Improved method for the obtaining DTTA-appended 2,2’-bipyridine ligands for lanthanide cations Chimica Techno Acta LETTER published by Ural Federal University 2022, vol. 9(2), No. 20229210 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.2.10 1 of 4 Improved method for the obtaining DTTA-appended 2,2’-bipyridine ligands for lanthanide cations Dmitry S. Kopchuk ab , Alexey P. Krinochkin ab * , Мaria I. Valieva ab , Ekaterina S. Starnovskaya аb , Yaroslav K. Shtaitz a , Svetlana S. Rybakova a , Evgeny D. Ladin a, Ekaterina A. Kudryashova a , Elvira R. Sharafieva aс, Оleg N. Chupakhin ab a: Institute of Chemical Engineering, Ural Federal University, Ekaterinburg 620009, Russia b: Postovsky Institute of Organic Synthesis, Ural Brunch of Russian Academy of Sciences, Ekaterinburg 620990, Russia c: Ural State Medical University, Ministry of Healthcare of the Russian Federation, Ekaterinburg 620028, Russia * Corresponding author: a.p.krinochkin@urfu.ru This paper belongs to a Regular Issue. © 2022, the Authors. This article is published open access under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract The composition of the reaction mixture after DTTA tert-butyl ester alkylation with 6'-halomethyl-5-phenyl-2,2'-bipyridines was studied. In addition to the target product, DTTA-appended 2,2’-bipyridine, the corresponding 6'-hydroxymethyl-substituted 2,2’-bipyridine and (5'- phenyl-[2,2'-bipyridin]-6-yl)methyl formate were isolated as by- products in some cases. Finally, an improved procedure for the DTTA tert-butyl ester alkylation with 6'-halomethyl-5-phenyl-2,2'- bipyridines by using Finkelstein reaction was developed. Keywords DTTA tert-butyl ester 2,2'-bipyridines Finkelstein reaction ligands for lanthanide cations alkylation Received: 25.03.22 Revised: 24.05.22 Accepted: 24.05.22 Available online: 30.05.22 Key findings ● The composition of the reaction mixture after DTTA ester alkylation with 6-bromomethyl-2,2'- bipyridine was studied. ● An improved procedure for DTTA ether alkylation with 6-halomethyl-2,2'-bipyridines was proposed. The yield of the target product was increased up to 80%. 1. Introduction 2,2'-Bipyridines are the commonly used ligands for differ- ent metal cations [1, 2]. In case of the presence of polyam- inocarboxylic acid (DTTA, DO3A etc.) moiety at the C6 po- sition, these compounds are of interest as effective ligands for lanthanide cations [3–6]. As for the luminescent che- lates of lanthanide cations, the polyaminocarboxylic acid fragment as the chelating part of hard nature is necessary to saturate all lanthanide coordination bonds in order to prevent the incorporation of water molecules in the first coordination sphere of the lanthanide cation, which usual- ly leads to a significant quenching of luminescence [7]. The 2,2’-bipyridine part of the ligand is necessary for the absorption of energy and its transmission to the lantha- nide cation. Early we reported on our progress in the development in this direction. E.g., the chromophore systems with aro- matic substituent at position C6′ [8], C4 [9–11], C5 [12] and C5′ [6] have been researched for effectiveness of lan- thanide cations sensibilization. As a result, the main regu- larities