Piperazino-substituted benzo[b]furans 251
7
-Bromobenzo[b]furan (3d) This compound was obtained in
for the free base: δ , 7.60 (s, 1H), 7.12–7.22 (m, 2H), 6.74–6.79
(m, 2H), 3.38 (m, 4H), 2.68 (m, 4H), 2.39 (s, 3H). High resolu-
1
3
1% yield as a colorless oil. H-NMR δ 7.69 (m, 1H), 7.55 (m, 1H),
+
7
.48 (m, 1H), 7.13 (m, 1H), 6.85 (m, 1H).
tion ms (ESI, positive ion mode): calcd for C H N O, (M +1),
13
16
2
m/z 231.1497; found m/z 231.1490. A hydrobromide salt: mp 242–
244°C. Anal. Calcd for C H N O•2 HBr•H O: C, 39.42; H, 5.09;
N, 7.07. Found: C, 39.62; H, 5.21; N, 6.79.
7
-Bromo-5-methylbenzo[b]furan (3e) This compound was ob-
13
16
2
2
1
tained in 25% yield as a clear oil. H-NMR: δ 7.64 (s, 1H), 7.31 (s,
1
3
1H), 7.29 (s, 1H), 6.75 (s, 1H), 2.42 (s, 3H). C-NMR: δ 150.5,
145.7, 134.0, 128.7, 128.4, 120.3, 107.1, 103.5, 21.0.
5-Methyl-7-(N-methylpiperazino)benzo[b]furan hydrobromide
1
(
4e) The free base was obtained in 46% yield as a colorless oil. H
NMR: δ 7.58 (d, 1H, J=2.0 Hz), 6.99–7.01 (d, 1H, J=7.8 Hz), 6.62–
General procedure for the synthesis of arylpiperazine
hydrobromides 4a-f
6.64 (d, 1H, J=7.8 Hz), 6.77 (d, 1H, J=2.0 Hz), 3.19–3.22 (m, 4H),
2
.64–2.67 (m, 4H), 2.46 (s, 3H), 2.39 (s, 3H); 13C-NMR; δ 154. 9,
144.3, 143.3, 125.3, 119.9, 115.7, 109.8, 105.5, 55.4, 514, 46.2, 14.6.
Compounds 3a-e were allowed to react with commercially avail-
able piperazines under Buchwald-Hartwig conditions (Wolfe
and Buchwald, 2002). A mixture of the appropriate halide (3a-e,
High resolution ms (ESI, positive ion mode): calcd for C H N O,
13 16
2
+
(
M +1), m/z 231.1497; found m/z 231.1490. A hydrobromide salt:
mp 212–213°C (dec.). Anal. Calcd for C H N O•2 HBr: C, 42.88;
1
.0mmol),4-substitutedpiperazine(1.2mmol),sodiumtert-butoxide
14 18
2
H, 5.14; N, 7.14. Found: C, 42.76; H, 5.20; N, 7.14.
(2.0 mmol), tris(dibenzylideneacetone)dipalladium (0.01 mmol), and
racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.01 mmol)
in toluene (5 ml) was heated under reflux for 12 h before quench-
ing with water. The products were then extracted into diethyl ether
tert-Butyl 4-(5-methyl-7-benzo[b]furanyl)piperazino-1-carbox-
ylate (4f) The free base was obtained in 51% yield as an amor-
phous glass. H-NMR: δ 7.56 (d, 1H, J=1.6 Hz), 7.01 (s, 1H), 6.67
1
(3×20 ml), and the extract was dried over magnesium sulfate, filtered
(
3
1
d,1H, J=1.6 Hz), 6.57 (s, 1H), 3.66 (m, 4H) 3.26 (m, 4H), 2.40 (s,
and concentrated under reduced pressure. The residue was purified
by chromatography using a mobile phase of dichloromethane/meth-
anol (10:1). The purified compound was then dissolved in diethyl
ether/methanol (3 ml, 10:1) before the addition of hydrobromic
acid (0.2 ml, 48%). The treatment of the mixture with diethyl ether
caused crystallization of the hydrobromide salt.
H), 1.50 (s, 9H). 13C NMR: δ 154.7, 145.3, 144.1, 136.7, 133.0,
28.7, 114.3, 112.8, 106.7, 79.8, 49.8, 43.5, 28.4, 21.6.
5-Methyl-(7-piperazino)benzo[b]furan (5) To a solution of 4f
(
1.3 g, 4.1 mmol) in dichloromethane (5 ml) was added trifluoro-
acetic acid (2.0 ml). The mixture was stirred for several hours until
the starting material was no longer detected by TLC. Purification by
6
-(N-Methylpiperazino)benzo[b]furan hydrobromide (4a)
chromatography (dichloromethane:methanol, 10:1) gave 5 (0.78 g,
After workup as described above, an additional purification of 4a re-
quired three-fold crystallization from methanol/ether in the presence
of a small amount (one drop) of hydrobromic acid. A high-yield re-
covery of the product was achieved by treatment of the mixture with
an additional amount of ether. Compound 4a precipitated as a white
1
3
1
3
.6 mmol, 88%) as an amorphous yellow glass. H-NMR: δ 7.57 (d,
H), 7.07 (s, 1H), 6.69 (d, 1H, J=2.0 Hz), 6.58 (s, 1H), 3.57 (m, 4H),
.43 (m, 4H), 2.41 (s, 3H).
o
General procedure for the synthesis of compounds
6a,b
solid and was obtained in an overall yield of 38%; mp 206–207 C;
1
H - N M R ( 4 0 0 M H z , D M S O ) : δ 9.6 (broad s, 1H), 7.84 (d, J=2.0 Hz,
1
H), 7.52 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J=2.0 Hz, 8.5 Hz,
The bromides needed for the synthesis of 6a,b were synthesized ac-
cording to the literature (Raubo et al., 2006; Leopoldo et al., 2008).
