Paper
NJC
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(0.92 g, 2.2 mmol) in acetonitrile (10 mL). After stirring at room
Data for 4d: yield, 50%; white solid; Mp 68–69 1C; H NMR
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temperature for 1 h, the mixture was poured into water (50 mL), (400 MHz, CDCl3) d 1.41 (t, JHH = 6.9 Hz, 6H), 3.98–4.06
and then extracted with CH2Cl2 (20 mL Â 3). The combined (m, 4H), 4.13–4.18 (m, 1H), 4.81–4.87 (m, 1H), 5.59–5.66 (m,
organic layers were dried over anhydrous Na2SO4, and concen- 1H), 6.42–6.49 (m, 2H), 6.99 (t, 3JHH = 8.2 Hz, 2H), 7.30 (d, 3JHH
=
trated under reduced pressure to give 12 as a white solid (0.72 g, 7.9 Hz, 1H), 7.36–7.46 (m, 1H); anal. Calcd for C19H19F2NO3: C,
83%). Mp 134–136 1C; 1H NMR (400 MHz, CDCl3) d 1.39 65.70; H, 5.51; N, 4.03; found: C, 65.45; H, 5.44; N, 3.98.
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3
1
(t, JHH = 6.9 Hz, 3H), 2.05 (s, 3H), 3.96 (q, JHH = 6.9 Hz, 2H),
Data for 4e: yield, 90%; white solid, Mp 81–82 1C; H NMR
4.94 (s, 2H), 6.41 (d, 4JHH = 2.4 Hz, 1H), 6.72 (dd, 3JHH = 8.8 Hz, (400 MHz, CDCl3) d 2.36 (s, 3H), 4.11–4.15 (m, 2H), 4.39 (q, 3JHH
=
4JHH = 2.4 Hz, 1H,), 6.95 (d, JHH = 8.6 Hz, 2H), 7.02 (d, JHH
=
8.0 Hz, 2H), 4.86–4.91 (m, 1H), 5.66–5.71 (m, 1H), 6.65 (s, 1H), 6.89
(d, JHH = 7.9 Hz, 1H), 6.99 (t, JHH = 8.3 Hz, 2H), 7.37 (d, JHH
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3
3
3
3
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8.8 Hz, 1H), 7.41 (d, JHH = 8.6 Hz, 2H), 7.81 (s, 1H).
=
7.9 Hz, 1H), 7.39–7.44 (m, 2H); anal. Calcd for C18H14F5NO2: C,
58.23; H, 3.80; N, 3.77; found: C, 58.19; H, 3.99; N, 3.92.
General synthetic procedure for amide (13)
Data for 4f: yield, 89%; white solid; Mp 128–129 1C; 1H NMR
To a stirred mixture of amino alcohol 8 (2.17 mmol) and
triethylamine (0.24 g, 2.39 mmol) in THF (40 mL) was added
dropwise a solution of 2,6-difluorobenzoyl chloride (0.42 g,
2.39 mmol) in THF (20 mL) at 5 1C. After stirring the reaction
mixture at room temperature for 2 h, the precipitate was
removed by filtration, and the solution was concentrated under
reduced pressure to give crude compound 13, which was used
in the next reaction without further purification.
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(400 MHz, CDCl3) d 4.18–4.23 (m, 1H), 4.49–4.58 (q, JHH
8.0 Hz, 2H), 5.03–5.09 (m, 1H), 6.08–6.15 (m, 1H), 6.82 (d, 3JHH
=
=
8.0 Hz, 1H), 7.04 (t, 3JHH = 8.3 Hz, 2H), 7.41–7.49 (m, 1H), 7.55–
7.60 (m, 3H), 7.81 (dd, 3JHH = 7.7 Hz, 4JHH = 1.6 Hz, 1H), 8.37 (dd,
3JHH = 7.7 Hz, 4JHH = 1.6 Hz, 1H); anal. Calcd for C21H14F5NO2: C,
61.92; H, 3.46; N, 3.44; found: C, 61.60; H, 3.68; N, 3.33.
Data for 4g: yield, 82%; oil; 1H NMR (400 MHz, CDCl3) d 1.43
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3
(t, JHH = 6.9 Hz, 3H), 4.04 (q, JHH = 6.9 Hz, 2H), 4.11–4.17
4
(m, 1H), 4.81–4.89 (m, 1H), 5.63–5.72 (m, 1H), 6.81 (d, JHH
=
General synthetic procedure for 14
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4
2.5 Hz, 1H), 6.86 (dd, JHH = 8.5 Hz, JHH = 2.5 Hz, 1H), 7.01
To a mixture of crude 13 in toluene (50 mL), thionyl chloride
(0.75 g, 6.30 mmol) was added dropwise with stirring, and then
the mixture was heated to 80 1C for 3 h. After cooling, to the
reaction mixture was added a solution of Na2CO3 to make the
pH = 8, then the organic layer was separated and concentrated
under reduced pressure to give crude 14.
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3
(t, JHH = 8.2 Hz, 2H), 7.40 (d, JHH = 8.5 Hz, 1H), 7.42–7.46
(m, 1H); HRMS (ESI) m/z calcd for C18H15F5NO3 (M + H)+:
388.0967, found: 388.0967.
