Abstract
A new method for the preparation of tetrahydroquinolin-2-one derivatives is presented. This approach involves a two-step reaction between enaminones and acylating agents, immediately followed by electrophilic cyclization, all within a single synthesis procedure, eliminating the need to isolate intermediates. The entire process is facilitated by the use of acyl Meldrum’s acids which not only shortens the preparation time of the substrates but also easily extends the range of substituents That can be used. The method’s scope and limitations were evaluated with various reagent combinations thus demonstrating its general applicability to the synthesis of tetrahydroquinolin-2-one core. Interestingly, some exceptions to the regular reaction pathway were observed when a strong EDG (electron donating group) was introduced via acyl Meldrum’s acids. The underlying mechanism of this phenomenon was elucidated during the investigation.
Similar content being viewed by others
Introduction
The pyridone motif is commonly found in a diverse range of biologically active compounds, including pharmaceuticals, with a primary focus on the drug-like properties of pyridone derivatives. Consequently, pyridine molecules (Fig. 1) offer a wide range of potential biological targets. These include, for example, agonists of the cannabinoid CB2R receptor 1,1,2 analgesic agents featuring the 4-pyridone moiety 23,4 kinase inhibitors 3 with anaplastic anticancer properties5, and the topoisomerase inhibitor camptothecin 4. Additionally, anticancer and antiproliferative activities are observed in 2-pyridone compounds, as reported by Lvi and colleagues 56. Polycyclic pyridones 6 also exhibit antifungal activity against Candida albicans7. Notably. There are numerous commercially available drugs among pyridone derivatives, such as the antifungal and antibacterial agent ciclopirox 7, and the antisarcoma drug tazemetostat 8.
Examples of bioactive derivatives containing pyridone moiety.
On the other hand, the use of pyridines as biologically active agents comes with an additional advantage related to their rapid biodegradation8,9.
Our recent synthetic efforts have been directed towards the synthesis of 2-pyridone moieties fused with saturated rings, as well as the preparation of permanently aromatic systems that are isosteric with the pyridone scaffold10,11. As per our expectations these compounds have exhibited, according to the molecular docking results, anticancer activity, although the synthesis process had room for improvement. The chemical literature provides a significant number of synthetic methods for preparing the 2-pyridone moiety. Thus, from the most popular methods, we can distinguish two main approaches12. The first approach involves transforming existing heterocyclic rings into 2-pyridone and the second is based on the formation of the heterocyclic ring de novo. According to the first approach, pyrones could be easily transformed into pyridone rings by heating pyrones in boiling acetic acid in the presence of ammonium acetate13,14 (Fig. 2). Alternatively, pyridine N-oxides can be transformed into pyridines by heating with carboxylic acid anhydrides15.
Selected examples of the synthesis routes of 2-pyridones.
The second approach involves forming the ring from non-cyclic starting materials, frequently through the condensation of a nitrogen-bearing component with 1,3-dicarbonyl compounds. An example is the reaction of cyanoacetamide with ethyl 2,4-dioxovalerate16,17. Additionally, nitriles can serve as a source of nitrogen when reacting with highly reactive malonyl chloride18,19. A unique and interesting type of condensation to form 2-pyridones involves reactions where the nitrogen component takes the form of an enamine, reacting with 1,3 dicarbonyl derivatives. Sheibani and co-workers published a paper where they described the reaction of an enamine conjugated with carbonyl reacts with (chlorocarbonyl)phenyl ketene20. A somewhat similar approach was used by Guillemont and co-workers, who detailed the formation of the 2-pyridone scaffold in the reaction of a conjugated enamine with an activated malonic derivative21. A completely different approach assumes the application of methyl propiolate with enaminone22,23. The method using methoxymethylene Meldrum’s acid and enaminone also deserves mention24,25.
