Regioselective Formation Research Articles

Regioselective Formation of Pyridines by Cycloaddition/Cycloreversion of 1,4-Oxazinone Precursors with Bisalkyne Substrates

AbstractThis study explores the merged cycloaddition/cycloreversion of a 1,4-oxazinone substrate and conjugated bisalkyne precursors. Good regioselectivity in the Diels–Alder operation is observed and pyridines bearing 3-alkynyl functionality are afforded following cycloreversion and extrusion of CO2. Examples with both symmetric and nonsymmetric bisalkyne substrates are included.

Regioselective synthesis of 4-arylamino-1,2-naphthoquinones in eutectogel as a confined reaction medium using LED light.

Predicting selectivity and conversion in a confined reaction medium under photochemical conditions is highly challenging as compared to the corresponding conventional synthesis. Herein, we report the use of a simple carbohydrate-derived eutectogel to facilitate LED-light-induced regioselective synthesis of 4-arylamino-1,2-naphthoquinones in good yield. This methodology, by including a reusable reaction medium, proved to have the potential of affording the regioselective formation of various desired products in good yields.

Photocatalytic intermolecular bromonitroalkylation of styrenes: synthesis of cyclopropylamine derivatives and their evaluation as LSD1 inhibitors.

A mild and efficient method for photoredox-catalyzed bromonitroalkylation of alkenes is described herein. In this reaction, bromonitromethane serves as a source of both nitroalkyl and bromine for direct and regioselective formation of C-Br and C-C bonds from alkenes, and additional cyclization provides C-C bonds to the cyclopropylamine core as an LSD1 inhibitor.

Ligand Control of Copper-Mediated Cycloadditions of Acetylene to Azides: Chemo- and Regio-Selective Formation of Deutero- and Iodo-Substituted 1,2,3-Triazoles.

The participation of σ-monocopper and σ-bis-copper acetylide in mechanistic pathways for copper-catalyzed cycloaddition (CuAAC) reactions of acetylene with azides was probed by analysis of deuterium distributions in the 1,2,3-triazole product formed by deuterolysis of initially formed mono- and bis-copper triazoles. The results show that, when Cu(Phen)(PPh3)2NO3 is used as the catalyst for reactions of acetylene with azides in DMF/D2O, 1-substituted-5-deutero-1,2,3-triazoles are generated selectively. This finding demonstrates that the Cu(Phen)(PPh3)2NO3-catalyzed cycloadditions utilize monocopper acetylide as the substrate and produce 5-copper-1,2,3-triazoles initially. Conversely, when DBU or Et3N is the copper ligand, the process takes place through initial formation and cycloaddition of bis-copper acetylide to produce 4,5-bis-copper-triazole, which reacts with D2O to form the corresponding 4,5-bis-deutero-triazole. Moreover, when C2D2 is used as the substrate, Cu(Phen)(PPh3)2NO3 as the Cu ligand, and H2O/DMF as the solvent, mono-C4-deutreo 1,2,3-triazoles are generated in high yields and excellent levels of regioselectivity. Lastly, CuAAC reactions of acetylene with azides, promoted by CuCl2·2H2O and NaI, yield 4,5-diiodo-1,2,3-triazoles with moderate to high efficiencies.

Kaskadenreaktionen von aryl‐substituierten terminalen Alkinen unter Beteiligung von in situ erzeugten α‐Imino‐Goldcarbenen

AbstractWir berichten über eine effiziente, hochselektive und divergente Synthesemethode zur Herstellung von 2‐substituierten Indolen und aryl‐anellierten Carbazolen über die intermolekulare Erzeugung von α‐Imino‐Goldcarbenen aus terminalen Alkinen oder Diinen in Kombination mit Sulfiliminen. Wichtig ist, dass die Tandemreaktion durch eine intermolekulare Goldcarbenbildung/C−H‐ Anellierung, gefolgt von der Aktivierung eines zweiten Alkins, die zu einer 6‐endo‐dig‐Zyklisierung führt, abläuft, was sich deutlich von früheren Ansätzen der dualen Aktivierung oder 1,6‐Carbenverschiebung für Diin‐Systeme unterscheidet. Im Falle von ortho‐Alkinylanilin als Ausgangsmaterial wurde eine unerwartete regioselektive Bildung der Indolkomponente über den intermolekularen Weg anstelle einer intramolekularen Hydroaminierung entdeckt. Diese Reaktivität ebnete den Weg für eine Eintopfsynthese des 11H‐Indolo‐[3,2‐c]‐Chinolin‐Gerüsts, indem das gebildete Aminoindol für eine anschließende Pictet–Spengler‐Reaktion mit Aldehyden genutzt wurde. Die photophysikalischen Eigenschaften der Carbazole zeigten eine gute violett‐blaue Emission mit Quantenausbeuten von bis zu 40 %.

