Trisubstituted Alkenes Research Articles

Intermolecular Organophotocatalytic Cyclopropanation of Unactivated Olefins.

Intermolecular cyclopropanation of mono-, di-, and trisubstituted olefins with α-bromo-β-ketoesters and α-bromomalonates under organophotocatalysis is reported. The reaction displays broad functional group tolerance, including substrates bearing acids, alcohols, halides, ethers, ketones, nitriles, esters, amides, carbamates, silanes, stannanes, boronic esters, as well as arenes, and furnishes highly substituted cyclopropanes. The transformation may be performed in the presence of air and moisture with 0.5 mol% of a benzothiazinoquinoxaline as organophotocatalyst. Mechanistic investigations, involving Stern-Volmer quenching, quantum yield determination, and deuteration experiments, are carried out, and a catalytic cycle for the transformation is discussed.

Rhodium-catalyzed atroposelective access to trisubstituted olefins via C-H bond olefination of diverse arenes.

The atroposelective synthesis of axially chiral acyclic olefins remains a daunting challenge due to their relatively lower racemization barriers, especially for trisubstituted ones. In this work, atroposelective C-H olefination has been realized for synthesis of open-chain trisubstituted olefins via C-H activation of two classes of (hetero)arenes in the coupling with sterically hindered alkynes. The employment of phenyl N-methoxycarbamates as arene reagents afforded phenol-tethered olefins, with the carbamate being a traceless directing group. The olefination of N-methoxy-2-indolylcarboxamides afforded the corresponding chiral olefin by circumventing the redox-neutral [4 + 2] annulation. The reactions proceeded with excellent Z/E selectivity, chemoselectivity, regioselectivity, and enantioselectivity in both hydroarylation systems.

Monomeric lithium and sodium silylbenzyl complexes: syntheses, structures, and CO bond olefination.

Herein we report the syntheses, structures and reactivity studies of two new monomeric alkali metal silylbenzyl complexes stabilised by a tetradentate amine ligand, tris[2-(dimethylamino)ethyl]amine (Me6Tren). The two complexes, namely [MR'(Me6Tren)] (R': CH(Ph)(SiMe3)) (2-Li: M = Li; 2-Na: M = Na), exhibit significant different coordination modes according to their metal identity (Li: σ-coordination; Na: π-coordination). Reactivity studies of 2-Li and 2-Na reveal that they are efficient in promoting a widely-used class of organic functional group interconversion: CO bond olefination of ketones, aldehydes and amides, to produce tri-substituted internal alkenes.

Solvent-free and catalyst-free direct alkylation of alkenes

A convenient method for synthesizing trisubstituted alkenes through direct alkylation of alkenes was achieved under solvent-free and catalyst-free conditions. This reaction highlighted by a low E-factor and a high atom- and step-economy.

Organocatalytic Asymmetric Bromohydroxylation of Tri-Substituted Alkenes

Organocatalytic Asymmetric Bromohydroxylation of Tri-Substituted Alkenes

Regio- and stereocontrolled synthesis of borylated E-enynes, Z-enediynes and derivatives from alkenyl-1,2-bis-(boronates).

An efficient stereo-controlled synthesis of enyne and enediyne derivatives, via sequential Suzuki-Miyaura coupling reactions from easily prepared 1-alkene-1,2-diboronic esters and alkynyl bromides, is reported. The resulting enyne boronic esters were subjected to Borono-Mannich and Suzuki coupling reactions independently to obtain α,β-unsaturated aminoester and tri-substituted olefin derivatives, respectively. Additionally, divergent syntheses of triazole and cyclopropylboronate derivatives are also reported.

Citronella-based polyesters by organocatalyzed ring-opening polymerization and their recyclable crosslinked films

Independence of food supply chain is a grand challenge encountered by the development of bio-based polymers. Here, we demonstrate the synthesis of amorphous aliphatic polyesters via organocatalyzed ring-opening polymerization of 9-membered lactone monomer, a novel downstream product of non-edible citronella oil. In particular, chemical transformation of trisubstituted alkene moiety owned by this renewable biomass was achieved by cross-metathesis of this bulky group with methyl acrylate. Three-armed star polymers were converted to free-standing films by UV-induced crosslinking. In particular, these crosslinked thin films could be efficiently recycled as ω-hydroxy ester upon methanolysis. This work opens a new avenue for the synthesis and application of terpene- and terpenoid-based polymers.

