Metal-Free Synthesis of Pyrrolo[2,1-a]isoquinolines as a Versatile Platform for Type I Photodynamic Therapy and Thermally Activated Delayed Fluorescence Materials

Metal-Free Synthesis of Pyrrolo[2,1-a]isoquinolines as a Versatile Platform for Type I Photodynamic Therapy and Thermally Activated Delayed Fluorescence Materials | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 4 January 2026 V1 Latest version Share on Metal-Free Synthesis of Pyrrolo[2,1-a]isoquinolines as a Versatile Platform for Type I Photodynamic Therapy and Thermally Activated Delayed Fluorescence Materials Authors : Jianbo Hu , Meiyin Wu , Jingxin Guo , Xinyuan Liu , Lin Chen , Manjin Shi , Haoke Zhang , Anxin Wu 0000-0001-7673-210X , Xuemei Yang , and Kailu Zheng [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176751020.00670767/v1 242 views 131 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Herein, we report a metal-free, acid-promoted cascade cyclization reaction for the efficient synthesis of various pyrrolo[2,1- a ]isoquinolines in good to excellent yields under mild condition. This one-pot synthetic strategy features simple operation, a broad substrate scope, and scalability for large-scale preparation. The target molecules can serve as acceptor units to construct thermally activated delayed fluorescence (TADF) materials with aggregation-induced emission (AIE) properties, opening a new pathway for developing multifunctional organic luminescent materials. Notably, utilizing this strategy, we have developed two green fluorescent materials with good biocompatibility. Without the need for nanocarriers, these materials can efficiently endocytosed into the HeLa cells for bioimaging. Furthermore, upon light irradiation, this material generates significant reactive oxygen species and achieves photodynamic therapy of HeLa cells via a type I mechanism. Cite this paper: Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.202500XXX Metal-Free Synthesis of Pyrrolo[2,1- a ]isoquinolines as a Versatile Platform for Type I Photodynamic Therapy and Thermally Activated Delayed Fluorescence Materials Jianbo Hu, a,b Meiyin Wu, a,b Jingxin Guo, a,b Xinyuan Liu, a,b Lin Chen, a,b Manjin Shi, a,b Haoke Zhang, a Anxin Wu,* ,c Xuemei Yang,* b and Kailu Zheng* ,a,b a State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Dongguan Affiliated Hospital, Guangdong Medical University. Dongguan, 523710, P.R. China b Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, P.R. China c State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan, 523710, P.R. China Metal-free | Pyrrolo[2,1- a ]isoquinolines | Type I photosensitizer | Photodynamic therapy | Acceptor units | Thermally activated delayed fluorescence | Aggregation-induced emission Comprehensive Summary Herein, we report a metal-free, acid-promoted cascade cyclization reaction for the efficient synthesis of various pyrrolo[2,1- a ]isoquinolines in good to excellent yields under mild condition. This one-pot synthetic strategy features simple operation, a broad substrate scope, and scalability for large-scale preparation. The target molecules can serve as acceptor units to construct thermally activated delayed fluorescence (TADF) materials with aggregation-induced emission (AIE) properties, opening a new pathway for developing multifunctional organic luminescent materials. Notably, utilizing this strategy, we have developed two green fluorescent materials with good biocompatibility. Without the need for nanocarriers, these materials can efficiently endocytosed into the HeLa cells for bioimaging. Furthermore, upon light irradiation, this material generates significant reactive oxygen species and achieves photodynamic therapy of HeLa cells via a type I mechanism. Background and Originality Content The pyrrolo[2,1- a ]isoquinoline scaffold represents a privileged structural motif present in a wide range of bioactive natural products, [1] including crispine A and marine-derived lamellarin alkaloids. [2] This framework exhibits diverse pharmacological activities, such as antitumor effects, [3] reversal of multidrug resistance, [4] and antimicrobial properties. [5] Over the past decades, a variety of synthetic strategies have been developed for constructing