Heterocyclic Alcohols Research Articles

Boosting electrocatalytic oxidation of heterocyclic alcohols with low usage aminoxyl radicals via MOF‐derived NiOOH

AbstractAminoxyl‐mediated electrocatalysis offers a sustainable approach for the oxidation of alcohols to carboxylic acids. However, the high dosage of aminoxyl radicals and the limiting current density hinder the practicality of industrial application. Herein, a nickel‐based electrocatalyst (Ni‐tpdc) was synthesized on a three‐dimensional porous graphite felt substrate. Taking advantage of the synergistic effect of the electrochemically activated Ni‐tpdc/GF electrocatalyst with 4‐acetamido‐TEMPO, the yield of 4‐pyridinecarboxylic acid was up to 99% with only 1 mol% ACT. A series of in situ measurements showed that NiOOH enhanced the activity of the intrinsic electrocatalyst. In addition, the synergistic system was extended to the oxidation of various heterocyclic alcohols. The scale‐up synthesis of chiral acid (LEV‐CO2H) was achieved in an improved electrolyzer with a yield of 95.4%, enantiomeric retention of 99.2%, and space–time yield of 34.12 kg/m3 h. The practicality and effectiveness of this synergistic electrocatalytic strategy in practical electrosynthesis was further demonstrated.

One-pot Tandem Synthesis and Spontaneous Product Separation of N-heterocycles based on Bifunctional Small-molecule Photocatalyst.

Homogeneous and heterogeneous reactions wherein the resulting products remain dissolved in solvents generally require complicated separation and purification process, despite the advantage of heterogeneous systems allowing retrieval of catalysts. Herein, we have developed an efficient approach for the one-pot tandem synthesis of quinazolines, quinazolinones and benzothiadiazine 1,1-dioxides from alcohols and amines utilizing a bifunctional bipyridinium photocatalyst with redox and Lewis acid sites using air as an oxidant. Through solvent-modulation strategy, the photocatalytic system exhibits high performance and enables most products to separate spontaneously. Consequently, the homogeneous catalyst can be reused by direct centrifugation isolation of the products. Notably, the method is also applicable to the less active substrates, such as heterocyclic alcohols and aliphatic alcohols, and thus provides an efficient and environmentally friendly photocatalytic route with spontaneous separation of N-heterocycles to reduce production costs and meet the needs of atomic economy and green chemistry.

Copper(II) quinoxolinol imidazolium complexes in catalytic oxidation of benzylic and heterocyclic alcohols.

A novel copper(II) quinoxolinol complex has been prepared using a condensation reaction based on previous studies. The copper(II) quinoxolinol salen complex has been applied as a catalyst using tert-butyl hydroperoxide (TBHP) as the oxidant, demonstrating that benzylic and heterocyclic alcohols can be converted efficiently to the corresponding aldehydes. Excellent yields can be achieved (up to 99%) within a short reaction time and with great tolerance for functional groups.

Borrowing hydrogen C-alkylation with secondary saturated heterocyclic alcohols.

The borrowing hydrogen methodology (BH) has emerged as a powerful tool for the rapid construction of C-C bonds, offering a greener alternative to traditional multi-step syntheses. This methodology involves the activation of inactivated alcohols followed by condensation or aldolization, ultimately leading to the regeneration of the saturated product. Herein, we report the C-alkylation of a hindered ketone with challenging secondary saturated heterocyclic alcohols. Our study encompasses the optimization of reaction conditions using either an iridium or a ruthenium catalyst and exploration of substrate scope. We demonstrate the efficient synthesis of substituted pyrrolidines and piperidines directly from a triol precursor, showcasing the versatility of this methodology. Moreover, we illustrate the post-functionalization of BH products, significantly broadening their chemical utility.

Phosphate-supported palladium single atom and nanoparticle boost ambient temperature tandem hydrogenolysis–hydrogenation of furan alcohols/aldehydes

Developing a one-pot method for tandem hydrogenolysis–hydrogenation of biomass-derived furan-based alcohols to methyltetrahydrofurans is challenging but crucial for synthesizing sustainable biofuels and chemicals. Herein, we report the efficient hydrogenolysis–hydrogenation of furan alcohol to 2-methyltetrahydrofuran using a phosphate-supported synergistic palladium single atom and nanoparticle at an ambient temperature. Comprehensive characterizations and theoretical calculations reveal that in situ H2 heterolysis at the palladium single atom–AlPO4 interface generates frustrated Lewis H+–H− pairs, which selectively cleaves the C–OH bond in furan alcohol to form 2-methylfuran, and H atoms on the palladium nanoparticle surface promotes the subsequent CC hydrogenation of 2-methylfuran to 2-methyltetrahydrofuran. Additionally, the catalyst shows generality for various furan and heterocyclic alcohols. Furthermore, the catalyst exhibits excellent activity in the hydrogenation–hydrogenolysis–hydrogenation of furan aldehydes to methyltetrahydrofurans. The results provide a highly efficient reaction for synthesizing methyltetrahydrofurans at ambient temperature, which has excellent potential for industrial applications.

