2-(2-(Dimethylamino)vinyl)-4H-pyran-4-ones as Novel and Convenient Building-Blocks for the Synthesis of Conjugated 4-Pyrone Derivatives

A straightforward approach for the construction of the new class of conjugated pyrans based on enamination of 2-methyl-4-pyrones with DMF-DMA was developed. 2-(2-(Dimethylamino)vinyl)-4-pyrones are highly reactive substrates that undergo 1,6-conjugate addition/elimination or 1,3-dipolar cycloaddition/elimination followed by substitution of the dimethylamino group without ring opening. This strategy includes selective transformations leading to conjugated and isoxazolyl-substituted 4-pyrone structures. The photophysical properties of the prepared 4-pyrones were determined in view of further design of novel merocyanine fluorophores. A solvatochromism was found for enamino-substituted 4-pyrones accompanied by a strong increase in fluorescence intensity in alcohols. The prepared conjugated structures demonstrated valuable photophysical properties, such as a large Stokes shift (up to 204 nm) and a good quantum yield (up to 28%).

The introduction of an additional electron-withdrawing substituent into the C-4 position of the pyrone ring by means of the Knoevenagel reaction leads to one of the most popular merocyanines, DCM (Figure 1), and other 4-methylene-4H-pyrans, which have found wide application due to their important photophysical properties [20][21][22][23][24].
In this paper, we describe a general strategy to 4-pyrone-bearing merocyanines based on an enamination with DMF-DMA and subsequent transformation of the dimethylaminovinyl group via a nucleophilic 1,6-addition or cycloaddition reaction. This approach opens straightforward access to a wide range of new promising pyran fluorophores.

Synthesis of 2-Enamino-substituted 4-Pyrones and Their Chemical Properties
The functionalization of the pyrone ring was carried out via an enamination reaction at the active methyl group using DMF-DMA as a reagent and a solvent (Scheme 2) [35]. N-Methylimidazole (NMI) was selected as a convenient base for the promotion of the transformation [36]. Enamination of 2-(tert-butyl)-6-methyl-4H-pyran-4-one (1a) with DMF-DMA (3 equiv.) and NMI (3 equiv.) at 100 • C in an autoclave afforded enamino-substituted 4-pyrone 2a in only 15% yield ( Table 1, entry 1). We decided to increase the reaction temperature to 120 • C and study the influence of the base amount on both the reaction outcome and time (TLC monitoring). When one equivalent of NMI was used, the reaction was completed in 15 h and the product was prepared in 40% yield (entry 2). We found that a further decrease in the amount of NMI (0.25-0.5 equivalent) allowed the improvement of the enamination reaction outcome until 67-72%, but it required longer heating (20-25 h) (TLC monitoring) (entries 3,4). The best yield (72%) of pyrone 2a was achieved using 0.25 equivalents of N-methylimidazole though it took 25 h (entry 4). The isolation of the pyrone included simple recrystallization from n-heptane. Interestingly, the reaction also occurred without promotion of the base and gave the product in a lower yield (57%) under heating at 120 • C for 25 h (entry 5). Increasing temperature to 130 • C led to pyrone 2a in 54% yield (entry 6). The enamination with the use of pyridine as a solvent and DMF-DMA (1.2 equiv.) at 100 • C or 120 • C did not produce the desired product.
In this paper, we describe a general strategy to 4-pyrone-bearing merocyanines based on an enamination with DMF-DMA and subsequent transformation of the dimethylaminovinyl group via a nucleophilic 1,6-addition or cycloaddition reaction. This approach opens straightforward access to a wide range of new promising pyran fluorophores.

Synthesis of 2-Enamino-Substituted 4-Pyrones and Their Chemical Properties
The functionalization of the pyrone ring was carried out via an enamination reaction at the active methyl group using DMF-DMA as a reagent and a solvent (Scheme 2) [35]. N-Methylimidazole (NMI) was selected as a convenient base for the promotion of the transformation [36]. Enamination of 2-(tert-butyl)-6-methyl-4H-pyran-4-one (1a) with DMF-DMA (3 equiv.) and NMI (3 equiv.) at 100 °C in an autoclave afforded enaminosubstituted 4-pyrone 2a in only 15% yield ( Table 1, entry 1). We decided to increase the reaction temperature to 120 °C and study the influence of the base amount on both the reaction outcome and time (TLC monitoring). When one equivalent of NMI was used, the reaction was completed in 15 h and the product was prepared in 40% yield (entry 2). We found that a further decrease in the amount of NMI (0.25-0.5 equivalent) allowed the improvement of the enamination reaction outcome until 67-72%, but it required longer heating (20-25 h) (TLC monitoring) (entries 3,4). The best yield (72%) of pyrone 2a was achieved using 0.25 equivalents of N-methylimidazole though it took 25 h (entry 4). The isolation of the pyrone included simple recrystallization from n-heptane. Interestingly, the reaction also occurred without promotion of the base and gave the product in a lower yield (57%) under heating at 120 °C for 25 h (entry 5). Increasing temperature to 130 °C led to pyrone 2a in 54% yield (entry 6). The enamination with the use of pyridine as a solvent and DMF-DMA (1.2 equiv.) at 100 °C or 120 °C did not produce the desired product.