the pyrrolo[2,1- a ]isoquinoline scaffold. [6] Among these, the 1,3-dipolar cycloaddition strategy has emerged as a particularly efficient approach, enabling assembly of the core framework with high stereoselectivity and regioselectivity. [7] However, current synthetic methodologies for pyrrolo[2,1- a ]isoquinolines predominantly depend on transition-metal catalysis, [8] photocatalysis, [9] or stoichiometric oxidants. [10] These approaches generally require pre-functionalized substrates and involve multi-step sequences, thereby constraining their overall efficiency and practical applicability. In line with the principles of green chemistry, the development of concise, metal-free, and environmentally benign synthetic routes to access this privileged scaffold remains a highly desirable goal. Scheme 1 (a) Representative bioactive alkaloids. (b) Previously reported [3+2] cycloaddition pathway. (c) Reaction design and practical utility in this work. Photodynamic therapy (PDT) represents a promising photochemical-based anticancer modality, offering excellent spatiotemporal controllability, minimal invasiveness, and inherent tissue selectivity. [11] Based on the photosensitizer’s reaction pathway, PDT mechanisms are classified into type I and type II. [12] In conventional type II PDT, photoexcited photosensitizers undergo intersystem crossing (ISC) from the singlet to the triplet state, followed by energy transfer to ground-state oxygen (³O₂) to generate highly cytotoxic singlet oxygen (¹O₂). [13] In contrast, type I PDT proceeds via an electron transfer pathway, wherein the excited triplet-state photosensitizer interacts directly with surrounding biomolecules to yield highly reactive radical species, including superoxide anion (·O₂⁻) and hydroxyl radical (·OH). [14] Under the hypoxic conditions typical of solid tumors, type I photodynamic mechanisms demonstrate superior therapeutic potential. [15] Thermally activated delayed fluorescence (TADF) materials are a class of purely organic emitters characterized by a minimal singlet–triplet energy gap (Δ E ST ). [16] They offer unique advantages such as low cost, high luminescence efficiency, structural stability, and rich excited-state processes, rendering them highly applicable in organic light-emitting diodes, [17] photocatalytic synthesis, [18] bioimaging, [19] biosensing, [20] and nanomedicine. [21] Most TADF materials used in biomedicine and sensing are designed based on donor–acceptor (D–A) molecular architecture. [22] However, the current repertoire of high-performance acceptor units—such as triazine, quinoxaline, and benzonitrile—remains limit. Developing novel acceptor units is essential to enrich the structural diversity of TADF molecular libraries and establish universal design strategies for advanced acceptor motifs. Herein, we report a transition-metal-free 1,3-dipolar cycloaddition strategy for efficiently synthesizing pyrrolo[2,1- a ]isoquinoline derivatives under mild conditions with air as the terminal oxidant. This method features high atom economy, a broad substrate scope, and practical scalability. The resulting compounds serve as versatile acceptor building blocks for constructing a series of TADF materials that exhibit aggregation-induced emission (AIE). Moreover, we have developed a biocompatible photosensitizer with intrinsic fluorescence, which demonstrates self-delivering cellular uptake without requiring nanocarriers and concurrently enables integrated cellular imaging and type I photodynamic therapy. Results and Discussion In pursuit of an efficient and concise one-pot synthesis of pyrrolo[2,1- a ]isoquinoline derivatives, we conducted a systematic screening of reaction parameters—including solvent, Brønsted acid identity and stoichiometry, and temperature (see the Supporting Information (SI), Table S1). The optimized conditions were established as follows: a mixture of α-bromophenylethanones 1a (1.0 equiv.), 1,2,3,4-tetrahydroisoquinoline (THIQ) 2a (1.0 equiv.), acrylonitrile 3a (1.0 equiv.), and AcOH (2.0 equiv.) in DMF was heated at 80 °C for 6 h. Under the optimized conditions, we proceeded to investigate the functional group tolerance of this transformation, and substrates bearing diverse