The appropriate bromide (0.25 mmol) in acetonitrile (5 ml) was treat-
ed with 5 (0.25 mmol) and K CO (0.50 mmol).After heating at reflux
1
3
H), 6.83 (d, J=1.4 Hz, 1H), 3.4–3.6 ( m, 2H), 3.8–4.0 (m, 2H), 3.1–
.3 (m, 2H), 2.9–3.1 (m, 2H), 2.87 (s, 3H). Anal. Calculated (Calcd)
C H N O•HBr: C, 52.54; H, 5.77; N, 9.43. Found: C, 53.07; H, 5.92;
13 16 2
N, 9.71.
2
3
for 12 h, purification by chromatography (dichloromethane:methanol,
0:1) yielded 6a,b.
1
7-Methyl-4-(N-methylpiperazino)benzo[b]furan dihydrobro-
mide (4b) The free base was obtained in 38% yield as a white
crystalline solid; mp 62–64°C; H NMR for the free base: δ 7.58
1
1-[4-(Benzenesulfonyl)-4-methylpentyl]-4-(5-methyl-7-
benzo[b]furanyl)piperazine (6a) The free base was obtained in
(
1
(
1
4
d, J=2.0 Hz, 1H), 6.99–7.01 (d, J=7.8 Hz, 1H), 6.77 (d, J=2.0 Hz,
H), 6.62–6.64 (d, J=7.8 Hz, 1H), 3.19–3.22 (m, 4H), 2.64–2.67
m, 4H), 2.46 (s, 3H), 2.39 (s, 3H); C-NMR for the free base: δ
54.9, 144.3, 143.3, 125.3, 119.9, 115.7, 109.8, 105.5, 55.4, 51.4,
1
3
0% yield as a light yellow oil; H NMR: δ 7.89 (d, J=7.4 Hz, 2H),
1
3
7.66 (t, J=7.4 Hz, 1H), 7.56 (m, 3H), 6.99 (m, 1H), 6.66 (m, 1H),
6
1
.56 (m, 1H), 3.33 (m, 4H), 2.68 (m, 4H), 2.41 (m, 5H), 1.76 (m, 2H),
.64 (m, 2H), 1.32 (s, 6H); 13C-NMR: δ 145.3, 144.0, 136.9, 135.6,
6.2, 14.6. High resolution ms (ESI, positive ion mode): calcd for
+
133.5, 133.0, 130.6, 128.7, 128.6, 113.9, 112.6, 106.6, 62.9, 58.7,
3.4, 49.8, 32.8, 21.7, 21.5, 20.9; C H N 0 S.
C H N O, (M +H), m/z 231.1497; found m/z 231.1490. A hydro-
1
4
18
2
5
bromide salt: mp 263–265°C. Anal. Calcd for C H N O•2 HBr:
25 32
2 3
1
4
18
2
C, 42.88; H, 5.14; N, 7.14. Found: C, 42.76; H, 5.20; N, 7.14.
N-(4-Cyanobenzyl)-6-(4-(5-methyl-7-benzo[b]furanyl)pipera-
zine-1)-hexanamide (6b) The free base was obtained as an oil in
28% yield; H NMR: δ 7.60 (d, J=7.8 Hz, 2H), 7.56 (s, 1H), 7.38 (d,
5
-(N-Methylpiperazino)benzo[b]furan hydrobromide (4c)
1
1
The free base was obtained as an oil in 34% yield. H NMR for the
J=7.8 Hz, 2H), 7.00 (s, 1H), 6.67 (m, 1H), 6.56 (m, 1H), 6.16 (broad
s, 1H), 4.49 (d, J=5.8 Hz, 2H), 3.38 (m, 4H), 2.75 (m, 4H), 2.49
free base: δ 7.56 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.11 (s, 1H), 7.00
(
d, J=9.0 Hz, 1H), 6.68 (s, 1H), 3.19 (m, 4H), 2.64 (m, 4H), 2.38 (s,
(
(
t, J=7.6 Hz), 2.40 (s, 3H), 2.28 (t, J=7.4 Hz), 1.72 (m, 2H), 1.62
m, 2H), 1.40 (m, 2H); 13C NMR: δ 173.1, 145.2, 144.1 (2 signals),
3
H). A hydrobromide salt. Anal. Calcd for C H N O•HBr•½ H O:
1
3
16
2
2
C, 50.99; H, 5.93; N, 9.15. Found: C, 51.19; H, 5.93; N, 9.32.
1
36.6, 133.1, 132.4, 128.6, 128.2, 118.7, 114.1, 112.6, 111.2, 106.7,
7
-(N-Methylpiperazino)benzo[b]furan dihydrobromide (4d)
58.3, 53.2, 49.4, 43.0, 36.3, 26.9, 26.1, 25.4, 21.7. High resolution
+
The free base was obtained in 39% yield and characterization
matched that previously reported (van Steen et al., 1993). H NMR
ms: (ESI, positive ion mode): calcd for C H N O , (M +1), m/z
27
32
4
2
1
445.2604; found m/z 445.2591.
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