Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles.

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o-iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

Rhodium-Catalyzed Enantioselective Formal [4+1] Cyclization of Benzyl Alcohols and Benzaldimines: Facile Access to Silicon-Stereogenic Heterocycles.

The carbon-to-silicon switch in formation of bioactive sila-heterocycles with a silicon-stereogenic center has garnered significant interest in drug discovery. However, metal-catalyzed synthesis of such scaffolds is still in its infancy. Herein, a rhodium-catalyzed enantioselective formal [4+1] cyclization of benzyl alcohols and benzaldimines has been realized by enantioselective difunctionalization of a secondary silane reagent, affording chiral-at-silicon cyclic silyl ethers and sila-isoindolines, respectively. Mechanistic studies reveal a dual role of the rhodium-hydride catalyst. The coupling system proceeds via rhodium-catalyzed enantio-determining dehydrogenative OH silylation of the benzyl alcohol or hydrosilylation of the imine to give an enantioenriched silyl ether or silazane intermediate, respectively. The same rhodium catalyst also enables subsequent intramolecular cyclative C-H silylation directed by the pendent Si-H group. Experimental and DFT studies have been conducted to explore the mechanism of the OH bond silylation of benzyl alcohol, where the Si-O reductive elimination from a Rh(III) hydride intermediate has been established as the enantiodetermining step.

Rhodium-Catalyzed Enantioselective 1,4-Oxyamination of Conjugated gem-Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones.

The incorporation of fluorine atoms in organics improves their bioactivity and lipophilicity. Catalytic functionalization of gem-difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. In contrast to the regular 1,3-dienes that undergo diverse asymmetric di/hydrofunctionalizations, the regio- and enantioselective oxyamination of gem-difluorodienes remains untouched. Herein, we report asymmetric 1,4-oxyamination of gem-difluorodiene by chiral rhodium-catalyzed three-component coupling with readily available carboxylic acid and dioxazolone, affording gem-difluorinated 1,4-amino alcohol derivatives. Our asymmetric protocol exhibits high 1,4-regio- and enantioselectivity with utility in the late-stage modification of pharmaceuticals and natural products. Stoichiometric experiments provide evidences for the π-allylrhodium pathway. Related oxyamination was also realized when trifluoroethanol was used as an oxygen nucleophile.

O-Allylhydroxyamine: A Bifunctional Olefin for Construction of Axially and Centrally Chiral Amino Alcohols via Asymmetric Carboamidation.

Difunctionalization of olefins offers an attractive approach to access complex chiral structures. Reported herein is the design of N-protected O-allylhydroxyamines as bifunctional olefins that undergo catalytic asymmetric 1,2-carboamidation with three classes of (hetero)arenes to afford chiral amino alcohols via C-H activation. The C═C bond in O-allylhydroxyamine is activated by the intramolecular electrophilic amidating moiety as well as a migrating directing group. The asymmetric carboamidation reaction pattern depends on the nature of the (hetero)arene reagent. Simple achiral (hetero)arenes reacted to give centrally chiral ß-amino alcohols in excellent enantioselectivity. The employment of axially prochiral or axially racemic heteroarenes afforded amino alcohols with both axial and central chirality in excellent enantio- and diastereoselectivity. In the case of axially racemic heteroarenes, the coupling follows a kinetic resolution pattern with an s-factor of up to >600. A nitrene-based reaction mechanism has been suggested based on experimental studies, and a unique mode of induction of enantio- and diastereoselectivity has been proposed. Applications of the amino alcohol products have been demonstrated.

Cobalt-Catalyzed Fluoroallyllation of Carbonyls via C-C Activation of gem-Difluorocyclopropanes.

A new Co-catalyzed sequential C-C and C-F activation of gem-difluorinated cyclopropanes (gem-FCPs) to form nucleophilic fluoroallylcobalt, followed by addition to aldehydes, is reported. The protocol features the regioselective cleavage of dual chemical bonds of readily available gem-FCPs to prepare easily separable linear (Z)- and (E)-fluorinated homoallylic alcohols with a broad scope. This discovery established a new strategy for the efficient transformation of gem-FCPs as well as the synthesis of challenging fluorinated homoallylic alcohols.

Palladium-Catalyzed Stagewise Strain-Release-Driven C-C Activation of Bicyclo[1.1.1]pentanyl Alcohols.

A palladium-catalyzed chemoselective coupling of readily available bicyclo[1.1.1]pentanyl alcohols (BCP-OH) with various halides is reported, which offers expedient approaches to a wide range of cyclobutanone and ß,γ-enone skeletons via single or double C-C activation. The chemistry shows a broad substrate scope in terms of both the range of BCP-OH and halides including a series of natural product derivatives. Moreover, dependency of reaction chemodivergence on base additive has been investigated through experimental and density functional theory (DFT) studies, which is expected to significantly enrich the reaction modes and increase the synthetic potential of BCP-OH in preparing more complex molecules.

