Complete Regioselectivity Research Articles

Regioselective Construction of Indolylated Cyclic Tetrasubstituted Carbon Centers through Brønsted Acid‐Catalyzed Dearomative Skeletal Rearrangement of Azofurans

AbstractA Brønsted acid‐catalyzed dearomative skeletal rearrangement of azofurans with indoles is reported, enabling a regioselective 1,6‐addition, ring‐opening and 1,4‐addition cascade to produce 26 examples of indolylated pyrrol‐2‐ones with a cyclic tetrasubstituted stereocenter in 58–94% yields. This protocol demonstrates remarkable compatibility regarding azofurans and indoles with different substitution patterns, featuring complete regioselectivity.

Catalyst‐Controlled Divergent C3/C5 Site‐Selective C−H Arylation of 2‐Pyridylthiophenes

AbstractThe development of a rational protocol to realize the complete regioselectivity and the capability to switch regioselectivity is an appealing yet challenging task. Herein, a regiodivergent C−H arylation of 2‐pyridylthiophenes has been demonstrated via the choice of RuII and PdII catalysts. The reactions proceeded smoothly in a good regioselective manner to afford the corresponding C3‐ and C5‐arylated thiophenes. Late‐stage diversification of biologically relevant scaffold derived from estrone and successful transformation of the products further highlighted the potential utility and importance of this synthetic strategy.

Visible‐Light‐Mediated Synthesis of Bicalutamide by Regioselective Hydroxysulfonylation of Acrylamides

AbstractSynthesis of anticancer drug bicalutamide promoted by visible light in one step from the corresponding N‐arylacrylamide is described. This approach involves a one‐pot hydroxysulfonylation reaction through a photocatalytic redox process. The use of Na2Eosin Y as photocatalyst and blue light allows the access to a broad range of α‐hydroxysulfonylamides bearing a quaternary center in moderate to good yields with complete regioselectivity via radical process.

Electrophilic C3−H Alkenylation of 2,6‐Dialkoxypyridine Derivatives via Pd(II)/Tl(III) Reaction System

AbstractHerein, we report the reaction system based on Pd(II) catalyst and Tl(OCOCF3)3 for the electrophilic C3−H alkenylation of 2,6‐dialkokypyridines with alkenes. Synergistic action of the Pd/thioether ligand catalytic system and Tl(III) results in efficient C−H alkenylation of various nitrogen heteroaromatics with complete regioselectivity. Remarkably, the use of a sterically hindered thioether ligand and the Pd(II)/Tl(III) system enables mono‐selective C3(5)−H alkenylation of 2,6‐dialkoxypyridines, and subsequent introduction of a second, different alkene affords unsymmetrical, multi‐substituted pyridine derivatives. Mechanistic studies indicate that the reaction proceeds via electrophilic thallation of heteroarenes followed by Pd‐catalyzed Heck‐type reaction. The utility of this method is showcased by its application to the late‐stage functionalization of structurally complex bioactive molecules having 2,6‐dialkoxypyridine as a core structure.

Substituent‐Controlled Regiodivergent Palladium‐Catalyzed Annulative Dearomatization of Phenols toward Skeletally Diverse Spirocyclohexadienones

AbstractA palladium‐catalyzed intermolecular dearomative formal [4+2] annulation of phenols with propargyl electrophiles is reported, enabling substituent‐controlled regiodivergent synthesis of a wide range of skeletally diverse spirocyclohexadienones with good yields. The regiodivergence could be precisely controlled by adjusting the steric hindrance of O‐ and N‐substituents from binucleophilic substrates, where substrates with an O‐nucleophilic site were converted into spiro[chromane‐4,1′‐cyclohexane]‐2′,5′‐dien‐4′‐ones with complete regioselectivity and (Z)‐selectivity, whereas N‐nucleophiles enabled a different regiodivergent process to access spiro[cyclohexane‐1,4′‐quinoline]‐2,5‐dien‐4‐ones.

Green Chemistry Approach toward the Regioselective Synthesis of α,α-Disubstituted Allylic Amines.

