Greener alternatives for synthesis of isoquinoline and its derivatives: a comparative review of eco-compatible synthetic routes

Abstract

Isoquinoline derivatives, a prominent class of nitrogen-containing heterocycles, serve a pivotal role in medicinal chemistry due to their broad spectrum of bioactivities. While traditional synthetic routes for these scaffolds are well-established, conventional methods often rely on transition-metal catalysts, harsh conditions, expensive reagents, and toxic solvents, raising environmental and economic concerns. In response to the pressing demand for sustainable practices, this review underscores the integration of green chemistry principles into modern synthetic design, offering environmentally acceptable methods for accessing isoquinoline frameworks. Despite extensive research on isoquinoline synthesis and its therapeutic relevance, a dedicated analysis of sustainable methodologies remains absent. This work bridges that gap by critically evaluating recent innovations in green synthesis, including the use of benign solvents, recyclable catalytic systems, atom-economical reactions, and energy-efficient processes.

This review highlights green synthesis of isoquinolines via photocatalysis, microwave-assisted, metal-free, solvent-free methods, and recyclable catalysts, emphasizing atom economy, low toxicity, energy efficiency, and minimal waste.

1. Introduction

Isoquinoline is a privileged nitrogen-containing heterocyclic scaffold with broad relevance in natural and synthetic chemistry.^1,2 Found extensively in bioactive alkaloids and therapeutic agents, isoquinoline derivatives have been documented to exhibit a wide range of pharmacological activities, including anticancer, antiviral, antitubercular, antifungal, antimalarial, and neuroprotective properties.^3–8 Moreover, their utility extends beyond pharmaceuticals into agrochemicals, dyes, and materials science, further underscoring their synthetic and industrial significance.^9,10

The isoquinoline scaffold plays a pivotal role in diverse scientific fields due to its structural versatility and biological relevance. In medicinal chemistry, isoquinoline derivatives serve as key pharmacophores in several clinically approved drugs (Fig. 1), such as papaverine (a vasodilator),^11,12 emetine (an anti-amoebic agent),¹³ palonosetron (used to treat chemotherapy-induced nausea),¹⁴ gliquidone (anti-diabetic),¹⁵ tetrabenazine (vesicular monoamine transporter type 2 inhibitor)¹⁶ and revaprazan (treatment of peptic ulcer).¹⁷

Fig. 1. Example of isoquinoline-based clinically approved drugs.

Synthetic analogues have shown promising activity against cancer, malaria, tuberculosis, and neurodegenerative diseases, reflecting the scaffold's broad therapeutic potential. In natural product chemistry, isoquinoline alkaloids such as berberine, sanguinarine, and noscapine, which typically belong to Berberidaceae, Papaveraceae, and Ranunculaceae families, exhibit diverse pharmacological actions including antimicrobial, anticancer, and anti-inflammatory effects.¹⁸ Isoquinoline and its structurally related heterocycles, including isoquinolinones, indolo-isoquinolines, and pyrido-isoquinolinones, represent a versatile family of nitrogen-containing frameworks with significant prominence in both natural products and synthetic chemistry. The structural diversity imparted by annulation (such as indole or pyridine fusion) and functionalization (such as oxidation to isoquinolinones) further enhances these heterocycles' utility across pharmaceuticals, agrochemicals, and materials science landscape.^19–21 Furthermore, in materials science, isoquinoline derivatives have been employed in the development of organic semiconductors, fluorescent dyes, and metal-chelating ligands due to their electronic and photophysical properties.^22–26Fig. 2 highlights the application of the isoquinoline scaffold across various diverse fields.

Fig. 2. Application of isoquinoline scaffold in various diverse fields.

Isoquinoline frameworks have traditionally been synthesized using various methods like the Bischler–Napieralski, Pomeranz–Fritsch, Pictet–Gams, and Pictet–Spengler reactions (Fig. 3). While commercially and pharmaceutically important and versatile, these methods pose challenges in modern green chemistry. These multistep protocols often employ harsh conditions, including strong acids (e.g., POCl₃ or P₂O₅ in Bischler–Napieralski reaction),²⁷ toxic reagents, and hazardous solvents, while generating environmentally detrimental byproducts and exhibiting poor atom economy. The Pomeranz–Fritsch method^28–30 involves acid-catalyzed benzaldehyde-amine condensation, and the Pictet–Spengler reaction,³¹ pivotal for tetrahydroisoquinoline alkaloid synthesis via β-arylethylamine-aldehyde cyclization, further exemplifying these challenges through their narrow substrate scope, energy-intensive procedures, and reliance on precise parameter control. Over the years, the synthesis of isoquinoline derivatives has evolved considerably, expanding into a broad spectrum of modern methodologies. Many of these synthetic approaches involve transition metal catalysis playing key roles.^32–34 Nitrogen-containing substrates like benzylamines, arylnitriles, benzoic acid amides, imines, and oximes derived from aromatic aldehydes and ketones are frequently used in these transformations.^35,36

Fig. 3. Representative schemes for the conventional isoquinoline synthesis.

Despite significant advancements, many existing methods suffer from drawbacks such as poor regioselectivity, generation of unwanted byproducts, and limited adherence to the principles of green chemistry. Since the late 1990s, rising environmental awareness has fuelled the growth of green chemistry, which advocates for the design of safer, cleaner chemical processes that reduce waste and rely on renewable feedstocks.^37,38 Green chemistry has emerged as a transformative paradigm in chemical synthesis, aiming to minimize the environmental footprint of chemical processes while maximizing efficiency and safety. The twelve principles of green chemistry, introduced by Anastas and Warner,³⁹ serve as the cornerstone for developing such environmentally responsible methodologies. The foundational principles of green chemistry-such as the use of renewable feedstocks, safer solvents, energy efficiency, catalysis, and waste prevention offer a roadmap for redesigning traditional synthetic pathways. Within the realm of isoquinoline chemistry, researchers have increasingly adopted these principles to develop greener methodologies that reduce reliance on toxic reagents, minimize energy input, and improve overall. Non-metal catalyzed or organocatalytic methods utilize small organic molecules as catalysts, offering environmentally friendly and operationally simple alternatives. Ultrasound-assisted catalysis leverages sound waves to enhance reaction rates and yields through improved mixing and energy transfer, supporting greener processes. Visible light and photoredox catalysis harness light energy to activate catalysts, enabling redox reactions under mild conditions and facilitating the construction of intricate molecular architectures. Nanocatalysts, with their high surface area-to-volume ratio, play a crucial role by increasing the interaction between reactant molecules, which leads to higher yields, shorter reaction times, and improved efficiency; they are often reusable, environmentally benign, and can be magnetically separated for easy recovery, making them highly attractive for sustainable synthesis. Electrochemical catalysis uses electrical energy to drive chemical reactions, offering precise control over redox processes and reducing reliance on hazardous reagents. Metal-free or non-metal catalyzed syntheses advance green chemistry by eliminating metals altogether, employing organic molecules or ionic liquids to achieve high efficiency and selectivity while minimizing environmental impact. Fig. 4 highlights the advantages of the green methods over the classical methods of synthesis. Several reviews have been published highlighting the pharmacological importance of isoquinoline derivatives^40,41 and their synthetic strategies.^42,43 However, to the best of our knowledge, there is no comprehensive review focused specifically on the green and sustainable synthesis of isoquinoline based scaffolds. Therefore, this review aims to highlight and consolidate the eco-friendly methods currently used for the synthesis of isoquinoline and its' derivative compounds. This review aims to bridge this gap by providing an in-depth analysis of the methodological innovations in the green synthesis of isoquinoline and isoquinoline-based scaffolds. Examples of various isoquinoline-based heterocycles—including isoquinolines, isoquinolinones, indolo-isoquinolines, pyrido-isoquinolinones, and their derivatives—are comprehensively included in the current review. The study is structured to highlight recent developments categorized by the green technique used. The advantages, limitations, and environmental metrics of these approaches are highlighted compared to classical synthesis. We hope that this critical assessment will help to map the current landscape of sustainable synthesis of isoquinoline and its' derivatives, as well as highlight research gaps and future initiatives in this quickly growing subject.

Fig. 4. Overview of classical vs. green isoquinoline synthesis methods.

2. Green synthesis of isoquinoline and isoquinoline derivatives

2.1. Microwave assisted synthesis

Microwave (MW) irradiation is widely used in chemistry due to its ability to rapidly and uniformly heat substances, leading to faster reaction rates, higher yields, fewer side products, and easier purification compared to conventional heating. It also enables unique reactions and selectivities not achievable by traditional methods.^44,45

2.1.1. Metal catalyzed-microwave assisted methods

In 2021, Xu et al.⁴⁶ and the group developed an efficient palladium-catalyzed reaction of N-propargyl oxazolidines (1) for the construction of 4-substituted isoquinolines (2) under microwave irradiation (Scheme 1). The protocol is flexible with a larger substrate scope than that of other 4-substituted isoquinoline synthesized by the cross-coupling of 4-bromoisoquinolines with organometallic reagents or dehydrogenation of N-heterocycles.^47–49 The optimal conditions were obtained using Pd(PPh₃)₄, HCOONa, and a DMF/H₂O (3 : 1) system at 100 °C for 30 min. Electron-donating aryl (2a) and alkyl groups (2b) gave higher yields than electron-withdrawing ones (2c–d). Water was key for proton transfer, as confirmed by deuterium labelling. The reaction follows a cascade mechanism starting with Pd(0) catalyzed oxidative addition to the aryl bromide (A), followed by syn-insertion into a triple bond to form a cyclized intermediate (B). Ligand exchange with sodium formate and decarboxylation generate a Pd–H species, which undergoes reductive elimination to yield a new intermediate (C) while regenerating Pd(0). Subsequent C–O and C–N bond cleavages in the oxazole ring produce a rearranged intermediate (D) and an epoxide by product. Final aromatization delivers the target molecule. Overall, this efficient, oxidant free process allows rapid and scalable synthesis.

