Synthesis of Oxazoles Containing CF3-Substituted Alcohol Unit via Tandem Cycloisomerization/Hydroxyalkylation from N-Propargylamides with Trifluoropyruvates

Abstract

Oxazoles are important five-membered heterocycles that contain both nitrogen and oxygen atoms. Due to their wide range of biological activities, many oxazoles demonstrate potential for extensive application in various fields, including medicinal chemistry. Trifluoromethyl carbinol, an important pharmacophore, contains both trifluoromethyl and hydroxyl groups and is common in molecules with important biological activities. Constructing oxazoles that contain a trifluoromethyl carbinol unit is undoubtedly important and valuable for expanding the chemical space in drug discovery. In this study, a simple and efficient method was developed for the synthesis of oxazoles containing a CF₃-substituted alcohol unit via the tandem cycloisomerization/hydroxyalkylation of N-propargylamides with trifluoropyruvates through a rational Lewis acid catalytic mechanism. This Zn(OTf)₂-catalyzed synthetic protocol is operationally simple and provides a series of oxazoles in moderate to good yields. The protocol demonstrates broad substrate scope, high functional group tolerance, and high atom economy and can achieve gram-level reactions, indicating the strong possibility of its practical application.

1. Introduction

Due to their unique pharmacokinetic properties, such as bioavailability, binding selectivity, metabolic stability, and cell membrane permeability, fluorine-containing groups have been widely used in drug design in recent years [1]. In particular, trifluoromethyl carbinols containing both trifluoromethyl and hydroxyl groups are a class of molecules that often exhibit significant biological activities [2,3]; some typical examples can be seen in Figure 1 [4,5,6]. Therefore, constructing molecules that contain trifluoromethyl carbinol is undoubtedly important and valuable for expanding the chemical space in drug discovery [7,8].

The oxazole moiety is one of the most common heterocycles in structurally diverse natural products and pharmaceutically active ingredients [9,10]. As an important class of heterocycles in medicinal chemistry, oxazole-containing compounds typically exhibit significant biological activities, such as anticancer [11], antidiabetic [12], antiepileptic [13], anti-inflammatory [14], antimalarial [15], antimicrobial [16], antitubercular [17], and antiviral activities [18,19] (Figure 2). Moreover, oxazole derivatives have important applications as intermediates and metal catalysis ligands in organic synthesis [20]. Additionally, oxazole compounds have important structural motif applications in fluorescent probes [21] and agricultural chemicals [22].

Therefore, the synthesis of oxazole derivatives containing multiple substituents has received widespread attention [23,24]. It should be noted that although methods of synthesizing structurally diverse oxazole derivatives have been continuously developed and successfully applied to the synthesis of various bioactive molecules [25,26], efficient and green synthesis methods for oxazole derivatives containing special functionalized components still require further research and development [27].

Among the different synthesis methods, those involving fluorinated oxazole derivatives are constantly being investigated [28,29,30]. For example, Doherty’s group [31] synthesized oxazolines through the 5-exo-dig cycloisomerization of N-propargylamides catalyzed using gold complexes, and then, via the carbonyl-ene reaction of oxazolines with ethyl trifluoropyruvate, they synthesized the corresponding hydroxytrifluoroalkylated oxazoles under the catalysis of [PdCl₂{(S)-BINAP}]. However, a drawback of this method is that, in addition to requiring two steps, it uses Au and Pd catalysts, which are costly, thus necessitating the further development of novel methods involving the tandem reaction shown in Scheme 1.

In fact, it has been demonstrated that the use of a tandem reaction involving the cyclization of N-propargylamides with various fluorinating reagents is a common, efficient strategy for synthesizing 5-substituted oxazole derivatives (including fluorinated oxazoles) [32,33]. For example, Waldvogel’s group utilized electrochemistry to synthesize 5-fluoromethyl-2-oxazoles starting with easily available N-propargylamides (Scheme 1a) [34].

Notably, Liang’s group [35] and Li’s group [36] successfully used the palladium-catalyzed and photo-mediated cascade reactions of ethyl halodifluoroacetates, respectively, to synthesize 5-difluoromethylated oxazole compounds from N-propargylamides (Scheme 1b).

Although the abovementioned methods are useful for constructing fluorinated oxazoles, it is important to develop other green, simple, and effective routes, including the cascade reaction of trifluoropyruvates [7,8], for the synthesis of more oxazole compounds with diverse fluorinated structures, particularly bioactive oxazoles containing a trifluoromethyl carbinol unit, from low-cost fluorinating reagents.

Therefore, due to the potential applications of fluorinated heterocycles and based on our interest in methods of synthesizing heterocycles [37,38,39], particularly the synthesis and derivation of fluorinated heterocycles [40,41], we herein disclose a facile, efficient, and Zn(OTf)₂-catalyzed method for the synthesis of oxazoles containing CF₃-substituted alcohols via tandem cycloisomerization/hydroxyalkylation using N-propargylamides with trifluoropyruvates (Scheme 1c).

This synthetic protocol has the following advantages: simple operation, 100% atom economy, lack of oxidants, good functional group tolerance, and applicability to a wide range of substrates. Critically, this newly developed strategy will contribute to the further design and rapid synthesis of fluorinated oxazole derivatives with potential biological activities.

2. Results and Discussion

2.1. Optimization of Reaction Conditions

Initially, the reaction of N-(prop-2-yn-1-yl)benzamide 1a (0.3 mmol) and ethyl trifluoropyruvate 2a (0.36 mmol) was selected to screen proper conditions for the expected reaction. The reaction conditions were optimized, and the reaction parameters were established, which are listed in Table 1.

Obviously, the desired product, 3a, cannot be obtained via a reaction in dichloroethane (DCE) at 70 °C for 12 h in the absence of any catalysts (Table 1, entry 1). Fortunately, when 20 mol% FeCl₃, a Lewis acid, was added as a catalyst, compound 3a could be successfully obtained with a yield of 56% (entry 2). Other Lewis acids, such as InCl₃, Y(OTf)₃, Sc(OTf)₃, In(OTf)₃, Cu(OTf)₂, and Zn(OTf)₂, were also examined (entries 3–8). The results show that Zn(OTf)₂ is the most efficient and can result in 83% yield (entry 8).

To remove the effect of TfOH liberated from Zn(OTf)₂, we conducted the experiment using trifluoromethanesulfonic acid (TfOH) as a catalyst. The research results indicate that 3a (entry 9) could not be achieved using only TfOH as a catalyst. The amount of Zn(OTf)₂ was further optimized (entries 8, 10–12). The results reveal that using 15 mol% Zn(OTf)₂ is the most effective strategy (entry 11).

The solvents used were further optimized. Compared to other solvents (such as toluene, 1,4-dioxane, acetonitrile, chloroform, THF, and DMF), DCE provided the best result (entry 11 vs. entries 13–18). Upon examining the reaction temperatures, it was found that 70 °C was the optimum temperature (entry 11 vs. entries 19, 20). In addition, 12 h was the most suitable reaction time (entry 11 vs. entries 21, 22). Thus, the optimized reaction conditions were identified as 1a (0.3 mmol), 2a (0.36 mmol), the use of 15 mol% Zn(OTf)₂ as a catalyst, and the use of 1.5 mL of DCE as the solvent at 70 °C for 12 h.

