6+257 3$3(5
A Short Synthesis of Hippadine
ꢀꢁꢂꢀ
5-Bromo-6-(bromomethyl)-1,3-benzodioxole ꢅꢉꢆ was prepared in
54% yield by the procedure of Barthel et al.26 Physical [mp 91–
93 °C (petroleum ether/Et2O); Lit.29 mp 94°C (petroleum ether);
Lit.26 mp 92−93 °C (MeOH)] and spectral characteristics were iden-
tical to those data previously reported.
MS (APCI+ve): m/z (%) = 411 ([M+4]+, 60), 409 ([M+2]+, 90), 407
([M]+, 30), 215 (90), 213 (100).
Anal. calcd. C, 46.98; Br, 39.07; H, 2.71; N, 3.42. Found C 47.14;
Br, 39.10; H, 2.61; N, 3.42.
ꢉ+ꢍꢀꢎꢁꢍ'LR[RORꢍꢄꢎꢊꢍMꢍS\UURORꢍꢁꢎꢇꢎꢀꢍGHꢍSKHQDQWKULGLQH ꢅꢌꢆ
To a stirred solution of the dibromide ꢋ (0.60 g, 1.47 mmol) in THF
(10 mL) at –78°C and under N2 was added over 30 seconds BuLi
(2.65 mL of a 1.3 M solution in hexane, 3.45 mmol). After 20 min
copper(I) iodide triethylphosphite complex (1.57 g, 4.40 mmol) was
added in a single portion. The mixture was allowed to warm to r.t.
over 3 h, then stirred for 21 h. The mixture was diluted with Et2O
(40 mL), then washed with concd ammonia solution (10 x 40 mL),
H2O (50 mL) and brine (30 mL), dried (MgSO4), filtered and con-
centrated in vacuo to a pink solid (0.79g). Purification by column
chromatography (silica gel, 0 to 4% Et2O in petroleum ether) gave
a white solid (0.179 g, 0.72 mmol, 49%); mp partial sublimation
above 151 °C, melting at 158–161 °C [Lit.23 mp 159−161 °C
(MeOH); Lit.9 mp 154−156 °C].
ꢉꢍ%URPRLQGROH ꢅꢈꢆ
Following the general procedure reported by Bartoli et al.,25 vinyl-
magnesium chloride (86.3 mL of a 1.72 M solution in THF, 148.5
mmol) was added over 30 min to cooled solution (–70 °C) of 2-bro-
monitrobenzene (ꢊ; 10.0 g, 49.5 mmol) in THF (150 mL). After 3 h
the mixture was warmed to r.t. and poured onto satd aq NH4Cl so-
lution (300 mL). The phases were separated and the aqueous phase
was extracted with Et2O (3 × 100 mL). The combined organic phas-
es were washed with brine (200 mL), then dried (MgSO4), filtered
and concentrated in vacuo to a brown oil (13.9 g). Purification by
column chromatography (silica gel, petroleum ether) gave a yellow
solid (5.4 g) which was recrystallised from pentane to give the title
compound ꢈ (5.1 g, 53%) as colourless crystals; mp 42–44°C [Lit.30
mp 42−43 °C; Lit.26 mp 43−44°C].
IR: ν = 3097w, 2897w, 1496m, 1483m, 1335s, 1236s, 1038s, 938w,
IR: n = 3398s, 1671w, 1560m, 1533w, 1426m, 1329s, 1189s,
790s cm–1.
1133s, 1094s, 919s cm–1.
UV (CH2Cl2): λ (ε) = 355 (11300), 344 (12250) nm.
UV (MeOH): λ (ε) = 273 (4400) nm.
1H NMR (300 MHz, DMSOꢀq6): δ 7.59 (1 H, s, ArH), 7.44 (1 H,
d, E = 7.2 Hz, ArH), 7.40–7.30 (2 H, m, NCH+ArH), 6.96 (1 H, app
t, E = 7.6 Hz, ArH), 6.88 (1 H, s, ArH), 6.46 (1 H, d, E = 2.9 Hz,
NCHCC), 6.07 (2 H, s, OCH2O), 5.48 (2 H, s, NCH2).
13C NMR (75 MHz, DMSOꢀq6): δ 147.4 (C), 147.3 (C), 132.5
(C), 127.0 (CH), 125.3 (C), 124.3 (C), 123.3 (C), 120.2 (CH), 119.7
(CH), 118.4 (C), 113.0 (CH), 107.5 (CH), 102.9 (CH), 101.9 (CH),
101.4 (CH2), 47.4 (CH2).
1H NMR (300 MHz, CDCl3): δ 8.34 (1 H, br s, NH), 7.62 (1H, d,
E = 7.9 Hz, ArH), 7.39 (1 H, d, E = 7.6 Hz, ArH), 7.27 (1 H, app. t,
E = 2.8 Hz, NCH), 7.05 (1 H, app t, E = 7.8 Hz, ArH), 6.66 (1 H, dd,
E = 2.8, 2.0 Hz, NCHCC).
13C NMR (75 MHz, CDCl3): δ 134.7 (C), 129.2 (C), 124.9 (CH),
124.5 (CH), 121.2 (CH), 120.1 (CH), 104.8 (C), 104.0 (CH).
MS (APCI+ve): m/z (%) = 197 ([M+2]+, 100), 195 (M+, 80).