Enantioselective Regulation of Short‐Chain Dehydrogenases via Key Sites in its Loop and Adjacent Regions for the Enantiodivergent Reduction of Difficult‐To‐Reduce Ketones

AbstractShort‐chain dehydrogenases (SDRs) are powerful catalysts for the asymmetric reduction of prochiral ketones in pharmaceutical products. Herein, through gene mining and evolutionary analysis, we obtained two major types of SDRs (SDR‐1 and SDR‐2) for the enantioselective complementary reduction of N‐Boc‐piperidone, which gives the corresponding product (R)‐ or (S)‐N‐Boc‐piperidol, an intermediate of the interleukin inhibitor and lymphoma treatment drug (imbruvica), respectively. By integrating multiple sequence alignment, site‐directed mutagenesis and computational modeling, we proposed a “loop regulation” mechanism for the enantioselective control of SDRs, through which residues in the loop region could potentially fine‐tune their enantioselectivity. Further, site‐directed mutagenesis assays showed that two key residues (L201 and F205 for SDR‐1, F92 and H93 for SDR‐2) in the loop and its adjacent region played critical roles in fine‐tuning the enantioselectivity of SDRs. Understanding this mechanism of SDR stereo preference in catalyzing asymmetric reduction, we further switched the enantioselectivity of the homologous enzymes. The obtained enzymes catalyzed the enantiodivergent synthesis of chiral heterocyclic alcohols with different ring sizes and substituents (25–99% conversion and 25–99% ee (R/S)), including piperidols, 4‐hydroxy azepanes, 3‐hydroxy azepanes and pyrrolidinols. These findings could potentially guide future attempts at protein engineering of stereoselective SDRs.

Green synthesis of (S)-1-(furan-2-yl)propan-1-ol from asymmetric bioreduction of 1-(furan-2-yl)propan-1-one using whole-cell of Lactobacillus paracasei BD101.

Chiral heterocyclic alcohols are important precursors for production of pharmaceutical medicines and natural products. (S)-1-(furan-2-yl)propan-1-ol ((S)-2) can be used production of pyranone, which can be used in the synthesis of sugar analogues, antibiotics, tirantamycines, and anticancer drugs. The synthetic approaches for (S)-2, however, have substantial difficulties in terms of inadequate enantiomeric excess (ee) and gram scale synthesis. Moreover, the biocatalytic synthesis of (S)-2 is unknown until now. In this study, the synthesis of (S)-2 was carried out by performing the asymmetric bioreduction of 1-(furan-2-yl)propan-1-one (1) using the Lactobacillus paracasei BD101 biocatalyst obtained from boza, a grain-based fermented beverage. (S)-2 was obtained with >99% conversion, >99% ee, and 96% yield under the optimized conditions. Furthermore, in 50 h, 8.37 g of 1 was entirely transformed into (S)-2 on gram scale (96% isolated yield, 8.11 g). This is the first report on the high-gram scale biocatalyzed synthesis of enantiopure (S)-2. These data suggest that L.paracasei BD101 can be used to bioreduction of 1 in gram scale and efficiently produce (S)-2. Furthermore, these findings laid the base for future study into the biocatalytic production of (S)-2. It was particularly notable as it was the highest known to date optical purity of (S)-2 generated by asymmetric reduction using a biocatalyst. This work offers a productive environmentally friendly method for producing (S)-2 using biocatalysts.

Analysis of thermodynamics, kinetics, and reaction pathways in the amination of secondary alcohols over Ru/SiO2

This work considers the Ru-mediated amination of secondary alcohols with ammonia in vapor and liquid media. We map thermodynamic constraints, and we probe the impacts of species partial pressure, residence time, and reaction temperature on rate, selectivity, and catalyst stability. Alcohol amination consumes no H2, and H2 has no significant impact on amination kinetics; however, operating under H2 benefits Ru stability. Primary amine selectivity increases with ammonia pressure and alcohol conversion, and the latter observation is consistent with the formation of primary amines through a network of sequential reactions. Unfortunately, primary amines are susceptible to secondary deamination to form hydrocarbons. As is typical of processes that seek to isolate a reactive intermediate, the main selectivity challenge here is identifying residence times that are long enough to accumulate high substrate conversion but short enough to avoid secondary deamination. In general, moderate residence times will maximize the production of primary amines. Insights extend across a broad substrate scope, and we observe 70 – 90% yield of primary amines from linear, cyclic, and heterocyclic alcohols. That said, heterocyclic alcohols appear susceptible to product inhibition, so achieving high conversions requires longer residence times and/or increased ammonia pressures.

