MgBr2OEt2-promoted direct Aldol reactions of S-aryl 2-fluoroethanethioate

MgBr2OEt2-promoted direct Aldol reactions of S-aryl 2-fluoroethanethioate

Journal of Fluorine Chemistry 227 (2019) 109368 Contents lists available at ScienceDirect Journal of Fluorine Chemistry journal homepage: www.elsevi...

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Journal of Fluorine Chemistry 227 (2019) 109368

Contents lists available at ScienceDirect

Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor

MgBr2%OEt2-promoted direct Aldol reactions of S-aryl 2-fluoroethanethioate Zi-bin Qiu, Xin-feng Ren , Xiang-Yu Chen, Ling-yan Chen, Jian Ji, Ya Li ⁎



T

College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai, 201620, China

ARTICLE INFO

ABSTRACT

Keywords: Fluorine Fluoroalkylation Aldol reaction Thioester Enolization

MgBr2%OEt2-promoted direct Aldol reactions of S-aryl 2-fluoroethanethioates has been developed. A wide range of aromatic aldehydes is successfully used to give the corresponding α-fluoro-β-hydroxythioesters in good yields.

1. Introduction The Aldol reaction, one of the most important reactions in organic synthesis, has been widely used for regioselective carbon-carbon bond formations. The Aldol reaction of simple thioesters provides an efficient method for the synthesis of synthetically valuable β-hydroxythioesters [1–3]. Because of the versatile transformations of the thioester group, the Aldol reaction of thioesters has found widespread use in the natural and unnatural product synthesis [4–8]. Not surprisingly, a number of reports have been documented on the Aldol reaction of thioesters. In general, the reaction is classified into two types: use of preformed enolates (especially the boron enolates) to react with the carbonyl acceptor [9–12], and use of in situ generated metal enolates to react with the carbonyl acceptor [13–19]. In the latter case, a Lewis acid is generally used in combination with a Lewis base to promote the formation of thioesters enolates. Organofluorine molecules are highly important in the pharmaceutical, agrochemical and material science industries because of the unique physical and chemical benefits caused by the incorporation of fluorine(s) [20,21]. Nowadays, approximately 30% of all agrochemicals and 20% of all pharmaceuticals contain at least one fluorine atom [22,23]. Not surprisingly, intense research efforts have been devoted to the construction of structurally diverse organofluorine compounds. In this context, considerable progress toward the synthesis of α-fluoro-βhydroxycarbonyl compounds has been achieved, through the Aldol reaction of α-fluorocarbonyl compounds (including α-fluoroketones [24–29], α-fluorocarboxylate esters [30–34], and their equivalents (such as fluorinated silyl enol ethers [35–43])). In sharp contrast, the use of α-fluorothioesters in the Aldol reaction has been scarcely explored. To the best of knowledge, there is only one paper documenting



the use of 2-fluoropropanethioates in the synthesis of α-fluoro-β-hydroxythioesters, where the 2-fluoropropanethioates is deprotonated by LDA to generate the corresponding metal fluoroenolates (Scheme 1a) [44]. As part of our continuing effort in the functionalization of αfluorocarbonyl compounds [45–47], herein we report MgBr2·OEt2-promoted Aldol reactions of S-aryl 2-fluoroethanethioate (Scheme 1b). The reaction enabled the synthesis of a series of α-fluoro-β-hydroxythioesters under mild reaction conditions. 2. Results and discussion At the outset, S-(p-tolyl) 2-fluoroethanethioates 2 was chosen as the model substrate and its Aldol reaction with benzaldehyde 1a was examined (Table 1). Using LiHMDS as the base, 2-fluoroethanethioates 1a was rapidly consumed, but the desired Aldol product 3aa was not obtained (entry 1). This result indicated that the trisubstituted fluoroenolate of α-fluoroethanethioates 2a was kinetically very unstable under the reaction conditions. We then investigated the use of a relatively weakly basic amine in combination with a Lewis-acid to effect αdeprotonation. While reagent TiCl4-iPr2NEt had no effect on the reaction (entry 2), reagent MgBr2·OEt2-iPr2NEt enabled the reaction to proceed and gave the corresponding product 3a in 72% yield, albeit with no stereoselectivity (entry 3). Considering that increasing the steric bulk of the S-aryl component may result in an increase in the stereoselectivity, we tried α-fluoroethanethioates 2b and 2c which are derived from more sterically-demanding 2,6-dimethylbenzenethiol and 2,4,6-triisopropylbenzenethiol, respectively (entries 4 and 5). To our delight, 2-fluoroethanethioates 2b and 2c each gave the expected Aldol product 3 in a good yield with a higher diastereoselectivity (entry 4: 3ab, 67% yield, 67:33 dr; entry 5: 3ac, 71% yield, 66:34 dr). Using

Corresponding author. E-mail addresses: [email protected] (X.-f. Ren), [email protected] (Y. Li).

https://doi.org/10.1016/j.jfluchem.2019.109368 Received 26 June 2019; Received in revised form 29 August 2019; Accepted 3 September 2019 Available online 04 September 2019 0022-1139/ © 2019 Elsevier B.V. All rights reserved.

Journal of Fluorine Chemistry 227 (2019) 109368

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4. Experimental 4.1. General DCM was dried with 4 Å molecular sieves. Flash chromatography was performed on silica gel with petroleum ether/ethyl acetate as the eluent. Melting points were measured on an electrothermal digital melting point apparatus. 1H, 13C and 19F NMR spectra were recorded on a 400 or 500 MHz NMR spectrometer. IR spectra were recorded on an FT-IR spectrometer by using KBr pellets. HRMS data were obtained on an ESI-FTMS mass spectrometer.

Scheme 1. Aldol reactions of α-fluorothioesters.

