Alkenyl Bromides Research Articles

Heteroaryl Group Containing Trisubstituted Alkenes: Synthesis and Anti-tumor Activity.

Pancreatobililary cancers are fatal solid tumors that pose a significant threat to human life. It is imperative to investigate novel small molecule active compounds for controlling these cancers. Heterocyclic compounds (e. g. gemcitabine) and multi-substituted alkenes (e. g. resveratrol) are commonly applied in tumor treatment. Researchers have proposed that the synthesis of new trisubstituted alkenes containing heteroaromatic rings by combining these two scaffolds may be a fresh strategy to develop new active molecules. In this study, we utilized alkenyl bromide and heteroaryl boronic acid as substrates, employing Suzuki coupling to generate a series of triarylethylenes featuring nitrogen, oxygen, and sulfur atoms. Through in vitro experiments, the results indicated that some compounds exhibited remarkable anti-tumor efficacy (e. g. IC50[3be, GBC-SD]=0.13 μM and IC50[3be, PANC-1]=0.27 μM). The results further demonstrated that the antitumor efficacy of these compounds was dependent on the heteroatom, π-system, skeleton-bonding site, and substituent type.

Optimization of Palladium-Catalyzed One-Pot Synthesis of Functionalized Furans for High-Yield Production: A Study of Catalytic and Reaction Parameters

This study investigates the palladium-catalyzed one-pot synthesis of functionalized furans from 1,3-Dicarbonyl compounds and alkenyl bromides, focusing on various catalysts and reaction parameters. Different catalysts, including PdCl₂(CH₃CN)₂, Pd(OAc)₂, and Pd(acac)2 as well as solvents, bases, and oxidants, were systematically evaluated. PdCl₂(CH₃CN)₂ emerged as the most effective catalyst, achieving a remarkable yield of 94%. Optimal reaction conditions were identified as PdCl₂(CH₃CN)₂ in dioxane at 80 °C with K₂CO₃ as the base and CuCl₂ as the oxidant. This study also explored various 1,3-diketones including Cyclohexane-1,3-dione, 5,5-Dimethylcyclohexane-1,3-dione, 2H-Pyran-3,5(4H,6H)-dione, Cyclopentane-1,3-dione, Pentane-2,4-dione, Ethyl 3-oxobutanoate, 1,3-Diphenylpropane-1,3-dione, 1,3-Dip-tolylpropane-1,3-dione, 1,3-Bis(4-chlorophenyl)propane-1,3-dione, and 1,3-Bis(4-bromo- phenyl)propane-1,3-dione, alongside different alkenyl bromides such as allyl bromide, (E)-1-Bromo-3,4-dimethylpent-2-ene, 1-Bromo-3-methylbut-2-ene, 3-Bromocyclohex-1-ene, and (E)-1-Bromohex-2-ene. These variations demonstrated the method’s versatility and the significant impact of substituents on reactivity and reaction yield. These findings highlight the importance of optimizing reaction conditions to maximize efficiency and provide insights into improving catalytic processes for enhanced product yields.

Synthesis of P-Stereogenic Phosphinamides via Nickel-Catalyzed Kinetic Resolution of H-Phosphinamides by Alkenylation and Arylation.

A nickel-catalyzed enantioselective cross-coupling for the synthesis of P-stereogenic phosphinamides has been developed. The asymmetric alkenylation and arylation of racemic H-phosphinamides using alkenyl and aryl bromides resulted in the formation of P-stereogenic N-phosphinyl compounds with good yields and high enantioselectivities. This method tolerates a variety of functional groups, and its applications are explored through scale-up reactions and product transformations.

Electrochemically Driven Nickel-Catalyzed Enantioselective Hydro-Arylation/Alkenylation of Enones.

Herein, the study reports the first electrochemical nickel-catalyzed enantioselective hydro-arylation/alkenylation of enones in an undivided cell with low-cost electrodes in the absence of external reductants and supporting electrolytes. Aryl bromides/iodides/triflates or alkenyl bromides are employed as electrophiles for the efficient preparation of more than 56 valuable β-arylated/alkenylated ketones in a simple manner (up to 97% yield, 97% ee). With the advantages of electrochemistry, excellent functional group tolerance and late-stage modification of complex natural products and pharmaceuticals made the established protocol greener and more economic. Mechanism investigation suggests that a NiI/NiIII cycle may be involved in this electro-reductive reaction rather than metal reductant driven Ni0/NiII cycle. Overall, the efficient electrochemical activation and turnover of the nickel catalyst avoid the drawbacks posed by the employment of stoichiometric amount of sensitive metal powder reductants.

