2-Aryl-6-Polyfluoroalkyl-4-Pyrones as Promising RF-Building-Blocks: Synthesis and Application for Construction of Fluorinated Azaheterocycles

A convenient and general method for the direct synthesis of 2-aryl-6-(trifluoromethyl)-4-pyrones and 2-aryl-5-bromo-6-(trifluoromethyl)-4-pyrones has been developed on the basis of one-pot oxidative cyclization of (E)-6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones via a bromination/dehydrobromination approach. This strategy was also applied for the preparation of 2-phenyl-6-polyfluoroalkyl-4-pyrones and their 5-bromo derivatives. Conditions of chemoselective enediones bromination were found and the key intermediates of the cyclization of bromo-derivatives to 4-pyrones were characterized. Synthetic application of the prepared 4-pyrones has been demonstrated for the construction of biologically important CF3-bearing azaheterocycles, such as pyrazoles, pyridones, and triazoles.

It is known that fluorine-bearing compounds are of considerable interest for medicinal chemistry and agrochemistry [17]. The search for readily available and highly functionalized fluorinated building blocks for the construction of complex molecules is an important task for the synthesis of new bioactive substances.
Inspired by the chemistry of 2-CF 3 -chromones (benzopyrones) [27] and 2-CF 3 -4pyrones [18], we decided to find an approach for the construction of a range of novel arylated 2-R F -4-pyrones as useful building-blocks for the preparation of fluorinated heterocycles. The number of 2-aryl-6-(trifluoromethyl)-4-pyrones described in the literature is limited by several examples [23][24][25], and there is also the publication regarding the reaction of 2-phenyl-6-(trifluoromethyl)-4-pyrone and salicylic aldehyde with no mention of its synthesis [28]. Thus, there is no general method for the synthesis of the fluorinated 2-aryl-4-pyrones at the moment.
Recently, methods for the preparation of pyrones based on the cyclization of acetylenyl-1,3-diketones have been actively developed [29][30][31][32][33], which allows the switchable preparation of 4-pyrones or furanones. Similar approach is the use of dibromo derivatives, which can react as synthetic equivalents of acetylenyl-1,3-diketones and undergo dehydrobromination reactions under basic conditions [34][35][36][37]. This method was applied for the preparation of 2-aryl-4-pyrones bearing the methyl and carboethoxy substituents. However, low selectivity of the bromination reaction of the starting enediones, difficult isolation of intermediate products, low yields, and very high sensitivity to the nature of the substituents strongly restrict its utilization.
The chemical properties of 6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones remain unexplored, but they can be considered as a platform for the preparation of new fluorinated compounds [38][39][40][41]. The presence of several functional groups (conjugated double bonds and the diketone moiety) in their molecules makes them attractive and useful tools in organic synthesis. The introduction of the strong electron-withdrawing trifluoromethyl group can lead to a change in the chemoselectivity of the bromination reaction of 6-aryl-1,1,1trifluorohex-5-ene-2,4-diones in comparison with non-fluorinated analogs and to changes in the cyclization step due to the ability of this group to stabilize cyclic and hemiacetal forms [17].
In the present work, we have developed a general method for the preparation of 2-aryl-6-polyfluoroalkyl-4-pyrones and their 3-bromo derivatives based on one-pot cyclization through the stage of bromination/dehydrobromination of enediones. The synthetic potential of the pyrones was demonstrated on the example of regioselective reactions with N-nucleophiles.