4.2. Synthesis of 2 (general procedure)

MgBr2·OEt2 as the Lewis acid, further screening of reaction variables, which included the reaction solvent (THF, DMF or CHCl3, entries 6–8), base (2,6-lutidine, entry 9) and the reaction temperature (entry 10), did not improve the reaction. Using the optimized reaction conditions, we then investigated the substrate scope with respect to aldehydes (Table 2). Generally, aromatic aldehydes proved to be competent substrates, giving the desired products (3ab–3pb) in a moderate to very good yield with low syn/anti selectivity. Notably, the reaction conditions tolerated a wide range of groups, including methyl, methoxyl, phenyl, halogen(s), methoxycarbonyl, cynao, and nitro. For 4-substituted benzaldehydes, good yields were obtained when an electron-donating (3bc–3dc) or electronwithdrawing group (3eb–3ic) was located. However, strong electronwithdrawing group (3hc and 3ic) led to diminished stereoselectivity: the 4-nitro substrate gave the corresponding product 3ic in 77% yield with a syn/anti ratio of 50:50. The 3-substituted and 3,4-disubstituted benzaldehydes also reacted smoothly to give the corresponding products (3ib–3ob) in good yields with a syn/anti ratio ranging from 63:37 to 71:29. In addition, 2-methylbenzaldehyde (2p) was successfully used, affording the corresponding product 3pb in 80% yield with a syn/ anti ratio of 67:33. These results suggested that steric hindrance had no noticeable effects on the reaction. What’s more, cinnamaldehyde (2q) could also participate in the reaction, giving product (3qb) in 63% yield with a syn/anti ratio of 63:37. Finally, aliphatic butyraldehyde (2r) failed to give the desired Aldol product, which was probably caused by enolization. The syn- and anti-stereomers (shown in Table 2) could be easily separated from each other via flash column chromatography. In the 19F NMR spectrum, the fluorine atom of the steromers absorbs around −200 ppm, with the absorption of the minor stereomer at a lower field. The relative configuration of the minor stereomer of product 3hc was determined by single-crystal X-ray analysis [49], where the fluoro and hydroxyl group were found to adopt an anti configuration. By analogy, a syn configuration was assigned to the major stereomer of product 3. To demonstrate the utility of the method for preparing useful organofluorine compounds, compound syn-3nb was used as a representative substrate for further transformations (Scheme 2). Using MeOH as the solvent, compound syn-3 nb reacted smoothly with benzylamine 4a and methylamine 4b at 0 °C and gave the corresponding amide 5a and 5b in 55% and 61% yield, respectively.

Under a N2 atmosphere, dicyclohexylcarbodiimide (1.2 mmol) in DCM (10 mL) was added dropwisely to a mixture of the specific thiol (1.0 mmol), 2-fluoroacetic acid (1.2 mmol), 4-dimethylaminopyridine (0.2 mmol) at 0 °C. The reaction mixture was kept stirring for 10 h at 0 °C and concentrated under a reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/ ethyl acetate = 30:1) to give the corresponding 2-fluorothioesters 2. Caution: the reaction should be carried out in a well-ventilated hood because of the highly toxic nature of 2-fluoroacetic acid derivatives. 4.2.1. S-(p-tolyl) 2-fluoroethanethioate (2a) Colorless oil. Yield = 75%. 1H NMR (400 MHz, CDCl3) δ = 7.37–7.32 (m, 2 H), 7.31–7.26 (m, 2 H), 5.01 (d, 2JHF =44.0 Hz, 2 H), 2.42 (s, 3 H). 19F NMR (376 MHz, CDCl3) δ = −225.3 (t, 2JHF =45.1 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.8 (d, 2JCF =25.2 Hz), 140.3 (s), 134.8 (s), 130.3 (s), 121.6 (d, JCF =5.0 Hz), 84.7 (d, 1JCF =188.9 Hz), 21.3 (s). IR (cm−1): 2923, 1772, 1699, 1598, 1577, 1507, 1115, 805. MS (ESI) m/z: 185.0 [M+H]+. HRMS (ESI) m/z: calcd for C9H9FNaOS+ [M + Na]+ 207.0256, found 207.0250. 4.2.2. S-(2,6-dimethylphenyl) 2-fluoroethanethioate (2b) Colorless oil. Yield = 72%. 1H NMR (400 MHz, CDCl3) δ = 7.32–7.28 (m, 1 H), 7.22 (s, 1 H), 7.20 (s, 1 H), 5.02 (d, 2JHF = 48.0 Hz, 2 H), 2.39 (s, 6 H). 19F NMR (376 MHz, CDCl3) δ = −224.0 (t, 2JHF = 45.1 Hz). 13C NMR (101 MHz, CDCl3) δ = 194.2 (d, 2JCF =25.2 Hz), 143.1 (s), 130.2 (s), 128.5 (s), 124.5 (d, JCF = 4.0 Hz), 84.9 (d, 1JCF =188.9 Hz), 21.6 (s). IR (cm−1): 2926, 1694, 1654, 1617, 1577, 1507, 1108, 782. MS (ESI) m/z: 199.1 [M+H]+. HRMS (ESI) m/z: calcd for C10H11FNaOS+ [M + Na]+ 221.0412, found 221.0407. 4.2.3. S-(2,4,6-triisopropylphenyl) 2-fluoroethanethioate (2c) Colorless oil. Yield = 73%. 1H NMR (400 MHz, CDCl3) δ = 7.15 (s, 2 H), 5.03 (d, 2JHF = 48.0 Hz, 2 H), 3.45–3.32 (m, 2 H), 3.02–2.89 (m, 1 H), 1.31 (d, 3J = 8.0 Hz, 6 H), 1.23 (d, 3J =4.0 Hz, 12 H). 19F NMR (376 MHz, CDCl3) δ = −223.8 (t, 2JHF =48.9 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.6 (d, 2JCF =25.2 Hz), 152.8 (s), 151.6 (s), 122.3 (s), 118.8 (d, JCF = 4.0 Hz), 84.9 (d, 1JCF =188.9 Hz), 34.4 (s), 32.0 (s), 24.3 (s), 23.8 (s), 23.5 (s). IR (cm−1): 2961, 1695, 1654, 1596, 1577, 1507, 1109, 776. MS (ESI) m/z: 297.2 [M+H]+. HRMS (ESI) m/z: calcd for C17H25FNaOS+ [M + Na]+ 319.1508, found 319.1502.

3. Conclusions

4.3. Synthesis of 3 (general procedure)

We have developed MgBr2·OEt2-promoted Aldol reaction of S-aryl 2fluoroethanethioates, which allows for the synthesis of a wide range of α-fluoro-β-hydroxythioesters. This method has the advantage of using commercially available reagents and mild reaction conditions, and it is operationally simple.

Under a N2 atmosphere, 2-fluoroethanethioate (2b, 0.6 mmol) in DCM (1.0 mL) was added to a mixture of MgBr2·OEt2 (1.0 mmol), aromatic aldehyde (1, 0.5 mmol), N, N-Diisopropylethylamine (1.5 mmol) and DCM (1.0 mL) at rt. After 5 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the corresponding product 3. 2

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Table 1 Optimization of the Aldol reaction of 2-fluoroethanethioate 2 and benzaldehyde 1aa.

entry

2

reaction conditions

product

yield (%)b

syn/anti

1d 2 3 4 5 6 7 8 9 10

2a 2a 2a 2b 2c 2c 2c 2c 2c 2c

LiHMDS, THF, −70 °C TiCl4, iPr2NEt, DCM, 25 °C MgBr2·OEt2, iPr2NEt, DCM, 25 °C MgBr2·OEt2, iPr2NEt, DCM, 25 °C MgBr2·OEt2, iPr2NEt, DCM, 25 °C MgBr2·OEt2, iPr2NEt, THF, 25 °C MgBr2·OEt2, iPr2NEt, DMF, 25 °C MgBr2·OEt2, iPr2NEt, CHCl3, 25 °C MgBr2·OEt2, 2,6-lutidine, CHCl3, 25 °C MgBr2·OEt2, iPr2NEt, DCM, 0 °C

