Bifunctional Reagent Research Articles

Three-Component Photochemical 1,2,5-Trifunctionalizations of Alkenes toward Densely Functionalized Lynchpins.

Radical remote 1,n-difunctionalization reactions (n > 2) of alkenes are powerful tools to efficiently introduce functional groups with selected distances into target molecules. Among these reactions, 1,5-difunctionalizations are an important subclass, leading to sought-after scaffolds, but typically suffer from tailored starting materials and strict limitations for the formed functional group in 2-position. Seeking to address these issues and to make radical 1,5-difunctionalizations of alkenes more applicable, we report a novel three-component 1,2,5-trifunctionalization reaction between imine-based bifunctional reagents and two distinct alkenes, driven by visible light energy transfer-catalysis. Key to achieving this selective one-step installation of three different functional groups via the choreographed formation of four bonds was the utilization of a 1,2-boron shift and the rigorous capitalization of radical polarities and stabilities. Thorough mechanistic studies were carried out, and the synthetic utility of the obtained products was demonstrated by various downstream modifications. Notably, in addition to the functionalization of individual functional groups, their interplay gave rise to a unique array of cyclic products.

Utilizing Ionic Liquids as Bifunctional Reagents for the Ionothermal Synthesis of Uranyl Compounds

Utilizing Ionic Liquids as Bifunctional Reagents for the Ionothermal Synthesis of Uranyl Compounds

Palladium/Charcoal-Catalysed Olefin Reduction for the Simple and Efficient Synthesis of Substituted gem-Diborylalkanes

Abstract gem-Diborylalkanes have recently emerged as valuable synthons for diverse C–C bond-forming reactions. They represent an important class of bifunctional reagents that can be applied for the synthesis of simple to complex skeletons. Herein, we report a Pd-catalysed hydrogenation method for the synthesis of gem-diborylalkanes from the corresponding gem-diborylalkenes, which are themselves prepared from the corresponding aldehydes and ketones using known procedures. In addition, transformations of two representative gem-diborylalkane products are discussed leading to a range of functionalised derivatives.

One-Pot Synthesis of Sulfonamides from Unactivated Acids and Amines via Aromatic Decarboxylative Halosulfonylation.

The coupling of carboxylic acids and amines to form amide linkages is the most commonly performed reaction in the pharmaceutical industry. Herein, we report a new strategy that merges these traditional amide coupling partners to generate sulfonamides, important amide bioisosteres. This method leverages copper ligand-to-metal charge transfer (LMCT) to convert aromatic acids to sulfonyl chlorides, followed by one-pot amination to form the corresponding sulfonamide. This process requires no prefunctionalization of the native acid or amine and extends to a diverse set of aryl, heteroaryl, and s-rich aliphatic substrates. Further, we extend this strategy to the synthesis of (hetero)aryl sulfonyl fluorides, which have found utility as "click" handles in chemical probes and programmable bifunctional reagents. Finally, we demonstrate the utility of these protocols in pharmaceutical analogue synthesis.

Photochemical Oximesulfonylation of Alkenes Using Sulfonyl-oxime-ethers as Bifunctional Reagents.

Utilization of oxime ethers as bifunctional reagents remains unknown. Herein, we present a mechanistically distinct strategy that enables oximesulfonylation of olefins using sulfonyl-oxime-ethers as bifunctional reagents under metal-free photochemical conditions. Via concomitant C-S and C-C bond formation, the process permits incorporation of oxime and sulfonyl groups into olefins in a complete atom-economic fashion, providing rapid access to multi-functionalized β-sulfonyl oxime ethers with good yields and stereoselectivity. The method is amenable to functionalization of complex bioactive molecules and is shown to be scalable. A radical chain mechanism initiated via photochemical Hydrogen Atom Transfer (HAT) mediated N-O bond cleavage is suggested for the process, based on our results on mechanistic investigations.

Derivatives Incorporating Acridine, Pyrrole, and Thiazolidine Rings as Promising Antitumor Agents.

