Beckmann Rearrangement Research Articles

Synthesis of Helical-Shaped Axially Chiral Bisoxime Ethers via Chiral Phosphoric-Acid-Catalyzed Sequential Enantioselective Condensations.

A successful synthesis of helical-shaped axially chiral bisoxime ethers is reported. This approach utilized symmetric L-shaped diketone scaffolds as carbonyl components for the enantioselective condensation with hydroxylamines, delivering dual axially chiral oxime ethers with up to 99% ee. Additionally, the axially chiral mono-oxime ethers of azabicyclic ketones with high ee's were also successfully produced. Various chiral bicyclic lactams can be readily synthesized via Beckmann rearrangement, demonstrating a potential application in organic synthetic chemistry.

Sustainable Beckmann Rearrangement using Bead-Milling Technology: The Route to Paracetamol.

To address the growing demand for more sustainable and greener chemistry, mechanochemical methodologies are emerging as key players. However, to date there has been little data highlighting the benefits of these rising mechanochemical technologies with regard to process scale-up activities or implementation in commercial production scale. Herein, we report the first application of bead-mill technology (Dyno®-mill) for the sustainable mechanochemical synthesis of Acetaminophen, known under the brand name Paracetamol. Using the Beckmann rearrangement, the optimized solvent-free methodology delivered a final product on a scale of several tens of grams. In comparison to current production solvent-based process, the proposed process achieves a higher yield while also allowing the removal of solvents in the chemical reaction, hereby reducing one of the extensive drivers to waste generation. The mechanochemical approach was compared to solvent-based process using a combination of green metrics and EcoScale score. The mechanochemical synthesis of paracetamol scores the highest for all the metrics over currently used solution-based processes.

Enantioselective Total Synthesis of (-)-Hunterine A Enabled by a Desymmetrization/Rearrangement Strategy.

The first enantioselective total synthesis of (-)-hunterine A is disclosed. Our strategy employs a catalytic asymmetric desymmetrization of a symmetrical diketone and subsequent Beckmann rearrangement to construct a 5,6-α-aminoketone. A convergent 1,2-addition joins a vinyl dianion nucleophile and the enantioenriched ketone. The endgame of the synthesis features an aza-Cope/Mannich reaction and azide-olefin dipolar cycloaddition to complete the pentacyclic ring system. The synthesis is completed through a regioselective aziridine ring opening.

Comprehensive updates on Beckmann Rearrangement

AbstractBeckmann rearrangement has been quite successful in the preparation of many medicinally potent scaffolds. In synthetic organic chemistry, the Beckmann rearrangement is quite popular, caprolactam is synthesized from cyclohexanone oxime on a large scale for Nylon‐6 production. The function of numerous catalysts and media in the Beckmann rearrangement has been discussed in depth in this review. In the last 20 years, Beckmann rearrangement catalysis has evolved from a potentially hazardous to a more environmentally friendly catalyst, as a result of greater usage. Catalytic performance and synthetic performance of various catalytic systems have been re‐evaluated in the present review article.

Silica Gel Supported Chlorosulfonic Acid Catalyzed Beckmann Rearrangement of Cyclohexanone Oxime in Liquid Phase

The Beckmann rearrangement of cyclohexanone oxime in the liquid phase using fuming sulfuric acid as a catalyst is a traditional method, which brings many problems, such as environmental pollution, corrosion of equipment, and difficulty in treating the by-product ammonium sulfate. This paper designs and prepares a silica gel-supported chlorosulfonic acid solid acid catalyst for the liquid-phase Beckmann rearrangement of cyclohexanone oxime to caprolactam. The factors affecting the preparation of the catalyst and the optimal reaction conditions for Beckmann rearrangement were investigated. It was found that the best catalyst preparation conditions were as follows: mass ratio of silica gel: chlorosulfonic acid of 1:0.2, room temperature, stirring time of 3 hours, solvent dichloromethane, and silica gel mesh size of 100-200 mesh, and best Beckmann rearrangement conditions were as follows: mass ratio of cyclohexanone oxime: catalyst of 1:1, temperature of 140°C, solvent benzonitrile volume of 40 mL/g cyclohexanone oxime, reaction time of 5 hours. Under the above conditions, the conversion of cyclohexanone oxime is 74%, and the selectivity of caprolactam is 40%.

Synthesis of the large pore aluminophosphate STA-1 and its application as a catalyst for the Beckmann rearrangement of cyclohexanone oxime

Microporous AlPO4 STA-1 has been synthesised and studied by NMR crystallography; it is an effective catalyst for the Beckmann rearrangement of cyclohexanone oxime.

