Functionalized Grignard Reagents Research Articles

Synthesis of biaryl ketones by arylation of Weinreb amides with functionalized Grignard reagents under thermodynamic control vs. kinetic control of N,N-Boc2-amides.

A highly efficient method for chemoselective synthesis of biaryl ketones by arylation of Weinreb amides (N-methoxy-N-methylamides) with functionalized Grignard reagents is reported. This protocol offers rapid entry to functionalized biaryl ketones after Mg/halide exchange with i-PrMgCl·LiCl under operationally-simple and practical reaction conditions. The scope of the method is highlighted in >40 examples, including bioactive compounds and pharmaceutical derivatives. Collectively, this transition-metal-free approach offers a major advantage over the recently established cross-coupling of amides by oxidative addition of N-C(O) bonds. Considering the utility of amide acylation reactions in modern synthesis, we expect that this method will be of broad interest.

Kinetically Controlled, Highly Chemoselective Acylation of Functionalized Grignard Reagents with Amides by N-C Cleavage.

The direct transition-metal-free acylation of amides with functionalized Grignard reagents by highly chemoselective N-C cleavage under kinetic control has been accomplished. The method offers rapid and convergent access to functionalized biaryl ketones through transient tetrahedral intermediates. The direct access to functionalized Grignard reagents by in situ halogen-magnesium exchange promoted by the versatile turbo-Grignard reagent (iPrMgCl⋅LiCl) permits excellent substrate scope with respect to both the amide and Grignard coupling partners. These reactions enable facile, operationally simple and chemoselective access to tetrahedral intermediates from amides under significantly milder conditions than chelation-controlled intermediates. This novel direct two-component coupling sets the stage for using amides as acylating reagents in an alternative paradigm to the metal-chelated approach, acyl metals and Weinreb amides.

LiCl-Accelerated Nickel Catalyzed Cross-Coupling of Aryl Tosylates with the Aryl Grignard Reagents

A mild coupling reaction catalyzed by Ni(acac)2-L4 has been studied. The catalyst acts efficiently in the reaction of biaryl coupling between various electrophiles and common or functionalized aryl Grignard reagents with high functional group tolerance. The study demonstrates that LiCl acts as an essential component in efficient cross-coupling by accelerating reduction of Ni(II) to Ni(0). The new catalytic system for selective couplings of aryl tosylates with aryl chlorides has been developed.

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-IPentCl (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.

ChemInform Abstract: Convenient Access to Di‐ and Trifluoroethylamines for Lead Structure Research.

AbstractThe title compounds are obtained by addition of functionalized Grignard reagents to di‐ and trifluoromethylated N‐aryl‐substituted N,O‐acetals.

ChemInform Abstract: Progress and Developments in the Turbo Grignard Reagent i‐PrMgCl·LiCl: A Ten‐Year Journey

AbstractReview: [57 refs.

A versatile two-step method for the reductive alkylation and formal [4 + 2] annulation of secondary lactams: step economical syntheses of the ant venom alkaloids (2R,5S)-2-butyl-5-propylpyrrolidine and (+)-monomorine I

The reductive alkylation of secondary lactams is an important transformation in the total synthesis of alkaloids and pharmaceuticals. Methods for this transformation are scarce. We report in this paper a versatile two-step approach consisting of N-benzylation and one-pot reductive alkylation–debenzylation. With suitably functionalized Grignard reagents, a formal [4 + 2] annulation reaction has been achieved. Using this method, we have successfully synthesized several N-α-alkyl and N-α,α′-dialkyl heterocycles, including (±)-coniine (7) and the ant venom alkaloids (2R,5S)-cis-2-butyl-5-propylpyrrolidine (8) and (+)-monomorine I (10) each in two steps starting from readily available secondary lactams.

Synthesis and applications of 1-iodo-4-MgCl-1,3-dienes and 1-iodovinyl phenylmagnesium chlorides

This work reports on selective generation and synthetic applications of functionalized Grignard reagents (1-iodo-4-MgCl-1,3-dienes and 1-iodovinyl phenylmagnesium chlorides).

ChemInform Abstract: Diversity‐Oriented Enantioselective Synthesis of Highly Functionalized Cyclic and Bicyclic Alcohols.

AbstractA highly regio‐ and enantioselective Cu‐catalyzed hetero‐allylic asymmetric alkylation with functionalized Grignard reagents is developed.

Dilithium Tetrachlorocuprate(II) Catalyzed Oxidative Homocoupling of Functionalized Grignard Reagents

An efficient procedure is described for the oxidative homocoupling of functionalized Grignard reagents using a catalytic amount of dilithium tetrachlorocuprate(II) (CuLi₂Cl₄) in the presence of pure oxygen gas. This method is applied successfully to a variety of aryl, heteroaryl, alkyl, alkenyl and alkynyl halides, which are converted into the corresponding homocoupled products in good to excellent yields.

Diversity‐Oriented Enantioselective Synthesis of Highly Functionalized Cyclic and Bicyclic Alcohols

The copper-catalyzed hetero-allylic asymmetric alkylation (h-AAA) of functionalized Grignard reagents that contain alkene or alkyne moieties has been achieved with excellent regio- and enantioselectivity. The corresponding alkylation products were further transformed into a variety of highly functionalized cyclic and bicyclic alcohols with excellent control over the chemo-, regio-, and stereoselectivity.

