Novel combinatorial approach to the synthesis of dihydropyridine (quinoline) based merocyanine dyes

A novel, efficient, two-step approach to the synthesis of merocyanine dyes was developed. Initially, N-substituted picolinium salts were formylated with N,N -dimethylformamide dimethyl acetal to produce enamine derivatives. Then a series of merocyanine dyes were obtained by the high-yield reaction between the enamines and various active methylene compounds. The described reactions, carried out in mild conditions, provide access to the synthesis of a wide range of dyes. This innovative method enabled the synthesis of a number of new merocyanine dyes and increased the yields of the known compounds. N


Introduction
Merocyanines are important class of dyes. Both theoretical studies and practical applications of merocyanines are well illustrated in reviews. [1][2][3][4][5] In spite of significant attention to merocyanine dyes, based on azoheterocycles, such as pyridine and quinoline, these compounds have not been studied as well as other classes. The most common structure of merocyanine dyes includes an electron-withdrawing group linked to a cyclic electron-donor fragment via two methine groups. The maJor approach to the synthesis of these merocyanine systems involves the interaction between a methyl group of N-alkylazinium salts and the acetaldehyde derivatives (EWG)2CHCHO and their analogs. [6][7][8][9][10][11][12][13][14][15][16][17] The disubstituted acetaldehyde derivatives can be obtained by the formylation of methylene active compounds. According to this synthetic protocol, the selected heterocyclic substrate generally reacts with a set of methylene active compounds, each of which must be previously formylated. Following this synthetic protocol we synthesized a series of dyes 18,19 utilizing 2and 4-picoline as substrates. The products were purified by column chromatography. Despite the fact that this approach is quite simple and provides good yields, this method requires time-consuming purification techniques, making it inefficient for the synthesis of large dye libraries. An interesting variation of this method is formylation of an active methylene compound by DMF/Ac2O mixture with heating and condensation with azinium salt (2 examples in 54 -60% yield) without isolation of intermediate. 20 Thus, there are gaps in the published data for pyridine-or quinoline-containing merocyanine dyes.
Another synthetic approach appears to be more practical. A methyl group from an azinium salt is formylated to produce (N-phenyl-N-acetyl)enamines. [21][22][23][24] Next, the enamine derivatives react with active methylene compounds to form cyanine cationic dyes. However, this approach is less common for the synthesis of merocyanine dyes because enamine formation requires extreme conditions and the yields of the reaction are small.
In this paper we describe a novel and facile approach to the synthesis of merocyanine dyes. The reactions are based on mild formylation of a methyl group in the heterocyclic substrate by N,N-dimethylformamide dimethyl acetal (DMFDMA). This leads to the formation of enamine derivatives with high yields. The obtained enamines can be reacted with a series of readily accessible active methylene compounds, providing the capacity to quickly create compound libraries containing a wide range of desired merocyanine dyes.

Results and Discussion
As starting materials we chose quaternary azinium salts 1 (R C1 -C4 alkyl, Ph) prepared from picolines and methyl quinolines according to previously described procedures. [25][26][27][28] In the first step, the condensation reaction between the salts 1 and DMFDMA (2) was carried out in mild conditions in DMF at room temperature and without any catalyst. This resulted in the formation of enamines 3-12 with high yields (Scheme 1, Table 1, Figure 1). In the second step, enamines 3-12 reacted in DMF with a series of commercially available methylene active compounds 13-18 ( Figure 2) to form merocyanine dyes 19-45. This approach can be efficiently applied to the synthesis of dyes 19-45 based on the enamine derivatives of 4-methylazines (Scheme 2, Table 2), as well as the 2-methylazines (Scheme 3, Table 3).   For dye syntheses based on methylene components 13, 17, 18 the reaction mixture was simply kept at room temperature for 12 h. For the other methylene components used, the best results were achieved by heating reaction mixtures at 60 °C for 5 hours in the presence of sodium acetate. In both cases the products were isolated by diluting reaction mixtures with water followed by filtration after 12 hours (see the Supporting Information for general procedure). The resulting dyes 19-45 were obtained in moderate to high yields. Unlike the previously described method, 18,19 no further purification was needed.   The proposed two-step approach will significantly facilitate the practical production of a wide-range merocyanine dyes based on methyl-substituted quaternary azinium salts. For the synthesis of the known merocyanines 21 and 34, a 30-40% yield increase was achieved in comparison to previously reported methods. [32][33][34][35] All other dyes were synthesized by us for the first time.

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UV/Vis absorption spectra of all the synthesized dyes 19-45 were recorded in acetone solution. The combined data for the maximum absorption wavelength and the extinction coefficient for each compound are shown in Table 4. Analysis of the UV/Vis absorption spectra of the merocyanines 24-29 with various electron withdrawing groups ( Figure 2) shows that the variation of an acceptor group smoothly shifts the absorption maximum within 25 nm. Dissolving the synthesized dyes in trifluoroacetic acids had interesting results. We previously showed 18 that in trifluoroacetic acid the α-carbon of the polyene chain in dye 25 becomes protonated which, according to 1 H NMR data, disrupts the conJugation. This is fully in line with the dye structure, approaching the cyanine limit. This process also occurs in the case of protonation of compound 25 ( Figure 4). On the other hand, the protonation of dye 39 occurs without affecting the polyene system. The oxygen atom in the barbituric acid residue is apparently involved in the protonation. This possibly indicates that compound 39 is strongly polarized and that its structure is close to that of a betaine. The X-ray data for 39 (see the Supporting Information for X-ray data) ( Figure 5) supports this hypothesis: the values of the determined bond lengths between С(9) -С(8) 1.436А, С(8) -С(7) 1.358А and С(7) -С(4) 1.422А demonstrate that single and double bonds are altered in this molecule, which is consistent with its betaine nature.

Conclusions
In conclusion, we have reported a new facile approach to the combinatorial synthesis of merocyanine dyes based on readily available starting materials. This promising method for the synthesis of merocyanine dye libraries does not require additional purification of the final products.