Allylic Dearomatization Research Articles

A Homo-Mannich Reaction Strategy Enables Collective Access to Ibophyllidine, Aspidosperma, Kopsia, and Melodinus Alkaloids.

We report here a homo-Mannich reaction of cyclopropanol with iminium ion generated by an asymmetric allylic dearomatization of indole to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this skeleton-constructing process, an all-carbon quaternary stereogenic center as well as an allyl and a ketone groups were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e., five-, six-, and seven-membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families.

A Homo‐Mannich Reaction Strategy Enables Collective Access to Ibophyllidine, Aspidosperma, Kopsia, and Melodinus Alkaloids

AbstractWe report here a homo‐Mannich reaction of cyclopropanol with an iminium ion, generated by an asymmetric allylic dearomatization of indole, to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this approach, an all‐carbon quaternary stereogenic center as well as an allyl and a ketone group were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e., five‐, six‐, and seven‐membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families.

One-pot synthesis of multisubstituted propenylbenzenes from benzyl chlorides through relay catalysis of palladium.

A strategy for the synthesis of multisubstituted propenylbenzenes using benzyl chlorides as starting materials is described. The palladium-catalyzed allylative dearomatization and the subsequent Wagner-Meerwein rearrangement as well as the olefin isomerization proceeded smoothly under mild conditions to produce propenylation products in good yields with high regioselectivity. Control experiments and cyclic voltammetry analysis suggest that Bu3SnCl, a by-product generated in the first step of allylative dearomatization, plays an essential role in the third step of olefin isomerization in the presence of a Brønsted acid.

Pd-Catalyzed intermolecular asymmetric allylic dearomatization of 1-nitro-2-naphthols with MBH adducts.

An asymmetric allylic dearomatization reaction of 1-nitro-2-naphthol derivatives with Morita-Baylis-Hillman (MBH) adducts has been developed. By utilizing Pd catalyst derived from Pd(OAc)2 and Trost ligand (R,R)-L1, the reaction proceeded smoothly in 1,4-dioxane at room temperature, affording substituted β-naphthalenones in good yields (up to 92%) and enantioselectivity (up to 90% ee). A range of substituted 1-nitro-2-naphthols and MBH adducts were found to be compatible under the optimized conditions. This reaction provides a convenient method for the synthesis of enantioenriched 1-nitro-β-naphthalenone derivatives.

Palladium(0)-Catalyzed Intermolecular Asymmetric Allylic Dearomatization of Substituted β-Naphthols with Morita-Baylis-Hillman (MBH) Adducts.

Pd-catalyzed intermolecular asymmetric allylic dearomatization of substituted β-naphthol derivatives with Boc-protected Morita-Baylis-Hillman (MBH) adducts was developed. The reaction occurs smoothly in 1,4-dioxane at room temperature in the presence of [Pd(C3H5)Cl]2 (2.5 mol %), (S, Sp)-PHOX ligand (5.5 mol %), and Li2CO3 (1.0 equiv). A series of dearomatized products were afforded in moderate to excellent yields and enantioselectivity (up to 99% yield, 97% ee). Furthermore, the compatibility with gram-scale reaction and mild conditions make the current method synthetically useful.

Electrophilic Trapping of Semibenzenes.

In this work, we demonstrate how allylative dearomatization of benzyl chlorides can provide direct access to a variety of semibenzenes. These scaffolds behave as highly reactive nucleophiles in the presence of carbocations. In addition, semibenzenes are susceptible to intramolecular rearrangements rendering a broad scope of functionalized arenes. An analysis of this new reactivity is reported, as well as the rationale behind the observed intramolecular reorganizations.

Spirocarbocycle Synthesis from Chloromethylarenes via Transition-Metal-Catalyzed Allylative Dearomatization and Ring Closure Metathesis.

A strategy for the synthesis of spirocarbocycles by using chloromethyl arenes as starting materials is described in this paper. The palladium-catalyzed allylative dearomatization and the subsequent ruthenium-catalyzed ring closure metathesis proceeded smoothly under mild conditions to produce the corresponding spirocarbocycle products with moderate to high yields. Benzene-ring-, naphthalene-ring-, and anthracene-ring-containing substrates can be easily transformed into spirocarbocycles by using the proposed method.

