RESUMEN
The reaction regioselectivity of gem-difluoroalkenes is dependent on the intrinsic polarity. Thus, the reversal of the regioselectivity of the addition reaction of gem-difluoroalkenes remains a formidable challenge. Herein, we described an unprecedented reversal of regioselectivity of hydrogen atom transfer (HAT) to gem-difluoroalkenes triggered by Fe-H species for the formation of difluoroalkyl radicals. Hydrogenation of the in situ generated radicals gave difluoromethylated products. Mechanism experiments and theoretical studies revealed that the kinetic effect of the irreversible HAT process resulted in the reversal of the regioselectivity of this scenario, leading to the formation of a less stable α-difluoroalkyl radical regioisomer. On basis of this new reaction of gem-difluoroalkene, the iron-promoted hydrohalogenation of gem-difluoroalkenes for the efficient synthesis of aliphatic chlorodifluoromethyl-, bromodifluoromethyl- and iododifluoromethyl-containing compounds was developed. Particularly, this novel hydrohalogenation of gem-difluoroalkenes provided an effect and large-scale access to various iododifluoromethylated compounds of high value for synthetic application.
RESUMEN
The beauty of one-pot cascade reaction lies in the efficient disconnection and construction of several bonds in a single reaction flask, without the isolation of any intermediates. Herein, we report the first photoinduced thermally promoted cascade reactions of readily available aromatic ketones and aromatic gem-difluoroalkenes for the synthesis of phenanthrenes which possess potential utility in drug design and materials science. The reaction combines carbonyl-olefin metathesis (cascade photoinduced [2+2] cyclization and thermally controlled retro [2+2] cyclization) and dehydrogenative cyclization (cascade photoinduced conrotatory 6π electrocyclization and collidine-promoted dehydrogenative aromatization) together in one pot. The oxidant-free, acid-free and metal-free reaction shows broad substrate scope and wide functional group tolerance.
RESUMEN
This report describes a one-pot multi-step procedure to obtain double azahelicenes via nucleophilic fluorine substitution of 2,2-di(2-bromophenyl)-1,1-difluoroalkenes and palladium-catalysed ring closing reaction. The developed synthesis approach allows easy diversification of substituents at all four fragments of the obtained X-shaped aza[4,6]helicene entity. Yields range from 20 % to 60 % among 12 product examples. X-ray single crystal analysis reveals formation of (P,P) and (M,M) enantiomer mixture of products. Optical and electrochemical properties of selected products were studied by performing UV/Vis absorption, photoluminescence and cyclic voltammetry measurements. Experimental results are supported by (TD)-DFT, NICS and NICS2BC calculations.
RESUMEN
Here, we report the first transition-metal-free defluorinative cycloaddition of gem-difluoroalkenes with organic azides in morpholine as a solvent to construct fully decorated morpholine-substituted 1,2,3-triazoles. Mechanistic studies revealed the formation of an addition-elimination intermediate of morpholine and gem-difluoroalkenes prior to the triazolization reaction via two plausible pathways. Attractive elements include the regioselective and straightforward direct synthesis of fully substituted 1,2,3-triazoles, which are otherwise difficult to access, from readily available starting materials.
RESUMEN
Divergent synthesis of fluorine-containing scaffolds starting from a suite of raw materials is an intriguing topic. Herein, we report the solvent-controlled rhodium-catalyzed tunable arylation of 1-bromo-2,2-difluoroethylene. The selection of the reaction solvents provides switchable defluorinated or debrominated arylation from readily available feedstock resources (both arylboronic acids/esters and 1-bromo-2,2-difluoroethylene are commercially available). This switch is feasible because of the difference in coordination ability between the solvent (CH2 Cl2 or CH3 CN) and the rhodium center, resulting in different olefin insertion. This protocol allows the convenient synthesis of monofluoroalkenes and gem-difluoroalkenes, both of which are important scaffolds in the fields of medicine and materials. Moreover, this newly developed solvent-regulated reaction system can be applied to the site-selective dechlorinated arylation of trichloroethylene. Overall, this study provides a useful strategy for the divergent synthesis of fluorine-containing scaffolds and provides insight into the importance of solvent selection in catalytic reactions.
