Regioselective Research Articles

Double Regioselective Thermal Azide-Alkyne Cycloaddition of 1,3-Diynes.

A double regioselective cycloaddition reaction of 1,3-diynes with azide is reported to synthesize fully substituted 5-alkynyl-1,2,3-triazoles without any catalyst, metal, or other factor. Computational studies revealed that the 5-alkynyl-1,2,3-triazole derivative is both kinetically and thermodynamically favorable irrespective of the nature of the substituents at the alkyne termini in 1,3-diynes. The simplicity of the reaction, extremely high regioselectivity under metal-free conditions, wide substrate scope, and good to excellent yields might inspire further studies of the cycloaddition of 1,3-diynes in addition to click chemistry.

Synthesis of the First Representatives of new 3,3a‐Dihydro‐1H‐Imidazo[4′,5′:4,5]Imidazo[2,1‐b]thia(selena)zole Heterocyclic Systems with Fungicidal Activity

AbstractThe first representatives of new fused tricyclic heterosystems, namely 3,3a‐dihydro‐1H‐imidazo[4′,5′:4,5]imidazo[2,1‐b]thiazoles and 3,3a‐dihydro‐1H‐imidazo[4′,5′:4,5]imidazo[2,1‐b][1,3]selenazoles have been synthesized through the regioselective reaction of diethyl acetylenedicarboxylate with semithioglycolurils, thioglycolurils or selenoglycolurils. Study of antifungal properties of the obtained compounds against Venturia inaequalis (V. i.), Rhizoctonia solani (R. s.), Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana (B. s.) and Sclerotinia sclerotiorum phytopathogenic fungi has been performed. Tested compounds possessed good inhibition activity against R. s., B. s. with 45–94 % by mycelium growth inhibition test method, which were more active than the well–known azole fungicide triadimefon as positive control. The best active thiazole derivative was established to be effective against R. s. (94 %), B.s. (65 %) and V. i. (60 %). Two selenazole derivatives showed good activity with 69 % inhibition against R. s.

Synthesis of new representatives of A3B-type carboranylporphyrins based on meso-tetra(pentafluorophenyl)porphyrin transformations.

A carboranylporphyrin of A3B-type bearing a single pentafluorophenyl ring was prepared through the regioselective nucleophilic aromatic substitution reaction of the p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin with 9-mercapto-m-carborane. The reaction of this porphyrin with sodium azide led to the selective substitution of the p-fluorine atom in the pentafluorophenyl substituent with an azide functionality which upon reduction with SnCl2 resulted in the formation of the corresponding porphyrin with an amino group. Pentafluorophenyl-substituted A3B-porphyrins were studied and transformed to thiol and amino-substituted compounds allowing for the preparation of porphyrins with different reactive groups such as hydroxy and amino derivatives capable for further functionalization and conjugation of these porphyrins to other substrates. In addition, conjugates containing maleimide or biotin entities in the structure of carborane A3B-porphyrin were also synthesized based on the amino-substituted A3B-porphyrin. The structures of the prepared carboranylporphyrins were determined by UV-vis, IR, 1H, 19F, 11B NMR spectroscopic data and MALDI mass spectrometry.

Regioselective cation exchange reaction for photoelectrochemical water splitting

Regioselective cation exchange reaction for photoelectrochemical water splitting

Tandem Electrochemical Oxidation of Polycyclic Aromatic Amines Towards Carbazoles and Phenazine-based Aza-helicenes.

Experimental and theoretical study of the regioselectivity and mechanism of polycyclic aromatic amine (PAA) electrochemical oxidation is important for designing nitrogen doped large π-conjugated functional molecules. Herein, we used binary-, ternary-, and quaternary-fused PAAs as electro-oxidative reaction substrates to investigate the yield changes of carbazole and phenazine based aza-helicene other than oligomers, which were obtained through pyrrole and pyrazine annulation pathways. Combined with the restrained electrostatic potential (RESP) and steric hindrance factor analysis of the substrate, the electron spin density distribution of free radical resonance hybrid and the spin population analysis of the atoms in the structure of each free radical tautomer indicate that the degree of delocalized dispersion of N free radical and the resulting change in the spin density distribution of C free radical tautomers determine the reaction regioselectivity. The potential charge of the K-region, Bay-region, and L-region adjacent to the C(α)-C(β1) bond is higher than that of other regions within the molecule, and the charge in these high RESP regions tends to delocalize more strongly toward electron-deficient N free radicals. Thus, the activity of N-C(α)-C(β1) region is increased, which supports the proposed free radical addition and free radical coupling mechanism for the electro-oxidative reaction of PAA.

