Synthesis of 1-aryltetrahydroisoquinoline alkaloids and their analogs

Article abstract of DOI:10.1007/s10600-013-0507-2

Three alkaloids of the cryptostylin series and 20 monomolecular and 3 bimolecular 1-aryltetrahydroisoquinoline derivatives were prepared using the Picte-Spengler reaction.

Full text of DOI:10.1007/s10600-013-0507-2

Chemistry of Natural Compounds, Vol. 49, No. 1, March, 2013 [Russian original No. 1, January–February, 2013]
SYNTHESIS OF 1-ARYLTETRAHYDROISOQUINOLINE
ALKALOIDS AND THEIR ANALOGS
*
Sh. N. Zhurakulov, V. I. Vinogradova, and M. G. Levkovich
UDC 547.945
Three alkaloids of the cryptostylin series and 20 monomolecular and 3 bimolecular
1-aryltetrahydroisoquinoline derivatives were prepared using the Picte–Spengler reaction.
Keywords: 1-aryltetrahydroisoquinoline alkaloids, analogs, Pictet–Spengler reaction.
The synthesis of condensed N-containing heterocycles has recently been attracting more and more attention.
1-Aryltetrahydroisoquinolines are interesting because of their valuable pharmacological properties. In addition to natural
alkaloids of this type [1], including cryptostylins I, II, and III (2–5) [2], synthetic 1-aryltetrahydroisoquinolines, e.g., antiepileptic
agent 1A [3] or muscarinic acetylcholine receptor antagonist 1B (solifenacin agent) are interesting [4].
MeO
MeO
H CO
3
N
O
N
N CH
3
H
H CO
3
O
N
R
1
R
3
Cl
R
2
2 - 5
1A
1B
2: R = H, R = R = OCH O; 3: R = H, R = R = OCH
3
1
2
3
2
1
2
3
4: R = R = R = OCH ; 5: R = R = R = H
1
2
3
3
1
2
3
1-Phenyltetrahydroisoquinoline alkaloids 2–5 were isolated previously only from two species of the genus Cryptostylus
[5]. Isolation of 5 from Adhatoda vasica Nees has now also been reported [6].
This group of compounds was synthesized using the Pictet–Spengler reaction [5] starting from homoveratrylamine
(6) and substituted aldehydes (7a–t). This turned out to be more effective than Bischler–Napieralski cyclization [7].
Condensation of amine 6 with aldehydes 7a–t occurred in two steps. Schiff bases 8a–t were easily obtained for all
aldehydes upon refluxing in C H for 1–1.5 h. The condensing agent in the second step was CF CO H. The yields of the
6
6
3
2
target isoquinolines 9 were lower if HCl was used.
Racemates of alkaloids 2, 3, and 5 and N-methyl derivative 9r were obtained by methylation of 9a, n, q, and r [8].
Having developed a synthetic method for isoquinolines 9, we extended it to the preparation of bimolecular compounds
10–12 by using vanillin oxidation to synthesize dehydrodivanillin [9].
The majority of the products were characterized by IR and NMR spectroscopy. The spectral properties of compounds
9, namely the lack of an absorption band for the imine in the IR spectra and the presence of singlets for aromatic protons
(H-5 and H-8 at ꢀ 6.14–6.67 ppm) in PMR spectra in addition to a singlet for methine proton H-1 at ꢀ 4.80–5.15 ppm,
confirmed that substituted 1-phenyltetrahydroisoquinolines had formed.
A feature of mass spectra of compounds 9 was a base peak for the molecular ion. The principal fragmentation
pathway of the 1-phenyltetrahydroisoquinoline bases was due to cleavage of C1-Ph bonds to form fragments with m/z 192
(stable 6,7-dimethoxy-3,4-dihydroisoquinoline ion) and a phenyl moiety.
S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan,
Tashkent, fax: (99871) 120-64-75, e-mail: j.sherzod.78@mail.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 1,
January–February, 2013, pp. 62–66. Original article submitted November 27, 2012.
