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Synthesis of tetrahydroberberine (10): NaBH4 (1.2 g, 30 mmol)
was added in a portionwise manner to a stirred solution of
1 (3.7 g, 10 mmol) and K2CO3 (3.6 g, 30 mmol) in MeOH (60 mL),
and the resulting mixture was heated at reflux for 1 h, leading to
the formation of a yellow solid.[19] The solid was collected by filtra-
tion and purified by flash chromatography over silica gel to give
title compound 10 (2.5 g, 74%) as a yellow solid.
a dropwise manner to a solution of corresponding intermediate
12a–d (2.0 mmol), respectively, in CH3CN (50 mL), and the resulting
mixture was heated at reflux for 6 h.[21] The mixture was then
cooled to ambient temperature and the solvent removed in vacuo
to give the crude residue, which was purified by flash chromatog-
raphy over silica gel to give the final compounds 4a–o, respective-
ly. Compound 4a was isolated as a yellow solid (543 mg, 58%):
1H NMR (300 MHz, CDCl3): d=7.89 (s, 1H), 7.50–7.49 (m, 1H), 7.43–
7.36 (m, 4H), 6.87–6.82 (m, 3H), 6.17–6.15 (d, 2H, J=6.9 Hz), 5.64
(s, 2H), 4.21–4.16 (t, 2H, J=7.4 Hz), 3.50–3.33 (t, 2H, J=7.4 Hz),
1.30 ppm (s, 9H); ESIMS m/z: 388.2 [MÀBr]+; Purity: 99.6%.
General procedure for the synthesis of 13-benzylberberine de-
rivatives 2a–j: o-Bromo benzyl bromide (1.0 mmol) was added in
a dropwise manner to a stirred solution of KI (310 mg, 2.06 mmol)
and 9 (337 mg, 1.0 mmol) in CH3CN (40 mL), and the resulting mix-
ture was held at reflux for 4 h.[19] The reaction mixture was then fil-
tered, and the filtrate was collected and distilled to dryness in
vacuo to give the crude residue, which was purified by flash chro-
matography over neutral alumina to give the final compound 2a
General procedure for the synthesis of 5,6-disubstituted-5,6,7,8-
tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-6-ium bromide deriva-
tives 5a–e: A solution of 2-benzo[1,3]dioxol-5-ylethylamine 15
(16.5 g, 100 mmol) and the corresponding aldehyde (100 mmol) in
formic acid (50 mL) was stirred at reflux for 24 h. The mixture was
then cooled to room temperature and diluted with H2O
(100 mL).[22,23] The solution was then adjusted to pH 8–9 with a 1n
aqueous NaOH solution and extracted with CH2Cl2 (3ꢂ100 mL).
The combined organics were then dried for 1 h over anhydrous
MgSO4 before being distilled to dryness in vacuo to give the crude
residue, which was purified by flash chromatography over silica gel
to give intermediate products 13a–b, respectively, as white solids.
Iodomethane or the substituted benzyl bromide was added to
a stirred mixture of intermediate 13a or 13b (10 mmol) and anhy-
drous K2CO3 (1.38 g, 10 mmol) in EtOH (50 mL), and the resulting
mixture was heated at reflux for 12 h. The mixture was then
cooled and the resulting precipitation removed by filtration. The
filtrates were then collected and distilled to dryness in vacuo to
give the crude residue, which was purified by flash chromatogra-
phy over silica gel to give the intermediate products 14a–d, re-
spectively, as white solids. 2,3-Dimethoxybenzyl bromide (264 mg,
2.0 mmol) was added in a dropwise manner to a stirred solution of
intermediate 14a–d (2.0 mmol) in CH3CN (50 mL), and the resulting
mixture was heated at reflux for 8 h. The mixture was then cooled
and the solvent was removed in vacuo to give the crude residue,
which was purified by flash chromatography over silica gel to give
products 5a–e, respectively. Compound 5a was isolated as a white
solid (700 mg, 83%): 1H NMR (300 MHz, CDCl3): d=7.44–7.41 (d,
1H, J=8.1 Hz), 7.13–7.08 (m, 1H), 7.01–6.98 (d, 1H, J=8.1 Hz), 6.59
(s, 1H), 6.50 (s, 1H), 5.91 (s, 2H), 5.17–5.13 (d, 1H, J=12.3 Hz),
5.04–4.00 (d, 1H, J=12.3 Hz), 4.73–4.68 (d, 1H, J=15.0 Hz), 4.50–
4.45 (d, 1H, J=15.0 Hz), 4.12–3.92 (m, 2H), 3.87 (s, 3H), 3.84 (s,
3H), 3.19 (s, 3H), 3.15–3.03 ppm (m, 2H); ESIMS m/z: 342.1
[MÀBr]+; Purity: 95.2%.
