Ethyl Difluoroiodoacetate Research Articles

Visible-light-induced photocatalytic iododi(per)fluoroalkylation of 5-amino-N-allyl-1,2,3-triazole-4-carboxamides

Readily available di(per)fluoroalkyl iodides and ethyl difluoroiodoacetate have been efficiently reacted with 5-amino-N-allyl-1,2,3-triazole-4-carboxamides in the presence of DIPEA under visible-light induction and fluorescein catalysis to produce high yields of the corresponding adducts, N-(n-propyl) carboxamides vicinally difunctionalized with the iodine atom and the di(per)fluoroalkyl or (methoxycarbonyl)difluoromethyl moiety. As shown experimentally, this regiospecific and triazole amino group tolerant reaction involves a radical process.

Integrating Olefin Carboamination and Hofmann-Löffler-Freytag Reaction by Radical Deconstruction of Hydrazonyl N-N Bond.

As a type of elementary organic compounds containing N-N single bond, hydrazone involved chemical conversions are extremely extensive, but they are mainly limited to N2-retention and N2-removal modes. We report herein an unprecedented protocol for the realization of division utilization of the N2-moiety of hydrazone by a radical facilitated N-N bond deconstruction strategy. This new conversion mode enables the successful combination of alkene carboamination and Hofmann-Löffler-Freytag reaction by the reaction of N-homoallyl mesitylenesulfonyl hydrazones with ethyl difluoroiodoacetate under photocatalytic redox neutral conditions. Mechanism studies reveal that the reaction undergoes a radical relay involving addition, crucial remote imino-N migration and H-atom transfer. Consequently, a series of structurally significant ϵ-N-sulphonamide-α,α-difluoro-γ-amino acid esters are efficiently produced via continuous C-C bond and dual C-N bonds forging.

Integrating Olefin Carboamination and Hofmann‐Löffler‐Freytag Reaction by Radical Deconstruction of Hydrazonyl N−N Bond

AbstractAs a type of elementary organic compounds containing N−N single bond, hydrazone involved chemical conversions are extremely extensive, but they are mainly limited to N2‐retention and N2‐removal modes. We report herein an unprecedented protocol for the realization of division utilization of the N2‐moiety of hydrazone by a radical facilitated N−N bond deconstruction strategy. This new conversion mode enables the successful combination of alkene carboamination and Hofmann‐Löffler‐Freytag reaction by the reaction of N‐homoallyl mesitylenesulfonyl hydrazones with ethyl difluoroiodoacetate under photocatalytic redox neutral conditions. Mechanism studies reveal that the reaction undergoes a radical relay involving addition, crucial remote imino‐N migration and H‐atom transfer. Consequently, a series of structurally significant ϵ‐N‐sulphonamide‐α,α‐difluoro‐γ‐amino acid esters are efficiently produced via continuous C−C bond and dual C−N bonds forging.

The Merger of Halogen Atom Transfer (XAT) and Energy Transfer Catalysis (EnT) for the Modular 1,2-Iminylalkylation of Diazenes.

The 1,2-iminylalkylation of diazenes using alkyl iodides in combination with an O-benzoyl oxime is reported. In this transformation, O-benzoyl oxime acted as a radical precursor and XAT mediator. In addition to common alkyl iodides, other alkyl iodides such as iodomethane, iodomethane-d3, trifluoroiodomethane, ethyl difluoroiodoacetate, and iodoalkanes containing unprotected hydroxyl and amide groups can also serve as C-radical precursors in the 1,2-iminylalkylation with electrophilic diazenes as radical acceptors.

Difluoroalkylation of Anilines via Photoinduced Methods.

The development of sustainable and mild protocols for the fluoroalkylation of organic backbones is of current interest in chemical organic synthesis. Herein, we present operationally simple and practical transition-metal-free methods for the preparation of difluoroalkyl anilines. First, a visible-light organophotocatalytic system working via oxidative quenching is described, providing access to a wide range of difluoroalkyl anilines under mild conditions. In addition, the formation of an unprecedented electron donor-acceptor (EDA) complex between anilines and ethyl difluoroiodoacetate is reported and exploited as an alternative, efficient, and straightforward strategy to prepare difluoroalkyl derivatives.

