Construction of Various Bridged Polycyclic Skeletons by Palladium-Catalyzed Dearomatization

A powerful palladium-catalyzed dearomative cyclization was developed that provides facile access to eight types of bridged tetracyclic skeletons bearing various ring sizes and heterocycles. With this method, several skeletons or analogues of natural products, including tubingensin B and dracaenones, were synthesized. Asymmetric dearomative cyclization enables the construction of various enantiomerically enriched bridged polycyclic systems with up to 99 % ee by employing a chiral palladium catalyst.     

Palladium(0)‐Catalyzed Intermolecular Carbocyclization of (1,n)‐Diynes and Bromophenols: An Efficient Route to Tricyclic Scaffolds

A novel palladium(0)‐catalyzed dearomative cyclization reaction of bromophenols with (1,n)‐diynes has been developed for building two new types of tricyclic architectures containing a quaternary carbon center. This method employs inexpensive bromophenols, and easily accessible tethered diynes. It exhibits a broad substrate scope and tolerates various functional groups. Preliminary results with commercially available chiral ligands indicate that enantioselective variants are feasible for both cyclization processes.     

Total syntheses of melinonine-E and strychnoxanthine: Evolution of the synthetic strategy enabled by novel method development

In this full account, the evolution of a synthetic strategy was detailed from a nitroso-ene cyclization to an aza-Wacker reaction for ring construction in the syntheses of melinonine-E and strychnoxanthine. The aza-Wacker cyclization to form the bridged ring was successfully developed and applied in the first asymmetric syntheses of melinonine-E and strychnoxanthine in 5–6 steps from a readily available chiral lactone. The proposed biogenesis of these two rare β-carbolinium alkaloids was revised based on their absolute configurations. Moreover, the substrate scope of the aza-Wacker cyclization demonstrated its potential for accessing various bridged ring skeletons. The mechanistic investigation established that the profound effect of the N-substituent on the amide was crucial to the success of the cyclization via the tunable amidopalladation pathway.     

Enantioselective Palladium‐Catalyzed Dearomative Cyclization for the Efficient Synthesis of Terpenes and Steroids

A novel enantioselective palladium‐catalyzed dearomative cyclization has been developed for the efficient construction of a series of chiral phenanthrenone derivatives bearing an all‐carbon quaternary center. The effectiveness of this method in the synthesis of terpenes and steroids was demonstrated by a highly efficient synthesis of a kaurene intermediate, the facile construction of the skeleton of the anabolic steroid boldenone, and the enantioselective total synthesis of the antimicrobial diterpene natural product (?)‐totaradiol.     

Palladium‐Catalyzed Cascade Cyclization/Alkynylation Reactions

Palladium‐catalyzed cascade cyclization reactions have witnessed significant improvements in recent years. Among them, palladium‐catalyzed cascade cyclization/alkynylation are especially attractive, which can assemble structurally diverse monocyclic, bicyclic, fused polycyclic, and spirocyclic skeletons with excellent chemoselectivities. In this Minireview, palladium‐catalyzed cascade cyclization/alkynylation have been summarized and discussed in detail with focus on oxypalladation and aminopalladation‐initiated cascade cyclization, intramolecular Heck‐type cascade cyclization, carbocyclizations, cascade cyclizations, and other types of cascade cyclization reactions. Some significant and representative synthetic methodologies and their synthetic applications and reaction mechanisms have also been described.     

Copper‐Catalyzed Cascade Cyclization of Indolyl Homopropargyl Amides: Stereospecific Construction of Bridged Aza‐[n.2.1] Skeletons

Catalytic cycloisomerization‐initiated cascade cyclizations of terminal alkynes have received tremendous interest, and been widely used in the facile synthesis of a diverse array of valuable complex heterocycles. However, these tandem reactions have been mostly limited to noble‐metal catalysis, and are initiated by an exo‐cyclization pathway. Reported herein is an unprecedented copper‐catalyzed endo‐cyclization‐initiated tandem reaction of indolyl homopropargyl amides, where copper catalyzes both the hydroamination and Friedel–Crafts alkylation process. This method allows the practical and atom‐economical synthesis of valuable bridged aza‐[n.2.1] skeletons (n=3–6) with wide substrate scope, and excellent diastereoselectivity and enantioselectivity by a chirality‐transfer strategy. Moreover, the mechanistic rationale for this novel cascade cyclization is also strongly supported by control experiments, and is distinctively different from the related gold catalysis.     

