4416
N. Cabedo et al. / Tetrahedron 62 (2006) 4408–4418
a 37% aqueous solution) in concd HCl (5 mL) was heated
for 30 min at 95 8C. Then concd HCl (1 mL) and
formaldehyde (0.5 mL) were added and the mixture was
heated at 95 8C for another 3 h. The mixture reaction was
allowed to cool to room temperature overnight and the solid
was filtered and washed with H2O. Then, the residue of
THIQ 2 hydrochloride was dissolved in hot MeOH (10 mL),
treated with concd H2SO4 (0.2 mL) and shaken at room
temperature for 2 h. The solvent was concentrated under
reduced pressure to give 204 mg of the methyl ester
hydrochloride 3 (0.9 mmol, 30%) as a white solid, which
was used directly in the next step.
the reaction mixture was cool to room temperature, and
washed with H2O, brine, dried over NaSO4, filtered and
evaporated under reduced pressure. The residue was
purified by flash chromatography (CH2Cl2/MeOH/
NH4OH, 9.6:0.4:1 drop) to obtain 60 mg of compound 6
(57%). The same procedure using 1-(2-aminoethyl)pyrroli-
dine was accomplished for compound 5 (49 mg, 49%).
Compound 5. [a]DZK1428 (c 0.9, EtOH); IR (dry film)
nmax: 3470, 2944, 1673, 1456, 1325 cmK1 1H NMR
;
(300 MHz, CDCl3) d: 1.70–1.84 (m, 4H, CH2-50 and CH2-
60), 2.50–2.60 (m, 4H, CH2-40 and CH2-70), 2.71 (t, JZ
6.5 Hz, 2H, CH2-20), 3.01 (dd, JZ15.9, 3.4 Hz, 1H, CH2a-
11), 3.43 (dd, JZ15.9, 12.4 Hz, 1H, CH2b-11), 3.50–3.66
(m, 2H, CH2-10), 4.19 (s, 2H, CH2-3), 4.16–4.25 (m, 1H,
CH-11a), 4.33 (d, JZ17.1 Hz, 1H, CH2a-6), 5.29 (d, JZ
17.1 Hz, 1H, CH2b-6), 7.10–7.30 (m, 4H, ArH); 13C NMR
(75 MHz, CDCl3) d: 23.4 (CH2-50 and CH2-60), 33.5 (CH2-
11), 43.89 (CH2-6), 44.9 (CH2-10), 50.3 (CH2-3), 53.0 (CH2-
40and CH2-70), 54.1 (CH2-20), 55.5 (CH-11a), 126.2 (CH),
126.9 (CH), 128.6 (2CH), 131.2 (C-10a), 132.4 (C-6a),
162.6 (C-1), 164.8 (C-4); LSIMS m/z 314 [MHC].
1H NMR (300 MHz, CDCl3) d: 2.86 (br s, 1H, NH), 2.91
(dd, JZ16.2, 10.2 Hz, 1H, CH2-4a), 3.05 (dd, JZ16.2,
4.8 Hz, 1H, CH2-4b), 3.71 (dd, JZ10.2, 4.8 Hz, 1H, CH-3),
3.73 (s, 3H, OCH3), 4.05 (s, 2H, CH2-1), 6.95–7.14 (m, 4H,
ArH); 13C NMR (300 MHz, CDCl3) d: 31.0 (CH2-4), 46.6
(CH2-1), 52.0 (OCH3), 55.3 (CH-3), 125.9 (CH), 126.1
(CH), 126.2 (CH), 128.8 (CH), 132.4 (2C), 172.9
(COOCH3); APIES positive m/z (%): 214 (100) [MCC
NaC], 192 (52) [MHC].
Compound 6. [a]2D5 K1568 (c 0.8, EtOH); IR (dry film) nmax
:
4.1.2. (S)-Methyl-2-(2-bromoacetyl)-1,2,3,4-tetrahydro-
isoquinoline-3-carboxylate (4a,4b). Under N2, bromoace-
tyl bromide (0.045 mL, 0.52 mmol, 1 equiv) was added to a
stirred solution of THIQ methyl ester hydrochloride, 3
(118 mg, 0.52 mmol, 1 equiv) and Et3N (0.11 mL,
0.78 mmol, 1.5 equiv) in anhydrous CH2Cl2 (4 mL) at
0 8C and then, stirred at room temperature for 3 h. The
reaction mixture was washed with saturated NaHCO3
solution, H2O and brine, dried over Na2SO4, filtered and
evaporated under reduced pressure. The residue was
purified by flash chromatography (CH2Cl2/EtOAc, 9.6:0.4)
to afford 105 mg of bromoacetamide-THIQ derivative 4
(65%) as a mixture of rotamers in a 2:1 ratio of 4a:4b
rotamers.
