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Communication

Regio- and Stereoselective Switchable Synthesis of (E)- and (Z)-N-Carbonylvinylated Pyrazoles

by
Xue Zhang
,
Zheyu Zhang
,
Haifeng Yu
* and
Guangbo Che
*
College of Chemistry, Baicheng Normal University, Baicheng 137000, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(11), 4347; https://doi.org/10.3390/molecules28114347
Submission received: 27 April 2023 / Revised: 18 May 2023 / Accepted: 23 May 2023 / Published: 25 May 2023
(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Nitrogen-Containing Heterocyclic Compounds)
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Abstract

:
Regio- and stereoselective switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. Ag2CO3 plays a key role in the switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles. Ag2CO3-free reactions lead to thermodynamically stable (E)-N-carbonylvinylated pyrazoles in excellent yields whereas reactions with Ag2CO3 give (Z)-N-carbonylvinylated pyrazoles in good yields. It is noteworthy that (E)- or (Z)-N1-carbonylvinylated pyrazoles are obtained with high regioselectivity when asymmetrically substituted pyrazoles react with conjugated carbonyl alkynes. The method can also extend to the gram scale. A plausible mechanism is proposed on the basis of the detailed studies, wherein Ag+ acts as coordination guidance.

1. Introduction

N-Functionalized pyrazoles are often found in many products with high biological and pharmacological activities [1,2,3,4,5,6,7,8]. During the past two decades, the synthesis of N-vinylated pyrazoles as an important subset of N-functionalized pyrazoles has attracted huge interest from chemists due to their privileged core structures in many biologically active products (Figure 1) [9,10,11,12] and the good further transformations of their alkenyl group in organic synthesis [13,14,15]; therefore, various synthetic methods have been developed. These methods include the La(OTf)3-catalyzed tandem aza-Michael addition/cyclization reactions of N-tosylhydrazones and alkynes [16], Et3N-mediated N-vinylation of (β-trifluoromethyl)vinyl sulfonium salt and pyrazoles [17], copper-catalyzed N-vinylation of pyrazoles and vinyl halides or vinylboronic acids [18,19,20,21,22], photocatalytic dehydrogenative cross-coupling of pyrazoles with electron-poor alkenes [23], and the Lewis-acid- or Ruthenium-complex-catalyzed addition of pyrazoles to alkynes [24,25]. However, these reported methods have usually produced thermodynamically stable (E)-N-vinylated pyrazoles or a mixture of E/Z isomers. In fact, the Z and E isomers of products usually exhibit different biological activities. For example, (Z)-1-ethyl-7-((4-methoxy-3-methylphenyl)diazenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was found to be 4- and 8-fold active on E. coli (Gram-negative) and M. luteus (Gram-positive) [26,27]. Therefore, it was necessary and highly desirable to develop the switchable synthesis of (Z)- and (E)-N-vinylated pyrazoles in regio- and stereoselective fashions. Recently, several research groups have focused on this investigation. In 2010, Cook and co-workers stereoselectively prepared (Z)- and (E)-N-vinylated pyrazoles by copper-catalyzed cross-coupling reactions of pyrazoles with (Z)- and (E)-vinyl halides (Scheme 1A) [28]. From the viewpoint of green chemistry, this method is not atomically economical and environmentally friendly due to it producing large amounts of alkali halide and using expansive vinyl halides. Later, to develop synthetic methods with atomic economy, based on the strategy of catalyst-controlled product stereoselectivity, Bhattacharjee and co-workers developed Ru complex- (i.e., [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4] and [Ru(dppp)2(CH3CN)Cl][BPh4])-catalyzed stereoselective N-vinylation of pyrazoles and alkynes, and efficiently synthesized (E)- and (Z)-N-vinylated pyrazoles, respectively (Scheme 1B) [29]. In another recent report, Verma and co-workers realized KOH-mediated stereoselective synthesis of (Z)- and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, in which the stereochemical outcome of the reaction was governed by time and the quantity of the base (Scheme 1C) [30]. Although two examples revealed good stereoselective synthesis of (Z)- and (E)-N-vinylated pyrazoles by the addition of pyrazoles to alkynes, no work has been directed to study the stereoselective addition of pyrazoles with conjugated carbonyl alkynes to prepare N-carbonylvinylated pyrazoles, presumably due to the incompatibility of carbonyl group with its optimal reaction conditions. In addition, in their work, no in-depth and detailed investigations into the regio- and stereoselective N1 or N2 vinylation of the asymmetrically substituted pyrazoles and alkynes were performed. So, the regio- and stereoselective switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles is challenging.
Considering the importance of pyrazoles, our recent research interests have focused on the synthesis of pyrazoles. A variety of N-unsubstituted pyrazoles bearing indole units have been synthesized from the cyclocondensation reaction of β-ethyltho-β-indolyl-α, β-unsaturated ketones and hydrazine hydrate or semicarbazide hydrochlorides as a hydrazine equivalent in organic solvent or water [31,32,33]. Furthermore, by controlling the reaction conditions, the regioselective synthesis of isomeric 3-(1-substituted pyrazol-3(5)-yl) indoles was also successfully realized when β- ethyltho-β-indolyl-α, β-unsaturated ketones reacted with monosubstituted hydrazines [34]. Subsequently, we developed the Ag2CO3-catalyzed aza-Michael addition of pyrazoles to α, β- unsaturated carbonyl compounds, to afford a series of N-alkylated pyrazoles in excellent yields and with high regioselectivity [35]. As a continuation of our interest in the synthesis of pyrazole derivatives, most recently, we studied the regio- and stereoselective aza-Michael addition of pyrazoles and conjugated carbonyl alkynes for the switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles (Scheme 1D). It was found that pyrazoles efficiently reacted with the conjugated carbonyl alkynes in the absence of Ag2CO3 to preferentially generate (E)-N-carbonylvinylated pyrazoles in excellent yields, while in the presence of 50 mol% of Ag2CO3, the reactions favored to afford (Z)-N-carbonylvinylated pyrazoles in good yields, in which Ag2CO3 played the key role. Herein, we report our finding.

