Chemoselective Reaction Research Articles

Divergent Synthesis of 2-Chromonyl-3-hydrazono-chromones and 2-Alkoxy-3-hydrazono-chromones through Switchable Annulation Reactions of o-Hydroxyphenylenaminones with Aryldiazonium Salts.

An unprecedented selective chromone annulation reaction controlled by solvent for the divergent synthesis of two types of 2,3-disubstituted chromone skeletons has been developed. A variety of 2-chromonyl-3-hydrazono-chromones and 2-alkoxy-3-hydrazono-chromones were constructed efficiently from readily available o-hydroxyphenylenaminones (o-HPEs) and aryldiazonium salts at room temperature. This strategy is highly chemoselective and features mild reaction conditions, broad substrate scope, broad functional group tolerance, easy gram-scale preparation, and simple filtration to obtain the pure products without tedious column chromatography.

Copper‐based nanocatalysts toward chemoselective hydrogenation reaction

AbstractCu‐based catalysts are widely used in various heterogeneous catalytic reaction systems, the precise control of their electronic structure is an intrinsic requirement for the rational design of metal catalysts, and it is also an important basis for clarifying their structure‐activity relationships. Changing the electronic structure of Cu‐based catalysts is an important way to improve the catalytic hydrogenation performance of Cu‐based catalysts by controlling the adsorption intensity between the reaction adsorbate and the active center. In this paper, the application of selective hydrogenation of Cu‐based catalysts is reviewed, with a special emphasis on the selective catalytic hydrogenation reduction of p‐nitrostyrene and CO2. This review particularly emphasizes the application of Cu‐based catalysts in the field of selective hydrogenation and discusses the influence of their different properties on selective hydrogenation performance.

Synthesis of p-phenylene-based chiral dicarboxamides via aminocarbonylation of 1’,4-diiodostyrene

Chiral p-phenylene-based dicarboxamides featuring carboxamide and 2-arylacrylamide motifs were synthesised through a synthetic sequence involving conventional organic reactions followed by palladium-catalysed aminocarbonylation. 4-Iodoacetophenone was used as starting material to prepare to 1’,4-diiodostyrene, which underwent several aminocarbonylation reactions, using in situ formed palladium-phosphine catalysts and various biologically relevant amines as N-nucleophiles such as, amino acid esters, nortropine, and aminoandrostane derivatives. By exploring the remarkable difference in reactivity between the iodoalkene and iodoarene functionalities, the aminocarbonylation of the iodoalkene moiety was carried first with high chemoselectivity, followed by sequential transformation of the iodoarene functionality into the corresponding carboxamide using a different nucleophile. This approach allowed us to obtain a range of otherwise challenging chiral dicarboxamides, in moderate to high isolated yields through highly chemoselective reactions.

Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents.

Cinchona alkaloid derivatives as Brønsted base catalysts have attracted considerable attention in the field of asymmetric catalysis. However, their potential application as chiral solvating agents has not been described. In this research, we investigated the use of the Cinchona alkaloid dimer, namely, (DHQ)2PHAL, as a chiral solvating agent for discerning various mandelic acid derivatives through 1H NMR spectroscopy. The addition of catalytic amounts of DMAP facilitated this process. Our experimental results demonstrate that dimeric (DHQ)2PHAL exhibits remarkable chiral discrimination properties regarding the diagnostic split protons of 1H NMR signals (including 24 examples, up to 0.321 ppm). Furthermore, it serves as an excellent chiral discriminating agent and provides good resolution for racemic chiral phosphoric acid as determined by 31P NMR spectroscopy. The quality of enantiodifferentiation has also been evaluated by means of the parameter "resolution (Rs)". Significantly, this class of CSAs based on (alkaloid)2linker systems with an azaaromatic linker can be directly employed, which is commercially available in an enantiopure form at very low cost and exhibits promising potential in determining the enantiopurity of α-hydroxy acids by chemoselective and biocatalytic reactions.

Switchable chemoselective aryne reactions between nucleophiles and pericyclic reaction partners using either 3-methoxybenzyne or 3-silylbenzyne.