The method previously used in our laboratory for the synthesis of the tetrahydroquinolin-2-one scaffold10,11 was a combination and adaptation procedures described by several research groups26,27,28. However, due to difficulties with the direct procedure involving benzoyl acetate, ammonium acetate, and cyclohexanone, where the in-situ formation of an amide was expected, followed by subsequent reaction with cyclohexanone, we opted to synthesize the amide separately, isolate it, and then proceed to condense the 1,3-dicarbonyl amide with cyclohexanone to obtain the desired 2-pyridone fused with a six-membered ring. Although this method was successful, it proved to be tedious and time-consuming in practice, prompting our search for an improved method for the preparation of a 2-pyridone scaffold.
Results and discussion
In this current paper, using our experience in synthesizing pyridones along with our knowledge about the applications of Meldrum’s acid29,30,31,32,33,34 in synthesis, and considering the available literature, we would like to introduce a new approach for the preparation of 2-pyridones.
Taking into account our past experience, we identified a key step to be obtaining a 1,3-dicarbonyl amide with an already attached fragment that allows cyclization, resulting in a 2-pyridone fused with a hexagonal ring, like the tetrahydroquinolin-2-one. The enamide 11 in Fig. 3 aligns with these criteria. At this stage, we assumed that such an enamide would readily undergo the desired cyclization under acidic conditions.
Preparation of enamide 11aa with benzoyl Meldrum’s acid 9a.
In theory, obtaining the appropriate enamide should be straightforward with the enaminone and acylating reagent being available. However, using acyl-acetate esters is not recommended due to their low reactivity with amino groups and potential side reactions with the ketone fragment. However, the use of strong acylating reagents like chlorides, anhydrides, or ketenes, as seen in cited works18,19,20,21, presents challenges in preparation and storage. This led us to consider exploiting the acylating properties of Meldrum’s acid derivatives, which would allow us to introduce 1,3-dicarbonyl moiety together with the possibility of introducing a broad scope of side chains. It should be noted that the used acyl derivatives of Meldrum’s acid are stable compounds, easily purified and prepared from commercially available starting materials.
First, we conducted several experiments with 4 eq of 5-(hydroxy(phenyl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9a) and 1 eq of 3-amino-5,5-dimethylcyclohex-2-enone (10a) under various conditions to optimize the method (Table S1 in SI). With these experiments, we observed the formation of the desired conjugated enamide, with yields ranging from a moderate 30% in the case of a reaction performed in boiling DCE (1,2-dichloroethane) without molecular sieves, up to a quantitative yield of 97% when molecular sieves were present, and the reaction was carried out at 55 °C in DCE (Fig. 3).
Having isolated and purified enamide 11aa, we proceeded with its cyclization to form 7,7-dimethyl-4-phenyl-7,8-dihydroquinoline-2,5(1H,6H)-dione (12aa). Our initial attempts focused on the application of mild Lewis acids as transition metals triflates, especially scandium triflate. Unfortunately, this approach proved unsuccessful under various conditions.. This failure prompted us to search for an effective catalyst for the preparation of product 12aa. We focused on protic acid catalysts, especially on polyphosphoric acid (PPA) known for its moderate acidity and its ability to catalyze similar reactions, including Knorr-type cyclization35,36,37,38,39,40,41.
We conducted two experiments with the cyclization of enamide 11aa in the presence of PPA. The first, carried out in boiling dichlorobenzene (DCB) for 2 h, resulted in the formation of compound 12aa with a 37% yield, while the second was performed in boiling dichloroethane (DCE) within 6 h, yielding 34% (Fig. 4).
Formation of 7,7-dimethyl-4-phenyl-7,8-dihydroquinoline-2,5(1H,6H)-dione (12aa).
With these outcomes, we explored the possibility of conducting both the intermolecular and intramolecular processes without the isolation of the enamide intermediate in a “one-pot” reaction. To test this hypothesis, we initiated the condensation of a fourfold excess of benzoyl Meldrum’s acid 9a with enaminone 10a. Once the enamide formation was complete and the disappearance of benzoyl Meldrum acid was confirmed through TLC analysis, PPA was introduced to the reaction, and the entire mixture was heated to its boiling point for 6 h. This resulted in the formation of product 12aa with a yield of 32% (Fig. 5). As an alternative to the use of PPA we tested TsOH in toluene; however, this resulted in a weaker outcome since the yield after both steps combined was only 15%.