Scheme 2.
Reaction of pyrone 1a with DMF-DMA. The enamination reaction conditions were extended for various 2-methyl-4-pyrones (Scheme 3, Table 2), but this transformation turned out to be very sensitive to the nature of substituents at the pyrone ring. The enamination of 2-methyl-6-phenyl-4-pyrone (1b) Scheme 2. Reaction of pyrone 1a with DMF-DMA. The enamination reaction conditions were extended for various 2-methyl-4-pyrones (Scheme 3, Table 2), but this transformation turned out to be very sensitive to the nature of substituents at the pyrone ring. The enamination of 2-methyl-6-phenyl-4-pyrone (1b) with DMF-DMA proceeded for 12 h under the optimized conditions; as a result, pyrone 2b was obtained in 53% yield. However, the reaction of 2-methyl-6-trifluoromethyl-4-pyrone (1c) was completed in 5 h at 120 • C, leading to the desired product in only low yield (12%). This result can be explained by side processes due to the presence of the trifluoromethyl group and high CH-acidity). Lowering the temperature to 100 • C made it possible to increase the yield up to 43%.
with DMF-DMA proceeded for 12 h under the optimized conditions; as a result, pyrone 2b was obtained in 53% yield. However, the reaction of 2-methyl-6-trifluoromethyl-4-pyrone (1c) was completed in 5 h at 120 °C, leading to the desired product in only low yield (12%). This result can be explained by side processes due to the presence of the trifluoromethyl group and high CH-acidity). Lowering the temperature to 100 °C made it possible to increase the yield up to 43%. Scheme 3. Enamination of pyrones 1. It was found that the enamination of ethyl 6-methylcomanate (1d') with DMF-DMA and an excess of NMI (3 equiv.) at 120 °C was accompanied by the transesterification reaction to produce product 2d in 27% yield (Scheme 3 Table 2). It is interesting to note that direct enamination of methyl 6-methylcomanate (1d) at 100 °C in the presence of NMI (0.25 equiv.) led to the desired product 2d in only 8% yield.
We tried to extend the enamination on 2-methyl-6-styryl-4-pyrones 1e-g for the synthesis of unsymmetrical 2,6-divinyl-4-pyrones 2e-g ( Table 2). The reaction of 2-methyl-6styryl-4-pyrone (1e) at 120 °C with a threefold excess of DMF-DMA and different amounts of N-methylimidazole did not lead to the desired product. Lowering the temperature to 100 °C made it possible to obtain product 2e in 22% yield for 4 h (TLC monitoring). For starting 2-methyl-6-styryl-4-pyrones 1f,g, the use of the optimized conditions did not give the desired products because of low solubility of the starting materials. The enamination of pyrones 1f,g with threefold excess of N-methylimidazole and heating at 120 °C for 3 h led to complete conversion of the starting 4-pyrone, and products 2f,g were isolated by the treatment with diethyl ether in 72 and 51% yields, respectively. Such a difference in the behavior of styrylpyrones may be connected with the presence of electron-donating substituents, which deactivated the double bond of the styryl fragment and reduced the possibility of side reactions.
The reaction of 2,6-dimethyl-4-pyrone 3a with three equivalent DMF-DMA and 0.5 equiv. of NMI was carried out at 120 °C for 15 h, resulting in a mixture of products of enamination 4a and 5a (Scheme 4). Recrystallization from n-heptane easily allowed the separation of pyrones 4a and 5a and isolation them in pure form in 17% and 23% yields, respectively. All our attempts to carry out more selective monoenamination by lowering  It was found that the enamination of ethyl 6-methylcomanate (1d') with DMF-DMA and an excess of NMI (3 equiv.) at 120 • C was accompanied by the transesterification reaction to produce product 2d in 27% yield (Scheme 3 Table 2). It is interesting to note that direct enamination of methyl 6-methylcomanate (1d) at 100 • C in the presence of NMI (0.25 equiv.) led to the desired product 2d in only 8% yield.
We tried to extend the enamination on 2-methyl-6-styryl-4-pyrones 1e-g for the synthesis of unsymmetrical 2,6-divinyl-4-pyrones 2e-g ( Table 2). The reaction of 2-methyl-6-styryl-4-pyrone (1e) at 120 • C with a threefold excess of DMF-DMA and different amounts of N-methylimidazole did not lead to the desired product. Lowering the temperature to 100 • C made it possible to obtain product 2e in 22% yield for 4 h (TLC monitoring). For starting 2-methyl-6-styryl-4-pyrones 1f,g, the use of the optimized conditions did not give the desired products because of low solubility of the starting materials. The enamination of pyrones 1f,g with threefold excess of N-methylimidazole and heating at 120 • C for 3 h led to complete conversion of the starting 4-pyrone, and products 2f,g were isolated by the treatment with diethyl ether in 72 and 51% yields, respectively. Such a difference in the behavior of styrylpyrones may be connected with the presence of electron-donating substituents, which deactivated the double bond of the styryl fragment and reduced the possibility of side reactions.
The reaction of 2,6-dimethyl-4-pyrone 3a with three equivalent DMF-DMA and 0.5 equiv. of NMI was carried out at 120 • C for 15 h, resulting in a mixture of products of enamination 4a and 5a (Scheme 4). Recrystallization from n-heptane easily allowed the separation of pyrones 4a and 5a and isolation them in pure form in 17% and 23% yields, respectively. All our attempts to carry out more selective monoenamination by lowering the temperature, variation of reagent amounts, and increasing the reaction time were unsuccessful and accompanied by incomplete conversion and the formation of the bis(enamino) derivative, which did not allow the preparation of product 4a in pure form directly.
The use of an excess of DMF-DMA (5 equiv.) and heating at 130 • C for 15 h made it possible to increase the yield of bisenamine 5a to 51%. At the same time, the formation of monoenamino derivative 4a was not observed. Carrying out the reaction without using NMI or using one equivalent of NMI resulted in product 5a in 41 and 45% yields, respectively. The transformation of 3-bromo-2,6-dimethyl-4-pyrone (3b) led to a double enamination product 5b in 53% yield. This result can probably be explained by a higher CH-acidity of the methyl groups. We also managed to carry out monoenamination selectively at the methyl group located near the electron-withdrawing bromine atom, and pyrone 4b was prepared in high yield (80%) (Scheme 4). The structure of the product was assigned on the basis of the chemical shift of the methyl group in comparison with the starting 2,6-dimethyl-3-bromo-4-pyrone (3b) and product 4b.
Molecules 2022, 27, 8996 5 of 24 the temperature, variation of reagent amounts, and increasing the reaction time were unsuccessful and accompanied by incomplete conversion and the formation of the bis(enamino) derivative, which did not allow the preparation of product 4a in pure form directly. The use of an excess of DMF-DMA (5 equiv.) and heating at 130 °C for 15 h made it possible to increase the yield of bisenamine 5a to 51%. At the same time, the formation of monoenamino derivative 4a was not observed. Carrying out the reaction without using NMI or using one equivalent of NMI resulted in product 5a in 41 and 45% yields, respectively. The transformation of 3-bromo-2,6-dimethyl-4-pyrone (3b) led to a double enamination product 5b in 53% yield. This result can probably be explained by a higher CHacidity of the methyl groups. We also managed to carry out monoenamination selectively at the methyl group located near the electron-withdrawing bromine atom, and pyrone 4b was prepared in high yield (80%) (Scheme 4). The structure of the product was assigned on the basis of the chemical shift of the methyl group in comparison with the starting 2,6dimethyl-3-bromo-4-pyrone (3b) and product 4b.
The 1 H NMR spectra of the obtained dimethylamino-substituted pyrones 2,4,5 demonstrate a characteristic set of two doublets of the enamino group with 3 J coupling of 12.6-13. 3 Hz, which indicates the E-configuration of the double bond and its partially double order due to the strong push-pull nature [31,36].
To study the chemical properties of monoenamino-substituted 4-pyrones 2 with various nucleophilic reagents, compound 2g was used as an example to obtain conjugated structures (Scheme 5). We found that heating in AcOH turned out to be convenient conditions for carrying out the reactions. The transformation of pyrone 2g with aniline or diphenylamine at 90 °C led to the substitution of the dimethylamino group and the formation of products 6a,b in 82-86% yield. The reaction of substance 2g with p-phenylenediamine as a binucleophile gave product 6c as the result of an attack on both amino groups. It was found that pyrone 2g reacted with benzylamine under reflux in acetonitrile to form product 6d in 76% yield. The transformation of bis(enamino)pyrone 5a with aniline was found to proceed at room temperature, leading to product 6e in 55% yield. Thus, it has been shown that the side chain of γ-pyrone can easily be functionalized with aliphatic and aromatic amines.
Enamino-substituted pyrones 2g and 5a were able to react with 2-methylindole as a C-nucleophile to form indolyl-substituted 4-pyrones 7a,b in 52-62% yields under reflux in AcOH for 7-10 h (Scheme 5). The transformation of bisenamine 5a with 2-methylindole included the substitution at two enamino fragments and led to bis(indolylvinyl)-4-pyrone 7b in 52% yield. The 1 H NMR spectra of the obtained dimethylamino-substituted pyrones 2,4,5 demonstrate a characteristic set of two doublets of the enamino group with 3 J coupling of 12.6-13. 3 Hz, which indicates the E-configuration of the double bond and its partially double order due to the strong push-pull nature [31,36].
To study the chemical properties of monoenamino-substituted 4-pyrones 2 with various nucleophilic reagents, compound 2g was used as an example to obtain conjugated structures (Scheme 5). We found that heating in AcOH turned out to be convenient conditions for carrying out the reactions. The transformation of pyrone 2g with aniline or diphenylamine at 90 • C led to the substitution of the dimethylamino group and the formation of products 6a,b in 82-86% yield. The reaction of substance 2g with p-phenylenediamine as a binucleophile gave product 6c as the result of an attack on both amino groups. It was found that pyrone 2g reacted with benzylamine under reflux in acetonitrile to form product 6d in 76% yield. The transformation of bis(enamino)pyrone 5a with aniline was found to proceed at room temperature, leading to product 6e in 55% yield. Thus, it has been shown that the side chain of γ-pyrone can easily be functionalized with aliphatic and aromatic amines.
Next, we investigated the cycloaddition of enamino-substituted 4-pyrones with 1,3-dipoles (Scheme 6). It was observed that organic azides and diphenylnitrilimine did not give the desired products, which is probably due to the electron-withdrawing properties of the pyrone ring. The reaction with benzonitrile oxide, which was generated in situ from N-hydroxybenzimidoyl chloride [25], in dioxane without the use of a base led to the formation of isoxazolyl-substituted 4-pyrones in 39-80% yields. Although compounds 2f,g bear two double bonds of different nature, the transformation proceeded chemoselectively at the enamino fragment. In the case of bis(enamino) derivative 5a, the cycloaddition occurred at both enamino moieties to give 2,6-bis(isoxazolyl)-4-pyrone 9 in 39% yield. Next, we investigated the cycloaddition of enamino-substituted 4-pyrones with 1,3dipoles (Scheme 6). It was observed that organic azides and diphenylnitrilimine did not give the desired products, which is probably due to the electron-withdrawing properties of the pyrone ring. The reaction with benzonitrile oxide, which was generated in situ from N-hydroxybenzimidoyl chloride [25], in dioxane without the use of a base led to the formation of isoxazolyl-substituted 4-pyrones in 39-80% yields. Although compounds 2f,g bear two double bonds of different nature, the transformation proceeded chemoselectively at the enamino fragment. In the case of bis(enamino) derivative 5a, the cycloaddition occurred at both enamino moieties to give 2,6-bis(isoxazolyl)-4-pyrone 9 in 39% yield.
For the monoenamino-substituted compound 4a, the absorption spectrum includes one-band at 334-363 nm with an extinction coefficient of 29,200-35,900 M −1 cm −1 (Figure 2, Table 3). In aprotic solvents, the absorption maximum is observed at 334-350 nm. For alco-hol solutions of pyrone 4a, the absorption maximum shifts slightly to the long-wavelength region and appears at 356 (i-PrOH), 361 (EtOH), 363 nm (MeOH) in accordance with the solvent polarity. The emission spectrum demonstrates a single maximum and depends strongly on the nature of the solvent. In alcohols as protic solvents, the fluorescence intensity increases many times over in comparison with aprotic polar solvents, such as DMSO.
The highest values of quantum yields are achieved in MeOH (3.6%) and EtOH (1.4%), where the substance exhibits blue fluorescence. The largest Stokes shifts (67-71 nm) are also observed in MeOH and EtOH, while it is equal to 26-59 nm in the other solvents. The peculiarity of fluorescence in protic solvents can be related to the specific solvation of carbonyl oxygen in the excited state due to intramolecular charge transfer (ICT). The solvatochromism of 4-pyrones was previously unknown and distinguishes the studied conjugated 4-pyrones from 4-methylene-4H-pyrans, popular merocyanine dyes whose fluorescence is related to the solvent polarity and is most pronounced in DMSO.
For the monoenamino-substituted compound 4a, the absorption spectrum includes one-band at 334-363 nm with an extinction coefficient of 29,200-35,900 M -1 cm -1 ( Figure 2, Table 3). In aprotic solvents, the absorption maximum is observed at 334-350 nm. For alcohol solutions of pyrone 4a, the absorption maximum shifts slightly to the long-wavelength region and appears at 356 (i-PrOH), 361 (EtOH), 363 nm (MeOH) in accordance with the solvent polarity. The emission spectrum demonstrates a single maximum and depends strongly on the nature of the solvent. In alcohols as protic solvents, the fluorescence intensity increases many times over in comparison with aprotic polar solvents, such as DMSO. The highest values of quantum yields are achieved in MeOH (3.6%) and EtOH (1.4%), where the substance exhibits blue fluorescence. The largest Stokes shifts (67-71 nm) are also observed in MeOH and EtOH, while it is equal to 26-59 nm in the other solvents. The peculiarity of fluorescence in protic solvents can be related to the specific Scheme 6. Cycloaddition of enamino-substituted 4-pyrones 2f,g and 5a.
In the case of bis(enamino) derivative 5a, two maxima are observed in the absorption spectra. The most intense and structured band is in the short wavelength region at 300-304 nm (ε = 41,400-54,400 M −1 cm −1 ), and at 378-408 nm there is a second maximum with an extinction coefficient of 17,400-22,300 M −1 cm −1 (Figure 3, Table 4). The nature of the solvent most strongly affects the second maximum, which can be associated with intramolecular electron transfer. The strongest redshift of the second band is observed in alcohols (395-408 nm) compared to aprotic solvents (378-381 nm). As in the case of monoenamino derivative 4a, the fluorescence spectra turned out to be highly sensitive to the nature of the solvent and has one emission maximum located in the range of 455-490 nm. The fluorescence intensity in polar aprotic solvents is observed to be low (QY = 2.3-4.1%). The substance exhibits green fluorescence, and the highest quantum yield is found in methanol (QY = 28%), ethanol (QY = 21%), and isopropanol (QY = 11%). Also, in these solvents, the largest Stokes shifts are observed, which are equal to 83 nm, 82 nm, and 80 nm, respectively.    a Absorption maximum wavelength. b Excitation wavelength corresponds to λabs. c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QYstd = 94%, λex = 480 nm) according to the described method [35]. d The relative fluorescence quantum yield (QY) was estimated using a 0.1 M H2SO4 solution of quinine sulfate solution (QYstd = 54%, λex = 360 nm) according to the described method [37].
In the case of bis(enamino) derivative 5a, two maxima are observed in the absorption spectra. The most intense and structured band is in the short wavelength region at 300-304 nm (ε = 41,400-54,400 M −1 cm −1 ), and at 378-408 nm there is a second maximum with an extinction coefficient of 17,400-22,300 M −1 cm −1 (Figure 3, Table 4). The nature of the solvent most strongly affects the second maximum, which can be associated with intramolecular electron transfer. The strongest redshift of the second band is observed in alco- a Absorption maximum wavelength. b Excitation wavelength corresponds to λ abs . c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QY std = 94%, λ ex = 480 nm) according to the described method [35]. d The relative fluorescence quantum yield (QY) was estimated using a 0.1 M H 2 SO 4 solution of quinine sulfate solution (QY std = 54%, λ ex = 360 nm) according to the described method [37].
The substance exhibits green fluorescence, and the highest quantum yield is found in methanol (QY = 28%), ethanol (QY = 21%), and isopropanol (QY = 11%). Also, in these solvents, the largest Stokes shifts are observed, which are equal to 83 nm, 82 nm, and 80 nm, respectively.  a Absorption maximum wavelengths. b Excitation wavelength corresponds to λabs. c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QYstd = 94%, λex = 480 nm) according to the described method [37].
For the design of new fluorophores, we studied a number of functionalized enaminosubstituted 4-pyrones ( Figure 4, Table 5). The introduction of the tert-butyl group, compared to the methyl group, has practically no effect on the photophysical properties. The absorption and emission spectra of (tert-butyl)-6-(2-(dimethylamino)vinyl)-4H-pyran-4one (2a) are very similar for monoenamine derivative 4a. The introduction of the phenyl group complicates the absorption spectrum, as a result, several maxima are observed. In   a Absorption maximum wavelengths. b Excitation wavelength corresponds to λabs. c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QYstd = 94%, λex = 480 nm) according to the described method [37].
For the design of new fluorophores, we studied a number of functionalized enaminosubstituted 4-pyrones ( Figure 4, Table 5). The introduction of the tert-butyl group, compared to the methyl group, has practically no effect on the photophysical properties. The absorption and emission spectra of (tert-butyl)-6-(2-(dimethylamino)vinyl)-4H-pyran-4one (2a) are very similar for monoenamine derivative 4a. The introduction of the phenyl group complicates the absorption spectrum, as a result, several maxima are observed. In  For the design of new fluorophores, we studied a number of functionalized enamino-substituted 4-pyrones ( Figure 4, Table 5). The introduction of the tert-butyl group, compared to the methyl group, has practically no effect on the photophysical properties. The absorption and emission spectra of (tert-butyl)-6-(2-(dimethylamino)vinyl)-4H-pyran-4-one (2a) are very similar for monoenamine derivative 4a. The introduction of the phenyl group complicates the absorption spectrum, as a result, several maxima are observed. In this case, the major absorption maximum appears at 380 nm with an extinction coefficient of 19,700 M −1 cm −1 . An important feature of fluorescence is the large Stokes shift, which amounts to 147 nm (QY = 3.4%). For dimethylenamino derivative 2f bearing the p-dimethylaminostyryl moiety, the absorption spectra show several maxima with approximately the same value of the extinction coefficient. The fluorescence spectrum exhibits one-band emission at 572 nm (λ ex = 368 nm), which is characterized by higher quantum yield (18%) and a significant Stokes shift (204 nm). Similarly, the p-MeO-styryl-substituted compound 2g has several bands with low intensity in absorption spectra and very weak fluorescence emission. dimethylaminostyryl moiety, the absorption spectra show several maxima with approximately the same value of the extinction coefficient. The fluorescence spectrum exhibits one-band emission at 572 nm (λex = 368 nm), which is characterized by higher quantum yield (18%) and a significant Stokes shift (204 nm). Similarly, the p-MeO-styryl-substituted compound 2g has several bands with low intensity in absorption spectra and very weak fluorescence emission.    a Absorption maximum wavelengths. b Excitation wavelength corresponds to λabs. c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QYstd = 94%, λex = 480 nm) according to the described method [37].
Introduction of the diphenylamino substituent allows the improvement of photophysical properties. Thus, for p-MeO-styryl derivative 6b, two intense maxima are found in the absorption spectrum at 404 nm and 350 nm. This substance shows one maximum in the emission spectrum at 546 nm (λex = 368 nm) and a quantum yield of 3.4%. Next, the bis(indolyl) derivative 7b was investigated as a symmetrical compound with an extended conjugation system. Its absorption spectrum (MeOH) contains a major maximum at 433 nm, a plateau in the range of 375-348 nm, and a minor maximum at 286 nm. The emission spectrum contains one band at 571 nm, while the quantum yield reaches 15%.

