Photoredox catalysis has experienced a revitalized interest from the synthesis community during the past decade. For example, photoredox/Ni dual catalysis protocols have been developed to overcome ...several inherent limitations of palladium-catalyzed cross-couplings by invoking a single-electron transmetalation pathway. This Perspective highlights advances made by our laboratory since the inception of the photoredox/Ni cross-coupling of benzyltrifluoroborates with aryl bromides. In addition to broadening the scope of trifluoroborate coupling partners, research using readily oxidized hypervalent silicates as radical precursors that demonstrate functional group compatibility is highlighted. The pursuit of electrophilic coupling partners beyond (hetero)aryl bromides has also led to the incorporation of several new classes of C(sp2)-hybridized substrates into light-mediated cross-coupling. Advances to expand the radical toolbox by utilizing feedstock chemicals (e.g., aldehydes) to access radicals that were previously inaccessible from trifluoroborates and silicates are also emphasized. Additionally, several organic photocatalysts have been investigated as replacements for their expensive iridium- and ruthenium-based counterparts. Lastly, the net C–H functionalization of the radical partner in an effort to improve atom economy is presented. An underlying theme in all of these studies is the value of generating radicals in a catalytic manner, rather than stoichiometrically.
Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a Csp3 -centered radical that can engage in the C–H alkylation of heterocyclic bases and ...1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C–H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears.
The incorporation of C‐glycosides in drug design has become a routine practice for medicinal chemists. These naturally occurring building blocks exhibit attractive pharmaceutical profiles, and have ...become an important target of synthetic efforts in recent decades. Described herein is a practical, scalable, and versatile route for the synthesis of non‐anomeric and unexploited C‐acyl glycosides through a Ni/photoredox dual catalytic system. By utilizing an organic photocatalyst, a range of glycosyl‐based radicals are generated and efficiently coupled with highly functionalized carboxylic acids at room temperature. Distinctive features of this transformation include its mild conditions, impressive compatibility with a wide array of functional groups, and most significantly, preservation of the anomeric carbon: a handle for further, late‐stage derivatization.
Leading light: A practical and versatile route toward C‐acyl glycosides through Ni/Photoredox dual catalysis was developed. Key to this transformation is preservation of the anomeric carbon atom as a handle for further derivatization. An organic photocatalyst is utilized to generate an array of glycosyl‐based radicals that engage in cross‐coupling with in situ activated carboxylic acids. This process is operationally simple and shows broad functional‐group tolerance.
The development of synthetic tools to introduce saccharide derivatives into functionally complex molecules is of great interest, particularly in the field of drug discovery. Herein, we report a new ...route toward highly functionalized, arylated saccharides, which involves nickel‐catalyzed cross‐coupling of photoredox‐generated saccharyl radicals with a range of aryl‐ and heteroaryl bromides, triggered by an organic photocatalyst. In contrast to existing methods, the mild reaction conditions achieve arylation of saccharide motifs while leaving the anomeric carbon available, thus providing access to a class of arylated glycosides that has been underexplored until now. To demonstrate the potential of this strategy in late‐stage functionalization, a variety of structurally complex molecules incorporating saccharide moieties were synthesized.
Running mild: A new route toward highly functionalized, arylated saccharides through nickel‐catalyzed cross‐coupling of photoredox‐generated saccharyl radicals with a range of aryl‐ and heteroaryl bromides, triggered by an organic photocatalyst, was developed. In contrast to existing methods, the mild reaction conditions achieve arylation of saccharide motifs while leaving the anomeric carbon atom available, thereby providing access to underexplored arylated glycosides.
Heteroarylation via C–H functionalization has been synthetically challenging, but such transformations represent an atom-economical and highly convergent route toward complex molecules. Reported ...herein is a photoredox-catalyzed coupling between 2-trifluoroborato-4-chromanones and various heteroarenes through a Minisci pathway. Mesitylacridinium perchlorate, an organic photocatalyst, proved to be a better photocatalyst than transition-metal counterparts for such transformations. To highlight the utility of this approach, a library of unprecedented heteroaryl-substituted chromanones was generated that was composed of numerous, specifically substituted molecules containing a broad range of functional groups.
A photoredox-catalyzed C-H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild ...oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts. Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by
H and
C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF
.
A regioselective, nickel‐catalyzed photoredox allylation of secondary, benzyl, and α‐alkoxy radical precursors is disclosed. Through this manifold, a variety of linear allylic alcohols and allylated ...monosaccharides are accessible in high yields under mild reaction conditions. Quantum mechanical calculations DFT and DLPNO‐CCSD(T) support the mechanistic hypothesis of a Ni0 to NiII oxidative addition pathway followed by radical addition and inner‐sphere allylation.
Coming to light: Report herein is a highly regioselective, intermolecular, nickel‐catalyzed photoredox allylic substitution that expands both the radical and electrophile scope of dual photoredox/Ni‐catalyzed reactions. Quantum mechanical calculations shed light on the mechanistic pathway, supporting a Ni0 to NiII oxidative addition followed by an inner‐sphere radical addition. PC=photocatalyst, RP=radical precursor.
Utilizing photoredox/nickel dual catalysis, diverse flavanones have been synthesized by coupling novel 2-trifluoroboratochromanone building blocks with aryl and heteroaryl bromide partners. The newly ...reported trifluoroboratochromanones can be easily accessed from the corresponding chromones on multigram scale. This represents a general route for accessing natural and unnatural flavanones that were previously formed through a synthetically more restrictive ring closure route from chalcone precursors.
Photoredox-mediated radical/polar crossover (RPC) processes offer new avenues for the synthesis of cyclic molecules. This process has been realized for the construction of medium-sized saturated ...nitrogen heterocycles. Photocatalytically generated alkyl radicals possessing pendant leaving groups engage imines in C–C bond formation, and subsequent reduction of the intermediate nitrogen-centered radical triggers anionic ring closure. With the aid of visible light irradiation, substituted pyrrolidines, piperidines, and azepanes can be prepared under mild, redox-neutral conditions.
Minisci-type alkylation of electron-deficient heteroarenes has been a pivotal technique for medicinal chemists in the synthesis of drug-like molecules. However, such transformations usually require ...harsh conditions (
, strong acids, stoichiometric amount of oxidants, elevated temperatures,
). Herein, by utilizing photoredox catalysis, a highly-selective alkylation method using heteroaryl sulfones has been developed that can be carried out under acid-free and redox-neutral conditions. Because of these mild conditions, challenging yet privileged structures, such as monosaccharides and unprotected secondary amines, can be installed.
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