1830
N. Sakai et al.
Paper
Synthesis
General procedure B was followed with N,N-dimethylaniline (214 mg,
1.77 mmol), Me3SiBr (114 mg, 0.754 mmol), and ethyl diazoacetate
(61.3 mg, 0.537 mmol) for 12 h. Column chromatography
(hexane/EtOAc 20:1 containing 1 wt% of Et3N) afforded 12; yield: 38.3
mg (25%); pale yellow oil.
13C NMR (CDCl3, 125 MHz): = 171.0, 147.8, 129.4, 117.4, 112.1, 62.0,
57.8, 39.3, 18.1, 13.7.
HRMS (FAB): m/z [M]+ calcd for C12H16INO2: 333.0226; found:
333.0221.
1H NMR (CDCl3, 500 MHz): = 7.26 (t, J = 7.5 Hz, 2 H, ArH), 6.77 (t, J =
7.0 Hz, 1 H, ArH), 6.71 (d, J = 8.0 Hz, 2 H, ArH), 4.41 (dd, J = 9.5, 5.0 Hz,
1 H, CH), 4.24–4.14 (m, 2 H, CH2), 4.03 (dd, J = 15.0, 9.5 Hz, 1 H, CH),
3.81 (dd, J = 15.0, 5.0 Hz, 1 H, CH), 3.00 (s, 3 H, CH3), 1.26 (t, J = 7.0 Hz,
3 H, CH3).
13C NMR (CDCl3, 125 MHz): = 169.3, 147.9, 129.4, 117.5, 112.2, 62.2,
56.5, 41.3, 39.3, 13.9.
Ethyl 2-Chloro-3-[(4-chlorophenyl)(methyl)amino]propanoate
(16)
General procedure B was followed with Cu(acac)2 (25.7 mg, 0.0981
mmol), 4-chloro-N,N-dimethylaniline (273 mg, 1.75 mmol), Me3SiCl
(83.6 mg, 0.770 mmol), ethyl diazoacetate (60.4 mg, 0.529 mmol), and
TBHP (1.59 mmol, 0.288 mL, 5.5 M solution in decane) for 12 h. Col-
umn chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et3N)
afforded 16; yield: 64.3 mg (44%); colorless oil.
MS (FAB): m/z = 286 (M + H)+.
1H NMR (CDCl3, 500 MHz): = 7.18 (d, J = 9.0 Hz, 2 H, ArH), 6.63 (d, J =
9.0 Hz, 2 H, ArH), 4.46 (dd, J = 8.0, 6.0 Hz, 1 H, CH), 4.25–4.14 (m, 2 H,
CH2), 3.99 (dd, J = 15.5, 8.0 Hz, 1 H, CH), 3.71 (dd, J = 15.5, 6.5 Hz, 1 H,
CH), 2.99 (s, 3 H, CH3), 1.27 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (CDCl3, 125 MHz): = 168.8, 146.6, 129.1, 122.4, 113.4, 62.4,
56.7, 53.1, 39.5, 13.9.
Ethyl 2-Bromo-3-[(4-methylphenyl)(methyl)amino]propanoate
(13)
General procedure A was followed with 4-methyl-N-(methoxymeth-
yl)-N-methylaniline (160 mg, 0.969 mmol) and Me3SiBr (236 mg, 1.54
mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 contain-
ing 1 wt% of Et3N) afforded 13; yield: 175 mg (60%); yellow oil.
HRMS (FAB): m/z [M]+ calcd for C12H15Cl2NO2: 275.0480; found:
1H NMR (CDCl3, 500 MHz): = 7.08 (d, J = 9.0 Hz, 2 H, ArH), 6.65 (d, J =
8.5 Hz, 2 H, ArH), 4.39 (dd, J = 10.0, 5.5 Hz, 1 H, CH), 4.24–4.14 (m, 2 H,
CH2), 3.99 (dd, J = 14.5, 5.0 Hz, 1 H, CH), 3.77 (dd, J = 15.0, 5.0 Hz, 1 H,
CH), 2.96 (s, 3 H, CH3), 2.26 (s, 3 H, CH3), 1.26 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (CDCl3, 125 MHz): = 169.4, 145.9, 129.9, 126.8, 112.4, 62.2,
56.8, 41.4, 39.4, 20.2, 13.9.
275.0480.
Ethyl 2-Chloro-3-[(4-bromophenyl)(methyl)amino]propanoate
(17)
General procedure B was followed with Cu(acac)2 (26.7 mg, 0.102
mmol), 4-bromo-N,N-dimethylaniline (350 mg, 1.75 mmol), Me3SiCl
(82.4 mg, 0.758 mmol), ethyl diazoacetate (56.5 mg, 0.495 mmol), and
TBHP (1.49 mmol, 0.269 mL, 5.5 M solution in decane) for 12 h. Col-
umn chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et3N)
afforded 17; yield: 38.1 mg (24%); brown oil.
