Ionic liquids-assisted synthesis of 3,4-dihydroisoquinolines by the Bishler-Napieralski reaction

Article abstract of DOI:10.1016/j.mencom.2012.09.014

The Bishler-Napieralski cyclodehydration of N-acyl-2-arylethylamines into the corresponding 3,4-dihydroisoquinolines with POCl3 as a dehydration reagent proceeds in ionic liquids under milder conditions and in higher yields.

Full text of DOI:10.1016/j.mencom.2012.09.014

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 267–269
Ionic liquids-assisted synthesis of 3,4-dihydroisoquinolines
by the Bishler–Napieralski reaction
Margarita A. Epishina,a Alexander S. Kulikov,a Marina I. Struchkova,a
Nikolai V. Ignat’ev,b Michael Schulteb and Nina N. Makhova*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: mnn@ioc.ac.ru
b Ionic Liquid Research Laboratory, Merck KGaA, 64293 Darmstadt, Germany. E-mail: nikolai.ignatiev@merck.de
DOI: 10.1016/j.mencom.2012.09.014
The Bishler–Napieralski cyclodehydration of N-acyl-2-arylethylamines into the corresponding 3,4-dihydroisoquinolines with POCl3
as a dehydration reagent proceeds in ionic liquids under milder conditions and in higher yields.
Over a few recent years our research1 has been focused on the
use of ionic liquids (ILs) as reaction media and/or catalysts. ILs
are known to have considerable advantages against commercial
organic solvents – they are fire-resistant and recyclable, and have
limited vapor pressure thus allowing efficient recovery of organic
products. We studied a possibility of implementing 1,3-dipolar
cycloaddition reactions in ILs, dealing with syntheses of triazoles,2
tetrazoles3 and fused systems,4,5 Henry and Mannich reactions,6
synthesis of aminothiadiazoles,7 Schmidt rearrangement,8 etc.
These reactions in ILs required milder conditions and provided
higher yields. If acidic catalysis was necessary (e.g., in case of
Henry and Mannich reactions) so-called acidic ILs (1,3-dialkyl-
imidazolium hydrogen sulfate or triflate) played a part both of a
catalyst and reaction medium.
This paper discusses the Bishler–Napieralski reaction – cyclo-
dehydration of N-acyl-2-arylethylamines 1 to 3,4-dihydroiso-
quinolines 2 in ILs in the presence of POCl3 as a dehydration
reagent (Scheme 1). The isoquinoline ring is a common structural
motif found in a variety of natural products and biologically active
compounds.9,10 1,2,3,4-Tetrahydroisoquinoline derivatives are
constituents of D1-dopamine antagonists11 and have a potential
for the treatment of Parkinson’s disease.12
the cyclization. Non-substituted amides 1 and especially those
containing electron-withdrawing groups in the aromatic ring
undergo the Bishler–Napieralski cyclization under very drastic
conditions providing low yields of the products. In the previous
years various modifications of the Bishler–Napieralski reaction have
been proposed, e.g., use of (CO)2Cl2/FeCl315 and Tf2O/2-ClPy16
as dehydration systems. 1-Butyl-3-methylimidazolium hexafluoro-
phosphate IL [bmim][PF6] was tested as a reaction medium for
for this purpose, too.17 In this paper the cyclization of non-sub-
stituted N-acetyl-2-phenylethylamine 1c and N-acetyl-2-arylethyl-
amines 1a,b containing one or two MeO groups under the action
of POCl3 as a dehydration reagent (the molar ratio 1a–c:POCl3
of 1:9) at 95–100°C within 1 h was studied. The corresponding
3,4-dihydroisoquinolines 2a,b were obtained in 74–80% yields.
N-Acetyl-2-phenylethylamine 1c did not react under these con-
ditions.
Since the Bishler–Napieralski reaction is carried out in the
presence of dehydration reagents having acidic nature one can expect
that acidic ILs used either as a reaction medium or as a catalyst
would be effective for cyclization of deactivated of N-acyl-2-aryl-
ethylamines 1. In the current study we have synthesized various
N-acyl-2-arylethylamines 1a–h and tested them in the Bishler–
Napieralski reaction in the presence of POCl3 in different ILs,
namely, in 1-butyl-3-methylimidazolium hydrogen sulfate ([bmim]-
[HSO4]), 1-ethyl-3-methylimidazolium and 1-butyl-3-methylpyr-
rolidinium triflates ([emim][CF3SO3], [bmpyrr][CF3SO3]) and
for comparison with published data17 in [bmim][PF6] (Scheme 1).†
The reaction time was monitored by TLC until the full con-
sumption of the starting amides 1. First, we applied the described
procedure17 to substrates using [bmim][PF6] as a medium and
found that for cyclization of amides 1a,b molar ratio POCl3:amide
can be reduced to 2.5:1 (Table 1, entries 1,4). Amides 1c,d did
not yield corresponding 3,4-dihydroisoquinolines 2c,d under these
conditions.
