One-pot Cascade Reaction Research Articles

Divergent Synthesis of Five-Membered Nitrogen Heterocycles via Cascade Reactions of 4-Arylfuroxans

A novel method for the synthesis of a diverse series of functionally substituted five-membered heterocyclic compounds via atom-economic, regio-, and diastereoselective one-pot reaction cascade was developed. This approach involves a ring opening in 4-arylfuroxans to α-oximinoarylacetonitrile oxides followed by [3+2] cycloaddition to various dipolarophiles to afford multisubstituted isoxazoles and isoxazolines. Subsequent azole–azole rearrangement of (oximino)isoxazolines/-isoxazoles, which can be conducted in a one-pot manner, results into functionally substituted furazans formation. The developed protocol is operationally simple, proceeds in mild conditions and with high yields of target heterocyclic systems. Overall, this study represents a new mode of isoxazole and 1,2,5-oxadiazole functionalization strategy, which is useful in medicinal and materials chemistry.

Microwave-assisted efficient and facile synthesis of tetramic acid derivatives via a one-pot post-Ugi cascade reaction.

A facile microwave-assisted method for the synthesis of tetramic acid derivatives has been developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction has the potential to produce a large number of tetramic acid analogues, which cannot be easily accessed by the classic synthetic methods.

In Situ Acetaldehyde Synthesis for Carboligation Reactions.

The enzyme 4‐oxalocrotonate tautomerase (4‐OT) can promiscuously catalyze various carboligation reactions using acetaldehyde as a nucleophile. However, the highly reactive nature of acetaldehyde requires intricate handling, which can impede its usage in practical synthesis. Therefore, we investigated three enzymatic routes to synthesize acetaldehyde in situ in one‐pot cascade reactions with 4‐OT. Two routes afforded practical acetaldehyde concentrations, using an environmental pollutant, trans‐3‐chloroacrylic acid, or a bio‐renewable, ethanol, as starting substrate. These routes can be combined with 4‐OT catalyzed Michael‐type additions and aldol condensations in one pot. This modular systems biocatalysis methodology provides a stepping stone towards the development of larger artificial metabolic networks for the practical synthesis of important chemical synthons.

Highly Mesoporous Metal-Organic Frameworks as Synergistic Multimodal Catalytic Platforms for Divergent Cascade Reactions.

Rational engineering and assimilation of diverse chemo- and biocatalytic functionalities in a single nanostructure is highly desired for efficient multistep chemical reactions but has so far remained elusive. Here, we design and synthesize multimodal catalytic nanoreactors (MCNRs) based on a mesoporous metal-organic framework (MOF). The MCNRs consist of customizable metal nanocrystals and stably anchored enzymes in the mesopores, as well as coordinatively unsaturated cationic metal MOF nodes, all within a single nanoreactor space. The highly intimate and diverse catalytic mesoporous microenvironments and facile accessibility to the active site in the MCNR enables the cooperative and synergistic participation from different chemo- and biocatalytic components. This was shown by one-pot multistep cascade reactions involving a heterogeneous catalytic nitroaldol reaction followed by a [Pd/lipase]-catalyzed chemoenzymatic dynamic kinetic resolution to yield optically pure (>99 % ee) nitroalcohol derivatives in quantitative yields.

Diversity oriented multi-component reaction (DOS-MCR) approach to access natural product analogues: regio- and chemo-selective synthesis of polyheterocyclic scaffolds via one-pot cascade reactions.

Skeletally diverse and complex aza-cyclopenta(cd)diindene, pyrrolo(3,4-d)pyridine-13-carboxamide, and furo-pyrrolo(1,2-a)imidazole-4-carboxamide fused polyheterocyclic hybrid scaffolds and a furo(2,3-b)furan core have been accessed via one-pot three-component reaction by exploiting the build/couple/pair strategy of diversity oriented synthesis (DOS). This protocol is metal free, has a good substrate scope and affords products with good to excellent yields and regio- and chemo-selectivity. The heterocyclic skeletons obtained in this study mimic natural products such as eupolauramine, gracilamine and presilphiperfolanol.

Substituent-controlled chemoselective synthesis of multi-substituted pyridones via a one-pot three-component cascade reaction.

