One-pot Multistep Synthesis Research Articles

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light.

Spiro-heterocyclic indolenines are privileged scaffolds widely present in numerous indole alkaloids. Here, we develop a novel approach for the one-pot multistep synthesis of different spiro[indole-isoquinolines]. The protocol proposed involves the visible light mediated oxidation of N-aryl tertiary amines using bromochloroform with the generation of a reactive iminium species, which reacts with an isocyanide and an electron-rich aniline in a three-component Ugi-type reaction to give an α-aminoamidine. This compound might undergo an additional visible light-mediated oxidation to furnish a second iminium intermediate, which acts as electrophile in an intramolecular electrophilic aromatic substitution giving the final spiro-indolenine. The scope of the process has been investigated with respect to all three components. Simple operations, mild conditions, and good yields make this strategy a convenient and sustainable way to obtain novel spiro-indolenine derivatives.

Water-mediated one-pot multi-step synthesis of chiral 1,3-diarylpropan-1-ols by the asymmetric hydrofunctionalisation of simple alkynes

An enantioselective hydration–condensation-asymmetric transfer hydrogenation cascade process of simple alkynes and aldehydes in only water to prepare chiral 1,3-diarylpropan-1-ols has been developed.

One-pot multistep synthesis of 1-fluoroalkylisoquinolines and fused fluoroalkylpyridines from N-fluoroalkyl-1,2,3-triazoles

Microwave heating of N-fluoroalkyl-1,2,3-triazoles proceeding via ketenimines and difluoroazadienes provided 1-fluoroalkyl-3-fluoroisoquinolines.

One-pot multi-step synthesis of gamma-valerolactone from furfuryl alcohol: Microwave vs continuous flow reaction studies

Mesoporous materials Al-SBA-15 have been synthesized and functionalized with different Al/Zr molar ratio and 0.5% Au and Ru, respectively, by a mechanochemical approach. Textural and structural properties of synthesized materials have been analysed by TEM (Transmission Electron Microscopy), SEM (Scanning Electron Microscopy), XPS (X-ray photoelectron spectroscopy), XRD (X-ray Diffraction) and N2 adsorption/desorption technique, among others. The catalytic activity of synthesized materials has been evaluated in the one-pot conversion of furfuryl alcohol (FAL) employing 2-propanol as H-donor solvent to obtain γ-valerolactone (GVL), both under microwave-assisted irradiation (CEM Discover® 2.0) and continuous flow conditions (Phoenix Flow ReactorTM, ThalesNano). All materials displayed conversions up to 99%, with a GVL selectivity of ca. 20–41% after one-hour reaction time. The study of the reusability of the materials showed a good GVL production during 3 reaction cycles employing both microwave-assisted and flow reaction conditions.

One-pot multi-step synthesis of high-aspect-ratio Cu nanowires based on an environment-friendly manner for low-cost and high-performance transparent conductive films

High-aspect-ratio Cu nanowires (NWs) were synthesized based on an environment-friendly synthesis method in which aqueous Cu–Cl complexes were reduced to Cu atoms in a weak ascorbic acid solution. Constant reaction temperatures led to many reduced Cu atoms relative to NWs and then the synthesized Cu atoms were deposited on the end and side faces of Cu NWs, resulting in low aspect ratios. Two-step temperature synthesis was suggested to suppress Cu atoms during the Cu NW growth. High temperatures during the early reaction stage maximized NW seeds and low temperatures in the late stage decreased the number of Cu atoms under precisely controlled temperature and temperature drop time, leading to Cu deposition on the end faces rather than side faces. Additionally, optimum Cu-source additions continuously facilitated the preferential growth in length of Cu NWs. The one-pot multi-step synthesis controlled the reduction rate of Cu complexes and substantially increased the aspect ratio of Cu NW from 313 to 760, showing that the precise control was suitable for changing the NW sizes. Finally, transparent conductive films comprising the NWs showed high performances (transmittance = 90.8 %, sheet resistance = 94 Ω/sq).

Practical One-Pot Multistep Synthesis of 2H-1,3-Benzoxazines Using Copper, Hydrogen Peroxide and Triethylamine.

In this article, we describe simple one-pot syntheses of 2H-1,3-benzoxazines from ketones utilizing an imino-pyridine directing group (R1R2-C=N-CH2-Pyr), which promotes a Cu-directed sp2 hydroxylation using H2O2 as oxidant and followed by an oxidative intramolecular C-O bond formation upon addition of NEt3. This synthetic protocol is utilized in the gram scale synthesis of the 2H-1,3-benzoxazine derived from benzophenone. Mechanistic studies reveal that the cyclization occurs via deprotonation of the benzylic position of the directing group to produce a 2-azallyl anion intermediate, which is oxidized to the corresponding 2-azaallyl radical before the C-O bond formation event. Understanding of the cyclization mechanism also allowed us to develop reaction conditions that utilize catalytic amounts of Cu.

Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids.

The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.

A Bifunctional Metal/Acid Catalyst for One-pot Multistep Synthesis of Pharmaceuticals

Financial support by the Ministerio de Economia y Competitividad, Programa Severo Ochoa (SEV2016-0683) and Ministerio de Ciencia Innovacion y Universidades, Programa Estatal de Generacion de Conocimiento (PGC2018-101247-B-100) are gratefully acknowledged.

One-pot multistep synthesis of bipolar carbazolo-phenazines: Hydrogen bond control of Diels-Alder cycloaddition and application for fluoride sensing

Access to novel bipolar carbazolo-phenazines is demonstrated by one-pot IBX-initiated multistep cascade, which involves oxidation of 2-naphthols to 1,2-naphthoquinones, Diels-Alder cycloaddition, aerial dehydroaromatization and cyclocondensation. With unprotected dienic indolylacrylates, NH⋯O hydrogen bonding in the transition state controls the product selectivity almost exclusively in favor of Diels-Alder cycloaddition over the competing Michael addition. The utility of one of the carbazolo-phenzines as applied to selective naked-eye sensing of fluoride is demonstrated.

Increased availability of NADH in metabolically engineered baker's yeast improves transaminase-oxidoreductase coupled asymmetric whole-cell bioconversion.

BackgroundSaccharomyces cerevisiae can be engineered to perform a multitude of different chemical reactions that are not programmed in its original genetic code. It has a large potential to function as whole-cell biocatalyst for one-pot multistep synthesis of various organic molecules, and it may thus serve as a powerful alternative or complement to traditional organic synthetic routes for new chemical entities (NCEs). However, although the selectivity in many cases is high, the catalytic activity is often low which results in low space-time-yields. In the case for NADH-dependent heterologous reductive reactions, a possible constraint is the availability of cytosolic NADH, which may be limited due to competition with native oxidative enzymes that act to maintain redox homeostasis. In this study, the effect of increasing the availability of cytosolic NADH on the catalytic activity of engineered yeast for transamination-reduction coupled asymmetric one-pot conversion was investigated.ResultsA series of active whole-cell biocatalysts were constructed by over-expressing the (S)-selective ω-transaminase (VAMT) from Capsicum chinense together with the NADH-dependent (S)-selective alcohol dehydrogenase (SADH) originating from Rhodococcus erythropolis in strains with or without deletion of glycerol-3-phosphate dehydrogenases 1 and 2 (GPD1 and GPD2). The yeast strains were evaluated as catalysts for simultaneous: (a) kinetic resolution of the racemic mixture to (R)-1-phenylethylamine, and (b) reduction of the produced acetophenone to (S)-1-phenylethanol. For the gpd1Δgpd2Δ strain, cell metabolism was effectively used for the supply of both amine acceptors and the co-factor pyridoxal-5′-phosphate (PLP) for the ω-transaminase, as well as for regenerating NADH for the reduction. In contrast, there was nearly no formation of (S)-1-phenylethanol when using the control strain with intact GPDs and over-expressing the VAMT-SADH coupling. It was found that a gpd1Δgpd2Δ strain over-expressing SADH had a 3-fold higher reduction rate and a 3-fold lower glucose requirement than the strain with intact GPDs over-expressing SADH.ConclusionsOverall the results demonstrate that the deletion of the GPD1 and GPD2 genes significantly increases activity of the whole-cell biocatalyst, and at the same time reduces the co-substrate demand in a process configuration where only yeast and sugar is added to drive the reactions, i.e. without addition of external co-factors or prosthetic groups.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0430-x) contains supplementary material, which is available to authorized users.

ChemInform Abstract: Electron‐Rich Aromatics under Ball Milling: Oxidative Aryl‐Iodination Using I2‐Oxone and Biarylation with I2.

Abstract We report here a simple, efficient, and environmentally friendly methodology for electrophilic aryl-iodination of electron-rich arenes using I2-oxone under ball milling. The reactions work efficiently under solvent-free conditions at room temperature. We have also shown that iodine could be used as catalyst for metal-free biaryl coupling of a few electron-rich substrates. In addition, one-pot multistep synthesis has been demonstrated for one substrate.