“One-pot” process for synthesis of derivative 12aa.
Encouraged by these findings, we decided to perform a series of reactions using various derivatives of Meldrum's acid and enaminones to evaluate the scope and limitations of this newly developed method. With our new method, we were able to prepare a wide range of compounds efficiently with a 7,8-dihydroquinoline-2,5(1H,6H)-dione scaffold in a single laboratory step, achieving moderate yields (Table 1).
In the case of 5-(1-hydroxy-2-(naphthalen-1-yl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9f) used as a Meldrum’s acid (Table 1, Run 9), enamide formation was observed but subsequent condensation using PPA was unsuccessful. A similar situation arose when 3-aminocyclopent-2-enone was applied. Surprisingly, when derivative 9c was used as a Meldrum’s component (Table 1, Run 3), a notably different product compared to the other results was isolated from the reaction mixture. Determining the structure of this unexpected product was an essential step in our analysis. In became evident that this compound contained a double fragment originating from the Meldrum derivative and only one from the enaminone. Based on data from NMR and MS, we proposed the following structure, which may exist in equilibrium with its keto form (Fig. 6).
Proposed structure of unexpected cyclization product.
This prompted us to investigate the reaction mechanism behind this particular outcome. First, we sought to determine the step in the process that was responsible for the formation of this unusual product. Since the unexpected product contained an “excess” of moieties originating from acyl Meldrum’s acid, it suggested that the surplus of compound 9c used in a “one-step” process might be causing this atypical reaction course. To test this, we prepared enamide 11ca following the stepwise procedure, and isolated and purified it. In the next step, we attempted to cyclize purified 11ca using PPA. This reaction again yielded compound 13ca with a 21% yield (Fig. 7).
Formation of “unexpected” product during cyclization of enamide.
The result confirmed that the excess of acyl Meldrum’s acid used in the “one-pot” reaction wasn’t responsible for the unusual course of the reaction. Compound 13ca seemed to be formed through the interaction of two molecules of enamide 11ca. To explain the formation of product 13ca we proposed a tentative reaction mechanism presented in Fig. 8A.
(A) Tentative reaction mechanism proposed for the intermolecular formation of 13ca; (B) Competitive intramolecular reaction for compounds 11 with weak EDG or EWG.
Obviously, we paid attention to the fact that only the reaction of p-methoxy derivative of Meldrum’s acid with dimedone enaminone gave us an unexpected product. Thus, to explain this phenomenon, we hypothesized that EDG caused a decrease in the electrophilicity of the keto carbonyl carbon in enamide 11ca. This inhibited preferred intramolecular cyclization process (Fig. 8B) which would typically lead to the usual product 12ca and simultaneously enabled the observation of a more entropically challenging intermolecular process. To validate our hypothesis, we decided to obtain and purify enamide 11ga with a furyl substituent possessing a strong M+ effect (Fig. 9a). Subsequently, we carried out the intramolecular condensation with PPA once again, resulting in the formation of compound 13ga which confirmed that an EDG indeed affects the course of the reaction (Fig. 9b).
Reactions carried out to investigate the effect of the strong EDG on the course of condensation.
In both intermolecular (Fig. 8A) and intramolecular (Fig. 8B) reactions, the enaminone fragment plays the role of the nucleophile, with the largest contribution to the HOMO orbital of the molecule. In the discussed intermolecular condensation, it is theoretically possible for the nucleophile to attack either the keto-carbonyl (not shown in Fig. 8A) or the amide carbonyl carbon atom. Considering the factors affecting the transition of the reaction from intramolecular to intermolecular (the presence of ED group decreases the electrophilicity of keto-carbonyl carbon atom) it is likely that the enaminone nucleophile initiates the reaction with the amide carbonyl, as otherwise, we would observe with intramolecular cyclization like in substrates 11aa–ad, ba, da, ea when a weak EDG or EWG (electron withdrawing group) is present, which implies higher electrophilicity of keto-carbonyl than amide carbonyl carbon atom.
