Isoquinolinone Derivatives Research Articles

Ru(II)-Catalyzed Decarboxylative (4 + 2)-Annulation of Benzoic Acids and Benzamides with Propargyl Cyclic Carbonates.

Propargyl cyclic carbonates have emerged as versatile precursors in synthetic chemistry. However, their reactivity has so far been limited to transition metal-catalyzed substitution and cyclization reactions. Herein, we illustrate the successful employment of propargyl cyclic carbonates as coupling partners in Ru(II)-catalyzed C-H annulation of benzoic acids and benzamides. This approach allowed us to access a broad range of biologically relevant isocoumarin and isoquinolinone derivatives in good to excellent yields, utilizing bench-stable and easily accessible precursors. Preliminary mechanistic studies indicated that the C-H metalation step is both reversible and rate-determining in the reaction pathway. Furthermore, the utility of the developed methodology has been illustrated by scale-up and postfunctionalization experiments.

Ru(II)-Catalyzed C(sp2)-H Activation Annulation: Synthesis of Fluorescent Benzoisoquinolonyl Acetate/Peptides from N-Arylamides and Ethyne at Room Temperature.

Benzoisoquinolones are aryl ring extended isoquinolinone derivatives, which are constituents of alkaloid natural products. This report describes the synthesis of novel benzoisoquinolone amino acid/peptide derivatives from the respective N-aryl amino esters/peptides through Ru-catalyzed C(sp2)-H annulation at room temperature. The N-terminal amide acts as an intrinsic directing group and coordinates with the active Ru(II) catalyst for the C-H bond activation and annulation of the aryl ring to produce benzoisoqunolone derivatives. Importantly, these benzoisoquinolinones exhibit fluorescence (QY ∼35%) in protic polar solvents, possibly due to charge transfer, and exhibit cell internalization to the cell nucleus without any significant cytotoxicity to human cell lines (HEK293T). Hence, our results are exceptional to transform standard amino acids/peptides into fluorescent peptides at room temperature in the late stage, which could be applicable for tracking specific target peptides by fluorescence microscopy.

An efficient access to tetrahydropyrrolo[2,1-a]isoquinoline derivatives based on phosphoranylidene succinimide

A simple and convenient synthesis of new isoquinolinone derivatives based on N-(homoveratryl)succinimide phosphorus ylide and natural aldehydes is suggested. The final formation of the tetrahydropyrrolo[2,1-a]isoquinoline framework occurs via the Pictet–Spengler cyclization.

In Situ Activation of Azaarenes and Terminal Alkynes to Construct Bridged Polycyclic Compounds Containing Isoquinolinones.

A copper-catalyzed [4+2] cyclization reaction of isoquinolines and alkynes is developed for the one-step construction of isoquinolinone derivatives with multisubstituted bridging rings. The unique feature of this three-component tandem cyclization reaction is the functionalization of the C1, N2, C3, and C4 positions of 3-haloisoquinolines via the construction of new C-N, C═O, and C-C bonds. This dearomatization strategy for the synthesis of structurally complex isoquinolinone-bridged cyclic compounds offers good chemoselectivity, broad functional group compatibility, greenness, and high step economy.

Dess-Martin Periodinane-Mediated Oxidative Coupling Reaction of Isoquinoline with Benzyl Bromide.

Dess-Martin periodinane (DMP) is a broadly applicable oxidant in chemical synthesis. In this work, an efficient and convenient synthesis of N-substituted isoquinolinone derivatives mediated by DMP was achieved through the oxidative coupling reaction of functionalized isoquinoline with readily available benzyl bromide, which is a metal-free, mild, and practical method for synthesizing isoquinoline-1,3-dione or isoquinoline-1,3,4-trione derivatives in excellent yields. The H2O18-labeling experiment was performed to gain insight into the possible mechanism for this reaction.

Intramolecular Heck Reaction of Arylbromides as a Route to Isoquinolinone Derivatives

Intramolecular Heck Reaction of Arylbromides as a Route to Isoquinolinone Derivatives

Cu2O-Promoted cascade reaction of O-halobenzoate and enaminones for the synthesis of isoquinolinone derivatives

A practical Cu-catalyzed cascade cyclization of o-halobenzoate with enaminones to construct isoquinolinone derivatives is described. The process involves a Cu-catalyzed intermolecular CC coupling and intramolecular azacyclization, wherein a wide range of enaminones could be tolerated.

