Copper-catalyzed coupling reaction of unactivated secondary alkyl iodides with alkyl Grignard reagents in the presence of 1,3-butadiene as an effective additive

Cu-catalyzed cross-coupling of unactivated secondary alkyl iodides with alkyl Grignard reagents in the presence of 1,3-butadiene as a ligand precursor was developed. The use of 1,3-butadiene resulted in improved yields of alkyl-alkyl products with improved selectivities.     

Nickel-catalyzed cross-coupling reaction of grignard reagents with alkyl halides and tosylates: remarkable effect of 1,3-butadienes

A new method for the cross-coupling reaction of Grignard reagents with alkyl chlorides, bromides, and tosylates has been developed by the use of a nickel catalyst in the presence of a diene as an additive. This reaction proceeds efficiently at 0-25 degrees C in THF using primary and secondary alkyl and aryl Grignard reagents. Nickel complexes bearing no phosphine ligands, such as NiCl2, Ni(acac)2, and Ni(COD)2, afford the coupling products in good yields, whereas NiCl2(PPh3)2 and NiCl2(dppp) were less effective. 1,3-Butadiene shows the highest activity as an additive for the present coupling reaction. A plausible reaction pathway was proposed.     

Cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic and benzylic Grignard reagents and their application to tandem radical cyclization/cross-coupling reactions

Details of cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic Grignard reagents are disclosed. A combination of cobalt(II) chloride and 1,2-bis(diphenylphosphino)ethane (DPPE) or 1,3-bis(diphenylphosphino)propane (DPPP) is suitable as a precatalyst and allows secondary and tertiary alkyl halides--as well as primary ones--to be employed as coupling partners for allyl Grignard reagents. The reaction offers a facile synthesis of quaternary carbon centers, which has practically never been possible with palladium, nickel, and copper catalysts. Benzyl, methallyl, and crotyl Grignard reagents can all couple with alkyl halides. The benzylation definitely requires DPPE or DPPP as a ligand. The reaction mechanism should include the generation of an alkyl radical from the parent alkyl halide. The mechanism can be interpreted in terms of a tandem radical cyclization/cross-coupling reaction. In addition, serendipitous tandem radical cyclization/cyclopropanation/carbonyl allylation of 5-alkoxy-6-halo-4-oxa-1-hexene derivatives is also described. The intermediacy of a carbon-centered radical results in the loss of the original stereochemistry of the parent alkyl halides, creating the potential for asymmetric cross-coupling of racemic alkyl halides.     

A Convenient Synthesis of 3-Alkylthiophenes

The known procedures for the synthesis of 3-alkylthiophenes are rather lengthy or involved. By using the NiDPPP⁺⁺ catalyzed cross-coupling method between 3-bromothiophene and Grignard reagents derived from alkyl halides a number of 3-alkylthiophenes have been prepared in a one-step reaction in good to excellent yields.     

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.     

Ni-catalyzed alkylative dimerization of vinyl grignard reagents using alkyl fluorides

Alkyl halides underwent unique cross-coupling reaction with vinylmagnesium chloride in the presence of Ni catalyst to give 2-alkyl-3-butenyl Grignard reagent (1) in high yields. This reaction proceeded efficiently at 25 degrees C in THF using primary and secondary alkyl fluorides. On the other hand, PhCH=CHMgBr gave double alkylative vinyl coupling product 4 in good yield as the sole coupling product. Alkyl fluorides react as the most suitable alkylating reagent in comparison to the corresponding chlorides, bromides, and iodides.     

Novel stereoselective synthesis of 1,3-dienylsilanes via hydromagnesiation reaction of alkynylsilanes

Hydromagnesiation of alkynylsilanes gives (Z)-α-silylvinyl Grignard reagents, which undergo palladium-catalyzed cross-coupling reactions with alkenyl halides to afford stereoselectively 1,3-dienylsilanes in good yields.     

Synthesis and Structural Characterization of Butadienylcalcium-based Heavy Grignard Reagents and a Ca4[O] Inverse Crown Ether Complex

The structure elucidation of heavy Grignard reagents (RAeX, Ae=Ca, Sr, and Ba, X=halides) has been greatly strived after, mainly because of their inaccessibility and remarkable instability. The synthesis of a series of butadienylcalcium compounds is presented, including 1-calcio-4-lithio-1,3-butadiene, 1,4-dicalcio-1,3-butadiene, and a Ca₄[O] inverse crown ether complex, via the reaction between 1,4-dilithio-1,3-butadienes and calcium iodide in THF. Single-crystal X-ray analysis of these unprecedented heavy Grignard reagents revealed unique structural characteristics and bonding modes. Preliminary reaction chemistry was investigated. This study provides a novel class of alkenyl heavy Grignard reagents and a useful synthetic strategy for otherwise unavailable reactive organometallic compounds.     

An unprecedented iron-catalyzed cross-coupling of primary and secondary alkyl Grignard reagents with non-activated aryl chlorides

The use of N-heterocyclic carbene ligands in the iron-catalyzed cross-coupling of alkyl Grignards has allowed, for the first time, coupling of non-activated, electron rich aryl chlorides. Surprisingly, the tetrahydrate of FeCl₂ was found to be a better pre-catalyst than anhydrous FeCl₂. Primary Grignard reagents coupled in excellent yields while secondary Grignard reagents coupled in modest yields. The use of acyclic secondary Grignard reagents resulted in the formation of isomers in addition to the desired product. These isomeric products were formed via reversible β-hydrogen elimination, indicating that the cross-coupling proceeds through an ionic pathway.     

