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. 2020 Jul;583(7817):548-553.
doi: 10.1038/s41586-020-2399-1. Epub 2020 Jun 1.

Desymmetrization of difluoromethylene groups by C-F bond activation

Trevor W Butcher  1 , Jonathan L Yang  1 , Willi M Amberg  1 , Nicholas B Watkins  1 , Natalie D Wilkinson  1 , John F Hartwig  2
Affiliations

Desymmetrization of difluoromethylene groups by C-F bond activation

Trevor W Butcher et al. Nature. 2020 Jul.

Abstract

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1-3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.

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Conflict of interest statement

Competing interests The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. Approaches to the desymmetrization of methylene units.
a, The desymmetrization of methylene groups by enantioselective C–H activation is a general strategy for the construction of simple tertiary stereocentres. b, The analogous desymmetrization of difluoromethylene groups by enantioselective C–F activation has not been reported so far. c, The cooperation of a chiral, low-valent transition metal complex and a hard fluorophilic activator enables the enantioselective activation of a single C–F bond at an allylic position. FG, functional group; AG, activating group (for example, electron-withdrawing group, aryl group, heteroatom or directing group; few examples lack an activating group); Nu, nucleophile; M, transition metal; OA, oxidative addition.
Fig. 2 |
Fig. 2 |. Reaction development and mechanistic studies.
The identity of the fluorophilic cation strongly affects the rate of C–F activation. Modulation of the steric profile of the cyclometalated iridium catalyst improves the enantioselectivity. a, Effect of the catalyst, the catalyst loading and the base on conversion and enantioselectivity. The conversion of the starting material is determined by 1H NMR spectroscopy. The enantiomeric ratio (e.r.) is determined by chiral high-performance liquid chromatography (HPLC) after purification by preparative thin-layer chromatography (TLC). b, Development of a highly enantioselective iridium catalyst. c, Quantification of the role of the cation in C–F activation reactions. Kinetic studies were conducted according to the scheme in a with substrate 1b (PhCF2CH = CH2) and catalyst Cω (4 mol%). Error bars in c correspond to ±2% yield error associated with quantitative NMR spectroscopy. THF, tetrahydrofuran; 2-Np, 2-naphthyl; Ph, phenyl; Ar, aryl; Me, methyl; BINOLate, 1,1′-bi(2-naphtholate); RT, room temperature; vrel, relative rate; κ denotes binding of non-contiguous atoms in a chelating ligand.
Fig. 3 |
Fig. 3 |. Scope of nucleophiles and electrophiles that participate in defluorinative alkylation reactions and transformations of the products.
a, Nucleophilic lithium salts in defluorinative alkylation reactions. b, Silyl ketene acetals in defluorinative alkylation reactions. c, 3-Substituted 3,3-difluoropropenes in defluorinative alkylation reactions. d, Synthesis of fluorinated derivatives of medicinally active compounds from the substitution products. Isolated yields reported unless otherwise noted. a2 mol% Cω, −10 °C, 72 h. b96 h. c5 mol% Cω’, 0 °C, 72 h. d2 mol% Cω’, 5 equiv. LiBr, RT, 24 h. e6 mol% Cγ, 5 mol% NaCMe(CO2Et)2, RT, 48 h. ftert-Butyl dimethyl silyl ketene acetal, 6 mol% Cγ, RT, 53 h. g2 mol% TMSOTf, 4 mol% Cγ, dioxane, RT, 40 h. h5 mol% Cω’, 5 equiv. LiBr, RT, 48 h. i5 mol% Cω, 65 °C, 96 h. j2 mol% Cω, 3 equiv. Ba(OTf)2, RT, 19 h. k20 mol% Cω, 3 equiv. Ba(OTf)2, dioxane, RT, 24 h. EWG, electron-withdrawing group; TMS, trimethylsilyl; MOM, methoxymethyl; Bz, benzoyl; CSA, camphor sulfonic acid; DME, 1,2-dimethoxyethane; DMS, dimethylsulfide; 1-Np, 1-naphthyl; d.r., diastereometric ratio.
Fig. 4 |
Fig. 4 |. Selective activation of a single benzylic C–F bond.
The cooperation between a low-valent transition metal and a fluorophilic cation enables the activation of benzylic C–F bonds in difluoromethylarenes, and reactions conducted with a chiral ligand are enantioselective. aYield determined by 1H and 19F NMR spectroscopy. bReaction conducted with 5 mol% [Pd(crotyl)Cl]2 and 15 mol% (R)-BINAP. cEnantiomeric ratio determined by chiral HPLC. LiOTf, lithium triflate.
Fig. 5 |
Fig. 5 |. Mechanistic studies support a cation-assisted, turnover-limiting, enantiodetermining and irreversible oxidative addition from a rapidly interconverting mixture of diastereomeric olefin complexes under Curtin–Hammett control.
a, Proposed mechanism. b, NMR spectroscopic characterization of the catalyst resting state. c, Comparison of allylic fluoroalkylation reactions with 3-fluorocinnamyl electrophiles and 3-substituted 3,3-difluoropropenes. d, η1 allyl intermediates are too high in energy to participate. e, Quadrant diagram for Ir(i) olefin complexes. f, Stereochemical model for 3-fluorocinnamyl electrophiles and 3-substituted 3,3-difluoropropenes; see Supplementary Information for a more detailed discussion. OA, oxidative addition; RE, reductive elimination; LS, ligand substitution; TLS, turnover-limiting step; EDS, enantiodetermining step; EXSY, exchange spectroscopy; krel, relative rate constant; ΔGrel, relative Gibbs free energy.
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