Reactions of Trifluorotriacetic Acid Lactone and Hexafluorodehydroacetic Acid with Amines: Synthesis of Trifluoromethylated 4-Pyridones and Aminoenones

Dehydroacetic acid and triacetic acid lactone are known to be versatile substrates for the synthesis of a variety of azaheterocycles. However, their fluorinated analogs were poorly described in the literature. In the present work, we have investigated reactions of trifluorotriacetic acid lactone and hexafluorodehydroacetic acid with primary amines, phenylenediamine, and phenylhydrazine. While hexafluorodehydroacetic acid reacted the same way as non-fluorinated analog giving 2,6-bis(trifluoromethyl)-4-pyridones, trifluorotriacetic acid lactone had different regioselectivity of nucleophilic attack compared to the parent structure, and corresponding 3-amino-6,6,6-trifluoro-5-oxohex-3-eneamides were formed as the products. In the case of binucleophiles, further cyclization took place, forming corresponding benzodiazepine and pyrazoles. The obtained 2,6-bis(trifluoromethyl)-4-pyridones were able to react with active methylene compounds giving fluorinated merocyanine dyes.


Introduction
Oxygen heterocycles are common precursors in organic synthesis and have a special place in the synthesis of important nitrogen heterocycles by various methodologies. Among others, pyrones attract significant interest both due to a variety of chemical properties and a wide distribution in nature [1][2][3][4]. Particular attention is paid to 4-hydroxy-2-pyrones, namely, triacetic acid lactone (TAL), dehydroacetic acid (DHA, Figure 1), and their derivatives, which belong to polyketides and occur widely in living organisms [5][6][7][8]. The availability of these compounds and the possibility of their biochemical synthesis contributed to their extensive research and to the development of a wide range of options for their modification, considering them as platform compounds [9][10][11][12].
On the other hand, the introduction of fluorine into the structure of molecules often leads to a modification of their chemical properties [13] and is a common strategy in drug design [14][15][16][17][18], pesticides synthesis [19,20], and other areas [21][22][23][24]. However, there are very limited data on fluorine-containing analogs of TAL and DHA in the literature, which practically do not cover their properties. The only synthesis of 4-hydroxy-3-trifluoroacetyl-6-trifluoromethyl-2H-pyran-2-one (hexafluorodehydroacetic acid, DHA-f 6 , Figure 1) was performed by the heating of trifluoroacetoacetic ester in the presence of P 2 O 5 and proceeds through formation and dimerization of trifluoroacetylketene [25]. Hydrolysis of DHA-f 6 in aqueous NaHCO 3 leads to 4-hydroxy-6-trifluoromethyl-2H-pyran-2-one (trifluorotriacetic acid lactone, TAL-f 3 , Figure 1) [25]. The second route for the synthesis of TAL-f 3 presented in the literature comprises cyclization of the corresponding trifluorodioxocaproic acid with acetic anhydride [26]. Among the properties of TAL-f 3 , only modification of the 4-OH group is known, which was methylated with Me 2 SO 4 [27] and triflated with Tf 2 O [26]. The ring-opening of the O-methyl derivative on treatment with magnesium methylate gave Figure 1) [25]. The second route for the synthesis of TAL-f3 presented in the literature comprises cyclization of the corresponding trifluorodioxocaproic acid with acetic anhydride [26]. Among the properties of TAL-f3, only modification of the 4-OH group is known, which was methylated with Me2SO4 [27] and triflated with Tf2O [26]. The ring-opening of the O-methyl derivative on treatment with magnesium methylate gave methyl 3-methoxy-5-oxo-6,6,6-trifluoro-5-hexenoate [27] and the 4-OTf derivative reacted with 4-(methylthio)phenylboronic acid to give a Suzuki coupling product [26]. Thus, compounds that are attractive in terms of reactivity and properties of possible products turned out to be completely unexplored, and in this work, we have studied the interaction of DHA-f6 and TAL-f3 with primary amines as typical nucleophiles.

Results and Discussion
To begin with, we reproduced the synthesis described by German et al. (Scheme 1) [25], as it gives access both to DHA-f6 and TAL-f3. The results of the first step were quite inconsistent, and the yield ranged from 0% to 75%, presumably due to heating with a flame burner, which is hard to control. Nevertheless, the product was obtained in a satisfactory quantity for the further research. It should be noted that no variation in reaction conditions has improved the yield. Thus, the lowering of P2O5 loading or increasing reaction time resulted in the formation of complex mixtures, either of open-chain condensation products and trimerization ones characterized by the ester methylene quartets in 1 H NMR spectra or triads of equal intensity in 19 F NMR spectra correspondingly. The hydrolysis of DHA-f6 was more reproducible; however, we could never achieve the literature yield of 95% and had 40% on average (Scheme 1). Apart from NaHCO3, we have used NaOH and Na2CO3 as a base, but the yields were slightly lower. Adjusting pH to 4-5 during hydrolysis as the original procedure claims was quite difficult because it dropped down in time due to trifluoroacetic acid formation, so 2.0 equiv. of NaHCO3 was used instead. Moreover, crystallization of TAL-f3 did not occur until acidification to pH 0-1. We tried, as well, to carry out the detrifluoroacetylation of DHA-f6 by boiling it in water or by treatment with 93% H2SO4 or 70% HClO4 at room temperature, but the conversion was negligible. Thus, compounds that are attractive in terms of reactivity and properties of possible products turned out to be completely unexplored, and in this work, we have studied the interaction of DHA-f 6 and TAL-f 3 with primary amines as typical nucleophiles.

