Direct methods for the trifluoromethylation of heteroaromatic systems are in extremely high demand in nearly every sector of chemical industry. Here we report the discovery of a general procedure using a benchtop stable trifluoromethyl radical source that functions broadly on a variety of electron deficient and rich heteroaromatic systems and demonstrates high functional group tolerance. This C-H trifluoromethylation protocol is operationally simple (avoids gaseous CF 3 I), scalable, proceeds at ambient temperature, can be used directly on unprotected molecules, and is demonstrated to proceed at the innately reactive positions of the substrate. The unique and orthogonal reactivity of the trifluoromethyl radical relative to aryl radicals has also been investigated on both a complex natural product and a pharmaceutical agent. Finally, preliminary data suggest that the regioselectivity of C-H trifluoromethylation can be fine-tuned simply by judicious solvent choice.medicinal chemistry | C-H functionalization | synthetic methodology T he trifluoromethyl group is becoming an increasingly common trait among molecules found in billion-dollar pharmaceuticals, agrochemicals, liquid crystals, dyes, and polymers (1-6). The inclusion of this motif and the unique properties its presence elicits is a testament to the success of chemical synthesis, as it is notably absent in Nature. Methodologies for the trifluoromethylation of arenes can be divided into two general categories (Fig. 1A): those that functionalize the inherently reactive positions of the substrate ("innate trifluoromethylation") and those that utilize substrate prefunctionalization or a directing group ("programmed trifluoromethylation"). For most applications, "programmed" aryl trifluoromethylation holds a distinct advantage because it can selectively functionalize positions that are not naturally reactive. Indeed, incredibly powerful methods have recently emerged in this arena (10-18). On the other hand, methods that capitalize on innate reactivity avoid the complication of preparing prefunctionalized substrates. We became interested in exploring "innate" aryl trifluoromethylation during our recent studies in the area of direct C-H arylation of heterocycles (19) and quinones (20) using radicals derived from boronic acid precursors. Aromatic heterocycles containing the trifluoromethyl group represent an important subsection of molecules of practical interest, particularly for pharmaceuticals, and therefore previously undescribed methods for their rapid assembly are in high demand. Our goal was to identify a reagent that would circumvent the use of gaseous CF 3 I (21), a reagent that is often avoided in pharmaceutical settings. At the start of our work, the task of replacing this reagent for the innate trifluormethylation of nitrogen containing heterocycles remained an unmet challenge.As briefly illustrated in Fig. 1, we evaluated numerous reagents for the trifluoromethylation of 4-t-butylpyridine as a model compound, with the aim of exploring those that might p...

The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.

Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H O or O as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value-added ketone products. Lastly, NMR spectroscopy using in situ LED-irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

This Concept article highlights the development of a novel analytical tool, LED-NMR (a combination of in situ light illumination using a light-emitting diode and NMR spectroscopy) and its variant UVNMR (LED-NMR coupled with UV/Vis absorption spectroscopy), as well as their applications in the mechanistic investigation of light-induced transformations. The utility of these new tools has been demonstrated by providing rich kinetic and structural data of reaction species offering mechanistic insights into photochemical and photocatalytic reactions. Furthermore, NMR actinometry has been recently developed as a practical and simple method for quantum yield measurements. Quantum yield is an important parameter in photoinduced processes, but is rarely measured in practice because of the barriers associated with traditional actinometry. These new tools and techniques streamline measurements of the quantum efficiency while affording informative mechanistic insights into photochemical reactions. We anticipate these techniques will enable chemists to further advance the rapidly emerging photochemistry field. adoption of LED-NMR will make this powerful technique a standard method in the field of photochemistry.

A simplified approach to quantum yield ([Formula: see text]) measurement using in situ LED NMR spectroscopy has been developed. The utility and performance of NMR actinometry has been demonstrated for the well-known chemical actinometers potassium ferrioxalate and o-nitrobenzaldehyde. A novel NMR-friendly actinometer, 2,4-dinitrobenzaldehyde, has been introduced for both 365 and 440 nm wavelengths. The method has been utilized successfully to measure the quantum yield of several recently published photochemical reactions.

We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical approach circumvents the need for azo radical initiators and proceeds at room temperature. Implementation of continuous flow technology allowed tight control of irradiation and residence time, resulting in a robust process with minimized byproduct formation. This method was selected for the manufacturing process for belzutifan and represents the first commercial continuous flow photochemical process in our company, laying the foundation for the utilization of photochemistry in the pharmaceutical industry.