Visible Light-Induced Reactions of Diazo Compounds and Their Precursors.

In recent years, visible light-induced reactions of diazo compounds have attracted increasing attention in organic synthesis, leading to improvement of existing reactions, as well as to the discovery of unprecedented transformations. Thus, photochemical or photocatalytic generation of both carbenes and radicals provide milder tools toward these key intermediates for many valuable transformations. However, the vast majority of the transformations represent new reactivity modes of diazo compounds, which are achieved by the photochemical decomposition of diazo compounds and photoredox catalysis. In particular, the use of a redox-active photocatalysts opens the avenue to a plethora of radical reactions. The application of these methods to diazo compounds led to discovery of transformations inaccessible by the classical reactivity associated with carbenes and metal carbenes. In most cases, diazo compounds act as radical sources but can also serve as radical acceptors. Importantly, the described processes operate under mild, practical conditions. This Review describes this subfield of diazo compound chemistry, particularly focusing on recent advancements.

Targeting lipid-protein interaction to treat Syk-mediated acute myeloid leukemia.

Membrane lipids control the cellular activity of kinases containing the Src homology 2 (SH2) domain through direct lipid-SH2 domain interactions. Here we report development of new nonlipidic small molecule inhibitors of the lipid-SH2 domain interaction that block the cellular activity of their host proteins. As a pilot study, we evaluated the efficacy of lipid-SH2 domain interaction inhibitors for spleen tyrosine kinase (Syk), which is implicated in hematopoietic malignancies, including acute myeloid leukemia (AML). An optimized inhibitor (WC36) specifically and potently suppressed oncogenic activities of Syk in AML cell lines and patient-derived AML cells. Unlike ATP-competitive Syk inhibitors, WC36 was refractory to de novo and acquired drug resistance due to its ability to block not only the Syk kinase activity, but also its noncatalytic scaffolding function that is linked to drug resistance. Collectively, our study shows that targeting lipid-protein interaction is a powerful approach to developing new small molecule drugs.

General Regio- and Diastereoselective Allylic C-H Oxygenation of Internal Alkenes.

Branched allylic esters and carboxylates are fundamental motifs prevalent in natural products and drug molecules. The direct allylic C-H oxygenation of internal alkenes represents one of the most straightforward approaches, bypassing the requirement for an allylic leaving group as in the classical Tsuji-Trost reaction. However, current methods suffer from limited scope─often accompanied by selectivity issues─thus hampering further development. Herein we report a photocatalytic platform as a general solution to these problems, enabling the coupling of diverse internal alkenes with carboxylic acids, alcohols, and other O-nucleophiles, typically in a highly regio- and diastereoselective manner.

Visible Light-Induced Transition Metal Catalysis.

In recent years, visible light-induced transition metal catalysis has emerged as a new paradigm in organic photocatalysis, which has led to the discovery of unprecedented transformations as well as the improvement of known reactions. In this subfield of photocatalysis, a transition metal complex serves a double duty by harvesting photon energy and then enabling bond forming/breaking events mostly via a single catalytic cycle, thus contrasting the established dual photocatalysis in which an exogenous photosensitizer is employed. In addition, this approach often synergistically combines catalyst-substrate interaction with photoinduced process, a feature that is uncommon in conventional photoredox chemistry. This Review describes the early development and recent advances of this emerging field.

Recent Advances in Visible Light Induced Palladium Catalysis.

Visible light-induced Pd catalysis has emerged as a promising subfield of photocatalysis. The hybrid nature of Pd radical species has enabled a wide array of radical-based transformations otherwise challenging or unknown via conventional Pd chemistry. In parallel to the ongoing pursuit of alternative, readily available radical precursors, notable discoveries have demonstrated that photoexcitation can alter not only oxidative addition but also other elementary steps. This Minireview highlights the recent progress in this area.

Merging of Light/Dark Palladium Catalytic Cycles Enables Multicomponent Tandem Alkyl Heck/Tsuji-Trost Homologative Amination Reaction toward Allylic Amines.

A visible light-induced palladium-catalyzed homologative three-component synthesis of allylic amines has been developed. This protocol proceeds via a unique mechanism involving two distinct cycles enabled by the same Pd(0) catalyst: a visible light-induced hybrid radical alkyl Heck reaction between 1,1-dielectrophile and styrene, followed by the "in dark" classical Tsuji-Trost-type allylic substitution reaction. This method works well with a broad range of primary and secondary amines, aryl alkenes, dielectrophiles, and in complex settings. The regiochemistry of the obtained products is primarily governed by the structure of 1,1-dielectrophile. Involvement of π-allyl palladium intermediates allowed for the control of stereoselectivity, which has been demonstrated with up to 95:5 er.

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.

Escape from Hydrofunctionalization: Palladium Hydride-Enabled Difunctionalization of Conjugated Dienes and Enynes.

