Green Synthesis of Quinazolinone Scaffolds from the Cascade Reaction of o-Aminobenzamides/o-Aminobenzonitrile and Calcium Carbide mediated by K2S

Green Synthesis of Quinazolinone Scaffolds from the Cascade Reaction of o-Aminobenzamides/o-Aminobenzonitrile and Calcium Carbide mediated by K2S | 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 Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed.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. 23 September 2025 V2 Latest version Share on Green Synthesis of Quinazolinone Scaffolds from the Cascade Reaction of o-Aminobenzamides/o-Aminobenzonitrile and Calcium Carbide mediated by K2S Authors : Shuyi Li 0009-0009-5053-1946 , Yunzhe Du , Ligang Yan , Siliu Cheng , Shuang Cao , Ruijun Xie , Limin Han , and Ning Zhu 0000-0002-7535-1310 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175826891.12252406/v2 179 views 841 downloads Contents Abstract Introduction Results and Discussion Conclusions Acknowledgement Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract An efficient multicomponent methodology has been developed for the synthesis of quinazolinones and dihydroquinazolinones through the reaction of o-aminobenzamides or o-aminobenzonitriles with CaC 2 mediated by K 2 S. The process begins with the formation of thioacetaldehyde, which results from the direct nucleophilic attack of sulfur anions on the acetylene generated from CaC 2 . Subsequently, the thioacetaldehyde reacts with o-aminobenzamides to produce an imine intermediate, which then undergoes cyclization to generate the target compound in moderate to excellent yields. Moreover, this methodology has been extended to a one-pot synthesis of dihydroquinazolinone using 2-aminobenzonitrile and CaC 2 . In this approach, the nitrile group is hydrolyzed to form an amide, and then reacts with CaC 2 to yield the target product. Notably, this protocol exhibits excellent scalability and has been successfully applied to sythesize pharmaceutical compounds or drug intermediates. By using cost-effective and eco-friendly reagents such as CaC 2 and inorganic sulfides, this strategy provides a valuable and sustainable alternative to existing methods for the synthesis of quinazolinones. Green Synthesis of Quinazolinone Scaffolds from the Cascade Reaction of o-Aminobenzamides/o-Aminobenzonitrile and Calcium Carbide mediated by K2S Shuyi Li, a Yunzhe Du, a Ligang Yan, a Siliu Cheng, a Shuang Cao, a Ruijun Xie, a Limin Han* ab and Ning Zhu* a a College of Chemical Engineering, Inner Mongolia University of Technology, Inner Mongolia Engineering Research Center for CO 2 Capture and Utilization, and Key Laboratory of CO 2 Resource Utilization at Universities of Inner Mongolia Autonomous Region, Aimin street 49, Xincheng District, Hohhot 010051, China; b Inner Mongolia Vocational College of Chemical Engineering, Higher vocational college park, Saihan District, Hohhot, 010070, China Quinazolinones, Dihydroquinazolinones, Calcium carbide, Sulfur anions, One-pot synthesis, Quasi-Kucherov reaction Abstract An efficient multicomponent methodology has been developed for the synthesis of quinazolinones and dihydroquinazolinones through the reaction of o-aminobenzamides or o-aminobenzonitriles with CaC₂ mediated by K₂S. The process begins with the formation of thioacetaldehyde, which results from the direct nucleophilic attack of sulfur anions on the acetylene generated from CaC₂. Subsequently, the thioacetaldehyde reacts with o-aminobenzamides to produce an imine intermediate, which then undergoes cyclization to generate the target compound in moderate to excellent yields. Moreover, this methodology has been extended to a one-pot synthesis of dihydroquinazolinone using 2-aminobenzonitrile and CaC₂. In this approach, the nitrile group is hydrolyzed to form an amide, and then reacts with CaC₂ to yield the target product. Notably, this protocol exhibits excellent scalability and has been successfully applied to sythesize pharmaceutical compounds or drug intermediates. By using cost-effective and eco-friendly reagents such as CaC₂ and inorganic sulfides, this strategy provides a valuable and sustainable alternative to existing methods for the synthesis of quinazolinones. Introduction Quinazolinone and dihydroquinazolinone derivatives, commonly found in natural alkaloids and synthetic pharmaceuticals (e.g., Arborine, Quinethazone, Metolazone, and Methaqualone), exhibit diverse biological activities (Figure 1). 