Stefan Verhoog

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.

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).

Trifluoromethylation of Allylsilanes under Photoredox Catalysis

A new catalytic method to access allylic secondary CF3 products is described. These reactions use the visible light excited Ru(bpy)3Cl2·6H2O catalyst and the Togni or Umemoto reagent as the CF3 source. The photoredox catalytic manifold delivers enantioenriched allylic trifluoromethylated products not accessible under Cu(I) catalysis.

Metal‐Free Oxidative Fluorination of Phenols with [18F]Fluoride

The radiochemical synthesis of [18F]4‐fluorophenols is based on phenol umpolung under oxidative conditions and direct nucleophilic fluorination with [18F]fluoride (see scheme, TBAF=tetra‐n‐butylammonium fluoride, TFA=trifluoroacetic acid). Readily available O‐unprotected 4‐tert‐butyl phenols are used as precursors in this one‐pot protocol. The reaction is completed in less than 30 minutes at room temperature and can be performed using standard or microfluidic technology.

18F‐Labeling of Aryl‐SCF3, ‐OCF3 and ‐OCHF2 with [18F]Fluoride

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic (18)F-fluorination of aryl-OCHFCl, -OCF2Br and -SCF2Br precursors under mild conditions. This Ag(I)-mediated process allows for the first time access to a range of (18)F-labeled aryl-OCHF2, -OCF3 and -SCF3 derivatives, inclusive of [(18)F]riluzole. The (18)F-labeling of these medicinally important motifs expands the radiochemical space available for PET applications.

18F-Trifluoromethylation of Unmodified Peptides with 5-18F-(Trifluoromethyl)dibenzothiophenium Trifluoromethanesulfonate

The 18F-labeling of 5-(trifluoromethyl)-dibenzothiophenium trifluoromethanesulfonate, commonly referred to as the Umemoto reagent, has been accomplished applying a halogen exchange 18F-fluorination with 18F-fluoride, followed by oxidative cyclization with Oxone and trifluoromethanesulfonic anhydride. This new 18F-reagent allows for the direct chemoselective 18F-labeling of unmodified peptides at the thiol cysteine residue.

Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands

Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.

Radiosynthesis of SPECT tracers via a copper mediated 123I iodination of (hetero)aryl boron reagents

A general method for the copper mediated nucleophilic 123I-iodination of (hetero)aryl boronic esters and acids has been developed. The broad substrate scope of this radiosynthetic approach allows access to [123I]DPA-713, [123I]IMPY, [123I]MIBG and [123I]IPEB that are four commonly used SPECT radiotracers. Our results infer that aryl boronic reagents can now be employed as common precursors for both fluorine-18 and iodine-123 radiolabelling.

Synthesis and Reactivity of 18F-Labeled α,α-Difluoro-α-(aryloxy)acetic Acids

In this work, we describe the 18F-labeling of α,α-difluoro-α-(aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-18F-fluorination functionalization. Protodecarboxylation offers a new entry to 18F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative 18F-labeled TRPV1 inhibitors and TRPV1 antagonists.