1
718
Vol. 54, No. 12
were removed by filtration, the filtrate was concentrated under vacuum to
about 30 ml. Then the solution was subjected to ODS column chromatogra- (KBr): 3431, 1636 cm
3,4-Dibromophenylglycine (27): White powder, mp 193—195 °C. IR
ꢂ1
1
. H-NMR (400 MHz, CDCl ) d: 7.83 (d, 1H,
3
phy eluted with H O : MeOH (10 : 1—1 : 5) to give pure 3,5-dibromo-L-tyro-
Jꢁ2.0 Hz), 7.72 (d, 1H, Jꢁ8.0 Hz), 7.35 (dd, 1H, Jꢁ8.0, 2.0 Hz), 5.17 (1H,
2
3
1)
ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ
sine (21, 242 mg, 71%) as colorless powder; mp 221—224 °C (lit. 242—
s). MS (ESI): m/z: 308 [M ] , 310 [M ꢀ2] , 312 [M ꢀ4] . Elemental
analysis was carried out as N-acetyl-3,4-dibromophenylglycine methyl ester:
white powder, mp 115—117 °C. Anal. Calcd for C H Br NO : C, 36.19; H,
ꢂ1
1
2
56 °C); IR: nmax (KBr) cm : 3428, 3035, 1625; H-NMR (400 MHz,
CD OD) d: 2.93 (1H, dd, Jꢁ8, 14 Hz), 3.17 (1H, dd, Jꢁ4, 14 Hz), 3.74 (1H,
3
11 11
2
3
ꢀ
ꢀ
dd, Jꢁ4, 8 Hz), 7.45 (2H, s); ESI-MS m/z: 342 (M ꢀ3), 340 (M ꢀ1 Base 3.04; N, 3.84. Found: C, 36.12; H, 3.06; N, 3.33.
ꢀ
Peak), 338 (M ꢂ1); Anal. Calcd C H Br NO ·H O: C, 30.28; H, 3.11; N,
Bromination of 2-Phenylethylamine (28) To
a
solution of 2-
1
2
13
2
4
2
3
.92; Found: C, 30.15; H, 2.95; N, 3.87. The optical purities of 21 were phenylethyamine (28, 126 ml, 1.0 mmol) in 60% aq. H SO (2.0 ml) was
2 4
ꢃ99% e.e. [6.24 min, Chirabiotic T (Tokyo Kasei), EtOH : H O : AcOHꢁ added BICA-Na (11) (312 mg, 1.0 mmol) in one portion at 0 °C, and stirred
2
1
00 : 100 : 1].
.1 eq of BICA-Na (11): To a solution of L-tyrosine (19, 181 mg,
.0 mmol) in 60% aq. H SO (8.8 ml) was added BICA-Na (11) (312 mg) in
for 2.5 h at same temperature. After addition of H O (5.0 ml), the mixture
2
1
was basified with 30% NaOH (pHꢁ13) and extracted with Et O for 3 times.
2
1
The combined organic layer was washed successively with sat. NaHCO and
2
4
3
one portion at 0 °C. After stirring for 2 h at same temperature, the mixture
sat. NaCl, and dried over MgSO . After evaporation of the solvent, resulting
4
was quenched with H O (20 ml). Then the mixture was neutralized with yellow oil (118 mg) was acetylated with Ac O (0.50 ml) in pyridine (1.0 ml)
2
2
Ba(OH) (pHꢁ7) and the resulting precipitates (BaSO ) was removed by fil- at room temperature for 2 h. Then the mixture was quenched with water,
2
4
tration. The filtrate was concentrated under vacuum to about 30 ml. Then the acidified with 10% HCl, and extracted with Et O for 3 times. Combined or-
2
solution was subjected to weak basic ionic exchange resin (IRA96SB, 50 ml) ganic layer was washed with successively with sat. NaHCO , sat. NaCl, and
3
and eluted with water (2 l) to remove remaining inorganic compounds and dried over MgSO . After evaporation of the solvent, the resulting pale yel-
4
5
(
% aq. AcOH–MeOH (20 : 1, 350 ml) to elute the mixture of amino acids
20, 21). After evaporation of the solvent, the resulting residue (293 mg) was tion of benzyl proton at 2.77 ppm (p-) and 2.98 (o-) ppm showed that the
subjected to synthetic resin (SP20SS, 50 ml). The first fraction was 3-bromo- yields of the 29 and 30 were 21% and 22% respectively. Each product was
low oil (105 mg) was measured NMR spectrum. The intensity of the integra-
31)
L-tyrosine (20, 75 mg, 29%) as a colorless powder. mp 232—234 °C (lit.
