Acid-Switchable Synthesis of Trifluoromethylated Triazoles and Isoxazoles via Reaction of CF3-Ynones with NaN3: DFT Study of the Reaction Mechanism

A detailed study of the reaction of CF3-ynones with NaN3 was performed. It was found that the reaction permits the selective synthesis of either 4-trifluoroacetyltriazoles or 5-CF3-isoxazoles. The chemoselectivity of the reaction was switchable via acid catalysis. The reaction of CF3-ynones with NaN3 in EtOH produced high yields of 4-trifluoroacetyltriazoles. In contrast, the formation of 5-CF3-isoxazoles was observed under catalysis by acids. This acid-switchable procedure can be performed at sub-gram scale. The possible reaction mechanism was supported by DFT calculations. The synthetic utility of the prepared 4-trifluoroacetyltriazoles was demonstrated.


Results
We envisioned that the reaction of CF3-ynones with sodium azide would lead to triazoles 2 via a Michael addition followed by spontaneous cyclization of the intermediates formed. We chose CF3-ynone 1a as a model compound for exploring the cyclization conditions. First, several solvents were tested to search for an optimal reaction medium. It was found that the reaction is extremely sensitive to the nature of a solvent. Thus, the transformation of CF3-ynone 1a in non-polar toluene led to triazole 2a in a 2% yield only (see Table 1). Better yields of 2a were observed in more polar acetone, acetonitrile, THF and ethyl acetate (entries [2][3][4][5]. In the case of most polar aprotic solvents in the row (DMF, DMSO and NMP, entries 6-8) the yields of 2a increased to about 50%. Eventually, we found that the best yields of 2a can be obtained in alcohols. Thus, the reactions in methanol and ethanol led to 2a in 77% and 81% yields, respectively (entries 9-10). It should be noted that full conversion of CF3-ynone 1a was observed in all mentioned solvents. It was also found that the main byproduct of the reaction was isoxazole 3a, which was formed in small amounts. CF 3 -ynones are valuable building-blocks for the synthesis of various fluorinated heterocycles [49,50]. Recently, on the basis of CF 3 -ynones, we elaborated novel approaches to fluorinated diazepines [51], pyrimidines [52], thiophenes [53], triazoles [54], pyrazoles [55][56][57], 1,3-oxazinoquinolines [58][59][60][61] and quinolones [62]. This article reports novel effective acidswitchable pathways to 4-trifluoroacetyltriazoles and 5-trifluoromethylisoxazoles based on the reaction of CF 3 -ynones with sodium azide.

Results
We envisioned that the reaction of CF 3 -ynones with sodium azide would lead to triazoles 2 via a Michael addition followed by spontaneous cyclization of the intermediates formed. We chose CF 3 -ynone 1a as a model compound for exploring the cyclization conditions. First, several solvents were tested to search for an optimal reaction medium. It was found that the reaction is extremely sensitive to the nature of a solvent. Thus, the transformation of CF 3 -ynone 1a in non-polar toluene led to triazole 2a in a 2% yield only (see Table 1). Better yields of 2a were observed in more polar acetone, acetonitrile, THF and ethyl acetate (entries 2-5). In the case of most polar aprotic solvents in the row (DMF, DMSO and NMP, entries 6-8) the yields of 2a increased to about 50%. Eventually, we found that the best yields of 2a can be obtained in alcohols. Thus, the reactions in methanol and ethanol led to 2a in 77% and 81% yields, respectively (entries 9-10). It should be noted that full conversion of CF 3 -ynone 1a was observed in all mentioned solvents. It was also found that the main byproduct of the reaction was isoxazole 3a, which was formed in small amounts. Having optimal conditions in hand, we decided to study the scope of the synthesis of trifluoroacylated triazoles. To this end, we performed a series of reactions with various CF3-ynones. To our delight, the reaction was found to be very general. The yield of 3 did not depend on electronic nature of the substituents in the aryl ring of CF3-ynones to give target triazoles in 70-80% yields (2a-k). The steric demand was found to be more crucial for the reaction