Nickel‐Catalyzed Transfer Hydrogenation of Unactivated Aryl Alkenes with Hydrosilane as Hydrogen Source

AbstractA nickel‐catalyzed transfer hydrogenation of aryl alkenes has been developed using hydrosilane as the hydrogen source. Sterically hindered disubstituted or trisubstituted alkenes were employed to test the efficiency of this transformation. Mechanism studies showed that hydrogenation took place smoothly with more sterically‐hinderedtrans‐alkenes. While uncongestedcis‐alkenes could hardly convert to the alkanes but hydrosilylation products were generated instead. Moreover, certain amount of water was found to be a promotion for the protonation process and could partly serve as the hydrogen source. Not only for simple stilbenes, this easy handle protocol also showed tolerance for substrates involving other unsaturated groups as well as heterocycles.

Chemical Degradation-Inspired Total Synthesis of the Antibiotic Macrodiolide, Luminamicin.

This article describes the first total synthesis of luminamicin using a strategy combining chemical degradation with synthesis. Chemical degradation studies provided a sense of the inherent reactivity of the natural product, and deconstruction of the molecule gave rise to a key intermediate, which became the target for chemical synthesis. The core structure of the southern part of luminamicin was constructed by a 1,6-oxa-Michael reaction to form an oxa-bridged ring, followed by coupling with a functionalized organolithium species. Modified Shiina macrolactonization conditions forged the strained 10-membered lactone containing a tri-substituted olefin. Diastereoselective α-oxidation of the 10-membered lactone completed the center part to provide the key intermediate. Inspired by the degradation study, an unprecedented enol ether/maleic anhydride moiety was constructed with a one-pot chlorosulfide coupling and thiol β-elimination sequence. Finally, macrolactonization to the 14-membered ring in the presence of the highly electrophilic maleic anhydride moiety was accomplished using modified Mukaiyama reagents to complete the synthesis of luminamicin.

Ir-Catalyzed Asymmetric Hydroarylation of Alkynes for the Synthesis of Axially Chiral Heterobiaryls

The catalytic hydroarylation of alkynes has emerged as an excellent methodology for the synthesis of functionalized alkenes with excellent levels of regio- and stereocontrol (syn). However, in spite of the great progress in this field, the number of asymmetric methodologies is still scarce. Herein, we report an atroposelective Ir-catalyzed C–H hydroarylation of alkynes, which enables the asymmetric synthesis of axially chiral heterobiaryl trisubstituted olefins in good to high yields and enantioselectivities up to 98% ee.

Regio- and Stereoselective Reductive Coupling of Alkynes and Crotononitrile.

A new regio- and stereoselective reductive coupling of alkynes and crotononitrile has been developed via visible light organophotoredox cobalt dual catalysis. A variety of enantioenriched homoallylic nitriles bearing a stereodefined trisubstituted alkene have been easily synthesized with good to excellent regio- (up to >20:1 rr), stereo- (>20:1 E/Z), and enantioselectivity (up to 98% ee) control under mild conditions. The corresponding nitrile products were smoothly converted into various chiral building blocks. Remarkably, a simple organic base together with water have been utilized as hydrogen sources in this photoinduced reductive reaction.

Diastereoselective Radical Aminoacylation of Olefins through N-Heterocyclic Carbene Catalysis.

There have been significant advancements in radical-mediated reactions through covalent-based organocatalysis. Here, we present the generation of iminyl and amidyl radicals via N-heterocyclic carbene (NHC) catalysis, enabling diastereoselective aminoacylation of trisubstituted alkenes. Different from photoredox catalysis, single electron transfer from the deprotonated Breslow intermediate to O-aryl hydroxylamine generates an NHC-bound ketyl radical, which undergoes diastereocontrolled cross-coupling with the prochiral C-centered radical. This operationally simple method provides a straightforward access to a variety of pyrroline and oxazolidinone heterocycles with vicinal stereocenters (77 examples, up to >19:1 d.r.). Electrochemical studies of the acyl thiazolium salts support our reaction design and highlight the reducing ability of Breslow-type derivatives. A detailed computational analysis of this organocatalytic system suggests that radical-radical coupling is the rate-determining step, in which π-π stacking interaction between the radical intermediates subtly controls the diastereoselectivity.

Development, Synthesis, and in silico Investigations of Novel Acyclic Allyl Fluoride Derivatives

AbstractA one step electrophilic fluorination of alkenes is reported, which furnishes the products in a highly regioselective manner via allylic rearrangement. The reaction proceeds efficiently under mild conditions with the use of trisubstituted alkenes as olefin partner and Selectfluor as an electrophilic fluorinating agent without the need of any transition metal catalyst or pre-functionalized substrates. Virtual screening of the newly synthesized compounds shows their potential application as herbicides by inhibiting protoporphyrinogen oxidase (PPO) enzyme.

