Improved method for the obtaining DTTA-appended 2,2’-bipyridine ligands for lanthanide cations

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


Introduction
2,2'-Bipyridines are the commonly used ligands for different metal cations [1,2].In case of the presence of polyaminocarboxylic acid (DTTA, DO3A etc.) moiety at the C6 position, these compounds are of interest as effective ligands for lanthanide cations [3][4][5][6].As for the luminescent chelates 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 usually 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 lanthanide cation.
Early we reported on our progress in the development in this direction.E.g., the chromophore systems with aromatic substituent at position C6′ [8], C4 [9][10][11], C5 [12] and C5′ [6] have been researched for effectiveness of lanthanide cations sensibilization.As a result, the main regularities of the influence of the bipyridine chromophore structure on the properties of the complexes were revealed.
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 optimization of the reaction conditions and the analysis of the reaction mixture of the above mentioned reaction.

Experimental
All reagents were purchased from commercial sources and used without further purification.NMR spectra were recorded on a Bruker Avance-400 spectrometer, 298 K, digital 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 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).

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 column 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 1 H 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 1 Н NMR, mass spectrometry and elemental 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 1 H NMR spectra.Presumably, the formation 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].