Catalytic Synthesis of 5-Fluoro-2-oxazolines: Using BF3·Et2O as the Fluorine Source and Activating Reagent.

Hypervalent iodine catalyst-catalyzed nucleophilic fluorination of unsaturated amides using BF3·Et2O as the fluorine source and activating reagent was reported. Various 5-fluoro-2-oxazoline derivatives were synthesized in good to excellent yields (up to 95% isolated yield) within 10 min. The process was efficient and metal-free under mild conditions. A mechanism involving a fluorination/1,2-aryl migration/cyclization cascade was proposed on the basis of previous work and experimental results.

Introduction

Fluorine plays a significant role in medicinal, agrochemical, and material chemistry due to the unique properties of the F atom.[1] The introduction of F atom(s) into a compound can greatly impact the chemical, physical, and biological properties of the original compound.[1] The fluorinated molecule often displays excellent performance such as higher thermal and metabolic stabilities and weaker intermolecular interactions compared to the primary molecule.[2] However, despite its natural abundance, fluorine-containing natural products are very scarce and there are only a limited number of simple structures that contain fluorine.[3] Thus, the development of efficient strategies to introduce fluorine atom(s) into a molecule is currently one of the most hectic areas of chemistry, as F. Dean Toste wrote, “The current research activity in fluorine chemistry is at an all-time high”.[1e]

2-Oxazolines are core scaffolds present in a variety of natural products and bioactive molecule, and derivatives have been found as antifungal,[4] antibacterial,[5] and antituberculosis agents.[6] Besides, 2-oxazolines are widely used in catalytic asymmetric transformations as chiral ligands for different reactions.[7] Moreover, 2-oxazolines are important intermediates in various organic reactions.[8] They can also undergo ring-opening polymerization that allows the preparation of polymer architectures.[9] The application examples of 2-oxazoline derivatives are shown in Scheme a.[6,10] Therefore, much attention has been devoted to the development of efficient processes for the synthesis of oxazolines.[11] Undoubtedly, in view of the excellent properties of the fluorinated molecule, an efficient, metal-free, and mild protocol will be welcome for the synthesis of fluorinated oxazolines. During the development of fluorination reactions, the choice of fluorine source is the key issue. The past few decades witnessed the wide applications of fluorine sources such as DAST and its derivatives,[12] Selectfluor,[13]N-fluorobenzenesulfonimide (NFSI),[14] Py·HF,[15] and Et3N·3HF;[16] however, the low atom economy and high cost of the electrophilic fluorine source and the high toxicity of the HF-based nucleophilic fluorine source were issues in the strategies encountered, which set up obstacles for its wide applications. Thus, the development of an efficient fluorination method using a low-cost, low-toxic, and atom-economic fluorine source is our goal. As a versatile, cheap, and easily handled Lewis acid, BF3·Et2O could also act as a fluorine source in various fluorination reactions.[17] Among them, aminofluorinations could result in fluorinated N-compounds, including useful N-heterocycles (Scheme b).[18] In view of operational and environmental advantages associated with hypervalent iodine reagent applied in fluorination reactions,[15,19] we recently reported hypervalent iodine-catalyzed fluorinations using BF3·Et2O as s fluorine source. Various fluorinated six-membered and seven-membered N,O-heterocycles were synthesized through the metal-free strategy.[18e] To further expand the scope of the catalytic fluorination system, herein, we disclosed a catalytic metal-free oxidative fluorination to provide 5-fluoro-2-oxazolines using BF3·Et2O as the fluorine reagent and iodobenzene (IB) as a catalyst precursor in the presence of meta-chloroperoxybenzoic acid (m-CPBA) (Scheme c).

Scheme 1

Examples of 2-Oxazoline Derivatives (a) and Synthesis of Heterocycles via Aminofluorinations (b, c)

Results and Discussion

The initial investigation was explored by treating the model substrate N-(2-phenylallyl)benzamide (1a) with 10.0 equiv of Py·HF, 10 mol % of IB, and 1.2 equiv of m-CPBA in dichloromethane (DCM) at 0 °C. After 10 min, it was found that the desired fluorinated product 2a could be obtained in a very low yield (10%, Table , entry 1). When Py·HF was replaced by Et3N·3HF or KF (CsF), no desired product was detected (Table , entries 2 and 3). To our delight, when BF3·Et2O was used, the desired 2a was obtained in 83% yield within 10 min and the substrate 1a was completely converted (Table , entry 4). The experimental results indicated that using neither 2 equiv nor 5 equiv of BF3·Et2O would result in a lower yield of the fluorinated products (Table , entries 5 and 6). Using more than 10 equiv of BF3·Et2O did not show better results (Table , entry 7). Solvent screening experiments indicated that the desired fluorine product 2a could not be generated when EtOAc, Et2O, MeCN, THF, or acetone was employed as the solvent (Table , entries 5–12). The employment of 1,2-dichloroethane (DCE), CHCl3, C6H5F, C6H5Cl, and toluene did not show superior results compared with that in DCM, producing 2a in moderate to good yields (55–81%, Table , entries 13–17). A decrease in temperature would lead to a long transformation time and low yield (Table , entry 15). We then obtained the optimal conditions of the catalytic nucleophilic fluorination reaction: the reaction was carried out in DCM (0.05 M) with 10.0 equiv of BF3·Et2O, 10 mol % of IB, and 1.2 equiv of m-CPBA at 0 °C for 10 min. It should be noted that we used an excess amount of BF3·Et2O (2.0 equiv of BF3·Et2O were needed according to our possible catalytic cycle) in the reactions because the reaction rate is so fast that the substrates were completely converted within 10 min. So, the excess amount of BF3·Et2O would avoid the side reactions (such as oxidative rearrangement, oxidative cyclization). Besides, in organocatalyst-catalyzed nucleophilic fluorinations, an excess amount of fluorine source was usually needed to improve the yields of the products.[15a,15b]

