Benzyl Grignard Reagents Research Articles

Investigating the Photoactivity of Low-Valent Zirconium Catalyst in Ether Activation

AbstractThe cross-coupling of two distinct C(sp3 )–O bonds provides a highly valuable pathway for the construction of C(sp3 )–C(sp3 ) bonds, but it remains underdeveloped. Recently, we reported an innovative photoinduced Zr-catalyzed carbomagnesiation for the reductive coupling of ethers with high cross-selectivity. Mechanistic investigation reveals that photoexcitation of low-valent zirconocene facilitates the activation of C(sp3 )–O bonds of benzylic ethers. This leads to the formation of functionalized benzylic Grignard reagents for downstream coupling with aliphatic ethers through an SN2-like pathway.1 Introduction2 Concept of Our Design on this Work3 Photoinduced Zr-Catalyzed Cross-Coupling of Ethers4 Photoinduced Zr-Catalyzed Cross-Coupling of Benzylic Magnesium Alkoxide with Ethers5 Our Methods for Mechanism Investigation6 Conclusion

Photoinduced Low‐Valent Zirconium Catalysis for Cross‐Electrophile Coupling of Ethers

AbstractAccessing versatile C(sp3)−C(sp3) bond through the cross‐electrophile coupling of two distinct etheric C−O bonds is crucial in organic synthesis but remains barely explored. Herein, we report an innovative photoinduced low‐valent zirconocene catalysis enabling the reductive coupling of ethers with high activity and cross‐selectivity. Mechanistic investigation suggests that photoexcitation of low‐valent zirconocene facilitates the C(sp3)−O bond scission of benzylic ethers, leading to the benzylic radicals intermediate via a single‐electron reduction pathway. The subsequent recombination of this benzylic radical with the Zr center followed by carbomagnesiation generates benzylic Grignard reagents for downstream coupling with aliphatic ethers through an SN2‐like mechanism. In application, a wide range of ethers readily in situ derived from aldehydes and ketones becomes feasible with high functional group compatibility as well as excellent cross‐selectivity.

Photoinduced Low-Valent Zirconium Catalysis for Cross-Electrophile Coupling of Ethers.

Accessing versatile C(sp3)-C(sp3) bond through the cross-electrophile coupling of two distinct etheric C-O bonds is crucial in organic synthesis but remains barely explored. Herein, we report an innovative photoinduced low-valent zirconocene catalysis enabling the reductive coupling of ethers with high activity and cross-selectivity. Mechanistic investigation suggests that photoexcitation of low-valent zirconocene facilitates the C(sp3)-O bond scission of benzylic ethers, leading to the benzylic radicals intermediate via a single-electron reduction pathway. The subsequent recombination of this benzylic radical with the Zr center followed by carbomagnesiation generates benzylic Grignard reagents for downstream coupling with aliphatic ethers through an SN2-like mechanism. In application, a wide range of ethers readily in situ derived from aldehydes and ketones becomes feasible with high functional group compatibility as well as excellent cross-selectivity.

Cobalt‐Catalyzed Multi‐Substituted Alkene Synthesis from 1,3‐Dithiolanes and Grignard Reagents

AbstractThe cobalt‐catalyzed reaction between 1,3‐dithiolanes and Grignard reagents, for the efficient synthesis of multi‐substituted alkene products, is described. The method was applicable to a variety of benzylic dithiolane substrates, affording di‐, tri‐, and tetra‐substituted 1,1‐diaryl alkene products in good to excellent yields. The use of benzylic Grignard reagents with aryl aldehyde‐derived 1,3‐dithiolanes enabled access to natural product‐derived stilbene architectures with exquisite E selectivity. The operational simplicity, low catalyst loadings, and scalability demonstrate the general utility of the method.

Synthesis of benzyl sulfidesviasubstitution reaction at the sulfur of phosphinic acid thioesters

An ambident electrophilicity of phosphinic acid thioesters is disclosed. Unexpected carbon-sulfur bond formation took place in the reaction between phosphinic acid thioesters and benzyl Grignard reagents. The developed method for benzyl sulfides has a wide substrate scope and was applicable for the synthesis of a drug analog.

Mechanism of the Bis(imino)pyridine-Iron-Catalyzed Hydromagnesiation of Styrene Derivatives.