outcome. Thus, the reaction with ortho-substituted CF3-ynones 1l,m and naphthalene derivative 1n produced triazoles in 41-59% yields. Alkyl-substituted ynone 1o was also successfully involved in the reaction to form triazole 2o in good yields. We also demonstrated scalability of the method (Scheme 1). Gram-scale synthesis of triazoles 2a,b was performed to give the products in high yields (80-85%). It should be noted, that NH-triazoles 2 are a novel class of fluorinated triazoles which have not been reported yet. The structure of triazoles 2 was confirmed beyond doubt by NMR, FT-IR and HRMS spectra. Thus, the presence of the trifluoroacetyl group (2a as an example) was proven by quadruplets in 13 C NMR at 174.4 ppm (C=O) and 116.2 ppm (CF3) as well as by the signal at 1719 cm −1 (C=O) in FT-IR. Two signals in the low field in 13 C NMR at 147.7 ppm and 136.1 ppm were the quaternary carbons of the triazole moiety. A broad singlet at 12.75 ppm in 1 H NMR and a broad band near 3000 cm −1 in FT-IR confirm the presence of a NHtriazole moiety. Having optimal conditions in hand, we decided to study the scope of the synthesis of trifluoroacylated triazoles. To this end, we performed a series of reactions with various CF 3 -ynones. To our delight, the reaction was found to be very general. The yield of 3 did not depend on electronic nature of the substituents in the aryl ring of CF 3 -ynones to give target triazoles in 70-80% yields (2a-k). The steric demand was found to be more crucial for the reaction outcome. Thus, the reaction with ortho-substituted CF 3 -ynones 1l,m and naphthalene derivative 1n produced triazoles in 41-59% yields. Alkyl-substituted ynone 1o was also successfully involved in the reaction to form triazole 2o in good yields. We also demonstrated scalability of the method (Scheme 1). Gram-scale synthesis of triazoles 2a,b was performed to give the products in high yields (80-85%). It should be noted, that NH-triazoles 2 are a novel class of fluorinated triazoles which have not been reported yet. The structure of triazoles 2 was confirmed beyond doubt by NMR, FT-IR and HRMS spectra. Thus, the presence of the trifluoroacetyl group (2a as an example) was proven by quadruplets in 13 C NMR at 174.4 ppm (C=O) and 116.2 ppm (CF 3 ) as well as by the signal at 1719 cm −1 (C=O) in FT-IR. Two signals in the low field in 13 C NMR at 147.7 ppm and 136.1 ppm were the quaternary carbons of the triazole moiety. A broad singlet at 12.75 ppm in 1 H NMR and a broad band near 3000 cm −1 in FT-IR confirm the presence of a NH-triazole moiety.
The acidic nature of NH-triazoles is well known (pKa~9.26) [63]. The presence of the electron-withdrawing trifluoroacetyl group made triazoles 2 highly acidic and soluble in water at basic pH. We successfully used this feature of triazoles 2 for their purification. After the evaporation of ethanol, the residue was dispersed between water and a mixture of heptane and ethyl acetate. The organic phase containing all by-products was thrown away and the water phase was acidified to form pure triazole 2. It should be noted that all solvents used in this protocol are listed as green ones and the amount of waste was minimal. The E-factor calculated for gram scale synthesis of 2a was 13.6, which is a good value for fine chemicals. Therefore, we can describe the method proposed as a green one. The acidic nature of NH-triazoles is well known (pKa~9.26) [63]. The presence of the electron-withdrawing trifluoroacetyl group made triazoles 2 highly acidic and soluble in water at basic pH. We successfully used this feature of triazoles 2 for their purification. After the evaporation of ethanol, the residue was dispersed between water and a mixture of heptane and ethyl acetate. The organic phase containing all by-products was thrown away and the water phase was acidified to form pure triazole 2. It should be noted that all solvents used in this protocol are listed as green ones and the amount of waste was minimal. The E-factor calculated for gram scale synthesis of 2a was 13.6, which is a good value for fine chemicals. Therefore, we can describe the method proposed as a green one.