Stereo and regioselective addition of N-heterocycles on internal alkynes through C[sbnd]N bond formations

We report, regio and stereoselective addition of N-heterocycles on internal alkynes through C(sp2)-N(sp3) bond formation. We have synthesized a series of 1H-indole, 1H-benzimidazole and tetrahydroquinolines (THQ) functionalized Maleate, Fumarate and Acrylate derivatives through N- alkenylation reactions. We have demonstrated the selective formation of E- Isomers. Further substrate dependent formation of E and Z isomers are also observed.

Regioselective amination of 4-methylene-5,7-dinitroquinazoline: a mechanistic consideration on non-conventional N-H—π interactions between amine and ethylene moiety

ABSTRACT Pi (π) interactions originating from the N-H bond of amine and ethylene moiety have been explored on the mechanism of aromatic nucleophilic substitution (ArSN) of the nitro group of 4-methylene-5,7-dinitroquinazoline with methylamine in the gas phase and solvent media within DFT framework. The free energy profiles confirmed that the amination should take place at peri-position and calculations support the one-step mechanism through a transition state with no intermediate in the reaction route. Stabilisation of peri-transition state by intramolecular weak interaction akin to hydrogen bonding N-H—CH2 = C leads to the regioselective amination at peri-position of 4-methylene-5,7-dinitroquinazoline. The intramolecular hydrogen bond interactions at N-H—CH2 = C in the peri-transition state are strongly supported by a red shift in N-H stretching vibrations in simulated IR spectra and are confirmed by studying energetics of amination of structural/electronic analogues of 4-methylene-5,7-dinitroquinazoline. The present study established that ethylene plays an important role as an efficient H-bond acceptor in fixing the regioselectivity at peri-position in the amination of 4-methylene-5,7-dinitroquinazoline. This is the first-ever report for the exploration of the role of ethylene moiety as a hydrogen bond acceptor in mediating the regioselectivity of organic reactions.

Electrochemically driven regioselective organoselenation for selective synthesis of β- hydroxy substituted selanylated ketones

A simple yet efficient approach towards the synthesis of β-hydroxy selanylated ketones was developed from easily accessible chalcones and diphenyl diselenide through an electrochemical pathway. In this technique, diphenyl diselenide and water are the source of PhSe. and hydroxyl (–OH) groups that can be inserted at the α and β positions respectively producing β-hydroxy selanylated ketones in moderate to good yields. The reaction features difunctionalization of ketones, catalyst free, mild reaction conditions, stereo and regioselectivity in an undivided electrochemical cell at room temperature. For this transformation, a plausible radical mechanism has been put out.

Chemodivergence in Fluorine Source-Controlled Cascade Reaction of Aryne Precursors to Synthesize Pyrrolo[3,4-b]indoles and 3-Arylated Maleimides.

Reactions allowing chemodivergence prove to be attractive strategies in synthetic organic chemistry. We herein described a highly practical, transition-metal-free, highly regioselective and chemodivergent cascade reaction controlled by fluorine sources, which involved a [3 + 2] cycloaddition or C-arylation process between aryne precursors and 3-aminomaleimides. These two pathways led to a wide scope of structurally diverse pyrrolo[3,4-b]indoles (19 examples) and 3-arylated maleimides (25 examples) in good-to-excellent yields. Furthermore, the reaction could be scaled up, and several synthetic transformations were accomplished for the preparation of functionalized molecules and might provide new opportunities for the discovery of N-heterocyclic drugs.

Nucleophilic Addition of Amides to Haloalkynes: Synthesis of (Z)-β-Halovinyl Amides as Dual Precursors of Alkylidene Carbenes and Allyl Halides.

Toward a regioselective method for the synthesis of β-halovinyl amides, we developed a transition-metal-free nucleophilic addition reaction of amides to haloalkynes. The regioselective nucleophilic addition was achieved under solvent-free conditions using phosphonates to protonate the intermediate alkylidene carbenoids, thus suppressing their decomposition. Furthermore, we demonstrate that β-halovinyl amides can serve as dual precursors of allyl halides and alkylidene carbenes to obtain functionalized indoles and pyrrolidones.

