1,2,4-Triazines in organic synthesis. 9. Synthesis of 3-(3-ethylindol-2-yl)-5,6,7,8-tetrahydroisoquinoline using the fischer reaction under the usual conditions and with microwave irradiation

Article abstract of DOI:10.1023/A:1017575718196

The nucleophilic substitution of hydrogen in 3-methylthio-1, 2,4-triazine by the carbanions of nitrobutane and 4-nitrobut-1-ene gave oximes, the selective fission of which using sodium dithionite gave ketones in the case of compounds with a saturated carb

Full text of DOI:10.1023/A:1017575718196

Chemistry of Heterocyclic Compounds, Vol. 37, No. 2, 2001
1,2,4-TRIAZINES IN ORGANIC SYNTHESIS.
9*. SYNTHESIS OF 3-(3-ETHYLINDOL-2-YL)-
5,6,7,8-TETRAHYDROISOQUINOLINE USING
THE FISCHER REACTION UNDER THE USUAL
CONDITIONS AND WITH MICROWAVE IRRADIATION*2
T. Lipin'ska
The nucleophilic substitution of hydrogen in 3-methylthio-1,2,4-triazine by the carbanions of
nitrobutane and 4-nitrobut-1-ene gave oximes, the selective fission of which using sodium dithionite
gave ketones in the case of compounds with a saturated carbon chain. Ketones in Diels-Alder reaction
with
1-pyrrolidinocyclohex-1-ene
gave
3-acyl-1-methylthio-5,6,7,8-tetrahydroisoquinolines.
Phenylhydrazones of the compounds obtained underwent Fischer reaction under usual conditions and
also when using microwave irradiation on a solid support. The final 3-(3-ethylindol-2-yl)-5,6,7,8-
tetrahydroisoquinoline was obtained via reductive desulfuration using Raney nickel in ethanol.
Keywords:
3-acyl-1-methylthio-5,6,7,8-tetrahydroisoquinoline,
3-(3-ethylindol-2-yl)-5,6,7,8-
tetrahydroisoquinoline, 1,2,4-triazines, Diels-Alder reaction, Fischer reaction, microwave irradiation.
The zwitterionic pentacyclic alkaloid sempervirine (1) shows antitumor activity [2-4]. It is contained in
trace amounts in the plant material Gelsemium sempervirens. Since 1949 systematic investigations have been
carried out on the complete synthesis of this alkaloid using various strategies for constructing molecule 1 [5].
The synthesis of sempervirine from (3-indol-2-yl)-5,6,7,8-tetrahydroisoquinoline (2a) is elaborated in
studies [6, 7].
R
(+)
_
N
N
N
H
N
_
2a–c
1
2 a R = H, b R = Et, c R = CH=CH2
_______
* For Communication 8 see [1].
*2 Respectfully dedicated to Professor L. I. Belen'kii.
____________________________________________________________________________________________
Podlasie University, Siedlce 08-110, Poland; e-mail: tlip@ap.siedlce.pl. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 2, pp. 256-261, February, 2001. Original article submitted October 5,
1999; revision submitted April 30, 2000.
0009-3122/01/3702-0231$25.00©2001 Plenum Publishing Corporation
231

