Nucleophilic Catalyst Research Articles

Feedstock chemical dichloromethane as the C1 source for the chemoselective multicomponent synthesis of valuable 1,4,2-dioxazoles

The development of mild and practical strategies to produce value-added fine chemicals directly from inexpensive and readily available commodity chemicals is actively pursued by chemists. However, the application of feedstock chemical dichloromethane (DCM) as the C1 source in organic synthesis is still in its infancy. Herein, we describe a multicomponent strategy for the chemoselective synthesis of valuable 1,4,2-dioxazoles by using DCM as a C1 source. Critical to the success of this process is tuning of the type of nucleophiles to inhibit the easily-occurring side reactions. This approach features mild and simple conditions, excellent chemoselectivity, metal free, and broad substrate scope covering different types of nucleophiles. Furthermore, its synthetic utility is further demonstrated by the preparation of deuterated 1,4,2-dioxazoles, the late-stage functionalization of complex molecules and large-scale synthesis. Preliminary mechanistic studies indicate the dual roles of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as both a proton scavenger and a nucleophilic catalyst. This work provides not only a platform for DCM application, but also an excellent complementary strategy to the established 1,4,2-dioxazoles synthesis.

Chemoselective Intramolecular Rauhut‐Currier Reaction on a Labile Framework of Enone and Acrylamide: Tricyclohexylphosphine as a Stable and Economical Catalyst

AbstractIntramolecular Rauhut‐Currier (IRC) reaction is an atom‐economical way of making carbocyclic and heterocyclic rings. However, its sensitivity towards electronic and steric parameters limits the reaction and stems the need for further development. Acrylamides have been one such left out of their sensitivity. Herein we report an IRC reaction, using acrylamide as a source of initial enolate. The cyclization has been achieved on a labile and challenging framework, prone to decomposition. Different control experiments have addressed the instability of the precursor. Protocol was further extendable to annulation for benzo analogs. We also report tricyclohexylphosphine (PCy3) as a stable, commercial, and easy‐to‐use nucleophilic catalyst in the field of IRC reactions as compared to earlier well‐established trimethyl and tributyl phosphines. Me3P and Bu3P although useful, are sensitive, prone to oxidation, and need careful handling. The protocol leads to the synthesis of piperidone and dihydroquinolone frameworks. A quick study to test the feasibility of catalyzing the Morita‐Baylis‐Hillman (MBH) reaction by PCy3 was also done successfully, although in moderate yields.

Asymmetric Conjugate Addition of Vinyl Arene-Derived Chiral Benzylcopper Nucleophiles.

We report the copper-catalyzed asymmetric conjugate addition of vinyl arene-derived nucleophiles to α,β-unsaturated diesters. Due to the high electrophilicity of α,β-unsaturated diesters toward nucleophilic copper catalysts, inclusion of vinyl arenes as pronucleophiles is challenging due to chemoselectivity issues in a multicomponent reaction compared with those of other successful examples of dienes, allenes, and enynes. In this method, chemoselective in situ generation of a chiral benzylic copper intermediate and its stereoselective addition to α,β-unsaturated diesters provided organoboron adducts with contiguous stereogenic centers with good levels of diastereoselectivity and enantioselectivity (≤85:15 diastereomeric ratio and 99% enantiomeric excess, respectively).

Effects of Nucleophilic Catalysts on the Self‐Assembly of Hydrazone‐Based Supramolecular Hydrogels

AbstractCatalytic control over molecular self‐assembly provides a powerful approach to regulate the structures as well as the functionalities of supramolecular materials. Revealing how the catalysts affect the molecular self‐assembly process is crucial for rational design and control of the supramolecular self‐assembly systems. Herein, relying on a hydrazone‐based dynamic supramolecular hydrogel system, the effects of various nucleophilic catalysts on the self‐assembly of the hydrogels are investigated, demonstrating that the catalyst influences the hydrogelators self‐assembly via facilitating both the reaction and hydrogelators nucleation processes. The catalyst with higher catalytic activity accelerates the formation thereon the self‐assembly of hydrazone‐based hydrogelators, leading to hydrogels with more branched networks and higher stiffness. Importantly, we also verify that the catalysts, depending on the molecular structure, can also accelerate the self‐assembly process by affecting the hydrogelators nucleation process. These findings not only add more details to the effects of nucleophilic catalysts on the hydrazone‐based hydrogelation system, but also suggest that both the catalysis activity and chemical structures should be considered for catalytically controlled molecular self‐assembly.

