Alkyl Grignard Reagents Research Articles

Titanium‐Mediated Synthesis of Spirocyclic NH‐Azetidines from Oxime Ethers

AbstractThe TiIV‐mediated synthesis of spirocyclic NH‐azetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through a proposed Kulinkovich‐type mechanism, a titanacyclopropane intermediate forms and serves as a 1,2‐aliphatic dianion equivalent, inserting into the 1,2‐dielectrophilc oxime ether to ultimately give rise to the desired N‐heterocyclic four‐membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH‐azetidines in a single step.

Titanium-Mediated Synthesis of Spirocyclic NH-Azetidines from Oxime Ethers.

The TiIV -mediated synthesis of spirocyclic NH-azetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through a proposed Kulinkovich-type mechanism, a titanacyclopropane intermediate forms and serves as a 1,2-aliphatic dianion equivalent, inserting into the 1,2-dielectrophilc oxime ether to ultimately give rise to the desired N-heterocyclic four-membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH-azetidines in a single step.

Chemoselective Synthesis of Aryl Ketones from Amides and Grignard Reagents via C(O)–N Bond Cleavage under Catalyst-Free Conditions

Conversion of a wide range of N-Boc amides to aryl ketones was achieved with Grignard reagents via chemoselective C(O)-N bond cleavage. The reactions proceeded under catalyst-free conditions with different aryl, alkyl, and alkynyl Grignard reagents. α-Ketoamide was successfully converted to aryl diketones, while α,β-unsaturated amide underwent 1,4-addition followed by C(O)-N bond cleavage to provide diaryl propiophenones. N-Boc amides displayed higher reactivity than Weinreb amides with Grignard reagents. A broad substrate scope, excellent yields, and quick conversion are important features of this methodology.

Chemoselective Kumada‐Type Iron Catalysis with Alkyl Grignard Reagents: Reductive Cyclization and Cyclomethylation

AbstractA chemoselective reductive cyclization and cyclomethylation reaction of 7‐iodohept‐2‐yne and 7‐iodohepta‐1,2‐diene derivatives has been carried out using an iron catalyst and various alkyl Grignard reagents, resulting in the formation of pyrrolidines, tetrahydrofurans, and carbocycles with an alkene functional group. The reaction is initiated by single‐electron transfer from reduced Fe species to alkyl iodides and the resulting Fe−H or Fe−Me compound differentiated the structures of the cyclized products, which exhibited diverse complexities and synthetic utilities.

P-Chiral Monophosphorus Ligands for Asymmetric Copper-Catalyzed Allylic Alkylation

Asymmetric copper-catalyzed allylic alkylation between allyl bromides and alkyl Grignard reagents using a P-chiral monophosphorus ligand is described. A range of terminal olefins bearing tertiary o...

Gram-Scale, Cheap, and Eco-Friendly Iron-Catalyzed Cross-Coupling between Alkyl Grignard Reagents and Alkenyl or Aryl Halides.

A new robust methodology for gram-scale iron-catalyzed cross-coupling between alkyl Grignard reagents and alkenyl or aryl halides is developed. This method does not require toxic additives such as NMP or expensive ligands. Its efficiency relies on the use of simple alkoxide magnesium salts as additives. On the basis of these results, a new procedure for one-pot synthesis of substituted benzamides from chloroesters is also proposed.

Nickel‐Catalyzed C(sp2)−C(sp3) Kumada Cross‐Coupling of Aryl Tosylates with Alkyl Grignard Reagents

AbstractAryl tosylates are an attractive class of electrophiles for cross‐coupling reactions due to ease of synthesis, low price, and the employment of C−O electrophiles, however, the reactivity of aryl tosylates is low. Herein, we report the Ni‐catalyzed C(sp2)−C(sp3) Kumada cross‐coupling of aryl tosylates with primary and secondary alkyl Grignard reagents. The method delivers valuable alkyl arenes by cross‐coupling with challenging alkyl organometallics possessing β‐hydrogens that are prone to β‐hydride elimination and homo‐coupling. The reaction is catalyzed by an air‐ and moisture stable‐Ni(II) precatalyst. A broad range of electronically‐varied aryl tosylates, including bis‐tosylates, underwent this transformation, and many examples are suitable at mild room temperature conditions. The combination of Ar−X cross‐coupling with the facile Ar−OH activation/cross‐coupling strategy permits for orthogonal cross‐coupling with challenging alkyl organometallics. Furthermore, we demonstrate that the method operates with TON reaching 2000, which is one of the highest turnovers observed to date in Ni‐catalyzed cross‐couplings.magnified image

