Total synthesis of racemic 1-aryl-tetrahydroisoquinoline alkaloids

Article abstract of DOI:10.1007/s00706-015-1564-y

A new synthetic route was developed for the preparation of natural products cryptostyline I, II, III and 1-phenyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. The Liebeskind-Srogl palladium-catalyzed carbon-carbon cross-coupling protocol was use

Full text of DOI:10.1007/s00706-015-1564-y

Monatsh Chem
DOI 10.1007/s00706-015-1564-y
ORIGINAL PAPER
Total synthesis of racemic 1-aryl-tetrahydroisoquinoline alkaloids
1
Peter Abranyi-Balogh Tamas Foldesi Matyas Milen
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Received: 29 June 2015 / Accepted: 23 August 2015
Ó Springer-Verlag Wien 2015
Abstract A new synthetic route was developed for the
preparation of natural products cryptostyline I, II, III and
1-phenyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquin-
oline. The Liebeskind–Srogl palladium-catalyzed carbon–
carbon cross-coupling protocol was used in the key step of
the total synthesis.
been isolated from Cryptostylis fulva [1, 2]. Later, the
absolute configuration of these compounds was determined
[3, 4]. In 1974, Agurell et al. isolated (-)-cryptostyline I,
II, and III from Cryptostylis erythroglossa [5]. The
unsubstituted variation, the 1-phenyl-6,7-dimethoxy-2-
methyl-1,2,3,4-tetrahydroisoquinoline alkaloid (1d) (un-
named trivially), was isolated from Adhatoda vasica in
1998 [6].
Graphical abstract
The 1,2,3,4-tetrahydroisoquinoline ring is an important
scaffold in organic and medicinal chemistry [7–12].
Accordingly, various methodologies have been described
for the preparation of alkaloids 1a–1d in both racemic [13–
18] and enantiopure forms [19–28]. The retrosynthetic
approaches to the construction of alkaloids 1a–1d as the
key step are outlined in Fig. 1. The most common proce-
dures are the Pictet–Spengler condensation and the
Bischler–Napieralski reaction (Fig. 1, Pathways A [15, 16]
and B [18, 19, 21, 25, 28]). Takano et al. described the aryl
radical-initiated cyclization for the synthesis of racemic
cryptostylines I–III (1a–1c) (Fig. 1, Pathway C [17]).
Another ring closure reaction has been described for the
construction of the isoquinoline skeleton. For example, in
the asymmetric synthesis of (S)-(?)-cryptostyline II,
intramolecular lactamization was applied (Fig. 1, Pathway
D [20, 26]). The C-1 arylation of N-alkyltetrahydroisoquin-
olines was reported as the key step of the synthesis of
cryptostyline alkaloids 1a–1c (Fig. 1, Pathway E [13, 14,
22–24, 27]).
Keywords Natural products Á Heterocycles Á Catalysis Á
Thionation Á Liebeskind–Srogl reaction
Introduction
Cryptostylines (1a–1c) are rarely occurring tetrahydroisoquin-
oline alkaloids that contain variously substituted phenyl
ring at position C-1 (Fig. 1). (?)-Cryptostyline I–III have
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1564-y) contains supplementary
material, which is available to authorized users.
The simple one-pot preparation of ( )-cryptostylines I–
III (1a–1c) was described by Ruchiravat et al. starting from
homoveratrylamine (2) and the appropriate aromatic alde-
hydes 3a–3c (Scheme 1) [16]. The Pictet–Spengler
condensation was carried out in formic acid. After that,
formaldehyde was added to this mixture and the reaction
continued. The products were obtained in good yields.
´
´
& Matyas Milen
matyas.milen@gmail.com;
milen.matyas@gmail.com
1
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest,
Hungary
123