RESUMEN
A series of thienoindolizine structural isomers have been synthesized in a one-pot, two-step procedure starting from easily accessible gem-difluoroalkene functionalized bromothiophenes. The developed method gives easy access to a range of thienoindolizine products containing thieno[3,2-g]-, thieno[3,4-g]- and thieno[2,3-g]indolizine core structures. The described synthesis strategy consists of a base mediated, transition metal free nucleophilic substitution of fluorine atoms by nitrogen containing heterocycles followed by a Pd catalyzed intramolecular cyclization. A series of 22 final product examples has been obtained with yields ranging from 29 % to 95 %. UV/Vis absorption, fluorescence spectroscopy, fluorescence lifetime measurements and cyclic voltammetry were carried out with selected final products to evaluate structural effects on photophysical and electrochemical properties. (TD)DFT and NICS calculations were performed to provide insight into the electronic properties of the four core molecular structures.
RESUMEN
Monofluoroalkenes are nonhydrolyzable mimetics of amides. Previous work focused on the synthesis of non-cyclic monofluoroalkenes. However, diastereoselective synthesis of monofluorocyclohexenes from non-cyclic substrates is challenging. Herein, we report the first photocatalyzed cascade cyclization reactions of readily available α,ß-unsaturated carbonyl compounds and gem-difluoroalkenes for the synthesis of highly functionalized monofluorocyclohexenes. The reaction shows broad substrate scope with high diastereoselectivity (>30 examples, up to 86 % yield, >20 : 1 dr). The post-reaction transformations of the products demonstrate the synthetic potential of this methodology.
RESUMEN
We describe regio- and enantioselective bromocyclization of difluoroalkenes catalyzed by chiral bisphosphine oxides. Owing to the simultaneous activation of both the brominating reagent and amide substrate, the desired cyclization reaction proceeds smoothly even at low temperature to provide bromodifluoromethyl-containing oxazolines with a chiral quaternary center in a highly enantioselective fashion (up to 99% ee). This protocol features the use of commercially available brominating reagents and readily accessible chiral catalysts. The regioselectivity and enantioselectivity are influenced by the catalyst structure, the brominating reagent, and the reaction temperature. Under the optimal conditions, 5-exo cyclization proceeds preferentially compared with 6-endo cyclization, depending on the electronic properties of the alkene substrates. A gram-scale synthesis of chiral oxazoline was achieved with as little as 1â mol % of the catalyst.
RESUMEN
Stereo- and enantioselective cross-electrophile coupling involving C-F bond activation is reported. Treatment of gem-difluoroalkenes with racemic benzyl electrophiles in the presence of a chiral nickel complex using B2 pin2 as a stoichiometric reductant allows the construction of a C(sp2 )-C(sp3 ) bond under mild conditions, affording a broad range of monofluoroalkenes bearing stereogenic allylic centers. Initial mechanistic studies indicate that a radical chain pathway may be operating, wherein the ester group in the gem-difluoroalkene promotes C-F bond activation through oxidative addition to a Ni species.
RESUMEN
The synthesis of small organic molecules with a difluoromethylated stereocenter is particularly attractive in drug discovery. Herein, we have developed an efficient method for the direct generation of difluoromethylated stereocenters through Ni0 -catalyzed regio- and enantioselective hydrosilylation of gem-difluoroalkenes. The reaction also represents the enantioselective construction of carbon(sp3 )-silicon bonds with nickel catalysis, which provides an atom- and step-economical synthesis route of high-value optically active α-difluoromethylsilanes. This protocol features readily available starting materials and commercial chiral catalysis, broad substrates spanning a range of functional groups with high yield (up to 99 % yield) and excellent enantioselectivity (up to 96 % ee). The enantioenriched products undergo a variety of stereospecific transformations. Preliminary mechanistic studies were performed.
