High Regioselectivity Research Articles

Highly Regioselective Dehydrogenative Hydrazination of Tropones.

Direct C(sp2)-H bond functionalization of the tropone skeleton constitutes an atom-economical strategy to access substituted tropones that exist in some bioactive compounds. Herein, we report a convenient method for the preparation of 2-hydrazinotropones via C(sp2)-H bond functionalization. A variety of tropones participated in the dehydrogenative hydrazination reaction with hydrazine, delivering structurally diverse 2-hydrazinotropones in moderate to good yields with extremely high regioselectivity. This method is featured by operational simplicity and metal-free reaction conditions, thereby tolerating various functional groups.

Stereospecific 3‐Aza‐Cope Rearrangement Interrupted Asymmetric Allylic Substitution‐Isomerization

AbstractTransition‐metal catalyzed asymmetric allylic substitution with alkyl and heteroaryl carbon nucleophiles has been well‐established. However, the asymmetric allylic arylation of acyclic internal alkenes with aryl nucleophiles remains challenging and underdeveloped. Herein we report a stereospecific 3‐aza‐Cope rearrangement interrupted asymmetric allylic substitution‐isomerization (Int‐AASI) that enables asymmetric allylic arylation. By means of this stepwise strategy, both enantioenriched allylic arylation products and axially chiral alkenes could be readily obtained in high enantioselectivities. Experimental studies support a mechanism involving a cascade of asymmetric allylic amination, stereospecific 3‐aza‐Cope rearrangement and alkene isomerization. Density functional theory studies detailed the reasons of achieving the high chemoselectivity, regioselectivity, stereoselectivity and stereospecificity, respectively.

Remote Enantioselective ϵ-Alkylation of Copper Ethynylallenylidenes: Precise Control of Central and Axial Chirality.

Chiral tetrasubstituted allenes have emerged as important architectures for engineering biologically active compounds. The construction of unique tetrasubstituted allene scaffolds with precise control of continuous central and axial chirality remains yet to be developed. Here, we report a remote enantioselective ϵ-alkylation of yne-propargylic acetates with enals enabled by NHC and copper cooperative catalysis, leading to a series of tetrasubstituted allenes with excellent enantioselectivities (up to >99 % ee) and diastereoselectivities (up to >95 : 5 dr). This method features high regioselectivity and simultaneous control of axial and central chirality. Mechanistic studies suggest a cooperative activation mode and synergistic control of distal chirality created from the copper ethynylallenylidenes.

Remote Enantioselective ϵ‐Alkylation of Copper Ethynylallenylidenes: Precise Control of Central and Axial Chirality

AbstractChiral tetrasubstituted allenes have emerged as important architectures for engineering biologically active compounds. The construction of unique tetrasubstituted allene scaffolds with precise control of continuous central and axial chirality remains yet to be developed. Here, we report a remote enantioselective ϵ‐alkylation of yne‐propargylic acetates with enals enabled by NHC and copper cooperative catalysis, leading to a series of tetrasubstituted allenes with excellent enantioselectivities (up to >99 % ee) and diastereoselectivities (up to >95 : 5 dr). This method features high regioselectivity and simultaneous control of axial and central chirality. Mechanistic studies suggest a cooperative activation mode and synergistic control of distal chirality created from the copper ethynylallenylidenes.

Iodide Ion-Promoted Highly Regioselective Triazolization of Aldehydes via Desulfonation-Associated Direct Radical Coupling.

A highly efficient iodide ion (I-)-promoted method for direct α-C(sp2)-H triazolization of aldehydes has been developed for the regioselective synthesis of N2-substituted triazole derivatives. The developed method features the corresponding products in good yields (up to 99%) with an excellent functional group tolerance via an intermolecular oxidative radical coupling. Experimental mechanistic investigations indicate that the reaction proceeds via an I--promoted synergistic desulfonylation process, which provides a high regioselectivity. The developed method provides a direct, metal-free, operationally simple, and highly regioselective approach to C(sp2)-H triazolization from easily accessible aldehydes in air.