MS (APCI+ve): m/z (%) = 250 (MH+, 100), 249 (M+, 40), 111 (30),
101 (20)
ꢀꢍꢅꢊꢍ%URPREHQ]R>ꢀꢎꢁ@GLR[ROꢍꢈꢍ\OꢆꢍPHWK\OꢍꢉꢍEURPRꢍꢀ+ꢍLQGROH
ꢅꢋꢆ
HRMS (EI): m/z (%) = Found 249.0768. C16H11NO2 requires
249.0789.
The general procedure for Iꢀalkylation of indoles described by
Heaney and Ley31 was followed. Thus, to a stirred solution of pow-
dered KOH (2.29 g, 40.8 mmol) in DMSO (20 mL) under N2 and at
r.t. was added 7-bromoindole (ꢈ; 2.00 g, 10.2 mmol). After 30 min
the dibromide ꢉ (6.00g, 20.4 mmol) was added in a single portion.
After a further 2 h H2O (25 mL) was added and the resultant mixture
extracted with Et2O (3 × 30 mL). The organic phases were com-
bined, washed with brine (30 mL), dried (MgSO4), filtered and con-
centrated in vacuo to a yellow solid (7.09 g). Purification by column
chromatography (silica gel, 5 to 10% ether in petroleum ether) and
recrystallisation from Et2O/petroleum ether gave the title compound
(2.97 g, 72%) as a pale brown solid; mp 138–140°C.
ꢀꢎꢁꢍ'LR[RORꢍꢄꢎꢊꢍMꢍS\UURORꢍꢁꢎꢇꢎꢀꢍGHꢍSKHQDQWKULGLQꢍꢉꢍRQH ꢅ+LSꢍ
SDGLQHꢎ ꢀꢆ
A solution of pentacycle ꢌ (0.091 g, 0.36 mmol) in CH2Cl2 (10 mL)
was stirred at r.t. with BaMnO4 (0.93 g, 3.6 mmol) for 12 h. The
mixture was then filtered through a pad of Celite and the cake
washed with CH2Cl2 (50 mL). Removal of the solvent in vacuo gave
a white solid (0.101 g) which was recrystallised from acetone/petro-
leum ether to give hippadine (0.075 g, 0.29 mmol, 79%) as a white
powder; mp 216–218°C (acetone/petroleum ether) [Lit.23 mp 217–
218°C (MeOH); Lit.9 mp 207–209°C].
IR: ν = 3104w, 2904w, 1557w, 1515w, 1479s, 1392m, 1318s,
1235s, 1033s, 927s cm–1.
IR: ν = 3020w, 2920w, 1658m, 1602m, 1490m, 1440m, 1359w,
1253s, 1091m, 1037m cm–1.
UV (MeOH): λ (ε) = 289 (7600), 272 (9400) nm.
UV (CH2Cl2): λ (ε) = 360 inf (6050), 350 (7900), 300 (17100) nm.
1H NMR (300 MHz, CDCl3): δ 7.62 (1 H, d, E = 7.9 Hz, ArH),
7.36 (1 H, d, E = 7.5 Hz, ArH), 7.09 (1 H, d, E = 3.1 Hz, NCH), 7.07
(1 H, s, ArH), 6.98 (1 H, app t, E = 7.7 Hz, ArH), 6.61 (1 H, d,
E = 3.1 Hz, NCHCC), 5.90 (2 H, s, OCH2O), 5.82 (1 H, s, ArH),
5.71 (2 H, s, NCH2).
1H NMR (400 MHz, DMSOꢀq6): δ 8.18 (1 H, d, E = 8.0 Hz, ArH),
8.10 (1 H, d, E = 3.6 Hz, NCH), 7.96 (1 H, s, ArH), 7.89 (1 H, s,
ArH), 7.87 (1 H, d, E = 7.7 Hz, ArH), 7.56 (1 H, app t, E = 7.7 Hz,
ArH), 7.06 (1 H, d, E = 3.6 Hz, NCHCC), 6.29 (2 H, s, OCH2O).
13C NMR (100 MHz, DMSOꢀq6): δ 155.8 (C), 151.2 (C), 147.0
(C), 129.9 (C), 129.1 (C), 126.5 (C), 122.4 (CH), 121.6 (CH), 121.1
(CH), 120.4 (C), 117.4 (CH), 114.9 (C), 109.3 (CH), 105.5 (CH),
101.0 (CH2), 100.7 (CH).
MS (APCI+ve): m/z (%) = 264 (MH+, 15), 146 (5), 127 (70), 125
(100).
1H NMR (300 MHz, DMSOꢀq6): δ 7.64 (1 H, d, E = 7.9 Hz, ArH),
7.50 (1 H, d, E = 3.1 Hz, NCH), 7.36 (1 H, d, E = 7.5 Hz, ArH), 7.29
(1 H, s, ArH), 6.98 (1 H, app t, E = 7.7 Hz, ArH), 6.65 (1 H, d,
E = 3.1 Hz, NCHCH), 5.96 (2 H, s, OCH2O), 5.68 (2 H, s, NCH2),
5.43 (1 H, s, ArH).
13C NMR (75 MHz, DMSOꢀq6): δ 147.6 (C), 147.4 (C), 132.6
(C), 131.9 (C), 131.7 (C), 126.7 (CH), 121.2 (CH), 120.8 (CH),
112.7 (CH), 110.6 (C), 106.2 (CH), 103.1 (C), 102.4 (CH), 102.1
(CH2), 52.3 (CH2).
Anal. calc. C, 73.00; H, 3.45; N, 5.32. Found C, 72.80; H 3.29; N,
5.02.
Synthesis 1999, No. 8, 1300–1302 ISSN 0039-7881 © Thieme Stuttgart · New York