Base/B2pin2-Mediated Iodofluoroalkylation of Alkynes and Alkenes

AbstractA base/B2pin2-mediated iodofluoroalkylation of alkynes and a part of alkenes, using ethyl difluoroiodoacetate (ICF2CO2Et) or ICnF2n+1 (n = 3, 4, 6) as difluoroacetylating or perfluoroalkylating reagent, is disclosed. The reaction proceeds under mild conditions, and iododifluoroalkylation, hydrodifluoroalkylation and several perfluoroalkylation products were generated from alkynes or alkenes. Notably, this methodology provides a simple access to difluoroalkylated and perfluoroalkylated organic compounds starting from simple alkynes or alkenes.

Visible‐Light‐Driven Base‐Promoted Radical Cascade Difluoroalkylation‐Cyclization‐Iodination of 1,6‐Enynes with Ethyl Difluoroiodoacetate

AbstractA visible‐light‐driven base‐promoted radical cascade difluoroalkylation/5‐exo‐dig cyclization/iodination of 1,6‐enynes with ethyl difluoroiodoacetate was developed under catalyst‐free and oxidant‐free conditions. The difluoroalkylated pyrrolidines and tetrahydrofuran derivatives were generated with good functional group tolerance and high Z/E stereoselectivity. This reaction provided an alternative and mild method for the preparation of highly functionalized and vinyl C−I bonds containing five‐membered heterocyclic products.

Palladium-Catalyzed Cascade Difluoroalkylation and Phosphinoylation of 2-Vinyloxy Arylalkynes: Selective Synthesis of Difluoroalkyl-Containing Tetrasubstituted Alkenylphosphine Oxides.

A Pd-catalyzed difluoroalkylation/cyclization/phosphinoylation of 2-vinyloxy arylalkynes with ethyl difluoroiodoacetate and diarylphosphine oxides has been successfully developed. This reaction allows the formation of Csp3-CF2, Csp3-Csp2, and Csp2-P(O) bonds in one step, providing a straightforward route to difluoroalkyl-containing tetrasubstituted alkenylphosphine oxides with complete stereoselectivities under mild conditions.

