Electron-rich Alkenes Research Articles

Photoinduced dehydrogenation of protected piperazines

Abstract Piperazine represents one of the most important building blocks of pharmaceuticals. Hence, the development of various piperazine derivatives is important. Herein we report photoinduced dehydrogenation of protected piperazines. The reaction proceeded with various alkyl-substituted piperazines. The resulting products have electron-rich olefin moieties that can react with benzyne, carbene, or acyl anhydride.

Brønsted Acid Catalyzed Stereospecific Dearomative Spirocyclization of Benzothiophenyl Analogues of Tertiary cis-β-Benzylstyrenes

Abstract3-Substituted benzothiophenyl analogues of tertiary cis-β-benzylstyrenes undergo triflic acid catalyzed dearomative spirocyclization at room temperature to afford compounds containing vicinal quaternary centers. Hydroarylation of the styrene is a competing process that occurs preferentially within substrates possessing electron-rich styrenyl alkenes, or an indole in place of the benzothiophene.

Rh(III)-Catalyzed [4 + 1] Annulation of Benzamides with Vinyl Cyclic Carbonates for the Synthesis of Isoindolinones.

A Rh(III)-catalyzed C-H bond activation and subsequent [4+1] annulation of benzamides with vinyl cyclic carbonates have been developed for the synthesis of isoindolinones, in which the electron-rich alkenes could serve as one-carbon units. This reaction proceeds smoothly with high regioselectivity under oxidant- and silver-free conditions and exhibits broad substrate scope and functional group tolerance including some biological active materials. The scale-up reaction and derivatizations of the product further demonstrate the potential synthetic utility of this transformation.

Benzyl Deuteriodifluoromethyl Sulfoxide: An Easily Accessible and Stable Reagent for Direct Deuterodifluoromethylthiolation.

A new, stable and scalable reagent based on a sulfoxide skeleton for direct deuteriodifluoromethylthiolation has been developed. The reagent displays excellent reactivities toward Tf2O promoted C-H deuteriodifluoromethylthiolation of electron-rich arenes, indoles, alkenes, and intramolecular lactonization of 2-alkynylbenzoates. Moreover, high deuteration rates and good to excellent yields were achieved under metal-free reaction conditions. As a result, a wide range of deuteriodifluoromethylthilolated compounds were prepared, enabling further applications in drug discovery.

Pyridinium-Derived Mesoionic N-Heterocyclic Olefins (py-mNHOs).

Mesoionic polarization allows access to electron-rich olefins that have found application as organocatalysts, ligands, or nucleophiles. Herein, we report the synthesis and characterization of a series of 3-methylpyridinium-derived mesoionic olefins (py-mNHOs). We used a DFT-supported design concept, which showed that the introduction of aryl groups in the 1-, 2-, 4-, and 6-positions of the heterocyclic core allowed the kinetic stabilization of the novel mesoionic compounds. Tolman electronic parameters indicate that py-mNHOs are remarkably strong σ-donor ligands toward transition metals and main group Lewis acids. Additionally, they are among the strongest nucleophiles on the Mayr reactivity scale. In reactions of py-mNHOs with electron-poor π-systems, a gradual transition from the formation of zwitterionic adducts via stepwise to concerted 1,3-dipolar cycloadditions was observed experimentally and analyzed by quantum-chemical calculations.

Anodic Cyclizations, Densely Functionalized Synthetic Building Blocks, and the Importance of Recent Mechanistic Observations.

Anodic cyclization reactions can provide a versatile method for converting newly obtained chiral lactols to densely functionalized cyclic building blocks. The method works by first converting the lactol into an electron-rich olefin and then oxidatively generating a radical cation that is trapped by a nucleophile. Historically, such reactions have benefited from the use of less polar radical cations when the trapping nucleophile is a heteroatom and more polar radical cations when the reaction forms C-C bonds. This forced one to optimize underperforming reactions by resynthesizing the substrate. Here, we show that by taking advantage of methods that serve to drive a reversible initial cyclization reaction toward the product, this dichotomy and need to manipulate the substrate can be avoided. Two such methods were utilized: a faster second oxidation step and a mediated electrolysis. Both led to successful cyclizations using a polar radical cation and heteroatom nucleophiles.

