I. Andreu et al. / Tetrahedron 58 (2002) 10173–10179
10177
3340, 2933, 2867, 2251 (CN), 1744 (CO), 1611, 1513, 1444,
1426, 1121, 1018, 799 cm21; 1H NMR (CDCl3, 400 MHz) d
3.64 (2H, s, CH2–CN), 3.76 (3H, s, OCH3-2), 3.81 (3H, s,
OCH3-40), 3.83 (2H, s, CH2–CO), 6.90 (2H, d, J¼8.6 Hz,
H-30, 50), 6.92 (1H, d, J¼8.5 Hz, H-3), 6.96 (1H, d, J¼
2.4 Hz, H-6), 7.13 0(1H, dd, J¼8.5, 2.4 Hz, H-4), 7.32 (2H,
d, J¼8.6 Hz, H-2 ,60); 13C NMR (CDCl3, 100 MHz) d
22.5(CH2–CN), 39.9 (CH2–CO), 55.2 (OCH3-40), 55.9
(OCH3-2), 112.8 (C-3), 113.9 (C-30,50), 117.7 (CN), 122.0
(C-5), 122.4 (C-6), 125.3 (C-10), 126.2 (C-4), 130.3 (C-
20,60), 140.0 (C-1), 150.8 (C-2), 158.7 (C-40), 169.7 (CO);
EIMS m/z (%) 311 [M]þ (57), 163 (35), 148 (100), 121 (73),
105 (17.6), 91 (45), 77 (51); LC-MS (APIES negative mode)
m/z 310 [M21]þ.
3.3.2. cis-1-(40-Methoxycyclohexylmethyl)-7-methoxy-8-
hydroxy-1,2,3,4-tetrahydroisoquinoline, 3. C18H27NO3;
mp 275–2768; IR (film) nmax 3350, 2926, 2847, 1615, 1589,
1496, 1440, 1282, 1088, 794 cm21 1H NMR (CDCl3,
;
500 MHz) d 1.40–1.90 (8H, m, CH2-20, 30, 50, 60), 1.70 (1H,
m, H-10), 1.50, 1.80 (2H, 2m, CH2-a), 2.61, 2.70 (2H, 2m,
CH2-4), 3.01, 3.10 (2H, 2m, CH2-3), 3.31 (3H, s, OCH3-40),
3.40 (1Heq, sept, J¼2.7 Hz, CH-40), 3.84 (3H, s, OCH3-7),
4.30 (1H, dd, J¼10.7, 2.3 Hz, H-1), 5.5 (1H, brs, OH,
exchange with D2O), 6.57 (1H, d, J¼8.2 Hz, H-5) 6.69 (1H,
d, J¼8.2 Hz, H-6); 13C NMR (CDCl3, 125 MHz) d 26.2
(C-600), 29.0 (C-20), 29.3 (C-50), 29.4 (C-30), 29.5 (C-4), 330.5
(C-1 ), 38.4 (C-3), 39.4 (C-a), 48.9, (C-1), 55.9 (OCH3-4 ),
56.5 (OCH3-7), 76.7 (C-40), 109.0 (C-6), 119.5 (C-5), 127.7
(C-8a), 128.5 (C-4a), 142.1 (C-8), 144.5 (C-7); LC-MS
(APIES negative mode) m/z 304 [M21]þ; EIMS m/z (%)
178 (100), 163 (15); HRLSIMS m/z 306.20577 [MH]þ
(306.20692 calcd for C18H28NO3).
3.3. Synthesis of 1-cyclohexylmethyl THIQ derivatives
A degassed (Ar) solution of compound 1 (500 mg,
1.61 mmol) in a mixture of t-BuOH/H2O/THF (7:7:2
v/v/v) (190 mL), was distributed among four Vycor tubes
that were placed at the center of a cilindral photochemical
reactor equipped with six low pressure Hg lamps (Sylvania
G8T5). The solution was irradiated at 254 nm for 16 h, and
the reaction was monitored by analytical TLC and HPLC.
The reaction solution was made acid with 2.5% aq HCl
(200 mL) and extracted with CHCl3 (3£300 mL). The
combined organic layers were washed with H2O, dried over
anhydrous Mg(SO4)2 and the solvent removed under
reduced pressure to give the photochemical crude. In a
flask of a hydrogenation apparatus, this photochemical
crude was dissolved in EtOH (60 mL) and CHCl3 (2 mL).
The stirred solution was degassed and a slow stream of
nitrogen was passed through the solution. After addition of
PtO2, hydrogenation was carried out with a vigorous stirring
at room temperature for 72 h at low pressure (58 psi). The
mixture was brought to a boil under vacuum, the catalyst
filtered off, and the filtrate was evaporated. The residue
obtained was dissolved with CH2Cl2, and extracted with
HCl 5%. The aqueous solution was basified with NH3 (aq)
and extracted with CH2Cl2. The organic layer was washed
with H2O and brine, dried over anhydrous Na2SO4 and
concentrated, yielded 350 mg of a residue wich was purified
through 60 H silicagel column (toluene/AcOEt/DEA
66:32:2) to afford the compounds 2 (75 mg, 17%), 3
(76 mg, 15.5%), 4 (46 mg, 9.5%), 5 (37 mg, 8.4%), 6 and
7 (56 mg, 11.4%), corresponding to the yields from
compound 1, with an 62% overall yield of the reaction.