Palladium hydrides are traditionally employed in hydrofunctionalization (i.e. monofunctionalization) of conjugated dienes and enynes, owning to its facile protic hydropalladation of electron-rich (or neutral) unsaturated bonds. Herein, we report a mild PdH-catalyzed difunctionalization of conjugated dienes and enynes. This protocol is enabled by the chemoselectivity switch of the initial hydropalladation step achieved by visible light enhancement of hydricity of PdH species. This method allows for cascade annulation of dienes and enynes with various easily available and abundant substrates, such as acrylic acids, acrylic amides, and Baylis-Hillman adducts, toward a wide range of alkenyl or alkynyl lactones, lactams, and tetrahydrofurans. This protocol also provides an easy access to complex spiro-fused tricyclic frameworks.

Palladium Hydride-Enabled Hydroalkenylation of Strained Molecules.

We report the first palladium hydride enabled hydroalkenylation of strained molecules. This new mild protocol proceeds via a regio- and chemoselective hydropalladation step, followed by a photoinduced radical alkyl Heck reaction. This methodology represents a new reactivity mode for strained molecules and opens new avenues for photoinduced palladium catalysis. The reaction is compatible with a wide range of functional groups and can be applied to complex structures, delivering a diverse array of highly valuable and modifiable alkenylated cyclobutanes and cyclopropanes. A hydroalkenylation/diastereoselective rearrangement cascade toward a cyclopentene scaffold has also been demonstrated.

Contemporary methods for generation of aryl radicals.

The synthetic utility of aryl radicals has been established in the last century, however, their broad applications were hampered by ineffective generation methods. It was in the last decade, that a rapid development of various redox systems took place, thus triggering a renaissance of aryl radical chemistry. This tutorial review focuses on the start-of-the-art methods for generation of aryl radicals. Primarily, various light-induced systems, including photoredox catalysis, visible light transition metal catalysis, and chemistry of electron donor-acceptor complexes, are reviewed. The main current precursors of aryl radicals are evaluated together with the selected examples of their modern applications.

Visible Light Induced Brønsted Acid Assisted Pd-Catalyzed Alkyl Heck Reaction of Diazo Compounds and N-Tosylhydrazones.

A mild visible light-induced palladium-catalyzed alkyl Heck reaction of diazo compounds and N-tosylhydrazones is reported. A broad range of vinyl arenes and heteroarenes with high functional group tolerance, as well as a range of different diazo compounds, can efficiently undergo this transformation. This method features Brønsted acid-assisted generation of hybrid palladium C(sp3 )-centered radical intermediate, which allowed for new selective C-H functionalization protocol.

Photoinduced Palladium-Catalyzed Carbofunctionalization of Conjugated Dienes Proceeding via Radical-Polar Crossover Scenario: 1,2-Aminoalkylation and Beyond.

A photoinduced palladium-catalyzed 1,2-carbofunctionalization of conjugated dienes has been developed. This mild modular approach, which does not require employment of exogeneous photosensitizers and external oxidants, allows for efficient and highly regio- and stereoselective synthesis of a broad range of allylic amines from readily available 1,3-dienes, alkyl iodides, and amines. Employment of O- and C-nucleophiles toward oxyalkylation and dialkylation products was also demonstrated. A putative π-allyl palladium radical-polar crossover path is proposed as a key event in this three-component coupling process. The utility of this protocol is highlighted by its application for derivatization of several amine-containing drugs.

Denitrogenative Transformations of Pyridotriazoles and Related Compounds: Synthesis of N-Containing Heterocyclic Compounds and Beyond.

The high demand for new and efficient routes toward synthesis of nitrogen-containing heterocyclic scaffolds has inspired organic chemists to discover several methodologies over recent years. This Perspective highlights one standout approach, which involves the use of pyridotriazoles and related compounds in denitrogenative transformations. Readily available pyridotriazoles undergo ring-chain isomerization to produce uniquely reactive α-diazoimines. Such reactivity, enabled by metal catalysts, additives, or visible-light irradiation, can be applied in transannulation, insertion, cyclopropanation, and many other transformations.

Visible-Light-Induced Palladium-Catalyzed Generation of Aryl Radicals from Aryl Triflates.

A mild visible-light-induced Pd-catalyzed intramolecular C-H arylation of amides is reported. The method operates by cleavage of a C(sp2 )-O bond, leading to hybrid aryl Pd-radical intermediates. The following 1,5-hydrogen atom translocation, intramolecular cyclization, and rearomatization steps lead to valuable oxindole and isoindoline-1-one motifs. Notably, this method provides access to products with readily enolizable functional groups that are incompatible with traditional Pd-catalyzed conditions.