Arynes are known to serve as highly reactive benzene-based synthons, which have gained numerous successes in preparing functionalized arenes. Due to the superb electrophilic nature of these fleeting species, however, it is challenging to modulate the designated aryne transformation chemoselectively, when substrates possess multiple competing reaction sites. Here, we showcase our effort to manipulate chemoselective control between two major types of aryne transformations using either 3-methoxybenzyne or 3-silylbenzyne, where nucleophilic addition-triggered reactions and non-polar pericyclic reactions could be differentiated. This orthogonal chemoselective protocol is found to be applicable between various nucleophiles, i.e., imidazole, N-tosylated/N-alkyl aniline, phenol, and alcohol, and an array of pericyclic reaction partners, i.e., furan, cyclopentadiene, pyrrole, cycloheptatrienone, and cyclohexene. Beyond arylation reactions, C-N bond insertion, Truce-Smiles rearrangement, and nucleophilic annulation are appropriate reaction modes as well. Moreover, this chemoselective protocol can find potential synthetic application.

Halogen-Bond-Promoted Direct Cross-Coupling of Trifluoromethylated Alkyl Bromides with Coumarins/Quinolinones: Unraveling Trifluoromethyl Effects.

This study introduces a novel approach involving XB-mediated cross-coupling of α-trifluoromethylated alkyl bromides with coumarins and quinolinones under visible light irradiation. Both density functional theory (DFT) calculations and experimental studies converge to suggest that the noncovalent interaction between alkyl bromides and DMAP, intensified by the α-trifluoromethyl group, plays a pivotal role in facilitating this chemoselective reaction.

Nickel(I)-catalysed multicomponent reductive hydrocarbonylation of alkenes: A theoretical study of mechanism, regio-, enantio-, and chemoselectivity

In the present study, theoretical calculations were performed to gain a deeper understanding of the nickel-catalysed multicomponent reductive hydrocarbonylation of alkenes using ethyl chloroformate as the CO source and hydrosilane as the hydride source. The computations show Ni(I) species acts as the active catalyst entering the catalytic cycle. The calculated mechanism corroborates the experimental mechanistic proposals on the elementary steps. Nonetheless, the sequence of elementary steps and the oxidation state of the nickel center are different from the experimental proposal. The calculations reproduced quite well the experimentally observed regio- and enantioselectivity. The distortion/interaction analysis and frontier molecular orbital theory confirm that the interaction energy determines the regioselectivity. The high S-enantioselectivity arises from the stronger C–H/π interactions in the S-configuration compared to those in the R-type enantiomer. One of the biggest challenges faced by multicomponent reactions is competing side-reactions. To explore the reaction's chemoselectivity, we calculated the formation mechanisms of five potential by-products and analyzed the driving force behind the formation of the desired product.

A Synthetic Strategy toward S-, N-, and O-Heterocyclooctynes Facilitates Bioconjugation Using Multifunctional Handles.

Over the past two decades, the introduction of bioorthogonal reactions has transformed the ways in which chemoselective labeling, isolation, imaging, and drug delivery are carried out in a complex biological milieu. A key feature of a good bioorthogonal probe is the ease with which it can be attached to a target compound through bioconjugation. This paper describes the expansion of the utility of a class of unique S-, N-, and O-containing heterocyclooctynes (SNO-OCTs), which show chemoselective reactivity with type I and type II dipoles and divergent reactivities in response to electronic tuning of the alkyne. Currently, bioconjugation of SNO-OCTs to a desired target is achieved through an inconvenient aryl or amide linker at the sulfamate nitrogen. Herein, a new synthetic approach toward general SNO-OCT scaffolds is demonstrated that enables the installation of functional handles at both propargylic carbons of the heterocycloalkyne. This capability increases the utility of SNO-OCTs as labeling reagents through the design of bifunctional bioorthogonal probes with expanded capabilities. NMR kinetics also revealed up to sixfold improvement in cycloaddition rates of new analogues compared to first-generation SNO-OCTs.