D-π-A-Based Trisubstituted Alkenes as Environmentally Sensitive Fluorescent Probes to Detect Lewy Pathologies.

Lewy pathologies, which mainly consist of insoluble α-synuclein (α-syn) aggregates, are the hallmarks of Parkinson's disease and many other neurodegenerative diseases termed "synucleinopathies". Detection of Lewy pathologies with optical methods is of interest for preclinical studies, while the α-syn fluorescent probe is still in great demand. By rational design, we obtained a series of D-π-A-based trisubstituted alkenes with acceptable optical properties and high binding affinities to α-syn fibrils. Among these probes, FPQXN and TQXN-2 exhibited high binding affinities (6 and 8 nM, respectively), significant fluorescence enhancements (17.2- and 26.6-fold, respectively), and satisfying quantum yields (36.5% and 10.4%, respectively), which met the need for the in vitro neuropathological staining of Lewy pathologies in the PD brain sections. In addition, TQXN-2 showed great potential in fluorescent discrimination of Lewy pathologies and Aβ plaques. Our research provides flexible tools for in vitro detection of α-syn aggregates and offers new structural frameworks for the further development of α-syn fluorescent probes.

Selective Reductive Coupling of Vinyl Azaarenes and Alkynes via Photoredox Cobalt Dual Catalysis.

A visible light-induced Co-catalyzed highly regio- and stereoselective reductive coupling of vinyl azaarenes and alkynes has been developed. Notably, Hünig's base together with simple ethanol has been successfully applied as the hydrogen sources instead of commonly used Hantzsch esters in this catalytic photoredox reaction. This approach has considerable advantages for the straightforward synthesis of stereodefined multiple substituted alkenes bearing an azaarene motif, such as excellent regioselectivity (>20 : 1 for >30 examples) and stereoselectivity (>20 : 1 E/Z), broad substrate scope and good functional group compatibility under mild reaction conditions, which has been utilized in the concise synthesis of natural product monomorine I. A reasonable catalytic reaction pathway involving protolysis of the cobaltacyclopentene intermediate has been proposed based on the mechanistic studies.

Palladium-catalyzed asymmetric hydrophosphination of internal alkynes: Atroposelective access to phosphine-functionalized olefins

•Atroposelective hydrophosphination of internal alkynes •Construction of axial and P-chirality •Broad reaction scope, including symmetrical and nonsymmetrical secondary phosphines •Excellent regioselectivity, E-selectivity, enantioselectivity, and diastereoselectivity Palladium-catalyzed underexplored atroposelective hydrophosphination of sterically hindered internal alkynes with secondary phosphines has been realized, affording C-N axially chiral trisubstituted olefins (vinylphosphines) in excellent regioselectivity, (E)-selectivity, and enantioselectivity. The axial chirality was constructed via the integration of hydrophosphination and dynamic kinetic transformation of the alkynes, with both symmetrical and nonsymmetrical secondary phosphines being applicable. Palladium-catalyzed underexplored atroposelective hydrophosphination of sterically hindered internal alkynes with secondary phosphines has been realized, affording C-N axially chiral trisubstituted olefins (vinylphosphines) in excellent regioselectivity, (E)-selectivity, and enantioselectivity. The axial chirality was constructed via the integration of hydrophosphination and dynamic kinetic transformation of the alkynes, with both symmetrical and nonsymmetrical secondary phosphines being applicable.

Iridium-Catalyzed Branch-Selective and Enantioselective Hydroalkenylation of α-Olefins through C-H Cleavage of Enamides.

Catalytic branch-selective hydrofunctionalization of feedstock α-olefins to form enantioenriched chiral compounds is a particularly attractive yet challenging transformation in asymmetric catalysis. Herein we report an iridium-catalyzed asymmetric hydroalkenylation of α-olefins through directed C-H cleavage of enamides. This atom-economical addition process is highly branch-selective and enantioselective, delivering trisubstituted alkenes with an allylic stereocenter. DFT calculations reveal the origin of regio- and enantioselectivity.

Rhodium(II)-Catalyzed Enantioselective Intermolecular Aziridination of Alkenes.