A Continuous-Flow Protocol for the Synthesis of Alkenyl Thioethers Based on the Photochemical Activation of Halogen-Bonding Complexes

AbstractWe report a useful flow protocol for the preparation of alkenyl thioethers from alkenyl bromides and thiols in basic media with visible-light irradiation. The reactions exhibit a wide functional-group tolerance, proceed under mild conditions, are stereoselective, and do not require the use of catalysts. The transformations can be successfully scaled up to 5 mmol scale without compromising the yield. The key to the success of these reactions is the photochemical excitation of halogen-bonding complexes to form alkenyl and sulfur-centered radicals, a protocol recently developed in our laboratories.

Synthesis of Vinyl and 1,3‐Dienyl Sulfones Enabled by Photochemical Excitation of Halogen‐Bonding Complexes

AbstractThe photochemical catalyst‐free radical‐based synthesis of vinyl and 1,3‐dienyl sulfones is disclosed. Mechanistic investigations support that the transformations rely on a visible‐light‐promoted activation of a halogen‐bonding complex, which is formed between an alkenyl (or 1,3‐dienyl) bromide and a sodium sulfinate salt. The reactions exhibit a wide functional group tolerance (compatible with heteroatoms, electron‐withdrawing and electron‐donating groups), finding application in the structural modification of biologically relevant molecules. Eventually, a continuous flow protocol was developed to upscale these transformations.

Visible-light-driven synthesis of alkenyl thiocyanates: novel building blocks for assembly of diverse sulfur-containing molecules.

The first visible-light-induced protocol for the general preparation of alkenyl thiocyanates from alkenyl bromides is presented. The reaction is simple, proceeds under very mild conditions and demonstrates broad functional group tolerance. Additionally, a flow protocol was developed to enable efficient scale-up of alkenyl thiocyanate synthesis, further enhancing the practicality and value of the method. Importantly, these alkenyl thiocyanates serve as valuable building blocks for the construction of diverse families of sulfur-containing molecules through trifluoromethylations, cycloadditions, oxidations, and C-S or P-S bond forming reactions.

Aromatization-driven deconstructive functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis.

Aromatization-driven deconstruction and functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis is developed. The aromatization effect was introduced to synergistically drive unstrained cyclic C-C bond cleavage, with the aim of overcoming the ring-size limitation of nitrogen-centered radical induced deconstruction of carbocycles. Herein, we demonstrate the synergistic photoredox/nickel catalyzed deconstructive cross-coupling of spiro dihydroquinazolinones with organic halides. Remarkably, structurally diverse organic halides including aryl, alkenyl, alkynyl, and alkyl bromides were compatible for the coupling. In addition, this protocol is also characterized by its mild and redox-neutral conditions, excellent functional group compatibility, high atom economy, and easy scalability. A telescoped procedure involving condensation and ring-opening/coupling was found to be accessible. This work provides a complementary strategy to the existing radical-mediated C-C bond cleavage of unstrained carbocycles.

Highly effective and selective FeBr3-promoted deuterium bromination/cyclization of 1,n-enynes.

A highly effective and selective FeBr3-promoted deuterium bromination/cyclization of 1,n-enynes is reported. On the one hand, the Lewis acid FeBr3 as a catalyst promotes cyclization of 1,n-enynes to afford deuterium heterocyclic frameworks with high efficiency. On the other hand, FeBr3 serves as the bromine source (with D2O as the deuterium source) to promote the formation of the desired deuterated pyrrole derivatives containing alkenyl bromide groups. This protocol provides an effective pathway to afford deuterated alkenyl brominative compounds as (Z)-isomers with high yields and selectivity, offering a new method for introducing 2H into organic compounds.

Substrate-directed regioselective alkene functionalizations of (E)-β,γ-unsaturated carboxylic acids.

A carboxylate-directed regioselective Heck-type alkenylation and alkenylative lactonization of (E)-β,γ-unsaturated carboxylic acids by simply substrate control is reported. (E)- and (Z)-alkenyl bromides reacted to give energetically more favorable palladacyles, allowing access to fully stereocontrolled conjugated 1,3-dienes and alkenyled γ-lactones. Mechanistic studies suggest that excellent regioselectivity may be strongly influenced by the steric factors of reactants involved in the palladacycle intermediates.

