Catalytic Cyclization Research Articles

Experimental Investigation of Microwave-Specific Effect on Nazarov Cyclization

Abstract A copper-catalyzed Nazarov cyclization using an aryl vinyl ketone derivative containing a 1,3-dicarbonyl moiety was carried out under microwave irradiation conditions. The Nazarov cyclization was dramatically accelerated and the kinetic rate of the microwave irradiation was 5.8 times faster than that by conventional heating conditions. A theoretical interpretation of the microwave-specific effect as physical phenomena of the molecules based on chemical kinetics and dynamics was attempted. The microwave-specific effect in terms of the pre-exponential factor in the Arrhenius equation is discussed, thus a hypothesis of the conformational equilibrium activation by microwaves is theoretically supported. To further investigate the microwave-specific effect, a catalytic asymmetric Nazarov cyclization was finally performed. As the enantioselectivity is defined as the function of the reaction temperature, observation of the same enantioselectivity implies the same reaction temperature. Interestingly, when the asymmetric Nazarov cyclization was conducted using a chiral copper catalyst, the Nazarov reaction was subsequently enhanced by the microwave irradiation without any loss of the enantioselectivity. It is suggested that the drastic enhancement with the retention of the enantioselectivity was caused not by a thermal effect, but by a microwave-specific effect on the enantioselective reaction.

Substrate-Dependent Selectivity in Sc(OTf)3-Catalyzed Cyclization of Alkenoic Acids and N-Protected Alkenamides

Five- and six-membered ring lactones and lactams are ubiquitous frameworks in various natural and synthetic molecules and are key building blocks in organic synthesis. Catalytic addition of an O-H or N-H bond across an unactivated C–C double bond is an appealing approach to rapidly access such highly valuable N- and O-containing skeletons in a waste-free and 100% atom efficient process. Herein, we report, for the first time, the efficient and high-yield cyclization of δ/ε-alkenoic acids and N-protected δ-alkenamides catalyzedby practical and easily accessible Lewis acid scandium(III) triflate under thermal and microwave conditions. The selectivity outcome of the reaction of δ/ε-alkenoic acids was dependent on the substitution patterns of the backbone chain and alkene moiety, leading to the exclusive formation of either the corresponding γ/δ-lactones via an O-selective cyclization or the Friedel–Crafts-type product by C-selective cyclization. An uncommon and rarely disclosed O-selective cyclization occurred preferentially or exclusively when N-protected δ-alkenamides were engaged in the reaction. The atom selectivity of the cyclization was unambiguously confirmed by single crystal X-ray crystallography.

Synthesis of Phenanthrene‐Based Polycycles by Gold(I)‐Catalyzed Cyclization of Biphenyl‐Embedded Trienynes

AbstractGold(I)‐catalyzed cyclization of o‐alkenyl‐o’‐alkynylbiaryls in the presence of external or internal nucleophiles provides a straightforward access to phenanthrene‐based polycycles, which are of considerable interest in materials science. Thus, their reactions with alcohols yield functionalized dihydrophenanthrenes, in a process that can also be carried out intramolecularly, to provide phenanthrene‐derived heteropolycyclic compounds. Moreover, benzo[b]triphenylenes can be synthesized from o‐methoxyvinyl‐o’‐alkynylbiaryls, in a reaction in which an (hetero)aryl substituent at the triple bond acts as an internal nucleophile.magnified image

Effects of ambient pressure on structural characteristics of polyacrylonitrile pre‐oxidized fibers

AbstractDuring the pre‐oxidation process, skin‐core structure is easily formed in the fibers due to the competitive mechanism of oxygen capture and oxygen diffusion, which would degrade the tensile properties of the resulting carbon fibers. To prepare high‐performance carbon fibers, it is vital to optimize the radial structure of polyacrylonitrile (PAN) pre‐oxidized fibers. Methods commonly used to solve the skin‐core structure would result in low productivity and comprehensive performance. Here, we examine the effects of pressure on the chemical structure and the evolution of radial structure in PAN pre‐oxidized fibers under 225°C in the air, by using 13C Solid‐state NMR analysis (13C‐NMR), Optical density test (OD), and Thermogravimetric Analysis (TG). It was found out that under the positive pressure of 30 kPa, the reaction area expands to the core of the fibers with the shell thickness increasing from 88.11% under normal pressure to 98.67%, and the radial structure homogeneity is effectively improved. As the pressure increases above 22 kPa, oxygen diffusion is accelerated, allowing for breaking the barrier of the fiber surface capture and promoting the oxygen catalytic cyclization reaction in the core. Consequently, PAN pre‐oxidized fibers prepared under positive pressure have a more uniform radial structures and higher thermal stability. The carbonization yield at 800°C of the fibers prepared at 30 kPa is 13.10% higher than that of the fibers prepared at atmospheric pressure.

