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Communication

Palladium-Catalyzed α-Arylation of Esters: Synthesis of the Tetrahydroisoquinoline Ring

by
Georgeta Serban
1,* and
Faïza Diaba
2,*
1
Pharmaceutical Chemistry Department, Faculty of Medicine and Pharmacy, University of Oradea, Nicolae Jiga 29, 410028 Oradea, Romania
2
Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB, Universitat de Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Reactions 2025, 6(1), 17; https://doi.org/10.3390/reactions6010017
Submission received: 7 January 2025 / Revised: 9 February 2025 / Accepted: 25 February 2025 / Published: 1 March 2025
(This article belongs to the Special Issue Feature Papers in Reactions in 2025)
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Abstract

:
The palladium-catalyzed cross-coupling reaction used for carbon–carbon bond formation is one of the most commonly applied reactions in modern organic synthesis. In this work, a concise strategy was developed for constructing the tetrahydroisoquinoline core, a key structural motif found in many biologically active compounds. This method involves the palladium-catalyzed intramolecular coupling of aryl iodides with ester enolates generated in the presence of K3PO4 as a base, resulting in the formation of the tetrahydroisoquinoline ring with an exceptionally high yield of 84%.

1. Introduction

Heterocyclic compounds play a crucial role in various applied fields of organic chemistry, including medicinal, agrochemical, and veterinary [1,2]. Carbon atoms ensure the stability of carbon rings. The substitution of carbon atoms in carbocycles with heteroatoms such as nitrogen, oxygen, or sulphur imparts unique physical and chemical properties to the heterocycles. These properties are primarily due to the high electron density of the lone pair electrons, which can modify or influence the biological effects of the parent compound [2].
The tetrahydroisoquinoline moiety is a privileged scaffold in one of the largest classes of alkaloids, known for their diverse biological effects and particularly complex structures, such as the following: Erythrina alkaloids, for example erythravine, 11-α-hydroxyerythravine, and 11-α-hydroxyerysotrine have an anxiolytic effect. Additionally, erysodine is a competitive antagonist of neuronal nicotinic acetylcholine receptors nAChRs and moderates radical scavenging activity. Eysovine, erysotrine, erythraline have an insecticidal activity [3]. Aporphine alkaloids, such as boldine, magnoflorine, nuciferin, and thaliporphine, decrease intestinal glucose absorption and also the fasting blood glucose level, improve glucose metabolism, stimulate insulin secretion, and therefore prevent type 2 diabetes mellitus and other components of metabolic syndrome [4]. Apomorphine–D1 and D2 are dopamine agonists used for Parkinson’s disease treatment, meanwhile glaucine is a bronchodilator, antitussive and a psychoactive substance [5,6]. In addition, Protoberberine alkaloids namely tetrahydropalmatine has an analgesic and sedative effects and is used in anti-cocaine addiction medication [7]. Benzyltetrahydroisoquinoline alkaloids for instance reticuline, a dopamine receptor antagonist has a central nervous system depressing effect [8]. Additionally, (+)-laudanosine, which shows affinity for various neuronal receptors such as GABA, opioids, and nAChRs, has shown