1 Consequently, there has been considerable interest in developing straightforward methods for assembling the N-heterocyclic core of quinazolinones. 2 Traditional strategies typically involve the reaction of o-substituted anilines (such as o-aminobenzamide and 2-aminobenzonitrile) with aldehydes or alcohols through aldol condensation, facilitated by alkali, transition metals (such as Pd, Au, Ni, Cu, Zn, Co, Bi, etc.), 3 photoexcitation, 4 or metal-organic frameworks (MOFs) (Scheme 1.1, a). 5 Moreover, the addition reaction of terminal alkynes with o-aminobenzamide, catalyzed by Au + , Pt 2+ , and Cu + has also drawn attention due to its high atomic economy (Scheme 1.1, b). 6 Despite these advancements, there is a strong demand for the development of a transition metal-free, cost-effective, and sustainable method for constructing quinazolinone rings from inexpensive industrial raw materials. Figure 1 Natural product and drugs containing quinazolinone scaffolds Calcium carbide (CaC₂), an economical industrial raw material, has been widely used for the production of acetylene, which can be further converted into acetaldehyde through the Kucherov reaction. 7 However, the traditional Kucherov reaction relies on mercury-based catalysts to polarize the alkyne group and enhance electrophilicity, posing significant environmental concerns. Thus, the development of a metal-free alternative is necessity from a green chemistry perspective. Theoretically, a highly nucleophilic reagent has the potential to directly attack the alkynyl group without transition-metal catalysis. In this regard, sulfur anions, known for their strong nucleophilicity, safety, and accessibility, emerge as a promising option. 8 For example, thioamides can be synthesized from sulfur, alkynes, and amines in the absence of metal catalysts, 9 and the C=N bond in 2-methylbenzothiazole can be constructed from CaC₂ and o-amino disulfide via the mediation of the trisulfur radical anion (Scheme 1.2). 10 Based on these precedents, we hypothesize that inorganic sulfide salts (e.g., K₂S, Na₂S, and NaHS) can directly conduct a nucleophilic attack on alkynes to form vinyl thiol intermediates, which then tautomerize to thioacetaldehyde. This reactive species can subsequently engage in an annulation cascade reaction with o-aminobenzamide, integrating the quasi-Kucherov reaction and aldol condensation into a one-pot process to construct dihydroquinazolinone, presenting a more atom- and step- economical strategy. Furthermore, we extended this approach to enable one-pot synthesis of dihydroquinazolinone starting from 2-aminobenzonitrile, CaC₂, and H₂O by incorporating nitrile hydrolysis and the annulation cascade reaction into a one-pot tandem reaction, which demonstrate superior atom and step economy. The corresponding quinazolinones were additionally obtained through in-situ oxidation of dihydroquinazolinones using KMnO₄ at room temperature (Scheme 1.3). Herein, we developed a one-pot strategy for selective synthesizing dihydroquinazolinones or quinazolinones from CaC₂ and o-aminobenzamides or 2-aminobenzonitrile, mediated by inorganic sulfide salts. This approach simplifies the reaction process, enhances efficiency, and improves sustainability, offering a promising route for synthesizing biologically relevant heterocycles. Scheme 1 Previous works and our strategy for the synthesis of quinazolinone scaffolds Results and Discussion To elucidate the reaction conditions and mechanism for the K 2 S-mediated synthesis of dihydroquinazolinones from CaC₂ and o-aminobenzonitrile, the preparation of 2-methyl-2,3-dihydroquinazolin-4(1H)-one 3a using 2-aminobenzamide 1a and CaC₂ was initially optimized. The yield of the target product was significantly influenced by the quantity of water