3aa 3aa 3aa 3ab 3ac 3ac 3ac 3ac 3ac 3ac

0 0 72 67 71 51 0 57 32 67

n. n. 50:50 67:33 66:34 67:33 n. 67:33 67:33 67:33

c

a Reaction conditions: 2-fluoroethanethioate (2, 0.6 mmol) in solvent (1.0 mL) was added to a mixture of Lewis acid (TiCl4, or MgBr2%OEt2, 1.0 mmol), benzaldehyde (1a, 0.5 mmol), base (N, N-diisopropylethylamine, or 2,6-lutidine, 1.5 mmol) and solvent (1.0 mL) at the specified temperature. The reaction mixture was monitored by TLC, followed by routine workup. b Isolated yield of the combined syn- and anti-3. c The syn/anti ratio was determined by 19F NMR on the crude product 3. d LiHMDS (1.0 mol/L in THF, 0.6 mmol) was added to a mixture of 2-fluoroethanethioate (2, 0.6 mmol), benzaldehyde (1a, 0.5 mmol) and THF (1.0 mL) at −70 °C.

Table 2 The Aldol reaction of S-aryl 2-fluoroethanethioate with aldehydesa,b,c.

a

Reaction conditions: 2-fluoroethanethioate (2, 0.6 mmol) in DCM (1.0 mL) was added to a mixture of MgBr2%OEt2 (1.0 mmol), aldehyde (1a, 0.5 mmol), N, Ndiisopropylethylamine (1.5 mmol) and DCM (1.0 mL) at rt. The reaction mixture was kept stirring for 10 h, followed by routine workup. b The yield referred to the isolated yield of the syn- and anti-3. c The dr was determined by 19F NMR spectroscopy on the crude product 3. d 2b was used. e 2c was used. 3

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[M+H]+. HRMS (ESI) m/z: calcd for C25H33FO2SNa+ [M + Na]+ 439.2078, found 439.2077. 4.3.5. S-(2,4,6-triisopropylphenyl) 2-fluoro-3-hydroxy-3-(4-methoxyphenyl)- propanethioate (syn-3cc) Colorless solid. m. p. 109–110 °C. 1H NMR (400 MHz, CDCl3) δ = 7.44–7.37 (m, 2 H), 7.12 (s, 2 H), 6.99–6.91 (m, 2 H), 5.18 (d, 2J =20.0 Hz, 1 H), 5.17 (dd, 2J =48.0 Hz, 3J =4.0 Hz, 1 H), 3.85 (s, 3 H), 3.31–3.19 (m, 2 H), 2.99–2.89 (m, 1 H), 2.70 (d, 3J = 4.0 Hz, 1 H), 1.30 (d, 3J = 4.0 Hz, 6 H), 1.18 (dd, 2J =12.0 Hz, 3J =8.0 Hz, 12 H). 19F NMR (376 MHz, CDCl3) δ = −199.3 (dd, 2JHF = 48.3 Hz, 3 JHF = 22.1 Hz). 13C NMR (101 MHz, CDCl3) δ = 196.9 (d, 2JCF =35.4 Hz), 159.8 (s), 152.9 (s), 152.6 (s), 151.5 (s), 130.1 (d, JCF =2.0 Hz), 128.0 (d, JCF =1.0 Hz), 122.3 (s), 122.2 (s), 119.2 (d, JCF =4.0 Hz), 114.0 (s), 97.1 (d, 1JCF =197.0 Hz), 73.4 (d, 2JCF =20.2 Hz), 55.3 (s), 34.4 (s), 31.9 (s), 31.8 (s), 24.5 (s), 24.4 (s), 23.9 (s), 23.8 (s), 23.6 (s). IR (cm−1): 3517, 2963, 1690, 1651, 1611, 1598, 1517, 1455, 1254, 832. MS (ESI) m/z: 433.2 [M+H]+. HRMS (ESI) m/z: calcd for C25H33FO3SNa+ [M + Na]+ 455.2027, found 455.2027.

Scheme 2. Transformation of S-(p-tolyl) α-fluoro-β-hydroxythioester syn-3 nb into the corresponding amide 5.

4.3.1. S-p-tolyl 2-fluoro-3-hydroxy-3-phenylpropanethioate (syn-3aa) Colorless solid. m. p. 141.0–142.1 °C. 1H NMR (400 MHz, CDCl3) δ = 7.49–7.38 (m, 5 H), 7.33–7.27 (m, 4 H), 5.29–5.21 (m, 1 H), 5.14 (dd, 2J = 47.4 Hz, 3J =2.8 Hz, 1 H), 2.78 (d, 3J =8.0 Hz, 1 H), 2.42 (s, 3 H). 19F NMR (376 MHz, CDCl3) δ = −202.0 (dd, 2JHF =47.4 Hz, 3 JHF = 24.5 Hz). 13C NMR (101 MHz, CDCl3) δ = 197.2 (d, 2JCF =29.3 Hz), 140.2 (s), 138.1 (d, JCF =2.0 Hz), 134.7 (s), 130.3 (s), 128.6 (d, JCF =2.0 Hz), 126.6 (s), 122.0 (s), 122.0 (s), 97.0 (d, 1JCF =198.0 Hz), 73.7 (d, 2JCF =19.2 Hz), 21.35 (s). IR (cm−1): 3567, 2939, 1680, 1654, 1599, 1559, 1507, 1115, 802. MS (ESI) m/z: 291.1 [M +H]+. HRMS (ESI) m/z: calcd for C16H16FO2S+ [M+H]+ 291.0855, found 291.0850.

4.3.6. S-(2,4,6-triisopropylphenyl) 3-([1,1′-biphenyl]-4-yl)- 2-fluoro-3hydroxypropanethioate (syn-3dc) Colorless solid. m. p. 135–136 °C. 1H NMR (400 MHz, CDCl3) δ = 7.68–7.61 (m, 4 H), 7.57–7.53 (m, 2 H), 7.51–7.46 (m, 2 H), 7.42–7.37 (m, 1 H), 7.12 (s, 2 H), 5.34–5.24 (m, 1 H), 5.26 (dd, 2J =48.0 Hz, 3J =4.0 Hz, 1 H), 3.38–3.16 (m, 2 H), 2.98–2.90 (m, 1 H), 2.78 (d, 3J =8.0 Hz, 1 H), 1.29 (d, 3J =8.0 Hz, 6 H), 1.22–1.10 (m, 12 H). 19F NMR (376 MHz, CDCl3) δ = −200.3 (dd, 2JHF =46.9 Hz, 3JHF =23.4 Hz). 13 C NMR (101 MHz, CDCl3) δ = 197.2 (d, 2JCF =29.3 Hz), 152.9 (s), 152.6 (s), 151.6 (s), 141.4 (s), 140.5 (s), 137.1 (d, JCF =2.0 Hz), 128.9 (s), 127.5 (s), 127.4 (s), 127.1 (s), 127.0 (d, JCF =1.0 Hz), 122.4 (s), 122.3 (s), 119.1 (d, JCF =4.0 Hz), 96.9 (d, 1JCF =197.0 Hz), 73.5 (d, 2 JCF =19.2 Hz), 34.4 (s), 32.0 (s), 31.8 (s), 24.5 (s), 24.4 (s), 23.9 (s), 23.8 (s), 23.6 (s). IR (cm−1): 3560, 2962, 1690, 1651, 1599, 1567, 1486, 1103, 748. MS (ESI) m/z: 479.2 [M+H]+. HRMS (ESI) m/z: calcd for C30H35FO2SNa+ [M + Na]+501.2234, found 501.2231.