potential as treatment for various CNS disorders such as depression, schizophrenia, Alzheimer’s, and Parkinson’s diseases [9,10,11]. Furthermore, bisbenzyltetrahydroisoquinoline alkaloids, like (-)-antioquine has an anti-Trypanosoma cruzi activity [12], D-(+)-tubocurarine is a non-depolarizing neuromuscular blocking agent [13]) and Morphinan alkaloids in particular morphine and codeine have analgesic and antitussive effects [13]). It is also worth mentioning Saframycin alkaloids namely Saframycins, Safracins, and Renieramycins, are natural antibiotics with antiproliferative and antimicrobial activities [14,15,16], Ecteinascidin alkaloids like Ecteinascidin ET-743 with commercial name Trabectedin/Yondelis, is a DNA alkylating agent of specific nucleotide sequences in the minor groove, approved in combination with other antitumor drugs for the treatment of several types of soft tissue sarcomas [15,17,18], Pavine and Isopavine alkaloids e.g., (-)-argemonine, is a protein kinase inhibitor and potential anticancer drug, and neocaryachine and its derivatives which have antiarythmic properties [19,20]. Not to mention Quinocarcin alkaloids e.g., quinocarcinol, tetrazomine as antitumor agents [13,21]), Phtalide-tetrahydroisoquinoline alkaloids e.g., noscapine, which has antitussive and antitumor activities) [22,23], or other known compounds such as emetine, an anti-protozoal, and potential chemotherapeutic agent [9,22,24] (Figure 1). For these reasons, the 1,2,3,4-tetrahydroisoquinoline ring system has attracted much attention in the scientific community, leading to the development of many synthetic analogues that possess a wide spectrum of biological properties, such as OX1 and/or OX2 orexin receptor ligands with potential in the treatment of sleep disorders [25]; D1 and/or D2 dopamine receptor ligands with potential in the treatment of psychiatric and neurological disorders [26,27], neuroprotective effect in Parkinson’s disease [28], antidepressant activity [29]; and acetyl- and butyrylcholinesterase inhibition and their potential as anti-Alzheimer agents [30], anti-inflammatory properties [31], antitumor activity [32,33], antispasmodic effect [34], anti-tuberculosis activity [35], antibacterial activity against both Gram-positive and Gram-negative bacterial strains [36], anf finally antiviral activity [37] among others.
Given the importance of the tetrahydroisoquinoline scaffold for organic and medicinal chemistry, extensive research has been dedicated to the synthesis of this bicyclic structure. The literature highlights the Pictet–Spengler and Bischler–Napieralski reactions as the most widely used methods for synthesizing the tetrahydroisoquinoline moiety [13,27,35,38,39]). Other strategies, defined as multicomponent reactions [40], lead to the synthesis of the tetrahydroisoquinoline ring by applying different types of reactions, such as Heck/aza–Michael cyclization [9,41,42], Knoevenagel condensation/Michael addition/Thorpe–Ziegler cyclization-tautomerization [43], aza–Diels–Alder [44] or Ugi reaction [45], etc.
As part of our concerns regarding nitrogen heterocycles [46,47,48,49,50], our aim was to carry out a study on the synthesis of tetrahydroisoquinoline core via carbon–carbon bond formation using palladium-catalyzed intramolecular coupling of aryl iodides with ester enolates. Herein we present our preliminary results on this methodology.