Iron-catalyzed hydromagnesiation of styrene derivatives offers a rapid and efficient method to generate benzylic Grignard reagents, which can be applied in a range of transformations to provide products of formal hydrofunctionalization. While iron-catalyzed methodologies exist for the hydromagnesiation of terminal alkenes, internal alkynes, and styrene derivatives, the underlying mechanisms of catalysis remain largely undefined. To address this issue and determine the divergent reactivity from established cross-coupling and hydrofunctionalization reactions, a detailed study of the bis(imino)pyridine iron-catalyzed hydromagnesiation of styrene derivatives is reported. Using a combination of kinetic analysis, deuterium labeling, and reactivity studies as well as in situ 57Fe Mössbauer spectroscopy, key mechanistic features and species were established. A formally iron(0) ate complex [ iPrBIPFe(Et)(CH2═CH2)]- was identified as the principle resting state of the catalyst. Dissociation of ethene forms the catalytically active species which can reversibly coordinate the styrene derivative and mediate a direct and reversible β-hydride transfer, negating the necessity of a discrete iron hydride intermediate. Finally, displacement of the tridentate bis(imino)pyridine ligand over the course of the reaction results in the formation of a tris-styrene-coordinated iron(0) complex, which is also a competent catalyst for hydromagnesiation.

A one-pot electrophilic cyanation–functionalization strategy for the synthesis of disubstituted malononitriles

Malononitriles are valuable synthetic intermediates for many applications, including the synthesis of herbicides and other biologically active molecules, and the synthesis of chiral ligands for asymmetric catalysis. This article describes the development of a procedure for the conversion of primary nitriles to malononitriles using dimethylmalononitrile, a commercial, non-toxic, carbon-bound source of electrophilic cyanide. This procedure avoids the use of toxic cyanide or malononitrile as a starting material. This protocol is further applied to the dicyanation of benzyl Grignard reagents, generated from benzyl bromides, yielding fully functionalized malononitriles from a nitrile-free precursor.

ChemInform Abstract: Alkylation of Pyridines at Their 4‐Positions with Styrenes Plus Yttrium Reagent or Benzyl Grignard Reagents.

A new regioselective alkylation of pyridines at their 4-position was achieved with styrenes in the presence of yttrium trichloride, BuLi, and diisobutylaluminium hydride (DIBAL-H) in THF. Alternatively, similar products were more simply prepared from pyridines and benzyl Grignard reagents. These reactions are not only a useful preparation of 4-substituted pyridines but are also complementary to other relevant reactions usually giving 2-substituted pyridines.

ChemInform Abstract: Broad Scope Hydrofunctionalization of Styrene Derivatives Using Iron‐Catalyzed Hydromagnesiation.

AbstractAn operationally simple, chemo‐ and regioselective hydromagnesiation reaction generates benzylic Grignard reagents.

Alkylation of pyridines at their 4-positions with styrenes plus yttrium reagent or benzyl Grignard reagents.

A new regioselective alkylation of pyridines at their 4-position was achieved with styrenes in the presence of yttrium trichloride, BuLi, and diisobutylaluminium hydride (DIBAL-H) in THF. Alternatively, similar products were more simply prepared from pyridines and benzyl Grignard reagents. These reactions are not only a useful preparation of 4-substituted pyridines but are also complementary to other relevant reactions usually giving 2-substituted pyridines.

Iron-Catalyzed Hydromagnesiation: Synthesis and Characterization of Benzylic Grignard Reagent Intermediate and Application in the Synthesis of Ibuprofen

Iron-catalyzed hydromagnesiation of styrene derivatives using ethylmagnesium bromide has been investigated for the synthesis of benzylic Grignard reagents. The benzylic Grignard reagent formed in the reaction was observed directly and its conformation in solution characterized by multinuclear and variable-temperature NMR spectroscopy. The Grignard reagent could be stored for at least 2 weeks without significant loss in activity. Hydromagnesiation of styrene in tetrahydrofuran gave a mixture of monoalkyl- and dialkylmagnesium species, (1-phenylethyl)magnesium bromide (2; RMgBr) and bis(1-phenylethyl)magnesium (3; R2Mg), with the equilibrium between these species lying in favor of the dialkylmagnesium species. The thermodynamic parameters of alkyl exchange for the reaction MgBr2 + R2Mg (3) ⇌ 2RMgBr (2) were quantified, with the enthalpy and entropy of formation of 2 from MgBr2 and 3 calculated as 32 ± 7 and 0.10 ± 0.03 kJ mol–1, respectively. This methodology was applied, on a 10 mmol scale, as the key step in the synthesis of ibuprofen, using sequential iron-catalyzed alkyl–aryl and aryl–vinyl cross-coupling reactions to give 4-isobutylstyrene, which following hydromagnesiation and reaction with CO2 gave ibuprofen. Each step proceeded in excellent yield, at temperatures between 0 °C and room temperature, at atmospheric pressure. Inexpensive, nontoxic, and air- and moisture-stable iron(III) acetylacetonate was used as the precatalyst in each step in combination with inexpensive amine ligands.