2.2. Scope of Substrates

With the optimized conditions in hand, we explored the generality of the developed method using a variety of N-propargylamides (Table 2).

Representative arylamide substrates with a hydrocarbyl group (e.g., methyl, ethyl, methoxy, chloromethyl, and phenyl), as well as a halogen group (e.g., fluoro, chloro, and bromo) in the para position, all worked well with 2a to afford the desired trifluoroalkylated oxazoles (3b–3i) in yields ranging from 73% to 83%. Moreover, arylamide substrates with electron-withdrawing groups in the para position, e.g., cyano, methyl ester group (methoxyformyl), and trifluoromethyl, were also suitable for this conversion, resulting in 3j–3l in 68–73% yields.

This conversion was also applicable to substituted arylamide substrates in the ortho or meta positions, producing the corresponding products in moderate yields (72% for 3m, and 70% for 3n). Even the use of disubstituted benzamides, such as 3,5-dimethylbenzamide (1o) and 3,5-dichlorobenzamide (1p), could result in the desired products 3o and 3p, with yields of 78% and 75%, respectively.

As expected, both 1-naphthamide (1q) and 2-naphthamide (1r) substrates exhibited good activity in this conversion, smoothly furnishing the corresponding CF₃-substituted tertiary carbinols 3q and 3r in 70% and 73% yields, respectively. Some typical heteroarylamide substrates 1, e.g., 2-chloronicotinamide (1s), furan-2-carboxamide (1t), thiophene-2-carboxamide (1u), and 5-chlorothiophene-2-carboxamide (1v), could also be smoothly converted, affording 3s–3v in 56–68% yields.

2-Phenyl-N-(prop-2-yn-1-yl)acetamide (1w), a type of aliphatic amide, was also suitable for use in the protocol, producing a satisfactory result (3w). In addition, the use of cinnamamide (1x), a specially functionalized amide, resulted in a normal reaction, producing the corresponding trifluoroalkylated oxazole 3x with a yield of 51%. Captivatingly, when using N¹,N⁴-di(prop-2-yn-1-yl)terephthalamide (1y) as the starting material, 3y was obtained under standard conditions with a yield of 48%.

More importantly, considering the potential applications of these trifluoroalkylated oxazole compounds in organic synthesis and biomedicine [4,42], gram-scale synthesis was carried out to demonstrate the practicability of this method. By reacting 4.5 mmol (0.716 g) of 1a with 2a (0.918 g) under standard conditions, 3a could be produced with a yield of 80% (1.183 g).

Next, the substrate scope of different trifluoroacetyl compounds 2 was further evaluated. As shown in Table 3, N-(prop-2-yn-1-yl)benzamide 1a could also react smoothly with methyl trifluoropyruvate 2b instead of ethyl trifluoropyruvate 2a under the same conditions to obtain the desired product, 3z, in good yield (81%).

Interestingly, excellent substrate applicability was also observed when 1,1,1,3,3,3-hexafluoropropan-2-one (2c) was used to replace the substrate trifluoropyruvate 2a or 2b. For example, N-(prop-2-yn-1-yl)benzamide (1a) reacted well with 2c, producing 3aa with an 86% yield. Various arylamide substrates 1 with either electron-withdrawing (e.g., F, CF₃, and CN) or electron-donating (e.g., Me) groups all worked well with 2c to afford the desired oxazoles 3ab–3ae in moderate to good yields (75–80%).

As expected, 5-chlorothiophene-2-carboxamide (1v), as a type of heteroarylamide substrate 1, reacted smoothly with 2c to produce 3af with a yield of 56%. Unfortunately, when using 2,2,2-trifluoro-1-phenylethan-1-one (2d) and 1,1,1-trifluoropropan-2-one (2e) under standard conditions, it was difficult to obtain the corresponding products 3ag and 3ah, respectively. This may be due to greater spatial hindrance (for 2d) or less reactivity (for 2e) [43,44].

Moreover, the NMR (¹H, ¹³C, and ¹⁹F) and HRMS data of products 3a–3af are in good agreement with the anticipated structures (for more details, see the Supplementary Materials). Thus, we successfully characterized the structures of serial compounds 3a–3af.

2.3. The Control Experiments and Plausible Reaction Mechanism

In order to further explore the possible reaction mechanism, we conducted several relevant control experiments (Scheme 2).

First, adding two equivalents of the radical scavenger butylated hydroxytoluene (BHT) or 2,2,6,6-tetrameth yl-1-piperidinoxy (TEMPO) [45,46] into the reaction system, the corresponding compound 3a was obtained at 75% and 78% yields, respectively (Scheme 2a). This result indicates that this reaction may not involve a radical pathway.

Second, small amounts of oxazolines and oxazoles were detected in the reaction. We therefore referred to the relevant literature [47,48] and synthesized oxazole 4a (Scheme 2b) and oxazoline 5a (Scheme 2c), using FeCl₃ and ZnI₂ as catalysts, respectively. When oxazole 4a was reacted with 2a under standard conditions, 3a was not produced (Scheme 2d), indicating that the reaction process might not involve the formation of 4a. Notably, 4a was simply a byproduct of the reaction, while oxazoline 5a could further react with 2a to afford the final product 3a in an isolated yield of 79% (Scheme 2e). This implies that oxazoline 5a is a key intermediate in this process.

Therefore, based on previously reported studies [35,47,48,49,50,51,52,53,54,55,56,57] and the aforementioned control experiments, a possible reaction pathway is proposed using the reaction of 1a and 2a as an example, as shown in Scheme 3.

First, as a Lewis acid, Zn(OTf)₂ can activate the triple bond of 1a to enhance the electrophilicity of alkyne A, and the intermediate B is formed through the loss of HOTf from A [49,50,51,52]. Then, the regioselective intramolecular 5-exo-dig cyclization of B affords the intermediate C [53,54]. Hydrolysis with HOTf (which is generated in situ, as mentioned above) occurs, resulting in the oxazoline intermediate 5a [49,51].

On the other hand, Zn(OTf)₂ can separately coordinate with the carbonyl group of 2a to form an electrophilic intermediate D [55,57]. Subsequently, the carbonyl-ene reaction between 5a and D gives F via the intermediate E with the loss of a proton [56,57].

In the end, with the hydrolysis via HOTf generated in situ, the final product 3a is produced from the intermediate F with the regeneration of Zn(OTf)₂ [52], completing the catalyst cycle.