Scheme 1. Pd catalyzed domino reaction for the synthesis of 4-substituted isoquinolines by Xu et al.⁴⁶.

Quang Dao et al.⁵⁰ reported a microwave-assisted synthesis of 1-aminoisoquinolines (5) from 5-(2-bromoaryl)-tetrazoles (3) and 1,3-diketones (4) using a recyclable magnetic Cu-MOF-74 (Fe₃O₄@SiO₂@Cu-MOF-74) catalyst they previously synthesized in DMF.⁵¹ The reaction proceeds via copper-catalyzed C–C coupling, retro-Claisen or direct cyclo-condensation, and denitrogenation. The proposed mechanism, supported by control experiments and prior literature, begins with a Cu-MOF-catalyzed C(sp²)–C(sp³) coupling between substrates (3) and (4), forming intermediate (A). This intermediate undergoes either retro-Claisen deacylative cyclocondensation (for acyclic diketones) or direct cyclocondensation (for cyclic diketones), leading to the formation of tetrazole-fused isoquinolines (B). These intermediates are subsequently transformed into 1-aminoisoquinolines via a copper-catalyzed denitrogenation involving N–N bond cleavage, formation of a copper–azide complex, hydrolysis, and DMF-assisted reduction. Optimal conditions involved excess diketone, Cs₂CO₃ or K₃PO₄ base, and 150 °C heating. Electron-donating diketones gave higher yields, and l-proline enhanced outcomes with electron-withdrawing or cyclic substrates. The catalyst was reusable for four cycles with minimal activity loss, and intermediate studies confirmed the proposed mechanism (Scheme 2).

Scheme 2. Synthesis of 1-aminoisoquinolines by Dao et al.⁵⁰.

Deshmukh et al.⁵² reported a green, efficient method for synthesizing isoquinolines (8) and isoquinolinones (10) using a recyclable homogeneous ruthenium catalyst in PEG-400 under microwave irradiation (Scheme 3). The protocol employs dibenzoyl hydrazine (6) and ketazine (9) for C–H/N–N activation and annulation with internal alkynes (7), avoiding external oxidants, silver, or antimony salts. Optimized conditions (Ru catalyst, KPF₆, 150–160 °C, 10–15 min) gave high yields (62–92%) across a broad substrate scope, including heterocyclic and aliphatic alkynes. The Ru/PEG system is recyclable up to five times with minimal loss in activity and scalable to gram level synthesis, offering an eco-friendly, rapid, and atom efficient alternative. A similar Co-based annulation which uses conventional heating reported by the researchers has been included in Scheme 40.

Scheme 3. Microwave assisted synthesis of isoquinolines and isoquinolinones by Deshmukh et al.⁵².

Scheme 40. Synthesis of substituted isoquinolines by Deshmukh et al.¹¹¹.

Xu et al.⁵³ developed a microwave-assisted method for multi-substituted isoquinolines (13), which proceeded via SEAr (Electrophilic Aromatic substitution) radical insertion/cyclization of vinyl isocyanides (11) having a C(sp3)-H bond adjacent to a heteroatom (Scheme 4). The method comprises an oxidative cascade reaction, consisting of environmentally benign iron, tertiary-butyl hydrogenperoxide (TBHP) as oxidant, and 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) as ligand. The proposed mechanism begins with the generation of a tertiary-butoxy radical and Fe³⁺ (OH) from Fe²⁺ under microwave-assisted conditions. The tertiary-butoxy radical then abstracts a hydrogen from the substrate (12), forming a radical intermediate (A). This radical adds to methyl 2-isocyano-3,3-diphenylacrylate, yielding the imidoyl radical intermediate (B), which undergoes intramolecular hydrogen atom shift (HAS) to form the cyclized radical intermediate (C). From here, two possible pathways may lead to the final product: either intermediate (C) loses a hydrogen atom (abstracted by Fe³⁺ (OH)) to form isoquinoline (13), or it undergoes deprotonation in the presence of DBU to form a radical anion (D), which is then oxidized by Fe³⁺ (OH) to produce the same isoquinoline product. The developed method showed broad substrate scope, environmentally benign iron catalysis, shorter reaction time, and gram-scale scalability compared to conventional methods that employ Friedel–Crafts-type acylation with drawbacks such as harsh reaction conditions, strong acidic groups, and low functional group tolerance.⁵⁴

Scheme 4. Microwave irradiated isoquinoline synthesis by Xu et al.⁵³.

Hu et al.⁵⁵ reported a simple Cu-catalyzed, one -pot, microwave assisted method for the synthesis of 3,4-diaryl isoquinolines (17) (Scheme 5). The reaction proceeded via CuI/2,2′-biimidazole-catalyzed tandem process from N-tert-butyl-o-iodobenzaldimine (14). The mechanism involves two main steps. First, CuI/2,2′-biimidazole catalyzes the coupling of N-tertiary-butyl-o-iodobenzaldimine (14) with an aryl alkyne (15) to form compound (16). Then, oxidative addition of an aryl iodide to CuI forms an electrophilic copper species that coordinates with the alkyne to activate it, forming a π-complex. This undergoes electrophilic cyclization, followed by SN₂ displacement of the tertiary-butyl group to form. Finally, reductive elimination yields the 3,4-diaryl isoquinoline product (17). The reaction showed poor yields in the case of an electron-withdrawing aryl acetylene.

Scheme 5. Synthesis of aryl-substituted isoquinoline by Hu et al.⁵⁵.

Swamy et al.⁵⁶ replaced a costly rhodium catalyst with a low-cost alternative, Ruthenium catalyst to develop intermolecular alkyne-amide (18) annulation under microwave irradiation to give fused tricyclic isoquinolinones (19) (Scheme 6). The reaction was highly efficient using Ru(ii) as a catalyst and Cu(OAc)₂·H₂O as a co-oxidant and toluene as a solvent. The one-pot strategy proceeds via domino C–C and C–N bond formation, with advantages of improved yields and milder and better reaction rates over the conventional C–H activation methods.^57–59 The proposed mechanism involves initial formation of a five-membered ruthenacycle (A) via oxidative insertion of Ru(ii) into the ortho C–H bond of the benzamide. This metallacycle then reacts with a tethered alkyne, leading to either C–N bond formation (B) or ortho-functionalization (C). Reductive elimination from the Ru(0) intermediate yields the final product, and Ru(0) is reoxidized to Ru(ii) by Cu(OAc)₂, completing the catalytic cycle.

Scheme 6. Synthesis of tricyclic isoquinolinones by Swamy et al.⁵⁶.

2.1.2. Non-metal catalysed-microwave assisted methods

In 2023, et al.⁶⁰ developed an eco-friendly method to synthesize 3-arylisoquinoline (21) from 2-alkynylbenzaldehydes (20) using Nafion® NR50 as an acidic catalyst and hexamethyldisilazane (HMDS) as a nitrogen source (Scheme 7). The reaction proceeded via a 6-exo-dig cyclization under microwave irradiation, giving the corresponding isoquinolines in excellent yields. The proposed mechanism begins with protonation of substrate (A) by Nafion® NR50, forming intermediate (B). Upon addition of HMDS, a nucleophilic addition occurs, yielding intermediate (C), which undergoes proton transfer to form (D), followed by dehydration to give (E). The Nafion® NR50 anion then activates the TMS group in intermediate (F). Coordination of the alkynyl group with the Nafion–H complex facilitates cyclization via the nitrogen atom, forming TMS-isoquinoline (G). Finally, activation by the Nafion anion leads to the formation of the desired isoquinoline product (21). The advantages of this protocol over the conventional methods that use toxic chemicals and require high temperatures include the use of recyclable acid catalysts, transition metal free catalysis, and better yields.

Scheme 7. Synthesis of 3-aryl substituted isoquinolines by Lin et al.⁶⁰.

Kubickova et al.⁶¹ reported a one-pot, microwave-assisted method for synthesizing 1-fluoroalkyl-3-fluoroisoquinolines (23) from N-fluoroalkylated 1,2,3-triazoles (22) using potassium fluoride (Scheme 8). The reaction features broad substrate scope and proceeds via N-fluoroalkylated ketenimines (A), and difluoroazadiene (B) intermediates. The mechanism involves triazole ring opening, –N₂ elimination, 1,3-F-shift, and cyclization. The resulting isoquinolines, bearing fluorine at position 3 and halogens at position 4, enable further functionalization via substitution and cross-coupling. The method was applied to synthesize several derivatives of drug candidates.

Scheme 8. Synthesis of fluoro isoquinolines by Kubickova et al.⁶¹.

Xue et al.⁶² reported a metal-free, microwave-assisted radical cyclization of vinyl isonitriles (24) with alcohols (25) to give hydroxyl-containing isoquinolines (26) (Scheme 9). Vinyl isonitriles undergo coupling with alkyl radicals via direct catalytic activation of the α-sp³ C–H bond in alcohols. This approach features a wide substrate range, excellent compatibility with various functional groups, and offers high atom economy and efficiency. Mechanistic studies, including KIE experiments, revealed that C–H bond cleavage in alcohols is the rate-determining step, as shown by a significant KIE (k_H/k_D = 6.7) with methanol/[D4]-methanol. The reaction was strongly inhibited by TEMPO, and a radical adduct was detected, confirming a radical pathway. The mechanism involves tertiary-butoxy radical generation from TBPB (A), which abstracts an α-hydrogen from alcohol to form a hydroxyalkyl radical (B). This undergoes radical addition (C) and cyclization (D), followed by hydrogen abstraction or oxidation to give the final product (26).

Scheme 9. Synthesis of hydroxyl-containing isoquinolines by Xue et al.⁶².