4.3.2. S-(2,6-dimethylphenyl) 2-fluoro-3-hydroxy-3-phenylpropanethioate (syn-3ab) Colorless solid. m. p. 118.0–118.6 °C. 1H NMR (400 MHz, CDCl3) δ =7.51–7.36 (m, 5 H), 7.32–7.28 (m, 1 H), 7.23–7.17 (m, 2 H), 5.29–5.19 (m, 1 H), 5.18 (dd, 2J =48.0 Hz, 3J =4.0 Hz, 1 H), 2.79 (d, 3 J = 4.0 Hz, 1 H), 2.33 (s, 6 H). 19F NMR (376 MHz, CDCl3) δ = −196.2 (dd, 2JHF =48.3 Hz, 3JHF =19.1 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.7 (d, 2JCF =29.3 Hz), 143.2 (s), 138.2 (d, JCF =2.0 Hz), 130.2 (s), 128.7 (s), 128.6 (s), 128.5 (s), 126.6 (d, JCF =1.0 Hz), 124.8 (d, JCF =5.1 Hz), 97.0 (d, 1JCF =197.0 Hz), 73.8 (d, 2JCF =19.2 Hz), 21.5 (s). IR (cm−1): 3376, 2923, 1669, 1654, 1577, 1558, 1507, 1255, 712. MS (ESI) m/z: 305.1 [M+H]+. HRMS (ESI) m/z: calcd for C17H17FNaO2S+ [M + Na]+ 327.0831, found 327.0825. 4.3.3. S-(2,4,6-triisopropylphenyl) 2-fluoro-3-hydroxy-3-phenylpropanethioate (syn-3ac) Colorless solid. m. p. 100–102 °C. 1H NMR (500 MHz, CDCl3) δ = 7.50–7.46 (m, 2 H), 7.46–7.42 (m, 2 H), 7.41–7.37 (m, 1 H), 7.14–7.10 (m, 2 H), 5.21 (dd, 2J = 37.6 Hz, 3J = 0.8 Hz, 1 H), 5.24–5.14 (m, 1 H), 3.34–3.19 (m, 2 H), 2.98–2.91 (m, 1 H), 2.74 (d, 3J =5.0 Hz,1 H), 1.30 (dd, 3J =7.0 Hz, 3J =1.5 Hz, 6 H), 1.22–1.13 (m, 12 H). 19F NMR (376 MHz, CDCl3) δ = −200.2 (dd, 2JHF =47.1 Hz, 3JHF =23.9 Hz). 13 C NMR (126 MHz, CDCl3) δ = 197.1 (d, 2JCF =27.7 Hz), 152.9 (s), 152.6 (s), 151.5 (s), 138.1 (s), 128.6 (s), 128.5 (s), 126.6 (s), 122.3 (s), 122.2 (s), 119.1 (d, JCF =5.0 Hz), 96.9 (d, 1JCF =196.6 Hz), 73.7 (d, 2 JCF =20.2 Hz), 34.4 (s), 31.9 (s), 31.8 (s), 24.5 (s), 24.4 (s), 23.9 (s), 23.8 (s), 23.6 (s). IR (cm−1): 3570, 2964, 1688, 1651, 1599, 1567, 1495, 1100, 706. MS (ESI) m/z: 403.2 [M+H]+. HRMS (ESI) m/z: calcd for C24H31FO2SNa+ [M + Na]+ 425.1921, found 425.1926.

4.3.7. methyl 4-(3-((2,6-dimethylphenyl)thio) -2-fluoro-1-hydroxy- 3oxopropyl)benzoate (syn-3eb) Colorless solid. m. p. 118.6–118.9 °C. 1H NMR (400 MHz, CDCl3) δ = 8.15–8.03 (m, 2 H), 7.59–7.49 (m, 2 H), 7.32–7.27 (m, 1 H), 7.21–7.14 (m, 2 H), 5.36–5.25 (m, 1 H), 5.18 (dd, 2J =47.2 Hz, 3J =3.2 Hz, 1 H), 3.95 (s, 3 H), 2.90 (d, 3J =8.0 Hz, 1 H), 2.30 (s, 6 H). 19F NMR (376 MHz, CDCl3) δ = −195.3 (dd, 2JHF =49.1 Hz, 3JHF =17.2 Hz). 13C NMR (126 MHz, CDCl3) δ = 195.8 (d, 2JCF =29.0 Hz), 166.7 (s), 143.1 (s), 130.34 (s), 130.30 (s), 129.9 (s), 128.5 (s), 126.5 (d, JCF =1.3 Hz), 124.6 (d, JCF =5.0 Hz), 96.6 (d, 1JCF =197.8 Hz), 73.4 (d, 2JCF =20.2 Hz), 52.2 (s), 21.5 (s). IR (cm−1): 3530, 2955, 1721, 1669, 1609, 1583, 1508, 1434, 1107, 724. MS (ESI) m/z: 363.1 [M+H]+. HRMS (ESI) m/z: calcd for C19H20FO4S+ [M+H]+ 363.1061, found 363.1059. 4.3.8. S-(2,4,6-triisopropylphenyl) 3-(4-chlorophenyl)2-fluoro-3hydroxypropanethioate (syn-3fc) Colorless solid. m. p. 120–121 °C. 1H NMR (400 MHz, CDCl3) δ = 7.42–7.40 (m, 4 H), 7.12 (s, 2 H), 5.27–5.17 (m, 1 H), 5.20 (dd, 2J =48.0 Hz, 3J =4.0 Hz, 1 H), 3.31–3.21 (m, 1 H), 3.14–3.04 (m, 1 H), 2.98–2.88 (m, 1 H), 2.85–2.79 (m, 1 H), 1.29 (d, 3J =8.0 Hz, 6 H), 1.20–1.11 (m, 12 H). 19F NMR (376 MHz, CDCl3) δ = −199.2 (dd, 2JHF =47.0 Hz, 3JHF =22.7 Hz). 13C NMR (101 MHz, CDCl3) δ = 197.3 (d, 2 JCF =29.3 Hz), 152.8 (s), 152.6 (s), 151.7 (s), 136.5 (s), 134.4 (s), 128.8 (s), 127.9 (s), 122.4 (s), 122.3 (s), 118.8 (d, JCF =4.0 Hz), 96.5 (d, 1JCF =198.0 Hz), 73.0 (d, 2JCF =19.2 Hz), 34.4 (s), 32.0 (s), 31.8 (s), 24.5 (s), 24.4 (s), 23.9 (s), 23.8 (s), 23.5 (d, JCF =6.1 Hz). IR (cm−1): 3570, 2963, 1688, 1671, 1598, 1566, 1493, 1099, 738, 705. MS (ESI) m/z: 437.2 [M+H]+. HRMS (ESI) m/z: calcd for

