Stereospecific Nickel‐Catalyzed Cross‐Coupling Reactions of Alkyl Grignard Reagents and Identification of Selective Anti‐Breast‐Cancer Agents

Alkyl Grignard reagents that contain β‐hydrogen atoms were used in a stereospecific nickel‐catalyzed cross‐coupling reaction to form C(sp³)? C(sp³) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1‐diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF‐7 breast cancer cells.     

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.     

Copper catalyzed magnesium-Barbier reaction for γ-selective alkyl-allyl coupling

CuCN catalyzed alkyl-allyl coupling under magnesium-Barbier conditions occurs regioselectively and affords predominantly the γ-products in good to high yields. This one-pot CuCN catalyzed reaction utilising Mg, an alkyl halide and an allylic substrate in THF at room temperature provides an easy alternative to the classical CuCN catalyzed γ-allylation of alkyl Grignard reagents.     

Copper‐Free Asymmetric Allylic Alkylation with a Grignard Reagent: Design of the Ligand and Mechanistic Studies

The Cu‐free asymmetric allylic alkylation, catalysed by NHC, with Grignard reagents is reported on allyl bromide derivatives with good results. The enantioselectivity was quite homogeneous (around 85 % ee) on large and various substrates, regardless of the nature of the Grignard reagent. The formation of stereogenic quaternary centres was highly regioselective for both aliphatic and aromatic derivatives with good enantiomeric excess (up to 92 % ee). The methodology developed was found to be complementary with the Cu‐catalysed version. Several new NHCs were tested with improved efficiency. In addition, mechanistic studies, using NMR spectroscopy, led to the discovery of the catalytically active species.     

One-Pot Sequential Kumada–Tamao–Corriu Couplings of (Hetero)Aryl Polyhalides in the Presence of Grignard-Sensitive Functional Groups Using Pd-PEPPSI-IPentCl

We report a general and rapid chemoselective Kumada–Tamao–Corriu (KTC) cross-coupling of aryl bromides in the presence of chlorides or triflates with functionalized Grignard reagents at 0 °C in 15 min by using Pd-PEPPSI-IPent^Cl ( C4 ). Nucleophiles and electrophiles (or both) can contain Grignard-sensitive functional groups (-CN, -COOR, etc.). Control experiments together with DFT calculations suggest that transmetallation is rate limiting for the selective cross-coupling of Br in the presence of Cl/OTf with functionalized Grignard reagents. One-pot sequential KTC/KTC cross-couplings with bromo–chloro arenes have been demonstrated for the first time. We also report the one-pot sequential KTC/Negishi cross-couplings using C4 showcasing the versatility of this methodology.     

Practical Iron‐ and Cobalt‐Catalyzed Cross‐Coupling Reactions between N‐Heterocyclic Halides and Aryl or Heteroaryl Magnesium Reagents

The reaction scope of iron‐ and cobalt‐catalyzed cross‐coupling reactions in the presence of isoquinoline (quinoline) in the solvent mixture tBuOMe/THF has been further investigated. Various 2‐halogenated pyridine, pyrimidine, and triazine derivatives were arylated under these mild conditions in excellent yields. The presence of isoquinoline allows us to perform Fe‐catalyzed cross‐coupling reactions between 6‐chloroquinoline and aryl magnesium reagents. Furthermore, it was found that the use of 10 % N,N‐dimethylquinoline‐8‐amine increases the yields of some Co‐catalyzed cross‐coupling reactions with chloropyridines bearing electron‐withdrawing substituents.     

Preparation of Solid,Substituted Allylic Zinc Reagents and Their Reactions with Electrophiles

The treatment of various allylic chlorides or bromides with zinc dust in the presence of lithium chloride and magnesium pivalate (Mg(OCOtBu)₂) in THF affords allylic zinc reagents which, after evaporation of the solvent, produce solid zinc reagents that display excellent thermal stability. These allylic reagents undergo Pd‐catalyzed cross‐coupling reactions with PEPPSI‐IPent, as well as highly regioselective and diastereoselective additions to aryl ketones and aldehydes. Acylation with various acid chlorides regioselectively produces the corresponding homoallylic ketones, with the new C? C bond always being formed on the most hindered carbon of the allylic system.     

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.     