1H NMR (CDCl3, 500 MHz): = 7.32 (d, J = 9.0 Hz, 2 H, ArH), 6.59 (d, J =
9.0 Hz, 2 H, ArH), 4.45 (dd, J = 8.0, 6.5 Hz, 1 H, CH), 4.25–4.14 (m, 2 H,
CH2), 3.98 (dd, J = 15.5, 8.0 Hz, 1 H, CH), 3.71 (dd, J = 15.5, 6.0 Hz, 1 H,
CH), 2.99 (s, 3 H, CH3), 1.27 (t, J = 7.5 Hz, 3 H, CH3).
HRMS (FAB): m/z [M]+ calcd for C13H18BrNO2: 299.0521; found:
299.0525.
Ethyl 2-Bromo-3-[(4-fluorophenyl)(methyl)amino]propanoate
(14)
General procedure A was followed with 4-fluoro-N-(methoxymeth-
yl)-N-methylaniline (151 mg, 0.892 mmol) and Me3SiBr (230 mg, 1.50
mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 contain-
ing 1 wt% of Et3N) afforded 14; yield: 219 mg (81%); yellow oil.
13C NMR (CDCl3, 125 MHz): = 168.8, 147.0, 132.0, 113.8, 109.5, 62.4,
56.6, 53.1, 39.5, 14.0.
HRMS (FAB): m/z [M]+ calcd for C12H15BrChlNO2: 318.9975; found:
318.9978.
1H NMR (CDCl3, 500 MHz): = 6.96 (t, J = 9.0 Hz, 2 H, ArH), 6.68–6.65
(m, 2 H, ArH), 4.37 (dd, J = 9.5, 5.0 Hz, 1 H, CH), 4.24–4.14 (m, 2 H,
CH2), 3.99 (dd, J = 15.0, 9.5 Hz, 1 H, CH), 3.73 (dd, J = 15.0, 5.0 Hz, 1 H,
CH), 2.95 (s, 3 H, CH3), 1.26 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (CDCl3, 125 MHz): = 169.3, 155.0 (d, JC,F = 236.5 Hz), 144.7,
115.6 (d, JC,F = 22.6 Hz), 113.6 (d, JC,F = 7.5 Hz), 62.3, 57.2, 41.2, 39.6,
13.9.
HRMS (FAB): m/z [M]+ calcd for C12H15BrFNO2: 303.0270; found:
303.0268.
Ethyl 2-Chloro-3-{4-[(trifluoromethyl)phenyl](methyl)amino}-
propanoate (18)
General procedure B was followed with Cu(acac)2 (26.2 mg, 0.100
mmol), 4-trifluoromethyl-N,N-dimethylaniline (325 mg, 1.72 mmol),
Me3SiCl (85.4 mg, 0.786 mmol), ethyl diazoacetate (56.0 mg, 0.491
mmol), and TBHP (1.47 mmol, 0.267 mL, 5.5 M solution in decane) for
14 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt%
of Et3N) afforded 18; yield: 27.3 mg (18%); colorless oil.
1H NMR (CDCl3, 500 MHz): = 7.48 (d, J = 8.5 Hz, 2 H, ArH), 6.73 (d, J =
9.0 Hz, 2 H, ArH), 4.48 (dd, J = 7.5, 6.5 Hz, 1 H, CH), 4.26–4.15 (m, 2 H,
CH2), 4.08 (dd, J = 15.5, 8.0 Hz, 1 H, CH), 3.79 (dd, J = 15.5, 6.5 Hz, 1 H,
CH), 3.07 (s, 3 H, CH3), 1.27 (t, J = 7.0 Hz, 3 H, CH3).
Ethyl 2-Iodo-3-[methyl(phenyl)amino]propanoate (15)
General procedure A was followed with N-(methoxymethyl)-N-meth-
ylaniline (159 mg, 1.05 mmol) and Me3SiI (320 mg, 1.60 mmol) for 1
h. Column chromatography (hexane containing 1 wt% of Et3N) afford-
ed 15; yield: 83.3 mg (25%); pale yellow oil.
1H NMR (CDCl3, 500 MHz): = 7.26 (t, J = 8.0 Hz, 2 H, ArH), 6.77 (t, J =
9.0 Hz, 1 H, ArH), 6.68 (d, J = 8.0 Hz, 2 H, ArH), 4.50 (dd, J = 10.5, 4.0
Hz, 1 H, CH), 4.22–4.12 (m, 2 H, CH2), 3.99 (dd, J = 15.0, 10.5 Hz, 1 H,
CH), 3.85 (dd, J = 15.0, 4.0 Hz, 1 H, CH), 2.99 (s, 3 H, CH3), 1.24 (t, J =
7.5 Hz, 3 H, CH3).
13C NMR (CDCl3, 125 MHz): = 168.7, 150.1, 126.6 (q, JC,F = 3.8 Hz),
125.9 (t, JC,F = 270.4 Hz), 119.0 (q, JC,F = 32.7 Hz), 62.5, 56.2, 53.0, 39.5,
13.9.
HRMS (FAB): m/z [M]+ calcd for C13H15ClF3NO2: 309.0743; found:
309.0733.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1823–1832