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. This review article summarizes recent continuous flow techniques that address the limitations and challenges of fluorination reactions. Approaches based on different flow techniques are discussed, including gas-liquid reactions, packed-bed reactors, in-line purifications, streamlined multistep synthesis, large-scale reactions well as flow photoredox- and electrocatalysis.

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. Flow chemistry is an emerging and promising technique to address long-standing challenges in gas-liquid batch reactions such as insufficient interfacial contact and scalability issues. In this review, we highlight recent advances in continuous flow strategies toward enabling the use of fluorinated greenhouse gases in organic synthesis.

Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF2 H in Continuous Flow.

The deuteriodifluoromethyl group (CF2 D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF2 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 D2 O to provide α-deuteriodifluoromethylated benzyl alcohols or undergo a retro [2+2] cycloaddition under thermal conditions to provide the gem-difluoroalkenylated product.

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. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixtures.

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. The method described is scalable and adaptable to a three-component reaction with in situ generation of the hydrazone group. Preliminary mechanistic investigations have been conducted.

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. Unlike in previously reported palladium-catalyzed three-component annulations, alkyne carbopalladation is the last step of this tandem reaction.

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 (0.1-1.0 mol%), the reaction provides mono-α-alkenylated ketones in good yields and exhibits excellent substrate tolerance. Highly congested, tri- and tetra-substituted alkenyl tosylates react smoothly and even problematic heteroaryl and aliphatic ketones are applicable substrates. Notably, small ß,γ-unsaturated ketones are successfully prepared using acetone as a simple three-carbon feedstock.

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. Highly sterically hindered substrates and small vinyl tosylate can be coupled successfully. Moreover, our method enables a rapid diversification of oxazole-based C^N ligands which can be readily derived into new group 9 organometallic compounds.

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. In the presence of Pd(OAc)2 (0.25-2.5 mol %) and L7, selective monoarylations are achieved with ample reaction scope and product yields up to 95%. Importantly, we demonstrated the applicability of this protocol with the modification of biological phenolic compounds, rendering it amenable for functionalization of phenolic (pro)drugs.

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. The mesylated derivatives of biologically active compounds such as 17ß-estradiol and 6-hydroxyflavone are also shown to be applicable substrates. A one-pot phosphorylation-amination sequence is described for the facile synthesis of potential pharmacophores.

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. Preliminary investigations suggest that the rate-limiting step for the proposed system is the oxidative addition of aryl chlorides, in which it contradicts previous findings regarding the α-arylation of acetone with aryl halides.

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.

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. The iridium(III) complex shows high specificity for Hg(2+) ions over eighteen other cations. The system is capable of detecting micromolar levels of Hg(2+) ions, which is within the range of many chemical systems.

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., methylated EGC) (14) as well as natural epigallocatechin (EGC, 6). The DNA G-quadruplex binding activity of 16 and 18 is even more potent than strong G-quadruplex binder quercetin, which has a more planar structure. These two synthetic compounds also showed a higher binding strength to human telomeric RNA G-quadruplex than its DNA counterpart. Analysis of the structure-activity relationship revealed that the more basic compound, 16, has a higher binding capacity with DNA and RNA G-quadruplexes than its N-acetyl derivative, 18, suggesting the importance of the basicity of the aminoglycoside for G-quadruplex binding activity. Molecular docking simulation predicted that the aromatic ring of 16 π-stacks with the aromatic ring of guanine nucleotides, with the glucosamine moiety residing in the groove of G-quadruplex. This research indicates that glycosylation of natural products with aminosugar can significantly enhance their G-quadruplex binding activities, thus is an effective way to generate small molecules targeting G-quadruplexes in nucleic acids. In addition, this is the first report that green tea catechin can bind to nucleic acid G-quadruplex structures.

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). The interaction between the most potent compound of the series and the c-myc G-quadruplex was examined in depth using UV-Vis titration, molecular modeling and CD spectroscopy. Our results suggest that in addition to stabilizing the c-myc G-quadruplex, the flavone derivatives were capable of inducing the formation of the G-quadruplex structure even in the absence of monovalent cations. The flavone derivatives were found to be potent inhibitors of c-myc promoters within the cellular environment and displayed promising cytotoxic behavior against human cancer cell lines.

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. Furthermore, the interaction between carbamide analogues and the c-myc G-quadruplex was also investigated by in vitro experiments in order to generate a brief structure-activity relationship (SAR) for the observed potency of carbamide 1.