Difluoroalkyl Bromides Research Articles

Ru/Photocatalyzed Decarboxylative Coupling of α-Fluoroacrylic Acids with Difluoroalkyl Bromides

Ru/Photocatalyzed Decarboxylative Coupling of α-Fluoroacrylic Acids with Difluoroalkyl Bromides

Photo-induced C(sp2)-H difluoroalkylation of anilines.

A photoinduced protocol for the direct difluoroalkylation of C(sp2)-H bonds in anilines under catalyst-free reaction conditions is presented. This transformation is characterized by a wide substrate scope, mild reaction conditions, and operational simplicity, and could serve as an alternative tool to established methods for the synthesis of difluoroalkylated anilines. Mechanistic studies suggest the formation of an electron-donor-acceptor (EDA) complex between anilines and difluoroalkyl bromides in this reaction.

Visible-light-induced photocatalytic four-component fluoroalkylation-dithiocarbamylation via difunctionalization of styrenes.

Herein we demonstrate that a visible-light-induced photocatalytic four-component fluoroalkylation-dithiocarbamylation is a unified method for the fluoroalkylation of diverse activated fluoroalkyl halides, including monofluoroalkyl bromides, difluoroalkyl bromides, trifluoromethyl iodide, and perfluoroalkyl iodides. The synthetic value of this method has been demonstrated by the transformations of various substrates containing drug/natural product skeletons, gram scale reactions, and further derivatizations of the fluorodithiocarbamate products. This work features an atom economical protocol that is simple to operate, does not require any additives or strong bases, and can be carried out under mild conditions.

Manganese/Cobalt Bimetallic Relay Catalysis for Divergent Dehydrogenative Difluoroalkylation of Alkenes

AbstractThe involvement of manganese radical for halogen atom transfer (XAT) reactions has been esteemed as one reliable method but encountered with limited catalytic models. In this paper, a novel bimetallic relay catalysis of Mn2(CO)10 and cobaloxime has been developed for divergent dehydrogenative difluoroalkylation of alkenes using commercially available difluoroalkyl bromides. A wide range of structurally diverse terminal, cyclic and internal alkenes as well as tetrasubstituted alkenes are found to be good coupling partners to deliver difluoroalkylated allylic products and difluoromethylated cyclic products, accompanied with the production of H2 as the by‐product. This bimetallic relay strategy features broad substrate scope, mild reaction conditions and excellent functional group compatibility. Its success represents an important step‐forward to expedite the construction of a rich library of difluoroalkylated products.

Construction of Difluoroalkylated Cyclopentenones through Photocatalytic Difluoroalkylative 5‐endo Cyclization Cascades of Ynones

AbstractDifluoroalkyl groups and cyclopentenones are both important units in synthetic and medicinal chemistry. The difuoroalkylation coupled with a cyclopentenone formation still remains a challenge. Herein, we report a visible‐light‐induced cascade difluoroalkylative 5‐endo cyclization of ynones with difluoroalkyl bromides to access difluoroalkylated cyclopentenones, which may find wide applications for the concise synthesis of fluorinated cyclic molecules.

Highly Regioselective Difluoroalkylarylation of Butadiene through a Nickel-Catalyzed Tandem Radical Process

A nickel-catalyzed reaction of 1,3-butadiene with easily accessible difluoroalkyl bromides and arylboronic acids has been realized, affording the corresponding 1,4-difluoroalkylarylation products i...

Organozinc pivalates for cobalt-catalyzed difluoroalkylarylation of alkenes

Installation of fluorine into pharmaceutically relevant molecules plays a vital role in their properties of biology or medicinal chemistry. Direct difunctionalization of alkenes and 1,3-dienes to achieve fluorinated compounds through transition-metal catalysis is challenging, due to the facile β-H elimination from the Csp3‒[M] intermediate. Here we report a cobalt-catalyzed regioselective difluoroalkylarylation of both activated and unactivated alkenes with solid arylzinc pivalates and difluoroalkyl bromides through a cascade Csp3‒Csp3/Csp3‒Csp2 bond formation under mild reaction conditions. Indeed, a wide range of functional groups on difluoroalkyl bromides, olefins, 1,3-dienes as well as (hetero)arylzinc pivalates are well tolerated by the cobalt-catalyst, thus furnishing three-component coupling products in good yields and with high regio- and diastereoselectivity. Kinetic experiments comparing arylzinc pivalates and conventional arylzinc halides highlight the unique reactivity of these organozinc pivalates. Mechanistic studies strongly support that the reaction involves direct halogen atom abstraction via single electron transfer to difluoroalkyl bromides from the in situ formed cobalt(I) species, thus realizing a Co(I)/Co(II)/Co(III) catalytic cycle.