Silica Gel Supported Trifluoromethanesulfonic Acid Catalyzed Beckmann Rearrangement of Cyclohexanone Oxime in Liquid Phase

Silica Gel Supported Trifluoromethanesulfonic Acid Catalyzed Beckmann Rearrangement of Cyclohexanone Oxime in Liquid Phase

Synthesis of Functionalized Hexahydrocarbazoles by Beckmann Elimination and Nucleophile-Intercepted Beckmann Fragmentation.

The Beckmann elimination and nucleophile-intercepted Beckmann fragmentation (NuBFr) of oximes starting from regioisomeric indolinyl bicyclic ketones lead to products that are subjected to further synthetic manipulations and ultimately result in the stereospecific formation of densely functionalized hexahydrocarbazoles. The Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of a key alkenyl bromide intermediate with various boronic acids gives arylated products.

The Synthesis of Novel aza-Steroids and α, β-Unsaturated-Cyanoketone from Diosgenin.

Recent studies have demonstrated the antiproliferative and cytotoxic effects of aza-steroids and steroidal sapogenins on human cancer cell lines. The scientific community has shown a growing interest in these compounds as drug candidates for cancer treatment. In the current work, we report the synthesis of new diosgenin oxime derivatives as potential antiproliferative agents. From (25 R)-5α-spirost-3,5,6-triol (1), a diosgenin derivative, ketones 2, 3, 4, and 9 were obtained and used as precursors of the new oximes. A condensation reaction was carried out between the steroidal ketones (2, 3, 4, and 9) with hydroxylamine hydrochloride in 2,4,6-trimethylpyridine to produce five spirostanic oximes (four of them are not reported before) with a 42-96% yield. Also, a new spirostanic α, β-unsaturated cyanoketone was synthesized via Beckmann fragmentation using thionyl chloride with a 62% yield. Furthermore, we proposed a reaction mechanism with the aim of explaining such transformation.

Green synthesis of reduced graphene oxide anchored Fe3O4‐Pd hetero‐nanostructure: An efficient, magnetically separable and reusable catalyst for Beckmann rearrangement of aldoximes to amides

The multifaceted Fe3O4‐Pd@rGO nanocomposite (NC) has been synthesized successfully by a biogenic method using Ocimum tenuiflorum leaf extract. The preparation of graphene oxide (GO) was done by the well‐known modified Hummer method. The as‐synthesized Fe3O4‐Pd@rGO NC was extensively characterized by various analytical techniques, namely, Fourier transform infrared (FTIR), X‐ray diffraction (XRD), field emission scanning electron microscopy‐energy‐dispersive X‐ray spectroscopy (FESEM‐EDX), high‐resolution transmission electron microscopy (HRTEM), inductively coupled plasma‐atomic emission spectrometry (ICP‐AES), X‐ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM) and Brunauer–Emmett–Teller (BET) surface area analysis. The absence of peak corresponding to υ(CO) at 1732 cm−1 in the FTIR spectrum of Fe3O4‐Pd@rGO enumerates the reduction of GO to reduced graphene oxide (rGO) during Fe3O4‐Pd nanoparticle (NP) synthesis with O. tenuiflorum leaf extract. The XRD pattern reveals the existence of rGO, cubic‐phased spinel‐structured Fe3O4 along with the formation of metallic Pd NP without any impurities. The FESEM image designates the spherical and flake‐like morphology of the NC. The crystallite size of the NC was calculated employing the Debye–Scherrer equation and was found to be 3.45 nm corresponding to the (220) plane. The average particle size of Fe3O4‐Pd NPs as estimated from the particle size distribution curve was ascertained as 3.03 nm. The utmost saturation magnetization value of the NC as evaluated by VSM study has appeared at 0.6219 emu g−1 having coercivity value of 335.1 Oe and remanent magnetization value of 0.0767 emu g−1, suggesting the existence of a ferromagnetic material in the synthesized NC. It was a stable and highly efficient catalyst for Beckmann rearrangement of aldoximes using in an environment‐friendly medium. It afforded up to 99% isolated yield of the preferred products under acid‐free condition, avoiding the use of any harsh chemicals that will be beneficial for future industrial applications. Finally, the magnetic component of the NC allowed for easy recovery of the catalyst, thereby eliminating the chance of leaching of metal atoms, and was reusable till six successive cycles without apparent loss of its catalytic performance.