2. Results and Discussion

The reaction of 3, 5-dimethyl-1H-pyrazole 1aa and ethyl propiolate 2a was chosen to screen the reaction conditions. The summary of these results is listed in Table 1. We proceeded the first reaction without any additives in 1, 2-dichloroethane (DCE) at room temperature for 24 h, and found this reaction produced two stable products in 60% and 30% yields, respectively (Table 1, entry 1). The products were characterized as (E)-ethyl 3-(3, 5-dimethyl-1H-pyrazol-1-yl) acrylate 3a (60%) and its (Z)-isomer 4a (30%) from the spectral and analytical data, which indicated that the reaction gave (E)-3a in preference to (Z)-4a. The reaction showed dependence on the reaction temperature; with increasing reaction temperature, the reaction became more efficient, in which the reaction time was significantly shorter and the yield of (E)-3a was markedly higher (Table 1, entries 2–5), and (E)-3a was obtained at 90% yield when the reaction ran at 60 °C for 8 h (Table 1, entry 4). Using other solvents such as toluene and 1, 4-dioxane, the reaction efficiency was not significantly improved (Table 1, entries 6 and 7). Because Ag+ easily coordinates with both the nitrogen atom of imine and oxygen atom of the carbonyl group [35,36,37,38], we envisioned that the coordination guidance of Ag+ probably favors the formation of (Z)-isomer 4a. Thus, with 10 mol% of readily available Ag2CO3 as the catalyst, we proceeded the reaction in DCE at 60 °C and 20 °C, respectively. As expected, 4a as the major product was generated at 51% and 29% yields, respectively (Table 1, entries 8 and 9). Encouraged by this result, we further increased the amount of Ag2CO3 (Table 1, entries 10–15). Raising the amount of Ag2CO3 to 50 mol% effectively improved the yield of 4a to 81% (Table 1, entry 13), while when further raising the amount of Ag2CO3, the yield of 4a failed to be obviously improved (Table 1, entries 14 and 15). Of the various reaction temperatures checked, 60 °C was found to be optimal (Table 1, entries 16 and 17). The use of AgOAc and AgNO3 as the catalyst led to the low formation of 4a (Table 1, entries 18 and 19). Accordingly, the reaction conditions were optimized as follows: condition A for the synthesis of 3 (Table 1, entry 4): DCE as solvent and 60 °C; condition B for the synthesis of 4 (Table 1, entry 12): DCE as solvent, 50 mol% of Ag2CO3 as catalyst and 60 °C.
After optimizing the reaction conditions, we explored the universality of the procedure (Scheme 2). Firstly, the generality of the reactions of various symmetrically substituted pyrazoles and conjugated carbonyl alkynes was examined, and the results are summarized in Scheme 2. Using ethyl propionate 2a as the partner, we initially studied the scope of symmetrically substituted pyrazoles 1a. A variety of 1a, such as 3, 5-identically disubstituted pyrazoles 1aa–1ad, 4-substituted pyrazoles 1ae–1ao, and 3, 5-identical disubstituted-4-substituted pyrazoles 1ap–1ar, smoothly reacted with 2a under the optimized conditions A and B to efficiently afford corresponding N-carbonylvinylated pyrazoles 3a–3r and 4a–4r in good yield and with good stereoselectivity, respectively. Clearly, the steric effects and electronic characters of substituents in 1a revealed a significant effect on the reaction rate. With the increase in steric bulk of the C3 or C5 substituent of 1aa–1ad, the reaction rate decreases. Pyrazoles with electron-donating groups, such as Me (1af), OCH3 (1ag) and Ph (1ah), displayed faster reaction rates than pyrazoles with electron-withdrawing groups, such as X (1ai–1ak), NO2 (1al), CN (1am), CO2Et (1an), and COCH3 (1ao). Moreover, many active