Theoretical Calculations of the Absorption and Emission
We performed a DFT/TD-DFT quantum chemical calculations of absorption/emission maxima for representative compounds 4a and 5a in vacuo and in solvated phase (DMSO, EtOH, and MeOH) using the conductor-like polar continuum model (C-PCM). In the series of the ground state (GS), the first singlet excited state (S1) optimizations were made and the energies of the first seven Franck-Condon singlet states were computed. All calculations were carried out at the (TD-)DFT (CAM-)B3LYP/6-31++G** level of theory for the most stable s-trans conformations [13]. Results of this calculations are provided in Table 6; the optimized geometries of GS and S1 are listed in Supplementary Materials.  Introduction of the diphenylamino substituent allows the improvement of photophysical properties. Thus, for p-MeO-styryl derivative 6b, two intense maxima are found in the absorption spectrum at 404 nm and 350 nm. This substance shows one maximum in the emission spectrum at 546 nm (λex = 368 nm) and a quantum yield of 3.4%. Next, the bis(indolyl) derivative 7b was investigated as a symmetrical compound with an extended conjugation system. Its absorption spectrum (MeOH) contains a major maximum at 433 nm, a plateau in the range of 375-348 nm, and a minor maximum at 286 nm. The emission spectrum contains one band at 571 nm, while the quantum yield reaches 15%.