Cascade Reactions of Aryl-Substituted Terminal Alkynes Involving in Situ-Generated α-Imino Gold Carbenes.

An efficient, highly selective and divergent synthetic method to construct 2-substituted indoles and aryl-annulated carbazoles via the intermolecular generation of α-imino gold carbenes from terminal alkynes or diynes in combination with sulfilimines is disclosed. Importantly, the tandem reaction is proposed to proceed through an intermolecular gold carbene generation/C-H annulation followed by the activation of a second alkyne leading to 6-endo-dig cyclization, which is significantly different from previous dual activation or 1,6-carbene shift approaches for diyne systems. In the case of ortho-alkynylaniline as starting material, an unexpected regioselective formation of the indole moiety via the intermolecular path, instead of intramolecular hydroamination was discovered. This reactivity paved the way for a one-pot synthesis of the 11H-indolo [3,2-c] quinoline scaffold by exploiting the formed amino indole for a subsequent Pictet-Spengler reaction with aldehydes. The photophysical properties of the carbazoles indicated good violet-blue emission with quantum yields up to 40 %.

Mechanistic Studies of Regiocontrolled Bisaddition of Fullerenes Driven by Oriented External Electric Fields.

The challenge of achieving regioselective multifunctionalization on highly symmetric C60 and C70 fullerenes persists as a significant hurdle. In this study, we present a novel approach involving the participation of an oriented external electric field (OEEF) to facilitate the regioselective formation of bisadducts in C60/C70 fullerenes. These products are obtained through consecutive Diels-Alder cycloaddition reactions. We constructed the field strength-barrier relationship and elucidated the OEEF-driven modulation mechanisms quantitatively. Leveraging the interplay between molecular dipoles and electric fields, the diverse reactions at distinct sites exhibit varying degrees of sensitivity to the applied electric fields, thereby leading to a pronounced regioselectivity in the bisaddition process. Our proposition suggests that the angle formed between the bonding direction (referred to as the reaction axis) and the external field can conveniently function as a predictive descriptor for the reactivity of different sites on the fullerene surface when subjected to electric fields.

Theoretical insight into the regioselective formation of pyrazolo[1,4]-oxazepine and -oxazines

AuCl-, AuCl3-, or AuClPEt3-catalyzed formation mechanisms of pyrazolo[1,4]oxazepines and the NaH-promoted mechanism of pyrazolo[1,4]oxazines were investigated computationally. The structural properties of the reactants were studied in various solvents and with different functionals. The hybrid functionals B3LYP, M06, M06-2X, PBEPBE, and wB97X-D in density functional theory were used to determine and discuss the energetics of the compounds. The electronic properties of groups (R = H or R ≠ H) attached to the alkyne moiety played an essential role in the corresponding 7-endo-dig cyclization or 6-exo-dig cyclization in the presence of a gold catalyst. The regioselectivities of the products were investigated, and the natural bond orbitals of the reactants were determined. Furthermore, a gold-catalyzed alternative mechanism is suggested for synthesizing pyrazolo[1,4]oxazines using a terminal alkyne (R = H) moiety as substrate.

Butterfly-Shaped Dibenz[a,j]anthracenes: Synthesis and Photophysical Properties.

A strategy for the synthesis of dibenz[a,j]anthracenes (DBAs) from cyclohexa-2,5-diene-1-carboxylic acids is presented. Our approach involves sequential C-H olefination, cycloaddition, and decarboxylative aromatization. In the key step for DBA skeleton construction, the bis-C-H olefination products, 1,3-dienes, are utilized as substrates for [4 + 2] cycloaddition with benzyne. This concise synthetic route allows for regioselective ring formation and functional group introduction. The structural features and photophysical properties of the resulting DBA molecules are discussed.

Total syntheses and antibacterial evaluations of cudraflavones A-C and related Flavones

The total syntheses of the natural prenylated flavones cudraflavones A–C (1–3), artoheterophyllin D (28) and artelasticin (29) are reported, along with the evaluations of their antibacterial activities. The key steps of the synthesis involved a Baker-Venkataraman rearrangement and an intramolecular cyclization for the construction of the flavone core and the regioselective formation of the pyran and isopentenyl scaffolds. The tested natural flavones 1–3 and 27–29 exhibited potent activity against S. aureus ATCC 29213, S. epidermidis ATCC 14990, E. faecalis ATCC 29212 and B. subtilis ATCC 6633 with MIC values ranging from 0.125 μg/mL to 16 μg/mL. Compound 3 displayed the strongest potency, with MIC values in the range between 0.125 and 1 μg/mL, as a potential candidate to combat G+ bacterial infections. Preliminary mechanism of action studies suggested that this compound killed bacteria by disrupting bacterial membrane integrity.