Table 1

Optimization of the Reaction Conditionsa

entry	solventb	F– sourcec	yieldd (%)
1	CH2Cl2	Py·HF	10
2	CH2Cl2	Et3N·3HF	0
3	CH2Cl2	KF or CsF	0
4	CH2Cl2	BF3·Et2O	83
5e	CH2Cl2	BF3·Et2O	32
6f	CH2Cl2	BF3·Et2O	66
7g	CH2Cl2	BF3·Et2O	82
8	EtOAc	BF3·Et2O	0
9	Et2O	BF3·Et2O	0
10	MeCN	BF3·Et2O	0
11	THF	BF3·Et2O	0
12	acetone	BF3·Et2O	0
13	CHCl3	BF3·Et2O	66
14	ClCH2CH2Cl	BF3·Et2O	81
15	C6H5F	BF3·Et2O	72
16	C6H5Cl	BF3·Et2O	73
17	Toluene	BF3·Et2O	55
18h	CH2Cl2	BF3·Et2O	33

The reaction was carried out on a 0.2 mmol scale at 0 °C for 10 min.

4.0 mL of solvent was used.

10 equiv of F– source was used.

Isolated yield.

2 equiv of BF3·Et2O were used.

5 equiv of BF3·Et2O were used.

20 equiv of BF3·Et2O were used.

The reaction was carried out at −20 °C.

With the optimal reaction conditions in hand, we then investigated the substrate scope (Figure ). The reactions were carried out on a 0.2 mmol scale in 4.0 mL of DCM under the optimal conditions and isolated yields are reported. The structure of 8b was assigned by X-ray crystallography (Figure , CCDC: 2067469, see the Supporting Information), and the structure of all other products was assigned by analogy. As shown in Figure , variation of the electronic properties of substituents of N-(2-phenylallyl)benzamide with different steric parameters were tolerated, affording the desired fluorinated products with moderate to excellent yields (62–95% isolated yields). The N-(2-phenylallyl)benzamides with electron-donating group substituents exhibited higher yields than 1a upon catalytic nucleophilic fluorinations (Figure , 2b–5b vs 1b), while the electron-withdrawing group-substituted substrates displayed comparatively low yields (Figure , 6b–13b vs 1b). Especially, the substrates with strong electron-withdrawing groups underwent the process affording the fluorinated products with 62–70% yields (Figure , 12b and 13b). As for steric hindrance substrates, the corresponding fluorinated products with excellent yields were obtained (Figure , 85 and 82% yields for 3b and 9b, respectively). Substrates with heterocyclic or naphthyl groups could also be tolerated and gave the corresponding fluorinated products with high yields (Figure , 16b–19b, 30b, and 31b). Gram-scale experiment was conducted to evaluate the applicability of our fluorination method using 4a (Figure ) as the substrate, and the desired product was obtained in 85% isolated yields. The result suggested that our protocol was promising in future synthetic applications. Moreover, either electron-donating group- or electron-withdrawing group-substituted phenyl activated alkenes would also undergo fluorinations, giving the corresponding fluorinated oxazolines in good to excellent yields (Figure , 20b–31b).

Figure 1

Substrate scope of fluorination reaction using BF3·Et2O as the fluorine source.

On the basis of previous work[15a,18a,18b,18d] and our experimental results, we then proposed the plausible catalytic cycle (as shown in Scheme ). First, the catalyst precursor IB is oxidized by m-CPBA to form Ar–I=O with the formation of m-chlorobenzoic acid (m-CBA). Then, IntA is formed through the activation of Ar–I=O by BF3·Et2O.[20] The electrophilic addition of iodine(III) to the double bond of la forms IntB (anionic [BF4]− was released with the assistance of BF3). The transformation from the hypervalent iodine compound IntB to iodonium salt IntC is achieved through intermolecular nucleophilic attack of the F– ([BF4]− as the fluorine source) with the simultaneous release of anionic [BF3OBF2]−. We initially thought BF3 could attack the cation IntB directly; however, this hypothesis was denied by DFT calculations (DFT calculations carried out in our previous report using a related protocol were considered when proposing a reaction mechanism), which were less favorable in energy.[18e] The bond energy of B–F in BF3 is higher than that in [BF4]−; thus, the direct breaking of the B–F bond of BF3 to release a F–, which could attack the cation IntB directly, is unfavorable under the current reaction conditions. The cyclopropyl compound IntD is formed from IntC by the displacement of the IB by the nucleophilic attack of the aryl ring.[18b,18e] Ring opening of the spirocyclopropyl ring IntD takes place intramolecularly via a cyclization with simultaneous ring expansion to the five-membered cation, which formed the oxazoline 1b with the assistance of anionic [BF3OBF2]−. Here, the nucleophilic attack of the amide oxygen takes place regioselectively at the higher-substituted carbon atom of the cyclopropane unit.[18b,18e] In addition, Ding and co-workers have proposed a different mechanism for their oxidative arrangement because their process does not have a stoichiometric fluorine nucleophile.[11e] However, combined with our previous DFT calculations[18e] and the reaction process (the hypervalent iodine reagent-mediated fluorinations (5–10 min for our work and Gulder’s work) was faster than the oxidative rearrangement (3 h) in ref (11), which might indicate a different conversion process), we thought Gulder’s study on the mechanism is more suitable for our reaction.[18b] Besides, if Ar1 or Ar2 was changed into aliphatic substituents, the substrates could not undergo the fluorination process to afford the fluorinated products.[18e] This might be because Ar1 was essential for the formation and stabilization of the “spirocyclopropyl ring” intermediate,[18b] while the Ar2 contributed to the stabilization of the C=N bond of the products. In a word, the formation of fluorinated 2-oxazoline follows a fluorination/1,2-aryl migration/cyclization cascade.[18b,18d]