Theoretical Calculations of the Absorption and Emission
We performed a DFT/TD-DFT quantum chemical calculations of absorption/emission maxima for representative compounds 4a and 5a in vacuo and in solvated phase (DMSO, EtOH, and MeOH) using the conductor-like polar continuum model (C-PCM). In the series of the ground state (GS), the first singlet excited state (S1) optimizations were made and the energies of the first seven Franck-Condon singlet states were computed. All calculations were carried out at the (TD-)DFT (CAM-)B3LYP/6-31++G** level of theory for the most stable s-trans conformations [13]. Results of this calculations are provided in Table 6; the optimized geometries of GS and S1 are listed in Supplementary Materials.  a Absorption maximum wavelengths. b Excitation wavelength corresponds to λabs. c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QYstd = 94%, λex = 480 nm) according to the described method [37].
Introduction of the diphenylamino substituent allows the improvement of photophysical properties. Thus, for p-MeO-styryl derivative 6b, two intense maxima are found in the absorption spectrum at 404 nm and 350 nm. This substance shows one maximum in the emission spectrum at 546 nm (λex = 368 nm) and a quantum yield of 3.4%. Next, the bis(indolyl) derivative 7b was investigated as a symmetrical compound with an extended conjugation system. Its absorption spectrum (MeOH) contains a major maximum at 433 nm, a plateau in the range of 375-348 nm, and a minor maximum at 286 nm. The emission spectrum contains one band at 571 nm, while the quantum yield reaches 15%.