Results and Discussion
We started our research with the preparation of fluorinated enediones 2 based on the condensation reaction of 4-aryl-3-buten-2-ones 1 with ethyl polyfluoroalkanoates in the presence of sodium hydride in diethyl ether at room temperature or lithium hydride in benzene under reflux (Scheme 2, Table 1). Both methods were comparably effective, and CF 3 -bearing products 2a-i were obtained in 51-92% yields. Compounds 2a,f-h have been described in the literature, but they were prepared by other methods [38][39][40][41]. Besides, this approach was applied for the preparation of polyfluorinated enediones 2j-l in 43-51%. We first focused on the bromination of CF 3 -containing compounds 2a-i in order to obtain active intermediates and to develop a general method for the construction of pyrones based on enediones 2. Both the double bond and the diketone moiety in 6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones 2 can undergo an electrophilic attack of bromine. To estimate the influence of conditions on conversion, the chemo-and stereoselectivity (see detailed data in Supplementary Materials), the bromination reaction was examined for compound 2b bearing the para-fluorophenyl substituent (Scheme 3, Table 2). It was shown that the most active fragment is the double bond that leads to the initial formation of dibromo derivative 3b, and no product of initial attack only at the methylene group of the diketone moiety was found. At the same time, compounds 3 due to the absence of conjugation were able to react with Br 2 by the diketone moiety at a comparable rate with the starting enediones 2 giving tribromo derivatives 4.   When 1 equiv. of bromine was used, incomplete conversion was usually observed, accompanied by the formation of tribromo derivative 4b. Bromination in acetic acid gave low conversion (26%) and predominant formation of the tribromo derivative (3b:4b = 9:17) (entry 1). Carrying out the reaction in aprotic polar solvents CH 2 Cl 2 and t-BuOMe made it possible to increase the conversion to 58 and 83%, respectively, but the selectivity turned out to be low (entries 2,4). The use of non-polar aprotic solvents (dioxane, CS 2 ) led to the improved 3b:4b ratio and 71-75% conversion (entries 5,6). When the reaction was carried out in benzene, the highest conversion (88%), the highest NMR yield of 3b, and the good selectivity of the reaction were found (3b:4b = 78:10) (entry 7). A slight increase in the amount of bromine (up to 1.2 equiv.) led to a decrease in selectivity (3b:4b = 79:21), although the starting compound 2b was not detected at all (entry 8).
Further investigation showed that the bromination reaction is very sensitive to the nature of the substituents in the aromatic ring (Scheme 3, Table 2, and Table S1 in Supplementary Materials). Thus, the reaction proceeded with the highest selectivity with one equivalent of bromine in benzene for compounds bearing moderate and good π-donors (4-MeO, 4-F or Ar = 2-Th) (entries 7,10,11). The introduction of electron-withdrawing substituents (4-Cl, 3-NO 2 ) into the aromatic ring decreased the selectivity of the transformation for compounds 2c,e due to incomplete conversion and the formation of tribromo derivatives 4 as major products (entries 12,13). Even in the case of enedione 2a (Ar = Ph), selectivity and conversion of bromination in benzene turned out to be poor (entry 14), however, the use of CH 2 Cl 2 as a solvent improved the selectivity and the conversion (entry 15). The introduction of the strong electron-donating substituent (4-Me 2 N) led to preferential bromination at the aromatic ring rather than at the double bond followed by cyclization because of basic properties of the substituent (Scheme S1 in Supplementary Materials). It should be noted that, in all cases, compounds 3 were formed as a sole anti-dibromo diastereoisomer according to the classical concept of electrophilic addition of bromine to alkenes via the cyclic bromonium cation [42].
Further, we decided to develop a procedure for the bromination of both fragments of enediones 2 simultaneously for the selective preparation of tribromo derivatives 4. The reaction of enedione 2b with an excess of bromine (2.2 equiv.) in benzene gave products with low selectivity (3b:4b = 56:44) ( Table 2, entry 9). Moreover, significant amounts of corresponding dihydropyrones were formed as a result of spontaneous acidcatalyzed cyclization. One of the highest yields of compound 4b in reaction with 1 equiv. of bromine was observed in dichloromethane (entry 2). The use of bromine (2.5 equiv.) in this solvent led to the almost selective formation of tribromo derivative 4b as a mixture of two diastereoisomers in a ratio of 80:20 (entry 3).
Although the reaction of enediones 2 with Br 2 gave dibromo derivatives 3 or tribromo derivatives 4 as major products, we did not usually isolate them in pure form to avoid additional losses because of their ability to cyclize and high reactivity. But for several cases, these compounds were obtained as a single isomer by recrystallization. The reaction of enediones 2a,g with one equivalent of bromine in acetic acid made it possible to obtain dibromo derivatives 3a and 3g in 71 and 28% yields, respectively (Scheme 4).