Results and Discussion
To begin with, we reproduced the synthesis described by German et al. (Scheme 1) [25], as it gives access both to DHA-f 6 and TAL-f 3 . The results of the first step were quite inconsistent, and the yield ranged from 0% to 75%, presumably due to heating with a flame burner, which is hard to control. Nevertheless, the product was obtained in a satisfactory quantity for the further research. It should be noted that no variation in reaction conditions has improved the yield. Thus, the lowering of P 2 O 5 loading or increasing reaction time resulted in the formation of complex mixtures, either of open-chain condensation products and trimerization ones characterized by the ester methylene quartets in 1 H NMR spectra or triads of equal intensity in 19 F NMR spectra correspondingly. The hydrolysis of DHA-f 6 was more reproducible; however, we could never achieve the literature yield of 95% and had 40% on average (Scheme 1). Apart from NaHCO 3 , we have used NaOH and Na 2 CO 3 as a base, but the yields were slightly lower. Adjusting pH to 4-5 during hydrolysis as the original procedure claims was quite difficult because it dropped down in time due to trifluoroacetic acid formation, so 2.0 equiv. of NaHCO 3 was used instead. Moreover, crystallization of TAL-f 3 did not occur until acidification to pH 0-1. We tried, as well, to carry out the detrifluoroacetylation of DHA-f 6 by boiling it in water or by treatment with 93% H 2 SO 4 or 70% HClO 4 at room temperature, but the conversion was negligible. At the first step, we studied the reaction of DHA-f6 with aniline. There are three main consecutive products that can be expected based on the literature data (Scheme 2) [28,29]. While a formation of Schiff bases usually proceeds readily in acidic media, no conversion was observed when we attempted the synthesis of intermediate A in aqueous HCl with 1.5 equiv. of PhNH2 (Table 1, entry 1). When EtOH was used as a solvent, spontaneous decarboxylation took place and N-phenylpyridone 3a was isolated in 60% Scheme 1. Synthesis of DHA-f 6 (1) and TAL-f 3 (2).
At the first step, we studied the reaction of DHA-f 6 with aniline. There are three main consecutive products that can be expected based on the literature data (Scheme 2) [28,29].
While a formation of Schiff bases usually proceeds readily in acidic media, no conversion was observed when we attempted the synthesis of intermediate A in aqueous HCl with 1.5 equiv. of PhNH 2 ( Table 1, entry 1). When EtOH was used as a solvent, spontaneous decarboxylation took place and N-phenylpyridone 3a was isolated in 60% yield (Table 1, entry 2). Formation of intermediate B was also observed and will be discussed later. Increasing the amount of PhNH 2 and carrying out the reaction in a less polar solvent or without it as well as raising the temperature did not improve the yield (Table 1, entries 3-10). Scheme 1. Synthesis of DHA-f6 (1) and TAL-f3 (2).
At the first step, we studied the reaction of DHA-f6 with aniline. There are three main consecutive products that can be expected based on the literature data (Scheme 2) [28,29]. While a formation of Schiff bases usually proceeds readily in acidic media, no conversion was observed when we attempted the synthesis of intermediate A in aqueous HCl with 1.5 equiv. of PhNH2 (Table 1, entry 1). When EtOH was used as a solvent, spontaneous decarboxylation took place and N-phenylpyridone 3a was isolated in 60% yield (Table 1, entry 2). Formation of intermediate B was also observed and will be discussed later. Increasing the amount of PhNH2 and carrying out the reaction in a less polar solvent or without it as well as raising the temperature did not improve the yield (Table  1, entries 3-10).

Scheme 2.
Reaction of DHA-f6 with aniline. Exploring the scope of the synthesis of 4-pyridones 3 from DHA-f 6 , we found that the reaction rates and the yields correlate with nucleophilicity of amine. Thus, aniline derivatives bearing π-donor substituents (MeO, F) at the 4-position react considerably faster, whereas those bearing strong acceptor substituents (Ac, CF 3 ) at the 3-position or a weak acceptor substituent (Br) at the 4-position react at a comparable rate but give slightly lower yields (Scheme 3, Table 2). Noteworthy, even extremely weakly nucleophilic 4-nitroaniline was able to react although the conversion was low even after 6 days, and pyridone 3k was formed in only 8% yield. The characteristic signals of pyridones 3 in the NMR spectra acquired in CDCl 3  weak acceptor substituent (Br) at the 4-position react at a comparable rate but give slightly lower yields (Scheme 3, Table 2). Noteworthy, even extremely weakly nucleophilic 4-nitroaniline was able to react although the conversion was low even after 6 days, and pyridone 3k was formed in only 8% yield. The characteristic signals of pyridones 3 in the NMR spectra acquired in CDCl3 are the singlet of vinylic CH with double intensity at 6.95-7.02 ppm ( 1 H NMR) and the quartets of symmetric carbons at 119.2-119.4 ppm (CF3), 140.8-141.6 ppm (C-2 and C-6), and 119.0-119.6 ppm (C-3 and C-5).

