Cross-coupling Of Alkyl Halides Research Articles

Electrochemical Nickel-Catalyzed C(sp3)-C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates.

Formation of new C(sp3)-C(sp3) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp3)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates. Selective cross-coupling transformations were achieved even between C(sp3)-secondary bromides and tosylates. Key to achieve high selectivity was the combination of the tosylates with sodium bromide as the supporting electrolyte, gradually generating small amounts of the more reactive bromide by substitution and ensuring that one of the reaction partners in the nickel-catalyzed electroreductive process is maintained in excess during a large part of the process. The method has been demonstrated for a wide range of substrates (>30 compounds) in moderate to good yields. Further expanding the scope of electroorganic synthesis to C(sp3)-C(sp3) cross-coupling reactions is anticipated to facilitate the switch to green organic synthesis and encourage future innovative electrochemical transformations.

Copper-Catalyzed Enantioconvergent Radical C(sp3 )-N Cross-Coupling: Access to α,α-Disubstituted Amino Acids.

Transition-metal catalyzed enantioconvergent cross-coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α-disubstituted amino acids. However, the construction of chiral C-N bonds between tertiary-carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper-catalyzed enantioconvergent radical C-N cross-coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N-ligand with a long spreading side arm. An array of α,α-disubstituted amino acid derivatives were obtained with good efficiency and enantioselectivity. The synthetic utility of the strategy has been showcased by the elaboration of the coupling products into different chiral α-fully substituted amine building blocks.

Photobiocatalysis enables asymmetric Csp3–Csp3 cross-electrophile coupling

Asymmetric C sp 3 –C sp 3 cross-electrophile coupling is a powerful tool for C–C bond formation yet still a great challenge in organic chemistry. Recently in Nature , Hyster and co-workers reported a highly stereoselective C sp 3 –C sp 3 cross-coupling of alkyl halides with nitroalkanes by photoexciting the ene-reductase (ERED)-templated charge-transfer (CT) complex. Asymmetric C sp 3 –C sp 3 cross-electrophile coupling is a powerful tool for C–C bond formation yet still a great challenge in organic chemistry. Recently in Nature , Hyster and co-workers reported a highly stereoselective C sp 3 –C sp 3 cross-coupling of alkyl halides with nitroalkanes by photoexciting the ene-reductase (ERED)-templated charge-transfer (CT) complex.

Design of Hemilabile N,N,N-Ligands in Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Benzyl/Propargyl Halides with Alkenylboronate Esters

The enantioconvergent radical C(sp3)-C(sp2) cross-coupling of alkyl halides with alkenylboronate esters is an appealing tool in the assembly of synthetically valuable enantioenriched alkenes owing to the ready availability, low toxicity, and air/moisture stability of alkenylboronate esters. Here, we report a copper/chiral N,N,N-ligand catalytic system for the enantioconvergent cross-coupling of benzyl/propargyl halides with alkenylboronate esters (>80 examples) with good functional group tolerance. The key to the success is the rational design of hemilabile N,N,N-ligands by mounting steric hindrance at the ortho position of one coordinating quinoline ring. Thus, the newly designed ligand could not only promote the radical cross-coupling process in the tridentate form but also deliver enantiocontrol over highly reactive alkyl radicals in the bidentate form. Facile follow-up transformations highlight its potential utility in the synthesis of various enantioenriched building blocks as well as in the late-stage functionalization for drug discovery.

Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

Migratory Cross-Coupling of Alkyl Halides via Nickel Catalysis

Migratory Cross-Coupling of Alkyl Halides via Nickel Catalysis

Diastereoselective sp3 C-O Bond Formation via Visible Light-Induced, Copper-Catalyzed Cross-Couplings of Glycosyl Bromides with Aliphatic Alcohols.