Molybdenum-catalyzed allylic substitution reactions are known to provide direct and practical ways to construct new carbon-carbon bonds and privileged compounds. However, due to the lack of reports on carbon-heteroatom bond formation as a common deficiency, these reactions still face a great challenge. Described herein is a robust and convenient molybdenum-catalyzed regioselective allylic amination of tertiary allylic carbonates with an amine as the heteroatom nucleophile. Both aromatic and aliphatic amines react with various tertiary allylic alcohol derivatives to deliver the desired α,α-disubstituted allylic amines in high yield with complete regioselectivity. In addition, ethanol as the green solvent, a recyclable catalyst system through simple centrifugation techniques, and simple handling procedures make the current approach green, economic, and sustainable.

Regioselective and Stereospecific β-Arabinofuranosylation by Boron-Mediated Aglycon Delivery.

Regio- and stereoselective formation of the 1,2-cis-furanosidic linkage has been in great demand for efficient synthesis of biologically active natural glycosides. In this study, we developed a regioselective and β-stereospecific d-/l-arabinofuranosylation promoted by a boronic acid catalyst under mild conditions. The glycosylations proceeded smoothly for a variety of diols, triols, and unprotected sugar acceptors to give the corresponding β-arabinofuranosides (β-Arbf) in high yields with complete β-stereoselectivity and high regioselectivity. The regioselectivity was completely reversed depending on the optical isomerism of the donor used and was predictable a priori using predictive models. Mechanistic studies based on DFT calculations revealed that the present glycosylation occurs through a highly dissociative concerted SN i mechanism. The usefulness of the glycosylation method was demonstrated by the chemical synthesis of trisaccharide structures of arabinogalactan fragments.

Regioselective N-alkylation of 2-amino-azoles with alcohols for the synthesis of 2-N-(alkylamino)azoles catalyzed by a ruthenium complex bearing a functional ligand

A ruthenium complex bearing a functional ligand [(p-cymene)Ru(2,2′-bpyO)(H2O)] was found to be a general and efficient catalyst for the direct N-alkylation of 2-amino-azoles with alcohols to 2-(N-alkylamino)zoles. In the presence of catalyst (0.5 mol %), a range of desirable products were obtained with complete regioselectivity. Mechanistic experiments supported that functional groups in bpy ligand are crucially important for the catalytic activity of ruthenium complexes. Notably, this research would facilitate the progress of metal–ligand bifunctional catalysts for the hydrogen autotransfer process.

Access to Polysulfides through Photocatalyzed Dithiosulfonylation.

In this study, we outline a general method for photocatalyzed difunctionalization of alkenes, a diene, alkynes, 1,3-enynes, and [1.1.1]propellane using dithiosulfonate reagents (ArSO2 -SSR) with improved atom economy. Both "ArSO2 -" and "-SSR" on the dithiosulfonate are transferred under mild conditions with broad substrate scope, high stereoselectivity, and complete regioselectivity. Significantly, the resulting dithiosulfonylated styrene is a general and practical nucleophilic disulfuration reagent, reacting with a variety of electrophiles efficiently. Both reactions can be conducted on gram scale, rendering the approach highly valuable.

Access to Polysulfides through Photocatalyzed Dithiosulfonylation

AbstractIn this study, we outline a general method for photocatalyzed difunctionalization of alkenes, a diene, alkynes, 1,3‐enynes, and [1.1.1]propellane using dithiosulfonate reagents (ArSO2‐SSR) with improved atom economy. Both “ArSO2‐” and “‐SSR” on the dithiosulfonate are transferred under mild conditions with broad substrate scope, high stereoselectivity, and complete regioselectivity. Significantly, the resulting dithiosulfonylated styrene is a general and practical nucleophilic disulfuration reagent, reacting with a variety of electrophiles efficiently. Both reactions can be conducted on gram scale, rendering the approach highly valuable.