substituents on the aromatic ring of α-bromophenylethanones were well tolerated in the reaction. As illustrated in Scheme 2, substrates with electron-donating groups (Me, i Pr, OMe, 3,4-OCH 2 O, SMe) on the phenyl ring underwent smooth conversion, affording the target products in good yields ( 4b–4g , 65%–78%). Halogen-substituted substrates were subsequently examined, meta - and para -substituted variants delivered satisfactory results ( 4i–4p , 54%–89%), whereas ortho -bromo substitution led to a diminished yield ( 4h , 25%), presumably due to steric constraints. Furthermore, substrates incorporating electron-withdrawing groups (NO₂, CN, OCF₃, CO₂Me) were also well tolerated, providing the target products 4q–4u in moderate to excellent yields (42%–83%). The scope was successfully extended to sterically hindered and heteroaromatic systems. Notably, thiophene-, pyridine-, benzofuran-, biphenyl-, and 2-naphthyl-functionalized substrates underwent efficient conversion, delivering products 4v–4z in excellent yields (75%–91%). ( E )-1-bromo-4-phenylbut-3-en-2-one was also compatible, furnishing the target product 4aa in 56% yield. However, the 1-(bromoadamantyl) ketone substrate failed to produce the desired product under the standard conditions. Scheme 2 Scope of α-bromophenylethanones a,b a Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol), AcOH (2.0 mmol), 80 °C, DMF (6 mL). b Isolated yields. Scheme 3 Scope of THIQs and electron-deficient alkene a,b a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), AcOH (2.0 mmol), 80 °C, DMF (6 mL). b Isolated yields. Subsequently, the substrate scope of THIQ derivatives was evaluate. As shown in Scheme 3, halogen substituents at various positions on the aromatic ring of THIQ demonstrated excellent reactivity ( 5a–5e , 70%–84%). THIQ derivatives bearing electron-donating (OMe) and electron-withdrawing (NO 2 ) substituents afforded the target products in 74% yields ( 5f–5g ). It is noteworthy that isoquinoline and β-carboline are also compatible with this transformation, providing the target product in moderate to good yields ( 5h–5m , 42%–83%). The structure of 5l was confirmed by X-ray crystallography (CCDC: 2505511; see the SI). Furthermore, the effect of different electron-deficient alkenes was investigated, including methyl, tert -butyl, and n -butyl substituted acrylates, ( E )-(2-nitrovinyl)benzene, ( E )-2-(2-nitrovinyl)thiophen, N -methylmaleimide, as well as coumarin and naphthoquinone derivatives. (Scheme 3). It is pleasing to observe that the products were successfully accessed for the substrates, and the desired products could be afforded in excellent yields ( 6a-6k , 72%-92%), further validating the broad scope and functional group tolerance of this methodology. Based on control experiments (Scheme S1) and literature precedents, [7-10][23] a plausible reaction mechanism has been proposed (Scheme S2). The process proceeds via acetic acid-promoted in situ generation of azomethine ylides from α-bromophenylethanones and THIQs, followed by a sequential 1,3-dipolar cycloaddition/aromatization cascade with electron-deficient alkenes to afforded the desired products. Scheme 4 Study on the practicability of reactions To demonstrate the practical utility of this synthetic strategy, we noted that compound 5k has been previously reported to exhibit significant antibacterial and antimalarial activities. [5] Building on this finding, we scaled up the synthesis of this compound, successfully obtaining the target product in 61% isolated yield on a gram scale (Scheme 4a). To our delight, the pyrrolo[2,1- a ]isoquinoline scaffold can serve as an electron acceptor unit for constructing thermally acti-vated delayed fluorescence (TADF) materials with aggregation-induced emission (AIE) properties. Halogen-substituted substrates ( 4j , 4l , 4n ) were functionalized with different electron donors—9 H -carbazole (Cz), 3,6-dimethoxy-9 H -carbazole (DMCz), 7 H -benzo[ c ]carbazole (BCz), phenothiazine (PTZ), and 9,9-dimethyl-9,10-dihydroacridine (DMAC)— via base-promoted nucleophilic substitution or palladium-catalyzed coupling reactions to afford the target compounds 7–12 . The synthetic route is illustrated in Scheme 4b and Scheme