Direct Alkenylation Research Articles

Direct C3-H Alkylation and Alkenylation of Quinolines with Enones.

Conversion of quinoline C-H bonds into C-C bonds is essential for obtaining the enormous array of derivatives required for pharmaceutical and agrochemical development. Despite over a century of synthetic efforts, direct alkylation and alkenylation at C3-H positions in a wide array of quinoline precursors remain predominantly challenging and elusive. This report outlines the first successful quinoline C3-H alkylation and alkenylation reactions, exhibiting exceptional regio- and stereoselectivity, all achieved under redox-neutral and transition-metal-free conditions. The method involves a three-step, one-pot or two-pot sequence, including 1,4-dearomative addition, functionalization at C3, and elimination or transalkylation to produce 3-alkylated/alkenylated quinolines. The presence of a carbonyl group in these products allows for further synthetic manipulations, enabling the production of cyanides, amides, amines, and simple alkyl derivatives.

Asymmetric C–H Dehydrogenative Alkenylation via a Photo-induced Chiral α‑Imino Radical Intermediate

The direct alkenylation with simple alkenes stands out as the most ideal yet challenging strategy for obtaining high-valued desaturated alkanes. Here we present a direct asymmetric dehydrogenative α-C(sp3)-H alkenylation of carbonyls based on synergistic photoredox-cobalt-chiral primary amine catalysis under visible light. The ternary catalytic system enables the direct coupling of β-keto-carbonyls and alkenes through a cooperative radical addition-dehydrogenation process involving a chiral α-imino radical and Co(II)-metalloradical intermediate. A catalytic H-transfer process involving nitrobenzene is engaged to quench in situ generated cobalt hydride species, ensuring a chemoselective alkenylation in good yields and high enantioselectivities.

Direct Heterocycle C-H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation.

One of the major challenges in developing catalytic methods for C-C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C-H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo) halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr-H substrate classes undergoing C-H activation without the need for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ-generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle and the palladacycle effects C-H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale.

Dual Transition Metal Electrocatalysis: Direct Decarboxylative Alkenylation of Aliphatic Carboxylic Acids.

Direct decarboxylative alkenylation of widely available aliphatic carboxylic acids with vinyl halides for the synthesis of alkenes with all substitution patterns has been accomplished by means of Ce/Ni dual transition metal electrocatalysis. The reactions employ alkyl acids as the limiting reagents and exhibit a broad scope with respect to both coupling partners. Notably, simple primary alkyl carboxylic acids could be readily engaged as carbon-centered radical precursors in the reaction. This new alkenylation protocol has been successfully demonstrated in direct modification of naturally occurring complex acids and is amenable to the enantioselective decarboxylative alkenylation of arylacetic acid. Mechanistic studies, including a series of controlled experiments and cyclic voltammetry data, allow us to probe the key intermediates and the pathway of the reaction.

Ferrous Salt-Catalyzed Oxidative Alkenylation of Indoles: Facile Access to 3-Alkylideneindolin-2-Ones

The direct oxidative alkenylation of indoles is achieved by ferrous salts under mild conditions, which provides one effective strategy for the synthesis of 3-alkylideneindolin-2-one in a single step. This reaction system features simple and readily available materials, mild conditions, and easy accessibility. The control experiments also demonstrate a radical pathway was involved in the reaction. Moreover, the method performs well on the gram-scale experiment, which indicates that this method enjoys a broad prospect in synthetic chemistry.

Aryl-, Akynyl-, and Alkenylbenziodoxoles: Synthesis and Synthetic Applications.

Hypervalent iodine reagents are in high current demand due to their exceptional reactivity in oxidative transformations, as well as in diverse umpolung functionalization reactions. Cyclic hypervalent iodine compounds, known under the general name of benziodoxoles, possess improved thermal stability and synthetic versatility in comparison with their acyclic analogs. Aryl-, alkenyl-, and alkynylbenziodoxoles have recently received wide synthetic applications as efficient reagents for direct arylation, alkenylation, and alkynylation under mild reaction conditions, including transition metal-free conditions as well as photoredox and transition metal catalysis. Using these reagents, a plethora of valuable, hard-to-reach, and structurally diverse complex products can be synthesized by convenient procedures. The review covers the main aspects of the chemistry of benziodoxole-based aryl-, alkynyl-, and alkenyl- transfer reagents, including preparation and synthetic applications.

Ligand-Dependant Selective Synthesis of Mono-and Dialkenylcarbazoles through Rhodium(III)-Catalyzed C-H Alkenylation.

