Organic reactions in ionic liquids: A simple and highly regioselective N-substitution of pyrrole

Article abstract of DOI:10.1055/s-2004-829182

In ionic liquids [Bmim][PF₆] or [Bmim][BF₄], pyrrole replaced the halogen atom of an alkyl halide to give the corresponding N-substituted pyrrole in excellent yield. Benzenesulfonyl chloride, p-methylbenzenesulfonyl chloride and benzoyl chloride reacted similarly with pyrroles to afford the N-substituted pyrroles in quantitative yield. Michael addition reaction of pyrrole with electrophilic olefins was completed in a highly regioselective manner to afford the N-alkylpyrroles.

Full text of DOI:10.1055/s-2004-829182

PAPER
1951
Organic Reactions in Ionic Liquids: A Simple and Highly Regioselective
N-Substitution of Pyrrole
H
ighly Regiose
h
lective N-S
u
a
bstitution
o
n
f
Pyrroles in
g
Ionic
L
iquid
-
s
Gao Le,a,b,c Zhen-Chu Chen,*a,b Yi Hu,b Qin-Guo Zhengd
a
Ningbo Institute of Technology, Zhejiang University, Ningbo, 315100, P. R. China
b
Department of Chemistry, Zhejiang University (xi xi campus), Hangzhou, 310028, P. R. China
E-mail: zhenchuc@mail.hz.zj.cn
c
Department of Applied Chemistry, East China Institute of Technology, Fuzhou, 344000, P. R. China
Pharmaceutical Science Reseach Institute, Aston University, Aston Triangle, Birmingham B4 TET, UK
d
Received 25 March 2004; revised 12 May 2004
little or no interference from C-alkylation.5 However,
these methods are limited by harsh reaction conditions,
relatively long reaction time, low yield and use of toxic
solvents or catalysts. Therefore, the development of a
Abstract: In ionic liquids [Bmim][PF6] or [Bmim][BF4], pyrrole
replaced the halogen atom of an alkyl halide to give the correspond-
ing N-substituted pyrrole in excellent yield. Benzenesulfonyl chlo-
ride, p-methylbenzenesulfonyl chloride and benzoyl chloride
reacted similarly with pyrroles to afford the N-substituted pyrroles mild, efficient, and highly regioselective N-substitution of
in quantitative yield. Michael addition reaction of pyrrole with elec-
trophilic olefins was completed in a highly regioselective manner to
afford the N-alkylpyrroles.
pyrrole (1) is still a much sought out process.
It has been demonstrated that the solvent can dramatically
influence the ratio of N to C alkylation of pyrrolyl anion,
Key words: pyrroles, substitution, ionic liquids, alkylation, sulfo-
nylation, acylation
and dipolar aprotic solvents can give rise to predominant
N-substituted pyrrole.4a,6 In recent years, the room tem-
perature ionic liquids are attracting increasing interest as
a ‘green’ recyclable alternative to classical molecular sol-
The development of simple, efficient and highly selective
vents in synthetic organic chemistry.7 They appear to have
synthetic methods for widely used organic compounds
solvent characteristics similar to moderately polar organic
from readily available reagents is one of the major chal-
solvents and have been compared to various alcohols and
lenges in organic synthesis. The synthesis and reaction of
dipolar aprotic solvents.8 For example, [Bmim][PF6] is
pyrroles have been a topic of research interest for over a
more polar than acetonitrile and less polar than metha-
century because a number of their derivatives occur in
nol.8b To date, some of the important reactions have been
nature1 and possess a variety of important biological ac-
carried out and investigated, and it has been demonstrated
tivities.2 N-Substituted pyrroles are usually obtained by
in some cases that the reactions in ionic liquids show high
the reaction of pyrrolyl anion with the appropriate alkylat-
selectivity or rate acceleration compared to conventional
ing agents.3 However, since the pyrroyl anion exhibits
solvents.9
ambident behavior as nucleophile, alkylation can occur at
carbon as well as at nitrogen4 (Scheme 1). Thus, when the
anion from pyrrole (1) is alkylated, 2- and 3-alkylpyrroles
may contaminate the required product N-alkylpyrrole 2.
To date, several new procedures have been developed in
which the N-alkylation of pyrrole can be achieved with
Our recent interest has been in the development of new
synthetic methods using ionic liquids as reaction media
and promoters.10 As part of a program to investigate the
range of organic reactions possible in ionic liquids, we ex-
amined the reactions of pyrrole (1) with some electro-
Scheme 1
SYNTHESIS 2004, No. 12, pp 1951–1954
x
x.
x
x
.
2
0
0
4
Advanced online publication: 30.07.2004
DOI: 10.1055/s-2004-829182; Art ID: F04204SS
© Georg Thieme Verlag Stuttgart · New York

