Electrochemical C-H Alkylation of Azauracils Using N-(Acyloxy)phthalimides.

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.

Overriding Cage Effect in Electron Donor-Acceptor Photoactivation of Diaryliodonium Reagents: Synthesis of Chalcogenides.

In recent times, diaryliodonium reagents (DAIRs) have witnessed a resurgence as arylating reagents, especially under photoinduced conditions. However, reactions proceeding through electron donor-acceptor (EDA) complex formation with DAIRs are restricted to electron-rich reacting partners serving as donors due to the well-known cage effect. We discovered a practical and high-yielding visible-light-induced EDA platform to generate aryl radicals from the corresponding DAIRs and use them to synthesize key chalcogenides. In this process, an array of DAIRs and dichalcogenides react in the presence of 1,4 diazabicyclo[2.2.2]octane (DABCO) as a cheap and readily available donor, furnishing a variety of di(hetero)aryl and aryl/alkyl chalcogenides in good yields. The method is scalable, features a broad scope with good yields, and operates under open-to-air conditions. The photoinduced chalcogenation technology is suitable for late-stage functionalizations and disulfide bioconjugations and facilitates access to biologically relevant thioesters, dithiocarbamates, sulfoximines, and sulfones. Moreover, the method applies to synthesizing diverse pharmaceuticals, such as vortioxetine, promazine, mequitazine, and dapsone, under amenable conditions.

Visible light-mediated difluoromethylation/cyclization in batch and flow: scalable synthesis of CHF2-containing benzimidazo- and indolo[2,1-a]isoquinolin-6(5H)-ones.

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.

Cost-Effective Carbon Quaternization with Redox-Active Esters and Olefins.

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 coworkers 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 radical intermediates. The method enabled 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.

Direct C-H alkylation of 3,4-dihydroquinoxaline-2-ones with N-(acyloxy)phthalimides via radical-radical cross coupling.

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.

Photodecarboxylative Radical Cascade Involving N-(Acyloxy)phthalimides for the Synthesis of Pyrazolones.

We disclose N'-arylidene-N-acryloyltosylhydrazides as novel skeletons for the synthesis of biologically relevant alkylated pyrazolones through a photoinduced radical cascade with N-(acyloxy)pthalimides as readily available alkyl surrogates. The reaction proceeds through the formation of a photoactivated electron donor-acceptor (EDA) complex between alkyl N-(acyloxy)phthalimide (NHPI) esters and LiI/PPh3 as a commercially available donor system. The reaction exhibits a broad scope and scalability, thereby enabling synthesis of a broad spectrum of functionally orchestrated alkylated pyrazolones under mild and transition-metal-free conditions.

Visible Light-Induced Imide Alkylation of Azauracils with Aryl Diazoesters.

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.

A General Electron Donor-Acceptor Photoactivation Platform of Diaryliodonium Reagents: Arylation of Heterocycles.

We report a photoredox system comprising sodium iodide, triphenyl phosphine, and N,N,N',N'-tetramethylethylenediamine (TMEDA) that can form a self-assembled tetrameric electron donor-acceptor (EDA) complex with diaryliodonium reagents (DAIRs) and furnish aryl radicals upon visible light irradiation. This practical mode of activation of DAIRs enables arylation of an array of heterocycles under mild conditions to provide the respective heteroaryl-(hetero)aryl assembly in moderate to excellent yields. Detailed mechanistic investigations comprising photophysical and DFT studies provided insight into the reaction mechanism.

Organophotoredox-Catalyzed Arylation and Aryl Sulfonylation of Morita-Baylis-Hillman Acetates with Diaryliodonium Reagents.

We report an organophotoredox-catalyzed stereoselective allylic arylation of MBH acetates with a palette of diaryliodonium triflates (DAIRs) to provide the corresponding trisubstituted alkenes in moderate to good yields. The method could be extended to three-component coupling involving 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a sulfur dioxide surrogate for the synthesis of biologically relevant allylic sulfones. Both of these reactions were carried out under mild conditions featuring broad scope, robustness, and appreciable functional group tolerance.

Copper-catalyzed tandem cyclization/arylation of α,ß-alkynic hydrazones with diaryliodonium salts: synthesis of N-arylpyrazoles.

