RhodiumIII/SilverI Relay Catalyzed C—H Aminomethylation with Imine Equivalents and Lewis Acid Catalyzed [4+2] Cycloaddition of Indoles with Triarylhexahydrotriazine†

A Rh^III/Ag^I relay‐catalyzed C(sp²)—H coupling of indoles with triarylhexahydrotriazine (THT) is reported in this context. Upon merging Rh^III‐catalyzed C(sp²)—H bond activation and silver promoted THT dissociation, an efficient indole's C3 aminomethylation protocol is uncovered, providing C3 aminomethyl indoles in good yields and exhibiting potential applications for the synthesis of complicated bioactive compounds. We revealed the C3‐selectivity of this reaction through a detailed mechanistic investigation. Meanwhile, during the examination of the reaction conditions, we discovered another [4+2] cycloaddition pathway to afford tetrahydro‐indolo[3,2‐c]quinoline scaffold products via silver or Lewis acid catalysis.     

From propargylic biscarbonate to diaryl[n]dendralenes

An efficient cross-coupling reaction using a low cost carbon-supported palladium (Pd/C) catalyst for the synthesis of cross-conjugated compounds, diaryl[n]dendralenes, has been developed. The reaction of a propargylic biscarbonate with phenylboronic acid using Pd/C and phosphine ligand (S-Phos) gave 2,3-diphenyl[2]dendralene in high yield. We found that Pd/C was an effective catalyst for the synthesis of dialyl[n]dendralenes. The synthesis of various dendralenes was successfully achieved under the optimized conditions, giving dialyl [2] and [4] dendralenes in good yields.     

Engaging Allene‐Derived Zwitterions in an Unprecedented Mode of Asymmetric [3+2]‐Annulation Reaction

Catalytic addition of chiral phosphine, that is, (R)‐ or (S)‐SITCP, to an α‐substituted allene ester generated a zwitterionic dipole. Under optimized reaction conditions, this dipole could engage isatine‐derived N‐Boc‐ketimines in a novel mode of [3+2] annulation reaction. Pyrrolinyl spirooxindoles are thus afforded in high yields and with excellent enantioselectivities. The unprecedented annulation reaction successfully facilitated the construction of sp³‐rich and highly substituted 3,2′‐pyrrolidinyl spirooxindoles supporting many chiral centers.     

Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt‐Catalyzed Multiple C(sp3)−H Activation Strategy

A cobalt‐catalyzed dual C(sp³)−H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation‐induced methylene C(sp³)−H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp³)−H activation, has also been demonstrated.     

[1+1+1] Cyclotrimerization for the Synthesis of Cyclopropanes

The synthesis of small rings by functionalization of C(sp³)?H bonds remains a great challenge. We report for the first time a copper‐catalyzed [1+1+1] cyclotrimerization of acetophenone derivatives under mild reaction conditions. The reaction has a broad scope for the stereoselective synthesis of cyclopropanes by trimerization of acetophenone. The developed transformation is based on an extraordinary copper‐catalyzed cascade process that allows saturated carbocycles to be obtained for the first time by cyclotrimerization through functionalization of C(sp³)?H bonds. The cascade of sixfold C(sp³)?H bond functionalization allows the synthesis of cyclopropanes in a highly stereoselective approach.     

Controllable Si−C Bond Activation Enables Stereocontrol in the Palladium‐Catalyzed [4+2] Annulation of Cyclopropenes with Benzosilacyclobutanes

A novel and unusual palladium‐catalyzed [4+2] annulation of cyclopropenes with benzosilacyclobutanes is reported. This reaction occurred through chemoselective Si?C(sp²) bond activation in synergy with ring expansion/insertion of cyclopropenes to form new C(sp²)?C(sp³) and Si?C(sp³) bonds. An array of previously elusive bicyclic skeleton with high strain, silabicyclo[4.1.0]heptanes, were formed in good yields with excellent diastereoselectivity under mild conditions. An asymmetric version of the reaction with a chiral phosphoramidite ligand furnished a variety of chiral bicyclic silaheterocycle derivatives with good enantioselectivity (up to 95.5:4.5 er). Owing to the mild reaction conditions, the good stereoselectivity profile, and the ready availability of the functionalized precursors, this process constitutes a useful and straightforward strategy for the synthesis of densely functionalized silacycles.     