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P. Abranyi-Balogh et al.
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The same synthetic route was applied for the preparation
of racemic alkaloids 1a, 1b, and 1d [15]. In this case, the
Pictet–Spengler reaction was performed in boiling benzene
catalyzed by triflouroacetic acid. Subsequent reductive
methylation of the 1-aryl-1,2,3,4-tetrahydroisoquinoline
intermediates (4a, b, d) with formaldehyde and NaBH4
furnished compounds 1a, 1b, and 1d in 62, 46, and 58 %
yield, respectively.
in situ-prepared a-amino carbanion and appropriate aryl
chloride [13] or direct arylation of 6 with aryl Grignard
reagents via diethyl azodicarboxylate (DEAD)-mediated
oxidative C–H activation [14].
Mollov’s group reported a new synthetic method for the
preparation of racemic cryptostiline III (1c) by the fol-
lowing route (Scheme 4) [18]. The treatment of (3,4-
dimethoxyphenyl)acetic acid (7) and 3,4,5-trimethoxy-N-
methylbenzamide (8) with POCl3 produced isoquinoline
derivative 9. After this, intermediate 9 was transformed to
( )-cryptostyline III (1c) by a two-step reduction and the
product was obtained in 31 % overall yield.
Takano and co-workers reported an interesting synthesis
of ( )-cryptostylines I–III (1a–1c) (Scheme 2) [17]. The
Schiff base 5 was used as the starting material, which was
treated with Bu3SnH and azobisisobutyronitrile (AIBN). In
the next step, a reductive methylation of intermediate 4a–
4c using formaldehyde and NaBH4 gave the desired
products in reasonable overall yields.
In continuation of our efforts in the field of alkaloid
chemistry [29–31], we now describe a new synthesis of
natural products ( )-1a–1d. In this approach, our earlier
results were used for the preparation of 1-aryl-3,4-di-
hydroisoquinoline intermediates [32].
Recently, Singh et al. utilized the direct C-1 arylation of
6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (6)
in the synthesis of natural products ( )-1a–1d (Scheme 3).
The target molecules were obtained by the reaction of
Results and discussion
The starting material for the synthesis of alkaloids 1a–1d
was 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (11).
This compound was prepared in acid-catalyzed Pictet–
Spengler reaction according to literature procedure from
2-(3,4-dimethoxyphenyl)ethylamine and paraformaldehyde
in a yield of 94 % [33]. The tetrahydroisoquinoline
derivative 11 was then thionated with elemental sulfur
according to our earlier microwave-assisted procedure in
dimethylformamide at 170 °C [34] (Scheme 5). Thioamide
12 was obtained in 63 % yield after purification by chro-
matography. The key intermediate, 6,7-dimethoxy-(1-
Fig. 1 Structure of the cryptostyline derivatives 1a–1d described and
the disconnection approaches leading to them
Scheme 1
Scheme 2
123

Total synthesis of racemic 1-aryl-tetrahydroisoquinoline alkaloids
Scheme 3
Scheme 4
methylsulfanyl)-3,4-dihydroisoquinoline (13) was prepared
by solid–liquid phase S-methylation of the thioamide 12
with 1.1 equivalent of methyl iodide using Cs2CO3 in
acetonitrile/dichloromethane at room temperature for 24 h
[35] and was obtained in a yield of 99 %. The next step of
the synthesis was the palladium-catalyzed Liebeskind–
Srogl cross-coupling [32] with the appropriate boronic
acids, 3,4-(methylenedioxy)phenylboronic acid (14a), 3,4-
excellent yields. 1-Aryl-3,4-dihydroisoquinoline deriva-
tives 15a–15d were then reduced by NaBH4 in methanol
[36] to give products 4a–4d in a yield of 80–95 %. Finally,
the racemic cryptostyline I, II, III and 1-phenyl-6,7-dime-
thoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline alkaloids
(1a–1d) were synthesized by Eschweiler–Clarke methyla-
tion of amines 4a–4d, respectively [11]. The products were
obtained in reasonable yields (65–82 %). Compound 1a
was prepared only in 44 % yield, when the N-alkylation
was carried out with CH3I in the presence of Cs2CO3 using
CH3CN.
dimethoxyphenylboronic
acid
(14b),
3,4,5-
trimethoxyphenylboronic acid (14c), and phenylboronic
acid (14d). In this reaction, 10 mol% of Pd(PPh3)4 and 3
equivalents of copper(I)-thiophene-2-carboxylate (CuTC)
cofactor were used. Intermediates 15a–15d were isolated in
The reactions were followed by thin layer chromatog-
raphy (TLC) and HPLC–MS. The intermediates and
123