In 2017, Hekal et al.⁶³ gave an efficient method for the synthesis of isoquinolinone (29) using homophthalic anhydride (27) and anthranilic acid (28) under microwave irradiation (Scheme 10). The reaction proceeded via a tetrahedral mechanism-nucleophile attack of the amino group of anthranilic acid at the carbonyl of homopthalic anhydride to give (A), followed by removal of proton and 1,6-exo-trig cyclization with water elimination to give isoquinolone (B), which undergoes cyclization to give (C). Further, amine was added to get the final product (30). The method provided improved yields and shortened reaction time.

Scheme 10. Synthesis of isoquinolinones by Hekal et al.⁶³.

2.2. Ultrasound-assisted synthesis

In recent years, ultrasound (US) irradiation has emerged as a powerful technique in modern science, particularly within medicinal and organic chemistry.⁴⁴ Compared to conventional methods, the use of ultrasound energy in chemical reactions offers several notable advantages, such as higher yields, improved product purity, shorter reaction times, and the ability to achieve selectivity and reactivity. Furthermore, ultrasound-assisted reactions often operate under milder conditions, require less energy, minimize or eliminate side reactions, and can be performed with little or no solvent, making these processes more environmentally friendly.^64,65

Sangepu et al.⁶⁶ demonstrated a green and efficient ultrasound-assisted one-pot synthesis of isoquinolin-1(2H)-one derivatives (33) (Scheme 11). The methodology involves a sequential two-step transformation: a copper-catalyzed α-arylation of ketones (32) with 2-iodobenzamide (31) via C–C bond formation, followed by intramolecular C–N bond cyclization—both steps occurring in the same reaction pot under ultrasound irradiation. The mechanism starts with ultrasound-assisted formation of a Cu(i)–DMSO complex (A), which undergoes oxidative addition with an aryl iodide to form a Cu(iii) intermediate (B). This reacts with a ketone-derived enolate to give a Cu(iii)-alkyl species (C), which undergoes reductive elimination to form intermediate (D) and regenerate the catalyst. Intermediate (D) quickly cyclizes to form isoquinolinone (33). The synergy between ultrasound and catalysis, likely through cavitation induced catalyst activation, significantly enhances reaction efficiency. The process does not require additional ligands or additives, making it environmentally benign. The scope of the method was explored using a wide range of substrates, affording moderate to excellent yields (49–93%). However, the reaction failed when a nitro-substituted 2-iodobenzamide was used, indicating some limitations in functional group tolerance.

Scheme 11. Synthesis of 3-substituted isoquinolinone by Sangepu et al.⁶⁶.

An efficient and environmentally friendly multi-component synthetic protocol for pyrido-[2,1-a]-isoquinoline derivatives (37) was developed by Sharafian et al.⁶⁷ utilizing ultrasonic irradiation to drive the reaction in water at room temperature (Scheme 12). This method involves the combination of phthalaldehyde (34), methylamine, α-halo substituted carbonyl compounds (36), activated acetylenes (35), and triphenylphosphine (PPh₃), affording the target compounds in excellent yields within short reaction times. The ultrasonic conditions significantly accelerate the transformation, providing clean reaction profiles and simplifying product isolation. Under ultrasonic irradiation in water at room temperature, phthalaldehyde reacts with methylamine to form an iminium intermediate (A), while triphenylphosphine (PPh₃) and an α-halo carbonyl compound generate a phosphorus ylide. The activated acetylene undergoes Michael addition with the iminium ion, followed by a Wittig-type olefination with the ylide to give (B). This sequence leads to intramolecular cyclization, forming pyrido-[2,1-a]-isoquinoline derivatives (37) in excellent yields. Furthermore, additional Diels–Alder transformations of the resulting heterocycles under similar ultrasonic conditions were explored, expanding the scope of the methodology. The presence of the isoquinoline core also prompted an investigation into the antioxidant potential of selected products, confirming their relevance for medicinal chemistry applications. Additionally, a Diels–Alder reaction of the formed isoquinoline with activated acetylenes under ultrasound further expands the molecular framework. Ultrasonication enhances reaction rates, product purity, and supports green synthesis.

Scheme 12. Synthesis of fused pyrido isoquinoline scaffold by Sharafian et al.⁶⁷.

In 2020, Araujo et al.⁶⁸ reported a green and efficient ultrasound-assisted method for synthesizing 3-organyl-4-(organyl chalcogenyl)-isoquinoline-2-oxides (39) via Oxone-promoted electrophilic cyclization of 2-alkynylbenzaldoximes (38) with diorganyl dichalcogenides (Scheme 13). The reaction, driven by ultrasound irradiation as an alternative energy source, proceeds under mild conditions with short reaction times (10–70 min) and delivers high yields (up to 93%) across a broad substrate scope. This protocol extends the authors' previous work,^69,70 on oxone/dichalcogenide-mediated heterocycle synthesis and highlights the compatibility of ultrasound with green synthetic strategies. These results underscore the method's potential for generating novel organochalcogen–isoquinoline N-oxide hybrids with promising synthetic and pharmacological relevance. They also reported the synthesis of 4-(selanyl)-isoquinoline-N-oxides via ultrasound-assisted selenocyclization of o-alkynyl benzaldehyde oximes with diorganyl diselenides (39a, c) in the presence of Oxone. The proposed mechanism for the 6-endo-dig electrophilic cyclization begins with the activation of the dichalcogenide reagent by oxone, generating electrophilic chalcogenium species. These react with the oxime substrate to form a three-membered chalcogeniranium intermediate (A). Intramolecular nucleophilic attack by the oxime nitrogen then initiates ring closure, yielding an isoquinoline intermediate (B). Subsequent deprotonation of this intermediate furnishes the final isoquinoline product (39). This approach delivered excellent yields in short reaction times; however, it required a high loading of oxidants, resulting in increased waste generation and limiting its sustainability.

Scheme 13. Synthesis of isoquinoline-N-oxide by Araujo et al.⁶⁸.

To overcome these drawbacks, a novel and greener protocol was developed by Anghinoni et al.⁷¹ using benzeneseleninic acid (BSA) (41) derivatives as bench-stable, odorless, and easy to handle selenium sources (Scheme 14). This method involves the thermal selenocyclization of o-alkynyl benzaldehyde oximes (40) in refluxing methanol, enabling the in situ generation of electrophilic selenium species without the need for strong oxidants or additives. The process afforded up to 96% yields, displayed excellent substrate tolerance, and was successfully scaled up by 10-fold. Additionally, the only by product formed was water, making it a more sustainable and environmentally friendly alternative to previous methods.

Scheme 14. Greener modification to isoquinoline-N-oxide synthesis by Anghinoni et al.⁷¹.

2.3. Visible light and photo-redox-assisted synthesis

Visible light and photo-redox assisted synthesis has emerged as a transformative approach in organic chemistry, enabling the activation of molecules under mild, sustainable conditions. By harnessing visible light and suitable photocatalysts often transition metal complexes or organic dyes this method facilitates single-electron transfer and energy transfer processes, generating reactive intermediates such as radicals.⁷² This allows chemists to perform highly selective and previously challenging transformations, including C–H functionalization, cross-coupling, and late-stage modifications, with broad functional group tolerance and operational simplicity.⁷³ The mild reaction conditions, compatibility with aqueous environments, and avoidance of harsh reagents make visible light photo-redox catalysis especially attractive for pharmaceutical and natural product synthesis, driving innovation in both academic and industrial settings.⁷⁴

Yuan et al.⁷⁵ introduced a sustainable and efficient method for synthesizing isoquinolines using inexpensive organic dyes as visible-light photoredox catalysts, with a focus on the underexplored nitrogen-centered radical (NCR) chemistry. The authors generate iminyl radicals from dinitroaryloxime derivatives (43), which undergo intramolecular 6-endo-dig cyclization on vicinal alkynes to form isoquinoline scaffolds (44) (Scheme 15). Addressing the scarcity of NCR-mediated cyclizations, especially on alkynes, they optimize reaction conditions using eosin Y (EY) as the photocatalyst under green LED irradiation, with 1,4 cyclohexadiene (CHD) as a hydrogen donor and K₂CO₃ in DMF as the base-solvent system conditions where conventional metal-based photocatalysts proved ineffective. The mechanism involves eosin Y-mediated single-electron transfer producing iminyl radicals (A) that attack nearby alkyne, triggering 6-endo-dig cyclization to form carbon-centered radicals (B), which upon hydrogen abstraction from CHD yield the final product (44), regenerating the catalyst and giving benzene as a by-product. Substrate scope reveals that electron-withdrawing groups on alkynes and aromatic rings enhance yields, while steric hindrance and electron-donating substituents lower efficiency. Overall, this work offers a novel, metal-free, and green approach to construct biologically important isoquinolines via visible-light induced NCR cyclization on alkynes, significantly advancing sustainable radical-based heterocycle synthesis.

Scheme 15. Synthesis of alkyl/aryl substituted isoquinolines by Yuan et al.⁷⁵.

Gong et al.⁷⁶ developed a simple and efficient visible-light-promoted selenylation/cyclization method for the synthesis of seleno-substituted isoquinoline derivatives (47) from o-alkynyl benzylazides (45) and o-propargyl arylazides (Scheme 16). This strategy enables the construction of one C(sp²)–Se bond and one C–N bond in a single step, providing access to valuable seleno-substituted heterocycles. Based on experimental results, two possible reaction pathways are proposed. Upon irradiation, Se-phenyl 4-methylbenzenesulfonoselenoate (46) generates Ts˙ (A) and PhSe˙ (B) radicals, which are oxidized under air to TsO⁻ and PhSe⁺, respectively. In path (a), electrophilic addition of PhSe⁺ to the alkyne forms a selenonium ion intermediate (C). Subsequent intramolecular nucleophilic cyclization by the azide group yields intermediate (D), which undergoes deprotonation by TsO⁺ (with TsOH detected by LC-MS) and nitrogen extrusion to produce the final product (47). In path (b), the PhSe˙ radical adds to the alkyne to form intermediate (E), which undergoes a 6-endo-dig cyclization to give radical anion intermediate (F). Loss of nitrogen leads to nitrogen radical intermediate (G), which abstracts a hydrogen atom from Ts˙ (with TsH detected by LC-MS) to furnish product (47).