Regioselectivity Issues in the Addition of Grignard Reagents to Trifluoromethylated α‐Bromoenones

The regioselectivity of addition of organomagnesium reagents to trifluoromethylated α‐bromoenones is reported. Alkyl and aryl Grignard reagents undergo 1,4‐ and/or 1,2‐addition but, in contrast to non‐fluorinated α‐bromoenones, the former direction is dominant for these fluorinated analogs. The high 1,4‐regioselectivity observed in most cases reflects the influence of the trifluoromethyl group on the direction of nucleophilic attack.

The Effect of β‐Hydrogen Atoms on Iron Speciation in Cross‐Couplings with Simple Iron Salts and Alkyl Grignard Reagents

AbstractThe effects of β‐hydrogen‐containing alkyl Grignard reagents in simple ferric salt cross‐couplings have been elucidated. The reaction of FeCl3 with EtMgBr in THF leads to the formation of the cluster species [Fe8Et12]2−, a rare example of a structurally characterized metal complex with bridging ethyl ligands. Analogous reactions in the presence of NMP, a key additive for effective cross‐coupling with simple ferric salts and β‐hydrogen‐containing alkyl nucleophiles, result in the formation of [FeEt3]−. Reactivity studies demonstrate the effectiveness of [FeEt3]− in rapidly and selectively forming the cross‐coupled product upon reaction with electrophiles. The identification of iron‐ate species with EtMgBr analogous to those previously observed with MeMgBr is a critical insight, indicating that analogous iron species can be operative in catalysis for these two classes of alkyl nucleophiles.

The Effect of β-Hydrogen Atoms on Iron Speciation in Cross-Couplings with Simple Iron Salts and Alkyl Grignard Reagents.

The effects of β-hydrogen-containing alkyl Grignard reagents in simple ferric salt cross-couplings have been elucidated. The reaction of FeCl3 with EtMgBr in THF leads to the formation of the cluster species [Fe8 Et12 ]2- , a rare example of a structurally characterized metal complex with bridging ethyl ligands. Analogous reactions in the presence of NMP, a key additive for effective cross-coupling with simple ferric salts and β-hydrogen-containing alkyl nucleophiles, result in the formation of [FeEt3 ]- . Reactivity studies demonstrate the effectiveness of [FeEt3 ]- in rapidly and selectively forming the cross-coupled product upon reaction with electrophiles. The identification of iron-ate species with EtMgBr analogous to those previously observed with MeMgBr is a critical insight, indicating that analogous iron species can be operative in catalysis for these two classes of alkyl nucleophiles.

Iron-Catalyzed C(sp2)-C(sp3) Cross-Coupling of Chlorobenzenesulfonamides with Alkyl Grignard Reagents: Entry to Alkylated Aromatics.

Alkylated benzosulfonamides are compounds of high importance in organic synthesis, including the production of pharmaceuticals, agrochemicals, and plasticizers. We report the iron-catalyzed C(sp2)-C(sp3) cross-coupling of chlorobenzosulfonamides with alkyl Grignard reagents under mild and sustainable conditions. Electronically and sterically varied benzosulfonamides as well as challenging alkyl organometallics containing β-hydrogen afford alkylated benzosulfonamides in high to excellent yields. Sulfonamide represents the most reactive activating group for iron-catalyzed cross-coupling. The process affords alkylated benzenesulfonamides poised for medicinal chemistry applications and traceless reductive cleavage.