3. Materials and Methods

3.1. General Information

The melting point (m.p.) was measured using a Büchi Melting Point B-545 instrument (Büchi, Flawil, Switzerland) without correction. ¹H, ¹³C, and ¹⁹F NMR spectra were recorded on a BRUKER DRX-400 spectrometer (Bruker, Ettlingen, Germany) (¹H NMR at 400 MHz, ¹³C NMR at 100 MHz, and ¹⁹F NMR at 376 MHz), using tetramethylsilane (TMS) as an internal standard. High-resolution mass spectra (HRMS) were recorded on an LCMS-IT-TOF mass spectrometer (Waters Corporation, Milford, MA, USA). Thin-layer chromatography (TLC) was performed on commercially prepared silica gel plates (GF254). Visualization of TLC was performed with a 254 nm UV lamp. The crude products were purified via column chromatography using 100–200-mesh silica gel.

All chemicals and organic solvents were used as received from commercial sources without further purification, and the substrates N-propargylamides 1 were synthesized from prop-2-yn-1-amine and various acyl chlorides as reported in [49,54].

3.2. Experimental Procedure for Compounds 1a–1y

As shown in Table 4, compounds 1a–1y were synthesized according to the reported procedure [49,54].

Propargylamine (10 mmol) was dissolved in 20 mL of dry dichloromethane (DCM), and 12 mmol Et₃N was added. The reaction mixture was cooled to 0 °C, and 10 mmol of acid chloride was added. The mixture was stirred for 15 min at 0 °C and then for 2–4 h at room temperature. After the reaction was completed, water was added, and the mixture was then extracted with DCM. The combined organic layer was dried over MgSO₄, and the solvent was removed in vacuo. The crude N-propargylamides 1a–1y, as substrates, were further purified via column chromatography or by recrystallization with 80–96% yields.

3.3. Experimental Procedure for Compounds 3a–3af

N-propargylamides 1 (0.3 mmol, 1.0 equiv.), trifluoroacetyl compound 2 (0.36 mmol, 1.2 equiv.), and Zn(OTf)₂ (0.045 mmol, 15 mol%) were dissolved in 1.5 mL of 1,2-dichloroethane (DCE). The reaction mixture was stirred for 12 h at 70 °C. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried over MgSO₄, and the solvent was removed under reduced pressure. The crude products 3a–3af were further purified via column chromatography.

3.4. Experimental Procedure for Compounds 4a

A mixture of N-(prop-2-yn-1-yl)benzamide 1a (0.3 mmol, 1.0 equiv.) and FeCl₃ (0.03 mmol, 10 mol%) was dissolved in 1.5 mL of DCE. The mixture was stirred for 12 h at 70 °C. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried over MgSO₄, and the solvent was removed under reduced pressure. The crude product 4a was further purified via column chromatography.

3.5. Experimental Procedure for Compounds 5a

A mixture of N-(prop-2-yn-1-yl)benzamide 1a (0.3 mmol, 1.0 equiv.) and ZnI₂ (0.03 mmol, 10 mol%) was dissolved in 1.5 mL of dichloromethane (DCM). The mixture was stirred for 4 h at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried over MgSO₄, and the solvent was removed under reduced pressure. The crude product 5a was further purified via column chromatography.

3.6. Characterization Data for All Products 3a–3af, 4a, and 5a

The structures of the target products have been well characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR, and HRMS. The corresponding data are summarized in the following.

• (1). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-phenyloxazol-5-yl)methylpropanoate (3a): colorless oil, 84% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.97–7.95 (m, 2H, ArH), 7.45–7.43 (m, 3H, ArH), 7.01 (s, 1H, ArH), 4.43–4.35 (m, 2H, OCH₂), 4.24 (s, 1H, OH), 3.54 (d, J = 15.2 Hz, 1H, CH₂-a), 3.35 (d, J = 15.2 Hz, 1H, CH₂-b), 1.34 (t, J = 7.2 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 161.8, 144.9, 130.4, 128.8, 127.4, 127.2, 126.2, 123.1 (q, J = 285.0 Hz), 76.6 (q, J = 29.1 Hz), 64,2, 29.1, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₅H₁₅F₃NO₄⁺ [M + H]⁺: 330.0948, found: 330.0943.

• (2). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(p-tolyl)oxazol-5-yl)methylpropanoate (3b): colorless oil, 83% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.84 (d, J = 8.4 Hz, 2H, ArH), 7.24 (d, J = 8.4 Hz, 2H, ArH), 6.99 (s, 1H, ArH), 4.42–4.34 (m, 2H, OCH₂), 4.22 (br, 1H, OH), 3.53 (d, J = 14.8 Hz, 1H, CH₂-a), 3.34 (d, J = 14.8 Hz, 1H, CH₂-b), 1.33 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.53 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 162.0, 144.5, 140.7, 129.5, 127.3, 126.1, 125.9 (q, J = 285.2 Hz), 124.5, 76.6 (q, J = 29.1 Hz), 64,2, 29.1, 21.5, 13.9 ppm; ESI-HRMS, m/z: Calcd for C₁₆H₁₇F₃NO₄⁺ [M + H]⁺: 344.1104, found: 344.1120.

• (3). Ethyl 2-(2-(4-ethylphenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypropanoate (3c): colorless oil, 76% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.87 (d, J = 7.6 Hz, 2H, ArH), 7.26 (d, J = 7.6 Hz, 2H, ArH), 6.98 (s, 1H, ArH), 4.41 (br, 1H, OH), 4.38–4.33 (m, 2H, OCH₂), 3.52 (d, J = 14.8 Hz, 1H, CH₂-a), 3.33 (d, J = 14.8 Hz, 1H, CH₂-b), 2.68 (q, J = 7.6 Hz, 3H, CH₂), 1.33 (t, J = 7.6 Hz, 3H, CH₃), 1.25 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.51 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 167.1, 160.9, 146.0, 143.5, 127.3, 126.2, 125.2, 123.7, 122.1 (q, J = 285.0 Hz), 75.6 (q, J = 29.2 Hz), 63,1, 28.1, 27.8, 14.3, 12.9 ppm; ESI-HRMS, m/z: Calcd for C₁₇H₁₉F₃NO₄⁺ [M + H]⁺: 358.1261, found: 358.1269.

• (4). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(4-methoxyphenyl)oxazol-5-yl)methylpropano- ate (3d): white solid, 81% yield, m.p. 73–75 °C; ¹H NMR (400 MHz, CDCl₃), δ: 7.89 (d, J = 8.4 Hz, 2H, ArH), 6.97 (s, 1H, ArH), 6.95 (d, J = 8.4 Hz, 2H, ArH), 4.39–4.23 (m, 2H, OCH₂), 3.85 (br, 1H, OH), 3.51 (d, J = 15.2 Hz, 1H, CH₂-a), 3.32 (d, J = 15.2 Hz, 1H, CH₂-b), 1.33 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 167.4, 161.5, 144.3, 128.0, 126.7, 123.1 (q, J = 285.2 Hz), 119.6, 114.3, 76.6 (q, J = 29.1 Hz), 64,3, 55.4, 29.0, 13.9 ppm; ESI-HRMS, m/z: Calcd for C₁₆H₁₇F₃NO₅⁺ [M + H]⁺: 360.1053, found: 360.1075.