Nickel-Catalyzed Carbonylation of Difluoroalkyl Bromides with Arylboronic Acids.

A nickel-catalyzed carbonylative difluoroalkylation reaction with arylboronic acids under 1 atm of CO has been developed. The reaction proceeds under mild reaction conditions with high efficiency and high functional group tolerance. Preliminary mechanistic studies reveal that the arylacyl nickel complex is the key intermediate to circumvent the formation of labile fluoroacyl nickel, and bimetallic oxidative addition is likely the key step to facilitate the catalytic cycle.

Nickel-Catalyzed Regioselective C(2)-H Difluoroalkylation of Indoles with Difluoroalkyl Bromides.

Regioselective C(2)-H difluoroalkylation of C-3 unsubstituted indoles with commonly available fluoroalkyl bromides is successfully achieved employing a simple nickel catalyst system, (DME)NiCl2 /Xantphos. This methodology shows excellent regioselectivity and exhibits a broad substrate scope. Various functional groups, such as -OMe, -F, and -Br, are tolerated on the indole backbone to give the difluoroalkylated products in moderate to good yields. Preliminary mechanistic findings demonstrate that the reaction is homogeneous in nature and involves a radical manifold. Synthetic utility of this nickel-catalyzed method is demonstrated by synthesizing melatonin receptor antagonist Luzindole derivative.

Bulky Diamine Ligand Promotes Cross‐Coupling of Difluoroalkyl Bromides by Iron Catalysis

AbstractAlthough iron‐catalyzed cross‐coupling of Grignard reagents with alkyl halides has been well established, the adoption of the reaction for fluoroalkylations has not been reported because traditional catalytic systems often lead to defluorination reactions. Described herein is the investigation of an iron‐catalyzed cross‐coupling between arylmagnesium bromides and difluoroalkyl bromides with modified N,N,N′,N′‐tetramethyl‐ethane‐1,2‐diamine (TMEDA) as a ligand. The use of this bulky diamine, in which a butylene is substituted at one carbon atom of the ethylene backbone in TMEDA, enables the iron‐catalyzed difluoroalkylation under mild reaction conditions with a wide range of difluoroalkyl bromides, including vulnerable bromodifluoromethane, thus providing a general and cost‐efficient route for applications in medicinal chemistry.

Bulky Diamine Ligand Promotes Cross-Coupling of Difluoroalkyl Bromides by Iron Catalysis.

Although iron-catalyzed cross-coupling of Grignard reagents with alkyl halides has been well established, the adoption of the reaction for fluoroalkylations has not been reported because traditional catalytic systems often lead to defluorination reactions. Described herein is the investigation of an iron-catalyzed cross-coupling between arylmagnesium bromides and difluoroalkyl bromides with modified N,N,N',N'-tetramethyl-ethane-1,2-diamine (TMEDA) as a ligand. The use of this bulky diamine, in which a butylene is substituted at one carbon atom of the ethylene backbone in TMEDA, enables the iron-catalyzed difluoroalkylation under mild reaction conditions with a wide range of difluoroalkyl bromides, including vulnerable bromodifluoromethane, thus providing a general and cost-efficient route for applications in medicinal chemistry.

Iron-Catalyzed Cross-Coupling of Diarylzinc or Aryl Grignard Reagents with Difluoroalkyl Bromides

Iron-Catalyzed Cross-Coupling of Diarylzinc or Aryl Grignard Reagents with Difluoroalkyl Bromides

Copper‐Catalyzed 1,6‐Hydrodifluoroacetylation of para‐Quinone Methides at Ambient Temperature with Bis(pinacolato)diboron as Reductant

AbstractAn original and efficient copper‐catalyzed 1,6‐hydrodifluoroacetylation of para‐quinone methides with difluoroalkyl bromides has been described with bis(pinacolato)diboron (B2pin2) as reductant. In this reaction, a new C(sp3)–CF2 bond is constructed under smart conditions. A broad substrate scope of para‐quinone methides (p‐QMs) make this protocol very practical and attractive. Preliminary mechanistic studies manifested that a difluoroalkyl radical pathway was involved in this reaction. Also the presence of the diboron reagent was an essential requisite in this transformation.magnified image

Tandem Difluoroalkylation-Arylation of Enamides Catalyzed by Nickel.