Scheme 2

Proposed Mechanism for the Catalytic Nucleophilic Fluorination Reaction

Conclusions

In conclusion, we have developed a mild and efficient catalytic nucleophilic fluorination reaction of alkenes to provide 5-fluoro-2-oxazoline derivatives in which a commonly used Lewis acid BF3·Et2O was employed as the fluorine source with iodobenzene as the catalyst precursor in the presence of m-CPBA. The corresponding fluorinated oxazolines with good to excellent yields were obtained within 10 min under the mild and metal-free process. This work expanded the scope of hypervalent iodine-catalyzed fluorinations using BF3·Et2O as a fluorine source. The studies of the applicability of this catalytic nucleophilic fluorination methodology using other substrates are going on in our group.

Experimental Section

General Information

Reagents of analytical grade were purchased from commercial suppliers, and unless otherwise noted, all commercial reagents were used without further purification. Merck F-254 silica gel plates were used for thin-layer analytical chromatography (TLC). Column chromatography purification was carried out using EMD (Merck) Silica Gel 60 (40–63 am). 1H, 13C, and 19F NMR spectra were recorded with a BRUKER Ascend 400M and a BRUKER Ascend 500 M at 25 °C. The spectra were recorded in CDCl3 as a solvent. Multiplicity was described as follows: b (broad), s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets), etc., and coupling constants (J) were given in hertz. Chemical shifts are reported in ppm relative to TMS as an internal standard. The peak around delta value of 1H NMR (7.25) is corresponding to deuterated solvent chloroform, and the peaks around delta value of 1H NMR (1.56) are corresponding to water contained in the solvent. The peak around the delta value of 13C NMR (76.7–77.4) is referenced to the appropriate NMR solvent residual peaks. High-resolution mass spectrometric data were obtained on an Agilent 6210 time-of-flight HPLC/MS spectrometer (ESI-TOF). Substrates were synthesized according to previous work.[11e]

General Procedures for Catalytic Nucleophilic Aminofluorination

The substrate (0.2 mmol) and iodobenzene (15 mol %) were mixed into the reaction tube, and then DCE (4.0 mL) was added. The mixture was cooled to 0 °C, and after stirring for 5 min at this temperature, m-CPBA (1.2 equiv) was added in one portion, followed by the addition of BF3·Et2O (10.0 equiv) dropwise. After 10 min, the reaction mixture was poured into saturated NaHCO3 (aq), and the organic layer was collected, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc-hexanes (0.5% Et3N) elution: hexanes/EtOAc (V/V) = 50:1–10:1) to provide the corresponding fluorinated products.

5-Benzyl-5-fluoro-2-phenyl-4,5-dihydrooxazole (1b)

White solid, Rf: 0.25 (PE/EtOAc (V/V) = 20:1), 42.3 mg, 83% yield. 1H NMR (400 MHz, CDCl3) δ 7.90–7.88 (m, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 7.28–7.19 (m, 5H), 4.03–3.84 (m, 2H), 3.39–3.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.6, 133.6, 132.0, 130.2, 128.7, 128.6, 128.3, 127.5, 126.7, 120.4 (d, J = 234.3 Hz), 63.3 (d, J = 28.4 Hz), 41.7 (d, J = 31.1 Hz); 19F NMR (376 MHz, CDCl3) δ −92.17. HRMS (ESI) m/z: [M + H]+ Calcd for C16H14FNO [M + H]+: 256.1132; found 256.1130.

5-Benzyl-5-fluoro-2-(p-tolyl)-4,5-dihydrooxazole (2b)

White solid, Rf: 0.23 (PE/EtOAc (V/V) = 20:1), 50.0 mg, 93% yield. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H), 7.38–7.28 (m, 7H), 4.13–3.93 (m, 2H), 3.49–3.37 (m, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 142.4, 133.7, 130.2, 129.2, 128.6, 128.2, 127.4, 124.0, 120.3 (d, J = 233.9 Hz), 63.4 (d, J = 28.2 Hz), 41.7 (d, J = 31.2 Hz), 21.6; 19F NMR (376 MHz, CDCl3) δ −92.22. HRMS (ESI) m/z: [M + H]+ Calcd for C17H16FNO [M + H]+: 270.1289; found 270.1279.

