Negishi Cross-coupling Research Articles

C1 Functionalization of β-Carboline via Knochel-Hauser Base-Directed Metalation and Negishi Coupling.

The synthesis of C1-functionalized β-carbolines from N-Boc norharman is described. Substitution is realized by employing the Knochel-Hauser base (TMPMgCl·LiCl) followed by transmetalation with ZnCl2 and subsequent Negishi cross-coupling of the resulting organozinc species. A variety of aryl or heteroaryl bromides participated in this one-pot reaction sequence, allowing for rapid diversification of the β-carboline scaffold in moderate to excellent yields. The reaction protocol has been applied to the synthesis of natural alkaloids nitramarine, nitraridine, eudistomin U, and perlolyrine.

Enantioconvergent Negishi Cross-Couplings of Racemic Secondary Organozinc Reagents to Access Privileged Scaffolds: A Combined Experimental and Theoretical Study.

An enantioconvergent palladium-catalyzed Negishi cross-coupling with racemic secondary organozinc reagents has been developed, enabling access to enantioenriched 1,1-diarylalkane motifs in high yields and enantioselectivities. Computational data indicates that the racemization of organozinc compounds most likely occurs through a bridged bimolecular mechanism.

Synthesis and Biological Profiling of Quinolino-Fused 7-Deazapurine Nucleosides.

A series of quinolino-fused 7-deazapurine (pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline) ribonucleosides were designed and synthesized. The synthesis of the key 11-chloro-pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline was based on the Negishi cross-coupling of iodoquinoline with zincated 4,6-dichloropyrimidine followed by azidation and thermal or photochemical cyclization. Vorbrüggen glycosylation of the tetracyclic heterocycle followed by cross-coupling or substitution reactions at position 11 gave the desired set of final nucleosides that showed moderate to weak cytostatic activity and fluorescent properties. The corresponding fused adenosine derivative was converted to the triphosphate and successfully incorporated to RNA using in vitro transcription with T7 RNA polymerase.

Nickel-Catalyzed Carbonylative Negishi Cross-Coupling of Unactivated Secondary Alkyl Electrophiles with 1 atm CO Gas.

We describe a nickel-catalyzed carbonylative cross-coupling of unactivated secondary alkyl electrophiles with the organozinc reagent at atmospheric CO gas, thus allowing the expedient construction of unsymmetric dialkyl ketones with broad functional group tolerance. The leverage of a newly developed NN2-pincer type ligand enables the chemoselective three-component carbonylation by overcoming the competing Negishi coupling, the undesired β-hydride elimination, and dehalogenation of alkyl iodides side pathways. Both alkyl iodides and alkyl tosylates are compatible in the single electron transfer involved mechanism.

Atroposelective NiII -Catalyzed Cross-Coupling Reactions Enable a Deeper Understanding of Negishi Couplings: Isolation and Application of Solid Aryl Higher-Order Zincates.

The Negishi cross-coupling reactions involves the application of organozinc reagents and is a highly versatile reaction in synthetic organic chemistry. The transmetallation step plays a pivotal role in the mechanism of these types of cross-coupling reactions. In this study, mechanistic investigations are presented indicating that higher-order zincates are the transmetallating active species in Pd- and Ni-catalyzed Negishi cross-coupling reactions. These findings are supported by halide salt addition experiments and by obtaining a single X-ray crystal structure of the solid monoaryl higher-order zincate [1-NaphthylZnX3 ]2- Mg(THF)2 2+ . The procedure developed in this work was further applied to the synthesis of various monoaryl higher-order zincates, after which their synthetic usefulness in terms of high reactivity towards transmetallation in Negishi cross-couplings, as well as stability, was exemplified in several reactions.

Nickel-Catalyzed Negishi Cross-Coupling of Alkyl Halides, Including Unactivated Tertiary Halides, with a Boron-Stabilized Organozinc Reagent.

Nickel-catalyzed cross-coupling of unactivated tertiary alkyl electrophiles with alkylmetal reagents is still a challenge. We report herein a nickel-catalyzed Negishi cross-coupling of alkyl halides, including unactivated tertiary halides, with boron-stabilized organozinc reagent BpinCH2ZnI, yielding versatile organoboron products with high functional-group tolerance. Importantly, the Bpin group was found to be indispensable for accessing the quaternary carbon center. The synthetic practicability of the prepared quaternary organoboronates was demonstrated by their conversion to other useful compounds.

RGD Peptidomimetic MMAE-Conjugate Addressing Integrin αVβ3-Expressing Cells with High Targeting Index.