Transition-Metal- and Light-Free Directed Amination of Remote Unactivated C(sp3)-H Bonds of Alcohols.

Due to the great value of amino alcohols, new methods for their synthesis are in high demand. Abundant aliphatic alcohols represent the ideal feedstock for the method development toward this important motif. To date, transition-metal-catalyzed approaches for the directed remote amination of alcohols have been well established. Yet, they have certain disadvantages such as the use of expensive catalysts and limited scope. Very recently, transition-metal-free visible-light-induced radical approaches have emerged as new powerful tools for directed remote amination of alcohols. Relying on 1,5-HAT reactivity, these methods are limited to ß - or δ-amination only. Herein, we report a novel transition-metal- and visible-light-free room-temperature radical approach for remote ß -, γ-, and δ-C(sp3)-N bond formation in aliphatic alcohols using mild basic conditions and readily available diazonium salt reagents.

Antibacterial effects of iron oxide (Fe3O4) nanoparticles: distinguishing concentration-dependent effects with different bacterial cells growth and membrane-associated mechanisms.

Nowadays, the influence of nanoparticles (NPs) on microorganisms attracts a great deal of attention as an alternative to antibiotics. Iron oxide (Fe3O4) NPs' effects on Gram-negative Escherichia coli BW 25113 and Gram-positive Enterococcus hirae ATCC 9790 growth and membrane-associated mechanisms have been investigated in this study. Growth specific rate of E. coli was decreased, indicating the bactericidal effect of Fe3O4 NPs. This inhibitory effect of NPs had a concentration-dependent manner. The reactive oxygen species together with superoxide radicals and singlet oxygen formed by Fe3O4 NPs could be the inhibition cause. Fe3O4 NPs showed opposite effects on E. hirae: the growth stimulation or inhibition was observed depending on NPs concentration used. Addition of NPs altered redox potential kinetics and inhibited H2 yield in E. coli; no change in intracellular pH was determined. Fe3O4 NPs decreased H+-fluxes through bacterial membrane more in E. coli than in E. hirae even in the presence of DCCD and increased ATPase activity more in E. hirae than in E. coli. Our results showed that the Fe3O4 NPs demonstrate differentiating effects on Gram-negative and Gram-positive bacteria likely due to the differences in bacterial cell wall structure and metabolic peculiarities. Fe3O4 NPs of different concentrations have no hemolytic (cytotoxic) activity against erythrocytes. Therefore, they can be proposed as antibacterial agents in biomedicine, biotechnology, and pharmaceutics.

Catalysis with Palladium Complexes Photoexcited by Visible Light.

Palladium catalysis induced by visible light is an emerging field of catalysis. In contrast to classical reactions catalyzed by Pd complexes in the ground state, which mostly proceed through two-electron redox processes, the mechanisms of these new methods based on photoexcited Pd complexes usually operate through transfer of a single electron. Such processes lead to putative hybrid Pd/radical species, which exhibit both radical and classical Pd-type reactivity. This Minireview highlights the recent progress in this rapidly growing area.

Aliphatic Radical Relay Heck Reaction at Unactivated C(sp3 )-H Sites of Alcohols.

The Mizoroki-Heck reaction is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. Given its innate nature, this protocol requires the employment of compounds possessing a halogen atom at the site of functionalization. However, the accessibility of organic molecules possessing a halogen atom at a particular site in aliphatic systems is extremely limited. Thus, a protocol that allows a Heck reaction to occur at a specific nonfunctionalized C(sp3 )-H site is desirable. Reported here is a radical relay Heck reaction which allows selective remote alkenylation of aliphatic alcohols at unactivated ß-, γ-, and δ-C(sp3 )-H sites. The use of an easily installed/removed Si-based auxiliary enables selective I-atom/radical translocation events at remote C-H sites followed by the Heck reaction. Notably, the reaction proceeds smoothly under mild visible-light-mediated conditions at room temperature, producing highly modifiable and valuable alkenol products from readily available alcohols feedstocks.

General, Mild, and Selective Method for Desaturation of Aliphatic Amines.

A novel method for desaturation of aliphatic amines into enamines as well as allylic and homoallylic amines has been developed. This general protocol operates via putative aryl hybrid Pd-radical intermediates, which combine the signature features of radical chemistry, a hydrogen atom transfer (HAT) process, and transition metal chemistry, a selective ß-hydride elimination step, to achieve efficient and selective desaturation of amines. These hybrid Pd-radical intermediates are efficiently generated under mild photoinduced conditions and are capable of a 1,n-HAT (n = 5-7) event at C(sp3)-H sites. The selectivity of HAT is tunable by varying different auxiliaries, which highlight the generality of this method. Remarkably, this desaturation method, which operates under mild conditions and does not require employment of exogenous photosensitizers or oxidants, can be performed in a practical scalable fashion from simple amines.