Ring-opening of cyclic ethers with carbon–carbon bond formation by Grignard reagents

The ring-opening of cyclic ethers with concomitant C–C bond formation was studied with a number of Grignard reagents. The transformation was performed in a sealed vial by heating to ∼160 °C in an aluminum block or at 180 °C in a microwave oven. Good yields of the product alcohols were obtained with allyl- and benzylmagnesium halides when the ether was tetrahydrofuran or 3,3-dimethyloxetane. Lower yields were obtained with substituted tetrahydrofurans while no ring-opening was observed with tetrahydropyran. Only highly reactive allyl and benzyl Grignard reagents participated in the transformation while no reaction occurred with other alkylmagnesium halides.

ChemInform Abstract: 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.

ChemInform Abstract: Fe‐Promoted Cross Coupling of Homobenzylic Methyl Ethers with Grignard Reagents via sp3 C—O Bond Cleavage.

AbstractThe title reaction is proposed to proceed through a sequence of dehydroalkoxylation to form a vinyl intermediate, followed by Fe‐catalyzed selective carbometallation to form a benzylic Grignard reagent.

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.

Fe-promoted cross coupling of homobenzylic methyl ethers with Grignard reagents via sp3 C–O bond cleavage

The first iron-catalyzed formal cross coupling of homobenzylic methyl ethers with alkyl Grignard reagents is realized. The reaction is proposed to proceed through a sequence of dehydroalkoxylation to form the vinyl-intermediate, followed by Fe-catalyzed selective carbometalation to form a benzylic Grignard reagent.

Direct Arylation/Alkylation/Magnesiation of Benzyl Alcohols in the Presence of Grignard Reagents via Ni-, Fe-, or Co-Catalyzed sp3 C–O Bond Activation

Direct application of benzyl alcohols (or their magnesium salts) as electrophiles in various reactions with Grignard reagents has been developed via transition metal-catalyzed sp(3) C-O bond activation. Ni complex was found to be an efficient catalyst for the first direct cross coupling of benzyl alcohols with aryl/alkyl Grignard reagents, while Fe, Co, or Ni catalysts could promote the unprecedented conversion of benzyl alcohols to benzyl Grignard reagents in the presence of (n)hexylMgCl. These methods offer straightforward pathways to transform benzyl alcohols into a variety of functionalities.

Di-μ-bromido-bis[benzyl(diethyl ether)magnesium

The title benzyl Grignard reagent, [Mg2Br2(C7H7)2(C4H10O)2], was obtained by reaction of benzyl bromide with magnesium in diethyl ether, followed by crystallization from toluene. The asymmetric unit comprises one half-mol­ecule, the structural dimeric unit being generated by inversion symmetry with an Mg⋯Mg distance of 3.469 (2) Å. The Mg(II) atom exhibits a distorted tetrahedral coordination geometry. The crystal packing is defined by van der Waals inter­actions only.

ChemInform Abstract: A Facile Synthesis of 4-Benzylpyridines (VII) by Regiospecific Addition of Substituted Benzylic Grignard Reagents (III) to Pyridinium Salts (VI).

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Silver-Catalyzed Diallylation and Dibenzylation of gem-Dibromoalkanes with Grignard Reagents

Treatment of gem-dibromoalkanes with allylic Grignard reagents in the presence of a catalytic amount of silver triflate in diethyl ether leads to diallylation to afford 1,6-heptadiene derivatives. Benzylic Grignard reagents also undergo a similar transformation to yield 1,3-diphenylpropanes. Controlled sequential treatment of gem-dibromoalkane with two different Grignard reagents results in selective displacement of the two bromine atoms with allylic and benzylic moieties.