A Catecholaldimine-Based NiII-Complex as an Effective Catalyst for the Direct Conversion of Alcohols to trans-Cinnamonitriles and Aldehydes.

A nickel(II) complex [Ni(HL)2] 1 was synthesized by treatment of a new catecholaldimine-based ligand with NiCl2·6H2O in methanol at room temperature. Complex 1 showed excellent catalytic activity where aromatic and heterocyclic alcohols were rapidly converted into trans-cinnamonitrile in a one-pot manner via oxidative olefination in the presence of KOH. The potential of the disclosed catalyst and the results obtained for the direct conversion of alcohols to two different functionalities (trans-cinnamonitrile and aldehydes) are well supported by DFT studies.

Regulating the stereoselectivity of medium-chain dehydrogenase/reductase by creating an additional active pocket accommodating prochiral heterocyclic ketones.

Medium chain dehydrogenase/reductase (MDR) is a robust catalyst for the asymmetric synthesis of chiral heterocyclic alcohols, essential building blocks in pharmaceuticals. However, the regulatory mechanism of stereoselective complementary reduction of heterocyclic ketones by carbonyl reductase (CR) is unclear. Structure-guided creation of an additional substrate-binding active pocket inversed the stereoselectivity of SpCR from Spathaspora passalidarum. The mutant m48 showed improved catalytic activity towards the 12 tested heterocyclic ketones (conversion rate >99%, ee value > 99%). Hence, we regulated the stereoselectivity of MDR by creating an active pocket suitable for substrate localisation. This strategy has a guiding significance in addition to the conventional method for stereoselectivity modification of MDR.

Heteroployacid on the composite of boehmite and polyionic liquid as a catalyst for alcohol oxidation and tandem alcohol oxidation Knoevenagel condensation reactions

Using boehmite as an available and low-cost natural compound, a bi-functional catalytic composite is prepared through vinyl-functionalization of boehmite, followed by polymerization with the as-prepared bis-vinylimidazolium bromide ionic liquid and supporting of phosphotungstic acid. The catalyst was characterized via ICP, XRD, TGA, FTIR, SEM/EDS and elemental mapping analysis and applied for promoting alcohol oxidation reaction and one-pot tandem alcohol oxidation/Knoevenagel condensation reaction in aqueous media under mild reaction condition. The results indicated high catalytic activity of the catalyst for both reactions. This protocol showed high generality and aliphatic, aromatic and heterocyclic alcohols could be applied as substrates to furnish the corresponding products in high to excellent yields. Furthermore, hot filtration test confirmed true heterogeneous nature of the catalysis. The catalyst could also be recovered readily and reused for at least five runs of the reaction with low loss of the activity and phosphotungstic acid leaching upon each run.

Heterogeneous catalytic reduction of substituted 5-acyl-1,3-dioxanes

Objectives. To study the hydrogenation of substituted 5-acyl-1,3-dioxanes in the presence of metal-containing catalysts (Pt/Re, Pd/C, Ni/kieselguhr, and Ni/Mo).Methods. In order to determine the qualitative and quantitative composition of the reaction masses, the following analysis methods were used: gas-liquid chromatography (using the Kristall 2000 hardware complex); mass-spectroscopy (using Chromatec-Kristall 5000M device with NIST 2012); nuclear magnetic resonance (NMR) spectrometry (using Bruker AM-500 device with operating frequencies of 500 and 125 MHz).Results. Hydrogenation of substituted 5-acyl-1,3-dioxanes obtained by condensation of carbonyl compounds with paraformaldehyde and sulfuric acid was used to synthesize heterocyclic alcohols in the presence of metal-containing catalysts with a conversion of the initial ketones of 60–90% and a formation selectivity of target products of 70–90%. Substances were analyzed and confirmed by gas-liquid chromatography, mass spectrometry and NMR spectroscopy.Conclusions. The best catalyst for the reduction of substituted 5-acyl-1,3-dioxanes is Pd/C. By using this catalyst, it is possible to achieve a high selectivity for the formation of the corresponding heterocyclic alcohols at a conversion rate of the initial ketones of 60–90%.

Acceptorless dehydrogenation of alcohols to carboxylic acids by palladium nanoparticles supported on NiO: delving into metal-support cooperation in catalysis.

