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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.

Chiral allene and N-heteroaryl motifs are present in an ever-growing list of biologically active natural products and synthetic drugs. Although significant progress has been made in asymmetric syntheses of chiral allenes, general and practical protocols for enantioselective syntheses of chiral N-heteroaryl-substituted allenes from readily available starting materials still remain rare. Here we report a highly enantioselective synthesis of quinolinyl-substituted chiral allenes through a copper-catalyzed asymmetric allenylation of quinoline N-oxides with readily available 1,3-enynes. A variety of 1,3-enynes react with quinoline N-oxides, affording the corresponding quinolinyl-substituted allenes in high yields (up to 95%) and high enantioselectivities (up to 99% ee). This transformation tolerates a variety of functional groups, such as chloro, bromo, trifluoromethyl ether, tertiary amine, siloxy, carboxylic ester, imide, pyridine, and thiophene moieties. DFT calculations suggest a pathway involving an intramolecular nucleophilic addition of an allenyl copper intermediate with a coordinated quinoline N-oxide through a five-membered, rather than seven-membered, transition state. Chiral allenes are useful chemical reagents, but efficient access to chiral heteroaryl allenes remains challenging. Here the authors report a copper-catalyzed asymmetric allenylation of quinoline N-oxides using 1,3-enynes, providing efficient access to axially chiral allenes bearing heteroarenes.

We report a copper-catalyzed enantioselective hydroboration of 1,3-enynes with the catalyst generated from Cu(OAc) and (S,S)-Ph-BPE. A wide range of alkyl- and aryl-substituted 1,3-enynes undergo this asymmetric hydroboration with pinacolborane, yielding the corresponding allenes in good yields with high to excellent enantioselectivities (up to 99% ee). This asymmetric transformation tolerates a variety of reactive groups, such as chloro, bromo, trifluoromethyl ether, siloxy, carboxylic ester and imido functionalities.

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

A mild and efficient oxidative synthesis of isoindolinones has been realized by Rh(III)-catalyzed C–H activation of benzamides and [4 + 1] coupling with propargyl alcohols. This coupling system proceeds with broad substrate scope and mild conditions and provides a new approach to access the useful skeleton of γ -lactams with a stereogenic center.

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).

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.

[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.

An efficient synthesis of 2-substituted quinolines from readily available cyclopropanols and imidamides has been developed, where the cyclopropanol acts as a C3 synthon. With the assistance of a bifunctional imidamide directing group, the reaction occurred via sequential C–H/C–C cleavage and C–C/C–N bond formation.

Carbonyl groups are ubiquitous in functional molecules. Although C–H bond acylation has been well-studied via different mechanisms, transition-metal-catalyzed redox-neutral C(sp3)–H acylation under mild conditions is unprecedented. In this work, ketene is designed as a acylating reagent for both C(sp3)–H and C(sp2)–H bonds under Rh(III) catalysis, affording a diverse array of carbonyl compounds in high yields and high atom economy under mild conditions.

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.

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 β-oxygen elimination. A broad range of synthetically useful functional groups are compatible, thus providing a new entry to access diversely 2-functionalized 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.

Previous direct C-H nitrogenation suffered from simple amidation/amination with limited atom-economy and is mostly limited to C(sp(2) )-H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp(2) )-H and C(sp(3) )-H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species.

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.

Iridium(III) and rhodium(III) complexes can catalyze the carbocyclization between 2-phenylimidazo[1,2-a]pyridine and α-diazo esters. The reaction occurs via CH activation and dialkylation of the arene followed by intramolecular nucleophilic substitution. Iridium(III) and rhodium(III) catalysis offer complementary scopes with respect to the α-diazo esters.

The synthesis of N-unprotected indoles has been realized via Rh(III)-catalyzed C-H activation/annulation of imidamides with α-diazo β-ketoesters. The reaction occurs with the release of an amide coproduct, which originates from both the imidamide and the diazo as a result of C═N cleavage of the imidamide and C-C(acyl) cleavage of the diazo. A rhodacyclic intermediate has been isolated and a plausible mechanism has been proposed.

C-H activation assisted by a bifunctional directing group has allowed the construction of heterocycles. This is ideally catalyzed by earth-abundant and eco-friendly transition metals. We report Co(III)-catalyzed redox-neutral coupling between arenes and alkynes using an NH amide as an electrophilic directing group. The redox-neutral C-H activation/coupling afforded quinolines with water as the sole byproduct.

Cobalt(III)-catalyzed C–H activation of simple benzoate esters has been achieved, and redox-neutral annulative coupling with internal alkynes allowed efficient synthesis of indenones. The employment of the weak and simple ester directing group makes it an attractive protocol in carbocycle synthesis.