of the influence of the bipyridine chromophore structure on the properties of the complexes were re- vealed. The most common method for the preparation of such ligands involves direct alkylation of the DTTA tert-butyl ester with the corresponding halomethyl derivatives of 2,2’- bipyridine and subsequent cleaving of tert-butyl protection. However, the yields of target products at this stage do not exceed 35–40% with formation of by-products. In this manuscript we wish to report the results of the optimiza- tion of the reaction conditions and the analysis of the re- action mixture of the above mentioned reaction. http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.2.10 mailto:a.p.krinochkin@urfu.ru http://creativecommons.org/licenses/by/4.0/ http://orcid.org/0000-0002-0397-4033 http://orcid.org/0000-0002-6712-1136 https://orcid.org/0000-0001-5965-1527 http://orcid.org/0000-0002-9679-8269 http://orcid.org/0000-0002-4786-5568 https://orcid.org/0000-0003-2408-7166 https://orcid.org/0000-0002-7031-5230 http://orcid.org/0000-0002-1672-2476 https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2022.9.2.10&domain=pdf&date_stamp=2022-5-30 Chimica Techno Acta 2022, vol. 9(2), No. 20229210 LETTER 2 of 4 2. Experimental All reagents were purchased from commercial sources and used without further purification. NMR spectra were rec- orded on a Bruker Avance-400 spectrometer, 298 K, digi- tal resolution ± 0.01 ppm, using TMS as the internal standard. Mass spectra were recorded on a MicrOTOF-Q II mass spectrometer (Broker Daltonics) with electrospray ionization. The starting (5'-phenyl-[2,2'-bipyridin]-6-yl)methanol 1 [6], 6'-(bromomethyl)-5-phenyl-2,2'-bipyridine 2a [6] and ester of DTTA 3 [13, 14] were synthesized as described in literature. 6'-(Chloromethyl)-5-phenyl-2,2'-bipyridine (2b). Hy- droxymethylbipyridine 1 (140 mg, 0.53 mmol) was dis- solved in 1,2-dichloroethane (35 ml). Then SOCl2 (0.08 ml, 1.07 mmol) was added to that solution and the mixture was stirred at 50 °C for 2 h. The resulting mixture was washed with aqueous solution of Na2CO3. The organic lay- er was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The analytical sam- ple was obtained by recrystallization (ethanol). Yield 116 mg (0.41 mmol, 77%). NMR 1Н (CDCl3, δ, ppm): 4.78 (s, 2Н, CH2), 7.41–7.46 (m, 1H, Ph), 7.49–7.54 (m, 3H, Ph, Н-5'), 7.64–7.68 (m, 2H, Ph), 7.88 (d, 1H, 3J 7.6, 7.6 Hz, Н-4'), 8.05 (dd, 1H, 3J 8.0 Hz, 4J 1.6 Hz, Н-4), 8.39– 8.43 (m, 1H, Н-3'), 8.53 (d, 1H, 3J 8.0 Hz, Н-3), 8.93 (d, 1H, 4J 1.6 Hz, Н-6). ESI-MS, m/z: 281.08 (М+Н)+. Found, %: С 72.61, Н 4.52, N 9.81. С17Н13ClN2. Calculated, %: С 72.73, Н 4.67, N 9.98. 2.1. The methods for the alkylation of DTTA ester Method A. The corresponding compound 2 (1.53 mmol), DTTA tetra-tert-butyl ester 3 (946 mg, 1.69 mmol), and anhydrous potassium carbonate (1062 mg, 7.68 mmol) were mixed in dry acetonitrile (90 mL). The mixture was stirred under reflux for 48 h under argon atmosphere. Then solvent was removed in vacuum and water (30 mL) was added, the product was extracted by chloroform (2x35 mL). The extract was dried with anhydrous sodium sulfate and solvent was removed under reduced pressure. The products were separated by column