Theoretical Calculations of the Absorption and Emission
We performed a DFT/TD-DFT quantum chemical calculations of absorption/emission maxima for representative compounds 4a and 5a in vacuo and in solvated phase (DMSO, EtOH, and MeOH) using the conductor-like polar continuum model (C-PCM). In the series of the ground state (GS), the first singlet excited state (S1) optimizations were made and the energies of the first seven Franck-Condon singlet states were computed. All calculations were carried out at the (TD-)DFT (CAM-)B3LYP/6-31++G** level of theory for the most stable s-trans conformations [13]. Results of this calculations are provided in Table 6; the optimized geometries of GS and S1 are listed in Supplementary Materials.  a Absorption maximum wavelengths. b Excitation wavelength corresponds to λabs. c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QYstd = 94%, λex = 480 nm) according to the described method [37].
Introduction of the diphenylamino substituent allows the improvement of photophysical properties. Thus, for p-MeO-styryl derivative 6b, two intense maxima are found in the absorption spectrum at 404 nm and 350 nm. This substance shows one maximum in the emission spectrum at 546 nm (λex = 368 nm) and a quantum yield of 3.4%. Next, the bis(indolyl) derivative 7b was investigated as a symmetrical compound with an extended conjugation system. Its absorption spectrum (MeOH) contains a major maximum at 433 nm, a plateau in the range of 375-348 nm, and a minor maximum at 286 nm. The emission spectrum contains one band at 571 nm, while the quantum yield reaches 15%.

Theoretical Calculations of the Absorption and Emission
We performed a DFT/TD-DFT quantum chemical calculations of absorption/emission maxima for representative compounds 4a and 5a in vacuo and in solvated phase (DMSO, EtOH, and MeOH) using the conductor-like polar continuum model (C-PCM). In the series of the ground state (GS), the first singlet excited state (S1) optimizations were made and the energies of the first seven Franck-Condon singlet states were computed. All calculations were carried out at the (TD-)DFT (CAM-)B3LYP/6-31++G** level of theory for the most stable s-trans conformations [13]. Results of this calculations are provided in Table 6; the optimized geometries of GS and S1 are listed in Supplementary Materials.  a Absorption maximum wavelengths. b Excitation wavelength corresponds to λabs. c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QYstd = 94%, λex = 480 nm) according to the described method [37].
Introduction of the diphenylamino substituent allows the improvement of photophysical properties. Thus, for p-MeO-styryl derivative 6b, two intense maxima are found in the absorption spectrum at 404 nm and 350 nm. This substance shows one maximum in the emission spectrum at 546 nm (λex = 368 nm) and a quantum yield of 3.4%. Next, the bis(indolyl) derivative 7b was investigated as a symmetrical compound with an extended conjugation system. Its absorption spectrum (MeOH) contains a major maximum at 433 nm, a plateau in the range of 375-348 nm, and a minor maximum at 286 nm. The emission spectrum contains one band at 571 nm, while the quantum yield reaches 15%.