The C-H alkenylation of N-acetylcarbazoles proceeds smoothly at the C1-position in the presence of a cationic Cp*Rh(III) catalyst to produce 1-alkenylcarbazoles. The use of a cationic CpERh(III) catalyst enables further alkenylation to give 1,8-dialkenylcarbazoles. The direct alkenylation procedure in combination with the ready removal of the acetyl directing group provides a straightforward synthetic pathway to 1- and/or 8-alkenyl-N-H-carbazole derivatives. One of 1-alkenyl-N-H-carbazoles obtained by the present C-H alkenylation/deacetylation exhibits solvatochromism.

Synthesis of alkenylated tetrathienoacenes obtained by palladium catalyzed direct C–H alkenylations

The palladium-catalyzed direct alkenylation of alkyl chain-substituted tetrathienoacenes has been developed under mild conditions. This effective and feasible approach could be readily applied to a variety of dialkenylated tetrathienoacenes using different functionalized alkenes as the coupling substrates, such as linear α,β-unsaturated esters, alkenyl phosphonate, sulfone, acrolein, asn styrene derivatives.

Rhodium‐Catalyzed Oxidative Coupling of Potassium Vinyltrifluoroborate with Arenes: A Direct Access to Functionalized Styrene Derivatives

AbstractHerein, we report a Rh(III)‐catalyzed direct alkenylation of arenes with readily available vinyltrifluoroborate to direct access to functionalized styrenes. This method tolerates a wide range of functional groups in 33 examples with excellent site‐ and regioselectivity under mild conditions. The synthetic utility was demonstrated through the further transformation of thus‐obtained functionalized styrenes. Preliminary mechanistic studies indicated that the reaction probably proceeds through an Rh(III)‐catalyzed C−H activation/Suzuki coupling pathway.magnified image

Correction to “Access to Cyclopropyl-Fused Azacycles via a Palladium-Catalyzed Direct Alkenylation Strategy”

ADVERTISEMENT RETURN TO ARTICLES ASAPPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to “Access to Cyclopropyl-Fused Azacycles via a Palladium-Catalyzed Direct Alkenylation Strategy”Carolyn L. LaddCarolyn L. LaddMore by Carolyn L. Ladd and André B. Charette*André B. CharetteMore by André B. Charettehttps://orcid.org/0000-0001-5622-5063Cite this: Org. Lett. 2022, XXXX, XXX, XXX-XXXPublication Date (Web):June 16, 2022Publication History Received2 June 2022Published online16 June 2022https://doi.org/10.1021/acs.orglett.2c01874© 2022 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceArticle Views374Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (398 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Construction of chiral 3-alkenyl-3-substituted oxindoles by stereoselective direct alkenylation of isatin derivatives and 3-vinylindoles

An efficient asymmetric alkenylation between 3-vinylindoles and isatin derivatives was developed under catalysis of a chiral copper complex. A series of optically active 3-alkenyl-3-substituted oxindoles were obtained in excellent yields and stereoselectivities. The reaction mechanism was proposed and supported by DFT calculation.

Cobalt-catalyzed tandem one-pot synthesis of polysubstituted imidazo[1,5-a]pyridines and imidazo[1,5-a]isoquinolines.

An efficient cobalt-catalyzed tandem one-pot method has been developed for the synthesis of polysubstituted imidazo[1,5-a]-N-heteroaromatics. The method involves Knoevenagel condensation followed by cobalt-catalyzed direct alkenylation to give the desired polysubstituted imidazo[1,5-a]pyridines and imidazo[1,5-a]isoquinolines in a one-pot manner. This method exhibits a broad substrate scope, provides moderate to good (39-74%) yields and is amenable to scale-up to the gram scale.

Chemodivergent manganese-catalyzed C\u2013H activation: modular synthesis of fluorogenic probes

Bioorthogonal late-stage diversification of amino acids and peptides bears enormous potential for drug discovery and molecular imaging. Despite major accomplishments, these strategies largely rely on traditional, lengthy prefunctionalization methods, heavily involving precious transition-metal catalysis. Herein, we report on a resource-economical manganese(I)-catalyzed C–H fluorescent labeling of structurally complex peptides ensured by direct alkynylation and alkenylation manifolds. This modular strategy sets the stage for unraveling structure-activity relationships between structurally discrete fluorophores towards the rational design of BODIPY fluorogenic probes for real-time analysis of immune cell function.