Terminal Alkynes as One‐Carbon Donors in [5+1] Heteroannulation: Synthesis of Pyridines via Ynimine Intermediates and Application in the Total Synthesis of Anibamine B

AbstractTransition‐metal‐catalyzed [4+2] heteroannulation of α,β‐unsaturated oximes and their derivatives with alkynes has been developed into a powerful strategy for the synthesis of pyridines. It nevertheless lacks regioselectivity when unsymmetrically substituted alkynes are used. We report herein the unprecedented synthesis of polysubstituted pyridines by a formal [5+1] heteroannulation of two readily accessible building blocks. A copper‐catalyzed aza‐Sonogashira cross‐coupling between β,γ‐unsaturated oxime esters and terminal alkynes affords ynimines, which, without isolation, undergo an acid‐catalyzed domino reaction involving ketenimine formation, 6π‐electrocyclization and aromatization to afford pyridines. Terminal alkynes served as a one‐carbon donor to the pyridine core in this transformation. Di‐ through pentasubstituted pyridines are accessible with complete regioselectivity and excellent functional‐group compatibility. The first total synthesis of anibamine B, an indolizinium alkaloid with potent antiplasmodial activity, was accomplished featuring this reaction as a key step.

Terminal Alkynes as One-Carbon Donors in [5+1] Heteroannulation: Synthesis of Pyridines via Ynimine Intermediates and Application in the Total Synthesis of Anibamine B.

Transition-metal-catalyzed [4+2] heteroannulation of α,β-unsaturated oximes and their derivatives with alkynes has been developed into a powerful strategy for the synthesis of pyridines. It nevertheless lacks regioselectivity when unsymmetrically substituted alkynes are used. We report herein the unprecedented synthesis of polysubstituted pyridines by a formal [5+1] heteroannulation of two readily accessible building blocks. A copper-catalyzed aza-Sonogashira cross-coupling between β,γ-unsaturated oxime esters and terminal alkynes affords ynimines, which, without isolation, undergo an acid-catalyzed domino reaction involving ketenimine formation, 6π-electrocyclization and aromatization to afford pyridines. Terminal alkynes served as a one-carbon donor to the pyridine core in this transformation. Di- through pentasubstituted pyridines are accessible with complete regioselectivity and excellent functional-group compatibility. The first total synthesis of anibamine B, an indolizinium alkaloid with potent antiplasmodial activity, was accomplished featuring this reaction as a key step.

Rh(III)- catalyzed allylation-intramolecular hydroamination sequence of 5-arylsubstituted pyrazoles with allyl methyl carbonate: Access to 5,6-dihydropyrazolo[5,1–a]isoquinolines

We report a facile and direct rhodium(III)-catalyzed allylation-intramolecular hydroamination sequence of 5-arylsubstituted pyrazoles with allyl methyl carbonate to deliver various 5,6-dihydropyrazolo[5,1–a]isoquinolines involving CH bond activation/cyclization process. This approach features good functional-group compatibility and complete regioselectivity. The detailed control experiments show that CH cleavage may be the rate-determining step.

Unveiling substituent effects in [3+2] cycloaddition reactions of benzonitrile N-oxide and benzylideneanilines from the molecular electron density theory perspective

The zw- type [3+2] cycloaddition (32CA) reactions of benzonitrile N-oxide with a series of substituted benzylideneanilines have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-31G(d) computational level. The presence of dimethylamino and methoxy substituents in the aromatic rings of benzylideneaniline makes the reaction more facile relative to the unsubstituted one, while the electron withdrawing nitro substituents relatively induce minimal changes in the energy profile complying with the experimentally observed reaction rates. The presence of non-bonding electron density at the nitrogen atom and the formation of pseudoradical centre at the carbon atom of benzonitrile N-oxide characterise the difference in electronic structure of the TSs relative to the reagents, while the topological analysis of the electron localization function (ELF) and the atoms-in-molecules (AIM) reveal no covalent bond formation at the early TSs. The present MEDT study analyses the experimentally observed substituent effects and complete regioselectivity in the studied 32CA reactions.

Base-Induced Sulfoxide-Sulfenate Rearrangement of 2-Sulfinyl Dienes for the Regio- and Stereoselective Synthesis of Enantioenriched Dienyl Diols.

The base-induced [2,3]-sigmatropic rearrangement of a series of enantiopure 2-sulfinyl dienes has been examined and optimized using a combination of NaH and iPrOH. The reaction takes place by allylic deprotonation of the 2-sulfinyl diene to give a bis-allylic sulfoxide anion intermediate that after protonation undergoes sulfoxide-sulfenate rearrangement. Different substitution at the starting 2-sulfinyl dienes has allowed us to study the rearrangement finding that a terminal allylic alcohol is determinant to achieve complete regioselectivity and high enantioselectivities (90:10-95:5) with the sulfoxide as the only element of stereocontrol. Density functional theory (DFT) calculations provide an interpretation of these results.