Distinct Bimetallic Cooperativity Among Water Reduction Catalysts Containing [CoIIICoIII], [NiIINiII], and [ZnIIZnII] Cores

Three binuclear species [LCo^III₂(μ-Pz)₂](ClO₄)₃ ( 1 ), [LNi^II₂(CH₃OH)₂Cl₂]ClO₄ ( 2 ), and [LZn^II₂Cl₂]PF₆ ( 3 ) supported by the deprotonated form of the ligand 2,6-bis[bis(2-pyridylmethyl) amino-methyl]-4-methylphenol were synthesized, structurally characterized as solids and in solution, and had their electrochemical and spectroscopic behavior established. Species 1 – 3 had their water reduction ability studied aiming to interrogate the possible cooperative catalytic activity between two neighboring metal centers. Species 1 and 2 reduced H₂O to H₂ effectively at an applied potential of −1.6 V_Ag/AgCl, yielding turnover numbers of 2,820 and 2,290, respectively, after 30 minutes. Species 3 lacked activity and was used as a negative control to eliminate the possibility of ligand-based catalysis. Pre- and post-catalytic data gave evidence of the molecular nature of the process within the timeframe of the experiments. Species 1 showed structural, rather than electronic cooperativity, while species 2 displayed no obvious cooperativity. DFT methods complemented the experimental results determining plausible mechanisms.     

Visible light photoredox catalysis with N-hydroxyphthalimide for [4+2] cyclization between N-methylanilines and maleimides

An efficient [4+2] cyclization of N-methylanilines with maleimides to afford tetrahydroquinolines using N-hydroxyphthalimide as a metal-free and cheap organophotoredox catalyst is reported. The protocol involves C(sp³)H activation of N-methylanilines for the formation of α-amino radical without an oxidant at room temperature. The present method describes an easy preparation of tricyclic heterocycles in good to excellent yields under mild reaction conditions.     

Theoretical investigation toward organophosphine‐catalyzed [3 + 3] annulation of Morita–Baylis–Hillman carbonates with azomethine imines: Mechanism,origin of stereoselectivity,and role of catalyst

A computational study on the detailed mechanism and stereoselectivity of the chiral phosphine‐catalyzed C(sp²)? H activation/[3 + 3] annulation between Morita–Baylis–Hillman (MBH) carbonates and C,N‐cyclic azomethine imines has been performed. Generally, the catalytic cycle consists of two stages, that is, C(sp²)? H activation companied by the dissociation of the t‐BuO group forming phosphonium enolate, and [3 + 3] cycloaddition process followed by regeneration of the catalyst. The calculated results indicate that C(sp²)? H activation is rate‐determining while [3 + 3] cycloaddition is stereoselectivity‐determining. Furthermore, the advantageous hydrogen bond interactions and less steric hindrance in the RR configurational C? C bond forming transition states should be responsible for the favorability of RR‐configured product among the four possible products. The special role of the organocatalyst was also identified by natural bond orbital (NBO) and global reactivity index (GRI) analyses. The mechanistic insights obtained in the present study should be useful for understanding the novel organocatalytic C(sp²)? H activation and cycloaddition cascade reaction of MBH carbonates, and thus provide valuable clues on rational design of efficient organocatalysts for the C(sp²)? H activation/functionalizations.     

Enantioselective Synthesis of 1-Aryl Benzo[5]helicenes Using BINOL-Derived Cationic Phosphonites as Ancillary Ligands

The synthesis of unprecedented BINOL-derived cationic phosphonites is described. Through the use of these phosphanes as ancillary ligands in Au^I catalysis, a highly regio- and enantioselective assembly of appropriately designed alkynes into 1-(aryl)benzo[5]carbohelicenes is achieved. The modular synthesis of these ligands and the enhanced reactivity that they impart to Au^I-centers after coordination have been found to be the key features that allow an optimization of the reaction conditions until the desired benzo[5]helicenes are obtained with high yield and enantioselectivity.     