©
70
0009-3130/13/4901-0070 2013 Springer Science+Business Media New York

4
H CO
3
H CO
3
H CO
3
H CO
3
+
-H O
a, b
H
3
2
+ ArCHO
N
NH
Ar
NH
N CH
3
2
1
H CO
3
H CO
3
H CO
3
H CO
3
CH
Ar
Ar
6
7a - t
8a - t
9a - t
OCH
2 - 5
R
+
OHC
H CO
3
3
-H O
2
NH HN
Ar
H CO
OCH
3
3
CHO
10: R = R = H
1
2
H CO
3
OCH
3
11: R = H, R = CH
1
2
3
OR
OR
2
12: R = R = CH
1
1
2
3
10 - 12
OH
Ar =
X
OCH
3
X
OCH
X
X
3
3
OH
i, j
OH
d, e
NO
h
OCH
f, g
2
a
b, c
b, d, f, i: X = H; c, e, g, j: X = Br
X
X
X
X
1
2
O
OH
OCH
3
OCH
3
O
OCH
O
3
k, l, m
n, o, p
q, r, s
t
q: X = H
r: X = Br
s: X = Cl
k: X = X = H
n: X = H
o: X = Br
p: X = NO
1
2
l: X = Br, X = H
1
2
m: X = H, X = Br
1
2
2
a. CH O; b. NaBH
2
4
Decomposition of alkaloids 2, 3, and 5 and methyl derivative 9r by electron impact began with loss of a
+
+
methyl radical and subsequent elimination of the C-6 methoxyl to form peaks for ions with m/z [M] (100%), [M – 15] , and
[M – 15 – 31] . Loss of the methyl radical and methoxyl favored formation of a stable ion.
+
EXPERIMENTAL
IR spectra were recorded from KBr pellets on a System 2000 FTIR instrument (Perkin-Elmer); mass spectra, on a
Kratos M90; PMR spectra, on Tesla BS-567A(100 MHz) and Varian Unity-400+ spectrometers (CDCl , Py, DMSO-d solvents,
3
6
HMDS internal standard). R values were determined on LS 5/40 silica gel plates (Czech. SSR) using CHCl :MeOH (4:1).
f
3
Melting points of all synthesized compounds were measured on a Boetius microstage.
General Method for Preparing Substituted 1-Phenyltetrahydroisoquinolines. A solution of
3,4-dimethoxyphenylethylamine (1.81 g, 0.01 mol) in C H (30 mL) was treated with substituted benzaldehyde (0.01 mol)
6
6
and refluxed with a Dean–Stark trap until water separation was complete (1–2 h). The solvent was distilled off. The resulting
imine was treated with CF CO H (10 mL), heated on a water bath for ~2 h, cooled, and made basic with NH to pH 9–10. The
3
2
3
amine was extracted exhaustively with CHCl . The crude product was purified by preparing the hydrochloride or by column
3
chromatography over silica gel using CHCl :MeOH (100:1ꢁ100:10). The resulting product was crystallized from Me CO.
3
2
1-(Phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9a). C H O N. Prepared from 6 (1.81 g, 0.01 mol)
17 19
2
and benzaldehyde (7a, 1.06 g, 0.01 mol). Yield 2.17 g (81%), mp 118–121°C (Me CO), mp 102–103°C [10], R 0.47. PMR
2
f
*
spectrum (100 MHz, CDCl , ꢀ, ppm): 2.68 (1H, m, H-4), 2.85 (2H, m, H-3, 4), 3.25 (1H, m, H-3), 3.42 (3H, s, 7-OCH ),
3.67 (3H, s, 6-OCH ), 4.85 (1H, s, H-1), 6.14 (1H, s, H-8), 6.67 (1H, s, H-5), 7.20 (5H, m, Ar-H).
3
3
*
3
1-(2ꢂ-Hydroxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9b). C H O N. Prepared from 6 (1.9 g,
17 18
3
0.01 mol) and 2-hydroxybenzaldehyde (1.33 g, 0.01 mol). Yield 2.11 g (70%), mp 159–162°C (Me CO), R 0.58. PMR
2
f
71

*
*
spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.73 (2H, m, H-4), 2.87 (2H, m, H-3), 3.46 (3H, s, 7-OCH ), 3.66 (3H, s,
6
3
6-OCH ), 5.05 (1H, s, H-1), 6.31 (1H, s, H-8), 6.64 (1H, d, J = 7, H-3ꢂ), 6.68 (1H, s, H-5), 6.72 (1H, d, J = 7, H-6ꢂ), 6.99 (2H,
3
m, H-4ꢂ, 5ꢂ).