Moreover, in our search for the most basic position of the molecule, we estimated pKa values for the conjugate acids of enamide 11ca and its enol form 11ca′ using the “Chemaxon pKa calculator”42. The calculated pKa values were 1.0 and 0.4, respectively (Fig. 10).
Conjugate acids to ketone and enol form of N-(5,5-dimethyl-3-oxo-cyclohexene-1-yl)-3-(4-methoxyphenyl)-3-oxo-propanamide.
In an environment with an excess of PPA, these compounds will be predominantly in the protonated form. The protonated forms are more electrophilic than the non-protonated ones. When considering the participation of these two forms in the actual course of the reaction, the position of the keto-enol equilibrium of protonated and deprotonated forms should also be taken into account. Based on the 1H NMR spectra for EDG-substituted enamides in a non-polar solvent, the enol form was negligibly small. Consequently the most electrophilic species in our reaction mixture would be the protonated enamide 11ca (Fig. 10), providing further support for our proposed mechanism.
Conclusion
In this paper, we introduced a “one-pot” reaction developed by our team for the synthesis of 4-phenyltetrahydroquinolone cores. This process involves an initial formation of an appropriate enamide as an intermediate, followed by its condensation with PPA. The presented method has significant advantages over previously used procedures26,27. The “one-pot” synthesis allows obtaining the desired tetrahydroquinolone core within several hours, in mild conditions, without the intermediate isolation. The yields of the proposed synthesis are higher than those previously published (e.g. 12%27; 18–21% in two steps43; 16% in two steps, 27%25). The condensation of Meldrum's acid derivatives with enaminones also allows the tetrahydroquinolone core functionalization in the 4-position with alkyl substituents, which was not possible before due to the difficulties of ethyl acetoacetate and its alkyl derivatives ammonolysis. Additionally, the presence of carbonyl carbon in the 5-position opens new possibilities for tetrahydroquinolone core modification. Nevertheless, the presented method does have its limitations. The reaction predominantly proceeds through intramolecular cyclization for enamides that lack strong EDG. In contrast, for those with ED groups, we observed an intermolecular condensation pathway.
Methods
General
Commercially available reagents were purchased from Sigma Aldrich or Acros and used without further purification. Acyl Meldrum’s acids 9a–f and enaminones 10a–d were prepared according to literature procedures; 9a, 9b, 9c, 9f44, 9d, 9e45, 10a–d46. Analytical thin layer chromatography was performed on aluminum sheets of UV 254 Merck silica gel, and flash chromatography using SilicaFlash P60 silica gel (40–63 µm). 1H and 13C NMR spectra were recorded with Bruker Avance III HD 400 MHz or Varian Gemini 500 MHz and NMR chemic al shifts were reported in δ (ppm) using residual solvent peaks as standards, with the coupling constant J measured in Hz. High resolution mass spectra were recorded with an Agilent 6540 Q TOF system High resolution (HRMS) was recorded on Agilent 6540 QTOF.
General procedure for preparation of compounds 12aa-da, 13ga
A solution of enaminone 10a–d (0.5 mmol) in 5 ml of DCE and molecular sieves were placed in a round bottom flask with a stir bar and heated to 55 °C. Then 2 mmol of acyl Meldrum's acid 9a–f were added in 4 portions every 1 h. The formation of enamide was monitored by TLC. When the spot of enaminone was no longer observed 0.8 g of PPA was added. The reaction mixture was then heated to reflux, left for 6 h and after that DCE was evaporated. The residue was then suspended in water, cooled in the ice bath and neutralized with NaOH. Next, the resulting suspension was subjected to extraction with AcOEt and DCM. Organic layers were washed with brine and dried with anhydrous MgSO4 The final product was isolated by flash column chromatography (C:M 200:1 and if needed A:H 2:1).