5-Benzyl-5-fluoro-2-mesityl-4,5-dihydrooxazole (3b)

White solid, Rf: 0.38 (PE/EtOAc (V/V) = 20:1), 50.5 mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ 7.25–7.16 (m, 5H), 6.78 (s, 2H), 4.05–3.86 (m, 2H), 3.36–3.25 (m, 2H), 2.20 (s, 3H), 2.11 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 163.1, 139.9, 137.4, 133.7, 130.4, 128.6, 128.3, 127.5, 124.9, 120.0 (d, J = 233.3 Hz), 63.1 (d, J = 28.3 Hz), 41.2 (d, J = 31.6 Hz), 21.2, 19.5; 19F NMR (471 MHz, CDCl3) δ −90.95. HRMS (ESI) m/z: [M + H]+ Calcd for C19H20FNO [M + H]+: 298.1602; found 298.1604.

5-Benzyl-5-fluoro-2-(4-methoxyphenyl)-4,5-dihydrooxazole (4b)

White solid, Rf: 0.13(PE/EtOAc (V/V) = 20:1), 54.2 mg, 95% yield. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H), 7.35–7.28 (m, 5H), 6.94 (d, J = 8.8 Hz, 2H), 4.09–3.89 (m, 2H), 3.85 (s, 3H), 3.46–3.34 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.5, 162.3, 133.8, 130.2, 130.0, 128.6, 127.4, 120.3 (d, J = 233.7 Hz), 119.2, 113.9, 63.4 (d, J = 28.3 Hz), 55.4, 41.7 (d, J = 31.3 Hz); 19F NMR (376 MHz, CDCl3) δ −92.30. HRMS (ESI) m/z: [M + H]+ Calcd for C17H16FNO2 [M + H]+: 286.1238; found 286.1236.

5-Benzyl-2-(3,5-dimethoxyphenyl)-5-fluoro-4,5-dihydrooxazole (5b)

White solid, Rf: 0.13 (PE/EtOAc (V/V) = 20:1), 50.9 mg, 90% yield. 1H NMR (500 MHz, CDCl3) δ 7.35–7.27 (m, 5H), 7.11 (d, J = 2.3 Hz, 2H), 6.60 (t, J = 2.3 Hz, 1H), 4.08–3.92 (m, 2H), 3.83 (s, 6H), 3.46–3.36 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 162.4, 160.7, 133.6, 130.2, 128.7, 128.5, 127.5, 120.4 (d, J = 234.3 Hz), 105.9, 104.8, 63.3 (d, J = 28.3 Hz), 55.6 (s), 41.6 (d, J = 31.1 Hz); 19F NMR (471 MHz, CDCl3) δ −92.01. HRMS (ESI) m/z: [M + H]+ Calcd for C18H18FNO [M + H]+: 284.1445; found 284.1449.

5-Benzyl-5-fluoro-2-(4-fluorophenyl)-4,5-dihydrooxazole (6b)

White solid, Rf: 0.33 (PE/EtOAc (V/V) = 20:1), 40.4 mg, 74% yield. 1H NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 8.7, 5.4 Hz, 2H), 7.27–7.20 (m, 5H), 7.04 (t, J = 8.6 Hz, 2H), 4.01–3.85 (m, 2H), 3.38–3.28 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 165.0 (d, J = 252.8 Hz), 161.6, 133.5, 130.6, 130.2, 128.7, 127.5, 123.0, 120.5 (d, J = 234.5 Hz), 115.8 (d, J = 22.1 Hz), 63.4 (d, J = 28.3 Hz), 41.6 (d, J = 31.0 Hz); 19F NMR (376 MHz, CDCl3) δ −92.29, −107.11. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13F2NO [M + H]+: 274.1038; found 274.1035.

5-Benzyl-2-(4-chlorophenyl)-5-fluoro-4,5-dihydrooxazole (7b)

White solid, Rf: 0.28 (PE/EtOAc (V/V) = 20:1), 49.1 mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.27–7.18 (m, 5H), 4.02–3.85 (m, 2H), 3.38–3.28 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 161.7, 138.3, 133.5, 130.2, 129.6, 128.9, 128.7, 127.6, 125.2, 120.5 (d, J = 235.0 Hz), 63.4 (d, J = 28.2 Hz), 41.6 (d, J = 30.9 Hz); 19F NMR (471 MHz, CDCl3) δ −92.14. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13FNOCl [M + H]+: 290.0742; found 290.0737.

5-Benzyl-2-(4-bromophenyl)-5-fluoro-4,5-dihydrooxazole (8b)

White solid, Rf: 0.28 (PE/EtOAc (V/V) = 20:1), 53.4 mg, 80% yield. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.27–7.20 (m, 5H), 4.01–3.84 (m, 2H), 3.38–3.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.8, 133.4, 131.9, 130.2, 129.8, 128.7, 127.6, 126.8, 125.6, 120.5 (d, J = 235.0 Hz), 63.4 (d, J = 28.3 Hz), 41.6 (d, J = 30.9 Hz); 19F NMR (376 MHz, CDCl3) δ −92.14. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13FNOBr [M + H]+: 334.0237, 336.0218; found 334.0232, 336.0215.