Ultrasound Assisted α‐Arylation of Ketones: A Rapid Access to Isoquinolinone Derivatives

AbstractIn the current study we have demonstrated the effectiveness of ultrasound, a source of green energy, in accessing various isoquinolin‐1(2H)‐one derivatives via the sequential two‐step reaction in a single pot. The methodology involved ultrasound assisted Cu‐catalyzed α‐arylation of ketones with 2‐iodobenzamide (via a C−C bond formation) followed by intramolecular cyclization (via the C−N bond formation) in the same pot. The role of ultrasound, catalyst, base and solvent in the current transformation was evaluated and the generality as well as scope of the methodology was examined via synthesizing a variety of compounds in acceptable to good (49–93 %) yields. The application potential of the methodology was demonstrated further via synthesizing a reported bioactive arylisoquinolinamine derivative of medicinal significance. Further, the encouraging inhibition of TNF‐α in vitro (>50 % at 10 μM) was shown by some of the synthesized compounds e. g. 3 j, 3 m and 3 p.

Nucleophilic Dearomatization Strategy to Synthesize Disubstituted 3-Isoquinolinones under Transition Metal-Free Conditions.

Herein, a one-pot protocol for constructing the disubstituted isoquinolinone derivatives via the three-component reactions of 3-haloisoquinolines, alkyl halides, and indoles under transition-metal-free conditions is described. The reaction realized the trifunctionalization of isoquinoline via a dearomatization strategy, which displayed high chemical selectivity, excellent functional group tolerance, and a wide range of substrates, and is environmentally friendly. The three-component coupling involves the construction of new C-N, C═O, and C-C bonds in one step.

Cu2o-Promoted Cascade Reaction of O-Halobenzoate and Enaminones for the Synthesis of Isoquinolinone Derivatives

Cu2o-Promoted Cascade Reaction of O-Halobenzoate and Enaminones for the Synthesis of Isoquinolinone Derivatives

Development of isoquinolinone derivatives as immunoproteasome inhibitors

The inhibition of immunoproteasome is considered nowadays a promising strategy for the treatment of hematologic malignancies. In this paper we report the design, synthesis, and biological evaluation as immunoproteasome inhibitors of a new series of isoquinolinone derivatives characterized by a (E)-prop-1-ene fragment that connects the heterocycle to a distal amide functionality. Among all the synthesized compounds, we identified an inhibitor with Ki values in the low micromolar or submicromolar range towards the chymotrypsin-like activities of both proteasome and immunoproteasome (β5c, β5i and β1i subunits). Molecular modeling studies suggest that the most potent compound of the series may act a single-site binder. In particular, through its isopentyl group, it might dock into P1 site in the case of the β1i catalytic subunit, while in the case of β5c and β5i subunits, the P3 site might be the preferred binding site.

Cobalt-Catalyzed 2-(1-Methylhydrazinyl)pyridine-Assisted C-H Alkylation/Annulation: Mechanistic Insights and Rapid Access to Cyclopenta[c]isoquinolinone Derivatives.

We have developed cobalt-catalyzed, bidentate 2-(1-methylhydrazinyl)pyridine (MHP)-directed C(sp2)-H alkylation/annulation of benzoic hydrazides with various alkenes. Notably, diverse cyclopenta[c]isoquinolinones and dihydroisoquinolinones were obtained via this functional group-tolerant protocol. The reaction can be performed on a gram scale while maintaining an excellent yield, and the directing group can be removed efficiently under mild conditions. Furthermore, density-functional theory (DFT) calculations provide an incisive understanding of the observed regioselectivities for different olefins.

Synthetic approaches to N- and 4-substituted 1,4-dihydro-3(2H)-isoquinolinone derivatives

Reaction of methyl-2-(2-formylphenyl)acetate with primary amines in a reductive amination/cyclisation process resulted in N-substituted 1,4-dihydro-3(2H)-isoquinolinones. With H2NCH2R sodium borohyride is a suitable reductant (11 examples), but H2NCHR1R2 required a transfer hydrogenation using ammonium formate catalysed by palladium on carbon (9 examples). 4-Substituted-1,4-dihydro-3(2H)-isoquinolinones were synthesised by deprotonation (n-butyllithium) and addition of R3CH2Br (12 examples with R3 = alkyl, Ar, CHCH2, CCH). Modest diastereoselectivity was achieved with 1,4-dihydro-3(2H)-isoquinolinones derived from H2NCHMeR2 [R2 = (η5-C5H4)Co(η4-C4Ph4) - max. dr = 1.9 : 1], but use of H2NCHMeFc (Fc = ferrocenyl) provided a new method of 1,4-dihydro-3(2H)-isoquinolinone N-deprotection with formic acid.

Molecular Oxygen‐Mediated Radical Cyclization of Acrylamides with Boronic Acids

AbstractA radical alkylarylation of 2‐aryl‐N‐methacryloyl indoles via autoxidation of alkylboronic acids was developed under metal‐free conditions for the construction of indolo[2,1‐a]isoquinolinone derivatives. Primary and secondary alkyl boronic acids were utilized as suitable alkyl sources with O2 as the clean and green oxidant in a simple operate mode. Moreover, this protocol can also be applied to the construction of benzimidazo‐[2,1‐a]isoquinolinone derivatives.magnified image

Photoredox-catalyzed chemoselective aerobic Cα–H oxidation of propargylamines: synthesis of substituted 2-ynamide and oxazolo[2,3-a]isoquinolinone derivatives

Visible light-initiated chemoselective aerobic Cα–H oxidation of propargylamines.