Modular Assembly and Optimization of an Artificial Esterase from Functionalised Surfactants

AbstractA strategy for the screening and optimization of an artificial esterase is presented that utilizes the self‐assembly of amphiphilic molecules. Unlike conventional approaches that rely on the attachment of key functional groups onto molecular scaffolds or surfaces, the modular assembly of amphiphiles allows a large number of catalytic combinations to be investigated with minimal synthetic effort. In this study, iterative combinatorial screens led to an optimized esterase comprising amphiphiles that act as a nucleophilic catalyst, an oxyanion hole and a metal ion chelator. Cooperativity is observed between the functional headgroups of the amphiphiles, an effect that is diminished when co‐assembled with non‐functionalized surfactants. Assessment of the catalytic efficiency (kcat/KM) of our optimized catalysts against recently reported artificial esterases shows comparable efficiency, indicating that efficient catalysis is possible with dynamic self‐assembled systems despite the absence of pre‐defined rigid binding pockets.

Advancing Recyclable Thermosets through C═C/C═N Dynamic Covalent Metathesis Chemistry.

Thermoset polymers have become integral to our daily lives due to their exceptional durability, making them feasible for a myriad of applications; however, this ubiquity also raises serious environmental concerns. Covalent adaptable networks (CANs) with dynamic covalent linkages that impart efficient reprocessability and recyclability to thermosets have garnered increasing attention. While various dynamic exchange reactions have been explored in CANs, many rely on the stimuli of active nucleophilic groups and/or catalysts, introducing performance instability and escalating the initial investment. Herein, we propose a new direct and catalyst-free C═C/C═N metathesis reaction between α-cyanocinnamate and aldimine as a novel dynamic covalent motif for constructing recyclable thermosets. This chemistry offers mild reaction conditions (room temperature and catalyst-free), ensuring high yields and simple isolation procedures. By incorporating dynamic C═C/C═N linkages into covalently cross-linked polymer networks, we obtained dynamic thermosets that exhibit both malleability and reconfigurability. The resulting tunable dynamic properties, coupled with the high thermal stability and recyclability of the C═C/C═N linkage-based networks, enrich the toolbox of dynamic covalent chemistry.

Nucleophilic Organocatalyst for Photochemical Carbon Radical Generation via SN2 Substitution.

Photochemical generation of radicals is a powerful way to construct various molecules. But most of these methods rely on initiators or the redox properties of radical precursors. Herein, we report a photochemical organic catalyst that reacts with benzyl halide to generate carbon radical via an SN2 pathway. This nucleophilic catalyst can be easily prepared and is bench-stable. The SN2 process does not rely on the redox properties of halides, showing potential synthetic utility. Control experiments and UV-vis spectroscopic analysis indicate that the SN2 substitution adduct is the key intermediate.

Phosphine-Catalyzed Synthesis and Cytotoxic Evaluation of Michael Adducts of the Sesquiterpene Lactone Arglabin.

A general method for chemo- and diastereoselective modification of anticancer natural product arglabin with nitrogen- and carbon-centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s-cis-geometry of α-methylene-γ-butyrolactone moiety of arglabin favors for the additional stabilization of the zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly high efficiency of the phosphine-catalyzed Michael additions to this sesquiterpene lactone. Using n-Bu3P as the catalyst, pyrazole, phthalimide, 2-oxazolidinone, 4-quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n-Bu3P-catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2-Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential.

Enantioselective Synthesis of 3‐Allylindoles from Indolin‐2‐imines and MBH Carbonates via Nucleophilic Catalysis

AbstractWith chiral amine (DHQD)2PHAL as nucleophilic catalyst, asymmetric synthesis of enantioenriched 3‐allylindoles was achieved from indolone‐2‐imines and MBH carbonates. Compared with our previous chiral phosphine catalysis, the chiral amine had exactly the opposite effect in terms of enantioselectivity. Importantly, we could obtain each enantiomer by adjusting the catalyst system.

Photochemical Deoxygenative Hydroalkylation of Unactivated Alkenes Promoted by a Nucleophilic Organocatalyst

AbstractThe direct utilization of simple and abundant feedstocks in carbon‐carbon bond‐forming reactions to embellish sp3‐enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid‐, alcohol‐, ester‐, ketone‐, amide‐, silane‐, and boronic ester groups, as well as nitrile‐containing substrates. The reaction is operationally simple, mild, and water‐tolerant, and can be carried out on multigram‐scale, which highlights the utility of the method to prepare value‐added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T‐cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.

Photochemical Deoxygenative Hydroalkylation of Unactivated Alkenes Promoted by a Nucleophilic Organocatalyst.

The direct utilization of simple and abundant feedstocks in carbon-carbon bond-forming reactions to embellish sp3 -enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid-, alcohol-, ester-, ketone-, amide-, silane-, and boronic ester groups, as well as nitrile-containing substrates. The reaction is operationally simple, mild, and water-tolerant, and can be carried out on multigram-scale, which highlights the utility of the method to prepare value-added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T-cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.