Rhodium-catalyzed C–H activation of arenes has been established as an important strategy for the rapid construction of new bonds. On the other hand, ring-opening of readily available cyclopropanols has served as a driving force for the coupling with various nucleophiles and electrophiles. Nevertheless, these two important areas evolved separately, and coupling of arenes with cyclopropanols via C–H activation has been rarely explored. In this work, the oxidative coupling between arenes and cyclopropanols has been realized with high efficiency and selectivity under Rh(III)-catalysis, providing an efficient route to access β-aryl ketones. Moreover, the C–H bond has been extended to benzylic C–H bonds.

Rh-catalyzed redox-neutral coupling between N-aryl nitrones and alkynes has been achieved under relatively mild conditions. The reaction proceeded via C–H activation at the N-aryl ring with subsequent O-atom transfer, affording trisubstituted indolines in good chemoselectivity and moderate to good diasteroselectivity.

Rhodium(III)-catalyzed coupling between ketoximes and alkynes via C-H activation and annulation typically followed the [4+2] selectivity to afford isoquinolines. By designing alkynes bearing a highly electron-withdrawing group and under substrate control, we have successfully switched the selectivity of the coupling between oximes and alkynes to the alternative [3+2] annulation, leading to the efficient synthesis of indenamines. This process features good regioselectivity for both substrates, high efficiency, broad substrate scope, and excellent functional group tolerance.

Rh(III)-catalyzed C-H activation of 2-phenylimidazo[1,2-a]pyridines in divergent oxidative coupling with alkynes has been achieved. Selective mono versus 2-fold C-H activation has been attained under condition control. When AgOAc was used as an oxidant, the coupling afforded 5,6-disubstituted naphtho[1',2':4,5]imidazo[1,2-a]pyridines as a result of initial nitrogen chelation-assisted C-H activation at the benzene ring followed by rollover C-H activation. In contrast, the reaction afforded a fused isoquinolinium salt as a result of C-C and C-N coupling when AgBF4 was employed as a co-oxidant. A rhodacyclic intermediate has been isolated.

The first transition metal-catalyzed stereoconvergent Markovnikov 1,2-hydrosilylation of (E/Z)-dienes was effectively achieved with excellent E-selectivities using a cobalt catalyst., 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.

Rh(III)-catalyzed, chelation-assisted C-H activation and selenylation of arenes has been achieved. Arenes bearing oxime, azo, pyridyl, and N-oxide chelating groups are viable substrates, and electrophilic selenyl chlorides and diselenides are used as selenylating reagents. The catalytic system is highly efficient under mild conditions over a broad range of substrates with excellent functional group tolerance.

Rhodium(III)-catalyzed arylation of arenes bearing a chelating group has been realized via a redox-economy process using 4-hydroxycyclohexa-2,5-dienones as the arylating reagents, leading to the synthesis of 3-arylated phenols. This redox-neutral process proceeds via a C-H activation pathway with rearomatization being the driving force.

Rhodium(III)-catalyzed C-H activation-amidation of arenes bearing chelating groups has been achieved using N-arenesulfonated imides as efficient amidating reagents without using any base additive. Pyridine, oxime, and pyrimidine proved to be viable directing groups.

Cp*Rh(III)-catalyzed intermolecular C-C couplings between activated α-diazocarbonyl compounds and arenes bearing a range of azacyclic directing groups have been achieved. This catalytic alkylation reaction operates under mild conditions with good functional group tolerance.

Making C-C from C-H: [{RhCp*Cl(2)}(2)]/AgSbF(6) (Cp*=pentamethylcyclopentadienyl) can regioselectively catalyze the C-C coupling of arenes with aziridines by a C-H activation pathway. An eight-membered rhodacyclic intermediate resulting from the insertion of the Rh-C bond into the aziridine was isolated.

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 β-oxygen elimination. A broad range of synthetically useful functional groups are compatible, thus providing a new entry to access diversely 2-functionalized indoles.

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.

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.

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.

Cobalt(III)-catalyzed C–H activation of simple benzoate esters has been achieved, and redox-neutral annulative coupling with internal alkynes allowed efficient synthesis of indenones. The employment of the weak and simple ester directing group makes it an attractive protocol in carbocycle synthesis.

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.

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.

Iridium(III) and rhodium(III) complexes can catalyze the carbocyclization between 2-phenylimidazo[1,2-a]pyridine and α-diazo esters. The reaction occurs via CH activation and dialkylation of the arene followed by intramolecular nucleophilic substitution. Iridium(III) and rhodium(III) catalysis offer complementary scopes with respect to the α-diazo esters.

C–H activation of arenes has been established as an important strategy for heterocycle synthesis via annulations between arenes and unsaturated coupling partners. However, nitriles failed to act as such a coupling partner. Dioxazolones have been employed as a synthon of nitriles, and subsequent coupling with arenes such as N-sulfinylimines and benzimidates bearing a functionalizable directing group provided facile access to two classes of quinazolines under Co(III)-catalysis.

