Synthesis of 3,8‐Dichloro‐6‐ethyl‐1,2,5,7‐tetramethyl–BODIPY from an Asymmetric Dipyrroketone and Reactivity Studies at the 3,5,8‐Positions

The asymmetric BODIPY 1 a (BODIPY=4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene), containing two chloro substituents at the 3,8‐positions and a reactive 5‐methyl group, was synthesized from the asymmetric dipyrroketone 3 , which was readily obtained from available pyrrole 2 a . The reactivity of 3,8‐dichloro‐6‐ethyl‐1,2,5,7‐tetramethyl‐BODIPY 1 a was investigated by using four types of reactions. This versatile BODIPY undergoes regioselective Pd⁰‐catalyzed Stille coupling reactions and/or regioselective nucleophilic addition/elimination reactions, first at the 8‐chloro and then at the 3‐chloro group, using a variety of organostannanes and N‐, O‐, and S‐centered nucleophiles. On the other hand, the more reactive 5‐methyl group undergoes regioselective Knoevenagel condensation with an aryl aldehyde to produce a monostyryl‐BODIPY, and oxidation with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) gives the corresponding 5‐formyl‐BODIPY. Investigation of the reactivity of asymmetric BODIPY 1 a led to the preparation of a variety of functionalized BODIPYs with λ_max of absorption and emission in the ranges 487–587 and 521–617 nm, respectively. The longest absorbing/emitting compound was the monostyryl‐BODIPY 16 , and the largest Stokes shift (49 nm) and fluorescence quantum yield (0.94) were measured for 5‐thienyl‐8‐phenoxy‐BODIPY 15 . The structural properties (including 16 X‐ray structures) of the new series of BODIPYs were investigated.     

Cobalt(III)‐Catalyzed Intramolecular Cross‐Dehydrogenative C−H/X−H Coupling: Efficient Synthesis of Indoles and Benzofurans

An efficient cobalt(III)‐catalyzed intramolecular cross‐dehydrogenative C?H/N?H coupling of ortho‐alkenylanilines has been developed utilizing O₂ as a terminal oxidant. The developed reaction tolerates various reactive functional groups and allows the synthesis of diverse indole derivatives in good to excellent yields. The method was successfully extended to the synthesis of benzofurans through the intramolecular cross‐dehydrogenative C?H/O?H coupling of ortho‐alkenylphenols.     

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for the Total Synthesis of (−)‐17‐nor‐Excelsinidine

We report the first total synthesis of (?)‐17‐nor‐excelsinidine, a zwitterionic monoterpene indole alkaloid that displays an unusual N4?C16 connection. Inspired by the postulated biosynthesis, we explored an oxidative coupling approach from the geissoschizine framework to forge the key ammonium–acetate connection. Two strategies allowed us to achieve this goal, namely an intramolecular nucleophilic substitution on a 16‐chlorolactam with the N4 nitrogen atom or a direct I₂‐mediated N4?C16 oxidative coupling from the enolate of geissoschizine.     

Pd‐Catalyzed Enantioselective Ring Opening/Cross‐Coupling and Cyclopropanation of Cyclobutanones

A palladium‐catalyzed enantioselective sequential ring‐opening/cross‐coupling of cyclobutanones is disclosed that provides chiral indanones bearing C3‐quaternary stereocenters. The reaction process involves palladium‐catalyzed nucleophilic addition of cyclobutanones and aryl halides, enantioselective β‐carbon elimination, and intermolecular trapping of a transient σ‐alkylpalladium complex with boronic acids. Alternatively, an intramolecular cyclopropanation is realized through C?H bond functionalization in the absence of external coupling reagents, affording chiral cyclopropane‐fused‐indanones in good yields and enantioselectivity.     