Cobalt- and rhodium-catalyzed cross-coupling reaction of allylic ethers and halides with organometallic reagents

Reactions of 2-alkenyl methyl ether with phenyl, trimethylsilylmethyl, and allyl Grignard reagents in the presence of cobalt(II) complexes are discussed. The success of the reactions heavily depends on the combination of the substrate, ligand, and Grignard reagent. In the reaction of cinnamyl methyl ether, the formation of the linear coupling products predominates over that of the relevant branched products. In the cobalt-catalyzed allylation of allylic ethers, addition of a diphosphine ligand can change the regioselectivity, mainly providing the corresponding branched products. Rhodium complexes catalyze the reactions of allylic ethers and halides with allylmagnesium chloride and allylzinc bromide, respectively, in which the branched coupling product is the major product.     

Iron‐catalyzed cross‐coupling of heteroaromatic tosylates with alkyl and aryl Grignard reagents

An Fe(III)‐catalyzed cross‐coupling of N‐heteroaromatic tosylates with aryl and alkyl Grignard reagents is presented. The reaction proceeds at ?20°C to room temperature with short reaction time (15–30 min.), and the corresponding products are obtained with moderate to high yields. In particular, low‐cost and abundantly available FeCl₃ or Fe(acetylacetonate)₃ catalyze the reaction without other special ligands. All tested N‐heteroaromatic tosylates that are available including pyridine and pyrimidine derivatives were subject to the reaction, resulting in the expected products. Copyright © 2015 John Wiley & Sons, Ltd.     

Palladium-catalyzed desulfinylative C-C allylation of Grignard reagents and enolates using allylsulfonyl chlorides and esters

2-Methylprop-2-ene-, prop-2-ene-, 1-methylprop-2-ene-, and (E)-but-2-enesulfonyl chlorides have been used as electrophilic partners in desulfinylative palladium-catalyzed C-C coupling with Grignard reagents and sodium salts of dimethyl malonate and methyl acetoacetate. Neopentyl alk-2-ene sulfonates can also be used as electrophilic partners in desulfinylative allylic arylations and allylic alkylations. The regioselectivity of the allylic arylation and alkylation depends on the nature of the catalyst. With PdCl₂(PhCN)₂, (E)-crotyl derivatives are formed in high regioselectivity using either 1-methylprop-2-ene- or (E)-but-2-enesulfonyl chloride.     

Allylic Functionalization of Unactivated Olefins with Grignard Reagents

New advances in the functionalization of unactivated olefins with carbon nucleophiles have provided more efficient and practical approaches to convert inexpensive starting materials into valuable products. Recent examples have been reported with stabilized carbon nucleophiles, tethered carbon nucleophiles, diazoesters, and trifluoromethane donors. A general method for functionalizing olefins with aromatic, aliphatic, and vinyl Grignard reagents was developed. In a one‐pot process, olefins are oxidized by a commercially available reagent to allylic electrophiles, which undergo selective copper‐catalyzed allylic alkylation with Grignard reagents. Products are formed in high yield and with high regioselectivity. This was utilized to synthesize a series of skipped dienes, a class of compounds that are prevalent in natural products and are difficult to synthesize by known allylic alkylation methods.     

Cu‐Catalyzed Asymmetric Allylic Alkylation of Phosphonates and Phosphine Oxides with Grignard Reagents

An efficient and highly enantioselective copper‐catalyzed allylic alkylation of phosphonates and phosphine oxides with Grignard reagents and Taniaphos or phosphoramidites as chiral ligands is reported. Transformation of these products leads to a variety of new phosphorus‐containing chiral intermediates.     

Stereospecific and Stereodivergent Construction of Tertiary and Quaternary Carbon Centers through Switchable Directed/Nondirected Allylic Substitution

This study introduces the ortho‐diphenylphosphanylbenzoate (o‐DPPB)/o‐DPPB oxide system as a switchable directing/nondirecting leaving group in a copper‐mediated allylic substitution with Grignard and organozinc reagents. With this system, the regioselective, stereospecific, and stereodivergent construction of quaternary as well as tertiary carbon centers is possible in a reliable and predictable fashion. Starting from one substrate enantiomer, both optical antipodes of the substitution products are readily available. Hence, this methodology features reversed polarity in comparison to established enolate alkylation chemistry and may be an interesting alternative, particularly for the construction of quaternary stereogenic carbon centers.     