In this work, we have developed a simple NiO-supported Pd nanocatalyst (Pd@NiO) for oxidant-free dehydrogenative oxidation of primary alcohols to carboxylic acids along with hydrogen gas as a byproduct. The catalyst has been characterized by techniques like XRD, HRTEM, SEM-EDX, XPS and ICP-AES. The nanostructured Pd@NiO material showed excellent dehydrogenative oxidation activity and outperformed the activity of free NiO or Pd nanoparticles supported on silica/carbon as a catalyst, which could be attributed to synergistic effect of Pd and NiO. A diverse range of aromatic and aliphatic primary alcohols could be efficiently converted to their corresponding carboxylates in high yields with a catalyst loading as low as 0.08 mol%. Notably, highly challenging biomass derived heterocyclic alcohols such as furfuryl alcohol and piperonyl alcohol can also be efficiently converted to their corresponding acids. Moreover, our catalyst can convert benzyl alcohol to benzoic acid on a gram scale with 89% yield. Interestingly, the H2 gas liberated in the reaction can also be used as a substrate for the hydrogenation of 3a to 4a in 65% yield. The nanostructured catalyst is highly reusable and no significant decrease in activity was observed after six reaction cycles. A kinetic study revealed that the reaction followed first-order kinetics with a rate constant of k = 1.47 × 10-4 s-1, under optimized conditions. The extent of reactivity of different functionalities towards dehydrogenation was also investigated using a Hammett plot showing good linearity.

Scope, Limitations and Mechanistic Analysis of the HyperBTM‐Catalyzed Acylative Kinetic Resolution of Tertiary Heterocyclic Alcohols**

AbstractThe full scope and limitations of the catalytic acylative kinetic resolution of a range of tertiary heterocyclic alcohols (78 examples,sup to >200) is reported under operationally‐simple conditions, using low loadings of a commercially available Lewis basic isothiourea catalyst, HyperBTM (generally 1 mol %). The protocol is highly effective for the kinetic resolution of 3‐substituted 3‐hydroxyoxindole and α‐substituted α‐hydroxylactam derivatives bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. The full power of this methodology has been showcased through the synthesis of highly enantioenriched biologically‐active target compounds in both enantiomeric forms. To provide further insight into the reaction mechanism, a detailed kinetic analysis of this Lewis base‐catalyzed acylation of tertiary alcohols is reported using the variable time normalization analysis (VTNA) method.

Synthesis of heterocyclic bromacetylene alcohols and their acryl -, methacryl ethers

The article presents a method for obtaining heterocyclic bromoacetylenic alcohols by the action of sodium hypobromide on cyclic and heterocyclic acetylene alcohols, as well as their acrylic and methacrylic esters using lithium aluminum complexes. The composition and structure of the obtained products were confirmed by the data of elemental analysis, IR and PMR spectra. As a result of the study, it was found that in the presence of lithium aluminum hydride, the product yield in all cases is higher than 80 %.

Electrophysiological Responses of the Mediterranean Fruit Fly, Ceratitis capitata, to the Cera Trap® Lure: Exploring Released Antennally-Active Compounds

The Mediterranean fruit fly (medfly), Ceratitis capitata, is a worldwide pest of agriculture able to use olfactory cues to locate habitat, food sources, mates and oviposition sites. The sensitivity of medfly olfaction has been exploited to develop olfactory-based attractants that are currently important tools for detection, control and eradication of its populations. Among these is Cera Trap® (BIOIBERICA, S.A.U.), a cost-effective bait. Here we used coupled gas chromatography/electroantennographic detection (GC-EAD) and GC/mass spectrometry (GC-MS) approaches to characterize the medfly antennally-active compounds released by this lure. We identified GC peaks corresponding to chemicals belonging to six different classes including heterocyclic aromatic compounds, aliphatic alcohols, aldehydes, esters, sesquiterpene hydrocarbons, and aromatic alcohols. We tested ten potential candidate volatiles belonging to these classes and predicted to be emitted by the lure and found that they were eliciting electroantennographic responses in medfly adults. These results will help in unravelling the physiological mechanisms of odor perception in both sexes, especially in relation to Cera Trap® attractant activity, which in the field has been shown to be female-specific. These findings and their developments will ultimately expand the toolbox for medfly control in the field.