Electron-Rich Aromatics Under Ball Milling: Oxidative Aryl-iodination Using I2-Oxone and Biarylation with I2

We report here a simple, efficient, and environmentally friendly methodology for electrophilic aryl-iodination of electron-rich arenes using I2-oxone under ball milling. The reactions work efficiently under solvent-free conditions at room temperature. We have also shown that iodine could be used as catalyst for metal-free biaryl coupling of a few electron-rich substrates. In addition, one-pot multistep synthesis has been demonstrated for one substrate.

CDP-Ethanolamine and CDP-Choline: one-pot synthesis and 31P NMR study

Herein we report a one-pot multi-step synthesis of the cofactors CDP-Ethanolamine and CDP-Choline starting from cytidine 5′-monophosphate and using commercially available and/or easily prepared reagents. While studying the 31P NMR spectrum of CDP-Ethanolamine, an unexpected characteristic for a pyrophosphate diester was observed as it showed a singlet or two doublets depending upon the pH. Therefore, further NMR studies were undertaken to investigate the pH dependence of the peak splitting pattern and measure the acid dissociation constants of the compounds.

One-Pot Multistep Synthesis of Trisubstituted Alkenes from N-Tosylhydrazones and Alcohols

A one-pot procedure for the synthesis of trisubstituted alkenes from <i>N</i>-tosylhydrazones and alcohols is reported. This procedure combines the aerobic oxidation reaction and Wittig reaction in one pot, which avoids using of environmentally toxic oxidants and isolation of the intermediates. The simple procedure makes it very attractive for the synthesis of trisubstituted alkenes when alcohols are used as starting materials. A variety of trisubstituted alkenes as well as trifluoromethyl-substituted alkenes were obtained in moderate to good yields (up to 84%) with good <i>E</i>-selectivity (up to 99%).

One-pot multistep synthesis of 3,4-fused isoquinolin-1(2H)-one analogs

We have developed a robust approach for the synthesis of 3,4-fused isoquinolin-1(2H)-one analogs. A benzonitrile or a nicotinonitrile bearing an ortho-substituent, such as –OH, –SH, or –NHR (R=alkyl or aryl) can be deprotonated by KOtBu and then reacted with methyl 2-(bromomethyl)benzoate (8) to form its corresponding O-, S-, or N-alkylation product. The product thus formed is then treated with KOtBu again to initiate a cascade process that will lead to the formation of its corresponding 3,4-fused isoquinolin-1(2H)-one. This multistep synthesis as well as the final product purification is achieved in a one-pot manner.

The Baylis–Hillman Adducts as Valuable Source for One‐Pot Multi‐Step Synthesis: A Facile Synthesis of Substituted Piperidin‐2‐ones

AbstractA facile, convenient, and one‐pot multi‐step synthesis of substituted piperidin‐2‐ones from the Baylis–Hillman alcohols derived from various aldehydes and acrylonitrile, involving Johnson–Claisen rearrangement, reduction of an α,β‐unsaturated nitrile moiety into the saturated amine‐skeleton, followed by cyclization, in an operationally simple procedure, is described.

The Baylis−Hillman Acetates as a Valuable Source for One-Pot Multistep Synthesis: A Facile Synthesis of Functionalized Tri-/Tetracyclic Frameworks Containing Azocine Moiety

The Baylis-Hillman acetates have been conveniently transformed into tri-/tetracyclic heterocyclic frameworks containing an important azocine moiety via one-pot multistep protocol involving alkylation, reduction, and cyclization sequence.

One-pot multi-step synthesis: a challenge spawning innovation

Creating one-pot synthetic routes is a challenge that is already spawning new chemistry, enzymes, materials, and mechanistic insight. Through one-pot reactions, the chemical products that add value to our lives can be produced with less waste and greater economic benefits. Within this Emerging Area, we describe models for designing one-pot reactions as well as advanced catalysts created to facilitate their realization.

Palladium on activated carbon: a valuable heterogeneous catalyst for one-pot multi-step synthesis

Pd on activated carbon (Pd/C) is demonstrated to be active and selective as one single catalyst in a series of one-pot multi-step reactions. The carefully chosen Pd/C catalysts were successfully applied in domino and tandem reactions involving (1) Heck reactions and hydrogenations for the synthesis of (a) dibenzyl and (b) 2-styryl-phenylamine, (2) Sonogashira coupling and intramolecular heteroannulation to form indole ring systems, and (3) Heck and Suzuki coupling reactions to produce 4-styryl-biphenyl. Total yields between 72 and 93% could be achieved. All reaction steps were performed with one and the same Pd/C catalyst, solvent, and additives. Temperature and pressure were adjusted as necessary. The order of the different reactions, the consecutive addition of educt(s) and optimization of reaction conditions was found to be crucial.