chromatography (eluent: acetonitrile). Method B. The corresponding compound 2 (1.53 mmol), DTTA tetra-tert-butyl ester 3 (946 mg, 1.69 mmol), potas- sium iodide (257 mg, 1.70 mmol), and anhydrous potassi- um carbonate (1062 mg, 7.68 mmol) were mixed in dry acetonitrile (90 mL). The resulted reaction mixture was stirred under reflux for 48 h under argon atmosphere. The following work-up was done similarly to the Method A. tert-Butyl 2,2',2'',2'''-(2,2'-((5'-phenyl-2,2'-bipyridin- 6-yl)methylazanediyl)bis(ethane-2,1-diyl)bis(azanetriyl))- tetraacetate (4). Rf 0.15. Yield 0.56 g (0.7 mmol, 45%, method A); 0.98 g (1.224 mmol, 80%, method B from compound 2a); 0.92 g (1.148 mmol, 75%, method B from compound 2b). 1H NMR (CDCl3, δ, ppm): 1.42 (s, 36H, tBu), 2.75 (t, 4H, 3J 7.0 Hz, CH2), 2.92 (t, 4H, 3J 7.0 Hz, CH2), 3.45 (s, 8H, CH2COOtBu), 3.93 (s, 2H, bipy-CH2), 7.42 (m, 1H, Ph), 7.51 (m, 3H, Ph, H-5'), 7.66 (m, 2H, Ph), 7.77 (dd, 1H, 3J 8.0, 7.8 Hz, H-4'), 8.00 (dd, 1H, 3J 8.2 Hz, 4J 2.2 Hz, H-4), 8.28 (d, 1H, 3J 7.8 Hz, H-3'), 8.51 (d, 1H, 3J 8.4 Hz, H-3), 8.91 (d, 1H, 3J 2.4 Hz, H-6). ESI-MS, m/z: found 804.48 (M+H)+, calcd 804.48. 5'-Phenyl-2,2'-bipyridin-6-yl)methanol (1). Rf 0.45. Yield 80 mg (0.3 mmol, 20%) (method A). 1H NMR (CDCl3, δ, ppm): 4.66 (2H, d, 3J 5.5 Hz, CH2OH), 5.24 (1H, t, 3J 5.5 Hz, OH), 7.38–7.43 (1H, m, Ph), 7.46–7.53 (2H, m, Ph), 7.72 (2H, m, Ph), 7.88 (1H, dd, 3J 7.8, 7.8 Hz, H-4'), 8.10 (1H, dd, 3J 8.3, 4J 2.1 Hz, H-4), 8.29 (1H, d, 3J 7.8 Hz, H-3'), 8.49 (1H, d, 3J 8.3 Hz, H-3), 8.90 (1H, d, 4J 2.1 Hz, H- 6). ESI-MS, m/z: found 263.12, calcd 263.12 [M+H]+. 5'-Phenyl-[2,2'-bipyridin]-6-yl)methyl formate (5). Rf 0.85. Yield 30 mg (0.1 mmol, 7%) (method A). 1H NMR (CDCl3, δ, ppm): 5.42 (s, 2H, CH2), 7.39–7.45 (m, 2H, Ph, H-3' (Py)), 7.49–7.54 (m, 2H, Ph), 7.64–7.68 (m, 2H, Ph), 7.87 (dd, 1H, 3J 7.6, 7.6 Hz, H-4' (Py)), 8.03 (dd, 1H, 3J 8.0, 4J 2.4 Hz, H-4 (Py)), 8.28 (s, 1H, CHO), 8.38–8.42 (m, 1H, H-5' (Py)), 8.51 (d, 1H, 3J 8.0 Hz, H-3 (Py)), 8.89 (1H, d, 4J 2.1 Hz, H-6). ESI-MS, m/z: found 291.11, calcd 291.11 [M+H]+. 3. Results and Discussion Thе starting 6'-bromomethyl-5-phenyl-2,2'-bipyridine 2a was obtained according to the described method [6]. The alkylation of the DTTA ether [13, 14] using this compound was carried with the yield of the target product of 45%, as it was reported earlier [6]. A more detailed analysis of the reaction mass showed the presence of two side-products in the reaction mixture, and they were separated by col- umn chromatography (Scheme 1). One of the of products (20% yield) was identified as hydroxymethyl-substituted 2,2’-bipyridine 1. Its structure was confirmed by comparing the data of 1H NMR spectrum with those described earlier in the literature [6], as well as by means of mass spectrometry and elemental analysis data. Another product was identified as (5'-phenyl-[2,2'- bipyridin]-6-yl)methyl formate 5 (yield 7%). The structure was confirmed by 1Н NMR, mass spectrometry and ele- mental analysis data. E.g. the singlets of methylene group at 5.42 ppm and proton of formic acid moiety at 8.27 ppm can be observed in 1H NMR spectra. Presumably, the for- mation of product 5 can be due to the presence of traces of