General procedure for preparation of compounds 11aa–ga
A solution of dimedone enaminone 10a (0.5 mmol) in 5 ml of DCE and molecular sieves were placed in a round bottom flask with a stir bar and heated to 55 °C. Then 2 mmol of acyl Meldrum's acid 9a–g were added in 4 portions every 1 h. The formation of enamide was monitored by TLC. When the spot of enaminone was no longer observed, DCE was evaporated. The final product was isolated by flash column chromatography C:M 120:1.
Data availability
The datasets presented in the current study are available from the corresponding author on reasonable request.
References
Faúndez-Parraguez, M. et al. New pyridone-based derivatives as cannabinoid receptor type 2 agonists. Int. J. Mol. Sci. 22, 11212 (2021).
Huffman, J. W., Lu, J., Hynd, G., Wiley, J. L. & Martin, B. R. A pyridone analogue of traditional cannabinoids. A new class of selective ligands for the CB2 receptor. Bioorg. Med. Chem. 9, 2863–2870 (2001).
Aytemir, M. D., Uzbay, T. & Erol, D. D. New 4(1H)-pyridinone derivatives as analgesic agents. Arzneimittelforschung 49, 250–254 (1999).
Öztürk, G., Erol, D. D., Aytemir, M. D. & Uzbay, T. New analgesic and antiinflammatory agents 4(1H)-pyridinone derivatives. Eur. J. Med. Chem. 37, 829–834 (2002).
Li, R. et al. Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase. J. Med. Chem. 49, 1006–1015 (2006).
Lv, Z. et al. Design and synthesis of novel 2′-hydroxy group substituted 2-pyridone derivatives as anticancer agents. Eur. J. Med. Chem. 67, 447–453 (2013).
Kamauchi, H. et al. Synthesis and antifungal activity of polycyclic pyridone derivatives with anti-hyphal and biofilm formation activity against Candida albicans. Bioorg. Med. Chem. Lett. 37, 127845 (2021).
Sims, G. K. & Sommers, L. E. Degradation of pyridine derivatives in soil. J. Environ. Qual. 14, 580–584 (1985).
Ensign, J. C. & Rittenberg, S. C. A crystalline pigment produced from 2-hydroxypyridine by Arthrobacter crystallopoietes n.sp. Arch. Mikrobiol. 47, 137–153 (1963).
Ryczkowska, M., Maciejewska, N., Olszewski, M., Witkowska, M. & Makowiec, S. Design, synthesis, and biological evaluation of tetrahydroquinolinones and tetrahydroquinolines with anticancer activity. Sci. Rep. 12, 9985 (2022).
Ryczkowska, M., Maciejewska, N., Olszewski, M., Witkowska, M. & Makowiec, S. Tetrahydroquinolinone derivatives exert antiproliferative effect on lung cancer cells through apoptosis induction. Sci. Rep. 12, 19076 (2022).
Lin, S. et al. Recent advances of pyridinone in medicinal chemistry. Frot. Chem. 10, 869860 (2022).
Fried, J. & Elderfield, R. C. Studies on lactones related to the cardiac aglycones. V. Synthesis of 5-alkyl-α-pyrones. J. Org. Chem. 06, 566–576 (1941).
Konno, K., Hashimoto, K., Ohfune, Y., Shirahama, H. & Matsumoto, T. Acromelic acids A and B. Potent neuroexcitatory amino acids isolated from Clitocybe acromelalga. J. Am. Chem. Soc. 110, 4807–4815 (1988).
Nagano, H., Nawata, Y. & Hamana, M. Reactions of nicotinic acid 1-oxide with propionic, phenylacetic and benzoic anhydrides. Chem. Pharm. Bull. 35, 4093–4100 (1987).
Schmidt, G., Reber, S., Bolli, M. H. & Abele, S. Practical and scalable synthesis of S1P1 receptor agonist ACT-209905. Org. Process Res. Dev. 16, 595–604 (2012).