C4-Symmetrical dirhodium(II) tetracarboxylates are highly efficient catalysts for the asymmetric intermolecular aziridination of substituted alkenes with sulfamates. The reaction proceeds with high levels of efficiency and chemoselectivity to afford aziridines with excellent yields of up to 95% and enantiomeric excesses of up to 99%. The scope of the alkene aziridination includes mono-, di-, and trisubstituted olefins as well as the late-stage functionalization of complex substrates. The reaction can be performed on a gram-scale with a catalyst loading of 0.1 mol %. Our DFT study led us to propose a two-spin-state mechanism, involving a triplet Rh-nitrene species as key intermediate to drive the stereocontrolled approach and activation of the substrate.

Rate of Formation of Industrial Lubricant Additive Precursors from Maleic Anhydride and Polyisobutylene

The Alder-ene reaction of neat polyisobutylene (PIB) and maleic anhydride (MAA) to produce the industrially important lubricant additive precursor polyisobutylene succinic anhydride (PIBSA) is studied at 150–180 °C. Under anaerobic conditions with [PIB] ∼ 1.24 M (550 g mol–1 grade, >80% exo alkene) and [MAA] ∼ 1.75 M, conversion of exo-PIB and MAA follows second-order near-equal rate laws with kobs up to 5 × 10–5 M–1 s–1 for both components. The exo-alkene-derived primary product PIBSA-I is formed at an equivalent rate. The less reactive olefinic protons of exo-PIB also react with MAA to form isomeric PIBSA-II (kobs up to 6 × 10–5 M–1 s–1). Some exo-PIB is converted to endo-PIB (containing trisubstituted alkene) in a first-order process (kobs ∼ 1 × 10–5 s–1), while PIBSA-I is difunctionalized by MAA to bis-PIBSAs very slowly. The MAA- and PIB-derived activation parameter ΔG‡(150 °C) 34.3 ± 0.3 kcal mol–1 supports a concerted process, with that of PIBSA-I suggesting a late (product-like) transition state.

Indane-Based Chiral Aryl Chalcogenide Catalysts: Development and Applications in Asymmetric Electrophilic Reactions.

Asymmetric electrophilic reactions provide an ideal method for the construction of chiral molecules by incorporating one or more functional groups into the parent substrates under mild conditions. However, due to the issues of the reactivities of electrophilic species and the possible racemization of chiral intermediates as well as the restriction of the chiral scaffolds of chiral catalysts, many limitations remain in this field, such as the narrow scopes of substrates and electrophiles as well as the limited types of nucleophiles and reactions. To overcome the limitations in the synthesis of diversified chiral molecules, we developed a series of indane-based chiral amino aryl chalcogenide catalysts. These catalysts are easily prepared based on the privileged chiral indane scaffold. They can provide an appropriate H-bonding effect by varying the amino protecting groups as well as offer a proper Lewis basicity and steric hindrance by adjusting different substituents on the aryl chalcogenide motifs. These features allow for them to meet the requirements of reactivity and the chiral environment of the reactions. Notably, they have been successfully applied to various asymmetric electrophilic reactions of alkenes, alkynes, and arenes, expanding the field of electrophilic reactions.Using these catalysts, we realized the enantioselective CF3S-lactonization of olefinic carboxylic acids, enantioselective CF3S-aminocyclization of olefinic sulfonamides, desymmetrizing enantioselective CF3S-carbocyclization of gem-diaryl-tethered alkenes, enantioselective CF3S-oxycyclization of N-allylamides, enantioselective intermolecular trifluoromethylthiolating difunctionalization and allylic C-H trifluoromethylthiolation of trisubstituted alkenes, formally the intermolecular CF3S-oxyfunctionalization of aliphatic internal alkenes, intermolecular azidothiolation, oxythiolation, thioarylation of N-allyl sulfonamides, desymmetrizing enantioselective chlorocarbocyclization of aryl-tethered diolefins, enantioselective Friedel-Crafts-type electrophilic chlorination of N-allyl anilides, and enantioselective chlorocarbocyclization and dearomatization of N-allyl 1-naphthanilides. Additionally, the enantioselective electrophilic carbothiolation of alkynes to construct enantiopure carbon chirality center-containing molecules and axially chiral amino sulfide vinyl arenes and the electrophilic aromatic halogenation to produce P-chirogenic compounds can be accomplished. In these reactions, a bifunctional binding mode is proposed in the catalytic cycles, in which an acid-derived anion-binding interaction might exist and account for the high enantioselectivities of the reactions.In this Account, we demonstrate our achievements in asymmetric electrophilic reactions and share our thoughts on catalyst design, our understanding of asymmetric electrophilic reactions, and our perspectives in the field of chiral chalcogenide-catalyzed asymmetric electrophilic reactions. We hope that the experience we share will promote the design and development of other novel organocatalysts and new challenging reactions.