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Data for 4h: yield, 75%; white solid; Mp 86–87 1C; H NMR
(400 MHz, CDCl3) d 4.17 (t, JHH = 4.2 Hz, 1H), 4.23–4.29
(m, 2H), 4.69 (t, JHH = 4.2 Hz, 1H), 4.76–4.82 (m, 2H), 5.39–
5.45 (m, 1H), 6.93 (d, JHH = 8.6 Hz, 2H), 7.00 (t, JHH = 8.3 Hz,
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3
3
3
General synthetic procedure for target compound 4
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2H), 7.27 (d, JHH = 8.3 Hz, 2H), 7.38–7.46 (m, 1H); anal. Calcd
Compound 14 was dissolved in MeOH (50 mL) and treated with for C17H14F3NO2: C, 63.55; H, 4.39; N, 4.36; found: C, 63.57; H,
NaOH (0.15 g, 3.80 mmol). After stirring for 1 h at 50 1C, the 4.24; N, 4.53.
reaction mixture was poured into water and extracted with
Data for 4i: yield, 82%; oil; 1H NMR (400 MHz, CDCl3) d 1.25–
EtOAc. The organic layer was washed with water and brine, 1.49 (m, 6H), 1.77–1.82 (m, 2H), 1.95–1.99 (m, 2H), 2.31 (s, 3H),
and dried over anhydrous Na2SO4, and concentrated under 4.13–4.18 (m, 1H), 4.19–4.23 (m, 1H), 4.80–4.85 (m, 1H), 5.57–
reduced pressure. The residue was purified by column chro- 5.62 (m, 1H), 6.73 (d, 4JHH = 2.5 Hz, 1H), 6.75 (dd, 3JHH = 8.5 Hz,
matography to afford product 4.
4JHH = 2.5 Hz, 1H), 7.00 (t, 3JHH = 8.3 Hz, 2H), 7.26 (d, 3JHH = 8.5
Data for 4a: yield, 80%; oil; 1H NMR (400 MHz, CDCl3) d 1.41 Hz, 1H), 7.39–7.46 (m, 1H); HRMS (ESI) m/z calcd for
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(t, JHH = 7.0 Hz, 3H), 2.23 (s, 3H), 4.02 (q, JHH = 7.0 Hz, 2H),
C
22H24F2NO2 (M + H)+: 372.1770, found: 372.1766.
4.25–4.31 (m, 1H), 4.74–4.81 (m, 1H), 5.35–5.41 (m, 1H), 6.79
Data for 4j: yield, 63%; oil; 1H NMR (400 MHz, CDCl3) d 0.90
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(d, JHH = 8.7 Hz, 1H), 6.99 (t, JHH = 8.2 Hz, 2H), 7.08–7.12 (t, 3JHH = 6.9 Hz, 3H), 1.30–1.47 (m, 8H), 1.73–1.81 (m, 2H), 2.32
(m, 2H), 7.36–7.46 (m, 1H); HRMS (ESI) m/z calcd for (s, 3H), 3.93 (t, 3JHH = 6.6 Hz, 2H), 4.11–4.17 (m, 1H), 4.80–4.86
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C
18H18F2NO2 (M + H)+: 318.1300, found: 318.1296.
(m, 1H), 5.57–5.63 (m, 1H), 6.74–6.78 (m, 2H), 7.00 (t, JHH
=
1
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Data for 4b: yield, 71%; white solid; Mp 71–72 1C; H NMR 8.3 Hz, 2H), 7.28 (d, JHH = 8.6 Hz, 1H), 7.38–7.46 (m, 1H);
(400 MHz, CDCl3) d 1.41–1.47 (m, 6H), 4.05–4.15 (m, 4H), 4.26– HRMS (ESI) m/z calcd for C23H27F2NO2Na (M + Na)+: 410.1902,
4.32 (m, 1H), 4.75–4.81 (m, 1H), 5.36–5.42 (m, 1H), 6.82–6.89 found: 410.1902.
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(m, 3H), 7.00 (t, JHH = 8.2 Hz, 2H), 7.37–7.47 (m, 1H); anal.
Data for 4k: yield, 81%; oil; 1H NMR (400 MHz, CDCl3) d 0.90
Calcd for C19H19F2NO3: C, 65.70; H, 5.51; N, 4.03; found: C, (t, 3JHH = 6.9 Hz, 3H), 1.30–1.47 (m, 8H), 1.73–1.80 (m, 2H), 3.93
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65.83; H, 5.65; N, 4.01.
(t, JHH = 6.6 Hz, 2H), 4.12–4.17 (m, 1H), 4.90–4.95 (m, 1H),
Data for 4c: yield, 76%; oil; 1H NMR (400 MHz, CDCl3) d 1.55 5.71–5.76 (m, 1H), 6.82 (dd, JHH = 8.6 Hz, JHH = 2.5 Hz, 1H),
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4
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4
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(t, JHH = 7.0 Hz, 3H), 4.19–4.24 (m, 3H), 5.03–5.08 (m, 1H), 6.94 (d, JHH = 2.5 Hz, 1H), 7.01 (t, JHH = 8.3 Hz, 2H), 7.38
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6.08–6.13 (m, 1H), 6.82 (d, JHH = 8.0 Hz, 1H), 7.03 (t, JHH
=
=
(d, 3JHH = 8.6 Hz, 1H), 7.41–7.47 (m, 1H); HRMS (ESI) m/z calcd
for C22H24ClF2NO2Na (M + Na)+: 430.1356, found: 430.1357.
Data for 4l: yield, 87%; oil; 1H NMR (400 MHz, CDCl3) d 0.90
(t, 3JHH = 6.9 Hz, 3H), 1.31–1.45 (m, 8H), 1.74–1.82 (m, 2H), 3.95
8.2 Hz, 2H), 7.42–7.47 (m, 1H), 7.52–7.60 (m, 3H), 7.77 (d, 3JHH
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8.2 Hz, 1H,), 8.40 (d, JHH = 8.2 Hz, 1H); HRMS (ESI) m/z calcd
for C21H17F2NO2Na (M + Na)+: 376.1120, found: 376.1126.
c
1808 New J. Chem., 2013, 37, 1803--1810
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013