Synthesis of Tri- and Difluoromethoxylated Compounds by Visible-Light Photoredox Catalysis.

Trifluoromethoxy (OCF ) and difluoromethoxy (OCF H) groups are fluorinated structural motifs that exhibit unique physicochemical characteristics. Incorporation of these substituents into organic molecules is a highly desirable approach used in medicinal chemistry and drug discovery processes to alter the properties of a parent compound. Recently, tri- and difluoromethyl ethers have received increasing attention and several innovative strategies to access these valuable functional groups have been developed.

Recent Development of Catalytic Trifluoromethoxylation Reactions.

Trifluoromethoxy (OCF) group exhibits unique properties, which render it a highly desirable structural motif in life and materials sciences. The numbers of newly synthesized trifluoromethyl ethers are booming as new synthetic methods are constantly being developed to access these valuable compounds. This Review summarizes recent catalytic approaches towards preparation of trifluoromethyl ethers.

Transition-metal-free C-H amidation and chlorination: synthesis of N/N'-mono-substituted imidazopyridin-2-ones from N-pyridyl-N-hydroxylamine intermediates.

Non-symmetric 1,3-substituted imidazopyridin-2-ones are a common structural scaffold found among many biologically active molecules. Herein we report an efficient, mild, and transition-metal free C-H amidation strategy to access such a pyrido-fused cyclic urea framework in good yields and with a broad functional group tolerance.

Recent developments in transition-metal photoredox-catalysed reactions of carbonyl derivatives.

Single-electron reduction of C[double bond, length as m-dash]O and C[double bond, length as m-dash]N bonds of aldehydes, ketones, and imines results in the formation of ketyl and α-aminoalkyl anion radicals, respectively. These reactive intermediates are characterized by an altered electronic character with respect to their parent molecules and undergo a diverse range of synthetically useful transformations, which are not available to even-electron species. This Review summarizes the reactions of ketyl and α-aminyl radicals generated from carbonyl derivatives under transition-metal photoredox-catalysed conditions.

β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis.

Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chemistry by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed β-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivatives with the aid of a Lewis acid co-catalyst. Our process tolerates complex molecular scaffolds (e.

Development of [F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.

Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3β and central nervous system disorders in living organisms, and it would enable early detection of the enzyme's aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3β inhibitors.

Synthesis of Trifluoromethoxylated (Hetero)Arenes OCF Migration.

Incorporation of the OCF group into organic molecules, especially aromatic and heteroaromatic compounds, is recognized as one of the major challenges in synthetic organic chemistry. Although many attempts have been made to develop efficient trifluoromethoxylation strategies, most of the current approaches still require use of highly toxic, thermally unstable reagents, or impractical reaction conditions. Herein, we highlight a recent contribution from our group towards the synthesis of (hetero)aryltrifluoromethyl ethers.

Access to a new class of synthetic building blocks trifluoromethoxylation of pyridines and pyrimidines.

Since the first synthesis of trifluoromethyl ethers in 1935, the trifluoromethoxy (OCF) group has made a remarkable impact in medicinal, agrochemical, and materials science research. However, our inability to facilely incorporate the OCF group into molecules, especially heteroaromatics, has limited its potential across a broad spectrum of technological applications. Herein, we report a scalable and operationally simple protocol for regioselective trifluoromethoxylation of a wide range of functionalized pyridines and pyrimidines under mild reaction conditions.

Mechanistic studies on intramolecular C-H trifluoromethoxylation of (hetero)arenes via OCF3-migration.

The one-pot two-step intramolecular aryl and heteroaryl C-H trifluoromethoxylation recently reported by our group has provided a general, scalable, and operationally simple approach to access a wide range of unprecedented and valuable OCF3-containing building blocks. Herein we describe our investigations to elucidate its reaction mechanism. Experimental data indicate that the O-trifluoromethylation of N-(hetero)aryl-N-hydroxylamine derivatives is a radical process, whereas the OCF3-migration step proceeds via a heterolytic cleavage of the N-OCF3 bond followed by rapid recombination of a short-lived ion pair.