1952
Z.-G. Le et al.
PAPER
philic reagents in ionic liquids (Scheme 2), which would nated over N-alkylated material.4c In order to explore the
provide a highly regioselective synthetic method to N- generality of the method developed for the alkylation of
substituted pyrroles 2.
pyrrole, we conducted experiments in which some of
eletrophilic olefins, such as methyl acrylate, acrylonitrile
and methyl vinyl ketone in ionic liquid [Bmim][PF6] were
employed and efficiently gave the corresponding N-sub-
stituted pyrrole derivatives as the only isomer (Table 1,
entries 9–11). Furthermore, in a similar fashion we tried
the reaction of pyrrole with benzenesulfonyl chloride, p-
methylbenzenesulfonyl chloride and benzoyl chloride;
here also the N-substituted pyrroles were obtained in
quantitative yields (Table 1, entries 12–14). The related
ionic liquid 1-butyl-3-methylimidazolium tetrafluorobo-
rate, [Bmim][BF4], is also effective (Table 1, entries 3, 10,
12).
Scheme 2
First, we found that in the presence of KOH, the reaction
of pyrrole (1) with methyl iodide, could proceed smoothly
at 40 °C in the ionic liquid 1-butyl-3-methylimidazolium
hexafluorophosphate, [Bmim][PF6]. The product is N-
methylpyrrole (2a) as the only isomer by GC-MS analysis
and the yield is 82% (Table 1, entry 1). In a similar fash-
ion, the reactions of pyrrole (1) with a variety of halogen
derivatives were investigated. We found that the reaction
is general and applicable to primary alkyl halides contain-
ing iodide, bromide and chloride (Table 1, entries 1,3,4,6–
8). For secondary bromide, the yield is also good (Table 1,
entry 2). It is noteworthy that tert-butyl bromide can effi-
ciently react (Table 1, entry 5), but in the reported meth-
ods,4a,5b the reaction did not occur. When allyl bromide is
employed as the alkylating agent, N-allylpyrrole (2e) can
be produced in quantitative yield (Table 1, entry 6), and in
the reported procedures,4 a mixture of C- and N-allylpyr-
roles was obtained, even C-alkylated material predomi-
1
All the products gave satisfactory mps, IR and H NMR
data, which were consistent with the literature data.
The ionic liquid can be typically recovered, after extrac-
tion of the product followed by drying under vacuum, and
filtering the suspension to remove residual solid. The re-
covered solvent can be reused with no appreciable de-
crease in yield. The representative results are summarized
in Table 2.
The present method has many obvious advantages, com-
pared to those reported in literature, including high regio-
selectivity,
generality,
higher
yield,
being
environmentally more benign, and potential for recycling
of ionic liquids. In conclusion, we have demonstrated that
the N-substitution of pyrrole can effectively be performed
Table 1 N-Substitution of Pyrrole in Ionic Liquidsa
Entry
1
RX
Reaction Conditions
2 h, 40 °C
2 h, 60 °C
1 h, 80 °C
2 h, 80 °C
2 h, 70 °C
1 h, 70 °C
1 h, 80 °C
1 h, 80 °C
1 h, 80 °C
1 h, 80 °C
1 h, 80 °C
1 h, 80 °C
1 h, 80 °C
1 h, 80 °C
Product
2a
2b
2c
Yield (%)b
82 (80c)
CH3I
2
i-C3H7Br
70 (65c)
3
n-C4H9Br
98 (95c) (95d)
76 (73c)
4
n-C4H9Cl
2c
5
t-C4H9Br
2d
2e
57 (51c)
6
CH2=CHCH2Br
C6H5CH2Br
C6H5CH2Cl
CH2=CHCN
CH2=CHCO2CH3
CH2=CHCOCH3
C6H5SO2Cl
p-CH3C6H5SO2Cl
C6H5COCl
100 (96c)
100 (98c)
99 (98c)
7
2f
8
2f
9
2g
2h
2i
82 (80c)
10
11
12
13
14
78 (72c) (70d)
80 (75c)
2j
100 (99c) (100d)
100 (98c)
100 (98c)
2k
2l
a All reaction were run with pyrrole (2 mmol), RX (4 mmol), KOH (4 mmol) in ionic liquid [Bmim][PF6] (2 mL).
b Determined by GC-MS (internal standard: cyclohexanone) based on pyrrole.
c Isolated yield.
d In ionic liquid [Bmim][BF4].
Synthesis 2004, No. 12, 1951–1954 © Thieme Stuttgart · New York