Ru-Catalyzed Ortho C-H Alkylation of 4-Aryl-pyrrolo[2,3-d]pyrimidines with Diazo Compounds: An Access to Fluorescent Fused Heteroarenes.

A Ru(II)-catalyzed migratory insertion of carbene into ortho C-H bonds of 4-aryl-pyrrolo[2,3-d]pyrimidines has been developed. This transformation endows the facile fabrication of C-C bonds with high atom economy, good regioselectivity, and wide functional group tolerance, exploiting the directing properties of pyrimidinic nitrogen. In addition, the planar polycyclic pyrrolo-pyrimido-isoindole framework has been accomplished from a cascade reaction of bromination, cyclization, and decarboxylation of synthesized products. Furthermore, the fluorescence properties of C-N annulated compounds have also been determined, which are valuable in the field of fluorescence properties of heterocycles.

Metal‐Free Nitration of Indazoles with tert‐Butyl Nitrile in Air to Prepare 3‐Nitroindazoles and 3‐Aminoindazoles

Comprehensive SummaryA variety of 3‐nitroindazoles and 3‐aminoindazoles were prepared in good to excellent yields with high regioselectivity through TBN‐mediated nitration at the C3‐position of indazoles under the air conditions and sequential reduction. Mechanistic studies revealed that TBN played crucial roles to produce •NO2 radical source in the presence of air conditions and C3‐nitration of indazoles was initiated by N1‐nitration and sequential migration of NO2 group to C3‐position. Moreover, this method could be easily applied in the gram scalable synthesis of ibuprofen and ciprofibrate‐derived 3‐aminoindazoles. The present method highlights air as mild oxidant, metal‐free radical nitration of indazole, N—N bond formation and cleavage, and late‐stage modification of drugs.

Shape‐Selective Zeolites for Tandem CO2 Hydrogenation‐Carbonylation Reactions

The valorization of carbon dioxide as a C1 building block in C‐C bond forming reactions is a critical link on the road to carbon‐circular chemistry. Activation of this inert molecule through reduction with H2 to carbon monoxide in the reverse water‐gas shift (RWGS) reaction can be followed by a wide spectrum of consecutive carbonylation reactions, but the RWGS is severely equilibrium limited at the moderate temperatures of carbonylations. Here we successfully reconcile both reactions in one pot, while avoiding incompatibilities through a zeolite‐based compartmentalized approach. More specifically, Pt encapsulated in a small‐pore LTA zeolite selectively generates carbon monoxide in mild reaction conditions; an ensuing one‐pot carbonylation reaction allows to shift the equilibrium through continuous consumption of CO. Moreover, the zeolite encapsulation avoids undesired reactions like hydrogenation of the olefin reactant through a molecular sieving effect. This strategy was first studied in‐depth for Rh‐catalyzed olefin hydroformylation with CO2/H2, affording aldehydes in good yields with high regioselectivities. The methodology was then extended to a variety of carbonylations using CO2 for the synthesis of bulk and fine chemicals.

Shape-Selective Zeolites for Tandem CO2 Hydrogenation-Carbonylation Reactions.

The valorization of carbon dioxide as a C1 building block in C-C bond forming reactions is a critical link on the road to carbon-circular chemistry. Activation of this inert molecule through reduction with H2 to carbon monoxide in the reverse water-gas shift (RWGS) reaction can be followed by a wide spectrum of consecutive carbonylation reactions, but the RWGS is severely equilibrium limited at the moderate temperatures of carbonylations. Here we successfully reconcile both reactions in one pot, while avoiding incompatibilities through a zeolite-based compartmentalized approach. More specifically, Pt encapsulated in a small-pore LTA zeolite selectively generates carbon monoxide in mild reaction conditions; an ensuing one-pot carbonylation reaction allows to shift the equilibrium through continuous consumption of CO. Moreover, the zeolite encapsulation avoids undesired reactions like hydrogenation of the olefin reactant through a molecular sieving effect. This strategy was first studied in-depth for Rh-catalyzed olefin hydroformylation with CO2/H2, affording aldehydes in good yields with high regioselectivities. The methodology was then extended to a variety of carbonylations using CO2 for the synthesis of bulk and fine chemicals.