5-Benzyl-2-(2-bromophenyl)-5-fluoro-4,5-dihydrooxazole (9b)

White solid, Rf: 0.28 (PE/EtOAc (V/V) = 20:1), 54.6 mg, 82% yield. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.39–7.28 (m, 7H), 4.16–3.99 (m, 2H), 3.47–3.37 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 161.4, 134.3, 133.5, 132.2, 131.6, 130.2, 128.7, 128.2, 127.5, 127.2, 122.0, 120.2 (d, J = 235.2 Hz), 63.6 (d, J = 28.2 Hz), 41.6 (d, J = 30.9 Hz); 19F NMR (376 MHz, CDCl3) δ −92.44. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13FNOBr [M + H]+: 334.0237, 336.0218; found 334.0233, 336.0214.

5-Benzyl-2-(3-bromophenyl)-5-fluoro-4,5-dihydrooxazole (10b)

White solid, Rf: 0.33 (PE/EtOAc (V/V) = 20:1), 52.6 mg, 79% yield. 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.36–7.30 (m, 6H), 4.10–3.94 (m, 2H), 3.46–3.36 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 161.3, 135.0, 133.4, 131.3, 130.2, 130.1, 128.7, 128.5, 127.6, 126.9, 122.6, 120.6 (d, J = 235.5 Hz), 63.2 (d, J = 28.6 Hz), 41.6 (d, J = 30.8 Hz); 19F NMR (471 MHz, CDCl3) δ −92.11. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13FNOBr [M + H]+: 334.0237, 336.0218; found 334.0225, 336.0188.

5-Benzyl-5-fluoro-2-(4-nitrophenyl)-4,5-dihydrooxazole (11b)

White solid, Rf: 0.15 (PE/EtOAc (V/V) = 20:1), 52.8 mg, 88% yield. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H), 7.29–7.19 (m, 5H), 4.09–3.89 (m, 2H), 3.42–3.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.7, 149.8, 133.2, 132.4, 130.2, 129.3, 128.8, 127.7, 123.8, 120.8 (d, J = 236.2 Hz), 63.6 (d, J = 28.4 Hz), 41.6 (d, J = 30.7 Hz); 19F NMR (376 MHz, CDCl3) δ −92.01. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13FN2O3 [M + H]+: 301.0983; found 301.0980.

5-benzyl-5-fluoro-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (12b)

White solid, Rf: 0.35 (PE/EtOAc (V/V) = 20:1), 45.2 mg, 70% yield. 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.28–7.18 (m, 5H), 4.05–3.89 (m, 2H), 3.39–3.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 133.53 (q, J = 32.6 Hz), 133.32 (s).13C NMR (126 MHz, CDCl3) δ 161.3, 133.53 (q, J = 32.6 Hz), 133.3, 130.2, 130.0, 128.7, 128.7, 127.6, 125.5, 123.7 (q, J = 272.6 Hz), 120.6 (d, J = 235.5 Hz), 63.4 (d, J = 28.3 Hz), 41.6 (d, J = 30.8 Hz); 19F NMR (376 MHz, CDCl3) δ −63.04 (3F), 92.08 (1F). HRMS (ESI) m/z: [M + H]+ Calcd for C17H13F4NO [M + H]+: 324.1006; found 324.1002.

5-Benzyl-2-(3,5-bis(trifluoromethyl)phenyl)-5-fluoro-4,5-dihydrooxazole (13b)

White solid, Rf: 0.58 (PE/EtOAc (V/V) = 20:1), 48.5 mg, 62% yield. 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 2H), 7.94 (s, 1H), 7.29–7.23 (m, 5H), 4.07-3.91 (m, 2H), 3.44–3.31 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 159.9, 133.1, 132.3 (q, J = 34.0 Hz), 130.1, 129.0, 128.8, 128.3, 127.7, 125.3, 122.9 (q, J = 272.8 Hz), 121.0 (d, J = 236.8 Hz), 63.4 (d, J = 28.4 Hz), 41.5 (d, J = 30.4 Hz); 19F NMR (471 MHz, CDCl3) δ −63.02 (6F), −91.90 (1F). HRMS (ESI) m/z: [M + H]+ Calcd for C18H12F7NO [M + H]+: 392.0880; found 392.0880.

5-Benzyl-2-(4-(tert-butyl)phenyl)-5-fluoro-4,5-dihydrooxazole (14b)

White solid, Rf: 0.28 (PE/EtOAc (V/V) = 20:1), 57.8 mg, 93% yield. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.26–7.17 (m, 5H), 4.01–3.84 (m, 2H), 3.37–3.28 (m, 2H), 1.26 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 162.6, 155.6, 133.7, 130.2, 128.7, 128.1, 127.5, 125.5, 123.8, 120.3 (d, J = 233.9 Hz), 63.2 (d, J = 28.2 Hz), 41.6 (d, J = 31.2 Hz), 35.1, 31.2; 19F NMR (471 MHz, CDCl3) δ −92.03. HRMS (ESI) m/z: [M + H]+ Calcd for C20H22FNO [M + H]+: 312.1758; found 312.1756.

