Organophosphine as an Alkyl Transfer Shuttle for the Direct ß-Alkylation of Chalcones Using Alkyl Halides.

We report an efficient alkyl transfer strategy for the direct ß-alkylation of chalcones using commercially available alkyl bromides as alkyl reagents. In this transformation, the ortho-phosphanyl substituent in the chalcones is crucial for controlling their reactivity and selectivity. It also serves as a reliable alkyl transfer shuttle to transform electrophilic alkyl bromides into nucleophilic alkyl species in the form of quaternary phosphonium salts and transfer the alkyl group effectively to the ß-position of the chalcones. This alkyl transfer strategy can be further extended to the alkenylation of ortho-phosphanyl benzaldehydes to assemble functionalized polyenes.

Delivering 2-Aryl Benzoxazoles through Metal-Free and Redox-Neutral De-CF3 Process.

An unexpected cleavage of the Csp3-CF3 bond of CF3-hydrobenzoxazoles has been disclosed, affording a range of 2-aryl benzoxazoles under metal-free and redox-neutral conditions. This transformation has demonstrated broad substrate scope and good compatibility of functional groups. 2-Aryl benzothiazole and 2-aryl benzoimidazole could be smoothly assembled in the same manner. On the basis of preliminary mechanistic studies, base initiated and aromatization driven ß-carbon elimination was considered to be the key step for the formation of 2. This reaction offers an alternative, facile, and sustainable route to access important 2-aryl benzoxazole motifs.

Construction of bridged polycycles through dearomatization strategies.

Bridged polycycles are privileged molecular skeletons with wide occurrence in bioactive natural products and pharmaceuticals. Therefore, they have been the pursing target molecules of numerous chemists. The rapid and convenient generation of sp3-rich complex three-dimensional molecular skeletons from simple and easily available aromatics has made dearomatization a highly valuable synthetic tool for the construction of rigid and challenging bridged rings. This review summarizes the-state-of-the-art advances of dearomatization strategies in the application of bridged ring formation, discusses their advantages and limitations and the in-depth mechanism, and highlights their synthetic value in the total synthesis of natural products. We wish this review will provide an important reference for medicinal and synthetic chemists and will inspire further development in this intriguing research area.

Diastereoselective Construction of Indole-Bridged Chroman Spirooxindoles through a TfOH-Catalyzed Michael Addition-Inspired Cascade Reaction.

The first highly diastereoselective Michael addition/condensation/Friedel-Crafts alkylation cascade reaction of 3-indolyl-substituted oxindoles with ortho-hydroxychalcones was established, which afforded a wide range of polycyclic indole-bridged chroman spirooxindoles with novel and complex scaffolds in moderate to excellent yields.

Diastereoselective construction of pyrrolo[2,1-a]isoquinoline-based bispirooxindoles through a three-component [3 + 2] cycloaddition.

An efficient three-component one-pot [3 + 2] cycloaddition of isatins, 1,2,3,4-tetrahydroisoquinolines and methyleneindolinones has been developed. This reaction proceeded in a highly diastereoselective manner to afford a wide range of pyrrolo[1,2-a]isoquinoline-based bispirooxindoles in up to 91% yields. Additionally, a gram-scale experiment and some chemical transformations were conducted.

Construction of bridged cyclic N,O-ketal spirooxindoles through a Michael addition/N,O-ketalization sequence.

The first highly diastereoselective TfOH-catalyzed Michael addition/N,O-ketalization sequence of 3-aminooxindoles and ortho-hydroxychalcones was achieved, delivering a wide range of bridged cyclic N,O-ketal spirooxindoles with complex and strained structures in 41-97% yields. Moreover, a gram-scale experiment and some chemical conversions were conducted to further demonstrate the synthetic value.

A Copper-Catalyzed Friedel-Crafts Alkylation/Cyclization Sequence: an Approach to Functionalized Pyrrolo[1,2-a]indole Spirooxindoles and 9H-Pyrrolo[1,2-a]indoles.

