Dihydroisoquinoline Derivatives Research Articles

Photo-induced imine reduction by a photoredox biocatalyst consisting of a pentapeptide and a Ru bipyridine terpyridine complex

Imine reduction is a useful reaction in the preparation of amine derivatives. Various catalysts have been reported to promote this reaction and photoredox catalysts are promising candidates for sustainable amine synthesis. Improvement of this reaction using biomolecule-based reaction scaffolds is expected to increase the utility of the reaction. In this context, we have recently investigated photoredox Ru complexes with pentapeptide scaffolds via coordination bonds as catalysts for photoreduction of dihydroisoquinoline derivatives. First, Ru bipyridine terpyridine complexes coordinated with five different pentapeptides (XVHVV: X = V, F, W, Y, C) were prepared and characterized by mass spectrometry. Catalytic activities of the Ru complexes with XVHVV were evaluated for photoreduction of dihydroisoquinoline derivatives in the presence of ascorbate and thiol compounds as sacrificial reagents and hydrogen sources. Interestingly, the turnover number of the Ru complex with VVHVV is 531, which is two-fold higher than that of a simple Ru complex with an imidazole ligand. The detailed emission lifetime measurements indicate that the enhanced catalytic activity provided by the peptide scaffold is caused by an efficient reaction with the thiol derivative to accelerate reductive quenching of Ru complex. The quenching behavior suggests formation of an active species such as a Ru(I) complex. These findings reveal that the simple pentapeptide serves as an effective scaffold to enhance the photocatalytic activity of a photoactive Ru complex.

Synthesis, crystal structure investigation and computational studies binding of (7S,8R)-7-acetyl-8-(4-chlorophenyl)-3-(ethylthio)-1,6-dimethyl-7,8-dihydroisoquinoline-4-carbonitrile with monoamine oxidase B

This work reports the preparation of a new dihydroisoquinoline derivative whose structure was characterized by IR, NMR (1H, 13C), MS and verified through single-crystal X-ray analysis. The mean planes of the acetyl and 4-chlorophenyl groups in the title molecule are nearly perpendicular to that of the pyridine ring. In the crystal, π-stacking and C—H···O hydrogen bond interactions involving the pyridine ring and the nitrile group of an adjacent molecule form the full 3-D structure. Hirshfeld surface (HS) analysis shows the topology of the molecules in the crystal packing. Fingerprint (FP) diagrams show the percentage contribution of several intermolecular interactions where H‧‧‧H interactions have a significant contribution (46%). The DFT study reveals a low HOMO-LUMO gap and significant charge transfer is indicated by the natural bonding orbitals (NBO) and frontier molecular orbital (FMO) analyses. Non-covalent interactions and bond characteristics were investigated using the quantum theory of atom in the molecule (QTAIM) and ELF analysis. FMO analysis was used to calculate the HOMO-LUMO energy gap and orbital energies. Using the DFT method, parameters such as global reactivity were calculated. Using the implicit solvent model, properties such as optical and nonlinear optical (NLO) were characterized in the solvent (water) phase and gas phase. The affinity of the title molecule for Monoamine Oxidase B was examined using molecular docking and molecular dynamics studies and these results showed good binding of the target molecule.

Urea-Promoted Neat Synthesis of Fused Dihydroisoquinolines and Disubstituted Pyridines: A Mechanistic Observation with Molecular-Sensing Studies.

An efficient and short synthesis of fused dihydroisoquinolines, diaryl substituted pyridine derivatives in good to high yields has been established by using an environmentally safe, solvent-metal-oxidant-free tandem approach. In this article, we discuss how the electrocyclic reaction is more pronounced in the solid phase in the presence of urea, whereas the typical aza-Michael addition is more prominent in presence of arylamine in the solution phase for 3-(2-formylcycloalkenyl)acrylic ester derivative substrates. The wide range of substrates and urea-promoted neat synthesis made our approach more significant in medical and also analytical science. Moreover, an isoquinoline alkaloid decumbenine B analogue has been synthesized by using our newly developed neat methodology. We have also investigated the photophysical properties of the synthesized fused dihydroisoquinoline derivatives. One of the synthesized molecules was used as a sensor for the selective detection of toxic picric acid. Therefore, the effective neat synthesis and molecular sensing applications of these compounds made our approach more exciting in the field of heterocyclic chemistry.

