Negishi Coupling Research Articles

Warming Up to Oxazole: Noncryogenic Oxazole Metalation and Negishi Coupling Development

This report details the development of several suitable noncryogenic metalation conditions for the synthesis of oxazole zincate. Subsequent rounds of high-throughput catalyst screening ultimately led to the identification of several suitable Pd sources that can be used for the Negishi coupling of unsubstituted oxazole. The scope and generality for one of the reported conditions is also presented.

One-pot Negishi cross-coupling reaction of aryldiazonium salts via Ni catalysis induced by visible-light

Visible-light induced catalysis is of high interest for its mild and environmentally benign properties. Herein, a general Ni catalysis accelerated by visible-light was successfully developed for one-pot Negishi coupling reactions at room temperature in a short reaction time (<2 h), using diazonium salts with Ar2Zn generated in situ from Grignard reagents and ZnBr2. This protocol provides a convenient access to CC bond formation for important biaryl components. It tolerates various functional groups, and Hammett study illuminates the possiblility of Ni(III)/Ni(I) redox catalytic cycle.

A Concise Approach for the Synthesis of the ABCD Ring System of Alpkinidine

AbstractA two step synthesis of a benzo analog of alpkinidine is described via Negishi coupling followed by a base mediated annulation reaction strategy. The organozinc compound prepared from ethyl 2‐iodobenzoate was coupled with 4‐chloro‐2‐methyl‐2,3‐dihydro‐1H‐pyrrolo[3,4‐c]quinolin‐1‐one to obtain ethyl 2‐(2‐methyl‐1‐oxo‐2,3‐dihydro‐1H‐pyrrolo[3,4‐c]quinolin‐4‐yl)‐benzoate which on further treatment with a base provided ABCD ring system of alpkinidine.

In Situ Generation of Alkynylzinc and Its Subsequent Negishi Reaction in a Flow Reactor

A highly efficient and convenient Negishi cross‐coupling reaction has been developed for the synthesis of unsymmetrical alkynes and enynes in a continuous‐flow process. The reaction proceeds through an in situ generated alkynylzinc reagent by the reaction of lithium acetylide with zinc halide at room temperature followed by a cross‐coupling reaction with aryl or vinyl iodides. The notable features of this work compared to the conventional benchtop method are mild reaction conditions, good to excellent yields, broad functional‐group compatibility, short residence time (73 sec) and especially desilylation of TMS group with the residence time of only 10.5 sec.

Synthesis of an EGFR T790M Inhibitor

Key words EGFR T790M inhibitor - Buchwald–Hartwig reaction - amination - Negishi reaction

Advanced Approaches to Post-Assembly Modification of Peptides by Transition-Metal-Catalyzed Reactions

We have summarized diverse synthetic approaches for the modification of peptides by employing transition-metal-catalyzed reactions. These methods can deliver unusual peptides suitable for peptidomimetics. To this end, several popular reactions such as Diels–Alder, 1,3-dipolar cycloaddition, [2+2+2] cyclotrimerization, metathesis, Suzuki­–Miyaura cross-coupling, and Negishi coupling have been used to assemble modified peptides by post-assembly chemical modification strategies. 1 Introduction 2 Synthesis of a Cyclic α-Amino Acid Derivative via a Ring-Closing Metathesis Protocol 3 Peptide Modification Using a Ring-Closing Metathesis Strategy 4 Peptide Modification via a [2+2+2] Cyclotrimerization Reaction 5 Peptide Modification by Using [2+2+2] Cyclotrimerization and Suzuki Coupling 6 Peptide Modification via a Suzuki–Miyaura Cross-Coupling 7 Peptide Modification via Cross-Enyne Metathesis and a Diels–Alder­ Reaction as Key Steps 8 Peptide Modification via 1,3-Dipolar Cycloaddition Reactions 9 Modified Peptides via Negishi Coupling 10 A Modified Dipeptide via Ethyl Isocyanoacetate 11 Conclusions

Catalytic asymmetric synthesis of stereoisomers of 1-C-n-butyl-LABs for the SAR study of α-glucosidase inhibition