• (5). Ethyl 2-(2-(4-(chloromethyl)phenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxy- propanoate (3e): colorless oil, 75% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.95 (d, J = 8.4 Hz, 2H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH), 7.02 (s, 1H, ArH), 4.61 (s, 1H, ClCH₂), 4.43–4.32 (m, 2H, OCH₂), 4.20 (br, 1H, OH), 3.53 (d, J = 15.2 Hz, 1H, CH₂-a), 3.34 (d, J = 15.2 Hz, 1H, CH₂-b), 1.34 (t, J = 8.0 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 161.2, 145.2, 139.7, 129.1, 127.4, 127.1, 126.5, 123.0 (q, J = 285.0 Hz), 76.7 (q, J = 29.2 Hz), 64.3, 45.6, 29.1, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₆H₁₆ClF₃NO₄⁺ [M + H]⁺: 378.0714, found: 378.0714.

• (6). Ethyl 2-(2-([1,1′-biphenyl]-4-yl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypro- panoate (3f): white solid, 74% yield, m.p. 107–109 °C; ¹H NMR (400 MHz, CDCl₃), δ: 8.01 (d, J = 8.4 Hz, 2H, ArH), 7.63 (d, J = 8.4 Hz, 2H, ArH), 7.58 (d, J = 8.0 Hz, 2H, ArH), 7.44–7.40 (m, 2H, ArH), 7.35 (t, J = 8.0 Hz, 1H, ArH), 7.03 (s, 1H, ArH), 4.72 (br, 1H, OH), 4.41–4.33 (m, 2H, OCH₂), 3.54 (d, J = 15.6 Hz, 1H, CH₂-a), 3.35 (d, J = 15.6 Hz, 1H, CH₂-b), 1.32 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.41 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 161.6, 145.1, 143.1, 140.1, 128.9, 127.9, 127.5, 127.4, 127.1, 126.7, 126.0, 123.2 (q, J = 285.1 Hz), 76.8 (q, J = 31.8 Hz), 64.1, 29.2, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₂₁H₁₉F₃NO₄⁺ [M + H]⁺: 406.1261, found: 406.1254.

• (7). Ethyl 3,3,3-trifluoro-2-(2-(4-fluorophenyl)oxazol-5-yl)methyl-2-hydroxypropanoate (3g): colorless oil, 80% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.96–7.93 (m, 2H, ArH), 7.15–7.10 (m, 2H, ArH), 6.99 (s, 1H, ArH), 4.41–4.33 (m, 2H, OCH₂), 4.31 (br, 1H, OH), 3.52 (d, J = 14.4 Hz, 1H, CH₂-a), 3.34 (d, J = 14.4 Hz, 1H, CH₂-b), 1.33 (t, J = 7.2 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.53, −109.32 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 164.1 (d, J = 250.2 Hz), 160.9, 145.0, 128.3 (d, J = 8.8 Hz), 127.4, 123.6 (d, J = 3.2 Hz), 123.1 (q, J = 285.2 Hz), 116.0 (d, J = 22.8 Hz), 76.6 (q, J = 29.1 Hz), 64,2, 29.0, 13.9 ppm; ESI-HRMS, m/z: Calcd for C₁₅H₁₄F₄NO₄⁺ [M + H]⁺: 348.0853, found: 348.0844.

• (8). Ethyl 2-(2-(4-chlorophenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypropanoate (3h): colorless oil, 77% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.89 (d, J = 8.0 Hz, 2H, ArH), 7.42 (d, J = 8.4 Hz, 2H, ArH), 7.01 (s, 1H, ArH), 4.43–4.33 (m, 2H, OCH₂), 4.19 (br, 1H, OH), 3.53 (d, J = 15.2 Hz, 1H, CH₂-a), 3.35 (d, J = 15.2 Hz, 1H, CH₂-b), 1.34 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.53 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 160.9, 145.2, 136.6, 129.2, 127.6, 127.4, 125.7, 123.0 (q, J = 285.2 Hz), 76.6 (q, J = 31.8 Hz), 64,3, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₅H₁₄ClF₃NO₄⁺ [M + H]⁺: 364.0558, found: 364.0578.

• (9). Ethyl 2-(2-(4-bromophenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypropanoate (3i): white solid, 75% yield, m.p. 100–102 °C; ¹H NMR (400 MHz, CDCl₃), δ: 7.81 (d, J = 8.4 Hz, 2H, ArH), 7.57 (d, J = 8.4 Hz, 2H, ArH), 7.01 (s, 1H, ArH), 4.42–4.33 (m, 2H, OCH₂), 4.29 (br, 1H, OH), 3.52 (d, J = 15.6 Hz, 1H, CH₂-a), 3.35 (d, J = 15.6 Hz, 1H, CH₂-b), 1.33 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 167.4, 159.9, 144.3, 131.1, 126.6, 126.5, 125.1, 123.9, 122.0 (q, J = 285.0 Hz), 75.6 (q, J = 31.8 Hz), 63,2, 28.0, 12.9 ppm; ESI-HRMS, m/z: Calcd for C₁₅H₁₄BrF₃NO₄⁺ [M + H]⁺: 408.0053, found: 408.0071.

• (10). Ethyl 2-(2-(4-cyanophenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypropanoate (3j): colorless oil, 71% yield; ¹H NMR (400 MHz, CDCl₃), δ: 8.06 (d, J = 8.8 Hz, 2H, ArH), 7.74 (d, J = 8.8 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 4.44–4.34 (m, 2H, OCH₂), 4.26 (br, 1H, OH), 3.54 (d, J = 15.2 Hz, 1H, CH₂-a), 3.38 (d, J = 15.2 Hz, 1H, CH₂-b), 1.34 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.4, 159.9, 146.5, 132.7, 130.8, 128.0, 126.6, 123.0 (q, J = 285.0 Hz), 118.2, 113.7, 76.7 (q, J = 29.2 Hz), 64,4, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₆H₁₄F₃N₂O₄⁺ [M + H]⁺: 355.0900, found: 355.0911.

• (11). Methyl 4-(5-(2-(ethoxycarbonyl)-3,3,3-trifluoro-2-hydroxypropyl)oxazol-2-yl)-benzoate (3k): colorless oil, 68% yield; ¹H NMR (400 MHz, CDCl₃), δ: 8.11 (d, J = 9.2 Hz, 2H, ArH), 8.03 (d, J = 9.2 Hz, 2H, ArH), 7.07 (s, 1H, ArH), 4.44–4.35 (m, 2H, OCH₂), 4.17 (br, 1H, OH), 3.94 (s, 3H, OCH₃), 3.55 (d, J = 15.2 Hz, 1H, CH₂-a), 3.38 (d, J = 15.2 Hz, 1H, CH₂-b), 1.35 (t, J = 7.2 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.54 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 167.4, 165.4, 159.7, 144.8, 130.5, 129.2, 129.1, 126.8, 125.0, 122.0 (q, J = 285.2 Hz), 75.6 (q, J = 29.1 Hz), 63.3, 51.3, 28.0, 12.9 ppm; ESI-HRMS, m/z: Calcd for C₁₇H₁₇F₃NO₆⁺ [M + H]⁺: 388.1002, found: 388.0991.