substituents, such as X, NO2, CN, CO2Et, and COCH3, of 1a could be well tolerated in the chemical transformations. Then, under the optimized reaction conditions A and B, the scope of conjugated carbonyl alkynes 2 was examined. Like 2a, methyl propionate 2b, isopropyl propionate 2c and tert-butyl propiolate 2d efficiently reacted with 1aa to produce N-carbonylvinylated pyrazoles 3s–3u and 4s–4u at good yields and with high stereoselectivity, respectively. In the case of 1-phenylprop-2-yn-1-one 2e, the desired products 3v and 4v were also obtained at 92% yield and 87% yield, respectively.
Next, under the optimal reaction conditions A and B, we investigated in detail the reactions of the asymmetrically substituted pyrazoles 1b with conjugated carbonyl alkynes 2 to examine the regioselectivity of the method. When 3-substituted pyrazoles 1ba–1bh reacted with 2a, N1-carbonylvinylated pyrazoles 5a–5h and 6a–6h were always obtained as major products with good regioselectivity, respectively, and, especially, 1bg exclusively afforded 5g (82% yield) and 6g (84% yield). Although the electronic character imparted an obvious impact on the reaction rates, they had no significant influence on the regioselectivity of the reactions. Notably, since Rf values of 5h and 5h′ are the same, their mixtures were obtained when the reaction of 1bh and 2a was carried out under condition A, in which their molar ratio was determined as 2:1 from 1H NMR analysis. The compound 3-Methyl-5-phenyl-1H-pyrazole 1i also favored the formation of 5i with a 5i/5i′ ratio of 2:1 and 6i with a 6i/6i’ratio of 2:1, suggesting that the steric effect of the C5 substituent of 1i seemingly exerted a negligible influence on the regioselectivity. In the same fashion, a variety of conjugated carbonyl alkynes 2b–2e also efficiently reacted with 1ba to afford 5j–5m and 6j–6m with good regioselectivity. Except for 5h and 5h′, the other isomeric products of 5 and 5′, or 6 and 6′ could easily be isolated by column chromatography due to their different Rf values. It is noteworthy that the molecular structures of 3l, 4o, 5c, 5k′ and 6c were further confirmed by X-ray crystallographic analysis (Figure 2) [39]. In 3l, 5c and 5k′, the pyrazolyl and carbonyl groups are positioned anti to each other (E configuration), and these two groups are positioned cis to each other in 4o and 6c (Z configuration).
Furthermore, we carried out gram-scale reactions to demonstrate the practicality of the chemical procedure (Scheme 3 and Scheme 4). Gratifyingly, 1aa (0.96 g, 10.0 mmol) effectively reacted with 2a (1.18 mL, 12.0 mmol) to successfully afford 1.57 g (81% yield) of 3a and 1.455 g (75% yield) of 4a under the optimized conditions A and B.
Based on the above results, a plausible mechanistic pathway for the formation of 3 and 4 was proposed (Scheme 5). In the absence of Ag2CO3, 1aa and 2a underwent a Michael addition reaction to directly give (E)-3a due to thermodynamical stability of the E configuration (Path a). In the presence of Ag2CO3, the reaction proceeded based on Path b. Since Ag+ easily coordinates with both the nitrogen atom of imine and oxygen atom of the carbonyl group [35,36,37,38], it is clear that the reaction commenced from the coordination of Ag+ to N2 of 1aa and carbonyl of 2a to form intermediate I, in which 1aa and 2a are close enough and 2a is also fully activated. Subsequently, I occurs Michael addition to produce the intermediate II, in which pyrazolyl and acyl groups are positioned cis to each other by the coordination of Ag+. Finally, in the presence of AgCO3−, intermediate II produces (Z)-4a. The generated Ag2CO3 further completes the catalytic cycle.

