Suzuki cross-couplings of unactivated secondary alkyl bromides and iodides

The capacity to employ unactivated alkyl electrophiles as coupling partners will markedly increase the already exceptional utility of metal-catalyzed cross-coupling processes. This communication describes the development of a method that achieves the first Suzuki reactions of unactivated secondary alkyl bromides and iodides. The ability to couple readily available, easy-to-handle boronic acids is an attractive feature of this catalyst system.     

Stille cross-couplings of unactivated secondary alkyl halides using monoorganotin reagents

The first catalyst that achieves Stille cross-couplings of secondary (as well as primary) alkyl halides has been developed. The method employs easily handled and inexpensive catalyst components (NiCl2 and 2,2'-bipyridine) and, through the use of monoorganotin reagents, avoids the formation of toxic and difficult-to-remove triorganotin side products.     

Nickel-catalyzed reductive coupling of unactivated alkyl bromides and aliphatic aldehydes

A mild, convenient coupling of aliphatic aldehydes and unactivated alkyl bromides has been developed. The catalytic system features the use of a common Ni(ii) precatalyst and a readily available bioxazoline ligand and affords silyl-protected secondary alcohols. The reaction is operationally simple, utilizing Mn as a stoichiometric reductant, and tolerates a wide range of functional groups. The use of 1,5-hexadiene as an additive is an important reaction parameter that provides significant benefits in yield optimizations. Initial mechanistic experiments support a mechanism featuring an alpha-silyloxy Ni species that undergoes formal oxidative addition to the alkyl bromide via a reductive cross-coupling pathway.

Aliphatic aldehydes and alkyl bromides are reductively coupled using nickel catalysis. A BiOX ligand and 1,5-hexadiene paired with a silyl chloride and Mn as the terminal reductant are important features of the process.     

The first palladium-catalyzed Sonogashira coupling of unactivated secondary alkyl bromides

A palladium-carbene catalyzed Sonogashira coupling of unactivated alkyl bromides with alkyl substituted alkynes is reported. For the first time, unactivated secondary alkyl halides were successfully employed in Sonogashira reactions.     

Nickel-catalyzed cross-coupling of unactivated alkyl halides and tosylate carrying a functional group with alkyl and phenyl Grignard reagents

By the use of catalytic amounts of a nickel salt and a 1,3-butadiene, primary and secondary alkyl Grignard reagents undergo cross-coupling with alkyl bromides, iodide, and tosylate carrying a functional group such as amide, ester, and ketone at 0 °C in THF. The present procedure provides a simple, convenient, and practical method for construction of carbon chains in the presence of various functional groups. PhMgBr also gave the corresponding coupling product in a moderate yield.     

Nickel-catalyzed reductive coupling of aryl halides with secondary alkyl bromides and allylic acetate

A room-temperature Ni-catalyzed reductive method for the coupling of aryl bromides with secondary alkyl bromides has been developed, providing C(sp(2))-C(sp(3)) products in good to excellent yields. Slight modification of this protocol allows efficient coupling of activated aryl chlorides with cyclohexyl bromide and aryl bromides with allylic acetate.     

Room-temperature Stille cross-couplings of alkenyltin reagents and functionalized alkyl bromides that possess beta hydrogens

This communication describes a significant expansion in the scope of Stille reactions of Csp3-X electrophiles, specifically, that Pd/P(t-Bu)2Me catalyzes the room-temperature cross-coupling of a variety of functionalized, beta-hydrogen-containing alkyl bromides with an array of alkenyltin reagents. The structure of the phosphine (P(t-Bu)2Me) is well suited for facilitating oxidative addition and avoiding beta-hydride elimination, while the fluoride serves to activate the tin reagent for efficient transmetalation.     

Nickel-catalyzed asymmetric cross-couplings of racemic propargylic halides with arylzinc reagents

A stereoconvergent method for the catalytic asymmetric Negishi cross-coupling of racemic secondary propargylic halides with arylzinc reagents has been developed. Neither family of compounds has previously been shown to be a suitable partner in such coupling processes. From a practical point of view, it is noteworthy that the catalyst components (NiCl2.glyme and pybox ligand 1) are commercially available.     

Nickel-catalyzed reductive cross-coupling of unactivated alkyl halides

A Ni-catalyzed reductive approach to the cross-coupling of two unactivated alkyl halides has been successfully developed. The reaction works efficiently for primary and secondary halides, with at least one being bromide. The mild reaction conditions allow for excellent functional group tolerance and provide the C(sp(3))-C(sp(3)) coupling products in moderate to excellent yields.     