An efficient and concise one-pot strategy for the synthesis of multisubstituted pyridones via a one-pot three-component cascade reaction catalyzed by Cs2CO3 under solvent-free conditions has been developed. The substituent-controlled chemoselective cycloaddition process involved steps including a Michael addition/ethanol elimination/intermolecular cyclization sequence utilizing anilines, diethyl acetylenedicarboxylate, and diethyl ethoxymethylenemalonate. In doing so, various 2-pyridone and 4-pyridone species (41 examples) could be obtained in good to excellent yields.

New efficient synthesis of benzofuro[2,3-b]pyrroles utilizing a reactive nitrilium trapping approach by an acid-promoted cascade addition/cyclization sequence

The first p-TSA·H2O-catalyzed highly efficient one-pot cascade reaction for the synthesis of novel fused tricyclic benzofuro[2,3-b]pyrroles has been discovered.

Physically mixed catalytic system of amino and sulfo-functional porous organic polymers as efficiently synergistic co-catalysts for one-pot cascade reactions

Acid/base bi-functional polymeric materials were prepared using physically mixed porous polymers P(DVB-VBS) with sulfonic acid and P(DVB-VBA) with amino groups for various cascade reactions.

Recent Progress in Asymmetric Relay Catalysis of Metal Complex with Chiral Phosphoric Acid.

Asymmetric metal/organo relay catalysis, utilizing a metal complex and a chiral organocatalyst in a one-pot cascade reaction, is aimed to sequentially impart activation on multiple steps by distinct catalysts. Such a catalysis merges the advantages of both metal catalysis and organocatalysis, providing step-economy, and, more importantly, the potential to achieve inaccessible reactivity by a single catalyst. Chiral phosphoric acids are among the most robust organocatalysts, rendering a broad range of enantioselective bond-forming reactions. The combination of metal complexes and chiral phosphoric acids in a single vessel has been well documented. In particular, the asymmetric relay catalysis of metal complex with chiral phosphoric acid has grown rapidly since 2008. Several excellent reviews have been published to cover almost all examples in this area from 2008 to early 2014; therefore, in this chapter, we will mainly highlight progress from 2014 to mid-2019.

One-Pot Synthesis of Thieno[3,2-e]pyrrolo[1,2-a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors.

A new, efficient, and versatile one-pot cascade reaction of diverse Gewald's aminothiophenes, 2-hydroxy-4-oxobut-2-enoic acid, and derivatives of cyanoacetic acid catalyzed by Et3N is presented. It enables direct synthesis of diverse 1-(2-oxoethylidene)-2-oxothieno[3,2-e]pyrrolo[1,2-a]pyrimidine in good to excellent yields. The reaction exhibits a broad substrate scope and also presents an opportunity for further modification of the structure. The method offers a convenient practical alternative to the known procedures. The synthesized thieno[3,2-e]pyrrolo[1,2-a]pyrimidine scaffold is an important structural motif of new poly(ADP-ribose) polymerase (PARP) inhibitors, playing a useful role in multiple pharmacological applications.

Chemists synthesize natural insecticide in 16 steps

Although chemists have known about the molecule perseanol since the 1990s, no one has completed a total synthesis of the complex, polycyclic insecticide, until now. California Institute of Technology chemistry professor Sarah E. Reisman and graduate students Arthur Han and Yujia Tao constructed perseanol in just 16 steps, starting from a commercially available vinylogous ester and pulegone—a compound found in plants like catnip. The chemists’ strategy features a one-pot palladium-catalyzed cascade and carbon monoxide insertion reaction that stitches together most of perseanol’s polycyclic core (Nature 2019, DOI: 10.1038/s41586-019-1580-x). Learn more at cenm.ag/perseanol. Subscribe to our YouTube channel to catch all of our chemistry news videos. The following is the script for the video. We have edited the interviews within for length and clarity. Matt Davenport: In the 1990s, a team of scientists was in Tenerife, in the Canary Islands, hoping to find some interesting molecules in the island’s plants. They

Precise 2D-Patterned Incompatible Catalysts for Reactions in One-Pot.

