Regioselective bromination of 6-hydroxytetrahydroisoquinolines

Article abstract of DOI:10.1002/jhet.4121

Regioselective bromination of 6-hydroxytetrahydroisoquinolines using molecular bromine was disclosed. Treatment of 6-hydroxytetrahydroisoquinolines with molecular bromine under different temperatures afforded 5-bromo-6-hydroxytetrahydroisoquinolines as so

Full text of DOI:10.1002/jhet.4121

Regioselective Bromination of 6-Hydroxytetrahydroisoquinolines
Ke Wang, Xuan Pan, Kun Peng, Zhan Zhu Liu*
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica,
Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China
liuzhanzhu@imm.ac.cn
Regioselective bromination of 6-hydroxytetrahydroisoquinolines using molecular bromine was
disclosed. Treatment of 6-hydroxytetrahydroisoquinolines with molecular bromine under different
temperatures afforded 5-bromo-6-hydroxytetrahydroisoquinolines as sole products in high isolated
yield with excellent regioselectivity.
Key words: Regioselectivity, bromination, tetrahydroisoquinoline
.
INTRODUCTION
The bromination of aromatics is a common
transformation in organic chemistry. These
brominated compounds not only exhibit a
wide variety of biological activities, but also
can be used for the carbon-carbon bond
formation via cross-coupling reaction such as
Suzuki4, Heck5, and Sonogashira6, or the
carbon-heteroatom bond formation.
1,2,3,4-tetrahydroisoquinolines are important
compounds of great interest due to their
significantly biological and pharmacological
activities. They are common structural
moieties in biologically active compounds and
important intermediates in organic synthesis.
For
instance,
1-methyl-
and
So far, no synthetic study has been reported on
the bromination of tetrahydroisoquinolines. In
the present paper, we reported an efficiently
1-phenyl-tetrahydroisoquinolines are involved
in the treatment of Parkinson’s and other
nervous
diseases1.
Moreover,
regioselective
bromination
of
tetrahydroisoquinoline derivatives display a
wide range of biological activities, such as
6-hydroxytetrahydroisoquinoline derivatives
using molecular bromine in CH2Cl2 solution,
which would provide invaluable synthetic
intermediates for the synthesis of complex
natural products and active pharmaceuticals.
anti-HIV,
antitumor,
antipsychotic,
antidiabetes, ß-adrenoceptor antagonist and so
on2. In addition, tetrahydroisoquinolines are
also key intermediates for the synthesis of
more complex natural alkaloids, represented
by saframycins, renieramycins, lemonomycins
and ecteinascidins3, which possess potential
antitumor and antimicrobial activities.
RESULTS AND DISCUSSIONS
The synthetic route is outlined in Scheme 1. In
the presence of acetic acid, the reaction of
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3-hydroxyphenethylamine
1
with
operational convenience and higher yield.
benzaldehyde
proceeded
2
in methanol solution
To establish the scope of this bromination
smoothly
to
give
via
procedure,
other
eleven
6-hydroxytetrahydroisoquinoline
3
6-hydroxytetrahydroisoquinoline derivatives
were investigated. The reactions were carried
out under room temperature and the results are
presented in Table 2. It was clear that this
method was both general and efficient. In all
Pictect-Spengler reaction, followed by
N-protected with CbzCl. Treatment 4 with one
equivalent of bromine in CH2Cl2 solution
afforded corresponding brominated product.
cases,
6-hydroxytetrahydroisoquinolines
resulted in conversion to the desired
5-bromo-6-hydroxytetrahydroisoquinolines in
over 80% isolated yield with excellent
regioselectivity.
Table 2.
Thus a remarkably regioselective bromination
technique
was
discovered
for
6-hydroxytetrahydroisoquinolines,
which
Scheme1. Reagents and conditions: (a)
CH3COOH, CH3OH, 50oC; (b) CbzCl,
NaHCO3, CHCl3, H2O; (c) Br2, CH2Cl2.
specifically afforded corresponding 5-bromo
products in over 80% isolated yield. The
reason leading to this result was apparently
owing to the specific structure of the
6-hydroxytetrahydroisoquinoline molecules.
At
first,
we
chose
N-protected
tetrahydroisoquinoline 4a bearing 1-phenyl
substituent as the model molecule to
investigate the regioselectivity of the
When
6-hydroxytetrahydroisoquinoline
reacted with molecular bromine, the reactivity
of C-5 was much higher than C-7, which was
possibly due to the fact that both steric
hindrance effect of the 1-aryl substituents and
electronic effects were beneficial for the
bromination
under
different
reaction
temperatures. The results are summarized in
Table 1.
Table 1.
formation
of
As can be seen from Table 1, an excellent
regioselectivity was observed. No matter at
what temperature the reaction was carried out,
5-bromo-6-hydroxytetrahydroisoquinoline 5a
was produced as the sole product without