Copper-catalyzed cross-coupling reactions have become one of the most powerful methods for generating carbon-heteroatom bonds, an important framework of many organic molecules. However, copper-catalyzed C(sp3)-O cross-coupling of alkyl halides with alkyl alcohols remains elusive because of the sluggish nature of oxidative addition to copper. To address this challenge, we have developed a catalytic copper system, which overcomes the copper oxidative addition barrier with the aid of visible light and effectively facilitates the cross-couplings of glycosyl bromides with aliphatic alcohols to afford C(sp3)-O bonds with high levels of diastereoselectivity. Importantly, this catalytic system leads to a mild and efficient method for stereoselective construction of α-1,2-cis glycosides, which are of paramount importance, but challenging. In general, stereochemical outcomes in α-1,2-cis glycosidic C-O bond-forming processes are unpredictable and dependent on the steric and electronic nature of protecting groups bound to carbohydrate coupling partners. Currently, the most reliable approaches rely on the use of a chiral auxiliary or hydrogen-bond directing group at the C2- and C4-position of carbohydrate electrophiles to control α-1,2-cis selectivity. In our approach, earth-abundant copper not only acts as a photocatalyst and a bond-forming catalyst, but also enforces the stereocontrolled formation of anomeric C-O bonds. This cross-coupling protocol enables highly diastereoselective access to a wide variety of α-1,2-cis-glycosides and biologically relevant α-glycan oligosaccharides. Our work provides a foundation for developing new methods for the stereoselective construction of natural and unnatural anomeric carbon(sp3)-heteroatom bonds.

Nickel/Cobalt-Catalyzed C(sp3)–C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates

The C(sp3)–C(sp3) cross-coupling of alkyl halides with alkyl tosylates has been developed by employing a combination of nickel and nucleophilic cobalt catalysts in the presence of a manganese reduc...

Redox-Active Esters in Fe-Catalyzed C-C Coupling.

Cross-couplings of alkyl halides and organometallic species based on single electron transfer using Ni and Fe catalyst systems have been studied extensively, and separately, for decades. Here we demonstrate the first couplings of redox-active esters (both isolated and derived in situ from carboxylic acids) with organozinc and organomagnesium species using an Fe-based catalyst system originally developed for alkyl halides. This work is placed in context by showing a direct comparison with a Ni catalyst for >40 examples spanning a range of primary, secondary, and tertiary substrates. This new C–C coupling is scalable and sustainable, and it exhibits a number of clear advantages in several cases over its Ni-based counterpart.

Copper-catalyzed alkyl-alkyl cross-coupling reactions using hydrocarbon additives: efficiency of catalyst and roles of additives.

Cross-coupling of alkyl halides with alkyl Grignard reagents proceeds with extremely high TONs of up to 1230000 using a Cu/unsaturated hydrocarbon catalytic system. Alkyl fluorides, chlorides, bromides, and tosylates are all suitable electrophiles, and a TOF as high as 31200 h(-1) was attained using an alkyl iodide. Side reactions of this catalytic system, i.e., reduction, dehydrohalogenation (elimination), and the homocoupling of alkyl halides, occur in the absence of additives. It appears that the reaction involves the β-hydrogen elimination of alkylcopper intermediates, giving rise to olefins and Cu-H species, and that this process triggers both side reactions and the degradation of the Cu catalyst. The formed Cu-H promotes the reduction of alkyl halides to give alkanes and Cu-X or the generation of Cu(0), probably by disproportionation, which can oxidatively add to alkyl halides to yield olefins and, in some cases, homocoupling products. Unsaturated hydrocarbon additives such as 1,3-butadiene and phenylpropyne play important roles in achieving highly efficient cross-coupling by suppressing β-hydrogen elimination, which inhibits both the degradation of the Cu catalyst and undesirable side reactions.

ChemInform Abstract: Nickel and Cobalt‐Catalyzed Coupling of Alkyl Halides with Alkenes via Heck Reactions and Radical Conjugate Addition

AbstractReview: 56 refs.

