Skeletal Editing by Hypervalent Iodine Mediated Nitrogen Insertion.

Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single-nitrogen-atom insertion reaction, and skeletal editing to construct N-heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen-atom into hydrocarbons to generate N-heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen-containing heterocycles, and the current mechanistic understanding of these processes.

Modular synthesis of pyrrole-fused heterocycles via glucose-mediated nitro-reductive cyclization.

A novel biomass-derived glucose-mediated one-pot multicomponent nitro-reductive cyclization method is presented for the direct synthesis of diverse pyrrole-fused heterocycles. The process involves two-component reactions of alkyl (NH)-pyrrole-2-carboxylates and 2-fluoronitroarenes, yielding pyrrolo[1,2-a]quinoxalin-4(5H)-ones, as well as three-component reactions utilizing (NH)-pyrroles, nitroarenes, and DMSO as carbon sources, resulting in various pyrrolo[1,2-a]quinoxaline derivatives. High yields were achieved with broad substrate scope and gram-scale synthesis capability, including pharmaceuticals featuring pyrroloquinoxaline scaffolds. The method's key innovation lies in enabling three or four reactions in a single-pot setup, previously unexplored in pyrrole chemistry. The simplicity of nitro group reduction by biomass-derived glucose ensures practical safety during scale-up, while mechanistic insights from control experiments reveal a new paradigm in pyrrole chemistry. The tandem process demonstrates low PMI values and high step and atom economies, aligning well with green chemistry principles.

Iron(II)-Catalyzed Aerobic Biomimetic Oxidation of N-Heterocycles.

Herein, an iron(II)-catalyzed biomimetic oxidation of N-heterocycles under aerobic conditions is described. The dehydrogenation process, involving several electron-transfer steps, is inspired by oxidations occurring in the respiratory chain. An environmentally friendly and inexpensive iron catalyst together with a hydroquinone/cobalt Schiff base hybrid catalyst as electron-transfer mediator were used for the substrate-selective dehydrogenation reaction of various N-heterocycles. The method shows a broad substrate scope and delivers important heterocycles in good-to-excellent yields.

Iron(II)-Catalyzed Aerobic Biomimetic Oxidation of Amines using a Hybrid Hydroquinone/Cobalt Catalyst as Electron Transfer Mediator.

Herein we report the first FeII -catalyzed aerobic biomimetic oxidation of amines. This oxidation reaction involves several electron transfer steps and is inspired by biological oxidation in the respiratory chain. The electron transfer from the amine to molecular oxygen is aided by two coupled catalytic redox systems, which lower the energy barrier and improve the selectivity of the oxidation reaction. An iron hydrogen transfer complex was utilized as the substrate-selective dehydrogenation catalyst along with a bifunctional hydroquinone/cobalt Schiff base complex as a hybrid electron transfer mediator. Various primary and secondary amines were oxidized in air to their corresponding aldimines or ketimines in good to excellent yield.

Enantioselective Copper-Catalyzed Borylative Cyclization for the Synthesis of Quinazolinones.

Quinazolinones are common substructures in molecules of medicinal importance. We report an enantioselective copper-catalyzed borylative cyclization for the assembly of privileged pyrroloquinazolinone motifs. The reaction proceeds with high enantio- and diastereocontrol, and can deliver products containing quaternary stereocenters. The utility of the products is demonstrated through further manipulations.

Enantio- and Diastereoselective Synthesis of Homopropargyl Amines by Copper-Catalyzed Coupling of Imines, 1,3-Enynes, and Diborons.

An efficient, enantio- and diastereoselective, copper-catalyzed coupling of imines, 1,3-enynes, and diborons is reported. The process shows broad substrate scope and delivers complex, chiral homopropargyl amines; useful building blocks on the way to biologically-relevant compounds. In particular, functionalized homopropargyl amines bearing up to three contiguous stereocenters can be prepared in a single step.

Copper-Catalyzed Borylative Couplings with C-N Electrophiles.

Copper-catalyzed borylative multicomponent reactions (MCRs) involving olefins and C-N electrophiles are a powerful tool to rapidly build up molecular complexity. The products from these reactions contain multiple functionalities, such as amino, cyano and boronate groups, that are ubiquitous in medicinal and process chemistry programs. Copper-catalyzed MCRs are particularly attractive because they use a relatively abundant and non-toxic catalyst to selectively deliver high-value products from simple feedstocks such as olefins. In this Minireview, we explore this rapidly emerging field and survey the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C-N electrophiles.

Real time detection of the nerve agent simulant diethylchlorophosphate by nonfluorophoric small molecules generating a cyclization-induced fluorogenic response.

Chemical warfare agents (CWA) are some of the most nefarious weapons, and their possible use in terrorist attacks has led to growing interest in the development of reliable and accurate methods to detect these lethal chemicals. In this paper, we have prepared three nonfluorophores containing 2-(2-hydroxybenzylidene)-malononitrile with various 5-substituents as chemosensor probes for a nerve-agent simulant, diethylchlorophosphate (DCP). The phenolic group of the probes, as the active site, can be rapidly phosphorylated by DCP via nucleophilic substitution and then undergo a simultaneous intramolecular cyclization reaction within 45 s, which can respond to DCP in turn-on fluorescence mode. To the best of our knowledge, this is the first report on the utilization of non-fluorophoric small molecule species to generate a fluorogenic response from DCP along with an investigation of substituent effects on the sensing response. The detection process can be visualized by the naked eye and under a UV lamp the probe HNBM exhibits a strong green fluorescence upon interaction with DCP. Among the three chemosensors, probe HNBM displayed several beneficial attributes such as an extremely fast response time along with high selectivity, sensitivity and the lowest limit of detection (0.10 µM) with DCP in solution. TDDFT calculations were performed in order to demonstrate the electronic properties of the probe and the cyclized product. Furthermore, the probe was used to develop a low cost portable cellulose paper strip for real-time visual detection of DCP vapor. Also, the probe has been extensively used to detect DCP in live cells.