Small molecule-drug conjugates (SMDCs) mimicking the RGD sequence (-Arg-Gly-Asp-) with a non-peptide moiety require a pharmacophore-independent attachment site. A library of 36 sulfonamide-modified RGD mimetics with nM to pM affinity for integrin αV β3 was synthesized and analysed via DAD mapping. The best structure of the conjugable RGD mimetic was used and a linker was attached to an aromatic ring by Negishi cross-coupling. The product retained high affinity and selectivity for integrin αV β3 . The conjugable RGD mimetic was then attached to an enzymatically cleavable GKGEVA linker equipped with a self-immolative PABC and the antimitotic drug monomethyl auristatin E (MMAE). The resulting SMDC preferred binding to integrin αV β3 over α5 β1 in a ratio of 1 : 4519 (ELISA) and showed selectivity for αV β3 -positive WM115 cells over αV β3 -negative M21-L cells in the in vitro cell adhesion assay as well as in cell viability assays with a targeting index of 134 (M21-L/WM115).

Synthesis and vectorial functionalisation of pyrazolo[3,4-c]pyridines.

Heterocycles are a cornerstone of fragment-based drug discovery (FBDD) due to their prevalence in biologically active compounds. However, novel heterocyclic fragments are only valuable if they can be suitably elaborated to compliment a chosen target protein. Here we describe the synthesis of 5-halo-1H-pyrazolo[3,4-c]pyridine scaffolds and demonstrate how these compounds can be selectively elaborated along multiple growth-vectors. Specifically, N-1 and N-2 are accessed through protection-group and N-alkylation reactions; C-3 through tandem borylation and Suzuki-Miyaura cross-coupling reactions; C-5 through Pd-catalysed Buchwald-Hartwig amination; and C-7 through selective metalation with TMPMgCl.LiCl followed by reaction with electrophiles or transmetalation to ZnCl2 and Negishi cross-coupling. Linking multiple functionalisation strategies emulates a hit-to-lead pathway and demonstrates the utility of pyrazolo[3,4-c]pyridines to FBDD.

Calculation-assisted regioselective functionalization of the imidazo[1,2-a]pyrazine scaffold via zinc and magnesium organometallic intermediates.

Straightforward calculations such as determinations of pKa values and N-basicities have allowed the development of a set of organometallic reactions for the regioselective functionalization of the underexplored fused N-heterocycle imidazo[1,2-a]pyrazine. Thus, regioselective metalations of 6-chloroimidazo[1,2-a]pyrazine using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) such as TMPMgCl·LiCl and TMP2Zn·2MgCl2·2LiCl provided Zn- and Mg-intermediates, that after quenching with various electrophiles gave access to polyfunctionalized imidazopyrazine heterocycles. Additionally, the use of TMP2Zn·2MgCl2·2LiCl as base for the first metalation allowed an alternative regioselective metalation. Nucleophilic additions at position 8 as well as selective Negishi cross-couplings complete the set of methods for selectively decorating this heterocycle of the future.

Stereo- and Regioselective Synthesis of (E,E)-Dienes: Evolution from the Transition-Metal-Catalyzed Cross-Coupling to Titanium Alkoxide-Based Alkyne–Alkyne Reductive Coupling

AbstractThe pursuit of step- and atom-economy in natural product and complex molecule syntheses continuously inspires the development of synthetic methodologies. In this context, to enable efficient synthesis of (E,E)-dienes as common structural subunits in natural products, our lab has established robust protocols based on modified Negishi cross-couplings and evolved them to more concise titanium-mediated alkyne–alkyne reductive coupling. In this review, we summarize the natural product synthesis driven methodology development and their applications in the total synthesis of complex molecules, focusing on the studies from our laboratory.1 Introduction2 Transition-Metal-Catalyzed Cross-Coupling in Natural Product Synthesis2.1 Synthesis of Branched Trisubstituted Conjugated Dienes by Negishi Coupling2.2 Stereo- and Regiocontrolled Synthesis of Branched Trisubstituted Conjugated Dienes by Modified Negishi Coupling2.3 Enantioselective Total Synthesis of Reveromycin B by Drouet & Theodorakis2.4 Enantioselective Synthesis of the Protein Phosphatase Inhibitor (–)-Motuporin by Hu & Panek2.5 Total Synthesis of (–)-Callystatin A by Langille & Panek2.6 Total Synthesis of Brevisamide by Lee & Panek3 Titanium Alkoxide-Mediated Reductive Coupling in Natural Product Synthesis3.1 Titanium Alkoxide-Mediated Alkyne–Alkyne Reductive Coupling3.2 Total Synthesis of Callystatin A by Reichard & Micalizio3.3 Total Synthesis of (–)-Virginiamycin M2 by Wu & Panek3.4 Total Synthesis of Nuclear Factor of Activated T-Cells-68 (NFAT-68) by Cai & Panek3.5 Titanium Alkoxide-Based Regioselective Alkyne–Alkyne Reductive Coupling Mediated by in situ Generated Arylamidate4 Summary