S3-S8. The UV-Vis absorption spectra and fluorescence spectra of these molecules in toluene are shown in Figure S2-3. All molecules exhibited distinct microsecond-scale long-lived luminescence (Figure 1), confirming their delayed fluorescence feature. The photophysical data are summarized in Table S3. Additionally, in the THF/H₂O mixed system, the variation in luminescence intensity with the water fraction ( f w ) indicates that all three molecules possess distinct AIE characteristics (Figure S4-5). Figure 1 Normalized transient fluorescence decay spectra of compounds 7-12 in toluene solution. To our surprise, the target compounds 5l and 5m , synthesized from α-bromophenylethanones, β-carboline, and ( E )-(2-nitrovinyl)benzene, exhibit distinct luminescent properties. The UV-Vis absorption and fluorescence spectra of both molecules in toluene solution are shown in Figure S6. To explore their potential biomedical applications, we first evaluated the biosafety of the compounds using mouse fibroblast (L929) cells via the cell counting kit-8 (CCK-8) assay (Figure 2a-b), and the results indicated excellent biocompatibility. We then performed confocal fluorescence imaging of HeLa cells incubated with 5l and 5m . As illustrated in Figure 2c-d, co-localization experiments with the nuclear dye Hoechst 33342 confirmed effective cellular internalization of both compounds, along with bright and stable green fluorescence emission. Figure 2 Cell viability of L929 cells with varying concentrations of (a) 5l and (b) 5m using CCK-8 working solution (n=3). Confocal fluorescence and merged images of HeLa cells with 25 μM of (c) 5l and (d) 5m in DMEM medium (excitation: 488 nm, emission: 550-600 nm). The nuclei were stained with Hoechst 33342 (excitation: 330 nm, emission: 430-450 nm, scale bar: 8 μm). We then investigated the reactive oxygen species (ROS) generation capability of these materials with the aim of developing them as theranostic fluorescent probes. First, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) was employed as a fluorescent indicator to assess ROS production under light irradiation. As shown in Figure 3a and Figure S7, the fluorescence intensity of DCFH-DA alone remained nearly unchanged under irradiation. In contrast, in the presence of 5m or 5l , a time-dependent increase in fluorescence intensity at 525 nm was observed, reaching over 500-folds enhancement compared to the probe control. This clearly demonstrates the remarkable ROS-generation capability of the compounds. We further utilized dihydrorhodamine 123 (DHR123 ), hydroxyphenyl fluorescein ( HPF ), and 9,10-anthracenediyl-bis(methylene)dimalonic acid ( ABDA ) as specific probes to detect superoxide anion O₂•⁻, hydroxyl radical •OH, and ¹O₂, respectively, with the commercial type II photosensitizer chlorin e6 (Ce6) serving as a control. As illustrated in Figure 3b-d and Figure S8-10, compounds 5l and 5m were demonstrated to efficiently generate superoxide anion (O₂•⁻) and hydroxyl radical (•OH) through a type-I photodynamic pathway upon photoactivation, while producing negligible singlet oxygen (¹O₂). Specifically, DHR123 and HPF assays revealed rapid fluorescence enhancement upon irradiation, indicating substantial formation of O₂•⁻ and an 11-fold increase in •OH generation, respectively. In contrast, ABDA degradation assays confirmed minimal ¹O₂ production. These findings establish compounds 5m and 5l as promising type-I photosensitizers, highlighting their strong potential for PDT applications. Encouraged by these results, we evaluated the cytotoxicity under both light and dark conditions using the CCK-8 assay in HeLa cells. To address the water solubility of the pure organic compounds, we prepared nanoparticle formulations (designated 5l NPs and 5m NPs ) using DSPE-PEG₂₀₀₀ and NH 2 -PEG-FA to improve biocompatibility. As shown in Figure 3e-f, both compounds showed negligible effects on cell viability in the dark. In contrast, light irradiation induced a concentration-dependent decrease in cell viability. At equivalent concentrations, 5l NPs and 5m NPs exhibited stronger photoinduced antitumor efficacy than the pure compounds (Figure S11), which can likely be attributed to enhanced cellular uptake. Figure 