1,4-Addition of an aryllithium reagent to diethyl ketomalonate. Scalable synthesis of ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate

While optimizing the synthesis of pharmaceutical building block 3 [ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate], we encountered an unusual addition of an aryllithium reagent to the ketone oxygen atom of diethyl ketomalonate. Compound 3 was ultimately prepared on a large scale by a two-step sequence involving (1) annulation of a functionalized Grignard reagent with diethyl ketomalonate and (2) selective mono-reduction of a geminal diester using lithium tri-tert-butoxyaluminum hydride.

ChemInform Abstract: Catalytic Enantioselective Arylation of Aldehydes by Using Functionalized Grignard Reagents Generated from Aryl Bromides.

AbstractAn efficient protocol is developed for the enantioselective synthesis of diarylmethanols.

ChemInform Abstract: 35 Years of Palladium‐Catalyzed Cross‐Coupling with Grignard Reagents: How Far Have we Come?

AbstractReview: ca. 80 refs.

Catalytic Enantioselective Arylation of Aldehydes by Using Functionalized Grignard Reagents Generated from Aryl Bromides

Catalytic Enantioselective Arylation of Aldehydes by Using Functionalized Grignard Reagents Generated from Aryl Bromides

Surface-Confined Nickel Mediated Cross-Coupling Reactions: Characterization of Initiator Environment in Kumada Catalyst-Transfer Polycondensation

Kumada catalyst-transfer polycondensation (KCTP) has proven to be an excellent strategy toward the synthesis of well-defined conjugated polymers. In this report, Ni(0) species are reacted with surface-bound aryl bromides to yield KCTP initiators of structure (aryl)Ni(II)-Br. Surface-confined Kumada reactions are carried out with a ferrocene functionalized Grignard reagent to quantify initiator coverage, ligand exchange, and Kumada reaction kinetics. In addition, surface-initiated Kumada catalyst-transfer polycondensation (SI-KCTP) is carried out from the fabricated initiators to modify SiO(2) and ITO surfaces. Uniform poly(3-methylthiophene) films with thicknesses between 40 and 65 nm were characterized using a variety of spectroscopic and electrochemical techniques.

35 years of palladium-catalyzed cross-coupling with Grignard reagents: how far have we come?

This tutorial review is intended to provide the reader with a timely review of major developments and the current state-of-the-art of palladium-catalyzed cross-coupling reactions with Grignard reagents. Organomagnesium reagents, the most reactive and most easily accessible nucleophiles for carbon-carbon bond forming cross-coupling reactions, were the first nucleophiles ever employed in cross-coupling reactions, but have only recently been re-discovered for highly efficient and (stereo)selective coupling reactions. This is mostly a consequence of improved catalyst systems with bulky phosphine, phosphonate or carbene ligands and new metal-halogen exchange procedures for the generation of functionalized Grignard reagents.

Functionalized Grignard Reagents in Kumada Cross‐Coupling Reactions

Hakuna Kumada: Several efficient Kumada cross-coupling protocols of functionalized arylmagnesium halides and functionalized aryl and alkyl halides have been recently reported, including the first examples of the catalytic asymmetric Kumada coupling of racemic secondary alkyl halides. These procedures dramatically improve the synthetic potential of the Kumada cross-coupling reaction.

Asymmetric Kumada Couplings of α-Bromo Ketones

Kumada reactions (metal-catalyzed couplings of organic electrophiles with Grignard reagents) were among the first studied cross-­coupling reactions. Despite the early success of Kumada reactions with alkyl electrophiles, no examples of the enantioselective version have been reported. The authors described a novel asymmetric Kumada coupling of racemic α-bromo ­ketones with aryl Grignard reagents. The scope of the reaction is quite broad, exploiting Knochel’s methods for synthesizing functionalized Grignard reagents. High yields and ee values can be obtained, even with dialkyl ketones using modified bis(oxazoline) ligand 2. Furthermore, the cross-coupling products can be derivatized with good diastereoselectivity without racemization.

Functional Group Tolerant Kumada−Corriu−Tamao Coupling of Nonactivated Alkyl Halides with Aryl and Heteroaryl Nucleophiles: Catalysis by a Nickel Pincer Complex Permits the Coupling of Functionalized Grignard Reagents

A nickel(II) pincer complex [((Me)NN(2))NiCl] (1) catalyzes Kumada-Corriu-Tamao cross coupling of nonactivated alkyl halides with aryl and heteroaryl Grignard reagents. The coupling of octyl bromide with phenylmagnesium chloride was used as a test reaction. Using 3 mol % of 1 as the precatalyst and THF as the solvent, and in the presence of a catalytic amount of TMEDA, the coupling product was obtained in a high yield. The reaction conditions could be applied to cross coupling of other primary and secondary alkyl bromides and iodides. The coupling is tolerant to a wide range of functional groups. Therefore, alkyl halides containing ester, amide, ether, thioether, alcohol, pyrrole, indole, furan, nitrile, conjugated enone, and aryl halide moieties were coupled to give high isolated yields of products in which these units stay intact. For the coupling of ester-containing substrates, O-TMEDA is a better additive than TMEDA. The reaction protocol proves to be efficient for the coupling of Knochel-type functionalized Grignard reagents. Thus aryl Grignard reagents containing electron-deficient and/or sensitive ester, nitrile, amide, and CF(3) substituents could be successfully coupled to nonactivated and functionalized alkyl iodides. The catalysis is also efficient for the coupling of alkyl iodides with functionalized heteroaryl Grignard reagents, giving rise to pyridine-, thiophene-, pyrazole-, furan-containing molecules with additional functionalities. Concerning the mechanism of the catalysis, [((Me)NN(2))Ni-(hetero)Ar] was identified as an intermediate, and the activation of alkyl halides was found to take place through a radical-rebound process.