PAPER
Highly Regioselective N-Substitution of Pyrroles in Ionic Liquids
1953
1H NMR (CDCl3): d = 6.61 (t, J = 2.4 Hz, 2 H), 6.17 (t, J = 2.4 Hz,
2 H), 3.82 (t, J = 6.8 Hz, 2 H), 1.70 (m, 2 H), 1.27 (m, 2 H), 0.91 (t,
J = 7.2 Hz, 3 H).
in the ionic liquids [Bmim][PF6] or [Bmim][BF4] with
high regioselectivity, which provides a simple and effi-
cient method for the synthesis of the N-substituted pyr-
roles 2.
N-tert-Butylpyrrole (2d)
Oil.12
Table 2 Recycling of [Bmim][PF6 ] in N-Butylation of Pyrrolea
IR (film): 3123, 2984, 1530, 1481, 1375, 1267, 1094, 713 cm–1.
Entry
Cycle
N-Butylpyrrole (2c)
1H NMR (CDCl3): d = 6.65 (t, J = 2.4 Hz, 2 H), 6.09 (t, J = 2.4 Hz,
2 H), 1.42 (s, 9 H).
Yield b (%)
1
2
3
1
2
3
98
96
97
N-Allylpyrrole (2e)
Oil.12
IR (film): 3118, 2967, 1498, 1282, 1090, 718 cm–1.
1H NMR (CDCl3): d = 6.56 (t, J = 2.4 Hz, 2 H), 6.12 (t, J = 2.4 Hz,
2 H), 5.64–6.06 (m, 1 H), 4.84–5.30 (m, 2 H), 4.42 (m, 2 H).
a All reaction were run with pyrrole (2 mmol), butyl bromide (4
mmol), KOH (4 mmol) in ionic liquid [Bmim][PF6 ] (2 mL) at 80 °C
for 1.0 h.
N-Benzylpyrrole (2f)
b Determined by GC-MS based on pyrrole.
Oil.12
IR (film): 3118, 3018, 2918, 1656, 1495, 1452, 1208, 1065, 775,
745, 718 cm–1.
Melting points were determined on digital melting point apparatus
and were not corrected. IR spectra were recorded on a Bruker
VECTOR22 spectrometer. NMR spectra were recorded on Bruker
Avance DMX 200 spectrometer. The ionic liquids [bmim][BF4] and
[bmim][PF6] were synthesized according to reported procedures.11
The other materials are commercially available and were used with-
out further purification.
1H NMR (CDCl3): d = 7.25 (m, 3 H), 7.08 (m, 2 H), 6.64 (t, J = 2.6
Hz, 2 H), 6.17 (t, J = 2.6 Hz, 2 H), 4.96 (s, 2 H).
N-(2-Cyanoethyl)pyrrole (2g)
Oil.5c
IR (film): 2950, 2925, 2250, 1500, 1290 cm–1.
1H NMR (CDCl3): d = 6.71 (t, J = 2.2 Hz, 2 H), 6.20 (t, J = 2.2 Hz,
2 H), 4.17 (t, J = 6.8, 2 H), 2.69 (t, J = 6.8, 2 H).
N-Substitution of Pyrrole (1); General Procedure
A mixture of pyrrole (1; 134.2 mg, 2 mmol), an alkyl halide (4
mmol), powdered KOH (224 mg, 4 mmol) and an ionic liquid (2
mL) was stirred for 1–2 h at 40–80 °C (for reaction conditions, see
Table 1). After the reaction was complete, the mixture was extract-