Tailoring Zn-based diacidic functionalization of Deep eutectic solvent Catalyst: Green and efficient synthesis of ε-Caprolactam under mild conditions

A novel Zn-based acidic functionalized deep eutectic solvent (DES) catalyst were prepared by a “tailoring” mixing procedure of Brønsted acidic hydrogen bond donors (HBD) and Lewis acidic hydrogen bond acceptor (HBA). It is found that the hydrogen bonded cluster with thermal stability and adjustable acidity has an excellent flexible hydrogen bond “assembly mode”, providing a suitable coordination microenvironment for Zn active center. The functionalized DESs were investigated to produce caprolactam from cyclohexanone oxime. The results showed that DES [ZnCl2][ChCl][TCA]2 had an excellent catalytic performance for the reaction with 100% cyclohexanone oxime conversion and ε-caprolactam 99.4% selectivity at 80 °C for 1.5 h, attributing to the strong complexing ability of Zn active center and the synergistic effect of BrØnsted and Lewis acid sites of DES, which also decreased the energy barriers of the intermediates and transition states, thus reducing the reaction energy (Ea = 29.22 kJ mol−1 and ΔG = –32.8 kJ mol−1). Otherwise, the recovered DES [ZnCl2][ChCl][TCA]2 was reused seven times with no significant decrease in its catalytic performance. The advantages of this method, such as high yield, short reaction time, and easy catalyst recovery, make the DES catalytic system a potential method for Beckmann rearrangement.

Unexpected but prominent imines formation in Beckmann rearrangement of (spiro)pyranocoumarin oximes

This paper presents the successful implementation of Beckmann rearrangement on a series of (spiro)pyranocoumarin oximes in polyphosphoric acid (PPA) medium. The method demonstrated excellent proficiency in the synthesis of unexpected imines as major products and amides as minor products. The labeled 15NH2OH·HCl control experiment yielded oxime and rearrangement products that incorporated the 15N label. Furthermore, we have proposed a possible rearrangement mechanism. NMR spectroscopy data (correlation HMBC and 15N NMR) confirmed the structure of the synthesized products. These findings provide a new and efficient approach for constructing complex imines with diverse applications in synthetic organic chemistry.

A Strategic Synthesis of Fluoroethers via Ring-Opening Fluorinative Beckmann Fragmentation.

An SN1-type fluorination method for monofluoroethers is developed. The key to this reaction is fluorinative C-C bond cleavage that is driven by oxygen-assisted Beckmann fragmentation. To enable this transformation, cyclic α-aryloxyoximes derived from 3-coumaranone and 1-indanones were investigated as substrates, using N,N-diethylaminosulfur trifluoride (DAST) as a dual-role reagent of an oxime activator and fluoride donor. This method features the synthesis of an underdeveloped chemical motif with simple and mild operating conditions.

Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1S,6R)-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry. The developed approach utilizes (S)-phenylethylamine as a chiral auxiliary handle for CIDT, and the starting nortropinone derivative is prepared in one step from commercially available materials. The resulting E-oxime is subjected to a stereospecific Beckmann rearrangement, followed by reduction of the resulting lactam with LiAlH4 to afford the monoprotected (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative. The development of the CIDT and understanding of the mechanistic implications leading to the high selectivity are reported.

Modulating the Microenvironment of Silanols in Pure-Silicon Zeolites for Boosting Vapor-phase Beckmann Rearrangement of Cyclohexanone Oxime.

Vapor-phase Beckmann rearrangement of cyclohexanone oxime (CHO) to ε-caprolactam (CPL) is still difficult to commercialize at the industrial scale due to its relatively low catalytic activity and poor lifetime. Herein, we synthesized a series of pure-silicon zeolites (including MFI, MEL, and -SVR) with three-dimensional 10-member-ring topolgies, diverse silanol status, and hierarchical porosity to investigate the synergistic effects of inner diffusivity and reactivity. S-1 zeolite of MFI-type topology with plentiful silanol nests exhibits a more preferable catalytic performance in terms of CHO conversion (99.7%) and CPL selectivity (89.7%), much higher than those of MEL- and -SVR-type zeolites mainly due to their diverse silanol distribution. With the construction of hierarchical porosity, S-1-P shows improved CPL selectivity of 94.1% owing to the enhanced diffusivity to shorten the retention time of the reactant and product molecules. The reaction mechanism and network have been further revealed by density functional theory (DFT) calculations and experimental designs, which indicate that silanol nests are major active sites due to their suitable interaction with CHO rather than terminal silanols. Particularly, the microenvironments of silanols can be modulated by alcohol solvents, ascribed to their different charge transfer and steric hindrance. Consequently, S-1-P shows superior CPL selectivity of 97.3% in ethonal solvents, which have higher adsorb energy of -0.627 eV with silanol nests than other alcohols. The present study not only provides a fundamental guide for the design of zeolite catalysts but also provides a reference for modulating the microenvironment of active sites according to the catalytic mechanism.

