N. Burdzhiev, E. Stanoeva / C. R. Chimie 13 (2010) 1443–1449
1447
triethylamine (0.14 mL, 1 mmol) and methyl 2-aminoace-
tate hydrochloride (0.126 g, 1 mmol) were added. The
reaction mixture was cooled (-10 8C) and DCC (0.275 g,
1.3 mmol) was added in portions. The mixture was stirred
for 2 h at -10 8C and then 12 h at room temperature. The
resulting precipitate of 1,3-dicyclohexylurea was filtered
and discarded. The filtrate was evaporated under reduced
pressure and the resulting oil was dissolved in ethyl
acetate (30 mL). The solution was successively washed
with 10% HCl, water, 10% Na2CO3 and brine. Organic layer
was dried (Na2SO4) and the solvent was removed in vacuo.
Recrystallization from light petroleum/ethyl acetate
yielded 0.167 g (44%), mp 130–131 8C; IR (Nujol): 1610,
acetate (50 mL) and the organic solution was washed with
water (3 20 mL). Organic layer was dried (Na2SO4). Crude
products were purified by means of column chromatogra-
phy and/or recrystallization from ethyl acetate.
Methyl (2S)-2-(((Æ)-trans-1-benzyl-6-oxo-2-phenyl-
piperidine-3-carbonyl)amino)-3-phenylpropanoate (5).
Synthesized from acid chloride 2 and L-a-phenylalanine
methyl ester. Recrystallization from ethyl acetate yielded
0.245 g (52%) of 5 as white crystals, mp 148–150 8C; IR
(Nujol): 1640, 1670 and 1700 (E = ?), 3380 (NH) cmÀ1; 1H
x
NMR (CDCl3):
d 1.79–2.12 (m, 4H, 2xH-4, 2xH-4*), 2.45–
2.76 (m, 7H, H-3, H-3*, 2xH-5, 2xH-5*, CHCH2Ph), 2.82 (dd,
1H, CHCH2Ph*, J = 6.8, 13.9 Hz), 2.91 (dd, 1H, CHCH2Ph,
J = 4.9, 13.8 Hz), 3.09 (dd, 1H, CHCH2Ph*, J = 5.6, 13.9 Hz),
3.36 (d, 1H, CH2Ph, J = 14.8 Hz), 3.37 (d, 1H, CH2Ph*,
J = 14.8 Hz), 3.65 (s, 3H, OCH3), 3.66 (s, 3H, OCH3*), 4.62–
4.81 (m, 4H, H-2, H-2*, CHNH, CHNH*), 5.45 (d, 1H, CH2Ph,
J = 14.8 Hz), 5.48 (d, 1H, CH2Ph*, J = 14.8 Hz), 5.58–5.73 (m,
2H, NHCO, NHCO*), 6.39–6.50 (m, 2H, Ph, Ph*), 6.88–7.43
(m, 28H, Ph, Ph*). Anal. Calcd. for C29H30N2O4: C, 74.02; H,
6.43; N, 5.95; Found: E, 74.60; =, 6.41; N, 5.92.
1680 and 1750 (C = O), 3280 (NH) cmÀ1; 1H NMR (CDCl3):
d
1.91–2.13 (m, 2H, H-4), 2.50–2.82 (m, 3H, H-3, 2xH-5), 3.35
(d, 1H, CH2Ph, J = 14.7 Hz), 3.69 (dd, 1H, CH2NH, J = 5.1,
18.2 Hz), 3.69 (s, 3H, OCH3), 3.84 (dd, 1H, CH2NH, J = 5.6,
18.2 Hz), 4.69 (d, 1H, H-2, J = 6.6 Hz), 5.54 (d, 1H, CH2Ph,
J = 14.7 Hz), 5.65 (t, 1H, NHCO, J = 5.0 Hz), 7.07–7.42 (m,
10H, Ph). Anal. Calcd. for C22H24N2O4: C, 69.46; H, 6.36; N,
7.36; Found: E, 69.70; =, 6.37; N, 7.31.
