Véronique Gouverneur

Catalytic Hydrotrifluoromethylation of Unactivated Alkenes

A visible-light-mediated hydrotrifluoromethylation of unactivated alkenes that uses the Umemoto reagent as the CF(3) source and MeOH as the reductant is disclosed. This effective transformation operates at room temperature in the presence of 5 mol % Ru(bpy)(3)Cl(2); the process is characterized by its operational simplicity and functional group tolerance.

Organocatalyzed Enantioselective Fluorocyclizations

Enantioenriched fluorinated heterocycles can be prepared through fluorocyclizations of prochiral indoles (see scheme; Ts=tosyl, Bn=benzyl, Boc=tert-butoxycarbonyl). More than twenty examples for this cascade fluorination-cyclization, which is catalyzed by cinchona alkaloids and employs N-fluorobenzenesulfonimide as the electrophilic fluorine source have been explored, and an unprecedented catalytic asymmetric difluorocyclization has also been identified.

AuI/AuIII Catalysis: An Alternative Approach for CC Oxidative Coupling

When reacted in the presence of external oxidants, gold complexes are capable of catalyzing oxidative homo- and cross-coupling reactions involving the formation of new C-C bonds. Over the last few years, several cascade processes have been reported in which coupling is preceded by a gold-mediated aryl C-H functionalization or nucleophilic addition. These reactions combine the unique reactivity of gold with oxidative coupling, enabling the construction of C-C bonds between coupling partners that are not easily accessed using alternative catalysts. In this Concept paper, the development of gold-catalyzed oxidative coupling reactions is discussed focusing on C-C bond-forming reactions of broad synthetic appeal.

18F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

Diverse radiochemistry is an essential component of nuclear medicine; this includes imaging techniques such as positron emission tomography (PET). As such, PET can track diseases at an early stage of development, help patient care planning through personalized medicine and support drug discovery programs. Fluorine-18 is the most frequently used radioisotope in PET radiopharmaceuticals for both clinical and preclinical research. Its physical and nuclear characteristics (97% β(+) decay, 109.8 min half-life, 635 keV positron energy) and high specific activity make it an attractive nuclide for labeling and molecular imaging. Arenes and heteroarenes are privileged candidates for (18)F-incorporation as they are metabolically robust and therefore widely used by medicinal chemists and radiochemists alike. For many years, the range of (hetero)arenes amenable to (18)F-fluorination was limited by the lack of chemically diverse precursors, and of radiochemical methods allowing (18)F-incorporation in high selectivity and efficiency (radiochemical yield and purity, specific activity, and radio-scalability). The appearance of late-stage fluorination reactions catalyzed by transition metal or small organic molecules (organocatalysis) has encouraged much research on the use of these activation manifolds for (18)F-fluorination. In this piece, we review all of the reactions known to date to install the (18)F substituent and other key (18)F-motifs (e.g., CF3, CHF2, OCF3, SCF3, OCHF2) of medicinal relevance onto (hetero)arenes. The field has changed significantly in the past five years, and the current trend suggests that the radiochemical space available for PET applications will expand rapidly in the near future.

18F Labeling of Arenes

Molecular imaging has witnessed an upsurge in growth, with positron emission tomography leading the way. This trend has encouraged numerous synthetic chemists to enter the field of (18) F-radiochemistry and provide generic solutions to address the well-recognized challenges of late-stage fluorination. This Minireview focuses on recent developments in the (18)F-labeling of aromatic substrates.

Palladium‐Catalyzed Allylic Fluorination

The title reaction is presented and its applicability to 18F radiolabeling is demonstrated (see scheme; TBAF=tetra‐n‐butylammonium fluoride, THF=tetrahydrofuran, dba=dibenzylideneacetone). The use of p‐nitrobenzoate as the leaving group is significant to the success of this catalytic organometallic fluorination process. A range of allylic fluorides were synthesized by this method.

Catalytic asymmetric fluorinations

The appearance of structurally diverse fluorinating reagents displaying a large spectrum of reactivity has been critical to the development of the catalytic asymmetric fluorination processes known to date. In this article, we discuss how this area of research emerged and which strategies have allowed for the successful development of both nucleophilic and electrophilic catalytic enantioselective fluorinations. We also present the fundamental understanding of catalytic activity and enantioselectivity for the most efficient processes and highlight the first synthetic application with the preparation of a complex fluorinated target.

A General Copper-Mediated Nucleophilic 18F Fluorination of Arenes†

Molecules labeled with fluorine-18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (SNAr) with [(18)F]F(-). In the ideal case, the (18)F fluorination of these substrates would be performed through reaction of [(18)F]KF with shelf-stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of (18)F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [(18)F]KF/K222 and [Cu(OTf)2(py)4] (OTf = trifluoromethanesulfonate, py = pyridine). This method tolerates electron-poor and electron-rich arenes and various functional groups, and allows access to 6-[(18)F]fluoro-L-DOPA, 6-[(18)F]fluoro-m-tyrosine, and the translocator protein (TSPO) PET ligand [(18)F]DAA1106.

Catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes.

Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [(18)F]labeling is demonstrated using [(18)F]Selectfluor bis(triflate), a reagent affording [(18)F]tri- and [(18)F]difluoromethylarenes not within reach with [(18)F]F2.

Trifluoromethylation of Allylsilanes under Copper Catalysis

Medicinal chemists commonly incorporate a trifluoromethyl group into druglike molecules to enhance binding selectivity, improve metabolic stability and increase lipophilicity. To date, various methods are available for the introduction of the CF3 group onto functionalized arenes and heteroarenes. Numerous catalytic trifluoromethylation reactions of ketones or aldehydes have also been developed, leading to the formation of Csp3–CF3 bonds, including elegant asymmetric variants. The construction of Csp3–CF3 stereogenicity from poorly activated substrates is less common. In this context, the direct selective installation of a CF3 group on an allylic position remains a challenging synthetic problem. Isolated examples of Pd-catalyzed trifluoromethylation of allylstannanes with CF3I [5] and Cu-mediated nucleophilic trifluoromethylation of allyl bromide using the Ruppert–Prakash reagent (CF3SiMe3) are known, [6] giving linear allylic CF3 products. Recently, Buchwald, [7] Wang, and Liu and their co-workers reported that terminal alkenes are amenable to allylic trifluoromethylation under copper catalysis, a reaction also affording linear allylic CF3 products with very good control over E :Z geometry. Access to branched acyclic allylic CF3 products has not been demonstrated, and only two branched cyclic products have been prepared through application of this C H functionalization methodology. To address this synthetic challenge, we reasoned that we could access allylic CF3 products using alkenes temporarily activated with a regiodirecting silyl group. Since our first report in 2003, we have demonstrated that a diverse range of allylic fluorides are accessible upon electrophilic fluorination of allylsilanes under very mild conditions and have found that this reaction is broad in scope and tolerant of various functional groups. The presence of the allylic trimethylsilyl group is essential to increase the nucleophilicity of the proximal alkene and to dictate the regiochemistry of the fluorination. Based on these principles and the availability of various electrophilic trifluoromethylating reagents (e.g., hypervalent iodine reagents I and II, and the sulfonium salts III and IV), we describe herein a copper-catalyzed trifluoromethylation reaction to prepare various branched allylic CF3 products from allylsilanes (Figure 1).