PPh3-Catalyzed Intramolecular Cyclization of hydroxypropargylamides: Synthesis of Structurally Diverse Morpholinone Derivatives

The metal-free synthesis of functionalized morpholinones through a sequential intramolecular post-ugi cyclization strategy is described. In the subsequent step, Ugi adducts hydroxypropargylamides derivative undergoes chemo- and regioselective 6- exo-dig catalytic cyclization to afford O -cyclized product in the presence of triphenylphosphine. This sequence offers an engrossing functionalized morpholinones scaffolds involving moderate reaction conditions with broad substrate scopes and moderate to good yields.

Palladium‐Catalyzed Enantioselective Cyclization of 1,6‐Enynes through Intramolecular Chlorine Transfer as a Novel Strategy for Asymmetric Halopalladation

Palladium-catalyzed enantioselective cyclization of enynes has contributed significantly to the construction of chiral cyclic molecules. In contrast, the catalytic asymmetric cyclization involving halopalladation remains an unresolved challenge with the inevitable disturbance of the halide ions. Herein, an intramolecular chlorine transfer strategy is used to accomplish the enantioselective chloropalladation cyclization of 1,6-enynes. This reaction provides a redox-neutral approach to a variety of chiral α-chloromethylene-γ-butyrolactones with excellent E selectivity and enantioselectivity. The precisely controlled coordination of palladium with both the in situ generated nucleophilic species and the monodentate phosphoramidite ligand is crucial for enantioselectivity.

Annulation of the Ugi Products Using Palladium Catalysts

AbstractFor almost half a century of efforts to make them, the importance of Ugi products has substantially expanded because they are used as precursors for the synthesis of more complex structures, such as peptides, amino acids, pharmaceutical compounds, and heterocycles. Through the introduction of a double or triple bond along with a carbon‐halide bond in the starting materials, the Ugi adduct can be cyclized through Pd‐catalyzed intramolecular reactions to create sophisticated heterocycles. This article discusses the role of palladium in the catalytic cyclization of the Ugi adducts and covers the published research from 2000 to 2022. Moreover, the proposed mechanisms of Pd‐catalyzed annulation of Ugi adducts are also reviewed.

Synthesis of Bis(β‐Oximinoalkyl)malonates and Their Catalytic Reductive Cyclization to Piperidines

AbstractHitherto unknown bis(β‐oximinoalkyl)malonates were demonstrated to be convenient platforms for the synthesis of saturated N‐heterocycles. Upon heterogeneous catalytic hydrogenation, these dioximes undergo reductive cyclization to give substituted piperidine‐4,4’‐dicarboxylates, which are valuable building blocks in medicinal chemistry. By using dioximes bearing an additional ester group in the side chain, tandem piperidine/pyrrolidinone ring closure leading to indolizidinone framework was showcased in this work. A modular synthesis of initial bis(β‐oximinoalkyl)malonates (both symmetrically and unsymmetrically substituted) was accomplished via a sequential Michael addition of two nitrosoalkene molecules to malonic ester. The mechanism of the reductive cyclization of dioximes to piperidines was investigated by isotope scrambling experiments and isolation of intermediates.magnified image

Unified Approach to Diverse Fused Fragments via Catalytic Dehydrative Cyclization.

A range of highly functionalized polycyclic fragments have been synthesized, employing a catalytic dehydrative cyclization. A range of nucleophiles are shown to be successful, with the reaction producing numerous high value motifs.

Synthesis of Cyclic Fragrances via Transformations of Alkenes, Alkynes and Enynes: Strategies and Recent Progress.

With increasing demand for customized commodities and the greater insight and understanding of olfaction, the synthesis of fragrances with diverse structures and odor characters has become a core task. Recent progress in organic synthesis and catalysis enables the rapid construction of carbocycles and heterocycles from readily available unsaturated molecular building blocks, with increased selectivity, atom economy, sustainability and product diversity. In this review, synthetic methods for creating cyclic fragrances, including both natural and synthetic ones, will be discussed, with a focus on the key transformations of alkenes, alkynes, dienes and enynes. Several strategies will be discussed, including cycloaddition, catalytic cyclization, ring-closing metathesis, intramolecular addition, and rearrangement reactions. Representative examples and the featured olfactory investigations will be highlighted, along with some perspectives on future developments in this area.