Enantioselective Propargylic C(sp3)-H Acyloxylation Enabled by Photoexcited Copper Catalysis.

Direct C-H bond functionalization is an efficient method for modifying organic molecules. However, achieving high enantioselectivity and regioselectivity in asymmetric C-H functionalization, particularly of C(sp3)-H bonds, remains challenging. This study introduces an enantioselective propargylic C(sp3)-H acyloxylation using photoexcited copper catalysis. The reaction demonstrated tolerance for various alkynes and peroxides, producing chiral propargyl esters in high yields and enantiomeric excess. Furthermore, the method was successfully extended to a diverse array of carboxylic acids in the presence of di-tert-butyl peroxide (DTBP), significantly broadening its applicability.

Direct Synthesis of Benzhydryl-Functionalized 3,4-Dihydropyridin-2-ones from 2-Pyridones and Their Use in the Formation of Bridged δ-Lactams

A method for the synthesis of C4-benzhydryl-functionalized 3,4-dihydropyridin-2-ones using complementary addition of benzhydryllithium and/or benzhydrylmagnesiate reagents to 2-pyridones, with high regioselectivity triggered by substituents, is described. A partially stereoselective cyclization was successfully demonstrated using TfOH and/or TIPSOTf as Brønsted and Lewis acids, respectively, leading to C6-phenyl-functionalized 7,8-benzomorphanones. It is also shown that the use of functionalized δ-enelactams obtained with an active methoxy-substituted benzyl group at C3 enabled the preparation of a new C3–C6 bridged system within the δ-lactam framework.

Photocatalytic One-Pot Three-Component Reaction for the Regioselective Synthesis of Bromo-Substituted Pyrazoles.

A photocatalytic three-component cascade reaction of readily available enaminones, hydrazines, and CBr4 for the synthesis of bromo-substituted pyrazoles in one pot has been demonstrated. This strategy involves intermolecular C-N/C-Br bond formation and represents an efficient approach to the construction of 4-bromo-substituted pyrazoles with high regioselectivity, broad substrate scope, good functional group tolerance, convenient operation, and mild reaction conditions. Mechanistic investigations show that this reaction proceeds via intermolecular cyclization of enaminones with hydrazines, followed by a regioselective bromination of pyrazoles using CBr4 as a "Br" source.

Asymmetric Carbene Insertion into Se-S Bonds by Synergistic Rh(II)/Guanidine Catalysis Involving Chalcogen-Bond Assistance.

The efficient construction of chalcogen-atom-based chiral compounds remains a challenge, despite the importance of organoselenium and organosulfur compounds in life and materials science. Chalcogen atoms can form net attractive interactions called chalcogen bonds, but it is an undeveloped tool to assist asymmetric catalysis. Herein, we report an enantioselective insertion platform to install a stereogenic center bearing selanyl and thiocyano functional groups. Our method operates by synergistic catalysis by a chiral guanidine and an achiral dirhodium complex in a three-component or four-component reaction, through Se-S bond insertion into carbene species, competing successfully with the spontaneous racemic process and showing high regioselectivity. As elucidated by spectroscopic experiments and computational studies, a unique mechanism involving chalcogen as well as hydrogen bonding was established to account for the enantiocontrol. The high stereoselectivity holds for a broad array of selanylthiocyanatopropanoates, which showed excellent anti-inflammatory toward IL-1β and low cytotoxicity.

Alkylsulfonic acid functionalized aluminoborate: A highly efficient and regioselective solid acid catalyst for ring-opening addition of epoxide under solvent-free condition

Functionalized solid acid material has more accessible active surface and therefore is usually considered as an important substitute for conventional liquid mineral acid. In this work, a novel alkylsulfonic acid functionalized porous aluminoborate molecular sieve (PKU-1) has been prepared through 3-step post-synthetic method, and the high-density acidic sites were tailored and comprehensively characterized by various measurements. These acidity-controllable active sites exhibit high activity and specific regioselectivity towards alcoholysis reaction for the solvent-free production of methoxyl alcohol, and turnover frequency reaches ∼1000 h–1, which is much superior to previous reports. Comprehensive characterizations indicate catalytic centers exclusively come from –SO3H acid sites, rather than other type of Brönsted or Lewis acid sites. A plausible reaction mechanism was proposed to interpret the key role of –SO3H active sites on alcoholysis reaction based on the related experimental results. This work offers a promising solution to generate the controllable acidity and provides an available candidate in the environmentally benign catalysis for selective synthesis of some value-added compounds.