added. Insufficient water hindered the complete dissociation of CaC₂, while an excess of water led to rapid hydrolysis of CaC₂ and facilitated the escape of acetylene from the reaction solution (Table S1, Entries 1-5). Additionally, the optimal yield of 3a was achieved after 1a reacted with CaC₂ for 5 h (Table S1, Entries 6-9). It was also observed that even without KOH, 3a was still obtained with a 42% yield, which could be attributed to the inherent alkalinity of Ca(OH) 2 generated from the hydrolysis of CaC 2 . Nevertheless, excessive KOH may hydrolyze the amide to form carboxylic acid, thus reducing the yield of the target product (Table 1, Entries 1-3). 11 In this reaction system, strong base (eg: KOH, KOtBu, and NaOH) outperformed weak base (eg: Et 3 N and CH 3 COONa) (Table S1, Entries 14-17). Notably, the reaction was completely inhibited in the absence of K₂S, highlighting its essential role (Table 1, Entry 4). A positive correlation was observed between the reaction rate and the K₂S concentration (Table S1, Entries 18-19). Substituting K₂S with NaHS also afforded 3a with good efficiency, whereas elemental sulfur showed poor performance due to its weak nucleophilicity (Table 1, Entries 5-6). Solvent screening revealed that moderate yields were achieved in DMSO or DMF, while CH₃CN performed poorly, primarily because water was consumed in nitrile hydrolysis (Table 1, Entries 7-9). Satisfactory yields were also achieved in polar protic solvents such as n -butanol and n -hexanol (Table 1, Entry 10-11). Furthermore, the highest yield of the target product was obtained at 110 o C (Table 1, Entries 11-13). able 1 Optimization of Reaction Conditions a Entry Additive Ratio T (℃) Time (h) Solvent Yield b (%) 1 K 2 S 1: 2: 1: 3: 3 120 5 NMP 96 (93) 2 K 2 S 1: 2: 0: 3: 3 120 5 NMP 42 3 K 2 S 1: 2: 2: 3: 3 120 5 NMP 53 4 - 1: 2: 1: 0: 3 120 5 NMP trace 5 NaHS 1: 2: 1: 3: 3 120 5 NMP 91 6 S 1: 2: 1: 3: 3 120 5 NMP trace 7 K 2 S 1: 2: 1: 3: 3 120 5 DMSO 58 8 K 2 S 1: 2: 1: 3: 3 120 5 CH3CN 12 9 K 2 S 1: 2: 1: 3: 3 120 5 DMF 46 10 K 2 S 1: 2: 1: 3: 3 120 5 n-hexanol 85 11 K 2 S 1: 2: 1: 3: 3 120 5 n-butanol 97 12 K 2 S 1: 2: 1: 3: 3 110 5 n-butanol 97 (95) 13 K 2 S 1: 2: 1: 3: 3 100 5 n-butanol 83 a Reaction conditions: 1a (1.0 mmol), mole ratio of 1a: CaC 2 : KOH: K 2 S: H 2 O, and solvent (3.0 mL). b Yields were determined by 1 H NMR using pyrazine as an internal standard, isolated yields are given in parentheses. Under the optimized reaction conditions, we systematically investigated the substrate scope of the reaction between 2-aminobenzamides and CaC₂ for the synthesis of 2-methyl-2,3-dihydroquinazolin-4(1H)-ones. The experimental results indicated excellent functional group tolerance, with both electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) on the aromatic ring being well-accommodated (Scheme 2). Specifically, substrates bearing alkyl or substituted phenyl groups at the amino or carbamoyl positions 1h-p produced the corresponding products 3h-p in moderate to excellent yields. Notably, substrate 1q yielded product 4q instead of the expected 3q, primarily due to the high electron density at the α-position of the thiophene ring, which makes the dihydropyrazoline 3q highly susceptible to oxidation, leading to the formation of the quinazolinone 4q. Additionally, substrate 1r provided product 4r in 71% yield, suggesting that the strong electron-withdrawing property of the sulfonamide group facilitates the elimination of compound 3r under alkaline conditions, resulting in the formation of 4r. Moreover, substrate 1n, containing a hydrazide group, was smoothly converted to 3n with a 68% yield. Furthermore, dihydroquinazolinones such as 3a and 3m could be easily oxidized to the corresponding quinazolinones 4a and 4m using KMnO 4 at room temperature within 2 hours. This oxidation step enabled the successful synthesis of methaqualone 4m, a known sedative drug. These results indicated the versatility of the current strategy, which allows for the selective synthesis of either dihydroquinazolinones or quinazolinones from the reaction of 2-aminobenzamides and CaC₂ by simply regulating the reaction conditions. Benzamide can be readily obtained from the hydrolysis of benzonitrile under basic conditions, and the hydrolysis of CaC₂ generates Ca(OH)₂, which provides a suitable alkaline environment for this reaction. 