3. Materials and Methods

3.1. General Information

1H and 13C{1H} NMR spectra were recorded on a Bruker DRX-600 spectrometer and all chemical shift values referred to δ TMS = 0.00 ppm (δ (1H)) and CDCl3(δ (13C), 77.16 ppm). The HRMS analysis was achieved on a Bruck microTof by using the ESI method. All the melting points were uncorrected. Analytical TLC plates with Sigma-Aldrich silica gel 60F200 were viewed by UV light (254 nm). Chromatographic purifications were performed on SDZF silica gel 160 (Supplementary Materials).

3.2. Typical Procedure for the Synthesis of 3a

A solution of 3,5-dimethyl-1H-pyrazole (1aa) (24.0 mg, 0.25 mmol) and ethyl propionate (2a) (30.4 μL, 0.3 mmol) was reacted in DCE (1 mL) at 60 °C. After the reaction was finished as indicated by TLC (reaction time, 8 h), the resulting mixture was poured into water (10 mL) and extracted with DCM (CH2Cl2, 3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude product with flash column chromatography (petroleum ether (60–90 °C)/ethyl acetate = 10:1, v/v) was carried out to give 3a (43.7 mg, 90%).

3.3. Typical Procedure for the Synthesis of 4a

Ag2CO3 (34.5 mg, 0.125 mmol) was added to a solution of 3,5-dimethyl-1H-pyrazole (1aa) (24.0 mg, 0.25 mmol) and ethyl propionate (2a) (30.4 μL, 0.3 mmol) in DCE (1 mL) at 60 °C. After the reaction was finished as indicated by TLC (reaction time, 12 h), the resulting mixture was poured into water (10 mL) and extracted with DCM (CH2Cl2, 10 mL × 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude product with flash column chromatography (petroleum ether (60–90 °C)/ethyl acetate = 8:1, v/v) was carried out to give 4a (39.3 mg, 81%).

