P.-Y. Chen et al. / Tetrahedron 68 (2012) 3030e3036
3035
mixture was heated to reflux for 13 h (monitored by TLC) and
quenched with saturated NH4Cl solution (30 mL), solvent was re-
moved in vacuo afterward. The obtained residue was extracted with
CH2Cl2 (50 mLꢂ3). The extracted solution was combined and
washed with brine (30 mLꢂ2), dried with MgSO4, and filtered
subsequently. The filtrate was dried in vacuo and purified by column
chromatography (ethyl acetate/n-hexane¼1:3) to afford pure 7aef.
cmꢁ1:3162 cmꢁ1 (NH), 2252 cmꢁ1 (CN), 1676 cmꢁ1 (C]O); 1H
NMR (CDCl3, 400 MHz)
0.97 (d, J¼6.4 Hz, 6H, ArOCH2CH2CHMe2),
d
1.67 (q, J¼6.8 Hz, 2H, ArOCH2CH2CHMe2), 1.85 (m, 1H,
ArOCH2CH2CHMe2), 2.63 (dd, J¼16.4, 6.8 Hz, 1H, Ha-4), 2.70 (dd,
J¼16.4, 6.0 Hz, 1H, Hb-4), 3.07 (dd, J¼16.4, 6.8 Hz, 1H, CHaHbCN),
3.26 (dd, J¼16.4, 5.2 Hz, 1H, CHaHbCN), 3.92 (s, 3H, ArOCH3), 3.98 (t,
J¼6.8 Hz, 2H, ArOCH2CH2CHMe2), 4.06 (m, 1H, H-3), 6.92 (d,
J¼8.4 Hz, 1H, ArH), 7.29 (br s, 1H, NH), 7.83 (d, J¼8.8 Hz, 1H, ArH);
4.6.1. 5,6-Dimethoxy-3-methylcyano-3,4-dihydroisoquino-lin-1(2H)-
one (7a). The analyzed data for 7a (0.35 g, 71%) was described
previously in 4.5.1 of this experimental section.
13C NMR (CDCl3, 100 MHz)
d 22.5, 22.6, 23.8, 24.9, 26.7, 39.0, 47.6,
55.7, 71.8, 110.7, 116.6, 120.8, 124.8, 129.8, 144.7, 156.4, 165.8; EI-MS
(70 eV) m/z (rel intensity, %) 302 (Mþ,11), 233 (9), 232 (45),193 (12),
192 (100), 191 (20), 160 (18); HRMS calcd for C17H22N2O3: 302.1625.
Found: 302.1628; Anal. Calcd for C17H22N2O3: C, 67.53; H, 7.33; N,
9.26. Found: C, 67.44; H, 7.39; N, 9.22.
4.6.2. 5-Ethoxy-3-methylcyano-6-methoxy-3,4-dihydroisoquinolin-
1(2H)-one (7b). Compound 7b (0.42 g, 81%) was obtained as col-
orless crystals, mp 198e199 ꢀC, Rf¼0.42 (ethyl acetate); IRmax (neat)
cmꢁ1: 3193 cmꢁ1 (NH), 2249 (CN), 1675 cmꢁ1 (C]O); 1H NMR
4.6.6. 5-Benzyloxy-3-methylcyano-6-methoxy-3,4-dihydroisoquinolin-
1(2H)-one (7f). Compound 7f (0.47 g, 75%) was obtained as color-
less crystals, mp 170e171 ꢀC, Rf¼0.49 (ethyl acetate); IRmax (neat)
cmꢁ1: 3173 cmꢁ1 (NH), 2248 cmꢁ1 (CN),1664 cmꢁ1 (C]O); 1H NMR
(CDCl3, 400 MHz)
d
1.38 (t, J¼7.2 Hz, 3H, ArOCH2CH3), 2.63 (dd,
J¼16.8, 6.8 Hz, 1H, Ha-4), 2.70 (dd, J¼16.8, 6.0 Hz, 1H, Hb-4), 3.08
(dd, J¼16.4, 6.8 Hz, 1H, CHaHbCN), 3.26 (dd, J¼16.4, 5.2 Hz, 1H,
CHaHbCN), 3.92 (s, 3H, ArOCH3), 4.05 (q, J¼7.2 Hz, 2H, ArOCH2CH3),
4.06 (m, 1H, H-3), 6.92(d, J¼8.8 Hz, 1H, ArH), 7.10 (br s, 1H, NH), 7.83
(CDCl3, 400 MHz)
d
2.37 (dd, J¼16.8, 6.8 Hz, 1H, Ha-4), 2.48 (dd,
J¼16.8, 6.4 Hz, 1H, Hb-4), 2.77 (dd, J¼16.4, 6.8 Hz, 1H, CHaHbCN),
2.96 (dd, J¼16.4, 5.2 Hz,1H, CHaHbCN), 3.82 (m,1H, H-3), 3.97 (s, 3H,
ArOCH3), 5.04 (s, 2H, ArOCH2C6H5), 6.95 (d, J¼8.4 Hz, 1H, ArH), 7.09
(br s, 1H, NH), 7.35 (m, 5H, ArH), 7.84 (d, J¼8.4 Hz, 1H, ArH); 13C
(d, J¼8.8 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz)
d 15.6, 23.8, 26.8,
47.6, 55.8, 68.9, 110.6, 116.6, 120.8, 124.9, 130.0, 144.4, 156.5, 165.7;
EI-MS (70 eV) m/z (rel intensity, %) 260 (Mþ, 46),192 (100),191 (25),
160 (26), 92 (37), 77 (26), 63 (25); HRMS calcd for C14H16N2O3:
260.1155. Found: 260.1158; Anal. Calcd for C14H16N2O3: C, 64.60;
H, 6.20; N, 10.76. Found: C, 64.45; H, 6.20; N, 10.71.