Mechanism and Evolution of [4+2] Cyclases in Monoterpene Indole Alkaloid Biosynthesis

Monoterpene indole alkaloids (MIAs) comprise a large and diverse class of plant natural products, many of which exhibit potent biological activities such as anticancer, antimalarial, and antihypertensive. While the biosynthetic construction of these compounds has been a subject of intensive study for the past six decades, the identification of specific pathway genes remains an active area of investigation. MIAs belonging to the aspidosperma and iboga structural classes are produced only by select plants in the Apocynaceae (dogbane) family. The most well‐known of these is Catharanthus roseus, which produces the bisindole anticancer compounds vinblastine and vincristine through a complex pathway involving more than thirty individual enzymatic steps. Recently, we characterized three carboxylesterase‐like enzymes from C. roseus and Tabernanthe iboga that catalyze regio‐ and enantiodivergent [4+2] cycloadditions to generate the aspidosperma (tabersonine synthase, TS) and iboga (catharanthine synthase, CS; coronaridine synthase, CorS) scaffolds from a common biosynthetic intermediate. While crystal structures, computational docking, and site‐directed mutagenesis provided some key insights into the catalytic mechanism and cyclization specificity of these enzymes, several important questions remained unanswered. Here, we use a combination of computation and experiment to demonstrate that the [4+2] cyclases in MIA biosynthesis employ a stepwise rather than a concerted mechanism of cyclization. We also isolate and characterize the direct product of the CorS reaction and show that it can serve as a branch point in the biosynthesis of both iboga and pseudo‐aspidosperma alkaloids. Using a phylogenetic approach, we subsequently explore the evolution and diversification of MIA cyclase function. Reconstruction and functional analysis of ancestral enzymes allows us to trace an evolutionary trajectory from carboxylesterase to TS, from TS to CorS, and from CorS to CS. We further generate and test a panel of mutants based on both extant and ancestral cyclases to probe the molecular basis for differential cyclization activity. Our results provide insight into the mechanism and evolution of a unique class of biosynthetic enzymes and offer a means by which they could be leveraged for the facile production of new MIAs.

Catalytic reductive cyclization of 2-nitrobiphenyls using phenyl formate as CO surrogate: A robust synthesis of 9H-carbazoles

A palladium/phenanthroline catalyzed reductive cyclization of o-nitrobiphenyls to 9H-carbazoles operated by in situ released CO is described. In the present method, the presence of phenyl formate is essential to avoid the use of high-pressure equipment and allows to perform the reaction in a single thick-walled glass tube. The identity of the base, which catalyzes the formate decomposition, is crucial to the selectivity of the reaction. Stability of the catalyst is influenced by the presence of chloride anions. Carbazole yields are most often higher than those previously reported using pressurized CO. The optimized catalytic system features excellent stability and moisture and air tolerance allowing to perform the reaction with low catalyst loadings.

Catalytic Intramolecular Cyclization of Alkynyl Cyclic Acetals via Chemoselective Activation Leading to a Phenanthrene Core

Abstract An intramolecular cyclization reaction of alkynyl cyclic acetals to synthesize various phenanthrene derivatives in the presence of silver triflate (AgOTf) or boron trifluoride etherate (BF3·OEt2) as catalysts has been developed. By using AgOTf or BF3·OEt2 appropriately depending on the substituents various alkynyl cyclic acetals were converted to the corresponding phenanthrene derivatives. Investigations of reaction mechanisms, X-ray structure of the product, and computational density functional theory (DFT) study suggested that the reaction proceeds via alkyne activation (π-activation) or acetal activation (σ-activation) pathways based on π- or σ-Lewis acidities.

Bismuth(III) Triflate-Catalyzed Intermolecular Cyclization of Phenols with Diols: Direct Access to O-Heterocycles

AbstractA direct access to O-heterocycles by Bi(OTf)3-catalyzed intermolecular cyclization of phenols with diols is described. Catalytic dehydrative tandem formation of C–O and C–C bonds was achieved by using a Bi(OTf)3 catalyst without any additives. The catalytic intermolecular cyclization of phenols with various diols proceeded to give the corresponding chromanes in up to 91% yield and/or pyran derivatives in up to 66% yield.

Computational Mechanism of Methyl Levulinate Conversion to γ-Valerolactone on UiO-66 Metal Organic Frameworks.

Metal–organic frameworks (MOFs) are gaining importance in the field of biomass conversion and valorization due to their porosity, well-defined active sites, and broad tunability. But for a proper catalyst design, we first need detailed insight of the system at the atomic level. Herein, we present the reaction mechanism of methyl levulinate to γ-valerolactone on Zr-based UiO-66 by means of periodic density functional theory (DFT). We demonstrate the role of Zr-based nodes in the catalytic transfer hydrogenation (CTH) and cyclization steps. From there, we perform a computational screening to reveal key catalyst modifications to improve the process, such as node doping and linker exchange.

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E.

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β′-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicyclic core in near-perfect enantio- and diastereo-selectivity, concurrently established three stereogenic centers, including a quaternary carbon, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclization were probed using density functional theory (DFT) calculations, which revealed the crucial substrate/catalyst interactions in the enantio-determining step. Following construction of the bicyclic core, the total synthesis of madangamine E could be completed, with key steps including a mild one-pot oxidative lactamization of an amino alcohol, a two-step Z-selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.