We achieved synthesis of seven stereoisomers of 1-C-n-butyl-L-iminofuranose derivatives using catalytic asymmetric alkylation and Negishi coupling as key reactions. The synthetic strategy based on these key reactions was quite useful, since both α- and β-iminofuranoses could be obtained by switching the chirality of the ligand employed for the AAA reaction. The common intermediates for α- and β-isomers were subjected to further manipulations to install a diol unit at C2 and C3 to give the desired stereoisomers of L-iminofuranose derivatives. We achieved the preparation of all stereoisomers of 1-C-n-butyl-L-iminofuranose derivatives, with the exception of β-lyxo type iminofuranose. It is noteworthy that a synthetic route for many stereoisomers of iminofuranose derivatives was developed. Unfortunately, none of the L-iminofuranoses obtained showed inhibitory activity against the α-glycosidases examined—e.g., maltase, sucrase, and isomaltase.

Bis-4-aza[6]helicene: A Bis-helicenic 2,2'-Bipyridine with Chemically Triggered Chiroptical Switching Activity.

A novel enantiopure bis-helicenic 2,2'-bipyridine system was prepared using a Negishi coupling. Thanks to the bipyridine unit, the coordination with ZnII and protonation processes were studied, revealing efficient tuning of photophysical (UV/visible and emission) and chiroptical properties (electronic circular dichroism and circularly polarized emission) of the system. The coordination/decoordination and protonation/deprotonation processes appeared reversible, thus constituting novel chiroptical switches.

Advanced Approaches to Post-Assembly Modification of Peptides by Transition-Metal-Catalyzed Reactions

We have summarized diverse synthetic approaches for the modification of peptides by employing transition-metal-catalyzed reactions. These methods can deliver unusual peptides suitable for peptidomimetics. To this end, several popular reactions such as Diels–Alder, 1,3-dipolar cycloaddition, [2+2+2] cyclotrimerization, metathesis, Suzuki­–Miyaura cross-coupling, and Negishi coupling have been used to assemble modified peptides by post-assembly chemical modification strategies.1 Introduction2 Synthesis of a Cyclic α-Amino Acid Derivative via a Ring-Closing Metathesis Protocol3 Peptide Modification Using a Ring-Closing Metathesis Strategy4 Peptide Modification via a [2+2+2] Cyclotrimerization Reaction5 Peptide Modification by Using [2+2+2] Cyclotrimerization and Suzuki Coupling6 Peptide Modification via a Suzuki–Miyaura Cross-Coupling7 Peptide Modification via Cross-Enyne Metathesis and a Diels–Alder­ Reaction as Key Steps8 Peptide Modification via 1,3-Dipolar Cycloaddition Reactions9 Modified Peptides via Negishi Coupling10 A Modified Dipeptide via Ethyl Isocyanoacetate11 Conclusions

Iron-catalyzed Alkyl–Alkyl Negishi Coupling of Organoaluminum Reagents

The first iron-catalyzed cross-coupling reaction of alkyl halides with alkylaluminum reagents (alkyl–alkyl Negishi coupling) is developed using an iron/bisphosphine catalyst system. The reaction sh...

A Broad-Spectrum Synthesis of Tetravinylethylenes.

The first general synthesis of compounds of the tetravinylethylene (TVE) family is reported. Ramirez-type dibromo-olefination of readily accessible penta-1,4-dien-3-ones generates 3,3-dibromo[3]dendralenes, which undergo twofold Negishi, Suzuki-Miyaura or Mizoroki-Heck reactions with a wide variety of olefinic coupling partners. This route delivers a broad range of unsymmetrically substituted tetravinylethylenes with up to three different alkenyl substituents attached to the central C=C bond. The extensive scope of the approach is demonstrated by the preparation of the first higher order oligo-alkenic through-conjugated/cross-conjugated hybrid compounds. An unsymmetrically substituted TVE is shown to undergo a domino electrocyclization-cycloaddition with high site-selectivity and diastereoselectivity, thereby demonstrating the substantial synthetic potential of substituted TVEs for controlled, rapid structural complexity generation.