Palladium Catalyzed Direct Alkenylation of Dihydropyrrolo[2,1‐a]isoquinolines through the Oxidative Heck Reaction

We have developed a Pd(II) catalyzed direct modification of dihydropyrrolo[2,1‐a]isoquinoline derivatives with various alkenes including acrylates, acrylamide, cyclohexenone, maleimide and styrenes. A series of highly functionalized alkenylated dihydropyrroloisoquinolines could be prepared in acceptable to good yields (up to 98 %) through oxidative Heck coupling.

A Facile Regioselectively Synthesis of 2‐Alkenylbenzo[1,2‐b:4,5‐b’]dithiophene by Pd/Cu/Ag‐Catalyzed C‐H Functionalization

AbstractIn this work, several alkenylated benzo[1,2‐b:4,5‐b′]dithiophene were synthesized by Pd‐catalyzed C−H functionalization of benzo[1,2‐b:4,5‐b′]dithiophene with various alkenes. This direct alkenylation took place regioselectively at the C‐2 position of the fused heterocycle. The obtained compounds were structurally characterized by NMR and MS spectroscopic methods. Moreover, DFT calculations have been employed to shed light on the regioselectivity of the reaction as well as on the geometry and electronic properties of the newly formed C=C double bonds.

Photoinduced site-selective alkenylation of alkanes and aldehydes with aryl alkenes

The dehydrogenative alkenylation of C-H bonds with alkenes represents an atom- and step-economical approach for olefin synthesis and molecular editing. Site-selective alkenylation of alkanes and aldehydes with the C-H substrate as the limiting reagent holds significant synthetic value. We herein report a photocatalytic method for the direct alkenylation of alkanes and aldehydes with aryl alkenes in the absence of any external oxidant. A diverse range of commodity feedstocks and pharmaceutical compounds are smoothly alkenylated in useful yields with the C-H partner as the limiting reagent. The late-stage alkenylation of complex molecules occurs with high levels of site selectivity for sterically accessible and electron-rich C-H bonds. This strategy relies on the synergistic combination of direct hydrogen atom transfer photocatalysis with cobaloxime-mediated hydrogen-evolution cross-coupling, which promises to inspire additional perspectives for selective C-H functionalizations in a green manner.

Copper-catalyzed O-alkenylation of phosphonates.

Copper catalysis allows the direct oxygen alkenylation of dialkyl phosphonates with alkenyl(aryl)iodonium salts with selective transfer of the alkenyl group. This novel methodology proceeds with a wide range of phosphonates under mild conditions and gives straightforward access to valuable enol phosphonates in very good yields.

Recent Advances in Transition Metal-O Weak Coordinated C(sp2)—H Direct Alkenylation Reaction

Recent Advances in Transition Metal-O Weak Coordinated C(sp²)—H Direct Alkenylation Reaction

Palladium-Catalyzed C-H/C-H Cross-Coupling by Mechanochemistry: Direct Alkenylation and Heteroarylation of N1-Protected 1H-Indazoles.

C3-alkenylated and C3-(hetero)arylated 1H-indazoles are privileged structural motifs in numerous pharmaceuticals. Direct C3-alkenylation and C3-(hetero)arylation of 1H-indazoles have been significantly challenging because of the inert nature of this carbon center. Herein, we present an efficient mechanochemical strategy for palladium-catalyzed C-H/C-H cross-coupling to construct C3-alkenylated and C3-heteroarylated 1H-indazoles using low-cost copper oxidants with satisfactory product yields and broad functional group tolerance. The robustness of the developed protocols was further demonstrated by the unprecedented total mechanosynthesis of the intermediate of PLK4 inhibitor CFI-400945 and HIF-1α inhibitor YC-1.

Copper-Mediated One-Pot Synthesis of Indoles through Sequential Hydroamination and Cross-Dehydrogenative Coupling Reaction

Starting from simple anilines and ester arylpropiolates, an efficient one-pot synthesis of 2-arylindole-3-carboxylate derivatives has been developed through copper-mediated sequential hydroamination and cross-dehydrogenative coupling (CDC) reaction. The initial hydroamination of anilines to ester arylpropiolates in benzene can proceed in a stereoselective manner to give ester (Z)-3-(arylamino)acrylates in the presence of CuCl2/phenanthroline, KMnO4, and KHCO3 at 120 °C. Sequentially, these in situ functionalized adducts can undergo direct intramolecular oxidative alkenylation of aromatic C–H bond in mixed solvents (benzene/DMSO 1:1) at 130 °C affording multi-substituted­ indoles in good to high yields.