4.3.4. S-(2,4,6-triisopropylphenyl) 2-fluoro-3-hydroxy-3-(p-tolyl)propanethioate (syn-3bc) Colorless solid. m. p. 88–90 °C. 1H NMR (500 MHz, CDCl3) δ = 7.39–7.34 (m, 2 H), 7.25–7.21 (m, 2 H), 7.11 (s, 2 H), 5.22–5.15 (m, 1 H), 5.18 (dd, 2J =37.2 Hz, 3J =1.2 Hz, 1 H), 3.30–3.19 (m, 2 H), 2.96–2.90 (m, 1 H), 2.66 (d, 3J =5.0 Hz, 1 H), 2.39 (s, 3 H), 1.29 (d, 3J =5.0 Hz, 6 H), 1.17 (dd, 2J =15.0 Hz, 3J =10.0 Hz, 12 H). 19F NMR (376 MHz, CDCl3) δ = −199.8 (dd, 2JHF =47.9 Hz, 3JHF =22.7 Hz). 13 C NMR (126 MHz, CDCl3) δ = 197.0 (d, 2JCF =29.0 Hz), 152.9 (s), 152.6 (s), 151.5 (s), 138.3 (s), 135.1 (d, JCF =1.3 Hz), 129.3 (s), 126.5 (d, JCF =1.3 Hz), 122.3 (s), 122.2 (s), 119.2 (d, JCF =5.0 Hz), 97.0 (d, 1 JCF =196.6 Hz), 73.6 (d, 2JCF =20.2 Hz), 34.4 (s), 31.9 (s), 31.8 (s), 24.5 (s), 24.4 (s), 23.9 (s), 23.8 (s), 23.6 (s), 21.2 (s). IR (cm−1): 3518, 2962, 1690, 1674, 1598, 1566, 1516, 1252, 855. MS (ESI) m/z: 417.2 4

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C24H30ClFO2SNa+ [M + Na]+ 459.1531, found 459.1531.

found 470.1776.

4.3.9. S-(2,4,6-triisopropylphenyl) 3-(4-bromophenyl)2-fluoro-3hydroxypropanethioate (syn-3gc) Colorless solid. m. p. 123–125 °C. 1H NMR (400 MHz, CDCl3) δ = 7.58–7.54 (m, 2 H), 7.38–7.33 (m, 2 H), 7.12 (s, 2 H), 5.18 (dd, 2J =48.0 Hz, 3J =4.0 Hz, 1 H), 5.17 (s, 1 H), 3.33–3.19 (m, 1 H), 3.16–3.03 (m, 1 H), 3.01–2.89 (m, 1 H), 2.85 (s, 1 H), 1.29 (d, 3J =8.0 Hz, 6 H), 1.22–1.10 (m, 12 H). 19F NMR (376 MHz, CDCl3) δ = −199.1 (dd, 2JHF =46.9 Hz, 3JHF =22.4 Hz). 13C NMR (101 MHz, CDCl3) δ = 197.2 (d, 2JCF =28.3 Hz), 152.8 (s), 152.6 (s), 151.7 (s), 137.0 (s), 131.8 (s), 128.2 (d, JCF =2.0 Hz), 122.6 (s), 122.4 (s), 122.3 (s), 118.8 (d, JCF =5.1 Hz), 96.4 (d, 1JCF =199.0 Hz), 73.0 (d, 2JCF =20.2 Hz), 34.4 (s), 32.0 (s), 31.8 (s), 24.5 (s), 24.4 (s), 23.8 (s), 23.8 (s), 23.5 (d, JCF =6.1 Hz). IR (cm−1): 3513, 2962, 1778, 1670, 1596, 1486, 1455, 1113, 859, 701. MS (ESI) m/z: 481.1 [M+H]+. HRMS (ESI) m/z: calcd for C24H30BrFO2SNa+ [M + Na]+ 505.1008, found 505.1010.

4.3.13. S-(2,6-dimethylphenyl) 2-fluoro-3-hydroxy-3-(m-tolyl)propanethioate (syn-3jb) Colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.34–7.26 (m, 4 H), 7.23–7.16 (m, 3 H), 5.27–5.15 (m, 1 H), 5.17 (dd, 2J = 46.8 Hz, 3J =2.4 Hz, 1 H), 2.68 (d, 3J = 8.0 Hz, 1 H), 2.41 (s, 3 H), 2.33 (s, 6 H). 19 F NMR (376 MHz, CDCl3) δ = −201.0 (dd, 2 JHF = 47.3 Hz,3JHF = 24.8 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.7 (d, 2JCF =29.3 Hz), 143.2 (s), 138.4 (s), 138.1 (s), 130.2 (s), 129.3 (s), 128.6 (s), 128.4 (s), 127.2 (s), 124.9 (d, JCF = 5.1 Hz), 123.6 (s), 97.1 (d, 1JCF =198.0 Hz), 73.9 (d, 2JCF = 19.2 Hz), 21.5 (s), 21.4 (s). IR (cm−1): 3609, 2922, 1679, 1653, 1628, 1588, 1495, 1110, 766. MS (ESI) m/z: 319.1 [M+H]+. HRMS (ESI) m/z: calcd for C18H19FO2SNa+ [M + Na]+ 341.0982, found 341.0981. 4.3.14. S-(2,6-dimethylphenyl) 2-fluoro-3-hydroxy-3-(3-methoxyphenyl)propanethioate (syn-3 kb) Colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.37–7.28 (m, 2 H), 7.23–7.15 (m, 2 H), 7.07–7.00 (m, 2 H), 6.95–6.88 (m, 1 H), 5.26–5.15 (m, 1 H), 5.16 (dd, 2J = 47.2 Hz, 3J =1.6 Hz, 1 H), 3.84 (s, 3 H), 2.79 (d, 3J = 4.0 Hz, 1 H), 2.33 (s, 6 H). 19F NMR (376 MHz, CDCl3) δ = −195.4 (dd, 2JHF = 48.4 Hz, 3JHF = 18.5 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.9 (d, 2JCF = 29.3 Hz), 159.9 (s), 143.2 (s), 139.9 (d, JCF =1.0 Hz), 130.3 (s), 129.7 (s), 128.5 (s), 124.8 (d, JCF = 5.1 Hz), 118.7 (s), 114.2 (s), 112.04 (s), 97.0 (d, 1JCF = 198.0 Hz), 73.7 (d, 2 JCF = 19.2 Hz), 55.3 (s), 21.6 (s). IR (cm−1): 3478, 2926, 1770, 1691, 1603, 1538, 1490, 1462, 1103, 773. MS (ESI) m/z: 335.1 [M+H]+. HRMS (ESI) m/z: calcd for C18H20FO3S+ [M+H]+ 335.1112, found 335.1109.