Sustainable, Oxidative, and Metal-Free Annulation.

Annulation has received steadily growing interest in the interplay with the increasing emphasis towards selective C-H bond functionalization reactions. Metal-free oxidative annulation through functionalization of inert and abundant C-H bonds offers great improvements in terms of atom- and step-economics as well as reduced waste production under mild reaction conditions. Annulation is considered to be a highly efficient strategy for the construction of cyclic molecules because at least two new bonds are formed within a single reaction step. The combination of annulation and direct C-H bond functionalization allows the efficient and straightforward synthesis of carbo- and heterocyclic molecules using simple and non-prefunctionalized precursors. This Concept highlights novel strategies and recent breakthroughs for metal-free annulation through C-H bond functionalization giving access to a variety of important structural motifs.

A Metal-Free Oxidative Dehydrogenative Diels-Alder Reaction for Selective Functionalization of Alkylbenzenes.

Functionalization of C(sp3 )-H bonds under metal-free reaction conditions is a great challenge due to poor bond reactivity. A novel metal-free oxidative dehydrogenative Diels-Alder reaction of alkylbenzene derivatives with alkenes through C(sp3 )-H bond functionalization is described. The developed oxidative method provides a straightforward approach to biologically relevant 1,4-phenanthraquinone and isoindole derivatives from readily available starting materials. Furthermore, the synthesis of nitrostyrenes from enylbenzene derivatives by selective C(sp3 )-H bond functionalization has been demonstrated.

[1+1+1] Cyclotrimerization for the Synthesis of Cyclopropanes.

The synthesis of small rings by functionalization of C(sp(3) )-H bonds remains a great challenge. We report for the first time a copper-catalyzed [1+1+1] cyclotrimerization of acetophenone derivatives under mild reaction conditions. The reaction has a broad scope for the stereoselective synthesis of cyclopropanes by trimerization of acetophenone. The developed transformation is based on an extraordinary copper-catalyzed cascade process that allows saturated carbocycles to be obtained for the first time by cyclotrimerization through functionalization of C(sp(3) )-H bonds. The cascade of sixfold C(sp(3) )-H bond functionalization allows the synthesis of cyclopropanes in a highly stereoselective approach.

Copper-Catalyzed (2+1) Annulation of Acetophenones with Maleimides: Direct Synthesis of Cyclopropanes.

A practical copper-catalyzed direct oxidative cyclopropanation of electron-deficient alkenes with acetophenone derivatives is reported. The dehydrogenative annulation involves a double C-H bond functionalization at the α-position of the ketone using di-tert-butyl peroxide as oxidant. The broad scope of the reaction and excellent functional-group tolerance is demonstrated for the stereoselective synthesis of fused cyclopropanes. The developed transformation revealed an unprecedented reactivity for copper-catalyzed processes.

Organocatalytic oxidative annulation of benzamide derivatives with alkynes.

Organocatalytic annulation by functionalization of benzamide derivatives with alkynes has been developed. We report a new approach of cycloaddition under mild reaction conditions using simple catalysts, such as iodobenzene and peracetic acid, as oxidant. Those novel, mild reaction conditions provided a straightforward synthesis of isoquinolones with fast reaction rate. Notable selectivity in annulation of unsymmetrically disubstituted alkynes was demonstrated.

Metal-free annulation of arenes with 2-aminopyridine derivatives: the methyl group as a traceless non-chelating directing group.

A novel annulation reaction between 2-aminopyridine derivatives and arenes under metal-free conditions is described. The presented intermolecular transformation provided straightforward access to the important pyrido[1,2-a]benzimidazole scaffold under mild reaction conditions. The unprecedented application of the methyl group of methylbenzenes as a traceless, non-chelating, and highly regioselective directing group is reported.

Efficient and stereoselective nitration of mono- and disubstituted olefins with AgNO2 and TEMPO.

Nitroolefin is a common and versatile reagent. Its synthesis from olefin is generally limited by the formation of mixture of cis and trans compounds. Here we report that silver nitrite (AgNO2) along with TEMPO can promote the regio- and stereoselective nitration of a broad range of olefins. This work discloses a new and efficient approach wherein starting from olefin, nitroalkane radical formation and subsequent transformations lead to the desired nitroolefin in a stereoselective manner.

Copper-catalyzed functionalization of enynes.

The copper-catalyzed functionalization of enyne derivatives has recently emerged as a powerful approach in contemporary synthesis. Enynes are versatile and readily accessible substrates that can undergo a variety of reactions to yield densely functionalized, enantioenriched products. In this perspective, we review copper-catalyzed transformations of enynes, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations. Particular attention is given to the regiodivergent functionalization of 1,3-enynes, and the current mechanistic understanding of such processes.

Catalytic Transfer Hydrogenation Using Biomass as Hydrogen Source.

We developed an operationally simple method for the direct use of biomass-derived chemical entities in a fundamentally important process, such as hydrogenation. Various carbohydrates, starch, and lignin were used for stereoselective hydrogenation. Employing a transition metal catalyst and a novel catalytic system, the reduction of alkynes, alkenes, and carbonyl groups with high yields was demonstrated. The regioselective hydrogenation to access different stereoisomers was established by simple variations in the reaction conditions. This work is based on an unprecedented catalytic system and represents a straightforward application of biomass as a reducing reagent in chemical reactions.