Project description:We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.
Project description:Carbon-14 (14C) is a gold standard technology routinely utilized in pharmaceutical and agrochemical industries for tracking synthetic organic molecules and providing their metabolic and safety profiles. While the state of the art has been dominated for decades by traditional multistep synthetic approaches, the recent emergence of late-stage carbon isotope labeling has provided new avenues to rapidly access carbon-14-labeled biologically relevant compounds. In particular, the development of carbon isotope exchange has represented a fundamental paradigm change, opening the way to unexplored synthetic transformations. In this Perspective, we discuss the recent developments in the field with a critical assessment of the literature. We subsequently discuss research directions and future challenges within this rapidly evolving field.
Project description:Carbon-fluorine bond formation by transition metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed. All reported transition-metal-catalyzed fluorination reactions for the synthesis of functionalized arenes are based on palladium. Here we present silver catalysis for carbon-fluorine bond formation. Our report is the first example of the use of the transition metal silver to form carbon-heteroatom bonds by cross-coupling catalysis. The functional group tolerance and substrate scope presented here have not been demonstrated for any other fluorination reaction to date.
Project description:It is a long-standing challenge to achieve efficient and highly selective aerobic oxidation of methylarenes to benzaldehydes, owing to overoxidation problem stemming from the oxidizability of benzaldehyde far higher than the toluene under usual aerobic conditions. Herein we report a bio-inspired iron-catalyzed polymethylhydrosiloxane-promoted aerobic oxidation of methylarenes to benzaldehydes with high yields and selectivities. Notably, this method can tolerate oxidation-labile and reactive boronic acid group, which is normally required to be transformed immediately after its introduction, and represents a significant advance in the area of the chemistry of organoboronic acids, including the ability to incorporate both aldehyde and ketone functionalities into unprotected arylboronic acids, a class that can be difficult to access by current means. The robustness of this protocol is demonstrated on the late-stage oxidation of complex bioactive molecules, including dehydroabietic acid, Gemfibrozil, Tocopherol nicotinate, a complex polyol structure, and structurally complex arylboronic acids.
Project description:Herein, we communicate a selective and efficient protocol for oxidative arylating carbocyclization of enallenynes using O2 as the oxidant. The key to success for this aerobic transformation is the application of a specific electron transfer mediator (ETM), a bifunctional catalyst consisting of a metal-macrocycle and quinone moieties. This catalyst significantly facilitates the reoxidation of Pd0 to PdII under atmospheric pressure of O2 . Diverse functionalized enallenynes react with aryl boronic acids to afford the corresponding cyclic tetraenes in moderate to good yields.
Project description:We disclose herein an unprecedented Pd-catalyzed difluorocarbene transfer reaction, which assembles a series of structurally interesting chiral spiro ketones with generally over 90% ee. Commercially available BrCF2CO2K serves as the difluorocarbene precursor, which is harnessed as a user-friendly and safe carbonyl source in this transformation. Preliminary mechanistic studies exclude the formation of free CO in the reaction process, and importantly, we also find that BrCF2CO2K outcompete gaseous CO and several common CO surrogates in this asymmetric process. The reaction mechanism, including the in-situ progressive release of the difluorocarbene, the rapid migratory insertion of ArPd(II) = CF2 species, and subsequent defluorination hydrolysis by water to introduce the carbonyl group, accounts for the overall high efficiency and uniqueness. This work clearly showcases the advantage and potential of the difluorocarbene in synthesis and supplies a mechanistically distinct route for asymmetric carbonylative cyclization reactions.
Project description:A visible-light-mediated late-stage aminocarbonylation of unactivated alkyl iodides with stoichiometric amounts of carbon monoxide is presented. The method provides a mild, one-step route to [carbonyl-13/14C] alkyl amides, thereby reducing radioactive waste, and handling of radioactive materials. Easily accessible and low-cost equipment and a palladium catalyst were successfully used for the synthesis of a wide range of alkyl amides.
Project description:Palladium and nickel catalysts promoted highly selective carbon-carbon bond insertion reactions with di-tert-butyl-alkylidenesilacyclopropanes. Pd(PPh(3))(4) was demonstrated to be the optimal catalyst, allowing for a variety of carbon-carbon pi-bond insertion reactions. Depending on the nature of the carbon-carbon pi bond, the insertion reaction proceeded with either direct insertion into the carbon(sp(2))-silicon bond or with allylic transposition. Ring-substituted alkylidenesilacyclopropanes required a nickel catalyst to afford insertion products. Using Ni(cod)(2) as the carbon-carbon bond insertion catalyst, new double alkyne insertion products and alkene isomerization products were observed.
Project description:Peptide macrocycles often display diverse bioactivities and self-assembly properties, which lead to a variety of applications in medicinal and material sciences. Transition metal-catalyzed C▬H activations are emerging strategies for site-selective functionalization of amino acids and peptides, as well as the construction of cyclic peptides. Here, we report the development of a peptide-directed method for the macrocyclization of peptidoarylacetamides by Pd(II)-catalyzed late-stage C(sp2)▬H olefination. In this protocol, peptide backbones act as internal directing groups and enable facile preparation of diverse cyclic peptides that are difficult to synthesize by conventional macrolactamization. Furthermore, we show that the incorporation of aryl-alkene cross-link in the backbone constrains cyclic peptides into conformations for self-assembly.
Project description:A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade transformation leads with high regioselectivity to the desired products in good yields and avoids the need for additional purification steps.