Three-step Sequence Research Articles

Modular Synthesis of Highly Substituted 3-Azapyrroles by Rh(II)-Catalyzed N-H Bond Insertion and Cyclodehydration.

A modular synthesis of highly substituted 3-azapyrroles has been developed using a three-step sequence comprising copper-catalyzed alkyne-azide cycloaddition (CuAAC), N-H bond insertion, and cyclodehydration. 1-Sulfonyl-1,2,3-triazoles (1-STs) can be accessed from common alkyne and sulfonyl azide building blocks by CuAAC using CuTC. Rhodium(II)-acetate-promoted 1-ST denitrogenation results in highly electrophilic rhodium azavinyl carbenes that, here, underwent insertion into the N-H bond of secondary α-aminoketones to form 1,2-aminoalkenes. These products were cyclized and dehydrated using BF3·OEt2 into highly substituted 3-azapyrroles. The three steps (CuAAC, N-H bond insertion, and cyclodehydration) could be telescoped into a one-pot process. The method proved to be highly efficient and tolerated a wide range of substituents.

Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine.

Two routes to the antimalarial drug Pyronaridine are described. The first is a linear sequence that includes a two-step, one-pot transformation in an aqueous surfactant medium, leading to an overall yield of 87%. Alternatively, a convergent route utilizes a telescoped three-step sequence involving an initial neat reaction, followed by two steps performed under aqueous micellar catalysis conditions affording Pyronaridine in 95% overall yield. Comparisons to existing literature performed exclusively in organic solvents reveal a 5-fold decrease in environmental impact as measured by E Factors.

Synthetic Efforts and Ultimate Limitation to an Asymmetric Achmatowicz Approach Toward EBC-23.

An effort toward the total synthesis of the polyketide natural product EBC-23 is reported. The asymmetric approach is convergent and uses a late-stage Claisen-like enolate/acid chloride coupling to establish a key 1,3-diketone intermediate. The 1,3-diketone target is an oxidized form of the hydrated natural product, which fails to spiroketalize. The convergent asymmetric synthesis uses an asymmetric Noyori transfer hydrogenation of a β-furyl ketoester to enantioselectively form a chiral furyl alcohol. An Achmatowicz/Jones/Luche three-step reaction sequence was used to stereoselectively convert the furyl alcohol into the 5-hydroxy-pyran-2-one. The absolute stereochemistry of the 1,3-polyol fragment was established by a Leighton allylation. A subsequent Grubbs cross-metathesis, and Evans acetalation were used to install the 1,3-syn-diol stereochemistry.

Synthesis, Reactivity, and Properties of Benz[a]azulenes via the [8 + 2] Cycloaddition of 2H-Cyclohepta[b]furan-2-ones with an Enamine.

Starting with the reaction of 2H-cyclohepta[b]furan-2-ones with an enamine, which was prepared from 4-tert-butylcyclohexanone and pyrrolidine, benz[a]azulenes having both formyl and tert-butyl groups were obtained in the three-step sequence. Subsequently, both the formyl and tert-butyl groups were eliminated by heating the benz[a]azulene derivatives in 100% H3PO4 to give benz[a]azulenes without these substituents in high yields. In terms of product yield, this method is the best one ever reported for the synthesis of the parent benz[a]azulene so far. The conversion of the benz[a]azulene derivatives with a formyl group into cyclohept[a]acenaphthylen-3-one derivatives was also investigated via Knoevenagel condensation with dimethyl malonate, followed by Brønsted acid-mediated intramolecular cyclization. The structural features including the bond alternation in the benz[a]azulene derivatives were revealed by NMR studies, NICS calculations, and a single-crystal X-ray structural analysis. The optical and electrochemical properties of a series of benz[a]azulene derivatives were evaluated by UV/Vis, fluorescence spectroscopy, and voltammetry experiments. As a result, we found that some benz[a]azulene derivatives showed remarkable luminescence in acidic media. In addition, the benz[a]azulene derivatives with the electron-withdrawing group and cyclohept[a]acenaphthylen-3-one derivative displayed good reversibility in the spectral changes under the electrochemical redox conditions.

Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence

Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence

Ex vivo Evaluation of a New Drill System for Placement of Percutaneous Bone Conduction Devices.