3 Changes in relative emission intensities of (a) DCFH-DA, (b) DHR 123 and (c) HPF in the three systems under laser irradiation (white light, 1 W cm −2 ). Plots of absorbance of (d) ABDA at 378 nm for photodegradation rate detection in the four systems. Cell viability of HeLa cells with varying concentrations of (e) 5l NPs, (f) 5m NPs using CCK-8 working solution (n=3) under non-irradiation and irradiation conditions (white light, 1 W cm −2 ). Conclusions In summary, this work establishes a metal-free strategy for synthesizing pyrrolo[2,1- a ]isoquinolines from readily available starting materials under mild conditions with broad substrate compatibility. The protocol demonstrates significant practical utility, enabling scalable one-step construction of antimicrobial frameworks in 61% yield. Furthermore, the resulting scaffold functions as an efficient electron-acceptor unit for high-performance AIE-TADF emitters and allows direct assembly of self-deliverable photosensitizers that integrate bioimaging with type-I photodynamic therapy. Future studies will expand the applications of this privileged heterocyclic architecture in pharmaceutical and materials science research. Experimental Gene ral procedure for the synthesis of products 4 A mixture of α-bromophenylethanones 1 (1.0 mmol, 1.0 equiv.), 1,2,3,4-tetrahydroisoquinolines 2 (1.0 mmol, 1.0 equiv.), electron-deficient alkenes 3 (1.0 mmol, 1.0 equiv.), AcOH (2.0 mmol, 2.0 equiv.) in N , N -dimethylformamide (DMF, 6.0 mL) was stirred at 80 °C for 6 h under air. Upon completion of the reaction, the solvent was evaporated un-der reduced pressure and the residue was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc = 10:1) to afford the desired products 4. Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.202500xxx. Acknowledgement Financial support from the National Natural Science Foundation of China (No. 22405062), the State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases Fund (SKL-HIDCA-2025-GD6), the Clinical & Basic Science Technology Innovation Project of Guangdong Medical University (GDMULCJC2025250), Funds for Ph.D. Researchers of Guangdong Medical University in 2025 (4SG25007G), and the Guangdong Medical University Undergraduate Innovation and Entrepreneurship Education Base Project (2JD24014, JDXM2024189). References 1. (a) Balewski, Ł.; Kornicka, A. Recent Advances in Synthetic Isoquinoline-Based Derivatives in Drug Design. Molecules 2025, 30 , 4760. (b) Li, Q.; Han, L.; Zhou, H.; Hou, J.; Shi, X. Advances in Synthetic Strategies for Indolo[2,1- a ]isoquinoline Derivatives. Adv. Synth. Catal . 2025, 367 , e202500035. 2. (a) Mohan, C.; Krishna, R. B.; Sivanandan, S. T.; Ibnusaud, I. Synthesis of Pyrrolo[2,1- a ]isoquinoline Class of Natural Product Crispine A. Eur. J. Org. Chem . 2021 , 4911-4926. (b) Wei, M.; Chen, J.; Song, Y.; Monserrat, J.-P.; Zhang, Y.; Shen, L. Progress on Synthesis and Structure-Activity Relationships of Lamellarins over the Past Decade. Eur. J. Med. Chem . 2024 , 269 , 116294. (c) Sivaganesan, P.; VL, S.; Sahoo, A.; Elanchezhian, C.; Nataraj, G.; Chaudhuri, S. A Comprehensive Review of Synthetic Approaches Toward Lamellarin D and its Analogous. ChemistrySelect 2024, 9 , e202403112. 3. García Maza, L. J.; Salgado, A. M.; Kouznetsov, V. V.; Meléndez, C. M. Pyrrolo[2,1- a ]isoquinoline Scaffolds for Developing Anti-cancer Agents. RSC Adv. 2024, 14 , 1710-1728. 4. Salehian, F.; Nadri, H.; Jalili-Baleh, L.; Youseftabar-Miri, L.; Bukhari, S. N. A.; Foroumadi, A.; Küçükkilinç, T. T.; Sharifzadeh, M.; Khoobi, M. A Review: Biologically Active 3,4-Heterocycle-Fused Coumarins. Eur. J. Med. Chem . 2021 , 212 , 113034. 5. Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira, R.; Sahu, K. B.; Paira, P.; Ghosh, S.; Sinha, C. Amberlite–IRA-402 (OH) ion Exchange Resin Mediated Synthesis of Indolizines, Pyrrolo[1,2- a ]quinolines and Isoquinolines: Antibacterial and Antifungal Evaluation of the Products. Eur. J. Med. Chem . 2011 , 46 , 2132-2140. 6. (a) Zheng, K.-L; You, M.-Q.; Shu, W.-M.; Wu, Y.-D.; Wu, A.-X. Acid-Mediated Intermolecular [3 + 2] Cycloaddition toward Pyrrolo[2,1- a ]isoquinolines: Total Synthesis of the Lamellarin Core and Lamellarin G Trimethyl Ether. Org. Lett. 2017, 19 , 2262-2265. (b) Zheng, K.