2. Results and Discussion

Synthesis of the tetrahydroisoquinoline ring by intramolecular palladium-catalyzed α-arylation of α-amino acid esters carrying an aryl-bromide moiety was reported by Buchwald [51]. On the other hand, the tetrahydroisoquinoline ring formation by intramolecular palladium-catalyzed α-arylation of β-amino acid esters bearing an aryl-bromide moiety has also been reported [52,53]. Our approach to the synthesis of tetrahydroisoquinoline core A involves the formation of a carbon–carbon bond by palladium-catalyzed intramolecular α-arylation of β-(N-2-iodobenzyl)-amino ester B which in turn can be obtained from the commercially available benzylamine 1 (Scheme 1).
Methyl 1,2,3,4-tetrahydro-2-(phenylmethyl)-4-isoquinolinecarboxylate 4 was synthesized as follows. Benzylamine 1 was subjected to a one-pot sequential intermolecular aza–Michael addition and alkylation to give tertiary amine 3. Thus, benzylamine 1 underwent an intermolecular aza–Michael addition to methyl acrylate in anhydrous ethanol at room temperature [54], yielding the corresponding secondary amine 2. The ethanol was then removed under vacuum, and the reaction mixture was subjected to subsequent alkylation with 2-iodobenzyl chloride under basic conditions (K2CO3) in the presence of a catalytic amount of LiI, resulting in the formation of tertiary amine 3 in an excellent yield (95%) (Scheme 2). The latter features a complex structure that combines the β-alanine methyl ester and 2-iodobenzyl moieties, positioning this molecule as a valuable intermediate for the intramolecular palladium-catalyzed arylation of enolate-type nucleophiles. Moreover, previous studies showed that two alternative cyclization pathways involving either intramolecular enolate α-arylation of β-amino acid esters (giving the tetrahydroisoquinoline 4) or the nucleophilic substitution at the ester group (giving the tetrahydrobenzazepinone 5) can operate in the palladium-catalyzed intramolecular coupling of nitrogen-containing substrates [55,56]. Therefore, studying the intramolecular coupling pathway of 3 was another challenge (Scheme 3).
The palladium-assisted coupling reaction of 3 in dry THF was then examined. When amine 3 was submitted to the cyclization conditions using Pd(PPh3)4 (0.05 equiv) as catalyst, t-BuOK (2.5 equiv) as base, and PhOH (3 equiv) as additive in THF at reflux and under argon atmosphere, the coupling reaction did not proceed, giving only acid 6 resulting from ester hydrolysis and the recovered starting material (3, 67%) (Table 1, entry 1). Using a higher amount of catalyst Pd(PPh3)4 (0.2 equiv) under the same reaction conditions let us recover starting material in a lower amount (3, 31%) without other product, but there is a very interesting NMR chart of the crude extract showing the characteristic signals of the azapalladacycle 7 (Tabel 1, entry 2). This proved that the ligand and the catalyst could be effective and certain changes in the nature and concentration of the base can increase the enolization rate of the ester and favour the cyclization reaction. When K3PO4 was used instead of t-BuOK and the reaction was carried out in a sealed tube at 110 °C in THF without PhOH, the intramolecular coupling occurred exclusively at the α-position following the enolate arylation pathway and giving the tetrahydroisoquinoline 4 in a very good yield (84%) (Tabel 1, entry 3).
It should be noted that Pd(PPh3)4 as a catalyst enabled the cyclization reaction, showing that more bulky, hindered ligands can be very effective for these experiments. A single reaction product was obtained, showing that there was no competition between enolate α-arylation and the nucleophilic substitution at the methoxycarbonyl group. Tetrahydroisoquinoline 4 was obtained in a good yield, even though the cyclization reaction to form the six-membered ring was slower. The base has an important role in the deprotonation step of enolate formation. tBuOK and PhOK, which are formed in situ from PhOH and tBuOK, were ineffective in our study. Anyway, the pKa of phenol is lower compared to that of esters, which could justify this result [56]. A weak base, such as K3PO4, accomplished the cyclization in good yield. In addition, the potassium ion may play a significant role in the azapalladacycle formation step [52], as well as in the removal step of the iodide ligand [57].
Scheme 4 shows a plausible mechanism for the palladium-catalyzed intramolecular cyclization. The reaction exploits the electrophilic character of the palladium atom and it is presumed to proceed by sequential oxidative addition of aryl iodide 3 to Pd(0) species and deprotonation under basic conditions to form the enolate, followed by conversion to the five-membered azapalladacycle that undergoes transmetalation and reductive elimination steps to regenerate the Pd(0) catalyst and give the cyclization product 4 [56].
To examine the applicability of this methodology, we tried to obtain a more hindered tetrahydroisoquinoline and methyl-3-[N-(2-iodobenzyl)-N-benzylamino]-2-methyl propanoate 9 was synthesized through a synthetic route similar to that used for compound 3 (one-pot sequential intermolecular aza–Michael addition and alkylation). Therefore, benzylamine 1 was treated with methyl methacrylate in anhydrous methanol, under reflux. After removal of methanol under vacuum, the obtained secondary amine 8 was subjected to alkylation with 2-iodobenzyl chloride giving the tertiary amine 9 (63%) (Scheme 5). When 9 was submitted to the optimized conditions for the palladium-catalyzed intramolecular α-arylation, no cyclization took place. The steric hindrance at the α position, as well as the lower reactivity and higher instability of the β-amino ester moiety under basic conditions made the enolization a more difficult step and prevented obtaining the substituted terahydroisoquinoline 10. The 1H-NMR and 13C-NMR spectra of compounds 3, 4 and 9 are available in the Supplementary Material.

