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J=6.2 Hz, CH2ꢀO), 3.01 (s, 3H, CH3), 2.38 (t, 2H,
J=7.1 Hz, CH2ꢀCN), 1.82–1.58 (m, 6H).
using the HCl salt of compound 6c. Crystallization of
the crude product (HCl salt) from MeOH–EtOAc
(1:2) gave pure compound 8, which showed: m.p.
Methyl-8-mesylate-3-amino-2-phenyl-2-octenoate
(5c). Using the same method for the synthesis of 5a,
4.6 g (70 mmol) of activated Zn dust, 8.8 mL total (56
mmol) of methyl-a-bromophenylacetate and 2.75 g
(14 mmol) of compound 4c gave an oily residue,
which was purified by column chromatography on
120 g of silica gel using an elutant of EtOAc–hexane
(1:1, v/v). This gave 3.5 g (74%) of 5c, which crystal-
lized on standing. The solid was washed with ether to
1
221–222°C; H-NMR (D2O): l 7.35–7.23 (m, 5H,
Ar), 3.94 (d, J=7.6 Hz, 1H, HCꢀAr), 3.85–3.81 (m,
1H), 3.59 (s, 3H, CH3), 3.50–3.45 (m, 2H), 1.64–1.34
(m, 8H). MS-CI; m/z: 284 (M+H).
threo-4-Trifluoromethylmethylphenidate (7d). Using
the same procedures described in making 5c, 1.3 g
(0.02 mmol) of activated Zn dust, 5.95 g (20.0 mmol)
of
methyl-a-bromo-4-trifluoromethlyphenylacetate
1
give pure 5c, which showed: m.p. 53–55°C; H-NMR
and 0.73 g (10 mmol) of compound 4b gave an oily
residue, which was purified by column chromatogra-
phy on silica gel using an elutant of EtOAc–hexane
(1:1) to give 0.57 g (35%) of 5d. Using the same
method for the synthesis of 7a, 0.57 g of 5d and 0.36
g of NaBH3CN gave a crude product as a mixture of
threo and erythro isomers in a ratio of about 1:3 by
1H-NMR analysis. The crude product was converted
to an HCl salt and yellow solid washed with diethyl
ether several times to afford 0.37 g (75%) of 6d as a
white solid. Using the epimerization–esterification
procedure described in the synthesis of 7a, 0.37 g of
6d gave 88 mg (24%) of 7d, which showed: m.p.
(CDCl3): l 7.34–7.25 (m, 3H, Ar), 7.14 (m, 2H, Ar),
4.12 (t, 2H, J=5.9 Hz, CH2ꢀO), 3.58 (s, 3H, CH3ꢀO),
2.97 (s, 3H, CH3ꢀS), 2.02 (t, 2H, J=7.1 Hz,
CH2ꢀCꢁ), 1.60–1.25 (m, 6H).
erythro-Methyl-8-mesylate-3-amino-2-phenyl-2-oc-
tanoate (6c). Using the same method for the synthesis
of 7a, 1.62 g (4.47 mmol) of 5c and 1.2 g (19 mmol) of
NaBH3CN gave 1.77 g of crude product as a mixture
of threo and erythro isomers in a ratio of about 1:5 by
1H-NMR analysis. The crude product was converted
to an HCl salt and yellow solid washed with EtOAc
several times to afford the pure erythro isomer 6c as a
white solid, 0.93 g (57%), which showed: m.p. 158–
1
196–197°C; H-NMR (D2O): l 7.62 (d, J=8.2 Hz,
1
160°C; H-NMR (D2O): l 7.31–7.20 (m, 5H, Ar),
2H, Ar), 7.37 (d, J=8.2 Hz, 2H, Ar), 3.96 (d, J=9.4
Hz, 1H, HC2%), 3.78–3.71 (m, 1H, HC2¦), 3.59 (s, 3H,
CH3), 3.34–3.33 (m, 1H, HC6¦), 2.95 (dt, J=3.3 Hz,
12.9 Hz, HC6¦), 1.76–1.19 (m, 6H). Anal. Calc. for
C15H19ClNO2F3·0.4H2O: C, H, N, Cl.
4.17 (t, 2H, J=6.1 Hz, CH2ꢀO), 3.92 (d, 1H, J=7.2
Hz, CHꢀAr), 3.80–3.78 (m, 1H, HCꢀN), 3.55 (s, 3H,
CH3ꢀO), 3.01 (s, 3H, CH3ꢀS), 1.63–1.32 (m, 8H).
erythro - Methyl - 2 - phenyl - 2 - (2 - azacycloheptyl)-
acetate (7c). A 240-mg (7.1 mmol) portion of 6c was
added to a suspension of 570 mg of K2CO3 in 5 mL of
DMF under a nitrogen atmosphere. The mixture was
heated to 80°C for 2 h, cooled and decanted. The
solid residue was rinsed with diethyl ether (4×20 mL)
and the combined organic layer washed with water
(5×20 mL) and dried. Evaporation of the solvent
gave 160 mg crude product as a pale yellow oil which
was converted to an HCl salt and crystallized from
EtOAc–MeOH (2:1) to give 73 mg (42%) of white
solid as the pure erythro isomer (7c) which showed:
threo - Methyl - 2 - piperidyl - 2 - [(2 - naphthyl)]acetate
(7e). Using the same procedures described in making
5c, 1.0 g (16 mmol) of activated Zn dust, 4.4 g (16
mmol) of methyl-a-bromo-(2-naphthyl)acetate and
0.58 g (3.2 mmol) of compound 4b gave an oily
residue, which was purified by column chromatogra-
phy on silica gel using an elutant of EtOAc–hexane
(1:1) to give 0.72 g (59%) of 5e. Using the same
method for the synthesis of 7a, 0.61 g of 5e, and 0.36
g of NaBH3CN gave a crude product as a mixture of
threo and erythro isomers in a ratio of about 1:3 by
1H-NMR analysis. The crude product was converted
to an HCl salt and yellow solid washed with diethyl
ether several times to afford 0.31 g (68%) of 6e as a
white solid. Using the epimerization–esterification
procedure described in the synthesis of 7a, 0.31 g of
6e gave 0.13 g (54%) of 7e, which showed: m.p.
1
m.p. 178–180°C; H-NMR (D2O): l 7.39–7.29 (m,
5H, Ar), 3.99 (d, J=8.8 Hz, 1H, HC2%), 3.92 (m, 1H,
HC2¦), 3.60 (s, 3H, CH3), 3.09–3.04 (m, 2H, HC7¦),
1.93–1.90 (m, 1H), 1.71–1.41 (m, 7H). MS-CI; m/z:
248 (M+H). Anal. Calc. for C15H22ClNO2·0.25H2O:
C, H, N, Cl.
erythro-Methyl-3-amino-8-chloro-2-phenyloctano-
ate (8). This compound was obtained as a byproduct
when the above cyclization reaction was conducted
1
219–220°C; H-NMR (D2O): l 7.84–7.76 (m, 3H,
Ar), 7.70 (m, 1H, Ar), 7.47–7.43 (m, 2H, Ar), 7.26
(dd, J=1.8, 8.4 Hz, 1H, Ar), 4.00 (d, J=9.3 Hz, 1H,