2022’s synthesis showstoppers

Evolved enzymes built biaryl bonds Chemists use biaryl molecules, which feature aryl groups tethered to one another by a single bond, as chiral ligands, materials building blocks, and pharmaceuticals. But making the biaryl motif with metal-catalyzed reactions, such as Suzuki and Negishi cross-couplings, typically requires several synthetic steps to make the coupling partners. What’s more, these metal-catalyzed reactions falter when making bulky biaryls. Inspired by enzymes’ ability to catalyze reactions, a team led by the University of Michigan’s Alison R. H. Narayan used directed evolution to create a cytochrome P450 enzyme that builds a biaryl molecule via oxidative coupling of aromatic carbon-hydrogen bonds. The enzyme weds aromatic molecules to create one stereoisomer around a bond with hindered rotation (shown). The researchers think this biocatalytic approach could become a bread-and-butter transformation for making biaryl bonds ( Nature 2022, DOI: 10.1038/s41586-021-04365-7 ). Recipe for tertiary amines relied on a little salt Mixing

Synthesis of Benzofuropyridines and Dibenzofurans by a Metalation/Negishi Cross-Coupling/SNAr Reaction Sequence.

An efficient methodology for the synthesis of benzofuropyridines and dibenzofurans from fluoropyridines or fluoroarenes and 2-bromophenyl acetates is reported. This streamlined one-pot procedure consists of a four-step directed ortho-lithiation, zincation, Negishi cross-coupling, and intramolecular nucleophilic aromatic substitution, allowing for the facile assembly of a diverse set of fused benzofuro heterocycles.

Molecular Tuning in Diaryl-Capped Pyrrolo[2,3-d:5,4-d']bisthiazoles: Effects of Terminal Aryl Unit and Comparison to Dithieno[3,2-b:2',3'-d]pyrrole Analogues.

A series of six conjugated oligomers consisting of a central pyrrolo[2,3-d:5,4-d′]bisthiazole (PBTz) end-capped with either thienyl, furyl, or phenyl groups have been prepared from N-alkyl-and N-aryl-pyrrolo[2,3-d:5,4-d′]bisthiazoles via Stille and Negishi cross-coupling. The full oligomeric series was thoroughly investigated via photophysical and electrochemical studies, in parallel with density functional theory (DFT) calculations, in order to correlate the cumulative effects of both aryl end-groups and N-functionalization on the resulting optical and electronic properties. Through comparison with the analogous dithieno[3,2-b:2′,3′-d]pyrrole (DTP) materials, the effect of replacing DTP with PBTz on the material HOMO energy and visible light absorption is quantified.

Zincation of Styrylsulfonium Salts.

We report the formation of zinc reagents by the reaction of styrylsulfonium salts with zinc powder. Transition metals and other additives are not required for promoting zincation. Zincation tolerates a variety of sensitive functional groups, including esters, bromides, and boronic esters, and proceeds with complete retention of stereochemistry. This method presents a practical approach to the formation of zinc reagents that can be used in a variety of functionalizations, such as halogenation, carboxylation, and Negishi cross-couplings.

Well-Defined Ni(0) and Ni(II) Complexes of Bicyclic (Alkyl)(Amino)Carbene (Me BICAAC): Catalytic Activity and Mechanistic Insights in Negishi Cross-Coupling Reaction.

Negishi cross-coupling reaction of organozinc compounds as nucleophiles with aryl halides has drawn immense focus for C-C bond formation reactions. In comparison to the well-established library of Pd complexes, the C-C cross-coupling of this particular approach is largely primitive with nickel-complexes. Herein, we describe the syntheses of Ni(II) complexes, [(Me BICAAC)2 NiX2 ] (X=Cl (1), Br (2), and I (3)) by employing the bicyclic (alkyl)(amino)carbene (Me BICAAC) ligand. The reduction of complexes 1-3 using KC8 afforded the two coordinate low valent, Ni(0) complex, [(Me BICAAC)2 Ni(0)] (4). Complexes 1-4 have been characterized by spectroscopic techniques and their solid-state structures were also confirmed by X-ray crystallography. Furthermore, complexes 1-4 have been applied in a direct and convenient method to catalyze the Negishi cross-coupling reaction of various aryl halides with 2,6-difluorophenylzinc bromide or phenylzinc bromide as the coupling partner in the presence of 3 mol % catalyst. Comparatively, among all-pristine complexes, 1 exhibit high catalytic potential to afford value-added C-C coupled products without the use of any additive. The UV-vis studies and HRMS measurements of controlled stochiometric reactions vindicate the involvement of Ni(I)-NI(III) cycle featured with a penta-coordinated Ni(III)-aryl species as the key intermediate for 1 whereas Ni(0)/Ni(II) species are potentially involved in the catalytic cycle of 4.