12 In light of this, we further extended our synthetic strategy to develop a one-pot synthesis of dihydroquinazolinones 3 using 2-aminobenzonitrile, CaC 2 , and H 2 O. This approach combines the in-situ hydrolysis of the benzonitrile to a benzamide intermediate with the hydrolysis of CaC₂, enabling a streamlined multicomponent reaction with higher step and atom economy. The optimal parameters for this transformation were determined (details in Table S2 in the Supporting Information). Solvent screening revealed that polar protic solvents such as n -butanol, n -hexanol, and ethanol outperformed polar aprotic solvents like NMP, DMF, and DMSO (Table S2, Entries 1-7). This is primarily because aprotic solvents promote side reactions between nitrile and sulfide species. 13 Notably, the reaction was completely inhibited in the absence of K₂S, underscoring its crucial role in the reaction process (Table S2, Entries 8-11). Furthermore, the optimal yield of the target compound was achieved when 2.5 equivalents of NaOH was used relative to 2-aminobenzonitrile (Table S2, Entries 12-17). Replacing n -hexanol with n -butanol as the solvent afforded the same yield of 3a in a shorter time, mainly due to the enhanced solubility of the reactants (Table S2, Entries 26-28). As a result, the optimized conditions were established as follows: 2-aminobenzonitrile 2a (1mmol, 118.1 mg, 1.0 equiv.), CaC 2 (2.0 equiv.), H 2 O (6.0 equiv.), NaOH (2.5 equiv.) and K 2 S (3.0 equiv.) in n -butanol at 110 °C for 8 hours, producing the target compound 3a with a yield of 98%. Scheme 2 The universality of substrates for the synthesis of 2-methyl-2,3-dihydroquinazolin-4(1H)-ones from 2-aminobenzamides and CaC 2 a a Reaction conditions: 1: CaC 2 : KOH: K 2 S: H 2 O = 1: 2: 1: 3: 3, n -butanol (2 mL), 110 o C, 5 h. b The isolated yields were based on 1. c Reaction for 10 h. d Oxidize corresponding dihydroquinazolinones with KMnO 4 for 2 h, r.t. After optimizing the reaction conditions, the substrate scope was investigated using a series of substituted o-aminobenzonitriles 2a-al bearing diverse functional groups (Scheme 3). The reaction exhibited remarkable tolerance to both EDGs and EWGs. The vast majority of the substrates 2a-ah, containing methyl, amino, methoxy, and halogen substituents at the ortho, meta, and para positions, reacted efficiently with CaC 2 to afford the target products in excellent yields. Notably, during the column chromatography separation process, compound 3y was spontaneously converted into 4y’ through the coupling of nitro group reduction with C-N bond oxidation. Additionally, substrates 2q and 2aj predominantly yielded quinazolinones 4q and 4aj, respectively. This result might be attributed to the increased electron density at the α-position of the thiophene ring, which facilitates the oxidation of dihydroquinazolinones 3q and 3aj to their corresponding quinazolinone derivatives. Furthermore, the naphthalene-fused dihydroquinazolinone derivative 3ak was successfully synthesized in excellent yield, demonstrating the versatility of this synthetic methodology for preparing diverse dihydroquinazolinones. Unfortunately, the compounds 3al was obtained in poor yields due to the formation of multiple by-products. Scheme 3 The universality of substrates for the synthesis of 2-methyl-2,3-dihydroquinazolin-4(1H)-on es from 2-aminobenzonitriles and CaC 2 a a Reaction conditions: 1 (1.0 mmol), CaC 2 (2 mmol), H 2 O (6 mmol), NaOH (2.5 mmol), and n -Butanol (2.0 mL), 110 o C, 8 h. b The isolated yields were based on 2. To evaluate the scalability and practicality of this synthetic methodology, a gram-scale reaction for synthesizing methaqualone 4m, a sedative drug used to treat conditions like insomnia, neurasthenia, and for pre-anesthesia administration, was carried out under standard reaction conditions (Scheme 4, a). The experiment results showed that