Scheme 3.
Reaction of DHA-f6 with aromatic amines. The existence of an ortho-substituent did not affect the initial two steps of the reaction sequence and CO2 evolution occurred during first 1-2 h; however, the cyclization of bisenamines B depends on electron properties of the substituent. In the case of more reactive o-toluidine and 2,5-xylidine, the overall duration was 24 h, whereas 2-chloro-and 2,5-difluoroaniline required twice as much time ( Table 2). It allowed us to isolate and characterize the intermediate B′ (Scheme 3), although in the mixture with starting 2-chloroaniline, which did not separate by the column chromatography. Its structure was confirmed by very distinguishable singlets of symmetric groups at 5.78 ppm (vinylic CH) Scheme 3. Reaction of DHA-f 6 with aromatic amines. The existence of an ortho-substituent did not affect the initial two steps of the reaction sequence and CO 2 evolution occurred during first 1-2 h; however, the cyclization of bisenamines B depends on electron properties of the substituent. In the case of more reactive o-toluidine and 2,5-xylidine, the overall duration was 24 h, whereas 2-chloroand 2,5-difluoroaniline required twice as much time ( Table 2). It allowed us to isolate and characterize the intermediate B (Scheme 3), although in the mixture with starting 2-chloroaniline, which did not separate by the column chromatography. Its structure was confirmed by very distinguishable singlets of symmetric groups at 5.78 ppm (vinylic CH) and 11.49 ppm (enaminone NH) in 1 H NMR and at 97.8 ppm in 19 F NMR spectra in CDCl 3 . The formation of adducts with the structure of B was observed by TLC in all the cases, but for most of them the simultaneous cyclization to pyridones 3 occurred, so their isolation was impractical.
Surprisingly, aliphatic amines such as butylamine, N,N-dimethylethylenediamine and benzylamine did not react with DHA-f 6 under the conditions found, even after several weeks. It can be attributed to their much higher basicity and fixation of the substrate in an anionic form that prevents further nucleophilic attack. This assumption was supported by the formation of the salt 4 (Scheme 3) in the reaction with 2-aminopyridine, which precipitated in nearly quantitative yield and remained unchanged after 8 days at 60 • C in EtOH. The signals in the 19 F NMR spectrum of compound 4 in DMSO-d 6 almost exactly match the signals of DHA-f 6 (91.0 and 89.8 ppm compared to 91.1 and 89.6 ppm, respectively) and the singlet of pyrone CH in the 1 H NMR spectrum is shifted upfield by 0.09 ppm (6.15 compared to 6.24 ppm) in agreement with its anionic character.
Reactivity of 4-pyridones 3 is greatly affected by strongly acceptor CF 3 -groups. Thus, electrophilic bromination of 3a with NBS proceeded poorly compared to the non-fluorinated analog [30] and no distinct product was obtained. On the contrary, Knoevenagel condensation did well with malononitrile, barbituric acid, and indane-1,3-dione in acetic anhydride, leading to fluorinated merocyanine dyes 5 (Scheme 4, Table 3). This reveals that the electron deficiency of a heterocycle plays an important role for this reaction, as 1-aryl-2,6-dimethyl-4-pyridones are less active [31,32] compared both to the CF 3 -substituted pyridone 3a and to the oxygen analog, 2,6-dimethyl-4-pyrone [33]. The time required for the reaction completion is in accordance with the acidity of an active methylene compound, so one can assume that deprotonation is a rate-limiting step, and a high activity of a substrate is necessary to prevent self-condensation of CH 2 X 2 .
in an anionic form that prevents further nucleophilic attack. This assumption was supported by the formation of the salt 4 (Scheme 3) in the reaction with 2-aminopyridine, which precipitated in nearly quantitative yield and remained unchanged after 8 days at 60 °C in EtOH. The signals in the 19 F NMR spectrum of compound 4 in DMSO-d6 almost exactly match the signals of DHA-f6 (91.0 and 89.8 ppm compared to 91.1 and 89.6 ppm, respectively) and the singlet of pyrone CH in the 1 H NMR spectrum is shifted upfield by 0.09 ppm (6.15 compared to 6.24 ppm) in agreement with its anionic character.
