Electrochemical Reductive Cross-Coupling of Alkyl or Alkenyl Halides with gem-Difluoroalkenes.

Herein, we describe an electroreductive cross-electrophile coupling protocol for the construction of valuable monofluoroalkenes from easily accessible alkyl or alkenyl halides with gem-difluoroalkenes. The reaction can be conducted under sustainable and mild conditions delivering valuable and functionalized monofluoroalkenes with excellent Z-selectivity. The protocol's most notable advantage is the in situ release of nickel catalyst from the inexpensive electrodes without the addition of extra hazardous metal catalyst and superstoichiometric reductant.

Electrochemical Reductive Cross-Coupling of Vinyl Bromides for the Synthesis of 1,3-Dienes.

An electroreductive cross-electrophile coupling protocol was developed for the construction of valuable 1,3-dienes from vinyl bromides. Furthermore, this scalable method can also be used to forge complex [4 + 2] cycloadducts in a one-pot manner. One of the most important advantages of this green and sustainable protocol is the in situ release of nickel catalyst from the inexpensive electrodes without the addition of extra harmful metal catalysts and reductant.

meta-Selective O-Arylation of Cyclic Diaryliodonium Salts with Phenols via Aryne Intermediates.

Herein, we report a base-mediated, highly meta-selective O-arylation process of phenols and cyclic diaryliodonium salts without usage of transition metals. This novel and practical method was proved to be useful for the synthesis of iodine-containing meta-functionalized biaryl ethers in a broad functional group tolerance and environmentally friendly manner. Diversity-oriented transformations of the products were carried out to give various valuable functionalized biaryls. Preliminary mechanistic studies support the proposed aryne generation mechanism.

Discovery of a potent and selective allosteric inhibitor targeting the SHP2 tunnel site for RTK-driven cancer treatment.

Src homology 2 domain-containing phosphatase 2 (SHP2) is a cytoplasmic protein tyrosine phosphatase (PTP) that regulates signal transduction of receptor tyrosine kinases (RTKs). Abnormal SHP2 activity is associated with tumorigenesis and metastasis. Because SHP2 contains multiple allosteric sites, identifying inhibitors at specific allosteric binding sites remains challenging. Here, we used structure-based virtual screening to directly search for the SHP2 "tunnel site" allosteric inhibitor. A novel hit (70) was identified as the SHP2 allosteric inhibitor with an IC50 of 10.2 µM against full-length SHP2. Derivatization of hit compound 70 using molecular modeling-guided structure-based modification allowed the discovery of an effective and selective SHP2 inhibitor, compound 129, with 122-fold improved potency compared to the hit. Further studies revealed that 129 effectively inhibited signaling in multiple RTK-driven cancers and RTK inhibitor-resistant cancer cells. Remarkably, 129 was orally bioavailable (F = 55%) and significantly inhibited tumor growth in haematological malignancy. Taken together, compound 129 developed in this study may serve as a promising lead or candidate for cancers bearing RTK oncogenic drivers and SHP2-related diseases.

Synthesis of 1,3-Dioxepine-Fused (Tricyclic) Bispyrazoles Involved with Pyrazolone Derivatives and Dichloromethane.

A simple and novel method for the synthesis of novel 1,3-dioxepine-fused (tricyclic) bispyrazoles is described. It involves a Cs2CO3-mediated O-alkylation of readily available pyrazolone derivatives with dichloromethane as the methylene source followed by PhI(OAc)2-mediated intramolecular oxidative biheteroaryl coupling under mild conditions. This scalable protocol was applied for the preparation of valuable and novel 1,3-dioxepine-fused (tricyclic) bispyrazoles that could find applications in medicinal or material chemistry.

Electrochemical Difunctionalization of Styrenes via Chemoselective Oxo-Azidation or Oxo-Hydroxyphthalimidation.

Atom- and step-economic oxo-azidation and oxo-hydroxyphthalimidation of styrenes have been developed under mild electrolytic conditions, respectively. Various valuable alpha-azido or hydroxyphthalimide aromatic ketones were synthesized efficiently from readily available styrenes, azides, and N-hydroxyphthalimides. Mechanism studies show that two different pathways involved in these two transformations.

Recent progress on electrochemical synthesis involving carboxylic acids.

Carboxylic acids are not only essential sections of medicinal molecules, natural products and agrochemicals but also basic building blocks for organic synthesis. However, high temperature, expensive catalysts and excess oxidants are normally required for carboxylic acid group transformations. Therefore, more eco-friendly and efficient methods are urgently needed. Organic electrochemistry, as an environmentally friendly and sustainable synthetic method, can potentially avoid the above problems and is favored by more and more organic chemists. This review summarized the recent progress on the electrochemical synthesis of carboxylic acids to construct more complex compounds, emphasizing the development of electrosynthesis methodologies and mechanisms in order to attract more chemists to recognize the importance and applications of electrochemical synthesis.