Design, synthesis, biological evaluation and molecular modelling of substituted pyrrolo[2,1-a]isoquinolinone derivatives: discovery of potent inhibitors of AChE and BChE

Study of the molecular interactions in L–R complexes of acetyl- and butyryl-cholinesterase using MD/QTAIM calculations for designing new potent cholinesterase inhibitors.

Nickel-Catalyzed C-F/N-H Annulation of Aromatic Amides with Alkynes: Activation of C-F Bonds under Mild Reaction Conditions.

The Ni-catalyzed reaction of ortho-fluoro-substituted aromatic amides with alkynes results in C-F/N-H annulation to give 1(2H)-isoquinolinones. A key to the success of the reaction is the use of KOtBu or even weak base, such as Cs2CO3. The reaction proceeds in the absence of a ligand and under mild reaction conditions (40-60 °C). DFT calculations suggest that the pathway for this Ni-catalyzed C-F/N-H annulation involves N-H deprotonation, oxidative addition of a C-F bond, migratory insertion of an alkyne, and reductive elimination to form 1(2H)-isoquinolinone derivatives.

Isoquinolinone derivatives as potent CNS multi-receptor D2/5-HT1A/5-HT2A/5-HT6/5-HT7 agents: Synthesis and pharmacological evaluation.

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D2 and serotonin 5-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors, showed low affinity for off-target receptors (5-HT2C, H1, and α1), and negligible effects on ether-a-gogo-related gene (hERG; i.e., reduced QT interval prolongation). An animal behavioral study revealed that compound 13 reversed APO-induced hyperlocomotion, MK-801-induced hyperactivity, and DOI-induced head twitch. Moreover, compound 13 exhibited a high threshold for acute toxicity, a lack of tendency to induce catalepsy, and did not cause prolactin secretion or weight gain when compared to risperidone. Furthermore, in the forced swim test, tail suspension test, and novel object recognition test, treatment with compound 13 resulted in improvements in depression and cognitive impairment. In addition, compound 13 had a favorable pharmacokinetic profile in rats. Thus, the antipsychotic drug-like effects of compound 13 indicate that it may be useful for developing a novel class of drugs for the treatment of schizophrenia.

Rh(III)‐Catalyzed Redox‐Neutral Cascade Annulation of Benzamides withp‐Quinone Methides

Herein, we demonstrate a [RhCp*Cl2]2catalyzed synthesis of isoindolo[2,1‐b]isoquinolin‐5(7H)‐one derivatives fromN‐(pivaloyloxy)benzamides andp‐quinone methides under redox neutral conditions.p‐Quinone methide derivatives were engaged for the first time as precursors in C–H activation reactions and the cascade sequence consists of Rh(III)‐catalyzed C–H activation, alkyne insertion followed by an intramolecular 1,6‐conjugate addition. This novel tandem reaction strategy offers a rapid and straightforward access to complex fused isoquinolinone derivatives in an efficient manner.

Molecular basis defining the selectivity of substituted isoquinolinones for the melatonin MT2 receptor

Melatonin MT1 and MT2 receptors represent attractive drug targets for the treatment of various disorders. However, the high conservation of the melatonin binding pocket has hindered the development of subtype-selective compounds. By leveraging on the recently resolved crystal structures of MT1 and MT2 receptors, this study aims to elucidate the structural basis of MT2-selectivity of a panel of isoquinolinone derivatives. Molecular modelling and ligand docking approaches were employed to predict residues involved in forming interactions with the MT2-selective isoquinolinones. Seven conserved residues (Asn175, His208, Trp264, Asn268, Gly271, Tyr294 and Tyr298) were selected as targets for site-directed mutagenesis. Ca2+ mobilization, cAMP inhibition, phosphorylation of extracellular signal-regulated kinase, and ligand binding assays were performed to functionally characterize the receptor mutants in transfected CHO cells. Unlike melatonin, isoquinolinones bearing a 3-methoxybenzyloxyl substituent were unaffected by alanine substitution at His208 of MT2. Although alanine substitutions at Tyr294 or Tyr298 reduced the potency of melatonin and some isoquinolinones on MT2, similar mutations on MT1 allowed five hitherto ineffective isoquinolinones to act as agonists. An isoquinolinone antagonist bearing a 4-methoxybenzyloxyl moiety turned into an agonist at MT2 mutants with alanine substitutions at His208, Tyr294 or Tyr298. A subset of residues is apparently involved in forming a hydrophobic binding cavity to confer selectivity upon the aromatic substituent of isoquinolinone compounds. Two conserved tyrosine residues on transmembrane helix 7 may confer ligand selectivity at MT1 and MT2 receptors, while a conserved histidine on transmembrane helix 5 is apparently involved in receptor activation.