Reactivity of 4-pyridones 3 is greatly affected by strongly acceptor CF3-groups. Thus, electrophilic bromination of 3a with NBS proceeded poorly compared to the non-fluorinated analog [30] and no distinct product was obtained. On the contrary, Knoevenagel condensation did well with malononitrile, barbituric acid, and indane-1,3-dione in acetic anhydride, leading to fluorinated merocyanine dyes 5 (Scheme 4, Table 3). This reveals that the electron deficiency of a heterocycle plays an important role for this reaction, as 1-aryl-2,6-dimethyl-4-pyridones are less active [31,32] compared both to the CF3-substituted pyridone 3a and to the oxygen analog, 2,6-dimethyl-4-pyrone [33]. The time required for the reaction completion is in accordance with the acidity of an active methylene compound, so one can assume that deprotonation is a rate-limiting step, and a high activity of a substrate is necessary to prevent self-condensation of CH2X2.  The prepared compounds, 5a-c, are found to be yellow solids and exhibit an absorbance major maximum at 382-437 nm in the visible region of the spectra. For barbitu-Scheme 4. Reaction of 4-pyridone 3a with active methylene compounds. Table 3. Synthesis and structure of adducts 5a-c a .

Compound
Structure eral weeks. It can be attributed to their much higher basicity and fixation of the substrate in an anionic form that prevents further nucleophilic attack. This assumption was supported by the formation of the salt 4 (Scheme 3) in the reaction with 2-aminopyridine, which precipitated in nearly quantitative yield and remained unchanged after 8 days at 60 °C in EtOH. The signals in the 19 F NMR spectrum of compound 4 in DMSO-d6 almost exactly match the signals of DHA-f6 (91.0 and 89.8 ppm compared to 91.1 and 89.6 ppm, respectively) and the singlet of pyrone CH in the 1 H NMR spectrum is shifted upfield by 0.09 ppm (6.15 compared to 6.24 ppm) in agreement with its anionic character. Reactivity of 4-pyridones 3 is greatly affected by strongly acceptor CF3-groups. Thus, electrophilic bromination of 3a with NBS proceeded poorly compared to the non-fluorinated analog [30] and no distinct product was obtained. On the contrary, Knoevenagel condensation did well with malononitrile, barbituric acid, and indane-1,3-dione in acetic anhydride, leading to fluorinated merocyanine dyes 5 (Scheme 4, Table 3). This reveals that the electron deficiency of a heterocycle plays an important role for this reaction, as 1-aryl-2,6-dimethyl-4-pyridones are less active [31,32] compared both to the CF3-substituted pyridone 3a and to the oxygen analog, 2,6-dimethyl-4-pyrone [33]. The time required for the reaction completion is in accordance with the acidity of an active methylene compound, so one can assume that deprotonation is a rate-limiting step, and a high activity of a substrate is necessary to prevent self-condensation of CH2X2.  The prepared compounds, 5a-c, are found to be yellow solids and exhibit an absorbance major maximum at 382-437 nm in the visible region of the spectra. For barbitu-10 65 172-173 5b eral weeks. It can be attributed to their much higher basicity and fixation of the substrate in an anionic form that prevents further nucleophilic attack. This assumption was supported by the formation of the salt 4 (Scheme 3) in the reaction with 2-aminopyridine, which precipitated in nearly quantitative yield and remained unchanged after 8 days at 60 °C in EtOH. The signals in the 19 F NMR spectrum of compound 4 in DMSO-d6 almost exactly match the signals of DHA-f6 (91.0 and 89.8 ppm compared to 91.1 and 89.6 ppm, respectively) and the singlet of pyrone CH in the 1 H NMR spectrum is shifted upfield by 0.09 ppm (6.15 compared to 6.24 ppm) in agreement with its anionic character. Reactivity of 4-pyridones 3 is greatly affected by strongly acceptor CF3-groups. Thus, electrophilic bromination of 3a with NBS proceeded poorly compared to the non-fluorinated analog [30] and no distinct product was obtained. On the contrary, Knoevenagel condensation did well with malononitrile, barbituric acid, and indane-1,3-dione in acetic anhydride, leading to fluorinated merocyanine dyes 5 (Scheme 4, Table 3). This reveals that the electron deficiency of a heterocycle plays an important role for this reaction, as 1-aryl-2,6-dimethyl-4-pyridones are less active [31,32] compared both to the CF3-substituted pyridone 3a and to the oxygen analog, 2,6-dimethyl-4-pyrone [33]. The time required for the reaction completion is in accordance with the acidity of an active methylene compound, so one can assume that deprotonation is a rate-limiting step, and a high activity of a substrate is necessary to prevent self-condensation of CH2X2.  The prepared compounds, 5a-c, are found to be yellow solids and exhibit an absorbance major maximum at 382-437 nm in the visible region of the spectra. For barbitu- eral weeks. It can be attributed to their much higher basicity and fixation of the substrate in an anionic form that prevents further nucleophilic attack. This assumption was supported by the formation of the salt 4 (Scheme 3) in the reaction with 2-aminopyridine, which precipitated in nearly quantitative yield and remained unchanged after 8 days at 60 °C in EtOH. The signals in the 19 F NMR spectrum of compound 4 in DMSO-d6 almost exactly match the signals of DHA-f6 (91.0 and 89.8 ppm compared to 91.1 and 89.6 ppm, respectively) and the singlet of pyrone CH in the 1 H NMR spectrum is shifted upfield by 0.09 ppm (6.15 compared to 6.24 ppm) in agreement with its anionic character. Reactivity of 4-pyridones 3 is greatly affected by strongly acceptor CF3-groups. Thus, electrophilic bromination of 3a with NBS proceeded poorly compared to the non-fluorinated analog [30] and no distinct product was obtained. On the contrary, Knoevenagel condensation did well with malononitrile, barbituric acid, and indane-1,3-dione in acetic anhydride, leading to fluorinated merocyanine dyes 5 (Scheme 4, Table 3). This reveals that the electron deficiency of a heterocycle plays an important role for this reaction, as 1-aryl-2,6-dimethyl-4-pyridones are less active [31,32] compared both to the CF3-substituted pyridone 3a and to the oxygen analog, 2,6-dimethyl-4-pyrone [33]. The time required for the reaction completion is in accordance with the acidity of an active methylene compound, so one can assume that deprotonation is a rate-limiting step, and a high activity of a substrate is necessary to prevent self-condensation of CH2X2.  The prepared compounds, 5a-c, are found to be yellow solids and exhibit an absorbance major maximum at 382-437 nm in the visible region of the spectra. For barbitu- 6 43 208-209 a A solution of 4-pyridone 3a (100 mg, 0.33 mmol) and the corresponding CH 2 X 2 (0.4 mmol) in Ac 2 O was stirred at 140 • C for a given amount of time.