3.4. Typical Procedure for the Synthesis of 5a and 5a’

A solution of 3-phenyl-1H-pyrazole (1ba) (72.0 mg, 0.5 mmol) and ethyl propionate (2a) (101.5 μL, 1.0 mmol) in DCE (1 mL) was reacted at 60 °C. After the reaction was finished as indicated by TLC (reaction time, 8 h), the resulting mixture was poured into water (10 mL) and extracted with DCM (CH2Cl2, 3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude product with flash column chromatography (petroleum ether (60–90 °C)/ethyl acetate = 10:1, v/v) was performed to give 5a (79.8 mg, 66%) and 5a′ (24.2 mg, 20%).

3.5. Typical Procedure for the Synthesis of 6a and 6a’

Ag2CO3 (69.0 mg, 0.25 mmol) was added to a solution of 3-phenyl-1H-pyrazole (1ba) (72.0 mg, 0.5 mmol) and ethyl propionate (2a) (101.5 μL, 1.0 mmol) in DCE (1 mL) at 60 °C. After the reaction was finished as indicated by TLC (reaction time, 12 h), the resulting mixture was poured into water (10 mL) and extracted with DCM (CH2Cl2, 3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude product with flash column chromatography (petroleum ether (60–90 °C)/ethyl acetate = 8:1, v/v) was performed to give 6a (86.0 mg, 71%) and 6a′ (21.8 mg, 18%).

4. Conclusions

In summary, for the first time, the regio- and stereoselective synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles was successfully realized by the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. Symmetrically substituted pyrazoles stereoselectively gave (E)- and (Z)-N-carbonylvinylated pyrazoles in good yields, respectively. In the case of asymmetrically substituted pyrazoles, the reaction revealed not only excellent stereo-selectivity but also good regioselectivity. These features, such as the high regio- and stereoselectivity, commercially available catalyst, good substrate scope, mild conditions and scalability, made the methodology very practical and attractive. Further investigations on the applications of N-carbonyl vinylated pyrazoles are currently underway in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28114347/s1, Characterization data for product 3, 4, 5, 5’, 6 and 6’ Including 1 HNMR and 13 CNMR spectroscopies, are available online.

Author Contributions

Conceptualization and writing—review and editing, H.Y.; methodology, H.Y. and G.C.; investigation, data curation and writing—original draft preparation and writing—review and editing, X.Z. and Z.Z.; project administration, X.Z. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to Funds for the Natural Science Foundation of Jilin Province, China [YDZJ202201ZYTS364, 20210101128JC, 20210203105SF], the Foundation of Science and Technology Research Projects of Jilin Provincial Department of Education (JJKH20210001KJ), the Project of Human Resources and Social Security Department of Jilin Province, China [2021Z007], the Science and Technology Innovation Center Project of Jilin Province, China (YDZJ202102CXJD049) and the Program for Innovative Research Team of Baicheng Normal University [012010].