Iridium‐Catalyzed Sequential Silylation and Borylation of Heteroarenes Based on Regioselective C−H Bond Activation

An iridium‐catalyzed regioselective sequential silylation and borylation of heteroarenes was developed, which represents a rare example of unsymmetrical intermolecular C?H bond difunctionalization through the introduction of two different functionalities during a one‐pot transformation. Although the substrate scope for the dehydrogenative silylation of heteroarenes has been limited mainly to electron‐rich five‐membered rings, the current reaction proceeds with both electron‐rich and electron‐deficient heteroarenes with the aid of heteroatom‐directing C?H bond activation. The regioselectivity of the second borylation was controlled by both steric factors and the electronic effect of the silyl group installed in the first step. In combination with the classic cross‐coupling reaction, this method provides rapid access to multisubstituted heteroarenes.     

Ligand‐Controlled Regiodivergent Nickel‐Catalyzed Annulation of Pyridones

The 1,6‐annulated 2‐pyridone motif is found in many biologically active compounds and its close relation to the indolizidine and quinolizidine alkaloid core makes it an attractive building block. A nickel‐catalyzed C? H functionalization of 2‐pyridones and subsequent cyclization affords 1,6‐annulated 2‐pyridones by selective intramolecular olefin hydroarylation. The switch between the exo‐ and endo‐cyclization modes is controlled by two complementary sets of ligands. Irrespective of the ring size, the regioselectivity during the cyclization is under full catalyst control. Simple cyclooctadiene promotes an exo‐selective cyclization, whereas a bulky N‐heterocyclic carbene ligand results in an endo‐selective mode. The method was further applied in the synthesis of the lupin alkaloid cytisine.     

Platinum‐Catalyzed Friedel–Crafts‐Type C−H Coupling–Allylic Amination Cascade to Synthesize 3,4‐Fused Tricyclic Indoles

A novel platinum‐catalyzed cascade cyclization reaction was developed by intramolecular Friedel–Crafts‐type C?H coupling of aniline derivatives with a propargyl carbonate unit‐allylic amination sequence. Treatment of various propargyl carbonates tethered to meta‐aniline derivatives with a Pt(dba)₃/DPEphos catalyst system afforded the corresponding 3,4‐fused tricyclic 3‐alkylidene indolines in 42–99 % yield, which were transformed into 3,4‐fused indole derivatives by reaction with trifluoroacetic acid. The reaction products exhibited antiproliferative activities against cancer cells, but not normal cells, revealing the potential usefulness of this reaction for medicinal chemistry.     

Rhodium(III)‐Catalyzed Enantio‐ and Diastereoselective C−H Cyclopropylation of N‐Phenoxylsulfonamides: Combined Experimental and Computational Studies

Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio‐ and diastereoselective construction of cyclopropanes through C?H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing‐group‐assisted C?H activation strategy was used to realize mild and redox‐neutral Rh^III‐catalyzed C?H activation and cyclopropylation of N‐phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a Rh^V nitrenoid intermediate, and Noyori‐type outer sphere concerted proton‐hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.     

Benzo[c,d]indole‐Containing Aza‐BODIPY Dyes: Asymmetrization‐Induced Solid‐State Emission and Aggregation‐Induced Emission Enhancement as New Properties of a Well‐Known Chromophore

A series of symmetric and asymmetric benzo[c,d]indole‐containing aza boron dipyrromethene (aza‐BODIPY) compounds was synthesized by a titanium tetrachloride‐mediated Schiff‐base formation reaction of commercially available benzo[c,d]indole‐2(1H)‐one and heteroaromatic amines. These aza‐BODIPY analogues show different electronic structures from those of regular aza‐BODIPYs, with hypsochromic shifts of the main absorption compared to their BODIPY counterparts. In addition to the intense fluorescence in solution, asymmetric compounds exhibited solid‐state fluorescence due to significant contribution of the vibronic bands to both absorption and fluorescence as well as reduced fluorescence quenching in the aggregates. Finally, aggregation‐induced emission enhancement, which is rare in BODIPY chromophores, was achieved by introducing a nonconjugated moiety into the core structure.     