Scheme 16. Synthesis of Se-substituted isoquinolines by Gong et al.⁷⁶.

Zhang et al.⁷⁷ introduced a novel and sustainable cascade cyclization strategy that utilizes visible light and operates without metal catalysts for the synthesis of 4-cyanoalkyl isoquinoline-1,3-diones (50) (Scheme 17). The method employs an electron donor–acceptor (EDA) complex mechanism, beginning with the ring-opening of cycloketone oxime esters (49) and followed by coupling with N-methacryloyl benzamides (48). A small amount of 1,4-diazabicyclo-[2.2.2]-octane (DABCO) serves as the catalyst, and prolonged reaction times aid in completing the transformation. The procedure is straightforward, showcasing a wide functional group tolerance and broad substrate compatibility under mild, photocatalyst-free conditions. Various radical acceptors can be integrated into the reaction, enabling the construction of a diverse range of heterocycles. Mechanistic studies confirmed that the formation of EDA complexes between Lewis bases and cycloketone oxime esters through weak interactions is essential for reactivity. The reaction begins with the formation of an electron donor–acceptor (EDA) complex between cyclobutanone oxime ester and DABCO. Upon blue LED irradiation, the complex undergoes single-electron transfer (SET), generating a benzoate anion, an imine radical (A), and a DABCO radical cation. The imine radical undergoes C–C bond cleavage to form a cyanoalkyl radical (B), which adds to a radical acceptor via cyclization, yielding a radical intermediate (C). Another SET between (C) and DABCO⁺ forms a cationic intermediate (D). Finally, deprotonation of (D) by DABCO or benzoate gives the final product. Impressively, high product yields were achieved even with only catalytic amounts of DABCO. This approach provides an efficient and environmentally friendly route to isoquinoline-1,3-dione derivatives.

Scheme 17. Synthesis of cyano-substituted isoquinolinones by Zhang et al.⁷⁷.

T. Zhang et al.⁷⁸ reported a sustainable and metal-free method using reusable Lewis acidic ionic liquids (LAILs) as catalysts for the radical-cascade alkylation and cyclization of N-alkyl-N-methacryloyl benzamides (51) with unactivated alkanes (52) to synthesize alkylated isoquinoline-1,3-(2H,4H)-diketones (53) (Scheme 18). This reaction proceeds efficiently under mild conditions in a mixed MeCN/DCE solvent system with ethanol as a hydrogen transfer agent, without requiring stoichiometric oxidants or high temperatures. The LAILs function as recyclable light-mediated charge-transfer (LMCT) catalysts, supporting green chemistry principles. The proposed mechanism begins with the oxidation of Ce³⁺-LAILs in air and ethanol, forming an EtO–Ce⁴⁺ complex and a superoxide radical (O₂⁻˙). Upon light irradiation, ligand-to-metal charge transfer (LMCT) generates an ethoxy radical (EtO˙), which abstracts a hydrogen atom from cyclohexaneto form a cyclohexyl radical. This radical undergoes addition and cyclization with compound (51) to yield intermediate (C). A final HAT from (C) to the superoxide radical forms the product (53) and hydrogen peroxide. Alternatively, a chloride radical could also initiate the HAT step, suggesting a possible parallel pathway. The protocol accommodates a broad range of electron-rich and electron-poor N-substituted benzamides, delivering the desired products in moderate to good yields. This approach offers excellent catalyst recyclability, scalability, and high atom economy, making it a promising alternative for the eco-friendly synthesis of functionalized isoquinoline derivatives.

Scheme 18. Synthesis of isoquinolinone by T. Zhang et al.⁷⁸.

Wang et al.⁷⁹ reported a novel, visible-light induced, radical cascade trifluoromethylation/cyclization of N-benzamides (54) using sodium trifluoromethanesulfinate (CF₃SO₂Na) (55) has been developed for the synthesis of CF₃-containing isoquinoline-1,3-diones (56) (Scheme 19). This metal-free protocol operates under air, without additives or expensive reagents, offering a practical and operationally simple method. The reaction utilizes CF₃SO₂Na as an inexpensive CF₃ source and proceeds via a radical pathway under visible light irradiation. Under visible-light irradiation, Eosin B is excited to its active form (Eosin B*), which accepts an electron from (55), generating a CF₃ radical and a radical anion of Eosin B. The CF₃ radical adds to the substrate, forming intermediate (A), which undergoes radical cyclization to give intermediate (B). Simultaneously, Eosin B* transfers an electron to O₂, producing superoxide (O₂˙⁻) and regenerating Eosin B. The resulting intermediate (C) then undergoes deprotonation to yield the final product (56). Compared to previous methods requiring transition metals or additives, this approach stands out for its eco-friendliness and cost-effectiveness.

Scheme 19. Synthesis of CF₃-substituted isoquinolinones by Wang et al.⁷⁹.

In 2025, Niu et al.⁸⁰ reported a novel, green, and efficient photocatalytic method for synthesizing amide-functionalized isoquinoline-1,3-diones via a cascade amidation/cyclization reaction (Scheme 20). The process utilizes readily available oxamic acids as amide donors and the organic photocatalyst 4CzIPN under mild, metal-free, and environmentally benign conditions. Upon irradiation with blue LED light, the organic photocatalyst 4CzIPN is excited to its singlet excited state 4CzIPN*. This excited species undergoes single-electron transfer (SET) with persulfate anion (S₂O₈²⁻), resulting in the formation of the 4CzIPN radical cation (4CzIPN˙⁺), sulfate radical anion (SO₄˙⁻), and a sulfate dianion (SO₄²⁻). The sulfate radical (SO₄˙⁻) then interacts with oxamic acid, abstracting a hydrogen atom (via hydrogen atom transfer, HAT) and promoting decarboxylation, leading to the formation of a carbamoyl radical (A). This carbamoyl radical (A) then undergoes a radical addition to the alkene moiety of the substrate, generating a new carbon-centered radical intermediate (B). Following this, intermediate (B) undergoes an intramolecular cyclization, typically a 6-endo-trig or 5-exo-trig process, forming a cyclic radical intermediate (C). The radical (C) is then oxidized by the radical cation 4CzIPN˙⁺ (generated in the first SET), which regenerates the ground state 4CzIPN catalyst and forms a carbocation intermediate (D). Finally, this carbocation (D) undergoes deprotonation, restoring aromaticity and affording the final isoquinoline-1,3-dione product (59).

Scheme 20. Synthesis of isoquinolinones by Niu et al.⁸⁰.

The protocol offers a broad substrate scope and excellent functional group tolerance. Moreover, its synthetic utility extends beyond isoquinoline diones to include the efficient preparation of amidated oxindoles and succinimides bearing α-quaternary carbon centers, highlighting the versatility and scalability of this approach.

Tang et al.⁸¹ also developed an efficient visible-light-promoted, organic-dye-catalyzed radical cascade cyclization was developed for the rapid synthesis of sulfonyl-substituted indolo-[2,1-a]-isoquinolines and benzimidazo-[2,1-a]-isoquinolin-6-(5H)-ones (65) (Scheme 21). Using the economical and environmentally friendly photocatalyst Eosin B, a wide range of indolo-[2,1-a]-isoquinoline derivatives were obtained in moderate to good yields. Mechanistic studies suggest involvement of a sulfonyl radical pathway initiated by visible-light excitation of Eosin B, which activates persulfate to generate sulfate radical anions that abstract hydrogen from sulfonyl hydrazides to form sulfonyl radicals. These radicals add to substrates, triggering a 6-endo-trig cyclization, oxidation, and deprotonation sequence to yield the final products. Compared to previous methods, this protocol avoids metals and bases, uses visible light as a clean energy source, operates under mild conditions, and features simple handling, making it attractive for organic and pharmaceutical applications. Despite existing sulfonation methods,^82,83 often requiring harsh conditions, expensive metals, or excess oxidants, this approach offers a facile, environmentally benign alternative.

Scheme 21. Synthesis of fused isoquinolinones by Tang et al.⁸¹.

In 2024, Lei et al.⁸⁶ presented an eco-friendly photocatalytic and photo induced strategy for synthesizing fused tetracyclic silylated indolo-[2,1-a]-isoquinoline-6-(5H)-ones (65) from 2-aryl-N-acryloyl indoles (63) and hydrosilanes (64) under mild, metal- and oxidant-free conditions (Scheme 22). The photocatalytic approach employs 9,10-dicyanoanthracene (DCA) with 3-acetoxyquinuclidine as a hydrogen atom transfer (HAT) catalyst, while the photoinduced method uses tris-(trimethylsilyl)-silane ((TMS)₃SiH) (66) under visible light. Both processes proceed via electron-donor–acceptor (EDA) complex formation and radical pathways, yielding products efficiently across a variety of substrates, with yields ranging from 42% to 70%. These methodologies offer significant advantages, including high atom economy, operational simplicity, environmental safety, and hydrogen gas as the only byproduct, making them promising for the sustainable synthesis of functionalized isoquinoline derivatives.

Scheme 22. Synthesis of indolo-isoquinolines by Lei et al.⁸⁴.