An efficient Cu(OTf)2-catalyzed Friedel-Crafts alkylation/cyclizaiton sequence of 3-substituted indoles with isatin-derived oxodienes was developed, and a series of structurally complex and diverse pyrrolo[1,2-a]indole spirooxindoles were first obtained in up to 99% yields. This protocol proved to be quite general and was also robust for the synthesis of 9H-pyrrolo[1,2-a]indoles.

A copper-catalyzed tandem reaction for the construction of coumarin fused 9H-pyrrolo[1,2-a]indoles.

An efficient copper-catalyzed Friedel-Crafts alkylation/cyclization/isomerization sequence of 3-arylcarbonyl coumarins and 3-methyl indole was developed to afford a wide range of functionalized coumarin fused 9H-pyrrolo[1,2-a]indoles, which feature a 6-6-5-5-6 pentacyclic core, in 34-99% yields. Moreover, gram-scale experiment and chemical transformations were conducted to demonstrate the synthetic value of this protocol.

A DBU-catalyzed Michael-Pinner-isomerization cascade reaction of 3-hydroxyoxindoles with isatylidene malononitriles: access to highly functionalized bispirooxindoles containing a fully substituted dihydrofuran motif.

The first DBU-catalyzed Michael/Pinner/isomerization cascade reaction of 3-hydrooxindoles with isatylidene malononitriles was developed, and the corresponding highly functionalized bispirooxindoles containing a fully substituted dihydrofuran motif were obtained in up to 92% yields. This protocol also provides an efficient method for the synthesis of an α-cyano-γ-butyrolactone bispirooxindole. In addition, a one-pot three-component cascade reaction was conducted. Also, the asymmetric version of the cascade reaction was achieved.

A FeCl3-catalyzed highly regioselective 1,2-addition/substitution sequence for the construction of coumarin-substituted bis(indolyl)methanes.

A FeCl3-catalyzed highly regioselective 1,2-addition/substitution sequence of 3-acetylcoumarins and indoles has been developed to afford highly hindered tetrasubstituted bis(indolyl)methanes bearing a biologically useful coumarin motif in 56-99% yields.

Solvent-controlled halohydroxylation or C3-C2 coupling of pyridinium salts through an interrupted dearomative reduction.

Herein, we report an efficient and easily operable method to halohydroxylate pyridiniums through an interrupted dearomative reduction strategy. In this process, we make the most of the halide anion from the pyridinium salts by performing the reaction in DMSO without the need of external HX added. Notably, by changing the solvents from DMSO into Et2O, the bimolecular C3-C2 coupling occurs successfully.

Dearomative Periphery Modification of Quinolinium Salts to Assemble Ring-Encumbered Pyrrolidine-Tetrahydroquinoline Polycycles.

We report an unexpected dearomative periphery modification strategy for transforming quinolinium salts into structurally crowded pyrrolidine-tetrahydroquinoline polycyclic systems with complete regio- and diastereoselectivity. Importantly, the reaction pathway was regulated by simply tuning the substituents, achieving substituent-directed divergent synthesis. The notable features of this transformation include readily available starting materials, green conditions, a simple workup procedure, high bond- and ring-forming efficiency, and substituent-directed diverse synthesis.

Diastereoselective trifunctionalization of pyridinium salts to access structurally crowded azaheteropolycycles.

A highly diastereoselective dearomative trifunctionalization of pyridinium salts with multifunctional o-hydroxyl aromatic azomethine ylides has been established, which not only provided a convenient and rapid method to assemble challenging and architecturally crowded chroman-pyrrolidine-hydrogenated pyridine fused pentacycles, but also represented a rare successful example of the higher-order multifunctionalization of pyridiniums.

Assembly of functionalized π-extended indolizine polycycles through dearomative [3+2] cycloaddition/oxidative decarbonylation.

Reported herein is an unexpected construction of functionalized π-extended indolizine polycycles through a one-pot two-step cascade process comprising the base-promoted dearomative [3+2] cycloaddition of quinilinium salts and 3-alkenyl oxindoles, followed by a DDQ-mediated oxidative decarbonylation. Moreover, we could achieve the substrate-controlled diverse synthesis of structurally strained cyclopropane spirooxindole by using pyridinium salts as starting materials.