-L; Zhuang, S.-Y; Shu, W.-M; Wu, Y.-D; Yang, C.-L; Wu, A.-X. Molecular Iodine-mediated Formal [2+1+1+1] Cycloaddition Access to Pyrrolo[2,1- a ]isoquinolines with DMSO as The Methylene Source. Chem. Commun. 2018, 54 , 11897-11900. (c) Ghosh, A.; Kolle, S.; Barak, D. S.; Kant, R.; Batra, S. Multicomponent Reaction for the Synthesis of 5,6-Dihydropyrrolo[2,1- a ]isoquinolines. ACS Omega 2019, 4 , 20854-20867. (d) Cui, H.-L. Recent Progress in the Synthesis of Pyrrolo[2,1- a ]isoquinolines. Org. Biomol. Chem. 2022, 20 , 2779-2801. (e) Zhuang, S.-Y.; Liu, J.-Y.; Guo, H.; Tang, Y.-X.; Chen, X.-L.; Ma, J.-T.; Wu, Y.-D.; Wu, A.-X.; Zheng, K.-L. I 2 -DMSO Mediated Multicomponent [3+2] Annulation Reaction: An Approach to Pyrrolo[2,1- a ]isoquinoline Derivatives with a Quaternary Center. Org. Lett. 2022, 24 , 8573-8577. (f) Jin, Z.; Shen, G.; Lv, X. Recent Advances in Domino Synthesis of Fused Polycyclic N-Heterocycles Based on Intramolecular Alkyne Hydroamination under Copper Catalysis. Chin. J. Chem . 2023, 41 , 3751-3771. (g) Bera, S.; Maji, A.; Patra, S.; Mahanty, D. S.; Samanta, S.; Samanta, S. K.; Biswas, B.; Patra, P. Recent Advances in the Synthesis of Chromenone Fused Pyrrolo[2,1- a ]isoquinoline Derivatives. New J. Chem . 2023, 47 , 22246-22268. (h) Shang, Z. H.; Zhang, X. Jin.; Li, Y. M.; Wu, R. X.; Zhang, H. R.; Qin, L. Y.; Ni, Xue.; Yan, Y.; Wu, A. X.; Zhu, Y. P. One-Pot Synthesis of Chromone-Fused Pyrrolo[2,1- a ]isoquinolines and Indolizino[8,7- b ]indoles: Iodine-Promoted Oxidative [2 + 2 + 1] Annulation of O -Acetylphenoxyacrylates with Tetrahydroisoquinolines and Noreleagnines. J. Org. Chem . 2021 , 86 , 15733-15742. 7. (a) Xi, W.; Zhang, Y.; Wu, H.; Li, J.; Wang, Y.; Yang, J.; Wang, Z.; Yao, W. Synthesis of Fluorinated Pyrrolo[2,1- a ]isoquinolines through Decarboxylative/Dehydrofluorinative [3 + 2] Cycloaddition Aromatization of Isoquinolinium N -Ylides with Difluoroenoxysilanes. Org. Lett . 2023, 25 , 4908-4912. (b) Osipov, D. V.; Demidov, M. R.; Artemenko, A. A.; Rashchepkina, D. A.; Krasnikov, P. E.; Osyanin, V. A. Cascade Synthesis of Pyrrolo[1,2- a ]quinolines and Pyrrolo[2,1- a ]isoquinolines via Formal [3 + 2]-Cycloaddition of Push–Pull Nitro Heterocycles with Carbonyl-Stabilized Quinolinium/Isoquinolinium Ylides. J. Org. Chem . 2024, 89 , 9816-9829. (c) Tang, Q.; Liu, Y.; Fei, B.; Tao, Q.; Wang, C.; Jiang, X.; He, X.; Shang, Y. Base-Mediated Cascade Lactonization/1,3-Dipolar Cycloaddition Pathway for the One-Pot Assembly of Coumarin-Functionalized Pyrrolo[2,1- a ]isoquinolines. J. Org. Chem . 2024, 89 , 8420-8434. 8. (a) Wu, L.; Sun, J.; Yan, C. Efficient Synthesis of Pyrrolo[2,1- a ]isoquinoline and Pyrrolo[1,2- a ]quinoline Derivatives via One-Pot Two-Step Metal-Catalyzed Three-Component Reactions. Chin. J. Chem . 2012, 30 , 590-596. (b) Chen, X.-H.; Pan, Y.-Y.; Wang, W.-X.; Cui, H.-L. Iron-Catalyzed Synthesis of Pyrrolo[2,1- a ]isoquinolines via 1,3-Dipolar Cycloaddition/Elimination/Aromatization Cascade and Modifications. Synlett 2022, 33 , 1645-1654. (c) Huang, J.; Li, C.; Li, X.; Li, G.; Yang, Z.; Yu, Y.; Xie, Y.; Huang, H.; Yu, F.; He, Z. Recent Advances in the Development of Indolizine Scaffolds: Synthetic Methodology and Mechanistic Insights. Chin. J. Chem . 2025, 43 , 315-348. (d) Cui, H.-L.; Chen, X.-H. Synthesis of Pyrrolo[2,1- a ]isoquinolines through Cu-Catalyzed Condensation/Addition/Oxidation/Cyclization Cascade. J. Org. Chem . 2022, 87 , 15435-15447. (e) Li, Y.-G.; Lu, J.-C.; Wang, M.-C.; Wu, B.; She, S.-K.; Wu, X. Pd/C-Catalyzed Dehydrogenative [3 + 2] Cycloaddition for the Synthesis of Dihydropyrrolo[2,1- a ]isoquinolines. J. Org. Chem . 2025, 90 , 7995-7999. 9. (a) Yu, D.; Liu, Y.; Che, C.-M. Tungsten Catalysed Decarboxylative [3 + 2] Cycloaddition Aromatization: One-Pot Synthesis of Trifluoromethyl-Pyrrolo[2,1- a ]isoquinolines with Visible Light Irradiation. Org. Chem. Front. 2022, 9 , 2779-2785. (b) Wen, Y.; Jin, H.-X.; Qiu, Y.-H.; Zong, Y.; Luo, W.; Chen, Z.; Yu, D., Photo-Induced Tungsten-Catalyzed Cascade Synthesis of Pyrrolo[2,1- a ]isoquinoline-1,3-dicarboxylate and Its Reaction Mechanism. Chem. Commun . 2024, 60 , 4573-4576. (c) Yi, Z.-Q.; Zhang, W.; Yi, B.; Liu, C.; Xie, Y.; Li, M.; Xiong, Y.; Wu, W.; Tan, J.