Selenide-catalyzed enantioselective synthesis of trifluoromethylthiolated tetrahydronaphthalenes by merging desymmetrization and trifluoromethylthiolation.
ABSTRACT: Trifluoromethylthiolated molecules are an important class of biologically active compounds and potential drug candidates. Because of the lack of efficient synthetic methods, catalytic enantioselective construction of these molecules is rare and remains a challenge. To expand this field, we herein disclose a bifunctional selenide-catalyzed approach for the synthesis of various chiral trifluoromethylthiolated tetrahydronaphthalenes bearing an all-carbon quaternary stereocenter with gem-diaryl-tethered alkenes and alkynes by merging desymmetrization and trifluoromethylthiolation strategy. The products are obtained in high yields with excellent enantio- and diastereo-selectivities. This method can be applied to the desymmetrization and sulfenylation of diols as well. Computational studies reveal that selenide can activate the electrophilic reagent better than sulfide, confirming the higher efficiency of selenide catalysis in these reactions. On the basis of the theoretical calculations, an acid-derived anion-binding interaction is suggested to exist in the whole pathway and accounts for the observed high selectivities.
Project description:Decarboxylative trifluoromethylthiolation of lithium pyridylacetates was achieved using <i>N</i>-(trifluoromethylthio)benzenesulfonimide as the electrophilic trifluoromethylthiolation reagent. The reaction afforded the corresponding trifluoromethyl thioethers in good yield. Furthermore, the preparation of lithium pyridylacetates by saponification of the corresponding methyl esters and subsequent decarboxylative trifluoromethylthiolation were performed in a one-pot fashion.
Project description:The first trifluoromethylthiolation and [(18)F]trifluoromethylthiolation of alkyl electrophiles with in?situ generated difluorocarbene in the presence of elemental sulfur and external (radioactive) fluoride ion is described. This transition-metal-free approach is high yielding, compatible with a variety of functional groups, and operated under mild reaction conditions. The conceptual advantage of this exogenous-fluoride-mediated transformation enables unprecedented syntheses of [(18)F]CF3S-labeled molecules from most commonly used [(18)F]fluoride ions. The rapid radiochemical reaction time (?1?min) and high functional-group tolerance allow access to a variety of aliphatic [(18)F]CF3S compounds in high yields.
Project description:The desymmetrization of p-peroxyquinols using a Brønsted acid-catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. Mechanistic studies suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cancer cell-growth inhibition.
Project description:The benzylic positions in drugs are sites that readily react with cytochrome P450 oxidases via single-electron oxidation. New synthetic methodologies to incorporate a fluoroalkyl group at the benzylic site are continually being developed, and in this paper, we report a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes. The precise and predictive regioselectivity among various C(sp3)-H bonds originates from an inner-sphere benzylic radical initiation mechanism, and avoids the use of external oxidants or hydrogen atom abstractors. Its practicality stems from the trifluoromethylthiolation of a series of drugs and complex organic molecules, which is overwhelmingly selective for benzyl groups. This operationally simple protocol can provide a general and practical access to structurally diverse benzylic trifluoromethyl sulfides produced from ubiquitous benzylic C-H bonds. Large scale trifluoromethylthiolation can be achieved with continuous flow photoredox technology.
Project description:Trifluoromethyl sulfoxides are a new class of trifluoromethylthiolating reagent. The sulfoxides engage in metal-free C-H trifluoromethylthiolation with a range of (hetero)arenes. The method is also applicable to the functionalization of important compound classes, such as ligand derivatives and polyaromatics, and in the late-stage trifluoromethylthiolation of medicines and agrochemicals. The isolation and characterization of a sulfonium salt intermediate supports an interrupted Pummerer reaction mechanism.
Project description:A new Zn-mediated trifluoromethylthiolation-based bifunctionalization reaction is developed. In this process, simultaneous C-SCF<sub>3</sub> and C-C bond formation takes place in a multicomponent reaction, in which an aryl and a SCF<sub>3</sub> group arise from different reagents. Our studies show that the reaction mechanism is similar to the Hooz multicomponent coupling. The process involves <i>in situ</i> generation of BAr<sub>3</sub>, which reacts with a diazocarbonyl compound, and the reaction is terminated by an electrophilic SCF<sub>3</sub> transfer. The reaction can also be extended to fluorination based bifunctionalization which proceeds with somewhat lower yield than the analogous trifluoromethylthiolation reaction.
Project description:The CF3SN moiety is a substituent with interesting properties. However, there is no easy synthetic access to molecules bearing this group. The trifluoromethanesulfenamide is a new reagent for the electrophilic trifluoromethylthiolation which reacts easily with amines to obtain trifluoromethylsulfanylamines with good yields.
Project description:Here we describe a deoxygenative trifluoromethylthiolation method that yields trifluoromethyl thioesters from readily available carboxylic acids. The method is built upon an "umpolung" strategy where triphenylphosphine is used to first activate an electrophilic trifluoromethylthiolating reagent and then serves as an oxygen acceptor for the deoxygenation. The method is mild, efficient, broad-scope, and tolerant. It can be applied for the late-stage functionalization of numerous natural products and drug molecules containing a carboxylic acid group. The trifluoromethyl thioesters can be converted into trifluoromethyl thioethers by Pd-catalyzed decarbonylation.
Project description:A direct and versatile copper-catalyzed trifluoromethylthiolation and trifluoromethylselenation of primary, secondary, and tertiary aliphatic C-H bonds was developed. The reaction provides direct access to molecules containing these emerging moieties in the presence of a wide range of common functional groups and in complex molecular environments.
Project description:2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one (diazo-triflone) (<b>2</b>) is not only a building block but also a reagent. In this study, diazo-triflone, which was originally used for the synthesis of ?-lactam triflones as a trifluoromethanesulfonyl (SO<sub>2</sub>CF<sub>3</sub>) building block under catalyst-free thermal conditions, is redisclosed as an effective electrophilic trifluoromethylthiolation reagent under copper catalysis. A broad set of enamines, indoles, ?-keto esters, pyrroles, and anilines were nicely transformed into corresponding trifluoromethylthio (SCF<sub>3</sub>) compounds in good to high yields by diazo-triflone under copper catalysis via an electrophilic-type reaction. A coupling-type trifluoromethylthiolation reaction of aryl iodides was also realized by diazo-triflone in acceptable yields.