Synthesis of Functionalized Hexahydrocarbazoles by Beckmann Elimination and Nucleophile-Intercepted Beckmann Fragmentation.

The Beckmann elimination and nucleophile-intercepted Beckmann fragmentation (NuBFr) of oximes starting from regioisomeric indolinyl bicyclic ketones lead to products that are subjected to further synthetic manipulations and ultimately result in the stereospecific formation of densely functionalized hexahydrocarbazoles. The Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of a key alkenyl bromide intermediate with various boronic acids gives arylated products.

Cobalt-Catalyzed Asymmetric Reductive Alkenylation and Arylation of Heterobiaryl Tosylates: Kinetic Resolution or Dynamic Kinetic Resolution?

Herein, we report a cobalt-catalyzed atroposelective reductive cross-coupling of racemic heterobiaryl tosylates with a C(sp2)-X type electrophile. Both aryl and alkenyl halides are competent precursors for this reaction, providing a variety of heterobiaryls as the products in a highly enantioselective manner with high functionality tolerance. The related asymmetric arylation and alkenylation are discovered to proceed with divergent mechanisms. The reaction pathway changes from kinetic resolution (KR) when alkenyl bromides and aryl iodides bearing strong electron-withdrawing substitution on the para-position are employed as the starting materials to an enantioconvergent transformation via dynamic KR of configurationally labile cobaltacycles when relatively electron-rich aryl iodides are used. The change of the reaction mechanisms turns out to arise from the relative rates of two competing elementary steps, which are the epimerization of the cyclic Co(I) intermediates and their trapping by the coupling electrophiles of the C(sp2)-type via oxidative addition.

Taking Olefin Metathesis to the Limit: Stereocontrolled Synthesis of Trisubstituted Alkenes.

ConspectusIn this Account, we share the story of the development of catalytic olefin metathesis processes that efficiently deliver a wide range of acyclic and macrocyclic E- or Z-trisubstituted alkenes. The tale starts with us unveiling, in collaboration with Richard Schrock and his team, the blueprint in 2009 for the design of kinetically controlled Z-selective olefin metathesis reactions. This paved the way for the development of Mo-, W-, and Ru-based catalysts and strategies for synthesizing countless linear and macrocyclic Z-olefins. Six years later, in 2015, we found that abundant Z-alkene feedstocks, such as oleic acid, can be directly transformed to high-value and more difficult-to-access alkenes through a cross-metathesis reaction promoted by a Ru-catechothiolate complex that we had developed; the approach, later coined stereoretentive olefin metathesis, was extended to the synthesis of E-alkenes.It was all about disubstituted alkenes until when in 2017 we addressed the challenge of accessing stereodefined Z- and E-trisubstituted alkenes, key to medicine and materials research. These transformations can be most effectively catalyzed by Mo monoaryloxides pyrrolide (MAP) and chloride (MAC) complexes. A central aspect of the advance is the merging of olefin metathesis, which delivered trisubstituted alkenyl fluorides, chlorides, and bromides with cross-coupling. These catalytic and stereoretentive transformations can be used in various combinations, thereby enabling access to assorted Z- or E-trisubstituted alkene. Ensuing work led to the emergence of other transformations involving substrates that can be purchased with high stereoisomeric purity, notably E- and Z-trihalo alkenes. Trisubstituted olefins, Z or E, bearing a chemoselectively and stereoretentively alterable F,Cl-terminus or B(pin),Cl-terminus may, thus, be easily and reliably synthesized. Methods for stereoretentive preparation of other alkenyl bromide regioisomers and α,β-unsaturated carboxylic and thiol esters, nitriles, and acid fluorides followed, along with stereoretentive ring-closing metathesis reactions that afford macrocyclic trisubstituted olefins. Z- and E-Macrocyclic trisubstituted olefins, including those that contain little or no entropic support for cyclization (minimally functionalized) and/or are disfavored under substrate-controlled conditions, can now be synthesized. The utility of this latest chapter in the history of olefin metathesis has been highlighted by applications to the synthesis of several biologically active compounds, as well as their analogues, such as those marked by one or more site-specifically incorporated fluorine atoms or more active but higher energy and otherwise unobtainable conformers.The investigations discussed here, which represent every stereoretentive method that has been reported thus far for preparing a trisubstituted olefin, underscore the inimitable power of Mo-based catalysts. This Account also showcases a variety of mechanistic attributes─some for the first time, and each instrumental in solving a problem. Extensive knowledge of mechanistic nuances will be needed if we are to address successfully the next challenging problem, namely, the development of catalysts and strategies that may be used to synthesize a wide range of tetrasubstituted alkenes, especially those that are readily modifiable, with high stereoisomeric purity.