Unexpected Formation of a [4]Radialene and Dendralenes by Addition of Tetracyanoethylene to a Tetraaryl[5]cumulene

The use of cumulenes in synthetic transformations offers the possibility to form structurally interesting and potentially useful conjugated molecules. The cycloaddition reaction of a tetraaryl[5]cumulene with the electron‐deficient olefin tetracyanoethylene affords unusual products, including functionalized dendralenes and alkylidene cyclobutanes, as well as a symmetric [4]radialene that shows unique solvatochromism, with λ_max values approaching the near‐IR region. These carbon‐rich products have been investigated spectroscopically and by X‐ray crystallographic analysis (five structures). The cycloaddition reaction sequence has also been explored by mechanistic and theoretical studies. The obtained results clearly demonstrate the potential of [5]cumulenes to serve as precursors for unprecedented conjugated structures.     

Phosphine-catalyzed annulations of azomethine imines: allene-dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] pathways

In this paper we describe the phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations of azomethine imines and allenoates. These processes mark the first use of azomethine imines in nucleophilic phosphine catalysis, producing dinitrogen-fused heterocycles, including tetrahydropyrazolo-pyrazolones, -pyridazinones, -diazepinones, and -diazocinones. Counting the two different reaction modes in the [3 + 3] cyclizations, there are five distinct reaction pathways-the choice of which depends on the structure and chemical properties of the allenoate. All reactions are operationally simple and proceed smoothly under mild reaction conditions, affording a broad range of 1,2-dinitrogen-containing heterocycles in moderate to excellent yields. A zwitterionic intermediate formed from a phosphine and two molecules of ethyl 2,3-butadienoate acted as a 1,5-dipole in the annulations of azomethine imines, leading to the [3 + 2 + 3] tetrahydropyrazolo-diazocinone products. The incorporation of two molecules of an allenoate into an eight-membered-ring product represents a new application of this versatile class of molecules in nucleophilic phosphine catalysis. The salient features of this protocol--the facile access to a diverse range of nitrogen-containing heterocycles and the simple preparation of azomethine imine substrates--suggest that it might find extensive applications in heterocycle synthesis.     

Pd-catalyzed Suzuki/Sonogashira cross-coupling reaction and the direct sp3 arylation of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

A rapid and efficient method is reported for the synthesis of the [1,2,4]triazolo[1,5-a]pyrimidine motif. Palladium catalyzed Suzuki and Sonogashira cross coupling reactions on 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine were performed. The direct sp³ arylation of compounds resulting from the Suzuki reaction was then carried out.     

Cu‐Catalyzed [4+1] Annulation toward Indolo[2,1‐a]isoquinolines through Oxidative C(sp3)/C(sp2)−H Bond Bifunctionalization

A Cu‐catalyzed [4+1] annulation of N‐aryl‐1,2,3,4‐tetrahydroisoquinolines (N‐aryl THIQs) with α‐diazoketones has been established under oxidative conditions, leading to the construction of a series of indolo[2,1‐a]isoquinolines with generally good yields. The reaction enables dediazotized dicarbonylation of α‐diazoketones, creating direct C(sp³)/C(sp²)?H bond bifunctionalization to access tetracyclic aza‐heterocyclic skeletons.     

Thermal cyclization of N-[2-(2-propenyl)-1-naphthyl] ketenimines: intramolecular Diels-Alder reaction versus [1,5] hydrogen migration. Synthesis of dibenz[b,h]acridines and benzo[h]quinolines

The thermal treatment of N-(2-propenyl)-1-naphthylamines provided the expected aza-Claisen rearranged products, 2-(2-propenyl)-1-naphthylamines and benz[g]indoles, these last derived from an intramolecular hydroamination reaction on those primary products. The 2-(2-propenyl)-1-naphthylamines were converted into their triphenylphosphazene derivatives, which by aza-Wittig reaction with disubstituted ketenes yielded N-[2-(2-propenyl)-1-naphthyl] ketenimines. The heating of these ketenimines in boiling toluene induced their cyclization either via an intramolecular Diels-Alder reaction, to afford dibenz[b,h]acridines, or via [1,5] hydrogen migration from the sp³ carbon atom of the propenyl substituent to the central carbon atom of the ketenimine fragment, followed by a 6π electrocyclic ring closure, to give benzo[h]quinolines.     