Henecka, H. β-Dicarbonyl compounds. V. The condensation of acetoneoxalic ester and O-ethylacetoneoxalic ester with cyanoacetamide. Chem. Ber. 82, 36–41 (1949).
Elvidge, J. A. & Zaidi, N. A. Heterocyclic syntheses with malonyl chloride. Part IX. 2-Substituted 4-chloro-6-pyrimidones from certain nitriles. J. Chem. Soc. C, 2188–2198 (1968).
Hung, N. C. & Bisagni, E. A general route to 5- and 6-substituted 4-amino-2-oxo-1,2-dihydropyridines. Synthesis 9, 765–766 (1984).
Abaszadeh, M., Sheibani, H. & Saidi, K. The reaction of (chlorocarbonyl)phenyl ketene with enaminones: A novel synthesis of some 5-acyl-4-hydroxy-2- (1H)-pyridinones and 7-hydroxy-5-oxo-1,4-diazepin derivative. J. Heterocycl. Chem. 46, 96–99 (2009).
Guillemont, J. et al. Synthesis and biological evaluation of C-5 methyl substituted 4-arylthio and 4-aryloxy-3-iodopyridin-2(1H)-one type anti-HIV agents. J. Med. Chem. 52, 7473–7487 (2009).
Pettit, G. R., Fleming, W. C. & Paull, K. D. Synthesis of the 6- and 7-hydroxy-5,8-dioxocarbostyrils. J. Org. Chem. 33, 1089–1092 (1968).
Fernández, M., de la Cuesta, E. & Avendaño, C. Synthesis of 5-methoxy-2(1H)-quinolinone. Heterocycles 38, 2615–2620 (1994).
Stokes, S. et al. Preparation of spirocyclohexane derivatives, pharmaceutical compositions containing them and their uses as anti-apoptotic inhibitors. WO2022152705A1 (2022).
Gatta, F., Del Giudice, M. R., Pomponi, M. & Marta, M. Synthesis of 1,2,3,4-tetrahydroacridine and 5,6,7,8-tetrahydroquinoline derivatives as potential acetylcholinesterase inhibitors. Heterocycles 34, 991–1004 (1992).
Huilai, Y., Jie, M. & Xuexi, S. A method of preparing of blonanserin. CN 104447551 (2015).
Sakurai, A. & Midorikawa, H. The cyclization of ethyl acetoacetate and ketones by ammonium acetate. Bull. Chem. Soc. Jpn. 41, 165–167 (1968).
Chen, G. et al. Ligand-enabled β-C–H arylation of α-amino acids without installing exogenous directing groups. Angew. Chem. Int. Ed. 56, 1506–1509 (2017).
Zakaszewska, A., Najda-Mocarska, E. & Makowiec, S. A new approach to the stereoselective synthesis of trans-3-carbamoyl-b-lactam moieties. N. J. Chem. 41, 2479 (2017).
Zakaszewska, A., Najda-Mocarska, E. & Makowiec, S. Evidence for an umpolung type of [2+2] cycloaddition of 2-carbamoyl ketenes. N. J. Chem. 41, 6067 (2017).
Janikowska, K., Pawelska, N. & Makowiec, S. One step synthesis of b-lactams with retro-amide side chain. Synthesis 1, 69–72 (2011).
Szewczyk, M., Punda, P., Janikowska, K. & Makowiec, S. Design, synthesis, and molecular docking of new 5-HT reuptake inhibitors based on modified 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold. J. Chem. Sci. 131, 45 (2019).
Lipson, V. V. & Gorobets, N. Y. One hundred years of Meldrum’s acid: Advances in the synthesis of pyridine and pyrimidine derivatives. Mol. Divers. 13, 399–419 (2009).
Dumas, A. M. & Fillion, E. Meldrum’s acids and 5-alkylidene Meldrum’s acids in catalytic carbon-carbon bond-forming processes. Acc. Chem. Res. 43, 440–454 (2010).