Scheme 4. Preparative bromination of enediones 2.
The reaction of chloro-substituted enedione 2c with an excess of bromine (2.5 equiv.) in CH 2 Cl 2 led to tribromo derivative 4c (dr = 80:20) smoothly in 82% yield. Compound 4c in pure crystalline form prepared by recrystallization from hexane is stable and can be stored for a long time without changes.
The structure of tribromo derivatives 4 was established on the basis of elemental analysis data and 1 H and 19 F NMR spectra (Table S3 in Supplementary Materials). In the 1 H NMR spectra of these compounds in CDCl 3 , two singlets of the diastereotopic OH groups were observed at δ 4.06-4.46 and 4.62-4.79 ppm. The 19 F NMR spectra exhibit the CF 3 group at δ 79.7-79.9 ppm indicating its location at the saturated carbon atom. For compounds 2 and 3, the characteristic chemical shifts of the trifluoromethyl group appeared at δ 84.5-85.0 and 86.0 ppm, respectively (Table S2 in Supplementary Materials).
At the next stage of our work, we studied the cyclization of dibromo derivatives 3a,g in the presence of bases. The use of t-BuOK in THF or pyridine, DIPEA, DBU, NaHCO 3 in various solvents (acetone, ethanol, DMSO) at room temperature did not allow us to obtain 4-pyrone 5a in an acceptable yield. The most favorable conditions turned out to be stirring with a 2.5-fold excess of triethylamine in acetone for three days (Scheme 5). In addition, the isolation of the product, in this case, does not require chromatography, and pyrones 5a,g precipitated in pure form upon dilution with water in 51-54% yields. This approach can be scaled up to 5 g of enedione 2a, and the yield of pyrone 5a was 36% in two stages. Scheme 5. Cyclization of dibromo derivatives 3 to pyrones 5.
The cyclization mechanism of compounds 3 includes the formation of dihydropyran intermediate B via two possible pathways. The first path comprises the elimination of hydrogen bromide (E) and the production of bromoenone A, which then undergoes an intramolecular Michael reaction (1,4-A N ). The second possibility is the direct intramolecular nucleophilic substitution of bromine (S N ). As mentioned above, the cyclic pyranic form B was observed in the bromination reaction mixtures (Table 2), whereas bromoenones A were detected by NMR spectroscopy on the treatment of the dibromo derivatives 3 with pyridine at room temperature. The easy formation of 2-bromoenones from 2,3-dibromoketones is also well presented in the literature [42]. Thus, it can be assumed that the first path is more preferable in basic conditions. Intermediate A was isolated in pure form with the use of column chromatography (56% yield) from enedione 2i via bromination (1 equiv.) and subsequent monodehydrobromination by DIPEA at room temperature.
Tribromo derivatives 4 undergo cyclization under the action of triethylamine in acetone at room temperature much slower, furthermore, the high basicity of the medium could provide a possibility of side reactions associated with detrifluoroacetylation [41]. Therefore, dehydrohalogenation of 4 was carried out by refluxing for 10 h in pyridine as a solvent and a weaker base (Scheme 6). The cyclization of compound 4c gave pyrone 6c in 36% yield. These results demonstrate that the cyclization step determines mainly total output of the pyrones. Moreover, the difference in reaction rates of cyclization of tribromo derivatives 4 and dibromo derivatives 3 allowed the isolation of pyrones 5 in the presence of Et 3 N in acetone selectively, even when the reaction mixtures of the brominated intermediates were used. Scheme 6. Cyclization of tribromo derivative 4c to pyrone 6c.
