Subsequent Cross-coupling Research Articles

Synthesis of core-functionalised naphthalene diimides from naphthalenetetracarboxylic dianhydride using a vibratory ball mill: bromination, imidization and Heck-type reactions.

The synthesis of 9 core-functionalised naphthalene diimide (c-NDI) residues is reported via a 3-step solvent free synthesis from naphthalenetetracarboxylic dianhydride using only mechanochemical activation. Selective dibromination and subsequent dimidiation were achieved for the first time in a vibratory ball mill, resulting in the key structural intermediate, 2,6-dibromonaphthalenediimide (DBND), which is the basis for elaboration into a multitude of organic electronic materials. Our new synthesis of DBND is achieved in just 5 hours' reaction time over two steps compared to typical solution state times of 24 hours. Subsequent Heck-type cross coupling reactions, with a range of styrene residues, produced a series of c-NDIs in good yields. The Heck-type reactions are rapid (1.5 hours), require no additional heating or solvent and are tolerant of atmospheric moisture and air.

Aerobic Copper-Catalyzed Oxysulfonylation of Vinylarenes with Sodium Sulfinates under Mild Conditions: A Modular Synthesis of β-Ketosulfones.

An aerobic copper-catalyzed oxysulfonylation of vinylarenes with sodium sulfinates is described. This protocol features mild reaction conditions, convenient operation, and broad substrate scope with respect to vinylarenes and sodium sulfinates. Notably, the protocol demonstrates excellent tolerance of functional groups such as chloro, bromo, ester, cyano, and nitro groups. Mechanistic investigations indicated that the reaction should undergo radical cascades involving a sulfonyl radical generated from sodium sulfinate with air as the terminal oxidant, addition across alkene to deliver a benzylic radical, and subsequent cross-coupling with air.

In situ copper photocatalysts triggering halide atom transfer of unactivated alkyl halides for general C(sp3)-N couplings

Direct reduction of unactivated alkyl halides for C(sp3)-N couplings under mild conditions presents a significant challenge in organic synthesis due to their low reduction potential. Herein, we introduce an in situ formed pyridyl-carbene-ligated copper (I) catalyst that is capable of abstracting halide atom and generating alkyl radicals for general C(sp3)-N couplings under visible light. Control experiments confirmed that the mono-pyridyl-carbene-ligated copper complex is the active species responsible for catalysis. Mechanistic investigations using transient absorption spectroscopy across multiple decades of timescales revealed ultrafast intersystem crossing (260 ps) of the photoexcited copper (I) complexes into their long-lived triplet excited states (>2 μs). The non-Stern-Volmer quenching dynamics of the triplets by unactivated alkyl halides suggests an association between copper (I) complexes and alkyl halides, thereby facilitating the abstraction of halide atoms via inner-sphere single electron transfer (SET), rather than outer-sphere SET, for the formation of alkyl radicals for subsequent cross couplings.

Photocatalytic Synthesis of β-Keto Primary Chlorides by Selective Chlorocarbonylation of Olefins.

Functionalized primary alkyl chlorides are precursors to a plethora of scaffolds but their access from chemical feedstocks remains challenging. Herein, we report a concise dual Ni/photoredox catalytic protocol for regioselective chlorocarbonylation of unactivated alkenes that enables rapid access to β-keto primary chlorides. The catalytic process features an extensive substrate scope, scalability and functional group tolerance. The Ni/photocatalytic Cl⋅ generation and subsequent cross-coupling is implicated for the process based on the control experiments and DFT study. The synthetic utility of the protocol has been further corroborated through functionalization of complex substrates and modifications of the product.

Photoredox-Catalyzed 1,4-Peroxidation-Sulfonylation of Enynones: A Three-Component Radical Coupling Approach for the Synthesis of Highly Functionalized Allenes.

An Eosin Y-catalyzed visible light-promoted 1,4-peroxidation-sulfonylation of enynones was achieved to give tetrasubstituted allenes. The photoredox catalysis of Eosin Y allowed the concomitant formation of peroxy and sulfonyl radicals, where the preferential peroxy radical addition to the alkene moiety of enynones resulted in the subsequent α-keto radical-sulfonyl radical cross couplings. The developed photoredox catalysis of Eosin Y demonstrates a regioselective 1,4-diradical addition strategy, opening up a new possibility of diradical functionalization of conjugate systems.

Total Synthesis of Syringin and Its Natural Analogues via C—C Bond Activation of Aryl Ketones†

Comprehensive SummarySyringin is found in the root of Acanthopanax senticosus (Rupr. Maxim.) Harms and belongs to the lignin chemical compound with many biological activities. In this study, we employed commercially available starting materials and accomplished the total synthesis of syringin in 5 steps with an overall yield of 58%. Palladium‐catalyzed C(O)–C bond activation and subsequent cross coupling reaction is the key to construct syringin and its natural analogues.

