Biaryl Systems Research Articles

Deciphering the Mechanistic Insights of Temporary Directing-Group-Assisted meta-Alkenylation of Complex Biaryl Systems

Deciphering the Mechanistic Insights of Temporary Directing-Group-Assisted <i>meta</i>-Alkenylation of Complex Biaryl Systems

Synthesis and stereodynamics of intramolecular hemiacetals in biaryl aldehyde-alcohols.

Soai's asymmetric autocatalysis represents a highly remarkable example for spontaneous symmetry breaking and enantioselective amplification in the enantioselective alkylation of pyrimidine-5-carbaldehydes to the corresponding chiral pyrimidine alcohols. Recently, zinc hemiacetalate complexes, formed from pyrimidine-5-carbaldehydes and the chiral product alcohol, were identified by in situ high-resolution mass spectrometric measurements as highly active transient asymmetric catalysts in this autocatalytic transformation. To study the formation of such hemiacetals and their stereodynamic properties, we focused on the synthesis of coumarin homolog biaryl systems with carbaldehyde and alcohol substituents. Such systems are able to form hemiacetals by intramolecular cyclization. An interesting feature of the substituted biaryl backbone is that tropos and atropos systems can be obtained, enabling or disabling the intramolecular cyclization to hemiacetals. Biaryl structures with various functional groups were synthesized, and the equilibrium and stereodynamics between the closed and open structures were investigated by dynamic enantioselective HPLC (DHPLC). The enantiomerization barriers ΔGǂ and activation parameters ΔHǂ and ΔSǂ were determined from temperature dependent kinetic measurements.

Synthesis, anti-cancer activity and molecular docking studies of new nicotinamide containing EP4 antagonists

Selective binding of the pleiotropic lipid mediator prostanoid Prostaglandin E2 (PGE2) towards the G-protein coupled EP4 receptor has been studied extensively for inflammatory and hyperalgesia models and has been implicated to have significant potential for the treatment of various forms of cancers. Interest of nicotinamides as EP4 antagonists for oncology research, led us to synthesize a small set of molecules using the nicotinamide derivative AAT-008 (1) as our starting point for design. Subtle changes by replacing the hydrogen bond accepting bi-aryl-ether moiety in (1) to hydrogen bond donating bi-aryl-amino moiety and thereafter modifications on the substituents in the bi-aryl ring systems, carboxyl and the amino groups enabled us to identify a modestly potent new EP4 antagonist compound 14 with IC50 = 0.543 ± 0.148 μM (n = 6). Compound 14 was found to be stable in ADME assays and had reasonably good solubility. The interplay of electronic parameters such as lipohilicity and polarity of the compounds did not seem to play a significant role in deriving the EP4 antagonism potency for these compounds. Thus, molecular docking studies were carried out to understand the structure activity relationships (SAR). The trend in activity range of the synthesized compounds and the lower EP4 activity of compound 14 in contrast to compound 1 was explained with aid of molecular docking studies that supported our experimental potency results also. Preliminary screening of compounds 1 and 14 for oncology showed weak activity at a modest dose of 500 μM in breast cancer cells (MDA-MB-231) and moderately significant activity in colon cancer cells (HCT-116) cytotoxicity assays. Since, there was relatively higher cytotoxic activity in colon cancer cell lines, the cytotoxic effects of these two compounds were further evaluated under PGE2 induced conditions in two colon cancer cell lines: HCT-116 cells (IC50 values of 46 µM and 50 µM for compounds 1 and 14, respectively) and HT-29 cells (IC50 values of 37 µM and 4.5 µM for compounds 1 and 14, respectively) which signifies the possible relevance of the prostanoid inhibition pathway and its interference through the PGE2 induced oncogenic pathway.