Pd-Catalyzed Enantioselective Dearomative Allylic Annulation to Access PPAPs Analogues.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) share a common bicyclo[3.3.1]alkenone core structure and attract numerous attention from synthetic organic chemists due to their fascinating biological properties and associated synthetic challenges. We present herein that Pd-phosphoramidite catalysts promote the enantioselective dearomative allylic annulation reaction between allyl desoxyhumulones and allylic dicarbonates, affording PPAPs analogues in good yields and enantioselectivities. The reaction likely proceeds through two-step dearomative allylation by Pd, and the C-allylation pathway is the dominant mechanistic model.

Palladium-catalyzed allylic alkylation dearomatization of β-naphthols and indoles with gem-difluorinated cyclopropanes.

A palladium-catalyzed allylic alkylation dearomatization of β-naphthols and indoles with gem-difluorinated cyclopropanes has been developed. This reaction provided an efficient route to access 2-fluoroallylic β-naphthalenones and indolenines bearing quaternary carbon centers in good yields with high Z-selectivity via C-C bond activation, C-F bond cleavage and the dearomatization process, benefiting from the wide substrate scope and good functional group tolerance. Moreover, 2-fluoroallylic furanoindoline and pyrroloindolines were achieved in good efficiency via cascade allylic alkylation, dearomatization and cyclization processes in the presence of Et3B.

Palladium-catalyzed dearomative allylation of indoles with cyclopropyl acetylenes: access to indolenine derivatives

A palladium-catalyzed redox-neutral allylic alkylation of indoles with cyclopropyl acetylenes has been disclosed. Various 1,3-diene indolenine framework bearing a quaternary stereocenter at the C3 position were synthesized straightforwardly in good to excellent yields with high regio- and stereoselectivities. The reaction could be further expanded to the dearomatization of naphthols to synthesize functionalized cyclohexadienones with 1,3-diene motifs. The reaction exhibited high atom economy and good functional group tolerance.

Enantioselective synthesis of polycyclic pyrrole derivatives by iridium-catalyzed asymmetric allylic dearomatization and ring-expansive migration reactions

Herein, we report an N-alkylation of pyrroles triggered by an unprecedented selective ring-expansive migration of the spiro-2H-pyrrole intermediates obtained via Ir-catalyzed asymmetric allylic dearomatization. The reaction affords a series of tetrahydropyrrolo[1,2-c]pyrimidine derivatives in good yields (up to 88%) with excellent enantioselectivity (up to >99% ee). The proposed reaction mechanism is supported by DFT calculations and the characterization of the key intermediate.

Enantioselective Desymmetrization of Bisphenol Derivatives via Ir-Catalyzed Allylic Dearomatization.

Spirocyclic hexadienones with multiple stereogenic centers are frequently found in natural products but remain challenging targets to synthesize. Herein, we report the enantioselective desymmetrization of bisphenol derivatives via Ir-catalyzed allylic dearomatization reactions, affording spirocyclic hexadienone derivatives with up to three contiguous stereogenic centers in good yields (up to 90%) and excellent enantioselectivity (up to 99% ee). The high efficiency of this reaction is exemplified by the short reaction time (30 min), low catalyst loading (down to 0.2 mol %), and ability to perform the reaction on a gram-scale. The total syntheses of (+)-tatanan B and (+)-tatanan C were also realized using this Ir-catalyzed allylic dearomatization reaction as a key step.

Allylic and Allenylic Dearomatization of Indoles Promoted by Graphene Oxide by Covalent Grafting Activation Mode.

The site-selective allylative and allenylative dearomatization of indoles with alcohols was performed under carbocatalytic regime in the presence of graphene oxide (GO, 10 wt % loading) as the promoter. Metal-free conditions, absence of stoichiometric additive, environmentally friendly conditions (H2 O/CH3 CN, 55 °C, 6 h), broad substrate scope (33 examples, yield up to 92 %) and excellent site- and stereoselectivity characterize the present methodology. Moreover, a covalent activation model exerted by GO functionalities was corroborated by spectroscopic, experimental and computational evidences. Recovering and regeneration of the GO catalyst through simple acidic treatment was also documented.

Dearomative Allylation of Naphthyl Cyanohydrins by Palladium Catalysis: Catalyst-Enhanced Site Selectivity.