With or without a co-solvent? highly efficient ultrafast phenanthrenequinone-electron rich alkene (PQ-ERA) photoclick reactions.

The light-induced photocycloaddition of 9,10-phenanthrenequinone (PQ) with electron-rich alkenes (ERA), known as the PQ-ERA reaction, is a highly attractive photoclick reaction characterized by its operational simplicity and high biocompatibility. One essential aspect of photoclick reactions is their high rate, however the limited solubility of PQs often requires the use of a co-solvent. Evaluating the effect of different co-solvents on the PQ-ERA reaction and their influence on the reaction rate, we discovered that sulfur-containing compounds, in particular the frequently used solubilizing co-solvent DMSO, quench the triplet state of the PQ. These experimental results, supported by nanosecond-microsecond and ultrafast transient absorption data, show that even minimal amounts of DMSO result in a decreased lifetime of the reactive triplet state, essential for the photoclick reaction. Without DMSO as co-solvent, exceptionally high photoreaction quantum yields ( Φ P up to 93% with only 1 equivalent ERA) and complete conversion in seconds can be achieved. With these outstanding efficiencies, the PQ-ERA reaction can be used without excess ERA and at low light intensities, facilitating photoclick transformations in various future applications.

Olefin dihydroxylation mediated by Os-Zn-Al hydrotalcite-like catalyst: The scope and reactivity using various co-oxidants

The heterogeneous oxidation of olefins to vicinal diols was investigated using an Os-Zn-Al hydrotalcite-like catalyst (HTlc). The Os-Zn-Al HTlc was synthesised by the co-precipitation method and characterised fully using XRD, FT-IR, TEM, SEM, ICP-OES and BET surface area measurements. The ability of the synthesised Os-Zn-Al HTlc to catalytically dihydroxylate olefins to vicinal diols using various co-oxidants (air, NMO, K3Fe(CN)6, H2O2 and t-BuOOH) was investigated. The focus was mostly on N-methylmorpholine N-oxide (NMO) and K3Fe(CN)6 since they are well established co-oxidants for osmium catalysed dihydroxylation. When NMO was used, 100 % olefin conversion was achieved for all olefins tested. While, 100% conversion was only achieved with electron rich olefins when K3Fe(CN)6 was used as co-oxidant. Recyclability and leaching tests were done, and it was found that the catalyst could be recycled at least 3 times in the NMO system and the K3Fe(CN)6-K2CO3 system was found to be truly heterogeneous.

A visible light-induced photoredox-catalyzed assembly-point di/trifunctionalization of diazomethyl radicals

A visible light-induced di/trifunctionalization of diazo compounds with electron-rich arenes or alkenes has been developed. This provides a new strategy for the synthesis of α,α-diaryl- and α,α,α-triaryl-carbonyl compounds, 1,4-dienes and indolizines.

Synthesis of tetrahydroquinolines and quinoline derivatives through the Lewis acid catalysed Povarov reaction: A comparative study between multi step and multi-component methods

In this work, we have synthesised a new disubstituted tetrahydroquinolines by the Povarov [4+2] cycloaddition reaction between imines derivatives and an electron-rich olefin such as vinyl ethers. These reactions were carried out in the presence of different acid catalysts in its two versions, multi-step reaction starting with imine synthesis and multi-component reaction in which the imine is formed in situ. The reactivity of the cycloaddition reaction is directly attributed to the nature of the reagents, the used synthetic strategy, in which the obtained yield is found in the case of multi-step reactions lower than that in the multi-component reaction one. Additionally, the multi-step reactions are faster kinetically in comparison with that of the multi-component one. The nature of the catalyst directly increases the rate and enhances the yield of the reactions.

Donor-Acceptor Covalent Organic Frameworks as a Heterogeneous Photoredox Catalyst for Scissoring Alkenes to Carbonyl Constituents.

