Synthesis of indolo[2,1-a]isoquinolines by CF3COOH-induced cyclization

Article abstract of DOI:10.1002/jhet.4078

Indolo[2,1-a]isoquinoline alkaloids and related compounds have been known to have interesting biological activities, such as antileukemic and antitumor activities. We found that 1-(3,4-dimethoxyphenethyl)indole gave 2,3-dimethoxyindolo[2,1-a]isoquinoline

Full text of DOI:10.1002/jhet.4078

1
Synthesis of indolo[2,1-a]isoquinolines by CF3COOH-induced
cyclization
Yasuhiro Wada,1,2 Nobuhito Kurono,1,3* Hisanori Senboku,1,4 and Kazuhiko Orito1*
1Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido
University
2Pharmaceutical Research Center, Asahi Kasei Pharma Corporation
3Department of Integrated Human Sciences, Hamamatsu University, School of
Medicine
4Division of Applied Chemistry, Faculty of Engineering, Hokkaido University
Correspondence
Nobuhito Kurono, Department of Integrated Human Sciences, Hamamatsu University,
School of Medicine, Hamamatsu, Shizuoka, Japan.
Email: chrono@hama-med.ac.jp
Abstract
Indolo[2,1-a]isoquinoline alkaloids and related compounds have been known to have
interesting biological activities such as antileukemic and antitumor activities. We found
that 1-(3,4-dimethoxyphenethyl)indole gave 2,3-dimethoxyindolo[2,1-a]isoquinoline
and 1-(3,4-dimethoxyphenylacetyl)indole gave 2,3-dimethoxy-6-oxoindolo[2,1-a]iso-
quinoline, respectively, by an intramolecular cyclization carried out in boiling
trifluoroacetic acid.
Keywords
Indolo[2,1-a]isoquinoline,
intramolecular
cyclization,
trifluoroacetic
acid,
1-phenethylindole
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2
INTRODUCTION
We have been interested in construction of an indolo[2,1-a]isoquinoline ring system,
the structural feature of which has been found in dibenzopyrrocoline alkaloids.[1,2]
Some of them have been shown to exhibit interesting biological activities[3] including
antileukemic and antitumor activities,[3a,3b,3c] nonsteroidal antiestrogen,[3e] and
anti-tubulin activity.[3f] Most of the reported methods for the synthesis of such alkaloids
and related indolo[2,1-a]isoquinolines[4-7] involve the procedures ending up with the
formation of the fused indole ring. We have also reported some synthetic methods, such
as radical cyclization,[5j] K2CO3-DMF induced cycloamination,[5m,5n,5o] or
phosphine-free Pd(0)-catalyzed cycloamination,[5t] which have been developed for
cyclization in route A shown in Figure 1. The present study deals with a new method for
route B, which completes with an isoquinoline nucleus fusion. The results will be added
in a limited number of the successful or very promising methods for the alkaloid
syntheses in route B.[5i,7c,7f,7k]
RESULTS AND DISCUSSION
One of the most basic and efficient methods for the preparation of berbines, a
structural feature of the protoberberine alkaloids, is the intramolecular acid-catalyzed
cyclization so-called Pictet-Spengler isoquinoline synthesis.[8]
N-Phenethyl-1,2-dihydroisoquinolines 2, which can be prepared by LiAlH4 reduction
of isoquinolinium salts 1, have been converted to the corresponding berbines 3 in heated
mineral acids.[9] It was reported by Dyke that acid-treatment (conc. HCl) of carbostyril 4,
which can be prepared by oxidation of 1 with K3[Fe(CN)6], afforded 8-oxoberbines
5,[9c] as shown in Figure 2. Dyke also reported a similar method for the preparation of 3
and 5 starting with disproportionation of 1 with alkali and ending up with the
Pictet-Spengler cyclization of the resultant 2 and 4, respectively. [9d]
On the other hand, under such acidic conditions, indoles cause polymerizations due to
their enamine and imine properties to form their dimers or trimers, depending on
experimental conditions, as reported before.[10] We tried to test the ring-closure in route
B using N-phenethylindole 6. Its treatments under the Dyke’s Pictet-Spengler conditions
using conc. HCl afforded a trace amount of terahydroindoloisoquinoline 7 in a dark
brown tarry substance. The use of diluted HCl solutions also afforded a colored tarry
mixture but none of 7.