1-(5ꢂ-Bromo-2ꢂ-hydroxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9c). C H O NBr. Prepared from
17 18
3
6 (1.52 g, 0.008 mol) and 5-bromo-2-hydroxybenzaldehyde (1.66 g, 0.008 mol). Yield 2.5 g (82%), mp of hydrochloride 189–
*
192°C (Me CO), R 0.51. PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.70 (2H, m, H-4), 2.86 (2H, m, H-3), 3.51
2
f
6
*
(3H, s, 7-OCH ), 3.67 (3H, s, 6-OCH ), 5.08 (1H, s, H-1), 6.37 (1H, s, H-8), 6.62 (1H, d, J = 8.5, H-3ꢂ), 6.67 (1H, s, H-5),
3
3
7.18 (1H, dd, J = 8.5, 2.3, H-4ꢂ), 7.05 (1H, d, J = 2.3, H-6ꢂ).
1-(4ꢂ-Hydroxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9d). C H O N. Prepared from 6 (1.9 g,
17 19
3
0.01 mol) and 4-hydroxybenzaldehyde (1.28 g, 0.01 mol). Yield 1.22 g (41%), mp of hydrochloride 216–218°C (Me CO),
2
R 0.35. PMR spectrum (400 MHz, CD OD, ꢀ, ppm, J/Hz): 2.77 and 2.96 (1H each, m, H-4), 2.95–3.15 (1H each, m, H-3),
f
3
*
*
3.56 (3H, s, 7-OCH ), 3.79 (3H, s, 6-OCH ), 4.92 (1H, s, H-1), 6.26 (1H, s, H-8), 6.71 (1H, s, H-5), 6.73 (2H, d, J = 8.5,
3
3
H-3ꢂ, 5ꢂ), 7.03 (2H, d, J = 8.5, H-2ꢂ, 6ꢂ).
1-(3ꢂ-Bromo-4ꢂ-hydroxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9e). C H O NBr. Prepared from
17 18
3
6 and 4-hydroxy-3-bromobenzaldehyde. Yield 40%, mp of hydrochloride 205–207°C (Me CO), R 0.9. PMR spectrum
2
f
*
*
(100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.64 and 2.80 (1H each, m, H-4), 3.26 (2H, m, H-3), 3.44 (3H, s, 7-OCH ), 3.66 (3H,
6
3
s, 6-OCH ), 4.78 (1H, s, H-1), 6.15 (1H, s, H-8), 6.62 (1H, s, H-5), 6.80 (1H, d, J = 8, H-5ꢂ), 6.94 (1H, dd, J = 1.8, 8, H-6ꢂ), 7.22
3
(1H, d, J = 1.8, H-2ꢂ).
1-(4ꢂ-Methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9f). C H O N. Prepared from 6 (2.39 g,
18 21
3
0.013 mol) and 4-methoxybenzaldehyde (1.79 g, 0.013 mol). Yield 2.4 g (62%), mp 265–267°C (Me CO), R 0.52. PMR
2
f
*
spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.70 (1H, m, H-4), 2.85 (2H, m, H-3, 4), 3.27 (1H, m, H-3), 3.42 (3H, s,
7-OCH ), 3.66 (6H, s, 6, 4ꢂ-OCH ), 4.82 (1H, s, H-1), 6.13 (1H, s, H-8), 6.63 (1H, s, H-5) 6.79 (2H, d, J = 8.9, H-3ꢂ, 5ꢂ), 7.09
6
*
3
3
(2H, d, J = 8.9, H-2ꢂ, 6ꢂ).
1-(3ꢂ-Bromo-4ꢂ-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9g). C H O NBr. Prepared
18 20
3
from 6 and 3-bromo-4-methoxybenzaldehyde. Yield 59%, mp 262–264°C (Me CO), R 0.9. PMR spectrum (100 MHz,
2
f
*
*
DMSO-d , ꢀ, ppm, J/Hz): 2.69 (2H, m, H-4), 2.83 (1H, m, H-3), 3.20 (1H, m, H-3), 3.46 (3H, s, 7-OCH ), 3.69 (3H, s,
6-OCH ), 3.78 (3H, s, 4ꢂ-OCH ), 4.85 (1H, s, H-1), 6.17 (1H, s, H-8), 6.64 (1H, s, H-5), 6.95 (1H, d, J = 8.5, H-5ꢂ), 7.13 (1H,
6
3
*
3
3
dd, J = 8.5, 2, H-6ꢂ), 7.37 (1H, d, J = 2, H-2ꢂ).