ZnCl2-Promoted Three-Component Reaction of 2-Aminochromenones, Aromatic Aldehydes, and Quinone Monoketals: Access to 5,6-Dihydro-12H-chromeno[2,3-c]isoquinolin-12-one Derivatives.

A three-component reaction of 2-amino-4H-chromen-4-ones, aromatic aldehydes, and 4,4-dialkoxycyclohexa-2,5-dien-1-ones for the concise synthesis of chromeno[2,3-c]dihydroisoquinoline derivatives has been investigated. This reaction involved consecutive ZnCl2-promoted Micheal addition and intramolecular Friedel-Crafts alkylation. This synthetic protocol offered several advantages, including the readily accessible starting materials, good functional group tolerance, and simplicity of operation. Additionally, the structures of products obtained were determined based on X-ray diffraction studies.

Synthesis, crystal structure investigation, Hirshfeld and DFT studies of newly synthesized dihydroisoquinoline derivatives

Isoquinoline and its derivatives, which constitute an important category of heterocyclic compounds and are found in a variety of naturally occurring alkaloids, serve a variety of biological purposes such as a potent agonist for human melatonin receptors 1. This research was conducted in an attempt to develop new dihydroisoquinoline molecules (III and IV). Single-crystal X-ray crystallography study validated their structures. The Hirshfeld surface analysis identifies intermolecular interactions by using a 2-D fingerprint map to recognize each type's relative contribution H⋅⋅⋅Hconnections are discovered to be dominating. The interaction energies between chemical pairs in crystal structures were found using an energy framework analysis. The DFT investigation demonstrates the electronic stability and reactivity of the compounds using the HOMO-LUMO and global reactivity descriptors, indicating that IV has higher chemical reactivity than III. The derived polarizability (αo) and hyperpolarizability (βo) values were used to calculate the optical and nonlinear optical characteristics of III and IV. The IV's significant βo value (488.94 au) indicates that it has good optical and NLO qualities. Molecular docking simulation using human melatonin receptors 1 was used to better understand the binding interaction mechanism of the title compounds. In addition, ADMET evaluations were performed to establish the therapeutic potential of III and IV.

Photosensitized selective semi-oxidation of tetrahydroisoquinoline: a singlet oxygen path.

Selective semi-oxidation of tetrahydroisoquinoline (THIQ) leads to a valuable dihydroisoquinoline (DHIQ) derivative via singlet oxygen photooxidation process. Typical photosensitisers (i.e., Ru complexes) can activate the reaction even under heterogeneous conditions that facilitate catalyst separation and reusability. In contrast to DHIQ, THIQ acts as an efficient singlet oxygen quencher driving the reaction selectivity. The reaction can also be facilitated by semiconductor catalysts such as MoCo@GW, a glass wool-based catalyst that is easy to separate and reuse and compatible with flow photochemistry. Its role is to mediate the formation of isoquinoline (IQ) and thus an in situ-generated singlet oxygen catalyst. Laser flash photolysis with NIR detection provides proof of the singlet oxygen mechanism proposed and rate constants for the key steps that mediate the oxidation.

