Protocol Features Mild Reaction Conditions Research Articles

Ligand‐Free Zn Catalyzed Synthesis of Functionalized iIdoloacridines

Abstract: An efficient, ligand‐free, and Zn‐catalyzed dehydrogenation of acridinol/ cyclization of imine product/ dehydrogenative C(sp3)‐H functionalization utilizing ChCl‐based deep eutectic solvent system for the assembly of functionalized indoloacridines 9 is reported. The protocol features mild reaction conditions, VOCs free process, broad substrate scope, and applicable gram‐scale synthesis. Furthermore, absorption and solvatochromism properties were explored for the synthesized compounds.

C−H Alkylation of N‐Benzyl Anilines via Visible‐Light‐Driven 1,5‐Hydrogen Atom Transfer (1,5‐HAT) of Hydroxamic Acid Derivatives

AbstractHere we reported the photo‐catalyzed C−H alkylation of pyridyl‐substituted N‐benzyl anilines through nitrogen‐centred radical 1,5‐hydrogen atom transfer. A broad range of methylpyridyl‐substituted aniline and hydroxylamine acid derivatives were successfully transformed into the corresponding products in moderate yields without adding any base and metal. This protocol features mild reaction conditions, a broad range of substrates, remarkable functional group tolerance and simple operation procedure.

Palladium‐Catalyzed Cyclization/Thiocarbonylation for the Synthesis of Thioester‐Substituted Benzofurans with S‐Aryl Thioformates as the Thioester Sources

AbstractA palladium‐catalyzed cyclization and thiocarbonylation reaction is disclosed for the synthesis of thioester‐containing benzofurans. By using S‐aryl thioformates as efficient and convenient thioester surrogates, a variety of thioester‐functionalized benzofurans were formed in moderate to excellent yields with very good functional group tolerance. This protocol features mild reaction conditions, broad substrate scope, and no manipulation of toxic CO gas and odorous thiols.

N-Halosuccinimide enables cascade oxidative trifluorination and halogenative cyclization of tryptamine-derived isocyanides

Both the pyrroloindoline core and N–CF3 moiety hold significant importance in medicinal chemistry. However, to date, no instances of constructing N–CF3-containing pyrroloindolines have been reported. Herein, we present a robust and operationally simple approach to assembling such intriguing skeletons from tryptamine-derived isocyanides through a cascade sequence, which includes an oxidative trifluorination and a subsequent halogenative cyclization. Key to the success lies in the development of a facile conversion of isocyanides to N–CF3 moiety with commercially available reagents N-halosuccinimide and Et3N·HF. The protocol features mild reaction conditions, broad functional group tolerance, good to excellent yields, and high diastereoselectivities. In addition, we demonstrate that the halide substituent within the products serves as a versatile functional handle for accessing diverse C3-quaternary-substituted N–CF3-pyrroloindolines.

Visible-Light-Mediated, Organophotocatalytic C-H Thiocyanation of Pyrazolo[1,5-a]pyrimidines.

Herein, we report a metal-free, organophotoredox-catalyzed sustainable C-H thiocyanation of a biologically active class of N-heterocycles, pyrazolo[1,5-a]pyrimidines, with potassium thiocyanate (KSCN) using 9-mesityl-10-methylacridinium perchlorate as the photocatalyst (PC) and molecular oxygen as the terminal oxidant under blue-light-emitting diode irradiation at room temperature. The developed catalytic protocol features mild reaction conditions, a broad substrate scope, a high yield of products, and a straightforward scalability. Mechanistic studies revealed a radical pathway involving reductive quenching of the PC by KSCN.

Aerobic Copper-Catalyzed Oxysulfonylation of Vinylarenes with Sodium Sulfinates under Mild Conditions: A Modular Synthesis of β-Ketosulfones.

An aerobic copper-catalyzed oxysulfonylation of vinylarenes with sodium sulfinates is described. This protocol features mild reaction conditions, convenient operation, and broad substrate scope with respect to vinylarenes and sodium sulfinates. Notably, the protocol demonstrates excellent tolerance of functional groups such as chloro, bromo, ester, cyano, and nitro groups. Mechanistic investigations indicated that the reaction should undergo radical cascades involving a sulfonyl radical generated from sodium sulfinate with air as the terminal oxidant, addition across alkene to deliver a benzylic radical, and subsequent cross-coupling with air.

Electrosynthesis of 1,2,3-Benzotriazines through an Iodide-Catalyzed Skeletal Editing of 3-Aminoindazoles.

This report describes an environmentally benign synthesis of 1,2,3-benzotriazines through an iodide-catalyzed electro-oxidative N-centered [1,2]-rearrangement of 3-aminoindazoles. The developed method demonstrates the activation of heteroatoms via electrochemically generated reactive iodide species without using any metal catalysts and peroxides. The protocol features practical and mild reaction conditions and displays a wide substrate scope. Various mechanistic experiments and cyclic voltammetric studies have been instrumental in elucidating the reaction mechanism, operating via a skeletal rearrangement of 3-aminoindazoles.