• (12). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(4-(trifluoromethyl)phenyl)oxazol-5-yl)methyl- propanoate (3l): white solid, 73% yield, m.p. 95–97 °C; ¹H NMR (400 MHz, CDCl₃), δ: 8.07 (d, J = 8.4 Hz, 2H, ArH), 7.70 (d, J = 8.4 Hz, 2H, ArH), 7.06 (s, 1H, ArH), 4.42–4.35 (m, 2H, OCH₂), 4.21 (br, 1H, OH), 3.55 (d, J = 15.2 Hz, 1H, CH₂-a), 3.38 (d, J = 15.2 Hz, 1H, CH₂-b), 1.35 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −62.97, −78.55 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 160.4, 145.9, 132.0 (q, J = 32.3 Hz), 130.3, 127.8, 126.4, 125.9 (q, J = 3.8 Hz), 123.8 (q, J = 271.4 Hz), 123.0 (q, J = 285.6 Hz), 76.6 (q, J = 29.2 Hz), 64.3, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₆H₁₄F₆NO₄⁺ [M + H]⁺: 398.0822, found: 398.0827.

• (13). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(o-tolyl)oxazol-5-yl)methylpropanoate (3m): colorless oil, 72% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.87 (d, J = 8.0 Hz, 2H, ArH), 7.35–7.25 (m, 3H, ArH), 7.05 (s, 1H, ArH), 4.44–4.30 (m, 2H, OCH₂), 4.05 (br, 1H, OH), 3.53 (d, J = 14.8 Hz, 1H, CH₂-a), 3.36 (d, J = 14.8 Hz, 1H, CH₂-b), 2.65 (s, 1H, CH₃), 1.33 (t, J = 7.2 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.6, 162.1, 144.3, 137.4, 131.6, 130.0, 128.6, 127.2, 126.2, 126.0, 123.1 (q, J = 285.2 Hz), 76.7 (q, J = 29.1 Hz), 64,3, 29.0, 21.9, 13.9 ppm; ESI-HRMS, m/z: Calcd for C₁₆H₁₇F₃NO₄⁺ [M + H]⁺: 344.1104, found: 344.1120.

• (14). Ethyl 2-(2-(3-bromophenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypropanoate (3n): white solid, 70% yield, m.p. 63–65 °C; ¹H NMR (400 MHz, CDCl₃), δ: 8.09 (s, 1H, ArH), 7.89 (d, J = 7.6 Hz, 1H, ArH), 7.56 (d, J = 7.6 Hz, 1H, ArH), 7.33–7.28 (m, 1H, ArH), 7.02 (s, 1H, ArH), 4.41–4.36 (m, 2H, OCH₂), 4.26 (br, 1H, OH), 3.53 (d, J = 14.8 Hz, 1H, CH₂-a), 3.35 (d, J = 14.8 Hz, 1H, CH₂-b), 1.35 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.51 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 160.3, 145.5, 133.3, 130.4, 129.1, 129.0, 127.7, 124.7, 122.9, 123.0 (q, J = 285.2 Hz), 76.7 (q, J = 31.8 Hz), 64.4, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₅H₁₄BrF₃NO₄⁺ [M + H]⁺: 408.0053, found: 408.0071.

• (15). Ethyl 2-(2-(3,5-dimethylphenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypro- panoate (3o): colorless oil, 78% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.59 (s, 1H, ArH), 7.07 (s, 1H, ArH), 6.99 (s, 1H, ArH), 4.40–4.35 (m, 2H, OCH₂), 4.30 (br, 1H, OH), 3.52 (d, J = 14.4 Hz, 1H, CH₂-a), 3.34 (d, J = 14.4 Hz, 1H, CH₂-b), 2.35 (s, 6H, 2CH₃), 1.34 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.4, 162.1, 144.7, 138.5, 132.2, 127.1, 126.8, 124.0, 123.0 (q, J = 285.2 Hz), 76.7 (q, J = 29.1 Hz), 64,2, 29.1, 21.2, 13.9 ppm; ESI-HRMS, m/z: Calcd for C₁₇H₁₉F₃NO₄⁺ [M + H]⁺: 358.1261, found: 358.1269.

• (16). Ethyl 2-(2-(3,5-dichlorophenyl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypropan- oate (3p): colorless oil, 75% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.83 (s, 2H, ArH), 7.41 (s, 1H, ArH), 7.04 (s, 1H, ArH), 4.44–4.36 (m, 2H, OCH₂), 4.32 (br, 1H, OH), 3.54 (d, J = 14.4 Hz, 1H, CH₂-a), 3.36 (d, J = 14.4 Hz, 1H, CH₂-b), 1.36 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.53 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.4, 159.2, 146.1, 135.7, 130.2, 129.7, 127.9, 124.5, 122.5 (q, J = 285.0 Hz), 76.7 (q, J = 29.2 Hz), 64,4, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₅H₁₃Cl₂F₃NO₄⁺ [M + H]⁺: 398.0168, found: 398.0174.

• (17). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(naphthalen-1-yl)oxazol-5-yl)methylpropanoate (3q): white solid, 70% yield, m.p. 105–107 °C; ¹H NMR (400 MHz, CDCl₃), δ: 9.15 (d, J = 7.6 Hz, 1H, ArH), 8.10 (d, J = 7.6 Hz, 1H, ArH), 7.95 (d, J = 8.0 Hz, 1H, ArH), 7.90 (d, J = 8.0 Hz, 1H, ArH), 7.65–7.61 (m, 1H, ArH), 7.57–7.6152 (m, 2H, ArH), 7.17 (s, 1H, ArH), 4.45–4.32 (m, 2H, OCH₂), 4.10 (br, 1H, OH), 3.60 (d, J = 14.8 Hz, 1H, CH₂-a), 3.42 (d, J = 14.8 Hz, 1H, CH₂-b), 1.32 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.49 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.6, 161.7, 144.6, 133.9, 131.3, 130.1, 128.6, 127.7, 127.6, 127.5, 126.4, 126.0, 124.9, 123.8, 123.1 (q, J = 285.0 Hz), 76.8 (q, J = 29.2 Hz), 64.4, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₉H₁₇F₃NO₄⁺ [M + H]⁺: 380.1104, found: 380.1103.

• (18). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(naphthalen-2-yl)oxazol-5-yl)methylpropanoate (3r): white solid, 73% yield, m.p. 111–113 °C, 73% yield; ¹H NMR (400 MHz, CDCl₃), δ: 8.36 (s, 1H, ArH), 7.96 (d, J = 8.4 Hz, 1H, ArH), 7.80 (d, J = 8.4 Hz, 2H, ArH), 7.76–7.74 (m, 1H, ArH), 7.45–7.43 (m, 2H, ArH), 6.98 (s, 1H, ArH), 4.35–4.29 (m, 3H, OCH₂, OH), 3.50 (d, J = 15.2 Hz, 1H, CH₂-a), 3.31 (d, J = 15.2 Hz, 1H, CH₂-b), 1.27 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.46 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 161.9, 145.1, 134.1, 133.0, 128.7, 128.7, 127.9, 127.6, 127.4, 126.8, 126.2, 124.5, 123.1, 123.1 (q, J = 285.3 Hz), 76.8 (q, J = 29.2 Hz), 64.3, 29.2, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₉H₁₇F₃NO₄⁺ [M + H]⁺: 380.1104, found: 380.1103.