5-Benzyl-2-(3,5-di-tert-butylphenyl)-5-fluoro-4,5-dihydrooxazole (15b)

White solid, Rf: 0.45 (PE/EtOAc (V/V) = 20:1), 66.1 mg, 90% yield. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 1.8 Hz, 2H), 7.60 (t, J = 1.8 Hz, 1H), 7.36–7.28 (m, 5H), 4.10–3.95 (m, 2H), 3.50–3.37 (m, 2H), 1.36 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 163.5, 151.3, 133.7, 130.2, 128.7, 127.5, 126.4, 125.8, 122.6, 120.4 (d, J = 234.2 Hz), 63.0 (d, J = 28.3 Hz), 41.7 (d, J = 31.2 Hz), 35.0, 31.4; 19F NMR (471 MHz, CDCl3) δ −91.96. HRMS (ESI) m/z: [M + H]+ Calcd for C24H30FNO [M + H]+: 368.2384; found 368.2383.

5-Benzyl-5-fluoro-2-(naphthalen-2-yl)-4,5-dihydrooxazole (16b)

White solid, Rf: 0.23 (PE/EtOAc (V/V) = 20:1), 51.9 mg, 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 7.3 Hz, 1H), 7.90–7.86 (m, 2H), 7.60-7.53 (m, 2H), 7.38–7.29 (m, 5H), 4.18–3.98 (m, 2H), 3.53–3.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.6, 135.0, 133.7, 132.6, 130.2, 129.1, 129.0, 128.7, 128.4, 127.9 (2C), 127.5, 126.8, 124.4, 124.1, 120.5 (d, J = 234.2 Hz), 63.5(d, J = 28.2 Hz), 41.7 (d, J = 31.1 Hz); 19F NMR (376 MHz, CDCl3) δ −92.00. HRMS (ESI) m/z: [M + H]+ Calcd for C20H16FNO [M + H]+: 306.1289; found 306.1280.

5-Benzyl-5-fluoro-2-(naphthalen-1-yl)-4,5-dihydrooxazole (17b)

White solid, Rf: 0.38 (PE/EtOAc (V/V) = 20:1), 53.1 mg, 87% yield. 1H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 7.3 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.54–7.49 (m, 1H), 7.47–7.41 (m, 2H), 7.29–7.19 (m, 5H), 4.20–4.00 (m, 2H), 3.44–3.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.4, 133.7, 132.7, 131.1, 130.3, 129.6, 128.8, 128.7, 128.6, 127.7, 127.5, 126.4, 126.2, 124.7, 123.1, 119.4 (d, J = 233.5 Hz), 64.0 (d, J = 28.4 Hz), 41.6 (d, J = 31.2 Hz); 19F NMR (376 MHz, CDCl3) δ −92.26. HRMS (ESI) m/z: [M + H]+ Calcd for C20H16FNO [M + H]+: 306.1289; found 306.1282.

5-Benzyl-5-fluoro-2-(furan-2-yl)-4,5-dihydrooxazole (18b)

White solid, Rf: 0.13 (PE/EtOAc (V/V) = 20:1), 39.2 mg, 80% yield. 1H NMR (500 MHz, CDCl3) δ 7.50 (s, 1H), 7.27–7.19 (m, 5H), 6.99 (s, 1H), 6.44 (s, 1H), 4.01–3.85 (m, 2H), 3.38–3.26 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 154.7, 146.0, 141.8, 133.4, 130.2, 128.7, 127.6, 121.4, 119.5, 113.7 (d, J = 491.7 Hz), 63.0 (d, J = 28.1 Hz), 41.5 (d, J = 30.6 Hz); 19F NMR (376 MHz, CDCl3) δ −92.55. HRMS (ESI) m/z: [M + H]+ Calcd for C14H12FNO2 [M + H]+: 246.0925; found 246.0929.

5-Benzyl-5-fluoro-2-(thiophen-2-yl)-4,5-dihydrooxazole (19b)

White solid, Rf: 0.20 (PE/EtOAc (V/V) = 20:1), 44.4 mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H), 7.42 (d, J = 4.7 Hz, 1H), 7.25–7.18 (m, 5H), 7.02 (s, 1H), 3.99–3.84 (m, 2H), 3.38–3.26 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 158.3, 133.5, 131.2, 130.8, 130.2, 129.1, 128.7, 127.8, 127.6, 120.7 (d, J = 235.7 Hz), 63.3 (d, J = 28.2 Hz), 41.6 (d, J = 30.8 Hz); 19F NMR (376 MHz, CDCl3) δ −92.25. HRMS (ESI) m/z: [M + H]+ Calcd for C14H12FNOS [M + H]+: 262.0696; found 262.0695.

5-Fluoro-5-(naphthalen-2-yl-methyl)-2-phenyl-4,5-dihydrooxazole (20b)

White solid, Rf: 0.45 (PE/EtOAc (V/V) = 20:1), 48.8 mg, 80% yield. 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz, 2H), 7.84–7.81 (m, 3H), 7.77 (s, 1H), 7.53–7.42 (m, 6H), 4.13–3.99 (m, 2H), 3.69–3.53 (m, 2H).13C NMR (125 MHz, CDCl3) δ 161.3, 133.4, 132.6, 131.9, 129.1, 128.5, 128.3, 128.2, 128.0, 127.7(2C), 126.8, 126.2, 126.0, 120.6 (d, J = 235.7 Hz), 63.6 (d, J = 28.2 Hz), 41.8 (d, J = 31.0 Hz).19F NMR (471 MHz, CDCl3) δ −91.8. HRMS (ESI) m/z: [M + H]+ Calcd for C20H16FNO [M + H]+: 306.1289; found 306.1289.