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Many thanks are due to Xihe Bi for his critical reading of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Molecules 28 04347 g001 550
Figure 1. Pharmaceutically important N-vinylated pyrazole moieties.
Figure 1. Pharmaceutically important N-vinylated pyrazole moieties.
Molecules 28 04347 g001
Molecules 28 04347 sch001 550
Scheme 1. Comparison of previous reports with current works.
Scheme 1. Comparison of previous reports with current works.
Molecules 28 04347 sch001
Molecules 28 04347 sch002 550
Scheme 2. Stereoselective synthesis of (E or Z)-N-carbonylvinylated pyrazoles a, b. a Reaction conditions: A: 1a (0.25 mmol), 2 (0.3 mmol), DCE (1.0 mL), 60 °C; B: 1a (0.25 mmol), 2 (0.3 mmol), Ag2CO3 (0.125 mmol), DCE (1.0 mL), 60 °C; b Isolated yield.
Scheme 2. Stereoselective synthesis of (E or Z)-N-carbonylvinylated pyrazoles a, b. a Reaction conditions: A: 1a (0.25 mmol), 2 (0.3 mmol), DCE (1.0 mL), 60 °C; B: 1a (0.25 mmol), 2 (0.3 mmol), Ag2CO3 (0.125 mmol), DCE (1.0 mL), 60 °C; b Isolated yield.
Molecules 28 04347 sch002
Molecules 28 04347 g002 550
Figure 2. Molecular structures of 3l, 4o, 5c, 5k′and 6c [39].
Figure 2. Molecular structures of 3l, 4o, 5c, 5k′and 6c [39].
Molecules 28 04347 g002
Molecules 28 04347 sch003 550
Scheme 3. Regio- and stereoselective synthesis of (E or Z)-N1 or N2-carbonylvinylated pyrazoles a, b. a Reaction conditions: A: 1b (0.5 mmol), 2 (1.0 mmol), DCE (1.0 mL), 60 °C; B: 1b (0.5 mmol), 2 (1.0 mmol), Ag2CO3 (0.25 mmol), DCE (1.0 mL), 60 °C; b Isolated yield.
Scheme 3. Regio- and stereoselective synthesis of (E or Z)-N1 or N2-carbonylvinylated pyrazoles a, b. a Reaction conditions: A: 1b (0.5 mmol), 2 (1.0 mmol), DCE (1.0 mL), 60 °C; B: 1b (0.5 mmol), 2 (1.0 mmol), Ag2CO3 (0.25 mmol), DCE (1.0 mL), 60 °C; b Isolated yield.
Molecules 28 04347 sch003
Molecules 28 04347 sch004 550
Scheme 4. Gram-scale reactions.
Scheme 4. Gram-scale reactions.
Molecules 28 04347 sch004
Molecules 28 04347 sch005 550
Scheme 5. Proposed mechanism.
Scheme 5. Proposed mechanism.
Molecules 28 04347 sch005
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 28 04347 i001
EntryCat. (x mol%)SolventTemp. (°C)Time (h)Yield (%) b
3a4a
1noneDCE25246030
2noneDCE40127519
3noneDCE50108412
4 noneDCE608909
5noneDCE70689 9
6nonetoluene60985 9
7none1,4-dioxane601282 11
8Ag2CO3 (10)DCE60243851
9Ag2CO3 (10)DCE20721729
10Ag2CO3 (20)DCE601625 62
11Ag2CO3 (30)DCE60112369
12Ag2CO3 (40)DCE6071675
13Ag2CO3 (50)DCE6059 81
14Ag2CO3 (60)DCE604876
15Ag2CO3 (70)DCE603673
16Ag2CO3 (50)DCE7041277
17Ag2CO3 (50)DCE50131868
18AgOAc (50)DCE60172161
19AgNO3 (50)DCE601514 67
a Reaction conditions: 1aa (0.25 mmol, 24 mg), and 2a (0.3 mmol, 29.4 mg) in 1.0 mL of solvent. b Isolated yield.
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MDPI and ACS Style

Zhang, X.; Zhang, Z.; Yu, H.; Che, G. Regio- and Stereoselective Switchable Synthesis of (E)- and (Z)-N-Carbonylvinylated Pyrazoles. Molecules 2023, 28, 4347. https://doi.org/10.3390/molecules28114347

AMA Style

Zhang X, Zhang Z, Yu H, Che G. Regio- and Stereoselective Switchable Synthesis of (E)- and (Z)-N-Carbonylvinylated Pyrazoles. Molecules. 2023; 28(11):4347. https://doi.org/10.3390/molecules28114347

Chicago/Turabian Style

Zhang, Xue, Zheyu Zhang, Haifeng Yu, and Guangbo Che. 2023. "Regio- and Stereoselective Switchable Synthesis of (E)- and (Z)-N-Carbonylvinylated Pyrazoles" Molecules 28, no. 11: 4347. https://doi.org/10.3390/molecules28114347

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