinogenic α-arylglycines that occur frequently in commercial drugs and bioactive molecules. We disclose a copper-photoredox-catalyzed site-selective α-Csp3-H arylation of glycine derivatives using diaryliodonium reagents (DAIRs) as arylating agents. This strategy harnesses the underexplored ability of DAIRs to serve as arylating agents under visible-light irradiation using copper salts as photocatalysts. The method applies to the glycine-selective C-H arylation of peptides with electronically and structurally diverse DAIRs. Moreover, we demonstrate that the photoinduced copper-catalyzed single electron transfer (SET) strategy can be coupled with the halogen atom transfer (XAT) process in the presence of alkyl iodides to accomplish site-selective α-Csp3-H alkylation of glycines and peptides. In this synergistic SET/XAT approach, phenyl radicals generated from diphenyl iodonium triflate mediate the XAT process to generate alkyl radicals from alkyl iodides. Both of these methods operate under mild conditions and exhibit broad scope with appreciable functional group tolerance. Overall, the divergent toolbox strategies presented here facilitate access to various alkylated and arylated glycines and peptides and enable bioconjugation between peptides and drug molecules.

Quaternary carbons are embedded in various natural products, pharmaceuticals, and organic materials. However, constructing this valuable motif is far from trivial. Conventional approaches mainly rely on classical polar disconnections and encounter bottlenecks concerning harsh conditions, functional group tolerance, regioselectivity, and step economy. In this context, Kawamata, Baran, Shenvi, and co-workers recently demonstrated that two feedstock chemicals, alkyl carboxylic acids and olefins, could be utilized to construct tetrasubstituted carbons in the presence of an inexpensive iron porphyrin catalyst and a suitable reductant combination through quaternization of the radical intermediates. The method enables access to various sterically encumbered quaternary carbons under mild and robust conditions. Taking a complete detour from conventional approaches, the present heteroselective radical–radical coupling simplifies the synthesis of quaternary carbon-containing molecules through an innovative and distinctive disconnection approach.

We report here a practical and cost-effective method for the synthesis of CHF2-containing benzimidazo- and indolo[2,1,a]-isoquinolin-6(5H)-ones through a visible light-mediated difluoromethylation/cyclization cascade. The method, which affords functionalized multifused N-heterocyclic scaffolds in moderate to high yields under mild reaction conditions, is also easily scalable using low-cost 3D printed photoflow reactors.

A visible light-induced green and sustainable N−H functionalization of (aza)uracils with α-diazo esters leading to imide alkylation is described. The reaction does not require any catalyst or additive and proceeds under mild conditions. Moreover, an intriguing three component coupling was observed when (aza)uracils were allowed to react with α-diazo esters in cyclic ethers (e. g. 1,4-dioxane, THF) as a solvent. Both the insertion and three-component coupling features broad scope with good to excellent yields and appreciable functional group tolerance. Notably, the divergent method enables modification of natural products and pharmaceuticals, thereby facilitates access to potentially biologically active compounds.

Diaryliodonium reagents (DAIRs) are highly electrophilic arylating agents widely utilized in organic synthesis, excelling in both metal-free and metal-catalyzed transformations. However, their reactivity and application as aryl radical precursors under visible-light irradiation remain relatively underexplored. Due to their easy availability, intrinsic reactivity, stability, and environmentally benign nature, they are promising candidates to serve as aryl radical surrogates in various visible light-induced synthetic transformations. In this feature article, we have reviewed our recent findings alongside other significant reports on the utility of DAIRs under visible-light irradiation. We have discussed the diverse reactivity of DAIRs in a palette of visible light-mediated reactions leading to the construction of carbon-carbon or carbon-heteroatom bonds. In addition, their role as atom transfer agents, including hydrogen atom transfer and halogen atom transfer, has also been discussed. © 2025 Elsevier B.V., All rights reserved.