Metal-Free Allylic C-H Amination of Vinylsilanes and Vinylboronates using Silicon or Boron as a Regioselectivity Switch.

Vinylsilanes and vinylboronates are common building blocks for organic synthesis, but direct functionalization of these species without the participation of either the C=C or C-Si/B bonds is rare. Herein, we report a metal-free allylic C-H amination reaction of these vinylmetalloid species that installs a new C-N bond without competing transmetallation or alkene addition. In this transformation, the silicon or boron substituent inverts the usual regioselectivity, directing amination to the site distal to that group. Subsequent cross-coupling or demetallation allows access to complementary regioisomeric products. Density Functional Theory computations revealed that the observed regioselectivity is due to a subtle combination of electronic and counterintuitive steric factors that favor initial attack of selenium at the silicon-bearing carbon atom.

Cooperative NHC/Photoredox Catalysis: Three Component Radical Coupling of Aroyl Fluorides, Styrenes and Alcohols

AbstractCooperative NHC/photoredox catalysis has emerged as an important research field in recent years. Herein, the use of tertiary alcohols as alkyl radical precursors to perform three component radical coupling with styrenes and aroyl fluorides for the preparation of α‐arylated alkyl aryl ketones is described. Reaction of an aroyl fluoride with the NHC catalyst provides an acyl azolium ion that can be reduced by the photoredox catalyst to the corresponding ketyl radical anion. Oxidatively generated C‐radicals derived from the alcohol add to the styrene derivative and subsequent cross coupling of the adduct radical with the ketyl radical delivers after NHC fragmentation the targeted ketone.magnified image

Homologation of aryl ketones to long-chain ketones and aldehydes via C–C bond cleavage

SummaryTransition metal-catalyzed C–C bond cleavage is a powerful tool for the reconstruction of a molecular skeleton. We report herein the multi-carbon homologation of aryl ketones to long-chain ketones and aldehydes via ligand-promoted Ar−C(O) bond cleavage and subsequent cross coupling with alkenols. Various (hetero)aryl ketones are compatible in the reaction, affording the corresponding products wtih good to excellent yields with high regioselectivity. Further applications in the late-stage diversification of biologically important molecules demonstrate the synthetic utility of this protocol. Mechanistic studies indicate that the ligand plays an important role in both C–C bond cleavage and the asymmetric migration-insertion process.

Palladium-Catalyzed One-Step Synthesis of Stereodefined Difunctionalized Glycals

Palladium-Catalyzed One-Step Synthesis of Stereodefined Difunctionalized Glycals

Stereodefined alkenes with a fluoro-chloro terminus as a uniquely enabling compound class.

Trisubstituted alkenyl fluorides are important compounds for drug discovery, agrochemical development and materials science. Despite notable progress, however, many stereochemically defined trisubstituted fluoroalkenes either cannot be prepared efficiently or can only be accessed in one isomeric form. Here we outline a general solution to this problem by first unveiling a practical, widely applicable and catalytic strategy for stereodivergent synthesis of olefins bearing a fluoro-chloro terminus. This has been accomplished by cross-metathesis between two trisubstituted olefins, one of which is a purchasable but scarcely utilized trihaloalkene. Subsequent cross-coupling can then be used to generate an assortment of trisubstituted alkenyl fluorides. The importance of the advance is highlighted by syntheses of, among others, a fluoronematic liquid-crystal component, peptide analogues bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluororumenic ester (an anti-cancer compound).

Desymmetrised pentaporphyrinic gears mounted on metallo-organic anchors.

Mastering intermolecular gearing is crucial for the emergence of complex functional nanoscale machineries. However, achieving correlated motion within trains of molecular gears remains highly challenging, due to the multiple degrees of freedom of each cogwheel. In this context, we designed and synthesised a series of star-shaped organometallic molecular gears incorporating a hydrotris(indazolyl)borate anchor to prevent diffusion on the surface, a central ruthenium atom as a fixed rotation axis, and an azimuthal pentaporphyrinic cyclopentadienyl cogwheel specifically labelled to monitor its motion by non-time-resolved Scanning Tunneling Microscopy (STM). Desymmetrisation of the cogwheels was first achieved sterically, i.e. by introducing one tooth longer than the other four. For optimal mechanical interactions, chemical labelling was also investigated as a preferential way to induce local contrast in STM images, and the electronic properties of one single paddle were modulated by varying the porphyrinic scaffold or the nature of the central metal. To reach such a structural diversity, our modular synthetic approach relied on sequential cross-coupling reactions on a penta(p-halogenophenyl)cyclopentadienyl ruthenium(ii) key building block, bearing a single pre-activated p-iodophenyl group. Chemoselective Sonogashira or more challenging Suzuki–Miyaura reactions allowed the controlled introduction of the tagged porphyrinic tooth, and the subsequent four-fold cross-couplings yielded the prototypes of pentaporphyrinic molecular gears for on-surface studies, incorporating desymmetrised cogwheels over 5 nm in diameter.