1-(3ꢂ-Methoxy-4ꢂ-nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9h). C H O N . Prepared from
18 20
5 2
6 and 3-methoxy-4-nitrobenzaldehyde. Yield 64%, mp 181–183°C (Me CO), R 0.44. PMR spectrum (100 MHz, DMSO-d ,
2
f
6
*
*
*
ꢀ, ppm, J/Hz): 2.71 (2H, m, H-4), 2.88 and 3.22 (2H, m, H-3), 3.49 (3H, s, 7-OCH ), 3.70 (3H, s, 6-OCH ), 3.81 (3H, s,
3
3
3ꢂ-OCH ), 5.0 (1H, s, H-1), 6.25 (1H, s, H-8), 6.68 (1H, s, H-5), 6.87 (1H, dd, J = 8, 1.2, H-6ꢂ), 7.30 (1H, d, J = 1.2, H-2ꢂ), 7.77
3
(1H, d, J = 8, H-5ꢂ).
1-(4ꢂ-Hydroxy-3ꢂ-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9i). C H O N. Prepared from
18 21
4
6 (1.91 g, 0.01 mol) and vanillin (1.52 g, 0.01 mol). Yield 2.73 g (82%), mp of hydrochloride 199–203°C (Me CO), R 0.55.
2
f
*
PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.66 (1H, m, H-4), 2.80 (1H, m, H-3, 4), 3.29 (1H, m, H-3), 3.45 (3H,
6
*
*
s, 7-OCH ), 3.74 (3H, s, 6-OCH ), 3.75 (3H, s, 3ꢂ-OCH ), 4.72 (1H, s, H-1), 6.14 (1H, s, H-8), 6.59 (1H, s, H-5), 6.56 (1H,
3
3
3
d, J = 1.8, H-2ꢂ), 6.57 (1H, dd, J = 1.8, 8, H-6ꢂ), 6.82 (1H, d, J = 8, H-5ꢂ).
1-(5ꢂ-Bromo-4ꢂ-hydroxy-3ꢂ-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9j). C H O NBr.
18 20
4
Prepared from 6 and 5-bromovanillin. Yield 38%, mp 193°C, R 0.84. PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz):
f
6
*
*
*
2.68 (2H, m, H-4), 2.81 and 3.28 (1H each, m, H-3), 3.47 (3H, s, 7-OCH ), 3.68 (3H, s, 6-OCH ), 3.72 (3H, s, 3ꢂ-OCH ),
3
3
3
*
*
4.75 (1H, s, H-1), 6.21 (1H, s, H-8), 6.64 (1H, s, H-5), 6.81 (1H, d, J = 1.2, H-6ꢂ), 6.82 (1H, d, J = 1.2, H-2ꢂ).
1-(3ꢂ-Hydroxy-4ꢂ-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9k). C H O N. Prepared
18 21
4
from 6 (1.81 g, 0.01 mol) and isovanillin (1.52 g, 0.01 mol) [11]. Yield 1.64 g (52%), mp 183–184°C (Me CO), R 0.52. PMR
2
f
*
*
spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.5–3.15 (4H, 2m, H-3, 4), 3.45 (3H, s, 7-OCH ), 3.67 (6H, s, 6, 4ꢂ-OCH ),
6
3
3
4.73 (1H, s, H-1), 6.19 (1H, s, H-8), 6.57 (1H, d, J = 9, H-5ꢂ), 6.61 (2H, s, H-5, 2ꢂ), 6.76 (1H, d, J = 9, H-6ꢂ).
1-(6ꢂ-Bromo-3ꢂ-hydroxy-4ꢂ-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9l). C H O NBr.