NMR (CDCl3, 100 MHz) d 23.7, 27.0, 23.9, 47.4, 55.8, 74.8, 110.7, 116.6,
120.8, 125.1, 128.4, 128.5, 128.9, 130.4, 136.9, 143.5, 156.4, 165.5; EI-
MS (70 eV) m/z (rel intensity, %) 322 (Mþ, 3), 304 (4), 216 (6), 160
(4), 92 (10), 91 (100), 65 (8); HRMS calcd for C19H18N2O3: 322.1317.
Found: 322.1315; Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N,
8.69. Found: C, 70.67; H, 5.70; N, 8.65.
4.6.3. 5-Isopropoxy-3-methylcyano-6-methoxy-3,4-dihydroisoquinolin-
1(2H)-one (7c). Compound 7c (0.42 g, 77%) was obtained as col-
orless crystals, mp 143e144 ꢀC, Rf¼0.45 (ethyl acetate); IRmax
(neat) cmꢁ1:3206 cmꢁ1 (NH), 2199 (CN), 1678 cmꢁ1(C]O),
4.6.7. Preparation of 5-hydroxy-3-methylcyano-6-methoxy-3,4-
dihydroisoquinolin-1(2H)-one (7g). A mixture of compound 7f
(0.35 g, 1.09 mmol), Pd(OH)2/C (20%, 0.05 g, 0.76 mmol), cyclo-
hexene (0.98 mL), and ethanol (20 mL) was refluxed for 4 h and
then purified by column chromatography (ethyl acetate/n-
hexane¼1:1) to give pure 7g.
2199 cmꢁ1 (CN); 1H NMR (CDCl3, 400 MHz)
d
1.29 (d, J¼6.0 Hz, 6H,
ArOCHMe2), 2.62 (dd, J¼16.8, 7.2 Hz, 1H, Ha-4), 2.68 (dd, J¼16.8,
6.0 Hz, 1H, Hb-4), 3.02 (dd, J¼16.0, 6.8 Hz, 1H, CHaHbCN), 3.25 (dd,
J¼16.0, 5.2 Hz, 1H, CHaHbCN), 3.91 (s, 3H, ArOCH3), 4.03 (m, 1H, H-
3), 4.51 (hept, J¼6.0 Hz, 1H, ArOCHMe2), 6.92 (d, J¼8.8 Hz, 1H, ArH),
7.29 (br s, 1H, NH), 7.83 (d, J¼8.8 Hz, 1H, ArH); 13C NMR (CDCl3,
Compound (7g) (0.22 g, 87%) was obtained as colorless crystals,
100 MHz)
d
22.6, 23.8, 27.4, 29.3, 47.7, 55.7, 74.9, 110.6, 116.6, 120.8,
mp 135e136 ꢀC, Rf¼0.37 (ethyl acetate); IRmax (neat) cmꢁ1
:
124.6, 130.4, 143.3, 156.5, 165.8; EI-MS (70 eV) m/z (rel intensity, %)
274 (Mþ, 7), 232 (44), 192 (100), 93 (20), 92 (29), 77 (18), 65 (16);
HRMS calcd for C15H18N2O3: 274.1312. Found: 274.1314; Anal. Calcd
for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.62; H, 6.75;
N, 10.01.
