Microwave-assisted convenient synthesis of N-arylpyrrolidines in water

Article abstract of DOI:10.1016/j.cclet.2010.09.034

An efficient and clean synthesis of N-arylpyrrolidines from arylamines and 1,4-dimesyloxybutane was developed using microwave irradiation in an aqueous potassium carbonate medium without any catalyst. The procedure is rapid, simple and convenient.

Full text of DOI:10.1016/j.cclet.2010.09.034

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 276–279
www.elsevier.com/locate/cclet
Microwave-assisted convenient synthesis of
N-arylpyrrolidines in water
*
Hong Bo Li , Wu Liang, Lang Liu, Kai Chen, Yi Wu
College of Material Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China
Received 9 June 2010
Available online 22 December 2010
Abstract
An efficient and clean synthesis of N-arylpyrrolidines from arylamines and 1,4-dimesyloxybutane was developed using
microwave irradiation in an aqueous potassium carbonate medium without any catalyst. The procedure is rapid, simple and
convenient.
# 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: N-Arylpyrrolidine; Arylamine; 1,4-Dimesyloxybutane; Microwave
Pyrrolidines are common structural subunits present in natural and unnatural products [1]. Depending upon the
substituents, pyrrolidines have been reported to possess a variety of important biological activities [2], including
antibacterial, neuromodulatory, glycosidase inhibitory, and fungicidal activities. Among these, N-arylpyrrolidines, an
important class of compounds, are prepared via alkylation of arylamines with glycol disulfonate in organic solvent for
long times [3], using complicated multistep reactions [4], under harsh reaction conditions [5], or via coupling reactions
using expensive metal [6] or active mesoporous Al2O3 as catalyst [7]. All the methods were efficient and successful but
they all needed catalysts, long reaction times or high reaction temperature. Recently a one-pot synthesis of N-
arylpyrrolidines from arylamines and 1,4-dihalogenobutane (1,4-ditosyloxybutane) was explored via microwave-
assisted organic synthesis (MAOS) in a mildly basic aqueous medium [8]. But in this procedure, the reaction occurred
under high pressure (456 kPa) and the products were purified by column chromatography. To make the direct N-
cyclocondensation of arylamines fully green, rapid and efficient under mild conditions, we studied the possibility of
carrying out the reaction with 1,4-dimesyloxybutane not only taking advantage of the MAOS technique in water and
avoiding the use of any catalyst, but moreover reacting at atmospheric pressure and purifying the product with simple
operation (Scheme 1).
Firstly the reaction between aniline and 1,4-dimesyloxybutane under MW heating conditions was carried out in
water at various ratios of reactants, microwave power and time (Table 1, entries 1–7), using a microwave reactor. To
avoid the hydrolysis of dimesylate effectively in an aqueous alkaline medium, K2CO3 was the most appropriate base to
achieve this N-cyclocondesation at 100 8C. Under the MW power of 100 W, the dimesylate was initially added in a
1.0:1.1 ratio of aniline/dimesylate (Table 1, entries 1–3), although the best yield of N-phenylpyrrolidine (60.2%) was
* Corresponding author.
E-mail address: li-honggg@163.com (H.B. Li).
1001-8417/$ – see front matter # 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2010.09.034

