Regioselective Research Articles

Rare-Earth-Metal-Catalyzed Regioselective Hydrosilylation of Internal Alkenes and Alkynes

AbstractA highly regioselective hydrosilylation reaction of internal alkenes was achieved by using commercially available lanthanum hexamethyldisilazane (La(HMDS)3). Notably, the Z- or E-configuration of internal alkenes has negligible influence on either the reactivity or regioselectivity. Internal alkynes could also be used, affording the mono di-hydrosilylation product in the presence of La(HMDS)3 or mono-hydrosilylation product with Y(HMDS)3 as the promoter.

Design, synthesis, and anti-breast cancer activity evaluation of novel 3-cyanopyridine derivatives as PIM-1 inhibitors.

A novel series of cyanopyridines 7a-j were synthesized via a one-pot multicomponent reaction of arylidene 4 with ammonium acetate 5 and respective methylaryl/heterylketones 6a-j in ethanol using vanillin as a natural starting material. Moreover, the regioselective alkylation reaction was studied by the treatment of cyanopyridines 7a-f and 7j with CH3I in the presence of K2CO3 in DMF to afford O-methylcyanopyridines 8a-g (major) and N-methylcyanopyridines 9a-g (minor), whereas bipyridine 7h gave bipyridinium iodide salt 10. All of the designed cyanopyridines were evaluated as anti-breast cancer (MCF-7) cell lines via PIM Kinase inhibitory activity, and the results displayed that some of them showed high activities, especially compounds 7h and 8f, which showed excellent activities against MCF-7 with IC50 values of 1.89 and 1.69 μM, respectively, more potent than the reference drug doxorubicin. Mechanistically, compounds 7h and 8f exhibited strong in vitro PIM-1 kinase inhibitory activity with an IC50 of 0.281 and 0.58 μM, respectively, compared to the reference staurosporine. Moreover, compound 7h arrested the tumor cells at the S phase and caused cell death mainly by inducing early and late apoptosis. Molecular docking studies against PIM-1 revealed good binding modes of the synthesized compound and showed agreement with the biological results.

A Precise Route to Tetrasubstituted Allyl Amines via Regioselective Dicarbofunctionalization of Masked Propargyl Amines.

Allyl amines are vital components in various biologically important molecules and play a significant role in their function. Presently, most methods are geared toward the preparation of di- and trisubstituted allyl amines, leaving a gap for the development of more versatile approaches. We herein describe an approach to yield tetrasubstituted allyl amines through palladium (Pd)-catalyzed regioselective dicarbofunctionalization of masked N-phthalimide-protected propargyl amines. The cationic Pd-intermediate in conjunction with the masked amine exerts collective control for the reaction regioselectivity. This method accommodates a wide range of alkynes, aryl boronic acids, and aryl diazonium salts offering direct access to a wide range of unusual tetrasubstituted allyl amines.

A Regioselective, One-Pot, Transition-Metal-Free α-Alkylation of Quinone Monoacetals for Various Organic Transformations.

Regioselective reactions of biologically significant quinones are challenging. An unprecedented advancement in quinone monoacetal (QMA) chemistry is proposed for constructing regioselective and less explored α-alkylated QMAs through the Morita-Baylis-Hillman (MBH) reaction. Electrophilic QMAs were transformed to nucleophilic umpolung reagents for aldol-type condensation with several electrophiles. Mechanistic studies reveal that solvent (TFE:water (1:1)) and in situ-generated potassium acetate accelerate the reaction. The ensuing MBH adducts were scalable and underwent several post-synthetic transformations and late-stage functionalization.

Theoretical investigation of Diels–Alder reaction mechanism and regioselectivity with functionalized fullerene derivatives

AbstractDensity functional theory (DFT) was used to study the mechanism of Diels–Alder (DA) reaction between 2‐Methyl‐ 1,3 Butadiene (MBD) with B12N12, B6N6C12 and B6C12N6 fullerens in the gas phase. In this mechanism, B‐N bonds of four‐membered and six‐membered rings of nanocages were chosen to react with MBD. Due to the existence of two types of B‐N bonds, two competitive pathways (a and b) were investigated. The effect of the substitution of carbon atoms instead of boron and nitrogen atoms on the stability of the structures and the regioselectivity of the DA reaction was examined. The potential energy of all structures and the activation barrier for all reaction pathways was evaluated. The chemical reactivity of fullerens using the molecular quantum descriptors was assessed. To evaluate the global electron density transfer in transition states (TS) structures, the natural bond orbital (NBO) analysis was performed.