Highly Regioselective Synthesis of 3,6‐Diaryl‐2‐(het)arylpyridines by aza‐Diels‐Alder Reactions between 6‐H‐1,2,4‐Triazine Dienes and 2‐Amino‐4‐aryloxazole‐Based Dienophiles

AbstractA solvent‐free reaction between C6‐unsubstituted 5‐aryl‐1,2,4‐triazines and 2‐amino‐4‐aryloxazoles at high temperature was studied. The reaction proceeds via inverse electron demand aza‐Diels‐Alder reaction between the oxazole moiety as dienophile and the 1,2,4‐triazine moiety as diene with the highly regioselective formation of 3,6‐diarylpyridines in up to 60 % isolated yield. The structure of one of the key‐products was proven by the X‐ray diffraction analysis, and the mechanism of the transformation was proposed. The reaction proceeds well for both 6‐aryl and 6‐hetaryl‐1,2,4‐triazines in the presence of the electron acceptor substituent at the position 3. In the case of the donor substituent in position 3, the pyridine yields are significantly reduced. In the case of 5,6‐nonsubstituted 1,2,4‐triazines, the triazine cycle is degraded without product formation. The high regioselectivity of the reaction as well as solvent‐free conditions are valuable advantages of the present synthetic approach.

Chemical synthesis of insulin-like peptide 1 and its potential role in vitellogenesis of the kuruma prawn Marsupenaeus japonicus.

The insulin superfamily comprises a group of peptides with diverse physiological functions and is conserved across the animal kingdom. Insulin-like peptides (ILPs) of crustaceans are classified into four major types: insulin, relaxin, gonadulin, and androgenic gland hormone (AGH)/insulin-like androgenic gland factor (IAG). Of these, the physiological functions of AGH/IAG have been clarified to be the regulation of male sex differentiation, but those of the other types have not been uncovered. In this study, we chemically synthesized Maj-ILP1, an ILP identified in the ovary of the kuruma prawn Marsupenaeus japonicus, using a combination of solid-phase peptide synthesis and regioselective disulfide bond formation reactions. As the circular dichroism spectral pattern of synthetic Maj-ILP1 is typical of other ILPs reported thus far, the synthetic peptide likely possessed the proper conformation. Functional analysis using ex vivo tissue incubation revealed that Maj-ILP1 significantly increased the expression of the yolk protein genes Maj-Vg1 and Maj-Vg2 in the hepatopancreas and Maj-Vg1 in the ovary of adolescent prawns. This is the first report on the synthesis of a crustacean ILP other than IAGs and also shows the positive relationship between the reproductive process and female-dominant ILP.

Merging decatungstate photocatalysis and copper‐catalyzed azide‐alkyne cycloaddition reaction for the formation of 1,2,3‐triazoles in water†

Merging photoredox and catalysis by transition metals, coined as metallaphotoredox catalysis, proved to be an excellent new platform for the development of new synthetic strategies for the formation of carbon–carbon and carbon‐heteroatom bonds. Herein, we report a dual catalytic system that has been successfully developed for the azide‐alkyne ligation process to yield 1,4‐disubstituted‐1,2,3‐triazoles. It consists of merging the decatungstate anion [W10O32]4−‐photocatalyzed hydrogen atom transfer from ethanol as a source of hydrogen atom abstraction to produce the one‐electron‐reduced form H+[W10O32]5−, which reduces Cu(II) precursor into Cu(I) starting then the copper‐catalyzed azide‐alkyne cycloaddition reaction (CuAAC). The resulting bifunctional H+[W10O32]5−/Cu catalytic system operates efficiently in an environmentally benign water–ethanol solvent mixture as reaction medium, resulting in the regioselective formation of 1,4‐disubstituted‐1,2,3‐triazole derivatives, with high yields up to 99% and large substrate application scope under mild conditions. This dual catalytic approach has proven to function under sunlight exposition too with recovery and reuse of the catalytic system for several times.

Reactivity of the Iboga Skeleton: Oxidation Study of Ibogaine and Voacangine.

The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio- and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C16-carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C3-oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C7 in the 7-hydroxyindolenine of voacangine was revised to be S, which corrects previous reports proposing an R configuration.