3. Conclusions

In conclusion, Pd-catalyzed intramolecular α-arylation of β-amino esters from the corresponding aryl iodide derivative was investigated in the presence of Pd(PPh3)4 to synthesize the tetrahydroisoquinoline ring with an excellent yield. Formation of the enolate, prior to cyclization, does not require a strong base, as it was reported previously, since K3PO4 was effective over t-BuOK or PhOK.

4. Experimental Section

General: 1H and 13C NMR spectra were recorded in CDCl3 solution by a Gemini-200 and a Bruker 400 spectrometers. Chemical shifts are reported as δ values (ppm) relative to internal standard Me4Si and 13C NMR spectra are referenced to the deuterated solvent signal (CDCl3: 77.00 ppm). The IR spectra were recorded on a Nicolet 320 FT-IR spectrophotometer and the only noteworthy absorptions are listed (cm−1). The FAB-MS spectra were determined on an AutoSpec-VG (HRMS). TLC was performed on SiO2 (silica gel 60 F254, Merck) plates. The spots were located by UV light and hexachloroplatinate reagent. Chromatography refers to flash chromatography and was carried out on Merck SiO2 (Silica 60A, 200–500 mesh). Solvents were dried and purified prior to use when necessary. Drying of organic extracts during the work-up of reactions was performed over anhydrous Na2SO4. Evaporation of solvents was accomplished with a rotary evaporator. All the experiments were carried out in an argon atmosphere, unless otherwise noted.
Methyl 3-[N-(2-iodobenzyl)-N-benzyl amino]propanoate (3). To a solution of benzylamine 1 (2 mL, 18.3 mmol) in absolute EtOH (5 mL), methyl acrylate (1.85 mL, 20.5 mmol) was added, and the mixture was stirred at room temperature for 24 h. The solvent was evaporated at a reduced pressure. The residue obtained, which contained the secondary amine 2, was dissolved in anhydrous acetonitrile (70 mL) and then 2-iodobenzyl chloride (5.05 g, 20 mmol), potassium carbonate (5.1 g, 36.6 mmol), and lithium iodide (0.1 g, catalytic amount) were added. The reaction mixture was stirred at 50 °C for 1.5 h and 16 h at room temperature. After that, the solvent was evaporated, and the residue was treated with water and extracted with CH2Cl2. The combined organic extracts were dried and concentrated and the residue obtained was purified by chromatography (SiO2, hexane-CH2Cl2 1:3) to give tertiary amine 3 (7.11 g, 95%) as a colourless oil.
Methyl 3-[N-(2-iodobenzyl)-N-benzylamino]propanoate (3). 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 7.9, 1.2 Hz, 1H), 7.50 (dd, J = 7.7, 1.7 Hz, 1H), 7.37–7.15 (m, 6H), 6.92 (ddd, J = 8.0, 7.3, 1.8 Hz, 1H), 3.64 (s, 2H), 3.62 (s, 2H), 3.61 (s, 3H), 2.84 (t, J = 7.3, 2H), 2.51 (t, J = 7.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 172.8, 141.2, 139.3, 138.9, 130.2, 128.8, 128.6, 128.2, 128.0, 127.0, 100.1, 62.4, 58.0, 51.5, 49.2, 32.3.δ. IR (NaCl) cm−1 1725, 1490, 1460, 1425, 1190, 1027. HRMS (FAB) m/z: calcd for C18H21INO2+ [M+H]+ 410.0617, found 410.0622.