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.

Gold Catalyzed [3+2] Oxidative Annulation of 1,3‐Enynes with Indoles

AbstractAn efficient new method has been developed for the synthesis of ketone‐integrated cyclopentene‐fused indoline derivatives with a high regioselectivity through gold‐catalyzed oxidative cyclo‐coupling of 1,3‐enynes with indoles by using 2,6‐dichloropyridine N‐oxide as the terminal oxidant. A plausible mechanism has been proposed, in which, a cascade process of nucleophilic trapping of the vinyl gold carbene surrogate with indole followed by the subsequent intramolecular cyclization provides the dearomative formal [3+2] cycloaddition product. In addition, a scale‐up reaction and further derivation via cyclopentene's epoxidation & hydrazone derivative's 1,5‐ electrocyclization have been performed.

Intermolecular Sulfenoamination of Alkenes with Free-Thiols and NIS to Access β-Succinimide Sulfides.

A convenient and practical multicomponent strategy for the sulfenoamination of alkenes was realized, which using free-thiols as the sulfur-reagent, NIS both as radical initiator and an N-nucleophile. This protocol excellent in terms of transition-metal-free, good functional group tolerance, easily available substrates and facile scale-up. And provided a direct- and general way to synthesize various β-succinimide sulfides with high regioselectivity.

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.

Lewis Acid-Catalyzed Unusual (4+3) Annulation of para-Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1]Octanes.

Over the past few years, there has been a surge of interest in the chemistry of bicyclobutanes (BCBs). Although BCBs have been used to synthesize bicyclo[2.1.1]hexanes and bicyclo[3.1.1]heptanes, the synthesis of bicyclo[4.1.1]octanes has remained elusive. Herein, we report the first Lewis acid-catalyzed unexpected (4+3) annulation of para-quinonemethides (p-QMs) with BCBs allowing the synthesis of oxabicyclo[4.1.1]octanes proceeding under mild conditions. With 5 mol % of Bi(OTf)3, the reaction afforded the (4+3) annulated product in high regioselectivity and good functional group compatibility via a simultaneous Lewis acid activation of BCBs and p-QMs. The reaction is likely initiated by the 1,6-addition of Lewis acid activated BCBs to p-QMs followed by the C2-selective intramolecular addition of the phenol moiety to the generated cyclobutyl cation intermediate. Moreover, detailed mechanistic studies provided insight into the mechanism of the reaction.

Lewis Acid‐Catalyzed Unusual (4+3) Annulation of para‐Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1]Octanes

AbstractOver the past few years, there has been a surge of interest in the chemistry of bicyclobutanes (BCBs). Although BCBs have been used to synthesize bicyclo[2.1.1]hexanes and bicyclo[3.1.1]heptanes, the synthesis of bicyclo[4.1.1]octanes has remained elusive. Herein, we report the first Lewis acid‐catalyzed unexpected (4+3) annulation of para‐quinonemethides (p‐QMs) with BCBs allowing the synthesis of oxabicyclo[4.1.1]octanes proceeding under mild conditions. With 5 mol % of Bi(OTf)3, the reaction afforded the (4+3) annulated product in high regioselectivity and good functional group compatibility via a simultaneous Lewis acid activation of BCBs and p‐QMs. The reaction is likely initiated by the 1,6‐addition of Lewis acid activated BCBs to p‐QMs followed by the C2‐selective intramolecular addition of the phenol moiety to the generated cyclobutyl cation intermediate. Moreover, detailed mechanistic studies provided insight into the mechanism of the reaction.