The Journal of Organic Chemistry
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amorphous solid: 1H NMR (300 MHz) δ 1.62 (m, 4H), 2.69 (s, 3H),
2.99 (m, 2H), 3.66 (m, 2H), 6.79 (ddd, J = 8.1, 7.2, and 1.5 Hz, 1H),
7.09 (dd, J = 7.8 and 1.5 Hz, 1H), 7.30 (ddd, J = 7.8, 7.2, and 1.5 Hz,
1H), 7.85 (dd, J = 8.1 and 1.5 Hz, 1H); 13C NMR (75.4 MHz) δ 24.0
(CH2), 30.3 (CH2), 43.0 (CH3), 56.0 (CH2), 62.8 (CH2), 99.2 (C),
122.0 (CH), 125.4 (CH), 128.9 (CH), 140.0 (CH), 154.0 (C).
4-[N-(2-Iodophenyl)-N-methylamino]butanal (6). A solution
of DMSO (0.53 mL, 7.46 mmol) in CH2Cl2 (5 mL) was added
dropwise to a solution of oxalyl chloride (0.32 mL, 3.83 mmol) in
CH2Cl2 (10 mL) at −60 °C. The reaction mixture was stirred for 5
min, and 4-[N-(2-iodophenyl)-N-methylamino]butanol (0.65 g, 2.13
mmol) in CH2Cl2 (30 mL) was added dropwise. The mixture was
stirred at −60 °C for 15 min, and Et3N (2.5 mL, 17.9 mmol) was
added. After 5 min, the reaction mixture was allowed to warm to room
temperature. Water was added, and the aqueous layer was extracted
with CH2Cl2. The combined organic extracts were dried, and the
solvent was removed under a vacuum. The residue was purified by
flash chromatography (SiO2, from hexanes to hexanes−EtOAc 20%)
to give 4-[N-(2-iodophenyl)-N-methylamino]butanal (6, 0.57 g, 88%)
major), 64.4 (CH2, minor), 80.9 (C), 99.8 (C, major), 100.1 (C,
minor), 128.4 (CH, minor), 128.8 (CH, major), 128.9 (CH, major),
129.0 (CH, minor), 129.1 (CH, minor), 129.5 (CH, major), 139.6
(CH, minor), 139.7 (CH, major), 144.3 (C, major), 145.7 (C, minor),
155.4 (C, minor), 155.7 (C, major); HRMS (ESI-TOF) calcd for
C15H23INO3 392.0717 [M + H]+, found 392.0731.
3-[N-tert-Butoxycarbonyl)-N-(2-iodophenyl)amino]-2-meth-
ylpropanal (10). A solution of DMSO (0.36 mL, 5 mmol) in CH2Cl2
(3 mL) was added dropwise to a solution of oxalyl chloride (0.22 mL,
2.57 mmol) in CH2Cl2 (7 mL) at −60 °C. The reaction mixture was
stirred for 5 min and 3-[N-tert-butoxycarbonyl)-N-(2-iodophenyl)-
amino]-2-methylpropanol (0.5 g, 1.28 mmol) in CH2Cl2 (20 mL) was
added dropwise. The mixture was stirred at −60 °C for 15 min, and
Et3N (1.7 mL, 12 mmol) was added. After 5 min, the reaction mixture
was allowed to warm to room temperature. Water was added, and the
aqueous layer was extracted with CH2Cl2. The combined organic
extracts were dried, and the solvent was removed under a vacuum. The
residue was purified by flash chromatography (SiO2, from hexanes to
hexanes−EtOAc 30%) to give 3-[N-tert-butoxycarbonyl)-N-(2-
iodophenyl)amino]-2-methylpropanal (10, 0.46 g, 93%) as a colorless
oil: 1H NMR (300 MHz, mixture of rotamers) δ 1.23 and 1.26 (two d,
J = 7.2 Hz, 3H), 1.43 and 1.45 (two s, 9H), 2.75 and 2.89 (two m,
1H), 3.31 (dd, J = 14.4 and 4.8 Hz, 0.5 H), 3.74 (dd, J = 14.4 and 7.5
Hz, 0.5 H), 4.01 (dd, J = 14.4 and 6 Hz, 0.5 H), 4.37 (dd, J = 14.4 and
10.2 Hz, 1H), 7.11 (m, 1H), 7.23−7.51 (m, 2H), 7.98 (d, J = 7.8 Hz,
1H), 9.76 (d, J = 3.3 Hz, 0.5 H), 9.82 (d, J = 1.5 Hz, 0.5 H); 13C NMR
(75.4 MHz, mixture of rotamers) δ 11.9 (CH3), 12.0 (CH3), 28.0
(CH3), 46.0 (CH), 46.1 (CH), 50.0 (CH2), 50.4 (CH2), 76.6 (C),
80.5 (C), 99.8 (C), 128.8 (CH), 128.9 (CH), 129.7 (CH), 103.2
(CH), 139.4 (CH), 139.5 (CH), 143.8 (C), 144.5 (C), 154.0 (C),
154.1 (C), 203.3 (CH), 203.4 (CH); HRMS (ESI-TOF) calcd for
C15H20INNaO3 412.0380 [M + Na]+, found 412.0375.
