Electrochemical oxidative C-C bond cleavage of methylenecyclopropanes with alcohols.

Herein, an electrochemical approach toward the ring opening functionalization of methylenecyclopropanes (MCPs) via C-C bond cleavage in the presence of alcohols is reported. The methodology avoids the usage of external oxidants and shows good functional group tolerance. The mechanistic studies suggest that the reaction proceeds via direct single electron oxidation of the C-C bond of MCPs followed by ring opening to form the desired product.

Electrochemical Oxidative Dearomatization Strategy for Accessing Spiro[4.5]dienones and Derivatives.

Electrochemical dearomatization has been recognized as an attractive tool for the rapid construction of structurally diverse molecules. The designed methodology encompasses an eco-friendly and efficient electrochemical approach to synthesizing spiro[4.5]dienones under mild reaction conditions. Furthermore, detailed mechanistic studies strongly bolster our hypothesis and emphasize the role of HFIP in the mechanism. The protocol is scalable and showcases a broad substrate scope with tolerance toward numerous functional groups. Henceforth, this strategy can be deployed as an alternative and sustainable tool for accessing spiro[4.5]dienones.

Organocatalytic (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes: a facile access to enantioenriched 1,2-oxazinanes.

The first asymmetric (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes has been demonstrated by secondary amine catalysts. While the other ortho-substituents gave 1,2-oxazinanes, ortho-hydroxy ones provided a novel class of tetrahydrochromeno-1,2-oxazine cores via rare 1,3-aryl migration, followed by cyclization. An unusual type of asymmetric approach was also recognized.

Electrochemical Synthesis and Reactivity of Three-Membered Strained Carbo- and Heterocycles.

Three-membered carbocyclic and heterocyclic ring structures are versatile synthetic building blocks in organic synthesis with biological importance. Moreover, the inherent strain of these three-membered rings leads to their ring-opening functionalization through C->C, C->N, and C-O bond cleavage. Traditional synthesis and ring-opening methods for these molecules require the use of acid catalysts or transition metals. Recently, electro-organic synthesis has emerged as a powerful tool for initiating new chemical transformations. In this review, the synthetic and mechanistic aspects of electro-mediated synthesis and ring-opening functionalization of three-membered carbo- and heterocycles are highlighted.

Organocatalytic Activation of Donor-Acceptor Cyclopropanes: A Tandem (3 + 3)-Cycloaddition/Aryl Migration toward the Synthesis of Enantioenriched Tetrahydropyridazines.

An organocatalytic enantioselective (3 + 3)-cycloaddition reaction of racemic cyclopropane carbaldehydes and aryl hydrazones has been demonstrated for the first time. A wide range of enantioenriched tetrahydropyridazines with an exocyclic double bond were obtained with moderate to good yields and good to excellent enantiomeric excesses. Mechanistic investigations hinted toward a matched/mismatched kinetic resolution, and control experiments and DFT calculations unveiled that 1,3-aryl migration was concerted and intramolecular and proceeds via a four-membered transition state.

Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo.

Rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) poses enormous challenge in the development of broad-spectrum antivirals that are effective against the existing and emerging viral strains. Virus entry through endocytosis represents an attractive target for drug development, as inhibition of this early infection step should block downstream infection processes, and potentially inhibit viruses sharing the same entry route. In this study, we report the identification of 1,3-diphenylurea (DPU) derivatives (DPUDs) as a new class of endocytosis inhibitors, which broadly restricted entry and replication of several SARS-CoV-2 and IAV strains. Importantly, the DPUDs did not induce any significant cytotoxicity at concentrations effective against the viral infections. Examining the uptake of cargoes specific to different endocytic pathways, we found that DPUDs majorly affected clathrin-mediated endocytosis, which both SARS-CoV-2 and IAV utilize for cellular entry. In the DPUD-treated cells, although virus binding on the cell surface was unaffected, internalization of both the viruses was drastically reduced. Since compounds similar to the DPUDs were previously reported to transport anions including chloride (Cl-) across lipid membrane and since intracellular Cl- concentration plays a critical role in regulating vesicular trafficking, we hypothesized that the observed defect in endocytosis by the DPUDs could be due to altered Cl- gradient across the cell membrane. Using in vitro assays we demonstrated that the DPUDs transported Cl- into the cell and led to intracellular Cl- accumulation, which possibly affected the endocytic machinery by perturbing intracellular Cl- homeostasis. Finally, we tested the DPUDs in mice challenged with IAV and mouse-adapted SARS-CoV-2 (MA 10). Treatment of the infected mice with the DPUDs led to remarkable body weight recovery, improved survival and significantly reduced lung viral load, highlighting their potential for development as broad-spectrum antivirals.

Electrochemical sulfinylation of phenols with sulfides: a metal- and oxidant-free cross-coupling for the synthesis of aromatic sulfoxides.

