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E. J. Homan et al. / Bioorg. Med. Chem. 7 (1999) 1263±1271
(S)-5-Methoxy-2-(N-n-propylamino)tetralin hydrochloride
[(S)-9]. Yield 95%; mp 276±278ꢀC dec (EtOH) [lit.40
20.9, 22.9, 26.5, 33.2, 38.6, 52.1, 55.2, 57.7, 107.2, 116.9,
121.5, 124.8, 126.3, 136.3, 157.1; MS (CI with AcOH):
m/z (rel. intensity) 220 (31), 259 (100, M+1).
22
ꢀ
mp 278±280ꢀC]; a
73 [lit.40 63ꢀ]; IR: cm 2967,
1
d
2835, 2793, 2735, 2525, 2443, 2588; 1H NMR (base, 200
MHz, CDCl3): d 0.97 (t, J=7.3 Hz, 3H), 1.51±1.67 (m,
3H), 1.80 (bs, 1H), 2.05±2.13 (m, 1H), 2.55±2.74 (m,
4H), 2.85±3.05 (m, 3H), 3.81 (s, 3H), 6.69 (dd, J=11.1
Hz, 7.7 Hz, 2H), 7.11 (t, J=8.1 Hz, 1H); 13C NMR
(base, 50 MHz, CDCl3): d 11.9, 22.2, 23.6, 29.2, 36.8,
49.1, 53.2, 55.2, 107.0, 121.5, 125.1, 126.2, 136.7, 157.2;
MS (CI with AcOH): m/z 220 (M+1).
General procedure for the preparation of (S)-11 and (R)-
11. The method adopted for the preparation of (S)-5-
methoxy-2-[N-(2-aminoethyl)-N-n-propylamino]tetralin
dihydrochloride [(S)-11] is described: a solution of the
free base of (S)-10 (2.35 g, 9.1 mmol) in dry THF (75
mL) was added to a stirred suspension of LiAlH4 (3.00
g) in dry THF (75 mL). After re¯uxing for 24 h under a
nitrogen atmosphere, the reaction mixture was cooled to
room temperature and excess LiAlH4 was decomposed
by adding H2O and 4 N aqueous NaOH solution. The
precipitate was removed by ®ltration and the ®ltrate was
concentrated under reduced pressure. The resulting oil
was dissolved in CH2Cl2, the solution was dried over
Na2SO4 and subsequently ®ltered. Removal of the sol-
vent under reduced pressure gave the pure base of (S)-
11 as a colourless oil, which was converted to the cor-
responding dihydrochloride salt.
(R)-5-Methoxy-2-(N-n-propylamino)tetralin hydrochloride
[(R)-9]. This compound was prepared as described for
(S)-9, starting from (R)-8. Yield 91%; mp 275±277ꢀC
22
dec (EtOH) [lit.40 mp 278±280ꢀC]; a +71ꢀ [lit.40+
d
70ꢀ]; IR: cm 1 2967, 2835, 2791, 2734, 2525, 2443, 1588;
1H NMR (base, 200 MHz, CDCl3): d 0.97 (t, J=7.3 Hz,
3H), 1.34 (bs, 1H), 1.50±1.61 (m, 3H), 2.06±2.13 (m,
1H), 2.54±2.74 (m, 4H), 2.85±3.07 (m, 3H), 3.82 (s, 3H),
6.67 (dd, J=9.0 Hz, 9.0 Hz, 2H), 7.11 (t, J=8.1 Hz,
1H); 13C NMR (base, 50 MHz, CDCl3): d 11.9, 22.2,
23.6, 29.3, 36.9, 49.1, 53.2, 55.2, 107.0, 121.5, 125.1,
126.1, 136.8, 157.2; MS (CI with AcOH): m/z 220
(M+1).
(S)-5-Methoxy-2-[N-(2-aminoethyl)-N-n-propylamino]-
tetralin dihydrochloride [(S)-11]. Yield 90%; mp 111±
22
d
112ꢀC; a
53ꢀ; IR: cm 3399 (b), 2939, 2881, 2836,
1
1
2633, 2519, 1588; H NMR (base, 200 MHz, CDCl3):
d 0.90 (t, J=7.3 Hz, 3H), 1.39±1.69 (m, 3H), 1.80 (bs,
2H), 1.98±2.08 (m, 1H), 2.28±3.07 (m, 11H), 3.82 (s,
3H), 6.69 (dd, J=11.7 Hz, 7.9 Hz, 2H), 7.10 (t, J=7.9
Hz, 1H); 13C NMR (base, 50 MHz, CDCl3): d 11.8,
22.3, 23.9, 25.5, 32.8, 40.6, 52.6, 53.0, 55.2, 56.2, 106.8,
121.6, 125.2, 126.1, 138.1, 157.2; MS (CI with AcOH):
m/z (rel. intensity) 220 (2), 263 (100, M+1).