the reaction between 1m and CaC₂ proceeded smoothly on a larger scale, affording the target product 4m with an isolated yield of 94%. Additionally, the natural product schizocummunin, which exhibits strong cytotoxic activity against murine lymphoma cells, was synthesized from the reaction of 4a and isatin with an overall yield of 95% (Scheme 4, b). These results demonstrate the practicality of this methodology, highlighting its significant potential in the synthesis of drugs and natural products. Scheme 4 The scalability and practical applicability for this synthetic methodology (a) Gram-Scale for the synthesis of methaqualone 4m from 1m and CaC 2 (b) Synthesis of the natural product schizocummunin 5aa To clarify the reaction mechanism, a series of mechanistic investigations were conducted. Initially, when 2,2,6,6-tetramethylpiperidinyl-1-oxide (TEMPO) was added to the reaction solution under standard conditions, product 3a was obtained in a 95% yield (Scheme 5, a). This experimental result suggests that this reaction does not proceed via a radical pathway. To further explore the role of sulfur anion in this reaction, a reaction was carried out using o-aminobenzamide, acetylene, and NaHS in n -butanol at 110 o C for 5 h, and the compound 3a was obtained in a 52% yield. Additionally, thioacetaldehyde, intermediates I/II and imines III/IV were detected in the reaction mixture by HRMS analysis (Scheme 5b, Figure S1). These experimental results imply that the reaction may start with the formation of thioacetaldehyde via a direct reaction between acetylene and the sulfur anion. Thioacetaldehyde is then attacked by either the amide or amino group of o-aminobenzamide to form intermediate I or II respectively. Subsequently, H₂S is eliminated from these intermediates to yield imines III or IV. Further control experiments revealed that the reaction of CaC₂ with the mixture substrates 1h (N-methylated on the amide) and 1o (N-methylated on the aniline) yielded the mixture product 3h and 3o under standard conditions (Scheme 5c). The experimental results confirmed that 3h is formed via intermediates II and IV (Scheme 6, route 1), while 3o is formed via intermediates I and III (Scheme 6, route 2). These findings demonstrated that both the amide and amino groups of o-aminobenzamide can react with thioacetaldehyde to form imines. Notably, the higher yield of 3h (60%) compared to 3o (36%) (Figure S2) indicates that route 2 is the predominant transformation pathway. Additionally, to further verify the crucial role of the imine in this transformation, substrate 1ha, in which both the amide and amino groups of o-aminobenzamide were substituted, did not react with CaC 2 and H₂O under standard conditions (Scheme 5, d). It was denmonstrated that the substrate 1ha could not react with thioacetaldehyde to form an imine, confirming that the imine intermediate is indispensable for this transformation process. Scheme 5 Mechanism Studies Furthermore, the reaction process of 1a and acetylene mediated by K 2 S was monitored using in situ FTIR spectroscopy (Figure 2). The observation of an initial increase followed by a decrease in the IR peak corresponding to the C=N bond (1674 cm -1 ) of an imine suggests the formation of intermediate imines III or IV. Concurrently, the appearance of peaks for the C-N bond of secondary amine (1125 cm⁻¹) and the C-N bond of the amide (1569 cm⁻¹) indicates the formation of dihydroquinazolinone 3a (experimental details in Supporting Information). These experimental results provide additional evidence for the stepwise transformation of 1a to 3a. Figure 2 The reaction progress from 1a to 3a monitored by in situ FTIR spectroscopy Based on prior research and a series of controlled experiments, a plausible mechanism for the synthesis of compounds 3a and 4a has been proposed (Scheme 6). The process initiates with the hydrolysis of the nitrile group of o-aminobenzonitrile under alkaline conditions, resulting in the product of o-aminobenzamide 1a. 12 Simultaneously, acetylene generated in situ from CaC 2 reacts with a sulfur anion to form thioacetaldehyde, a process similar