We shifted the reaction conditions from those mineral acids to organic acids. Soon,
we found that boiling CF3COOH (bp 72.4 °C) induced the desired ring-closure in 6.
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When a 0.1 M solution of 6 in CF3COOH was refluxed under nitrogen for 9-12 h,
tetrahydroindoloisoquinoline 7 formed in a 3:2 ratio with the 3-trifluoroacetylindole 8,
as shown in Scheme 1. 7 was air-sensitive, and, on standing in the air overnight, all
converted to 9, which was obtained in 50% isolated yield together with
3-trifluoroacetylindole 8 in 33% yield. This trifluoroacetylation is easily explained to
have occurred due to the nucleophilicity of the indole enamine system enhanced by its
N-alkylation, and could not be avoided even in use of a wet CF3COOH (CF3COOH :
H2O = 10:1). The product ratio and yields were the almost same as those of the above
dry version. Prolonged reaction times did not change the product ratio of 3:2. The use of
the catalytic amount of CF3COOH (10 mol%) in boiling benzene for 9 h did not
consume 6 at all. We have known that the treatment with hot BF3•Et2O induces an
efficient intramolecular triple cyclization of an indole derivative leading to a pentacyclic
nucleus of the Aspidosperma alkaloids.[11] Under a similar condition, a BF3•Et2O
solution of the indole 6 was heated at 80 °C for 10 h, but no cyclization occurred at all.
A catalytic amount of p-TsOH (0.1 eq) have been successfully used in boiling toluene
for the Pictet-Spengler isoquinoline synthesis to produce tetrahydro-β-carbolines.[12]
Under the same condition, indole 6, however, did not undergo the cyclization and even
in use of an increased amount of p-TsOH (2 eq), and was recovered unchanged after 10
h. In addition, treatment of 6 (0.1 M) in CCl3COOH at 80 °C, followed by the
air-oxidation, afforded 9 in a yield less than 20%.
In contrast, cyclization of N-acylindole derivative 10 in boiling CF3COOH proceeded
more slowly and selectively, compared with that of 6, to afford 6-oxoindoloisoquinoline
11 24 h later in 93% isolated yield (Scheme 1). The result may be explained that the
nucleophilicity of indole was effectively reduced by its N-acylation, so that the
competitive trifluoroacetylation was entirely suppressed, and the cyclization occurred
specifically. It should be noted that the conversion of 10 to 11 has been carried out in a
BF3•Et2O/(CF3)2CHOH system developed by Nishina.[7k]
CONCLUSIONS
The Pictet-Spengler type treatment, which is useful for preparation of protoberberine
alkaloids, has been limited for cyclization of the acid-sensitive substrates, such as indole
derivatives. Indoles polymerize to their dimers or trimers under strongly acidic
conditions. Cyclization of an acid-sensitive N-phenethylindole 6 was carried out in
boiling CF3COOH for 9 h to afford an air-sensitive tetrahydroindolo[2,1-a]isoquinoline
7, being isolated as its dihydro derivative 9 (50%), and a byproduct,
3-trifluoroacetylindole 8 (33%), competitively. In contrast, under the same condition, an
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N-protected indole, N-phenylacetylindole 10, was selectively converted to a
6-oxoindolo[2,1-a]isoquinoline 11 (93%) 24 h later.[13] Dibenzopyrrocoline alkaloids
and related compounds, indolo[2,1-a]isoquinolines, have been known to have
interesting biological activities. We believe that such compounds will be provided
efficiently along with the present methodology.
EXPERIMENTAL
General Remarks: Melting points were measured with a Yanagimoto micro melting
point apparatus, and were uncorrected. The IR spectra were recorded with a JASCO
1
13
IR-810 spectrometer. The H NMR (270 or 400 MHz) and C NMR (67.8 or 100.4
MHz) spectra were recorded with a JEOL JNM-JX270 or ECX-400P FT NMR
spectrometer, and the samples were prepared with CDCl3 (99.8 atom- % D; containing
0.03 % v/v, tetramethylsilane; Aldrich Co.), unless otherwise noted. The chemical shifts
were reported in ppm, relative to tetramethylsilane. The LR- and HR-EI-MS spectra
were determined with a JEOL JMS-HX110, JEOL JMS-FABmate or JEOL JMS-700TZ
mass spectrometer. Elemental analyses were performed with Yanako MT-6 CHN
CORDER and Dionex DX-500 at the Analytical Laboratory of Faculty of
Pharmaceutical Science, Hokkaido University.