The prepared compounds, 5a-c, are found to be yellow solids and exhibit an absorbance major maximum at 382-437 nm in the visible region of the spectra. For barbituric derivative 5b, the high molar extinction coefficient (91406 M −1 ·cm −1 at 412 nm) is observed and probably indicates the intramolecular charge-transfer described by the aromatic resonance form 5 (Figure 2). For dihydropyridine 5c bearing the indanedione moiety, additional intensive absorption maxima are observed at 246 and 224 nm. An interesting feature in NMR spectra of compounds 5 is a large difference compared to each other in chemical shifts of CH-groups in the dihydropyridine fragment attributed to the magnetic anisotropy of carbonyl and cyano groups, which have a closer proximity in derivative 5b (δ H3 = 9.77 ppm, δ C3 = 116.8 ppm) than in 5c (δ H3 = 9.10 ppm, δ C3 = 113.4 ppm) and in 5a (δ H3 = 7.26 ppm, δ C3 = 112.7 ppm). Another possible explanation for the difference is a greater contribution of the betaine resonance form 5 (Figure 2) for the adduct with barbituric acid, but this seems to have a smaller effect as the chemical shifts of the rest of carbon atoms diverge much less (Table S2 in Supplementary Materials). other in chemical shifts of CH-groups in the dihydropyridine fragment attributed to the magnetic anisotropy of carbonyl and cyano groups, which have a closer proximity in derivative 5b (δH3 = 9.77 ppm, δC3 = 116.8 ppm) than in 5c (δH3 = 9.10 ppm, δC3 = 113.4 ppm) and in 5a (δH3 = 7.26 ppm, δC3 = 112.7 ppm). Another possible explanation for the difference is a greater contribution of the betaine resonance form 5′ (Figure 2) for the adduct with barbituric acid, but this seems to have a smaller effect as the chemical shifts of the rest of carbon atoms diverge much less (Table S2 in Supplementary Materials). Moving on to the investigation of trifluorotriacetic acid lactone (2) properties, we focused on our previous work on the study of triacetic acid lactone (6) [34] and 2-cyano-6-(trifluoromethyl)-4H-pyran-4-one (7) [35], which gave carbamoylated enaminones 8 (Scheme 5), which proved to be a versatile building blocks for nitrogen heterocycles. In both cases, the substrates were attacked with two equivalents of amine at positions 2 and 6. We started the optimization of the reaction conditions of TAL-f3 (2) with aniline in EtOH using various amount of amine (Scheme 6, Table 4, entries 1-3). The product 9a with unexpected regiochemistry was formed with the best yield of 64% when only little excess of PhNH2 was applied. The reaction performs better in aprotic polar 1,4-dioxane ( Table 4, entry 4) and worse in non-polar toluene or without a solvent (Table 4; entries 5, 6). It should be noted that an increase in the reaction temperature did not improve the yield of enaminone 9a. Scheme 6. Reaction of TAL-f3 with aniline. Moving on to the investigation of trifluorotriacetic acid lactone (2) properties, we focused on our previous work on the study of triacetic acid lactone (6) [34] and 2-cyano-6-(trifluoromethyl)-4H-pyran-4-one (7) [35], which gave carbamoylated enaminones 8 (Scheme 5), which proved to be a versatile building blocks for nitrogen heterocycles. In both cases, the substrates were attacked with two equivalents of amine at positions 2 and 6. derivative 5b (δH3 = 9.77 ppm, δC3 = 116.8 ppm) than in 5c (δH3 = 9.10 ppm, δC3 = 113.4 ppm) and in 5a (δH3 = 7.26 ppm, δC3 = 112.7 ppm). Another possible explanation for the difference is a greater contribution of the betaine resonance form 5′ (Figure 2) for the adduct with barbituric acid, but this seems to have a smaller effect as the chemical shifts of the rest of carbon atoms diverge much less (Table S2 in Supplementary Materials). Moving on to the investigation of trifluorotriacetic acid lactone (2) properties, we focused on our previous work on the study of triacetic acid lactone (6) [34] and 2-cyano-6-(trifluoromethyl)-4H-pyran-4-one (7) [35], which gave carbamoylated enaminones 8 (Scheme 5), which proved to be a versatile building blocks for nitrogen heterocycles. In both cases, the substrates were attacked with two equivalents of amine at positions 2 and 6.

