Polyfluorinated aromatics are essential to materials science as well as the pharmaceutical and agrochemical industries and yet are often difficult to access. This Communication describes a photocatalytic hydrodefluorination approach which begins with easily accessible perfluoroarenes and selectively reduces the C-F bonds. The method allows facile access to a number of partially fluorinated arenes and takes place with unprecedented catalytic activity using a safe and inexpensive amine as the reductant.
Multifluorinated biaryls are challenging to synthesize and yet an important class of molecules. Owing to the difficulty associated with selective fluorination, this class of molecules represent a formidable synthetic challenge. An alternative approach to selective fluorination of biaryls is to couple an arene which already possess C–F bonds in the desired location. This strategy has been regularly utilized, relying heavily on traditional cross-coupling strategies which employ organometallics and halides (or pseudohalides) in order to achieve the coupling. Herein, we report conditions for the photocatalytic coupling via the direct functionalization of the C–F bond of a perfluoroarene and C–H bond of the other arene to provide an expedient route to multifluorinated biaryls. The mild conditions and good functional group tolerance enable a broad scope-including access to the anti-Minisci product of basic heterocycles. Finally, we demonstrate the value of the C–F functionalization approach by utilizing the high fluorine content to systematically build complex biaryls that contain between 2–5 Caryl–F bonds via synergistic use of photocatalysis and SNAr chemistry.
Molecular glues (MGs) are monovalent
small molecules
that induce
an interaction between proteins (native or non-native partners) by
altering the protein–protein interaction (PPI) interface toward
a higher-affinity state. Enhancing the PPI between a protein and E3
ubiquitin ligase can lead to degradation of the partnering protein.
Over the past decade, retrospective studies of clinical drugs identified
that immunomodulatory drugs (e.g., thalidomide and analogues) and
indisulam exhibit a molecular glue effect by driving the interaction
between non-native substrates to CRBN and DCAF15 ligases, respectively.
Ensuing reports of phenotypic screens focused on MG discovery have
suggested that these molecules may be more common than initially anticipated.
However, prospective discovery of MGs remains challenging. Thus, expanding
the repertoire of MGs will enhance our understanding of principles
for prospective design. Herein, we report the results of a CRISPR/Cas9
knockout screen of over 1000 ligases and ubiquitin proteasome system
components in a BRD4 degradation assay with a JQ1-based monovalent
degrader, compound 1a. We identified DCAF16, a substrate
recognition component of the Cul4 ligase complex, as essential for
compound activity, and we demonstrate that compound 1a drives the interaction between DCAF16 and BRD2/4 to promote target
degradation. Taken together, our data suggest that compound 1a functions as an MG degrader between BRD2/4 and DCAF16 and
provides a foundation for further mechanistic dissection to advance
prospective MG discovery.
This work describes the facile and mono-selective per- and polyfluoroarylation of Meldrum's acid to generate a versatile synthon for highly fluorinated α-phenyl acetic acid derivatives, which provide straightforward access to fluorinated building blocks. The reaction takes place quickly, and most products were isolated without the need for chromatography. Importantly, this method provides an alternative strategy to access α-arylated Meldrum's acids, which avoids the need for aryl-Pb(IV) salts or diaryliodonium salts. Furthermore, we demonstrate the synthetic versatility and utility of the Meldrum's acid products by subjecting our products to several derivatizations of the Meldrum's acid products as well as photocatalytic hydrodefluorination.
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