Real Metal-Free C–H Arylation of (Hetero)arenes: The Radical Way

AbstractSynthetic methodologies involving the formation of carbon–carbon bonds from carbon–hydrogen bonds are of significant synthetic interest, both for efficiency in terms of atom economy and for their undeniable usefulness in late-stage functionalization approaches. Combining these aspects with being metal-free, the radical C–H intermolecular arylation procedures covered by this review represent both powerful and green methods for the synthesis of (hetero)biaryl systems.1 Introduction2 Arylation with Arenediazonium Salts and Related Derivatives2.1 Ascorbic Acid as the Reductant2.2 Hydrazines as Reductants2.3 Gallic Acid as the Reductant2.4. Polyanilines as Reductants2.5 Chlorpromazine Hydrochloride as the Reductant2.6 Phenalenyl-Based Radicals as Reductants2.7 Electrolytic Reduction of Diazonium Salts2.8 Visible-Light-Mediated Arylation3 Arylation with Arylhydrazines: Generation of Aryl Radicals Using an Oxidant4 Arylation with Diaryliodonium Salts5 Arylation with Aryl Halides6 Conclusions

Transition-Metal-Free Oxidative Cross-Coupling of Tetraarylborates to Biaryls Using Organic Oxidants.

Readily prepared tetraarylborates undergo selective (cross)‐coupling through oxidation with Bobbitt's salt to give symmetric and unsymmetric biaryls. The organic oxoammonium salt can be used either as a stoichiometric oxidant or as a catalyst in combination with in situ generated NO2 and molecular oxygen as the terminal oxidant. For selected cases, oxidative coupling is also possible with NO2/O2 without any additional nitroxide‐based cocatalyst. Transition‐metal‐free catalytic oxidative ligand cross‐coupling of tetraarylborates is unprecedented and the introduced method provides access to various biaryl and heterobiaryl systems.

The Use of Chiral ortho‐Auxiliaries/Substituents and Remote Stereogenic Centers in Atropselective Biaryl Synthesis

Axially chiral biaryls are core structures of increasingly important organic molecules including bioactive natural products, drugs, chiral ligands and organocatalysts. Among established methods for accessing these axially chiral structures, chiral ortho‐auxiliaries/substituents and remote stereogenic centers have provided useful strategies for the preparation of highly functionalized enantiopure biaryl compounds such as gossypol, rugulotrosin A, korupensamine A, phosphine ligands, sulfoxides, and 2‐amino‐2′‐hydroxy‐1,1′‐binaphthyls (NOBINs). These strategies, which entail point‐to‐axial chirality transfer, have received increasing attention in the last thirty years. This minireview up to October 2019 describes these methods with attention to the atropselective formation of biaryl systems influenced by chiral ortho‐auxiliaries/substituents and remote stereogenic centers.

Mapping the reactivity of the quinoline ring-system – Synthesis of the tetracyclic ring-system of isocryptolepine and regioisomers

Bromoquinolines (2-bromoquinoline – 8-bromoquinoline and 5-bromo-3-methoxyquinoline) and 2-aminophenylboronic acid hydrochloride were subjected to Suzuki-Miyaura cross-coupling conditions resulting in formation of the desired biaryl systems in good yields. The resulting biaryls were then subjected to palladium catalyzed CH activation/CN bond formation utilizing PdCl2(dppf). The reactions revealed large differences in reactivity depending on the attachment point for the 2-aminophenyl group on the quinoline. The variation in the reactivity was rationalized based on the electron distribution around the quinoline ring-system.

Frontier molecular orbital effects control the hole-catalyzed racemization of atropisomeric biaryls.

Atropisomeric biaryl systems are privileged architectures used in asymmetric synthesis and pharmaceutical structures. We report that by simply removing a single-electron, the resistance of biaryls towards racemization is reduced dramatically. Even though the steric properties are unaltered, biaryl oxidation changes atropisomerization into a two step mechanism with considerably smaller activation barriers than closed-shell biaryls. The effect is general for a series of biaryls and helicenes studied and results from the dependence of frontier molecular orbital energies on biaryl conformation.

Probing the Aggregation and Signaling Behavior of Some Twisted 9,9'-Bianthryl Derivatives: Observation of Aggregation-Induced Blue-Shifted Emission.