Zhu et al.⁸⁵ developed a mild and efficient visible-light-induced photocatalytic radical cascade cyclization protocol for the synthesis of indolo-[2,1-a]-isoquinoline derivatives (70) (Scheme 23). This method employs alkyl 2-mercaptothiazolinium salts (69)—easily prepared from inexpensive alkyl halides as alkylating agents under oxidant- and base-free conditions. It enables the coupling of 2-aryl-N-acryloyl indoles (68) with primary, secondary, and tertiary alkyl groups, yielding products in moderate to good yields. The strategy forms two C–C bonds in a single step, constructing the indolo-[2,1-a]-isoquinoline core while introducing aliphatic side chains. Initially, thiazolinium salt (69) undergoes single-electron transfer (SET) with photoexcited Ir(iii)*, forming radical I and Ir(iv). A β-scission then cleaves the C–S bond, yielding an ethyl radical (A) and thione. The ethyl radical undergoes addition and cyclization with substrate (68), forming intermediate (C) via (B). Intermediate (C) is oxidized in a second SET step, generating cationic species (D) and regenerating Ir(iii). Final deprotonation of (D) gives the product (70). This green and practical approach features broad substrate scope, mild conditions, and avoids costly or sensitive reagents like stoichiometric oxidants, bases, or Katritzky salts.

Scheme 23. Synthesis of fused isoquinolinones by Zhu et al.⁸⁵.

2.4. Nano catalysts

Nanocatalysts have garnered considerable attention as a pivotal component of green chemistry strategies, owing to their unique physicochemical properties and remarkable catalytic efficiencies.⁸⁶ Their high surface area-to-volume ratio significantly enhances catalytic activity, enabling reactions to proceed under milder conditions with greater selectivity and reduced energy input compared to conventional catalysts. Furthermore, the facile recovery and recyclability of many nanocatalysts particularly those with magnetic properties contribute to minimizing waste and improving process sustainability.⁸⁷ The synthesis of nanocatalysts can often be achieved using environmentally benign methods and renewable resources, further aligning with the principles of green chemistry. Collectively, these attributes position nanocatalysts as promising tools for advancing sustainable and eco-friendly chemical transformations in both academic and industrial contexts.^88,89

The sustainable synthesis of isoquinolones, key pharmacophores in many natural products and drugs, has gained attention using heterogeneous transition metal-based nanocatalysts. A novel Cu₂O-decorated marigold-like hollow alumina microsphere (Cu₂O@MHAM) nanocatalyst was developed by Rawat et al.⁹⁰ for the green synthesis of isoquinolones (73) from 2-bromobenzonitriles (71) and ketones (72) under neat conditions (Scheme 24). This method offers significant advantages over previous systems, including excellent yields (up to 92%), broad substrate scope, and superior green chemistry metrics such as a low E-factor, high reaction mass efficiency, and high turnover number. The nanocatalyst was reusable for at least five cycles without loss of activity. Mechanistically, the reaction proceeds through nucleophilic substitution (B), electrocyclization (C), and nanoparticle-assisted cyclization (D). In summary, this Cu₂O@MHAM system provides an efficient, eco-friendly, and reusable catalytic platform for isoquinolone synthesis, demonstrating excellent performance and sustainability.

Scheme 24. Synthesis of isoquinolinone by Rawat et al.⁹⁰.

In 2022, Ezzatzadeh et al.⁹¹ reported a green and efficient method for synthesizing pyrido-[2,1-a]-isoquinolines (79) and pyrido-[1,2-a]-quinolines in excellent yields via multicomponent reactions of pthalaldehyde (74), methyl malonyl chloride (76), alkyl bromides (77), and triphenyl phosphine (78) using magnetically recoverable Fe₃O₄ nanoparticles as a catalyst in water at 80 °C (Scheme 25). The Fe₃O₄ nanoparticles were synthesized through a green approach using Clover Leaf extract. Phthalaldehyde and ammonium acetate react in the presence of Fe₃O₄ MNPs to form isoquinoline (A), which then couples with malonyl chloride to give an intermediate (B). Separately, alkyl bromide and triphenylphosphine form a phosphonium intermediate (C), which reacts with the isoquinoline derivative to give (D). Cyclization and elimination of triphenylphosphine oxide occur, followed by decarboxylation under heating to yield the final product. The synthesized compounds showed notable ferric ion reducing capacity and minimal DPPH radical scavenging activity, indicating potential antioxidant properties. Additionally, antimicrobial studies revealed that compounds exhibited growth inhibition against both Gram-positive and Gram-negative bacteria. This solvent free, eco-friendly method emphasizes the biological relevance of isoquinoline derivatives and highlights the ease of catalyst recovery using a magnet, better atom economy, and higher yields, aligning well with green chemistry principles.

Scheme 25. Synthesis of pyrido isoquinolines by Ezzatzadeh et al.⁹¹.

Hamedani et al.⁹² also reported a green and efficient method for synthesizing pyrido-[2,1-a]-isoquinoline derivatives (84) using KF/Clinoptilolite (KF/CP) nanoparticles as a heterogeneous catalyst via a four component reaction involving isoquinoline (79), two alkyl bromides (81, 82), and electron-deficient internal alkynes (83) in water at ambient temperature (Scheme 26). The KF/CP nanocatalyst, composed of natural and inexpensive materials, offers high catalytic activity due to its nanoscale properties and provides free fluoride anions as a basic species. The synthesis process is clean, straightforward, and requires no purification steps. Key advantages of this method include high product yields, green solvent usage, catalyst reusability, and ease of product and catalyst separation, making it an attractive and sustainable approach in heterocyclic synthesis.

Scheme 26. Synthesis of pyrido-isoquinolines by Hamedani et al.⁹².

S. Amiri et al.⁹³ reported a green, solvent-free method for synthesizing pyrrolo-[2,1-a]-isoquinoline derivatives (87) via a four-component reaction involving phthalaldehyde (74) or its derivatives, primary amines (85), alkyl bromides (82), and activated acetylenic compounds (86) using KF/Clinoptilolite (KF/CP) nanoparticles as a reusable catalyst at room temperature (Scheme 27). Additionally, Diels–Alder reactions between the synthesized isoquinolines, activated acetylenes, and triphenylphosphine also proceed efficiently under similar conditions. The method demonstrates excellent yields, fast reaction rates, environmental compatibility, and recyclability of the catalyst. Antioxidant evaluations of selected compounds showed promising activity compared to standard antioxidants (BHT and TBHQ), highlighting the biological relevance of the synthesized products.

Scheme 27. Synthesis of pyrrolo-fused isoquinolines by S. Amiri et al.⁹³.

In 2022, S. Amiri et al.⁹⁴ also reported a green and efficient method to synthesize pyrimido-isoquinoline derivatives via a four-component reaction in water using KF/CP@MWCNTs nanocatalysts at room temperature (Scheme 28). The process offers high yields, short reaction times, and easy catalyst recovery. The compounds showed promising antioxidant and antimicrobial activities, and a mechanism involving isoquinoline intermediate formation was proposed. The reaction starts with the condensation of (88) and (75) in the presence of KF/CP@MWCNTs nanocatalysts to form isoquinoline intermediate (A). Concurrently (89), reacts with (88), generating intermediates (B) and (C). The negatively charged intermediate (C) attacks intermediate (B), leading to the formation of intermediate (D). Finally, intramolecular cyclization of intermediate (D), catalyzed by KF/CP@MWCNTs, yields the final product (90).

Scheme 28. Synthesis of fused isoquinolines by S. Amiri et al.⁹⁴.

A green and efficient method was developed by Rawat et al.⁹⁵ for synthesizing indeno-isoquinolinone derivatives (93) using a novel CuO@NiO nanocatalyst prepared from malachite and nickel oxalate. The catalyst was characterized using multiple techniques and used in a base/additive-free reaction between 2-iodobenzamide (91) and 1,3-indanedione (92) in ethylene glycol (Scheme 29). This method offers high yields, broad substrate scope, short reaction time, and excellent green chemistry metrics (low E factor, high reaction mass efficiency, and minimal metal leaching). The catalyst was easily recoverable and reused for six cycles with negligible loss of activity. The reaction begins with the CuO@NiO nanocomposite activating the active methylene group of 1,3-indanedione (A), enabling its nucleophilic attack on 2-iodobenzamide to form intermediate (B). This is followed by an intramolecular nucleophilic cyclization and subsequent dehydration, ultimately yielding the isoquinoline-based product (93).

Scheme 29. Synthesis of fused isoquinolinone scaffold by Rawat et al.⁹⁵.

Hamedani et al.⁹⁶ reported a green, one-pot synthesis of pyrido-[2,1-a]-isoquinolinones (94) and pyrido-[1,2-a]-quinolinones using a multicomponent reaction of phthalaldehyde (74), methylamine (85), methyl malonyl chloride (76), alkyl bromides (81), and triphenylphosphine (78) in water at 80 °C, catalyzed by Fe₃O₄ magnetic nanoparticles (Fe₃O₄ MNPs) (Scheme 30). The method offers high yields, short reaction times, and easy catalyst/product separation. A detailed mechanism involving intermediate formation, nucleophilic addition, and cyclization was proposed. The method aligns with green chemistry principles due to high atom economy, water as a solvent, low catalyst loading, and catalyst reusability.

Scheme 30. Synthesis of pyrido-fused isoquinolinones by Hamedani et al.⁹⁶.

2.5. Electrochemical methods

Electrochemical methods are increasingly valued in green chemistry for their ability to drive chemical reactions using electricity instead of hazardous reagents.⁹⁷ By employing electrons as clean and efficient reactants, these techniques minimize waste and avoid toxic by-products. Electrochemical synthesis often proceeds under mild conditions and can be powered by renewable energy, making it both sustainable and energy-efficient. As a result, electrochemistry is recognized as a practical and eco-friendly method for modern synthesis.^98,99

In 2025, an electrochemical method was developed by Mei et al.¹⁰⁰ for the green and efficient synthesis of bis-trifluoromethylated indole-[2,1-a]-isoquinolines (96) using sodium trifluoromethanesulfinate (CF₃SO₂Na) (58) as the radical source (Scheme 31). The reaction begins with the anodic oxidation of sodium trifluoromethanesulfinate, generating a trifluoromethanesulfonyl radical (A) that releases SO₂ to form a reactive CF₃˙ radical. This radical adds to the substrate to form radical intermediate (B) via TS1 (ΔG = 10.5 kcal mol⁻¹), followed by intramolecular cyclization to give radical intermediate (C) through TS2 (ΔG = 19.1 kcal mol⁻¹). Subsequent anodic oxidation of (C) produces cationic intermediate (D), which undergoes deprotonation to yield intermediate (E). Another CF₃˙ radical adds to intermediate (E), forming radical intermediate (F) via TS3 (ΔG = 9.1 kcal mol⁻¹), which is then oxidized to cationic intermediate (G). Final deprotonation of (G) furnishes the target product (96). The strategy enables the efficient construction of bioactive indole-fused tricyclic systems bearing two CF₃ groups, offering a sustainable and versatile platform for the synthesis of fluorinated heterocycles with potential pharmaceutical relevance.