A nickel-catalyzed three-component reaction for the synthesis of difluoroalkylated compounds through tandem difluoroalkylation-arylation of enamides has been developed. The reaction tolerates a variety of arylboronic acids and widely available difluoroalkyl bromides, and even the relatively inert substrate chlorodifluoroacetate. The significant advantages of this protocol are the low-cost nickel catalyst, synthetic convenience, excellent functional-group compatibility and high reaction efficiency.

Tandem Difluoroalkylation‐Arylation of Enamides Catalyzed by Nickel

AbstractA nickel‐catalyzed three‐component reaction for the synthesis of difluoroalkylated compounds through tandem difluoroalkylation‐arylation of enamides has been developed. The reaction tolerates a variety of arylboronic acids and widely available difluoroalkyl bromides, and even the relatively inert substrate chlorodifluoroacetate. The significant advantages of this protocol are the low‐cost nickel catalyst, synthetic convenience, excellent functional‐group compatibility and high reaction efficiency.

Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium

AbstractAlthough important progress has been made in the fluoroalkylation reactions, the transition‐metal‐catalyzed carbonylative fluoroalkylation reaction remains challenging so far. Herein, we report the first example of a Pd‐catalyzed carbonylation of difluoroalkyl bromides with (hetero)arylboronic acids under one atmosphere pressure of CO. The reaction can also be extended to the aryl potassium trifluoroborate salts. The advantages of this protocol are synthetic simplicity, broad substrate scope, and excellent functional group compatibility. The resulting difluoroalkyl ketones can serve as versatile building blocks for the synthesis of various useful fluorinated compounds.

Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium.

Although important progress has been made in the fluoroalkylation reactions, the transition-metal-catalyzed carbonylative fluoroalkylation reaction remains challenging so far. Herein, we report the first example of a Pd-catalyzed carbonylation of difluoroalkyl bromides with (hetero)arylboronic acids under one atmosphere pressure of CO. The reaction can also be extended to the aryl potassium trifluoroborate salts. The advantages of this protocol are synthetic simplicity, broad substrate scope, and excellent functional group compatibility. The resulting difluoroalkyl ketones can serve as versatile building blocks for the synthesis of various useful fluorinated compounds.

Copper-Catalyzed C(sp(2))-H Difluoroalkylation of Aldehyde Derived Hydrazones with Diboron as Reductant.

An efficient and general method for C(sp(2))-H difluoroalkylation of aldehyde derived hydrazones via a Cu(II)/B2pin2-catalyzed reaction between difluoroalkyl bromides and hydrazones was developed. In this reaction, both aromatic and aliphatic difluoroalkylated aldehyde derived hydrazones could be achieved in good to excellent yields. For some heteroaromatic aldehyde derived hydrazones, two fluoroacetates could be introduced onto the final products. A preliminary mechanism study manifested that a difluoroalkyl radical via SET pathway was involved in the reaction. In addition, the catalytic diboron reagent plays an indispensable role in this transformation.

ChemInform Abstract: Palladium‐Catalyzed Difluoroalkylation of Isocyanides: Access to Difluoroalkylated Phenanthridine Derivatives.

An efficient and general method for the synthesis of difluoroalkylated phenanthridine derivatives through palladium-catalyzed reaction of difluoroalkyl bromides with isocyanides is described. The reaction can also be extended to perfluoroalkyl iodides. Mechanistic studies reveal that a difluoroalkyl radical via a single-electron-transfer pathway is involved in the reaction.

Visible-light-induced three-component 1,2-difluoroalkylarylation of styrenes with α-carbonyl difluoroalkyl bromides and indoles

A novel visible light photoredox catalysis three-component 1,2-difluoroalkylarylation of styrenes was disclosed, and two new C–C bonds were generated in a single step through regioselective incorporation of a CF2 group and a variety of indoles to CC bonds.