Photoredox-catalyzed C(sp3)─H radical functionalization to enable asymmetric synthesis of α-chiral alkyl phosphine.

α-Chiral alkyl phosphines are privileged structural motifs with a wide application in organic and medical synthesis. It is highly desirable to develop stereoselective methods to prepare these enantioenriched molecules. The incorporation of C(sp3)─H functionalization and chiral phosphine chemistry is much less explored, probably because of the weak reactivity of C(sp3)─H bonds and/or the challenging site- and stereoselectivity issues. Herein, we disclose a synergistic catalysis system to enable an enantioselective radical addition process of α-substituted vinylphosphine oxides. An array of diverse α-chiral alkyl phosphors compounds is smoothly accessed by using the readily available chemicals as the inert C(sp3)─H bond reagent, such as sulfides, amines, alkenes, and toluene derivatives, exerting remarkable chemo-, site-, and enantioselectivity. On the basis of the mechanistic studies, both the C(sp3)─H bond activation and the stereochemistry-determining step are proposed to involve a single-electron transfer/proton transfer process.

Reductive Functionalization of Pyridine-Fused N-Heteroarenes.

ConspectusThe selective functionalization/transformation of ubiquitous pyridine-fused N-heteroarenes is a practical method to synthesize structurally novel N-heterocycles, which is important for the development of medicines, bioactive agents, agrochemicals, materials, ligands, sensors, pigments, dyes, etc. However, owing to thermodynamic stability, kinetic inertness, and lone electron pair-induced catalyst deactivation of the pyridine-fused N-heteroarenes, limited strategies (e.g., C-H activation/functionalization, electrophilic substitution, and the Minisci reaction) are available to realize the synthetic purpose and maintain the aromaticity of the final products. Moreover, the relevant transformations have limitations such as needing harsh reaction conditions, requiring the preinstallation of specific coupling agents containing transformable functionalities or directing groups, using less environmentally benign oxidants and/or acidic activators, and poor selectivity. Herein, considering that imines, enamines, radicals, and cyclic amines are generated during the reduction of pyridine-fused N-heteroarenes, the precise transformation of these reductive intermediates offers a fundamental basis for developing novel tandem reactions. Our group revealed that a slow reduction rate, synergistic catalysis, and controlled electroreduction are effective strategies for fulfilling the selective reductive functionalization of pyridine-fused N-heteroarenes. Thus, we established a series of new synthetic methods that provide diverse construction modalities for functionalized N-heterocycles. The striking features of these synthetic methods include high efficiency, atom economy, and the use of readily accessible N-heteroarenes as transformable feedstocks in the absence of flammable and pressurized H2 gas, alongside a promising potential of the obtained N-heterocyclic products. The present study would be appealing to the fields of synthetic organic chemistry, catalysis, biomedical chemistry, and functional materials. This Account describes the application of reductive dearomatization as substrate-activating and tandem reaction-initiating modes and summarizes the reductive functionalization of pyridine-fused N-heteroarenes via selective alkylation, arylation, and annulation at nitrogen, α, ß, and other remote carbon sites achieved over the past 8 years. Details regarding the development of new reactions and their plausible mechanisms and perspectives are discussed. We hope our contributions to this field will aid in the further development of novel strategies for the functionalization/transformation of pyridine-fused N-heteroarenes and tackle the intractable challenges in this area.

Intermolecular diastereoselective annulation of azaarenes into fused N-heterocycles by Ru(II) reductive catalysis.

Derivatization of azaarenes can create molecules of biological importance, but reductive functionalization of weakly reactive azaarenes remains a challenge. Here the authors show a dearomative, diastereoselective annulation of azaarenes, via ruthenium(II) reductive catalysis, proceeding with excellent selectivity, mild conditions, and broad substrate and functional group compatibility. Mechanistic studies reveal that the products are formed via hydride transfer-initiated ß-aminomethylation and α-arylation of the pyridyl core in the azaarenes, and that paraformaldehyde serves as both the C1-building block and reductant precursor, and the use of Mg(OMe)2 base plays a critical role in determining the reaction chemo-selectivity by lowering the hydrogen transfer rate. The present work opens a door to further develop valuable reductive functionalization of unsaturated systems by taking profit of formaldehyde-endowed two functions.

Photoinduced Chemo-, Site- and Stereoselective α-C(sp3 )-H Functionalization of Sulfides.

