Yanchuan Zhao

Silver-mediated trifluoromethylation-iodination of arynes.

An unprecedented silver-mediated vicinal trifluoromethylation-iodination of arynes that quickly introduces CF(3) and I groups onto aromatic rings in a single step to give o-trifluoromethyl iodoarenes has been developed. A new reactivity of AgCF(3) has been revealed, and 2,2,6,6-tetramethylpiperidine plays an important role in this difunctionalization reaction.An unprecedented silver-mediated vicinal trifluoromethylation-iodination of arynes that quickly introduces CF3 and I groups onto aromatic rings in a single step to give o-trifluoromethyl iodoarenes has been developed. A new reactivity of AgCF3 has been re

Difluoromethyl 2-pyridyl sulfone: a new gem-difluoroolefination reagent for aldehydes and ketones.

Difluoromethyl 2-pyridyl sulfone, a previously unknown compound, was found to act as a novel and efficient gem-difluoroolefination reagent for both aldehydes and ketones. It was found that the fluorinated sulfinate intermediate in the reaction is relatively stable, which can be observed by (19)F NMR and trapped with CH(3)I.

Palladium‐Catalyzed 2,2,2‐Trifluoroethylation of Organoboronic Acids and Esters

The introduction of a fluorinated moiety into organic molecules can result in profound changes of the biological activities of these molecules, and therefore, this strategy has been widely used in drug design. Among various fluorinated moieties, the trifluoromethyl group (CF3) has been the focus of increasing attention owing to its capacity to act as a lipophilic electron-withdrawing group. In stark contrast to the tremendous progress that has been made toward the direct introduction of a trifluoromethyl group into functionalized aromatic compounds, the analogous transformation to form (2,2,2-trifluoroethyl)arenes remains largely unexplored, despite many potential utilities of CF3CH2-containing products in medicinal chemistry and related fields. The copper(0)-mediated direct 2,2,2-trifluoroethylation of iodobenzene with trifluoroethyl iodide (CF3CH2I) was reported by McLoughlin and Thrower in 1969. The product was obtained in only 15% yield despite the harsh reaction conditions and long reaction time employed by this method (Scheme 1a). Furthermore, trifluoromethylations of benzyl bromides with [CuCF3] species, which are generated from different precursors, are generally employed to afford (trifluoroethyl)arenes (Scheme 1b). Very recently, Shibata and co-workers reported the trifluoromethylation of benzyl bromides with [CuCF3] species, which were generated in situ from an electrophilic trifluoromethylating reagent and a stoichiometric amount of copper, under mild reaction conditions with good substrate generality. We surmised that a transition-metal-catalyzed 2,2,2-trifluoroethylation using readily available trifluoroethyl iodide (CF3CH2I) and organoboronic acids could provide an alternative method for the preparation of (2,2,2-trifluoroethyl)arenes; a process that has not been reported to date. Previously, it was believed that many (2,2,2-trifluoroethyl)metals (CF3CH2 M) are labile species (especially when the C M bond possesses a highly ionic nature) because of their high tendency to b eliminate a fluoride ion, and that their stability is thus greatly affected by the degree of covalency of the C M bond. The use of CF3CH2 M species in trifluoroethylation reactions is still largely unexplored. In 2004, Culkin and Hartwig reported a stoichiometric version of the formation of an Ar CH2CF3 bond from a Pd species by heating the complex [(DPPBz)Pd(CH2CF3)(p-tol)] (prepared from [(DPPBz)Pd(CH2CF3)(I)] and p-tolyllithium; DPPBz = 1,2bis(diphenylphosphanyl)benzene) at 110 8C for 36 h (Scheme 1c). However, slow oxidative addition of alkyl halides, high temperature and/or long reaction time for the reductive elimination, and an uncertain outcome of the transmetalation process with nucleophiles other than aryllithium reagents hampered the use of these methods as efficient catalytic processes. On the other hand, during the past decade, applications of bulky dialkylbiaryl and trialkyl phosphines along with N-heterocyclic carbenes (NHC) as supporting ligands have dramatically improved the efficiency and scope of Pd-catalyzed cross-coupling reactions, as exemplified by the remarkable success in the direct formation of aryl CF3 and aryl F bonds. In light of these progresses, we felt that by using a suitable ligand, the efficient Pdcatalyzed cross-coupling reaction between readily available 2,2,2-trifluoroethyl iodide (CF3CH2I) and organoboronic acids (or esters) might be accomplished under mild conditions (Scheme 1d). Considering that the reductive elimination may be ratelimiting in the cross-coupling reaction (as reported by Culkin and Hartwig), we first examined various supporting ligands for the palladium catalyst, especially those known to be able to efficiently facilitate reductive elimination (Scheme 2 and Table 1). 4-Biphenylboronic acid (1a) was used as a model substrate, and the reaction was carried out in dioxane at 80 8C using K3PO4 as a base (Table 1, entries 1–9). Flexible bidentate phosphine ligands (L1 and L2) and sterically hindered trialkyl phosphine ligands (L3 and L4) were Scheme 1. Traditional methods versus our method for the preparation of (2,2,2-trifluoroethyl)arenes (p-tol= para-tolyl).