The synthesis of 3,4-dihydroisoquinolines 2 by the Bishler–
Napieralski reaction is usually carried out by refluxing of N-acyl-
2-arylethylamines 1 in high-boiling solvents (xylene, toluene,
chlorobenzene) in the presence of dehydration reagents such as
P2O5,11 POCl3 or POCl3 + P2O5,10,13 PPA + POCl3.14 Typically
a significant molar excess of dehydration reagent is required,
electron-donating groups (e.g., MeO) in aromatic rings facilitating
R2
R1
R2
R1
POCl3
ILs
HN
O
N
R3
2a–c,e–h
R3
1a–h
†
All starting (1a–h) and final (2a–c,e–h) compounds were previously
a R1 = R2 = MeO, R3 = Me
b R1 = MeO, R2 = H, R3 = Me
c R1 = R2 = H, R3 = Me
reported. Their structures were confirmed by comparison of mp or bp and
1
spectral characteristics (IR, MS, H and 13C NMR) with literature data.
If the 1H and 13C NMR spectra of the prepared 3,4-dihydroisoquinolines
2 had not been published these data were determined in this work (see
below). The IR spectra were measured on an UR-20 spectrometer. The 1H
and 13C NMR spectra were recorded on a Bruker AM-300 spectrometer
(300 MHz for 1H and 75.5 MHz for 13C). The MS spectra were measured
on a Finnigan MAT INCOS-50 instrument. Melting points were deter-
mined on a Gallenkamp instrument (Sanyo). TLC was carried out on
Silufol plates (UV254).
d R1 = Cl, R2 = H, R3 = Me
e R1 = R2 = MeO, R3 = Ph
f
R1 = MeO, R2 = H, R3 = Ph
g R1 = R2 = H, R3 = Ph
h R1 = Cl, R2 = H, R3 = Ph
Scheme 1
© 2012 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2012, 22, 267–269
Table 1 Synthesis of 3,4-dihydroisoquinolines 2a–c,e–h by the Bishler–
None of the amides 1a–h reacted properly in [bmim][HSO4]
as the IL. Luckily, triflate ILs such as [emim][CF3SO3] and
[bmpyrr][CF3SO3] proved to be efficient reaction media for the
preparation of 3,4-dihydroisoquinoline 2c (2.5 molar excess of
POCl3, entries 7,8). These ILs were also good to prepare 3,4-di-
hydroisoquinolines 2a,b (entries 2,3,5,6). Amide 1d did not
produce 3,4-dihydroisoquinoline 2d in any tested ILs even by
heating at 95–100°C for 40 h. Raising the temperature to 130°C
resulted in the splitting of the amide bond.
Napieralski reaction of N-acyl-2-arylethylamines 1a–c,e–h (1 mmol) with
POCl3 in ILs at 95–100°C.
Initial POCl3/
amide mmol
Yield
of 2 (%) POCl3 (%)
Yield with
Entry
IL
t/h
1
1*
2
1a
1a
1a
1a
2.5
2.5
2.5
2.5
[bmim][PF6]
1
1
3
3
2a (85)
2a (84)
2a (90)
2a (88)
[bmim][PF6] (regen.)
[emim][CF3SO3]
[bmpyrr][CF3SO3]
74–8023,24,b
3
Similar results were obtained for the Bishler–Napieralski reac-
tion of N-benzoyl-2-arylethylamines 1e–h. Amides 1e and 1f
with MeO activating groups were converted into 3,4-dihydro-
isoquinolines 2e and 2f in [bmim][PF6] in high yields. However,
POCl3:amide molar ratio of 9:1 (Table 1, entries 9,11) and a longer
reaction time for 1f were required. Close results were obtained in
case of [emim][CF3SO3] (entries 10, 12). Conversion of 1f to 2f
proceeds faster in triflate ILs than in [bmim][PF6]. Triflate ILs,
[emim][CF3SO3] and [bmpyrr][CF3SO3], also favoured prepara-
tion of 3,4-dihydroisoquinolines 2g from amide 1g (reaction time
1–2.5 h, entries 13,14). The cyclization of N-benzoyl-2-(4-chloro-
phenyl)ethylamine 1h in triflate ILs was never complete even
within 44 h. However, raising the temperature to 130°C and
POCl3:amide molar ratio to 9:1 in [bmim][PF6] afforded the target
2h in 65% yield (entry 15). The IL [bmim][PF6] was regenerated
and reused in the same reactions without a remarkable drop in the
yield of the product (see entries 1*, 15*).