The procedure for installation of a percutaneous bone-conducting device has undergone significant improvements since its introduction 40 years ago. Today, the linear incision technique with tissue preservation (LITT-P) and the minimally invasive procedure (MIPS) are the most commonly used approaches. In both these techniques, a gradual increase of the osteotomy using a three-step drilling sequence is utilized, as this approach can allow a stepwise deepening and widening of the osteotomy in the mastoid and can prevent bone overheating. A new minimally invasive procedure (MONO) has been developed that allows an osteotomy to be performed and enables complete removal of the bone volume in one single drill step for a 4 mm implant using a novel parabolic twist drill. Here, the feasibility of the MONO procedure was qualitatively and quantitatively evaluated in terms of the dura response to drill trauma in comparison with the outcomes achieved with guide drills used for the LITT-P and MIPS techniques. Fresh frozen temporal bone from a human cadaver was subjected to penetration by three drills beyond the base of the mastoid bone to different depths. The sites were evaluated, and the damage to and possible penetration of the dura were determined. The results showed that for a drill depth exceeding mastoid bone thickness by not more than 1 mm, damage to the dura was limited or nonexistent, whereas for a drill depth exceeding bone thickness by 2 mm, damage increased, or the dura was penetrated. There was a trend toward more damage and penetration for both the round burr and MIPS guide drill compared with the MONO drill bit. From this experimental ex vivo study, it can be concluded that if the dura is encountered, the MONO system is not more inclined to penetrate the dura than the conventional LITT-P and MIPS systems.

Y-shaped alkynylimidazoles as effective push-pull fluorescent dyes for luminescent solar concentrators (LSCs)

The synthesis of three 2-arylalkynyl-4,5-diarylimidazoles endcapped with typical electron-donating (ED) and electron-withdrawing (EW) groups (push-pull system) and their evaluation as fluorescent dyes for thin-film luminescent solar concentrators (LSCs) is described. These novel Y-shaped imidazole-based fluorophores were easily assembled in good chemical yields through a three-step synthetic sequence involving a double Suzuki arylation, followed by a dehydrogenative alkynylation, and a Knoevenagel condensation. Their optical and spectroscopic properties were analyzed both in solution and in poly(methyl methacrylate) (PMMA) films. All the molecules in PMMA films showed an intense, red-shifted emission between 540 and 575 nm with large Stokes shift (>120 nm), moderate-to-good fluorescence quantum yields (QY) and good device efficiencies (ηdev), especially for compound 3.

Using Oxygen as the Primary Oxidant in a Continuous Process: Application to the Development of an Efficient Route to AZD4635

An aerobic oxidation operated in continuous flow is described as the key step in an efficient three-step route to AZD4635. By implementing this technique for the oxidation step, safety concerns in batch mode were addressed and an improved yield and quality of the product were obtained. Moreover, a PAT method (Fourier transform infrared (FTIR)) was employed to obtain a real-time analysis during the optimization in flow. The optimized three-step sequence was demonstrated on a multigram scale to give AZD4635 in 32% overall yield.

Asymmetric Synthesis of γ-Amino-Functionalised Vinyl Sulfones: De Novo Preparation of Cysteine Protease Inhibitors

AbstractThe enantioselective azo-based α-amination of an aldehyde followed by a Horner–Wadsworth–Emmons-based vinyl sulfone formation is reported. The thus obtained optically active N,N′-diprotected trans-(phenylsulfonyl)vinyl hydrazine products were then converted into the corresponding N-functionalised trans-(phenylsulfonyl)vinyl amines. Specifically, reaction of 4-phenylbutanal with di-tert-butyl azodicarboxylate (DBAD) in the presence of l- or d-proline, followed by addition of diethyl [(phenylsulfonyl)methyl]phosphonate, gave either enantiomer of di-tert-butyl trans-1-[5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl]hydrazine-1,2-dicarboxylate. The enantiomeric excesses of the (+)- and (–)-enantiomers prepared in this manner were in the range 86–89%. The conversion of these γ-hydrazino vinyl sulfones into the corresponding γ-amino-substituted compounds was achieved following a Boc deprotection, Zn reduction, N-functionalisation sequence. This three-step sequence was reasonably efficient (approx. 50%) and no erosion of enantiopurity was found to have taken place. The compounds accessed via this process include both enantiomers of tert-butyl trans-[5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl]carbamate and epimeric dipeptide mimetics including 4-methyl-N-{(S)-1-oxo-3-phenyl-1-[((S,E)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl)amino]propan-2-yl}piperazine-1-carboxamide (also known as K777).

Multistep Synthesis of a 3(2H)-Furanone Featuring a Green Aldol Condensation

A multistep synthesis of a novel arylidene 3(2H)-furanone has been designed and optimized for the second-year organic laboratory. The three-step sequence consists of a nucleophilic substitution, intramolecular cyclization, and acid-catalyzed aldol condensation, and can be carried out within two 3 h laboratory periods. The final product is a crystalline solid that does not require purification and bears structural resemblance to natural products with medicinal properties. Reactions are performed at room temperature, and the aldol condensation takes place without the need for organic solvent, providing students hands-on experience with chemical transformations that illustrate green chemistry principles.