• (19). Ethyl 2-(2-(2-chloropyridin-3-yl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxy-pro- panoate (3s): white solid, 62% yield, m.p. 92–94 °C; ¹H NMR (400 MHz, CDCl₃), δ: 8.43–4.41 (m, 1H, ArH), 8.25–8.20 (m, 1H, ArH), 7.34–7.28 (m, 1H, ArH), 7.07 (s, 1H, ArH), 4.37–4.31 (m, 2H, OCH₂), 4.13 (br, 1H, OH), 3.55–3.48 (m, 1H, CH₂), 3.37–3.31 (m, 1H, CH₂), 1.26 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: -76.51 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.4, 157.9, 150.6, 148.5, 146.4, 139.4, 127.9, 123.3, 123.1 (q, J = 285.2 Hz), 122.4, 76.8 (q, J = 29.1 Hz), 64.5, 29.0, 13.9 ppm; ESI-HRMS, m/z: Calcd for C₁₄H₁₃ClF₃N₂O₄⁺ [M + H]⁺: 365.0510, found: 365.0536.

• (20). Ethyl 3,3,3-trifluoro-2-(2-(furan-2-yl)oxazol-5-yl)methyl-2-hydroxypropanoate (3t): colorless oil, 68% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.54 (s, 1H, ArH), 7.01 (s, 1H, ArH), 6.96 (d, J = 4.8 Hz, 1H, ArH), 6.52 (s, 1H, ArH), 4.40 (q, 2H, J = 7.6 Hz, OCH₂), 4.19 (br, 1H, OH), 3.52 (d, J = 15.2 Hz, 1H, CH₂-a), 3.33 (d, J = 15.2 Hz, 1H, CH₂-b), 1.37 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.54 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.4, 154.5, 144.4, 142.7, 127.3, 123.0 (q, J = 285.3 Hz), 76.5 (q, J = 29.2 Hz), 111.9, 111.4, 64,4, 28.9, 13.9 ppm; ESI-HRMS, m/z: Calcd for C₁₃H₁₃F₃NO₅⁺ [M + H]⁺: 320.0740, found: 320.0751.

• (21). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(thiophen-2-yl)oxazol-5-yl)methylpropanoate (3u): white solid, 62% yield; m.p. 100–102 °C; ¹H NMR (400 MHz, CDCl₃), δ: 7.60 (d, J = 5.6 Hz, 1H, ArH), 7.42 (d, J = 5.6 Hz, 1H, ArH), 7.11–7.09 (m, 1H, ArH), 6.98 (s, 1H, ArH), 4.45–4.37 (m, 2H, OCH₂), 4.07 (br, 1H, OH), 3.52 (d, J = 14.8 Hz, 1H, CH₂-a), 3.32 (d, J = 14.8 Hz, 1H, CH₂-b), 1.37 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.53 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 157.9, 144.3, 129.7, 128.3, 128.0, 127.6, 127.5, 123.0 (q, J = 285.3 Hz), 76.8 (q, J = 29.1 Hz), 64.4, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₃H₁₃F₃NO₄S⁺ [M + H]⁺: 336.0512, found: 336.0518.

• (22). Ethyl 2-(2-(5-chlorothiophen-2-yl)oxazol-5-yl)methyl-3,3,3-trifluoro-2-hydrox-pro- panoate (3v): colorless oil, 56% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.29 (d, J = 4.0 Hz, 1H, ArH), 6.88 (s, 1H, ArH), 6.84 (d, J = 4.0 Hz, 1H, ArH), 4.38–4.26 (m, 2H, OCH₂), 4.06 (br, 1H, OH), 3.42 (d, J = 15.2 Hz, 1H, CH₂-a), 3.24 (d, J = 15.2 Hz, 1H, CH₂-b), 1.28 (t, J = 7.2 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.53 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.4, 156.8, 144.7, 133.4, 128.1, 127.5, 127.2, 126.8, 123.0 (q, J = 285.8 Hz), 76.5 (q, J = 29.1 Hz), 64.4, 28.9, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₃H₁₂ClF₃NO₄S⁺ [M + H]⁺: 370.0122, found: 370.0138.

• (23). Ethyl 2-(2-benzyloxazol-5-yl)methyl-3,3,3-trifluoro-2-hydroxypropanoate (3w): colorless oil, 59% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.30–7.27 (m, 2H, ArH), 7.23–7.19 (m, 1H, ArH), 7.16 (d, J = 7.6 Hz, 2H, ArH), 7.15 (s, 1H, ArH), 4.39–4.32 (m, 2H, OCH₂), 4.13 (br, 1H, OH), 3.40 (d, J = 15.2 Hz, 1H, CH₂-a), 3.23 (d, J = 15.2 Hz, 1H, CH₂-b), 3.02 (s, 2H, PhCH₂), 1.33 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.52 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 164.3, 144.6, 140.0, 128.6, 128.3, 126.4, 125.6, 123.0 (q, J = 285.6 Hz), 76.6 (q, J = 29.3 Hz), 64.2, 33.0, 28.9, 13.9 ppm. ESI-HRMS, m/z: Calcd for C₁₆H₁₇F₃NO₄⁺ [M + H]⁺: 344.1104, found: 344.1118.

• (24). Ethyl (E)-3,3,3-trifluoro-2-hydroxy-2-(2-styryloxazol-5-yl)methylpropanoate (3x): colorless oil, 51% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.51 (d, J = 7.6 Hz, 2H, ArH), 7.44–7.32 (m, 4H, ArH), 6.97 (s, 1H, ArH), 6.88 (d, J = 15.2 Hz, 1H, =CH), 4.40 (q, J = 7.6 Hz, 2H, OCH₂), 4.13 (br, 1H, OH), 3.50 (d, J = 14.8 Hz, 1H, CH₂-a), 3.32 (d, J = 14.8 Hz, 1H, CH₂-b), 1.37 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.51 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 168.5, 161.6, 144.5, 136.1, 135.3, 129.3, 128.9, 127.6, 127.2, 123.0 (q, J = 285.4 Hz), 113.7, 76.7 (q, J = 29.3 Hz), 64,3, 29.0, 14.0 ppm; ESI-HRMS, m/z: Calcd for C₁₇H₁₇F₃NO₄⁺ [M + H]⁺: 356.1104, found: 356.1132.

