Nitrogen-Centered Radicals Derived from Azidonucleosides.

Azido-modified nucleosides have been extensively explored as substrates for click chemistry and the metabolic labeling of DNA and RNA. These compounds are also of interest as precursors for further synthetic elaboration and as therapeutic agents. This review discusses the chemistry of azidonucleosides related to the generation of nitrogen-centered radicals (NCRs) from the azido groups that are selectively inserted into the nucleoside frame along with the subsequent chemistry and biological implications of NCRs. For instance, the critical role of the sulfinylimine radical generated during inhibition of ribonucleotide reductases by 2'-azido-2'-deoxy pyrimidine nucleotides as well as the NCRs generated from azidonucleosides by radiation-produced (prehydrated and aqueous) electrons are discussed. Regio and stereoselectivity of incorporation of an azido group ("radical arm") into the frame of nucleoside and selective generation of NCRs under reductive conditions, which often produce the same radical species that are observed upon ionization events due to radiation and/or other oxidative conditions that are emphasized. NCRs generated from nucleoside-modified precursors other than azidonucleosides are also discussed but only with the direct relation to the same/similar NCRs derived from azidonucleosides.

Remote C-H Pyridylation of Hydroxamates through Direct Photoexcitation of O-Aryl Oxime Pyridinium Intermediates.

Herein, we report an efficient strategy for the remote C-H pyridylation of hydroxamates with excellent ortho-selectivity by designing a new class of photon-absorbing O-aryl oxime pyridinium salts generated in situ from the corresponding pyridines and hydroxamates. When irradiated by visible light, the photoexcitation of oxime pyridinium intermediates generates iminyl radicals via the photolytic N-O bond cleavage, which does not require an external photocatalyst. The efficiency of light absorption and N-O bond cleavage of the oxime pyridinium salts can be modulated through the electronic effect of substitution on the O-aryl ring. The resultant iminyl radicals enable the installation of pyridyl rings at the γ-CN position, which yields synthetically valuable C2-substituted pyridyl derivatives. This novel synthetic approach provides significant advantages in terms of both efficiency and simplicity and exhibits broad functional group tolerance in complex settings under mild and metal-free conditions.

Diastereoselective and Stereodivergent Synthesis of 2-Cinnamylpyrrolines Enabled by Photoredox-Catalyzed Iminoalkenylation of Alkenes.

A photoredox-catalyzed iminoalkenylation of γ-alkenyl O-acyl oximes has been developed. Readily available alkenylboronic acids serve as alkenylation reagents, leading to densely functionalized pyrrolines. Both (E)- and (Z)-cinnamylpyrrolines are accessible depending on the reaction solvent. In dichloromethane, (E)-cinnamylpyrrolines are produced through a photoredox-mediated single-electron-transfer process. In tetrahydrofuran, (Z)-cinnamylpyrrolines are generated by photocatalytic contra-thermodynamic E-to-Z isomerization of (E)-cinnamylpyrrolines though an energy-transfer pathway. Two stereocenters are established with complete diastereoselectivity and only one diastereomer is isolated.

Synthesis of Functionalized Nitriles by Microwave-Promoted Fragmentations of Cyclic Iminyl Radicals.

The synthesis of functionalized nitriles via microwave-promoted radical fragmentations of cyclic O-phenyl oxime ethers is reported. A variety of radical traps can be employed, permitting the generation of diverse adducts via C-O, C-C, C-N, or C-X bond formation. Other salient features include a simple and practical protocol, very short reaction times, and the avoidance of metal catalysts and toxic cyanide reagents. The utility of this method is demonstrated by the ring-distortion of a steroid-derived substrate.

A Visible-Light-Driven Iminyl Radical-Mediated C-C Single Bond Cleavage/Radical Addition Cascade of Oxime Esters.

A room-temperature, visible-light-driven N-centered iminyl radical-mediated and redox-neutral C-C single bond cleavage/radical addition cascade reaction of oxime esters and unsaturated systems has been accomplished. The strategy tolerates a wide range of O-acyl oximes and unsaturated systems, such as alkenes, silyl enol ethers, alkynes, and isonitrile, enabling highly selective formation of various chemical bonds. This method thus provides an efficient approach to various diversely substituted cyano-containing alkenes, ketones, carbocycles, and heterocycles.

Visible-light-promoted iminyl-radical formation from acyl oximes: a unified approach to pyridines, quinolines, and phenanthridines.

A unified strategy involving visible-light-induced iminyl-radical formation has been established for the construction of pyridines, quinolines, and phenanthridines from acyl oximes. With fac-[Ir(ppy)3 ] as a photoredox catalyst, the acyl oximes were converted by 1 e(-) reduction into iminyl radical intermediates, which then underwent intramolecular homolytic aromatic substitution (HAS) to give the N-containing arenes. These reactions proceeded with a broad range of substrates at room temperature in high yield. This strategy of visible-light-induced iminyl-radical formation was successfully applied to a five-step concise synthesis of benzo[c]phenanthridine alkaloids.

Cascade Synthesis of New Indole-Containing Pentacyclic Scaffolds Mediated by Aryl and Iminyl Radicals.

A five-step approach, starting from simple 1,5-disubstituted indoles, has been implemented for the synthesis of diversely substituted indole-pyrido-indene pentacyclic compounds up to 54 % yield via domino radical-mediated processes in the presence of the radical reagents DLP/TTMSS and AIBN/TTMSS. Reactions proceeded with diverse key starting radical cyano-precursors strategically synthesized which were subsequently transformed into the target pentacyclic compounds through an aryl/iminyl radical-mediated domino reactions sequence. In addition to the routine spectroscopic techniques, the structure of radical precursors, as well as, the target pentacyclic products were unequivocally established by single crystal X-ray diffraction, confirming the effectiveness of the proposed synthetic sequence.