Site-Selective Carbonylative Cyclization with Two Allylic C-H Bonds Enabled by Radical Differentiation.

Controlling the site-selectivity of C-H functionalization is of significant importance and a formidable undertaking in synthetic organic chemistry, motivating the continuing development of efficient and sustainable technologies for activating C-H bonds. However, methods that control the site-selectivity for double C-H functionalization are rare. We herein report a conceptually new method to achieve highly site-selective C-H functionalization by implementing a radical single-out strategy. Leveraging the steric hindrance-sensitive CO-insertion as the radical differentiation process, a site-selective and stereoselective carbonylative formal [2 + 2] cycloaddition of imines and alkenes by sequential double allylic C-H bond activation was established without special and complicated HAT-reagents. This reaction was compatible with a wide range of alkenes and imines with diverse skeletons to deliver allylic ß-lactams that are of synthetic and medicinal interest.

Carbonylative Formal Cycloaddition between Alkylarenes and Aldimines Enabled by Palladium-Catalyzed Double C-H Bond Activation.

Double C-H bond activation can enable an expeditious reaction pathway to cyclic compounds, offering an efficient tool to synthesize valuable molecules. However, cyclization reaction enabled by double C-H bond activation at one carbon atom is nearly unknown. Herein, we report a carbonylative formal cycloaddition of alkylarenes with imines via double benzylic C-H bond activation at one carbon atom, allowing a straightforward synthesis of ß-lactams from readily accessible alkylarenes and imines, which paves the way for developing an annulation reaction through double C-H bond activation at one carbon atom.

Palladium-Catalyzed Chemodivergent Carbonylation of ortho-Bromoarylimine to Biisoindolinones and Spiroisoindolinones.

We herein report a palladium-catalyzed carbonylative cyclization reaction of ortho-bromoarylimines that allows for the chemodivergent synthesis of functionalized biisoindolinones and spirocyclic isoindolinones. Either product could be selectively obtained by switching the reaction temperatures and ligands, and the biisoindolinone products could be afforded facilely with catalyst loadings as low as 0.05 mol %. Further transformation of the biisoindolinone product is also described, which represents a novel and concise approach to the biisoindoline diamine ligand.

Nickel-Catalyzed Oxidative Carbonylation of Alkylarenes to Arylacetic Acids.

A catalytic system combined with NiBr2 and diphenylphosphine oxide that enabled direct access to the valuable arylacetic acids from inexpensive alkylarenes and H2O via oxidative carbonylation was developed. Alkylarenes with primary and secondary benzylic C-H bonds were compatible with this method. Remarkably, the marketed drugs ibuprofen and diclofenac could be easily obtained by this procedure straightforwardly.

Pd-Catalyzed carbonylative lactonization of 2-halidearomatic aldehydes with H2O as a nucleophile.

A palladium-catalyzed carbonylative cyclization reaction of 2-halidebenzaldehydes with H2O is described, which provides a strategy for the synthesis of diversely substituted 3,3'-oxyphthalides. Notably, the obtained 3,3'-oxyphthalide could be easily transformed into 3-aryl and alkyl phthalides with excellent efficiency using organozinc reagents under mild reaction conditions.

Carbonylative cycloaddition between two different alkenes enabled by reactive directing groups: expedited construction of bridged polycyclic skeletons.

A novel palladium-catalyzed highly selective hydrocarbonylative cycloaddition reaction with two different alkenes in the presence of CO enabled by a reactive directing-group is developed, which offers efficient and convenient access to lactone-containing bridged polycyclic compounds in high yield with high chemo- and stereoselectivities.

Palladium-Catalyzed Carbonylative Difunctionalization of C=N Bond of Azaarenes or Imines to Quinazolinones.

Supporting information for this article is given via a link at the end of the document. By intercepting the acylpalladium species with C=N bond of azaarenes or imines other than free amines or alcohols, the difunctionalization of C=N bond was established via palladium-catalyzed carbonylation/nucleophilic addition sequence. This method is compatible with a diverse range of azaarenes and imines and allows for the efficient synthesis of a wide range of quinazolinones and derivatives. The synthetic utility has been demonstrated by one-step synthesis of evodiamine and its analogue with inexpensive starting materials.

Transition-metal-catalyzed reactions involving reductive elimination between dative ligands and covalent ligands.