General procedure for the synthesis of amide derivatives 6a–e,
7a–m, and 8a–n: A mixture of the starting material 15 (1.65 g,
0.01 mol), HOBt (1.35 g, 0.01 mol), the corresponding carboxylic
acid (0.01 mol), and DCC (2.06 g, 0.01 mol) in THF (20 mL) was
stirred at room temperature for 12 h. The mixture was then filtered
to remove the white precipitate, and the filtrates were collected
and distilled to dryness in vacuo to give the crude residue, which
was dissolved in CH2Cl2 and washed three times with a saturated
solution of Na2CO3. The organic layers were then dried over anhy-
drous MgSO4 for 1 h and the solvent removed in vacuo to give the
crude residue, which was purified by flash column chromatography
over silica gel to give final compounds 6a–d and 7a–m, respec-
tively. Compounds 8a–n were also synthesized according to the
same procedure from 16, 17, or 18, respectively. Compound 7a
was isolated as a white solid (2.01 g, 71%): 1H NMR (300 MHz,
CDCl3): d=7.36–7.25 (m, 3H), 7.20–7.17 (m, 2H), 6.67–6.64 (d, 1H,
J=8.1 Hz), 6.53–6.52 (d, 1H, J=1.8 Hz), 6.45–6.42 (m, 1H), 5.92 (s,
1
as a yellow solid (350 mg, 60%): H NMR (300 MHz, [D6]DMSO): d=
10.08 (s, 1H), 8.13–8.10 (d, 1H, J=9.3 Hz), 7.85–7.83 (d, 1H, J=
9.3 Hz), 7.67–7.64 (d, 1H, J=9.3 Hz), 7.31–7.26 (m, 2H), 7.17 (s, 1H),
6.84–6.81 (m, 1H), 6.71 (s, 1H), 6.08 (s, 2H), 4.88 (s, 2H), 4.61 (2H,
s), 4.12 (s, 3H), 4.03 (s, 3H), 3.15 ppm (s, 2H); ESIMS m/z: 504.1
[MÀBr]+; Anal. (C27H23Br2NO4) calcd: C 55.41, H 3.96, N 2.39, found:
C 55.62, H 3.90, N 2.59. Compounds 2b–j were also synthesized ac-
cording to the same general procedure.
General procedure for the synthesis of 7-benyzltetrahydrober-
berine bromide derivatives 3a–e: A solution of o-nitrobenzyl bro-
mide (1.0 mmol) in CH3CN (40 mL) was added to a stirred solution
of 10 (339 mg, 1.0 mmol) in CH3CN (60 mL) in a dropwise manner,
and the resulting reaction mixture was held at reflux for 6 h.[19] The
mixture was then cooled and the solvent removed in vacuo to
give the crude residue, which was purified by flash chromatogra-
phy over neutral alumina to give title compound 3a as a yellow
solid (361 mg, 65%): 1H NMR (300 MHz, CDCl3): d=8.85–8.83 (d,
1H, J=7.2 Hz), 7.98–7.95 (d, 1H, J=8.1 Hz), 7.89–7.85 (t, 1H, J=
6.6 Hz), 7.73–7.68 (t, 1H, J=6.6 Hz), 6.91–6.84 (m, 3H), 6.73 (s, 1H),
6.02 (dd, 2H, J1 =1.2 Hz, J2 =3.6 Hz), 5.88–5.83 (d, 1H, J=13.2 Hz),
5.74–5.71 (m, 1H), 5.68–5.64 (d, 1H, J=13.2 Hz), 5.19–5.13 (d, 1H,
J=12.6 Hz), 4.45–4.40 (d, 1H, J=12.6 Hz), 3.99–3.94 (m, 1H), 3.86
(s, 3H), 3.83 (s, 3H), 3.56–3.40 (m, 2H), 3.37–3.29 (m, 1H), 3.22–
3.08 ppm (m, 2H); ESIMS m/z: 475.2 [MÀBr]+; Purity: 96.7%.
General procedure for the synthesis of 5,6-disubstituted-7,8-
dihydro[1,3]dioxolo[4,5-g]isoquinolin-6-ium bromide derivatives
4a–o: A solution of 15 (16.5 g, 0.1 mol), HOBt (13.5 g, 0.1 mol), car-
boxylic acid (0.1 mol), and DCC (20.6 g, 0.1 mol) in THF (200 mL)
was stirred at room temperature for 12 h. The mixture was then fil-
tered to remove the white precipitate, and the filtrates were col-
lected and distilled to dryness in vacuo to give the crude residue,
which was dissolved in CH2Cl2 and washed three times with a satu-
rated solution of Na2CO3 before being dried over anhydrous
MgSO4 for 1 h. The MgSO4 was then removed by filtration, then
evaporated in vacuo to give the crude residue, which was purified
by flash chromatography over silica gel to give intermediates 11 a–
d, respectively. POCl3 (7.67 g, 50 mmol) was added in a dropwise
manner over a period of 0.5 h to a cooled solution (ice bath) of
11 a–d (10 mmol) in toluene (50 mL), and the resulting mixture was
stirred at reflux for 12 h. The mixture was then cooled to ambient
temperature and quenched by the addition of H2O (100 mL). The
resulting mixture was then adjusted with ammonia to pH 8–9
under stirring, and the resulting aqueous mixture was extracted
with CH2Cl2 (3ꢂ100 mL). The combined organic extracts were then
distilled to dryness in vacuo to give the crude residue, which was
purified by flash chromatography over silica gel to give intermedi-
ates 12a–d, respectively. Benzyl bromide (2 mmol) was added in
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ChemMedChem 2014, 9, 207 – 216 214