-P. Stereoselective Synthesis of Biology-Oriented Pentacyclic Pyrrolo[2,1- a ]isoquinoline Scaffolds by Photoredox-Induced Radical Annulations. Org. Lett . 2025, 27 , 2197-2202. 10. (a) Xu, Y.-W.; Wang, J.; Wang, G.; Zhen, L. Diethyl Azodicarboxylate-Promoted Oxidative [3 + 2] Cycloaddition for the Synthesis of Pyrrolo[2,1- a ]isoquinolines. J. Org. Chem . 2021, 86 , 91-102. (b) Zhang, B.-H.; Hou, K.-L.; Li, R.-Z.; Qiu, F.-F.; Liu, G.-G.; Wei, Z.-Q.; Bao, W.; Zhang, Y.; Zhu, D.-Y.; Wang, S.-H. A One-Pot Synthesis of Substituted Pyrrolo[2,1- a ]isoquinolines via an Oxidation/Annulation Sequence of 2-(3,4-Dihydroisoquinolin-2(1 H )-yl)malononitriles. J. Org. Chem . 2025, 90 , 7134-7144. 11. (a) Gao, F.; Liu, Y.; Zhu, L.; Zhang, J.; Chang, Y.; Gao, W.; Ma, G.; Ma, X.; Guo, Y. An Intelligent Triple Assisted Gold Cluster-Based Nanosystem for Enhanced Tumor Photodynamic Therapy. Chin. J. Chem . 2025, 43 , 175-183. (b) Cao, Y.; Qian, X.; Shi, M.; Sun, X.; Zou, J.; Chen, X. Tactics to Improve the Photodynamic Therapeutic Efficacy Based on Nanomaterials. Chin. J. Chem . 2025, 43 , 1731-1755. (c) Yuan, X.; Zhou, J.-L.; Yuan, L.; Fan, J.; Yoon, J.; Zhang, X.-B.; Peng, X.; Tan, W. Phototherapy: Progress, Challenges, and Opportunities. Sci. China Chem . 2025, 68 , 826-865. 12. (a) Liu, S.; Wang, B.; Yu, Y.; Liu, Y.; Zhuang, Z.; Zhao, Z.; Feng, G.; Qin, A.; Tang, B. Z. Cationization-Enhanced Type I and Type II ROS Generation for Photodynamic Treatment of Drug-Resistant Bacteria. ACS Nano 2022, 16 , 9130-9141. (b) Wang, H.; Guo, S.; Yuan, Q.; Li, M.; Tang, Y. Cationic Conjugated Oligomers for Efficient and Rapid Antibacterial Photodynamic Therapy via Both Type I and Type II Pathways. Chin. J. Chem . 2024, 42 , 61-66. 13. Li, X.; Lee, S.; Yoon, J. Supramolecular Photosensitizers Rejuvenate Photodynamic Therapy. Chem. Soc. Rev . 2018, 47 , 1174-1188. 14. (a) Teng, K.-X.; Chen, W.-K.; Niu, L.-Y.; Fang, W.-H.; Cui, G.; Yang, Q.-Z. BODIPY-Based Photodynamic Agents for Exclusively Generating Superoxide Radical over Singlet Oxygen. Angew. Chem. Int. Ed . 2021, 60 , 19912-19920. (b) Dai, J.; Fang, L.; Fan, Z.; Wang, X.; Hua, J.; Dong, H.; Tu, Y.; Li, S.; He, K.; Fang, J.; Hang, L.; Li, S.; Wang, J.; Wang, W.; Ma, P. a.; Jiang, G. Triphenylamine-Substituted Nile Red Derivatives with Efficient Reactive Oxygen Species Generation for Robust and Broad-Spectrum Antimicrobial Photodynamic Therapy and Abscess Wound Healing. Adv. Funct. Mater . 2025, 35 , 2421072. 15. (a) Wang, Y.-Y.; Liu, Y.-C.; Sun, H.; Guo, D.-S., Type I Photodynamic Therapy by Organic–Inorganic Hybrid Materials: From Strategies to Applications. Coord. Chem. Rev . 2019, 395 , 46-62. (b) Zhang, W.; Kang, M.; Li, X.; Pan, Y.; Li, Z.; Zhang, Y.; Liao, C.; Xu, G.; Zhang, Z.; Tang, B. Z.; Xu, Z.; Wang, D. Fiber Optic-Mediated Type I Photodynamic Therapy of Brain Glioblastoma Based on an Aggregation-Induced Emission Photosensitizer. Adv. Mater . 2024, 36 , 2410142. 16. (a) Yang, H.-Y.; Zhang, M.; Zhao, J.-W.; Pu, C.-P.; Lin, H.; Tao, S.-L.; Zheng, C.-J.; Zhang, X.-H. Improving Efficiency of Red Thermally Activated Delayed Fluorescence Emitter by Introducing Quasi-Degenerate Orbital Distribution. Chin. J. Chem . 2022, 40 , 911-917. (b) Huang, R.; Yang, Z.; Chen, H.; Liu, H.; Tang, B. Z.; Zhao, Z. Sky-Blue Aggregation-Induced Delayed Fluorescence Luminogens with High Horizontal Dipole Orientation for Efficient Organic Light-Emitting Diodes. Chin. J. Chem . 2023, 41 , 527-534. (c) Ni, F.; Huang, Y.; Qiu, L.; Yang, C., Synthetic Progress of Organic Thermally Activated Delayed Fluorescence Emitters via C–H Activation and Functionalization. Chem. Soc. Rev ., 2024 , 53 , 5904-5955. 17. (a) Qu, Y.-K.; Zheng, Q.; Fan, J.; Liao, L.-S.; Jiang, Z.-Q. Spiro Compounds for Organic Light-Emitting Diodes. Acc. Mater. Res. 2021, 2 , 1261-1271. (b) Yuan, W.; Hu, W.; Wang, J.; Zhu, M.; Shi, C.; Sun, N.; Tao, Y. Fine Tuning of Donor-Acceptor Structures in Fused-Carbazole Containing Thermally Activated Delayed Fluorescence Materials towards High-Efficiency OLEDs. Chin. J. Chem . 2023, 41 , 1829-1835. (c) Liao, S.; Zhang, Z.; Gao, Y.; Chen, Z.; Miao, J.; Zou, Y.; Yang, C. Donor Engineering in TADF Emitters with Hybrid Short-Range and Long-Range Charge-Transfer Excitations toward High-Performance Electroluminescence. Chin. J. Chem . 