to the Kucherov reaction. The transformation of 1a into 3a proceeds through two distinct pathways. In route 1, the amide group of 1a undergoes nucleophilic addition with thioacetaldehyde, forming intermediate d. In route 2, the amino group of 1a reacts with thioacetaldehyde to produce intermediate d’. Both d and d’ then undergo H 2 S-elimination to yield imine intermediates e and e’, respectively. These intermediates subsequently undergo intramolecular cyclization to form f and f’, followed by proton transfer to form 3a. Finally, in the presence of an oxidant, 3a is easily oxidized to yield the corresponding quinazolinone 4a. Scheme 6 Proposed Mechanism Conclusions In conclusion, we have successfully developed an efficient, transition-metal-free methodology for the one-pot synthesis of quinazolinone and dihydroquinazolinone derivatives. This multicomponent approach employs CaC 2 as an acetylene source, which reacts with either o-aminobenzamide or 2-aminobenzonitrile under the mediation of sulfur anions to produce a diverse array of quinazolinone derivatives. This protocol demonstrates a broad substrate scope and exceptional functional group tolerance, underscoring its versatility for various synthetic applications. Mechanistic studies revealed that thioacetaldehyde, generated in situ from the reaction of sulfur anion and acetylene (derived from CaC₂), plays a critical role in facilitating imine formation and subsequent intramolecular cyclization, thereby enabling the efficient construction of the quinazolinone heterocyclic framework. By employing cost-effective starting materials and environmentally benign reagents, this strategy offers significant potential for applications in pharmaceutical synthesis and drug discovery. Acknowledgement We thank the National Natural Science Foundation of China (22569018), Natural Science Foundation of Inner Mongolia Autonomous Region (2024LHMS02011), Basic scientific Research Funds of Universities directly under the Inner Mongolia Autonomous Region (JY20240076), the Group Project of Developing Inner Mongolia through Talents from the Talents Work Leading Group under the CPC Inner Mongolia Autonomous Regional Committee (No. 2025TEL04) and the Innovative Research Team in Universities of Inner Mongolia Autonomous Region (NMGIRT2212) for financial support. References (1) (a) Kamal, A .; Bharathi, E. V.; Reddy, J. S.; Ramaiah, M. J.; Dastagiri, D.; Reddy, M. K.; Viswanath, A.; Reddy, T. L.; Shaik, T. B.; Pushpavalli, S. N. C. V. L.; et al. Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents. Eur. J. Med. Chem. 2011 , 46 , 691-703. (b) Chinigo, G. M.; Paige, M.; Grindrod, S.; Hamel, E.; Dakshanamurthy, S.; Chruszcz, M.; Minor, W.; Brown, M. L. Asymmetric Synthesis of 2,3-Dihydro-2-arylquinazolin-4-ones: Methodology and Application to a Potent Fluorescent Tubulin Inhibitor with Anticancer Activity. J. Med. Chem. 2008 , 51 , 4620-4631. (c) Sultana, N.; Sarfraz, M.; Tanoli, S. T.; Akram, M. S.; Sadiq, A.; Rashid, U.; Tariq, M. I. Synthesis, crystal structure determination, biological screening and docking studies of N 1 -substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases. Bioorg. Chem. 2017 , 72 , 256-267. (d) Jadhavar, P. S.; Dhameliya, T. M.; Vaja, M. D.; Kumar, D.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D.; Chakraborti, A. K. Synthesis, biological evaluation and structure–activity relationship of 2-styrylquinazolones as anti-tubercular agents. Bioorg. Med. Chem. Lett. 2016 , 26 , 2663-2669. (e) Han, X.; Peng, B.; Xiao, B. B.; Sheng-Li, C.; Yang, C. R.; Wang, W. Z.; Wang, F. C.; Li, H. Y.; Yuan, X. L.; Shi, R.; et al. Synthesis and evaluation of chalcone analogues containing a 4-oxoquinazolin-2-yl group as potential anti-tumor agents. Eur. J. Med. Chem. 2019 , 162 , 586-601. (f) Baska, F.; Sipos, A.; Orfi, Z.; Nemes, Z.; Dobos, J.; Szántai-Kis, C.; Szabó, E.; Szénási, G.; Dézsi, L.; Hamar, P.; et al. Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases. Eur. J. Med. Chem. 2019 , 184 , 111710. (g) Ashraf-Uz-Zaman, M.; Li, X.; Yao, Y.; Mishra, C. B.; Moku, B. K.; Song, Y. Quinazolinone Compounds Have Potent Antiviral Activity against Zika and Dengue Virus. J. Med. Chem. 2023 , 66 , 10746-10760. (h) Shetty, B. V.; Campanella, L. A.; Thomas, T. L.; Fedorchuk, M.; Davidson, T. A.; Michelson, L.; Volz, H.; Zimmerman, S. E.; Belair, E. J.; Truant, A. P. Synthesis and activity of some 3-aryl- and 3-aralkyl-1,2,3,4-tetrahydro-4-oxo-6-quinazolinesulfonamides. J. Med. Chem. 1970 , 13 , 886-895. (i) O’Brien, N. S.; Gilbert, J.; McCluskey, A.; Sakoff, J. A. 2,3-Dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones as broad-spectrum cytotoxic agents and their impact on tubulin polymerisation. RSC Med. Chem. 2024 , 15 , 1686-1708. (j) Parshuram Satpute, D.; Shirwadkar, U.; Kumar Tharalla, A.; Dattatray Shinde, S.; Nikhil Vaidya, G.; Joshi, S.; Patel Vatsa, P.; Jain, A.; Singh, A. A.; Garg, R.; et al. Discovery of fluorinated 2‑Styryl 4(3H)-quinazolinone as potential therapeutic hit for oral cancer. Bioorg. Med. Chem. 2023 , 81 , 117193. (k) Wang, J.; Battini, N.; Ansari, M. F.; Zhou, C. H. Synthesis and Biological Evaluation of Quinazolonethiazoles as New Potential Conquerors towards Pseudomonas Aeruginosa. Chin. J. Chem. 2021 , 39 , 1093-1103.(2) Badolato, M.; Aiello, F.; Neamati, N. 2,3-Dihydroquinazolin-4(1H)-one as a privileged scaffold in drug design. RSC Adv. 2018 , 8 , 20894-20921.(3) (a) Didó, C. A.; Mass, E. B.; Pereira, M. B.; Hinrichs, R.; D’Oca, M. G. M.; Costa, T. M. H.; Russowsky, D.; Benvenutti, E. V. Heterogeneous gold nanocatalyst applied in the synthesis of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones. Colloids Surf., A 2020 , 589 . (b) R, T.; Małecki, J. G.; Budagumpi, S.; Kshirsagar, U. A.; Dateer, R. B. Biomass derived Cu2O nanoparticles for N-atom insertion reactions: a base-free synthesis of quinazolinones with a green approach. Green Chem. 2024 , 26 , 4723-4732. (c) Batmani, H.; Noroozi Pesyan, N.; Havasi, F. Ni-Biurea complex anchored onto MCM-41: As an efficient and recyclable nanocatalyst for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones. Microporous Mesoporous Mater. 2018 , 257 , 27-34. (d) Li, Q.; Huang, Y.; Chen, T.; Zhou, Y.; Xu, Q.; Yin, S. F.; Han, L. B. Copper-catalyzed aerobic oxidative amination of sp3 C-H bonds: efficient synthesis of 2-hetarylquinazolin-4(3H)-ones. Org. Lett. 2014 , 16 , 3672-3675. (e) Li, Y.; Cao, Z.; Wang, Z.; Xu, L.; Wei, Y. Copper-Catalyzed Reactions of Alkenyl Boronic Esters via Chan-Evans-Lam Coupling/Annulation Cascades: Substrate Selective Synthesis of Dihydroquinazolin-4-ones and Polysubstituted Quinolines. Org. Lett. 2022 , 24 , 6554-6559. (f) Dutta, N.; Dutta, B.; Dutta, A.; Sarma, B.; Sarma, D. Room temperature ligand-free Cu2O–H2O2 catalyzed tandem oxidative synthesis of quinazoline-4(3H)-one and quinazoline derivatives. Org. Biomol. Chem. 2023 , 21 , 748-753. (g) Manna, S.; Sahoo, S.; Rit, A. Synthesis of quinazolinone scaffolds via a zinc(II)-stabilized amidyl radical-promoted deaminative approach. Chem. Commun. 2024 , 60 , 7097-7100. (h) Tang, J.; Chen, C.; Hong, T.; Zhang, Z.; Xie, C.; Li, S. Regulation of Chiral Phosphoric Acid Catalyzed Asymmetric Reaction through Crown Ether Based Host–Guest Chemistry. Org. Lett. 2022 , 24 , 7955-7960. (i) Wu, X.; Tian, Q.; Ge, J.; Liu, Y.; Li, Z.; Zhang, J.; Cheng, G. Cobalt‐Catalyzed Regio, Diastereo, and Enantioselective C–H Annulation of Aminoquinoline Amides with Internal Alkynes for the Construction of Diaxes. Chin. J. Chem. 2025 , 43 , 2669-2676.(4) (a) Halder, S.; Mandal, S.; Biswas, A.; Adhikari, D. Unlocking the photo-dehydrogenation ability of naphthalene monoimide towards the synthesis of quinazolinones. Green Chem. 2023 , 25 , 2840-2845. (b) Xie, Z.; Lan, J.; Zhu, H.; Lei, G.; Jiang, G.; Le, Z. Visible light induced tandem reactions: An efficient one pot strategy for constructing quinazolinones using in-situ formed aldehydes under photocatalyst-free and room-temperature conditions. Chin. Chem. Lett. 2021 , 32 , 1427-1431.(5) Nguyen, V. T.; Ngo, H. Q.; Le, D. T.; Truong, T.; Phan, N. T. S. Iron-catalyzed domino sequences: One-pot oxidative synthesis of quinazolinones using metal–organic framework Fe 3 O(BPDC) 3 as an efficient heterogeneous catalyst. Chem. Eng. J. 2016 , 284 , 778-785.