18 20
4
Prepared from 6 (1.33 g, 0.007 mol) and 6-bromoisovanillin (1.69 g, 0.007 mol) [12]. Yield 1.88 g (64%), mp 181–183°C
+
+
(Me CO), R 0.44. Mass spectrum: m/z 394 (M + 1, Br-79), 396 (M + 1, Br-81), 216 (80, Br-81), 214 (51, Br-79), 201 (56,
2
f
Br-81), 199 (34, Br-79), 174 (20, Br-81), 172 (13, Br-79), 161 (49), 146 (100), 121 (35). PMR spectrum (100 MHz,
72

*
*
*
DMSO-d , ꢀ, ppm): 2.8–3.2 (4H, m, H-3, 4), 3.48 (3H, s, 7-OCH ), 3.72 (3H, s, 6-OCH ), 3.75 (3H, s, 4ꢂ-OCH ), 5.48 (1H,
6
3
3
3
*
*
s, H-1), 6.15 (1H, s, H-8), 6.48 (1H, s, H-5), 6.76 (1H, s, H-2ꢂ), 7.15 (1H, s, H-5ꢂ).
1-(2ꢂ-Bromo-3ꢂ-hydroxy-4ꢂ-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9m). C H O NBr.
18 20
4
Prepared from 6 (1.52 g, 0.008 mol) and 2-bromo-3-hydroxy-4-methoxybenzaldehyde (1.92 g, 0.008 mol) [13]. Yield 2.15 g
(66%), mp 199–200°C (Me CO), R 0.54. PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.65 (2H, m, H-4), 2.78 (2H,
2
f
6
*
*
m, H-3), 3.44 (3H, s, 7-OCH ), 3.66 (3H, s, 6-OCH ), 3.70 (3H, s, 4ꢂ-OCH ), 5.22 (1H, s, H-1), 6.18 (1H, s, H-8), 6.27 (1H,
3
3
3
d, J = 8, H-5ꢂ), 6.64 (1H, s, H-5), 6.76 (1H, d, J = 8, H-6ꢂ).
1-(3ꢂ,4ꢂ-Dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9n). C H O N. Prepared from 6
19 23
4
(1.81 g, 0.01 mol) and veratrylaldehyde (1.66 g, 0.01 mol). Yield 2.38 g (72%), mp 72–74°C (Me CO), R 0.58. PMR
2
f
*
*
spectrum (100 MHz, DMSO-d , ꢀ, ppm): 2.65 and 2.80 (3H, 2m, 2H-4, H-3), 3.24 (1H, m, H-4), 3.44 (3H, s, 7-OCH ), 3.62
(3H, s, 3ꢂ-OCH ), 3.66 (6H, s, 6, 4ꢂ-OCH ), 4.78 (1H, s, H-1), 6.18 (1H, s, H-8), 6.77 (1H, s, H-5), 6.62, 6.68, 6.82 (1H each,
6
3
*
3
3
br.d, H-2ꢂ, 5ꢂ, 6ꢂ).
1-(6ꢂ-Bromo-3ꢂ,4ꢂ-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9o). C H O NBr. Prepared
19 22
4
from 6 (2.82 g, 0.015 mol) and 6-bromo-3,4-dimethoxybenzaldehdye (3.82 g, 0.015 mol). Yield 3.9 g (61%), mp 144°C
*
(Me CO), R 0.50. PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 2.56–2.76 (2H, m, H-4), 2.86–3.04 (2H, m, H-3), 3.43
2
f
6
*
*
*
(3H, s, 7-OCH ), 3.68 (3H, s, 6-OCH ), 3.51 (3H, s, 4ꢂ-OCH ), 3.73 (3H, s, 3ꢂ-OCH ), 5.14 (1H, s, H-1), 6.12 (1H, s, H-8),
3
3
3
3
6.65 (2H, s, H-5, H-2ꢂ), 7.11 (1H, s, H-5ꢂ).