Iron-Catalyzed Cross Coupling of Aryl Chlorides with Alkyl Grignard Reagents: Synthetic Scope and FeII/FeIV Mechanism Supported by X-ray Absorption Spectroscopy and Density Functional Theory Calculations

Abstract A combination of iron(III) fluoride and 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene (SIPr) catalyzes the high-yielding cross coupling of an electron-rich aryl chloride with an alkyl Grignard reagent, which cannot be attained using other iron catalysts. A variety of alkoxy- or amino-substituted aryl chlorides can be cross-coupled with various alkyl Grignard reagents regardless of the presence or absence of β-hydrogens in the alkyl group. A radical probe experiment using 1-(but-3-enyl)-2-chlorobenzene does not afford the corresponding cyclization product, therefore excluding the intermediacy of radical species. Solution-phase X-ray absorption spectroscopy (XAS) analysis, with the help of density functional theory (DFT) calculations, indicates the formation of a high-spin (S = 2) heteroleptic difluorido organoferrate(II), [MgX][FeIIF2(SIPr)(Me/alkyl)], in the reaction mixture. DFT calculations also support a feasible reaction pathway, including the formation of a difluorido organoferrate(II) intermediate which undergoes a novel Lewis acid-assisted oxidative addition to form a neutral organoiron(IV) intermediate, which leads to an FeII/FeIV catalytic cycle, where the fluorido ligand and the magnesium ion play key roles.

Iron- or Palladium-Catalyzed Reaction Cascades Merging Cycloisomerization and Cross-Coupling Chemistry.

A conceptually novel reaction cascade is presented, which allows readily available enynes to be converted into functionalized 1,3-dienes comprising a stereodefined tetrasubstituted alkene unit; such compounds are difficult to make by conventional means. The overall transformation is thought to commence with formation of a metallacyclic intermediate that evolves via cleavage of an unstrained C-X bond in its backbone. This non-canonical cycloisomerization process is followed by a cross-coupling step, such that reductive C-C bond formation regenerates the necessary low-valent metal fragment and hence closes an intricate catalytic cycle. The cascade entails the formation of two new C-C bonds at the expense of the constitutional C-X entity of the substrate: importantly, the extruded group X must not be a heteroelement (X=O, NR), since activated β-C-C bonds can also be broken. This concern was reduced to practice in two largely complementary formats: one procedure relies on the use of alkyl-Grignard reagents in combination with catalytic amounts of Fe(acac)3, whereas the second method amalgamates cycloisomerization with Suzuki coupling by recourse to arylboronic acids and phosphine-ligated palladium catalysts.

Synthesis of Cyclopropane Fatty Acids by C(sp3)−C(sp3) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid

AbstractAn iterative Ni‐catalyzed C(sp3)−C(sp3) cross‐coupling reaction of a novel cis‐cyclopropane containing bifunctional building blocks with alkyl halides and alkyl Grignard reagents enabled the introduction of a cyclopropane ring into the desired position(s) of saturated carbon frameworks, providing a straightforward synthetic route to cyclopropane fatty acids. The present method creates a direct route for the construction of saturated carbon frameworks, and can avoid the tedious multistep operations based on unsaturated functional group manipulations that are often employed in conventional synthetic routes. This method could be applicable to the synthesis of trans‐cyclopropane fatty acids and enantioenriched cyclopropane fatty acids. Formal synthesis of α‐mycolic acid was achieved by the C(sp3)−C(sp3) cross‐coupling reaction of cyclopropane‐containing bifunctional building blocks.magnified image

Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents.

A copper-catalyzed system has been introduced for the enantioselective defluoroalkylation of linear 1-(trifluoromethyl)alkenes through C-F activation to synthesize various gem-difluoroalkenes as carbonyl mimics. For the first time, arylboronate-activated alkyl Grignard reagents were uncovered in this cross-coupling reaction. Mechanistic studies confirmed that the tetraorganoborate complexes generated in situ were the key reactive species for this transformation.

Ni-Catalyzed Dimerization and Hydroperfluoroarylation of 1,3-Dienes.