5-(4-Chlorobenzyl)-5-fluoro-2-phenyl-4,5-dihydrooxazole (21b)

White solid, Rf: 0.55 (PE/EtOAc (V/V) = 20:1), 49.1 mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.27–7.25 (m, 2H), 4.12–3.90 (m, 2H), 3.38 (d, J = 14.5 Hz, 2H).13C NMR (125 MHz, CDCl3) δ 162.4, 133.6, 132.1, 131.9, 131.5, 128.8, 128.6, 128.2, 126.6, 119.9 (d, J = 234.4 Hz), 63.6 (d, J = 28.4 Hz), 41.1 (d, J = 31.6 Hz).19F NMR (471 MHz, CDCl3) δ −92.69. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13ClFNO [M + H]+: 290.0742; found 290.0742.

5-Fluoro-5-(4-fluorobenzyl)-2-phenyl-4,5-dihydrooxazole (22b)

White solid, Rf: 0.56 (PE/EtOAc (V/V) = 20:1), 45.3 mg, 83% yield. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.4 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.29 (dd, J = 8.3, 5.5 Hz, 2H), 7.02 (t, J = 8.6 Hz, 2H), 4.12–3.94 (m, 2H), 3.44–3.32 (m, 2H).13C NMR (125 MHz, CDCl3) δ 162.4, 162.3 (d, J = 243.7 Hz), 131.9, 131.8, 128.5, 128.2, 126.7, 126.1, 120.1 (d, J = 233.9 Hz), 115.6, 63.5 (d, J = 28.3 Hz), 40.9 (d, J = 31.5 Hz).19F NMR (376 MHz, CDCl3) δ −92.83 (1F), -115.14 (1F). HRMS (ESI) m/z: [M + H]+ Calcd for C16H13F2NO [M + H]+: 274.1038; found 274.1044.

5-(3-Bromobenzyl)-5-fluoro-2-phenyl-4,5-dihydrooxazole (23b)

White solid, Rf: 0.50 (PE/EtOAc (V/V) = 20:1), 53.4 mg, 80% yield. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.4 Hz, 2H), 7.55–7.50 (m, 2H), 7.46–7.42 (m, 3H), 7.27 (d, J = 7.4 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 4.15–3.91 (m, 2H), 3.37 (m, 2H).13C NMR (100 MHz, CDCl3) δ 162.5, 133.2, 132.0, 130.7, 130.2, 128.6, 128.3, 126.6, 122.6, 119.8 (d, J = 234.5 Hz), 63.6 (d, J = 28.3 Hz), 41.3 (d, J = 31.3 Hz). 19F NMR (376 MHz, CDCl3) δ −92.62. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13BrFNO [M + H]+: 334.0217; found 334.0213.

5-Fluoro-5-(4-methylbenzyl)-2-phenyl-4,5-dihydrooxazole (24b)

White solid, Rf: 0.35 (PE/EtOAc (V/V) = 20:1), 42.5 mg, 79% yield. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.46–7.42 (m, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 4.10–3.91 (m, 2H), 3.43–3.31 (m, 2H), 2.33 (s, 3H).13C NMR (100 MHz, CDCl3) δ 162.4, 137.1, 131.8, 130.1, 129.4, 128.5, 128.2, 126.9, 126.1, 120.5 (d, J = 233.9 Hz), 63.4 (d, J = 28.2 Hz), 41.2 (d, J = 31.1 Hz), 21.1. 19F NMR (376 MHz, CDCl3) δ −92.20. HRMS (ESI) m/z: [M + H]+ Calcd for C17H16FNO [M + H]+: 270.1300; found 270.1289.

5-(3,5-Dimethylbenzyl)-5-fluoro-2-phenyl-4,5-dihydrooxazole (25b)

White solid, Rf: 0.34 (PE/EtOAc (V/V) = 20:1), 48.1 mg, 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 6.96 (s, 2H), 6.93 (s, 1H), 4.09–3.95 (m, 2H), 3.44–3.29 (m, 2H), 2.30 (s, 6H).13C NMR (100 MHz, CDCl3) δ 162.4, 138.1, 133.4, 131.8, 129.1, 128.5, 128.2, 128.0, 126.9, 120.5 (d, J = 234.2 Hz), 63.4 (d, J = 28.2 Hz), 41.6 (d, J = 31.0 Hz), 21.3.19F NMR (376 MHz, CDCl3) δ −92.24. HRMS (ESI) m/z: [M + H]+ Calcd for C18H18FNO [M + H]+: 284.1452; found 284.1445.