Synthesis of arylphosphinoyl-functionalized dihydroisoquinolines by Reissert-type reaction and their biological evaluation

An efficient synthetic method for potentially biologically active new arylphosphinoyl-functionalized dihydroisoquinoline derivatives was developed by the Reissert-type reaction of isoquinoline, dialkyl acetylenedicarboxylates and secondary phosphine oxides or ethyl phenyl-H-phosphinate. The model reaction of isoquinoline, diethyl acetylenedicarboxylate and diphenylphosphine oxide was optimized in respect of the solvent, the temperature and the reaction time, as well as the dosing order of the starting materials. The protocol developed enabled the preparation of the target derivatives under mild conditions for a short reaction time. The in vitro cytotoxicity on different cell lines and the antibacterial effect of the phosphorylated dihydroisoquinolines synthesized were also investigated. Based on the IC50 values determined, the derivatives, which contain 3,5-dimethylphenyl or 2-naphtyl groups on the phosphorus atom, showed a promising activity against human promyelocytic leukemia (HL-60) cells and against Bacillus Subtilis Gram-positive bacteria.

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Enantio‐ and Diastereoselective Nucleophilic Addition of N‐tert‐Butylhydrazones to Isoquinolinium Ions through Anion‐Binding Catalysis

AbstractA highly enantio‐ and diastereoselective thiourea‐catalyzed dearomatization of isoquinolines employing N‐tert‐butylhydrazones as neutral α‐azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and high‐yielding transformations provide appealing dihydroisoquinoline derivatives.

Enantio- and Diastereoselective Nucleophilic Addition of N-tert-Butylhydrazones to Isoquinolinium Ions through Anion-Binding Catalysis.

A highly enantio- and diastereoselective thiourea-catalyzed dearomatization of isoquinolines employing N-tert-butylhydrazones as neutral α-azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and high-yielding transformations provide appealing dihydroisoquinoline derivatives.

Hydrolysis of dihydroisoquinoline derivatives activated by sulfonyl or acyl chloride

A new, efficient, and mild strategy for hydrolysis of 3,4-dihydroisoquinoline imines activated by sulfonyl chloride or acyl chloride has been developed, by which method ketosulfonamides and ketoamides have been synthesized. This process tolerates broad scope with respect to both the sulfonyl chloride and acyl chloride with moderate to excellent yields. This protocol features a broad substrate scope for various kinds of 3,4-dihydroisoquinoline and mild reaction conditions without using strong acidic or basic conditions. These features show that this user-friendly and simple system could be applied in the future to the synthesis of a broader range of amino benzophenones.

Synthesis of diverse nitrogen fused polycyclic dihydroisoquinoline (DHIQ) derivatives via GBB-based cyclic iminium induced double-annulation cascade

A highly efficient and distinct Bronsted acid-mediated unprecedented cyclic iminium induced double annulation cascade (DAC) protocol for the synthesis of novel dihydroindazolo[3′,2′:2,3]imidazo[5,1-a]isoquinolinamines has been achieved through the three-component Groebke–Blackburn–Bienayme reaction. The transformation is based on sequential cascade processes involving imine formation followed by an intramolecular nucleophilic substitution to generate a highly reactive cyclic iminium species, which would undergo a rapid [4 + 1] formal cycloaddition steps in one-pot fashion. This strategy provides novel skeletally diverse complex nitrogen fused polycyclic DHIQ derivatives by employing readily available substrates and a simple procedure, which would render this method potentially useful in organic synthesis.

The catalyst-free decarboxylative dearomatization of isoquinolines with β-keto acids and sulfonyl chlorides in water: access to dihydroisoquinoline derivatives.

An efficient and concise catalyst-free one-pot synthetic protocol for obtaining dihydroisoquinoline derivatives has been developed via the three-component condensation of isoquinolines with β-keto acids and sulfonyl chlorides. This transformation involving decarboxylative dearomatization worked well under mild and water-mediated conditions. The protocol tolerates diverse functional groups, furnishing the dihydroisoquinoline products in good to excellent yields.