Silver-Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles and bicyclobutane precursors is described. The strain-release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale-up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility.     

Highly stereoselective 6pi electrocyclization of bridged bicyclic 1,3,5-trienes

Conjugated 1,3,5-hexatrienes encased in bridged bicyclic skeletons are prepared by cross-coupling followed by half-reduction of the resulting dienynes. The trienes undergo 6pi electrocyclization at an ambient or elevated temperature to furnish complex, polycyclic cyclohexadienes. In all cases, complete selectivity in favor of cyclization from the exo face of the bridged bicyclic system was seen, in contrast to the corresponding 4pi Nazarov cyclizations.     

Construction of fused, bridged, and spiro bicyclic skeletons via nickel-catalyzed intramolecular cyclization of cyclic 1,3-dienes and a tethered aldehyde

Nickel-catalyzed intramolecular cyclization of cyclohexa-1,3-dienes and an aldehyde in a chain produced fused, bridged or spiro bicyclic skeletons depending on the length of the tether. This chemistry can be extended to cyclohepta-1,3-dienes and cyclohepta-1,3,5-trienes having an aldehyde moiety on the side chain.     

Palladium‐Catalyzed Dearomative syn‐1,4‐Oxyamination

A palladium‐catalyzed dearomative syn‐1,4‐oxyamination protocol using non‐activated arenes has been developed. This one‐pot procedure utilizes arenophile chemistry, and the corresponding para‐cycloadducts are treated with oxygen nucleophiles via formal allylic substitution, providing direct access to syn‐1,4‐oxyaminated products. The reaction conditions permit a range of arenes, as well as different O‐nucleophiles, such as oximes and benzyl alcohols. Moreover, this process was established in an asymmetric fashion, delivering products with high enantioselectivity. The dearomatized products are amenable to a multitude of further derivatizations ranging from olefin chemistry to C?H activation, giving rise to a diverse set of new functionalities. Overall, this dearomative functionalization offers rapid and controlled formation of molecular complexity, enabling straightforward access to functionalized small molecules from simple and readily available arenes.     

Synthesis of 1‐Difluoroalkylated Isoquinolines via Palladium‐Catalyzed Radical Cascade Difluoroalkylation–Cyclization of Vinyl Isocyanides with Bromodifluoroacetic Derivatives

A general method was developed for the synthesis of 1‐difluoroalkyl isoquinolines via the palladium‐catalyzed radical cascade difluoroalkylation–cyclization of vinyl isocyanides with bromodifluoroacetic derivatives. The difluoroalkylated cyclization products were readily converted to various other valuable gem ‐difluoro‐containing compounds.     

Synthesis of Heterocycles through Denitrogenative Cyclization of Triazoles and Benzotriazoles

During the past few decades, there has been considerable growth in the development of denitrogenative reactions of triazole skeletons to construct valuable cyclic compounds, particularly heterocycles. Despite the inherent difficulty of the ring-opening of triazole derivatives, many novel and efficient approaches have arisen in this area mainly with the use of transition metal (such as rhodium, palladium, silver, copper) catalysis, photolysis, or free radical mediated reactions. Generally, these procedures begin with the ring-opening of 1,2,3-triazoles or benzotriazoles followed by N₂ extrusion and subsequent diverse transformations, which enable the rapid synthesis of various heterocycles in a single step. To avoid overlap with other related reviews, this minireview covers the recent advances in the denitrogenative cyclization of 1,2,3-triazoles since 2016 and the denitrogenative cyclization of benzotriazoles since 2012.     

