Advances in Continuous Flow Fluorination Reactions.

Fluorination reactions are important in constructing organofluorine motifs, which contribute to favorable biological properties in pharmaceuticals and agrochemicals. However, fluorination reagents and reactions are associated with various problems, such as their hazardous nature, high exothermicity, and poor selectivity and scalability. Continuous flow has emerged as a transformative technology to provide many advantages relative to batch syntheses.

Continuous flow strategies for using fluorinated greenhouse gases in fluoroalkylations.

Large quantities of fluorinated gases are generated as intermediates or byproducts from fluorinated polymer production annually, and they are effective ozone depleting substances or greenhouse gases. On the other hand, the incorporation of fluoroalkyl groups into drug molecules or bioactive compounds has been shown to enhance biological properties such as the bioavailability, binding selectivity, and metabolic stability. Extraction of fluoroalkyl sources, including trifluoromethyl and difluoromethyl groups, from the fluorinated gases is highly desirable, yet challenging under regular batch reaction conditions.

Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF H in Continuous Flow.

The deuteriodifluoromethyl group (CF D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF H) gas in the continuous flow deuteriodifluoromethylation and gem-difluoroalkenylation of aldehydes. Mechanistic studies revealed that the difluorinated oxaphosphetane (OPA) intermediate can proceed via alkaline hydrolysis in the presence of D O to provide α-deuteriodifluoromethylated benzyl alcohols or undergo a retro [2+2] cycloaddition under thermal conditions to provide the gem-difluoroalkenylated product.

A denitrogenative palladium-catalyzed cascade for regioselective synthesis of fluorenes.

We herein report a denitrogenative palladium-catalyzed cascade for the modular and regioselective synthesis of polysubstituted fluorenes. Hydrazone facilitates the Pd(ii) to Pd(iv) oxidative addition in a Catellani pathway and is also the methylene synthon in the proposed reaction. Aryl iodides and 2-bromoarylaldehyde hydrazones undergo a norbornene-controlled tandem reaction sequence to give a broad scope of fluorenes in the presence of a palladium catalyst.

Modular Continuous Flow Synthesis of Imatinib and Analogues.

A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C-N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields.

Palladium-Catalyzed Regioselective Aromatic Extension of Internal Alkynes through a Norbornene-Controlled Reaction Sequence.

A regioselective aromatic π-extension reaction of internal alkynes is reported. The proposed method employs three easily available components, namely aryl halides, 2-haloarylcarboxylic acids, and disubstituted acetylenes. The transformation is driven by a controlled reaction sequence of C-H activation, decarboxylation, and annulation to give poly(hetero)aromatic compounds in a site-selective fashion.

Cascade Amination and Acetone Monoarylation with Aryl Iodides by Palladium/Norbornene Cooperative Catalysis.

A palladium/norbornene cocatalyzed three-component reaction of aryl iodides, O-benzoylhydroxylamines, and acetone is reported. o'-Aminoaryl acetones or o,o'-diaminoaryl acetones are efficiently prepared via tandem ortho-C-H amination/ipso-C-I α-arylation sequence, and the regiospecificity has been confirmed by X-ray analysis. The proposed method addresses the condensation/amination of free-N-H-bearing substrates in acetone monoarylations and the synthesis of extremely congested 2,6-disubstituted aryl acetones.

Regioselective Synthesis of Polycyclic and Heptagon-embedded Aromatic Compounds through a Versatile π-Extension of Aryl Halides.

A versatile π-extension reaction was developed based on the three-component cross-coupling of aryl halides, 2-haloarylcarboxylic acids, and norbornadiene. The transformation is driven by the direction and subsequent decarboxylation of the carboxyl group, while norbornadiene serves as an ortho-C-H activator and ethylene synthon via a retro-Diels-Alder reaction. Comprehensive DFT calculations were performed to account for the catalytic intermediates.

Palladium-catalysed mono-α-alkenylation of ketones with alkenyl tosylates.

The first example of palladium-catalysed selective mono-α-alkenylation of ketones with alkenyl tosylates is described. In the presence of a Pd/XPhos catalyst system (0.1-1.

Catalytic Direct C2-Alkenylation of Oxazoles at Parts per Million Levels of Palladium/PhMezole-Phos Complex.

General direct C2-alkenylation of oxazoles is reported using alkenyl tosylates at parts per million levels of palladium catalyst. From a series of ligands screened, PhMezole-Phos emerged as the promising ligand candidate to facilitate this reaction. Significantly, the method is scalable and exhibits excellent substrate tolerance.