With the optimized conditions of the bromination and cyclization of intermediate bromo derivatives in hand, we decided to develop a simple one-pot two-step preparative method for the synthesis of 4-pyrones 5 and 6 based on oxidative cyclization of enediones 2. Considering that the reaction mixtures of bromination contain various bromine-bearing forms (cyclic and acyclic), the overall efficiency and convenience of this two-step process without intermediate purification can improve (Scheme 7, Table 3). Scheme 7. One-pot preparation of pyrones 5 and 6 from enediones 2.
For the preparation of 4-pyrones 5 in the one-pot approach, enediones 2 were treated with 1 equiv. of bromine in benzene (Method A) for compounds bearing electron-donating substituents (F, Me, MeO) and in CH 2 Cl 2 (Method B) for compounds bearing weak electronwithdrawing substituents (Cl, Br) or H at the C-4 position. After bromination, the solvent was evaporated, and the cyclization was carried out using Et 3 N (2.5 equiv.) in acetone, as a result, pyrones 5 were obtained in 28-69% yields.
The preparation of 3-bromo-4-pyrones 6 with a one-pot method was possible only for substrates bearing weak electron-donating (H, 4-Me, 4-F) and electron-withdrawing groups (4-Cl, 3-NO 2 ) in the benzene ring since aromatic bromination was unavoidable with an excess of bromine in case of highly activated aryl substituents. At the first stage, enedione 2 was treated with 2.5 equiv. of bromine in CH 2 Cl 2 and subsequent heating at 100 • C in pyridine for 10 h led to the formation of pyrones 6 in 4-42% yields (Method C). This one-pot approach was also applied for the preparation of phenyl-4-pyrones bearing various polyfluoroalkyl substituent. No significant difference in reactivity was observed depending on fluorine content or chain length of R F -moiety, and the cyclization of enediones 2j-l in the presence of 1 equiv. of bromine (Method B) gave 4-pyrones 5j-l in 40-70% yields (Scheme 8). The use of Method C led to 3-bromopyrones 6j-l in 24-33% yields. The structure of 4-pyrones 5 and 6 was established on the basis of elemental analysis data, HRMS and NMR spectra. In the 1 H NMR spectra of compounds 5 in CDCl 3 , characteristic doublets of H-3 and H-5 protons of the pyrone ring were observed at δ 6.63-6.88 ppm with a coupling constant of 1.8-2.2 Hz. In the case of pyrones 6, the signal of the H-5 proton of the pyrone ring appeared as a singlet at δ 6.88-7.04 ppm (CDCl 3 ).
The next step was to study the chemical properties of 2-aryl-6-(trifluoromethyl)-4pyrones with N-nucleophiles to obtain azaheterocycles (Scheme 9). The reaction of pyrone 5a with ammonia in ethanol in an autoclave at 120 • C for 10 h led to the formation of pyridone 7 in 70% yield. The ring-opening transformation of pyrone 5a with sodium azide [43] in DMSO afforded triazole 8 in 55% yield. Phenylhydrazine reacted with pyrone 5a regioselectively attacking with the amino group at the C-2 and C-4 positions to give pyrazole 9. The structure of pyrazole 9 was assigned based on NMR spectra according to the literature data [16,34]. Thus, a convenient and general method for the synthesis of 2-aryl-6-polyfluoroalkyl-4-pyrones and their bromo derivatives has been developed based on one-pot oxidative cyclization of fluorinated enediones. The selectivity of monobromination of 6-aryl-1,1,1trifluorohex-5-ene-2,4-diones is connected with the predominant electrophilic attack on the double bond and strongly depends on the solvent used and the nature of the substituent in the aromatic ring, which determines the scope of obtained fluorinated 2-aryl-4-pyrones. 6-Aryl-1,1,1-trifluorohex-5-ene-2,4-diones bearing electron-withdrawing and weak electrondonating substituents in the aromatic ring react with an excess of bromine leading to tribromo derivatives as a result of bromination of the double bond and the diketone moiety. Di-and tribromo derivatives in a basic medium selectively undergo cyclization to form 4-pyrones. The resulting 4-pyrones have proven to be useful building blocks and have been utilized to synthesize CF 3 -bearing heterocycles, which are of further interest in terms of potential biological activity.