Prajakta, N. N., Nabil, A. H. A. & Radhika, S. K. Beckmann rearrangement for the synthesis of derivatives of β- and γ-carbolinones, dihydropyrrolopyridinone and tetrahydroisoquinolinone. ARKIVOC 7, 362 (2015).
Maertens, F., Toppet, S., Hoornaert, G. J. & Compernolle, F. Incorporation of an indole-containing diarylbutylamine pharmacophore into furo[2,3-a]carbazole ring systems. Tetrahedron 61, 1715 (2005).
Tunbridge, G. A., Oram, J. & Caggiano, L. Design, synthesis and antiproliferative activity of indole analogues of indanocine. Med. Chem. Commun. 4, 1452–1456 (2013).
Marcos, A., Pedregal, C. & Avendaño, C. Synthesis of 2- and 4-oxo-1H-1-azaanthracene-9,10-diones from 2-amino-1,4-naphthoquinone. Tetrahedron 50, 12941–12952 (1994).
Angelov, P., Velichkova, S. & Yanev, P. 4-Aminoalkyl quinolin-2-one derivatives via Knorr cyclisation of ω-amino-β-keto anilides. Molbank 3, M1266 (2021).
Gao, W. T., Hou, W. D., Zheng, M. R. & Tang, L. J. Clean and convenient one-pot synthesis of 4-hydroxycoumarin and 4-hydroxy-2-quinolinon derivatives. Synth. Commun. 40, 732–738 (2010).
Park, S. J., Lee, J. C. & Lee, K. I. A facile synthesis of 4-hydroxycoumarin and 4-hydroxy-2-quinolone derivative. Bull. Korean Chem. Soc. 28, 1203–1205 (2007).
Chemaxon pKa calculator. https://chemaxon.com/calculators-and-predictors
Khopade, T. M., Warghude, P. K., Mete, T. B. & Bhat, R. G. Acyl/aroyl Meldrum’s acid as an enol surrogate for the direct organocatalytic synthesis of α, β unsaturated ketones. Tetrahedron Lett. 60, 197–200 (2019).
Emtenäs, H., Alderin, L. & Almqvist, F. An enantioselective ketene-imine cycloaddition method for synthesis of substituted ring-fused 2-pyridinones. J. Org. Chem. 66, 6756–6761 (2001).
Pita, B., Masaguer, C. F. & Raviña, E. New synthetic approaches to CNS drugs. A straightforward, efficient synthesis of tetrahydroindol-4-ones and tetrahydroquinolin-5-ones via palladium-catalyzed oxidation of hydroxyenaminones. Tetrahedron Lett. 43, 7929–7932 (2002).
Chandran, R. et al. Copper-catalyzed thiolation of terminal alkynes employing thiocyanate as the sulfur source leading to enaminone-based alkynyl sulfides under ambient conditions. Org. Lett. 22, 6557–6561 (2020).
Acknowledgements
The financial support to maintenance of research facilities used in these studies from Gdańsk University of Technology by the DEC-2/2021/IDUB/V.6/Si grant under the SILICIUM SUPPORTING CORE R&D FACILITIES “Excellence Initiative—Research University” program is gratefully acknowledged.
Author information
Authors and Affiliations
Contributions
M.R. conducted the experiments of compounds synthesis, analyzed data, and wrote the manuscript; A.T. and A.H. analyzed data, wrote the manuscript; S.M. conceived the experiments, conducted preliminary experiments, wrote the manuscript, and analyzed data,. All authors reviewed the manuscript. The manuscript was written through the contributions of all authors. All authors approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Ryczkowska, M., Trocka, A., Hromova, A. et al. Meldrum’s acid assisted formation of tetrahydroquinolin-2-one derivatives a short synthetic pathway to the biologically useful scaffold. Sci Rep 14, 487 (2024). https://doi.org/10.1038/s41598-023-50535-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-023-50535-0
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