General procedure for the preparation of (S)-10 and (R)-
10. The method adopted for the preparation of (S)-5-
methoxy-2-(N-cyanomethyl-N-n-propylamino)tetralin
hydrochloride [(S)-10] is described: bromoacetonitrile
(3.55 g, 29.6 mmol) was added dropwise to a stirred
suspension of K2CO3 (4.10 g, 29.6 mmol) and (S)-9
(2.60 g, 11.9 mmol) in acetone (150 mL), and the reac-
tion mixture was re¯uxed under a nitrogen atmosphere
for 24 h. After cooling, the precipitate was removed by
®ltration and the ®ltrate was concentrated under
reduced pressure. The resulting crude oil was puri®ed by
column chromatography (eluent: CH2Cl2), yielding 2.62
g (10.1 mmol, 85%) of the pure base of (S)-10 as a col-
ourless oil, which was converted to the corresponding
hydrochloride salt.
(R)-5-Methoxy-2-[N-(2-aminoethyl)-N-n-propylamino]-
tetralin dihydrochloride [(R)-11]. This compound was
prepared as described for (S)-11, starting from (R)-10.
22
d
Yield 97%; mp 111±113ꢀC; a +54ꢀ; IR: cm 3400
1
(b), 2939, 2882, 2837, 2639, 2525, 1588; 1H NMR (base,
200 MHz, CDCl3): d 0.90 (t, J=7.3 Hz, 3H), 1.42±1.68
(m, 3H), 1.84 (bs, 2H), 1.99±2.08 (m, 1H), 2.46±2.67 (m,
5H), 2.70±3.07 (m, 5H), 3.81 (s, 3H), 6.69 (dd, J=12.2
Hz, 7.9 Hz, 2H), 7.10 (t, J=7.7 Hz, 1H); 13C NMR
(base, 50 MHz, CDCl3): d 11.8, 22.3, 23.9, 25.5, 32.2,
40.6, 52.6, 53.0, 55.2, 56.2, 106.8, 121.6, 125.2, 126.1,
138.1, 157.2; MS (CI with AcOH): m/z (rel. intensity)
220 (5), 263 (100, M+1).
(S)-5-Methoxy-2-(N-cyanomethyl-N-n-propylamino)-
tetralin hydrochloride [(S)-10]. Yield 85%; mp 189±
22
d
191ꢀC; a
66ꢀ; IR: cm 2922, 2833, 2737, 2368 (b),
1
1
2322 (b), 1590; H NMR (base, 200 MHz, CDCl3): d
0.96 (t, J=7.3 Hz, 3H), 1.45±1.72 (m, 3H), 2.12±2.22
(m, 1H), 2.59±3.06 (m, 7H), 3.68 (s, 2H), 3.83 (s, 3H),
6.71 (dd, J=8.3 Hz, 8.3 Hz, 2H), 7.17 (t, J=7.9 Hz,
1H); 13C NMR (base, 50 MHz, CDCl3): d 11.6, 20.9,
22.9, 26.5, 33.2, 38.6, 52.1, 55.2, 57.7, 107.2, 116.9,
121.5, 124.8, 126.3, 136.3, 157.1; MS (CI with AcOH):
m/z (rel. intensity) 220 (100), 259 (86, M+1).
General procedure for the preparation of (S)-5, (R)-5,
(S)-6, and (R)-6. The method adopted for the prepara-
tion of (S)-5-methoxy-2-[N-(2-(benzamidoethyl)-N-n-
propylamino]tetralin hydrochloride [(S)-5] is described:
benzoyl chloride (0.52 g, 3.7 mmol), dissolved in
CH2Cl2 (10 mL), was added dropwise to a vigorously
stirred mixture of (S)-11 (0.50 g, 1.5 mmol), 10% aqu-
eous NaOH solution (12 mL) and CH2Cl2 (50 mL).
After stirring at room temperature for 3 h, the reaction
mixture was poured into H2O (50 mL) and the organic
phase was separated. The H2O layer was extracted with
CH2Cl2 (2Â50 mL) and the combined organic layers were
subsequently washed with saturated aqueous NaHCO3
(3Â50 mL), H2O (50 mL) and brine (50 mL). After
drying over Na2SO4 the organic layer was concentrated
(R)-5-Methoxy-2-(N-cyanomethyl-N-n-propylamino)-
tetralin hydrochloride [(R)-10]. This compound was pre-
pared as described for (S)-10, starting from (R)-9. Yield
22
d
85%; mp 186±188ꢀC; a +66ꢀ; IR: cm 2922, 2834,
1
2367 (b), 2330 (b), 1590; 1H NMR (base, 200 MHz,
CDCl3): d0.96 (t, J=7.3 Hz, 3H), 1.49±1.72 (m, 3H),
2.15 (m, 1H), 2.60±3.06 (m, 7H), 3.68 (s, 2H), 3.83 (s,
3H), 6.71 (dd, J=8.3 Hz, 8.3 Hz, 2H), 7.13 (t, J=7.7
Hz, 1H); 13C NMR (base, 50 MHz, CDCl3): d 11.6,