Investigations on Superbase Mediated Reactivity of N‐Tosylhydrazones with Aza‐ortho‐Quinone Methide Precursors

We have encountered a superbase‐mediated chemoselective reaction of N‐tosylhydrazones with aza‐ortho‐quinone methide precursors. When tosylhydrazone was treated with ortho‐aminobenzyl alcohol in super basic conditions (KOH+DMSO), we observed the formation of 2‐substituted quinoline. The reaction was found to be general, and by this method, mono‐, di‐ and tri‐substituted quinolines could be made. We could prove experimentally and theoretically that the reaction proceeded via the formation of an azine from the basic decomposition of N‐tosylhydrazones. Finally, the reaction of tosylhydrazone with N‐(2‐(chloromethyl) phenyl)‐4‐methylbenzenesulfonamide (aza‐ortho‐quinone methide precursor) under super basic conditions afforded hydrazine substituted sulfonamides.

3-Acyl-4-Pyranone as a Lysine Residue-Selective Bioconjugation Reagent for Peptide and Protein Modification.

Chemoselective protein modification plays extremely important roles in various biological, medical, and pharmaceutical investigations. Mimicking the mechanism of the chemoselective reaction between natural azaphilones and primary amines, this work successfully simplified the azaphilone scaffold into much simpler 3-acyl-4-pyranones. Examinations confirmed that these slim-size mimics perfectly kept the unique reactivity for selective conjugation with the primary amines including lysine residues of peptides and proteins. The newly developed pyranone tool presents remarkably increased aqueous solubility and compatible second-order rate constant by comparison with the original azaphilone. Additional advantages also include the ease of biorthogonal combinative use with a copper-catalyzed azide-alkyne Click reaction, which was conveniently applied to decorate lysozyme with neutral-, positive- and negative-charged functionalities in parallel. Moderate-degree modification of lysozyme with positively charged quaternary ammoniums was revealed to increase the enzymatic activities.

Tunable molecular editing of indoles with fluoroalkyl carbenes.

Building molecular complexity from simple feedstocks through precise peripheral and skeletal modifications is central to modern organic synthesis. Nevertheless, a controllable strategy through which both the core skeleton and the periphery of an aromatic heterocycle can be modified with a common substrate remains elusive, despite its potential to maximize structural diversity and applications. Here we report a carbene-initiated chemodivergent molecular editing of indoles that allows both skeletal and peripheral editing by trapping an electrophilic fluoroalkyl carbene generated in situ from fluoroalkyl N-triftosylhydrazones. A variety of fluorine-containing N-heterocyclic scaffolds have been efficiently achieved through tunable chemoselective editing reactions at the skeleton or periphery of indoles, including one-carbon insertion, C3 gem-difluoroolefination, tandem cyclopropanation and N1 gem-difluoroolefination, and cyclopropanation. The power of this chemodivergent molecular editing strategy has been highlighted through the modification of the skeleton or periphery of natural products in a controllable and chemoselective manner. The reaction mechanism and origins of the chemo- and regioselectivity have been probed by both experimental and theoretical methods.

Mechanistic Studies on Rhodium-Catalyzed Chemoselective Cycloaddition of Ene-Vinylidenecyclopropanes: Water-Assisted Proton Transfer.

Rhodium-catalyzed cycloaddition reactions are a powerful tool for the construction of polycyclic compounds. Combined experimental and DFT studies were used to investigate the temperature-controlled chemoselectivity of cationic rhodium-catalyzed intramolecular cycloaddition reactions of ene-vinylidenecyclopropanes. After a series of mechanistic studies, it was found that trace amounts of water in the reaction system play an important role in generating the product with endo double bond located on a five-membered ring and revealed that trace amounts of water in the reaction system, including the rhodium catalyst, substrate and solvent, were sufficient to promote the formation of the product with endo double bond located on a five-membered ring, and additional water could not further accelerate the reaction. DFT calculation results show that the addition of water indeed significantly lowers the energy barrier of the proton transfer step, making the formation of the product with endo double bond located on a five-membered ring more likely to occur and confirming the rationality of water-assisted proton transfer occurring in the selective access to the product with endo double bond located on a five-membered ring.

