R. B. Miller et al. / Tetrahedron 58 (2002) 6061±6067
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3.1.7. 6-Bromo-4,7-dimethyl-5-nitro-1H-indene (14b,
XBr). Chromatography on Florisile (2:3 CH2Cl2/
pentane) gave white solid (86% yield): mp (MeOH)
3.1.11. 7-Amino-5,8-dimethylisoquinoline (5a, XH). A
mixture of 15a (2.5535 g, 12.54 mmol), hydrazine mono-
hydrate (3.77 g, 75 mmol), and 80% Raney nickel in H2O
(1.13 g, 15 mmol) in EtOH (75 mL) was re¯uxed for 2 h, by
which time the reaction was con®rmed to be complete by
TLC. Most of the EtOH was boiled away, and the cooled
mixture was diluted with EtOAc and ®ltered through celite.
The ®ltrate was extracted with dilute HCl and the combined
aqueous layers were basi®ed with NaHCO3. The aqueous
mixture was extracted with EtOAc, dried (Na2SO4) and
evaporated to give 1.9979 g (92% yield) of orange solid.
Recrystallization (MeOH) gave 5a (XH) as ¯at orange
1
134±1358C; H NMR d 2.33 (s, 3H), 2.40 (s, 3H), 3.36
(br s, 2H), 6.69 (br d, 1H, J3.6 Hz), 6.90 (br d, 1H,
J3.9 Hz); 13CNMR d 13.9, 19.3, 39.7, 110.8, 120.3,
129.6, 132.0, 136.2, 143.4, 144.3, 151.5; IR (CH2Cl2)
2940, 1535, 1385, 950, 880 cm21. Anal. calcd for
C11H10BrNO2: C, 49.23; H, 3.76; N, 5.22. Found: C,
49.09; H, 3.85; N, 5.25.
3.1.8. 5,8-Dimethyl-7-nitroisoquinoline (15a, XH). A
solution of 14a (6.3083 g, 33.3 mmol) in MeOH (167 mL)
and CH2Cl2 (167 mL) was cooled to 2788Cand treated with
ozone until the solution turned blue. The solution was
purged with oxygen until the blue color disappeared, then
added to Me2S (16.7 mL) and NaHCO3 (3.33 g), and the
sealed ¯ask was stirred for 4 h at room temperature. Conc.
NH4OH (167 mL) was added and the resealed ¯ask was
stirred overnight. The mixture was mostly evaporated and
the remaining aqueous suspension was extracted with
CHCl3 and the combined organic layers were washed with
brine, dried (Na2SO4) and evaporated to give 6.3196 g (94%
yield) of orange±yellow solid. Recrystallization (EtOAc)
gave 15a (XH) as bright yellow needles: mp 161±
1
rods: mp 201.5±202.58C; H NMR d 2.45 (s, 3H), 2.56 (s,
3H), 3.88 (bs, 2H), 6.98 (s, 1H), 7.60 (d, 1H, J5.7 Hz),
8.35 (d, 1H, J5.7 Hz), 9.31 (s, 1H); 13CNMR d 10.6, 18.3,
110.6, 117.1, 123.0, 128.9, 130.3, 132.2, 139.4, 142.0,
147.8; IR 3197br, 1645, 1609, 1386, 874, 809 cm21. Anal.
calcd for C11H12N2: C, 76.71; H, 7.02; N, 16.27. Found: C,
76.55; H, 6.97; N, 16.23.
3.1.12. 7-Amino-6-bromo-5,8-dimethylisoquinoline (5b,
XBr). Chromatography on silica gel (2% MeOH/CHCl3)
gave yellow solid (82% yield). Recrystallization (CH3CN)
gave ¯uffy white clumps: mp 163±1648C; 1H NMR d 2.49
(s, 3H), 2.70 (s, 3H), 4.48 (bs, 2H), 7.60 (dd, 1H, J5.9,
0.6 Hz), 8.33 (d, 1H, J5.9 Hz), 9.28 (d, 1H, J0.6 Hz);
13CNMR d 12.0, 18.9, 111.9, 117.1, 120.6, 127.2, 129.4,
131.7, 139.9, 140.1, 148.0; IR 3328br, 1627, 1381, 1235,
1005, 805 cm21. Anal. calcd for C11H11BrN2: C, 52.61; H,
4.41; N, 11.16. Found: C, 52.96; H, 4.28; N, 11.42.
1
1628C; H NMR d 2.69 (s, 3H), 2.88 (s, 3H), 7.79 (m,
2H), 8.73 (d, 1H, J6.0 Hz), 9.63 (d, 1H, J0.6 Hz); 13C
NMR d 13.4, 18.3, 117.1, 124.3, 127.3, 128.6, 133.8, 136.8,
145.4, 147.7, 151.0; IR 1521, 1386, 1365, 1348, 879,
824 cm21. Anal. calcd for C11H10N2O2: C, 65.34; H, 4.98;
N, 13.85. Found: C, 65.37; H, 4.97; N, 13.87.
