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Highly regio- and stereoselective transiodofluorination of ynamides enabling the synthesis of (E)-α-fluoro-β-iodoenamides† Yang Xi, Guohao Zhu, Luning Tang, Shihan Ma, Dongming Zhang, Rong Zhang, Guangke He* and Hongjun Zhu *

Received 16th June 2017, Accepted 9th August 2017 DOI: 10.1039/c7ob01470h rsc.li/obc

A highly regio- and stereoselective trans-iodofluorination reaction of ynamides with NIS and Et3N·3HF has been achieved, affording (E)-α-fluoro-β-iodoenamides in moderate to good yields. The reaction proceeds under mild reaction conditions and exhibits good functional group compatibility.

Introduction The introduction of a fluorine atom into organic molecules often drastically perturbs the chemical, physical, and biological properties of the parent compounds, which enables organofluorine compounds to attract considerable attention in medicinal, pharmaceutical, agricultural and materials sciences.1 Therefore, developing simple and efficient protocols to obtain structurally diversified fluorine-containing molecules is highly desired. Although notable progress has been made through transition-metal-catalyzed2 or mediated3 hydrofluorination of alkynes, from the view point of late-stage transformations, fluorination-based difunctionalizations (such as carbofluorination,4 oxyfluorination5 and aminofluorination,6 etc.) of unsaturated hydrocarbons appeared more powerful. By using appropriate methods not only one fluorine but also another functionality can be introduced into organic molecules, and the second functional group can be used to construct new fluorine-containing molecules7,8 through further chemical transformations. In this respect, iodofluorination of alkenes,9 alkynes10 and allenes11 is a particularly useful approach for the simultaneous incorporation of both iodo and fluoro functionalities into organic substrates. Usually, hypervalent fluoroiodine reagents were applicable for the iodofluorination of alkenes9c–e and alkynes.10 Due to the high reactivity and difficult access of the oxidative fluorine species, the metal-free N-iodosuccinimide (NIS)/HF-base (e.g., Et3N, pyridine, imid-

Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, People’s Republic of China. E-mail: [email protected], [email protected]; Fax: +86-25-83172358; Tel: +86-25-83172358 † Electronic supplementary information (ESI) available: Copies of 1H NMR, 13C NMR and 19F NMR spectra of compounds (E)-2a–(E)-2r, Z-2a, (E)-4, (Z)-4, (E)-5, (Z)-5, 6 and 7. CCDC 1554940. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7ob01470h

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azole derivatives)11,12 system has gradually gained much attention. However, rare examples have been involved in the iodofluorination of C–C triple bonds12b via the NIS/HF-base system. Inspired by the previous results and our recent exploration in the hydrofluorination2e,f of ynamides, we report here that the NIS-mediated highly regio- and stereoselective iodofluorination of ynamides in the presence of Et3N·3HF affords (E)-α-fluoro-β-iodoenamides (Scheme 1).

Results and discussion In initial experiments, the reactions of the N-sulfonyl ynamide 1a with NIS and Et3N·3HF in different solvents at 80 °C were conducted (Table 1, entries 1–7). However, no new product was observed when choosing DMF or NMP as the reaction solvent (entries 1 and 2). Further solvent screening revealed that the solvent effect had an important effect on the activity and selectivity of the iodofluorination (entries 3–7). Unexpectedly, the reaction in THF afforded the desired trans-iodofluorinated product (E)-2a in 49% NMR yield, along with a mixture of the stereo-isomer (Z)-2a and cis-hydrofluorinated 3a (entry 3).13 In contrast, some chlorinated solvents, such as 1,2-DCE, CHCl3 and CCl4, gave slightly better results (entries 4–6). Surprisingly, in the case of CH3CN, the yield of the iodofluorination could be dramatically increased to 95% with excellent selectivity (entry 7). And reducing the amount of Et3N·3HF to 0.50 equiv. or even lesser led to lower yield (entries 8 and 9). Only a good yield of (E)-2a was obtained when the reaction was conducted

Scheme 1

Iodofluorination of ynamides.

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Table 1

Paper

Screening of the reaction conditions of trans-iodofluorination of N-benzyl-4-methyl-N-( phenylethynyl)benzenesulfonamide (1a)a

Entry

X+

F− source (equiv.)

Solvent

Time (h)

NMR yield of (E)-2ab (%)

Ratio of (E)-2a/(Z)-2a/3ab

1 2 3 4 5 6 7 8 9 10c 11 12 13 14 15 16 17d 18e 19

NIS NIS NIS NIS NIS NIS NIS NIS NIS NIS I2 NIS NIS NIS NIS NIS NBS NCS NFSI

Et3N·3HF (1.0) Et3N·3HF (1.0) Et3N·3HF (1.0) Et3N·3HF (1.0) Et3N·3HF (1.0) Et3N·3HF (1.0) Et3N·3HF (1.0) Et3N·3HF (0.50) Et3N·3HF (0.35) Et3N·3HF (1.0) Et3N·3HF (1.0) Pyridine/HF (3.0) TBAF(t-BuOH)4 (3.0) TBAF·3H2O (3.0) TBAF·3H2O (1.5) CsF (3.0) Et3N·3HF (1.0) Et3N·3HF (1.0) Et3N·3HF (1.0)

DMF NMP THF 1,2-DCE CHCl3 CCl4 CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

0.83 3.3 22.7 0.83 0.83 3.8 3.3 3.3 3.3 3.3 3.5 3.3 15.3 20 21.3 22.5 3.5 3.5 3.5

0 0 49 76 63 69 95 71 54 81 33 80 5 8 14 15 37 43 0

— — 86/12/2 81/14/5 67/27/6 92/8/0 95/5/0 92/8/0 90/6/4 91/9/0 54/5/41 93/6/1 100/0/0 89/11/0 74/0/26 88/22/0 61/26/13 58/42/0 —/—/100

Reaction conditions: 1a (0.2 mmol), NIS (1.2 equiv.), F− sources (3.0 equiv.) and solvent (2.0 mL), reflux in a sealed tube, 80 °C. b Determined by F NMR analysis of the crude product. c The reaction was conducted at rt. d Formation of bromofluorinated 4a (E/Z = 61/26) and cisα-hydrofluorinated 3a. e Formation of chlorofluorinated 5a (E/Z = 58/42). a

19

at rt (entry 10), while the use of I2 instead of NIS led to the competitive formation of 3a (entry 11). Other nucleophilic fluorinating agents, such as pyridine/HF, TBAF(t-BuOH)4,14 TBAF·3H2O (3.0 equiv. or 1.5 equiv.) and CsF, cannot improve the reaction under otherwise identical conditions (entries 12–16). Then the halofluorination (halo = Br, Cl and F) of ynamide 1a was also evaluated employing NBS, NCS and NFSI as activators, respectively (entries 17–19). Compared with iodofluorination, bromofluorination and chlorofluorination exhibited relatively lower reactivities and selectivities (entries 17 and 18), and the α,β-difluorination of 1a with NFSI did not proceed (entry 19). With the optimized conditions in hand (Table 1, entry 7), we next studied the scope of the trans-iodofluorination reaction of ynamides15 possessing representative substitution patterns (Table 2). Aryl substituted N-benzyl ynesulfonamides were all able to undergo iodofluorination and provided the corresponding (E)-α-fluoro-β-iodoenamides in 68–85% yields with high levels of regio- and stereo-control (entries 1–5). And the variation of the substituents at the para-position on the arene ring has a negligible effect on the reaction outcome (entries 2–5). The reactions of alkyl- and alkenyl-substituted ynamides obtained higher stereoselectivities than those of the aryl substituted ones in spite of slightly lower yields (entries 6–8). In addition, the trans-iodofluorination occurred smoothly on the N-phenyl and N-methyl ynesulfonamides, affording (E)-2i–(E)-2k in moderate yields (entries 9–11). Disappointingly, the iodofluorination of the sterically demanding tert-butyl-

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substituted N-benzyl ynesulfonamide with NIS and Et3N·3HF did not work.16 It is noteworthy that N-allyl ynesulfonamide 1l works effectively, and the allyl group is not affected in the process (entry 12). In fact, when the N-Ms ynamides 1m and 1n were subjected to the standard conditions, the formation of products (E)-2m–(E)-2n confirmed the good compatibility with various N-substituents (entries 13 and 14). Furthermore, N-arylalkynylated and N-alkylalkynylated oxazolidinones (1o– 1p) were also smoothly iodofluorinated, allowing the synthesis of (E)-α-fluoro-β-iodoenamides in 50%–76% yields (entries 15 and 16). Although N-Boc substituted ynamides are readily prone to intermolecular 6-exo-dig cyclization17 with NIS at CH3CN, the iodofluorination of tert-butyl N-phenyl-N-( phenylethynyl)carbamate 1q with NIS and Et3N·3HF still proceeds well (entry 17). Arylethynyl pyrrolidinone 1r also participated in the reaction and gave the desired iodofluorinated enamide 2r in moderate yield (entry 18). For N-phenylethynylated fivemembered sultam, only a weak 19F signal was observed by 19F NMR analysis of the crude product. The regio- and stereochemical issue was unambiguously confirmed by an X-ray diffraction study of (E)-2a (Fig. 1).18 According to literature precedents19 and our initial experimental results, a plausible mechanism was proposed for the trans-iodofluorination of alkynamides (Scheme 2). In the presence of an iodine cation as a weak Lewis acid and activating reagent, 1 can form the iodonium intermediate A, which is in resonance with the keteniminium ion A′.20 Then, the nucleo-

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Table 2

Organic & Biomolecular Chemistry Scope of trans-iodofluorination of ynamides (1) with Et3N·3HFa

Yield of (E)-2 (%)

Ratio of (E)-2/(Z)-2b

Ph (1a) p-MeC6H4 (1b) p-MeOC6H4 (1c) p-BrC6H4 (1d) p-NO2C6H4 (1e) n-C4H9 (1f) n-C8H17 (1g) (E)-Styrenyl (1h)

85 (E-2a) 81 (E-2b) 68 (E-2c) 79 (E-2d) 75 (E-2e) 64 (E-2f) 62 (E-2g) 75 (E-2h)

95/5 92/8 92/8 95/5 96/4 98/2 98/2 99/1

9

Ph (1i)

60 (E-2i)

95/5

10 11

Ph (1j) c-Propyl (1k)

72 (E-2j) 78 (E-2k)

92/8 98/2

12

Ph (1l)

53 (E-2l)

93/7

13

Ph (1m)

77 (E-2m)

93/7

14

Ph (1n)

56 (E-2n)

95/5

15

Ph (1o)

50 (E-2o)

89/11

16

n-C4H9 (1p)

56 (E-2p)

98/2

17

Ph (1q)

76 (E-2q)

>99/1

Entry

R1

1 2 3 4 5 6 7 8

18

c

R2

Ph (1r)

51 (E-2r)

Scheme 2

Proposed reaction mechanism.

Scheme 3

Scale-up experiment of (E)-2a and its synthetic applications.

91/9

a

Reaction conditions: 1 (0.3 mmol), NIS (1.2 equiv.), Et3N·3HF (1.0 equiv.) and CH3CN (3 mL), reflux in a sealed tube, 80 °C. b Determined by 19F NMR analysis of the crude product. c Combined yield of a mixture of E-2r/Z-2r/3r which cannot be separated by flash column chromatography.

phile fluoride ion attacks A′ selectively from the less hindered face to afford (E)-2 as the major product. To demonstrate the synthetic utility of the methodology, the reaction of 1a with NIS and Et3N·3HF was extended to an 8 mmol scale and the expected compound E-2a was still furnished in 80% isolated yield (Scheme 3, eqn (1)). The α-fluoro-β-iodoenamide products obtained in this study are useful intermediates for the stereospecific synthesis of α-fluoroenamides (Scheme 3, eqn (2) and (3)). The α-fluoro-

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Fig. 1 ORTEP drawing of the X-ray structure of (E)-2a with 30% thermal ellipsoids.

β-phenylenamide 6 and the α-fluoro-β-cyanoenamide 7 can be efficiently afforded in moderate yields via Pd-catalyzed coupling21 and CuCN-mediated cyanation,22 respectively.

Conclusion In conclusion, we have developed a metal-free trans-iodofluorination of ynamides with high levels of regio- and stereocontrol, thus providing more opportunities to construct stereospecific α-fluoroenamides compared with our previous protocols.2e,f Additionally, the reaction employs mild Et3N·3HF as the fluorinating agent and tolerates a variety of functional groups such as –NO2, –X, –OMe, alkenyl, and other substituents. Further studies on the synthetic application of this protocol and the cis-iodofluorination of ynamides are underway in our laboratory.

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General methods All NMR spectra were recorded on a Bruker ASCEND™ 400 spectrometer. 1H and 13C NMR spectral data are reported as chemical shifts (δ) in parts per million ( ppm) relative to tetramethylsilane. 19F NMR spectra are referenced relative to CFCl3 (as the external standard) in CDCl3. Chemical shifts (δ) are quoted in parts per million ( ppm) and coupling constants ( J) are measured in hertz (Hz). The following abbreviations are used to describe multiplicities s = singlet, d = doublet, t = triplet, q = quartet, pent = pentet, br = broad, m = multiplet. NMR spectra were processed using the Bruker’s TopSpin™ software package. High resolution mass spectra (HRMS, m/z) were recorded on a Bruker MicroTOF spectrometer using positive electrospray ionization (ESI) or on a Micromass GCT spectrometer using field ionization (EI/FI) or chemical ionization (CI). IR spectra were recorded on a Thermo Scientific Nicolet iS5 FT-IR spectrometer. Absorptions are measured in wavenumbers and only the peaks of interest are reported. Melting points of solids were measured on a Griffin apparatus and are uncorrected. IUPAC names were obtained using the ACD/ILab service. Weighing was performed with a 4 decimal place balance. Reactions were monitored by thin-layer chromatography, carried out on 0.25 mm silica gel plates. Visualization was performed with a 254 nm UV lamp or iodine. Flash column chromatography was performed using silica gel. Characterization data for these compounds not described in the literature are provided. Materials Phenylacetylene, p-methylphenylacetylene, p-methoxyphenylacetylene, p-bromophenylacetylene, p-nitrophenylacetylene, 1-hexyne, dec-1-yne, oxazolidin-2-one and pyrrolidin-2-one were purchased from commercial sources and used as received. The ynamide substrates 1a–1r were prepared according to literature methods.15 General procedure for the trans-iodofluorination of ynamides (E)-N-Benzyl-N-(1-fluoro-2-iodo-2-phenylvinyl)-4-methylbenzenesulfonamide (E-2a). A sealed tube was charged with 1a (73.3 mg, 0.2 mmol) and NIS (54.1 mg, 0.24 mmol). To this mixture was added Et3N·3HF (32.5 mg, 0.2 mmol) in CH3CN (2.0 mL) and the reaction mixture was capped and heated at 80 °C for 3.3 h until no starting material was detected by TLC and KMnO4 solution monitoring. Then, the reaction was quenched by the addition of H2O (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (5 mL) and dried over anhydrous Na2SO4. Filtration, evaporation, and chromatography on silica gel (eluent: petroleum ether/acetone = 50/1) afforded E-2a (87.5 mg, yield: 85%) as a white solid. Mp: 117–118 °C. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.89 (d, J = 8.0 Hz, 2 H), 7.50 (d, J = 8.2 Hz, 2 H), 7.40–7.24 (m, 8 H), 7.11 (d, J = 8.0 Hz, 2 H), 4.52 (s, 2 H), 2.45 (s, 3 H). 1H NMR (400 MHz, DMSO-d6, 50 °C, ppm): δ 7.89 (d, J = 8.2 Hz, 2 H), 7.50 (d, J = 8.2 Hz, 2 H),

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7.39–7.24 (m, 8 H), 7.11 (d, J = 8.0 Hz, 2 H), 4.55 (s, 2 H), 2.45 (s, 3 H). 13C NMR (100 MHz, DMSO-d6, ppm): δ 145.9 (d, J = 281 Hz), 145.2, 137.8, 135.7, 133.9, 130.6, 130.1, 129.19, 129.17, 129.0, 128.8, 128.4, 86.1 (d, J = 40 Hz), 52.2, 21.6. DEPT135 (100 MHz, DMSO-d6, ppm): δ 130.6, 130.1, 129.20 (d, J = 1 Hz), 129.16, 129.0, 128.8, 128.4, 52.2, 21.6. 19F NMR (376 MHz, DMSO-d6, ppm): δ −75.5. HRMS (ESI, CH3OH): m/z 530.0033 (m/z theoretical: 530.0057) for C22H19FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 3088, 3057, 3038, 2946, 1661, 1596, 1489, 1460, 1444, 1352, 1164, 1089, 1021, 1010, 930. (E)-N-Benzyl-N-(1-fluoro-2-iodo-2-( p-tolyl)vinyl)-4-methylbenzenesulfonamide (E-2b). The reaction of 1b (112.5 mg, 0.3 mmol), NIS (81.9 mg, 0.36 mmol) and Et3N·3HF (48.2 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 3.3 h afforded E-2b (126.4 mg, yield: 81%) as a yellow solid. Mp: 113–116 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.86 (d, J = 7.6 Hz, 2 H), 7.46–7.26 (m, 7 H), 7.19–6.89 (m, 4 H), 4.50 (s, 2 H), 2.46 (s, 3 H), 2.31 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 145.7 (d, J = 281 Hz), 144.5, 138.9, 135.8, 134.4 (d, J = 2 Hz), 133.2, 130.0, 129.8, 129.1 (d, J = 3 Hz), 128.8, 128.6, 128.4, 128.3, 85.5 (d, J = 44 Hz), 52.4, 21.7, 21.2. 19F NMR (376 MHz, CDCl3, ppm): δ −76.2. HRMS (ESI, CH3OH): m/z 544.0192 (m/z theoretical: 544.0219) for C23H21FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 3028, 2921, 1657, 1594, 1456, 1361, 1168, 1087, 1003, 912. (E)-N-Benzyl-N-(1-fluoro-2-iodo-2-(4-methoxyphenyl)vinyl)-4methylbenzenesulfonamide (E-2c). The reaction of 1c (118.0 mg, 0.3 mmol), NIS (81.1 mg, 0.36 mmol) and Et3N·3HF (48.6 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 4.6 h afforded E-2c (109.8 mg, yield: 68%) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.86 (d, J = 8.0 Hz, 2 H), 7.39–7.28 (m, 7 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.77 (d, J = 9.2 Hz, 2 H), 4.50 (s, 2 H), 3.78 (s, 3 H), 2.46 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 159.7, 145.5 (d, J = 280 Hz), 144.5, 135.9, 133.2, 130.7 (d, J = 3 Hz), 130.0, 129.8, 129.5 (d, J = 2 Hz), 128.6, 128.4, 128.3, 113.4, 85.5 (d, J = 43 Hz), 55.3, 52.4, 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −76.9. HRMS (ESI, CH3OH): m/z 560.0142 (m/z theoretical: 560.0163) for C23H21FINNaO3S [M + Na]+. IR ν (KBr, cm−1): 2988, 2971, 2901, 1678, 1509, 1453, 1358, 1250, 1076, 1066, 964. (E)-N-Benzyl-N-(2-(4-bromophenyl)-1-fluoro-2-iodovinyl)-4-methyl benzenesulfonamide (E-2d). The reaction of 1d (132.6 mg, 0.3 mmol), NIS (81.6 mg, 0.36 mmol) and Et3N·3HF (48.6 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 5.0 h afforded E-2d (139.7 mg, yield: 79%) as a yellow solid. Mp: 85–88 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.85 (d, J = 8.4 Hz, 2 H), 7.42–7.28 (m, 9 H), 7.04 (d, J = 8.0 Hz, 2 H), 4.45 (s, 2 H), 2.47 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 146.3 (d, J = 283 Hz), 144.7, 136.2 (d, J = 3 Hz), 135.6, 133.0, 131.3, 130.8 (d, J = 3 Hz), 130.0, 129.9, 128.7, 128.5, 128.3, 122.9, 83.7 (d, J = 44 Hz), 52.3, 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −74.3. HRMS (ESI, CH3OH): m/z 607.9129 (m/z theoretical: 607.9163) for C22H18BrFINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2988, 2901, 1644, 1596, 1488, 1453, 1394, 1377, 1355, 1250, 1166, 1076, 1066, 1057, 926. (E)-N-Benzyl-N-(1-fluoro-2-iodo-2-(4-nitrophenyl)vinyl)-4-methylbenzenesulfonamide (E-2e). The reaction of 1e (122.1 mg,

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0.3 mmol), NIS (81.7 mg, 0.36 mmol) and Et3N·3HF (49.0 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 4.0 h afforded E-2e (125.0 mg, yield: 75%) as a yellow solid. Mp: 81–84 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 8.1 (d, J = 8.8 Hz, 2 H), 7.86 (d, J = 8.0 Hz, 2 H), 7.43–7.28 (m, 9 H), 4.51 (s, 2 H), 2.47 (s, 3 H). 13 C NMR (100 MHz, CDCl3, ppm): δ 147.5, 147.4 (d, J = 286 Hz), 145.0, 143.7 (d, J = 2 Hz), 135.4, 132.7, 130.3 (d, J = 3 Hz), 130.0 (d, J = 1 Hz), 128.9, 128.6, 128.3, 123.4, 81.7 (d, J = 43 Hz), 52.3, 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −71.3. HRMS (ESI, CH3OH): m/z 574.9980 (m/z theoretical: 574.9908) for C22H18FIN2NaO4S [M + Na]+. IR ν (KBr, cm−1): 2988, 2901, 1648, 1595, 1509, 1455, 1345, 1250, 1164, 1076, 1066, 1057, 924. (E)-N-Benzyl-N-(1-fluoro-2-iodohex-1-en-1-yl)-4-methyl-benzenesulfonamide (E-2f). The reaction of 1f (102.3 mg, 0.3 mmol), NIS (82.1 mg, 0.36 mmol) and Et3N·3HF (48.2 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 3.5 h afforded E-2f (93.9 mg, yield: 64%) as a yellow solid. Mp: 60–64 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.81 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.30–7.22 (m, 5 H), 4.33 (s, 2 H), 2.45 (s, 3 H), 2.38 (s, 2 H), 1.45–1.20 (m, 2 H), 1.19–0.95 (m, 2 H), 0.81 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 146.0 (d, J = 276 Hz), 144.4, 135.9, 133.3, 129.9, 129.8, 128.4, 128.3, 128.2, 91.0 (d, J = 47 Hz), 52.2, 35.8 (d, J = 1 Hz), 30.6 (d, J = 2 Hz), 21.7, 21.0, 13.7. 19F NMR (376 MHz, CDCl3, ppm): δ −81.5. HRMS (ESI, CH3OH): m/z 510.0347 (m/z theoretical: 510.0370) for C20H23FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 3068, 3033, 2957, 2922, 2871, 1673, 1596, 1495, 1463, 1352, 1249, 1172, 1088, 1022, 976. (E)-N-Benzyl-N-(1-fluoro-2-iododec-1-en-1-yl)-4-methylbenzenesulfonamide (E-2g). The reaction of 1g (119.7 mg, 0.3 mmol), NIS (81.0 mg, 0.36 mmol) and Et3N·3HF (48.8 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 4.6 h afforded E-2g (100.9 mg, yield: 62%) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.82 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 3 H), 7.27–7.24 (m, 4 H), 4.42 (s, 2 H), 2.46 (s, 3 H), 2.37 (s, 2 H), 1.40–1.16 (m, 12 H), 0.88 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 146.0 (d, J = 276 Hz), 144.4, 135.9, 133.3, 129.8, 129.7, 128.4, 128.3, 128.2, 91.0 (d, J = 47 Hz), 52.2, 36.1, 31.9, 29.2 (d, J = 6 Hz), 28.5 (d, J = 2 Hz), 27.9, 22.7, 21.7, 14.1. 19F NMR (376 MHz, CDCl3, ppm): δ −81.6. HRMS (ESI, CH3OH): m/z 566.0976 (m/z theoretical: 566.0996) for C24H31FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2926, 2856, 1671, 1597, 1496, 1456, 1363, 1167, 1089, 892. N-Benzyl-N-((1E,3E)-1-fluoro-2-iodo-4-phenylbuta-1,3-dien-1-yl)4-methylbenzenesulfonamide (E-2h). The reaction of 1h (116.1 mg, 0.3 mmol), NIS (81.5 mg, 0.36 mmol) and Et3N·3HF (48.6 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 20 h afforded E-2h (120.2 mg, yield: 75%) as a yellow solid. Mp: 125–129 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.84 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 7.2 Hz, 2 H), 7.38–7.21 (m, 10 H), 6.77 (d, J = 15.2 Hz, 1 H), 6.54 (dd, J = 15.2, 2.0 Hz, 1 H), 4.50 (s, 2 H), 2.46 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 147.0 (d, J = 288 Hz), 144.6, 140.6 (d, J = 4 Hz), 136.04, 135.96, 133.4, 129.9, 129.7, 128.8, 128.7, 128.6, 128.53, 128.45, 128.3, 127.3, 122.0 (d, J = 1 Hz), 88.9 (d, J = 38 Hz), 52.9 (d, J = 1 Hz), 21.7.

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Organic & Biomolecular Chemistry

F NMR (376 MHz, CDCl3, ppm): δ −73.9. HRMS (ESI, CH3OH): m/z 556.0196 (m/z theoretical: 556.0214) for C24H21FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2973, 2901, 1618, 1595, 1495, 1456, 1354, 1169, 1085, 942. (E)-N-(1-Fluoro-2-iodo-2-phenylvinyl)-4-methyl-N-phenyl-benzenesulfonamide (E-2i). The reaction of 1i (139.1 mg, 0.4 mmol), NIS (108.8 mg, 0.48 mmol) and Et3N·3HF (64.1 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 4 h afforded E-2i (118.7 mg, yield: 60%) as a yellow solid. Mp: 60–63 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.58 (d, J = 8.0 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.42–7.15 (m, 10 H), 2.38 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 147.1 (d, J = 285 Hz), 144.7, 137.5 (d, J = 5 Hz), 137.0 (d, J = 2 Hz), 135.3, 129.6 (d, J = 3 Hz), 129.5, 129.4, 129.1, 128.7, 128.5 (d, J = 1 Hz), 128.3, 127.8 (d, J = 2 Hz), 84.2 (d, J = 43 Hz), 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −72.0. HRMS (ESI, CH3OH): m/z 515.9880 (m/z theoretical: 515.9901) for C21H17FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2972, 2901, 1594, 1489, 1368, 1259, 1172, 1075, 1066, 1051, 991. (E)-N-(1-Fluoro-2-iodo-2-phenylvinyl)-N-4-dimethylbenzenesulfonamide (E-2j). The reaction of 1j (114.3 mg, 0.4 mmol), NIS (108.4 mg, 0.48 mmol) and Et3N·3HF (64.3 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 4 h afforded E-2j (122.7 mg, yield: 72%) as a brown oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.83 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 7.6 Hz, 2 H), 7.38–7.22 (m, 5 H), 3.06 (d, J = 1.6 Hz, 3 H), 2.43 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 146.9 (d, J = 284 Hz), 143.5, 135.7 (d, J = 3 Hz), 134.0, 128.7, 128.5 (d, J = 4 Hz), 127.9, 127.2, 81.6 (d, J = 44 Hz), 34.3 (d, J = 1 Hz), 20.6. 19F NMR (376 MHz, CDCl3, ppm): δ −79.9. HRMS (ESI, CH3OH): m/z 453.9727 (m/z theoretical: 453.9744) for C16H15FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2971, 2923, 1650, 1596, 1444, 1358, 1270, 1170, 1088, 1050, 939. (E)-N-(2-Cyclopropyl-1-fluoro-2-iodovinyl)-N-4-dimethylbenzenesulfonamide (E-2k). The reaction of 1k (99.6 mg, 0.4 mmol), NIS (108.2 mg, 0.48 mmol) and Et3N·3HF (65.0 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 3.7 h afforded E-2k (123.2 mg, yield: 78%) as a yellow solid. Mp: 66–69 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.81 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 2.96 (s, 3 H), 2.45 (s, 3 H), 1.26 (s, 1 H), 1.0–0.70 (m, 4 H). 13C NMR (100 MHz, CDCl3, ppm): δ 148.6 (d, J = 278 Hz), 144.3, 135.2, 129.7, 128.2, 94.8 (d, J = 44 Hz), 35.3 (d, J = 2 Hz), 21.6, 14.7 (d, J = 3 Hz), 9.0. 19F NMR (376 MHz, CDCl3, ppm): δ −86.1. HRMS (ESI, CH3OH): m/z 417.9727 (m/z theoretical: 417.9744) for C13H15FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2923, 1665, 1596, 1456, 1354, 1251, 1161, 1087, 1046, 994. (E)-N-Allyl-N-(1-fluoro-2-iodo-2-phenylvinyl)-4-methylbenzenesulfonamide (E-2l). The reaction of 1l (125.4 mg, 0.4 mmol), NIS (108.3 mg, 0.48 mmol) and Et3N·3HF (65.4 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 3.7 h afforded E-2l (97.2 mg, yield: 53%) as a brown solid. Mp: 79–82 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.83 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.37–7.24 (m, 5 H), 5.95–5.75 (m, 1 H), 5.35–5.15 (m, 2 H), 4.00 (s, 2 H), 2.44 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 146.3 (d, J = 283 Hz), 144.6, 137.1 (d, J = 2 Hz), 19

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135.8, 130.8, 129.8, 129.5 (d, J = 3 Hz), 128.9, 128.2, 120.9, 85.1 (d, J = 44 Hz), 51.6 (d, J = 2 Hz), 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −75.6. HRMS (ESI, CH3OH): m/z 479.9884 (m/z theoretical: 479.9901) for C18H17FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2971, 2923, 1654, 1444, 1359, 1166, 1088, 1047, 984. (E)-N-Benzyl-N-(1-fluoro-2-iodo-2-phenylvinyl)methanesulfonamide (E-2m). The reaction of 1m (85.4 mg, 0.3 mmol), NIS (81.0 mg, 0.36 mmol) and Et3N·3HF (49.1 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 5.5 h afforded E-2m (99.4 mg, yield: 77%) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.52–7.46 (m, 2 H), 7.44–7.37 (m, 3 H), 7.32–7.24 (m, 5 H), 4.73 (s, 2 H), 2.99 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 145.5 (d, J = 281 Hz), 135.8 (d, J = 2 Hz), 132.6, 128.9, 128.2 (d, J = 3 Hz), 127.9 (d, J = 5 Hz), 127.8, 127.2, 83.3 (d, J = 44 Hz), 52.6 (d, J = 2 Hz), 40.7. 19F NMR (376 MHz, CDCl3, ppm): δ −73.3. HRMS (ESI, CH3OH): m/z 453.9727 (m/z theoretical: 453.9744) for C16H15FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2930, 1656, 1456, 1443, 1352, 1155, 1038, 1026, 961. (E)-N-(1-Fluoro-2-iodo-2-phenylvinyl)-N-methylmethanesulfonamide (E-2n). The reaction of 1n (62.7 mg, 0.3 mmol), NIS (81.8 mg, 0.36 mmol) and Et3N·3HF (48.6 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 4.7 h afforded E-2n (70.5 mg, purity: 91%, yield: 56%) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.48 (d, J = 8.0 Hz, 2 H), 7.39–7.27 (m, 3 H), 3.25 (d, J = 2.0 Hz, 3 H), 3.10 (s, 3 H). 19F NMR (376 MHz, CDCl3, ppm): δ −79.7. HRMS (ESI, CH3OH): m/z 377.9433 (m/z theoretical: 377.9431) for C10H11FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 2940, 1689, 1655, 1529, 1443, 1346, 1273, 1151, 1048, 964. (E)-3-(1-Fluoro-2-iodo-2-phenylvinyl)oxazolidin-2-one (E-2o). The reaction of 1o (75.6 mg, 0.4 mmol), NIS (108.9 mg, 0.48 mmol) and Et3N·3HF (64.2 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 4.0 h afforded E-2o (67.1 mg, yield: 50%) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.51 (d, J = 7.2 Hz, 2 H), 7.40–7.20 (m, 3 H), 4.51 (t, J = 7.8 Hz, 2 H), 3.98 (t, J = 6.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3, ppm): δ 153.9 (d, J = 4 Hz), 144.3 (d, J = 275 Hz), 136.1 (d, J = 3 Hz), 129.6 (d, J = 3 Hz), 129.1, 128.3, 80.4 (d, J = 41 Hz), 63.0, 44.0 (d, J = 3 Hz). 19F NMR (376 MHz, CDCl3, ppm): δ −82.3. HRMS (ESI, CH3OH): m/z 355.9540 (m/z theoretical: 355.9554) for C11H9FINNaO2 [M + Na]+. IR ν (KBr, cm−1): 2962, 2922, 2853, 1768, 1660, 1478, 1444, 1395, 1298, 1206, 1131, 1041, 1008, 967. (E)-3-(1-Fluoro-2-iodohex-1-en-1-yl)oxazolidin-2-one (E-2p). The reaction of 1p (73.4 mg, 0.43 mmol), NIS (108.9 mg, 0.48 mmol) and Et3N·3HF (63.4 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 14 h afforded E-2p (77.5 mg, yield: 56%) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 4.48 (t, J = 8.0 Hz, 2 H), 3.88 (td, J = 8.3, 3.08 Hz, 2 H), 2.52 (td, J = 7.2, 2.9 Hz, 2 H), 1.57–1.47 (m, 2 H), 1.42–1.29 (m, 2 H), 0.93 (t, J = 7.2, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 154.2 (d, J = 4 Hz), 144.4 (d, J = 267 Hz), 86.1 (d, J = 45 Hz), 62.9, 43.9 (d, J = 3 Hz), 35.0, 30.9 (d, J = 3 Hz), 21.4, 13.8. 19F NMR (376 MHz, CDCl3, ppm): δ −87.1. HRMS (ESI, CH3OH): m/z 335.9851 (m/z theoretical: 335.9867) for C9H13FINNaO2 [M + Na]+. IR

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ν (KBr, cm−1): 2958, 2928, 2872, 1774, 1684, 1480, 1399, 1300, 1215, 1147, 1111, 1035, 983. (E)-tert-Butyl-(1-fluoro-2-iodo-2-phenylvinyl)(phenyl)carbamate (E-2q). The reaction of 1q (118.0 mg, 0.4 mmol), NIS (108.0 mg, 0.48 mmol) and Et3N·3HF (64.5 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 4.0 h afforded E-2q (132.7 mg, yield: 76%) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.54–7.44 (m, 4 H), 7.43–7.29 (m, 5 H), 7.26–7.18 (m, 1 H), 1.58 (s, 9 H). 13C NMR (100 MHz, CDCl3, ppm): δ 151.4 (d, J = 5 Hz), 148.4 (d, J = 278 Hz), 138.4 (d, J = 5 Hz), 137.2 (d, J = 3 Hz), 129.4 (d, J = 3 Hz), 129.0, 128.8, 128.3, 126.9, 125.2, 83.0, 80.3 (d, J = 44 Hz), 28.2. 19F NMR (376 MHz, CDCl3, ppm): δ −73.7. HRMS (ESI, CH3OH): m/z 462.0311 (m/z theoretical: 462.0337) for C19H19FINNaO2 [M + Na]+. IR ν (KBr, cm−1): 2977, 2929, 1784, 1733, 1667, 1596, 1495, 1394, 1369, 1318, 1155, 1057, 886. (E)-1-(1-Fluoro-2-iodo-2-phenylvinyl)pyrrolidin-2-one (E-2r). The reaction of 1r (75.1 mg, 0.4 mmol), NIS (108.6 mg, 0.48 mmol) and Et3N·3HF (64.3 mg, 0.4 mmol) in CH3CN (4.0 mL) at 80 °C for 4.7 h afforded 2r (66.9 mg, combined yield: 51%, E-2r/Z-2r/3r = 90/8/2) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.52 (d, J = 7.8 Hz, 2 H), 7.40–7.23 (m, 3 H), 7.04 (td, J = 7.0 Hz, 2.0 Hz, 2 H), 2.29–2.15 (m, 2 H). 19 F NMR (376 MHz, CDCl3, ppm): δ −80.5. HRMS (ESI, CH3OH): m/z 353.9764 (m/z theoretical: 353.9762) for C12H11FINNaO [M + Na]+. (E)-N-Benzyl-N-(2-bromo-1-fluoro-2-phenylvinyl)-4-methylbenzenesulfonamide (4). The reaction of 1a (108.3 mg, 0.3 mmol), NBS (64.7 mg, 0.36 mmol) and Et3N·3HF (49.0 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 3.6 h afforded E-4 (58.2 mg, yield: 42%) and Z-4 (32.9 mg, yield: 24%). E-4: yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.86 (d, J = 8.2 Hz, 2 H), 7.37–7.25 (m, 12 H), 4.54 (s, 2 H), 2.45 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 145.0 (d, J = 278 Hz), 144.6, 135.9, 134.3, 133.5, 129.9, 129.6, 129.2, 129.1 (d, J = 4 Hz), 128.6, 128.5, 128.2 (d, J = 3 Hz), 110.7 (d, J = 51 Hz), 52.2 (d, J = 2 Hz), 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −82.3. HRMS (ESI, CH3OH): m/z 482.0196 (m/z theoretical: 482.0196) for C22H19BrFNNaO2S [M + Na]+. IR ν (KBr, cm−1): 3060, 2925, 1655, 1597, 1459, 1444, 1360, 1172, 1088, 1048, 932. Z-4: yellow oil (impurity). 1H NMR (400 MHz, CDCl3, ppm): δ 7.72 (d, J = 8.1 Hz, 2 H), 7.36–7.08 (m, 12 H), 6.88 (d, J = 7.4 Hz, 2 H) 4.14 (s, 2 H), 2.46 (s, 3 H). 19F NMR (376 MHz, CDCl3, ppm): δ −79.7. HRMS (ESI, CH3OH): m/z 482.0194 (m/z theoretical: 482.0196) for C22H19BrFNNaO2S [M + Na]+. (E)-N-Benzyl-N-(2-chloro-1-fluoro-2-phenylvinyl)-4-methylbenzenesulfonamide (5). The reaction of 1a (108.5 mg, 0.3 mmol), NCS (48.5 mg, 0.36 mmol) and Et3N·3HF (49.0 mg, 0.3 mmol) in CH3CN (3.0 mL) at 80 °C for 3.5 h afforded E-5 (38.3 mg, yield: 31%) and Z-5 (30.0 mg, yield: 24%). E-5: yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.86 (d, J = 8.2 Hz, 2 H), 7.39–7.23 (m, 12 H), 4.55 (s, 2 H), 2.46 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 144.9 (d, J = 275 Hz), 144.6, 136.0, 133.7, 132.8, 129.9, 129.3 (d, J = 4 Hz), 129.3, 128.5 (d, J = 4 Hz), 128.53, 128.49, 128.4, 128.1 (d, J = 6 Hz), 120.2 (d, J = 53 Hz), 52.2 (d, J = 2 Hz), 21.7. 19F NMR (376 MHz, CDCl3,