Screening support effect of Pt/MOx for selective hydrogenation of cinnamaldehyde

In supported metal catalysts, solid support material is of great importance for immobilizing and dispersing metal species, which can affect the catalytic performance of supported metal catalysts in terms of selectivity. Rational design of supported metal catalysts with tailored performance, in particular with controlled catalytic performance, is highly desired yet poses challenges in chemoselective hydrogenation reactions. Here, platinum nanoparticles (Pt NPs) supported on a series of commercial oxides were synthesized by a facile wet impregnation and thermal treatment under the air. The catalytic performance of as-prepared catalysts was evaluated in chemoselective hydrogenation of cinnamaldehyde. The varied product distribution demonstrates that supports affect markedly on selectivity. Fourier transform infrared spectra (FTIR) spectroscopy reveals that the high selectivity towards cinnamyl alcohol could be attributed to the preferential adsorption of aldehyde group. Meanwhile, the existence of Ptδ+ could enhance activity markedly by facilitating the spillover of activated H species.

Base‐Promoted Structural Rearrangement of Ynamide and Simultaneous N‐Desulfonylation

AbstractHerein, we describe a base‐promoted regioselective and chemoselective cascade cyclization, ynamide N−Csp bond cleavage, selective intramolecular 1,3‐migration, and simultaneous N‐desulfonylation strategy for the synthesis of 2‐phenyl‐3‐(phenylethynyl)‐1H‐indole derivatives. We observed multiple bond breaking (−N−Ts, and Csp2−Ts, Csp2−I/Csp2−SePh) from (E)‐3‐(1‐iodo‐2‐phenyl‐2‐tosylvinyl)‐2‐phenyl‐1‐tosyl‐indole/(E)‐2‐phenyl‐3‐(2‐phenyl‐1‐(phenylselanyl)‐2‐tosylvinyl)‐1‐tosyl‐indole derivatives to prepare 2‐phenyl‐3‐(phenylethynyl)‐1H‐indole in 15–60 min using our standard reaction conditions. A gram‐scale experiment as well as postsynthetic transformations of the synthesized 2‐phenyl‐3‐(phenylethynyl)‐1H‐indole were performed to exhibit the advantages of this synthetic methodology.

Enhancing photocatalytic performance of atom transfer radical addition (ATRA) reactions in water using immobilized 10-Phenylphenothiazine catalysts on mesoporous silica supports

The development of catalysts is crucial for sustainable chemistry, and heterogeneous catalysis, specifically, can be environmentally friendly and recyclable. Catalyst immobilization in materials has been explored, in which mesoporous silica materials have shown outstanding results in catalysis. Photocatalysis has also gained attention, providing solutions for organic synthesis and late-state functionalization, mainly using homogeneous catalysts and organic solvents. The use of aqueous media for photocatalytic reactions is particularly attractive from a sustainability perspective yet can influence reaction chemoselectivity. However, poor solubility of the organic substrates and the catalyst limits photocatalytic methods in water. Mesoporous silicas are water-stable materials suitable for catalytic applications in such media, including photocatalysis. In this work, we demonstrate an atom transfer radical addition (ATRA) reaction in water using immobilized 10-phenylphenothiazine (PTH) catalyst on different mesoporous silica supports, showing improved photocatalytic performance compared to homogeneous conditions and substrate selectivity depending on the hydrophobicity of the alkene.

A Sequence-Defined ABC Dendritic Macromolecule with Amino Acid Peripheral Functionality via Iterative Chemoselective Reactions.

Chemoselective reactions allow near-precision control over the polymer composition and topology to create sequence-controlled polymers with similar secondary and tertiary structures to those found in proteins. Dendrimers are recognized as well-defined macromolecules with the potential to mimic protein surface functionality due to the large number of functional groups available at its periphery with the internal structure acting as the support scaffold. Transitioning from using small-molecule dendrimers to dendritic macromolecules will not only allow retention of the high peripheral functionality but also provide an internal scaffold with a desired polymer composition within each generational layer. Here, we exemplify a systematic approach to creating a dendritic macromolecule with the placement of different polymer building blocks in precise locations within the internal structure and the placement of three different amino acid moieties clustered at the periphery. The synthesis of this ABC dendritic macromolecule was accomplished through iterative chemoselective reactions.