Scheme 31. Synthesis of indolo-fused isoquinolines by Mei et al.¹⁰⁰.

Similarly, Lv et al. reported a novel electrochemical radical relay strategy for the direct synthesis of 5-(2,2,2-trifluoro)-ethyl dihydrobenzimidazo-[2,1-a]-isoquinoline derivatives (98) from benzimidazole-linked unactivated alkenes (97), utilizing an undivided electrochemical cell.¹⁰¹ This approach is compatible with both the Langlois reagent (58) as CF₃ source and its difluoro variant, exhibiting broad functional group tolerance including activated sp³ C–H bonds and eliminates the need for external oxidants (Scheme 32).

Scheme 32. Synthesis of benzimidazole-fused isoquinolines by Lv et al.¹⁰¹.

2.6. Non-metal-based/metal-free methods

Metal-free approaches in green chemistry offer sustainable alternatives by eliminating the need for toxic and expensive metal catalysts, thus reducing environmental impact and production costs. These methods often provide high selectivity and efficiency under mild conditions, making them attractive for eco-friendly synthesis in pharmaceuticals and fine chemicals.

Prasad et al.¹⁰² reported an efficient and transition-metal-free one-pot strategy for the synthesis of 3-ketoisoquinolines (101) from easily accessible 2-(formylphenyl)-acrylates (99) and phenacyl azides (100). The optimized reaction employs piperidinium acetate as a base in methanol at 80 °C and accommodates a wide range of substrates bearing electron-donating and electron-withdrawing groups, affording the desired products in very good to excellent yields (Scheme 33). Mechanistic studies suggest that the reaction proceeds through a cascade sequence involving iminium ion formation (A), nucleophilic addition (B), 1,3-dipolar cycloaddition (D), thermal denitrogenation to form an aziridine intermediate (E), followed by ring opening (F) and aromatization to furnish the 3-ketoisoquinoline core. This methodology efficiently integrates Knoevenagel condensation, amination, and elimination steps in a single operation. Furthermore, the synthetic utility of the resulting heterocycles was demonstrated through their successful conversion into pharmacologically relevant derivatives, highlighting the potential of this metal-free protocol for sustainable and practical organic synthesis.

Scheme 33. Synthesis of 3-substituted isoquinolines by Prasad et al.¹⁰².

A series of multi-substituted 1-aminoisoquinoline derivatives (104) exhibiting dual-state fluorescence emission were synthesized by Zhang et al.¹⁰³via a metal-free, mild, and efficient reaction between a readily available 4H-pyran derivative (102) and secondary amines (103) (Scheme 34). The reaction likely proceeds via ring-opening of compound (102) through nucleophilic addition of compound (103), forming enol (A), which tautomerizes to ketone (B). Then, compound (103) acts as a base, promoting intramolecular nucleophilic attack of the active methylene on the ketone group in (B), yielding intermediate compound (C). Dehydration and aromatization of the intermediate compound (C) lead to the phenol compound (D). Hydrolysis of the enamine unit in (D) produces compound (E). Subsequent nucleophilic addition forms intermediate compound (F), which undergoes intramolecular cyclization and elimination to yield the final product (104). The resulting compounds not only demonstrate good yields but also show promising fluorescence properties in both solution and solid states.

Scheme 34. Synthesis of functionalised isoquinolines by Zhang et al.¹⁰³.

Synthesis of functionalized isoquinolines involving benzannulation of substituted pyridines has also been reported.^104,105 Although functionally these methods use expensive catalysts, executing the benzannulation through the pyridine precursor takes considerable effort. Beesu et al.¹⁰⁶ applying domino Michael- SNAr (Nucleophilic Aromatic Substitution) approach reported a novel, simple to execute, transition metal free, one pot method, that utilized the propensity of nitromethane as an iterative carbanion source, to react with o-halopyridinyl-ynones (105) for giving nitro isoquinoline derivatives (106) (Scheme 35). The proposed domino mechanism begins with a Michael addition of the nitromethane anion to compound (105), forming intermediate (A), which undergoes tautomerization to yield enone (B). The resulting carbanion from (B) then performs a nucleophilic aromatic substitution by displacing the aryl chloride, forming intermediate (C). Aromatization of (C) affords the final product (106).

Scheme 35. Synthesis of 5-OH-8-NO₂- isoquinolines by Beesu et al.¹⁰⁶.

In 2025, Song et al.¹⁰⁷ reported a green and efficient synthetic strategy for isoquinoline derivatives (109) and benzoxazole-containing amino acids based on fluorinated glycine derivatives (Scheme 36). The key intermediate, ethyl 3-bromo-2-((diphenyl methylene)-amino)-3,3-difluoropropanoate (107), was synthesized from glycine and shown to undergo transformation under alkaline conditions to form gem-difluoroalkene intermediates, which exhibit both amino acid and reactive gem-difluoroalkene properties. When reacted with 2-aminophenol, a benzoxazole-containing amino acid derivative was obtained through a simple, metal-free, and eco-friendly method. Interestingly, using aniline (108) as the nucleophile led to the unexpected formation of isoquinoline derivatives (109), especially when electron-donating substituents were present on the aniline ring. The yields varied based on the electronic nature of the substituents, with electron-donating groups enhancing product formation. This reaction platform is notable for its operational simplicity, reliance on easily accessible materials, and environmental compatibility, offering a novel route to fluorinated heterocyclic compounds and expanding the scope of gem-difluoroalkene-based amino acid chemistry.

Scheme 36. Synthesis of substituted isoquinolines by Song et al.¹⁰⁷.

Sharma et al.¹⁰⁸ reported a novel metal- and additive-free synthetic protocol for the efficient activation of nitriles towards nucleophilic addition and annulation under aqueous conditions, marking the first such report in this context (Scheme 37). This strategy offers a green, atom-economical, and scalable approach to synthesize a diverse range of aminated isoquinolines (111) with excellent regioselectivity and functional group tolerance. Utilizing 2-(2-oxo-2-aryl/alkylethyl)-benzonitriles (110) and a variety of primary and secondary amines, the method proceeds via a mechanism involving nucleophilic attack on the nitrile group, formation of an iminium intermediate (A), further intramolecular cyclization gives (B), benzylic deprotonation, and final aromatization yields the final product.

Scheme 37. Synthesis of 1-amino substituted isoquinolines by Sharma et al.¹⁰⁸.

A green and efficient metal-free method for synthesizing nitro-substituted isoquinoline-1,3-diones (113) has been developed by Ma et al.¹⁰⁹ using tert-butyl nitrite (tBuONO) as a safe and stable nitro source (Scheme 38). This represents the first use of tBuONO in such a transformation, showcasing advantages such as safety, mild reaction conditions, and simple operation. The optimized reaction conducted with N-methyl-N-methacryloyl benzamide (112) in MeCN, using DTBP as an additive under aerobic heating achieved excellent yields (up to 82%). Substrate scope analysis revealed that electron-donating groups on the aromatic ring were well tolerated, while electron-withdrawing groups hindered the reaction due to the sensitivity of the ˙NO₂ radical intermediate. The reaction also tolerated various N-substituents, though unprotected NH groups impeded cyclization. Under aerobic conditions, t-BuONO decomposes to form t-BuO˙ and NO˙ radicals. The NO˙ is further oxidized by trace O₂ and H₂O to generate NO₂˙, which was confirmed by TEMPO trapping and HRMS analysis. This NO₂˙ radical adds to the vinyl group of imide (112), forming intermediate (B) via a low-energy transition state. Intramolecular cyclization of (B) then yields intermediate (C). Finally, t-BuO˙ abstracts a hydrogen atom from C or promotes a redox-deprotonation sequence, delivering the final product (113). This method provides a sustainable and scalable route to valuable nitro-functionalized isoquinoline scaffolds, with strong potential for pharmaceutical and synthetic applications.

Scheme 38. Synthesis of isoquinolinones by Ma et al.¹⁰⁹.

Qin et al.¹¹⁰ reported an efficient metal-free, three-component reaction for the synthesis of sulfonylated indolo-[2,1-a]-isoquinolines (116) using 2-aryl-N-acryloyl indoles (114), aryldiazonium tetrafluoroborates (115), and DABCO˙(SO₂)₂ as a sulfur dioxide surrogate under mild conditions (Scheme 39). This cascade process involves sulfur dioxide insertion, radical addition, and intramolecular cyclization, delivering a variety of sulfonylated products in moderate to excellent yields. The proposed mechanism includes the generation of aryl radicals, formation of arylsulfonyl radicals via SO₂ insertion (B), radical addition to the indole substrate gives intermediate (C), and cyclization forming (D), followed by oxidation and proton abstraction to give the final product. The method offers a sustainable and practical approach to functionalized isoquinoline derivatives, with further biological studies in progress.

Scheme 39. Synthesis of fused isoquinolinones by Qin et al.¹¹⁰.