A copper-catalyzed efficient method for the synthesis of a diverse variety of substituted N-aryl pyrazoles from readily available α,ß-alkynic N-tosyl hydrazones and diaryliodonium triflates is realized. This one-pot multi-step methodology features a broad scope with good yields, scalability, and appreciable functional group tolerance. Detailed control experiments reveal that the reaction proceeds through tandem cyclization/deprotection/arylation events where the copper catalyst plays a distinct role.

Photodecarboxylative C-H Alkylation of Azauracils with N-(Acyloxy)phthalimides.

We disclose a transition-metal-free NaI/PPh3-mediated direct C-H alkylation of azauracils using N-(acyloxy)pthalimides (NHPIs) as readily available alkyl surrogates under visible light irradiation. Detailed mechanistic studies reveal formation of a photoactivated electron donor-acceptor (EDA) complex between NaI/PPh3, TMEDA, and alkyl NHPI ester and establish the crucial role of TMEDA in increasing the activity of the photoredox system. The reaction demonstrates a broad scope, scalability, and appreciable functional group tolerance. A variety of azauracils are shown to undergo alkylation by primary, secondary, and tertiary NHPI esters under mild conditions, furnishing the desired products in good to excellent yields.

Visible light photoredox-catalyzed arylative cyclization to access benzimidazo[2,1-a]isoquinolin-6(5H)-ones.

A photoredox-catalyzed arylative radical cascade involving N-acryloyl-2-arylbenzoimidazoles and diaryliodonium triflates leading to the formation of a broad array of pharmaceutically important arylated-benzimidazo[2,1-a]isoquinolin-6(5H)-ones is described. Importantly, the synthesized benzimidazoisoquinolinones are amenable for further synthetic manipulation and allowed efficient access to benzimidazo-fused polycyclic heterocycles.

Photoinduced Electron Donor-Acceptor Complex-Mediated Radical Cascade Involving N-(Acyloxy)phthalimides: Synthesis of Tetrahydroquinolines.

We conceptualized a novel disconnection approach for the synthesis of fused tetrahydroquinolines that exploits a visible light-mediated radical (4 + 2) annulation between alkyl N-(acyloxy)phthalimides and N-substituted maleimides in the presence of DIPEA as an additive. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between alkyl NHPI esters and DIPEA, and the final tetrahydroquinolines were obtained in a complete regioselective fashion. The methodology features a broad scope and good functional group tolerance and operates under metal- and catalyst-free reaction conditions. Detailed mechanistic investigations including density functional theory studies provide insight into the reaction pathway.

Visible Light Photoredox-Catalyzed Direct C-H Arylation of Quinoxalin-2(1H)-ones with Diaryliodonium Salts.

A photoredox-catalyzed direct arylation of quinoxalin-2-(1H)-ones using diaryliodonium triflates as the convenient, stable, and cheap aryl source is described. A broad variety of quinoxalin-2-(1H)-ones are shown to react with structurally and electronically diverse diaryliodonium triflates, allowing efficient access to a wide variety of pharmaceutically important 3-arylquinoxalin-2-(1H)-ones. The presented method is attractive with regard to operational simplicity, mild conditions, broad scope, scalability, and high functional group tolerance.

Development of S-aryl dithiocarbamate derived novel antiproliferative compound exhibiting tubulin bundling.

Cancer is a leading cause of human death, and there is a need to identify efficient and novel chemical scaffolds which could provide flexibility to cancer chemotherapeutics. This work introduces S-aryl dithiocarbamates belonging to a versatile group of organo-sulfur containing compounds as a hitherto unexplored class of effective anticancer drugs with promising pharmacophore properties. We synthesized a series of N-Boc piperazine containing S-aryl dithiocarbamates and identified compound 1 as a potent antiproliferative agent in lung, cervical, and breast cancer cell lines. Compound 1 exhibited best inhibitory activity against cervical cancer cells, HeLa with an IC50 of 0.432 ± 0.138 µM for 72 h, and lung cancer cells, A549 with an IC50 of 0.447 ± 0.051 µM for 72 h. We further demonstrate that HeLa cells treated with this compound result in G2/M phase cell cycle arrest, causing cell apoptosis due to the upregulation of the p53-p21 signaling pathway. Importantly, cells treated with compound 1 showed a novel tubulin bundling phenotype in fluorescence microscopy, which is a characteristic of microtubule-stabilizing anticancer drugs like paclitaxel. Interestingly, molecular docking analysis revealed reasonable binding of compound 1 in the taxol-binding pocket of ß-tubulin, making it a promising candidate for microtubule stabilization based anticancer drug discovery.

