Synthesis Of Isoquinolines Research Articles

Efficient Synthesis of Isoquinoline and Its Derivatives: From Metal Сatalysts to Catalyst-free Processes in Water

Isoquinolines constitute an important class of natural alkaloids, that demonstrate a wide range of biological activities. Therefore, development of new methods for efficient synthesis of isoquinoline and its derivatives has attracted considerable attention of chemists and pharmacologists over recent years. In this review the progress of isoquinoline synthesis that provides creative inspiration and expands novel ideas for researchers in this field is summarized.

Traceless Bidentate Directing Group Assisted Cobalt-Catalyzed sp2-C-H Activation and [4 + 2]-Annulation Reaction with 1,3-Diynes.

An efficient cobalt-catalyzed [4 + 2] annulation of hydrazones and 1,3-diynes has been developed for the synthesis of 3-alkynylated isoquinolines engaging 2-aminopyridine as a traceless bidentate directing group. The strategy has been successfully extended for the synthesis of 3,3'-biisoquinoline moieties via both one-pot as well as sequential approaches. The utilization of a traceless bidentate directing group with an inexpensive and earth-abundant cobalt-catalyst under operationally simple reaction conditions makes the present transformation more valuable and appealing.

Efficient Access to Isoquinolines via Rhodium-Catalyzed Oxidative Annulation of Pyridyl C–H Bonds Directed by Carbonyl with Internal Alkynes

AbstractAn efficient synthesis of amino-substituted isoquinolines via Rh(III)-catalyzed oxidative [2+2+2] annulation of pyridines with alkynes has been developed, which is cooperatively enabled by a directing carbonyl and steric hindrance adjacent to the amino group of the pyridine, via a six-membered rhodacyclic intermediate without coordination with the pyridinic nitrogen. The establishment of this C–H activation strategy also paves the way for other oxidative transformations of heterocyclic C–H bonds.

Rh(III)−catalyzed synthesis of isoquinolines from N-hydroxyoximes and alkynes in γ-valerolactone

A Rh (III)−catalyzed synthesis of isoquinoline derivatives from N-hydroxyoximes and alkynes via C–H activation/annulation process in biomass-derived γ-valerolactone (GVL) has been developed. A series of functional groups were well tolerated, affording the desired products in good to excellent yields.

A green synthesis of isoquinolines using Ru(II)/PEG-400 as homogeneous recyclable catalyst via C-H/N-N bond activation

A novel and green synthesis of 1-phenyl isoquinoline derivatives has been developed by using Ru(II)/PEG-400 as homogeneous recyclable catalyst via C-H/N-N bond activation via C-H/N-N functionalization of 1-(diphenylmethylene) hydrazine and aryl substituted acetylenes. In order to realize the proposed protocol, Cu(OAc)2 and AgSbF6 are used as oxidant and additive respectively in PEG-400 biodegradable solvent. This protocol has a simple extraction procedure, uses biodegradable solvent, affords high atom economy, employs a reusable catalytic system, provides wide substrate scope with high yield of product, for the synthesis of isoquinoline derivatives.

Merging single-electron transfer and energy transfer processes of photocatalyst: An atom economical strategy for the synthesis of 1-trifluoroethylated isoquinolines from cis and trans vinyl isocyanides

Photoredox-catalyzed radical cascade trifluoroethylation-cyclization of cis and trans vinyl isocyanides with trifluoroethyl iodide involving an unusual single-electron transfer and energy transfer processes of photocatalyst provides an atom economical method for the synthesis of 1-trifluoroethylated isoquinolines. The process is notable for its operational simplicity and good functional group tolerance.

Rhodium-Catalyzed Synthesis of Isoquinolines from Aryl Ketones and Alkynes

Key words rhodium catalysis - hydroxylamine sulfonic acid - alkynes - ketones - isoquinolines - one-pot synthesis

Concurrent Formation of N-H Imines and Carbonyl Compounds by Ruthenium-Catalyzed C-C Bond Cleavage of β-Hydroxy Azides.

A commercial cyclopentadienylrutenium dicarbonyl dimer ([CpRu(CO)2]2) efficiently catalyzes the formation of N-H imines and carbonyl compounds simultaneously from β-hydroxy azides via C-C bond cleavage under visible light. Density functional theory calculations for the cleavage reaction support the mechanism involving chelation of alkoxy azide species and liberation of nitrogen as the driving force. The synthetic utility of the reaction was demonstrated by a new amine synthesis promoted by chemoselective allylation of imine and synthesis of isoquinoline.

Molecular Docking Study, Cytotoxicity, Cell Cycle Arrest and Apoptotic Induction of Novel Chalcones Incorporating Thiadiazolyl Isoquinoline in Cervical Cancer.