Room-temperature Negishi cross-coupling of unactivated alkyl bromides with alkyl organozinc reagents utilizing a Pd/N-heterocyclic carbene catalyst

A high-yielding cross-coupling reaction of unactivated alkyl bromides possessing beta-hydrogens with alkylzinc halides utilizing a Pd/N-heterocyclic carbene (NHC) catalyst at room temperature is described. A variety of Pd sources, Pd2(dba)3, Pd(OAc)2, or PdBr2, with the commercially available ligand precursor 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr.HCl) successfully coupled 1-bromo-3-phenylpropane with n-butylzinc bromide in THF/NMP. An investigation of different NHC precursors showed that the bulky 2,6-diisopropylphenyl moiety was necessary to achieve high coupling yields (75-85%). The corresponding ethyl analogue was moderately active (11%). A range of unsymmetrical NHC precursors were prepared and evaluated. The ligand precursor containing one 2,6-diisopropylphenyl and one 2,6-diethylphenyl afforded the coupling product in 47% yield, clearly suggesting a direct relationship between the steric topography created by the flanking N-substituents and catalyst activity. Under optimal conditions, a number of alkyl bromides and alkylzinc halides possessing common functional groups (amide, nitrile, ester, acetal, and alkyne) were effectively coupled (61-92%). It is noteworthy that beta-substituted alkyl bromides and alkylzinc halides successfully underwent cross-coupling. Also, under these conditions alkyl chlorides were unaffected.     

The first applications of carbene ligands in cross-couplings of alkyl electrophiles: sonogashira reactions of unactivated alkyl bromides and iodides

A Pd/N-heterocyclic carbene-based catalyst achieves the Sonogashira coupling of an array of functionalized, beta-hydrogen-containing alkyl bromides and iodides under mild conditions. By furnishing the first example of a nonphosphine-based palladium catalyst for cross-coupling unactivated alkyl electrophiles, this study provides an impetus for future efforts at catalyst development that extend beyond phosphine ligands.     

Nickel-catalyzed cross-coupling reaction of alkynyl bromides with Grignard reagents

We describe a convenient method for the synthesis of 1,2-disubstituted acetylenes via a cross-coupling reaction of （bromoethynyl）benzene with Grignard reagents. The reaction of （bromoethynyl）benzene （1 mmol） with Grignard reagent （1.3 mmol） mediated by NiCl2 （4 mol%） and （p-CH3Ph）3P （8 mol%） in THF could produce 1,2-disubstituted acetylenes in good yields at room temperature.     

Room-temperature Hiyama cross-couplings of arylsilanes with alkyl bromides and iodides

The first method for achieving Hiyama couplings of unactivated alkyl bromides and iodides is reported. The desired carbon-carbon bond formation proceeds under mild conditions (room temperature) with good functional-group tolerance.     

Cross-couplings of unactivated secondary alkyl halides: room-temperature nickel-catalyzed Negishi reactions of alkyl bromides and iodides

The development of a nickel- or palladium-catalyzed method for cross-coupling unactivated secondary alkyl halides has been a long-standing challenge in synthetic chemistry. This communication describes a simple catalyst system-Ni(cod)2/s-Bu-Pybox-that achieves room-temperature Negishi reactions of an array of functionalized primary and secondary alkyl bromides and iodides.     

Nickel-catalyzed cross-coupling of potassium aryl- and heteroaryltrifluoroborates with unactivated alkyl halides

A method for the cross-coupling of alkyl electrophiles with various potassium aryl- and heteroaryltrifluoroborates has been developed. Nearly stoichiometric amounts of organoboron species could be employed to cross-couple a large variety of challenging heteroaryl nucleophiles. Several functional groups were tolerated on both the electrophilic and the nucleophilic partners. Chemoselective reactivity of C(sp(3))-Br bonds in the presence of C(sp(2))-Br bonds was achieved.     

Nickel-catalyzed asymmetric negishi cross-couplings of secondary allylic chlorides with alkylzincs

Complementing previous advances in allylation chemistry, an effective nickel/Pybox catalyst for regioselective asymmetric Negishi cross-couplings of racemic secondary allylic chlorides with readily available organozinc halides has been developed. The method has been applied in two key steps of a formal total synthesis of fluvirucinine A1.     

Highly efficient,general procedure for the preparation of alkylzinc reagents from unactivated alkyl bromides and chlorides

[reaction: see text] Alkylzinc bromides have been efficiently prepared by the direct insertion of zinc metal (dust, powder, granule, shot), activated with 1-5 mol % I(2), into alkyl bromides in a polar aprotic solvent. The zinc reagents thus formed undergo Ni- and Pd-catalyzed cross-coupling with aryl halides to produce functionalized alkylarenes in excellent yields.     

Silver-catalyzed cross-coupling reactions of alkyl bromides with alkyl or aryl Grignard reagents

Treatment of secondary or tertiary alkyl bromides with alkyl Grignard reagents in the presence of catalytic amounts of silver bromide and potassium fluoride in CH₂Cl₂ afforded the corresponding cross-coupling products in reasonable yields. Moreover, silver showed catalytic activity for the cross-coupling reactions of alkyl bromides with aryl Grignard reagents.