1762
H. Hashima et al. / Bioorg. Med. Chem. 8 (2000) 1757±1766
2,4,6-Tribromo-3-(2-bromoethyl)anisole (11). An ether-
eal solution of diazomethane, which was prepared from
p-tolylsulfomethylnitrosamide (0.175 mg, 8 mmol), was
added dropwise to a suspension of 10 (2.177 g, 5.0 mmol)
in MeOH (25 mL) at 5 ꢀC until a pale yellow color was
developed, and the mixture was stirred for 30 min at the
ambient temperature and concentrated. The residue was
chromatographed on silica gel (hexane:EtOAc, 4:1), and
the oily product was recrystallized from hexane to pro-
vide colorless needles (1.785 g, 82%), mp 59 ꢀC; 1H
NMR: d 3.46±3.55 (m, 4H), 3.87 (s, 3H), 7.77 (s, 1H);
13C NMR: d 27.5, 40.4, 60.5, 117.1, 119.8, 121.8, 135.6,
138.7, 154.2. Anal. calcd for C9H8OBr4: C, 23.93; H,
1.78. Found: C, 23.91; H, 1.69.
NMR (DMSO-d6): d 2.56 (d, 3H, J=5.0 Hz), 3.28 (s,
2H), 6.59±6.67 (series of m, 3H), 7.06 (t, 1H, J=7.8 Hz),
9.29 (s, 1H); 13C NMR (DMSO-d6): d 25.7, 42.5, 113.4,
115.9, 119.7, 129.1, 137.7, 157.2, 170.6. Anal. calcd for
C9H11 NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.75,
H, 6.77; N, 8.53.
N-Methyl-3-methoxyphenethylamine (15). From 17.
Borane±THF complex (1.0 M in THF, 100 mL, 0.10 mol)
was added to a stirred solution of 17 (3.590g, 0.020 mmol)
in dry THF (100 mL), and the mixture was gently re¯uxed
for 18 h. After being cooled to rt and 6 M HCl added
(20 mL), the mixture was concentrated, diluted with
water (30 mL) and basi®ed with NaHCO3. The solution
was saturated with NaCl and extracted with BuOH
(3Â20 mL). The combined organic layers were washed
with brine (5 mL), dried (K2CO3) and concentrated.
Kugelrohr-distillation of the residue gave 15 (2.796 g,
84%) as a colorless oil, which was redistilled, bp 89±
Methyl (3-methoxyphenyl)acetate (16). A mixture of 6
(8.310 g, 50 mmol) in 10% HCl in MeOH solution
(50 mL) was stirred and re¯uxed with stirring for 5 h and
then concentrated. After addition of ice-water (30 mL),
the mixture was made basic with NaHCO3 and extracted
with EtOAc (3Â20 mL). The organic layers were washed
with water, dried (MgSO4) and concentrated. Puri®ca-
tion by Kugelrohr-distillation provided a colorless oil
(8.221 g, 91%). The analytical sample was obtained by
short-path distillation, bp 106±107 ꢀC/3 mmHg (lit.19
87±90 ꢀC/0.25 mmHg); 1H NMR: d 3.60 (s, 2H), 3.69 (s,
3H), 3.80 (s, 3H), 6.80±6.88 (series of m, 3H), 7.24 (t,
1H, J=7.6 Hz); 13C NMR: d 41.2, 52.1, 55.2, 112.6,
114.9, 121.6, 129.6, 135.4, 159.7, 171.9. Anal. calcd for
C10H12 O3: C, 66.65; H, 6.71. Found: C, 66.62; H, 6.78.
91 ꢀC/4 mmHg (lit.20 118 ꢀC/7 mmHg); H NMR: d 2.43
1
(s, 3H), 2.75±2.88 (m, 4H), 3.80 (s, 3H), 6.75±6.82 (series
of m, 3H), 7.21 (t, 1H, J=7.8 Hz); 13C NMR: d 36.2,
36.3, 53.0, 55.1, 111.4, 114.5, 121.1, 129.4, 141.6, 159.7.
From 9. A solution of 9 (0.206g, 1.2 mmol) and 40% aqu-
eous methylamine (5.2 mL, 60mmol) in EtOH (100mL)
was re¯uxed with stirring for 2 h, and then the methyl-
amine (2.6 mL) was added again. The mixture was further
heated for 1 h and concentrated. The residue was dissolved
in water (10 mL), and the mixture was made basic with
NaHCO3. Extraction with BuOH and successive work up
in the above manner gave a colorless oil (0.156g, 78%).