1-(3ꢂ,4ꢂ-Dimethoxy-6ꢂ-nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9p). C H O N . Prepared
19 22
6 2
from 6 (2.24 g, 0.012 mol) and 4,5-dimethoxy-2-nitrobenzaldehyde (2.73 g, 0.012 mol) [14]. Yield 3.28 g (71%), mp 224–
+
225°C (Me CO), R 0.53. Mass spectrum (+ESI) (m/z, I ,%): 375 (M + 1) 326 (20), 312 (38), 296 (100), 281 (35), 269 (17),
2
f
rel
*
252 (43). PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 2.80 (2H, m, H-4), 2.92, 3.4 (2H, m, H-3), 3.46 (3H, s, 7-OCH ),
3.59 (3H, s, 3ꢂ-OCH ), 3.68 (3H, s, 6-OCH ), 3.80 (3H, s, 4ꢂ-OCH ), 5.51 (1H, s, H-1), 6.27 (1H, s, H-8), 6.65 (1H, s,
6
3
*
*
*
*
3
3
3
*
H-5), 6.69 (1H, s, H-2ꢂ), 7.51 (1H, s, H-5ꢂ).
1-(3ꢂ,4ꢂ-Methylenedioxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9q). C H O N. Prepared from
18 19
4
6 (1.66 g, 0.009 mol) and 3,4-methylenedioxybenzaldehyde (1.37 g, 0.009 mol) [14]. Yield 2.06 g (72%), mp 254–257°C
*
*
(Me CO), R 0.5. PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 2.5–3.0 (4H, H-3, 4), 3.45 (3H, s, 7-OCH ), 3.66 (3H, s,
2
f
6
3
*
6-OCH ), 4.86 (1H, s, H-1), 5.92 (2H, s, 3ꢂ, 4ꢂ-OCH O), 6.17 (1H, s, H-8), 6.62–6.87 (4H, m, H-5, Ar-H).
3
2
1-(6ꢂ-Bromo-3ꢂ,4ꢂ-methylenedioxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9r). C H O NBr.
18 18
4
Prepared from 6 (2.54 g, 0.014 mol) and 6-bromo-3,4-methylenedioxybenzaldehyde (3.21 g, 0.014 mol). Yield 4.95 g (90%),
+
mp 201–203°C (Me CO), R 0.52. Mass spectrum (70 eV): m/z 393/391 (M 100, Br-79/81), 379/377 (24, Br-79/81), 363/361
2
f
(14/13, Br-79/81), 193 (22), 192 (65). PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 2.98 and 3.05 (2H, m, H-4), 3.31 and
6
*
*
*
3.43 (2H, m, H-3), 3.53 (3H, s, 7-OCH ), 3.73 (3H, s, 6-OCH ), 5.78 (1H, s, H-1), 6.07 (2H, s, 3ꢂ, 4ꢂ-OCH O), 6.15 (1H, s,
3
3
2
H-8), 6.65 (1H, s, H-5), 6.82 (1H, s, H-2ꢂ), 7.30 (1H, s, H-5ꢂ).
1-(6ꢂ-Bromo-3ꢂ,4ꢂ-methylenedioxyphenyl)-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (N-methyl 9r).
+
+
Mass spectrum (70 eV): m/z 407/405, 392/390 (M – 15) , 361/359 (M – 15 – OCH ) , 283 (31), 252, 207 (43), 206 (34), 191,
3
190 (24.8), 163 (22).
1-(6ꢂ-Chloro-3ꢂ,4ꢂ-methylenedioxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9s). C H O NCl.
18 18
4
Prepared from 6 (2.2 g, 0.012 mol) and 6-chloro-3,4-methylenedioxybenzaldehyde (2.24 g, 0.012 mol). Yield 1.79 g (42%),
mp 107–108°C (Me CO), R 0.55. PMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz): 2.8–2.85 (2H, ddd, J = 16.4, 6.2, 5.5,
2
f
3
*
*
*
H-4), 3.03–3.11 (2H, dt, J = 12.1, 6.2, 6.2, H-3), 3.71 (3H, s, 7-OCH ), 3.88 (3H, s, 6-OCH ), 5.48 (1H, s, H-1), 5.92 (1H,
d, J = 0.4, OCH O-3ꢂ, 4ꢂ), 5.93 (1H, d, J = 1.6, OCH O-3ꢂ, 4ꢂ), 6.27 (1H, s, H-8), 6.44 (1H, s, H-5), 6.63 (1H, s, H-2ꢂ), 6.88
3
3
*
2
2
(1H, s, H-5ꢂ).
1-(2ꢂ-Furanyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9t). C H O N. Prepared from 6 (1.56 g,
15 17
3
0.0086 mol) and furfurol (0.83 g, 0.0086 mol). Yield 0.78 g (35%), mp of hydrochloride 221–224°C (Me CO), R 0.55.