Exploiting Aryl Mesylates and Tosylates in Catalytic Mono-α-arylation of Aryl- and Heteroarylketones.

The first general palladium catalyst for the catalytic mono-α-arylation of aryl- and heteroarylketones with aryl mesylates and tosylates is described. The newly developed indolyl-derived phosphine ligand L7 has been identified to promote this reaction efficiently. The key to success is attributed to the enhanced steric congestion of the catalyst and effective oxidative addition of the C(Ar)-OMs bond.

Palladium-Catalyzed Phosphorylation of Aryl Mesylates and Tosylates.

The first general palladium catalyst for the phosphorylation of aryl mesylates and tosylates is reported. The newly developed system exhibits excellent functional group compatibility. For instance, free amino, keto, ester, and amido groups, as well as heterocycles, remain intact during the course of reaction.

Copper-Catalyzed Oxidative C-H Amination of Tetrahydrofuran with Indole/Carbazole Derivatives.

A simple α-C-H amination of cyclic ether with indole/carbazole derivatives has been accomplished by employing copper(II) chloride/bipy as the catalyst system. In the presence of the di-tert-butyl peroxide oxidant, cyclic ethers such as tetrahydrofuran, 1,4-dioxane, and tetrahydropyran successfully undergo C-H/N-H cross dehydrogenative coupling (CDC) with various carbazole or indole derivatives in good-to-excellent yields.

Design of an Indolylphosphine Ligand for Reductive Elimination-Demanding Monoarylation of Acetone Using Aryl Chlorides.

The rational design of a phosphine ligand for the reductive elimination-demanding Pd-catalyzed mono-α-arylation of acetone is demonstrated and reported. The catalyst is tolerant of previously proven challenging electron-deficient aryl chlorides and provides excellent product yields with down to 0.1 mol % Pd.

A highly selective and non-reaction based chemosensor for the detection of Hg2+ ions using a luminescent iridium(III) complex.

We report herein a novel luminescent iridium(III) complex with two hydrophobic carbon chains as a non-reaction based chemosensor for the detection of Hg(2+) ions in aqueous solution (<0.002% of organic solvent attributed to the probe solution). Upon the addition of Hg(2+) ions, the emission intensity of the complex was significantly enhanced and this change could be monitored by the naked eye under UV irradiation.

Phosphorescent imaging of living cells using a cyclometalated iridium (III) complex.

A cell permeable cyclometalated iridium(III) complex has been developed as a phosphorescent probe for cell imaging. The iridium(III) solvato complex [Ir(phq)2(H2O]2)] preferentially stains the cytoplasm of both live and dead cells with a bright luminescence.

Aminoglycosylation can enhance the G-quadruplex binding activity of epigallocatechin.

With the aim of enhancing G-quadruplex binding activity, two new glucosaminosides (16, 18) of penta-methylated epigallocatechin were synthesized by chemical glycosylation. Subsequent ESI-TOF-MS analysis demonstrated that these two glucosaminoside derivatives exhibit much stronger binding activity to human telomeric DNA and RNA G-quadruplexes than their parent structure (i.e.

Structure-based design of flavone derivatives as c-myc oncogene down-regulators.

Based on molecular docking analysis of complexes between flavone and the c-myc G-quadruplex, we designed and screened 30 flavone derivatives containing various side chains that could potentially form interactions with the G-quadruplex grooves. As a proof-of-concept, the highest-scoring flavone derivatives containing cationic pyridinium side chains were synthesized and their interactions with the c-myc G-quadruplex were examined using a PCR-stop assay. The stabilizing effects of the flavone derivatives were found to be selective towards the c-myc G-quadruplex over other biologically relevant G-quadruplex structures, such as the human telomeric sequence (HTS).

Discovery of a natural product-like c-myc G-quadruplex DNA groove-binder by molecular docking.

The natural product-like carbamide (1) has been identified as a stabilizer of the c-myc G-quadruplex through high-throughput virtual screening. NMR and molecular modeling experiments revealed a groove-binding mode for 1. The biological activity of 1 against the c-myc G-quadruplex was confirmed by its ability to inhibit Taq polymerase-mediated DNA extension and c-myc expression in vitro, demonstrating that 1 is able to control c-myc gene expression at the transcriptional level presumably through the stabilization of the c-myc promoter G-quadruplex.