confirmed by the comparison of the pure authentic samples synthesized by
us (see below).
1
2
24 °C). H-NMR (400 MHz, CD OD) d: 2.91 (1H, dd, Jꢁ8, 15 Hz), 3.17
3
(1H, dd, Jꢁ5, 15 Hz), 3.70 (1H, dd, Jꢁ5, 8 Hz), 6.86 (1H, d, Jꢁ8 Hz), 7.10
1H, dd, Jꢁ2, 8 Hz), 7.42 (1H, d, Jꢁ2 Hz). The second fraction was L-3,5-
Bromination of Benzylamine (31) To a solution of benzylamine (31,
109 ml, 1.0 mmol) in 60% aq. H SO (2.0 ml) was added BICA-Na (11)
(
2
4
dibromotyrosine (21, 65 mg, 19%). The third fraction was recovered starting (312 mg, 1.0 mmol) in one portion at 0 °C, and the reaction mixture was
L-tyrosine (65 mg, 35%).
stirred for 2.5 h at same temperature. The crude product (108 mg) was ob-
Bromination of DL-Phenylglycine (22) dl-Phenylglycine (22, 152 mg, tained as yellow oil by the procedure described for the bromination of 2-
1
mmol) was dissolved in 60% aq. H SO4 (10 ml). To this solution was phenylethylamine (28). This oil was acetylated as described above to give
2
added BICA-Na (11, 312 mg, 1.1 eq) under 5 °C, then the mixture was
the mixture of acetylated products (118 mg), which was measured NMR
stirred for 2.5 h under ice cooling. After dilution with H O (30 ml), spectrum to determine the yields. The intensities of the integration of benzyl
2
Ba(OH) ·8H O (36 g) was added to the mixture for neutralization (pH 6—7) proton at 4.51 ppm (o-), 4.42 ppm (m-), and 4.39 (p-) ppm showed that the
2
2
under ice cooling. Then the resulted precipitate (BaSO ) was removed by fil- yields of the 33, 32, and 34 were 21%, 15%, and 16% respectively. Each
4
tration and washed with small proportion of water. The combined filtrate product was confirmed by the comparison of the pure authentic sample syn-
was passed through weak basic ion-exchange resin [80 ml, Amberlite thesized by us (see below).
IRA96SB, (Organo)] and the resin was washed with water (700 ml) in order
to remove inorganic compounds completely. Then elution with 5% AcOH (KBr) cm : 3288, 1652; H-NMR (400 MHz, CDCl ) d: 1.96 (3H, s), 2.98
aq. : MeOH (ꢁ20 : 1, 700 ml) gave the crude product (198 mg) as a white
N-Acetyl-2-(2-bromophenyl)ethylamine (29): Pale yellow oil; IR n
max
ꢂ1 1
3
(2H, t, Jꢁ7 Hz), 3.53 (2H, q, Jꢁ7 Hz), 5.91 (1H, br s), 7.1 (2H, m), 7.2 (2H,
solid after evaporation of solvent. The crude product (198 mg) was purified m); Anal. Calcd for C H BrNO: C, 49.61; H, 5.00; N, 5.79. Found: C,
1
0
12
repeatedly by using synthetic resin [80 ml, Sepabeads SP20SS (Mitsubishi 49.50; H, 5.24; N, 5.56.