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as a colorless oil: H NMR (300 MHz) δ 1.86 (m, 2H), 2.59 (td, J =
7.2 and 1.5 Hz, 2H), 2.67 (s, 3H), 2.98 (t, J = 6.9 Hz, 2H), 6.80 (ddd, J
= 8.1, 7.2, and 1.5 Hz, 1H), 7.10 (dd, J = 8.1 and 1.5 Hz, 1H), 7.31
(ddd, J = 8.1, 7.2, and 1.5 Hz, 1H), 7.85 (dd, J = 8.1 and 1.5 Hz, 1H),
9.82 (t, J = 1.5 Hz, 1H); 13C NMR (75.4 MHz) δ 20.0 (CH2), 41.4
(CH2), 42.9 (CH3), 55.1 (CH2), 99.4 (C), 122.2 (CH), 125.7 (CH),
129.0 (CH), 139.9 (CH), 153.9 (C), 202.3 (CH); HRMS (ESI-TOF)
calcd for C11H15INO 304.0193 [M + H]+, found 304.0186.
N-(tert-Butoxycarbonyl)-N-(2-methyl-2-propenyl)-2-iodoani-
line. A solution of N-(tert-butoxycarbonyl)-2-iodoaniline (0.6 g, 1.88
mmol) in dry THF (2 mL) was added at 0 °C under Argon to a
suspension of NaH (60% in oil, 90 mg, 2.26 mmol) in dry THF (8
mL). The resulting mixture was stirred for 15 min at 25 °C and cooled
again to 0 °C. DMF (2 mL) and 3-bromo-2-methylpropene (0.23 mL,
2.26 mmol) were added, and the mixture was stirred for 10 min at 0
°C and at 25 °C overnight. Saturated aqueous NH4Cl was added, and
the mixture was extracted with EtOAc. The organic extracts were
dried, and the solvent evaporated under a vacuum. The residue was
purified by flash chromatography (SiO2, from hexanes to hexanes−
EtOAc 5%) to give N-(tert-butoxycarbonyl)-N-(2-methyl-2-propenyl)-
N-(3-Methyl-3-butenyl)-2-iodoaniline. Operating as in the
preparation of N-(3-butenyl)-2-iodoaniline and starting from 2-
iodoaniline (1 g, 4.56 mmol) and 4-bromo-2-methyl-1-butene (1.36
g, 9.13 mmol), N-(3-methyl-3-butenyl)-2-iodoaniline (0.45 g, 34%)
was obtained as a pale yellow oil after flash chromatography (SiO2,
1
hexanes): H NMR (300 MHz) δ 1.77 (s, 3H), 2.40 (t, J = 6.6 Hz,
2H), 3.23 (m, 2H), 4.20 (bb, 1H), 4.87 (m, 1H), 4.91 (m. 1H), 6.42
(ddd, J = 8.1, 7.5, and 1.5 Hz, 1H), 6.55 (dd, J = 8.1 and 1.5 Hz, 1H),
7.19 (ddd, J = 8.1, 7.5, and 1.5 Hz, 1H), 7.64 (dd, J = 8.1 and 1.5 Hz,
1H); 13C NMR (75.4 MHz) δ 21.9 (CH3), 37.1 (CH2), 41.7 (CH2),
85.3 (C), 110.5 (CH), 112.9 (CH2), 118.4 (CH), 129.3 (CH), 138.9
(CH), 142.5 (C), 147.2 (C).
1
2-iodoaniline (0.48 g, 69%) as a colorless oil: H NMR (300 MHz,
mixture of rotamers) δ 1.36 and 1.53 (two broad s, 9H), 1.82 (s, 3H),
3.49 (d, J = 15.6 Hz, 1H), 4.42−4.63 (m, 1H), 4.70−5.01 (m, 2H),
6.97 (m, 1H), 7.14 (m, 1H), 7.30 (m, 1H), 7.87 (d, J = 7.5 Hz, 1H);
13C NMR (75.4 MHz, major rotamer) δ 20.5 (CH3), 28.2 (CH3), 55.1
N-Methyl-N-(3-methyl-3-butenyl)-2-iodoaniline. Operating as
in the preparation of N-(3-butenyl)-2-iodo-N-methylaniline and
starting from N-(3-methyl-3-butenyl)-2-iodoaniline (0.58 g, 2
mmol), crude N-methyl-N-(3-methyl-3-butenyl)-2-iodoaniline (0.58
g, 97%) was obtained as a pale yellow oil, which was used in the next
(CH2), 80.2 (C), 100.0 (C), 113.2 (CH2), 128.5 (2 CH), 129.7 (CH),
139.4 (CH), 141.2 (C), 144.5 (C), 154.2 (C); HRMS (ESI-TOF)
calcd for C11H13INO2 317.9985 [M − C4H7]+, found 317.9986.