With an aim to understand the photophysical behavior of twisted organic fluorescent molecules in their aggregated state, two twisted biaryl molecules, namely, 9,9′-bianthryl and 10,10′-dicyano-9,9′-bianthryl, have been synthesized and characterized by conventional spectroscopic methods. To understand the role of C–C bond twisting on the photophysical response of biaryl aggregates, monoaryl counterparts (anthracene and 9-anthracenecarbonitrile) of the biaryl systems are also investigated. Photophysical behaviors of these systems along with their monoaryl counterpart are investigated in both solution and aggregated state. Investigations reveal that fluorescence spectra of the biaryl compounds show blue-shifted emission upon aggregation. Interestingly, no blue shift of the emission has been observed for monoaryl aggregates. Photophysical data of biaryl systems compared to monoaryl unit reveal that change in geometry, during self-assembly process, disfavors the formation of charge-transfer state, which eventually causes blue shift in the emission upon aggregation. In addition to this, potential of these systems toward signaling of nitroaromatic explosive has also been explored. Among all of the nitroaromatics, the highest fluorescence quenching is observed for nitrophenols (say picric acid (PA)). The investigation also reveals that compared to monoaryl systems, biaryl systems are more responsive to fluorescence quenching by nitroaromatics. Perrin’s model of quenching sphere action has been attributed to nitrophenol (PA) selective signaling behavior of biaryl systems.

Total Synthesis of Tetrahydroisoquinoline-Based Bioactive Natural Products Laudanosine, Romneine, Glaucine, Dicentrine, and Their Unnatural Analogues Isolaudanosine and Isoromneine

Starting from suitably substituted homophthalic acids, total synthesis of titled alkaloids have been demonstrated in very good yields. The obtained natural products laudanosine and romneine were utilized to accomplish synthesis of two isoquinoline-based alkaloids glaucine and dicentrine. Base-induced selective generation of two different types of benzylic carbanions, their coupling reactions with 3,4-dimethoxybenzyl mesylate, and the regioselective iodination followed by intramolecular aryl–aryl coupling reactions to form the fused biaryl systems were the strategic steps.

Pd(II)-Catalyzed Bidentate Directing Group-Aided Chemoselective Acetoxylation of Remote ε-C(sp2)-H Bonds in Heteroaryl-Aryl-Based Biaryl Systems.

In this Article, we report our successful attempt on the Pd(II)-catalyzed, bidentate directing group-aided, chemoselective acetoxylation/substitution of remote ε-C(sp2)-H bonds using heteroaryl-aryl-based biaryl systems. While the bidentate directing group (BDG)-aided, C-H activation, and functionalization/acetoxylation of the β-, γ-, and δ-C-H bonds of the appropriate carboxamide systems were well documented, there exist only rare reports dealing with the C-H activation and functionalization of remote ε-C-H bonds of appropriate substrates. Especially, the BDG-aided chemoselective acetoxylation of the remote ε-C(sp2)-H bond over cyclization has not been explored well. Accordingly, in this work, the treatment of various picolinamides/oxalylamides/pyrazine-2-carboxamides 4/7/9/11, which were derived from the corresponding C-3 arylated furfurylamines or thiophen-2-ylmethanamines with PhI(OAc)2 in the presence of the Pd(OAc)2 catalyst, successfully afforded the corresponding ε-C-H acetoxylated products. The chemoselective acetoxylation of the ε-C-H bond was possible and facilitated by the biaryl substrate 4/7/9/11 and not by the biaryl substrate 2a.

Rotationally Hindered Biphenyls and Terphenyls: Synthesis, Molecular Dynamics, and Configurational Assignment.

