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Saıd Yous et al. / Bioorg. Med. Chem. 11 (2003) 753–759
757
(7-Methoxy-3-phenyl-3,4-dihydro-2H-naphthalen-1-ylidene)
acetonitrile (10). Under stirring and N2, a solution of 6.3
mL (0.04 mol) of diethyl cyanomethylphosphonate in 30
mL of anhydrous THF was added dropwise in a mix-
ture of 1.60 g (0.04 mol) of NaH (60% in mineral oil)
and 50 mL of anhydrous THF cooled to À10 ꢀC. After 1
h, a solution of 5.04 g (0.02 mol) of 9 in 60 mL of
anhydrous THF was added dropwise and the mixture
was stirred at room temperature for 16 h. The mixture
was then poured into cold water and the solid was col-
lected by filtration, washed with water, and diethyl ether.
Recrystallization from ethanol gave 4.0 g (72%) of pure
10; mp 137–138 C; H NMR: (300 MHz, DMSO-d6) d:
2.86 (dd, 1H, J=14.6, 2.4 Hz), 3.0–3.16 (m, 3H), 3.39
(dd, 1H, J=15.3, 1.7 Hz), 3.85 (s, 3H), 5.79 (d, 1H,
J=2.0 Hz), 6.97 (dd, 1H, J=8.5, 2.4 Hz), 7.11 (d, 1H,
J=2.4 Hz), 7.15 (d, 1H, J=8.5 Hz), 7.27–7.38 (m, 5H).
(36%) of pure (Æ)-cis-13: mp 145–146 ꢀC; 1H NMR
(300 MHz, CDCl3) d: 0.72 (m, 2H), 0.95 (m, 2H), 1.27
(m, 1H), 1.68 (m, 1H), 2.25 (m, 2H), 2.89 (m, 3H), 3.12
(m, 1H), 3.38 (m, 2H), 3.81 (s, 3H), 5.61 (br s, 1H), 6.72
(dd, 1H, J=8.3, 2.3 Hz), 6.89 (d, 1H, J=2.3 Hz), 7.02
(d, 1H, J=8.3 Hz), 7.30–7.40 (m, 5H). Anal. calcd for
C23H27NO2: C, 79.04; H, 7.78; N, 4.00. Found: C,
79.15; H, 7.70; N, 4.16.
(Æ)-cis-N-[2-(7-Methoxy-3-phenyl-1,2,3,4-tetrahydro-
naphthalen-1-yl)ethyl]cyclobutyl carboxamide ((Æ)-cis-
14a). Recrystallization from isopropyl ethꢀer gave 0.42 g
ꢀ
1
1
(33%) of pure (Æ)-cis-14a: mp 160–162 C; H NMR
(300 MHz, CDCl3) d: 1.70–2.17 (m, 11H), 2.86–2.96 (m,
3H), 3.11 (m, 1H), 3.37 (m, 2H), 3.80 (s, 3H), 5.30 (br
s,1H), 6.72 (dd, 1H, J=8.5, 2.5 Hz), 6.88 (d, 1H, J=2.5
Hz), 7.02 (d, 1H, J=8.5 Hz), 7.28–7.34 (m, 5H). Anal.
calcd for C24H29NO2: C, 79.30; H, 8.04; N, 3.86. Found:
C, 79.03; H, 8.15; N, 3.70.
(Æ)-cis-2-(7-Methoxy-3-phenyl-1,2,3,4-tetrahydro-naph-
thalen-1-yl)ethylamine hydrochloride ((Æ)-cis-11).
A
NH3-saturated solution of 10 (3.3 g, 0.012 mol) in eth-
anol (150 mL) was hydrogenated over Raney nickel
under pressure (60 bars) at 60 ꢀCfor 12 h. After fil-
tration and evaporation, the residual oil was dissolved
in dry diethyl ether and treated with gaseous HCl. The
obtained solid was filtered to give 3.2 g (84%) of 11
[mixture of 2/3(Æ)-cis and 1/3(Æ)-trans].
(Æ)-trans-N-[2-(7-Methoxy-3-phenyl-1,2,3,4-tetrahydro-
naphthalen-1-yl)ethyl]cyclobutyl carboxamide ((Æ)-
trans–14b). Fractional crystallization of the mother
liquors of compound (Æ)-cis-14a gave 0.08 g (7%) of
pure (Æ)-trans-14b: mp 111–112 ꢀC; 1H NMR
(300 MHz, CDCl3) d: 1.70–2.25 (m, 11H), 2.81 (m, 1H),
3.11 (m, 1H), 3.89–3.00 (m, 2H), 3.40–3.51 (m, 2H), 3.81
(s, 3H), 5.33 (br s,1H), 6.71 (m, 1H), 6.75 (d, 1H, J=2.3
Hz), 7.02 (d, 1H, J=8.2 Hz), 7.26–742 (m, 5H). Anal.
calcd for C24H29NO2: C, 79.30; H, 8.04; N, 3.86. Found:
C, 79.35; H, 8.12; N, 3.75.