Methyl (3-hydoxyphenyl)acetate (19). The ester was pre-
pared using 18 in 83% yield by the above procedure for
the synthesis of 16 as colorless oil, bp 135±136 ꢀC/2
mmHg; 1H NMR: d 3.58 (s, 2H), 3.70 (s, 3H), 5.42 (br s,
1H), 6.72±6.84 (series of m, 3H), 7.17 (t, 1H, J=7.6 Hz);
13C NMR: d 41.0, 52.3, 114.3, 116.2, 121.3, 129.7, 135.0,
156.0, 172.9. Anal. calcd for C9H10O3: C, 65.05; H, 6.07.
Found: C, 64.78; H, 6.34.
3-Hydroxyphenethylamine (12). A mixture of 97% 3-
methoxyphenetylamine (14) (Aldrich, 4.680 g, 0.030 mol),
47% HBr (20 mL) and AcOH (20 mL) was re¯uxed with
stirring for 3 h and then concentrated. The residue was
basi®ed with 2 M aqueous NaOH and the solution was
washed with ether (2Â30 mL). The aqueous layer was
acidi®ed with 6 M HCl and then made basic with 28%
aqueous ammonium hydroxide. After saturating with
NaCl, the solution was extracted with BuOH (3Â20 mL),
dried (K2CO3) and concentrated. Kugelrohr-distillation
and recrystallization from EtOH gave colorless prisms
N-Methyl-(3-methoxyphenyl)acetamide (17). A solution
of 16 (5.412 g, 0.030 mol), and 40% aqueous methyl-
amine (40 mL, 0.47 mol) in EtOH (100 mL) was stirred
and heated at 70 ꢀC (bath temperature) for 2 h, and then
the methylamine (10 mL) was added. After being heated
for an additional 1 h, the mixture was concentrated, and
Kuagelrohr-distillation provided a colorless oil (5.342 g,
99%), which was redistilled; bp 163±164 ꢀC/4 mmHg,
which crystallized to o-white solid at room tempera-
(3.011 g, 73%), mp 102.5±103 ꢀC; H NMR: d 2.72 (t,
1
2H, J=6.6 Hz), 3.02 (t, 2H, J=6.6 Hz), 4.45 (br s, 3H),
6.63±6.69 (series of m, 3H), 7.16 (t, 1H, J=7.8 Hz); 13C
NMR: d 38.6, 42.7, 113.9, 116.0, 120.1, 130.0, 138.4,
140.8. Anal. calcd for C8H11NO: C, 70.04; H, 8.08; N,
10.21. Found: C, 70.00; H, 8.14; N, 10.04.
1
ture; H NMR: d 2.84 (d, 3H, J=5.0 Hz), 3.55 (s, 2H),
3.81 (s, 3H), 5.49 (br s, 1H), 6.80±6.85 (series of m, 3H),
7.27 (t, 1H, J=7.8 Hz); 13C NMR: d 26.5, 43.8, 55.3,
112.8, 115.2, 121.8, 130.1, 136.4, 160.1, 171.6. Anal.
calcd for C10H13NO: C, 67.02; H, 7.31; N, 7.82. Found:
C, 67.48; H, 7.55; N, 7.11.
N-Methyl-3-hydroxyphenethylamine (13). From 15. This
compound was obtained from 15 in 85% yield by the above
procedure for the demethylation of 14 to 12, at 138±139 ꢀC/
4 mmHg; 1H NMR: d 2.42 (s, 3H), 2.80 (t, 2H, J=6.5 Hz),
2.93 (t, 2H, J=6.0 Hz), 6.64±6.73 (series of m, 3H), 7.21 (t,
1H, J=7.9 Hz); 13C NMR: d 35.3, 35.7, 52.2, 114.1, 116.4,
118.9, 130.3, 140.4, 158.0. Anal. calcd for C9H13NO: C,
71.49; H, 8.67; N, 9.26. Found: C, 71.22; H, 9.03; N, 9.17.
N-Methyl-(3-hydoxyphenyl)acetamide (20). A solution of
19 (4.166 g, 0.025 mol) and 40% aqueous methylamine
(32+7 mL, 0.46 mol) in EtOH (75 mL) was worked up as
described for the synthesis of 17. Concentration of the
reaction mixture and successive refrigeration overnight
gave a colorless solid. Recrystallization from EtOH aor-
From 20. The amine was also prepared by borane
reduction using 20 in 83% yield by the above procedure
for the synthesis of 15 from 17, as a colorless oil.
ded colorless prisms (3.755 g, 91%), mp 150±151 ꢀC; H
1