Hypervalent Iodine Mediated Ring-Opening 1,3-Difluorination of Benzylidenecyclopropanes

Abstract1,3-Difluorinated compounds are characterized by their unique conformation, influenced by 1,3-dipolar minimization effects. However, their synthetic methods are relatively limited. Here, a ring-opening 1,3-difluorination of benzylidenecyclopropanes (BCPs) using HF·Py, mediated by an electron-poor hypervalent iodine reagent, which is generated in situ by the oxidation of o-nitroiodobenzene with mCPBA is described. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Additionally, the synthetic utility of this method is showcased by further transformations of the olefin group and allylic fluoride motif.

Selective Cleavage of Cβ-O-4 Bond for Lignin Depolymerization via Paired-Electrolysis in an Undivided Cell.

The cleavage of C-O bonds is one of the most promising strategies for lignin-to-chemicals conversion, which has attracted considerable attention in recent years. However, current catalytic system capable of selectively breaking C-O bonds in lignin often requires a precious metal catalyst and/or harsh conditions such as high-pressure H2 and elevated temperatures. Herein, we report a novel protocol of paired electrolysis to effectively cleave the Cβ-O-4 bond of lignin model compounds and real lignin at room temperature and ambient pressure. For the first time, "cathodic hydrogenolysis of Cβ-O-4 linkage" and "anodic C-H/N-H cross-coupling reaction" are paired in an undivided cell, thus the cleavage of C-O bonds and the synthesis of valuable triarylamine derivatives could be simultaneously achieved in an energy-effective manner. This protocol features mild reaction conditions, high atom economy, remarkable yield with excellent chemoselectivity, and feasibility for large-scale synthesis. Mechanistic studies indicate that indirect H* (chemical absorbed hydrogen) reduction instead of direct electron transfer might be the pathway for the cathodic hydrogenolysis of Cβ-O-4 linkage.

Selective Cleavage of Cβ−O−4 Bond for Lignin Depolymerization via Paired‐Electrolysis in an Undivided Cell

AbstractThe cleavage of C−O bonds is one of the most promising strategies for lignin‐to‐chemicals conversion, which has attracted considerable attention in recent years. However, current catalytic system capable of selectively breaking C−O bonds in lignin often requires a precious metal catalyst and/or harsh conditions such as high‐pressure H2 and elevated temperatures. Herein, we report a novel protocol of paired electrolysis to effectively cleave the Cβ−O−4 bond of lignin model compounds and real lignin at room temperature and ambient pressure. For the first time, “cathodic hydrogenolysis of Cβ−O−4 linkage” and “anodic C−H/N−H cross‐coupling reaction” are paired in an undivided cell, thus the cleavage of C−O bonds and the synthesis of valuable triarylamine derivatives could be simultaneously achieved in an energy‐effective manner. This protocol features mild reaction conditions, high atom economy, remarkable yield with excellent chemoselectivity, and feasibility for large‐scale synthesis. Mechanistic studies indicate that indirect H* (chemical absorbed hydrogen) reduction instead of direct electron transfer might be the pathway for the cathodic hydrogenolysis of Cβ−O−4 linkage.

Phosphoric Acid-Catalyzed Alkene Difunctionalization of 2-Vinylpyridines via HOMO/LUMO Biactivated Diels-Alder Reaction.

The difunctionalization of vinylpyridines based on the cyclization strategy remains rare and underdeveloped, in contrast to the well-developed hydrogen functionalization. Current exploration on [4 + 2] cyclization of vinylpyridines mainly relies on extremely high temperatures and the LUMO activation of vinylpyridines using boron trifluoride as a strong Lewis acid. Herein, we established a phosphoric acid-catalyzed [4 + 2] cyclization reaction of 3-vinyl-1H-indoles and 2-vinylpyridines by means of the LUMO/HOMO bifunctional activation model. This protocol features mild reaction conditions, high functional group tolerance, broad substrate compatibility, and high diastereoselectivity, enabling the efficient construction of various functionalized pyridine-substituted tetrahydrocarbazoles with prominent potential in drug discovery.

Silylation and (Hetero)aryl/alkenylation of Unactivated Alkenes via Radical-Mediated Distal 1,4-Migration with Hydrosilanes under Organophotocatalysis.

We report a novel organic photoredox catalysis to achieve unprecedented γ-(hetero)aryl/alkenyl-δ-silyl aliphatic amines via silyl-mediated distal (hetero)aryl/alkenyl migration of aromatic/alkenyl amines bearing unactivated alkenes with hydrosilanes. This protocol features mild and metal-free reaction conditions, high atom economy, excellent selectivity, and functional group compatibility. Mechanistic studies suggest that silylation and (hetero)aryl/alkenylation involve photoredox hydrogen atom transfer catalysis and subsequent 1,4-migration of a remote (hetero)aryl/alkenyl group from nitrogen to carbon.

Atroposelective Construction of Naphthylpyrazoles by Chiral Phosphoric Acid Catalyzed Enantioselective Cross‐Coupling of Pyrazoles with Naphthoquinone Esters

AbstractThe catalytic asymmetric reaction of 5‐aminopyrazoles with naphthoquinone esters has been established. A wide range of unprecedented axially chiral naphthylpyrazole derivatives (29 examples) have been synthesized in moderate to excellent yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) by utilizing chiral phosphoric acid as a catalyst. This protocol features mild reaction conditions, a broad substrate scope, good scalability and facile derivatization. Moreover, preliminary mechanistic investigation was conducted to elucidate the mechanism.