Reaction of methyl bromocycloalkanecarboxylates with zinc and dihydroisoquinoline derivative

The reaction of 5–7-membered methyl 1-bromocycloalkanecarboxylates with zinc and 6,7-dimethoxy-3,4-dihydroisoquinoline leads to 7,8-dimethoxy-5,9b-dihydro-2H,4H-spiro{azeto[2,1-a]isoquinoline-1,1′-cycloalkan}-2-ones. In the case of 1-bromocyclobutanecarboxylate, 9′,10′-dimethoxy-7′,11b′-dihydro-2′H,4′H,6′H-dispiro{cyclobutane-1,1′-pyrido[2,1-a]isoquinoline-3′,1″-cyclobutane}-2′,4′-dione is formed. The structures of the products were confirmed by X-ray diffraction.

Asymmetric synthesis of tetrazole and dihydroisoquinoline derivatives by isocyanide-based multicomponent reactions

Although isocyanide-based multicomponent reactions were proven to be simple, elegant and facile strategies for the synthesis of highly valuable nitrogen-containing heterocycles, their asymmetric versions accessing to optically active nitrogen heterocyclic compounds are rather limited. Here, we illustrate that, relying on the enantioselective addition of simple isocyanides to C=C bonds, several isocyanide-based multicomponent reactions are realized in the presence of a chiral MgII-N,Nʹ-dioxide catalyst. In the reaction among isocyanide, TMSN3, and alkylidene malonate, three- or four-component reactions could be precisely controlled by modulating reaction conditions, supplying two types of enantioenriched tetrazole-derivatives in moderate to high yields. Possible catalytic cycles via a key zwitterionic intermediate, and the vital roles of H2O or excess ligand are provided based on control experiments. Moreover, taking advantage of this zwitterionic intermediate as a 1,3-dipole, an enantioselective dearomative [3+2] annulation reaction of nonactivated isoquinolines is achieved, furnishing chiral 1,2-dihydroisoquinolines in good to excellent results.

Synthesis of Indole-Dihydroisoquinoline Sulfonyl Ureas via Three-Component Reactions

Isoquinolines activated with sulfamoyl chlorides were reacted with indoles in a 3-component reaction to generate a library of dihydroisoquinoline derivatives. Using a differential protecting group strategy, products could be further derivatised. Synthesis of isoquinoline starting materials using several different methods is also described.

Baylis–Hillman Reaction: In Situ Generated Isoquinolinium Species as Excellent Electrophiles for Coupling with Alkyl Acrylates and Acrylonitrile

Isoquinolinium species, generated in situ from 2‐alkynylbenzaldehydes, arylamines, and silver trifluoromethanesulfonate, were successfully employed as excellent electrophiles for Baylis–Hillman coupling with alkyl acrylates (or acrylonitrile) under the influence of 1,4‐diazabicyclo[2.2.2]octane to provide 1,2,3‐trisubstituted dihydroisoquinoline derivatives in high yields.

QSAR, docking studies and toxicology prediction of isoquinoline derivatives as leucine aminopeptidase inhibitors

Here, we report a theoretical study on leucine aminopeptidase (LAP) inhibitors. 3D quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of known substituted dihydroisoquinoline derivatives and other chemical compounds with inhibitory activity towards LAP. We also designed a series of 33 isoquinoline derivatives containing phosphonic/phosphinic acid moieties and applied the 3D-QSAR model to evaluate their possible LAP inhibitory activity. In silico studies showed that these compounds interact with zinc ions, form H-bonds and exhibit hydrophobic interactions with amino acids in the LAP binding pocket as well as present high scoring values. The obtained QSAR data provide useful information about the structural characteristics of inhibitors which contribute to their inhibitory potency.

ChemInform Abstract: Enantioselective Synthesis of Isoquinolines: Merging Chiral‐Phosphine and Gold Catalysis.

AbstractThis highly enantioselective synthesis of dihydroisoquinoline derivatives from aromatic sulfonated imines tethered with an alkyne moiety, through a one‐pot asymmetric relay catalysis of chiral‐phosphine and gold catalysts, is based on an asymmetric aza‐Morita—Baylis—Hillman reaction.

Molecular docking studies, biological and toxicity evaluation of dihydroisoquinoline derivatives as potential anticancer agents

We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt’s lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use.