The ubiquity of sulfur-containing molecules in biologically active natural products and pharmaceuticals has long attracted synthetic chemists to develop efficient strategies towards their synthesis. The strategy of direct α-C(sp3 )-H modification of sulfides provides a streamlining access to complex sulfur-containing molecules. Herein, we report a photoinduced chemo-, site- and stereoselective α-C(sp3 )-H functionalization of sulfides using isatins as the photoredox reagent and coupling partner catalyzed by a chiral gallium(III)-N,N'-dioxide complex. The reaction proceeds through a verified single-electron transfer (SET) mechanism with high efficiency, excellent functional group tolerance, as well as a broad substrate scope. Importantly, this cross-coupling protocol is highly selective for the direct late-stage functionalization of methionine-related peptides, regardless of the inherent structural similarity and complexity of diverse residues.

Ruthenium-Catalyzed Hydrogen Evolution o-Aminoalkylation of Phenols with Cyclic Amines.

Herein, we present a ruthenium-catalyzed new hydrogen evolution ortho-aminoalkylation of phenolic derivatives with cyclic amines as the coupling agents. The developed cross-coupling reaction offers a practical platform for direct access to a variety of functionalized phenols with the features of good substrate and functional group compatibility, readily available catalyst system and feedstocks, no need for additional sacrificial oxidants, and high atom efficiency.

Hydrogen Transfer-Mediated Multicomponent Reaction for Direct Synthesis of Quinazolines by a Naphthyridine-Based Iridium Catalyst.

Selective linkage of renewable alcohols and ammonia into functional products would not only eliminate the prepreparation steps to generate active amino agents but also help in the conservation of our finite fossil carbon resources and contribute to the reduction of CO2 emission. Herein the development of a novel 2-(4-methoxyphenyl)-1,8-naphthyridine-based iridium (III) complex is reported, which exhibits excellent catalytic performance toward a new hydrogen transfer-mediated annulation reaction of 2-nitrobenzylic alcohols with alcohols and ammonia. The catalytic transformation proceeds with the striking features of good substrate and functional group compatibility, high step and atom efficiency, no need for additional reductants, and liberation of H2O as the sole by-product, which endows a new platform for direct access to valuable quinazolines. Mechanistic investigations suggest that the non-coordinated N-atom in the ligand serves as a side arm to significantly promote the condensation process by hydrogen bonding.

Copper-Catalyzed Oxidative Multicomponent Annulation Reaction for Direct Synthesis of Quinazolinones via an Imine-Protection Strategy.

Via an imine-protection strategy, we herein present an unprecedented copper-catalyzed oxidative multicomponent annulation reaction for direct synthesis of quinazolinones. The construction of various products is achieved via formation of three C-N and one C-C bonds in conjunction with the benzylic functionalization. The merits of easily available feedstocks, naturally abundant catalyst, good functional group and substrate compatibility, and release of H2O as the byproduct make the developed chemistry a practical way to access quinazolinones.

Site-Specific Oxidative C-H Chalcogenation of (Hetero)Aryl-Fused Cyclic Amines Enabled by Nanocobalt Oxides.

By employing reusable nanocobalt oxides as the catalysts, a site-specific oxidative C-H chalcogenation of (hetero)aryl-fused cyclic amines with various thiols and diselenides is presented for the first time. The reaction proceeds selectively at the sites of the (hetero)aryl rings para to the N atom, and enables access to a wide array of chalcogenyl N-heteroarenes. The merits of the transformation involve high step- and atom-efficiency, excellent substrate and functional compatibility, operational simplicity, and the use of a naturally abundant Co/O2 system. The present work has offered a fundamental basis for the selective synthesis of functional N-heteroarenes from readily available feedstocks.

Direct α-C-H amination using various amino agents by selective oxidative copper catalysis: a divergent access to functional quinolines.

Herein, we present, for the first time, direct dehydrogenative α-C-H amination of tetrahydroquinolines (THQs) using various amino agents by selective aerobic copper catalysis, which enables divergent access to 2-aminoquinolines, the core structures of numerous functional products. In which, the catalyst system preferentially oxidizes the tetrahydroquinolines between two amino reactants, and the presence of TEMPO significantly enhances the capability of the first oxidation of THQs and makes it a kinetically controlled process, thus favoring the C-N bond-forming step. The developed chemistry features broad substrates, excellent functional tolerance, high chemo-selectivity, and no need for pre-preparation of specific aminating agents, which offers a practical way for diverse and atom-economic synthesis of 2-aminoquinolines that are difficult to prepare or inaccessible with the existing C-H amination approaches.