3-[N-tert-Butoxycarbonyl)-N-(2-iodophenyl)amino]-2-meth-
ylpropanol. To a solution of N-(tert-butoxycarbonyl)-N-(2-methyl-2-
propenyl)-2-iodoaniline (0.48 g, 1.29 mmol) in dry THF (2 mL), 9-
BBN (4.5 mL of 0.5 M solution in THF, 2.25 mmol) was added at
room temperature under Argon. The solution was stirred for 18 h,
cooled at 0 °C, and THF (15 mL) and water (2 mL) were added. The
mixture was allowed to warm to room temperature and then was
cooled again at 0 °C, and 3 M solution of NaOH (1.1 mL) and 30%
H2O2 (1.9 mL) was added. The mixture was stirred at room
temperature for 1.5 h and at 50 °C for 1.5 h. The reaction mixture was
extracted with EtOAc. The organic extracts were dried and
concentrated. The residue was purified by flash chromatography
(SiO2, from hexanes to hexanes−EtOAc 30%) to give 3-[N-tert-
butoxycarbonyl)-N-(2-iodophenyl)amino]-2-methylpropanol (0.5 g,
1
step without purification: H NMR (300 MHz) δ 1.74 (s, 3H), 2.27
(m, 2H), 2.73 (s, 3H), 3.06 (m, 2H), 4.68 (m, 1H), 4.73 (m, 1H), 6.77
(ddd, J = 8.1, 7.2, and 1.5 Hz, 1H), 7.09 (dd, J = 7.8 and 1.5 Hz, 1H),
7.30 (ddd, J = 7.8, 7.2, and 1.5 Hz, 1H), 7.85 (dd, J = 8.1 and 1.5 Hz,
1H); 13C NMR (75.4 MHz) δ 22.8 (CH3), 35.7 (CH2), 42.3 (CH3),
55.6 (CH2), 99.0 (C), 110.9 (CH2), 122.0 (CH), 125.2 (CH), 128.9
(CH), 140.0 (CH), 143.8 (C), 154.2 (C).
4-[N-(2-Iodophenyl)-N-methylamino]-2-methylbutanal (13).
Operating as in the preparation of 10, the sequence hydroboration/
oxidation−hydrolysis/Swern oxidation starting from N-methyl-N-(3-
methyl-3-butenyl)-2-iodoaniline (0.58 g, 1.93 mmol), afforded 4-[N-
(2-iodophenyl)-N-methylamino]-2-methylbutanal (13, 200 mg, 33%)
1
1
99%) as a colorless oil: H NMR (300 MHz, mixture of rotamers) δ
as a pale yellow oil after flash chromatography (SiO2, CH2Cl2): H
0.92 and 0.94 (two d, J = 6.9 Hz, 3H), 1.34 and 1.36 (two s, 9H), 2.85
(dd, J = 14.7 and 4.2 Hz, 1H), 3.41 (td, J = 14.4 and 4.8 Hz, 1H), 3.53
(broad t, J = 9.3 Hz, 1H), 3.70 (m, 1H), 3.82 (m, 1H), 3.97 (dd, J =
14.7 and 11.1 Hz, 1H), 6.94−7.04 (m, 1H), 7.08 and 7.20 (two dd, J =
8 and 1.5 Hz, 1H), 7.30−7.39 (m 1H), 7.84−7.92 (m, 1H); 13C NMR
(75.4 MHz, mixture of rotamers) δ 14.9 (CH3, major), 15.2 (CH3,
minor), 27.4 (CH3, minor), 28.1 (CH3, major), 34.3 (CH, major),
35.2 (CH, minor), 51.0 (CH2, major), 53.2 (CH2, minor), 63.3 (CH2,
NMR (300 MHz) δ 1.11 (d, J = 6.9 Hz, 3H), 1.53 (m, 1H), 2.01 (m,
1H), 2.58 (m, 1H), 2.68 (s, 3H), 3.01 (m, 2H), 6.80 (ddd, J = 8.1, 7.2,
and 1.5 Hz, 1H), 7.10 (dd, J = 8.1 and 1.5 Hz, 1H), 7.31 (ddd, J = 8.1,
7.2, and 1.5 Hz, 1H), 7.85 (dd, J = 8.1 and 1.5 Hz, 1H), 9.67 (t, J = 1.5
Hz, 1H); 13C NMR (75.4 MHz) δ 13.4 (CH3), 28.3 (CH2), 43.0
(CH3), 44.0 (CH), 53.6 (CH2), 99.4 (C), 122.2 (CH), 125.7 (CH),
129.0 (CH), 140.0 (CH), 153.9 (C), 204.7 (CH); HRMS (ESI-TOF)
calcd for C12H17INO 318.0349 [M + H]+, found 318.0346.
10281
dx.doi.org/10.1021/jo301924e | J. Org. Chem. 2012, 77, 10272−10284