Synthesis of C 3-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step.

We demonstrate a new synthetic strategy toward star-shaped C3-symmetric molecules containing α-amino acid (AAA) derivatives and dipeptides. In this regard, trimerization and Negishi cross-coupling reactions are used as the key steps starting from readily available 4’-iodoacetophenone and L-serine. These C3-symmetric molecules containing AAA moieties are useful to design new ligands suitable for asymmetric synthesis and peptide dendrimers.

Enantioconvergent Cross-Couplings of Alkyl Electrophiles: The Catalytic Asymmetric Synthesis of Organosilanes.

Metal-catalyzed enantioconvergent cross-coupling reactions of alkyl electrophiles are emerging as a powerful tool in asymmetric synthesis. To date, high enantioselectivity has been limited to couplings of electrophiles that bear a directing group or a proximal p/π orbital. Herein, we demonstrate for the first time that enantioconvergent cross-couplings can be achieved with electrophiles that lack such features; specifically, we establish that a chiral nickel catalyst can accomplish Negishi reactions of racemic α-halosilanes with alkylzinc reagents with good enantioselectivity under simple and mild conditions, thereby providing access to enantioenriched organosilanes, an important class of target molecules.

Enantioconvergent Cross‐Couplings of Alkyl Electrophiles: The Catalytic Asymmetric Synthesis of Organosilanes

AbstractMetal‐catalyzed enantioconvergent cross‐coupling reactions of alkyl electrophiles are emerging as a powerful tool in asymmetric synthesis. To date, high enantioselectivity has been limited to couplings of electrophiles that bear a directing group or a proximal p/π orbital. Herein, we demonstrate for the first time that enantioconvergent cross‐couplings can be achieved with electrophiles that lack such features; specifically, we establish that a chiral nickel catalyst can accomplish Negishi reactions of racemic α‐halosilanes with alkylzinc reagents with good enantioselectivity under simple and mild conditions, thereby providing access to enantioenriched organosilanes, an important class of target molecules.

Intracellular Catalysis with Selected Metal Complexes and Metallic Nanoparticles: Advances toward the Development of Catalytic Metallodrugs.

Platinum-containing drugs (e.g., cisplatin) are among the most frequently used chemotherapeutic agents. Their tremendous success has spurred research and development of other metal-based drugs, with notable achievements. Generally, the vast majority of metal-based drug candidates in clinical and developmental stages are stoichiometric agents, i.e., each metal complex reacts only once with their biological target. Additionally, many of these metal complexes are involved in side reactions, which not only reduce the effective amount of the drug but may also cause toxicity. On a separate note, transition metal complexes and nanoparticles have a well-established history of being potent catalysts for selective molecular transformations, with examples such as the Mo- and Ru-based catalysts for metathesis reactions (Nobel Prize in 2005) or palladium catalysts for C-C bond forming reactions such as Heck, Negishi, or Suzuki reactions (Nobel Prize in 2010). Also, notably, no direct biological equivalent of these transformations exists in a biological environment such as bacteria or mammalian cells. It is, therefore, only logical that recent interest has focused on developing transition-metal based catalytic systems that are capable of performing transformations inside cells, with the aim of inducing medicinally relevant cellular changes. Because unlike in stoichiometric reactions, a catalytically active compound may turn over many substrate molecules, only very small amounts of such a catalytic metallodrug are required to achieve a desired pharmacologic effect, and therefore, toxicity and side reactions are reduced. Furthermore, performing catalytic reactions in biological systems also opens the door for new methodologies to study the behavior of biomolecules in their natural state, e.g., via in situ labeling or by increasing/depleting their concentration at will. There is, of course, an art to the choice of catalysts and reactions which have to be compatible with biological conditions, namely an aqueous, oxygen-containing environment. In this review, we aim to describe new developments that bring together the far-distant worlds of transition-metal based catalysis and metal-based drugs, in what is termed "catalytic metallodrugs". Here we will focus on transformations that have been performed on small biomolecules (such as shifting equilibria like in the NAD+/NADH or GSH/GSSG couples), on non-natural molecules such as dyes for imaging purposes, or on biomacromolecules such as proteins. Neither reactions involving release (e.g., CO) or transformation of small molecules (e.g., 1O2 production), degradation of biomolecules such as proteins, RNA or DNA nor light-induced medicinal chemistry (e.g., photodynamic therapy) are covered, even if metal complexes are centrally involved in those. In each section, we describe the (inorganic) chemistry involved, as well as selected examples of biological applications in the hope that this snapshot of a new but quickly developing field will indeed inspire novel research and unprecedented interactions across disciplinary boundaries.