N-(3,4-Dimethoxyphenethyl)indole (6). To a stirred solution of NaH (0.324 g of 60%
dispersion in mineral oil, used by washing with hexane 3 times, 8.0 mmol) in anhydrous
THF (10 mL) at r.t. was added dropwise a solution of indole (0.89 g, 7.6 mmol) in dry
THF (7 mL) at –78 °C under Ar. The reaction mixture was stirred at r.t. for 30 min. To
this, a solution of 1-(3,4-dimethoxyphenyl)-2-(p-toluenesulfonyloxy)ethane (2.70 g, 8.0
mmol)[14] in dry THF (9 mL) was dropwise added at rt. The mixture was heated at
reflux overnight, quenched with water (20 mL), and extracted with CH2Cl2 (3 x 15 mL).
The extracts were washed with water (3 x 15 mL), dried over anhydrous Na2SO4, and
concentrated. The residue (2.55 g) was subjected to column chromatograpy on silica gel
(30 % hexane–CH2Cl2) to afford a colorless oil (1.99 g), which was distilled under
reduced pressure to give 6 as a colorless oil (1.68 g, 79 %), bp 200 °C/0.3 mmHg; IR
1
(neat): 1605, 1505 cm-1; H NMR (270 MHz):  3.03 (t, 2H, CH2, J = 7.2 Hz), 3.68 (s,
3H, OCH3), 3.84 (s, 3H, OCH3), 4.32 (t, 2H, CH2, J = 7.2 Hz), 6.34 (d, 1H, 2’-H, J =
2.0 Hz), 6.42 (d, 1H, 3-H, J = 3.2 Hz), 6.64 (dd, 1H, 6’-H, J = 8.2, 2.0 Hz), 6.76 (d, 1H,
5’-H, J = 8.2 Hz), 6.89 (d, 1H, 2-H, J = 3.2 Hz), 7.10 (dt, 1H, 5- or 6-H, J = 8.3, 1.3
Hz) , 7.19 (dt, 1H, 5- or 6-H, J = 8.3, 1.3 Hz), 7.31 (br. d, 1H, 7-H, J = 8.3 Hz), 7.61 (br.
d, 1H, 4-H, J = 8.3 Hz) ppm; 13C NMR (100.5 MHz, CDCl3):  36.1 (CH2), 48.2 (CH2),
55.6 (OCH3), 55.8 (OCH3), 100.8 (CH), 109.3 (C), 111.2 (CH), 112.0 (CH), 119.2 (CH),
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120.5 (CH), 120.9 (CH), 121.3 (CH), 128.0 (CH), 128.6 (CH), 131.1 (C), 135.6 (C),
147.6 (C), 148.7 (C) ppm; EI-MS: m/z 281 (M+, 19.4), 151 (19.3), 130 (100), 103 (7.5),
77 (8.6). Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.59; H,
6.72; N, 4.89.
Cyclization of 6. A stirred mixture of 6 (29 mg, 0.1 mmol) in CF3COOH (1 mL) was
refluxed under nitrogen for 9 h. The cooled reaction mixture was quenched with a
saturated Na2CO3 solution (10 mL), and extracted with CH2Cl2 (3 x 10 mL). The
combined CH2Cl2 layers were washed with water (3 x 10 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was essentially a 3:2 mixture (30 mg)
of air-sensitive 2,3-dimethoxy-5,6,12,12a-tetrahydroindolo[2,1-a]isoquinoline (7) [1H
NMR (270 MHz):  2.44 (dd, 1H, 5- or 6-H, J = 15.9, 3.7 Hz), 2.95-3.04 (m, 1H, 5- or