Ligand‐Controlled Palladium(II)‐Catalyzed Regiodivergent Carbonylation of Alkynes: Syntheses of Indolo[3,2‐c]coumarins and Benzofuro[3,2‐c]quinolinones

Regiodivergent syntheses of indolo[3,2‐c]coumarins and benzofuro[3,2‐c]quinolinones through a controllable palladium(II)‐catalyzed carbonylative cyclization are established. The chemo‐ and regioselectivity are exclusively tuned by the ligand on the palladium catalyst. The rigid framework of the electron‐deficient ligand promotes the O‐attack/N‐carbonylation cyclization leading to benzofuro[3,2‐c]quinolinones, while a sterically bulky and electron‐rich ligand facilitates N‐attack/O‐carbonylation cyclization to generate indolo[3,2‐c]coumarins. Furthermore, various other nucleophiles are applicable for delivering a variety of indoloquinolinones, pyranoquinolones, and chromeno[3,4‐c]quinolinones in one step, and serves as a method for creating compound libraries for drug discovery.     

A facile synthesis of 3-alkoxy phthalides by the palladium catalyzed carbonylative cyclization of o-bromobenzaldehyde

The palladium catalyzed carbonylative cyclization of o-bromobenzaldehyde 1 in alcoholic solution gave 3-alkoxyphthalides 3a-e in 61–85% isolated yields via intramolecular cyclization induced by the coordinated formyl group on the palladium.     

Dynamic NMR Studies of Some Halo and Mercaptide Bridged Palladium (II) Dimers

Some halo or mercaptide bridged palladium (II) dimers, [Pd(S₂CNR₂)X]₃ (R=ibutyl, X=Cl, Br, I, S-ethyl and S-t-butyl) were studied by variable temperature ¹H nmr spectroscopy. Line shape changes of the chloro and bromo bridged dimers were interpretated by the solvolytic breaking of the Pd-X bond, while mercaptide bridged complexes were explained in terms of slow N-C single bond rotation. The results consist with the strengthness of the class b metal ion with various soft donor ligands.     

Intramolecular alkene electrophilic bromination initiated ipso-bromocyclization for the synthesis of functionalized azaspirocyclohexadienones

Intramolecular alkene electrophilic bromination initiated dearomative cyclization has been realized in the presence of DBDMH to provide functionalized azaspirocyclohexadienones in excellent yields under mild conditions.     

A Photoredox‐Induced Stereoselective Dearomative Radical (4+2)‐Cyclization/1,4‐Addition Cascade for the Synthesis of Highly Functionalized Hexahydro‐1H‐carbazoles

A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox‐induced dearomative radical (4+2)‐cyclization/1,4‐addition cascade between 3‐(2‐iodoethyl)indoles and acceptor‐substituted alkenes. The title reaction simultaneously generates three C−C bonds and one C−H bond, along with three contiguous stereogenic centers. The hexahydro‐1H ‐carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids.     

Palladium‐Catalyzed Dearomative syn‐1,4‐Carboamination with Grignard Reagents

A protocol for palladium‐catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one‐pot method features a visible‐light‐mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium‐catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn‐1,4‐selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.     

Palladium‐Catalyzed Dearomative Cyclocarbonylation by CN Bond Activation

A fundamentally novel approach to bioactive quinolizinones is based on the palladium‐catalyzed intramolecular cyclocarbonylation of allylamines. [Pd(Xantphos)I₂], which features a very large bite angle, has been found to facilitate the rapid carbonylation of azaarene‐substituted allylamines into bioactive quinolizinones in good to excellent yields. This transformation represents the first dearomative carbonylation and is proposed to proceed by palladium‐catalyzed C? N bond activation, dearomatization, CO insertion, and a Heck reaction.     

Palladium‐Catalyzed Dearomative Cyclocarbonylation by C?N Bond Activation

A fundamentally novel approach to bioactive quinolizinones is based on the palladium‐catalyzed intramolecular cyclocarbonylation of allylamines. [Pd(Xantphos)I₂], which features a very large bite angle, has been found to facilitate the rapid carbonylation of azaarene‐substituted allylamines into bioactive quinolizinones in good to excellent yields. This transformation represents the first dearomative carbonylation and is proposed to proceed by palladium‐catalyzed C N bond activation, dearomatization, CO insertion, and a Heck reaction.