Combining Trifunctionalization of Alkynoic Acids, Arene ortho C-H Functionalization and Amination: An Approach to Unsymmetrical 2,3-Diaryl Substituted Indoles.

Here we report a simultaneous construction of two C-C and two C-N bonds in a unified procedure that incorporates alkynoic acid trifunctionalization, ortho C-H functionalization, and amination cascade. In an ordered process, the regioselective alkyne insertion reaction is favored over the decarboxylation process. The presence of the carboxyl group in alkynoic acid ensures the high regioselectivity in the carbopalladation process, paving the way for a novel method to synthesize unsymmetrically 2,3-diaryl substituted indole scaffolds with excellent regioselectivity. The protocol is demonstrated to be suitable for gram-scale synthesis.

An MEDT Study of the Reaction Mechanism and Selectivity of the Hetero-Diels-Alder Reaction Between 3-Methylene-2,4-Chromandione and Methyl Vinyl Ether.

The hetero-Diels-Alder (HDA) reaction between the ambident heterodiene 3-methylene-2,4-chromandione (MCDO) and non-symmetric methyl vinyl ether (MVE) is investigated using the molecular electron density theory (MEDT) at the B3LYP/6-311G(d,p) computational level. The aim of this study is to gain insight into its molecular mechanism and to elucidate the factors that control the selectivity found experimentally. DFT-based reactivity indices reveal that MCDO exhibits strong electrophilic characteristics, while MVE displays a strong nucleophilic character. Meanwhile, the Parr function explains the ortho regioselectivity of this HDA reaction. The highly polar nature of this HDA reaction, supported by the high global electron density transfer (GEDT) taking place at the transition state structures (TSs), accounts for the very low activation energy associated with the most favorable TS-4on. The ambident nature of MCDO allows for the formation of two constitutional isomeric cycloadducts. In the case of MVE, pseudocyclic selectivity is attained using a thermodynamic control. This polar HDA reaction displays an endo stereoselectivity and a complete ortho regioselectivity. A comparative relative interacting atomic energy (RIAE) analysis of the two diastereomeric structures TS-4on and TS-6on indicates a high degree of likeness, which explains the low pseudocyclic selectivity under kinetic control.

A Facile and Regioselective Synthesis of 2‐Formamidothiazoles via the C−H Formamidation of Thiazole N‐oxides with Isocyanides

A facile, microwave‐promoted, regioselective C−H formamidation of thiazole N‐oxides with isocyanides in the presence of TBDPSCl was developed. Various 2‐(N‐substituted formamido)thiazoles were obtained in moderate to high yields. In the case of the C2‐substituted thiazole N‐oxides, the C‐H formamidation took place selectively at the C4 position of the thiazole ring. This transformation is also applicable to some other N‐containing heterocyclic derivatives such as pyridine, quinoline, and pyridazine N‐oxides and has advantages such as broad substrate tolerance, high regioselectivity, and mild reaction conditions.

Chemoselective Pd-Based Dyotropic Rearrangement: Fluorocyclization and Regioselective Wacker Reaction of Homoallylic Amides.

Fluorocyclization of alkenes tethered with a pronucleophile is an efficient transformation that converts easily accessible starting materials to fluorinated heterocycles in a single step. We report herein an unprecedented Pd(II)-catalyzed oxidative domino process that transforms homoallylic amides to 5,6-dihydro-4H-1,3-oxazines through a domino oxypalladation/PdII-oxidation/dyotropic rearrangement/reductive elimination sequence. Three chemical bonds are created under these operationally simple conditions. Taking advantage of the facile hydrolysis of the α-fluoro tertiary alkyl ether under acidic conditions, a one-pot conversion of homoallylic amides to homologated ketones is subsequently developed, which represents a rare example of regioselective Wacker oxidation reaction of 1,1-disubstituted alkenes.

Expanding the biosynthesis spectrum of hydroxy fatty acids: unleashing the potential of novel bacterial fatty acid hydratases