Theoretical Calculations of the Absorption and Emission
We performed a DFT/TD-DFT quantum chemical calculations of absorption/emission maxima for representative compounds 4a and 5a in vacuo and in solvated phase (DMSO, EtOH, and MeOH) using the conductor-like polar continuum model (C-PCM). In the series of the ground state (GS), the first singlet excited state (S1) optimizations were made and the energies of the first seven Franck-Condon singlet states were computed. All calculations were carried out at the (TD-)DFT (CAM-)B3LYP/6-31++G** level of theory for the most stable s-trans conformations [13]. Results of this calculations are provided in Table 6; the optimized geometries of GS and S1 are listed in Supplementary Materials. a Absorption maximum wavelengths. b Excitation wavelength corresponds to λ abs . c The relative fluorescence quantum yield (QY) was estimated using the solution of rhodamine 6G in ethanol as a standard (QY std = 94%, λ ex = 480 nm) according to the described method [37].
Introduction of the diphenylamino substituent allows the improvement of photophysical properties. Thus, for p-MeO-styryl derivative 6b, two intense maxima are found in the absorption spectrum at 404 nm and 350 nm. This substance shows one maximum in the emission spectrum at 546 nm (λ ex = 368 nm) and a quantum yield of 3.4%. Next, the bis(indolyl) derivative 7b was investigated as a symmetrical compound with an extended conjugation system. Its absorption spectrum (MeOH) contains a major maximum at 433 nm, a plateau in the range of 375-348 nm, and a minor maximum at 286 nm. The emission spectrum contains one band at 571 nm, while the quantum yield reaches 15%.

Theoretical Calculations of the Absorption and Emission
We performed a DFT/TD-DFT quantum chemical calculations of absorption/emission maxima for representative compounds 4a and 5a in vacuo and in solvated phase (DMSO, EtOH, and MeOH) using the conductor-like polar continuum model (C-PCM). In the series of the ground state (GS), the first singlet excited state (S 1 ) optimizations were made and the energies of the first seven Franck-Condon singlet states were computed. All calculations were carried out at the (TD-)DFT (CAM-)B3LYP/6-31++G** level of theory for the most stable s-trans conformations [13]. Results of this calculations are provided in Table 6; the optimized geometries of GS and S 1 are listed in Supplementary Materials.
The optimizations of the ground state (GS) geometry revealed that both molecules have a planar structure of D-π-A conjugation chains. Calculated Stokes shift values in a solvated phase were 27-30 nm for 2-(2-(dimethylamino)vinyl)-6-methyl-4-pyrone (4a) and 92-103 nm for 2,6-bis(2-(dimethylamino)vinyl)-4-pyrone (5a), which are in agreement with the experimental Stokes shifts. Also, in all solvents the dipole moment values increased under excitation to S 1 . On the base of Franck-Condon (FC) excitations and S 1 optimized geometries energies and their oscillator strengths, we plotted theoretical absorption and emission spectra (See Supplementary Materials Figures S1-S6, absorption/emission maxima are also provided in Table S6). Because the DFT usually overestimates long-wavelength polymethine transitions, all calculated maxima are notably blue-shifted compared to the experimental ones [38]. According to TD-DFT calculations of S 1 FC -S 7 FC states in all solvents, the most intense absorption corresponds to π → π* transition and S 0 → S 1 from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) for compound 4a, whereas S 0 → S 2 (HOMO-1 → LUMO) transition prevails for compound 5a (Table 6). In the case of compound 5a, the S 0 → S 1 transition is less intense (f GS = 0.527 for MeOH) and redshifted (λ abs = 376 nm for MeOH), which agrees well with the experimental absorption spectrum demonstrating double bands. Table 6. Calculated absorption and emission properties of 4a and 5a in vacuo, DMSO, EtOH, and MeOH a .
To explain the strong influence of alcohols on fluorescence, the charges on the carbonyl oxygen of pyrones 4a and 5a in the ground and excited states were compared. An increase in the electron density on oxygen can cause its specific solvation due to the formation of hydrogen bonds, leading to the improvement of the fluorescence properties. The charge of pyrone 5a bearing two electron-donating substituents is in all cases higher than that of pyrone 4a in the corresponding solvent, which can be explained by the stronger push-pull nature of the former. In addition, the maximum negative charge was found in EtOH and MeOH, both in the ground (−0.731 and −0.746 for 4a; −0.758 and −0.776 for 5a) and excited (−0.823 and −0.839 for 4a; −0.905 and −0.925 for 5a) states (Table 7). For all excited states, an increase in the negative charge on carbonyl oxygen is observed (except for 4a in vacuum), which is in good agreement with the change in dipole moments. The strongest charge changes during the GS→S 1 transition were found in MeOH (0.093 for 4a, 0.149 for 5a). This result is related to the ICT effect in this solvent, which is more pronounced for pyrone 5a and determines the stabilization of the excited states via the hydrogen bonding interaction between the carbonyl group and alcohol molecules [39]. Besides, the ICT phenomena for the pyrones were confirmed with the use of electron density difference (EDD) maps (See Supplementary Materials Figures S7-S10). The analysis of the frontier MOs for the ground states in the solvents (DMSO, MeOH, EtOH) and the gas phase showed that both HOMO and LUMO frontier orbitals are localized chiefly on the polymethine chain atoms, which is known to be typical for merocyanine dyes [22] (Table 8, See Supplementary Materials Tables S1-S8). Opposite to mono(enamino) derivative 4a, bis(enamino) derivative 5a exhibited a complete absence of the electron density at the carbonyl moiety of the conjugation chain for the HOMO, whereas the LUMO localization involves the whole π-conjugation, indicating the ICT effect under excitation. This feature can be connected with a large Stokes shift of bis(enamino) derivative 5a and the red-shifted emission compared to 4a. Table 8. Ground state frontier orbitals of compounds 4a and 5a in MeOH a .