4
5
6
1b
1b
1b
2.5
2.5
2.5
[bmim][PF6]
[emim][CF3SO3]
[bmpyrr][CF3SO3]
5
6
2b (86)
2b (90) 3612,c
18 2b (82)
7
8
1c
1c
2.5
2.5
[emim][CF3SO3]
[bmpyrr][CF3SO3]
1
1
2c (93)
2c (94)
3512,c, 7525,d
>9027,e
6528,f
9
10
1e
1e
9.0
9.0
[bmim][PF6]
[emim][CF3SO3]
1
2e (83)
12 2e (85)
11
12
1f
1f
9.0
9.0
[bmim][PF6]
[emim][CF3SO3]
18 2f (80)
8
2f (78)
13
14
1g
1g
9.0
9.0
[emim][CF3SO3]
[bmpyrr][CF3SO3]
2.5 2g (75)
1
10a 2h (65)
9028,f
2g (81)
15
15* 1h
1h
9.0
9.0
[bmim][PF6]
[bmim][PF6] (regen.) 10a 2h (63)
5429,g
a Temperature 130°C. b POCl3, refluxing in toluene for 3 h. c POCl3 + P2O5,
refluxing in toluene for 3 h. d POCl3 + P2O5 in toluene, microwave irradiation
for 6 min. ePOCl3, refluxing in MeCN for 2 h. f POCl3 + P2O5, refluxing in
xylene for 4 h. g POCl3 + P2O5, refluxing in xylene for 6 h.
The anion of IL has a significant effect on its catalytic
activity.18,19 However, such studies were carried out only for an
optimization of scarce reactions. Both reported data20,21 and our
previous results4 confirm that ILs are substrate-specific solvents.
The general principles for selection of ILs for different reactions
are absent. Nevertheless, a high acidic-catalytic activity of triflate
ILs was indicated earlier. A series of pyridinium ILs with dif-
ferent anions was investigated for acid-catalysed transesterifica-
tion of Jatropha oil,22 when triflate IL showed the best catalytic
activity. Evidently, our success in the synthesis of 3,4-dihydro-
isoquinolines 2c,g with non-activated aromatic ring can be
rationalized in view of acid-catalytic activity of triflates used.
According to literature data12,23–28 preparation of 3,4-dihydro-
isoquinolines 2 from the corresponding N-acyl-2-arylethyl-
amines 1 in conventional organic solvent with POCl3 as dehydrat-
ing reagent required higher temperature and application of P2O5
additive, whereas the yields of products were usually lower.
In summary, the results obtained in this work exemplifying
the Bishler–Napieralski synthesis of 3,4-dihydroisoquinolines 2
demonstrate the preparative and environmental advantages of
ILs as reaction media and catalysts as compared to conventional
organic solvents.
General procedure for the preparation of 3,4-dihydroisoquinolines 2
in ILs. A mixture of N-acyl-2-arylethylamine 1 (1 mmol), POCl3 (2.5 or
9 mmol) and 2 g of the corresponding IL (Table 1) was heated with a
backflow condenser and protection from moisture at 95–100°C at stirring
until the full consumption of 1 (TLC control). Then the reaction mixture
was cooled to 20°C, diluted with water (3 ml) and NaOH aqueous solu-
tion was added dropwise to pH 10. The liberated 3,4-dihydroisoquinoline
was extracted with diethyl ether (5×3 ml), the ether solution was washed
with water (2×3 ml), dried with MgSO4 and the solvent was evaporated.
The residue was purified by flash chromatography through a short column
with SiO2 or by crystallization.
General procedure for the preparation of 3,4-dihydroisoquinolines 2
with [bmim][PF6] regeneration. To regenerate IL [bmim][PF6] after the
reaction completion, a POCl3 excess was pumped off, 3 ml water was
added, an IL layer was separated, washed with 2 ml water, dried in a vacuum
dessicator over P2O5 and reused in a similar reaction. NaOH aqueous
solution was added to the combined aqueous fraction to achieve pH 10 and
corresponding 3,4-dihydroisoquinoline was isolated as described above.
6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline 2a: mp 100–102°C
(lit.,29 mp 101–103°C).
This work was supported by Merck KGaA and the Russian
Academy of Sciences.
7-Methoxy-1-methyl-3,4-dihydroisoquinoline 2b: yellow oil. IR (n/cm–1):
997, 2938, 2837, 1630, 1609, 1573, 1513, 1496, 1462, 1431, 1372, 1312,
1295, 1245, 1218, 1180, 1082, 1063, 873, 821, 751, 699, 635. 1H NMR
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Received: 29th March 2012; Com. 12/3902
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