The multistage methods for the synthesis of synthon 2a and its conversion to sempervirine, are difficult
to realize and occur in low yield and this stimulates a novel investigation in this respect. We have reported [8] a
new method for the synthesis of compound 2a from 3-methylthio-1,2,4-triazine (3). In recent times a
modification of the key step (the Fischer synthesis) has been carried out, the basis of which is the use of
microwave irradiation [9]. In our work starting with the synthesis of some new potential synthons of
sempervirine (substituted analogs of compound 2a having ethyl (2b) or vinyl (2c) group in position 3 of the
indole fragment) the results of our investigations are presented which broaden the use of the methods developed
already. The R = Et and CH=CH2 substituents referred to can then form the missing central unit of the alkaloid 1
molecule.
The reaction scheme involving the original methods of synthesis of compounds 2a, 2b, and 2c is given
in Scheme 1.
Scheme 1
N
R
N
N
N
Na2S2O4
KOH
R
CH2 CH2
NO2
+
N
SMe
DMSO
N
3
SMe
N
4a,b,c
HO
N
N
R
N
1. PhNHNH2
R
N
SMe
2. ZnCl2, 220 oC
N
SMe
O
5a,b
O
6a,b
R
Ni(Ra)
N
SMe
2a
2b
N
H
7a,b
a R = H, b R = Et, c R = CH=CH2
The first step is the nucleophilic substitution of hydrogen in the 5 position of 3-methylthio-1,2,4-triazine
3 by the nitroalkane carbanion and the formation of oximes 4a-c [10]. The process can be considered as a
specific acylation of the 1,2,4-triazine system in those examples where the obtained oximes can selectively
undergo fission to ketones. The indole derivative 2a unsubstituted in the 3 position was obtained using
nitroethane [8].
Compound 2b is formed via the reaction of compound 3 with nitrobutane (R = Et). It was identified [11]
as the reduction product of sempervirine using Raney nickel and also discovered as one of the dehydration
products of yohimbine when using selenium [12].
In order to prepare 3-(3-vinylindol-2-yl)-5,6,7,8-tetrahydroisoquinoline (2c) as a further suitable synthon
in the synthesis of sempervirine, 4-nitrobut-1-ene was used in the first step of the reaction. By comparing the
reactions of 3-methylthio-1,2,4-triazine with three different nitro compounds it can be seen that oximes with a
saturated carbon atom chain 4a and 4b are obtained in good yield (70-75 %). Oxime of the allyl derivative 4c
was prepared in 35-40% yield.
232

a
N
N
H
N
d
b
H
SMe
c
H
N
OH
4c
The transfer from oximes 4a-c to ketones 5a-c was brought about under hydrolysis conditions at room
temperature using an aqueous-dioxane solution of Na2S2O4 [10]. The 1,2,4-triazine system was sensitive to other
methods of oxime fission, especially acidic. Hence use of the conditions that we have developed for the
synthesis provided the desired reaction. Propyl 3-(methylthio)-1,2,4-triazin-5-yl ketone (5b) was obtained in
51% yield [13], which is only a little less than the yield of the methyl-substituted compound 5a (64%) [8].
However, under the same conditions, ketone with the unsaturated carbon chain (5c) was not obtained. Under the
reaction conditions, oxime 4c undergoes complete degradation to low-molecular compounds which were not
identified and further investigations were carried out only with compounds 5a and 5b.
The next step in the synthesis is the Diels-Alder reaction between the heterocyclic azadienes 5a,b and
1-pyrrolidinocyclohex-1-ene [13]. Under the reaction conditions (refluxing in dioxane) the process does not stop
at the stage of formation of the cycloadduct but proceeds further with liberation of nitrogen and pyrrolidine to
give the aromatic derivatives 6a,b. As a result of the reaction the 1,2,4-triazine ring is converted to
5,6,7,8-tetrahydroisoquinoline derivative with retention of the functional groups in the heterocycle. The ease of
formation of the transition complex and then the adduct is well rationalized in terms of the theory of
compensation of the electric field in the molecule [14, 15].
Acylpyridines 6a,b are converted to the corresponding phenylhydrazones and are introduced into the
Fischer reaction with the aim of preparing the indole-substituted tetrahydroisoquinolines 7a [8, 9] and 7b.
Literature data [6] pointing to the need to carry out the Fischer reaction under drastic temperature conditions
were fully confirmed. Under classical conditions, heating a mixture of phenylhydrazone with excess solid
anhydrous zinc chloride at a temperature above 200°C in methylnaphthalene [8] gave compounds 7a,b but the
yield did not exceed 25-35%. The reason for the modest yield is the decomposition of the reagents and reaction
products due to the continuous heating at high temperature.
The subject of our investigation [9] was the modification of the Fischer reaction conditions which lead
to the pyridyl-substituted indole systems. Microwave irradiation of phenylhydrazone, coated on K10
montmorillonite modified by zinc chloride, led to the conversion to the indole derivative during a three minute
exposure to microwaves at 200-220°C. The yield of indoles was 50-65%. A longer irradiation at high
temperature led to lowering of the yield due to decomposition processes and, with a shorter irradiation, the
starting compounds did not fully undergo the reaction.
Compounds 7a and 7b possess a methylthio group which is absent in the natural sempervirine. Fission
and removal of this group was brought about [8] using the system NiCl2 + NaBH4 in aqueous ethanol solution.
In subsequent investigations it was found that it is more convenient to use excess Raney nickel in ethanol at
room temperature. The yield from desulfuration using this method is 60-65%. 3-(Indol-2-yl)-5,6,7,8-
tetrahydroisoquinoline 2a prepared following the developed method was identical to compounds obtained by
other methods [6, 7]. 3-(Ethylindol-2-yl)-5,6,7,8-tetrahydroisoquinoline (2b) has been obtained by us for the
first time using the reported reaction. For this compound, designated tetrahydroisoyobirine, which has been
found previously amongst the products of partial decomposition of sempervirine [11] and yohimbine [12], little
analytical data have been published. The spectroscopic investigation of compound 2b obtained by us fully
confirmed its structure.
233