3.1.13. 7-Amino-5,8-dimethyl-6-(phenylthio)isoquinoline
(5c, XSPh). Crude product (82% yield) was recrystallized
(i-PrOH) to give dark yellow needles: mp 141±141.58C; 1H
NMR d 2.51 (s, 3H), 2.83 (s, 3H), 4.78 (bs, 2H), 7.00 (d, 2H,
J8.1 Hz), 7.11 (t, 1H, J7.2 Hz), 7.20 (t, 2H, J7.2 Hz),
7.69 (d, 1H, J6.0 Hz), 8.36 (d, 1H, J6.0 Hz), 9.37 (s,
1H); 13CNMR d 11.8, 17.1, 111.0, 117.8, 123.0, 125.6,
126.2, 128.8, 129.2, 129.3, 135.6, 139.1, 139.6, 144.2,
148.2; IR 3312, 1631, 1563, 1477, 1375, 738 cm21. Anal.
calcd for C17H16N2S: C, 72.82; H, 5.75; N, 9.99. Found: C,
72.85; H, 5.93; N, 9.96.
3.1.9. 6-Bromo-5,8-dimethyl-7-nitroisoquinoline (15b,
XBr). Chromatography on basic alumina (9:1 CH2Cl2/
petroleum ether) gave yellow-tan solid (89% yield).
Recrystallization (EtOAc) followed by sublimation gave
1
15b (XBr) as a pale yellow solid: mp 194±1978C; H
NMR d 2.65 (s, 3H), 2.76 (s, 3H), 7.78 (d, 1H,
J5.9 Hz), 8.70 (d, 1H, J6.0 Hz), 9.42 (s, 1H); 13C
NMR d 13.2, 18.6, 115.8, 117.2, 125.4, 125.8, 134.5,
135.3, 145.6, 150.2, 157.4; IR 1604, 1532, 1387,
835 cm21. Anal. calcd for C11H9BrN2O2: C, 47.17; H,
2.88; N, 10.00. Found: C, 46.84; H, 3.09; N, 9.72.
3.1.14. 5-Methyl-3H-pyrazolo[3,4-h]isoquinoline (6a,
XH, RCH3). A stirring solution of 5a (0.4516 g,
2.62 mmol) in AcOH (20.7 mL) was placed in an ice bath.
After 2 min a solution of NaNO2 (0.199 g, 2.88 mmol) in
H2O (2.62 mL) was added over 4 min. The ice bath was
allowed to warm to room temperature overnight. The dark
red solution was diluted with H2O (50 mL) and basi®ed
using dilute NH4OH. Once cool, the mixture was extracted
with CH2Cl2 and the organic layer was dried (Na2SO4) and
directly chromatographed on silica gel (0±5% MeOH/
CHCl3) to give 18 mg (4% recovery) of starting material
and 0.401 g (83% conversion, 87% yield based on recovered
starting material) of product. Recrystallization (CHCl3, then
MeOH) gave light brown needles of 6a (XH, RCH3)
which were further puri®ed by sublimation at 1558Cunder
high vacuum: mp 292±2938C(dec.); 1H NMR (Me2SO-d6)
d 2.66 (s, 3H), 7.76 (s, 1H), 7.86 (d, 1H, J5.7 Hz), 8.57 (d,
1H, J5.7 Hz), 8.70 (s, 1H), 9.70 (s, 1H), 13.50 (bs, 1H); 1H
NMR (CD3CO2D) d 2.58 (s, 3H), 7.76 (s, 1H), 8.08 (d, 1H,
J6.4 Hz), 8.51 (s, 1H), 8.58 (d, 1H, J6.4 Hz), 9.55 (s,
3.1.10. 5,8-Dimethyl-7-nitro-6-(phenylthio)isoquinoline
(15c, XSPh). A solution of 15b (141 mg, 0.500 mmol),
thiophenol (111 mg, 1.01 mmol), NaOMe (28.5 mg,
0.528 mmol) and DMF (3 mL) were heated on a steam
bath for 6 h. The cooled mixture was diluted with H2O
(25 mL) and extracted with Et2O. The combined extracts
were washed with saturated NaHCO3, H2O, and brine,
dried and evaporated to a tan solid. Chromatography on
basic alumina (8:1 CH2Cl2/hexanes) gave 146 mg (94%
yield) of yellow-beige solid. Recrystallization (MeOH)
gave 15c (XSPh) as light yellow needles: mp
1
155.5±156.58C; H NMR d 2.69 (s, 3H), 2.76 (s, 3H),
7.1±7.3 (m, 5H), 7.83 (d, 1H, J6.6 Hz), 8.72 (d, 1H,
J5.7 Hz) and 9.53 (s, 1H); 13CNMR d: 13.1, 16.7,
117.6, 124.6, 125.0, 126.5, 126.7, 128.0, 129.1, 135.2,
135.5, 140.9, 145.3, 150.2, 153.6; IR 1533, 1440, 1361,
837, 739, 684 cm21. Anal. calcd for C17H14N2O2S:
C, 65.69; H, 4.49; N, 8.97. Found: C, 65.79; H, 4.55; N,
9.03.