Selective difluoromethylation of ketones promoted by sodium tert-butoxide

The incorporation of fluorine atoms into organic compound may lead to changes in the properties such as lipophilicity, metabolic stability, and bioavailability. Therefore, the fluorine-containing compounds are privileged molecules in the research and development of new medicines. From the synthetic perspective, the selective introduction of fluorine into the drug candidates represents a most straightforward and powerful strategy in drug design and screening. Therefore, the selective difluoromethylation has stood out as an effective tool for the access of fluorine-containing compounds. One of the strategies is using difluorocarbons as an active reaction intermediate for the incorporation of difluoromethyl group and has attracted considerable attention from the organic synthetic community. Recently the reaction of difluorocarbons with hetero-atoms such as alcohols, thiophenols, amines, and phosphine were studied, and provided the difluoromethyl products. However, the reaction of difluorocarbons with C(sp3)−H bond is relatively less developed. To solve this problem, ethyl 2-bromo-2,2-difluoroacetate has come into our sight, as it can generate the ethyl 2,2-difluoroacetate free radical and difluorocarbons. And the difluorocarbons can lead to the direct difluoromethylation reaction without the decarbonylation process, thus has offered a convenient preparation method for the fluorine-containing compounds. On the basis of our recent research in the photocatalyzed reactions and oxidant free difluoroalkylation reactions of alkynes, alkenes and aryl ketones with ethyl difluoroiodoacetate, the selective difluoromethylation of aryl ketones was studied and reported herein. In order to develop an effective direct difluoromethylation reaction with simple reaction conditions, some bases were screened as catalyst. The inorganic bases such as sodium tert-butoxide, lithium tert-butoxide, and potassium tert-butoxide were able to promote the reaction. When the relation was performed in dichloromethane (DCM) under 0°C with three equivalent of sodium tert-butoxide as additive, the desired difluoromethylation product was obtained in 88% yield. Subsequently, the substrate scope of current transformation was studied. It was proved the reaction yields were affected by the steric demanding groups in the ortho -positions of the phenyl rings of the 2-phenyl-3,4-dihydronaphthalen-1(2 H )-one. The reaction yields were not sensitive with electron withdraw and electron donating groups. Substrates with naphthyl and cyclohexyl moieties were also well tolerated to give the difluoromethylation products. The reaction was achieved under mild and simple reaction conditions, using cheap ethyl difluorobromoacetate as the source of difluorocarbene, promoted by sodium tert-butanol, showing high selectivity and good substrate applicability. To gain some insights in the reaction mechanism, some control experiments were conducted. The reaction of ethyl 2,2-difluoro-2-(1-oxo-2-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate under current reaction system failed to give any desired product, which has ruled out the possibility with it as decarbonylation intermediate. And only 46% yield was given by using (bro-modifluoromethyl)trimethylsilane instead of ethyl 2-bromo-2,2-difluoroacetate. According to the control experiment, we believe the present difluoromethylation reaction may initiate with the difluorocarbon, which generates from the BrCF2CO2Et by the debromination and decarbonylation process. And the tert-butyl ethyl carbonate was observed by GC-MS analysis as side-product. Meanwhile, the enol intermediate captures difluorocarbon to realize the selective difluoromethylation of aryl ketone saturated carbon. In this reaction, sodium tert-butanol, as a base, plays a dual catalytic role. In addition to promoting the conversion of ketone to enol, ethyl difluorobromoacetate is also applied to produce difluorocarbons. According to the results of control experiments and related references, sodium tert-butanol was proposed as an effective reagent for the generation of difluorocarbon from ethyl difluorobromoacetate. Therefore, the present study has provided an easy-handling and cost-effective method for the preparation of the valuable difluoromethyl compounds under mild reaction conditions with good functional group tolerance.

Metal-Catalyzed Spiroannulation-Fluoromethylfunctionaliztions of 1,5-Enynes for the Synthesis of Stereodefined (Z)-Spiroindenes.

Two classes of new catalytic spiroannulation-fluormethylfunctionaliztions of para-quinone methide (p-QM)-containing 1,5-enynes have been established under redox-neutral conditions. Palladium-catalyzed spiroannulation-iododifluoromethylation with ethyl difluoroiodoacetate oriented completely stereoselective access to (Z)-spiroindenes and the latter included copper-catalyzed three-component spiroannulation-cyanotrifluoromethylation starting from Togni's reagent and trimethylsilanecarbonitrile (TMSCN). Both reaction pathways involve fluoroalkyl radical-triggered 1,6-addition/5-exo-dig annulation/metal radical cross-coupling/reductive elimination sequence, providing practical and stereoselective protocols for rapidly constructing cyclohexadienone-containing spiroindenes with generally good yields.

Synthesis of Difluoroalkylated Benzofuran, Benzothiophene, and Indole Derivatives via Palladium-Catalyzed Cascade Difluoroalkylation and Arylation of 1,6-Enynes.

A novel and efficient method for the synthesis of difluoroalkylated benzofuran, benzothiophene, and indole derivatives via palladium-catalyzed aryldifluoroalkylation of 1,6-enynes with ethyl difluoroiodoacetate and arylboronic acids has been established. High reaction efficiency, mild conditions, broad substrate scope, and good functional group tolerance are the features of this protocol. Notablely, the resultant products can be smoothly converted into CF2-containing benzofurans, benzothiophenes and indoles through an isomerization process catalyzed by Fe(OTf)3.

Blue Light Induced Difluoroalkylation of Alkynes and Alkenes.

The difluoroalkylation of alkynes and alkenes by direct photoexcitation of ethyl difluoroiodoacetate is described. Under catalyst- and oxidant-free conditions, iododifluoroalkylation and hydrodifluoroalkylation products were generated from alkynes, and difluoroalkylation products were prepared from alkenes. This methodology provides a streamlined access to difluoroalkylated organic compounds starting from simple alkynes or alkenes.