6-H), 3.12 (dd, 1H, 12-H, J = 15.2, 3.5 Hz), 3.32 (ddd, 1H, 5- or 6-H, J = 13.6, 12.3,
3.9 Hz), 3.52 (dd, 1H, 12-H, J = 15.2, 9.2 Hz), 3.80 (s, 3H, OCH3), 3.86-3.90 (s, 3H,
OCH3 and m, 1H, 5- or 6-H), 4.84 (br. d, 1H, 12a-H, J = 7.7 Hz), 6.47 (s, 1H, 1- or 4-H),
6.65 (s, 1H, 4- or 1-H), 6.61-6.66 and 7.04-7.09 (each m, each 2H, 8-, 9-, 10-, and
11-H) ppm. These are essentially identical with the reported spectral data.[4c,5f]] and
N-(3,4-dimethoxyphenethyl)-3-trifluoroacetylindole (8), and allowed to stand in air
overnight, and subjected to preparative TLC on silica gel (CH2Cl2). A fraction with Rf
0.5–0.6 gave colorless crystals 14 mg (50 %), mp 180–181 °C (CH2Cl2–CH3OH), which
was identical in all respects with 2,3-dimethoxy-5,6-dihydroinolo[2,1-a]isoquinoline (9)
1
(lit. [5e] mp 147 °C; lit. [5o] mp 177.5–179.5 °C; lit. [4c] mp 183–185 °C). H NMR
(270 MHz):  3.12 (t, 2H, 5-H, J = 6.6 Hz), 3.93 (s, 3H, OCH3), 3.97 (s, 3H, OCH3),
4.23 (t, 2H, 6-H, J = 6.6, Hz), 6.76 (s, 1H, 1- or 4-H), 6.77 (s, 1H, 4- or 1-H), 7.09 (dt,
1H, 10- or 9-H, J = 7.9, 0.8 Hz), 7.19 (dt, 1H, 9- or 10-H, J = 7.9, 1.0 Hz), 7.24 (s, 1H,
12-H), 7.32 (br. d, 1H, 8- or 11-H, J = 7.9 Hz), 7.61 (br. d, 1H, 11- or 8-H, J = 7.9 Hz)
13
ppm; C NMR (100.5 MHz, CDCl3):  28.7 (CH2), 40.2 (CH2), 56.0 (OCH3), 56.1
(OCH3), 95.1 (CH), 107.3 (CH), 108.7 (CH), 111.2 (CH), 119.7 (CH), 120.4 (CH),
121.3 (CH), 121.6 (C), 124.9 (C), 128.9 (C), 135.8 (C), 136.6 (C), 148.3 (C), 148.7 (C)
ppm.
These are essentially identical with the reported spectral data.[5o,5r] A less mobile
fraction with Rf 0.2–0.4 gave 8 as a colorless oil (13 mg, 33%); IR (neat): 1664 (C=O)
cm-1; 1H NMR (270 MHz):  3.09 (t, 2H, CH2, J = 6.7 Hz), 3.69 (s, 3H, OCH3), 3.83 (s,
3H, OCH3), 4.42 (t, 2H, CH2, J = 6.7 Hz), 6.39 (d, 1H, 2’-H, J = 2.0 Hz), 6.51 (dd, 1H,
6’-H, J = 8.0, 2.0 Hz), 6.75 (d, 1H, 5’-H, J = 8.0 Hz), 7.36-7.42 (m, 3H, 5-, 6-, and 7-H),
13
7.55 (q, 1H, 2-H, J = 1.7 Hz), 8.37-8.42 (m, 1H, 4-H) ppm; C NMR (100.5 MHz,
CDCl3) :  35.6 (CH2), 49.4 (CH2), 55.7 (OCH3), 55.9 (OCH3), 109.1 (C), 110.2 (CH),
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111.5 (CH), 111.7 (CH), 116.9 (q, CF3, J = 291.0 Hz), 120.7 (CH), 122.7 (CH), 123.9
(CH), 124.5 (CH), 127.0 (C), 129.4 (C), 136.3 (C), 137.8 (q, CH, J = 5.0 Hz), 148.3 (C),
149.2 (C), 174.7 (q, CO, J = 35.5 Hz) ppm; EI-MS: m/z 377 (M+, 34.7), 308 (47.2), 226
(8.1), 151 (100), 129 (12.0); HR-MS calcd for C20H18NF3O3 377.12385, found
377.12371.
