The first Bischler-Napieralski cyclization in a room temperature ionic liquid

Article abstract of DOI:10.1016/S0040-4039(02)00998-X

We have demonstrated the use of the room temperature ionic liquid, 1-butyl-3-methylimidazoliumhexafluorophosphate ([bmim]PF₆), as an environmentally benign solvent for the preparation of isoquinoline derivatives through Bischler-Napieralski cyc

Full text of DOI:10.1016/S0040-4039(02)00998-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5089–5091
The first Bischler–Napieralski cyclization in a room temperature
ionic liquid
a,
a
a
b,†
Zaher M. A. Judeh, * Chi Bun Ching, Jie Bu and Adam McCluskey
a
Chemical and Process Engineering Centre, National University of Singapore, 10 Kent Ridge Crescent, Singapore 117576
Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
b
Received 19 March 2002; revised 15 May 2002; accepted 24 May 2002
Abstract—We have demonstrated the use of the room temperature ionic liquid, 1-butyl-3-methylimidazoliumhexafluorophosphate
[bmim]PF ), as an environmentally benign solvent for the preparation of isoquinoline derivatives through Bischler–Napieralski
(
6
cyclization under mild conditions with excellent purity and yields. The role of HF as a catalyst in the reaction was also
investigated. © 2002 Elsevier Science Ltd. All rights reserved.
1
Room-temperature ionic liquids such as [bmim]PF 1
tives using an ionic liquid as a substitute for chlorinated
and high boiling solvents.
6
are finding growing applications as alternative reaction
media for separations and organic transformations.
2
3–11
Recent examples of such organic transformations
The isoquinoline nucleus is widespread in the alkaloid
family and is found in many physiologically active
3
4
include hydrogenations, Friedel–Crafts reactions,
5
6
12
Diels–Alder reactions,
Heck reactions,
olefin
compounds. The most widely used methods for the
synthesis of isoquinolines are relatively classical syn-
7
hydrodimerizations/telomerizations, olefin dimeriza-
tions, cross-couplings, hydroformylations and oxi-
8
9
10
13
thetic methods and include the Bischler–Napieralski,
and the Pictet–Spengler
1
1
dations. The desirable advantages of ionic liquids
such as the lack of vapor pressure, wide liquid range
and thermal stability have made them exceptional reac-
tion media and environmentally benign solvents.
Accordingly, they are emerging as novel replacements
for volatile organic compounds (VOCs) which are used
as solvents in organic synthesis and transformations.
They are especially promising solvents for catalysis
where the activity, selectivity, and stability of catalysts
are enhanced (Fig. 1).
14
reactions. The Bischler–
Napieralski synthesis involves the cyclodehydration of
b-phenylethanamides to 3,4-dihydroisoquinolines using
15
a wide range of dehydrating agents. The reaction
often involves the use of toxic and hazardous chlori-
nated and high boiling point solvents (e.g. 1,2-
dichloroethane, 1,1%,2,2%-tetrachloroethane, chloro-
15d,16
benzene, dioxane)
at elevated temperatures. In our
experience, under these conditions and with the use of
phosphorus oxychloride as a dehydrating reagent, black
gummy products are obtained. The products require
extensive purification by chromatography and several
recrystallizations with decolourising charcoal to bring
them to acceptable purity. These difficulties are there-
fore limiting factors in such an important reaction.
In this communication we report an efficient and envi-
ronmentally friendly preparation of isoquinoline deriva-
-
PF6
N
N
The effectiveness of ionic liquids as solvents for the
Bischler–Napieralski reaction was examined in the
preparation of isoquinoline derivatives. We set out to
examine the reaction in the most widely used ionic
1
Figure 1. [bmim]PF6.
liquid, [bmim]PF 1, using phosphorus oxychloride as a
6
dehydrating reagent and N-(3%,4%-dimethoxyphenethyl)-
acetamide as the starting amide (entry 1, Table 1). The
Keywords: ionic liquids; isoquinolines; Bischler–Napieralski cycliza-
tion.
18
*
Corresponding author. Tel.: +65-8744216; e-mail: cpezj@nus.edu.sg
Ionic liquid sample prepared and supplied by Adam McCluskey.
reaction was carried out by dissolving 0.80 g of
†
the amide in 1.6 mL [bmim]PF followed by dropwise
6
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00998-X

