Alkenyl Amides Research Articles

Rhodium-Catalyzed Diastereoselective C-H Activation/[4 + 2] Annulation of α,β-Unsaturated Amides with Bicyclic Alkenes.

Herein, we report a rare example of rhodium-catalyzed C-H activation/[4 + 2] annulation of alkenyl amides with bicyclic alkenes under mild and green conditions. The reactivity of the rhodium catalyst in this study differed from that observed in cobalt-catalyzed C-H activation/[3 + 2] annulation between vinylic amides and bicyclic alkenes. In addition, the reaction was performed in EtOH at room temperature, which also displayed excellent diastereoselectivity, good functional group tolerance, and air compatibility. A series of novel bridged-ring skeletons were obtained in good to excellent yields. Scale-up experiments were carried out with 1 or 0.75 mol % rhodium catalyst, affording the desired bridged-ring skeleton in excellent yields.

Phosphine Ligand Effects in Nickel-Catalyzed Alkene Migratory Hydroalkylation

AbstractCatalytic alkene hydroalkylation has provided to be an efficient method for synthesizing C(sp3) centers, from readily available and inexpensive alkene starting materials through alkene hydrometallation followed by cross-coupling. One of the major tasks in this field is to develop diverse ligands to achieve regioselective control. Herein, we report the investigation of nickel–triphenylphosphine-catalyzed remote hydroalkylation of alkenyl amides to access α-branched amines. Various alkenes and alkyl iodides are suitable substrates to deliver the desired products with excellent regioselectivities (>20:1 regioisomeric ratio). Density functional theory calculations reveal the reaction mechanism.

Highly selective α-C(sp3)-H arylation of alkenyl amides via nickel chain-walking catalysis

Herein, we report the migratory hydroarylation of unactivated alkenes with aryl iodides using native and weakly coordinating amide directors under mild conditions. Synergistic coordination of the monodentate directing group and the ligand enable the highly regioselective migratory hydroarylation via a chain walking process to form the thermodynamically stable five-membered nickelacyle intermediate. The protocol provides a variety of valuable α-aryl-substituted alkylamine products, and exhibited good functional group tolerance. The modification of bioactive compounds such as fenofibrate and indomethacin further highlights the synthetic value of this protocol.

Nickel-Catalyzed 8-Aminoquinoline Directed Reductive Dialkylcyclization/Homodialkylation of Unactivated Alkenes.

Chemo and regioselective dialkylation of alkene is an efficient protocol for constructing useful chemicals, but challenges remain in the unrestricted application of alkylating reagents. Alkyl bromide belongs to the easy-to-access and operable alkyl electrophiles that can be used in reductive coupling with alkenes. Here, we reported convenient strategies for dialkylcyclization and homodialkylation of unactivated β,γ- and γ,δ-unsaturated alkenyl amides with 1,3-dibromoalkanes or primary alkyl bromides under nickel-catalyzed reductive conditions that exhibited high regioselectivity and functional-group tolerance.

Ligand-Controlled NiH-Catalyzed Regiodivergent and Enantioselective Hydroamination of Alkenyl Amides

Ligand-Controlled NiH-Catalyzed Regiodivergent and Enantioselective Hydroamination of Alkenyl Amides

Copper-catalyzed conjugate addition of allene-derived nucleophiles to alkenyl-substituted carboxamides

Catalytic Michael addition reaction represents a fundamental importance in organic synthetic chemistry. Whereas corresponding conversions toward intrinsically low reactive enamide remains an ongoing challenging. We herein report a copper-catalyzed conjugate addition of allenes to β-substituted alkenyl amides, one of the most challenging Michael acceptors. The present method utilizes readily available allenes as the latent carbon-based nucleophiles and simple, common β-substituted alkenyl amides as starting materials, unlike previous methods that usually preinstall an activating group to improve the reactivity of amide or uses highly reactive stoichiometric quantities of organometallics. Hence, this approach shows good functional group compatibility and can be implemented under mild reaction conditions with excellent level of chemo- and regioselectivities.