Regioselective and Diastereoselective Dearomative Multifunctionalization of In-Situ-Activated Azaarenes: An Access to Bridged Azaheterocycles.

Reported herein is an unprecedented multicomponent one-pot dearomative multifunctionalization of commercially available azaarenes through an in situ activation strategy, which not only achieved the first full exploitation of the reactive sites of the azaarenes, but also accomplished the efficient synthesis of bridged hydrogenated pyridines and (iso)quinolines in a highly regioselective and diastereoselective manner. In addition, we could successfully realize the step-controlled dearomative trifunctionalization and bifunctionalization of quinolines.

Chalcone-Based Pyridinium Salts and Their Diastereoselective Dearomatization To Access Bibridged Benzoazepines.

New chalcone-based pyridinium salts have been successfully exploited, which could smoothly participate in the highly diastereoselective dearomatization with binucleophilic enaminones by taking advantage of their multiple reactive sites to construct bibridged benzoazepines in up to 89% yields. The key to the success was the skillful and unprecedented C-3 functionalization of the new pyridinium salts. This work not only provides a kind of novel pyridinium salt synthon but also achieves the first C-3 functionalization of pyridinium salts to construct complex and challenging bibridged benzoazepines with high synthetic efficiency.

An unexpected multi-component one-pot cascade reaction to access furanobenzodihydropyran-fused polycyclic heterocycles.

An unexpected multi-component one-pot cascade reaction of hydroxyketones with ortho-hydroxychalcones has been developed to afford an array of new furanobenzopyran-fused polycyclic compounds with complex molecular architectures. This reaction not only establishes a new reaction mode of ortho-hydroxychalcones but also provides an expedient and convenient synthetic strategy to access complex furanobenzopyran-fused heterocycles.

An unexpected cascade reaction of 3-hydroxyoxindoles with coumarin-3-carboxylates to construct 2,3-dihydrobenzofuran spirooxindoles.

An unexpected Michael addition-inspired ring-opening/closure cascade reaction of 3-hydroxyoxindoles with coumarin-3-carboxylates was developed to access new dihydrobenzofuran or dihydrobenzothiophene spirooxindoles in 68-98% yields. This reaction not only provides an expedient and convenient method to assemble dihydrobenzofuran spirooxindoles, but also establishes a new reaction mode of coumarin-3-carboxylates. Moreover, it represents the first example of 3-hydroxyoxindoles serving as a C1 synthon possessing dual nucleophilic and electrophilic character with the hydroxyl group as a leaving group. Importantly, this methodology provides a rapid and robust approach to XEN907 analogues.

Regio- and diastereoselective dearomatizations of N-alkyl activated azaarenes: the maximization of the reactive sites.

An unprecedented base-promoted multi-component one-pot dearomatization of N-alkyl activated azaarenes was developed, which enabled the synthesis of complex and diverse bridged cyclic polycycles with multiple stereocenters in a highly regio- and diastereoselective manner. Besides, we realized the step-controlled dearomative bi- and trifunctionalization of quinolinium salts. These transformations not only achieved the maximization of the reaction sites of pyridinium, quinolinium and isoquinolinium salts to enhance structural complexity and diversity, but also opened up a new reaction mode of these N-activated azaarenes. A unique feature of this strategy is the use of easily accessible and bench-stable N-alkyl activated azaarenes to provide maximum reactive sites for dearomative cascade cyclizations. In addition, the salient characteristics including high synthetic efficiency, short reaction time, mild conditions and simple operation made this strategy particularly attractive.

An Unexpected FeCl3-Catalyzed Cascade Reaction of Indoles and o-Hydroxychalcones for the Assembly of Chromane-Bridged Polycyclic Indoles.

An unexpected FeCl3-catalyzed cascade reaction of simple indoles and o-hydroxychalcone was reported, leading to densely functionalized and strained chromane-bridged polycyclic indoles in moderate to good yields. This reaction not only establishes a new transformation of indoles and o-hydroxychalcones but also provides an efficient method for the synthesis of structurally complex and congested chromane-bridged polycyclic indoles.