Catalytic Synthesis of 1H-2-Benzoxocins: Cobalt(III)-Carbene Radical Approach to 8-Membered Heterocyclic Enol Ethers.

The metallo-radical activation of ortho-allylcarbonyl-aryl N-arylsulfonylhydrazones with the paramagnetic cobalt(II) porphyrin catalyst [CoII(TPP)] (TPP = tetraphenylporphyrin) provides an efficient and powerful method for the synthesis of novel 8-membered heterocyclic enol ethers. The synthetic protocol is versatile and practical and enables the synthesis of a wide range of unique 1H-2-benzoxocins in high yields. The catalytic cyclization reactions proceed with excellent chemoselectivities, have a high functional group tolerance, and provide several opportunities for the synthesis of new bioactive compounds. The reactions are shown to proceed via cobalt(III)-carbene radical intermediates, which are involved in intramolecular hydrogen transfer (HAT) from the allylic position to the carbene radical, followed by a near-barrierless radical rebound step in the coordination sphere of cobalt. The proposed mechanism is supported by experimental observations, density functional theory (DFT) calculations, and spin trapping experiments.

Reactions

REACTIONS Reactions ShareShare onFacebookTwitterWechatLinked InRedditEmail C&EN, 2021, 99 (36), p 3October 4, 2021Cite this:C&EN 99, 36, 3Letters to the editorDelta-8-THCThe recent C&EN cover article highlighted controversies surrounding a cannabidiol-derived ∆8-tetrahydrocannabinol (delta-8-THC) (Aug. 30, 2021, page 24). Unfortunately, it spoke mostly about concerns and anxieties rather than solutions to the problem and technology opportunities. Besides, the subject hasn’t been linked to the accurate history of the core chemistry. Consequently, a cannabidiol-derived delta-8-THC was introduced as merely a popular cannabinoid that results from some obscure chemical transformations that lurk in the underground labs.However, a facile isomerization of cannabidiol (CBD) to THC, catalyzed by acids and metal salts, had been discovered far earlier than in the 1960s and described in one of the seminal papers, published by the US pioneer of the cannabinoid research Roger Adams (Journal of the American Chemical Society, 1940). An interest in CBD-to-THC conversion remained dormant and purely academic for a long time. But it was destined to be reinvigorated, with CBD becoming in the last decade a major commercial cannabinoid. The decades of prohibition and barriers to conduct scientific research led to the current gaps in the existing legislation and also grew urban myths, some of which penetrated into the published piece. One of those concerns the exothermic nature of the catalytic CBD-to-THC conversion.The implication of olivetol as a common and major degradation product is an example of another unfounded claim. Certificates of analysis are now mandatory and include quantification of delta-8-THC and delta-9-THC, along with other cannabinoids and contaminants.We could not agree more that a full analysis of delta-8-THC-associated degradation products and the establishment of their safety are crucial. But this clarity is not far off. The general fundamentals of catalytic isomerization and cyclization processes are covered in chemistry textbooks. The scientific and business communities need only devote reasonable resources to address the information gap amplified in the article. It is no secret that cannabis business interests, not academic researchers, have continued to drive research into delta-8-THC’s safety .As THC explorations expand, cutting-edge cannabis companies will adopt emerging conversion methodologies, without toxic solvents and purification processes in place, to produce safe, fully characterized delta-8-THC and delta-9-THC from hemp-derived CBD. The economic and safety advantages inherent in these emerging technologies ensure their substitution for the current solution chemistry-based approaches, the shortcomings of which are presented as intractable and disqualifying. We hope coverage of this fundamental innovation, affecting what will eventually be a $200 billion global market, is worthy of a C&EN cover sooner rather than later.Alex Nivorozhkin (Boston), Jacob Weintraub (North Easton, Massachusetts), Charlie Sinn (San Diego) CorrectionSept. 27, 2021, page 10: The news story about novel phosphorus and nitrogen chemistry incorrectly says a prismatic P3N3compound survived about 10 µs. It survived at least that long.

Catalytic hydrative cyclization of aldehyde-ynamides with water for synthesis of medium-sized lactams

Catalytic hydrative cyclization of aldehyde-ynamides with water for synthesis of medium-sized lactams

Sequential Pd0 - and PdII -Catalyzed Cyclizations: Enantioselective Heck and Nucleopalladation Reactions.

An enantioselective consecutive cyclization/coupling process, catalyzed by palladium is reported. Stereoinduction arises from an enantioselective carbopalladation, generating an intermediate which promotes a nucleopalladation step. The dual cyclization sequence was compatible with a variety of alkyne-tethered oxygen- and nitrogen-centered nucleophiles, and a variety of alkenyl-tethered aryl iodides, to forge numerous bisheterocycles in good yields and high regio- and enantioselectivities.