Base‐Controlled Selectivity in the Synthesis of Linear and Angular Fused Quinazolinones by a Palladium‐Catalyzed Carbonylation/Nucleophilic Aromatic Substitution Sequence

A new approach for the facile synthesis of fused quinazolinone scaffolds through a palladium‐catalyzed carbonylative coupling followed by an intramolecular nucleophilic aromatic substitution is described. The base serves as the key modulator: Whereas DBU gives rise to the linear isomers, Et₃N promotes the preferential formation of angular products. Interestingly, a light‐induced 4+4 reaction of the product was also observed.     

Regio‐ and Stereoselective Thianthrenation of Olefins To Access Versatile Alkenyl Electrophiles

Herein, we report a regioselective alkenyl electrophile synthesis from unactivated olefins that is based on a direct and regioselective C?H thianthrenation reaction. The selectivity is proposed to arise from an unusual inverse‐electron‐demand hetero‐Diels–Alder reaction. The alkenyl sulfonium salts can serve as electrophiles in palladium‐ and ruthenium‐catalyzed cross‐coupling reactions to make alkenyl C?C, C?Cl, C?Br, and C?SCF₃ bonds with stereoretention.     

Palladium‐Catalyzed Construction of Heteroatom‐Containing π‐Conjugated Systems by Intramolecular Oxidative CH/CH Coupling Reaction

Synthesis of heteroatom‐containing ladder‐type π‐conjugated molecules was successfully achieved via a palladium‐catalyzed intramolecular oxidative C?H/C?H cross‐coupling reaction. This reaction provides a variety of π‐conjugated molecules bearing heteroatoms, such as nitrogen, oxygen, phosphorus, and sulfur atoms, and a carbonyl group. The π‐conjugated molecules were synthesized efficiently, even in gram scale, and larger π‐conjugated molecules were also obtained by a double C?H/C?H cross‐coupling reaction and successive oxidative cycloaromatization.     

Base‐Selective Five‐ versus Six‐Membered Ring Annulation in Palladium‐Catalyzed C–C Coupling Cascade Reactions: New Access to Electron‐Poor Polycyclic Aromatic Dicarboximides

Palladium‐catalyzed base‐selective annulation of dibromonaphthalimide to different aryl boronate esters by combined Suzuki–Miyaura cross‐coupling and direct C−H arylation afforded a series of new five‐ and six‐membered ring annulated electron‐poor polycyclic aromatic hydrocarbons. Cesium carbonate (Cs₂CO₃) as auxiliary base in these C−C coupling cascade reactions led exclusively to six‐membered ring annulation, while the use of organic base diazabicycloundecene (DBU) afforded the corresponding five‐membered ring annulated products. This base‐dependent selective mode of annulation is attributed to different mechanistic pathways directed by the applied base. The selective annulation was revealed by single crystal X‐ray analysis of the respective five‐ and six‐membered ring annulated products. The optical and redox properties of the new polycyclic aromatic dicarboximides were characterized by UV/Vis absorption and fluorescence spectroscopy and cyclic voltammetry.     

Heteroatom‐Guided,Palladium‐Catalyzed,Site‐Selective CH Arylation of 4H‐Chromenes: Diastereoselective Assembly of the Core Structure of Myristinin B through Dual CH Functionalization

A highly site‐selective, heteroatom‐guided, palladium‐catalyzed direct arylation of 4H‐chromenes is reported. The C?H functionalization is driven not only by the substituents and structure of the substrate but also by the coupling partner being used. The diastereoselective assembly of the core structure of Myristinin B has been achieved by using a dual C?H functionalization strategy for regioselective direct arylation.     