Scheme 5. Reaction of TAL and 2-cyano-6-(trifluoromethyl)-4-pyrone with primary amines.
We started the optimization of the reaction conditions of TAL-f3 (2) with aniline in EtOH using various amount of amine (Scheme 6, Table 4, entries 1-3). The product 9a with unexpected regiochemistry was formed with the best yield of 64% when only little excess of PhNH2 was applied. The reaction performs better in aprotic polar 1,4-dioxane ( Table 4, entry 4) and worse in non-polar toluene or without a solvent (Table 4; entries 5, 6). It should be noted that an increase in the reaction temperature did not improve the yield of enaminone 9a. Scheme 6. Reaction of TAL-f3 with aniline.

Scheme 5. Reaction of TAL and 2-cyano-6-(trifluoromethyl)-4-pyrone with primary amines.
We started the optimization of the reaction conditions of TAL-f 3 (2) with aniline in EtOH using various amount of amine (Scheme 6, Table 4, entries 1-3). The product 9a with unexpected regiochemistry was formed with the best yield of 64% when only little excess of PhNH 2 was applied. The reaction performs better in aprotic polar 1,4-dioxane ( Table 4, entry 4) and worse in non-polar toluene or without a solvent (Table 4; entries 5, 6). It should be noted that an increase in the reaction temperature did not improve the yield of enaminone 9a. derivative 5b (δH3 = 9.77 ppm, δC3 = 116.8 ppm) than in 5c (δH3 = 9.10 ppm, δC3 = 113.4 ppm) and in 5a (δH3 = 7.26 ppm, δC3 = 112.7 ppm). Another possible explanation for the difference is a greater contribution of the betaine resonance form 5′ (Figure 2) for the adduct with barbituric acid, but this seems to have a smaller effect as the chemical shifts of the rest of carbon atoms diverge much less (Table S2 in Supplementary Materials). Moving on to the investigation of trifluorotriacetic acid lactone (2) properties, we focused on our previous work on the study of triacetic acid lactone (6) [34] and 2-cyano-6-(trifluoromethyl)-4H-pyran-4-one (7) [35], which gave carbamoylated enaminones 8 (Scheme 5), which proved to be a versatile building blocks for nitrogen heterocycles. In both cases, the substrates were attacked with two equivalents of amine at positions 2 and 6.

Scheme 5. Reaction of TAL and 2-cyano-6-(trifluoromethyl)-4-pyrone with primary amines.
We started the optimization of the reaction conditions of TAL-f3 (2) with aniline in EtOH using various amount of amine (Scheme 6, Table 4, entries 1-3). The product 9a with unexpected regiochemistry was formed with the best yield of 64% when only little excess of PhNH2 was applied. The reaction performs better in aprotic polar 1,4-dioxane ( Table 4, entry 4) and worse in non-polar toluene or without a solvent (Table 4; entries 5, 6). It should be noted that an increase in the reaction temperature did not improve the yield of enaminone 9a. Scheme 6. Reaction of TAL-f3 with aniline. Scheme 6. Reaction of TAL-f 3 with aniline. The reaction with electron-rich p-anisidine proceeded equally well, whereas electronpoor p-bromoaniline gave lower yield (Scheme 7, Table 5). The reaction with aliphatic amines again has difficulties, probably due to the formation of salts; however, the lower acidity of TAL-f 3 compared to DHA-f 6 allowed enaminones 9d,e to form in low yields. In the case of butylamine, the heating to 60 • C was also needed. All amines reacted with the same regioselectivity, and no alternative isomers 8 were isolated.
The reaction with electron-rich p-anisidine proceeded equally well, whereas electron-poor p-bromoaniline gave lower yield (Scheme 7, Table 5). The reaction with aliphatic amines again has difficulties, probably due to the formation of salts; however, the lower acidity of TAL-f3 compared to DHA-f6 allowed enaminones 9d,e to form in low yields. In the case of butylamine, the heating to 60 °C was also needed. All amines reacted with the same regioselectivity, and no alternative isomers 8 were isolated. Scheme 7. Reaction of TAL-f3 with primary amines. Although Z-form of enaminones is predominant because of an effective intramolecular hydrogen bonding, the contribution of an E-isomer may be affected by the electronic nature of a substituent at a nitrogen atom [36] or by an alternative hydrogen bond formation [37], which is the case for product 9 (Figure 3). The ratio of isomers is solvent-dependent, and Z-form mostly prevails, except for compound 4a in DMSO-d6 ( Table  5). The assignment of isomers was conducted on the basis of 1 H and 13 C NMR spectra (Table S3 in Supplementary Materials). The key signals are low-field NH-protons of Z-9 isomers at 12.39-12.58 ppm (for N-arylenaminones 9a-c in CDCl3) and at 11.08-11.32 ppm (for N-alkylenaminones 9d,e in CDCl3). The corresponding signals for the E-isomers of 9 are under a much higher field in accordance with the literature [37,38]. Among the other features of the NMR spectra of compounds 9 is the existence of methylene protons and amide NH-protons at a lower field and methyne carbons at a higher field for the E-isomer (Figure 3).