Materials and Methods
NMR spectra were recorded on Bruker DRX-400 ( 1 H: 400 MHz, 13 C: 100 MHz, 19 F: 376.5 MHz) and Bruker Avance III-500 ( 1 H: 500 MHz, 13 C: 126 MHz, 19 F: 471 MHz) spectrometers in DMSO-d 6 and CDCl 3 . The chemical shifts (δ) are reported in ppm relative to the internal standard TMS ( 1 H NMR), C 6 F 6 ( 19 F NMR), and residual signals of the solvents ( 13 C NMR). IR spectra were recorded on a Shimadzu IRSpirit-T spectrometer using an attenuated total reflectance (ATR) unit (FTIR mode, ZnSe crystal), the absorbance maxima (ν) are reported in cm -1 . Elemental analyses were performed on an automatic analyzer PerkinElmer PE 2400. Melting points were determined using a Stuart SMP40 melting point apparatus. Column chromatography was performed on silica gel (Merck 60, 70-230 mesh). All solvents that were used were dried and distilled by standard procedures. Arylideneacetones 1 have been synthesized according to the procedure, previously described in the literature [44].

Synthesis of Enediones 2a-l
General Procedure. A suspension of NaH (60% by weight in mineral oil) (240 mg, 6.0 mmol) in dry Et 2 O (5 mL) was cooled on an ice bath, then CF 3 CO 2 Et (0.86 g, 6.0 mmol) and a solution of arylideneacetone 1 (4.0 mmol) in dry Et 2 O (3 mL) were successively added under stirring. The reaction mixture was warmed to room temperature and stirred for 20 h. Then 1M aqueous HCl (10 mL) was added, and the organic phase was separated (if the precipitate of diketonate formed, it was filtered and treated with 1M aqueous HCl (10 mL)). The aqueous phase was extracted with AcOEt (5 mL). The combined organics were washed with H 2 O and dried over anhydrous Na 2 SO 4 , the solvents evaporated, and the residue recrystallized from hexane with decantation of hot solution from insoluble tarry by-products.

Synthesis of Compounds 3a,g
General procedure. A solution of Br 2 (3.20 g, 0.020 mol) in glacial AcOH (5.7 mL) was added dropwise to enedione 2 (0.020 mol) in glacial AcOH (18 mL) cooled by a water bath. After that, the reaction mixture was stirred for 1 h at room temperature. The resulting solution was diluted by water (30 mL). The precipitate that formed was filtered. If it is needed, the pure product can be obtained by recrystallization from heptane.

Synthesis of Compound 4c
A solution of Br 2 (400 mg, 2.5 mmol) in CH 2 Cl 2 (2 mL) was added to enedione 2c (277 mg, 1 mmol) in CH 2 Cl 2 (8 mL) under cooling on an ice-bath. The reaction mixture was left at room temperature for 15 h, and then the solvent was evaporated without heating. The residue is a mixture of diastereoisomeres (dr = 80:20), which was recrystallized from hexane to obtain single isomer in pure form for analysis.

Synthesis of Compound A'
A solution of dibromide 3i, which was prepared by reaction of enedione 2i (248 mg, 1 mmol) with Br 2 (160 mg, 1 mmol) in CH 2 Cl 2 (3.4 mL) without additional purification, and DIPEA (323 mg, 2.5 mmol) in CH 2 Cl 2 (5 mL) was stirred at room temperature for 15 h. The reaction mixture was then quenched with aqueous HCl (10 mL, 0.5 M), the organic phase was separated, washed with water and brine, dried under Na 2 SO 4 , and evaporated. The crude product was purified by column chromatography (CH 2 Cl 2 ).

Synthesis of Pyrones 5
General procedure. A solution of Br 2 (160 mg, 1.0 mmol) in the solvent (1.7 mL) was added to enedione 2 (1 mmol) in the solvent (2.7 mL) under cooling on an ice-bath (C 6 H 6 was used for Method A, CH 2 Cl 2 -Method B). After that, the reaction mixture was stirred at room temperature for 15 h, and then the solvent was evaporated without heating. Then acetone (4.3 mL) was added to the residue, and the solution was treated with Et 3 N (0.253 g, 2.5 mmol) under cooling on an ice-bath. After that, the reaction mixture was stirred at room temperature for 3 days and was diluted with H 2 O (15 mL). The precipitate was filtered, washed with water, and recrystallized from hexane.

Synthesis of Pyrones 6
General procedure (Method C). A solution of Br 2 (400 mg, 2.5 mmol) in CH 2 Cl 2 (4.25 mL) was added to enedione 2 (1 mmol) in CH 2 Cl 2 (2.7 mL) under cooling on an ice-bath. After that, the reaction mixture was stirred at room temperature for 15 h, and then the solvent was evaporated without heating. The residue was refluxed in pyridine (3 mL) at 100 • C for 10 h. The excess of pyridine was evaporated under reduced pressure and the product was purified by flash-chromatography (EtOAc). The product was hot-extracted with hexane (3 × 5 mL). The solvent was evaporated until 2 mL of hexane, and the product crystallized from the extract after cooling.