4.3.10. S-(2,4,6-triisopropylphenyl) 3-(4-cyanophenyl)2-fluoro-3hydroxypropanethioate (syn-3hc) Colorless solid. m. p. 131–134 °C. 1H NMR (400 MHz, CDCl3) δ = 7.75–7.69 (m, 2 H), 7.63–7.58 (m, 2 H), 7.13 (s, 2 H), 5.36–5.28 (m, 1 H), 5.21 (dd, 2J =48.0 Hz, 3J =4.0 Hz, 1 H), 3.33–3.23 (m, 1 H), 3.14–3.03 (m, 2 H), 3.01–2.87 (m, 1 H), 1.29 (d, 3J =8.0 Hz, 6 H), 1.22–1.10 (m, 12 H). 19F NMR (376 MHz, CDCl3) δ = −200.4 (dd, 2JHF =47.1 Hz, 3JHF =22.8 Hz). 13C NMR (101 MHz, CDCl3) δ = 197.2 (d, 2 JCF =28.3 Hz), 152.7 (s), 152.6 (s), 151.8 (s), 143.4 (s), 132.3 (s), 127.3 (d, JCF =1.0 Hz), 122.4 (s), 118.6 (s), 118.5 (s), 118.4 (s), 112.4 (s), 96.2 (d, 1JCF = 199.0 Hz), 72.9 (d, 2JCF =19.2 Hz), 34.3 (s), 32.0 (s), 31.9 (s), 24.4 (s), 24.3 (s), 23.80 (s), 23.78 (s), 23.5 (s). IR (cm−1): 3480, 2963, 2228, 1681, 1653, 1607, 1566, 1504, 1096, 767. MS (ESI) m/z: 428.2 [M+H]+. HRMS (ESI) m/z: calcd for C25H30FNO2SNa+ [M + Na]+ 450.1873, found 450.1876.

4.3.15. S-(2,6-dimethylphenyl) 3-(3-chlorophenyl)2-fluoro-3hydroxypropanethioate (syn-3 lb) Colorless solid. m. p. 116.9–117.3 °C. 1H NMR (400 MHz, CDCl3) δ = 7.46 (s, 1 H), 7.40–7.32 (m, 3 H), 7.31–7.27 (m, 1 H), 7.21–7.14 (m, 2 H), 5.16 (dd, 2J = 48.0 Hz, 3J = 4.0 Hz, 1 H), 5.16–5.07 (m, 1 H), 2.95 (d, 3J = 3.3 Hz, 1 H), 2.25 (d, 2J = 48.0 Hz, 6 H). 19F NMR (376 MHz, CDCl3) δ = −201.0 (dd, 2JHF = 47.0 Hz, 3JHF = 24.9 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.7 (d, 2JCF = 28.3 Hz), 143.0 (s), 139.2 (s), 134.5 (s), 130.3 (s), 129.8 (s), 129.0 (s), 128.5 (s), 127.6 (s), 125.6 (s), 124.4 (d, JCF = 5.1 Hz), 96.4 (d, 1JCF = 197.0 Hz), 73.4 (d, 2 JCF = 21.2 Hz), 21.4 (s). IR (cm−1): 3362, 2924, 1691, 1660, 1598, 1575, 1507, 1101, 773, 697. MS (ESI) m/z: 339.1 [M+H]+. HRMS (ESI) m/z: calcd for C17H17ClFO2S+ [M+H]+ 339.0622, found 339.0616.

4.3.11. S-(2,4,6-triisopropylphenyl) 3-(4-cyanophenyl) -2-fluoro-3hydroxypropanethioate (anti-3hc) Colorless solid. m. p. 133.0–133.4 °C. 1H NMR (400 MHz, CDCl3) δ = 7.74–7.66 (m, 2 H), 7.62–7.55 (m, 2 H), 7.15–7.06 (m, 2 H), 5.28–5.21 (m, 1 H), 5.16 (dd, 2J =28.0 Hz, 3J =4.0 Hz, 1 H), 3.33–3.23 (m, 1 H), 3.18 (d, 3J = 4.0 Hz, 1 H), 3.05–2.87 (m, 2 H), 1.28 (d, 3 J = 4.0 Hz, 6 H), 1.23–1.06 (m, 12 H). 19F NMR (376 MHz, CDCl3) δ = −195.1 (dd, 2JHF =48.7 Hz, 3JHF =16.8 Hz). 13C NMR (101 MHz, CDCl3) δ = 197.1 (d, 2JCF =28.3 Hz), 152.6 (s), 152.5 (s), 151.8 (s), 142.4 (s), 142.3 (s), 132.2 (s), 128.2 (d, JCF =1.0 Hz), 122.4 (s), 118.5 (s), 118.4 (s), 112.5 (s), 96.2 (d, 1JCF = 198.0 Hz), 73.3 (d, 2 JCF = 20.2 Hz), 34.4 (s), 32.0 (s), 31.8 (s), 24.4 (s), 24.3 (s), 23.8 (s), 23.8 (s), 23.5 (s). IR (cm−1): 3485, 2965, 2230, 1675, 1650, 1603, 1562, 1501, 1093, 763. MS (ESI) m/z: 428.2 [M+H]+. HRMS (ESI) m/ z: calcd for C25H30FNO2SNa+ [M + Na]+ 450.1879, found 450.1873.