Precise and direct two-dimensional (2D) printing of the incompatible polymer acid-base catalysts and their utility in one-pot two-step reactions were shown. Multistep catalytic reactions using incompatible catalysts in a one-pot reaction cascade requires special methods and materials to isolate the catalysts from each other. In general, this is a tedious process requiring special polymer architectures as the carrier for the catalysts to preserve the activity of otherwise incompatible catalysts. We propose the immobilization of incompatible polymer catalysts, such as polymer acid and base catalysts, on a substrate in variable sizes and amounts by precise 2D printing. The terpolymers with basic (4-vinylpyridine) and acidic (styrene sulfonic acid) functionalities and methacryloyl benzophenone as a UV cross-linking unit were used for 2D printing on poly(ethylene terephthalate) (PET). The printed meshes were immersed together in a reaction solution containing (dimethoxymethyl)benzene and ethyl cyanoformate, resulting in a two-step acid-base catalyzed cascade reaction; that is, deacetalization followed by carbon-building reaction. The time-dependent consumption of (dimethoxymethyl)benzene to the intermediate benzaldehyde and the product was monitored, and a kinetic model was developed to investigate the underlying reaction dynamics. The complexity of multistep Wolf-Lamb-type reactions was generally significantly decreased by using our approach because of the easy polymerization and immobilization procedure.

Multi-functional metal-organic framework and metal-organic framework-zeolite nanocomposite for the synthesis of carbohydrate derived chemicals via one-pot cascade reaction

Zeolite-metal organic framework nanocomposite catalyst is developed for the synthesis of 2-((5-(hydroxymethyl)furan-2-yl)methylene)malononitrile from sucrose/fructose/glucose via one-pot cascade protocol. To accomplish this objective, zeolite Beta and Zr based metal- organic frameworks such as UiO-66 and UiO-66-NH2 are investigated for the independent steps, i.e. the conversion of sucrose to HMF and the Knoevenagel condensation of HMF and malononitrile. Beta zeolite exhibits the best activity in the sucrose to HMF conversion, whereas UiO-66-NH2 exhibits the best activity in the Knoevenagel condensation. Therefore, zeolite Beta and UiO-66-NH2 are integrated to develop a highly sustainable and efficient multi-functional catalyst for the conversion of sucrose to 2-((5-(hydroxymethyl)furan-2-yl)methylene)malononitrile via one-pot cascade reaction. The composite catalyst contains the optimum acidity and basicity for the cascade reaction. The presence of both the frameworks in the composite material is confirmed by using various physico-chemical characterization techniques. Further, the integration of both the active frameworks enhances the chemical stability and recyclability of the composite catalyst in the cascade reaction. This study demonstrates a unique approach to develop a synthesis strategy for the integration of inorganic zeolite and MOFs to achieve the desired activity, selectivity, and stability of the developed catalyst.

Construction of the A/B/C core of mexicanolides via a tandem double-aldol reaction

An efficient and concise approach for rapid assembly of the ABC tricyclic carbon skeleton of mexicanolide-type limonoids is described. The acetal/ketal diketoester precursors were prepared from simple starting materials by LiOH-mediated Michael reactions. The ABC tricyclic skeleton bearing multiple stereogenic centers was efficiently constructed by a powerful one-pot cascade reaction, which includes acetal/ketal hydrolysis, double intramolecular aldol condensation, and alkene migration.

A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: a mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates.

A new multicomponent reaction has been developed between isocyanides, sulfur and alcohols or thiols under mild reaction conditions to afford O-thiocarbamates and dithiocarbamates in moderate to good yields. The one-pot reaction cascade involves the formation of an isothiocyanate intermediate, thus a catalyst-free synthesis of isothiocyanates, as valuable building blocks from isocyanides and sulfur is proposed, as well. The synthetic procedure suits the demand of a modern organic chemist, as it tolerates a wide range of functional groups, it is atom economic and easily scalable.

Highly regio- and enantioselective synthesis of chiral intermediate for pregabalin using one-pot bienzymatic cascade of nitrilase and amidase.

Nitrilase-mediated hydrolysis of isobutylsuccinonitrile (IBSN) is a highly attractive approach for (S)-3-cyano-5-methylhexanoic acid ((S)-CMHA), the critical chiral intermediate of pregabalin. In this study, a robust nitrilase from Arabis alpina (AaNIT) was screened and engineered. The N258D mutant was obtained with high catalytic activity and excellent enantioselectivity (E > 300) towards IBSN at a high substrate concentration of 100gL-1. Byproduct (S)-3-cyano-5-methyl hexanoic amide ((S)-CMHM) was detected and identified for the first time during the catalytic process. By employing a feasible one-pot bienzymatic cascade of mutant N258D and amidase from Pantoea sp. (Pa-Ami) expressed separately in recombinant Escherichia coli cells, the byproduct (S)-CMHM was eliminated and (S)-CMHA was obtained with a conversion of 45.0% and eep of 99.3%. These results provided the novel plant-derived nitrilase as a promising biocatalyst for (S)-CMHA biosynthesis and demonstrated the feasibility of one-pot bienzymatic cascade reaction for large-scale production of the pregabalin precursor.