We proposed the possibility of switching the reaction direction from triazole 2 to isoxazole 3. One can notice that NaN 3 is a salt that is strongly basic and weakly acidic. As a result, solutions formed by NaN 3 have a slightly basic pH. We decided to add acid to the reaction in order to neutralize even acidic pH. To our delight, this manipulation permitted us to switch the selectivity of the reaction to make the formation of izoxazole 3 a major reaction path. Thus, the addition of various organic acids such as HCOOH, CH 3 COOH, CH 2 ClCOOH and CF 3 COOH changed the reaction direction in the same solvent (EtOH) to form isoxazole 3, while triazole 2 became a minor product. Moreover, similar results were obtained in the heptane-H 2 O system. Both conditions gave isoxazole 3a in isolated yields of 35-36%. A control experiment without the addition of any acid was performed in heptane-H 2 O. It was found, that CF 3 -ynone 1a was fully consumed and the reaction led to trace amounts of triazole 2a and isoxazole 3a along with much tarring. So, the role of acid is crucial in the formation of isoxazole 3a. Next, we examined several other solvents in the reaction using acetic acid as a catalyst (see Supplementary Materials). Again, the reaction in the presence of acid led to isoxazole 3a in 35-41% yields (by 19 F NMR) in MeOH, EtOAc, PhMe, dioxane and TCE (1,1,2-trichloroethylene) ( Table S2). The reaction in quite acidic CF 3 CH 2 OH could be performed without the addition of any acids to give isoxazole 3a in a 37% yield. Eventually, a reaction in acetic acid led to the same yield of isoxazole. It should be noted that the application of stronger acids (MeSO 3 H and HCl) blocks the conversion of CF 3 -ynone in the reaction mixture. Taking into account the list of green solvents, we chose the EtOH and n-heptane-water systems as solvents for further investigation of the reaction. Ethanol was chosen because, in this case, there was obviously a possibility of elegantly managing the reaction direction via the simple addition of acetic acid (also a green solvent). The use of n-heptane simplified the isolation and purification of isoxazoles 3. Thus, after completion of the reaction, isoxazole 3a was placed in n-heptane (upper phase), while the by-products were mostly present the third phase below water. n-Heptane phase could be easily separated to give a solution of pure isoxazole in most cases (Scheme 2).

23, x FOR PEER REVIEW 6 of 19
Scheme 2. Reactions of ynones 1 with NaN3 in ethanol and in n-heptane in the presence of acid.
Using the above-mentioned optimal conditions for the synthesis of isoxazoles 3, we carried out a series of reactions with a set of CF3-ynones. It was found that unlike in the synthesis of triazoles, the yields of isoxazoles were very sensitive to the electronic nature of the substituents in the aryl ring of CF3-ynones. Thus, the CF3-ynone with an electron-Scheme 2. Reactions of ynones 1 with NaN 3 in ethanol and in n-heptane in the presence of acid.
Using the above-mentioned optimal conditions for the synthesis of isoxazoles 3, we carried out a series of reactions with a set of CF 3 -ynones. It was found that unlike in the synthesis of triazoles, the yields of isoxazoles were very sensitive to the electronic nature of the substituents in the aryl ring of CF 3 -ynones. Thus, the CF 3 -ynone with an electron-withdrawing CF 3 group in the aryl ring produced isoxazole 3i yields of 48%. In contrast, the reaction with ynones bearing electron-donating alkoxy-groups (1b,k,m) led to isoxazoles 3 in lower yields. The yields of other aryl isoxazoles were in the range of 26-36%. Alkyl-substituted ynones 1o,p were also successfully used in the reaction to give isoxazoles 3o,p in 33 and 51% yields, respectively (Scheme 2).
To rationalize the observed selectivity of the reactions of sodium azide with ynones, we performed DFT modeling (for details, see supporting information). Precomplex A consists of ynone, and sodium azide solvated by four ethanol molecules. The addition of azide to the triple bond proceeds via low-lying transition state TS-AB to give allene B. Then, through transition state TS-BC, the triazolate C is formed. The reaction is highly exergonic (∆G = −78.2 kcal/mol). The rate-limiting energy barrier corresponds to TS-BC (∆∆G = = ∆G(TS-BC) − ∆G(B) = 12.6 kcal/mol) [67]. Thus, under non-acidic conditions, the reaction proceeds with a very low barrier to give triazole at a rate that is determined mainly by the rate of dissolution of sodium azide in the reaction medium (Scheme 3). Scheme 3. Plausible DFT mechanism of formation of triazoles in absence of acid (numbers are relative Gibbs free energies in kcal/mol; Na(s) + = Na(EtOH)4 + ).