ed with Et2O (3 × 5 mL). The combined Et2O extracts were evapo-
rated under reduced pressure and the resulting crude product was
analyzed by GC-MS (HP-5, 5% phenyl methyl siloxane), or was
separated by preparative TLC (silica gel). After isolation of the
product, the remainder of the ionic liquid was further washed with
Et2O, followed by drying under vacuum, filtering the suspension to
remove residual solid and recycled in subsequent runs (Table 1).
Methyl 3-(1-Pyrrolidyl)propionate (2h)
Oil.5c
IR (film): 2962, 1757, 1451, 1345, 1194, 1089, 724 cm–1.
1H NMR (CDCl3): d = 6.68 (t, J = 2.2 Hz, 2 H), 6.19 (t, J = 2.2 Hz,
2 H), 3.86 (t, J = 7.4 Hz, 2 H), 3.68 (s, 3 H), 2.76 (t, J = 7.4 Hz, 2 H).
(1-Pyrrolidyl)butan-2-one (2i)
Oil.5c
IR (film): 2990, 1730, 1366, 1174, 1088, 723 cm–1.
1H NMR (CDCl3): d = 6.67 (t, J = 2.2 Hz, 2 H), 6.17 (t, J = 2.2 Hz,
2 H), 3.85 (t, J = 7.4 Hz, 2 H) 2.40 (t, J = 7.4 Hz, 2 H), 1.89 (s, 3 H).
N-Methylpyrrole (2a)
Oil.12
IR (film): 2942, 2907, 2810, 1508, 1418, 1386, 1327, 1286, 1088,
1060, 968, 819, 723, 664, 606 cm–1.
1H NMR (CDCl3): d = 6.40 (t, J = 2.4 Hz, 2 H), 6.10 (t, J = 2.4 Hz,
2 H), 3.60 (s, 3 H).
N-Phenylsulfonylpyrrole (2j)
Mp 90 °C (Lit.3d mp 89–89.5 °C).
IR (KBr): 3077, 1576, 1454, 1393, 1059, 730, 622 cm–1.
1H NMR (CDCl3): d = 7.3–8.3 (m).
N-Isopropylpyrrole (2b)
Oil.12
N-(p-Methylbenzenesulfonyl)pyrrole (2k)
Mp 104–105 °C (Lit.3d mp 104.5 °C).
IR (film): 2955, 2811, 1510, 1418, 1386, 1375, 1286, 1088, 1059,
968, 819, 722, 664 cm–1.
1H NMR (CDCl3): d = 6.60 (t, J = 2.4 Hz, 2 H), 6.15 (t, J = 2.4 Hz,
2 H), 3.76 (q, J = 7.2 Hz, 1 H), 1.71 (t, J = 7.2 Hz, 6 H).
IR (KBr): 3076, 2957, 1574, 1454, 1393, 1059, 859 cm–1.
1H NMR (CDCl3): d = 7.3–8.3 (m, 8 H), 2.42 (s, 3 H).
N-Benzoylpyrrole (2l)
Oil.13
N-Butylpyrrole (2c)
Oil.12
IR (KBr): 3074, 1698, 1600, 1455, 724 cm–1.
1H NMR (CDCl3): d = 7.94 (d, J = 6.8 Hz, 2 H), 7.64 (m, 1 H), 7.51
(m, 2 H), 7.12 (t, J = 2.2 Hz, 2 H), 6.20 (t, J = 2.2 Hz, 2 H).
IR (film): 3118, 2967, 1565, 1465, 1498, 1282, 1117, 1090, 718
cm–1.
Synthesis 2004, No. 12, 1951–1954 © Thieme Stuttgart · New York

1954
Z.-G. Le et al.
PAPER
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Synthesis 2004, No. 12, 1951–1954 © Thieme Stuttgart · New York