The site-selective C-H functionalization of arenes is of indisputable importance in organic chemistry. Herein, we have demonstrated an electrochemical regioselective oxidative cross-coupling towards the direct C(sp2)-H sulfinylation of phenols with sulfides under mild reaction conditions. The designed methodology furnished aryl sulfoxides in good to moderate yields under exogenous metal and oxidant-free conditions. Moreover, the exploitation of traceless electrons to carry out the tandem site-selective oxidative aryl chalcogenation is the striking feature of this methodology.

Merging Two Strained Carbocycles: Lewis Acid Catalyzed Remote Site-Selective Friedel-Crafts Alkylation of in Situ Generated ß-Naphthol.

Lewis acid catalyzed tandem activation of the two smallest carbocycles, 3-ethoxy cyclobutanones, and donor-acceptor cyclopropanes has been demonstrated. The diphenyl-substituted 3-ethoxy cyclobutanone rearranges itself by intramolecular cyclization for the in situ generation of 1-phenyl 2-naphthol, which further undergoes remote site-selective Friedel-Crafts alkylation with donor-acceptor cyclopropane to synthesize a series of γ-naphthyl butyric acid derivatives. Further control experiments for mechanistic investigations and synthetic applications have also been carried out.

Switchable Reactivity of Cyclopropane Diesters toward (3 + 3) and (3 + 2) Cycloadditions with Benzoquinone Esters.

Herein, we describe an unprecedented (3 + 3) cycloaddition reaction of the donor-acceptor cyclopropanes with quinone esters toward the construction of chroman scaffolds in moderate to good yields. Interestingly, the strategy is also adjustable toward a (3 + 2) cycloaddition by just switching the Lewis acid to furnish benzofuran scaffolds. Based on the choice of Lewis acid used, the same set of precursors has been used to deliver the benzopyran and benzofuran derivatives.

Accessing Complex Tetrahydrofurobenzo-Pyran/Furan Scaffolds via Lewis-Acid Catalyzed Bicyclization of Cyclopropane Carbaldehydes with Quinone Methides/Esters.

Herein, we report a straightforward one-pot synthesis of tetrahydrofurobenzopyran and tetrahydrofurobenzofuran systems via an in situ ring-expansion of the cyclopropane carbaldehydes followed by a [2 + n] cycloaddition with the quinone derivatives. The transformation not only unveils a new reaction mode of cyclopropane carbaldehydes with quinone methides/esters, but also promotes a step-efficient diastereoselective route to the sophisticatedly fused oxygen tricycles that can be further dehydrogenated to access the valued dihydro-2H-furo[2,3-b]chromene frameworks.

α,ß-Unsaturated Carbonyls for One-Pot Transition-Metal-Free Access to 3,6-Dihydro-2H-pyrans.

An efficient protocol has been developed for accessing mono-, di-, and trisubstituted 3,6-dihydro-2H-pyran derivatives by simply subjecting α,ß-unsaturated carbonyls to the carefully optimized Corey-Chaykovsky reaction conditions. The strategy provides selectively substituted dihydropyran derivatives in good to excellent yields with a broad substrate scope under very mild reaction conditions. Easy transformation of the final 3,6-dihydro-2H-pyran to the valued 5,6-dihydro-2H-pyran-2-one and tetrahydro-2H-pyran derivatives expanded the scope of this methodology to diverse oxacycles. Further, the developed strategy also found application in a two-step route to racemic goniothalamin, which is widely studied for its cytotoxic behavior.

Direct Synthesis of Paracetamol via Site-Selective Electrochemical Ritter-type C-H Amination of Phenol.

The synthesis of paracetamol still relies on multistep protocols involving the utilization of a stoichiometric amount of oxidizing/reducing or other corrosive agents. Herein we report a regioselective electrochemical Ritter-type reaction at the C(sp2)-H of unprotected phenol toward the environmentally benign and direct synthesis of paracetamol. The reaction proceeds under exogenous oxidant- and catalyst-free conditions. The protocol is scalable, can be deployed to a variety of phenols, and offers a sustainable alternative for the synthesis of paracetamol.

Electricity mediated [3+2]-cycloaddition of N-sulfonylcyclopropanes with olefins via N-centered radical intermediates: access to cyclopentane analogs.

An external oxidant free electrochemical strategy is designed towards the ß-scission of strained C-C bonds in cyclopropylamine. Moreover, the mechanistic studies ascertained that the methodology encompasses the N-center radical (NCRs) route and provides access to di- or tri-substituted cyclopentane analogs.

Aza-Oxyallyl Cation Driven 3-Amido Oxetane Rearrangement to 2-Oxazolines: Access to Oxazoline Amide Ethers.