An organophotoredox-catalyzed redox-neutral cascade involving N-(acyloxy)phthalimides and allenamides: synthesis of indoles.

An organophotoredox-catalyzed radical cascade of allenamides and alkyl N-(acyloxy)phthalimides for the synthesis of indoles is documented. The method features mild and robust reaction conditions, and exhibits broad scope. The tandem process enriches the limited repertoire of alkyl NHPI ester addition on electron-rich π-bonds as well as radical chemistry involving allenamides.

Multicomponent Synthesis of Biologically Relevant S-Aryl Dithiocarbamates Using Diaryliodonium Salts.

A transition-metal-free one-pot three-component annulation between diaryliodonium triflates, cyclic and acyclic aliphatic amines, and carbon disulfide providing a convenient and efficient access to biologically relevant S-aryl dithiocarbamates is developed. The reaction does not require metal, base, or any other additive and operates under mild and ambient conditions. This methodology is robust, scalable, and exhibits a broad substrate scope. The in silico analysis revealed that the majority of the compounds have a drug-likeness and good ADMET characteristics.

Late-Stage Alkylation of Heterocycles Using N-(Acyloxy)phthalimides.

Synthetic methods enabling late-stage modification of heterocycles hold tremendous importance in the pharmaceutical and agrochemical industry and drug discovery. Accordingly, efficient, functional group tolerant and selective late-stage alkylation of valuable molecular entities is of enormous significance and well-acknowledged in medicinal chemistry. Radical alkylation of heteroarenes employing carboxylic acids as the alkyl radical precursor represents one of the most direct ways of C-H functionalizations of heterocycles. Recently, the field has undergone a revolutionary development especially with regard to the generation of alkyl radicals under much milder conditions. In this regard N-(acyloxy)phthalimides (NHPI esters) have emerged as a suitable precursor of a diverse set of alkyl radicals allowing formal C-H alkylation of not only N-heteroarenes but a diverse set of non-aromatic heterocycles under visible light photocatalysis or electrochemical conditions. This review delineates all these discoveries and provides readers a comprehensive overview of this rapidly expanding field.

Organophotoredox-Catalyzed Cascade Radical Annulation of 2-(Allyloxy)arylaldehydes with N-(acyloxy)phthalimides: Towards Alkylated Chroman-4-one Derivatives.

An organophotoredox catalyzed efficient and robust approach for the synthesis of highly important 3-alkyl substituted chroman-4-one scaffold is developed using visible light induced radical cascade cyclization strategy. The reaction is initiated through the generation of alkyl radicals from N-(acyloxy)phthalimides under photoredox conditions, which subsequently undergo intermolecular cascade radical cyclization on 2-(allyloxy)arylaldehydes to afford chroman-4-one scaffolds. The presented strategy is attractive with regard to mild reaction conditions, operational simplicity, high functional group tolerance and broad substrate scope.

Late stage functionalization of heterocycles using hypervalent iodine(iii) reagents.

Late stage functionalization (LSF) through direct X-H manipulations (X = C, N) enables synthetic chemists to accelerate the diversification of natural products, agrochemicals and pharmaceuticals allowing rapid access to novel bioactive molecules without resorting to arduous de novo synthesis. LSF does not only allow tapping of the hitherto unexplored chemical space but also renders the synthetic sequence more straightforward, atom economical and cost-effective. In this regard, the recent decade has witnessed the emergence of hypervalent iodine(iii) reagents as a powerful synthetic tool owing to their easy availability, mild reaction conditions, remarkable oxidizing properties and high functional group tolerance. Iodine(iii) reagents have tremendous applications in the regio- and chemo-selective late-stage functionalization of a diverse variety of heterocycles through an exciting range of transformations, such as oxidative amination, cross-dehydrogenative coupling (CDC), fluoroalkylation, azidation, halogenation and oxidation. The present review, classified according to the types of synthetic methods involved, encompasses all these recent developments in the field of transition-metal-free iodine(iii)-catalyzed/mediated direct functionalizations of heterocycles with representative examples and insightful mechanistic discussions.