Highly functionalized dispiropyrrolidine embedded indandione hybrids as potent cholinesterase inhibitors

New class of highly functionalized dispiropyrrolidine tethered indandione heterocycles in good yield were obtained through stereo- and regioselective single-pot three component cycloaddition methodology between benzylidene-indandione and non-stabilized azomethine ylide. The ylide generated from active diketone and aminophenylpropanoic acid via dehydration/decarboxylative pathway. The synthesized dispiropyrroldine comprising indandiones were elucidated through 1H and 13C NMR spectroscopic analysis, the stereo and regioselective formation of the dispiropyrrolidine were unequivocally assigned by X-ray diffraction analysis. Compound thus synthesized were assayed as potential inhibitor for the treatment of AD. Spiropyrrolidine 4h that bearing methoxy group on the phenyl ring showed significant activity, IC50 of 3.24 ± 0.25 and 10.25 ± 0.16 μM against acetyl and butyryl cholinesterase enzyme, respectively. The lead compound 4h executed to investigate for their docking simulation that showed strong binding affinity with binding site of the cholinesterase protein.

Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles.

Carbofunctionalization of Terminal Alkynes via Rhodium Catalysis Enabling Formations of Four Different Bonds.

Described here is the oxygenative carbofunctionalization of terminal alkynes mediated by combined rhodium catalysis that enables regioselective quadruple formation of C-C, C-H, C-O, and C-heteroatom bonds. Mechanistic studies suggest that a disubstituted rhodium vinylidene complex is generated upon C-C bond formation at the terminal alkyne with tethered electrophiles such as alkyl halides, aldehydes, imines, and Michael acceptors. Subsequent intermolecular transfer oxygenation of the rhodium vinylidene with pyridine N-oxide generates a rhodium-complexed ketene intermediate that reacts with a variety of heteroatom nucleophiles to give rise to cyclic carboxylic acid derivatives.

Metal-Free Intermolecular Allylic C–H Amination of Alkenes Using Primary Carbamates

The allylic C–H amination of alkenes is a powerful method for the regioselective formation of new C–N bonds. Though many methods for introducing a wide range of nitrogen groups intermolecularly have been developed, few of these utilize carbamates, which are an important class of bioactive compounds and are commonly used as protecting groups for free amines. Here, we report a convenient metal-free protocol for intermolecular allylic C–H amination using unactivated primary carbamates as the nitrogen source. A sterically hindered NHC-selenium catalyst was found to be critical to obtaining high yields. A wide range of trisubstituted and 1,1-disubstituted alkenes were regioselectively aminated, including terpenoid natural products. A range of common carbamate-protecting groups such as Cbz, Teoc, and Alloc could be successfully incorporated into alkene substrates. Additionally, trifluoroacetamide was shown to be a viable nitrogen source. The observed regio- and stereoselectivities can be explained by a sequential ene reaction/[2,3]-sigmatropic rearrangement mechanism in which cis C–H bonds are preferentially activated, but subsequent rearrangement results in selective formation of trans alkene products.

Rhodium‐Catalyzed Chemo‐, Regio‐, Diastereo‐, and Enantioselective Intermolecular [2+2+2] Cycloaddition of Three Unsymmetric 2π Components

AbstractWe have developed the Rh+/H8‐binap‐catalyzed chemo‐, regio‐, diastereo‐, and enantioselective intermolecular [2+2+2] cycloaddition of three unsymmetric 2π components. Thus, two arylacetylenes react with a cis‐enamide to yield a protected chiral cyclohexadienylamine. Moreover, replacing one arylacetylene with a silylacetylene enables the [2+2+2] cycloaddition of three distinct unsymmetric 2π components. These transformations proceed with excellent selectivity (complete regio‐ and diastereoselectivity and up to >99 % yield and >99 % ee). Mechanistic studies suggest the chemo‐ and regioselective formation of a rhodacyclopentadiene intermediate from the two terminal alkynes.

Rhodium-Catalyzed Chemo-, Regio-, Diastereo-, and Enantioselective Intermolecular [2+2+2] Cycloaddition of Three Unsymmetric 2π Components.

We have developed the Rh+ /H8 -binap-catalyzed chemo-, regio-, diastereo-, and enantioselective intermolecular [2+2+2] cycloaddition of three unsymmetric 2π components. Thus, two arylacetylenes react with a cis-enamide to yield a protected chiral cyclohexadienylamine. Moreover, replacing one arylacetylene with a silylacetylene enables the [2+2+2] cycloaddition of three distinct unsymmetric 2π components. These transformations proceed with excellent selectivity (complete regio- and diastereoselectivity and up to >99 % yield and >99 % ee). Mechanistic studies suggest the chemo- and regioselective formation of a rhodacyclopentadiene intermediate from the two terminal alkynes.