Synthesis of Polysubstituted 5,6-Dihydropyrrolo[3,4-B]Pyrrol-4(1h)-Ones from 2-[Aryl(Azido)Methyl]-1h-Pyrrole-3-Carboxylates Via a Concise Three-Step Sequence

Synthesis of Polysubstituted 5,6-Dihydropyrrolo[3,4-B]Pyrrol-4(1h)-Ones from 2-[Aryl(Azido)Methyl]-1h-Pyrrole-3-Carboxylates Via a Concise Three-Step Sequence

Industry 4.0: Predicting lead conversion opportunities with machine learning in small and medium sized enterprises

The crisis caused by COVID-19 accelerated processes of changes in the global economy, leading to changes in companies in structures, business models and routines. Small and Medium Enterprises (SME) in particular have faced challenges in finding paths for the journey of digital transformation and adaptation to the industry 4.0 era, which turns integration a key factor. The goal of this work is to predict the likelihood of conversion using Machine Learning (ML), with the purpose of improving the process of converting opportunities in SME in the education sector. The work is based on the Digital Transformation Model for SME (MTD_PMEs), a specific approach in ML technology and Knowledge Discovery in Databases (KDD). The methodology involves a three-step sequence of the KDD_AZ process. Data were collected from a university center in southern Brazil. Results indicate that the 8 attributes used are relevant for forecasting lead conversion and that the chosen technique, Logistic Regression reached a gross precision of 100%, implying an increase in the conversion rate, time savings for the teams and filter leads “unlikely”, helping marketing improvements in its targeting and providing qualified leads.

Design of a bifunctional TEMPO-tertiary amine mesoporous silica catalyst for the three-step cascade synthesis of a chromene derivative

A key challenge is design of materials and processes whereby competing reagents or conditions do not harm the multi-step sequence, thus allowing for more efficient chemical synthesis with elimination of work-up and separation steps. In this work, a three-step reaction cascade is performed using a porous bifunctional dimethylpropylamine-TEMPO-MCM41 catalyst, converting the commodity chemicals benzyl alcohol, sodium hypochlorite, and malononitrile to a biologically active anti-cancer, and anti-malarial 2-amino-chromene derivative. The cascade first utilizes a TEMPO-catalyzed oxidation of benzyl alcohol to benzaldehyde with NaOCl as the terminal oxidant. This is followed by a two-step, dual base catalyzed Knoevenagel condensation with malononitrile followed by a Michael addition with lawsone. Optimal conditions converting benzyl alcohol to 2-amino-5,10-dioxo-4-phenyl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile include the delayed addition of malononitrile and lawsone during the three-step reaction sequence, which results in a 2-amino-chromene yield of over 80%. The importance of stepwise reagent addition is rationalized due to the unfavorable adsorption of acidic lawsone on the surface-grafted base catalyst. Tertiary Brønsted base sites of dimethylpropylamine outperform the more Lewis basic primary propylamine functionalized catalyst. This work outlines a simple and effective method for generating mesoporous materials with two types of active sites via co-condensation and thiol-ene coupling procedures.

Bibenzyl synthesis in Cannabis sativa L.

This study focuses on the biosynthesis of a suite of specialized metabolites from Cannabis that are known as the 'bibenzyls'. In planta, bibenzyls accumulate in response to fungal infection and various other biotic stressors; however, it is their widely recognized anti-inflammatory properties in various animal cell models that have garnered recent therapeutic interest. We propose that these compounds are synthesized via a branch point from the core phenylpropanoid pathway in Cannabis, in a three-step sequence. First, various hydroxycinnamic acids are esterified to acyl-coenzyme A (CoA) by a member of the 4-coumarate-CoA ligase family (Cs4CL4). Next, these CoA esters are reduced by two double-bond reductases (CsDBR2 and CsDBR3) that form their corresponding dihydro-CoA derivatives from preferred substrates. Finally, the bibenzyl backbone is completed by a polyketide synthase that specifically condenses malonyl-CoA with these dihydro-hydroxycinnamoyl-CoA derivatives to form two bibenzyl scaffolds: dihydropiceatannol and dihydroresveratrol. Structural determination of this 'bibenzyl synthase' enzyme (CsBBS2) indicates that a narrowing of the hydrophobic pocket surrounding the active site evolved to sterically favor the non-canonical and more flexible dihydro-hydroxycinnamoyl-CoA substrates in comparison with their oxidized relatives. Accordingly, three point mutations that were introduced into CsBBS2 proved sufficient to restore some enzymatic activity with an oxidized substrate, in vitro. Together, the identification of this set of Cannabis enzymes provides a valuable contribution to the growing 'parts prospecting' inventory that supports the rational metabolic engineering of natural product therapeutics.

1,3]-Dithiolo-[4,5-d][1,3-dithiole]-2,5-dione

AbstractA safe, three-step reaction sequence to [1,3]-dithiolo-[4,5-d][1,3-dithiole]-2,5-dione starting from carbon disulfide is presented. Optimized reaction conditions, rigorous purification, and full characterization of all intermediates provide reproducibly a final product of superior quality with a melting point of 181 °C (dec.).