Palladium(II)-Catalyzed Regioselective Hydrocarbofunctionalization of N-Alkenyl Amides: Synthesis of Tryptamine Derivatives.

The hydrocarbofunctionalization of allyl amines connected to the picolinamide directing group is developed under Pd(II) catalysis. The strategy is grounded on a nucleopalladation concept, and a wide range of indoles effectively participated to produce valuable tryptamine derivatives in high yields. Synthetic utilities were showcased through the substrate diversification bearing bioactive core, Pictet-Spengler cyclization, and β-carboline synthesis. A mechanistic study suggested an irreversible nucleopalladation step, while protodepalladation follows a reversible pathway.

Ruthenium(II)-Catalyzed (4+2) Annulative Difunctionalization of Non-conjugated Alkenyl Amides with Hydroxamic Acid Esters.

Ru(II)-catalyzed C-H bond activation strategy has been capitalized through a (4+2) annulative difunctionalization of non-conjugated alkenyl amides. Under mild conditions, a broad range of (hetero)aromatic amides embedded with NH-OMe unit as an internal oxidant produced high-value dihydroisoquinolinone scaffolds in good to excellent yields. This heteroannulation is also effective with acrylamides to dispense dihydro-2-pyridones and accommodates bioactive scaffolds such as tocopherol, estrone, and amino acids.

Palladium-Catalyzed Formal [3+2], [4+2], and [5+2] Heteroannulation of Non-conjugated Alkenyl Amides

Key words palladium catalysis - annulation - 8-aminoquinoline - ambiphiles

Mapping Ambiphile Reactivity Trends in the Anti‐(Hetero)annulation of Non‐Conjugated Alkenes via PdII/PdIV Catalysis

AbstractIn this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti‐selective carbo‐ or heteroannulation with non‐conjugated alkenyl amides under PdII/PdIV catalysis. Detailed optimization of the reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n=3–5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through PdII/amine co‐catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct PdII/PdIV mechanism involving Wacker‐type directed nucleopalladation. This difference results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments.

Mapping Ambiphile Reactivity Trends in the Anti-(Hetero)annulation of Non-Conjugated Alkenes via PdII /PdIV Catalysis.

In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti-selective carbo- or heteroannulation with non-conjugated alkenyl amides under PdII /PdIV catalysis. Detailed optimization of the reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n=3-5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through PdII /amine co-catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct PdII /PdIV mechanism involving Wacker-type directed nucleopalladation. This difference results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments.

\u03b3-Selective C(sp3)\u2013H amination via controlled migratory hydroamination

Remote functionalization of alkenes via chain walking has generally been limited to C(sp3)–H bonds α and β to polar-functional units, while γ-C(sp3)–H functionalization through controlled alkene transposition is a longstanding challenge. Herein, we describe NiH-catalyzed migratory formal hydroamination of alkenyl amides achieved via chelation-assisted control, whereby various amino groups are installed at the γ-position of aliphatic chains. By tuning olefin isomerization and migratory hydroamination through ligand and directing group optimization, γ-selective amination can be achieved via stabilization of a 6-membered nickellacycle by an 8-aminoquinoline directing group and subsequent interception by an aminating reagent. A range of amines can be installed at the γ-C(sp3)–H bond of unactivated alkenes with varying alkyl chain lengths, enabling late-stage access to value-added γ-aminated products. Moreover, by employing picolinamide-coupled alkene substrates, this approach is further extended to δ-selective amination. The chain-walking mechanism and pathway selectivity are investigated by experimental and computational methods.

Regiodivergent alkene difunctionalizations

Lactams are ubiquitous moieties in a variety of natural products and pharmaceuticals. Due to the important biological roles of lactam-containing molecules, development of efficient methods to synthesize functionalized lactams is highly desired. In this regard, Rovis developed intramolecular cyclizations of alkenyl amides as an attractive strategy, which allows formation of lactams with concomitant installation of an additional functional group by trapping intermediates with amine and carboxylate.

Synthesis of N-CF3 Alkynamides and Derivatives Enabled by Ni-Catalyzed Alkynylation of N-CF3 Carbamoyl Fluorides.