Reductive elimination is a crucial bond-forming elementary reaction in various transition-metal mediated reactions. Apart from the well-developed classic reductive elimination, the non-classic reductive elimination occurring between a covalent ligand and a dative ligand, which has been known for over 50 years, has gradually attracted much attention from the organic community. By avoiding pπ-dπ repulsion between the filled metal d-orbital and the filled ligand p-orbital and forming a cationic-type molecule, non-classic reductive elimination could facilitate many catalytic reactions that were difficult to be realized via classic reductive elimination. In this review, transition-metal catalyzed C-P, C-S, C-N, and C-C bond-forming reactions with non-classic reductive elimination as the key elementary step are summarized.

Palladium-Catalyzed C(sp2)-H Olefination of Free Primary and Secondary 2-Phenylethylamines: Access to Tetrahydroisoquinolines.

A rapid construction of THIQs by a Pd(II)-catalyzed C(sp2)-H olefination of free primary and secondary 2-phenylethylamines with high step- and atom-economy was reported. Notably, no substituent was required at the α-position to the amino group of the 2-phenylethylamines. The substrate scope was broad, and the reaction could also be applied to generate THIQs from the biologically active molecules such as the drug molecule baclofen and phenylalanine ester.

Ligand Promoted, Palladium-Catalyzed C(sp2)-H Arylation of Free Primary 2-Phenylethylamines.

A mono- N-protected amino acid (MPAA) ligand promoted, Pd(II)-catalyzed C(sp2)-H arylation of free primary 2-phenylethylamines using the native NH2 as the directing group has been achieved. This method is compatible with challenging simple primary 2-phenylethylamines bearing α-hydrogen atoms. Application of this protocol in the direct structure modification of the drug molecule amphetamine is also demonstrated.

Palladium-Catalyzed Direct C-H Carbonylation of Free Primary Benzylamines: A Synthesis of Benzolactams.

A protocol for palladium-catalyzed C-H carbonylation of readily available free primary benzylamines using NH2 as the chelating group under an atmospheric pressure of CO has been achieved, providing a general, atom- and step-economic approach to benzolactams, an important structural motif found in many biologically active compounds. Application of this new method is also exemplified in the concise syntheses of two bioactive molecules.

Sulfinyl isobutyramide as an auxiliary for palladium(ii)-catalyzed C-H arylation and iodination of benzylamine derivatives.

A novel readily available bidentate 2-methylsulfinyl isobutyramide directing group has been developed for benzylamine derivatives. It promoted ortho-C-H arylation and iodination of various substrates in good to excellent yields. The auxiliary is promising to be used in organic synthesis due to its versatility and convenient preparation from inexpensive materials.

Palladium-Catalyzed C-H Trifluoroethoxylation of N-Sulfonylbenzamides.

The trifluoroethyl aryl ethers are important motifs in drug molecules. However, a report devoted specifically to the study of transition-metal-catalyzed C-H trifluoroethoxylation has not been reported to date. A protocol of Pd(II)-catalyzed o-C-H trifluoroethoxylation of a broad range of benzoic acid derivatives (i.e., N-sulfonylbenzamides) has been developed. This method is also applied to the formal synthesis of the drug molecule flecainide, wherein the first m-C-H trifluoroethoxylation is also exemplified.

Discovery of Multi-target Anticancer Agents Based on HDAC Inhibitor MS-275 and 5-FU.

Histone deacetylases (HDACs) inhibitors have multiple effects targeting the cancer cells and have become one of the promising cancer therapeutics with possibly broad applicability. Combination of HDAC inhibitors with the cytotoxic fluorouracil (5-FU) showed additive and synergistic effects both in vitro and in vivo. To explore the possibility in cancer therapy of a bivalent agent that combines two bioactive groups within a single molecular architecture, we designed and synthesized new dual-acting compounds by combining the bioactive fragment of MS-275, a clinical HDACs inhibitor, with cytotoxic agent 5-FU. The target compounds 9a and 9b showed comparable HDACs inhibition with MS-275 and moderate antiproliferative acitivities against six cancer cells lines.

Catalytic cross deoxygenative and dehydrogenative coupling of aldehydes and alkenes: a redox-neutral process to produce skipped dienes.

A novel catalytic cross deoxygenative and dehydrogenative coupling reaction of aldehydes and alkenes was established via a cooperative catalysis approach. This transformation provided an efficient and atom-economic protocol for the synthesis of 1,4-skipped dienes from aldehydes and simple alkenes under oxidant-free reaction conditions.