Iridium-Catalyzed Enantioselective Synthesis of α-Chiral Bicyclo[1.1.1]pentanes by 1,3-Difunctionalization of [1.1.1]Propellane.

Bicyclo[1.1.1]pentanes (BCPs) have found application as bioisosteres of aromatic rings in drug development. However, catalytic construction of this motif with adjacent stereocenters with high enantioselectivity from readily available starting materials still constitutes a significant synthetic challenge. Herein we report a direct stereoselective synthesis of α-chiral allylic BCPs by 1,3-difunctionalization of [1.1.1]propellane with Grignard reagents and allyl carbonates using iridium catalysis. This mild protocol proceeds via initial organometallic addition to [1.1.1]propellane followed by asymmetric allylic substitution, providing the products with high enantioselectivities over a broad range of substrates. Further derivatization of the products demonstrates the applicability of this method to the preparation of structurally diverse libraries of chiral BCP derivatives.

1,3-Difunctionalizations of [1.1.1]Propellane via 1,2-Metallate Rearrangements of Boronate Complexes.

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para-substituted aromatic rings. The most direct route to these structures is via multicomponent ring-opening reactions of [1.1.1]propellane. However, challenges associated with these transformations mean that difunctionalized BCPs are more commonly prepared by multistep reaction sequences with BCP-halide intermediates. Herein, we report three- and four-component 1,3-difunctionalizations of [1.1.1]propellane with organometallic reagents, organoboronic esters, and a variety of electrophiles. This process is achieved by trapping intermediate BCP-metal species with boronic esters to form boronate complexes, which are versatile intermediates whose electrophile-induced 1,2-metallate rearrangement chemistry enables a broad range of C-C bond-forming reactions.

Methylenespiro[2.3]hexanes via Nickel-Catalyzed Cyclopropanations with [1.1.1]Propellane.

[1.1.1]Propellane is a highly strained tricyclic hydrocarbon whose reactivity is dominated by addition reactions across the central inverted bond to provide bicyclo[1.1.1]pentane derivatives. These reactions proceed under both radical and two-electron pathways, hence, providing access to a diverse array of products. Conversely, transition metal-catalyzed reactions of [1.1.1]propellane are underdeveloped and lack synthetic utility, with reported examples generally yielding mixtures of ring-opened structural isomers, dimers, and trimers, often with poor selectivity. Herein, we report that nickel(0) catalysis enables the use of [1.1.1]propellane as a carbene precursor in cyclopropanations of a range of functionalized alkenes to give methylenespiro[2.3]hexane products. Computational studies provide support for initial formation of a Ni(0)-[1.1.1]propellane complex followed by concerted double C-C bond activation to give the key 3-methylenecyclobutylidene-nickel intermediate.

Redox-Neutral Access to Isoquinolinones via Rhodium(III)-Catalyzed Annulations of O-Pivaloyl Oximes with Ketenes.

A mild and redox-neutral [4 + 2] annulation of O-pivaloyl oximes with ketenes has been realized for synthesis of quaternary-carbon-stereocenter-containing (QCSC) isoquinolinones, where the N-OPiv not only acts as an oxidizing group but also offers coordination saturation to inhibit protonolysis. The reaction mechanism has been studied by DFT calculations.

Cobalt-catalyzed regioselective stereoconvergent Markovnikov 1,2-hydrosilylation of conjugated dienes.

We report the first stereoconvergent Markovnikov 1,2-hydrosilylation of conjugated dienes using catalysts generated from bench-stable Co(acac)2 and phosphine ligands. A wide range of E/Z-dienes underwent this Markovnikov 1,2-hydrosilylation in a stereoconvergent manner, affording (E)-allylsilanes in high isolated yields with high stereoselectivities (E/Z = >99 : 1) and high regioselectivities (b/l up to > 99 : 1). Mechanistic studies revealed that this stereoconvergence stems from a σ-π-σ isomerization of an allylcobalt species generated by the 1,4-hydrometalation of Z-dienes. In addition, a cobalt catalyst that can only catalyze the hydrosilylation of the E-isomer of an (E/Z)-diene was identified, which allows the separation of the (Z)-isomer from an isomeric mixture of (E/Z)-dienes. Furthermore, asymmetric hydrosilylation of (E)-1-aryl-1,3-dienes was studied with Co(acac)2/(R)-difluorphos and good enantioselectivities (er up to 90 : 10) were obtained.

Enantioselective Copper-Catalyzed Alkylation of Quinoline N-Oxides with Vinylarenes.

An asymmetric copper-catalyzed alkylation of quinoline N-oxides with chiral Cu-alkyl species, generated by migratory insertion of a vinylarene into a chiral Cu-H complex, is reported. A variety of quinoline N-oxides and vinylarenes underwent this Cu-catalyzed enantioselective alkylation reaction, affording the corresponding chiral alkylated N-heteroarenes in high yield with high-to-excellent enantioselectivity. This enantioselective protocol represents the first general and practical approach to access a wide range of chiral alkylated quinolines.