Hydrogen azide and acetic acid have virtually the same pKa values (in water), at 4.75 and 4.76, respectively. It should be expected that in the presence of acetic acid, NaN3 and HN3 are in equilibrium in the reaction media. Thus, it can be supposed that under such conditions, azide is bound to ynone to give allene B in the same manner as in the absence of acetic acid (Scheme 3). Importantly, the allene B can be regarded as sodium enolate, which is strongly basic. Thus, we suppose that under acidic conditions, enolate B is immediately protonated to give a neutral form of allene D (Scheme 4). Scheme 3. Plausible DFT mechanism of formation of triazoles in absence of acid (numbers are relative Gibbs free energies in kcal/mol; Na (s) + = Na(EtOH) 4 + ).
Hydrogen azide and acetic acid have virtually the same pKa values (in water), at 4.75 and 4.76, respectively. It should be expected that in the presence of acetic acid, NaN 3 and HN 3 are in equilibrium in the reaction media. Thus, it can be supposed that under such conditions, azide is bound to ynone to give allene B in the same manner as in the absence of acetic acid (Scheme 3). Importantly, the allene B can be regarded as sodium enolate, which is strongly basic. Thus, we suppose that under acidic conditions, enolate B is immediately protonated to give a neutral form of allene D (Scheme 4). The DFT calculation can also explain the lower yield of isoxazoles 3. We believe that only Z-configurated vinylazide E can cyclize into izoxazole. Another diastereomer has a disfavored arrangement of the azide group and the trifluoroacetyl moiety. As a result, the formation of polymeric products takes place. The DFT calculation can also explain the lower yield of isoxazoles 3. We believe that only Z-configurated vinylazide E can cyclize into izoxazole. Another diastereomer has a disfavored arrangement of the azide group and the trifluoroacetyl moiety. As a result, the formation of polymeric products takes place.
It should be noted that N-unsubstituted 4-trifluoroacyl triazoles 2 are a novel class of fluorinated compounds which have not been reported yet. In this article, we started an investigation of the chemical properties of triazoles. We found that trifluoroacetyl triazoles react with secondary amines at elevated temperatures to give the corresponding amides (derivatives of pyrrolidine, piperidine and morpholine) in quite good yields (Scheme 5). It should be noted that N-unsubstituted 4-trifluoroacyl triazoles 2 are a novel class of fluorinated compounds which have not been reported yet. In this article, we started an investigation of the chemical properties of triazoles. We found that trifluoroacetyl triazoles react with secondary amines at elevated temperatures to give the corresponding amides (derivatives of pyrrolidine, piperidine and morpholine) in quite good yields (Scheme 5). Next, we studied modification of the NH moiety of triazoles 2. We performed alkylation of model triazole 2a in DMF using Na2CO3 as a base. It was found that the reaction with benzyl bromide led mostly to 2-benzyltriazole 7 along with 1-benzylisomer 8 in an 81:19 ratio. In contrast, the arylation and sulfonylation of 2a proceeded 100% regioselectively to give only 2-substituted products, 9 and 10, in high yields. Similarly, the reaction with phenyl boronic acid in non-optimized conditions of the Chan-Lam reaction 100% regioselectively produced a 50% yield of 2-phenyltriazole 11. It should be noted that N-2aryl-1,2,3-triazoles are of special interest due to their possible properties of UV/blue-lightemitting fluorophores [36][37][38]. Thorough investigation of the alkylation and arylation of triazoles 2, as well as their UV/blue-light-emitting properties, is currently in progress and is going to be published soon (Scheme 6). Next, we studied modification of the NH moiety of triazoles 2. We performed alkylation of model triazole 2a in DMF using Na 2 CO 3 as a base. It was found that the reaction with benzyl bromide led mostly to 2-benzyltriazole 7 along with 1-benzylisomer 8 in an 81:19 ratio. In contrast, the arylation and sulfonylation of 2a proceeded 100% regioselectively to give only 2-substituted products, 9 and 10, in high yields. Similarly, the reaction with phenyl boronic acid in non-optimized conditions of the Chan-Lam reaction 100% regioselectively produced a 50% yield of 2-phenyltriazole 11. It should be noted that N-2-aryl-1,2,3-triazoles are of special interest due to their possible properties of UV/bluelight-emitting fluorophores [36][37][38]. Thorough investigation of the alkylation and arylation of triazoles 2, as well as their UV/blue-light-emitting properties, is currently in progress and is going to be published soon (Scheme 6). It should be noted that N-unsubstituted 4-trifluoroacyl triazoles 2 are a novel class of fluorinated compounds which have not been reported yet. In this article, we started an investigation of the chemical properties of triazoles. We found that trifluoroacetyl triazoles react with secondary amines at elevated temperatures to give the corresponding amides (derivatives of pyrrolidine, piperidine and morpholine) in quite good yields (Scheme 5). Next, we studied modification of the NH moiety of triazoles 2. We performed alkylation of model triazole 2a in DMF using Na2CO3 as a base. It was found that the reaction with benzyl bromide led mostly to 2-benzyltriazole 7 along with 1-benzylisomer 8 in an 81:19 ratio. In contrast, the arylation and sulfonylation of 2a proceeded 100% regioselectively to give only 2-substituted products, 9 and 10, in high yields. Similarly, the reaction with phenyl boronic acid in non-optimized conditions of the Chan-Lam reaction 100% regioselectively produced a 50% yield of 2-phenyltriazole 11. It should be noted that N-2aryl-1,2,3-triazoles are of special interest due to their possible properties of UV/blue-lightemitting fluorophores [36][37][38]. Thorough investigation of the alkylation and arylation of triazoles 2, as well as their UV/blue-light-emitting properties, is currently in progress and is going to be published soon (Scheme 6).