5
090
Z. M. A. Judeh et al. / Tetrahedron Letters 43 (2002) 5089–5091
Table 1. Cyclization of substituted phenethylamides
POCl3
bmim]PF6
R1
R2
R1
[
N
HN
O
R2
1 h, 90-100°C
R3
R3
Entry
R1
R2
R3
Using ionic liquid
Yield (%)
Literature
Yield (%)
1
2
3
4
OMe
OMe
H
OMe
H
H
Me
Me
Me
87
83
0
6115d,17*
6416*
1
3a
0
OMe
OMe
81
5615d*
*
Reaction solvent: ethanol:1,1,2,2-tetrachloroethane (11:3) or ethanol:1,2-dichloroethane (3:11) or chlorobenzene.
addition of phosphorus oxychloride, then heating at
fore can be present as a contaminant in the ionic liquid.
The role of HF as a catalyst in the Bischler–Napieralski
reaction was therefore studied and its effect on the yield
was investigated. Two reactions for the cyclization of
N-(3%,4%-dimethoxyphenethyl)acetamide with POCl3
9
0–100°C for 1 h. The product was recovered by simple
extraction as a white solid and the ionic liquid was
recycled and reused. The purity of the product was
1
confirmed by H NMR spectroscopic analysis as no
starting materials or decomposition products were
observed and therefore no further purification of the
product was needed. The yield (entry 1, Table 1) of the
product was found to be much higher than in the case
where other solvents were used. The black colour asso-
ciated with the ionic liquid after the reaction could be
removed by flash column chromatography using ethyl
acetate as eluent. The process was extended to the
cyclization of other amides (entries 2, 3 and 4, Table 1)
employing similar conditions. The results were again
excellent in terms of yields and product purity for
entries 2 and 4, while only the starting material was
recovered in the case of entry 3. This is not surprising
as the ease of the cyclization is greatly affected by the
electron density (and therefore electron donating
groups meta to the aminoethyl group) at the benzenoid
carbon undergoing cyclization. A double Bischler–
Napieralski reaction also proceeded under these condi-
tions with excellent yields and purity (entry 4, Scheme
(
entry 1, Table 1) using the same batch of ionic liquid
were investigated under similar conditions, except that
in one case, and prior to the reaction, the ionic liquid
was extracted several times with water to ensure it
contained no HF and was then dried under vacuum
over molecular sieves. The reactions were performed
under an inert atmosphere of nitrogen to exclude mois-
ture. Since the two sets of reactions gave similar yields
[
86 and 84% (treated with H O and therefore HF free)],
2
it was concluded that HF plays no catalytic part in the
reaction.
1
9
1
). Therefore, bisoxamide 2 was subjected to cyclization
in [bmim]PF using POCl to give bisimine 3.
6
3
Alternatively, cyclization of bisoxamide 2 to give
bisimine 3 could also be achieved in high yields (83%)
in one pot using [bmim]PF without the necessity of
6
separating bisoxamide 2 (Scheme 1). The cyclization
reactions using [bmim]PF6 are significant from the
viewpoint of pollution avoidance and excellent purity
of the products obtained.
It is a well-known fact that [bmim]PF6 ionic liquid
undergoes slow hydrolysis when it comes into contact
with water or humidity, producing hydrofluoric acid
among other hydrolysis products. HF can also be
Scheme 1. Double Bischler–Napieralski cyclization. Reagents
and conditions: (i) (C H O C) , toluene, 2.5 h, reflux; (ii)
2
5
2
2
POCl , [bmim]PF , 1 h, 90–100°C; (iii) (a) (C H O C) ,
3
6
2
5
2
2
formed during the preparation of [bmim]PF and there-
[bmim]PF , 3 h, 90–100°C, (b) POCl , 1 h, 90–100°C.
6 3
6

Z. M. A. Judeh et al. / Tetrahedron Letters 43 (2002) 5089–5091
5091
In conclusion we have demonstrated that Bischler–
Napieralski cyclization of phenethylamine derivatives
to the corresponding isoquinoline derivatives can be
12. Shamma, M. The Isoquinoline Alkaloids. Chemistry and
Pharmacology; Academic Press: New York, 1972.
13. (a) Whaley, W. M.; Govindachari, T. R. Org. React.
1951, 6, 74; (b) Bischler, A.; Napieralski, B. Chem. Ber.
1893, 1903; (c) Gerhard, B.; Matthias, W.; Ross, K. T.;
Micheal, R. B.; Robert, J. G.; Ronald, K. Tetrahedron
1999, 55, 1731.
achieved effectively using [bmim]PF 1 to give higher
6
yields and cleaner products in a shorter reaction time
than otherwise achieved under the typical conditions
employed for the Bischler–Napieralski cyclization.
14. (a) Whaley, W. M.; Govindachari, T. R. Org. React.
1951, 6, 151; (b) Czerwinski, K. M.; Cook, J. M. Adv.
Heterocycl. Nat. Prod. Synth. 1996, 3, 217.
Acknowledgements
1
5. (a) Sotomayer, N.; Dominguez, E.; Lete, E. J. Org.
Chem. 1996, 61, 4062; (b) Heaney, H.; Shuhaibar, K. F.;
Slawin, A. M. Z. Tetrahedron Lett. 1996, 37, 4275; (c)
Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.;
Hockless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A.
W. J. Chem. Soc., Chem. Commun. 1995, 255; (d)
Siegfried, M.-A.; Hilpert, H.; Rey, M.; Dreiding, A. S.
Helv. Chim. Acta 1980, 63, 938.
We would like to thank the National University of
Singapore (NUS) and the Agency for Science, Technol-
ogy and Research (A*STAR) for financial support. We
also would like to thank Roger Read for helpful
discussions.
1
1
6. Judeh, Z. M. A. Ph.D. Thesis, UNSW, Sydney, 2000.
7. Sp a¨ th, E.; Wiss, A.; Polgar, N. Monatsh. Chem. 1929, 51,
190–204.
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3
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1 1
775 cm . H NMR (300 MHz, CDCl
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(OCH -6, OCH -6%, OCH -7 and OCH -7%), 110.2 (C5
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3
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1
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