Functionalized Crumpled Graphene as Nanocatalysts for Organophosphate Neutralization

Organophosphates are prevalent in agrochemicals and chemical warfare agents, posing significant health and safety concerns. These compounds are known for their high chemical stability and to address this issue, nucleophilic catalysts have emerged as a promising solution for their degradation. Herein, we focus on a novel material created through the combined effects of imidazole and crumpled graphene (CG) to develop a nanocatalyst for the neutralization (i.e., degradation) of organophosphates (OPs). The strategy involves the covalent functionalization of CG with imidazole groups without disrupting the three-dimensional structure of CG. This unique combination results in a synergistic effect between neighboring imidazole groups within CG, significantly enhancing the catalytic performance. The catalytic increment (kCAT/kH2O) achieved is in the order of 104 , demonstrating the remarkable efficiency of this catalyst. The pioneering and promising use of functionalized CG for addressing concerns with chemical security can boost and be broadened to other applications.

Efficient dimerization of perfluoroolefin catalyzed by strong nucleophilic bifunctional ionic liquids

Ionic liquid, as a green and efficient nucleophilic catalyst, shows great potential in the dimerization of perfluoroolefin, which further promotes the greening of the fluorine chemical reaction process.

Highly stereoselective synthesis of α-glycosylated carboxylic acids by phenanthroline catalysis.

Carbohydrate molecules with an α-glycosylated carboxylic acid motif provide access to biologically relevant chemical space but are difficult to synthesize with high selectivity. To address this challenge, we report a mild and operationally simple protocol to synthesize a wide range of functionally and structurally diverse α-glycosylated carboxylic acids in good yields with high diastereoselectivity. Although there is no apparent correlation between reaction conversion and pK a of carboxylic acids, we found that carboxylic acids with a pK a of 4-5 provide high selectivity while those of a pK a of 2.5 or lower do not. Our strategy utilizes readily available 2,9-dibutyl-1,10-phenanthroline as an effective nucleophilic catalyst to displace a bromide leaving group from an activated sugar electrophile in a nucleophilic substitution reaction, forming phenanthrolinium intermediates. The attack of the carboxylic acid takes place from the α-face of the more reactive intermediate, resulting in the formation of α-glycosylated carboxylic acid. Previous calculations suggested that the hydroxyl group participates in the hydrogen bond interaction with the basic C2-oxygen of a sugar moiety and serves as a nucleophile to attack the C1-anomeric center. In contrast, our computational studies reveal that the carbonyl oxygen of the carboxylic acid serves as a nucleophile, with the carboxylic acid-OH forming a hydrogen bond with the basic C2-oxygen of the sugar moiety. This strong hydrogen bond (1.65 Å) interaction increases the nucleophilicity of the carbonyl oxygen of carboxylic acid and plays a critical role in the selectivity-determining step. In contrast, when alcohol acts as a nucleophile, this scenario is not possible since the -OH group of the alcohol interacts with the C2-oxygen and attacks the C1-anomeric carbon of the sugar moiety. This is also reflected in alcohol-OH's weak hydrogen bond (1.95 Å) interaction with the C2-oxygen. The O(C2)-HO (carboxylic acid) angle was measured to be 171° while the O(C2)-HO (alcohol) angle at 122° deviates from linearity, resulting in weak hydrogen bonding.

Recent Advances in Nucleophilic Lewis Base‐Catalyzed Cycloadditions for Synthesis of Spirooxindoles

AbstractSpirooxindoles are privileged scaffolds in diverse bioactive natural products and pharmaceuticals, significant achievements for the construction of these molecules have thus been made in the past years. Among them, organocatalysis, in particular, nucleophilic Lewis base catalysis, has recently emerged as an efficient and reliable method for the preparation of diverse and valuable functionalized spirooxindoles. According to different kinds of nucleophilic catalysts, we summarize and classify three catalytic strategies; these are tertiary amine‐catalyzed cycloadditions, NHC‐catalyzed cycloadditions, and tertiary phosphine‐catalyzed cycloadditions, respectively. Through these methods, potential bioactive spirooxindole skeletons owning various functional groups can be produced to enrich the small organic molecule library. In this review, we describe a comprehensive and updated advances of nucleophilic Lewis base catalytic cycloaddition reactions for the construction of spirooxindoles. Meanwhile, the related mechanism and the application of these annulation strategies in natural product total synthesis will be highlighted in detail.

Late-Stage Halogenation of Peptides, Drugs and (Hetero)aromatic Compounds with a Nucleophilic Hydrazide Catalyst.