Wolf-Lamb-type Catalysis in One Pot Using Electrospun Polymeric Catalyst Membranes.

Multistep catalytic transformations using incompatible catalysts (Wolf-Lamb-type) in a one-pot reaction cascade require site isolation of different catalysts by compartmentalization. In this work, the use of different electrospun catalytic membranes in a modular way as individual compartments is shown for one-pot Wolf-Lamb-type reaction cascades. The data are presented for one-pot cascade reaction sequences catalyzed by acidic and basic membranes made by electrospinning polymeric acid (poly(styrene-co-styrene sulfonic acid-co-4-methacryloyl-oxybenzophen)) and basic (poly(styrene-co-4-vinylpyridine-co-4-methacryloyl-oxybenzophen)) catalysts, respectively. The two-step, one-pot system used is the acidic catalyzed deacetylation of dimethoxybenzylacetale to benzaldehyde, which reacts with ethyl cyanoformate to result in a high yield of product (over 90%) under base-catalyzed conditions. The reaction kinetics are further monitored and evaluated by using differential equations, showing the necessity of a parameter Δt to represent a retarded start for the second reaction step. The concept provides an easy and upscalable approach for use in Wolf-Lamb-type systems.

Au/NiO Composite: A Catalyst for One-Pot Cascade Conversion of Furfural

Furfural is a promising renewable platform chemical that is widely produced from lignocellulosic biomass and has received significant attention as a sustainable precursor for the production of chemicals and fuels. To date, one-pot conversion of furfural with cellulosic ethanol is mostly limited to the synthesis of C5–C7 hydrocarbons, poising a challenge for the production of high-energy density fuel from biomass-derived compounds. In this study, we present gold nanoparticles supported over nickel oxide (Au/NiO) as robust catalysts for selective conversion of furfural to hydrocarbons. The catalysts present ∼92% furfural conversion with ∼81% selectivity toward the production of C7 and C9 hydrocarbons through a one-pot cascade reaction, viz., cross-aldol condensations in the presence of ethanol, O2, and K2CO3, followed by a hydrogenolysis process using H2(g). Results indicate the unprecedented production of C9 from furfural and ethanol is yielded via in situ cross-aldol condensation of 3-(2-furyl)acrolein, a...

Synergistic catalysis of one-pot cascade reactions by acidic and basic binary porous polymers

Acidic and basic porous polymers were facilely prepared through the radical copolymerization of target monomers and the crosslinker divinylbenzene (DVB), respectively. Combination of these polymers endowed highly efficient, heterogeneous recyclable acid-base binary catalysts for cascade deacetalization-Knoevenagel reaction, offering high yield and stable reusability. Binary polymers with strong acid sites and superior base sites afforded an unprecedented turnover frequency (TOF) in the condensation of benzaldehyde dimethylacetal and nitriles (285 h−1 for malononitrile and 57 h−1 for inert methylene substrate ethyl cyanoacetate). The excellent synergistically catalytic performance was ascribed to the unique self-protection effect of the in-situ formed acid and base sites embedded in the polymeric network. This study provided a facile, versatile and efficient strategy towards acid-base bifunctional heterogeneous catalysts by combining acidic and basic porous polymers.

Self-Assembly of Nanoparticles in a Modular Fashion to Prepare Multifunctional Catalysts for Cascade Reactions: From Simplicity to Complexity.

One-pot cascade reactions can simplify the synthetic route and reduce the use of solvents and energy. The critical part of the completion of the cascade reaction is the preparation of multifunctional catalysts. In this work, a novel and simple pathway was developed to construct multifunctional catalysts with acidic, basic, and magnetic properties at the same time. Mesoporous silica materials modified with different metal oxides were used as catalytic elements. Microspheres that assembled with catalytic components have a diameter of 150 μm and a specific surface area larger than 400 m2 g–1 and can be used as catalysts for cascade reactions. The yield of the final product in the deacetalization–Knoevenagel reaction is 92%. Microspheres integrated with Fe3O4 nanoparticles have a magnetic susceptibility of 7.2 emu g–1 and can be easily removed from the reaction system by applying an external magnetic field. This multimodule assembly method fully reflects the enormous power of complexity resulting from simplicity. This method provides a reference and practical technical support for the preparation of other multifunctional materials.