(6) (a) Patil, N. T.; Lakshmi, P. G. V. V.; Singh, V. AuI-Catalyzed Direct Hydroamination/Hydroarylation and Double Hydroamination of Terminal Alkynes. European J. Org. Chem. 2010 , 2010 , 4719-4731. (b) Patil, N. T.; Kavthe, R. D.; Raut, V. S.; Shinde, V. S.; Sridhar, B. Gold- and Platinum-Catalyzed Formal Markownikoff’s Double Hydroamination of Alkynes: A Rapid Access to Tetrahydroquinazolinones and Angularly-Fused Analogues Thereof. J. Org. Chem. 2010 , 75 , 1277-1280. (c) Srishyalam, V.; Devanna, N.; Basaveswara Rao, M. V.; Mulakayala, N. Novel one pot synthesis of substituted quinazolin-4(3 H )-ones and pyrazolo[4,3- d ]pyrimidin-7(6 H)-ones using copper iodide, azides and terminal alkynes. Tetrahedron Lett. 2017 , 58 , 2889-2892. (d) Wang, B. T.; Wang, Z. Q.; You, X. J.; Li, Z.; Yang, J. H. One-Step Construction of 2-Methylquinazolin-4(3)-ones Using Solid Calcium Carbide as an Alternative to Gaseous Acetylene. J. Org. Chem. 2024 , 90 , 385-393. (e) Yavari, I.; Akbarzadeh, S.; Ghorbanzadeh, M. Formation of quinazolin-4(3H)-ones from N-sulfonoketenimines and 2-aminobenzamides. J. Iran. Chem. Soc. 2024 , 21 , 1011-1019.(7) Kutscheroff, M. Ueber eine neue Methode direkter Addition von Wasser (Hydratation) an die Kohlenwasserstoffe der Acetylenreihe. Ber. Dtsch. Chem. Ges. 1881 , 14 , 1540-1542.(8) (a) Yue, T. J.; Ren, W. M.; Lu, X. B. Copolymerization Involving Sulfur-Containing Monomers. Chem. Rev. 2023 , 123 , 14038-14083. (b) Ledovskaya, M. S.; Voronin, V. V.; Valov, N. R.; Samoylenko, D. E. Calcium Carbide: From Elemental Carbon to Isotope‐Economic Synthesis of 13C2‐Labeled Heterocycles†. Chin. J. Chem. 2023 , 41 , 2810-2818.(9) Xu, K.; Li, Z.; Cheng, F.; Zuo, Z.; Wang, T.; Wang, M.; Liu, L. Transition-Metal-Free Cleavage of C-C Triple Bonds in Aromatic Alkynes with S(8) and Amides Leading to Aryl Thioamides. Org. Lett. 2018 , 20 , 2228-2231.(10) Li, S.; Cheng, S.; Du, Y.; Yan, L.; Wu, J.; Han, L.; Zhu, N. Selective Synthesis of Vinyl Sulfides or 2-Methyl Benzothiazoles from Disulfides and CaC2 Mediated by a Trisulfur Radical Anion. J. Org. Chem. 2024 , 89 , 18028-18038.(11) Daw, P.; Sinha, A.; Rahaman, S. M. W.; Dinda, S.; Bera, J. K. Bifunctional Water Activation for Catalytic Hydration of Organonitriles. Organometallics. 2012 , 31 , 3790-3797.(12) Midya, G. C.; Kapat, A.; Maiti, S.; Dash, J. Transition-Metal-Free Hydration of Nitriles Using Potassiumtert-Butoxide under Anhydrous Conditions. J. Org. Chem. 2015 , 80 , 4148-4151.(13) Oschatz, S.; Brunzel, T.; Wu, X.-F.; Langer, P. Catalyst-free synthesis of 2-aryl-1,2-dihydro-quinazolin-4(1H)-thiones from 2-aminobenzothio-amides and aldehydes in water. Org. Biomol. Chem. 2015 , 13 , 1150-1158. 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Keywords chalcium carbide dihydroquinazolinones one-pot synthesis quinazolinones sulfur anion Authors Affiliations Shuyi Li 0009-0009-5053-1946 Inner Mongolia University of Technology View all articles by this author Yunzhe Du Inner Mongolia University of Technology View all articles by this author Ligang Yan Inner Mongolia University of Technology View all articles by this author Siliu Cheng Inner Mongolia University of Technology View all articles by this author Shuang Cao Inner Mongolia University of Technology View all articles by this author Ruijun Xie Inner Mongolia University of Technology View all articles by this author Limin Han Inner Mongolia University of Technology View all articles by this author Ning Zhu 0000-0002-7535-1310 [email protected] Inner Mongolia University of Technology View all articles by this author Metrics & Citations Metrics Article Usage 179 views 841 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shuyi Li, Yunzhe Du, Ligang Yan, et al. Green Synthesis of Quinazolinone Scaffolds from the Cascade Reaction of o-Aminobenzamides/o-Aminobenzonitrile and Calcium Carbide mediated by K2S. Authorea . 23 September 2025. DOI: https://doi.org/10.22541/au.175826891.12252406/v2 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 . 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