3486, 2934, 1661, 1470, 1325 cmK1; H NMR (300 MHz,
CDCl3) d: 1.34–1.45 (m, 1H, H-60), 1.50–1.60 (m, 4H, CH2-
50and CH2-70), 2.35–2.48 (m, 4H, CH2-40 and CH2-80), 2.54
(t, JZ6.3 Hz, 2H, CH2-20), 3.01 (dd, JZ16.0, 12.4 Hz, 1H,
CH2a-11), 3.40 (dd, JZ16.0, 3.7 Hz, 1H, CH2b-11), 3.44–
3.54 (m, 1H, CH2a-10), 3.58–3.68 (m, 1H, CH2b-10), 4.15 (s,
2H, CH2-3), 4.18–4.24 (m, 1H, CH-11a), 4.30 (d, JZ17 Hz,
1H, CH2a-6), 5.25 (d, JZ17 Hz, 1H, CH2b-6), 7.12–7.30
(m, 4H, ArH); 13C NMR (75 MHz, CDCl3) d: 24.1 (CH2-60),
25.8 (CH2-50 and CH2-70), 33.4 (CH2-11), 43.1 (CH2-10),
43.7 (CH2-6), 50.3 (CH2-3), 54.5 (CH2-40 and CH2-80), 55.5
(CH-11a), 55.7 (CH2-20), 126.1 (CH), 126.8 (CH), 128.6
(2CH), 131.3 (C-10a), 132.4 (C-6a), 162.6 (C-4), 164.73
(C-1); HRMS (EI) m/z calcd for C19H25N3O2 [MC]
327.1947, found 327.1943.
1
1H NMR (400 MHz, CDCl3) d: 3.15 (dd, JZ16.0, 6.0 Hz,
1H, CH2a-4, rotamer-4a), 3.26 (dd, JZ16.0, 4.0 Hz, 1H,
CH2b-4, rotamer-4a), 3.29–3.42 (m, 2H, CH2-4, rotamer-
4b), 3.62 (s, 3H, OCH3, rotamer-4b), 3.63 (s, 3H, OCH3,
rotamer-4a), 3.93 (m, 2H, CH2Br, rotamer-4b), 4.0 (d, JZ
10.8 Hz, 1H, CH2a–Br, rotamer-4a), 4.06 (d, JZ10.8 Hz,
1H, CH2b–Br, rotamer-4a), 4.53 (d, JZ17.6 Hz, 1H, CH2a-
1, rotamer-4b), 4.78 (s, 2H, CH2-1, rotamer-4a), 4.95 (d, JZ
17.6 Hz, 2H, CHb-1 and CH-3, rotamer-4b), 5.37 (dd, JZ
6.0, 4.0 Hz, 1H, CH-3, rotamer-4a), 7.10–7.30 (m, 4H,
ArH); 13C NMR (100 MHz, CDCl3) d: 26.1 (CH2Br), 30.5
(CH2-4), 46.2 (CH2-1), 52.0 (OCH3), 52.4 (CH-3), 126.0
(CH), 126.8 (CH), 127.0 (CH), 128.3 (CH), 131.4 (C), 131.8
(C), 166.6 (CO), 170.8 (COOCH3); EIMS m/z (%): 312 (5)
[MC], 232 (100) [MCKBr], 190 (75) [MCKCOCH2Br],
146 (88) [MCKCOCH2Br–CH3], 130 (79).
4.2. Crystal structure determination of 6$HCl$2H2O
A colourless lath of 0.79!0.23!0.07 mm size was
mounted on a glass fibre and transferred to the diffracto-
meter (orthorhombic, P212121, aZ7.9742(16), bZ
3
˚
˚
12.875(3), cZ19.791(4) A, VZ2032.0(7) A , ZZ4, rcalcd
-
Z1.307 g cmK3, qmaxZ24.98, Mo Ka, lZ0.71073 A,
u-scan, diffractometer Nonius CAD4, TZ293(2) K, 5953
reflections collected of which 3557 were independent,
RintZ0.052). The structure was solved by direct methods
and refined anisotropically on F2 (SHELXS-97 and
˚
¨
SHELXL-97, Sheldrick, University of Gottingen, 1997).
The water hydrogen atoms were located in a difference
Fourier synthesis and refined with restrained O–H bond
length. Other hydrogen atoms were included using a riding
model. The absolute structure was determined (Flack
parameter 0.03(13); Flack, H. D. Acta Crystallogr., Sect. A,
1983, 39, 876).
4.1.3. (S)-2,3,11,11a-Tetrahydro-2-(20-(pyrrolidin-30-
yl)ethyl)-6H-pyrazino-[1,2-b]isoquinoline-1,4-dione (5)
and its 2-(20-piperidin-30-yl)ethyl homologue (6). Under
N2, a stirred suspension of (S)-methyl-2-(2-bromoacetyl)-
1,2,3,4-tetrahydro-isoquinoline-3-carboxylate, 4 (100 mg,
4.3. Theoretical calculations
0.32 mmol,
1 equiv),
1-(2-aminoethyl)piperidine
(0.046 mL, 0.32 mmol, 1 equiv) and anhydrous K2CO3
(70 mg) in dry CH2Cl2 (6 mL) was refluxed for 4 h. Then,
All the calculations have been performed with the
GAUSSIAN 03 suit of programs.15 The geometries of all