2.7. Metal-catalyzed methods

In 2019, Deshmukh et al.¹¹¹ reported a novel, efficient, and atom-economical method for the synthesis of isoquinolines (118) via cobalt-catalyzed annulation of azines (117) with alkynes through C–H and N–N bond activation (Scheme 40). The researchers have also reported similar Ru-based, microwave assisted method as previously included in Scheme 3. This protocol eliminates the need for external oxidants and silver salts, setting it apart from traditional approaches that often suffer from low atom economy and reliance on expensive rhodium catalysts or additives. By utilizing azines as both the directing and internal oxidizing groups, the method achieves full incorporation of both nitrogen atoms into the final isoquinoline products, thereby maximizing atom economy. Mechanistic studies suggest that the air-stable cobalt catalyst [Cp*Co(CO)I₂], complex undergoes decarbonylation in the presence of NaOAc to form the monocationic active species [CpCo(OAc)]⁺ (A). Initially, the nitrogen atom of ketazine (117) coordinates to the Cp*Co center, followed by ortho C–H bond activation and cyclometallation, forming a five-membered cobalt acycle (B). The π-bond of alkyne then coordinates to cobalt acycle (C), and subsequent insertion into the Co–C bond produces a seven-membered cobalt acyclic alkenyl intermediate (E). Regeneration of catalyst (A) occurs via acetate assistance, yielding intermediate (F). Complex (A) re-engages with intermediate (D), facilitating N–N bond cleavage and forming product (118) and complex (G). Next, acetate-promoted ortho C–H activation of arenes and cyclometallation forms a second five-membered cobalt acycle (H). Coordination and insertion of another molecule of alkyne into the Co–C bond of intermediate (I) produces a second seven-membered cobaltacycle (J). Finally, regeneration of catalytic species (A) from (J) completes the cycle, affording another molecule of product (118). The methodology shows broad substrate scope, good functional group tolerance, and scalability to gram-scale synthesis. In summary, this cobalt-catalyzed protocol offers a green, cost-effective, and highly atom-economic route to isoquinolines, addressing several limitations of existing metal-catalyzed annulation reactions.

Similarly, Nakkalwar et al.¹¹² reported that a green and efficient method has been developed for synthesizing 1-phenyl isoquinoline derivatives (120) via C–H/N–N functionalization of 1-(diphenylmethylene) hydrazine (119) and aryl-substituted alkynes (Scheme 41). The reaction employs [Ru(p-cymene)Cl₂]₂ as a recyclable homogeneous catalyst, with Cu(OAc)₂ and AgSbF₆ as oxidant and additive, respectively, in PEG-400 a biodegradable and eco-friendly solvent. Initially, the active Ru(ii) catalyst (complex A) is formed by the reaction of [Ru(p-cymene)Cl₂]₂ with AgSbF₆ and Cu(OAc)₂. This complex then undergoes cyclometalation with substrate (124) to form intermediate (B). Insertion of alkyne into (B) produces a seven-membered Ru-cyclic intermediate (C), which undergoes a proton transfer (assisted by acetic acid) to form (D). Finally, intramolecular substitution in (D) forms the C–N bond and cleaves the N–N bond, yielding isoquinoline (125) and regenerating the active Ru catalyst. This protocol offers advantages such as a simple extraction process, high atom economy, broad substrate scope, excellent yields, and a reusable catalytic system, making it a sustainable approach to isoquinoline synthesis.

Scheme 41. Synthesis of substituted isoquinoline by Nakkalwar et al.¹¹².

In 2017, Hu et al. reported a palladium-catalyzed tandem reaction of functionalized nitriles (121) with arylboronic acids (122) in water as an environmentally friendly and efficient strategy for the synthesis of aryl/alkyl substituted isoquinolines (123) (Scheme 42).¹¹³ This approach, utilizing substrates such as 2-(cyanomethyl)-benzonitriles or 2-(2-carbonylphenyl)-acetonitriles, demonstrates broad functional group tolerance and operates under mild conditions, with water serving as the green reaction medium. The use of organoboron reagents offers several advantages over traditional organolithium or Grignard reagents, including lower toxicity, greater stability, and compatibility with various functional groups. Mechanistic investigations reveal that the reaction proceeds primarily through carbopalladation of the C(sp³)-cyano group followed by intramolecular cyclization. Two potential mechanistic pathways have been proposed, involving sequential addition of aryl boronic acids and hydrolysis of the nitrile groups leading to imine intermediates (B/C) that undergo cyclization to furnish the isoquinoline framework (123). This metal-catalyzed tandem protocol not only avoids the limitations of previous methods requiring pre-functionalization or harsh reagents but also provides a versatile and scalable route to synthetically and pharmaceutically important isoquinoline derivatives. Ongoing studies aim to extend this catalytic system to the synthesis of other valuable nitrogen-containing heterocycles.

Scheme 42. Synthesis of aryl-substituted isoquinolines Hu et al.¹¹³.

3. Summary & discussion

A comprehensive evaluation of green synthetic methodologies for isoquinoline analogs construction reveals a fundamental shift toward environmentally responsible practices that directly address the major shortcomings of conventional synthetic strategies. Table 1 summarizes the array of green methods implemented in the synthesis of isoquinoline and its related scaffolds. The breadth of sustainable strategies—encompassing microwave and ultrasound-assisted reactions, visible light photoredox catalysis, nanocatalysis, and metal-free processes—demonstrates both the versatility of green chemistry and its ability to accommodate diverse substrates and reaction types. This review provides a critical analysis of recent developments in the green synthesis of isoquinoline and its derivatives, emphasizing not only the role of energy-efficient technologies—such as microwave, ultrasound, and visible light activation—but also the degree to which individual methods fulfil the twelve principles of Green Chemistry. For each protocol described (Table 1), we systematically annotate its green attributes, considering solvent choice, catalyst recoverability, the use of renewable feedstocks, atom economy, waste reduction, and scalability. This transparent, criterion-based approach allows clear differentiation between truly sustainable methods and those that only partially embody green chemistry principles, thereby informing the design and selection of future synthetic methodologies. Our findings indicate that the most promising approaches for sustainable isoquinoline synthesis are those integrating multiple green chemistry metrics, particularly through the employment of recyclable and non-toxic nanocatalysts (such as Fe₃O₄, CuO@NiO, KF/CP NPs) in environmentally benign solvents or under solvent-free conditions. Specifically, aqueous-phase nanocatalytic protocols (Table 1 entries 25–28) provide outstanding atom economy, high product yields, facile catalyst recovery, and minimal environmental impact, fulfilling several green principles including waste prevention, efficient catalysis, and the use of safe solvents. Conversely, methods that rely solely on non-traditional activation (e.g., microwaves, ultrasound, or photochemistry) are deemed genuinely green only when combined with non-hazardous solvents, minimal reagent excess, and catalyst reusability. Visible light photocatalytic methods employing organic dyes in benign solvents also compare favourably, especially when metals and hazardous solvents are avoided. It is important to note that traditional protocols utilizing solvents such as DMF, DMSO, MeCN, or benzene—despite sometimes offering rapid or high-yielding reactions—do not satisfy green chemistry requirements unless offset by compelling benefits such as high catalyst recyclability or superior atom economy. Furthermore, electrochemical and cascade/cyclization strategies (Table 1 entries 31–34) show promise as sustainable alternatives, provided that non-toxic solvents and electrode materials are employed. Throughout this analysis, both the strengths and weaknesses of individual methodologies (including issues of solvent selection, energy consumption, and byproduct formation) were addressed to provide a balanced perspective on the extent to which these methods fulfil the goals of green chemistry.

Table 1. Summary of green and sustainable methods for the synthesis of isoquinoline and isoquinoline scaffolds^a.