Sterically hindered naphthalene-substituted biphenyls and terphenyls were synthesized in good yields, by Michael addition of a conjugate base of core-substituted phenylacetones to substituted 2-oxo-2H-pyran-3-carbonitriles at room temperature under alkaline conditions. These diversely functionalized benzenes (1,2-teraryls or 1,3-teraryls), bearing naphthyl and substituted aryl rings, show the phenomenon of atropisomerism, with one or two stereogenic biaryl axes. The resolution of the respective four atropisomers of the naphthalene-substituted biphenyls and terphenyls bearing 1,2-type or 1,3-type chiral biaryl axes was achieved by HPLC on a chiral phase. The absolute stereostructures of 6a and 9a were determined by the combination of experimental electronic circular dichroism (ECD) investigations and quantum-chemical circular dichroism (QC-CD) calculations. For the atropisomerization of (1M,6M)-6a and (1M,5M)-9a to their (M,P)- and (P,M)-diastereomer, respectively, the possible transition states were investigated and the interconversion barriers (ΔG‡) were theoretically predicted. This study provides a general protocol for the synthesis, resolution, and stereochemical characterization of rotationally hindered naphthalene-substituted biphenyls and terphenyls. The strategy may be applied to investigate other, similarly hindered biaryl or teraryl systems either derived from natural sources or prepared through synthetic approaches.

The Hiyama Cross-Coupling Reaction: New Discoveries.

In this account recent developments in the Hiyama cross-coupling reaction from 2010 up today are presented. The most important methodology involves formation of biaryl systems by using aryl bromides or iodides and aryl trialkoxy silanes: other variants are far less studied. The most useful procedures are collected paying special attention to the synthetic application of this methodology in synthetic organic chemistry.

Palladium catalyzed selective distal C-H olefination of biaryl systems.

Palladium catalyzed selective distal C-H activation with nitrile based templates has been of significant research interest in recent times. In this report, we disclose the distal C-H olefination of biphenyl systems with high regio- and stereo-selectivity and useful synthetic yields. The utility of this method has been demonstrated through its wide olefin scope, its operation at the gram scale and the easy removal/recovery of the directing group.

Polyamine Anchored Palladium Catalyst for Suzuki–Miyaura and One-Pot O-Alkylation-Suzuki Reactions

Polymer anchored amine–palladium complexes were screened as catalysts for Suzuki–Miyaura coupling reactions of aryl halides. The robust, recyclable catalyst was effective in this reaction of aryl bromides and iodides. Aryl bromide was found to undergo selective Suzuki–Miyaura reaction with phenyl boronic acid, even in presence of styrene. The catalyst system was further employed for one-pot O-alkylation-Suzuki reaction to prepare alkoxy biaryl systems in good conversions.

ChemInform Abstract: Utilization of a Copper on Iron Catalyst for the Synthesis of Biaryl Systems and Benzoxazines via Oxidative Arylation of Anilide Derivatives.

AbstractThe transformation of (VIa) with (mesityl)(4‐nitrophenyl)iodonium triflate does not afford the desired product.

Utilization of a Copper on Iron Catalyst for the Synthesis of Biaryl Systems and Benzoxazines via Oxidative Arylation of Anilide Derivatives

Heterogeneous copper on iron catalyst serves as an efficient alternative copper source for arylation reactions using hypervalent iodonium salts. The copper(0) catalyst affords meta-arylation of pivalanilides, while 2-ethynylanilides undergo oxidative carbo­arylation–ring closure with diaryliodonium salts.

ChemInform Abstract: Palladium(II)‐Catalyzed Asymmetric Cycloisomerization of Enynes for Axially Chiral Biaryl Construction.

AbstractConditions A) or B) are highly suitable for the process, which affords different biaryl systems with good to excellent enantioselectivity.

Atropisomerism in a Belt‐Persistent Nanohoop Molecule: Rotational Restriction Forced by Macrocyclic Ring Strain

Enough strain! Strain in a macrocyclic ring hinders the rotation of an arylene panel in a nanohoop molecule containing four chrysenylene units (see picture). Unlike conventional rotational restrictions in biaryl systems, the new atropisomerism does not require any steric hinderance from the substituents. The study of atropisomerism also provides the first experimental insights into the relative stability of nanohoop structures.

ChemInform Abstract: Aryl—Aryl Bond Formation by the Fluoride‐Free Cross‐Coupling of Aryldisiloxanes with Aryl Bromides.

AbstractThe procedure described herein offers a novel, cost‐effective, fluoride‐free, operationally simple and robust alternative for the preparation of a wide range of substituted biaryl systems.