X-Ray crystal structure determination of 3·HCl: colourless
prism of 0.30£0.20£0.13 mm3 size, monoclinic, space
˚
group P21/c, a¼12.122(4), b¼11.460(4), c¼13.653(5) A,
3
˚
b¼104.082(7)8, V¼1839.6(10) A , Z¼4, rcalcd¼1.234
g cm23, 2umax¼61.18, diffractometre Bruker Smart CCD
˚
1000, Mo Ka(l¼0.71073 A), v-scan, T¼293(2) K, 36452
reflections collected of which 5615 (Rint¼0.1002) were
independent, direct primary solution and refinement on F 2
using SHELX97 program,18 211 refined parameters, rigid
hydroxyl and methyl groups hydrogen atoms, others riding,
R1[I.2s(I)]¼0.0551, wR2 (all data)¼0.1491, residual
23
˚
electron density 0.189 (20.244)e A
.
3.3.3. trans-1-(40-Methoxycyclohexylmethyl)-7-methoxy-
8-hydroxy-1,2,3,4-tetrahydroiso-quinoline, 4. C18H27NO3;
IR (film) nmax 3350, 2920, 2850, 1616, 1457, 1115, 1028,
1
668 cm21; H NMR (CDCl3, 400 MHz) d 1.11–2.10 (8H,
m, CH2-20, 30, 50, 60), 1.65 (3H, m, H-10 and CH2-a), 2.62,
2.75 (2H, 2m, CH2-4), 2.98, 3.13 (2H, 2m, CH2-3), 3.12
(1Hax, tt, Jax–ax¼11 Hz and Jax–eq¼4 Hz, H-40) 3.35 (3H, s,
OCH3-40), 3.84 (3H, s, OCH3-7), 4.24 (1H, dd, J¼8.2,
4.8 Hz, H-1), 6.57 (1H, d, J¼8.2 Hz, H-5) 6.69 (1H, d,
J¼8.2 Hz, H-6); 13C NMR (CDCl3, 100 MHz) d 28.8 (C-4),
29.7 (C-20), 31.6 (C-60), 31.8 (C-50), 32.5 (C-30), 34.0 (C-10),
37.9 (C-3), 39.9 (C-a), 48.5 (C-1), 55.6 (OCH3-40), 56.1
(OCH3-7), 79.8 (C-40), 108.6 (C-6), 119.7 (C-5), 127.1,
128.0 (C-4a and C-8a), 141.6 (C-8), 144.1 (C-7); LC-MS
(APIES negative mode) m/z 304 [M21]þ; EIMS m/z (%)
178 (100), 163 (10); HRLSIMS m/z 306.21350 [MH]þ
(306.20692 calcd for C18H28NO3).
3.3.1. 1-(Cyclohexylmethyl)-7-methoxy-8-hydroxy-1,2,
3,4-tetrahydroisoquinoline, 2. C17H25NO2; IR (film) nmax
3344, 2929, 2848, 1615, 1590, 1494, 1445, 1279, 1115,
1029, 790 cm21; 1H NMR (CDCl3, 500 MHz) d 1.10–1.70
(10H, m, CH2-20 to 60), 1.51, 1.70 (2H, 2m, CH2-a), 2.03
(1H, m, H-10), 2.60, 2.82 (2H, 2m, CH2-4), 2.90, 3.10 (2H,
2m, CH2-3), 3.84 (3H, s, OCH3-7), 4.29 (1H, dd, J¼10.2,
2.8 Hz, H-1), 6.57 (1H, d, J¼8.2 Hz, H-5), 6.69 (1H, d,
J¼8.2 Hz,0H-6); 13C NMR (CDCl3, 125 MHz) d 26.1 (C-40),
26.40 (C-5 ), 26.8 (C-30), 28.9 (C-4), 31.9 (C-60), 34.5
(C-1 ), 34.8 (C-20), 37.9 (C-3), 40.5 (C-a), 48.2, (C-1), 56.1
(OCH3-7), 108.5 (C-6), 119.5 (C-5), 127.4 and 128.1 (C-4a
and C-8a), 141.7 (C-8), 144.1 (C-7); EIMS m/z (%) 178
(100), 163 (14), 98 (5); HRLSIMS m/z 276.19587 [MH]þ
(276.19635 calcd for C17H26NO2).
3.3.4. 1-(Cyclohexylmethyl)-6-hydroxy-7-methoxy-1,2,
3,4-tetrahydroisoquinoline, 5. C17H25NO2; IR (film) nmax
1
3345, 2922, 2849, 1585, 1446, 1108, 790 cm21; H NMR
(CDCl3, 400 MHz) d 1.20–1.71 (10H, 2m, CH2-20 to 60),
1.55 (2H, m, CH2-a), 1.95 (H-10), 2.65 (2H, m, CH2-4),
2.95, 3.10 (2H, 2m, CH2-3), 3.86 (3H, s, OCH3-7), 3.95 (1H,
m, H-1), 6.54 (1H, s, H-8), 6.60 (1H, s, H-5); 13C NMR
(CDCl3, 100 MHz) d 26.2 (C-40), 26.4 (C-50), 26.7 (C-30),
29.2 (C-4), 32.3 (C-60), 34.3 (C-10), 34.8 (C-20), 40.6 (C-3),
44.9 (C-a), 52.4 (C-1), 56.0 (OCH3-7), 108.5 (C-8), 114.7
(C-5), 127.8, 131.7 (C-4a and C-8a), 143.7 (C-6), 144.9
(C-7); HREIMS m/z 276.19740 [MH]þ (276.19635 calcd
for C17H26NO2)