Synthesis of 3,4‐Fused Tricyclic Indoles Using 3‐Alkylidene Indolines as Versatile Precursors

In this personal account, our recent studies of novel synthetic methods of 3,4‐fused tricyclic indole derivatives using 3‐alkylidene indoline derivatives as versatile precursors are discussed. Two types of cascade reactions producing 3,4‐fused tricyclic 3‐alkylidene indolines were developed based on a palladium‐catalyzed intramolecular Heck insertion to an allene‐allylic amination cascade and a platinum‐catalyzed intramolecular Friedel‐Crafts type C?H coupling‐allylic amination cascade. Furthermore, three types of 3,4‐fused tricyclic indoles were accessible from a single 3‐alkylidene indoline precursor via acid‐promoted olefin isomerization or oxidative treatments. The application of the developed methods to the synthesis of natural products bearing a 3,4‐fused tricyclic indole skeleton, (?)‐aurantioclavine, fargesine, and synthetic studies of dragmacidin E are also highlighted.     

Synthesis,Characterization and Crystal Structure of Some Novel 1‐Aryl‐2‐Thioxo‐2,3‐Dihydro‐1H‐Quinazolin‐4‐Ones

The base catalyzed intramolecular nucleophilic cyclization of 1‐(2‐haloaroyl)‐3‐aryl thioureas ( 1a‐i ), in the presence of DMF afforded the 1‐aryl‐2‐thioxo‐2,3‐dihydro‐1H‐quinazolin‐4‐ones ( 2a‐i ). The structures were confirmed by spectroscopic data, elemental analyses and in case of the 2c by single crystal X‐ray diffraction data. The mechanistic studies support an intramolecular nucleophilic substitution (S_NAr mechanism) rather than intramolecular aromatic substitution (S_RN1 mechanism).     

Synthesis of a Benzannulated Pyrrolizidine by a Copper‐Catalyzed Intramolecular α‐Arylation Reaction

A synthetic route to the pyrrolo[1,2‐a]indole ring system (benzannulated pyrrolizidine) involving a base‐induced intramolecular aza‐Michael reaction as the key C? N bond‐forming penultimate step, followed by a Cu‐catalyzed intramolecular α‐arylation reaction, to provide the tricyclic framework over six steps is described.     

Pd‐Catalyzed Regioselective Activation of gem‐Difluorinated Cyclopropanes: A Highly Efficient Approach to 2‐Fluorinated Allylic Scaffolds

An unprecedented Pd‐catalyzed regioselective activation of gem‐difluorinated cyclopropanes induced by C? C bond cleavage is reported. It provides a general and efficient access to a variety of 2‐fluoroallylic amines, ethers, esters, and alkylation products in high Z‐selectivity, which are important skeletons in many biologically active molecules. In addition, the transformation represents the first general application of gem‐difluorinated cyclopropanes as reaction partners in transition‐metal‐catalyzed cross‐coupling reaction.     

Synthesis of Triarylpyridines in Thiopeptide Antibiotics by Using a C−H Arylation/Ring‐Transformation Strategy

We have described a C?H arylation/ring‐transformation strategy for the synthesis of triarylpyridines, which form the core structure of thiopeptide antibiotics. This synthetic method readily gave 2,3,6‐triarylpyridines in a regioselective manner by a two‐phase approach: C?H arylation (a nickel‐catalyzed decarbonylative Suzuki–Miyaura cross‐coupling and decarbonylative C?H coupling for the synthesis of 2,4‐diaryloxazoles) and ring transformation ([4+2] cycloaddition of 2,4‐diaryloxazoles with (hetero)arylacrylic acids). To showcase these methods, we have accomplished the formal synthesis of thiopeptide antibiotics GE2270 s and amythiamicins.     

Brønsted Acid Catalyzed Friedel–Crafts‐Type Coupling and Dedinitrogenation Reactions of Vinyldiazo Compounds

The direct Friedel–Crafts‐type coupling and dedinitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal‐free strategy are described. This Brønsted acid catalyzed method is efficient for the formation of α‐diazo β‐carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,β‐unsaturated esters, β‐indole‐substituted diazo esters, and dienes are obtained with good to high yields and selectivity. Experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3‐ and 1,4‐ hydride transfer processes as well as fragmentation.