• (25). Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-(4-(5-methyloxazol-2-yl)phenyl)oxazol-5-yl)- methylpropanoate (3y): colorless oil, 48% yield; ¹H NMR (400 MHz, CDCl₃), δ: 8.00 (d, J = 9.2 Hz, 2H, ArH), 7.95 (d, J = 9.2 Hz, 2H, ArH), 6.98 (s, 1H, ArH), 6.81 (s, 1H, ArH), 4.38–4.26 (m, 3H, OCH₂, OH), 3.48 (d, J = 15.2 Hz, 1H, CH₂-a), 3.30 (d, J = 15.2 Hz, 1H, CH₂-b), 2.33 (s, 3H, CH₃), 1.37 (t, J = 7.6 Hz, 3H, CH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.51 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 167.4, 160.1, 148.6, 144.4, 128.1, 127.1, 126.7, 125.4, 125.3, 123.6, 123.0, 122.0 (q, J = 285.6 Hz), 75.6 (q, J = 29.2 Hz), 63.3, 28.1, 13.0, 10.1 ppm; ESI-HRMS, m/z: Calcd for C₁₉H₁₈F₃N₂O₅⁺ [M + H]⁺: 411.1162, found: 411.1157.

• (26). Methyl 3,3,3-trifluoro-2-hydroxy-2-(2-phenyloxazol-5-yl)methylpropanoate (3z): colorless oil, 81% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.96–7.94 (m, 2H, ArH), 7.44–7.43 (m, 3H, ArH), 7.00 (s, 1H, ArH), 4.37 (br, 1H, OH), 3.94 (s, 1H, OCH₃), 3.53 (d, J = 15.2 Hz, 1H, CH₂-a), 3.34 (d, J = 15.2 Hz, 1H, CH₂-b) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −78.49 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 169.0, 161.8, 144.8, 130.4, 128.8, 127.5, 127.2, 126.2, 123.0 (q, J = 285.0 Hz), 76.8 (q, J = 28.7 Hz), 54.5, 29.2 ppm; ESI-HRMS, m/z: Calcd for C₁₄H₁₃F₃NO₄⁺ [M + H]⁺: 316.0791, found: 316.0808.

• (27). 1,1,1,3,3,3-Hexafluoro-2-(2-phenyloxazol-5-yl)methylpropan-2-ol (3aa): colorless oil, 86% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.83 (d, J = 7.6 Hz, 2H, ArH), 7.37–7.29 (m, 3H, ArH), 6.90 (s, 1H, ArH), 6.49 (br, 1H, OH), 3.31 (s, 2H, CH₂) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −76.51 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 162.3, 143.6, 130.8, 128.8, 127.9, 126.4, 126.4, 122.8 (q, J = 286.3 Hz), 76.5–74.7 (m), 27.3 ppm; ESI-HRMS, m/z: Calcd for C₁₃H₁₀F₆NO₂⁺ [M + H]⁺: 326.0610, found: 326.0637.

• (28). 1,1,1,3,3,3-Hexafluoro-2-(2-(4-fluorophenyl)oxazol-5-yl)methylpropan-2-ol (3ab): colorless oil, 80% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.93–7.90 (m, 2H, ArH), 7.13–7.09 (m, 2H, ArH), 7.01 (s, 1H, ArH), 5.38 (br, 1H, OH), 3.41 (s, 2H, CH₂) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −76.67, −108.45 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 164.3 (d, J = 251.4 Hz), 161.6, 143.3, 128.5 (d, J = 9.3 Hz), 128.3, 122.9 (d, J = 3.3 Hz), 122.7 (q, J = 285.8 Hz), 116.1 (d, J = 22.5 Hz), 76.2–75.0 (m), 27.2 ppm; ESI-HRMS, m/z: Calcd for C₁₃H₉F₇NO₂⁺ [M + H]⁺: 344.0516, found: 344.0513.

• (29). 1,1,1,3,3,3-Hexafluoro-2-(2-(4-(trifluoromethyl)phenyl)oxazol-5-yl)methylpropan-2-ol (3ac): white solid, 76% yield, m.p. 121–123 °C; ¹H NMR (400 MHz, CDCl₃), δ: 8.05 (d, J = 7.6 Hz, 2H, ArH), 7.68 (d, J = 7.6 Hz, 2H, ArH), 7.11 (s, 1H, ArH), 4.91 (br, 1H, OH), 3.45 (s, 2H, CH₂) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: -63.02, -76.69 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 160.9, 144.1, 132.3 (q, J = 31.8 Hz), 129.7, 128.8, 126.5, 125.9 (q, J = 3.6 Hz), 123.7 (q, J = 270.6 Hz), 122.6 (q, J = 287.7 Hz), 76.2–75.0 (m), 27.1 ppm; ESI-HRMS, m/z: Calcd for C₁₄H₉F₉NO₂⁺ [M + H]⁺: 394.0484, found: 394.0498.

• (30). 4-(5-(3,3,3-Trifluoro-2-hydroxy-2-trifluoromethylpropyl)oxazol-2-yl)benzonitrile (3ad): white solid, 78% yield, m.p. 122–124 °C; ¹H NMR (400 MHz, CDCl₃), δ: 8.06 (d, J = 8.0 Hz, 2H, ArH), 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.14 (s, 1H, ArH), 5.63 (br, 1H, OH), 3.45 (s, 2H, CH₂) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −76.51 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 160.3, 144.9, 132.7, 130.4, 128.9, 126.7, 122.7 (q, J = 285.4 Hz), 118.0, 113.9, 76.2–75.0 (m), 27.2 ppm; ESI-HRMS, m/z: Calcd for C₁₄H₉F₆N₂O₂⁺ [M + H]⁺: 351.0563, found: 351.0596.

• (31). 2-(2-(3,5-Dimethylphenyl)oxazol-5-yl)methyl-1,1,1,3,3,3-hexafluoropropan-2-ol (3ae): colorless oil, 75% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.44 (s, 2H, ArH), 6.99 (s, 1H, ArH), 6.87 (s, 1H, ArH), 5.95 (br, 1H, OH), 3.32 (s, 2H, CH₂), 2.25 (s, 6H, 2CH₃)ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −76.69 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 162.7, 143.0, 138.5, 132.6, 128.0, 126.1, 124.1, 122.8 (q, J = 285.6 Hz), 76.3–75.1 (m), 27.2, 21.1 ppm; ESI-HRMS, m/z: Calcd for C₁₅H₁₄F₆NO₂⁺ [M + H]⁺: 354.0923, found: 354.0935.

• (32). 2-(2-(5-Chlorothiophen-2-yl)oxazol-5-yl)methyl-1,1,1,3,3,3-hexafluoropropan-2-ol (3af): white solid, 56% yield, m.p. 101–103 °C; ¹H NMR (400 MHz, CDCl₃), δ: 7.40 (d, J = 6.8 Hz, 1H, ArH), 6.94 (s, 1H, ArH), 6.91 (d, J = 6.8 Hz, 1H, ArH), 5.80 (br, 1H, OH), 3.38 (s, 2H, CH₂) ppm; ¹⁹F NMR (376 MHz, CDCl₃), δ: −76.61 ppm; ¹³C NMR (100 MHz, CDCl₃), δ: 157.3, 143.2, 134.2, 128.0, 127.7, 127.3, 127.1, 122.7 (q, J = 285.2 Hz), 76.2–75.0 (m), 27.1 ppm; ESI-HRMS, m/z: Calcd for C₁₁H₇ClF₆NO₂S⁺ [M + H]⁺: 365.9785, found: 365.9803.