Preparation and Reactions of (1H-Tetrazol-5-yl)zinc Pivalates

The preparation and reactivity of new solid heterocyclic organozinc reagents, namely N-protected (1H-tetrazol-5-yl)zinc pivalates, as storable solids with appreciably air and moisture stability are reported. They are obtained in high yields from protected 1H-tetrazoles by de­protonation using the mixed zinc–magnesium base TMPZnCl·Mg(OPiv)2 (abbreviated as TMPZnOPiv; TMP = 2,2,6,6-tetramethylpiperidyl). Subsequent cross-couplings and copper-catalyzed electrophilic aminations using hydroxylamine benzoates give access to functionalized 1H-tetrazoles while tolerating many functional groups.

Copper-catalyzed oxidative dehydrogenative functionalization of alkanes to allylic esters

Herein, we report a general, efficient and solvent-free method for the one-pot synthesis of allylic esters via dehydrogenation of unactivated alkanes and subsequent oxidative cross coupling with different substituted carboxylic acids. A simple, well defined and air stable Cu(II)-complex, [Cu(MeTAA)], featuring a tetraaza-macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)) is used as the catalyst. A wide variety of substituted allylic esters were synthesized in high yields starting from readily available starting materials. Control reactions were carried out to understand the reaction sequence and the plausible mechanism.

Photocatalytic Isomerization of Styrenyl Halides: Stereodivergent Synthesis of Functionalized Alkenes

An efficient and general method for the isomerization of styrenyl halides under different photocatalytic conditions (fac‐Ir(ppy)3 in methanol for E to Z isomerization and fluorescein in 1,4‐dioxane for Z to E isomerization, respectively) is disclosed. A series of stereospecific transformations constitute preliminary validation of this strategy in the synthesis of functionalized alkenes, including two diaryl alkenes, a styrenyl boronic ester and an enyne. The photocatalytic isomerization and subsequent cross coupling reaction can be run in a one‐pot manner. The stereodivergent synthesis of all four isomers of a conjugated diene, as well as the antitumor agent DMU‐212 and its (Z)‐isomer highlights the synthetic applicability of this method.

Sequential ortho-C-H and ipso-C-O Functionalization Using a Bifunctional Directing Group.

Design of C-H activation directing groups that can serve as electrophiles for subsequent cross-coupling significantly improves the step economy of synthetic applications of directed C-H functionalization. Through using a well-defined bifunctional template, palladium-catalyzed ortho-C-H alkenylation and arylation of benzylic alcohols was achieved via an end-on nitrile-embedded 12-membered macrocyclic transition state. Thereafter, the directing template is used as a handle for palladium-catalyzed ipso-C-O cross-coupling to provide functionalized diarylmethanes.

Rapid Access to Highly Functionalized Alkyl Boronates by NiH-Catalyzed Remote Hydroarylation of Boron-Containing Alkenes.

The direct and selective functionalization of relatively simple and readily accessible precursors to produce highly functionalized alkyl boronates is a synthetically useful process. Herein we report a NiH-catalyzed remote hydroarylation process that can, through a synergistic combination of chain walking and subsequent cross-coupling, introduce an aryl group at the adjacent carbon atom of alkyl boronates under mild conditions. By means of a preliminary experiment with moderate enantioselectivity, it was shown that an asymmetric version could also be realized.

Continuous-Flow Preparation of Alkynylzinc and its Subsequent Cross-Coupling Reaction

Continuous-Flow Preparation of Alkynylzinc and its Subsequent Cross-Coupling Reaction

Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot Reduction/Cross-Coupling Procedure.

The synthesis of functionalized (benz)aldehydes, via a two-step, one-pot procedure, is presented. The method employs a stable aluminum hemiaminal as a tetrahedral intermediate, protecting a latent aldehyde, making it suitable for subsequent cross-coupling with (strong nucleophilic) organometallic reagents, leading to a variety of alkyl and aryl substituted benzaldehydes. This very fast methodology also facilitates the effective synthesis of a 11C radiolabeled aldehyde. Aluminum–ate complexes enable transmetalation of alkyl fragments onto palladium and subsequent cross-coupling.

Pd-catalyzed intramolecular addition of active methylene compounds to alkynes with subsequent cross-coupling with (hetero)aryl halides.

We report an efficient protocol for tandem Pd-catalyzed intramolecular addition of active methylene compounds to alkynes, followed by subsequent cross-coupling with (hetero)aryl bromides and chlorides. The reaction proceeds under mild conditions, providing excellent functional group tolerance, including unprotected OH, NH2 groups, enolizable ketones, or a variety of heterocycles. Mechanistic studies point towards a catalytic cycle involving oxidative addition, intramolecular nucleophilic addition to the Pd(ii)-activated alkyne, and reductive elimination, with 5-exo-dig cyclization being the rate limiting step.