Organic impurity profiling of 3,4-methylenedioxyamphetamine (MDA) synthesised from helional

The organic impurity profile of 3,4-methylenedioxyamphetamine (MDA) synthesised from helional via the “twodogs” method was examined to identify route-specific and condition-specific impurities. The synthesis used a condensation reaction, followed by a Beckmann rearrangement, then Hofmann rearrangement, and then conversion to a hydrochloride salt. Two chlorinating agents were investigated for the Hofmann rearrangement reaction, trichloroisocyanuric acid (TCCA) and sodium hypochlorite.Three route-specific impurities were identified in MDA using TCCA, and two of these impurities were condition-specific such that the impurities that formed were dependent on the alcohol used as solvent. Three additional impurities were identified as non-route-specific as they have previously been identified in MDA synthesised from 3,4-methylenedioxycinnamic acid or piperonal. These non-route-specific impurities were also identified in MDA synthesised using sodium hypochlorite. No impurities were detected in MDA hydrochloride. This study identified route- and condition-specific organic impurities in MDA synthesised via the “twodogs” synthetic route using helional as starting material. The results in this study provide further understanding into the illicit synthesis of MDA and highlight the expanding nature of precursors used for illicit drug manufacture. It provides valuable information to decision makers to enact legislative measures and restrict precursors of concern.

Tropylium‐BF4as Organocatalyst for Microwave‐assisted Beckmann rearrangement in [TMG][BF4]: One‐pot conversion of Ketones to Amides

AbstractThe microwave assisted one pot efficient conversion of ketones into respective amides has been achieved by utilization of environmentally benign catalytic system tailored by tropylium tetrafluoroborate (Tp+BF−4) and 1,1,3,3‐tetramethylguanidinium tetrafluoroborate [TMG][BF4]. The mild reaction conditions, shorter reaction time, and affordable catalytic system are the key points that highlight the importance. The high product yield and ease of recycling impacts the successful product conversion.

Novel Brønsted Acidic Ionic Liquids as High Efficiency Catalysts for Liquid-Phase Beckmann Rearrangement

Exploring environmentally friendly, efficient, cheap and recyclable catalysts are essential for the development of green, sustainable and mild processes for the liquid-phase Beckmann rearrangement. Herein, a novel caprolactam-based Brønsted acidic ionic liquid ([CPL][2MSA]) was developed for the conversion of cyclohexanone oxime (CHO) to caprolactam (CPL), not only as a catalyst, but also as a mild reaction medium. Under the reaction conditions for the reaction temperature (90 °C), reaction time (2 h) and mole ratio ([CPL][2MSA]: CHO = 3:1), [CPL][2MSA] possesses plenty of high sulfonate groups, which exhibit high conversion (100%) and selectivity (95%) without any other co-catalysts or metals. Based on the thermogravimetric (TGA) and differential scanning calorimetry (DSC) analyses, the decomposition and glass transition temperatures are gradually increased with the increase in MSA mole content, revealing the existence of hydrogen-bonded clusters. Interestingly, the occurrent route of the liquid-phase Beckmann rearrangement for CHO in [CPL][2MSA] is revealed by in situ FT-Raman. In addition, the dominating H-bond combination between CHO and [CPL][2MSA] is further confirmed by COSMO-RS model. The activation energy (Ea) of the reaction is calculated by the first-order reaction kinetics. Thus, the [CPL][2MSA] with plenty of acidic catalytic active species is an environmentally friendly and efficient candidate for the liquid-phase Beckmann rearrangement.

Role of cyanuric chloride in organic synthesis: A concise overview

AbstractCyanuric chloride, a chlorinated analog of 1,3,5‐triazine, is used as a catalyst, promoter, and activator to catalyze and initiate several reactions like Beckmann rearrangement, Lossen rearrangement, Biginelli reaction, Suzuki coupling reaction, Pictet Spengler reaction, Mannich reaction, etc. It is employed in several reactions due to its several properties like stable, non‐volatile, cost‐efficient, easy to handle, and easy commercial availability. Moreover, it is a very renowned precursor for the synthesis of triazine‐class pesticide atrazine, dyes, and crosslinking agents. Herein in this review article, the reactions initiated, catalyzed, and promoted by cyanuric chloride from 2010 to 2022 have been elaborated.

Photo-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds.

In recent years, photochemistry has increasingly emerged as an enabling methodology in both academia and the pharmaceutical industry. Long photolysis times and the gradual reduction of light penetration remained for many years unsolved issues for photochemical rearrangements, triggering the generation of highly reactive species in an uncontrolled fashion and causing the formation of multiple side products. The emergence of continuous-flow chemistry significantly helped to overcome these issues, thus prompting the implementation of photo-flow-based approaches for the generation of pharmaceutically relevant substructures. This Technology Note highlights the benefits of flow chemistry for photochemical rearrangements, including Wolff, Favorskii, Beckmann, Fries, and Claisen rearrangements. We showcase recent advances for photo-rearrangements in continuous flow applied to the synthesis of privileged scaffolds and active pharmaceutical ingredients.