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P. Abranyi-Balogh et al.
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Scheme 5
compounds prepared were identified and characterized by
1
purifications by flash column chromatography were carried
out using Merck 107736 silica gel 60 H and applying
hexane–dichloromethane or dichloromethane–methanol
solvent systems. All reagents were purchased from com-
mercial sources. Analytical samples of new compounds
were obtained by recrystallization from the solvents or
solvent mixtures given below in parentheses.
IR and H and 13C NMR spectroscopy.
Conclusion
In conclusion, a new synthetic route was developed for the
preparation of 1-aryl-tetrahydroisoquinoline alkaloids 1a–
1d. The thionation of the starting material, 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (11) with elemental sulfur
and the Liebeskind–Srogl cross-coupling reaction were
used as the pivotal steps in the total synthesis. The natural
products 1a–1d were obtained in five steps in good overall
yields.
6,7-Dimethoxy-3,4-dihydroisoquinoline-1(2H)-thione
(12)
A
mixture of 1.00 g of 6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (11, 5.17 mmol) and 0.33 g of sulfur
(2 equiv., 10.34 mmol) in 20 cm3 of DMF was kept in a
vial that was placed in the MW reactor and irradiated at
170 °C for 15 min. The mixture was cooled and concen-
trated under reduced pressure. Purification by flash column
chromatography afforded 0.73 g (63 %) 12. M.p.:
223–224 °C (CHCl3–EtOH 1:3) (Ref. [37] 223 °C).
Experimental
All melting points were determined on a Bu¨chi B-540
capillary melting point apparatus. IR spectra were obtained
6,7-Dimethoxy-1-(methylsulfanyl)-3,4-dihydroisoquinoline
(13)
1
on a Bruker Vector 22 FT spectrometer in KBr pellets. H
To a solution of 1.00 g of 6,7-dimethoxy-3,4-dihydroisoquin-
oline-1(2H)-thione (12, 4.48 mmol) and 1.75 g of Cs2CO3 (1.2
equiv., 5.38 mmol) in a mixture of 40 cm3 of acetonitrile and
20 cm3 of dichloromethane, 0.70 g of methyl iodide (1.1
equiv., 4.93 mmol) was added. The reaction mixture was
stirred at room temperature for 24 h. Then, the inorganic salts
were filtered off, and the filtrate was concentrated. The residue
was taken up in 30 cm3 dichloromethane and the mixture was
washed with 30 cm3 water. Finally, the organic phase was
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Yield: 1.05 g (99 %); m.p.: 91–92 °C (EtOH) (Ref.
[37] 94–96 °C).
NMR and 13C NMR spectra were recorded at 303 K on a
Varian Unity Inova 500 (500 and 125 MHz for 1H and 13
C
NMR spectra, respectively) or a Bruker Avance III (400
1
and 100 MHz for H and 13C NMR spectra, respectively)
or with a Bruker Avance III HD (600 and 150 MHz for 1H
and 13C NMR spectra, respectively) spectrometer. DMSO-
d6 or CDCl3 was used as the solvent and tetramethylsilane
(TMS) as the internal standard. Chemical shifts (d) and
coupling constants (J) are given in ppm and Hz, respec-
tively. The reactions were monitored by analytical TLC on
silica gel 60 F254 and LC–MS chromatography. The
123