Methyl (2S)-2-[((Æ)-trans-1-benzyl-6-oxo-2-phenyl-
Methyl (2S)-2-(((Æ)-trans-1-benzyl-6-oxo-2-phenyl-
piperidine-3-carbonyl)amino)-3-(1H-indol-3-yl)pro-
panoate (6). Synthesized from acid chloride 2 and L-
tryptophan methyl ester. Column chromatography with
light petroleum:ethyl acetate (1:2, v/v) and further recrys-
tallization from ethyl acetate afforded 0.378 g (74%) of 6 as
white crystals, mp 112–114 8C; IR (Nujol): 1620, 1650 and
piperidine-3-carbonyl)amino]-propanoate (4). A solu-
tion of acid chloride
dichloromethane (3 mL) was cooled (0 8C) and triethyla-
mine (0.41 mL, 3 mmol) was added to it. Solution of L-
2
[19] (1.5 mmol) in dry
a
-
alanine methyl ester hydrochloride (0.206 g, 1.5 mmol) in
dry dichloromethane (3 mL) was added and the reaction
mixture was stirred for 0.5 h at room temperature. The
solvent was removed under reduced pressure and the
residue was dissolved in ethyl acetate (50 mL). Organic
;
1750 (E = ?), 3190 and 3410 (NH) cmÀ1 1H NMR (DMSO-
d6): 1.55–1.91 (m, 4H, 2xH-4, 2xH-4*), 2.26–2.57 (m, 4H,
d
2xH-5, 2xH-5*), 2.66–3.01 (m, 5H, H-3, H-3*, 2xCH2Ind,
CH2Ind*), 3.10 (dd, 1H, CH2Ind*, J = 5.4, 14.5 Hz), 3.31 (d, 1H,
CH2Ph, J = 15.4 Hz), 3.33 (d, 1H, CH2Ph*, J = 15.4 Hz), 3.49 (s,
3H, OCH3), 3.51 (s, 3H, OCH3*), 4.34–4.49 (m, 2H, CHNH,
CHNH*), 4.62 (d, 1H, H-2, J = 6.6 Hz), 4.65 (d, 1H, H-2*,
J = 6.6 Hz), 5.15 (d, 1H, CH2Ph, J = 15.4 Hz), 5.17 (d, 1H,
CH2Ph*, J = 15.4 Hz), 6.70–7.47 (m, 30H, Ph, Ph*), 8.32 (d, 1H,
NHCO, J = 7.5 Hz), 8.35 (d, 1H, NHCO*, J = 8.0 Hz), 10.77 (d,
1H, indolic NH, J = 1.7 Hz), 10.85 (d, 1H, indolic NH*,
J = 1.8 Hz). Anal. Calcd. for C31H31N3O4: C, 73.06; H, 6.13;
N, 8.25; Found: E, 73.26; =, 6.10; N, 8.08.
solution was washed with water (3 20 mL) and dried
x
(Na2SO4). Recrystallization from ethyl acetate afforded
0.189 g (32%) of 20:1 diastereomeric mixture of 4, mp 197–
199 8C. Concentration of the filtrate yielded 0.228 g (38%)
of 1:4 diastereomeric mixture of 4, mp 199–201 8C. The
total yield was 0.417 g (70%) of 4 as white crystals. IR
(Nujol): 1635, 1675 and 1735 (E = ?), 3425 (NH) cmÀ1; 1H
NMR (CDCl3):
d 1.02 (d, 3H, CHCH3, J = 7.2 Hz), 1.19 (d, 3H,
CHCH3*, J = 7.2 Hz), 1.91–2.18 (m, 4H, 2xH-4, 2xH-4*),
2.48–2.83 (m, 6H, H-3, H-3*, 2xH-5, 2xH-5*), 3.37 (d, 1H,
CH2Ph, J = 14.7 Hz), 3.39 (d, 1H, CH2Ph*, J = 14.7 Hz), 3.66 (s,
3H, OCH3), 3.69 (s, 3H, OCH3*), 4.40 (dq, 2H, CHCH3,
CHCH3*, J = 7.2 Hz), 4.64 (d, 1H, H-2, J = 8.3 Hz), 4.71 (d, 1H,
H-2*, J = 6.3 Hz), 5.48 (d, 1H, CH2Ph, J = 14.7 Hz), 5.53 (d, 1H,
CH2Ph*, J = 14.7 Hz), 5.61 (d, 1H, NHCO, J = 7.9 Hz), 5.53 (d,
1H, NHCO*, J = 7.2 Hz), 7.03–7.42 (m, 20H, Ph, Ph*). Anal.
Calcd for C23H26N2O4: C, 70.03; H, 6.64; N, 7.10; Found: E,
70.67; =, 6.65; N, 7.40.
Synthesis of (Æ)-trans-5-amino-1-benzyl-6-phenyl-
piperidin-2-one (7). To a cooled (-5 8C) solution of NaOH
(0.480 g, 12 mmol) in water (6 mL), bromine (0.12 mL,
2.3 mmol) was added. The mixture was stirred for 0.5 h and
(Æ)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxa-
mide 8 [19] (0.616 g, 2 mmol) was added. The reaction mixture
was stirred at 60 8C for 1.5 h until completion of the reaction
(tlc). After extraction with ethyl acetate combined organic
layers were washed with 1:1 HCl (25 mL). The water layer was
then alkalized with 10% NaOH and extracted with ethyl
acetate. Organic phase was dried (Na2SO4) and solvent was
evaporated under vacuo. The oily product 0.410 g (73%) was
used for further transformations without additional purifica-
General procedure for the synthesis of (Æ)-trans-1-
benzyl-6-oxo-2-phenylpiperidine-3-carboxamides
5
and 6. Hydrochloride of the methyl ester of the corre-
sponding L- -amino acid (3 mmol) is transformed into a
a
base and extracted with dichloromethane. The organic
solution was dried (Na2SO4). The solvent was removed and
the residue was dissolved in dry dichloromethane (2 mL).
This solution was added dropwise to a cooled (0 8C)
solution of acid chloride 2 [19] (1 mmol) in dry dichlor-
omethane (3 mL). Reaction mixture was stirred for 0.5 h at
room temperature and solvent was removed under
reduced pressure. The residue was dissolved in ethyl
tion. IR (Nujol): 1620 (C = O), 3360 and 3480 (NH2) cmÀ1
Synthesis of (Æ)-trans-5-amino-1-benzyl-6-phenyl-
piperidin-2-one hydrobromide. Amine (0.450 g,
.
7
1.6 mmol) was dissolved in dry methanol (5 mL) and
48% hydrobromic acid was added until pH = 3. Dry diethyl
ether was added (1 mL) and crystallized solid was collected
by filtration. Yield 0.448 g (78%), mp 175–178 8C; IR