Scheme 2
N
O
R
N
N
N
SCH3
∆
N
O
R
5a, 5b
N
N
N
SCH3
-N2
-
N
R
N
H
O
SCH3
6a, 6b
Hence the reported method can be regarded as general method for the synthesis of indole derivatives
which are linked to a pyridine system and which have an alkyl chain at position 3.
EXPERIMENTAL
Melting points were measured on a Büchi apparatus and are not corrected. IR spectra were taken on a
Nicolet FTIR 670 instrument and mass spectra – on an AMD-604 spectrometer. 1H NMR spectra were recorded
on a Varian Gemini spectrometer (200 MHz) with TMS as internal standard and CDCl3 as solvent. The Fischer
reaction under microwave irradiation conditions was carried out in a Prolabo Synthewave 402 reactor (300 W)
with computer control of the programming and measurement of the temperature during the reaction (IR
detector). For the column chromatography Kieselgel 40 (0.063-0.200 mm) was used activated by heating in
vacuo at 1.3-2.0 kPa at 150°C for 2 h. Monitoring of the course of the reaction and the column chromatography
was carried out on Kieselgel 60F-254 plates and visualized using UV light. Montmorillonite K10, modified with
zinc chloride, was prepared according to the previously reported method [9]. The starting 3-methylthio-1,2,4-
triazine (3) was obtained from hydrogen iodide, S-methylthiosemicarbazide, and glyoxal according to the
method reported in the literature [16]. The synthesis of compounds 2a, 4a-7a has been described in a more
recent publication [8]. 1-Nitrobutene was a commercial reagent from Aldrich. Compounds 4b-6b were obtained
by the method described by us [13]. 4-Nitrobut-1-ene was prepared from 4-bromobut-1-ene (Aldrich) by the
method reported in [17].
234