Mechanochemical Pd-Catalyzed Cross-Coupling of Arylhalides and Organozinc Pivalates.

Cross-coupling reactions are essential tools in target molecule synthesis. However, the use of highly reactive organometallic reagents limits their applicability. Here, we present a mechanochemical Pd-catalyzed cross-coupling reaction between aryl halides and organozinc pivalates that can be carried out under ambient temperature and atmosphere. This operationally simple procedure affords a wide range of biaryl and aryl-heteroaryl derivatives in high yields and short times. The reaction tolerates various functional groups and can be realized on a synthetically useful scale. Its practical value was demonstrated in the short synthesis of the pharmaceutical diflunisal.

Versatile OPiv-Supported Organozinc Reagents for Transition-Metal-Catalyzed Cross-Couplings

AbstractAs one of the most important indispensable tools, organozinc-reagents-based Negishi cross-couplings have been extensively utilized for the synthesis of biologically active molecules and feedstock commodity chemicals. However, the use of air- and moisture-sensitive organozinc halides and expensive palladium catalysis still remain drawbacks. Recently, user-friendly solid OPiv-supported C–Zn, Si–Zn reagents with enhanced air and moisture stability have been prepared, which displayed superior reactivity in various transition-metal-catalyzed cross-couplings, especially in the earth-abundance cobalt and nickel catalysis. Herein, we summarized the recent advances and our research work in the field of the preparation and application of solid organozinc pivalates in the present short review.1 Introduction2 Development of Organozinc Pivalates in Two-Component Cross-Couplings3 Development of Organozinc Pivalates in Three-Component Cross-Couplings4 Conclusion and Outlook

Synthesis and crystal structures of unsymmetrical wave-shaped heptathienoacenes.

Three unsymmetrical wave-shaped heptathienoacenes (UHT-1, UHT-2 and UHT-3) with sulfur atoms at different isomeric locations in the two terminal thiophene rings were designed and synthesized. The synthetic strategy contains two crucial steps, including the cross-coupling of two different dithienothiophene isomers (DTT) from dithieno[2,3-b:3',2'-d]thiophene (bb-DTT), dithieno[2,3-b:2',3'-d]thiophene (bt-DTT) and dithieno[2,3-b:3',4'-d]thiophene (bs-DTT) as building blocks through the Negishi coupling and intramolecular cyclization reactions with (SnBu3)2S. X-ray crystal structures of UHT-1, UHT-2 and UHT-3 show that the molecules adopt a wave-shaped geometry with multiple intermolecular interactions, such as S-S, S-C and S-H, which result in different crystal packing patterns. The isomeric location of the sulfur atoms of the two terminal thiophene rings of UHT-1, UHT-2 and UHT-3 plays an important role in tuning π-electronic conjugation and spectroscopic behaviors.

Ni-Catalyzed C(sp3)-O Arylation of α-Hydroxy Esters.

A Negishi cross-coupling of α-hydroxy ester derivatives and arylzinc reagents has been developed. This reaction tolerates both primary and secondary C(sp3)-O alcohol precursors and achieves efficient cross-coupling under Ni catalysis without the need for added external metal reductant, photocatalyst, or additives. The arylation of readily accessible C(sp3)-O electrophiles in this operationally simple, rapid, and mild reaction provides a complementary way of accessing desirable α-aryl ester products.

Negishi Cross-Coupling Provides Alkylated Tryptophans and Tryptophan Regioisomers.

Mild transition‐metal catalysed cross‐couplings enable direct functionalisation of biocatalytically halogenated tryptophans with alkyl iodides, representing a new alternative for late‐stage derivatisations of halogenated aromatic amino acids. Moreover, this strategy enables preparation of (homo)tryptophan regioisomers in a simple two‐step synthesis using a Pd‐catalysed Negishi cross coupling. This method provides access to non‐canonical constitutional surrogates of tryptophan, ready for use in peptide synthesis.