Herein, we report a highly facile and unprecedented activation of 3-amido oxetanes to synthesize 2-oxazoline amide ethers using a transient electrophilic aza-oxyallyl cation as an activating as well as an alkylating agent under mild reaction conditions. The aza-oxyallyl cation driven intramolecular rearrangement of 3-amido oxetanes to 2-oxazolines is the hallmark of this transformation and is a new addition to the reactivity profile of aza-oxyallyl cations.

Electrochemical Generation of a Nonstabilized Azomethine Ylide: Access to Substituted N-Heterocycles.

Azomethine ylides are fascinating 1,3-dipoles for [3 + 2] cycloaddition reactions toward the construction of N-heterocycles. Herein, an efficient and environmentally benign electrochemical approach for the generation of a nonstabilized azomethine ylide has been established under metal-free and external oxidant-free conditions. The resulting 1,3-dipole undergoes a [3 + 2] cycloaddition reaction with olefins. This electrosynthetic methodology indulges a straightforward and facile approach for the construction of substituted pyrrolidines.

Arylcyclopropane yet in its infancy: the challenges and recent advances in its functionalization.

Electronically unbiased arylcyclopropane functionalization has always been a challenge to organic chemists, and the emergence of donor-acceptor cyclopropanes (DACs) has not only vehemently overshadowed them but still dominates the cyclopropane chemistry. Unlike DACs, the absence of pre-installed functional groups makes it harder for them to activate and participate in a reaction. The field has witnessed considerably slow progress since its inception due to the inherent challenges. There are only a few strategies available to open arylcyclopropanes. Therefore, this work is still in its infancy stage in spite of these materials being one of the earliest known type of cyclopropanes. This review manifests the history, endeavors, and achievements alongside the associated challenges, opportunities, and the need for concerted efforts to accomplish the long-awaited golden age of arylcyclopropanes.

Relieving the stress together: annulation of two different strained rings towards the formation of biologically significant heterocyclic scaffolds.

Small carbo- and heterocycles have become versatile building blocks owing to their intrinsic ring strain and ease of synthesis. However, the traditional approaches of heterocycle synthesis involved the combination of one strained-carbocycle or heterocycle with one unsaturated molecule. On the contrary, there is an exciting possibility of combining two different strained rings to furnish varieties of heterocycles, where one of the strained rings can act as a valuable alternative to the unsaturated molecule. These strategies are also useful to access multi-functionalized rings. Despite these distinctive synthetic benefits, this chemistry has not drawn considerable attention of the community. In this minireview, we explicitly choose this topic to reveal the unexplored possibilities with these different strained rings. This minireview provides comprehensive details with the mechanistic rationale about the reactivity of these pairs of small rings when they are allowed to react together in the presence of different Lewis acids. Subsequently, it will also open a new avenue for heterocycle synthesis.

Electrochemical rearrangement protocols towards the construction of diverse molecular frameworks.

Rearrangement reactions constitute a critical facet of synthetic organic chemistry and demonstrate an attractive way to take advantage of existing structures to access various important molecular frameworks. Electroorganic chemistry has emerged as an environmentally benign approach to carry out organic transformations by directly employing an electric current and avoids the use of stoichiometric chemical oxidants. The last few years have witnessed a resurgence of electroorganic chemistry that has promoted a renaissance of interest in the development of novel redox electroorganic transformations. This review manifests the evolution of electrosynthesis in the area of rearrangement chemistry and covers the achievements in the field of migration, ring expansion, and rearrangements along with the mechanisms involved.

Electrochemical access to benzimidazolone and quinazolinone derivatives via in situ generation of isocyanates.

Isocyanates are the key intermediates for several organic transformations towards the synthesis of diverse pharmaceutical targets. Herein, we report the development of an oxidant-free protocol for electrochemical in situ generation of isocyanates. This strategy highlights expedient access to benzimidazolones and quinazolinones and eliminates the need for exogenous oxidants. Furthermore, detailed mechanistic studies provide strong support towards our hypothesis of in situ isocyanate generation.

Palladium-catalyzed regio- and stereoselective access to allyl ureas/carbamates: facile synthesis of imidazolidinones and oxazepinones.

Typically, transition metal catalysis enforces the stereodefined outcome of a reaction. Here we disclose the palladium-catalyzed regio- and stereoselective access to allylic ureas/carbamates and their further exploitation to diverse cyclic structures under operationally simple reaction conditions. This protocol features palladium-catalyzed decarboxylative amidation of highly modular VECs with good to excellent yield, minimal waste production, wide substrate scope, and low catalyst loading. In follow-up chemistry, we demonstrated the debenzylation of vinylic imidazolidinones to N-hydroxycyclic ureas and regioselective derivatization towards the facile synthesis of halohydrins and oxiranes under mild reaction conditions in good to excellent yields.