Allyl 3-(methylthio)-1,2,4-triazin-5-yl ketoxime (4c). 3-Methylthio-1,2,4-triazine 3 (0.26 g, 2 mmol)
and 4-nitrobut-1-ene (0.41g, 4 mmol) in dry DMSO (1.5 ml) were added to suspension of potassium hydroxide
(0.8 g) in dry DMSO (1 ml). After the reaction had finished (monitored by TLC) the mixture was poured into
ice water (30 ml) and neutralized with acetic acid. The formed yellow precipitate was filtered off, washed with
cold water, dried in air, and then in a vacuum desiccator to give chromatographically pure compound 4c (0.17 g,
1
), δ, ppm,
40%) with mp 118-120°C. H NMR spectrum (CDCl3
J (Hz): 2.69 (3H, s, SCH3); 3.67 (2H, dt, d-H,
Jcd = 6.4, Jad = Jcd = 1.5); 5.09 (1H, dq, b-H, Jbc = 10.1, Jab = Jbd = 1.5); 5.16 (1H, dq, a-H, Jab = Jad = 1.5); 5.91
(1H, ddt, c-H, Jac = 17.3, Jbc = 10.1, Jcd = 1.5); 8.75 (1H, s, OH); 9.44 (1H, s, 6-H). Found: M+ 210.05753.
C8H10N4OS. Calculated: M 210.05896.
3-Butyryl-1-methylthio-5,6,7,8-tetrahydroisoquinoline Phenylhydrazone. Phenylhydrazine (0.37 g,
3.5 mmol) and 5 drops (about 0.06 g) of glacial acetic acid were added to ketone 6b (0.8 g, 3.2 mmol) in
anhydrous ethanol (10 ml). The mixture was heated to reflux for 15 min. After cooling to -5°C the precipitate
was filtered off, washed with cold ethanol, and dried to give a compound (1.05 g, 96%) with mp 125-126°C.
This was used without additional purification for the Fischer indolization process.
3-Ethyl-2-(1-methylthio-5,6,7,8-tetrahydroisoquinolin-3-yl)indole (7b). Fischer Reaction Under
Conventional Conditions. 1-Methylnaphthalene (3 ml) was added to a mixture of the obtained in previous
stage phenylhydrazone (0.34 g, 1 mmol) and freshly calcined zinc chloride (2.7 g, 20 mmol) and then heated in
stream of argon to 200-210°C for 3 h. After cooling the solvent was decanted. The mass remaining was treated
with 10% solution of sodium bicarbonate (10 ml) and toluene (20 ml), heated to reflux with vigorous stirring for
1 h, cooled, the toluene layer separated, and the aqueous layer extracted with toluene (4 × 20 ml). The toluene
extracts were combined, concentrated in vacuo, and purified on chromatography column (300 × 19 mm) using
chloroform-petroleum ether (1: 2) as eluent to give indole 7b (0.1 g, 32%); mp 36°C. IR spectrum: 3460 cm-1
1
), δ, ppm,
(NH). H NMR spectrum (CDCl3
J (Hz): 1.35 (3H, t, J = 7.5, CH2CH3); 1.72-1.97 (4H, m, 6-H, 7-H
isoquinoline); 2.61 (2H, t, J = 6.0, 5-H isoquinoline); 2.86 (3H, s, SCH3); 2.80 (2H, t, J = 5.7, 8-H isoquinoline);
3.10 (2H, q, J = 7.5, CH2CH3); 7.06-7.25 (3H, m, 4-H isoquinoline, 5-H, 6-H indole); 7.35-7.46 (1H, m, 7-H
indole); 7.60-7.69 (1H, m, 4-H indole); 9.16 (1H, s, NH). Mass spectrum, m/z (I, %): 322 (97.7) M+, 307 (100).
Found: M+ 322.15036. C20H22N2S. Calculated: M 322.15125.
3-Ethyl-2-(1-methylthio-5,6,7,8-tetrahydroisoquinolin-3-yl)indole (7b). Fischer Reaction Under
Microwave Irradiation Conditions. Montmorillonite K10 (0.25 g) modified with zinc chloride (0.012 g,
0.09 mmol) prepared as in the report [9] was added to 3-butyryl-1-methylthio-5,6,7,8-tetrahydroisoquinoline
phenylhydrazone (0.23 g, 0.7 mmol) dissolved in anhydrous chloroform (5 ml), vigorously stirred, and
chloroform distilled off in vacuo. The residue was transferred to a flat-bottomed flask (3 ml, Pyrex glass) and
placed in a reactor for microwave irradiation. A 10 minute irradiation was programmed with a maximum
temperature of 210°C, optimizing the temperature control by varying the power of the irradiation set to 100%.
Increase of the temperature to 200°C at 300 W power occurs over 4-5 min and irradiation was continued at this
temperature for 3 min before the process was stopped. The mixture was extracted with ether (5 × 15 ml). The
solvent was distilled off and the residue was purified on a chromatography column under conditions similar to
those in the previous experiment. Compound 7b was obtained (0.14 g, 65%). The spectroscopic data coincided
with those for the compound 7b prepared previously.
3-(3-Ethylindol-2-yl)-5,6,7,8-tetrahydroisoquinoline (2b). Raney nickel (W-2, ~0.75 g) in anhydrous
ethanol was added with stirring to solution of compound 7b (0.1 g, 0.3 mmol) in anhydrous ethanol (10 ml) at
room temperature. After 10 min stirring the reaction mixture was filtered and the solvent distilled off in vacuo to
give 0.05 g (63%) of residue; mp 160-163°C. After crystallization from ethanol the mp was 168-169°C (lit. [11]:
-1
1
), δ, ppm,
165.5-167.5). IR spectrum: 3420 cm (NH). H NMR spectrum (CDCl3
J (Hz): 1.36 (3H, t, J = 7.5,
CH2CH3); 1.72-1.92 (4H, m, 6-H, 7-H isoquinoline); 2.60 (2H, t, J = 6.0, 5-H isoquinoline); 2.75 (2H, t, J = 5.8,
8-H isoquinoline); 3.09 (2H, q, J = 7.5, CH2CH3); 7.02-7.65 (5H, m, 3-H isoquinoline, 4-H, 5-H, 6-H, 7-H
indole); 8.30 (1H, s, 1-H isoquinoline); 9.96 (1H, s, NH). Found, %: C 82.40; H 7.38; N 9.95. C19H20N2.
Calculated, %: C 82.56; H 7.30; N 10.14.
235

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