Palladium-Catalyzed Trans-Selective Synthesis of Spirocyclic Cyclobutanes Using α,α-Dialkylcrotyl- and Allylhydrazones.

Herein, we demonstrate the use of E/Z mixtures of α,α-disubstituted crotylhydrazones to obtain spirocyclic vinylcyclobutanes in a diastereoselective fashion. We show 24 examples of a 1,1-insertion/4-exo-trig tandem process to produce these motifs. Additionally, spirocyclic alkylidene cyclobutanes can be obtained by using α,α-disubstituted allylated hydrazones (11 examples). In this study, we show that the aryl migrating group has a dramatic impact on the course of the reaction. Specifically, allylic C-H insertion products can be obtained in good yields using bromoenones as reaction partners. When Pd(0) is used with no aryl or alkenyl bromide, an intramolecular cyclopropanation reaction takes place to afford [2.1.0]-bicycles.

Cobalt-Catalyzed Enantioselective Cross-Electrophile Couplings: Stereoselective Syntheses of 5-7-Membered Azacycles.

Cobalt complexes of chiral pyrox ligands catalyzed enantioselective reductive couplings of nonconjugated iododienes with aryl iodides or alkenyl bromides. The reaction enabled stereoselective syntheses of 5-7-membered azacycles carrying quaternary stereocenters. Mechanistically, cross-electrophile selectivity originated from selective coupling of alkylcobalt(I) complexes generated after cyclization with aryl iodides.

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group: Catalyst Generality through Rigidification.

The catalytic enantioselective synthesis of α-chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group (TDG) strategy to facilitate site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl bromides, respectively, allowing for construction of a stereocenter at the δ-position with respect to the aldehyde. Computational studies reveal the dual beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion with a variety of migrating groups.

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group: Catalyst Generality through Rigidification**

AbstractThe catalytic enantioselective synthesis of α‐chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group (TDG) strategy to facilitate site‐selective palladium‐catalyzed reductive Heck‐type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl bromides, respectively, allowing for construction of a stereocenter at the δ‐position with respect to the aldehyde. Computational studies reveal the dual beneficial roles of rigid TDGs, such as L‐tert‐leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion with a variety of migrating groups.

(Z)-Selective Synthesis of Bromofluoroalkenes via the TMSCF2Br-Mediated Tandem Reaction with para-Quinone Methides

We report herein a tandem reaction of para-quinone methides with TMSCF2Br to construct bromofluoroalkenes in a Z-selective manner. While TMSCF2Br has been documented as the precursor of difluoro carbene, it exhibits another possibility in this transformation, a formal bromofluoro carbene surrogate. The alkenyl bromide unit of the products could directly engage in a variety of transformations.

Nickel-Catalyzed Reductive Three-Component Cross-Coupling of Butadiene with Aldehydes and Alkenyl Triflates/Bromides: Access to Skipped Dienes

A regio- and stereoselective nickel-catalyzed reductive three-component cross-coupling of 1,3-butadiene with aldehydes and alkenyl triflates or bromides was realized. This protocol afforded a convenient approach to the synthesis of skipped diene compounds bearing various functionals and heterocyclic groups. The utility of this reaction was also demonstrated by scale-up preparation and diverse transformations.

Gold-Catalyzed Aryl-Alkenylation of Alkenes.

Herein, we report the gold-catalyzed aryl-alkenylation of unactivated alkenes with alkenyl iodides and bromides employing ligand-enabled gold redox catalysis. The present methodology followed the π-activation pathway rather than the migratory insertion pathway, which is predominant in other transition metal catalysis such as Pd, Ni, Cu, etc. Detailed mechanistic investigations such as 31P NMR, deuterium labeling, and HRMS studies have been carried out to underpin mechanistic insights.