The expansion of chemical space associated with ubiquitous motifs is key to unleash new properties and functions. In this context, alkynamides, prevalent in numerous drugs and materials, represent an untapped resource. We herein report the first synthetic access to N-trifluoromethyl alkynamides. Our strategy relies on a mild and operationally simple Ni-catalyzed coupling of N-CF3 carbamoyl fluorides with alkynyl silanes. The synthesized N-CF3 alkynamides proved to be highly robust and readily functioned as a platform to unlock access to valuable derivatives, such as N-CF3 decorated alkenyl amides, oxindoles, or quinolones, all of which were inaccessible to date.

Modular synthesis of non-conjugated N-(quinolin-8-yl) alkenyl amides via cross-metathesis

We report a direct and modular method to access non-conjugated alkenyl amides containing the 8-aminoquinoline (AQ) directing auxiliary and related groups via cross-metathesis. In this way, readily available, AQ-containing, terminal β,γ-unsaturated amides can be coupled with various terminal alkenes to furnish internal alkene products that are otherwise difficult to prepare. The value of this family of products stems from their ability to participate in a number of directed alkene functionalization reactions.

Rh-Catalyzed General Method for Directed C-H Functionalization via Decarbonylation of in-Situ-Generated Acid Fluorides from Carboxylic Acids.

A Rh-catalyzed decarbonylative C-H coupling of in-situ-generated acid fluorides with amide substrates bearing ortho-Csp2-H bonds has been developed. This method enables alkyl, aryl, and alkenyl carboxylic acids to undergo decarbonylative coupling with C-H bonds of (hetero)aromatic or alkenyl amides in generally good yields via the in situ conversion of carboxylic acids into acid fluorides and also allows for the functionalization of a series of structurally complex carboxyl-containing natural products and pharmaceuticals as well as pharmaceutical amide derivatives.

Intermolecular C–H Amidation of Alkenes with Carbon Monoxide and Azides via Tandem Palladium Catalysis

AbstractAn atom- and step-economic intermolecular multi-component palladium-catalyzed C–H amidation of alkenes with carbon monoxide and organic azides has been developed for the synthesis of alkenyl amides. The reaction proceeds efficiently without an ortho-directing group on the alkene substrates. Nontoxic dinitrogen is generated as the sole by-product. Computational studies and control experiments have revealed that the reaction takes place via an unexpected mechanism by tandem palladium catalysis.

CuCl2-catalyzed highly stereoselective and chemoselective reduction of alkynyl amides into α,β-unsaturated amides using silanes as hydrogen donors.

A CuH-catalyzed Z-selective partial reduction of alkynyl amides to afford α,β-unsaturated amides using silane as the hydrogen donor is developed. This reaction is carried out under mild conditions and able to accommodate a broad scope of alkynyl amides including those bearing a terminal carbon-carbon double bond or triple bond, affording alkenyl amides with high stereoselectivity and excellent yields.

Chemoselective Union of Olefins, Organohalides, and Redox-Active Esters Enables Regioselective Alkene Dialkylation.

Multicomponent catalytic processes that can generate multiple C(sp3)-C(sp3) bonds in a single step under mild conditions, particularly those that employ inexpensive catalysts and substrates, are highly sought-after in chemistry research for complex molecule synthesis. Here, we disclose an efficient Ni-catalyzed reductive protocol that chemoselectively merges alkenyl amides with two different aliphatic electrophiles. Starting materials are readily accessible from stable and abundant feedstock, and products are furnished in up to >98:2 regioisomeric ratios. The present strategy eliminates the use of sensitive organometallic reagents, tolerates a wide array of complex functionalities, and enables regiodivergent addition of two primary alkyl groups bearing similar electronic and steric attributes across aliphatic C═C bonds with exquisite control of site selectivity. Utility is underscored by the concise synthesis of bioactive compounds and postreaction functionalizations leading to structurally diverse scaffolds. DFT studies revealed that the regiochemical outcome originates from the orthogonal reactivity and chemoselectivity profiles of in situ generated organonickel species.

Anti-selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation

2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines, as well as free –NH2 variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational studies on reactions with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination.