Metal-free halonium mediated acetate shifts of ynamides to access α-halo acrylamides/acrylimides

Article abstract of DOI:10.1021/ol200269h

A metal-free acetate shift of 3-acetoxy ynamides to access α-iodo, bromo, and chloro acrylamides/acrylimides under very mild conditions is demonstrated. The inherent alkyne activation of ynamides is sufficient to ensure the α-halo acrylamides/acrylimides

Full text of DOI:10.1021/ol200269h

Metal-Free Halonium Mediated Acetate Shifts of Ynamides to
Access α-Halo Acrylamides/Acrylimides
Søren Kramer,1 Stig D. Friis,1 Zhuo Xin,1 Yann Odabachian,2 and Troels
Skrydstrup*,1
1 Department of Chemistry, Center for Insoluble Protein Structures,
and the Interdisciplinary Nanoscience Center,
Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
2 Département de Chimie, UMR 7652, CNRS/Ecole Polytechnique, 91128 Palaiseau, France
ts@chem.au.dk
CONTENTS:
1. General Methods
S2
S2
2. Synthesis of Ynamides
3. NIS and NBS Mediated Acetate Shift
4. NCS Mediated Acetate Shift
S4
S8
5. Selectfluor Mediated Acetate Shift
S10
S11
S12
S19
6. Attemps to Optimize the F+ Mediated Acetate Shift
7. 1H and 13C NMR of Ynamides (1a-g)
8. 1H and 13C NMR of α-Halo Acrylamides/Acrylimides (2a-n, 3a-g, 4)
1

1. General Methods
13
1H NMR spectra were recorded at 400 MHz and C NMR spectra were recorded at 100 MHz on
a Varian Mercury 400 spectrometer. The chemical shifts are reported in ppm relative to solvent
residual peak.1 The peak patterns are indicated as follows: br, broad; s, singlet; d, doublet; t,
triplet; q, quadruplet; m, multiplet; dd, doublet of doublets; dt, doublet of triplets; ddd, doublet of
doublet of doublets; ddt, doublet of doublet of triplets, and td, triplet of doublets. HRMS spectra
were recorded on a LC TOF (ES) apparatus. Flash chromatography was performed on silica gel
60 (230-400 mesh). All solvents were dried according to standard procedures. NIS, NBS, and
NCS were recrystalized before use. All reactions were carried out in a glove box under argon
atmosphere. All reactions were done in 8 mL sample vials with a Teflon sealed screwcap.
2. Synthesis of Ynamides
Preparation of the ynamides was done according to a modification of Hsung’s method2 on a 2.5
mmol scale based on the amide; however, K3PO4 was in all cases replaced by K2CO3.
Characterization of ynamides is listed below.
1-(N-Benzyl-4-methylphenylsulfonamido)oct-1-yn-3-yl acetate (1a)
1
Product obtained as a colorless solid. Yield: 87% (0.932 g). H NMR (400
MHz, CDCl3): δ (ppm) 7.73 (d, J = 8.4 Hz, 2H), 7.32-7.26 (m, 7H), 5.35 (t, J =
6.8 Hz, 1H), 4.54 (d, J = 13.6 Hz, 1H), 4.41 (d, J = 13.6 Hz, 1H), 2.44 (s, 3H), 2.00 (s, 3H), 1.66-
1.53 (m, 2H), 1.28-1.17 (m, 6H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm)
171.2, 144.7, 134.8, 134.5, 129.7 (2C), 129.0 (2C), 128.6 (2C), 128.4, 127.9 (2C), 79.2, 70.1,
64.6, 55.5, 34.7, 31.4, 24.8, 22.6, 21.8, 21.2, 14.1. HRMS: C24H29NO4S [M+Na+]; calculated:
450.1715, found: 450.1716.
3-(N-Benzyl-4-methylphenylsulfonamido)prop-2-ynyl acetate (1b)
Product obtained as a colorless solid. Yield: 54% (0.483 g). 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.74 (d, J = 8.4 Hz, 2H), 7.32-7.25 (m, 7H), 4.71 (s, 2H), 4.49
13
(s, 2H), 2.44 (s, 3H), 2.03 (s, 3H). C NMR (100 MHz, CDCl3): δ (ppm) 170.3, 144.8, 134.8,
1 Gottlieb, H.E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512.
2 (a) Sagamanova, I. K.; Kurtz, K. C. M.; Hsung, R. P. Org. Synth. 2007, 84, 359. (b) Zhang, X.; Zhang, Y.;
Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.;
Tracey, M. R.; J. Org. Chem. 2006, 71, 4170. (c) Zhang, Y.; Hsung, R. P. Tracey, M. R.; Kurtz, K. C. M.;
Vera, E. L. Org. Lett. 2004, 6, 1151. (d) Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J. Org.
Chem. 2008, 73, 9447.
2

134.4, 129.8 (2C), 128.8 (2C), 128.6 (2C), 128.4, 127.8 (2C), 80.4, 66.8, 55.5, 52.7, 21.7, 20.9.
HRMS: C19H19NO4S [M+Na+]; calculated: 380.0932, found: 380.0929.
3-(N-(2-Chlorophenethyl)-4-methylphenylsulfonamido)prop-2-ynyl acetate (1c)
1
The product was obtained as a colorless oil. Yield: 63% (0.641 g). H
NMR (400 MHz, CDCl3): δ (ppm) 7.73 (d, J = 8.4 Hz, 2H), 7.29 (m, 3H),
7.20-7.12 (m, 3H), 4.81 (s, 2H), 3.59 (t, J = 7.2 Hz, 2H), 3.04 (t, J = 7.2
13
Hz, 2H), 2.43 (s, 3H), 2.08 (s, 3H). C NMR (100 MHz, CDCl3): δ (ppm) 170.4, 144.8, 135.0,
134.7, 134.2, 131.4, 129.9 (2C), 129.6, 128.4, 127.7 (2C), 127.0, 79.9, 66.8, 52.8, 50.6, 32.4,
21.7, 20.9. HRMS: C20H20ClNO4S [M+Na+]; calculated: 428.0699, found: 428.0704.
1-(N-Isopropyl-4-methylphenylsulfonamido)oct-1-yn-3-yl acetate (1d)
1
Product was obtained as a pale yellow oil. Yield: 88% (0.837 g). H NMR
(400 MHz, CDCl3): δ (ppm) 7.78 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz,
2H), 5.47 (t, J = 6.8 Hz, 1H), 4.16 (septet, J = 6.4 Hz, 1H), 2.44 (s, 3H), 2.05 (s, 3H), 1.81-1.72
(m, 2H), 1.46-1.37 (m, 2H), 1.33-1.27 (m, 4H), 1.09 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H),
0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 170.2, 144.5, 136.0, 129.8 (2C),
127.6 (2C), 76.1, 71.5, 64.9, 52.4, 34.9, 31.4, 25.0, 22.6, 21.7, 21.2, 20.9, 20.7, 14.1. HRMS:
C20H29NO4S [M+Na+]; calculated: 402.1715, found: 402.1714.
1-(2-Oxooxazolidin-3-yl)oct-1-yn-3-yl acetate (1e)
1
Product obtained as a pale yellow oil. Yield: 68% (0.431 g). H NMR (400
MHz, CDCl3): δ (ppm) 5.49 (t, J = 6.8 Hz, 1H), 4.43 (dd, J = 8.4, 7.2 Hz,
2H), 3.91 (dd, J = 8.4, 7.2 Hz, 2H), 2.07 (s, 3H), 1.83-1.75 (m, 2H), 1.47-1.37
13
(m, 2H), 1.35-1.26 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl3): δ (ppm)
170.1, 156.0, 75.5, 69.5, 64.4, 64.1, 46.8, 34.8, 31.3, 24.8, 22.5, 21.2, 14.0. HRMS: C13H19NO4
[M+Na+]; calculated: 276.1212, found: 276.1212.
1-(N-Isopropyl-N-tosyl)-5-(4-methoxybenzyloxy)pent-1-yn-3-yl acetate (1f)
The product was obtained as a colorless oil. Yield: 62% (0.735 g). 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.76 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz,
2H), 7.24 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.64 (t, J = 6.8 Hz,
1H), 4.43 (d, J = 14.6 Hz, 1H), 4.40 (d, J = 14.6 Hz, 1H), 4.14 (septet, J = 6.6 Hz, 1H), 3.80 (s,
3H), 3.61-3.51 (m, 2H), 2.43 (s, 3H), 2.17-2.01 (m, 2H), 2.02 (s, 3H), 1.07 (d, J = 6.6 Hz, 3H),
3

13
1.05 (d, J = 6.6 Hz, 3H). C NMR (100 MHz, CDCl3): δ (ppm) 170.0, 159.3, 144.5, 136.0,
130.4, 129.8 (2C), 129.4 (2C), 127.6 (2C), 113.9 (2C), 76.3, 72.9, 71.2, 65.7, 62.3, 55.4, 52.5,
35.2, 21.7, 21.1, 20.9, 20.7. HRMS: C25H31NO6S [M+Na+]; calculated: 496.1770, found:
496.1772.
1-(N-Benzyl-4-methylphenylsulfonamido)-5-(1,3-dioxoisoindolin-2-yl)hex-1-yn-3-yl acetate
(1g)
1
Yield: 61% (0.809 g). H NMR (400 MHz, CDCl3): δ (ppm) 7.82-7.80 (m,
2H), 7.75 (d, J = 8.0 Hz, 2H), 7.70-7.68 (m, 2H), 7.31-7.24 (m, 7H), 5.37 (t, J
= 6.4 Hz, 1H), 4.50 (d , J = 13.6 Hz, 1H), 4.42 (d, J = 13.6 Hz, 1H), 3.79-3.72
13
(m, 1H), 3.68-3.61 (m, 1H), 2.42 (s, 3H), 2.04 (q, J = 6.4 Hz, 2H), 1.97 (s, 3H). C NMR (100
MHz, CDCl3): δ (ppm) 169.8, 168.2 (2C), 144.8, 134.8, 134.4, 134.1 (2C), 132.2 (2C), 129.9
(2C), 129.1 (2C), 128.6 (2C), 128.4, 128.0 (2C), 123.4 (2C), 80.0, 69.1, 62.1, 55.5, 34.1, 33.2,
21.8, 21.0. HRMS: C29H26N2O6S [M+Na+]; calculated: 553.1404, found: 553.1400.
3. NIS and NBS Mediated Acetate Shift
General Procedure A: To a vial were added the ynamide (0.200 mmol, 1 equiv), NaHCO3
(0.240 mmol, 1.2 equiv), and NXS (0.220 mmol, 1.1 equiv) followed by MeCN (4 mL) and the
vial sealed. Then the reaction was stirred at 40 °C. Upon reaction completion, the reaction
mixture was concentrated in vacuo. The crude reaction mixture was purified by flash
chromatography (15 cm silica gel, 2 cm diameter column), eluting with the solvent specified
below, yielding the product.
(Z)-N-Benzyl-2-iodo-N-tosyloct-2-enamide (2a)
The product was obtained according to general procedure A, as a colorless oil
(eluent 15% Et2O in pentane). Reaction Time: 30 min. Yield: 91% (93 mg).
1H NMR (400 MHz, CDCl3): δ (ppm) 7.69 (d, J = 8.4 Hz, 2H), 7.31-7.23 (m,
7H), 5.99 (t, J = 6.8 Hz, 1H), 4.98 (s, 2H), 2.42 (s, 3H), 2.07 (q, J = 6.8 Hz, 2H), 1.32-1.12 (m,
6H), 0.84 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 167.3, 146.8, 145.1, 136.3,
135.6, 129.6 (2C), 128.9 (2C), 128.8 (2C), 127.9, 127.8 (2C), 93.0, 51.4, 36.1, 31.4, 27.1, 22.5,
21.8, 14.0. HRMS: C22H26INO3S [M+Na+]; calculated: 534.0576, found: 534.0567.
4

(Z)-N-Benzyl-2-bromo-N-tosyloct-2-enamide (2b)
The product was obtained according to general procedure A, as a colorless oil
(eluent 20% EtOAc in pentane). Reaction Time: 30 min. Yield: 95% (89 mg).
1H NMR (400 MHz, CDCl3): δ (ppm) 6.68 (d, J = 8.4 Hz, 2H), 7.32-7.23 (m, 7H), 6.28 (t, J =
7.2 Hz, 1H), 4.99 (s, 2H), 2.42 (s, 3H), 2.15 (q, J = 7.2 Hz, 2H), 1.33-1.16 (m, 6H), 0.85 (t, J =
13
7.2 Hz, 3H). C NMR (100 MHz, CDCl3): δ (ppm) 166.4, 145.1, 141.5, 136.1, 135.5, 129.6
(2C), 128.8 (2C), 128.7 (2C), 128.0, 127.8 (2C), 115.7, 51.1, 31.4, 31.3, 27.1, 22.4, 22.8, 14.0.
HRMS: C22H26BrNO3S [M+Na+]; calculated: 486.0714, found: 486.0717.
N-Benzyl-2-iodo-N-tosylacrylamide (2c)
The product was obtained according to general procedure A, as a colorless solid
1
(eluent: 20% Et2O in pentane). Reaction Time: 45 min. Yield: 89% (79 mg). H
NMR (400 MHz, CDCl3): δ (ppm) 7.69 (d, J = 8.4 Hz, 2H), 7.32-7.24 (m, 7H), 6.29
(dd, J = 2.8, 0.4 Hz, 1H), 6.07 (dd, J = 2.8, 0.4 Hz, 1H), 5.02 (s, 2H), 2.42 (s, 3H). 13C NMR (100
MHz, CDCl3): δ (ppm) 166.8, 145.3, 136.1, 135.3, 133.0, 129.6 (2C), 128.9 (2C), 128.8 (2C),
128.0, 127.7 (2C), 94.0, 51.1, 21.8. HRMS: C17H16INO3S [M+Na+]; calculated: 463.9793, found:
463.9792.
N-Benzyl-2-bromo-N-tosylacrylamide (2d)
The product was obtained according to general procedure A, as a colorless oil (eluent
1
20% EtOAc in pentane). Reaction Time: 30 min. Yield: 87% (69 mg). H NMR
(400 MHz, CDCl3): δ (ppm) 7.68 (d, J =8.4 Hz, 2H), 7.33-7.25 (m, 7H), 5.98 (d, J = 2.8 Hz, 1H),
5.88 (d, J = 2.8 Hz, 1H), 5.03 (s, 2H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 165.6,
145.4, 136.0, 135.3, 129.6 (2C), 128.9 (2C), 128.8 (2C), 128.1, 127.8 (2C), 125.0, 120.5, 50.9,
21.8. HRMS: C17H16BrNO3S [M+Na+]; calculated: 415.9926, found: 415.9929.
2-Iodo-N-(2-chlorophenethyl)-N-tosylacrylamide (2e)
The product was obtained according to general procedure A, as a colorless oil
(eluent 20% Et2O in pentane). Reaction Time: 45 min. Yield: 85% (83 mg).
1H NMR (400 MHz, CDCl3): δ (ppm) 7.86 (d, J = 8.4 Hz, 2H), 7.35-7.30 (m,
4H), 7.24-7.17 (m, 2H), 5.99 (d, J = 2.6 Hz, 1H), 5.97 (d, J = 2.6 Hz, 1H), 4.06 (t, J = 7.2 Hz,
2H), 3.20 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 166.4, 145.4,
135.3, 135.1, 134.6, 132.3, 132.0, 129.7 (3C), 128.8 (2C), 128.7, 127.3, 93.3, 47.7, 34.4, 21.8.
HRMS: C18H17ClINO3S [M+Na+]; calculated: 511.9560, found: 511.9554.
5

2-Bromo-N-(2-chlorophenethyl)-N-tosylacrylamide (2f)
The product was obtained according to general procedure A, as a colorless oil
(eluent 20% Et2O in pentane). Reaction Time: 45 min. Yield: 72% (64 mg).
1H NMR (400 MHz, CDCl3): δ (ppm) 7.87 (d, J = 8.4 Hz, 2H), 7.34-7.27 (m,
4H), 7.23-7.17 (m, 2H), 5.77 (d, J = 2.8 Hz, 1H), 5.65 (d, J = 2.8 Hz, 1H), 4.10 (t, J = 7.2 Hz,
2H), 3.19 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 165.2, 145.4,
135.3, 135.1, 134.5, 131.9, 129.71 (2C), 129.68, 128.8 (2C), 128.7, 127.3, 124.2, 119.8, 47.3,
34.4, 21.8. HRMS: C18H17BrClNO3S [M+Na+]; calculated: 463.9699, found: 463.9696.
(Z)-2-Iodo-N-isopropyl-N-tosyloct-2-enamide (2g)
The product was obtained according to general procedure A, as a colorless oil
(eluent 10% Et2O in pentane). Reaction Time: 45 min. Yield: 91% (84 mg).
1H NMR (400 MHz, CDCl3): δ (ppm) 7.80 (d, J = 8.4 Hz, 2H), 7.32 (d, J =
8.4 Hz, 2H), 6.13 (t, J = 6.8 Hz, 1H), 4.32 (septet, J = 6.8 Hz, 1H), 2.44 (s, 3H), 2.18 (q, J = 6.2
Hz, 2H), 1.48 (d, J = 6.8 Hz, 6H), 1.46-1.38 (m, 2H), 1.34-1.27 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 167.9, 146.1, 144.8, 136.8, 129.7 (2C), 128.5 (2C), 95.9,
54.5, 36.2, 31.5, 27.2, 22.5, 21.7, 21.3 (2C), 14.0. HRMS: C18H26INO3S [M+Na+]; calculated:
486.0576, found: 486.0565.
(Z)-2-Bromo-N-isopropyl-N-tosyloct-2-enamide (2h)
The product was obtained according to general procedure A, as a colorless oil
(eluent 15% Et2O in pentane). Reaction Time: 45 min. Yield: 90% (75 mg).
1H NMR (400 MHz, CDCl3): δ (ppm) 7.80 (d, J = 8.4 Hz, 2H), 7.31 (d, J =
8.4 Hz, 2H), 6.37 (t, J = 6.8 Hz, 1H), 4.30 (septet, J = 6.8 Hz, 1H), 2.42 (s, 3H), 2.22 (q, J = 6.8
Hz, 2H), 1.46 (d, J = 6.8 Hz, 6H), 1.45-1.38 (m, 2H), 1.33-1.25 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 166.8, 144.8, 140.6, 136.6, 129.7 (2C), 128.5 (2C), 117.9,
54.4, 31.5, 31.4, 27.3, 22.4, 21.7, 21.4 (2C), 14.0. HRMS: C18H26BrNO3S [M+Na+]; calculated:
438.0714, found: 438.0714.
(Z)-3-(2-Iodooct-2-enoyl)oxazolidin-2-one (2i)
The product was obtained according to general procedure A, as a colorless oil
(eluent 50% Et2O in pentane). Reaction Time: 45 min. Yield: 89% (60 mg).
1H NMR (400 MHz, CDCl3): δ (ppm) 6.27 (t, J = 6.8 Hz, 1H), 4.44 (dd, J =
8.4, 7.2 Hz, 2H), 4.05 (dd, J = 8.4, 7.2 Hz, 2H), 2.29 (q, J = 6.8 Hz, 2H), 1.54-1.45 (m, 2H), 1.37-
6

13
1.29 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl3): δ (ppm) 166.4, 152.2,
147.1, 90.8, 62.3, 43.5, 36.3, 31.5, 27.3, 22.6, 14.1. HRMS: C11H16INO3 [M+Na+]; calculated:
360.0073, found: 360.0068.
(Z)-3-(2-Bromooct-2-enoyl)oxazolidin-2-one (2j)
The product was obtained according to general procedure A, as a colorless oil
(eluent 50 to 66% Et2O in pentane). Reaction Time: 30 min. Yield: 84% (49
mg). 1H NMR (400 MHz, CDCl3): δ (ppm) 6.51 (t, J = 7.1 Hz, 1H), 4.44 (t, J
= 7.8 Hz, 2H), 4.04 (d, J = 7.8 Hz, 2H), 2.33 (q, J = 7.3 Hz, 2H), 1.49 (quintet, J = 7.3 Hz, 2H),
1.37-1.27 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 165.1, 152.1,
141.8, 114.2, 62.3, 43.4, 31.5, 31.4, 27.3, 22.5, 14.0. HRMS: C11H16BrNO3 [M+Na+]; calculated:
312.0211, found: 312.0203.
(Z)-2-Iodo-N-isopropyl-5-(4-methoxybenzyloxy)-N-tosylpent-2-enamide (2k)
The product was obtained according to general procedure A, as a colorless
oil (eluent 30% Et2O in pentane). Reaction Time: 30 min. Yield: 91% (101
mg). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.81 (d, J = 8.4 Hz, 2H), 7.29 (d,
J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.21 (t, J = 6.6 Hz, 1H), 4.43
(s, 2H), 4.32 (septet, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.52 (t, J = 6.3 Hz, 2H), 2.48 (q, J = 6.4 Hz,
2H), 2.42 (s, 3H), 1.46 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm) 167.7, 159.4,
144.8, 142.4, 136.7, 130.2, 129.7 (2C), 129.4 (2C), 128.6 (2C), 113.9 (2C), 97.0, 72.8, 67.2, 55.4,
54.6, 36.8, 21.7, 21.2 (2C). HRMS: C23H28INO5S [M+Na+]; calculated: 580.0631, found:
580.0637.
(Z)-2-Bromo-N-isopropyl-5-(4-methoxybenzyloxy)-N-tosylpent-2-enamide (2l)
The product was obtained according to general procedure A, as a colorless
oil (eluent 30% Et2O in pentane). Reaction Time: 30 min. Yield: 93% (95
mg). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.82 (d, J = 8.4 Hz, 2H), 7.29 (d,
J = 8.4 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.44 (t, J = 6.8 Hz, 1H), 4.43
(s, 2H), 4.30 (septet, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 2.53 (q, J = 6.5 Hz,
2H), 2.42 (s, 3H), 1.46 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm) 166.6, 159.4,
144.9, 136.9, 136.6, 130.2, 129.7 (2C), 129.4 (2C), 128.6 (2C), 119.0, 113.9 (2C), 72.8, 67.3,
55.4, 54.4, 32.1, 21.8, 21.3 (2C). HRMS: C23H28BrNO5S [M+Na+]; calculated: 532.0769, found:
532.0762.
7

(Z)-N-Benzyl-5-(1,3-dioxoisoindolin-2-yl)-2-iodo-N-tosylpent-2-enamide (2m)
The product obtained according to general procedure A was a mixture of
isomers, seen as a colorless solid (eluent 0 to 3% Et2O in CH2Cl2). Reaction
Time: 30 min. Yield: 92% (113 mg, Z/E 93:7). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.84-7.77
(m, 2H), 7.71-7.68 (m, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.31-7.20 (m, 7H), 6.03 (t, J = 6.8 Hz, 1H),
4.94 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 2.49 (q, J = 6.8 Hz, 2H), 2.41 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 168.1 (2C), 166.8, 145.1, 141.7, 136.2, 135.5, 134.2 (2C), 132.0 (2C), 129.6
(2C), 128.8 (4C), 127.9, 127.8 (2C), 123.4 (2C), 95.6, 51.2, 35.5, 35.3, 21.8. HRMS:
C27H23IN2O5S [M+Na+]; calculated: 637.0265, found: 637.0276.
(Z)-N-Benzyl-2-bromo-5-(1,3-dioxoisoindolin-2-yl)-N-tosylpent-2-enamide (2n)
The product obtained according to general procedure A was a mixture of
isomers, seen as a colorless solid (eluent 0 to 2% Et2O in CH2Cl2). Reaction
1
Time: 30 min. Yield: 87% (99 mg, Z/E 95:5). H NMR (400 MHz, CDCl3): δ (ppm) 7.81-7.77
(m, 2H), 7.72-7.68 (m, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.30-7.21 (m, 7H), 6.29 (t, J = 6.8 Hz, 1H),
4.95 (s, 2H), 3.72 (t, J = 6.8 Hz, 2H), 2.58 (q, J = 6.8 Hz, 2H), 2.42 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 168.1 (2C), 165.8, 145.1, 136.2, 136.0, 135.4, 134.2 (2C), 132.0 (2C), 129.6
(2C), 128.73 (2C), 128.72 (2C), 127.9, 127.8 (2C), 123.4 (2C), 118.2, 51.0, 35.4, 30.7, 21.8.
HRMS: C27H23BrN2O5S [M+Na+]; calculated: 589.0409, found: 589.0404.
4. NCS Mediated Acetate Shift
General Procedure B: To a vial were added the ynamide (0.250 mmol, 1.0 equiv), NaHCO3
(0.375 mmol, 1.5 equiv), and NCS (0.375 mmol, 1.5 equiv) followed by MeCN (5 mL) and the
vial sealed. Then the reaction was stirred at 60 °C for 3 hours, unless otherwise noted. The
reaction mixture was concentrated in vacuo. The crude reaction mixture was purified by flash
chromatography (15 cm silica gel, 2 cm diameter column), eluting with the solvent specified
below, yielding the product.
(Z)-N-Benzyl-2-chloro-N-tosyloct-2-enamide (3a)
The product was obtained according to general procedure B, as a colorless oil
1
(eluent 15% Et2O in pentane). Yield: 70% (73 mg). H NMR (400 MHz,
CDCl3): δ (ppm) 7.67 (d, J = 8.4 Hz, 2H), 7.31-7.19 (m, 7H), 6.23 (t, J = 7.2
Hz, 1H), 4.95 (s, 2H), 2.41 (s, 3H), 2.19 (q, J = 7.2 Hz, 2H), 1.35-1.15 (m, 6H), 0.84 (t, J = 6.8
13
Hz, 3H). C NMR (100 MHz, CDCl3): δ (ppm) 166.4, 145.1, 139.6, 136.0, 135.5, 129.6 (2C),
8

128.8 (4C), 128.0, 127.9 (2C), 125.6, 51.0, 31.4, 28.8, 27.3, 22.4, 21.8, 14.0. HRMS:
C22H26ClNO3S [M+Na+]; calculated: 442.1220, found: 442.1220.
N-Benzyl-2-chloro-N-tosylacrylamide (3b)
The product was obtained according to general procedure B, as a colorless solid
(eluent 20% Et2O in pentane). Yield: 71% (62 mg). 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.67 (d, J = 8.4 Hz, 2H), 7.33-7.22 (m, 7H), 5.70 (d, J = 2.8 Hz, 1H), 5.67 (d,
J = 2.8 Hz, 1H), 5.00 (s, 2H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 165.4, 145.4,
135.8, 135.3, 132.2, 129.6 (2C), 128.81 (2C), 128.79 (2C), 128.1, 127.9 (2C), 121.4, 50.8, 21.8.
HRMS: C17H16ClNO3S [M+Na+]; calculated: 372.0437, found: 372.0437.
2-Chloro-N-(2-chlorophenethyl)-N-tosylacrylamide (3c)
The product was obtained according to general procedure B, as a colorless oil
1
(eluent 25% Et2O in pentane). Yield: 62% (50 mg). H NMR (400 MHz,
CDCl3): δ (ppm) 7.86 (d, J = 8.4 Hz, 2H), 7.34-7.16 (m, 6H), 5.59 (d, J = 2.6
Hz, 1H), 5.36 (d, J = 2.6 Hz, 1H), 4.09 (t, J = 7.2 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 165.0, 145.5, 135.3, 135.1, 134.5, 131.9, 131.6, 129.8
(2C), 129.7, 128.8 (2C), 128.7, 127.3, 120.6, 47.1, 34.3, 21.8. HRMS: C18H17Cl2NO3S [M+Na+];
calculated: 420.0204, found: 420.0208.
(Z)-3-(2-Chlorooct-2-enoyl)oxazolidin-2-one (3d)
The product was obtained according to general procedure B, as a colorless oil
1
(eluent 15% Et2O in pentane). Yield: 62% (58 mg). H NMR (400 MHz,
CDCl3): δ (ppm) 7.82 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.30 (t, J =
7.2 Hz, 1H), 4.26 (septet, J = 6.8 Hz, 1H), 2.44 (s, 3H), 2.27 (q, J = 7.2 Hz, 2H), 1.45 (d, J = 6.8
13
Hz, 6H), 1.44-1.38 (m, 2H), 1.34-1.27 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). C NMR (100 MHz,
CDCl3): δ (ppm) 166.8, 144.8, 138.6, 136.7, 129.7 (2C), 128.5 (2C), 127.5, 54.5, 31.5, 28.9, 27.2,
22.5, 21.7, 21.3 (2C), 14.0. HRMS: C18H26ClNO3S [M+Na+]; calculated: 394.1220, found:
394.1228.
9

(Z)-3-(2-Chlorooct-2-enoyl)oxazolidin-2-one (3e)
The product was obtained according to general procedure B, as a colorless oil
(eluent 20% Et2O in pentane). Reaction Time: 15 h. Yield: 46% (28 mg). 1H
NMR (400 MHz, CDCl3): δ (ppm) 6.43 (t, J = 7.2 Hz, 1H), 4.45 (t, J = 7.6
Hz, 2H), 4.03 (t, J = 7.6 Hz, 2H), 2.36 (q, J = 7.2 Hz, 2H), 1.53-1.44 (m, 2H), 1.36-1.29 (m, 4H),
0.90-0.87 (m, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 164.9, 152.2, 139.7, 124.3, 62.5, 43.5,
31.5, 29.0, 27.4, 22.6, 14.1. HRMS: C11H16ClNO3 [M+Na+]; calculated: 268.0719, found:
268.0718.
2-Chloro-N-(2-chlorophenethyl)-N-tosylacrylamide (3f)
The product was obtained according to general procedure B, as a colorless oil
1
(eluent 25% Et2O in pentane). Yield: 62% (50 mg). H NMR (400 MHz,
CDCl3): δ (ppm) 7.86 (d, J = 8.4 Hz, 2H), 7.34-7.16 (m, 6H), 5.59 (d, J = 2.6
Hz, 1H), 5.36 (d, J = 2.6 Hz, 1H), 4.09 (t, J = 7.2 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 165.0, 145.5, 135.3, 135.1, 134.5, 131.9, 131.6, 129.8
(2C), 129.7, 128.8 (2C), 128.7, 127.3, 120.6, 47.1, 34.3, 21.8. HRMS: C18H17Cl2NO3S [M+Na+];
calculated: 420.0204, found: 420.0208.
(Z)-N-Benzyl-2-chloro-5-(1,3-dioxoisoindolin-2-yl)-N-tosylpent-2-enamide (3g)
The product obtained according to general procedure B, on a 0.200 mmol
scale, as a colorless solid (eluent 0-3% Et2O in CH2Cl2). Yield: 64% (67
1
mg). H NMR (400 MHz, CDCl3): δ (ppm) 7.81-7.76 (m, 2H), 7.71-7.67 (m, 2H), 7.61 (d, J =
8.4 Hz, 2H), 7.28-7.18 (m, 7H), 6.21 (t, J = 6.8 Hz, 1H), 4.91 (s, 2H), 3.73 (t, J = 6.8 Hz, 2H),
2.63 (q, J = 6.8 Hz, 2H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 168.2 (2C), 165.7,
145.2, 135.9, 135.4, 134.2 (2C), 134.0, 132.0 (2C), 129.6 (3C), 128.8 (2C), 128.7 (2C), 128.0
(3C), 123.4 (2C), 50.8, 35.6, 28.2, 21.8. HRMS: C27H23ClN2O5S [M+Na+]; calculated: 545.0908,
found: 545.0916.
5. Selectfluor Mediated Acetate Shift
Procedure: To a vial were added the ynamide (0.200 mmol, 1.0 equiv), NaHCO3 (0.240 mmol,
1.2 equiv), and Selectfluor (0.400 mmol, 2.0 equiv) followed by MeCN (4 mL) and the vial
sealed. Then the reaction was stirred at 40 °C for 5 hours. The reaction mixture was concentrated
in vacuo. The crude reaction mixture was purified by flash chromatography (15 cm silica gel, 2
cm diameter column), eluting with a mixture of 30% Et2O in pentane, yielding the product.
10