Cobalt-Catalyzed Asymmetric Hydroboration/Cyclization of 1,6-Enynes with Pinacolborane.

We report a cobalt-catalyzed asymmetric hydroboration/cyclization of 1,6-enynes with catalysts generated from Co(acac)2 and chiral bisphosphine ligands and activated in situ by reaction with pinacolborane (HBpin). A variety of oxygen-, nitrogen-, and carbon-tethered 1,6-enynes underwent this asymmetric transformation, yielding both alkyl- and vinyl-substituted boronate esters containing chiral tetrahydrofuran, cyclopentane, and pyrrolidine moieties with high to excellent enantioselectivities (86%-99% ee).

Nitrone Directing Groups in Rhodium(III)-Catalyzed C-H Activation of Arenes: 1,3-Dipoles versus Traceless Directing Groups.

Functionalizable directing groups (DGs) are highly desirable in C-H activation chemistry. The nitrone DGs are explored in rhodium(III)-catalyzed C-H activation of arenes and couplings with cyclopropenones. N-tert-butyl nitrones bearing a small ortho substituent coupled to afford 1-naphthols, where the nitrone acts as a traceless DG. In contrast, coupling of N-tert-butyl nitrones bearing a bulky ortho group follows a C-H acylation/[3+2] dipolar addition pathway to give bicyclics. The coupling of N-arylnitrones follows the same acylation/[3+2] addition process but delivers different bicyclics.

Transition metal-catalysed couplings between arenes and strained or reactive rings: combination of C-H activation and ring scission.

Organic transformations that involve direct functionalization of C-H bonds represent an attractive synthetic strategy that maximizes atom- and step-economy. With the generally high stability of C-H bonds, these processes have mostly required harsh reaction conditions, in combination with the necessity of activation of the C-H substrates and/or the coupling partners. As a class of activated coupling partners, strained or reactive rings exhibited high activity in the coupling with aryl and alkyl C-H bonds. Such a high reactivity of the rings allowed the facile construction of various new structural platforms via coupling with scission of the ring structures. The combination of C-H activation and scission of the rings allowed for applications of a broader scope of C-H bonds, including those less reactive alkyl ones. This synthetic diversity of these rings has been realized owing to the intrinsically different mechanisms of the interactions of transition metal catalysts and the strained/reactive rings.

Cooperative Co(III)/Cu(II)-Catalyzed C-N/N-N Coupling of Imidates with Anthranils: Access to 1H-Indazoles via C-H Activation.

Cooperative cobalt- and copper-catalyzed C-H activation of imidate esters and oxidative coupling with anthranils allowed efficient synthesis of 1H-indazoles in the absence of metal oxidants. The anthranil acts as a convenient aminating reagent as well as an organic oxidant in this transformation. The copper catalyst likely functions at the stage of N-N formation.

Cobalt(III)-Catalyzed C-C Coupling of Arenes with 7-Oxabenzonorbornadiene and 2-Vinyloxirane via C-H Activation.

Co(III)-catalyzed mild C-C couplings of arenes with strained rings such as 7-oxabenzonorbornadienes and 2-vinyloxirane have been realized. The transformation is proposed to undergo ortho C-H activation, olefin insertion, and subsequent ß-oxygen elimination. A broad range of synthetically useful functional groups are compatible, thus providing a new entry to access diversely 2-functionalized indoles.

Access to Structurally Diverse Quinoline-Fused Heterocycles via Rhodium(III)-Catalyzed C-C/C-N Coupling of Bifunctional Substrates.

Rhodium(III)-catalyzed C-H activation of heteroarenes and functionalization with bifunctional substrates such as anthranils allows facile construction of quinoline-fused heterocycles under redox-neutral conditions. The couplings feature broad substrate scope and provide step-economical access to two classes of quinoline-fused condensed heterocycles.

Rh(III)-Catalyzed C-C/C-N Coupling of Imidates with α-Diazo Imidamide: Synthesis of Isoquinoline-Fused Indoles.

Imidate esters and diazo compounds have been established as bifunctional substrates for the construction of biologically active fused heterocycles via rhodium-catalyzed C-H activation and C-C/C-N coupling. This reaction occurs under mild conditions with high efficiency, step economy, and low catalyst loading.

Rhodium(III)-Catalyzed Mild Alkylation of (Hetero)Arenes with Cyclopropanols via C-H Activation and Ring Opening.

The rhodium(III)-catalyzed regioselective alkylation of (hetero)arenes using cyclopropanols as a reactive and efficient coupling partner under oxidative conditions has been developed. This coupling occurred at room temperature via C-H activation of arenes and C-C cleavage of cyclopropanols. Various types of (hetero)arenes (indolines, carbazole, tetrahydrocarbazole, pyrrole, thiophene, etc.) were all successfully reacted under the present conditions. This protocol provides the facile and efficient construction of C7-alkylated indoline scaffolds.