Chemical Co.) elution with H O] and ODS column chromatography [Ultra N-Acetyl-2-(4-bromophenyl)ethylamine (30): Colorless needles; mp
2
ꢂ1
Pack ODS-A-40B (Yamazen), elution with H O–10% aq. MeOH], to give 105—106 °C (from hexane and AcOEt). IR n
pure 24 (14 mg), 23 (41 mg), and a mixture of 26 and 27 (16 mg). 25 was pu-
rified by repeated ODS chromatography from the mixture of 24 and 25
(KBr) cm : 3294, 1639;
2
max
1
H-NMR (400 MHz, CDCl ) d: 1.95 (3H, s), 2.77 (2H, t, Jꢁ7 Hz), 3.48 (2H,
q, Jꢁ7 Hz), 5.39 (1H, br s), 7.08 (2H, d, Jꢁ6 Hz), 7.44 (2H, d, Jꢁ6 Hz); MS
3
ꢀ
ꢀ
(
107 mg). Product ratios of each inseparable fractions [22ꢀ24 (22 mg),
(EI) m/z: 243 (Mꢀ2) , 241 (M) , 184 (bp); Anal. Calcd for C H BrNO: C,
10 12
2
3ꢀ24 (4 mg), and 23ꢀ25 (107 mg)] were determined by the integration of 49.61; H, 5.00; N, 5.79. Found: C, 49.67; H, 5.06; N, 5.44.
aromatic protons of the NMR spectrum. The calculated combined yields
were shown in the Chart 4.
N-Acetyl-3-bromobenzylamine (32): Colorless needles; mp 76—78 °C
ꢂ1
1
(from hexane–AcOEt). IR: nmax (KBr) cm
: 3288, 1638; H-NMR
3
-Bromophenylglycine (23): White powder, mp 231—232 °C. IR (KBr): (400 MHz, CDCl ) d: 2.04 (3H, s), 4.41 (2H, d, Jꢁ6 Hz), 5.75 (1H, br s),
3
ꢂ1 1 ꢀ ꢀ
3
446, 1635, 1582 cm . H-NMR (400 MHz, CD OD) d: 7.69 (t, 1H, 7.21 (2H, m), 7.42 (2H, m); MS (EI) m/z: 227 (M) , 229 (Mꢀ2) , 106
Jꢁ1.6 Hz), 7.54 (ddd, 1H, Jꢁ8.0, 1.6, 0.9 Hz), 7.46 (br d, 1H, Jꢁ8 Hz), 7.33
t, 1H, Jꢁ8.0 Hz), 4.56 (s, 1H). MS (ESI): m/z: 230 [M ] , 232 [M ꢀ2] . C, 47.64; H, 4.47; N, 5.73.
3
(Base Peak); Anal. Calcd for C H BrNO: C, 47.39; H, 4.42; N, 6.14. Found:
9 10
ꢀ
ꢀ
ꢀ
ꢀ
(
7
9
HR-MS (ESI-TOFF) m/z Calcd for C H BrNO 229.9817, Found 229.9829
N-Acetyl-2-bromobenzylamine (33): Colorless needles; mp 82—84 °C
8
9
2
ꢀ
81
9
ꢀ
ꢂ1
1
(
M ). Calcd for C H BrNO 231.9796, Found 231.9808 (M ꢀ2).
(from hexane–AcOEt); IR nmax (KBr) cm : 3266, 1640; H-NMR
8
2
2
-Bromophenylglycine (24): White powder, mp ꢃ250 °C. IR (KBr):
(400 MHz, CDCl ) d: 2.02 (3H, s), 4.51 (2H, d, Jꢁ6 Hz), 5.96 (1H, br s),
3
ꢂ1
1
3
436, 1662, 1590 cm
Jꢁ8.0, 1.2 Hz), 7.54 (dd, 1H, Jꢁ8.0, 1.6 Hz), 7.41 (dt, 1H, Jꢁ8.0, 1.2 Hz),
.