2
f
*
*
PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.5–3.0 (2H, m, H-4), 3.16 (2H, m, H-3), 3.54 (3H, s, 7-OCH ), 3.65
6
3
(3H, s, 6-OCH ), 4.97 (1H, s, H-1), 6.45 (1H, s, H-8), 6.61 (1H, s, H-5), 5.94 (d, J = 3, H-4ꢂ), 6.28 (dd, J = 3, 1, H-3ꢂ), 7.49 (d,
3
J = 1, H-5ꢂ).
1,1ꢂ-Bis-[(4ꢃ,4ꢂꢃ-dihydroxy-5ꢃ,5ꢂꢃ-dimethoxyphenyl-3ꢃ,3ꢂꢃ-di)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]
(10). C H N O . Prepared from 6 (1.1 g, 0.0061 mol) and 2,2ꢂ-dihydroxy-3,3ꢂ-dimethoxy-5,5ꢂ-diformyldiphenyl
36 40
2 8
(dehydrodivanillin) (1.0 g, 0.0033 mol). Yield 0.78 g (35%), mp of hydrochloride 178–185°C (Me CO), R 0.75 (CHCl :MeOH
2
f
3
*
2:1). PMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 2.0 (2H, s, H-2, 2ꢂ), 2.78 and 2.99 (8H, m, H-3, 3ꢂ, 4, 4ꢂ), 3.45 (3H, s,
6
73

*
*
*
7-OCH ), 3.49 (3H, s, 6-OCH ), 3.65 (6H, s, 6ꢂ, 7ꢂ-OCH ), 3.69 (6H, s, 5ꢃ, 5ꢂꢃ-OCH ), 5.03 (2H, s, H-1, 1ꢂ), 6.27 (2H, s,
3
3
3
3
H-8, 8ꢂ), 6.54 (2H, s, H-5, 5ꢂ), 6.63 and 6.74 (4H, 2s, H-2ꢃ, 2ꢂꢃ, 6ꢃ, 6ꢂꢃ).
1,1ꢂ-Bis-[(4ꢃ-hydroxy-4ꢂꢃ,5ꢃ,5ꢂꢃ-trimethoxyphenyl-3ꢃ,3ꢂꢃ-di)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] (11).
C H N O . Prepared from 6 (0.65 g, 0.0036 mol) and 2-hydroxy-2ꢂ,3,3ꢂ-trimethoxy-5,5ꢂ-diformyldiphenyl (0.6 g,
37 42
2 8
0.0018 mol). Yield 0.87 g (71%), mp 198–203°C (Me CO), R 0.57 (CHCl :MeOH 2:1).
2
f
3
1,1ꢂ-Bis-(4ꢃ,4ꢂꢃ,5ꢃ,5ꢂꢃ-tetramethoxyphenyl-3ꢃ,3ꢂꢃ-di)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] (12).
C H N O . Prepared from 6 (1.68 g, 0.009 mol) and 2,2ꢂ,3,3ꢂ-tetramethoxy-5,5ꢂ-diformyldiphenyl (1.54 g, 0.0046 mol).
38 44
2 8
Yield 2.41 g (79%), mp of hydrochloride 242–245°C (Me CO), R 0.5 (CHCl :MeOH 2:1). PMR spectrum (100 MHz,
2
f
3
*
*
*
DMSO-d , ꢀ, ppm): 2.03 (2H, s, H-2, 2ꢂ), 3.33 (9H, s, 7, 6, 7ꢂ-OCH ), 3.46 (6H, s, 6ꢂ, 5ꢂꢃ-OCH ), 3.71 (6H, s,
4ꢃ, 4ꢂꢃ-OCH ), 3.81 (3H, s, 5ꢃ-OCH ), 5.59 (2H, s, H-1, 1ꢂ), 6.29 (1H, s, H-5), 6.31 (1H, s, H-5ꢂ), 6.45 (1H, s, H-8), 6.51 (1H,
6
3
3
*
3
3
s, H-8ꢂ), 6.79 (2H, s, H-6ꢃ, 6ꢂꢃ), 7.3 (2H, s, H-2ꢃ, 2ꢂꢃ).