4.3.16. S-(2,4,6-triisopropylphenyl) 3-(3,4-dimethylphenyl)- 2-fluoro-3hydroxypropanethioate (syn-3mc) Colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.30–7.27 (m, 1 H), 7.19–7.17 (m, 2 H), 7.11 (s, 2 H), 5.17 (dd, 2J = 48.0 Hz, 3J = 4.0 Hz, 1 H), 5.22–5.13 (m, 1 H), 3.31–3.22 (m, 2 H), 2.97–2.88 (m, 1 H), 2.61 (d, 3J =8.0 Hz, 1 H), 2.30 (d, 3J = 3.4 Hz, 6 H), 1.29 (d, 3J = 4.0 Hz, 6 H), 1.16 (d, 3J = 4.0 Hz, 12 H). 19F NMR (376 MHz, CDCl3) δ = −200.0 (dd, 2JHF =48.0 Hz, 3JHF =23.1 Hz). 13C NMR (101 MHz, CDCl3) δ = 196.9 (d, 2JCF =28.3 Hz), 152.9 (s), 152.6 (s), 151.5 (s), 137.0 (s), 136.9 (s), 135.5 (s), 129.9 (s), 127.8 (s), 123.9 (s), 122.3 (s), 122.2 (s), 119.3 (d, JCF = 5.1 Hz), 97.2 (d, 1JCF = 197.0 Hz), 73.7 (d, 2 JCF = 19.2 Hz), 34.3 (s), 31.9 (s), 31.8 (s), 24.4 (s), 24.3 (s), 23.8 (s), 23.7 (s), 23.5 (s), 19.8 (s), 19.5 (s). IR (cm−1): 3490, 2962, 1691, 1678, 1598, 1567, 1504, 1104, 840. MS (ESI) m/z: 431.2 [M+H]+. HRMS (ESI) m/z: calcd for C26H35FO2SNa+ [M + Na]+ 453.2234, found 453.2232.

4.3.12. S-(2,4,6-triisopropylphenyl) 2-fluoro-3-hydroxy-3-(4-nitrophenyl)propanethioate (syn-3ic) Colorless solid. m. p. 142–143 °C. 1H NMR (500 MHz, CDCl3) δ = 8.35–8.26 (m, 2 H), 7.75–7.62 (m, 2 H), 7.17–7.06 (m, 2 H), 5.37 (d, 2J = 25.0 Hz, 1 H), 5.24 (dd, 2J = 36.0 Hz, 3J =v2.4 Hz, 1 H), 3.31–3.25 (m, 1 H), 3.13–3.00 (m, 2 H), 2.98–2.90 (m, 1 H), 1.29 (d, 3J =10.0 Hz, 6 H), 1.24–1.08 (m, 12 H). 19F NMR (376 MHz, CDCl3) δ = −200.9 (dd, 2JHF = 46.9 Hz, 3JHF =22.9 Hz). 13C NMR (126 MHz, CDCl3) δ = 197.3 (d, 2JCF =27.7 Hz), 152.7 (s), 152.6 (s), 151.9 (s), 148.0 (s), 145.2 (d, JCF = 0.9 Hz), 127.5 (d, JCF = 1.3 Hz), 123.7 (s), 122.4 (s), 118.5 (s), 118.4 (s), 96.1 (d, 1JCF = 199.1 Hz), 72.8 (d, 2 JCF = 18.9 Hz), 34.4 (s), 32.0 (s), 31.9 (s), 24.4 (s), 24.3 (s), 23.8 (s), 23.7 (s), 23.53 (d, JCF = 3.8 Hz). IR (cm−1): 3541, 2964, 1678, 1653, 1636, 1599, 1558, 1513, 1098, 722. MS (ESI) m/z: 448.2 [M+H]+. HRMS (ESI) m/z: calcd for C24H30FNO4SNa+ [M + Na]+ 470.1772,

4.3.17. S-(2,6-dimethylphenyl) 3-(3,4-dimethoxyphenyl)- 2-fluoro-3hydroxypropanethioate (syn-3 nb) Colorless solid. m. p. 132.2–132.6 °C. 1H NMR (400 MHz, CDCl3) δ 5

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= 7.30–7.27 (m, 1 H), 7.21–7.17 (m, 2 H), 7.04–6.97 (m, 2 H), 6.92–6.88 (m, 1 H), 5.23–5.14 (m, 1 H), 5.15 (dd, 2J = 48.0 Hz, 3J = 4.0 Hz, 1 H), 3.92 (d, 3J = 4.0 Hz, 6 H), 2.61 (d, 3J =8.0 Hz, 1 H), 2.33 (s, 6 H). 19F NMR (376 MHz, CDCl3) δ = −200.5 (dd, 2JHF = 47.2 Hz, 3 JHF = 23.7 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.6 (d, 2JCF =30.3 Hz), 149.3 (s), 149.2 (s), 143.1 (s), 130.8 (s), 130.2 (s), 128.4 (s), 124.8 (d, JCF = 10.1 Hz), 119.0 (s), 111.2 (s), 109.9 (s), 97.1 (d, 1 JCF = 191.9 Hz), 73.6 (d, 2JCF =20.2 Hz), 56.0 (s), 21.5 (s). IR (cm−1): 3540, 2935, 1689, 1672, 1594, 1558, 1513, 1462, 1266, 790. MS (ESI) m/z: 365.1 [M+H]+. HRMS (ESI) m/z: calcd for C19H21FO4SNa+ [M + Na]+ 387.1037, found 387.1035.

4.4.1. N-benzyl-3-(3,4-dimethoxyphenyl)-2-fluoro-3-hydroxypropanamide (syn-5a) Colorless solid. m. p. 115.8–116.2 °C. 1H NMR (400 MHz, CDCl3) δ = 7.38–7.29 (m, 3 H), 7.17–7.14 (m, 2 H), 7.01–6.94 (m, 2 H), 6.89–6.85 (m, 1 H), 6.67–6.59 (m, 1 H), 5.23 (dd, 2J = 21.5 Hz, 3J =2.8 Hz, 1 H), 5.12 (dd, 2JHF = 47.4 Hz, 3J =2.9 Hz, 1 H), 4.58 (dd, 2 J = 14.9 Hz, 3J = 6.4 Hz, 1 H), 4.41 (dd, 2J = 14.9 Hz, 3J = 5.4 Hz, 1 H), 3.89 (d, 2J = 12.0 Hz, 6 H), 1.29 (s, 1 H). 19F NMR (376 MHz, CDCl3) δ = −202.4 (dd, 2JHF = 48.0 Hz, 3JHF = 20.9 Hz). 13C NMR (101 MHz, CDCl3) δ = 168.4 (d, 2JCF = 19.2 Hz), 149.0 (s), 148.9 (s), 137.0 (s), 131.3 (s), 128.7 (s), 127.7 (s), 127.5 (s), 118.7 (s), 111.0 (s), 109.7 (s), 92.4 (d, 1JCF = 198.0 Hz), 72.4 (d, 2JCF = 20.2 Hz), 55.9 (s), 43.0 (s), 1.0 (s). IR (cm−1): 3430, 3320, 2919, 1657, 1642, 1607, 1547, 1515, 1455, 1103, 736. MS (ESI) m/z: 334.1 [M+H]+. HRMS (ESI) m/z: calcd for C18H21FNO4+ [M+H]+ 334.1449, found 334.1448.