Derivatives combining acridine, pyrrole, and thiazolidine rings have emerged as promising candidates in the field of antitumor drug discovery. This paper aims to highlight the importance of these three structural motifs in developing potent and selective anticancer agents. The integration of these rings within a single molecule offers the potential for synergistic effects, targeting multiple pathways involved in tumor growth and progression. Spiro derivatives were efficiently synthesized in a two-step process starting from isothiocyanates and 2-cyanoacetohydrazide. The thiourea side chain in spiro derivatives was utilized as a key component for the construction of the thiazolidine-4-one ring through regioselective reactions with bifunctional reagents, namely methyl-bromoacetate, dietyl-acetylenedicarboxylate, ethyl-2-bromopropionate, and ethyl-2-bromovalerate. These reactions resulted in the formation of a single regioisomeric product for each derivative. Advanced spectroscopic techniques, including 1D and 2D NMR, FT-IR, HRMS, and single-crystal analysis, were employed to meticulously characterize the chemical structures of the synthesized derivatives. Furthermore, the influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. Notably, derivatives containing ester functional groups exhibited exceptional activity against all tested cancer cell lines, boasting IC50 values below 10 μM. Particularly striking were the spiro derivatives with methoxy groups at position 3 and nitro groups at position 4 of the phenyl ring. These compounds displayed remarkable selectivity and exhibited heightened activity against HCT-116 and Jurkat cell lines. Additionally, 4-oxo-1,3-thiazolidin-2-ylidene derivatives demonstrated a significant activity against MCF-7 and HCT-116 cancer cell lines.

Photochemical Oximesulfonylation of Alkenes Using Sulfonyl‐oxime‐ethers as Bifunctional Reagents

Utilization of oxime ethers as bifunctional reagents remains unknown. Herein, we present a mechanistically distinct strategy that enables oximesulfonylation of olefins using sulfonyl‐oxime‐ethers as bifunctional reagents under metal‐free photochemical conditions. Via concomitant C‐S and C‐C bond formation, the process permits incorporation of oxime and sulfonyl groups into olefins in a complete atom‐economic fashion, providing rapid access to multi‐functionalized β‐sulfonyl oxime ethers with good yields and stereoselectivity. The method is amenable to functionalization of complex bioactive molecules and is shown to be scalable. A radical chain mechanism initiated via photochemical Hydrogen Atom Transfer (HAT) mediated N‐O bond cleavage is suggested for the process, based on our results on mechanistic investigations.

A Rapid Bioinspired N‐Acyliminium Ion Strategy for the ABC Core of the Stemona Alkaloids

AbstractA concise and highly diastereoselective bioinspired key cationic cyclization strategy for the asymmetric synthesis of the tricyclic core of the (−)‐stemoamide, together with 8,9‐bis‐epi‐stemoamide has been described. The key N‐acyliminium ion precursors were accessed from L‐tartaric acid and L‐malic acid respectively. The use of ethyl acetoacetate derived bifunctional allylidenetriphenylphosphorane reagent in the early stage of the synthetic strategy is advantageous for the rapid construction of highly functionalized key pyrrolo[1,2‐α]azepine frameworks.

Preparation and Catalytic Properties of Lipase Immobilized on Epoxy‐functionalized Starch Nanoparticles

AbstractAs a natural macromolecular material, starch is an ideal carrier for enzyme immobilization because of its widely available source, easy regeneration and excellent biodegradability. However, the natural starch cannot be directly used for immobilization due to the large particle size and excessive hydrophilicity. In this paper, the epoxy groups were grafted onto esterified starch by bifunctional reagents. The grafting efficiency of epoxy groups was increased by starvation drop addition. The changes of contact angle and particle size are conducive to the adsorption of immobilized enzyme at the water oil interface in the subsequent enzyme catalytic reaction, hence improve of the lipase activity. The maximum amount of lipase mobilized on such modified starch was ∼143.7 mg/g, which was near 40 mg/g higher than that of those from direct crosslinking. The immobilized enzymes showed excellent resistance to organic solvents and good reusability. Immobilization of lipases on epoxy‐functionalized starch nanoparticles can potentially improves the possibility of enzymes industrial application.

EnT-Mediated Amino-Sulfonylation of Alkenes with Bifunctional Sulfonamides: Access to β-Amino Sulfone Derivatives.

β-Amino sulfones are commonly found structural motifs in biologically active compounds. Herein, we report a direct photocatalyzed amino-sulfonylation reaction of alkenes for the efficicient production of important compounds by simple hydrolysis without the need for additional oxidants and reductants. In this transformation, the sulfonamides worked as bifunctional reagents, simultaneously generating sulfonyl radicals and N-centered radicals which were added to alkene in a highly atom-economical fashion with high regioselectivity and diastereoselectivity. This approach showed high functional group tolerance and compatibility, facilitating the late-stage modification of some bioactive alkenes and sulfonamide molecules, thereby expanding the biologically relevant chemical space. Scaling up this reaction led to an efficient green synthesis of apremilast, one of the best-selling pharmceuticals, demonstrating the synthetic utility of the applied method. Moreover, mechanistic investigations suggest that an energy transfer (EnT) process was in operation.