PIDA-Mediated Rearrangement for the Synthesis of Enantiopure Triazolopyridinones.

A tandem oxidative cyclization/1,2-carbon migration of hydrazides for the synthesis of otherwise inaccessible hindered or enantiopure triazolopyridinones has been developed. This protocol exhibits broad substrate scope and can be easily scaled up by continuous flow synthesis under mild conditions. Most importantly, this method demonstrates a rearrangement with retention of configuration and can be readily applied for the late-stage modification of carboxylic-acid-containing pharmaceuticals, amino acids, and natural products to access enantiopure triazolopyridinones.

Enantiospecific electrochemical rearrangement for the synthesis of hindered triazolopyridinone derivatives.

Triazolopyridinone derivatives are of high value in both medicinal and material chemistry. However, the chiral or hindered triazolopyridinone derivatives remain an underexplored area of chemical space because they are difficult to prepare via conventional methods. Here we report an electrochemical rearrangement for the efficient synthesis of otherwise inaccessible triazolopyridinones with diverse alkyl carboxylic acids as starting materials. This enables the efficient preparation of more than 60 functionalized triazolopyridinones under mild conditions in a sustainable manner. This method is evaluated for the late stage modification of bioactive natural products, amino acids and pharmaceuticals, and it is further applied to the decagram scale preparation of enantiopure triazolopyridinones. The control experiments support a mechanism involving an oxidative cyclization and 1,2-carbon migration. This facile and scalable rearrangement demonstrates the power of electrochemical synthesis to access otherwise-inaccessible triazolopyridinones and may find wide application in organic, material and medicinal chemistry.

Synthesis of Tribenzo[b,d,f]azepines via Cascade π-Extended Decarboxylative Annulation Involving Cyclic Diaryliodonium Salts.

Various functionalized tribenzo[b,d,f]azepines were prepared efficiently with the readily available 2-aminobenzoic acids and cyclic hypervalent diaryliodonium reagents as starting materials under Pd(II) catalysis. The key of this step-economical protocol is that the carboxylic acid functionality was employed as both a traceless directing group for the N-H activation/arylation and a functional handle for the tandem π-extended decarboxylative annulation.

Cascade π-Extended Decarboxylative Annulation Involving Cyclic Diaryliodonium Salts: Site-Selective Synthesis of Phenanthridines and Benzocarbazoles via a Traceless Directing Group Strategy.

A novel cascade π-extended decarboxylative annulation (PEDA) involved with cyclic diaryliodonium salts is described. Via fine-tuning of the reaction conditions, the Pd(II)-catalyzed site-selective N1/C2 or C2/C3 annulation of commercially available indole-2-carboxylic acids can be achieved, affording valuable phenanthridines or benzocarbazoles, respectively. The key strategy is the carboxylic acid functionality being employed as both a traceless directing group for the ortho C-N or C-C coupling and a reactive group for the cascade π-extended decarboxylative annulation in a highly step economical manner.

Two-in-One Strategy for the Pd(II)-Catalyzed Tandem C-H Arylation/Decarboxylative Annulation Involved with Cyclic Diaryliodonium Salts.

We report here a two-in-one strategy for the Pd(II)-catalyzed tandem C-H arylation/decarboxylative annulation between readily available cyclic diaryliodonium salts and benzoic acids. The carboxylic acid functionality can be used as both a directing group for the ortho-C-H arylation and the reactive group for the tandem decarboxylative annulation. By a step-economical double cross-coupling annulation procedure, the privileged triphenylene frameworks were efficiently constructed, which have potential applications in material chemistry.

Highly Selective Palladium-Catalyzed Arene C-H Acyloxylation with Benzothiadiazole as a Modifiable Directing Group.

An efficient protocol for the palladium-catalyzed direct arene C-H acyloxylation of benzothiadiazole-arene derivatives is reported for the first time. The key strategy is the employment of benzothiadiazole as a modifiable directing group. The highly selective mono- or bis-acyloxylation can be achieved by tuning the reaction conditions, affording various acyloxylated benzothiadiazole derivatives, which could offer a rational tailoring of their electronic properties and be applied in organic electronic and optoelectronic materials. Finally, by diversity-oriented modification of the benzothiadiazole directing group, the acyloxylated products can be readily converted into various valuable functionalized (hetero)biaryls.