A sample of this mixture was recrystallized from etha-
nol to give pure (Æ)-cis 11: mp 203–205 ꢀC; H NMR
1
(300 MHz, DMSO-d6) d: 1.55–170 (m, 2H), 2.05–2.32
(m, 2H), 2.70–2.95 (m, 3H), 3.05 (m, 1H), 3.05–3.15 (m,
2H), 3.77 (s, 3H), 6.76 (dd, 1H, J=8.4, 2.5 Hz), 6.93 (d,
1H, J=2.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.23 (m, 1H),
7.28–7.37 (m, 4H), 8.18 (br s, 3H).
Resolution of (Æ)-cis-14a and (Æ)-trans-14b. (For
experimental procedure see Supplementary Material.)
(+)-cis-14a. Mp 165 ꢀC; MS: M+=363.2 (42%), 113.1
1
(88%), 91.1 (64%), 55.1 (100%); H NMR (300 MHz,
General procedure for the preparation of amides (12–14)
CDCl3) d: 1.70–2.18 (m, 11H), 2.88–2.98 (m, 3H), 3.11
(m, 1H), 3.37 (m, 2H), 3.81 (s, 3H), 5.31 (br s,1H), 6.72
(dd, 1H, J=8.5, 2.5 Hz), 6.87 (d, 1H, J=2.5 Hz), 7.02
(d, 1H, J=8.5 Hz), 7.27–7.36 (m, 5H); [a]D=53.20
(CH2Cl2); ee=99% (HPLC, Chiralcel OD-H).
Potassium carbonate (1.45 g, 0.0105 mol) was added to
a solution of crude 11 (1.1 g, 0.0035 mol), in 60 mL of
water and 80 mL of methylene chloride. After stirring
for 10 min at 0 ꢀC, 0.0040 mol of the appropriate acid
chloride was added dropwise at this temperature. The
reaction mixture was stirred at room temperature for 2
h. The organic phase was separated, washed with a 1 M
HCl solution and water, dried over MgSO4, filtered and
concentrated under reduced pressure to give the desired
amide as a mixture of 2/3(Æ)-cis and 1/3(Æ)-trans.
(À)-cis-14a. Mp 163 ꢀC; MS: M+=363.2 (38%), 113.1
1
(58%), 69.2 (74%), 55.1 (100%); H NMR (300 MHz,
CDCl3) d: 1.71–2.17 (m, 11H), 2.88–2.97 (m, 3H), 3.11
(m, 1H), 3.38 (m, 2H), 3.81 (s, 3H), 5.30 (br s,1H), 6.72
(dd, 1H, J=8.5, 2.5 Hz), 6.87 (d, 1H, J=2.5 Hz), 7.02
(d, 1H, J=8.5 Hz), 7.27–7.35 (m, 5H); [a]D=À52.33
(CH2Cl2); ee=99% (HPLC, Chiralcel OD-H).
(Æ)-cis-N-[2-(7-Methoxy-3-phenyl-1,2,3,4-tetrahydro-
naphthalen-1-yl)ethyl]acetamide [(Æ)-cis-12]. Recrys-
tallization from isopropyl ether gave 0.4 g (35%) of
(+)-trans-14b. Mp 111–112 ꢀC
;
MS: M=363.2
+.
pure (Æ)-cis-12: mp 126–127 ꢀC; H NMR (300 MHz,
(64%), 264.1 (76%), 113.1 (71%), 55.1 (100%); 1H
NMR (300 MHz, CDCl3) d: 1.72–2.24 (m, 11H), 2.82
(m, 1H), 3.11 (m, 1H), 3.88–3.00 (m, 2H), 3.42–3.50 (m,
2H), 3.81 (s, 3H), 5.33 (br s,1H), 6.71 (m, 1H), 6.75 (d,
1H, J=2.3 Hz), 7.02 (d, 1H, J=8.2 Hz), 7.30–7.42 (m,
5H); [a]D=43.0 (CH2Cl2); ee=99% (HPLC, Chiralcel
OD-H).
1
CDCl3) d: 1.70 (m, 1H), 1.85 (m, 1H), 1.95 (s, 3H), 2.15–
2.25 (m, 2H), 2.85–2.90 (m, 3H), 3.09 (m, 1H), 3.37 (m,
2H), 3.82 (s, 3H), 5.41 (br s, 1H), 6.72 (dd, 1H, J=8.4,
2.5 Hz), 6.87 (d, 1H, J=2.5 Hz), 7.03 (d, 1H, J=8.4 Hz),
7.20–7.40 (m, 5H). Anal. calcd for C21H25NO2: C, 77.98;
H, 7.79; N, 4.33. Found: C, 77.88; H, 7.41; N, 4.36.
(Æ)-cis-N-[2-(7-Methoxy-3-phenyl-1,2,3,4-tetrahydro-
naphthalen-yl)ethyl]cyclopropyl carboxamide [(Æ)-cis-13].
Recrystallisation from isopropyl ether gave 0.45 g
(À)-trans-14b. Mp 97–98 ꢀC; MS: M+.=363.1 (35%),
113.1 (73%), 91.1 (84%), 55.1 (100%); 1H NMR
(300 MHz, CDCl3) d: 1.72–2.25 (m, 11H), 2.81 (m, 1H),