Scheme 7.
Reaction of TAL-f 3 with primary amines. Although Z-form of enaminones is predominant because of an effective intramolecular hydrogen bonding, the contribution of an E-isomer may be affected by the electronic nature of a substituent at a nitrogen atom [36] or by an alternative hydrogen bond formation [37], which is the case for product 9 (Figure 3). The ratio of isomers is solvent-dependent, and Z-form mostly prevails, except for compound 4a in DMSO-d 6 ( Table 5). The assignment of isomers was conducted on the basis of 1 H and 13 C NMR spectra (Table S3 in Supplementary Materials). The key signals are low-field NH-protons of Z-9 isomers at 12.39-12.58 ppm (for N-arylenaminones 9a-c in CDCl 3 ) and at 11.08-11.32 ppm (for N-alkylenaminones 9d,e in CDCl 3 ). The corresponding signals for the E-isomers of 9 are under a much higher field in accordance with the literature [37,38]. Among the other features of the NMR spectra of compounds 9 is the existence of methylene protons and amide NH-protons at a lower field and methyne carbons at a higher field for the E-isomer (Figure 3).  For an explanation of the difference in the regioselectivity of the interaction of TAL and TAL-f3 with amines, we propose the following mechanism. The addition of the first equivalent of RNH2 leads to the formation of dioxoamide C (Scheme 8), which was isolated earlier (X = H) [39]. The intermediate C is then attacked by the second amine molecule at the less hindered atom, C-5, in the case of X = H forming product 8. A preference of the attack at C-3 for the fluorinated derivative may be attributed to a high content of cyclic form D (Scheme 8), analogs of which were described in the literature as the only tautomer in CDCl3 and DMSO-d6 solutions [40,41]. The semiaminal carbon atom is less susceptible to nucleophiles than the free keto group that leads to the selective formation of product 9. It also should be noted that a mixture of regioisomers is usually produced For an explanation of the difference in the regioselectivity of the interaction of TAL and TAL-f 3 with amines, we propose the following mechanism. The addition of the first equivalent of RNH 2 leads to the formation of dioxoamide C (Scheme 8), which was isolated earlier (X = H) [39]. The intermediate C is then attacked by the second amine molecule at the less hindered atom, C-5, in the case of X = H forming product 8. A preference of the attack at C-3 for the fluorinated derivative may be attributed to a high content of cyclic form D (Scheme 8), analogs of which were described in the literature as the only tautomer in CDCl 3 and DMSO-d 6 solutions [40,41]. The semiaminal carbon atom is less susceptible to nucleophiles than the free keto group that leads to the selective formation of product 9. It also should be noted that a mixture of regioisomers is usually produced when linear aliphatic CF 3 -diketones react with aniline [42].
shifts in H (in green) and C (in magenta) NMR in CDCl3.
For an explanation of the difference in the regioselectivity of the interaction of TAL and TAL-f3 with amines, we propose the following mechanism. The addition of the first equivalent of RNH2 leads to the formation of dioxoamide C (Scheme 8), which was isolated earlier (X = H) [39]. The intermediate C is then attacked by the second amine molecule at the less hindered atom, C-5, in the case of X = H forming product 8. A preference of the attack at C-3 for the fluorinated derivative may be attributed to a high content of cyclic form D (Scheme 8), analogs of which were described in the literature as the only tautomer in CDCl3 and DMSO-d6 solutions [40,41]. The semiaminal carbon atom is less susceptible to nucleophiles than the free keto group that leads to the selective formation of product 9. It also should be noted that a mixture of regioisomers is usually produced when linear aliphatic CF3-diketones react with aniline [42]. Scheme 8. Proposed mechanism of the reaction of TAL and TAL-f3 with primary amines.