Total synthesis of racemic 1-aryl-tetrahydroisoquinoline alkaloids
General procedure for the preparation
of 1-aryl-3,4-dihydroisoquinolines: synthesis
of compounds 15a–15d
crude material was purified by flash column
chromatography.
1-(1,3-Benzodioxol-5-yl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (4a)
To the stirred solution of 0.50 g 6,7-dimethoxy-1-
Yield: 0.39 g (90 %); m.p.: 128–129 °C (EtOH) (Ref. [41]
122–124 °C).
(methylsulfanyl)-3,4-dihydroisoquinoline
(13,
2.11 mmol) in 20 cm3 abs. THF under argon atmo-
sphere, the appropriate arylboronic acid (14a–14d, 1.2
equiv., 2.52 mmol), 1.21 g CuTC (3 equiv., 6.33 mmol),
and 0.24 g Pd(PPh3)4 (10 mol%, 0.21 mmol) were
added. The mixture was refluxed until the starting
material disappeared (1–1.5 h). After cooling, the sol-
vent was evaporated and a CHCl3–MeOH (7:1) mixture
(25 cm3) was added. The crude reaction mixture was
subsequently washed with 25 % aq NH3 (2 9 30 cm3).
The aqueous layer was extracted with a CHCl3–MeOH
(7:1) mixture (2 9 25 cm3). The combined organic
phase was dried (MgSO4), filtered, and the solvent
evaporated. The crude material was purified by flash
column chromatography.
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (4b)
Yield: 0.42 g (90 %); m.p.: 101–102 °C (EtOH) (Ref. [21]
104–105 °C).
6,7-Dimethoxy-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahy-
droisoquinoline (4c)
Yield: 0.40 g (80 %); m.p.: 106–108 °C (Et2O) (Ref. [4]
108–110 °C).
6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline
(4d)
Yield: 0.36 g (95 %); m.p.: 111–113 °C (EtOH) (Ref. [42]
110–111 °C).
1-(1,3-Benzodioxol-5-yl)-6,7-dimethoxy-3,4-
dihydroisoquinoline (15a)
General procedure for the preparation
of 1-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines:
synthesis of compounds 1a–1d
Yield: 0.64 g (98 %). The product was characterized as the
hydrochloride salt. M.p.: 219–221 °C (i-PrOH) (Ref. [38]
228 °C).
The compounds 4a–4d (0.80 mmol), 1.03 cm3 formalde-
hyde (35 %, 13.1 mmol), and 1.60 cm3 formic acid (98 %,
42.4 mmol) were stirred at reflux under argon atmosphere
until the starting material disappeared (2–4 h). After
cooling, the reaction mixture was concentrated. 10 %
NaHCO3 solution (15 cm3) was added and the mixture was
extracted with CH2Cl2 (2 9 15 cm3). The combined
organic layer was dried (MgSO4), filtered, and concen-
trated in vacuo. The crude product was purified by
recrystallization or flash column chromatography.
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline (15b)
Yield: 0.64 g (92 %); m.p.: 167–168 °C (MeCN) (Ref.
[26] 168–169 °C).
6,7-Dimethoxy-1-(3,4,5-trimethoxyphenyl)-3,4-
dihydroisoquinoline (15c)
Yield: 0.61 g (81 %); m.p.: 156–158 °C (EtOH–H2O)
(Ref. [39] 160 °C).
6,7-Dimethoxy-1-phenyl-3,4-dihydroisoquinoline (15d)
Yield: 0.52 g (93 %). The product was characterized as the
hydrochloride salt. M.p.: 214–216 °C (MeCN, decomp.)
(Ref. [40] 212–213 °C).
1-(1,3-Benzodioxol-5-yl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline, ( )-cryptostyline I (1a)
Yield: 0.18 g (68 %); m.p.: 115–117 °C (EtOH) (Ref. [13]
116–117 °C).
General procedure for the preparation
of 1-aryl-1,2,3,4-tetrahydroisoquinolines: synthesis
of compounds 4a–4d
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline, ( )-cryptostyline II (1b)
Yield: 0.18 g (65 %); m.p.: 88–89 °C (hexane) (Ref. [43]
89–90 °C).
To the stirred solution of 1-aryl-3,4-dihydroisoquinoline
derivatives 15a–15d (1.40 mmol) in 30 cm3 MeOH at 0 °C,
0.16 g NaBH4 (3 equiv., 4.20 mmol) was added. The
reaction mixture was stirred at 0 °C for 15 min and room
temperature for 15 min. The solvent was removed under
reduced pressure, and the reaction mixture was diluted with
20 cm3 saturated aqueous NaHCO3 and extracted with
EtOAc (2 9 20 cm3). The combined organic layer was
dried (MgSO4), filtered, and the solvent evaporated. The
6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-
1,2,3,4-tetrahydroisoquinoline, ( )-cryptostyline III (1c)
Yield: 0.22 g (72 %); m.p.: 137–139 °C (MeOH) (Ref.
[18] 137–138 °C).
1-Phenyl-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline (1d)
Yield: 0.19 g (82 %); m.p.: 75–76 °C (hexane) (Ref. [44]
74–76 °C).
123

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24. Umetsu K, Asao N (2008) Tetrahedron Lett 49:2722
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