Enantioselective reduction of heterocyclic ketones with low level of asymmetry using carrots

A whole spectrum of biocatalysts for asymmetric reduction of prochiral ketones is well known including the Daucus carota root. However, this type of reaction is still challenging when pro-chiral ketones present low level of asymmetry, like heterocyclic ketones. In this work, 4,5-dihydro-3(2H)-thiophenone (1), 2-methyltetrahydrofuran-3-one (2), N-Boc-3-pyrrolidinone (3), 1-Z-3-pyrrolidinone (4) and 1-benzyl-3-pyrrolidinone (5) were studied in order to obtain the respective enantioselective heterocyclic secondary alcohols. Except for 5, the corresponding alcohols were obtained in high values of conversion and with high selectivity. In order to circumvent the low isolated yield of the corresponding chiral alcohol from 2, we observed that the use of carrots in the absence of water is feasible. Addition of co-solvents was needed to the water-insoluble ketones 3 and 4. Comparatively, baker’s yeast was used for bio reductions of 1, 3 and 4. And in terms of conversion, selectivity and work-up, the use of carrots were a more efficient biocatalyst, as well as a viable method for obtaining 5-member heterocyclic secondary alcohols.

Engineering an Alcohol Dehydrogenase from Kluyveromyces polyspora for Efficient Synthesis of Ibrutinib Intermediate

Abstract(S)‐N‐Boc‐3‐hydroxypiperidine [(S)‐NBHP] is a key intermediate for the synthesis of mantle cell lymphoma drug, ibrutinib. Here, KpADH, an alcohol dehydrogenase from Kluyveromyces polyspora, exhibits evolutionary potential in the asymmetric reduction of N‐Boc‐3‐piperidone (NBPO) to (S)‐NBHP. By screening key residues in substrate binding pocket of KpADH, an excellent variant Y127W was obtained with 6‐fold improved activity of 119.3 U mg−1, 1.8‐fold enhanced half‐life of 147 h and strict S‐stereoselectivity (>99% ee). When catalyzed by Y127W, a complete conversion of 600 g L−1 NBPO was achieved at a substrate to catalyst ratio (S/C) of 30 in 10 h. Based on crystal‐structure of Y127W, molecular docking and dynamic simulations reveal hydrogen bonds formed between W127 and Boc group of NBPO, as well as improved structural stability mainly contribute to the increased catalytic activity and stereoselectivity of Y127W. This study offers guidance for engineering ADHs for biosynthesis of chiral heterocyclic alcohols, and provides insights into mechanisms in catalytic activity and stereoselectivity toward carbonyl‐containing heterocyclic substrates.magnified image

Biosynthesis of chiral cyclic and heterocyclic alcohols via CO/C–H/C–O asymmetric reactions

This review covers the recent progress in various biological approaches applied to the synthesis of enantiomerically pure cyclic and heterocyclic alcohols through CO/C–H/C–O asymmetric reactions.

Synthesis and Characterization of CoxOy–MnCO3 and CoxOy–Mn2O3 Catalysts: A Comparative Catalytic Assessment Towards the Aerial Oxidation of Various Kinds of Alcohols

CoxOy–manganese carbonate (X%)(CoxOy–MnCO3 catalysts (X = 1–7)) were synthesized via a straightforward co-precipitation strategy followed by calcination at 300 °C. Upon calcination at 500 °C, these were transformed to CoxOy–dimanganese trioxide i.e., (X%)CoxOy–Mn2O3. A relative catalytic evaluation was conducted to compare the catalytic efficiency of the two prepared catalysts for aerial oxidation of benzyl alcohol (BzOH) to benzaldehyde (BzH) using O2 molecule as a clean oxidant without utilizing any additives or alkalis. Amongst the different percentages of doping with CoxOy (0–7% wt./wt.) on MnCO3 support, the (1%)CoxOy–MnCO3 catalyst exhibited the highest catalytic activity. The influence of catalyst loading, calcination temperature, reaction time, and temperature and catalyst dosage was thoroughly assessed to find the optimum conditions of oxidation of benzyl alcohol (BzOH) for getting the highest catalytic efficiency. The (1%)CoxOy–MnCO3 catalyst which calcined at 300 °C displayed the best effectiveness and possessed the largest specific surface area i.e., 108.4 m2/g, which suggested that the calcination process and specific surface area play a vital role in this transformation. A 100% conversion of BzOH along with BzH selectivity >99% was achieved after just 20 min. Notably, the attained specific activity was found to be considerably larger than the previously-reported cobalt-containing catalysts for this transformation. The scope of this oxidation reaction was expanded to various alcohols containing aromatic, aliphatic, allylic, and heterocyclic alcohols without any further oxidation i.e., carboxylic acid formation. The scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and Brunauer–Emmett–Teller (BET) specific surface area analytical techniques were used to characterize the prepared catalysts. The obtained catalyst could be easily regenerated and reused for six consecutive runs without substantial decline in its efficiency.