Efficient and Direct Nucleophilic Difluoromethylation of Carbonyl Compounds and Imines with Me3SiCF2H at Ambient or Low Temperature

Since 1995, Me(3)SiCF(2)H has been widely believed to be an inefficient difluoromethylating agent, which requires harsh reaction conditions to cleave its rather inert Si-CF(2)H bond. However, it has now been found that, by using a proper Lewis base activator, Me(3)SiCF(2)H can efficiently difluoromethylate various aldehydes, ketones, and imines to give the corresponding products in good to excellent yields at room temperature or even at -78 °C.

From Olefination to Alkylation: In-Situ Halogenation of Julia–Kocienski Intermediates Leading to Formal Nucleophilic Iodo- and Bromodifluoromethylation of Carbonyl Compounds

Iodo- and bromodifluoromethylated compounds are important synthetic intermediates and halogen-bond acceptors. However, direct introduction of -CF(2)I and -CF(2)Br groups through nucleophilic addition is particularly challenging because of the high tendency of decomposition of CF(2)Br(-) and CF(2)I(-) to difluorocarbene. In this work, we have developed a formal nucleophilic iodo- and bromodifluoromethylation for carbonyl compounds. The key strategy of the method is the halogenation of in situ-generated sulfinate intermediates from the Julia-Kocienski reaction to change the reaction pathway from the traditional olefination to alkylation. Interesting halogen-π interactions between the halocarbon and aromatic donors were observed in the crystal structures of the products. The method could also be extended to the introduction of other fluorinated groups, such as -CFClBr, -CFClI, -CFBr(2), and -CFMeI, which opens up new avenues for the synthesis of a wide range of useful fluorinated products.

AgF-mediated fluorinative cross-coupling of two olefins: facile access to α-CF3 alkenes and β-CF3 ketones.

A AgF-mediated fluorination with a concomitant cross-coupling between a gem-difluoroolefin and a non-fluorinated olefin is reported. This highly efficient method provides facile access to both α-CF3 alkenes and β-CF3 ketones, which otherwise remain challenging to be directly prepared. The application of this method is further demonstrated by the synthesis of bioactive isoxazoline derivatives. This approach represents a conceptually novel route to trifluoromethylated compounds that combines the in situ generation of the CF3 moiety and a C-H functionalization in a single reaction system.

Simultaneous Chirality Sensing of Multiple Amines by 19F NMR

The rapid detection and differentiation of chiral compounds is important to synthetic, medicinal, and biological chemistry. Palladium complexes with chiral pincer ligands are demonstrated to have utility in determining the chirality of various amines. The binding of enantiomeric amines induces distinct (19)F NMR shifts of the fluorine atoms appended on the ligand that defines a chiral environment around palladium. It is further demonstrated that this method has the ability to evaluate the enantiomeric composition and discriminate between enantiomers with chiral centers several carbons away from the binding site. The wide detection window provided by optimized chiral chemosensors allows the simultaneous identification of as many as 12 chiral amines. The extraordinary discriminating ability of this method is demonstrated by the resolution of chiral aliphatic amines that are difficult to separate using chiral chromatography.

AgF-mediated fluorinative homocoupling of gem-difluoroalkenes.

A novel silver(I)-fluoride-mediated homocoupling reaction of β,β-difluorostyrene derivatives is described. The transformation is initiated via nucleophilic addition of silver(I) fluoride to β,β-difluorostyrenes, which is followed by dimerization of the corresponding benzylsilver intermediates. The reaction shows good substrate scope, functional group tolerance, and represents the first report on the reactivity of (α-trifluoromethyl)benzylsilver species.

gem‐Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2‐Pyridyl Sulfone: New Insights into the Julia–Kocienski Reaction

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem-difluoroalkenes has been a long-standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2-pyridyl sulfone as a general gem-difluoroolefination reagent. The gem-difluoroolefination of diaryl ketones proceeds by acid-promoted Smiles rearrangement of the carbinol intermediate; the gem-difluoroolefination is otherwise difficult to achieve through a conventional Julia-Kocienski olefination protocol under basic conditions due to the retro-aldol type decomposition of the key intermediate. Efficient gem-difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem-difluoroolefination of multi-carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia-Kocienski reaction.

Copper-Mediated Fluoroalkylation of Aryl Iodides Enables Facile Access to Diverse Fluorinated Compounds: The Important Role of the (2-Pyridyl)sulfonyl Group

The (2-pyridyl)sulfonyl group was found to be a multifunctional group in the preparation of structurally diverse fluorinated products. It not only facilitates the copper-mediated (or catalyzed) cross-coupling reaction between α-fluoro sulfone 4a and aryl iodides, but also enables further transformations of the coupling products 2.