(Z)-2-Fluoro-N-isopropyl-5-(4-methoxybenzyloxy)-N-tosylpent-2-enamide (4)
1
The product was obtained as a colorless oil. Yield: 17% (16 mg). H NMR
(400 MHz, CDCl3): δ (ppm) 7.86 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz,
2H), 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.91 (dt, J = 34.2, 7.6
Hz, 1H), 4.43 (s, 2H), 4.15 (septet, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.51 (t, J = 6.5 Hz, 2H), 2.57
(qd, J = 6.8, 2.3 Hz, 2H), 2.44 (s, 3H), 1.46 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ
2
1
(ppm) 163.3 (d, J = 33.8 Hz), 159.4, 152.4 (d, J CF = 263.1 Hz), 144.9, 136.8, 130.4, 129.8
CF
(2C), 129.5 (2C), 128.40, 128.37, 117.0 (d, 2J CF = 11.7 Hz), 114.0 (2C), 72.9, 68.0 (d, 4J CF = 1.9
4
3
Hz), 55.5, 54.4 (d, J
= 1.9 Hz), 25.4 (d, J
= 2.8 Hz), 21.9, 21.5 (2C). HRMS:
CF
CF
C23H28FNO5S [M+Na+]; calculated: 472.1570, found: 472.1573.
6. Attempts to Optimize the F+ Mediated Acetate Shift
temperature
reaction time
entry
solvent
base
F+ source
ratio (1a:4a:7)
(hours)
24
24
24
24
24
4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
(C)
40
40
40
40
40
40
60
80
60
60
60
60
80
1
2
3
4
5
6
7
8
9
10
11
12
13
Acetone
i-PrOH
DMF
DCM
Et2O
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
50:0:50
80:10:10
70:0:30
100:0:0
100:0:0
10:80:10 (17%)a
40:30:30
0:40:60
100:0:0
100:0:0
0:0:100
70:0:30
Cs2CO3
K3PO4
DIPEA
NaHCO3
100:0:0
N-fluoro-pyridinium
tetrafluoroborate
14
MeCN
NaHCO3
80
0.5
100:0:0
a Isolated yield with small impurities.
11

1-(N-Benzyl-4-methylphenylsulfonamido)oct-1-yn-3-yl acetate (1a)
12

3-(N-Benzyl-4-methylphenylsulfonamido)prop-2-ynyl acetate (1b)
13

3-(N-(2-Chlorophenethyl)-4-methylphenylsulfonamido)prop-2-ynyl acetate (1c)
14

1-(N-Isopropyl-4-methylphenylsulfonamido)oct-1-yn-3-yl acetate (1d)
15

1-(2-Oxooxazolidin-3-yl)oct-1-yn-3-yl acetate (1e)
16

1-(N-Isopropyl-N-tosyl)-5-(4-methoxybenzyloxy)pent-1-yn-3-yl acetate (1f)
17

1-(N-Benzyl-4-methylphenylsulfonamido)-5-(1,3-dioxoisoindolin-2-yl)hex-1-yn-3-yl acetate
(1g)
18

(Z)-N-Benzyl-2-iodo-N-tosyloct-2-enamide (2a)
19

(Z)-N-Benzyl-2-bromo-N-tosyloct-2-enamide (2b)
20

N-Benzyl-2-iodo-N-tosylacrylamide (2c)
21

N-Benzyl-2-bromo-N-tosylacrylamide (2d)
22

2-Iodo-N-(2-chlorophenethyl)-N-tosylacrylamide (2e)
23

2-Bromo-N-(2-chlorophenethyl)-N-tosylacrylamide (2f)
24

(Z)-2-Iodo-N-isopropyl-N-tosyloct-2-enamide (2g)
25

(Z)-2-Bromo-N-isopropyl-N-tosyloct-2-enamide (2h)
26

(Z)-3-(2-Iodooct-2-enoyl)oxazolidin-2-one (2i)
27

(Z)-3-(2-Bromooct-2-enoyl)oxazolidin-2-one (2j)
28

(Z)-2-Iodo-N-isopropyl-5-(4-methoxybenzyloxy)-N-tosylpent-2-enamide (2k)
29

(Z)-2-Bromo-N-isopropyl-5-(4-methoxybenzyloxy)-N-tosylpent-2-enamide (2l)
30