RESUMEN
A nickel-catalyzed highly γ-regioselective arylation and carbonylative arylation of 3-bromo-3,3-difluoropropene has been developed. The reaction proceeds under mild reaction conditions, providing the gem-difluoroalkenes with high efficiency and good functional group tolerance. The resulting gem-difluoroalkenes can serve as versatile building blocks for diversified synthesis. Preliminary mechanistic studies and density functional theory calculations reveal that both non-radical and radical pathways are possible for the reaction, and the radical pathway is more likely. The high γ-regioselectivity results from the ß-bromide elimination of alkylnickel(II) species or from the reductive elimination of nickel(III) species [(aryl)(CF2 =CHCH2 )NiIII (Ln )X]. The γ-selective carbonylation of 3-bromo-3,3-difluoropropene under 1â atm CO gas also provides a new way for nickel-catalyzed carbonylation.
RESUMEN
gem-Difluorinated alkenes are readily accessible building blocks that can undergo functionalization to provide a broad spectrum of fluorinated and non-fluorinated products. Herein, we review recent (since 2017) transition metal-catalyzed transformations of these specialized alkenes and summarize general reactivity patterns of these reactions. Many transition metal-catalyzed reactions undergo net C-F bond functionalization reactions to deliver monofluorinated products. These reactions typically proceed through ß-fluoro alkylmetal intermediates that readily eliminate a ß-fluoride to deliver monofluoroalkene products. A second series of reactions exploit coinage metal fluorides to add F- to the gem-difluorinated alkene, and further functionalization delivers trifluoromethyl-containing products. In stark contrast, few transition metal-catalyzed reactions proceed in net "fluorine-retentive processes" to deliver difluoromethylene-based products.
RESUMEN
Defluorinative C(sp3 )-P bond formation of α-trifluoromethyl alkenes with phosphine oxides or phosphonates have been achieved under catalyst- and oxidant-free conditions, giving phosphorylation gem-difluoroalkenes as products. α-Trifluoromethyl alkenes bearing various of aryl substituents such as halogen, cyano, ester and heterocyclic groups are available in this transformation. The results of control experiments demonstrated that the mechanism of dehydrogenative/defluorinative cross-coupling reactions was not a radical route, but might be an SN 2' process involving phosphine oxide anion.
RESUMEN
A facile synthetic procedure for the preparation of α-trifluoromethyl carboxylic acids and esters was achieved through multicomponent coupling reactions between gem-difluoroalkenes, cesium fluoride, and carbon dioxide. The products were generated in moderate to excellent yields, and the synthetic utility of this method was demonstrated through the preparation of trifluoromethylated versions of popular nonsteroidal anti-inflammatory drugs (NSAIDs).
RESUMEN
The introduction of a trifluoromethyl (CF3 ) group into an organic molecule can modify its chemical behavior and lead to changes in its physicochemical and pharmacological properties. The CF3 group is often chosen for its chemical inertness and stability, which are related to the strong C-F bonds. In recent years, the potential of gaining straightforward access to difluorinated compounds through selective single C-F activation in CF3 groups has been unveiled. This review describes the latest methodologies for the synthesis of difluoromethylated arenes, difluoroalkenes and difluorinated aldol products of potential synthetic and/or biological interest, employing low-valent metals, transition metal catalysis, FLP and Lewis acid mediated transformations as well as photoredox catalysis.
RESUMEN
Heavy metal on Lewis acid: The combination of lanthanide metals and AlCl3 has been employed for selective single C-F activation in benzofulvenes comprising an exocyclic CF3 substituent. Intermediate ϵ,ϵ-difluorinated metal-dienyl species react with a large variety of aldehydes in a highly regio- and diastereoselective fashion to afford 1,1-disubstituted indenes bearing a difluorovinyl group. These new building blocks have been further transformed through a hydrogenation-cyclization process into fluorinated heterocyclic spiro compounds.
RESUMEN
A Pd-catalyzed fluoroarylation of gem-difluoroalkenes with aryl halides is reported. By taking advantage of the inâ situ generated α-CF3 -benzylsilver intermediates derived from the nucleophilic addition of silver fluoride to gem-difluoroalkenes, this strategy bypasses the use of a strong base, thus enabling a mild and general synthetic method for ready access to non-symmetric α,α-disubstituted trifluoroethane derivatives.