Lewis Acid-Catalyzed Remote Site-Selective Ring Deconstruction of Cyclobuteno[a]naphthalene-4-ones to Access Unsymmetric 1,1-Diarylated Olefins.

A catalytic site-selective ring deconstruction of cyclobuteno[a]naphthalene-4-ones with alcohols is reported, enabling the direct production of a wide range of unsymmetric 1,1-diarylated olefins with good yields and complete regioselectivity. The late-stage application of these resulting terminal olefins demonstrates great possibilities to apply this strategy to complex molecules. The protocol features good functional group compatibility, broad substrate scope, and controllable site selectivity.

Synthesis of the diazatricycloundecane scaffold via gold(I)-catalysed Conia-ene-type 5-exo-dig cyclization and stepwise substituent assembly for the construction of an sp3-rich compound library.

The bridged diazatricycloundecane sp3-rich scaffold was synthesised via the gold(I)-catalysed Conia-ene reaction. The electron-donating property of the siloxymethyl group on alkyne 1 enabled 6-endo-dig cyclization, whereas the ethoxy carbonyl group on alkyne 4 led to 5-exo-dig cyclization with complete regioselectivity in the Conia-ene reaction. The resulting bridged diazatricycloundecane scaffold 5 allowed the construction of a library of sp3-rich compounds. Among the compounds synthesised, compounds 6e and 6f inhibited the hypoxia inducible factor 1 (HIF-1) downstream signaling pathway without affecting HIF-1α mRNA expression.

Rh(iii)-catalyzed highly site- and regio-selective alkenyl C-H activation/annulation of 4-amino-2-quinolones with alkynes via reversible alkyne insertion.

3,4-Fused 2-quinolone frameworks are important structural motifs found in natural products and biologically active compounds. Intermolecular alkenyl C-H activation/annulation of 4-amino-2-quinolone substrates with alkynes is one of the most efficient methods for accessing such structural motifs. However, this is a formidable challenge because 4-amino-2-quinolones have two cleavable C-H bonds: an alkenyl C-H bond at the C3-position and an aromatic C-H bond at the C5-position. Herein, we report the Rh(iii)-catalyzed highly site-selective alkenyl C-H functionalization of 4-amino-2-quinolones to afford 3,4-fused 2-quinolones. This method has a wide substrate scope, including unsymmetrical internal alkynes, with complete regioselectivity. Several control experiments using an isolated key intermediate analog suggested that the annulation reaction proceeds via reversible alkyne insertion involving a binuclear Rh complex although alkyne insertion is generally recognized as an irreversible process due to the high activation barrier of the reverse process.

Highly selective γ-alkoxylation, γ-amination and γ-alkylation of unbiased enals by means of photoredox catalysis.

We report herein a general and highly selective γ-functionalization protocol under visible light irradiation. This mild radical approach enables the expansion of the scope of application to unbiased enals and the introduction of a wide variety of alkoxy, amino and alkyl functionalities in the γ position with complete regioselectivity.

PEG-400 catalysed selective C-Se cross dehydrogenative coupling: An ultrasonication‐assisted green strategy

Metal free selective C-Se cross dehydrogenative coupling strategy has been established. The disclosed protocol unites structurally complex molecular hybrids with phenylselenol to sp2 carbon with complete regioselectivity to foster novel phenylseleno-substituted hydrazonoindolin-2-one hybrids. The product was achieved via C-H activation path and was impossible without transition metal catalysts till date. Herein we have achieved unification via Cross dehydrogenative Coupling in PEG-400 with sonication synergistic effect which sets new and easy method to achieve such a difficult path through easy reaction route. The simple reaction setup with PEG-400, a green and inexpensive catalyst solvent system, sonication a green energy source, suitable reaction time, better product yield serves as a complete green compendium to achieve metal free C-Se coupling reaction. Hence the reported methodology will act as a base for designing routes for other important molecular hybrids using green synergy of sonication and PEG-400.