A dearomative allylation of naphthyl cyanohydrins with allyl borates and allyl stannanes under palladium catalysis was developed. At the initial stage of this study, the dearomative reaction (C4 substitution of the aromatics) was competing with benzyl substitution. To circumvent this issue, the use of palladium and meta-disubstituted triarylphosphine as the catalyst in a 1:1 ratio was found to enhance the site selectivity, furnishing the desired dearomatized products. Further derivatizations of products were also successful.

Ni-Catalyzed Allylic Dearomatization Reaction of β-Naphthols with Allylic Alcohols.

Ni-catalyzed intermolecular allylic dearomatization reaction of β-naphthols with allylic alcohols was achieved. By utilizing Ni(cod)2 as a catalyst precursor, DPEphos as a ligand and 4 Å molecular sieves as additives, the dearomatization reaction of β-naphthols with aryl allylic alcohols proceeded smoothly under mild conditions, affording the desired β-naphthalenone products bearing a quaternary carbon center in moderate to good yields with excellent linear selectivity.

Ni-Catalyzed Intermolecular Allylic Dearomatization Reaction of Tryptophols and Tryptamines.

An efficient synthesis of pyrrolidinoindolines and tetrahydrofuranoindolines was achieved via Ni-catalyzed allylic dearomatization reactions of tryptophols and tryptamines. In the presence of 13 mol % of Ni(cod)2 and 10 mol % DPEphos, both tryptophols and tryptamines could react with aryl vinyl carbinols smoothly under mild conditions, affording 3-cinnamyl indolines in moderate to good yields with high chemo- and regioselectivity. This method features a broad substrate scope, a commercially available and inexpensive catalytic system, and readily available substrates.

Dearomative [4 + 2] Cycloaddition of Pyridine via Energy-Transfer Catalysis

In this issue of Chem, Glorius and coworkers report the first photocatalytic dearomative cycloaddition of pyridine with alkene. High-value isoquinuclidines could be easily assembled from N-cinamoyl picolinamides under mild and operationally simple conditions.

Rhodium-Catalyzed Asymmetric Allylic Dearomatization of β-Naphthols: Enantioselective Control of Prochiral Nucleophiles.

A highly enantioselective rhodium-catalyzed allylic dearomatization of β-naphthols with racemic aryl vinyl carbinol is described. In the presence of a Rh-catalyst derived from [Rh(C2H4)Cl]2 and chiral (P, olefin)-ligand with TFA as an additive, the functionalized β-naphthalenone compounds bearing an all-carbon-substituted quaternary stereogenic center were obtained in good yields with excellent enantioselectivity. In addition, this protocol features the enantioselective control of prochiral nucleophiles and provides the first illustration of Rh-catalyzed asymmetric allylic dearomatization.

Tandem Pd-Catalyzed Intermolecular Allylic Alkylation/Allylic Dearomatization Reaction of Benzoylmethyl pyridines, Pyrazines, and Quinolines.

An efficient synthesis of nitrogen-containing heterocycles via Pd-catalyzed tandem allylic alkylation and dearomatization reactions was reported. In this reaction design, heteroarenes such as pyridines, pyrazines, and quinolines serve as bis-nucleophiles by installing a benzoyl group at the C2 benzylic position. With but-2-ene-1,4-diyl dimethyl dicarbonate as the bis-electrophile, the tandem Pd-catalyzed intermolecular allylic alkylation/allylic dearomatization reaction of benzoylmethyl-substituted heteroarenes has been developed. 2,3-Dihydroindolizine, 6,7-dihydropyrrolo[1,2- a]pyrazine, and 1,2-dihydropyrrolo[1,2- a]quinolin derivatives were obtained in moderate to good yields.

Highly Diastereo- and Enantioselective Synthesis of Quinuclidine Derivatives by an Iridium-Catalyzed Intramolecular Allylic Dearomatization Reaction

Asymmetric construction of quinuclidine derivatives has been realized by an iridium-catalyzed allylic dearomatization reaction. The catalytic system, derived from [Ir(cod)Cl] 2 and the Feringa ligand, tolerates a broad range of substrates. A large array of quinuclidine derivatives can be obtained under mild conditions in good to excellent yields (68%–96%), diastereoselectivity (up to >20/1 dr), and enantioselectivity (up to >99% ee). These products feature versatile functional group diversity and can undergo diverse transformations. A model that accounts for the origin of the stereoselectivity has been proposed based on density functional theory (DFT) calculations.