N-(3,4-Dimethoxyphenylacetyl)indole (10). According to Illi’s procedure,[15] when a
mixture of indole (38 mg, 0.3 mmol), Bn4NHSO4 (2.3 mg, 0.006 mmol), NaOH (254
mg, 6.4 mmol) and 3,4-dimethoxyphenylacetyl chloride (prepared by treatment of
3,4-dimethoxyphenylacetic acid (90 mg, 0.45 mmol), with excess SOCl2 (0.5 mL) in
benzene at r.t. overnight, followed by removal of the excess reagent and the solvent in
vacuo) in CH2Cl2 (2 mL) was stirred at r.t. for 1 h. The reaction mixture was filtered
through a thin pad of powdered MgSO4. The solvent was evaporated, and the residue
(59 mg) was purified by preparative TLC (Rf 0.4–0.5, 2% EtOAc–CH2Cl2) to give 10 as
colorless crystals (23 mg, 24%), mp 127–128 °C (benzene–hexane); IR (Nujol): 1706
(C=O) cm-1; 1H NMR (270 MHz):  3.857(s, 3H, OCH3), 3.862 (s, 3H, OCH3), 4.17 (s,
2H, CH2), 6.62 (d, 1H, 3-H, J = 3.9 Hz), 6.84 (s, 3H, 2’, 5’, and 6’-H), 7.24–7.38 (m,
2H, 5- and 6-H), 7.52 (d, 1H, 2-H, J = 3.9 Hz), 7.55 (dd, 1H, 7-H, J = 7.3, 1.3 Hz), 8.50
13
(br. d, 1H, 4-H, J = 8.2 Hz) ppm; C NMR (67.8 MHz, CDCl3):  42.6 (CH2), 55.8 (2
OCH3), 109.4 (CH), 111.4 (CH), 112.1 (CH), 116.7 (CH), 120.8 (CH), 121.3 (CH),
123.8 (CH), 124.8 (CH), 125.2 (CH), 125.8 (C), 130.2 (C), 135.7 (C), 148.3 (C), 149.2
(C), 169.5 (CO) ppm; EI-MS: m/z 295 (M+, 74.8), 178 (100), 163 (13.8), 151 (71.3),
117 (13.0). Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.76. Found: C, 73.39; H,
5.93; N, 4.76.
Cyclization of 10. A stirred mixture of 10 (29 mg, 0.1 mmol) in CF3COOH (1 mL) was
refluxed for 24 h under nitrogen. The cooled reaction mixture was quenched with a
saturated Na2CO3 solution (10 mL), and extracted with CH2Cl2 (3 x 10 mL). The
combined CH2Cl2 layers were washed with water (3 x 10 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue (28 mg) was purified by preparative
TLC (3% MeOH–CH2Cl2). A band with Rf 0.3–0.5 gave 11 as a colorless solid, 27 mg
(0.9 mmol, 93%), mp 165–167 °C. An analytical sample was prepared by
recrystallization from MeOH, mp 167–169 °C (lit. [7k] mp 142-143 °C); IR (Nujol):
1
1656 (C=O) cm-1; H NMR (400 MHz, CDCl3):  3.46 (dd, 1H, 12-H, J = 15.1, 10.8
Hz), 3.62 (d, 1H, 5-H, J = 18.5 Hz), 3.64 (dd, 1H, 12-H, J = 15.1, 9.2 Hz), 3.78 (dd,
1H, 5-H, J = 18.5, 4.0 Hz), 3.90 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.40 (ddd, 1H,
12a-H (-H), J = 10.8, 9.2, 4.0 Hz), 6.74 (s, 1H, 1- or 4-H), 6.77 (s, 1H, 4- or 1-H),
7.07 (t, 1H, 10-H, J = 8.0 Hz), 7.25 (d, 1H, 11-H, J = 8.0 Hz), 7.27 (t, 1H, 9-H, J = 8.0
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13
Hz), and 8.22 (d, 1H, 8-H, J = 8.0 Hz) ppm; C NMR (100.5 MHz, CDCl3):  34.5
(CH2), 39.6 (CH2), 56.1 (OCH3), 56.2 (OCH3), 61.3 (CH), 107.6 (CH), 110.4 (CH),
116.5 (CH), 124.1 (CH), 124.5 (CH), 125.1 (C), 127.3 (C), 127.8 (CH), 129.8 (C),
141.9 (C), 148.2 (C), 148.8 (C), 167.0 (CO) ppm; EI-MS: m/z 295 (M+, 100), 278
(15.8), 266 (15.8), 253 (12.7). Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74.
Found: C, 72.93; H, 5.93; N, 4.67.
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information
section at the end of this article.
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10
FIGURE LEGENDS
Figure 1. Synthetic approaches to indolo[2,1-a]isoquinolines.
Figure 2. Reported intramolecular acid-catalyzed cyclizations of N-phenethyl-1,2-
dihydroisoquinolines.
Scheme 1. Intramolecular cyclization of N-phenethylindoles 6 and 10 in boiling
CF3COOH.
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11
This article is protected by copyright. All rights reserved.