4.3.18. S-(2,6-dimethylphenyl) 3-(3,4-dichlorophenyl)2-fluoro-3hydroxypropanethioate (syn-3ob) Colorless solid. m. p. 144.5–145.2 °C. 1H NMR (400 MHz, CDCl3) δ = 7.60–7.55 (m, 1 H), 7.51–7.47 (m, 1 H), 7.32–7.27 (m, 2 H), 7.22–7.15 (m, 2 H), 5.19 (d, 2J = 24.0 Hz, 1 H), 5.14 (dd, 2J = 48.0 Hz, 3J = 4.0 Hz, 1 H), 2.86 (s, 1 H), 2.26 (d, 2J =16.0 Hz, 6 H). 19F NMR (376 MHz, CDCl3) δ = −195.8 (dd, 2JHF =49.6 Hz, 3JHF = 15.2 Hz). 13 C NMR (101 MHz, CDCl3) δ = 195.8 (d, 2JCF = 29.3 Hz), 143.0 (s), 138.3 (s), 133.0 (s), 132.7 (s), 130.6 (s), 130.4 (s), 128.7 (s), 128.5 (s), 125.9 (d, JCF =1.0 Hz), 124.4 (d, JCF = 5.1 Hz), 96.3 (d, 1 JCF = 199.0 Hz), 72.6 (d, 2JCF =20.2 Hz), 21.4 (s). IR (cm−1): 3387, 2922, 1687, 1659, 1609, 1566, 1492, 1081, 773, 740. MS (ESI) m/z: 373.0 [M+H]+. HRMS (ESI) m/z: calcd for C17H15Cl2FO2SNa+ [M + Na]+ 395.0046, found 395.0050.

4.4.2. 3-(3,4-dimethoxyphenyl)-2-fluoro-3-hydroxy-N-methylpropanamide (syn-5b) Colorless solid. m. p. 146.1–146.9 °C. 1H NMR (400 MHz, CDCl3) δ = 7.01–6.93 (m, 2 H), 6.91–6.85 (m, 1 H), 6.36 (s, 1 H), 5.21 (dd, 2 J = 22.7 Hz, 3J = 2.0 Hz, 1 H), 5.04 (dd, 2JHF = 47.4 Hz, 3J = 2.7 Hz, 1 H), 3.90 (d, 3J = 4.0 Hz, 6 H), 3.35 (s, 1 H), 2.87 (d, 3J = 4.0 Hz, 3 H). 19 F NMR (376 MHz, CDCl3) δ = −203.2 (dd, 2JHF = 47.5 Hz, 3JHF =23.0 Hz). 13C NMR (101 MHz, CDCl3) δ = 169.0 (d, 2JCF = 19.2 Hz), 149.1 (s), 131.4 (s), 118.8 (s), 111.0 (s), 109.8 (s), 100.0 (s), 92.4 (d, 1 JCF = 197.0 Hz), 72.5 (d, 2JCF = 19.2 Hz), 55.9 (s), 35.0 (s), 25.7 (s). IR (cm−1): 3393, 3332, 2943, 1699, 1660, 1593, 1562, 1515, 1446, 1103, 779. MS (ESI) m/z: 258.1 [M+H]+. HRMS (ESI) m/z: calcd for C12H20FN2O4+ [M + NH4]+ 275.1402, found 275.1400.

4.3.19. S-(2,6-dimethylphenyl) 2-fluoro-3-hydroxy-3-(o-tolyl)propanethioate (syn-3pb) Colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.39–7.28 (m, 4 H), 7.26–7.18 (m, 3 H), 5.19 (d, 2J =20.0 Hz, 1 H), 5.16 (d, 2J = 48.0 Hz, 1 H), 3.02 (s, 1 H), 2.44 (s, 3 H), 2.38 (s, 6 H). 19F NMR (376 MHz, CDCl3) δ = −195.8 (dd, 2JHF = 48.5 Hz, 3JHF = 19.4 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.7 (d, 2JCF = 29.3 Hz), 143.2 (s), 138.4 (s), 138.3 (d, JCF = 2.0 Hz), 130.2 (s), 129.3 (s), 128.6 (s), 128.5 (s), 127.3 (s), 125.0 (d, JCF = 4.0 Hz), 123.7 (s), 97.2 (d, 1JCF = 198.0 Hz), 73.9 (d, 2JCF = 19.2 Hz), 21.6 (s), 21.5 (s). IR (cm−1): 3271, 2920, 1697, 1677, 1624, 1577, 1507, 1106, 766. MS (ESI) m/z: 319.1 [M+H]+. HRMS (ESI) m/z: calcd for C18H20FO2S+ [M+H]+ 319.1168, found 319.1163.

Acknowledgments The authors acknowledge financial support from the Natural Science Foundation of Shanghai (16ZR1413800), and Shanghai University of Engineering Science (2012td09, nhrc-2015-09). Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jfluchem.2019. 109368.

4.3.20. S-(2,6-dimethylphenyl) (E)-2-fluoro-3-hydroxy-5-phenylpent-4enethioate (syn-3qb) Yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.47–7.39 (m, 2 H), 7.39–7.29 (m, 3 H), 7.27–7.23 (m, 1 H), 7.21–7.12 (m, 2 H), 6.75 (d, 2 J = 16.0 Hz, 1 H), 6.39 (dd, 2J = 16.0 Hz, 3J = 4.0 Hz, 1 H), 5.16 (dd, 2 J =48.0 Hz, 3J =4.0 Hz, 1 H), 4.77 (dd, 2J =20.0 Hz, 3J = 4.0 Hz, 1 H), 2.52 (s, 1 H), 2.29 (d, 2J =52.0 Hz, 6 H). 19F NMR (376 MHz, CDCl3) δ = −197.8 (dd, 2JHF =48.9 Hz, 3JHF = 20.5 Hz). 13C NMR (101 MHz, CDCl3) δ = 195.2 (d, 2JCF =28.3 Hz), 143.1 (s), 135.9 (s), 134.8 (s), 130.2 (s), 128.6 (s), 128.4 (s), 128.3 (s), 126.8 (s), 124.7 (d, JCF =5.0 Hz), 123.7 (d, JCF =6.1 Hz), 97.0 (d, 1JCF = 195.9 Hz), 73.5 (d, 2JCF =20.2 Hz), 21.6 (s). IR (cm−1): 3308, 2959, 1697, 1654, 1647, 1617, 1577, 1491, 1166, 749. MS (ESI) m/z: 331.1 [M+H]+. HRMS (ESI) m/z: calcd for C19H19FNaO2S+ [M + Na]+ 353.0987, found 353.0982.

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4.4. Synthesis of 5 (general procedure) To a 10 mL flask with a magnetic stirring bar was added syn-3nb (0.2 mmol), the corresponding amine 4 (0.24 mmol) and MeOH (3.0 ML). The reaction mixture was kept stirring for 5 h at 0 °C and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the corresponding product 5. 6

Journal of Fluorine Chemistry 227 (2019) 109368

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