Chalcones are naturally occurring compounds found in various plant species which are widely used for the traditional popular treatments. Chalcones are distinguished secondary metabolites reported to display diverse biological activities such as antiviral, antiplatelet, anti-inflammatory, anticancer, antibacterial and antioxidant agents. The presence of a,ß-unsaturated carbonyl group in chalcones is assumed to be responsible for their bioactivity. In addition, heterocyclic compounds having nitrogen such as isoquinolines are of considerable interest as they constitute the core structural element of many alkaloids that have enormous pharmacological activities. The objective of this study is the synthesis and biological activity of novel chalcones incorporating thiadiazolyl isoquinoline as potential anticancer candidates. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer. An efficient one pot synthesis of novel chalcones incorporating thiadiazolyl isoquinoline was developed. The cytotoxic activity of the novel synthesized compounds was performed against four different kinds of cancer cell lines. Among all the tested derivatives, chalcone 3 has the best cytotoxic profile against A549, MCF7, and HeLa cell lines, with IC50s 66.1, 51.3, and 85.1μM, respectively. Molecular docking studies for chalcone 3 revealed that CDK2, and EGFRTK domains have strong binding affinities toward the novel chalcone 3, while tubulin-colchicine-ustiloxin, and VEGFRTK domains illustrated moderate mode of binding. We have developed an efficient method for the synthesis of novel chalcones incorporating thiadiazolyl isoquinoline. All compounds showed better cytotoxicity results against four kinds of cancer cell lines (A549, MCF7, HCT116, and HELA cells). The results depicted that chalcone 3 has a high and promising cytotoxic effect against HELA cell line and the mechanism of cytotoxicity was widely studied through different theoretical and experimental tools. Thus, the newly synthesized derivative 3 can be utilized as a novel chemotherapeutic compound for cervical carcinoma.

A green synthesis of isoquinolines using Ru(II)/peg-400 as homogeneous recyclable catalyst via C-H/N-N bond activation

A novel and green synthesis of 1-phenyl isoquinoline derivatives has been developed using [Ru(p-cymene)Cl2]2, as a homogeneous recyclable catalyst, with Cu(OAc)2 and AgSbF6 as oxidant and additive respectively, in PEG-400 biodegradable and green solvent via C-H/N-N functionalization of 1-(diphenylmethylene) hydrazine and aryl substituted acetylene. This protocol gives a simple extraction procedure, biodegradable and green solvent, high atom economy, reusable catalytic system and wide substrate scope with high yield of the product for the synthesis of isoquinoline derivatives.

Rh(III)-catalyzed synthesis of isoquinolines using the N-Cl bond of N-chloroimines as an internal oxidant

The Rh(III)-catalyzed coupling of N-chloroimines with alkynes for the efficient synthesis of isoquinolines is reported. This represents the first use of the N-Cl bond of N-chloroimines as an internal oxidant for construction of the isoquinoline skeleton. The synthesis features atom and step economy, a green solvent (EtOH), mild reaction conditions, and a broad substrate scope.

Hydroxylamine‐O‐Sulfonic Acid (HOSA) as a Redox‐Neutral Directing Group: Rhodium Catalyzed, Additive Free, One‐Pot Synthesis of Isoquinolines from Arylketones

A new application of hydroxylamine‐O‐sulfonic acid (HOSA) has been discovered whereby aromatic ketones react with HOSA and alkynes to form isoquinolines in the presence of a RhIII catalyst. This C–H/N–O annulation methodology gives excellent yields even without any silver additive, acid/base or metal oxidant. This is the first report wherein a directing group is simultaneously forming in situ, acting as acid additive, and also as an internal oxidant.

Oxidative radical decarboxylation of uronic acids: Convenient synthesis of C-Glycosylated isoquinolines

An expedient approach to C-glycosylated isoquinolines was established based on the coupling of vinyl isonitriles with tetrafuranos-4-yl and pentapyranos-5-yl radicals generated from oxidative decarboxylation of uronic acids derived from monosaccharides and complex oligosaccharides. This approach enjoyed a broad substrate scope and good functional group tolerance, and afforded structurally diverse C-glycosylated isoquinolines in the presence or absence of silver salts. Deprotection of the coupling products was conducted to yield C-glycosylated isoquinolines with multiple hydroxyl groups. These novel architectures would offer opportunities for investigation of their bioactivities.

Catalyst and additive free 6-endo-dig cyclization of ortho-alkynylarylaldimines in water: An environmentally friendly access to isoquinolines

A novel and sustainable route for the synthesis of isoquinoline was developed by reacting 2-ethynylbenzaldehyde with ammonium hydroxide in water. This method provides a convenient, atom-economical, and catalyst-free access to diversely substituted isoquinolines with moderate to good yields.