potassium formate in potassium carbonate used as a base in this reaction. Some examples of such transformations have previously been reported in the literature [15, 16]. Chimica Techno Acta 2022, vol. 9(2), No. 20229210 LETTER 3 of 4 Scheme 1 A detailed analysis of the reaction mass after DTTA ester 3 alkylation. Then the same reaction was carried out for the com- pound 2a in the presence of sodium iodide (1.70 eq.). In this case the desired compound 4 was isolated in yield up to 80% as the only product. This is due to the in situ con- version of the 6’-bromomethyl-5-phenyl-2,2’-bipyridine 2a to 6’-iodomethyl-5-phenyl-2,2’-bipyridine by means of the Finkelstein reaction [17]. Our further studies showed that the alkylation of DTTA tert-butyl ester can also be success- fully performed using 6'-chloromethyl-5-phenyl-2,2'- bipyridine 2b, which was easily obtained by reacting the corresponding alcohol 1 with thionyl chloride. The yield of the target product 4 in this case was 75%. In all cases, when using this method, the corresponding alcohol 1 was practically absent from the composition of the reaction mixture, and, thus, the application of this method for the preparation of DTTA-appended 2,2'-bipyridine ligands for lanthanide cations looks much more promising. 4. Conclusions Thus, we studied the alkylation reaction of DTTA tert- butyl ester with 6'-halomethyl-5-phenyl-2,2'-bipyridines. In case of 6'-bromomethyl-5-phenyl-2,2'-bipyridine the reaction afforded the desired product in 45% yield along with the corresponding 6'-hydroxymethyl-substituted bi- pyridine (yield 20%) and (5'-phenyl-[2,2'-bipyridin]-6- yl)methyl formate (7% yield) as by-products. In case of in situ formation of 6’-iodomethyl-5-phenyl-2,2’-bipyridine, the desired product was isolated in up to 80% yield, and both the corresponding 6’-bromomethyl or 6’- chloromethyl-2,2’-bipyridines can be used as starting compounds. The article is based on the materials of the report pre- sented at the V International Conference “Modern Synthet- ic Methodologies for the Creation of Drugs and Functional Materials” (November 8–12, 2021, Ekaterinburg and Perm). Supplementary materials No supplementary materials are available. Funding This work was supported by the Russian Science Founda- tion (grant no. 18-73-10119-P), https://www.rscf.ru/en. Acknowledgments None. Author contributions Conceptualization: D.S.K., O.N.C. Data curation: A.P.K. Formal Analysis: M.I.V, A.P.K. Funding acquisition: D.S.K. Investigation: E.S.S., Y.K.S., S.S.R. Methodology: D.S.K. Project administration: D.S.K. Resources: D.S.K. Software: A.P.K. Supervision: D.S.K. Validation: D.S.K. Visualization: E.D.L. Writing – original draft: D.S.K., A.P.K. Writing – review & editing: A.P.K. https://www.rscf.ru/en Chimica Techno Acta 2022, vol. 9(2), No. 20229210 LETTER 4 of 4 Conflict of interest The authors declare no conflict of interest. Additional information Authors IDs: Dmitry S. Kopchuk, Scopus ID 14123383900; Alexey P. Krinochkin, Scopus ID 56951324100; Мaria I. Valieva, Scopus ID 57204922642; Еkaterina S. Starnovskaya, Scopus ID 57197871733; Yaroslav K. Shtaitz, Scopus ID 57201778255; Svetlana S. 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