No change in selectivity was observed when bifunctional aromatic amine, o-phenylenediamine, was used in the optimized conditions. Benzodiazepinone 10 was formed as the only isolated product, although the yield was moderate (Scheme 9). Compound 10 was previously obtained from the corresponding dioxoester 11 in the mixture with diazepine 12 [43] (Scheme 9), so our method represents a good alternative with no specific separation needed. No change in selectivity was observed when bifunctional aromatic amine, ophenylenediamine, was used in the optimized conditions. Benzodiazepinone 10 was formed as the only isolated product, although the yield was moderate (Scheme 9). Compound 10 was previously obtained from the corresponding dioxoester 11 in the mixture with diazepine 12 [43] (Scheme 9), so our method represents a good alternative with no specific separation needed. Phenylhydrazine also reacted with TAL-f3 (2) regioselectively in 1,4-dioxane, giving pyrazolohydrazide 13, but the yield was poor. Changing the solvent to EtOH substantially increased the outcome, though isomer 14 was also formed and did not separate by the column chromatography (Scheme 10). Compound 14 was previously synthesized from cyanopyrone 7 [35] and its spectral characteristics are in a good correlation with our data. Both isomers appear as two sets of signals corresponding to a major syn-(presented at Scheme 10) and a minor anti-rotamer about the N-N bond. The key differences in the NMR spectra of the regioisomer 13 are the more downfield signal of the CF3 group in 19 F NMR (106.2 ppm compared to 101.9 ppm for 14) due to deshielding from the adjacent phenyl substituent, and more downfield signals of NH groups in 1 H NMR (9.91 and 7.82 ppm compared to 9.84 and 7.73 ppm for 14) due to additional hydrogen bonding. Phenylhydrazine also reacted with TAL-f 3 (2) regioselectively in 1,4-dioxane, giving pyrazolohydrazide 13, but the yield was poor. Changing the solvent to EtOH substantially increased the outcome, though isomer 14 was also formed and did not separate by the column chromatography (Scheme 10). Compound 14 was previously synthesized from cyanopyrone 7 [35] and its spectral characteristics are in a good correlation with our data. Both isomers appear as two sets of signals corresponding to a major syn-(presented at Scheme 10) and a minor anti-rotamer about the N-N bond. The key differences in the NMR spectra of the regioisomer 13 are the more downfield signal of the CF 3 group in 19 F NMR (106.2 ppm compared to 101.9 ppm for 14) due to deshielding from the adjacent phenyl substituent, and more downfield signals of NH groups in 1 H NMR (9.91 and 7.82 ppm compared to 9.84 and 7.73 ppm for 14) due to additional hydrogen bonding. from cyanopyrone 7 [35] and its spectral characteristics are in a good correlation with our data. Both isomers appear as two sets of signals corresponding to a major syn-(presented at Scheme 10) and a minor anti-rotamer about the N-N bond. The key differences in the NMR spectra of the regioisomer 13 are the more downfield signal of the CF3 group in 19 F NMR (106.2 ppm compared to 101.9 ppm for 14) due to deshielding from the adjacent phenyl substituent, and more downfield signals of NH groups in 1 H NMR (9.91 and 7.82 ppm compared to 9.84 and 7.73 ppm for 14) due to additional hydrogen bonding. Thus, hexafluorodehydroacetic acid and trifluorotriacetic acid lactone were shown to be active electrophiles and represent interesting fluorinated building blocks, which were transformed to a number of nitrogen heterocycles. Reaction of hexafluorodehydroacetic acid with primary aromatic amines leads to the formation of 2,6-bis(trifluoromethyl)-4-pyridones that are able to undergo Knoevenagel condensation to give merocyanine dyes. Trifluorotriacetic acid lactone undergoes ring-opening transformations with mono-and binucleophilic primary amines at the positions 2 and 4 and differs in regioselectivity compared to the non-fluorinated analog.

Materials and Methods
NMR spectra were recorded on Bruker DRX-400 (Bruker BioSpin GmbH, Ettlingen, Germany, work frequencies: 1 H-400 MHz, 13 C-100 MHz, 19 F-376.5 MHz) and Bruker Avance III-500 (Bruker BioSpin GmbH, Rheinstetten, Germany, work frequencies: 1 H-500 MHz, 13  Thus, hexafluorodehydroacetic acid and trifluorotriacetic acid lactone were shown to be active electrophiles and represent interesting fluorinated building blocks, which were transformed to a number of nitrogen heterocycles. Reaction of hexafluorodehydroacetic acid with primary aromatic amines leads to the formation of 2,6-bis(trifluoromethyl)-4pyridones that are able to undergo Knoevenagel condensation to give merocyanine dyes. Trifluorotriacetic acid lactone undergoes ring-opening transformations with mono-and binucleophilic primary amines at the positions 2 and 4 and differs in regioselectivity compared to the non-fluorinated analog.

Synthesis of Compounds 3a-k General Procedure
An aromatic amine (0.83 mmol) was added to a solution of hexafluorodehydroacetic acid (1) (100 mg, 0.36 mmol) in EtOH (1 mL). The reaction mixture was stirred at room temperature for a given amount of time and acidified with aqueous HCl (3 mL, 1 M). The precipitate was filtered off and washed with water. The crude product was recrystallized from hexane.

Synthesis of Compound B
o-Chloroaniline (106 mg, 0.83 mmol) was added to a solution of hexafluorodehydroacetic acid (1) (100 mg, 0.36 mmol) in EtOH (1 mL). The reaction mixture was stirred at room temperature for a 15 h and acidified with aqueous HCl (3 mL, 1 M). The precipitate was filtered off and washed with water. The crude product was purified by column chromatography (CHCl 3 ).