Transition-metal-catalyst-free synthesis of anthranilic acid derivatives by transfer hydrogenative coupling of 2-nitroaryl methanols with alcohols/amines.

By using a transfer hydrogenative coupling strategy, we herein describe a new method for the efficient synthesis of anthranilic acid derivatives, a significantly important class of compounds with extensive applications in organic synthesis and the discovery of bioactive molecules, from 2-nitroaryl methanols and readily available alcohols/amines. The synthesis proceeds with the merits of no need for a transition metal catalyst, operational simplicity, broad substrate scope, good functional tolerance, and high step efficiency, which offers a useful alternative to access anthranilic acid derivatives.

Aerobic Copper-Catalyzed Halocyclization of Methyl N-Heteroaromatics with Aliphatic Amines: Access to Functionalized Imidazo-Fused N-Heterocycles.

A new aerobic copper-catalyzed halocyclization reaction of methyl N-heteroaromatics and aliphatic amines has been developed, which enables straightforward access to functionalized imidazo-fused N-heterocycles with the merits of good functional tolerance, use of easily available copper salts as the catalysts, lithium halides as the halogen sources, and O2 as a sole oxidant. Due to the reaction features' selective introduction of halogen functionalities to the newly formed imidazo ring, further extensions of the developed chemistry toward synthetic diversity, including effective access to functional materials, are easily envisioned.

A novel iridium/acid co-catalyzed transfer hydrogenative C(sp(3))-H bond alkylation to access functionalized N-heteroaromatics.

A novel iridium/acid co-catalysed transfer hydrogenative coupling strategy, enabling direct alkylation of C(sp(3))-H bonds and atom-economic access to alkyl chain-lengthened N-heteroaromatics from six-membered 2-alkyl cyclic amines and aldehydes, has been demonstrated. This work has built an important basis to convert cyclic amines, a class of bulk chemical raw materials, into functionalized products.

Ruthenium-Catalyzed Dehydrogenative ß-Benzylation of 1,2,3,4-Tetrahydroquinolines with Aryl Aldehydes: Access to Functionalized Quinolines.

A new benzylation protocol, enabling straightforward access to ß-benzylated quinolines, has been demonstrated. By employing readily available [RuCl2(p-cymene)]2 as a catalyst and O2 as a sole green oxidant, various 1,2,3,4-tetrahydroquinolines were efficiently converted in combination with aryl aldehydes into desired products in a step- and atom-economic fashion together with the advantages of excellent functional group tolerance and chemoselectivity, offering an important basis for the transformation of saturated N-heterocycles into functionalized N-heteroaromatics via a dehydrogenative cross-coupling strategy. Mechanistic investigations support that the reaction undergoes a monodehydrogenation-triggered ß-benzylation mode.

Ruthenium-Catalyzed Straightforward Synthesis of 1,2,3,4-Tetrahydronaphthyridines via Selective Transfer Hydrogenation of Pyridyl Ring with Alcohols.

Through a ruthenium-catalyzed selective hydrogen transfer coupling reaction, a novel straightforward synthesis of 1,2,3,4-tetrahydronaphthyridines from o-aminopyridyl methanols and alcohols has been developed. The synthetic protocol proceeds in an atom- and step-economic fashion together with the advantages of operational simplicity, broad substrate scope, production of water as the only byproduct, and no need for external reducing reagents such as high pressure H2 gas, offering a highly practical approach for accessing this type of structurally unique products.

A novel ruthenium-catalyzed dehydrogenative synthesis of 2-arylquinazolines from 2-aminoaryl methanols and benzonitriles.

By employing a commercially available Ru3(CO)12/Xantphos/t-BuOK catalyst system, a novel and straightforward ruthenium-catalyzed dehydrogenative synthesis of 2-arylquinazolines has been demonstrated. A series of 2-aminoaryl methanols were efficiently converted in combination with different types of benzonitriles into various desired products in moderate to good yields upon isolation. The synthetic protocol proceeds with the advantages of operational simplicity, high atom efficiency, broad substrate scope, and no need for the use of less environmentally benign halogenated reagents, offering an important basis for accessing 2-arylquinazolines.