Nickel and Cobalt-Catalyzed Coupling of Alkyl Halides with Alkenes via Heck Reactions and Radical Conjugate Addition

Cross-coupling of alkyl halides with alkenes leading to Heck-type and addition products is summarized. The development of Heck reaction with aliphatic halides although has made significant progress in the past decade and particularly recently, it was much less explored in comparison with the aryl halides. The use of Ni- and Co-catalyzed protocols allowed efficient Heck coupling of activated and unactivated alkenes with 1°, 2° and 3° alkyl halides. In addition, radical conjugate addition to activated alkenes has become a well-established method that has led to efficient construction of many natural products. The utilization of Ni- and Co-catalyzed strategies would avoid toxic tin reagents, and therefore worth exploring. The recent development of Ni- and Co-catalyzed addition of alkyl halides to alkenes displays much improved reactivity and functional group tolerance. In this mini-review, we also attempt to overview the mechanisms that are proposed in the reactions, aiming at providing insight into the nickel and cobalt-catalyzed coupling of alkyl halides with alkenes.

Cross-coupling of alkyl halides with aryl or alkyl Grignards catalyzed by dinuclear Ni(ii) complexes containing functionalized tripodal amine-pyrazolyl ligands

Structurally distinctive dinuclear Ni(II) complexes with furan or thiophene tethered amine-pyrazolyl tripodal hybrid ligands have been synthesized and crystallographically characterized. All complexes are catalytically active towards cross-coupling of aryl/alkyl Grignard reagents with β-H containing alkyl halides at room temperature in the presence of N,N,N',N'-tetramethylethylenediamine (TMEDA). The catalytic efficacy of the complexes is dependent on the tether substituent at the central amine. Two species, Ni(II) TMEDA and Mg(II) TMEDA complexes, have been isolated from the catalytic reaction mixtures under different conditions. Some ligand-stabilized Ni(II) and Mg(II) bimetallic species have also been identified in the ESI-MS spectra.

Nickamine: A General Catalyst for Cross Coupling of Alkyl Halides and Direct Alkylation

A nickel pincer complex, Nickamine, is shown to be an active catalyst for a large number of reactions including cross coupling of non-activated alkyl halides and direct C-H alkylation of alkynes and aromatic heterocycles. This work was rewarded by the 2011 Werner Prize from the Swiss Chemical Society.

Cross-couplings of alkyl halides with heteroaromatic halides, in water at room temperature

Zn-mediated, Pd-catalyzed cross-coupling reactions between heteroaromatic and alkyl halides can be done at room temperature in pure water using a commercially available Pd catalyst and PTS, a nanomicelle-forming amphiphile. Notably, zinc metal inserts selectively into a carbon sp 3-halide bond, while palladium adds oxidatively to a carbon sp 2-bond.

Low-Valent Iron-Catalyzed C−C Bond Formation−Addition, Substitution, and C−H Bond Activation

The use of iron as a catalyst for organic synthesis has been increasingly attracting the interest of chemists from economical and ecological points of view. While Fe(III) and Fe(II) catalysts have long been used as Lewis acids for synthesis, we have been interested in exploration of catalysis based on rather unexplored organoiron chemistry since the late 1990s. This Perspective summarizes a series of iron-catalyzed C-C bond formation reactions developed by us, which include (asymmetric) carbometalation of olefins, cross-coupling of alkyl halides, and activation of sp(2) and sp(3) C-H bonds.

Selective Hydrogenation of Single Benzene Ring in Biphenyl Catalyzed by Skeletal Ni

Selective Hydrogenation of Single Benzene Ring in Biphenyl Catalyzed by Skeletal Ni

Cross-coupling of alkyl halides with Grignard reagents using nickel and palladium complexes bearing η3-allyl ligand as catalysts

The cross-coupling of Grignard reagents with alkyl bromides and tosylates has been achieved by the use of eta(3)-allylnickel and eta(3)-allylpalladium complexes as catalysts.