2025 , doi: 10.1002/cjoc.70363. 18. Bryden, M. A.; Zysman-Colman, E. Organic Thermally Activated Delayed Fluorescence (TADF) Compounds Used in Photocatalysis. Chem. Soc. Rev . 2021, 50 , 7587-7680. 19. Barman, D.; Rajamalli, P.; Bidkar, A. P.; Sarmah, T.; Ghosh, S. S.; Zysman-Colman, E.; Iyer, P. K. Modulation of Donor in Purely Organic Triplet Harvesting AIE-TADF Photosensitizer for Image-Guided Photodynamic Therapy. Small 2025, 21 , 2409533. 20. Diniz, A. M.; Crucho, C. I. C.; Ruedas-Rama, M. J.; Orte, A.; Dias, C. J.; Outis, M.; Pinto, S. N.; Faustino, M. A. F.; Berberan-Santos, M. N.; Avó, J. TADF-Emitting Nanoparticles for Application as Probes in Time-Resolved Imaging and 1 O 2 Photosensitizers. Adv. Opt. Mater . 2025, 13 , 2402063. 21. Chen, W.; Song, F. Thermally Activated Delayed Fluorescence Molecules and Their New Applications Aside from OLEDs. Chin. Chem. Lett . 2019, 30, 1717-1730. 22. (a) Ni, F.; Li, N.; Zhan, L.; Yang, C. Organic Thermally Activated Delayed Fluorescence Materials for Time-Resolved Luminescence Imaging and Sensing. Adv. Opt. Mater . 2020, 8 , 1902187. (b) Fang, F.; Zhu, L.; Li, M.; Song, Y.; Sun, M.; Zhao, D.; Zhang, J. Thermally Activated Delayed Fluorescence Material: An Emerging Class of Metal-Free Luminophores for Biomedical Applications. Adv. Sci . 2021, 8 , 2102970. 23. Tang, Y.-X.; Ma, J.; Wang, L.-S.; Song, Y.-M.; Wu, C.-Y.; Wu, Y.-D.; Xiang, J.-C.; Wu, A.-X. Unlocking Oxidative Cross-Coupling between Four Nucleophiles: Synthesis of Spiropyrrolo[2,1- a ]isoquinolines. Org. Lett . 2025, doi: 10.1021/acs.orglett.5c04423. Manuscript received: XXXX, 2025 Manuscript revised: XXXX, 2025 Manuscript accepted: XXXX, 2025 Version of record online: XXXX, 2025 Left to Right: (Top) Jianbo Hu, Meiyin Wu, Jingxin Guo, Xinyuan Liu, Lin Chen, Manjin Shi, Haoke Zhang, Anxin Wu, Xuemei Yang, and Kailu Zheng Entry for the Table of Contents A metal-free, acid-promoted cascade cyclization has been developed for the efficient synthesis of pyrrolo[2,1- a ]isoquinolines. This scalable one-pot strategy features broad substrate scope and operational simplicity, with the resulting products serving as acceptors for constructing AIE-active TADF materials. This approach enables the development of green-emissive bioprobes that exhibit good biocompatibility, can be directly endocytosed for bioimaging, and achieve type-I photodynamic therapy in HeLa cells upon irradiation. Information & Authors Information Version history V1 Version 1 04 January 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords 1-a]isoquinolines aggregation-induced emission metal-free photodynamic therapy pyrrolo[2 thermally activated delayed fluorescence type i photosensitizer Authors Affiliations Jianbo Hu The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Meiyin Wu The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Jingxin Guo The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Xinyuan Liu The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Lin Chen The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Manjin Shi The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Haoke Zhang The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Anxin Wu 0000-0001-7673-210X Central China Normal University School of Chemistry View all articles by this author Xuemei Yang Guangdong Medical University School of Pharmacy View all articles by this author Kailu Zheng [email protected] The First Dongguan Affiliated Hospital of Guangdong Medical University View all articles by this author Metrics & Citations Metrics Article Usage 242 views 131 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Jianbo Hu, Meiyin Wu, Jingxin Guo, et al. Metal-Free Synthesis of Pyrrolo[2,1-a]isoquinolines as a Versatile Platform for Type I Photodynamic Therapy and Thermally Activated Delayed Fluorescence Materials. Authorea . 04 January 2026. DOI: https://doi.org/10.22541/au.176751020.00670767/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.176751020.00670767/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9fe0a9ff3953e2c5',t:'MTc3OTE2ODE0OA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();