5-Fluoro-5-(naphthalen-2-yl-methyl)-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (26b)

White solid, Rf: 0.30 (PE/EtOAc (V/V) = 20:1), 48.5 mg, 65% yield. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H), 7.87–7.83 (m, 3H), 7.79 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.52–7.46 (m, 3H), 4.16–4.07 (m, 2H), 3.62 (dd, J = 14.5, 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 161.2, 133.4, 132.6, 130.9, 129.2, 128.6, 128.4, 127.9, 127.7(2C), 126.3, 126.1, 125.5 (q, J = 4.0 Hz), 120.7 (d, J = 235.7 Hz), 63.6 (d, J = 28.2 Hz), 41.8 (d, J = 31.0 Hz); 19F NMR (376 MHz, CDCl3) δ −91.71 (1F), −63.06 (3F). HRMS (ESI) m/z: [M + H]+ Calcd for C21H15F4NO [M + H]+: 374.1122; found 374.1127.

2-(4-Chlorophenyl)-5-fluoro-5-(naphthalen-2-yl-methyl)-4,5-dihydrooxazole (27b)

White solid, Rf: 0.25 (PE/EtOAc (V/V) = 20:1), 55.6 mg, 82% yield. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.76 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 4.08-4.01 (m, 2H), 3.62 (dd, J = 14.6, 7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 161.5, 138.2, 133.4, 132.6, 131.0, 129.6, 129.1, 128.9, 128.3, 128.0, 127.7 (2C), 126.3, 126.1, 125.3, 120.6 (d, J = 233.7 Hz), 63.6 (d, J = 27.5 Hz), 41.8 (d, J = 31.0 Hz); 19F NMR (376 MHz, CDCl3) δ −91.83. HRMS (ESI) m/z: [M + H]+ Calcd for C20H15ClFNO [M + H]+: 340.0862; found 340.0875.

2-(4-Bromophenyl)-5-fluoro-5-(naphthalen-2-yl-methyl)-4,5-dihydrooxazole (28b)

White solid, Rf: 0.25 (PE/EtOAc (V/V) = 20:1), 58.4 mg, 76% yield. 1H NMR (500 MHz, CDCl3) δ 7.83–7.80 (m, 5H), 7.76 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H),7.44 (d, J = 8.5 Hz, 1H), 4.07–4.00 (m, 2H), 3.62 (dd, J = 14.6, 7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 161.6, 133.4, 132.6, 131.8, 131.0, 129.7, 129.1, 128.3, 128.0, 127.7(2C), 126.7, 126.3, 126.1, 125.7, 120.6 (d, J = 233.8 Hz), 63.6 (d, J = 27.5 Hz), 41.8 (d, J = 31.6 Hz); 19F NMR (376 MHz, CDCl3) δ −91.79. HRMS (ESI) m/z: [M + H]+ Calcd for C20H15BrFNO [M + H]+: 384.0371; found 384.0370.

5-Fluoro-5-(4-methylbenzyl)-2-(p-tolyl)-4,5-dihydrooxazole (29b)

White solid, Rf: 0.25 (PE/EtOAc (V/V) = 20:1), 40.8 mg, 72% yield. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 2H), 7.24–7.19 (m, 4H), 7.12 (d, J = 8.0 Hz, 2H), 4.01–3.89 (m, 2H), 3.42–3.30 (m, 2H), 2.40 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 142.3, 137.1, 130.6, 130.0, 129.3, 129.2, 128.2, 124.0, 120.6 (d, J = 233.8 Hz), 63.3 (d, J = 28.3 Hz), 41.2 (d, J = 31.4 Hz), 21.6, 21.1; 19F NMR (376 MHz, CDCl3) δ −92.32. HRMS (ESI) m/z: [M + H]+ Calcd for C18H18FNO [M + H]+: 284.1453; found 284.1445.

5-Fluoro-2-(furan-2-yl)-5-(4-methylbenzyl)-4,5-dihydrooxazole (30b)

White solid, 38.5 mg, 74% yield. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 3.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 3.4 Hz, 1H), 6.51 (dd, J = 3.5 Hz, 1H), 4.03–3.89 (m, 2H), 3.41–3.27 (m, 2H), 2.32 (s, 3H).13C NMR (100 MHz, CDCl3) δ 154.7, 145.9, 141.9, 137.2, 130.3, 130.0, 129.4, 120.6 (d, J = 233.8 Hz), 115.4, 111.7, 63.1 (d, J = 28.2 Hz), 41.0 (d, J = 30.6 Hz), 21.1; 19F NMR (376 MHz, CDCl3) δ −92.64. HRMS (ESI) m/z: [M + H]+ Calcd for C15H14FNO2 [M + H]+: 260.1093; found 260.1081.

5-Fluoro-5-(4-methylbenzyl)-2-(thiophen-2-yl)-4,5-dihydrooxazole (31b)

White solid, 38.1 mg, 69% yield. 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 3.4 Hz, 1H), 7.48 (d, J = 3.4 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.09 (dd, J = 3.4 Hz, 1H), 4.01–3.90 (m, 2H), 3.40–3.29 (m, 2H), 2.32 (s, 3H); δ 13C NMR (125 MHz, CDCl3) δ 158.2, 137.2, 131.0, 130.5, 130.4, 130.0, 129.4, 127.7, 120.6 (d, J = 233.5 Hz), 63.3 (d, J = 30.9 Hz), 41.1 (d, J = 30.9 Hz), 21.1; 19F NMR (471 MHz, CDCl3) δ −92.35. HRMS (ESI) m/z: [M + H]+ Calcd for C15H14FNOS [M + H]+: 276.0861; found 276.0853.