• (33). 5-Methyl-2-phenyloxazole (4a) [45]: colorless oil, 87% yield; ¹H NMR (400 MHz, CDCl₃), δ: 8.0 (d, J = 7.2 Hz, 2H, ArH), 7.46–7.40 (m, 3H, ArH), 6.84 (s, 1H, ArH), 2.37 (s, 3H, CH₃) ppm.

• (34). 5-Methylene-2-phenyl-4,5-dihydrooxazole (5a) [45]: colorless oil, 83% yield; ¹H NMR (400 MHz, CDCl₃), δ: 7.96 (d, J = 7.2 Hz, 1H, ArH), 7.46 (t, J = 7.6 Hz, 1H, ArH), 7.41–7.38 (m, 2H, ArH), 4.79 (dd, J = 6.0, 2.8 Hz, 1H, =CH₂-a), 4.61 (t, J = 2.8 Hz, 2H, CH₂), 4.33 (dd, J = 6.0, 2.8 Hz, 1H, =CH₂-b) ppm.

The detailed spectra of ¹H, ¹³C NMR, and ¹⁹F NMR for all compounds 3a–3af, 4a, and 5a are provided in the Supplementary Materials.

4. Conclusions

In summary, Zn(OTf)₂-catalyzed tandem cycloisomerization/hydroxyalkylation has been developed for the concise synthesis of potentially bioactive oxazoles containing a unit of CF₃-substituted alcohol from N-propargylamides with trifluoropyruvates. This newly developed protocol is operationally simple and results in a wide range of oxazoles obtained in moderate to good yields. The method’s broad substrate scope, high functional group tolerance, and high atom economy are positive features. Additionally, the method enables gram-scale reaction with excellent yield, indicating its strong potential for practical application. This synthesis strategy will be helpful for the further design and rapid synthesis of structurally diverse CF₃-containing oxazole derivatives.

Author Contributions

Conceptualization, K.Y. and Z.-Y.W.; methodology, J.-J.G. and L.-H.W.; formal analysis, S.-Q.Y. and X.Z.; data curation, J.-J.G. and X.Z.; writing—original draft preparation, J.-J.G. and K.Y.; writing—review and editing, Y.Z. and Z.-Y.W.; project administration, Z.-Y.W.; funding acquisition, K.Y. and Z.-Y.W. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data supporting the findings of this study are available within the paper and its Supplementary Materials, which are published online.

Conflicts of Interest

The authors declare no conflicts of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures, Schemes and Tables

Figure 1. Examples of bioactive molecules containing trifluoromethyl carbinol.

Figure 2. Examples of natural products and biologically active molecules containing an oxazole unit.

Scheme 1. Typical examples of synthesis methods using tandem reactions to obtain fluorinated oxazoles.

Scheme 2. Control experiments: (a) Explore whether there is a free radical pathway. (b) Synthesis of 4a catalyzed by FeCl3. (c) Synthesis of 5a catalyzed by ZnI2. (d) Explore whether 4a is an intermediate in the reaction. (e) Explore whether 5a is an intermediate in the reaction.

Scheme 3. Proposed mechanisms.

Table 1

Optimization of reaction conditions ^[a].

[Image omitted. Please see PDF.]
Entry	Catalyst	Solvent	Temp. (°C)	Yield of 3a (%) [b]
1	-	DCE	70	Trace
2	FeCl3 (20 mol%)	DCE	70	56
3	InCl3 (20 mol%)	DCE	70	80
4	Y(OTf)3 (20 mol%)	DCE	70	Trace
5	Sc(OTf)3 (20 mol%)	DCE	70	Trace
6	In(OTf)3 (20 mol%)	DCE	70	78
7	Cu(OTf)2 (20 mol%)	DCE	70	32
8	Zn(OTf)2 (20 mol%)	DCE	70	83
9	TfOH (20 mol%)	DCE	70	Trace
10	Zn(OTf)2 (10 mol%)	DCE	70	66
11	Zn(OTf)2 (15 mol%)	DCE	70	84
12	Zn(OTf)2 (25 mol%)	DCE	70	80
13	Zn(OTf)2 (15 mol%)	Toluene	70	76
14	Zn(OTf)2 (15 mol%)	1,4-Dioxane	70	12
15	Zn(OTf)2 (15 mol%)	Acetonitrile	70	35
16	Zn(OTf)2 (15 mol%)	Chloroform	70	62
17	Zn(OTf)2 (15 mol%)	THF	70	Trace
18	Zn(OTf)2 (15 mol%)	DMF	70	Trace
19	Zn(OTf)2 (15 mol%)	DCE	50	56
20	Zn(OTf)2 (15 mol%)	DCE	90	73
21 [c]	Zn(OTf)2 (15 mol%)	DCE	70	72
22 [d]	Zn(OTf)2 (15 mol%)	DCE	70	83

^[a] Reaction conditions: 1a (0.3 mmol); 2a (0.36 mmol, 1.2 equiv.); catalyst; temperature; solvent (1.5 mL); 12 h. ^[b] Isolated yield based on 1a. DCE = 1,2-dichloroethane; THF = tetrahydrofuran; DMF = N,N-dimethylformamide. ^[c] 6 h. ^[d] 18 h.

Table 2

Substrate scope of various N-propargylamides 1 ^[a,b].

[Image omitted. Please see PDF.]

[Image omitted. Please see PDF.]

^[a] Reaction conditions: 1 (0.3 mmol), 2a (0.36 mmol, 1.2 equiv.), Zn(OTf)₂ (0.045 mmol, 15 mol%), DCE (1.5 mL), 70 °C, and 12 h. ^[b] Isolated yields based on 1. ^[c] Reaction performed on a 4.5 mmol scale: 1a (4.5 mmol), 2a (5.4 mmol), Zn(OTf)₂ (0.675 mmol, 15 mol%), DCE (25 mL), 70 °C, and 24 h.

Table 3

Substrate scope of various trifluoroacetyl compounds 2 ^[a,b].

[Image omitted. Please see PDF.]

[Image omitted. Please see PDF.]

^[a] Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol, 1.2 equiv.), Zn(OTf)₂ (0.045 mmol, 15 mol%), DCE (1.5 mL), 70 °C, and 12 h. ^[b] Isolated yields based on 1.

Table 4

Synthesis of 1a–1y ^[a,b].

[Image omitted. Please see PDF.]

[Image omitted. Please see PDF.]

^[a] Reaction conditions: acid chloride (10 mmol), propargylamine (10 mmol), Et₃N (12 mmol), DCM (20 mL), 0 °C, 15 min, r.t., 2–4 h. ^[b] Isolated yields. ^[c] Reaction conditions: terephthaloyl dichloride (10 mmol), propargylamine (20 mmol), Et₃N (22 mmol), DCM (30 mL), 0 °C, 15 min, rt, 4 h.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29245848/s1, which contains details on the ¹H, ¹³C, and ¹⁹F NMR spectra for all compounds.

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