Dexamethasone Electroanalysis at Copper Nanoparticle Modified Electrodes Formed Using a Potentiostatic Triple Pulse Sequence

Our goal is the electrochemical evaluation of anti-inflammatory/antioxidant therapeutic agents with quantification realised via electrode modifiers which facilitate detection at the appropriate level and selectivity for operation in complex clinical matrices. The analyte dexamethasone, a glucocorticosteroid and potent anti-inflammatory agent found to play a role in the treatment of severe COVID-19 cases [1], was examined in alkaline conditions at bare and copper nanoparticle (CuNP) modified glassy carbon electrodes (GCE). A three-step template free potentiostatic pulse sequence [2] was applied for the first time, realising electrodeposition of copper nanoparticles (CuNPs). This method comprised pre-treatment (E1) to remove adsorbed Cu2+ ions from the electrode surface, a nucleation pulse (E2) to seed Cu nuclei and finally a growth pulse (E3) to allow the formation of the CuNPs from the seeded nuclei, via diffusion. Optimisation was carried whereby E2 and E3 were varied along with their corresponding pulse times, where at the optimised CuNPs, the dexamethasone reduction response increased 4.5-fold, relative to the bare GCE.

Integrated Multistep Photochemical and Thermal Continuous Flow Reactions: Production of Bicyclic Lactones with Kilogram Productivity

Combining continuous photochemistry and flow reactions in high-temperature/high-pressure water has enabled us to integrate a multistep sequence into a single process with a reduction in reaction time to <10 min compared to >24 h in batch. At the same time, applying this approach to different substrates has allowed us to increase previously low yields to levels high enough to make these reactions potentially useful for multistage synthesis. In this paper, we describe the [2 + 2] cycloaddition/fragmentation of 3,4,5,6-tetrahydrophthalic anhydride and propargyl alcohol and analogous compounds leading to bicyclic lactones to demonstrate how photochemistry and thermal chemistry can be combined using continuous flow techniques to create complex structures on a relatively large scale. We show how photochemical and high-temperature water flow reactors can be used to carry out a three-step reaction sequence as a single integrated and continuous process. The reaction time has been reduced by exploiting the enhanced acidity of high-temperature water/acetonitrile mixtures. The overall process is demonstrated on an equivalent productivity of a >1 kg/day productivity using lab-scale equipment. Our approach should be simple to scale up in an appropriate facility, for larger scale production of chemicals. Process analytical technology and modeling were used to support the reaction development, while UV and IR time-resolved spectroscopies have been used to provide a deeper understanding of the reaction mechanism.

A new approach for the synthesis of novel naphthoquinone chalcone hybrid compounds

A facile and efficient synthesis of novel naphthoquinone-based chalcone hybrids (7 and 24) via the microwave-assisted one-pot three-component reactions of 2-substituted-1,4-naphthoquinones, N,N-dimethylformamide dimethyl acetal (DMF-DMA), and acetophenone derivatives has been reported. Whereas the synthesis of hybrids 7 proceeded via a condensation, 1,4-addition, rotation, elimination, and [1,3]-H shift sequence of steps, the synthesis of hybrids 24 were formed through a three-step sequence including condensation, 1,4-addition, and elimination reactions.

A Convenient Approach to meso-Uracil–4,4-Difluoro-4-bora-3a, 4a-diaza-s-indacene Derivatives

AbstractAn effective and convenient protocol for the synthesis of 1-substituted uracil-6-carbaldehyde derivatives has been developed. A three-step sequence permits the preparation of uracil-6-carbaldehydes with various substituents at the N-1 in large quantities by using low-cost precursors. The aldehyde-functionalized uracils served as useful precursors for the preparation of meso-(1-substituted 6-uracil)-derivatives of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY). In this way, regioselectively functionalized BODIPYs with a direct connection to a nucleobase were prepared in yields of 30–45%. MALDI-TOF mass spectrometry, NMR, UV/vis absorption, and steady-state and time-­resolved fluorescence spectroscopies were used to characterize the structures and the spectroscopic/photophysical properties of the resultant dyes.

Titanium and Cobalt Bimetallic Radical Redox Relay for the Isomerization of N-Bz Aziridines to Allylic Amides.

Herein a bimetallic radical redox-relay strategy is employed to generate alkyl radicals under mild conditions with titanium(III) catalysis and terminated via hydrogen atom transfer with cobalt(II) catalysis to enact base-free isomerizations of N-Bz aziridines to N-Bz allylic amides. This reaction provides an alternative strategy for the synthesis of allylic amides from alkenes via a three-step sequence to accomplish a formal transpositional allylic amination.