Materials and Methods
General remarks. 1 H, 13 C and 19 F NMR spectra were recorded using a Bruker AVANCE 400 MHz spectrometer in acetone-d 6 , CD 3 CN and CDCl 3 at 400, 100 and 376 MHz, respectively. Chemical shifts (δ) in ppm are reported based on the residual acetone-d 5 , CHD 2 CN and chloroform signals (2.04, 1.94 and 7.25 for 1 H and 29.8, 1.3, 77.0 for 13 C) as internal references. The 19 F chemical shifts were referenced to C 6 F 6 , (−162.9 ppm). The coupling constants (J) are given in Hertz (Hz). ESI-MS spectra were measured using an Orbitrap Elite instrument. For FT-IR, a spectrometer was employed using consoles of internal reflection iS3 with ATR element from ZnSe and a dip angle of 45 • C. TLC analysis was performed on "Merck 60 F 254 " plates. Column chromatography was performed usig silica gel "Macherey-Nagel 0.063-0.2 nm (Silica 60)". In all cases, gravity column chromatography was used. All reagents were of reagent grade and were used as such or were distilled prior to use. CF 3 -ynones 1 [68] were prepared as reported previously. Melting points were determined using Electrothermal 9100 apparatus.
Investigation of reaction of CF 3 -ynones with NaN 3 in various solvents. A 4 mL vial with a screw cap was charged with CF 3 -ynone 1a (0.099 g, 0.5 mmol), corresponding solvent (2 mL, see Table 1) and NaN 3 (0.039 g, 0.6 mmol, 1.2 equiv.). The reaction mixture was stirred overnight using a magnetic stirrer. The composition of the reaction mixture was established via 19 F NMR using PhCF 3 as a standard for calculation of the products' yields. It is important to note that all manipulations with azides demand significant care for safety reasons.

Investigation of reaction of CF 3 -ynones with NaN 3 in various solvents in the presence of acids.
A 4 mL vial with a screw cap was charged with CF 3 -ynone 1a (0.099 g, 0.5 mmol), the corresponding solvent (2 mL, see Table S2), the corresponding acid (for quantity of acid, see Table S2) and NaN 3 (for quantity, see Table S2). The reaction mixture was stirred for 1 day using a magnetic stirrer. The composition of the reaction mixture was established via 19 F NMR using PhCF 3 as a standard for calculation of the products' yields.
Synthesis of isoxazoles 3 in ethanol (general procedure A). An 8 mL vial with a screw cap was charged with the corresponding CF 3 -ynone 1 (0.5 mmol), ethanol (2 mL), acetic acid (0.120 g, 2 mmol, 4 equiv.) and NaN 3 (0.065 g, 1 mmol, 2 equiv.). The reaction mixture was stirred overnight using a magnetic stirrer. Next, ethanol was evaporated in vacuo at room temperature (it is important to note that isoxazoles 4a and 4x are quite volatile); the residue was suspended in the heptane-ethylacetate mixture (3:1, 0.5) and passed through a short silica gel pad via gradient elution using the heptane and heptaneethylacetate mixture (9:1). Evaporation of the solvents produced pure isoxazoles 3.