Hydroxy-directed fluorination of remote unactivated C(sp3)–H bonds: a new age of diastereoselective radical fluorination (original) (raw)
Related papers
Palladium-Catalyzed Site-Selective Fluorination of Unactivated C(sp(3))-H Bonds
Organic letters, 2015
The transition-metal-catalyzed direct C-H bond fluorination is an attractive synthetic tool toward the preparation of organofluorines. While many methods exist for the direct sp(3) C-H functionalization, site-selective fluorination of unactivated sp(3) carbons remains a challenge. Direct, highly site-selective and diastereoselective fluorination of aliphatic amides via a palladium-catalyzed bidentate ligand-directed C-H bond functionalization process on unactivated sp(3) carbons is reported. With this approach, a wide variety of β-fluorinated amino acid derivatives and aliphatic amides, important motifs in medicinal and agricultural chemistry, were prepared with palladium acetate as the catalyst and Selectfluor as the fluorine source.
Direct photocatalytic fluorination of benzylic C-H bonds with N-fluorobenzenesulfonimide
Chemical communications (Cambridge, England), 2015
The late-stage fluorination of common synthetic building blocks and drug leads is an appealing reaction for medicinal chemistry. In particular, fluorination of benzylic C-H bonds provides a means to attenuate drug metabolism at this metabolically labile position. Here we report two complimentary strategies for the direct fluorination of benzylic C-H bonds using N-fluorobenzenesulfonimide and either a decatungstate photocatalyst or AIBN-initiation.
Journal of the American Chemical Society, 2014
Recently, our group unveiled a system in which an unusual interplay between copper(I) and Selectfluor effects mild, catalytic sp 3 C−H fluorination. Herein, we report a detailed reaction mechanism based on exhaustive EPR, 19 F NMR, UV−vis, electrochemical, kinetic, synthetic, and computational studies that, to our surprise, was revealed to be a radical chain mechanism in which copper acts as an initiator. Furthermore, we offer an explanation for the notable but curious preference for monofluorination by ascribing an ionic character to the transition state.
Journal of the American Chemical Society, 2020
Recently, our group reported that enone and ketone functional groups, upon photoexcitation, can direct siteselective sp 3 C-H fluorination in terpenoid derivatives. How this transformation actually occurred remained mysterious, as a significant number of mechanistic possibilities came to mind. Herein, we report a comprehensive study describing the reaction mechanism through kinetic studies, isotope labeling experiments, 19 F NMR, electrochemical studies, synthetic probes, and computational experiments. To our surprise, the mechanism suggests intermolecular hydrogen atom transfer (HAT) chemistry at play, rather than classical Norrish hydrogen atom abstraction as initially conceived. What is more, we discovered a unique role for photopromoters such as benzil and related compounds that necessitates their chemical transformation through fluorination in order to be effective. Our findings provide documentation of an unusual form of directed HAT and are of crucial importance for defining the necessary parameters for the development of future methods.
Efficient Protiodesilylation of Unactivated C(sp3)−SiMe2Ph Bonds Using Tetrabutylammonium Fluoride
Organic Letters, 2005
The protiodesilylation of unactivated C(sp 3)-SiMe 2 Ph bonds proceeds efficiently by treatment with tetrabutylammonium fluoride in wet DMF or THF via isolable dimethylsilanol intermediates An important strategy for the stereoselective synthesis of highly substituted tetrahydrofurans involves the [3+2]-annulation of chiral crotyl-and allylsilanes with aldehydes. 1 Our laboratory has contributed to this area by demonstrating the predictable stereochemical outcome of [3+2]annulation reactions of chiral allylsilanes via a formal three-component coupling of two aldehydes and the chiral γ-silyl substituted allylborane 1 (Figure 1). 2,3 Initial coupling of chiral allylborane 1 with an aldehyde (R 1 CHO) followed by exposure of the protected α-hydroxy allylsilane 2 to a Lewis acid and a second aldehyde (R 2 CHO), selectively affords either c i sor trans-substituted tetrahydrofurans 3 or 4 in good yields. Importantly, the stereochemistry of the [3+2]-annulation reaction is determined by the nature of the Lewis acid employed (Figure 1). 2a The 2,5-cis tetrahydrofuran 3 is obtained typically with ≥20 : 1 selectivity when BF 3 •OEt 2 is employed, while the diastereomeric 2,5-trans disubstituted tetrahydrofuran 4 is obtained, also typically with ≥20 : 1 d.s., by using SnCl 4 (via a chelate controlled transition state, requiring that R 2 CHO be capable of chelate formation). In principle, manipulation of the-SiMe 2 Ph substituent in 3 or 4 via Tamao-Fleming oxidation 4 or protiodesilylation 5 should allow for general access to tetrahydrofurans 5 and 6, respectively.
Chemical Reviews, 2015
ABSTRACT C-F activation of highly fluorinated molecules can be an inspiring tool to access unique fluorinated building blocks. The approach involves hydrodefluorination reactions; element-carbon bonds other than C-H bonds can also be generated. Transition-metal-mediated C-F bond activations which involve a cleavage of a C-F bond in polyfluorinated molecules and its transformation into carbon- element bonds, excluding hydrodefluorination or defluorination reactions. On the other hand, fluorido complexes can also be crucial to complete a catalytic process, because of the higher reactivity of a fluorido ligand at d8-complexes. The catalytic generation of C-Si and C-B bonds is noteworthy, because the products might be very useful starting compounds for further transformations. Although carbon-fluorine bond activation reactions of fluoroalkenes have been thoroughly studied earlier, their functionalization via hydrodefluorination reactions is by far more explored than any other C-F bond transformations.
Photoinduced Remote Functionalisations by Iminyl Radical Promoted C-C and C-H Bond Cleavage Cascades
Angewandte Chemie (International ed. in English), 2018
A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp)-(sp) and C(sp)-H bond cleavage gives access to distal carbon radicals that undergo S2 functionalisations. These mild, visible-light-mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules.
Radical Fluoroalkylation Reactions
ACS Catalysis
Recent protocols and reactions for catalytic radical perfluoroalkylations (R F = C n F 2n+1 , n ≥ 2) will be described. The production of R F radicals that effect both addition and substitution reactions on organic substrates can be realized through a range of diverse methods such as the well-established visible light transition metal-mediated photocatalysis, organic dye-photocatalyzed reactions, by Electron Donor Acceptor (EDA) complexes or more recently through Frustrated Lewis Pairs (FLP). Thus, perfluoroalkylation reactions of carboncarbon multiple bonds, isocyanides, nitrones, hydrazones, β-ketoesters, αcyano arylacetates, sulfides, and (hetero)arenes will be described. Specially emphasis will be made on examples published after 2015 where higher fluorinated series of fluoroalkylating reagents are studied.
Direct arene C–H fluorination with 18F− via organic photoredox catalysis
Science, 2019
Positron emission tomography (PET) plays key roles in drug discovery and development, as well as medical imaging. However, there is a dearth of efficient and simple radiolabeling methods for aromatic C–H bonds, which limits advancements in PET radiotracer development. Here, we disclose a mild method for the fluorine-18 (18F)–fluorination of aromatic C–H bonds by an [18F]F− salt via organic photoredox catalysis under blue light illumination. This strategy was applied to the synthesis of a wide range of 18F-labeled arenes and heteroaromatics, including pharmaceutical compounds. These products can serve as diagnostic agents or provide key information about the in vivo fate of the labeled substrates, as showcased in preliminary tracer studies in mice.