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...
A direct arylation of a variety of electron-deficient heterocycles with arylboronic acids has been developed. This new reaction proceeds readily at room temperature using inexpensive reagents: catalytic silver(I)nitrate in the presence of persulfate co-oxidant. The scope with respect to heterocycle and boronic acid coupling partner is broad, and sensitive functional groups are tolerated. This method allows for rapid access to a variety of arylated heterocycles that would be more difficult to access with traditional methods.Methods for the cross-coupling of heterocycles with aryl groups are of fundamental importance in nearly all areas of chemical science. Among these, the Pd-catalyzed coupling of arylboronic acids with aromatic halides (Suzuki reaction) is widely employed.1 A far less studied and underappreciated coupling reaction is the Ag-catalyzed addition of nucleophilic, alkyl-centered radicals to electron-deficient heterocycles (Minisci reaction).2 One drawback of the Minisci reaction is the limited access to nucleophilic radicals, especially of the aryl variety.3 Our recent studies involving chemoselective silver-mediated oxidation reactions on highly complex alkaloids such as palau'amine4 led us to reexamine this gap in the scope of the classic Minisci reaction. Herein we report the development of a silver(I)-catalyzed addition of arylboronic acids to a range of electron-deficient heterocycles (see Figure 1A). This net C-H arylation proceeds at room temperature and is operationally simple, scalable, and has broad functional group compatibility and substrate scope.The most common method to arylate electron-deficient heterocycles is by the direct addition of an arylmetallate followed by rearomatization.5 However, this method often furnishes products in low to moderate yield, is only effective on electron-deficient heterocycles, and has low functional group compatibility. Due to these drawbacks, several powerful alternative methods have arisen in the literature to functionalize heterocycles.6 The direct coupling of heterocycles to aryl halides has been accomplished using palladium,7 rhodium,8 gold,9 and copper10 catalysis. Additionally, pyridine has been coupled to arylzinc reagents under nickel catalysis in good yield,11 and directed metallation of pyridine derivatives followed by Negishi coupling to aryl halides has demonstrated unique selectivity.12 Finally, pre-activation of heterocycles as their N-oxides has been shown to allow heterocycles to be directly arylated under palladium catalysis with a broad range of aryl halides.13
Multidimensional reaction screening of ortho-alkynyl benzaldehydes with a variety of catalysts and reaction partners was conducted in an effort to identify new chemical reactions. Reactions affording unique products were selected for investigation of preliminary scope and limitations.
The total synthesis of the complex pyrrole–imidazole alkaloids (±)–massadine and (±)–massadine chloride is described using a carefully orchestrated sequence of manipulations on highly polar and structurally complex intermediates. Key to the completion of this synthetic endeavor was the exploration of a unique and chemoselective method to oxidize unprotected guanidines under aqueous conditions in air. This oxidation has been optimized and applied to a selection of spirocyclic guanidines of varying complexity. Additionally, the 3,7–epi analogues of these interesting natural products have been synthesized and fully characterized.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.