BackgroundHydroxy fatty acids represent an emerging class of compounds with promising applications in the chemical, medicinal and functional food sectors. The challenges associated with their chemical synthesis have spurred exploration of biological synthesis as an alternative route, particularly through the use of fatty acid hydratases. Fatty acid hydratases catalyse the regioselective addition of a hydrogen atom and a hydroxyl group from a water molecule to the carbon–carbon cis-double bond of unsaturated fatty acids to form hydroxy fatty acids. Despite having been discovered in the early 1960s, previous research has primarily focused on characterizing single fatty acid hydratase variants with a limited range of substrates. Comprehensive studies that systematically examine and compare the characteristics of multiple variants of fatty acid hydratases are still lacking.ResultsIn this study, we employed an integrated bioinformatics workflow to identify 23 fatty acid hydratases and characterized their activities against nine unsaturated fatty acid substrates using whole-cell biotransformation assays. Additionally, we tested a dual-protein system involving two fatty acid hydratases of distinct regioselectivity and demonstrated its suitability in enhancing the biosynthesis of di-hydroxy fatty acids.ConclusionsOur study demonstrates that fatty acid hydratases can be classified into three subtypes based on their regioselectivity and provides insights into their preferred substrate structures. These understandings pave ways for the design of optimal fatty acid hydratase variants and bioprocesses for the cost-efficient biosynthesis of hydroxy fatty acids.

Ru-Catalyzed Redox-Neutral Coupling of N-Chlorobenzamides with Unsymmetrical Alkynes in Water.

In water, Ru-catalyzed annulation of N-chlorobenzamides with unsymmetrical internal alkynes bearing aryl, hydroxy, ester, and sulfonyl functionalities has been accomplished to afford isoquinolone scaffolds under external oxidant-free conditions at room temperature. Use of water as reaction medium, redox-neutral conditions, regioselectivity, and substrate scope are important practical features.

Recent Updates on Pd‐Incorporated Ionic Liquids Catalyzed Suzuki Cross‐Coupling Reaction: A Mini‐Review

ABSTRACTIonic liquids (ILs) have been recognized for their potential as environmentally friendly solvents when compared to traditional organic solvents. Additionally, their function goes beyond that of solvents, and cocatalysts, as they frequently act as stabilizing agents and ligands for the metal‐active species and intermediates in catalytic systems. This comprehensive review primarily focuses on the application of Pd‐incorporated ILs in catalyzing cross‐coupling Suzuki reactions. The responses play a vital role in creating a wide range of structurally diverse and highly functionalized organic compounds, focusing specifically on nucleopalladation Suzuki coupling reactions. The review provides a detailed summary of the reaction conditions, stereoselectivity and regioselectivity, and the underlying mechanisms. Furthermore, it underscores crucial and characteristic illustrations, displaying the practical implementations of these coupling reactions. The aim of this review is to stimulate further research efforts, with the ultimate goal of expanding our understanding and utilization of ILs in various fields in the future.

Recent Advances in Transition Metal-Catalyzed Ring-Opening Reaction of Aziridine

The smallest strained, saturated N-heterocycles, such as aziridine, can be a valuable building block in synthetic organic chemistry. Ring-opening reactions with various nucleophiles could be the most important strategy to synthesize various value-added molecular entities. Therefore, regioselective ring-opening reactions of aziridines with various heteroatomic nucleophiles and carbon nucleophiles establish a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. The regio-selective ring-opening of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging for Lewis acid-promoted reactions. Therefore, the development of a robust, catalytic ring-opening process that assists in the accurate prediction of regioselectivity and stereochemistry is highly desirable. Consequently, a large number of publications detailing distinct methods for aziridine ring-opening reactions can be found in the literature. In this review, we discuss several transition metal catalyzed cross-coupling reaction protocols for the ring opening of substituted aziridines with various carbon nucleophiles.

Palladium-Catalyzed Cyclization and Direct Arylation of 1-[2-(2,2-Dibromoethenyl)phenyl]-1H-pyrrole with Allenes.

A novel and efficient palladium-catalyzed highly regioselective reaction of 1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole with allenes was realized to synthesize pyrrolo[1,2-a]quinolones. The tandem process involves intermolecular cyclization and intramolecular direct arylation, leading to the formation three new C-C bonds and two new rings. Notably, this transformation exhibits broad substrate scope and high functional group tolerance.

PhI(OAc)2-Promoted Site-Selective C-H Chlorination of (Hetero)arenes with p-Toluenesulfonyl Chloride.

An efficient and practical system for metal-free catalytic chlorination of (hetero)arenes by using readily available and inexpensive TsCl and PhI(OAc)2 is described. This newly developed protocol has been achieved by the nonsymmetric iodane generated by a combination of PhI(OAc)2 and TsCl. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and short reaction times make this method attractive for the late-stage chlorination of complex drug-like scaffolds.

Insight into the Course of the Ferrier Rearrangement Used to Obtain Untypical Diosgenyl Saponins.