A Bimolecular Homolytic Substitution-Enabled Platform for Multicomponent Cross-Coupling of Unactivated Alkenes.

The construction of C(sp3)-C(sp3) bonds remains one of the most difficult challenges in cross-coupling chemistry. Here, we report a photoredox/nickel dual catalytic approach that enables the simultaneous formation of two C(sp3)-C(sp3) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction harnesses a bimolecular homolytic substitution (SH2) mechanism and chemoselective halogen-atom transfer (XAT) to orchestrate the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes without the need for a directing auxiliary. Utility is highlighted through late-stage (fluoro)alkylation and (trideutero)methylation of C═C bonds bearing different substitution patterns, offering straightforward access to drug-like molecules comprising sp3-hybridized carbon scaffolds.

Synthesis of 2-aryl quinoxaline derivatives and their in silico investigation for breast cancer medication

The main objective of the present work is to synthesize and identify the potential breast cancer medication of 2-aryl quinoxaline ­derivatives via in silico investigations. Synthesis of 2-aryl quinoxaline derivatives have been achieved via the reaction of 3-aroylmethylene-2H-indol-2-ones 1 with various 1,2-diamines. Good yields were obtained at 60 °C in methanol by using graphene oxide (GO) as catalyst, however, the regio selectivity in case of unsymmetrically substituted diamines were low to moderated. This is the first report of the oxidative cleavage of C = C bond during the course of the reaction. Molecular docking study of these synthesized compounds were employed to calculate the binding affinity with human epidermal growth factor receptor 2 (HER2). 6-Bromo-3-phenylpyrido[2,3-b]pyrazine 3k showed highest binding energy of −7.70 kcal/mol depicting the potential inhibitor of HER2 receptor protein. However, this study needs to be supported by in vitro and in vivo studies.

Synthesis of Multisubstituted 1,2,3-Triazoles: Regioselective Formation and Reaction Mechanism.

A synthetically useful approach to functionalized triazoles is described via the reaction of β-carbonyl phosphonates and azides. 1,4- and 1,5-disubstituted and 1,4,5-trisubstituted triazoles can be regio- and chemoselectively accessed under mild conditions in good to excellent yields (31 examples, up to 99%). A mechanism is proposed that rationalizes the avoidance of the 4-phosphonate byproducts, which is aligned with crystallographic and experimental evidence.

Copper-catalyzed stereo- and regioselective borylalkylation of silicon-tethered haloalkyl alkynes to access borylated benzosilolines

An efficient and practical route for the preparation of various functionalized benzosiloline derivatives via copper-catalyzed stereo- and regioselective borylalkylation reaction has been developed. Starting from silicon-tethered haloalkyl alkynes, a series of valuable benzosiloline and 2,3-dihydro-1-sila-1H-phenalene frameworks possessing a borylated exo-vinylidene moiety were efficiently prepared, which have high synthetic utility and are difficult to obtain in other aspects.

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann-Löffler-Freytag Reaction.

The Hofmann-Löffler-Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted. However, the obtained spectra lack the distinct features of the N-centered radicals expected for the employed reactants. This paper presents phenylbutylnitrone spin-trapped C-centered and N-centered radicals, generated via light irradiation from N-halogen-tosyl-sulfonamide derivatives and detected using EPR spectroscopy. NMR spectroscopy and DFT calculations are used to explain the observed regioselectivity of the HLF reaction.

Microwave-assisted palladium-catalyzed conjugate addition of arylsilanes to alkynes

Organosilanes, extensively employed as nucleophiles in coupling reactions, have seen limited application in the catalytic regioselective addition to unsaturated hydrocarbons. In this study, we present a microwave-assisted, palladium-catalyzed conjugate addition reaction involving arylsilanes and activated alkynes. This methodology for the catalytic functionalization of alkynes with organosilicon reagents offers a straightforward route to creating multisubstituted alkenes, boasting high regioselectivity. This efficient and versatile reaction tolerates a broad range of functional groups and substrates, heralding a potent new avenue in synthetic strategy.

Upper Rim-Bridged Calix[4]arenes via Cyclization of meta Alkynyl Intermediates with Diphenyl Diselenide.