Palladium catalyzed synthesis of 4 from 3. To a solution of 3 (75 mg, 0.183 mmol) in dry THF (15 mL) in a sealed tube, K3PO4 (116.5 mg, 0.549 mmol) and Pd(PPh3)4 (42.3 mg, 0.036 mmol) were added and the mixture was heated at 110 °C for 3 days. The reaction was then concentrated, and the residue was dissolved in CH2Cl2. The mixture was successively washed with a saturated solution of NaHCO3 and brine. The combined organic extracts were dried and concentrated, and the residue was purified by chromatography (SiO2, CH2Cl2) to give isoquinoline derivative 4 (43 mg, 84%) as a colourless oil.
Methyl 1,2,3,4-tetrahydro-2-(phenylmethyl)-4-isoquinolinecarboxylate (4). 1H NMR (400 MHz, CDCl3) δ 7.40–7.25 (m, 5H), 7.23–7.15 (m, 3H), 7.07–7.00 (m, 1H), 3.86 (t, J = 5.1 Hz, 1H), 3.80 (d, J = 15.0 Hz, 1H), 3.74 (d, J = 13.2 Hz, 1H), 3.68 (s, 3H), 3.65 (d, J = 13.2 Hz, 1H), 3.59 (d, J = 15.0 Hz, 1H), 3.17 (ddd, J = 11.5, 5.1, 1.0 Hz, 1H), 2.83 (ddd, J = 11.5, 5.1, 0.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 173.7, 138.0, 135.1, 131.4, 129.3, 128.9, 128.2, 127.2, 126.9, 126.7, 126.3, 62.2, 56.0, 52.8, 52.1, 45.4. IR (NaCl) cm−1 1722, 1620, 1493, 1452, 1120, 1093. HRMS (FAB) m/z: calcd for C18H20NO2+ [M+H]+ 282.1494, found 282.1503.
Methyl 3-(benzylamino)-2-methyl propanoate (8). To a solution of benzylamine 1 (1.15 mL, 10.5 mmol) in absolute MeOH (50 mL), methyl methacrylate (3.45 mL, 32.25 mmol) was added and the mixture was stirred at reflux for 72 h. The solvent was evaporated under reduced pressure to give secondary amine 8 as a colourless oil (1.88 g, 87%). 1H-NMR (200 MHz, CDCl3) δ 7.30-7.32 (m, 5H, Ar-H), 3.78 (s, 2H, CH2Ar), 3.67 (s, 3H, OCH3), 2.9 (q, J = 7.5 Hz, 1H, CH), 2.65 (d, J = 5 Hz, 2H, N-CH2), 1.74 (s, 1H, NH), 1.16 (d, J = 6.8 Hz, 3H, CH3).
Methyl 3-[N-(2-iodobenzyl)-N-benzylamino]-2-methylpropanoate (9). Amine 8 (0.76 g, 3.67 mmol) was dissolved in anhydrous acetonitrile (35 mL) and then 2-iodobenzyl chloride (1 g, 4 mmol), potassium carbonate (1.01 g, 7.34 mmol), and lithium iodide (0.05 g, catalytic amount) were added. The reaction mixture was stirred at 50 °C for 5 h and then for 3 days at room temperature. The reaction was concentrated and the residue was treated with water and extracted with CH2Cl2. The combined organic extracts were dried and concentrated, and the residue obtained was purified by chromatography (SiO2, hexane-CH2Cl2 1:1) to give tertiary amine 9 (0.98 g, 63%) as a colourless oil. 1H-NMR (200 MHz, CDCl3) δ 1.07 (d, J = 7 Hz, 3H, CH3), 2.45 (m, 2H), 2.79 (m, 3H), 3.60 (m, 2H), 3.62 (s, 3H, OCH3), 3.65 (m, 2H), 6.85 (m, 1H, Ar-H), 7.20-7.35 (m, 6H, Ar-H), 7.5 (m, 1H, Ar-H), 7.78 (m, 1H, Ar-H). 13C NMR (75 MHz, CDCl3) δ 15.51 (CH3), 38.55 (CH), 51.54 (CH3), 57.44 (CH2), 58.67 (CH2), 62.86 (CH2), 100.14 (C), 126.96 (CH), 127.99 (CH), 128.10 (2 CH), 128.56 (CH), 128.94 (2 CH), 130.21 (CH), 138.67 (C), 139.13 (CH), 141.20 (C), 175.99 (C). IR (NaCl) cm−1 1724, 1538, 1495, 1455, 1205, 1033. HRMS (FAB) m/z: calcd for C19H23INO2 424.0773 [M+H]+, found 424.0768.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/reactions6010017/s1, S1 and S2: 1H and 13C NMR spectra of 3, S3: 1H and 13C NMR spectra of 4, S4: 1H and 13C NMR spectra of 9.