The conversion of alkenes to carbonyl constituents via the cleavage of the C═C bond is unique due to its biological and pharmacological significance. Though a number of oxidative C═C cleavage protocols have been demonstrated for terminal and electron-rich alkene systems, none of them were optimized for electron-deficient and conjugated alkenes. In this work, a covalent organic framework containing triphenylamine and triazine units was revealed to cleave the C═C bond of alkenes under very mild conditions involving visible light irradiation due to its photoredox property. The alkenes can be conveniently broken across the double bond to their constituent carbonyl derivatives on light irradiation in the presence of air and the covalent organic framework photocatalyst. This protocol is applicable for a wide range of alkenes in an aqueous acetonitrile medium with high functional group tolerance and regioselectivity. Though the electron-deficient alkenes required tetramethylethylene diamine as a sacrificial donor, the electron-rich alkenes do not demand any additives.

Efficient, Near‐Infrared Light‐Induced Photoclick Reaction Enabled by Upconversion Nanoparticles

AbstractPhotoclick reactions combine the selectivity of classical click chemistry with the high precision and spatiotemporal control afforded by light, finding diverse utility in surface customization, polymer conjugation, photocross‐linking, protein labeling, and bioimaging. Nonetheless, UV light, pivotal in prevailing photoclick reactions, poses issues, especially in biological contexts, due to its limited tissue penetration and cell‐toxic nature. Herein, a reliable and versatile strategy of activating the photoclick reactions of 9,10‐phenanthrenequinones (PQs) with electron‐rich alkenes (ERAs) with near infrared (NIR) light transduced by spectrally and structurally customized upconversion nanoparticles (UCNPs) is introduced. Under NIR irradiation, the UCNPs become UV/blue nanoemitters uniformly distributed in the reaction system. Enabled by the customized UCNPs, 800 or 980 nm light effectively activates the photocycloaddition reactions via radiative energy transfer in both general and triplet–triplet energy transfer (TTET)‐mediated PQ‐ERA systems. In particular, the novel sandwich structure UCNPs achieve the click reaction with up to 76% production yield in 10 min under NIR light irradiation. Meanwhile, the tricky side effect of photoclick product absorption‐induced quenching is successfully circumvented from the fine‐tuning of the upconversion spectrum. Moreover, through‐tissue irradiation experiments, the authors show that the UCNP‐PQ‐ERA reaction unlocks the full potential of photoclick reactions for in vivo applications.

TfOH-Catalyzed Cascade Reaction: Metal-Free Access to 3,3-Disubstituted Phthalides from o-Alkynylbenzoic Acids.

A facile new method for the synthesis of 3,3-disubstituted phthalides is reported. A successive reaction process begins with the TfOH-catalyzed cyclization of o-alkynylbenzoic acids followed by an ortho-regioselective electrophilic alkylation of various electron-rich aromatic compounds or alkenes, which has been successfully developed. The corresponding regioselective products of 3-substituted phthalide were obtained in good to high yields.

One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development.

We report the first one-pot formal alkene carboradiofluorination reaction employing easily accessible alkenes as both prosthetic group precursors and coupling partners. The methodology features rapid sequential Markovnikov-selective iodofluorination and photoinduced Pd(0/I/II)-catalyzed alkyl Heck reaction as a mild and robust fluorine-18 (18F) radiochemical approach for positron emission tomography (PET) imaging probe development. A new class of prosthetic groups for PET imaging probe synthesis was isolated as iodofluorinated intermediates in moderate to excellent yields. The one-pot formal alkenylfluorination reaction was carried out to produce over 30 analogues of a wide range of bioactive molecules. Further application of the Pd(0/I/II) manifold in PET probe development was illustrated by the direct carbo(radio)fluorination of electron-rich alkenes. The methods were successfully translated to radiolabel a broad scope of medicinally relevant small molecules in generally good radiochemical conversion. The protocol was further optimized to accommodate no-carrier-added conditions with similar efficiency for future (pre)clinical translation. Moreover, the radiosynthesis of prosthetic groups was automated in a radiochemistry module to facilitate its practical use in multistep radiochemical reactions.

Enhanced Excited-State Hydricity of Pd-H Allows for Unusual Head-to-Tail Hydroalkenylation of Alkenes.

Photoinduced enhancement of hydricity of palladium hydride species enables unprecedented hydride addition-like ("hydridic") hydropalladation of electron-deficient alkenes, which allows for chemoselective head-to-tail cross-hydroalkenylation of electron-deficient and electron-rich alkenes. This mild and general protocol works with a wide range of densely functionalized and complex alkenes. Notably, this approach also allows for highly challenging cross-dimerization of electronically diverse vinyl arenes and heteroarenes.