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ppm): δ −88.3. HRMS (ESI, CH3OH): m/z 438.0741 (m/z theoretical: 438.0701) for C22H19ClFNNaO2S [M + Na]+. IR ν (KBr, cm−1): 3060, 2924, 1660, 1597, 1495, 1444, 1362, 1170, 1089, 1051, 957. Z-5: yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.74 (d, J = 8.0 Hz, 2 H), 7.38–7.08 (m, 10 H), 6.88 (d, J = 7.4 Hz, 2 H), 4.17 (s, 2 H), 2.45 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 144.7, 144.4 (d, J = 277 Hz), 135.3, 133.0 (d, J = 3 Hz), 129.9, 129.4, 129.0, 128.8 (d, J = 3 Hz), 128.44, 128.37, 128.3 (d, J = 2 Hz), 128.0, 118.5 (d, J = 35 Hz), 52.4 (d, J = 2 Hz), 81.0 (d, J = 44 Hz), 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −87.7. HRMS (ESI, CH3OH): m/z 438.0740 (m/z theoretical: 438.0701) for C22H19ClFNNaO2S [M + Na]+. IR ν (KBr, cm−1): 3065, 3033, 2923, 2852, 1673, 1597, 1494, 1446, 1359, 1166, 1090, 1027, 929. A large scale reaction (E)-N-Benzyl-N-(1-fluoro-2-iodo-2-phenylvinyl)-4-methylbenzenesulfonamide (E-2a) and (Z)-N-benzyl-N-(1-fluoro-2-iodo-2-phenylvinyl)-4-methylbenzenesulfonamide (Z-2a). A sealed round bottom flask was charged with 1a (2.8884 mg, 8.0 mmol) and NIS (2.1628 mg, 9.6 mmol). To this mixture was added Et3N·3HF (1.2289 mg, 8.0 mmol) in CH3CN (80 mL) and the reaction mixture was capped and heated at 80 °C for 3.3 h until no starting material was detected by TLC and KMnO4 solution monitoring. Then, the reaction was quenched by the addition of H2O (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous Na2SO4. Filtration, evaporation, and chromatography on silica gel (eluent: petroleum ether/acetone = 50/1) afforded E-2a (3.2448 mg, yield: 80%) and Z-2a (0.1622 g, yield: 4%). Z-2a: white solid. Mp: 105–107 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.70 (d, J = 7.9 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.27–7.13 (m, 6 H), 7.04 (d, J = 7.0 Hz, 2 H), 6.86 (d, J = 7.4 Hz, 2 H), 4.09 (s, 2 H), 2.45 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 146.8 (d, J = 272 Hz), 144.6, 137.0, 135.4, 133.2, 129.8, 129.4 (d, J = 3 Hz), 129.3, 128.5 (d, J = 4 Hz), 128.5, 128.3 (d, J = 3 Hz), 128.0, 81.0 (d, J = 44 Hz), 52.2, 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −66.5. HRMS (ESI, CH3OH): m/z 530.0032 (m/z theoretical: 530.0057) for C22H19FINNaO2S [M + Na]+. IR ν (KBr, cm−1): 3065, 2988, 2971, 2921, 2901, 1658, 1597, 1496, 1442, 1350, 1163, 1088, 1075, 1057, 923. N-Benzyl-N-(1-fluoro-2,2-diphenylvinyl)-4-methylbenzenesulfonamide (6). To a solution of E-2a (203.3 mg, 0.4 mmol) in DMF/H2O (3 mL/0.6 mL) were added Pd(PPh3)4 (9.3 mg, 0.008 mmol), K2CO3 (110.4 mg, 0.8 mmol), and phenylboronic acid (73.9 mg, 0.6 mmol). The resulting solution was stirred at 100 °C for 12.5 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with aqueous NH4Cl (3 × 10 mL). After drying the organic phase over anhydrous NaSO4, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using hexane and ethyl acetate (80 : 1) as eluents to give the desired fluorinated product 6 (137.1 mg, 75%) as a yellow solid. Mp: 113–117 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.73 (d, J = 7.2 Hz, 2 H), 7.41–7.11 (m, 11 H), 7.10–6.94 (m, 4 H), 6.87 (d, 2 H),

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Organic & Biomolecular Chemistry

4.17 (s, 2 H), 2.42 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 144.38, 144.36 (d, J = 276 Hz), 136.7 (d, J = 4 Hz), 136.4 (d, J = 4 Hz), 136.1, 134.0, 129.9 (d, J = 3 Hz), 129.7, 129.6 (d, J = 4 Hz), 129.4, 128.4, 128.3 (d, J = 4 Hz), 128.1 (d, J = 1 Hz), 127.7 (d, J = 9 Hz), 123.9, 123.6, 52.2, 21.7. 19F NMR (376 MHz, CDCl3, ppm): δ −90.2. HRMS (ESI, CH3OH): m/z 480.1386 (m/z theoretical: 480.1404) for C28H24FNNaO2S [M + Na]+. IR ν (KBr, cm−1): 2971, 2923, 1674, 1594, 1491, 1442, 1346, 1215, 1158, 1080, 1044, 1013, 940. (E)-N-Benzyl-N-(2-cyano-1-fluoro-2-phenylvinyl)-4-methyl-benzenesulfonamide (7). To a solution of E-2a (203.1 mg, 0.4 mmol) in DMF (4 mL) was added CuCN (43.6 mg, 0.48 mmol). The resulting solution was stirred at 140 °C for 11.5 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with aqueous NH4Cl (3 × 10 mL). After drying the organic phase over anhydrous NaSO4, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using hexane and ethyl acetate (40 : 1) as eluents to give the desired fluorinated product 7 (111.7 g, yield: 69%) as a yellow solid. Mp: 81–85 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.91 (d, J = 8.2 Hz, 2 H), 7.40 (d, J = 6.8 Hz, 4 H), 7.37–7.21 (m, 8 H), 4.59 (s, 2 H), 2.48 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 155.2 (d, J = 298 Hz), 145.5, 134.6, 132.7, 130.3, 129.7, 129.2, 128.93, 128.86 (d, J = 4 Hz), 128.3, 128.2 (d, J = 7 Hz), 128.0 (d, J = 7 Hz), 115.2 (d, J = 8 Hz), 101.5 (d, J = 43 Hz), 52.5, 21.8. 19F NMR (376 MHz, CDCl3, ppm): δ −68.6. HRMS (ESI, CH3OH): m/z 429.1033 (m/z theoretical: 429.1043) for C23H19FN2NaO2S [M + Na]+. IR ν (KBr, cm−1): 2966, 2923, 2236, 1647, 1597, 1496, 1449, 1372, 1266, 1253, 1172, 1088, 1066, 1051, 929.

Conflicts of interest There are no conflicts to declare.

Acknowledgements The authors greatly acknowledge the financial support by the National Natural Science Foundation of China (No. 21301091), the Natural Science Foundation of Jiangsu province, China (Grant No. BK20140937), Jiangsu Planned Projects for Postdoctoral Research Funds (Grant No. 1402213 C) and the Industry-Academy-Research Prospective joint project of Jiangsu Province (Grant No. BY2016005-06).

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Organic & Biomolecular Chemistry

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Highly regio- and stereoselective trans-iodofluorination of ynamides enabling the synthesis of (E)-α-fluoro-β-iodoenamides.

A highly regio- and stereoselective trans-iodofluorination reaction of ynamides with NIS and Et3N·3HF has been achieved, affording (E)-α-fluoro-β-iodo...
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