Entry
Compound HOMO LUMO The analysis of the frontier MOs for the ground states in the solvents (DMSO, MeOH EtOH) and the gas phase showed that both HOMO and LUMO frontier orbitals are loca ized chiefly on the polymethine chain atoms, which is known to be typical for merocya nine dyes [22] (Table 8, See Supplementary Materials Tables S1-S8). Opposite t mono(enamino) derivative 4a, bis(enamino) derivative 5a exhibited a complete absence o the electron density at the carbonyl moiety of the conjugation chain for the HOMO whereas the LUMO localization involves the whole π-conjugation, indicating the ICT e fect under excitation. This feature can be connected with a large Stokes shift of bis(enam ino) derivative 5a and the red-shifted emission compared to 4a. Thus, a convenient method of 4-pyrone functionalization is developed via enamina tion of 2-methyl-4-pyrones with DMF-DMA. Enamino-substituted 4-pyrones were able t react with nucleophiles and 1,3-dipoles with the substitution of the dimethylamino grou and the formation of conjugated push-pull and isoxazolyl-substituted 4-pyrones, respec tively. The transformations occured with high chemoselectivity without 4-pyrone rin opening and provided a convenient platform for the synthesis and design of 4-pyrone based fluorophores. For the first time, the solvatochromism of 4-pyrones in protic solvent due to specific solvation was discovered, leading to a strong increase in the fluorescenc intensity compared to aprotic solvents. 4-Pyrones bearing two enamino fragments show The analysis of the frontier MOs for the ground states in the solvents (DMSO, MeOH, EtOH) and the gas phase showed that both HOMO and LUMO frontier orbitals are localized chiefly on the polymethine chain atoms, which is known to be typical for merocyanine dyes [22] (Table 8, See Supplementary Materials Tables S1-S8). Opposite to mono(enamino) derivative 4a, bis(enamino) derivative 5a exhibited a complete absence of the electron density at the carbonyl moiety of the conjugation chain for the HOMO, whereas the LUMO localization involves the whole π-conjugation, indicating the ICT effect under excitation. This feature can be connected with a large Stokes shift of bis(enamino) derivative 5a and the red-shifted emission compared to 4a. Thus, a convenient method of 4-pyrone functionalization is developed via enamination of 2-methyl-4-pyrones with DMF-DMA. Enamino-substituted 4-pyrones were able to react with nucleophiles and 1,3-dipoles with the substitution of the dimethylamino group and the formation of conjugated push-pull and isoxazolyl-substituted 4-pyrones, respectively. The transformations occured with high chemoselectivity without 4-pyrone ring opening and provided a convenient platform for the synthesis and design of 4-pyronebased fluorophores. For the first time, the solvatochromism of 4-pyrones in protic solvents due to specific solvation was discovered, leading to a strong increase in the fluorescence intensity compared to aprotic solvents. 4-Pyrones bearing two enamino fragments show The analysis of the frontier MOs for the ground states in the solvents (DMSO, MeOH EtOH) and the gas phase showed that both HOMO and LUMO frontier orbitals are loca ized chiefly on the polymethine chain atoms, which is known to be typical for merocy nine dyes [22] (Table 8, See Supplementary Materials Tables S1-S8). Opposite t mono(enamino) derivative 4a, bis(enamino) derivative 5a exhibited a complete absence o the electron density at the carbonyl moiety of the conjugation chain for the HOMO whereas the LUMO localization involves the whole π-conjugation, indicating the ICT e fect under excitation. This feature can be connected with a large Stokes shift of bis(enam ino) derivative 5a and the red-shifted emission compared to 4a. Thus, a convenient method of 4-pyrone functionalization is developed via enamin tion of 2-methyl-4-pyrones with DMF-DMA. Enamino-substituted 4-pyrones were able t react with nucleophiles and 1,3-dipoles with the substitution of the dimethylamino grou and the formation of conjugated push-pull and isoxazolyl-substituted 4-pyrones, respe tively. The transformations occured with high chemoselectivity without 4-pyrone rin opening and provided a convenient platform for the synthesis and design of 4-pyron based fluorophores. For the first time, the solvatochromism of 4-pyrones in protic solven due to specific solvation was discovered, leading to a strong increase in the fluorescenc intensity compared to aprotic solvents. 4-Pyrones bearing two enamino fragments sho The analysis of the frontier MOs for the ground states in the solvents (DMSO, MeOH, EtOH) and the gas phase showed that both HOMO and LUMO frontier orbitals are localized chiefly on the polymethine chain atoms, which is known to be typical for merocyanine dyes [22] (Table 8, See Supplementary Materials Tables S1-S8). Opposite to mono(enamino) derivative 4a, bis(enamino) derivative 5a exhibited a complete absence of the electron density at the carbonyl moiety of the conjugation chain for the HOMO, whereas the LUMO localization involves the whole π-conjugation, indicating the ICT effect under excitation. This feature can be connected with a large Stokes shift of bis(enamino) derivative 5a and the red-shifted emission compared to 4a. Thus, a convenient method of 4-pyrone functionalization is developed via enamination of 2-methyl-4-pyrones with DMF-DMA. Enamino-substituted 4-pyrones were able to react with nucleophiles and 1,3-dipoles with the substitution of the dimethylamino group and the formation of conjugated push-pull and isoxazolyl-substituted 4-pyrones, respectively. The transformations occured with high chemoselectivity without 4-pyrone ring opening and provided a convenient platform for the synthesis and design of 4-pyronebased fluorophores. For the first time, the solvatochromism of 4-pyrones in protic solvents due to specific solvation was discovered, leading to a strong increase in the fluorescence intensity compared to aprotic solvents. 4-Pyrones bearing two enamino fragments show Thus, a convenient method of 4-pyrone functionalization is developed via enamination of 2-methyl-4-pyrones with DMF-DMA. Enamino-substituted 4-pyrones were able to react with nucleophiles and 1,3-dipoles with the substitution of the dimethylamino group and the formation of conjugated push-pull and isoxazolyl-substituted 4-pyrones, respectively. The transformations occured with high chemoselectivity without 4-pyrone ring opening and provided a convenient platform for the synthesis and design of 4-pyronebased fluorophores. For the first time, the solvatochromism of 4-pyrones in protic solvents due to specific solvation was discovered, leading to a strong increase in the fluorescence intensity compared to aprotic solvents. 4-Pyrones bearing two enamino fragments show a higher quantum yield and significant Stokes shift, which can be explained by their stronger push-pull character. The prepared pyrone merocyanines are of interest due to attractive photophysical properties and easy modification of the conjugated chain, which can contribute to the development of the synthesis of new organic fluorophores.