Synthesis of bioactive 2-(2-(difluoromethoxy)aryl)benzo[d]thiazole derivatives via base-promoted one-pot process

A convenient synthesis of 2-(2-(difluoromethoxy)aryl)benzo[d]thiazoles from 2- (o-hydroxyaryl)benzothiazoles and commercially available ethyl difluoroiodoacetate (ICF2CO2Et) is described. The transformation was amenable to a one-pot, sequential three-component protocol from o-hydroxybenzaldehyde, o-aminothiophenol, and ICF2CO2Et promoted by KOH. Additionally, some of the prepared compounds exhibited promising activity against human ovarian cancer cells.

Phosphinodifluoroalkylation of alkynes using P(O)H compounds and ethyl difluoroiodoacetate

The first phosphinodifluoroalkylation of alkynes is achieved and the simultaneous addition of both difluoromethylene and phosphinoyl groups across the alkynes with high regio- and stereoselectivity is of great significance.

Synthesis of β-Difluoroalkylated Acrylonitriles in the Presence of Copper Powder.

A highly regio- and stereoselective copper-mediated cyanodifluoroalkylation of alkynes with ethyl difluoroiodoacetate and trimethylsilyl cyanide (TMSCN) is described. The three-component coupling reaction provides straightforward access to a variety of useful difluoroalkyl-substituted acrylonitriles. The introduction of the nitrile unit is of great importance in drug discovery for the modification of this fragment. Preliminary mechanistic investigations indicate that a vinyl iodide intermediate and a difluoroalkyl radical might be involved in this transformation.

ChemInform Abstract: Palladium‐Catalyzed Cascade Cyclization of Allylamine‐Tethered Alkylidenecyclopropanes: Facile Access to Iodine/Difluoromethylene‐ and Perfluoroalkyl‐Containing 1‐Benzazepine Scaffolds.

The unprecedented palladium-catalyzed cascade cyclization of allylamine-tethered alkylidenecyclopropanes with an ethyl difluoroiodoacetate or perfluoroalkylated reagent is developed, providing facile access to a variety of synthetically and medicinally valuable iodine/difluoromethylene- and perfluoroalkyl-containing 1-benzazepine frameworks. These reactions exhibited good yields and functional group tolerance via a radical mechanism.

ChemInform Abstract: Palladium‐Catalyzed Intermolecular Aryldifluoroalkylation of Alkynes.

AbstractThe scalable reaction between aryl‐ or alkyl‐alkynes, arylboronic acids and ethyl difluoroiodoacetate tolerates various functional groups and delivers the products in high yields.

ChemInform Abstract: Palladium‐Catalyzed Radical Cascade Iododifluoromethylation/Cyclization of 1,6‐Enynes with Ethyl Difluoroiodoacetate.

AbstractThe title reaction proceeds under mild reaction conditions to give pyrrolidine derivatives with high stereoselectivity.

Palladium-Catalyzed Intermolecular Aryldifluoroalkylation of Alkynes.

A palladium-catalyzed aryldifluoroalkylation of alkynes with ethyl difluoroiodoacetate and arylboronic acids as reaction partners is described. The alkyne difunctionalization process provides various aryldifluoroalkylated products in one pot under mild reaction conditions. A wide range of alkynes and diverse arylboronic acids are compatible with these reaction conditions. High reaction efficiency and broad substrate scope are the notable features of this transformation. Preliminary mechanistic investigations indicate that a difluoroalkyl radical addition pathway is involved in this transformation.

Palladium-Catalyzed Radical Cascade Iododifluoromethylation/Cyclization of 1,6-Enynes with Ethyl Difluoroiodoacetate.

A novel and convenient Pd-catalyzed radical cascade iododifluoromethylation/cyclization of 1,6-enynes with ethyl difluoroiodoacetate is demonstrated. The proposed transformation presents high stereoselectivity under mild and facile reaction conditions, thereby allowing an efficient access to a variety of iodine-containing difluoromethylated pyrrolidines. A possible radical pathway for the transformation is proposed on the basis of the results of control experiments and relevant literature reviews.