A Sonogashira coupling of meta-iodocalix[4]arene with various terminal acetylenes confirmed that the meta position of calixarene is well addressable, and that both thermal and microwave protocols led to good yields of alkynylcalixarenes. Alkynes thus obtained were subjected to the ferric chloride and diphenyl diselenide-promoted electrophilic closure. It turns out that the calix[4]arenes give completely different bridging products than those described for the non-macrocyclic starting compounds. This can be demonstrated not only by the isolation of products with a six-membered ring (6-exo-dig), but mainly by the smooth formation of the 5-endo-dig cyclization, which has never been observed in the aliphatic series. An attempt at electrocyclization led to a high yield of the 1,2-diketone (oxidation of the starting alkyne), again in contrast to the reaction described for the acyclic derivatives. The structures of the unexpected products were unequivocally established by X-ray analysis and clearly demonstrate how the preorganized macrocyclic skeleton favors a completely different regioselectivity of cyclization reactions compared to common aliphatic compounds.

Effective Synthesis of N-Alkyl-3-(Indol-3-yl)Pyrazoles from Ag2CO3-Catalyzed Regioselective Aza-Michael Addition of 5-(Indol-3-yl)-1HPyrazoles

Abstract: In this study, the synthesis of N-alkyl-3-(indol-3-yl)pyrazoles was carried out from Ag2CO3 catalyzed regioselective aza-Michael addition of 5-(indol-3-yl)-1H-pyrazoles to a, bunsaturated carbonyl compounds. In the presence of 10 mol% of Ag2CO3, the reaction smoothly occurred in dichloroethane (DCE) at 120oC to preferentially afford a series of N-alkyl-3-(indol-3- yl)pyrazoles in high yields with good regioselectivity. It was found that 1-methyl-3-(3-methyl-1Hpyrazol- 5-yl)-2-phenyl-1H-indole, 1-benzyl-3-(3-methyl-1H-pyrazol-5-yl)-1H-indole, a, b-unsaturated ketone, and a, b-unsaturated amide exclusively gave 3-(pyrazol-3-yl)indoles in good yields. This reaction features high regioselectivity, mild reaction conditions, good substrate scope and yields, and a commercially available catalyst. Meanwhile, the reaction was also proven to be quite practical by the gram-scale synthesis of N-alkyl-3-(indol-3-yl)pyrazoles in excellent yields with good regioselectivity.

µSR studies for radical reactions of unsaturated organophosphorus compounds

In this paper, the µSR studies of some unsaturated organophosphorus compounds containing heavier congeners of cyclobutane-1,3-diyl and anthracene are reviewed by discussing the usefulness of µSR for main group chemistry. The regioselective addition of muonium (Mu = [µ+e–]) to one of the skeletal phosphorus atoms in an electron-donating air-stable crystalline 1,3-diphosphacyclobutane-2,4-diyl leading to the paramagnetic 4-membered P-heterocycle was characterized by the Δ1 (ΔM = ± 1) resonance signal observed by muon (avoided) level-crossing resonance (µLCR). Meanwhile, a crystalline 1,3-diphosphacyclobutane-2,4-diyl bearing an electron-deficient nitrogen heterocyclic unit was analyzed by transverse-field muon spin rotation (TF-µSR) to characterize predominant muoniation at the skeletal radical carbon centre. A 9-phosphaanthracene bearing the trifluoromethyl (CF3) stabilizing groups at the peri positions was also investigated from the views of radical reactivity, and the regioselective addition of muonium to the skeletal sp2-type phosphorus atom was characterized by the muon hyperfine coupling (hfc) constant observed by TF-µSR and the Δ0 (ΔM = 0) signal of µLCR. The light mass of muon (Mass = 0.1134 amu) causes the larger zero-point energy and promotes the high-energy molecular structure in which the fused aromatic rings are almost flat, although the CF3 groups would prefer the non-planar saddle-like 9-phosphaanthracene skeleton.

Radical Nitrososulfonation of Propargyl Alcohols: Thiazolidine-2,4-dione-Assisted Synthesis of 5-Alykyl-4-sulfonylisoxazoles.

In this study, we discover a good NO/HNO precursor, N-hydroxypyridinesulfonamide, and the regioselective radical nitrososulfonylation reaction of propargyl alcohols. Direct and unique isoxazole synthesis afforded a good-to-high yield of 5-alkyl-3-aryl-4-pyridinesulfonylisoxazoles. Copper-catalyzed aerobic oxidation could efficiently proceed in the presence of thiazolidine-2,4-dione. This work provides a powerful method for the synthesis and functionalization of alkyl-substituted isoxazoles and explores a new investigation route for drug-drug discovery.