3404 cmꢁ1 (OH), 3177 cmꢁ1 (NH), 2249 cmꢁ1 (CN), 1663 cmꢁ1 (C]
O); 1H NMR (DMSO-d6, 400 MHz)
d 2.78 (m, 1H, Ha-4), 2.79 (dd,
J¼16.8, 6.0 Hz, 1H, Hb-4), 2.85 (m, 1H, CHaHbCN), 3.12 (dd, J¼16.4,
5.2 Hz, 1H, CHaHbCN), 3.84 (m, 1H, H-3), 3.89 (s, 3H, OCH3), 7.00 (d,
J¼8.4 Hz, 1H, ArH), 7.44 (d, J¼8.4 Hz, 1H, ArH), 7.96 (br s, 1H, NH),
9.30 (br s, 1H, ArOH); 13C NMR (DMSO-d6, 100 MHz)
d 23.4, 26.4,
4.6.4. 5-n-Butoxy-3-methylcyano-6-methoxy-3,4-dihydroiso-quino-
lin-1(2H)-one (7d). Compound 7d (0.44 g, 80%) was obtained as
colorless crystals, mp 154e155 ꢀC, Rf¼0.45 (ethyl acetate); IRmax
(neat) cmꢁ1: 3195 cmꢁ1 (NH), 2251 (CN),1670 cmꢁ1 (C]O); 1H NMR
46.9, 56.3, 110.0, 118.6, 119.8, 121.4, 123.8, 142.7, 151.2, 165.6; EI-MS
(70 eV) m/z (rel intensity, %) 232 (Mþ, 47), 193 (11), 192 (100), 177
(22), 161 (6), 160 (51), 132 (7); HRMS calcd for C12H12N2O3:
232.0848. Found: 232.0849; Anal. Calcd for C12H12N2O3: C, 62.06;
H, 5.21; N, 12.06. Found: C, 61.83; H, 5.27; N, 12.05.
(CDCl3, 400 MHz)
d
0.98 (t, J¼7.2 Hz, 3H, ArOCH2CH2CH2CH3), 1.51
(sixt, J¼7.4 Hz, 2H, ArOCH2CH2CH2CH3), 1.75 (quint, J¼6.8 Hz, 2H,
ArOCH2CH2CH2CH3), 2.61 (dd, J¼16.8, 6.8 Hz, 1H, Ha-4), 2.68 (dd,
J¼16.4, 6.0 Hz,1H, Hb-4), 3.08 (dd, J¼16.4, 6.4 Hz,1H, CHaHbCN), 3.26
(dd, J¼16.4, 5.2 Hz, 1H, CHaHbCN), 3.92 (s, 3H, ArOCH3), 3.97 (t,
J¼6.8 Hz, 2H, ArOCH2CH2CH2CH3), 4.05 (m, 1H, H-3), 6.89 (br s, 1H,
NH), 6.92 (d, J¼8.8 Hz,1H, ArH), 7.83 (d, J¼8.8 Hz,1H, ArH); 13C NMR
4.7. X-ray investigations
A colorless rod plate crystal (0.20ꢂ0.20ꢂ0.60 mm) of C13H14N2O3
(7a) was obtained by crystallization from ethyl acetate and n-hexane.
Data collection was performed on a RIGAKU AFC7S diffractometer
(CDCl3, 100 MHz)
d
13.9, 19.2, 23.9, 26.8, 32.3, 47.6, 55.8, 73.2, 110.7,
with a graphite monochromator (
u
/2
q
scans, 2qmax¼52.0ꢀ) at 298 K.
116.5, 120.8, 124.8, 129.8, 144.7, 156.5, 165.6; EI-MS (70 eV) m/z (rel
intensity, %) 288 (Mþ, 12), 232 (32), 193 (11), 192 (100), 191 (12), 177
(7), 160 (19); HRMS calcd for C16H20N2O3: 288.1468. Found:
288.1470; Anal. Calcd for C16H20N2O3: C, 66.65; H, 6.99; N, 9.72.
Found: C, 66.32; H, 7.03; N, 9.63.
The crystal belongs to the monoclinic system, space group P21/c (No.
¼90.60(3)ꢀ,
ꢀ
ꢀ
ꢀ
14), with a¼7.338(6) A, b¼10.441(6) A, c¼15.846(3) A,
b
3
V¼1214.0(12) A , Z¼4, Dcalcd¼1.347 Mg/m3,
l(Mo-K
a)¼0.71069 A. A
ꢀ
ꢀ
total of 2379 unique reflections were collected. The structure was
solved by direct method and refined by full-matrix least-squares
procedure. The non-hydrogen atoms were given anisotropic thermal
parameters. The refinement converged to a final R¼0.0528 and
4.6.5. 5-Isopentyloxy-3-methylcyano-6-methoxy-3,4-dihy-droiso-
quinolin-1(2H)-one (7e). Compound 7e (0.44 g, 73%) was obtained
as colorless crystals, mp 142 ꢀC, Rf¼0.50 (ethyl acetate); IRmax (neat)
wR2¼0.145 for 1220 observed reflections [I>2.00
s(I)] using 167 pa-
rameters. Copies of the deposited crystal data (CCDC No. 810680) can