Photoinduced Palladium-Catalyzed 1,2-Difunctionalization of Electron-Rich Olefins via a Reductive Radical-Polar Crossover Reaction

Palladium-catalyzed cross-coupling reactions belong to the most important transformations for the construction of C–C or C-heteroatom bonds. More recently, the photochemical activation of palladium complexes emerged as a key strategy to leverage palladium catalysis at room temperature beyond the scope of conventional cross-coupling chemistry. Herein, we report on the photoinduced palladium-catalyzed 1,2-difunctionalization reaction of electron-rich olefins. Mechanistic experiments and computational studies reveal that this reaction proceeds via the addition of an alkyl radical, followed by the oxidation of a radical intermediate to access carbocation intermediates, which are inaccessible via classic thermal reaction conditions. The carbocation can then be applied to a variety of secondary C–C or C–N bond-forming reactions. This strategy now allows a general approach toward densely functionalized unsymmetric 1,1-bis(heterocyclyl)alkanes.

Development of Electrophilic Radical Perfluoroalkylation of Electron-Deficient Olefins.

Fluorinated organic compounds have attracted significant attention over the past few decades owing to their unique properties and versatility. An established method for the synthesis of fluorinated organic compounds involves radical perfluoroalkylation reactions towards double bonds. In this radical pathway, electrophilic perfluoroalkyl radicals exhibit excellent reactivity towards electron-rich olefins. Therefore, several splendid perfluoroalkylation reactions of electron-rich olefins have been reported. However, there are only a few examples of reaction involving electron-deficient olefins because of their poor electronic compatibility with perfluoroalkyl radicals. This review focuses on the reports that challenge this long-standing issue. Radical perfluoroalkylation/bifunctionalization reactions of electron-deficient olefins are described according to the radical generation methods.

Electrochemical Difluoromethylation of Electron-Rich Olefins.

The electrochemical difluoromethylation of electron-rich olefins (enamides and styrene derivatives) is disclosed. The addition of the electrogenerated difluoromethyl radical from the corresponding sodium sulfinate (i.e., HCF2SO2Na) to enamides and styrenes in an undivided cell allowed the formation of a large panel of difluoromethylated building blocks in good to excellent yields (42 examples, 23-87% yields). A plausible unified mechanism was suggested according to control experiments and cyclic voltammetry measurements.

Electrochemical Cycloaddition Reactions of Alkene Radical Cations: A Route toward Cyclopropanes and Cyclobutanes.

Herein, we describe a mild and efficient electrochemical method for cycloaddition reactions of alkene radical cations. Anodic oxidation of olefins produces electrophilic alkene radical cations, which further react with either diazo compounds in a [2 + 1] cycloaddition toward cyclopropane synthesis, or styrene derivatives in a [2 + 2] cycloaddition producing cyclobutanes. Both processes are green, metal- and catalyst-free, and scalable and tolerate a broad range of electron-rich olefins.

Establishing PQ-ERA photoclick reactions with unprecedented efficiency by engineering of the nature of the phenanthraquinone triplet state.

The light-induced photocycloaddition of 9,10-phenanthrenequinone (PQ) with electron-rich alkenes (ERA), known as the PQ-ERA reaction, is a highly attractive photoclick reaction characterized by high selectivity, external non-invasive control with light and biocompatibility. The conventionally used PQ compounds show limited reactivity, which hinders the overall efficiency of the PQ-ERA reaction. To address this issue, we present in this study a simple strategy to boost the reactivity of the PQ triplet state to further enhance the efficiency of the PQ-ERA reaction, enabled by thiophene substitution at the 3-position of the PQ scaffold. Our investigations show that this substitution pattern significantly increases the population of the reactive triplet state (3ππ*) during excitation of 3-thiophene PQs. This results in a superb photoreaction quantum yield (ΦP, up to 98%), high second order rate constants (k2, up to 1974 M-1 s-1), and notable oxygen tolerance for the PQ-ERA reaction system. These results have been supported by both experimental transient absorption data and theoretical calculations, providing further evidence for the effectiveness of this strategy, and offering fine prospects for fast and efficient photoclick transformations.