Unlike its other halogen atom siblings, chlorination of a bioactive compound can change its physiological characteristics, improve its pharmacological profile, and function as a point of diversification through cross-coupling reactions. As a result, it has been a crucial strategy for drug discovery and development. However, functional groups such as amines, amides, hydroxy groups, or carboxylic acids trap the Cl+ , severely limiting the reactivity and making direct chlorination far too difficult to be practical. Herein, we introduce a nucleophilic sulfonohydrazide catalyst for late-stage halogenation of peptides and drugs. This direct, mild and metal-free protocol shows high functional-group tolerance and is compatible with a range of structurally diverse peptides, drugs and aromatic compounds. Furthermore, DFT studies indicate that the reaction most likely proceeds via a cationic transition state. The gram-scale synthesis, high stability and efficiency of the catalyst provide a facile route for late-stage functionalization and intermediates for further derivatization.

Late‐Stage Halogenation of Peptides, Drugs and (Hetero)aromatic Compounds with a Nucleophilic Hydrazide Catalyst

AbstractUnlike its other halogen atom siblings, chlorination of a bioactive compound can change its physiological characteristics, improve its pharmacological profile, and function as a point of diversification through cross‐coupling reactions. As a result, it has been a crucial strategy for drug discovery and development. However, functional groups such as amines, amides, hydroxy groups, or carboxylic acids trap the Cl+, severely limiting the reactivity and making direct chlorination far too difficult to be practical. Herein, we introduce a nucleophilic sulfonohydrazide catalyst for late‐stage halogenation of peptides and drugs. This direct, mild and metal‐free protocol shows high functional‐group tolerance and is compatible with a range of structurally diverse peptides, drugs and aromatic compounds. Furthermore, DFT studies indicate that the reaction most likely proceeds via a cationic transition state. The gram‐scale synthesis, high stability and efficiency of the catalyst provide a facile route for late‐stage functionalization and intermediates for further derivatization.

Aziridine-derived poly(sulfonamide thioether)s: Synthesis and the self-healing elastomeric properties

We introduce a straightforward polymerization methodology for synthesizing poly(sulfonamide thioether)s by the step-growth polyaddition of dithiols to chiral bis(2-monosubstituted N-sulfonyl aziridine)s. Undesired cross-linking reactions do not occur when employing the nucleophilic catalyst tributylphosphine. The resulting polymers exhibit both optical activity and impressive thermal stability, with a decomposition temperature (Td,5%) up to 328.1 °C. Moreover, one of the synthesized polymers, incorporating the diethylene glycol unit, demonstrates remarkable mechanical properties, presenting a tensile strength exceeding 2.0 MPa and an extraordinary strain tensile rate exceeding 2,000%. Most notably, this elastomer exhibits rapid self-healing capabilities at room temperature without external stimuli. These findings not only contribute to the synthetic methods for aziridine-derived polymeric materials but also offer promising avenues for developing advanced elastomers with exceptional mechanical and self-healing attributes.

Fluoride-Catalyzed Cross-Coupling of Carbamoyl Fluorides and Alkynylsilanes.

We report the synthesis of alkynamides via the cross-coupling of carbamoyl fluorides and alkynylsilanes catalyzed by tetrabutylammonium fluoride (TBAF). In contrast to previously reported transformations of carbamoyl fluorides, C-F bond cleavage is achieved under exceptionally mild conditions (room temperature, low catalyst loadings, and short reaction times) without the need for strongly nucleophilic reagents and/or catalysts. This method offers distinct advantages over transition-metal-catalyzed approaches, such as tolerance to aryl halide moieties and complementary chemoselectivity.

Kinetics and Mechanism of Azole n-π*-Catalyzed Amine Acylation.

Azole anions are highly competent in the activation of weak acyl donors, but, unlike neutral (aprotic) Lewis bases, are not yet widely applied as acylation catalysts. Using a combination of in situ and stopped-flow 1H/19F NMR spectroscopy, kinetics, isotopic labeling, 1H DOSY, and electronic structure calculations, we have investigated azole-catalyzed aminolysis of p-fluorophenyl acetate. The global kinetics have been elucidated under four sets of conditions, and the key elementary steps underpinning catalysis deconvoluted using a range of intermediates and transition state probes. While all evidence points to an overarching mechanism involving n-π* catalysis via N-acylated azole intermediates, a diverse array of kinetic regimes emerges from this framework. Even seemingly minor changes to the solvent, auxiliary base, or azole catalyst can elicit profound changes in the temporal evolution, thermal sensitivity, and progressive inhibition of catalysis. These observations can only be rationalized by taking a holistic view of the mechanism and a set of limiting regimes for the kinetics. Overall, the analysis of 18 azole catalysts spanning nearly 10 orders of magnitude in acidity highlights the pitfall of pursuing ever more nucleophilic catalysts without regard for catalyst speciation.