detectable 7-bromo or 5,7-dibromo product.
Moreover, with the increase of temperature
from -78oC to 25oC, the isolated yield was
dramatically increased from 59% to 92%. The
product 5a was separated by column
chromatography and its structure was
characterized by 1H NMR, 13C NMR and
HRMS. According to the above results, the
room temperature was ultimately chosen as
the optimum reaction condition due to its
5-bromo-6-hydroxytetrahydroisoquinoline.
CONCLUSION
In conclusion, an efficient and facile
method was established for the preparation of
5-bromo-6-hydroxytetrahydroisoquinoline
derivatives through the highly regioselective
bromination
of
6-hydroxytetrahydroisoquinolines
molecular bromine in CH2Cl2 solution.
with
EXPERIMENTAL
General. All reagents and solvents were pure
analytical grade materials purchased from
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commercial sources and were used without
further purification, if not stated otherwise. 1H
NMR (300 or 400 MHz) spectra were
CHCl3 (12 mL) and H2O (9.0 mL), was added
a solution of benzyloxy carbonyl chloride
(0.61 mL, 4.26 mmol) in CHCl3 (3 mL) under
cooling below 5oC. The mixture was stirred at
5oC for 1 h and then at room temperature for 2
h. The CHCl3 layer was separated, washed
with H2O, 5% aqueous HCl and H2O, dried
over anhydrous Na2SO4, and concentrated.
The residue was purified by column
chromatography (PET/EtOAc = 5:1) to afford
N-Cbz protected product 4a (1.03 g, 76%) as
colorless oil. 1H NMR (400 MHz, DMSO-d6)
δ 9.36 (s, 1H), 7.35-7.21 (m, 8H), 7.15 (d, J =
7.2 Hz, 2H), 6.94 (d, J = 5.6 Hz, 1H), 6.61 (s,
1H), 6.60 (d, J = 5.6 Hz, 1H), 6.17 (s, 1H),
5.17 (d, J = 12.4, 1H), 5.10 (d, J = 12.4 Hz,
1H), 3.85-3.83 (m, 1H), 3.30-3.26 (m, 1H),
2.83-2.75 (m, 1H), 2.70-2.66 (m, 1H); HRMS
calcd for C23H22NO3 [M+H]+ 360.1594, found
360.1594.
o
recorded at 24 C. The data was reported as
chemical shift (ppm), and the interpretation of
peak with relevant coupling constants reported
in Hertz. 13C NMR spectra were recorded at
75MHz spectrometer at 24oC. Mass spectra
were obtained using an ion trap mass
spectrometer equipped with electrospray
ionization (ESI) ion source.
General procedure:
Synthesis of 6-hydroxytetrahydroisoquino-
line (3a)
To a solution of 3-hydroxyphenethylamine 1
(1.00 g, 7.30 mmol), benzaldehyde 2 (0.89 mL,
8.76 mmol) and 4Å molecular sieves (1.00 g)
in methanol (15 mL) was added acetic acid
(1.67 mL, 29.20 mmol) dropwise. The mixture
was stirred at 50 oC for 5 h under argon. After
filtration, the organic solvent was evaporated
under reduced pressure and the residue was
dissolved in EtOAc. The organic layer was
washed with saturated aqueous NaHCO3,
brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give
the crude product. Purification by column
chromatography (CH2Cl2/CH3OH = 50:1)
afforded 6-hydroxytetrahydroisoquinoline 3a
Synthesis of compound 5a
To a solution of N-Cbz protected compound
4a (0.898 g, 2.50 mmol) in CH2Cl2 (20 mL)
was added bromine (0.13 mL, 2.50 mmol) in
CH2Cl2 (15 mL) dropwise. The mixture was
stirred for 2 h and then was washed with
saturated aqueous NaHCO3, brine, dried over
anhydrous Na2SO4, and concentrated under
reduced pressure. Purification by column
chromatography (PET/EtOAc = 7:1) afforded
corresponding brominated product 5a (1.01 g,
92%) as a yellow solid. M.p.=143-145oC.
(1.38 g, 84%) as
a
white solid.
M.p.=108-110oC. 1H NMR (400 MHz,
DMSO-d6) δ 9.57 (s, 1H), 7.43-7.37 (m, 5H),
6.65 (d, J = 2.0 Hz, 1H), 6.57 (dd, J = 8.4, 2.0
Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 5.50 (s, 1H),
3.33-3.22 (m, 2H), 3.15-3.12 (m, 1H),
2.94-2.90 (m, 1H); HRMS calcd for
C15H16NO [M+H]+ 226.1226, found 226.1119.
1H NMR (400 MHz, DMSO-d6) δ 10.22 (s,
1H), 7.37-7.25 (m, 8H), 7.14 (d, J = 6.8 Hz,
2H), 6.97 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0
Hz, 1H), 6.24 (s, 1H), 5.18 (d, J = 12.4 Hz,
1H), 5.12 (d, J = 12.4 Hz, 1H), 3.99-3.95 (m,
1H), 3.20-3.13 (m, 1H), 2.84-2.76 (m, 2H);
13C NMR (75 MHz, DMSO-d6) δ 153.1(2C),
142.4, 136.7, 135.2(2C), 128.4(2C), 128.3(2C),
128.1, 127.9, 127.8(2C), 127.6, 127.3, 127.2,
114.1, 111.6, 66.6, 56.6, 37.4, 29.1; HRMS
calcd for C23H21BrNO3 [M+H]+ 438.0699,
Synthesis of compound 4a
To
a
stirred
mixture
of
6-hydroxytetrahydroisoquinoline 3a (0.855 g,
3.80 mmol), NaHCO3 (798 mg, 9.50 mmol),
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found 438.0685.
Prachayasittikul, V. Eur. J. Med. Chem.
2014, 81,192. (f) Capilla, A. S.; Soucek,
R.; Grau, L.; Romero, M.; Martinez, J. R.;
Caignard, D. H.; Pujol, M. D. Eur. J. Med.
Chem. 2018, 145, 51.
Supporting Information: Full experimental
1
detail, H NMR spectra, 13C NMR spectra,
HRMS.
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Matthews, K. S. J. Am. Chem. Soc. 2005,
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