A nickel-catalyzed three-component coupling reaction between perfluoroarenes and two molecules of a 1,3-diene in the presence of an alkyl Grignard reagent, which acted as a hydride source, provided 3-perfluoroarylated-1,7-octadienes via 1,3-diene dimerization and subsequent perfluoroarylation upon C-F bond cleavage. The reaction proceeded smoothly in a regioselective manner by simply combining NiCl2 and PPh3 as a catalyst and tolerated various functional groups on the perfluoroarenes. When substituted perfluoroarenes were employed, the reaction selectively occurred at the para-position. Mechanistic studies revealed that an anionic Ni complex, generated upon the reaction of Ni(0) with two molecules of a 1,3-diene and an alkyl Grignard reagent, played an important role in the C-C bond forming step with perfluoroarenes. The C-F bond cleavage was found to be a relatively fast step in the catalytic cycle.

Cross-coupling Reaction of Alkyl Halides with Alkyl Grignard Reagents Catalyzed by Cp-Iron Complexes in the Presence of 1,3-Butadiene

Iron-catalyzed cross-coupling reaction of alkyl halides with alkyl Grignard reagents by the combined use of cyclopentadienyl ligand and 1,3-butadiene additive is described. The reaction smoothly proceeds at room temperature using unactivated alkyl bromides and fluorides via non-radical mechanism, which is in sharp contrast with hitherto known Fe-catalyzed cross-coupling reactions of alkyl halides.

The N-Methylpyrrolidone (NMP) Effect in Iron-Catalyzed Cross-Coupling with Simple Ferric Salts and MeMgBr.

The use of N-methylpyrrolidone (NMP) as a co-solvent in ferric salt catalyzed cross-coupling reactions is crucial for achieving the highly selective, preparative scale formation of cross-coupled product in reactions utilizing alkyl Grignard reagents. Despite the critical importance of NMP, the molecular level effect of NMP on in situ formed and reactive iron species that enables effective catalysis remains undefined. Herein, we report the isolation and characterization of a novel trimethyliron(II) ferrate species, [Mg(NMP)6 ][FeMe3 ]2 (1), which forms as the major iron species in situ in reactions of Fe(acac)3 and MeMgBr under catalytically relevant conditions where NMP is employed as a co-solvent. Importantly, combined GC analysis and 57 Fe Mössbauer spectroscopic studies identified 1 as a highly reactive iron species for the selective formation generating cross-coupled product. These studies demonstrate that NMP does not directly interact with iron as a ligand in catalysis but, alternatively, interacts with the magnesium cations to preferentially stabilize the formation of 1 over [Fe8 Me12 ]- cluster generation, which occurs in the absence of NMP.

The N‐Methylpyrrolidone (NMP) Effect in Iron‐Catalyzed Cross‐Coupling with Simple Ferric Salts and MeMgBr

AbstractThe use of N‐methylpyrrolidone (NMP) as a co‐solvent in ferric salt catalyzed cross‐coupling reactions is crucial for achieving the highly selective, preparative scale formation of cross‐coupled product in reactions utilizing alkyl Grignard reagents. Despite the critical importance of NMP, the molecular level effect of NMP on in situ formed and reactive iron species that enables effective catalysis remains undefined. Herein, we report the isolation and characterization of a novel trimethyliron(II) ferrate species, [Mg(NMP)6][FeMe3]2 (1), which forms as the major iron species in situ in reactions of Fe(acac)3 and MeMgBr under catalytically relevant conditions where NMP is employed as a co‐solvent. Importantly, combined GC analysis and 57Fe Mössbauer spectroscopic studies identified 1 as a highly reactive iron species for the selective formation generating cross‐coupled product. These studies demonstrate that NMP does not directly interact with iron as a ligand in catalysis but, alternatively, interacts with the magnesium cations to preferentially stabilize the formation of 1 over [Fe8Me12]− cluster generation, which occurs in the absence of NMP.

Copper- and Nickel-Catalyzed Cross-Coupling Reaction of Monofluoroalkenes with Tertiary, Secondary, and Primary Alkyl and Aryl Grignard Reagents

A highly efficient cross-coupling reaction of monofluoroalkenes with tertiary, secondary, and primary alkyl and aryl Grignard reagents in the presence of a catalytic amount of copper or nickel catalyst, respectively, has been developed. The reactions proceeded smoothly at room temperature, providing (E)-alkene isomers in moderate to high yields. Plausible mechanisms of the Ni-catalyzed coupling reaction of monofluoroalkene with Grignard reagents are suggested.