The Ferrier rearrangement was utilized to obtain 2,3-unsaturated diosgenyl glycosides. This reaction proceeded with high stereoselectivity, yielding mostly saponins with an α configuration (hexoses) or predominantly with a β configuration (pentoses). The diversity of the glycals used and the glycosides obtained enabled a deep discussion of the Ferrier rearrangement mechanism. The mechanism was supported by DFT calculations concerning the intermediate ions. It was concluded that the vinylogous anomeric effect may influence the reactivity of the glycals. Two possible Ferrier rearrangement intermediates, dioxolenium and allyloxycarbenium ions, were hypothesized to exist in thermodynamic equilibrium that shifted toward the former. The allyloxycarbenium ion participates in the final rearrangement step and determines the reaction regioselectivity. Furthermore, the conformational stability of the 2,3-unsaturated pyranose ring determines the stereoselectivity of the reaction. Factors influencing this stability, as well as the NMR data enabling recognition of the 0H5 and 5H0 conformations, were identified. Chemoselective hydrogenation of 2,3-unsaturated diosgenyl glycosides provided a series of 2,3-dideoxy analogues. The anticancer, hemolytic, and antibacterial activities of the synthesized saponins are presented alongside a discussion of the structure-activity relationships.

Ag nanoparticles on arginine-cyanoguanidine functionalized magnetic g-C3N4: A catalyst for nitroaromatic hydrogenation and regioselective click reactions

This study describes the development of a novel hybrid nanocatalyst that was obtained by doping magnetic g-C3N4 with Ag nanoparticles and modifying it with arginine and cyanoguanidine (Ag@Fe3O4-g-C3N4-Arg-CG). Comprehensive characterization of the nanocatalyst using techniques such as FTIR, XRD, SEM, and TGA confirmed its structural and morphological properties. The catalytic efficiency of the synthesized nanostructure was evaluated in two key reactions: the reduction of nitroaromatic compounds and a click reaction for 1,2,3-triazole synthesis. The results demonstrate that Ag@Fe3O4-g-C3N4-Arg-CG effectively reduced various nitroaromatic compounds to substituted anilines at room temperature using NaBH4 as the reducing agent. Nitrobenzene reduction did not proceed in aprotic solvents such as acetonitrile, CH2Cl2, and dimethylformamide, whereas it exhibited a high reaction yield in protic solvents such as ethanol and water. The highest yield (100 %) was observed in water at 50 °C using H2O solvent. Additionally, the nanohybrid exhibited significant potential for “green” click chemistry by efficiently synthesizing 1,2,3-triazoles under mild conditions, with low catalyst loading. Its magnetic properties facilitated easy recovery, and the catalyst maintained high activity over six cycles, making it suitable for sustainable applications in organic transformations.

Benzoic Acid Serves as Precursor of Catalytic HAT Reagent in a Two-Molecule Photoredox System.

The photoinduced regioselective HAT reactions of acetals, ethers, and alcohols using benzoic acids in a two-molecule photoredox system led to the formation of new C-C bonds with alkenes under mild conditions. Aryl carboxy radicals generated from benzoic acids in a two-molecule photoredox system can function as catalytic HAT reagents, even though an excess amount of a hydrogen donor substrate is required. Various acetals, ethers, alcohols, and alkenes can be employed in the photoreaction to provide both high yields of adducts and high recoveries of benzoic acids.

Regioselective Synthesis of α-Vinyl Boronates via a Pd-Catalyzed Mizoroki-Heck Reaction.

We report a palladium-catalyzed synthesis of α-vinyl boronates via a regioselective Mizoroki-Heck reaction between aryl triflates and vinyl boronates. This selectivity is achieved by the use of a 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligand, which results in minimal formation of the more commonly observed (linear) β-product. The choice of base, solvent, and presence of water are shown to be critical for controlling this outcome, with organic bases, nonpolar solvents, and anhydrous conditions favoring the Heck product and suppressing the competitive Suzuki-Miyaura coupling product.

Photocatalyzed Direct C(sp3)-H Alkenylation of Unactivated Alkanes via Tandem C-C Activation of Cyclopropenes.

A highly adaptable method has been developed for the alkenylation of a broad spectrum of inert alkanes, employing milder reaction conditions. Tetrabutylammonium decatungstate (TBADT) serves as a photocatalyst for hydrogen atom transfer (HAT), instigating the formation of transient alkyl radicals through C(sp3)-H functionalization. These radicals exhibit regioselective addition to cyclopropenes, followed by the subsequent activation of C-C bonds, forming the corresponding vinylated derivatives. This methodology accommodates diverse unreactive C(sp3)-H bond motifs and multisubstituted cyclopropenes, enabling the efficient synthesis of highly functionalized olefins with high diastereoselectivity.