Palladium(II)-Catalyzed Annulative Difunctionalization of Two Inert C(sp3)–H Bonds by a Bifunctional Reagent

Illustrated herein is a Pd(II)-catalyzed direct difunctionalization of two C(sp3)–H bonds of aliphatic carboxylic acid derivatives by bifunctional reagents (BFRs) of the 2-iodobenzoic acid series. The methyl 2-pyridyl sulfoximine (MPyS) bidentate directing group (DG), 2-chloro-5-trifluoromethylpyridine ligand, AgOAc as a base, and NaBrO3 as a co-oxidant help the concerted metalation deprotonation (CMD) of inert C(sp3)–H bonds, as well as the reductive elimination; density functional theory (DFT) studies shed light on these crucial steps. This process makes two bonds [C–C and C–O] at gem-α,α′-di-Me groups in a single operation, offering access to unusual benzo-fused peripheral-substituted caprolactones. The transformation tolerates labile functional groups and allows the construction of a wide range of caprolactones with structural diversity. Mechanistic studies reveal the participation of monomeric Pd species in the catalytic cycle. The synthetic versatility of the complex molecular entities is also presented.

Photoinduced difunctionalization with bifunctional reagents containing N-heteroaryl moieties

Photoinduced difunctionalization with bifunctional reagents containing N-heteroaryl moieties

Regioselective Difunctionalization and Annulation of Ynamide

AbstractThe use of ynamides in organic synthesis has gained significant attention due to their ability to provide access to complex molecular structures through transformations such as 1,2‐difunctionalization and annulation reactions. These reactions enable the formation of highly functionalized N‐bearing olefins and unusual N‐bearing heterocycles. In this minireview, we present a systematic overview of the regioselective difunctionalization and annulation reactions of ynamides. We discuss the multi‐component reactions, and radical‐triggered functionalizations across the ynamides carbon–carbon multiple bonds and the use of bifunctional reagents in annulation of ynamides, highlighting their potential in expanding the substrate scope. Furthermore, we provide insights into the mechanistic breakthroughs that have been achieved in recent years in the development of these reactions. Finally, we emphasize the promising future prospects of ynamides as versatile building blocks for the synthesis of complex molecular architectures.

Regioselective Difunctionalization and Annulation of Ynamide.

The use of ynamides in organic synthesis has gained significant attention due to their ability to provide access to complex molecular structures through transformations such as 1,2-difunctionalization and annulation reactions. These reactions enable the formation of highly functionalized N-bearing olefins and unusual N-bearing heterocycles. In this minireview, we present a systematic overview of the regioselective difunctionalization and annulation reactions of ynamides. We discuss the multi-component reactions, and radical-triggered functionalizations across the ynamides carbon-carbon multiple bonds and the use of bifunctional reagents in annulation of ynamides, highlighting their potential in expanding the substrate scope. Furthermore, we provide insights into the mechanistic breakthroughs that have been achieved in recent years in the development of these reactions. Finally, we emphasize the promising future prospects of ynamides as versatile building blocks for the synthesis of complex molecular architectures.

Geminal/Vicinal Amino‐ and Oxy‐Trifluoromethylation of ortho‐Ethynyl Anilines and Phenols by Cu(III)−CF3 Compounds

AbstractThis study reports geminal amino‐ and oxy‐trifluoromethylation of ortho‐ethynyl anilines/phenols by phenCu(III)(CF3)3 (phen denotes 1,10‐phenanthroline), which constructs indole and benzofuran skeleton with concurrent incorporation of a CF3 group to the C2 position. Sequential trifluoromethylation of the terminal alkyne followed by 5‐endo‐trig cyclization of amino/hydroxyl with alkyne is involved. This method addresses the troublesome regioselectivity issue in C−H trifluoromethylation of arenes/heteroarenes wherein complicated mixtures of regioisomers were often obtained. A competing vicinal fluoro‐trifluoromethylation of terminal alkynes is suppressed under the optimal conditions wherein the Cu(III)−CF3 compound acts as a bifunctional reagent to provide both CF3 and F. Interestingly, when an acylamino group is present at the ortho‐position of phenylacetylene, vicinal syn‐amidate‐trifluoromethylation of the alkyne group occurs preferentially through 6‐exo‐trig cyclization to produce benzoxazines with a trifluoroethylidene at the C4‐position. The controllable and concise synthesis of valuable trifluoromethylated N‐ and O‐heterocyclic compounds shows the synthetic value of Cu(III)−CF3 compounds in medicinal chemistry.magnified image

Synthesis of pyrido-annelated [1,2,4,5]tetrazines, [1,2,4]triazepine, and [1,2,4,5]tetrazepines for anticancer, DFT, and molecular docking studies