Synthesis of α,α‐Difluoromethylene Alkynes by Palladium‐Catalyzed gem‐Difluoropropargylation of Aryl and Alkenyl Boron Reagents

gem‐Difluoropropargyl bromides are versatile intermediates in organic synthesis, but have rarely been employed in transition‐metal‐catalyzed cross‐coupling reactions. The first palladium‐catalyzed gem‐difluoropropargylation of organoboron reagents with gem‐difluoropropargyl bromides is now reported. The reaction proceeds under mild reaction conditions with high regioselectivity; it features a broad substrate scope and excellent functional‐group compatibility and thus provides an attractive approach for the synthesis of complex fluorinated molecules, in particular for drug discovery and development.     

Arylzinc species by microwave assisted Grignard formation-transmetallation sequence: application in the Negishi coupling

Arylmagnesium species can be efficiently generated from magnesium turnings and aryl chlorides or aryl bromides under dielectric heating conditions. Subsequent microwave assisted transmetallation using ZnCl₂-TMEDA afforded the corresponding arylzinc reagents. A sequential microwave assisted arylmagnesium formation-transmetallation-Negishi coupling protocol suitable for automated multiple parallel synthesis has been developed.     

Transformation of β-chalcogeno alkenylboranes into tetrasubstituted olefins

In view of generating trisubstituted vinylic chalcogen derivatives, β-chalcogeno alkenylboranes generated through the chalcogen electrophile induced rearrangements of 1-alkynyltrialkyl borates have been subjected to Suzuki-Miyaura coupling and to boron to copper transmetalation followed by alkylation. Some of the trisubstituted vinyl sulfides obtained by this latter strategy have been converted efficiently into the title olefins through the NiCl₂(dmpe) catalyzed coupling with various Grignard reagents.     

An insight into copper catalyzed allylation of alkyl zinc halides. Comparison of reactivity profiles for catalytic and stoichiometric alkylzinc-copper reagents

The γ-selective allylation of catalytic and stoichiometric alkylzinc-cuprates have been kinetically studied. The reactivity profiles generated by allylation reactions of n-butylzinc chloride catalyzed by CuX compounds (X = I, Br, Cl, CN, SCN) and also catalyzed by n-butylzinc-copper reagents and di n-butylzinc-copper reagents were evaluated. Reactivity profiles for allylation of stoichiometric n-butylzinc-copper reagents and di n-butylzinc-copper reagents were also prepared. All CuX compounds have been screened for the preparation of Grignard reagent derived n-butylzinc-copper reagents and di n-butylzinc-copper reagents.The evaluation of the profiles indicates that the active catalyst might be RCu(X)ZnCl and also to some degree, R₂CuZnCl · ZnClX, which both could favor formation of γ-product. All data supports the reductive elimination of σ-allyl Cu (III) complex formed at vinylic terminal to give γ-allylated product with a quite slow isomerization to σ-allyl Cu (III) complex formed at allylic terminal to give α-allylated product. In the allylation mechanism of zinc cuprates, the role of counter ion, ZnCl⁺ has been discussed.     

The first nucleophilic aromatic substitution of suitably activated 2-methoxyfurans with Grignard reagents

The reaction of 2-methoxyfuroates 1 with Grignard reagents 2 leads to tertiary alcohols or S_NAr products depending on the position of the alkoxycarbonyl group. OMe-Displacement occurs only for 3-substituted derivatives. It takes place even for 3-acetyl-2-methoxyfuran while the presence of a further ester function at 4 position induces the formation of the sole 4-tertiary alcohol. The OMe-substitution has been verified for a wide range of furans and Grignard reagents and low yields have been found only in the reactions with the benzylic and allylic reagents which are delocalized anions. A mechanistic interpretation is given.     

由(E)-β-碘代烯基砜和末端炔合成多取代的1,3-烯炔

通过(E)-b-碘代烯基砜与末端炔的Sonogashira偶联反应,以中等到良好的产率合成了磺酰基取代的1,3-烯炔。在NiCl2(PPh3)2催化下,产物与格氏试剂发生脱磺酰基偶联反应,磺酰基被进一步转化为不同的取代基。