Sequential One‐Pot Addition of Excess Aryl‐Grignard Reagents and Electrophiles to O‐Alkyl Thioformates

The sequential addition of aromatic Grignard reagents to O‐alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O‐alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O‐alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero‐Diels–Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2‐bis(phenylsulfanyl)‐1,2‐diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four‐component coupling products, that is, O‐alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate‐to‐good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four‐component coupling products. Finally, oxiranes and imines also participated in the coupling reaction.     

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.     

Titanocene-catalyzed carbosilylation of alkenes and dienes using alkyl halides and chlorosilanes

A new method for regioselective carbosilylation of alkenes and dienes has been developed by the use of a titanocene catalyst. This reaction proceeds efficiently at 0 degrees C in THF in the presence of Grignard reagents by the combined use of alkyl halides (R'-X, X = Br or Cl) and chlorotrialkylsilanes (R3'Si-Cl) as the alkylating and silylating reagents, respectively. Terminal alkenes having aryl or silyl substituents (YRC=CH2, Y = Ar or Me3Si, R = H or Me) afford addition products YRC-(SiR'3)-CH2R' in good yields, whereas 1-octene and internal alkenes were sluggish. When 2,3-disubstituted 1,3-butadienes were used instead of alkenes, alkyl and silyl units are introduced at the 1- and 4-positions giving rise to allylsilanes in high yields under similar conditions. The present reaction involves (i) addition of alkyl radicals toward alkenes or dienes, and (ii) electrophilic trapping of benzyl- or allylmagnesium halides with chlorosilanes. The titanocene catalyst plays important roles in generation of these active species, i.e., alkyl radicals and benzyl- or allylmagnesium halides.     

Silver-catalyzed benzylation and allylation reactions of tertiary and secondary alkyl halides with grignard reagents

Treatment of alkyl halides, including tertiary alkyl bromides, with benzylic or allylic Grignard reagent in the presence of a catalytic amount of silver nitrate in ether yielded the corresponding cross-coupling products in high yields. The coupling reactions of tertiary alkyl halides provide efficient access to quaternary carbon centers.     

An efficient route to heteroarene-substituted vinyl- and allyl-silanes via palladium-phosphine complex catalyzed cross-coupling

Heteroarene-substituted vinyl- and allyl-silanes were obtained in good yields by the cross-coupling reaction of either heteroaryl Grignard reagents with halovinyl- and haloallyl-silanes or, alternatively, silyl- and silylmethyl-substituted vinylmetallic reagents with heteroaryl halides in the presence of PdCl₂(dppb) as a catalyst.     

Iron-catalyzed Grignard cross-coupling with alkyl halides possessing beta-hydrogens

Tris(acetylacetonato)iron(III) (Fe(acac)(3)) was found to be an efficient catalyst for the cross-coupling reaction between aryl Grignard reagents and alkyl halides possessing beta-hydrogens. The reaction is applicable to secondary alkyl halides as well as primary ones. [reaction: see text]     

Oxidative addition of heteroaromatic halides to Negishi reagent and subsequent cross-coupling reactions

Heteroarylzirconocene halides were prepared via the oxidative addition of heteroaryl halides to the Negishi reagent ‘Cp₂ZrBu₂’. The palladium-catalyzed cross-coupling of the in situ generated organozirconium reagents with functionalized aryl and heteroaryl halides proceeded smoothly in the presence of CuCl to produce the cross-coupling products in high yields.     

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.     

Nickel-catalyzed cross-coupling of primary alkyl halides with phenylethynyl- and trimethylsilyethynyllithium reagents

A highly efficient alkyl-alkynyl coupling system is described which is promoted by a well-defined and moisture-stable pincer complex [NiCl{C₆H₃-2,6-(OPPh₂)₂}] (1). Non-activated alkyl halides could be efficiently coupled with phenylethynyl- and trimethylsilylethynyllithium reagents at room temperature. Compared to the alkylation of primary alkyl halides with alkynyllithium reagents in literatures, this method requires milder conditions (room temperature) and proceeds quickly. This research will make these readily available alkynyllithium reagents much more useful for organic synthesis.     

Synthesis of Cp*CH2PPh2 and its use as a ligand for the nickel-catalysed cross-coupling reaction of alkyl halides with aryl Grignard reagents

A new ligand, Cp*CH2PPh2 (Cp* = 1,2,3,4,5-pentamethyl-2,4-cyclopentadienyl), was prepared, and was used as a ligand for nickel-catalysed cross-coupling reaction of alkyl halides with aryl Grignard reagents, which nickel-phosphine complexes had never made possible.     

Iron nanoparticles in the coupling of alkyl halides with aryl Grignard reagents

Iron nanoparticles, either formed in situ stabilized by 1,6-bis(diphenylphosphino)hexane or polyethylene glycol (PEG), or preformed stabilized by PEG, are excellent catalysts for the cross-coupling of aryl Grignard reagents with primary and secondary alkyl halides bearing beta-hydrogens and they also prove effective in a tandem cyclization/cross-coupling reaction.