Author Contributions

Conceptualization, G.S. and F.D.; methodology, F.D. and G.S.; investigation, G.S. and F.D.; data curation, G.S. and F.D.; writing—original draft preparation, G.S.; writing—review and editing, F.D. and G.S.; supervision, F.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data are contained within the article and the Supplementary Material.

Acknowledgments

This research was carried out at the University of Barcelona. GS would like to thank the Romanian Government for the financial support through a “Nicolae Titulescu” scholarship, as well as to Daniel Sole, Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Spain for his advice and support.

Conflicts of Interest

The authors declare no conflicts of interest.

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Reactions 06 00017 g001
Figure 1. Representative examples of biologically active tetrahydroisoquinoline derivatives.
Figure 1. Representative examples of biologically active tetrahydroisoquinoline derivatives.
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Scheme 1. Retrosynthesis of the tetrahydroisoquinoline core.
Scheme 1. Retrosynthesis of the tetrahydroisoquinoline core.
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Scheme 2. Synthesis of methyl 3-[N-(2-iodobenzyl)-N-benzylamino]propanoate 3.
Scheme 2. Synthesis of methyl 3-[N-(2-iodobenzyl)-N-benzylamino]propanoate 3.
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Scheme 3. Two possible palladium-catalyzed intramolecular coupling pathways from 3.
Scheme 3. Two possible palladium-catalyzed intramolecular coupling pathways from 3.
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Scheme 4. Proposed mechanism for the intramolecular palladium-catalyzed α-arylation of compound 3.
Scheme 4. Proposed mechanism for the intramolecular palladium-catalyzed α-arylation of compound 3.
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Scheme 5. Synthesis and palladium-assisted coupling experiments of methyl-3-[N-(2-iodo benzyl)-N-benzylamino]-2-methylpropanoate 9.
Scheme 5. Synthesis and palladium-assisted coupling experiments of methyl-3-[N-(2-iodo benzyl)-N-benzylamino]-2-methylpropanoate 9.
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Table 1. Palladium-catalyzed intramolecular coupling of 3.
Table 1. Palladium-catalyzed intramolecular coupling of 3.
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EntryCatalyst
(equiv)		Additive (equiv)Base (equiv)Temp
(°C)		Time
(h)		Yield (%)
346
1Pd(PPh3)4 (0.05)PhOH (3)t-BuOK (2.5)reflux4867-31
2Pd(PPh3)4 (0.2)PhOH (3)t-BuOK (2.5)reflux4831--
3Pd(PPh3)4 (0.2)-K3PO4 (3)11072-84-
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Serban, G.; Diaba, F. Palladium-Catalyzed α-Arylation of Esters: Synthesis of the Tetrahydroisoquinoline Ring. Reactions 2025, 6, 17. https://doi.org/10.3390/reactions6010017

AMA Style

Serban G, Diaba F. Palladium-Catalyzed α-Arylation of Esters: Synthesis of the Tetrahydroisoquinoline Ring. Reactions. 2025; 6(1):17. https://doi.org/10.3390/reactions6010017

Chicago/Turabian Style

Serban, Georgeta, and Faïza Diaba. 2025. "Palladium-Catalyzed α-Arylation of Esters: Synthesis of the Tetrahydroisoquinoline Ring" Reactions 6, no. 1: 17. https://doi.org/10.3390/reactions6010017

APA Style

Serban, G., & Diaba, F. (2025). Palladium-Catalyzed α-Arylation of Esters: Synthesis of the Tetrahydroisoquinoline Ring. Reactions, 6(1), 17. https://doi.org/10.3390/reactions6010017

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