H-NMR (400 MHz, CD OD) d: 7.69 (dd, 1H, 7.15 (1H, dt, Jꢁ8, 2 Hz), 7.29 (1H, dt, Jꢁ8, 1 Hz), 7.40 (1H, dd, Jꢁ8, 2 Hz),
3
7.55 (1H, dd, Jꢁ8, 1 Hz); Anal. Calcd for C H BrNO: C, 47.39; H, 4.42; N,
9 10
ꢀ
ꢀ
7
[
.30 (dt, 1H, Jꢁ8.0, 1.6 Hz), 5.10 (s, 1H). MS (ESI): m/z: 230 [M ] , 232
6.14. Found: C, 47.49; H, 4.50; N, 5.80.
N-Acetyl-4-bromobenzylamine (34): Colorless needles; mp 123—125 °C
ꢀ
ꢀ
79
M ꢀ2] . HR-MS (ESI-TOFF) m/z Calcd for C H BrNO2 229.9817,
8 9
ꢀ
81
ꢂ1
1
Found 229.9821 (M ). Calcd for C H BrNO 231.9796, Found 231.9804 (from hexane–AcOEt); IR: nmax (KBr) cm
: 3279, 1639; H-NMR
8
9
2
ꢀ
(
M ꢀ2).
(400 MHz, CDCl ) d: 2.03 (3H, s), 4.39 (2H, d, Jꢁ6 Hz), 5.70 (1H, br s),
3
ꢀ
4
-Bromophenylglycine (25): White powder. mp ꢃ250 °C. IR (KBr):
7.16 (2H, d, Jꢁ9 Hz), 7.46 (2H, d, Jꢁ9 Hz). MS (EI) m/z: 227 (M) , 229
ꢂ1
1
ꢀ
3
438, 1635, 1581 cm
.
H-NMR (400 MHz, CD OD) d: 7.56 (d, 2H, (Mꢀ2) , 106 (Base Peak); Anal. Calcd for C H BrNO: C, 47.39; H, 4.42;
3
9
10
ꢀ
Jꢁ8.4 Hz), 7.39 (d, 2H, Jꢁ8.4 Hz), 4.56 (s, 1H). MS (ESI): m/z: 230 [M] , N, 6.14. Found: C, 47.56; H, 4.44; N, 5.72.
32 [Mꢀ2] . The structure of was confirmed by the comparison of commer-
ꢀ
2
cially available 25.
Acknowledgments This work was supported by a Grant-in-Aid for Sci-
2
,5-Dibromophenylglycine (26): White powder, mp 170—172 °C. IR entific Research (17590229-3668) from the Ministry of Education, Culture,
ꢂ1
1
(
KBr): 3441, 1625 cm
Jꢁ2.0 Hz), 7.51 (d, 1H, Jꢁ8.4 Hz), 7.36 (dd, 1H, Jꢁ8.4, 2.0 Hz), 4.91 (1H,
s). MS (ESI): m/z: 308 [M ] , 310 [M ꢀ2] , 312 [M ꢀ4] . Elemental and also supported by a Uehara Memorial Foundation. We are also grateful
analysis was carried out as N-acetyl-2,5-dibromophenyl-glycine methyl to Mr. H. Kamakura (Division of Pharmacognosy and Phytochemistry, Na-
.
H-NMR (400 MHz, CD OD) d: 7.62 (d, 1H, Sports, Science and Technology, Japan (MEXT), and by “Open Research
3
Center” project for private university matching fund subsidy from MEXT,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ester: white powder, mp 130—131 °C. Anal. Calcd for C H Br NO : C,
tional Institute of Health Science) for measurement of high resolution
TOFF-MASS.
1
1
11
2
3
3
6.19; H, 3.04; N, 3.84. Fond: C, 36.39; H, 3.16; N, 3.36.