General Method for Preparing Alkaloids 2, 3, and 5 and the Methyl Derivative of 9r. A solution of
1-(3ꢂ,4ꢂ-methylenedioxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.7 g, 0.002 mol) in MeOH (20 mL) was treated
with formalin (0.06 mL, 0.002 mol, 27%), refluxed for 1.5 h (TLC monitoring), cooled in ice, and reduced by NaBH (1 g).
4
The solvent was distilled off. The solid was dissolved in H O (10 mL) and extracted exhaustively with CHCl . The crude
2
3
product was purified by producing the hydrochloride or by chromatography over SiO using CHCl :MeOH (100:1ꢁ100:10).
2
3
The product was crystallized from Me CO or MeOH.
2
1-(3ꢂ,4ꢂ-Methylenedioxyphenyl)-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2). C H O N.
19 21
4
Prepared from 1-(3ꢂ,4ꢂ-methylenedioxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.7 g, 0.002 mol) and formalin
(0.06 mL, 0.002 mol, 27%). Yield 0.47 g (64%), mp 115–117°C (Me CO), R 0.82. NMR spectral data corresponded to those
2
f
for cryptostylin [2].
1-(3ꢂ,4ꢂ-Dimethoxyphenyl)-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3). C H O N. Prepared
20 22
4
from 1-(3ꢂ,4ꢂ-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.0 g, 0.003 mol) and formalin (0.08 mL,
0.003 mol, 27%). Yield 0.84 g (81%), mp of hydrochloride 206–209°C (Me CO), R 0.81. NMR spectral data corresponded
2
f
to those for cryptostylin II [2].
1-Phenyl-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5). C H O N. Prepared from 1-phenyl-6,7-
18 24
2
dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.5 g, 0.0018 mol) and formalin (0.05 mL, 0.0018 mol, 27%). Yield 0.4 g (76%),
mp of hydrochloride 234–239°C (Me CO), R 0.84. NMR spectral data corresponded to those for the natural alkaloid
2
f
(unnamed) [6].
REFERENCES
1.
2.
K. W. Bentley, Nat. Prod. Rep., 23, 444 (2006).
M. Shamma, The Isoquinoline Alkaloids. Chemistry and Pharmacology, Vol. 25, Academic Press, New York and
London, 1972, pp. 490-492.
3.
R. Gitto, M. L. Barreca, L. De Luca, G. De Sarro, G. Ferreri, S. Quartarone, E. Russo, A. Constanti, and A. Chimirri,
J. Med. Chem., 46, 197 (2003).
4.
5.
R. Naito, Y. Yonetoku, Y. Okamoto, A. Toyoshima, K. Ikeda, and M. Takeuchi, J. Med. Chem., 48, 6597 (2005).
M. Shamma and J. L. Moniot, Isoquinoline Alkaloids Research 1972–1977, Plenum Press, New York and London, 1978,
pp. 381–384.
6.
7.
8.
9.
10.
F. Abd El-Mageed Hashem and S. Ahmed Elsawi, Pharm. Pharmacol. Lett., 8, 167 (1998).
Organic Reactions [Russian translation], Coll. 6, Mir, Moscow, 1953, pp. 98, 177.
V. I. Vinogradova, T. I. Golodnyuk, N. Tulyaganov, M. S. Yunusov, and N. U. Baratov, Khim. Prir. Soedin., 404 (1993).
G. F. Zakis, Synthesis of Model Lignin Compounds [in Russian], Zinatne, Riga, 1980, pp. 220–223.
D. L. Minor, S. D. Wyrick, P. S. Charifson, V. J. Watts, D. E. Nichols, and R. B. Mailman, J. Med. Chem., 37,
4317 (1994).
11.
12.
13.
A. Brossi, H. Gurien, A. I. Rachlin, and S. Teitel, J. Org. Chem., 32, 1269 (1967).
T. A. Henry and T. M. Sharp, J. Chem. Soc., 2285 (1930).
T. Kametani, K. Fukumoto, S. Shibuya, H. Nemoto, T. Nakano, T. Sugahara, T. Takahashi, Y. Aizawa, and M. Toriyama,
J. Chem. Soc. Perkin Trans 1, 1435 (1972).
14.
74
Syntheses of Organic Compounds [Russian translation], Coll. 5, IL, Moscow, 1954, p. 9.