Transition metal-free access to 3-indolemalononitriles via a tandem decarboxylative propargylation/aromatization cascade

Herein, the construction of 3-indolemalononitriles via base-promoted tandem decarboxylative propargylation/aromatization cascade of 4-ethynyl benzoxazinones with N,N-disubstituted aminomalononitriles has been developed. This protocol features mild reaction conditions, high efficiency and no need of transition metals. Various 3-indolemalononitriles can be obtained in moderate to excellent yields from readily available starting materials. More importantly, this method can be further applied to the synthesis of a wide range of complex indole products.

Visible-Light-Driven Bifunctional Photocatalytic Radical-Cascade Selenocyanation/Cyclization of Acrylamides with KSeCN.

A visible-light-induced radical-cascade selenocyanation/cyclization of N-alkyl-N-methacryloyl benzamides, 2-aryl-N-acryloyl indoles, and N-methacryloyl-2-phenylbenzimidazoles with potassium isoselenocyanate (KSeCN) was developed. The reactions were carried out with inexpensive KSeCN as a selenocyanation reagent, potassium persulfate as an oxidant, 2,4,6-triphenylpyrylium tetrafluoroborate as a bifunctional catalyst for phase-transfer catalysis, and photocatalysis. A library of selenocyanate-containing isoquinoline-1,3(2H,4H)-diones, indolo[2,1-a]isoquinoline-6(5H)-ones, and benzimidazo[2,1-a]isoquinolin-6(5H)-ones were achieved in moderate to excellent yields at room temperature under visible-light and ambient conditions. Importantly, the present protocol features mild reaction conditions, large-scale synthesis, simple manipulation, product derivatization, good functional group, and heterocycle tolerance.

Photoredox-catalyzed synthesis of α,α-difluoromethyl-β-alkoxysulfones from sulfur dioxide

A photoredox-catalyzed synthesis of , -difluoromethyl sulfones from sulfur dioxide with readily available gem-difluoroalkenes is reported. This protocol features mild reaction conditions, broad substrate scope and good functional group compatibility, giving rise to the target , -difluoromethyl sulfones in moderate to excellent yields. Mechanistic studies indicate that this reaction is initiated by an aryl radical with the insertion of sulfur dioxide.

Copper-mediated synthesis of N-arylated cyclic urea from diaminecarbamate

A convenient base-promoted CuI-mediated intermolecular synthesis of N-arylated cyclic ureas from diaminecarbamate and aryl iodides was developed. A series of N-arylated five- and six-membered cyclic ureas were successfully afforded in moderate to good yields. This new protocol features mild reaction conditions, noble metal-free and ligand-free system, and diverse products.

Hypervalent Iodine Mediated Synthesis of Thiosulfonates from Sulfonyl Hydrazides and Their Transformation into Symmetrical Disulfides

AbstractA transition-metal-free synthesis of thiosulfonates has been accomplished by the disproportionate coupling of readily available and inexpensive sulfonyl hydrazides embracing hypervalent iodine(III) [phenyliodine(III) diacetate (PIDA)] as an oxidant. This synthesis involves cleavage of the S–N bond and is endowed with creation of a new S–S bond. The thiosulfonates were further reduced with CS2/KOH to obtain symmetrical disulfides. This protocol features mild reaction conditions in open air, an inexpensive oxidant, and high functional group tolerance with good to excellent product yields.

Cobalt‐Catalyzed Oxytrifluoromethylation of N‐Allylamides toward Trifluoromethyl‐Containing Oxazolines

AbstractWe herein report a cobalt‐catalyzed intramolecular oxytrifluoromethylation of N‐allylamides for the efficient synthesis of trifluoromethyl‐containing oxazolines with Togni's reagent II as the trifluoromethyl precursor. The protocol features mild reaction conditions and good functional group compatibility. Preliminary mechanistic investigations suggest the involvement of free radicals in this transformation.

Site‐Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines**

AbstractThe introduction of trifluoromethyl groups into organic molecules is of paramount importance in modern synthetic chemistry and medicinal chemistry. While methods for constructing C(sp2)−CF3 bonds have been well established, the advancement of practical and comprehensive approaches for forming C(sp3)−CF3 bonds remains considerably restricted. In this work, we describe an efficient and site‐specific deaminative trifluoromethylation reaction of aliphatic primary amines to afford the corresponding alkyl trifluoromethyl compounds. The reaction proceeds at room temperature with readily accessible N‐anomeric amide (Levin's reagent) and bench‐stable bpyCu(CF3)3 (Grushin's reagent, bpy=2,2′‐bipyridine) under blue light. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Remarkably, the method can be applied to the direct, late‐stage trifluoromethylation of natural products and bioactive molecules. Experimental mechanistic studies were conducted, and a radical mechanism is proposed, wherein the dual roles of Grushin's reagent have been elucidated.