Sch. no.	Substrate	Product	Catalyst	Conditions	Time	Yield (upto)	Key point	Green chemistry aspects/limitations	Ref.
1			Pd(PPh3)4	HCOONa, DMF/H2O, 100 °C, MW	30 min	91%	Domino reaction, microwave assisted	Short time, oxidant free, scalable (6,9)	46
								Limitation: DMF is toxic
2			Fe3O4@SiO2@Cu-MOF-74	K3PO4, DMF, 150 °C, N2, MW	1 h	75%	Microwave assisted, recyclable catalyst	Reusable, broad scope (9,1)	50
								Limitation: Uses DMF, excess base
3			[Ru(p-cymene)Cl2]2	KPF6, PEG 400, 150 °C, MW	10 min	92%	Microwave assisted, Ru/PEG homogenous recyclable catalyst	Atom economy, green solvent, recyclable, scalable (2,5,9,1,6)	52
4			Fe(acac)2	TBHP, DBU, benzene, MW, 120 °C	30 min	91%	Oxidative cascade, microwave assisted	Benign iron catalysis, broad scope (9)	53
								Limitation: Benzene is hazardous, TBHP is strong oxidant
5			Cul	CS2CO3, 2,2′-biimidazole, MW	20 min	76%	Microwave assisted, one-pot	Inexpensive catalyst, improved yields, short time (9,6)	55
6			[(Rucl2 (p-cymene))2]	Cu(OAc)2, H2O NA2CO3, toulene, 100 °C	10 min	90%	Microwave assisted, domino C–C and C–N bond formation	Improved rates, mild conditions (6,5)	56
								Limitations: Use of toluene is toxic
7			Nafion NR50	HMDS, EtOH,MW 150 °C	30 min	95%	Microwave acidic catalyst, recyclable	Transition-metal free, better efficiency (3,9,5)	60
								Limitation: HDMS is not green
8			—	KF, DCE, 165–185 °C, MW	1–5 h	87%	Microwave assisted, one-pot	Broad substrate scope, mild conditions, better yields (6, 1)	61
								Limitation: DCE is hazardous solvent, high temperature
9			—	DBU, TBPB, 120 °C, MW	1 h	94%	Microwave assisted, metal free oxidative cyclization	High atom economy, high efficiency, broad substrate scope (3,2,6)	62
								Limitation: TBPB is not green
10			—	MW, 700 W	5 min	96%	Microwave assisted	Improved yield, short time, simple (6,1)	63
11			Cul	Cs2CO3, DMSO, 80 °C, N2, US	2–4 h	93%	Ultrasound assisted, one-pot, ligand-free	Mild, additive-free, efficient (1,6,9)	66
								Limitations: DMSO is better than DMF, but still not ideal
12			—	CH3NH2, PPh3, H2O, US, rt	1 h	89%	Ultrasound assisted, multi-component reaction	Cataylst free, short time, green media (9,5,6)	67
13			—	Oxone, EtOH, US	10–70 min	93%	Ultrasound assisted, high regio selectivity	Green oxidant, better yield, metal free (3,5,6)	68
14			—	BSA, MeOH, reflux	8 h	96%	Oxidant-free, Se-isoquinoline derivative	Green solvent, mild conditions, scalable (5,6,1,3)	71
15			Eosin Y	CHD, K2CO3, anh. DMF, ar, rt, green LED 535 nm	12 h	80%	Visble-light catalysis, N– N-centered radicals	Mild conditions, recyclable catalyst, metal-free (6,9,3)	75
								Limitation: DMF
16			—	White LEDs 50 W, HOAc	4 h	83%	Visible light cyclization, radical pathway	Catalyst free, mild (9,6)	76
17			DABCO	DMSO, N2, 40 °C, 18W, blue LED light	24 h	96%	Visible-light induced, cascade reaction	Metal-free, broad scope (3,9)	77
								Limitation: DMSO, long time
18			LAILs	EtOH, MeCN/DCE, 12W purple LED, rt	12 h	73%	Light mediated, metal-free, ionic lquid catalyst	Recyclable catalyst, high atom economy, scalability (9,5,6)	78
								Limitation: MeCN/DCE less green
19			Eosin B	Air, 24 W white LED, DMSO, 70 °C	24 h	75%	Light-mediated, radical cascade reaction	Metal free, additive free, cost effective, simple (3,6)	79
								Limitation: DMSO
20			—	(NH4)2S2O8, Na2CO3, 4CzIPN, blue LEDs 45W, DMSO, ar, rt	10 h	81%	Visible-light photoredox, radical pathway	Mild, scalable, versatile (1,2,6)	80
								Limitation: DMSO
21			Eosin B	(NH4)2S2O8, 10W blue LED, rt	15 h	84%	Visible-light photoredox, No metals/bases	Mild, broad substrate scope (6)	81
22			Photocatalyst: DCA, HAT catalyst: 3-Acetoxyquinuclidine	MeCN, 10W blue LEDs, N2, rt	30 h	70%	Visible-light assisted, HAT, EDA complex	Hydrogen gas by-product, atom economy, metal-free (2,3,6)	84
								Limitation: MeCN, long time
23			[Ir(dtbbpy)(ppy)2]PF6	DMA, blue LED, N2, rt	12 h	80%	Visible-light assisted, alkyl radical source	Mild, no oxidants/bases, metal free (6,3)	85
								Limitation: DMA
24			Cu2O@MHAM	Neat, 100 °C	2 h	95%	Nano-catalyst	Low E-factor, recyclable, high mass efficiency, neat (1,6,9)	90
25			Fe3O4-MNPs	H2O, 80 °C	2 h	87%	Nano-catalyst	Green synthesis, magnetic recovery (5,9,1)	91
26			KF/CP NPs	H2O, rt	3 h	95%	Nano-catalyst	Natural material, reusable (5,9,1,7)	92
27			KF/CP NPs	rt	3 h	95%	Nano-catalyst	Fast, recyclable, solvent-free (6,9,5)	93
28			KF/CP@MWCNTs NPs	H2O, rt	4 h	95%	Nano-catalyst	Easy recovery, high yield (5,9,1)	94
29			CuO@NiO	90 °C, ethylene glycol (EG)	1 h	92%	Nano-catalyst	Short time, recyclable, low leaching, base/additive-free (6,9)	95
								Limitation: EG is only semi green
30			Fe3O4-MNPs	NaOH, 80 °C	6 h	87%	Nano-catalyst	Atom economy, low loading, reusable (2,9)	96
31			—	Langlois reagent, C | Pt, N2, LiClO4, AcOH, MeCN/H2O	10 h	56%	Electrochemical, anodic oxidation	Mild, fluorinated, sustainable, metal-free (6,10,1)	100
								Limitation: Pt, MeCN
32			—	Langlois reagent, (+) GF | Pt (−), 3 mA, CF3SO3H, 80 °C, MeCN/H2O	6 h	87%	Electrochemical, undivided cell	Broad scope, no metals, no oxidants (3,6)	101
								Limitation: Pt, MeCN
33			—	Piperidinium acetate, MeOH	3 h	85%	Metal-free, one-pot	Cascade, broad scope (8,5,1)	102
34			—	MeCN, air, 90 °C	5 h	92%	Metal-free, ring-opening/closing	Dual-state fluorescence, mild (6,3)	103
								Limitation: MeCN
35			—	CH3NO2, K2CO3, DMSO, 110 °C	8 h	75%	Metal-free, domino Michael SNAr (nucleophilic aromatic substitution)	One-pot, nitromethane as a carbanion (1,8)	106
								Limitation: DMSO
36			—	KHCO3, THF, 100 °C, Ar	8 h	80%	Metal-free, gem-difluoroalkene intermediates	Simple, eco-friendly (6)	107
								THF is okay but not optimal
37			—	H2O, 100 °C	4 h	99%	Metal-free	Regioselective, scalable, no additives (1,3,5)	108
38			—	DTBP, MeCN. Air, 70 °C	12 h	82%	Metal-free	Safe, simple, radical cascade (3,6,10)	109
								Limitation: MeCN
39			—	MeCN, rt	12 h	95%	Metal-free, three-component, sulfoxide insertion	Mild reaction conidtion (6)	110
								Limitation: MeCN
40			[Cp*Co(CO)I2]	NaOAc, TFE, 110 °C	12 h	93%	Metal-catalyzed	Atom economy, scalable (2,1,9)	111
								Limitation: TFE
41			[Ru(p-cymene)Cl2]2 – Cu(Oac)2	AgSbF6, PEG 400, 110 °C, air	12 h	90%	Metal-catalyzed	High atom economy, green solvent, recyclable (2,5,9)	112
42			Pd(acac)2,bpy	TsOH-H2O, H2O, 80 °C	24 h	94%	Metal catalyzed, tandem reaction	Mild, broad tolerance (5)	113
								Limitation: Metal, long time

^aNumbers in parentheses indicates the reference of Green Chemistry Principles: 1 (Prevention – waste minimization), 2 (Atom economy), 3 and 4 (Less hazardous synthesis/products), 5 (Safer solvents/auxiliaries), 6 (Energy efficiency), 7 (Renewable feedstocks), 8 (Reduce unnecessary derivatization), 9 (Catalysis/recyclability), 10 (Design for degradation).

Several classical synthetic methods—particularly the Pomeranz-Fritsch, Bischler–Napieralski, and Pictet–Spengler reactions—remain foundational for the commercial and pharmaceutical preparation of isoquinoline derivatives due to their scalability, broad substrate tolerance, and robust yields. Notably, products from Scheme 1 can serve as key intermediates for the synthesis of lamellarin analogues; Scheme 2 highlights that cyclohexanone derivatives may be converted into 6-aminophenanthridines, which are used in anti-pyrin drugs; and Scheme 8 demonstrates that the F-product is a valuable precursor for synthesizing valiglurax (potential agent for the treatment of Parkinson's disease) analogues. Moreover, various fused isoquinoline derivatives have exhibited significant antioxidant, antimalarial, and antifungal activities, further underscoring their pharmaceutical relevance.

4. Conclusion

Recent advances in green synthetic chemistry have transformed the assembly of isoquinoline and its derivatives. Newer approaches—such as solvent-free reactions, microwave or ultrasound activation, photoredox and electrochemical strategies, biocatalysis, and continuous flow techniques using green media like water or ionic liquids—offer not only reduced environmental impact, but also superior yields, faster reactions, and improved selectivity. Critically evaluating the breadth, advantages, and limitations of these methods is essential for both research development and industrial application. Looking ahead, the advancement of sustainable isoquinoline and it's derivatives synthesis will depend on the strategic, case-specific integration of several green approaches rather than exclusive reliance on any single technique. Adopting such a flexible, holistic framework ensures that green chemistry concepts are effectively translated into economically sound and environmentally responsible synthesis for these important pharmaceutical targets.

Ultimately, the most effective and environmentally benign methods combine multiple green chemistry principles: employing recoverable, non-toxic catalysts; using sustainable solvents such as water, ethanol, or PEG 400 (or running solvent-free); and maximizing atom economy while minimizing waste and hazards. Methods that focus solely on alternative energy input (like microwaves or ultrasound) without concurrent improvements in reagents or solvent choices do not fully meet the criteria for greenness. Our analysis highlights nanocatalytic systems in water and ruthenium catalysis in PEG-400 as leading examples, offering optimal speed, scalability, catalyst recovery, and minimal environmental impact. Future research should focus on replacing hazardous solvents in photoredox and electrochemical protocols, as well as further minimizing waste and energy use.

Several classical synthetic methods—particularly the Pomeranz-Fritsch, Bischler–Napieralski, and Pictet–Spengler reactions—remain the foundation for commercial and pharmaceutical preparation of isoquinoline derivatives, due to their scalability, substrate tolerance, and robust yields. While modern green chemistry strategies and metal-catalyzed or photoredox methods continue to advance, their full adoption in industrial manufacture awaits further demonstration of cost-effectiveness, environmental benefit at scale, and regulatory approval.

We advocate that further method development should embrace comprehensive green chemistry metrics, including thorough reporting of environmental parameters such as E-factor, solvent recycling, and catalyst reusability. Such transparency will enable meaningful comparisons and guide the progression towards truly sustainable heterocyclic synthesis.

Conflicts of interest

There are no conflicts of interest to declare.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.