From 3-Acyl-2-methylindoles to γ-Carbolines: Li-Promoted Cycloaddition Reaction and Its Quantum Chemical Study.

A one-pot cycloaddition strategy for obtaining γ-carbolines under mild conditions was developed. The reaction represents a new approach to the annulation of a pyridine ring to an indole core. Treating 2-methyl-3-benzoylindoles with lithium diisopropyl amide leads to the elimination of a proton from the 2-methyl group. The organolithium compounds generated were found to react with nitriles. The resulting 4,5-dihydro-1H-pyrido[4,3-b]indol-1-ols undergo spontaneous water elimination to give the corresponding γ-carbolines. The applicability of this reaction for the synthesis of isoquinolines has been shown. For the first time, a lithium atom was found to be part of an eight-centered polycyclic transition state according to a detailed DFT PCM/DFT/B3LYP/6-311++G(d,p) and ab initio PCM/MP2//HF/6-311++G(d,p) quantum chemical study.

Cp*Co(III) catalyzed annulation of N-Cbz hydrazones for the redox-neutral synthesis of isoquinolines via C–H/N–N bond activation

A new cascade oxidative cyclization reaction of N-Cbz hydrazones with internal alkynes has been explored for the preparation of isoquinoline derivatives using Cp*CoIII-catalyst through C–H and N–N bond functionalization. N-Cbz hydrazones are rarely explored as directing group for redox-neutral [4 + 2] cyclization reaction through the cyclometallation and this catalyst system does not require any external oxidizing agent, as well as, silver or antimony salt. The current efficient approach has been utilized for the synthesis of different isoquinoline derivatives with good regioselectivity and yields.

Influence of Inlet Capillary Temperature on the Microdroplet Chemistry Studied by Mass Spectrometry.

Often, studies of microdroplet chemistry using electrospray ionization mass spectrometry (MS) either find a negligible effect of the heated inlet capillary of the mass spectrometer on the reaction rate or do not consider its effect. In this context, we studied two reactions in microdroplets, the Pomeranz-Fritsch synthesis of isoquinoline and the Combes quinoline synthesis. The reagents were electrosprayed with methanol and aqueous solutions forming small and large microdroplets at flow rates of 1 and 20 μL/min, respectively. We also varied the inlet capillary temperature from 100 to 350 °C. Contrary to the view that the inlet temperature has little to no influence on the reaction rate, we found that the Pomeranz-Fritsch reaction was markedly accelerated for both solvents and for both droplet sizes on increasing the temperature, whereas the Combes synthesis showed the opposite behavior. We propose that these strikingly different behaviors result from a competition of two effects, the evaporative cooling versus the heating of ejected bare ions from the droplet, both taking place inside the heated inlet. This finding suggests that these phenomena must be taken into account while interpreting the microdroplet reactions studied by electrospray or a similar kind of ambient ionization MS.

Synthesis of Quinolines and Isoquinolines via Site-Selective, Domino Benzannulation of 2- and 3-Chloropyridyl Ynones with Nitromethane.

An approach of general applicability to diverse quinolines and isoquinolines via a tactic that utilizes the recursive anion from nitromethane as a 1C-connector to stitch easily and appropriately crafted pyridyl ynones through a transition-metal-free, tandem Michael addition-SNAr process is delineated. The straightforwardness, one-pot operation, and good yields mark this methodology for wider exploitation in targeting more embellished quinolines and isoquinolines and complex platforms embodying these moieties.

Cobalt-Catalyzed Synthesis of Isoquinolines by Using a Traceless Directing Group

Cobalt-Catalyzed Synthesis of Isoquinolines by Using a Traceless Directing Group

Rapid and Atom Economic Synthesis of Isoquinolines and Isoquinolinones by C–H/N–N Activation Using a Homogeneous Recyclable Ruthenium Catalyst in PEG Media

Herein, we report an atom‐efficient, rapid, green, and sustainable approach to synthesize isoquinolines and isoquinolinones using a homogeneous recyclable ruthenium catalyst in PEG Media assisted by microwave energy. Dibenzoylhydrazine was used for C–H/N–N activation reactions for the first time in combination with ketazine as oxidizing directing groups for annulation reactions with internal alkynes. The developed protocol is environmentally benign due to significantly shortened times with an easy extraction method, higher atom economy, external oxidant and silver or antimony salt free conditions, applicability to a gram scale synthesis, use of biodegradable solvent and wide substrate scope with higher product yields. Moreover, it is worth noting that the established methodology allowed reuse of the catalytic system for up to five successive runs with minimal loss in activity.