In this strategy, we attempt to design various novel nitrogen-rich heterocycles in one molecule. Green, simple, and efficient aza-annulations of an active, versatile building block, 1-amino-4-methyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile (1), with different bifunctional reagents were developed under solvent-free conditions, resulting in the bridgehead tetrazines and azepines (triazepine and tetrazepines). Pyrido[1,2,4,5]tetrazines have been synthesized through two pathways; [3 + 3]- and [5 + 1]-annulations. In addition, pyrido-azepines have been developed by applying [4 + 3]-and [5 + 2]-annulations. This protocol establishes an efficient technique for synthesizing essential biological derivatives of 1,2,4,5-tetrazines, 1,2,4-triazepines, and 1,2,4,5-tetrazepine, tolerating a diverse variety of functionalities without the need for catalysis and fast reaction rates in high yields. The National Cancer Institute (NCI, Bethesda, USA) examined twelve compounds produced at a single high dosage (10−5 M). Compounds 4, 8, and 9 were discovered to have potent anticancer action against certain cancer cell types. To explain NCI results, the density of states was calculated to conduct a better description of the FMOs. The molecular electrostatic potential maps were created to explain a molecule's chemical reactivity. In silico ADME experiments were performed to better understand their pharmacokinetic characteristics. Finally, the molecular docking investigations on Janus Kinase-2 (PDB ID: 4P7E) were carried out to study the binding mechanism, binding affinity, and non-bonding contacts.

Front Cover: Ruthenium‐Assisted Tellurium Abstraction in Bis(thiophen‐2‐yl) Ditelluride (Eur. J. Inorg. Chem. 14/2023)

The Front Cover shows the reaction of [RuCl2(CO)3]2 and Te2Tpn2 (Tpn=thiophen-2-yl) in dichloromethane. The dark winter night in the North, which is dimly illuminated by northern lights, illustrates that [RuCl2(CO)3]2 catalyzes the decomposition of Te2Tpn2 to TeTpn2 and elemental tellurium even in the absence of light, as shown on the right side of the picture. [RuCl2(CO)3]2 is a bifunctional reagent and reacts concurrently with the monotelluride, forming the cct-[RuCl2(CO)2(TeTpn2)2] [cis(Cl)-cis(CO)-trans(TeTpn2)] complex, as shown on the left side of the picture. The reactions were followed by NMR spectroscopy and modeled with the help of theoretical calculations. More information can be found in the Research Article by R. Oilunkaniemi, R. S. Laitinen and co-workers.

Photochemical and Atom-Economical Sulfonylimination of Alkenes with Bifunctional N-Sulfonyl Ketimine

An organo-photocatalytic sulfonylimination of alkenes was developed by employing readily available N-sulfonyl ketimines as bifunctional reagents. This transformation, featuring prominent functional group tolerance, provides a direct and atom-economic approach for the synthesis of valuable β-amino sulfone derivatives as a single regioisomer. In addition to terminal alkenes, internal alkenes participate in this reaction with high diastereoselectivity. N-Sulfonyl ketimines with aryl or alkyl substituents were found to be compatible with this reaction condition. This method could be applied in the late-stage modifications of drugs. Additionally, a formal insertion of alkene into cyclic sulfonyl imine was observed, affording a ring expansion product.

Photochemical Alkene Trifluoromethylimination Enabled by Trifluoromethylsulfonylamide as a Bifunctional Reagent.

Herein, we disclose a facile and versatile trifluoromethylimination of alkene with a rationally designed N-(diphenylmethylene)-1,1,1-trifluoromethanesulfonamide as a bench-stable and readily accessible carboamination reagent. Enabled by an energy transfer (EnT) process, an array of alkenes were able to be facilely CF3-iminated under metal-free photocatalytic conditions. The mild reaction conditions and good functional group compatibility render this protocol highly valuable for the difunctionalization of olefins with structural complexity and diversity.

1,2‐Difunctionalization of Acetylene Enabled by Light

AbstractAlthough the direct conversion of gaseous acetylene into value‐added liquid commodity chemicals is becoming increasingly attractive, the majority of the established methodologies are focused on cross‐coupling, hydro‐functionalization, and polymerization. Herein, we describe a 1,2‐difunctionalization method that inserts acetylene directly into readily available bifunctional reagents. This method provides access to diverse C2‐linked 1,2‐bis‐heteroatom products in high regio‐ and stereoselectivity along with opening up previously unexplored synthetic directions. In addition, we demonstrate this method's synthetic potential by converting the obtained products into diverse functionalized molecules and chiral sulfoxide‐containing bidentate ligands. Using a combination of experimental and theoretical methods, the mechanism for this insertion reaction was investigated.