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.

The synthesis of N-unprotected indoles has been realized via Rh(III)-catalyzed C–H activation/annulation of imidamides with α-diazo β-ketoesters. The reaction occurs with the release of an amide coproduct, which originates from both the imidamide and the diazo as a result of C═N cleavage of the imidamide and C–C(acyl) cleavage of the diazo. A rhodacyclic intermediate has been isolated and a plausible mechanism has been proposed.

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.

C–H activation of arenes has been established as an important strategy for heterocycle synthesis via annulations between arenes and unsaturated coupling partners. However, nitriles failed to act as such a coupling partner. Dioxazolones have been employed as a synthon of nitriles, and subsequent coupling with arenes such as N-sulfinylimines and benzimidates bearing a functionalizable directing group provided facile access to two classes of quinazolines under Co(III)-catalysis.

A series of Mn-complexes with tetradentate N 4 ligands, introducing aromatic groups into 2-pyridylmethyl positions of N,N′-dimethyl-N,N′-bis(2-pyridylmethyl)ethane-1,2-diamine ( mep ), N,N′-dimethyl-N,N′-bis(2-pyridylmethyl)cyclohexane- trans -diamine ( mcp ), have been synthesized and applied for epoxidation of olefins using H 2 O 2 as the oxidant. The Mn-complexes still possessed an octahedral mononuclear structure in a cis -α topology. These complexes showed good regioselectivity, high yields and turnover frequency (even up to 228,000 h −1 ) with low catalyst loading (0.1–0.01 mol%) for epoxidation of a family of olefins (including internal aromatic olefins, internal and terminal aliphatic olefins and diolefins).

Rhodium(III)-catalyzed direct alkylation of arenes using commercially available alkyltrifluoroborates is disclosed. Oximes, heteroarenes, azomethines, N-nitrosoamines, and amides are viable directing groups to entail this transformation. The alkyl group in the boron reagent can be extended to primary alkyls, benzyl, and cycloalkyls, and the reaction proceeded with controllable mono- and dialkylation selectivity when both ortho C–H sites are accessible.

While in the presence of AgOAc as oxidant only imidazopyridines are obtained, AgBF4 leads to isoquinolinium salts via mono C—H activation.

Rh(III)-catalyzed C–H activation assisted by an oxidizing directing group has evolved to a mild and redox-economic strategy for the construction of heterocycles. Despite the success, these coupling systems are currently limited to cleavage of an oxidizing N–O or N–N bond. Cleavage of an oxidizing C–N bond, which allows for complementary carbocycle synthesis, is unprecedented. In this article, α-ammonium acetophenones with an oxidizing C–N bond have been designed as substrates for Rh(III)-catalyzed C–H activation under redox-neutral conditions. The coupling with α-diazo esters afforded benzocyclopentanones, and the coupling with unactivated alkenes such as styrenes and aliphatic olefins gave ortho-olefinated acetophenoes. In both systems the reactions proceeded with a broad scope, high efficiency, and functional group tolerance. Moreover, efficient one-pot coupling of diazo esters has been realized starting from α-bromoacetophenones and triethylamine. The reaction mechanism for the coupling with diazo este...

Two alternative, simple procedures for the Rh(III)-catalyzed selenylation of arenes bearing a directing group (29 examples) are developed.

Rh(III)-catalyzed C-H activation assisted by an oxidizing directing group has evolved to a mild and redox-economic strategy for the construction of heterocycles. Despite the success, these coupling systems are currently limited to cleavage of an oxidizing N-O or N-N bond. Cleavage of an oxidizing C-N bond, which allows for complementary carbocycle synthesis, is unprecedented. In this article, α-ammonium acetophenones with an oxidizing C-N bond have been designed as substrates for Rh(III)-catalyzed C-H activation under redox-neutral conditions. The coupling with α-diazo esters afforded benzocyclopentanones, and the coupling with unactivated alkenes such as styrenes and aliphatic olefins gave ortho-olefinated acetophenoes. In both systems the reactions proceeded with a broad scope, high efficiency, and functional group tolerance. Moreover, efficient one-pot coupling of diazo esters has been realized starting from α-bromoacetophenones and triethylamine. The reaction mechanism for the coupling with diazo esters has been studied by a combination of experimental and theoretical methods. In particular, three distinct mechanistic pathways have been scrutinized by DFT studies, which revealed that the C-H activation occurs via a C-bound enolate-assisted concerted metalation-deprotonation mechanism and is rate-limiting. In subsequent C-C formation steps, the lowest energy pathway involves two rhodium carbene species as key intermediates.