Quantum Mechanical Calculations
The ground state molecular geometry of the compounds under investigation was fully optimized at density functional theory (DFT) level, both in vacuo and in the solvated phase (DMSO, EtOH, MeOH). For all geometry optimizations, the B3LYP hybrid functional [43] coupled with the 6-31G(d,p)++ basis set was chosen. Solvent effects were taken into account via the implicit conductor-like polarizable continuum model (C-PCM). For the evaluation of energetics, Solvation Model Density (SMD) parametrization was employed [44]. The vibrational frequencies and thermochemicals were computed in harmonic approximation at T = 298.15 K and p = 1 atm, and no imaginary frequencies were found.
The UV-vis absorption spectra for the equilibrium geometries were calculated at timedependent density functional theory (TD-DFT) level, accounting for S 0 → S n (n = 1 to 7). The nature of the vertical excited electronic state was analyzed both in vacuo and in the solvated phase.
The first singlet excited state (S 1 ) geometry was optimized using analytical gradients and the first transitions S 1 →S 0 of the emission. Properties of the excited states were calculated using the long-range corrected functional CAM-B3LYP [45,46] coupled with the 6-31G(d,p)++ basis set. The non-equilibrium solvation regime was set for vertical excited states calculations in the solvent phase, whereas the equilibrium solvation was used for adiabatic ones. All calculated UV-vis spectra were plotted as Gaussian curves with wavelengths of absorption/emission maxima as an expected value and σ = 0.4 eV.
The integration grid for the calculations was set to 96 radial shells and 302 angular points.
The RMS gradient convergence tolerance was set to 10 −7 Hartree/Bohr for GS optimizations and to 10 −5 Hartree/Bohr for S 1 optimizations. The density matrix convergence threshold for the self-consistent field was set to 10 −5 a.u. for all DFT and to 10 −6 a.u. for all TD-DFT optimizations.

Synthesis of Compounds 2
Corresponding 4-pyrone 1 (1.2 mmol) was heated with DMF-DMA (429.0 mg, 3.6 mmol), N-methylimidazole (0.3 mmol for 2a-c,e; 4.8 mmol for 2d; 3.6 mmol for 2f,g) in an autoclave at 100 • C (for 2c,e) or 120 • C (for 2a,b,d,f,g) for the needed time. For pyrones 2a-c, the reaction mixture was treated by boiling n-heptane (40 mL). The solvent was decanted and evaporated to 2 mL, and the solid was filtered. For products 2d,f,g, the reaction mixture was treated with Et 2 O and the solid that formed was filtered. Pyrone 2e was isolated by flash-chromatography with the use of CHCl 3 as an eluent.

General Method for the Synthesis of Bis(enamino)-substituted 4-Pyrones 5a,b
A mixture of 2,6-dimethyl-4-pyrone 3a or 3b (0.806 mmol), DMF-DMA (480 mg, 4.03 mmol), and N-methylimidazole (33.0 mg, 0.403 mmol) was heated in an autoclave for 15 h (for 5a) or 10 h (for 5b) at 130 • C. Then the reaction mixture was diluted with Et 2 O (5 mL) and the product filtered. (m, 8H, Ph); 7.55-7.60 (m, 2H, Ph), 9.13 (s, 2H, Isox). 13 Table S1: ground state frontier orbitals for compounds 4a and 5a in vacuo; Table S2: Ground state frontier orbitals for compounds 4a and 5a in DMSO; Table S3: ground state frontier orbitals for compounds 4a and 5a in ethanol; Table S4: ground state frontier orbitals for compounds 4a and 5a in methanol; Table S5: frontier orbitals of the first singlet excited state for the relaxed geometry of compounds 4a and 5a in vacuo; Table S6: frontier orbitals of the first singlet excited state for the relaxed geometry of compounds 4a and 5a in DMSO; Table S7: frontier orbitals of the first singlet-excited state for the relaxed geometry of compounds 4a and 5a in ethanol; Table S8: frontier orbitals of the first singlet-excited state for the relaxed geometry of compounds 4a and 5a in methanol; calculated normalized UV-vis spectra for compounds 4a and 5a in DMSO, methanol, and ethanol; electron density difference maps for compounds 4a and 5a; the method of preparation of 2-methyl-6-trifluoromethyl-4-pyrone; full 1 H, 19 F, and 13 C NMR spectra of all synthesized compounds; Figure S1: Normalized absorption and emission spectra of 4a in DMSO at a CAM-B3LYP level; Figure S2: Normalized absorption and emission spectra of 4a in ethanol at a CAM-B3LYP level; Figure S3: Normalized absorption and emission spectra of 4a in methanol at a CAM-B3LYP level; Figure S4: Normalized absorption and emission spectra of 5a in DMSO at a CAM-B3LYP level; Figure S5: Normalized absorption and emission spectra of 5a in ethanol at a CAM-B3LYP level; Figure S6: Normalized absorption and emission spectra of 5a in methanol at a CAM-B3LYP level; Figure S7: An electron density difference map for the S0→S1 transition of compound 4a in vacuo; Figure S8: An electron density difference map for the S0→S1 transition of compound 4a in methanol; Figure S9: An electron density difference map for the S0→S1 transition of compound 5a in vacuo; Figure S10: An electron density difference map for the S0→S1 transition of compound 5a in methanol.