Enantioselective Formal C(sp3)−H Bond Activation in the Synthesis of Bioactive Spiropyrazolone Derivatives

Herein, we report the first enantioselective annulation of α‐arylidene pyrazolones through a formal C(sp³)?H activation under mild conditions enabled by highly variable Rh^III‐Cp^x catalysts. The method has a wide substrate scope and proceeds with good to excellent yields and enantioselectivities. Its synthetic utility was demonstrated by the late‐stage functionalization of drugs and natural products as well as the preparation of enantioenriched [3]dendralenes. Preliminary biological investigations also identified the spiropyrazolones as a novel class of Hedgehog pathway inhibitors.     

Cucurbit[n]urils for Supramolecular Catalysis

The control over chemical reactivity and selectivity are always pursued. Using non-covalent interactions to achieve efficient and selective catalysis is an essential goal of supramolecular catalysis. Supramolecular catalysis based on cucurbit[n]urils (CB[n]s) possesses distinct characteristics for the unique structure of CB[n]s. CB[n]s are a family of pumpkin-shaped host molecules with various molecular sizes, rigid structures, electronegative portals and wealthy host-guest chemistry. Herein, we summarize the three major mechanisms of CB[n]s based supramolecular catalysis. Owing to the structural properties of CB[n]s, CB[n]s can serve as nanoreactors and steric hindrance to modulate the reactivity of substrates. They can also catalyze the reactions by modulating the reactivity of ionized intermediates. Recent progresses on the CB[n]s based supramolecular catalysis are introduced in this Minireview and the future development in this field is discussed. It is anticipated that this review provides insights into the mechanism of CB[n]s based supramolecular catalysis and may help scientists find new opportunities in this field.     

Silaboration of [1.1.1]Propellane: A Storable Feedstock for Bicyclo[1.1.1]pentane Derivatives

The silaboration of [1.1.1]propellane enables direct introduction of B and Si functional groups onto the bicyclo[1.1.1]pentane (BCP) scaffold in high yield under mild, additive‐free conditions. The silaborated BCP can be obtained on a gram‐scale in a single step without the need for column‐chromatographic purification, and is storable and easy to handle, providing a versatile synthetic intermediate for BCP derivatives. We also describe various conversions of the C?B/C?Si bonds on the BCP scaffold, including development of a modified Suzuki–Miyaura cross‐coupling reaction at the highly sterically hindered bridgehead sp³ carbon center of the BCP skeleton using a combination of highly activated BCP boronic esters, copper(I) oxide, and a PdCl₂(dppf) catalyst system.     

Decarboxylative [4+2] Cycloaddition by Synergistic Palladium and Organocatalysis

A novel reaction based on synergistic catalysis, combining palladium‐ and organocatalysis has been developed. The palladium catalyst activates vinyl benzoxazinanones via a decarboxylation to undergo a [4+2] cycloaddition with iminium‐ion activated α,β‐unsaturated aldehydes. The reaction is demonstrated to proceed for a number of combinations of vinyl benzoxazinanones reacting with α,β‐unsaturated aldehydes, providing highly substituted vinyl tetrahydroquinolines in good to high yields, and excellent enantio‐ and diastereoselectivities (>98 % ee and >20:1 d.r.). The palladium catalyst used in the synergistic catalysis can be re‐used in a one‐pot sequential coupling reaction with an aromatic boronic acid forming the coupling product in 95 % yield, >20:1 d.r. and 99 % ee.     

Cyclopenta[b]annulation of Heteroarenes by Organocatalytic γ′[C(sp3)−H] Functionalization of Ynones

A new approach for the cyclopenta[b]annulation of heteroarenes through metal‐free and directing‐group‐free γ′[C(sp³)?H] functionalization and intramolecular hydroalkylation of ynones has been developed. In an unprecedented event, nucleophilic addition of an organophosphine to the designed ynones triggers γ′[C(sp³)?H] functionalization, leading to the formation of heteroaryl‐based ortho‐quinodimethane (oQDM) intermediates that undergo carbocyclization to provide cyclopentannulated heteroarenes in good yields and excellent stereoselectivities. Deuterium‐labeling experiments substantiated the proposed reaction mechanism as well as the speculated epimerization.