Copper-Catalyzed Sulfimidation in Aqueous Media: a Fast, Chemoselective and Biomolecule-Compatible Reaction.

Performing transition metal-catalyzed reactions in cells and living systems has equipped scientists with a toolbox to study biological processes and release drugs on demand. Thus far, an impressive scope of reactions has been performed in these settings, but many are yet to be introduced. Nitrene transfer presents a rather unexplored new-to-nature reaction. The reaction products are frequently encountered motifs in pharmaceuticals, presenting opportunities for the controlled, intracellular synthesis of drugs. Hence, we explored the transition metal-catalyzed sulfimidation reaction in water for future in vivo application. Two Cu(I) complexes containing trispyrazolylborate ligands (Tpx ) were selected, and the catalytic system was evaluated with the aid of three fitness factors. The excellent nitrene transfer reactivity and high chemoselectivity of the catalysts, coupled with good biomolecule compatibility, successfully enabled the sulfimidation of thioethers in aqueous media. We envision that this copper-catalyzed sulfimidation reaction could be an interesting starting point to unlock the potential of nitrene transfer catalysis in vivo.

Site-selective chlorination of pyrrolic heterocycles by flavin dependent enzyme PrnC

Halogenation of pyrrole requires strong electrophilic reagents and often leads to undesired polyhalogenated products. Biocatalytic halogenation is a highly attractive approach given its chemoselectivity and benign reaction conditions. While there are several reports of enzymatic phenol and indole halogenation in organic synthesis, corresponding reports on enzymatic pyrrole halogenation have been lacking. Here we describe the in vitro functional and structural characterization of PrnC, a flavin-dependent halogenase that can act on free-standing pyrroles. Computational modeling and site mutagenesis studies identified three key residues in the catalytic pocket. A moderate resolution map using single-particle cryogenic electron microscopy reveals PrnC to be a dimer. This native PrnC can halogenate a library of structurally diverse pyrrolic heterocycles in a site-selective manner and be applied in the chemoenzymatic synthesis of a chlorinated analog of the agrochemical fungicide Fludioxonil.

Chemoselective Intramolecular Morita-Baylis-Hillman Reaction; Acrylamide and Ketone as Sluggish Reacting Partners on a Labile Framework.

Chemoselectivity is an important issue frequently encountered while working over labile precursors. Carbonyl compounds with a heteroatom at the β carbon are sensitive precursors because they are prone to elimination under different conditions. Morita-Baylis-Hillman (MBH) reaction, although a widespread method for C-C bond formation, has its own limitations. Acrylamide and ketone are such limitations of the MBH reaction. Using them together for an intramolecular MBH (IMBH) reaction on a labile framework prone to elimination is a significant 2-fold synthetic challenge. A highly chemoselective IMBH reaction on such precursors has been established using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a promoter. The protocol leads to quick access to a diversely substituted and functionalized piperidone framework in high yields. Various substitution patterns in the form of 34 successful examples have been studied. A diastereoselective version and tolerance to various functional and protecting groups are the added advantages of the developed methodology. A tertiary carbon at the β position of ketone, however, led to complete reversal of selectivity and gave only the elimination product. Control experiments toward a better understanding of the substitution pattern, role of catalyst, and mechanistic study have been carried out. As an application of the IMBH adduct, a one-step allylic rearrangement for the dihydropyridone framework has also been demonstrated.

Recent advances in the applications of gem-difluoromethylene alkynes.

As a special class of alkynes, gem-difluoromethylene alkynes exhibit a variety of fascinating properties due to the presence of the gem-difluoro substitution. This substitution highlights the distinctive fluorine effects in influencing the chemoselectivity of reactions. As a result, chemical scientists have shown great interest and enthusiasm for investigating their reactions. In this review, we briefly summarize recent advances in transition metal-catalysed reactions of gem-difluoromethylene alkynes with multiple reaction pathways. Their mechanistic studies and challenges will be highlighted. The purpose of this review is to provide illustrations of elegant gem-difluoromethylene alkynes and thereby elicit further interest among synthetic chemists in developing innovative transformations of gem-difluoromethylene alkynes.