Selective ortho-Metalation of a Fluoroarene with Knochel–Hauser Base and Reactions with Various Electrophiles

Selective ortho-metalation of 1-bromo-2-(1,1-difluoroethyl)-4-fluorobenzene was achieved with the Knochel–Hauser base (TMPMgCl·LiCl) in position 5 of the aromatic ring. The magnesiated intermediate was reacted with a variety of electrophiles to obtain the products in good yields. The work was successfully extended to a Negishi coupling, after transmetalation with ZnCl2 and Pd-catalyzed reaction with 4-iodotoluene.

Intermetallic species in the Negishi coupling and their involvement in inhibition pathways

The formation of M–Zn-intermetallic species (M = Ni, Pd) in the course of the Negishi reaction in THF solvent and their potential impact on in situ catalyst inhibition were investigated by DFT calculations carried out at two levels of theory.

Pd-catalyzed γ-arylation of γ,δ-unsaturated O-carbamates via an unusual haptotropic rearrangement.

An unusual γ-selectivity was observed in the arylation of γ,δ-unsaturated O-carbamates involving directed lithiation, transmetallation to zinc and Negishi coupling, when a specific combination of aryl electrophile and phosphine ligand is employed. Mechanistic studies indicate that an unusual, stereospecific haptotropic rearrangement of the palladium-diene intermediate is involved.

The highly surprising behaviour of diphosphine ligands in iron-catalysed Negishi cross-coupling

Iron-catalysed cross-coupling is undergoing explosive development, but mechanistic understanding lags far behind synthetic methodology. Here, we find that the activity of iron–diphosphine pre-catalysts in the Negishi coupling of benzyl halides is strongly dependent on the diphosphine, but the ligand does not appear to be coordinated to the iron during turnover. This was determined using time-resolved in operando X-ray absorption fine structure spectroscopy employing a custom-made flow cell and confirmed by 31P NMR spectroscopy. While the diphosphine ligands tested are all able to coordinate to iron(ii), in the presence of excess zinc(ii)—as in the catalytic reaction—they coordinate predominantly to the zinc. Furthermore, combined synthetic and kinetic investigations implicate the formation of a putative mixed Fe–Zn(dpbz) species before the rate-limiting step of catalysis. These unexpected findings may not only impact the field of iron-catalysed Negishi cross-coupling, but potentially beyond to reactions catalysed by other transition metal/diphosphine complexes. Despite the many recent developments in iron-catalysed cross-couplings, the mechanistic understanding of these reactions is lacking compared to the more studied palladium and nickel variants. Here, the authors find that during iron-catalysed Negishi reactions the diphosphine ligand predominately binds to the zinc—rather than the iron—centre.

Convergent Synthesis of PI3K Inhibitor GDC-0908 Featuring Palladium-Catalyzed Direct C-H Arylation toward Dihydrobenzothienooxepines.

A practical convergent synthesis of PI3K inhibitor GDC-0908 (1) is described. The process features a dihydrobenzothienooxepine formation via palladium-catalyzed intramolecular direct C-H arylation and a Negishi coupling to construct the key C-C bonds. We further developed a general synthesis of dihydrobenzothienooxepines in good to excellent yields via palladium-catalyzed intramolecular direct C-H arylation, which tolerates both electronically and sterically diverse substituents on the phenyl ring.