[()TD$FIG]
H.B. Li et al. / Chinese Chemical Letters 22 (2011) 276–279
277
MW
OMs
N
NH2
MsO
+
Ar
Ar
K2CO3/H2O, 1atm
Scheme 1. Microwave-assisted synthesis of N-arylpyrrolidines.
obtained in 80 min, a similar yield (57.4%) of reaction could also be obtained in 60 min, so the reaction time of 60 min
was enough in this condition. Different molar ratios of aniline/dimesylate were also tested under the same power of
100 W in 60 min (Table 1, entries 2, 4, and 7), finding that increase of dimesylate amount enhanced the yield of the
product up to 73.6% (Table 1, entry 7). Thereactionof aniline anddimesylate in 1.0:1.3 for60 minwas accelerated by the
improvementof the MWpower(Table 1, entries 4–6), the reactionunder200 W couldaffordgood product yield(78.6%),
even 300 W irradiation at the same reaction time did not result obvious improvement of the yield (Table 1, entry 6).
Very recently, N-arylpyrrolidines have been achieved from arylamines and alkyl dibromide (ditosylate) using
microwave irradiation in an aqueous potassium carbonate medium under a pressure of 456 kPa [8]. Thus, the reaction was
attemptedwith 1,4-dibromobutane or1,4-ditosyloxybutaneunder thesame optimizedconditions(Table 1, entries8 and 9).
With ditosylate the cyclocondensation could occur but the yield is lower than dimesylate. Using dibromide, the reaction
mixture contained unreacted dibromide, which is difficulty to remove with the method of column chromatography or
extraction. So dimesylate was the best choice among these starting materials and exhibited several advantages by not only
improving the reaction yield but also purifying the product with simple extraction method in the process.
On the basis of these results, we examined the N-heterocyclization of 1,4-dimesyloxybutane with a range of
different arylamines under the optimized conditions (arylamine/1,4-dimesyloxybutane/K2CO3 = 1:1.3:1.3, in water
under MW power of 200 W at 100 8C for 60 min). The results are summarized in Table 2.
Although the reaction mixture could be regarded as a multiphase system, as neither reactant was soluble in the
mildly basic aqueous medium, the microwave-assisted reaction proceeded readily without the use of phase-transfer
reagents. A detailed experiment was found that this reaction conditions were sufficiently mild to tolerate some
functional groups in aniline such as carbonyl and ester (Table 2, entries 7 and 8), which are easily transformed in the
reaction under conventional heating in an alkaline reaction medium [9]. This feature rendered the reaction even more
practically useful to construct the N-arylpyrrolidine moiety without tedious functional group protection/deprotection
procedures. Aniline and p-toluidine were easily cyclocondensed in good yields (Table 2, entries 1 and 2). Activated
anilines were well derivatized, as in the case of p-anisidine and piperonylamine (Table 2, entries 3 and 9). Introduction
of a weak electron-withdrawing substituent such as chlorine at the phenyl ring of aniline did not considerably affect the
yield (Table 2, entries 4–6). But if a strong deactivating group was present, as in the case of p-nitroaniline (Table 2,
Table 1
Synthesis of N-phenylpyrrolidine by the reaction of aniline and 1,4-disubstituted butane under various conditions.a
[TD$INLE]
MW
NH2
N
X
.
X
+
K2CO3/H2O,100oC
X = Br, OTs, OMs
Entry
X
Aniline/X(CH2)4X
MW power (W)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OTs
Br
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.3
1.0:1.3
1.0:1.3
1.0:1.5
1.0:1.3
1.0:1.3
100
100
100
100
200
300
100
200
200
40
60
80
60
60
60
60
60
60
48.8
57.4
60.2
68.7
78.6
80.5
73.6
59.8
43.2c
a
Reaction conditions: aniline (20 mmol), X(CH2)4X (22–30 mmol), K2CO3 (same number of equivalents as X(CH2)4X) at 100 8C in water
(40 mL)under MW irradiation.
b
Isolated yield based on aniline from extraction separation.
Determined by 1H NMR analysis.
c

278
H.B. Li et al. / Chinese Chemical Letters 22 (2011) 276–279
Table 2
Microwave-assisted synthesis of N-arylpyrrolidines from 1,4-dimesyloxybutane and different arylamines.a,b
[TD$INLE]
MW
NH2
.
N
OMs
K2CO3/H2O,100oC
Ar
Ar
+
MsO
Entry
Arylamine
Yieldc (%)
78.6
Entry
Arylamine
Yieldc (%)
65.5
NH2
NH2
[TD$INLINE]
O
1
2
3
4
5
7
Me
NH2
75.1
81.3
64.7
70.2
NH2
56.8
76.3
13.7
68.4
[TD$INLINE]
O
Me
8
OMe
NH2
NH2
O
[DT$INLE]
[TD$INLINE]
MeO
O
9
Cl
NH2
NH2
[DT$INLE]
[TD$INLINE]
O2N
10
11
NH2
NH2
Cl
[TD$INLINE]
[DT$INLE]
NH2
[TD$INLINE]
Cl
6
72.4
a
Reaction conditions: arylamine (20 mmol), 1,4-dimesyloxybutane (26 mmol), K2CO3 (26 mmol) in water (40 mL) under MW irradiation
(200 W) at 100 8C for 60 min.
b
Structures identified with 1H NMR spectra.
c
Yield of isolated product from extraction separation.
entry 10), the yield was rapidly reduced. a-Naphthylamine was also converted to the corresponding product with a
good yield (Table 2, entry 11).
In summary, a facile, rapid and green way has been developed for the preparation of N-arylpyrrolidine by use of
microwave irradiation in water at atmospheric pressure. The reaction was carried out in an aqueous potassium
carbonate medium at 100 8C with a slight excess of 1,4-dimesyloxybutane (1.3 equiv.) and without any phase
transfer- or transition-metal catalyst. This synthetic procedure works well with a variety of arylamines and the
products can be simply purified by the extraction processes instead of tedious column chromatography or reduced
pressure distillation.
1. Experimental
A mixture of arylamine (20.0 mmol), 1,4-dimesyloxybutane (26.0 mmol) and potassium carbonate (26.0 mmol) in
water (40 mL) was placed into a three-necked flask in a microwave reactor (XH-MC-1, Beijing Xianghu Science and
Technology Development Co. Ltd.) equipped with a temperature sensor and a reflux condenser, then the mixture was
stirred and irradiated for 60 min (200 W) at 100 8C. After completion of the reaction, the mixture was extracted with
petroleum ether (60–90 8C, 3 Â 20 mL) and washed with dilute hydrochloric acid (pH = 5–6, 2 Â 20 mL) and water
(2 Â 20 mL). The collected organic fractions were dried with anhydrous sodium sulfate, and removal of the solvent in
vacuo to give a purified N-arylpyrrolidine.
Acknowledgments
Financial support by China Sichuan Provincial Department of Science & Technology (No. 2006J13-143) and
Project of SWUST (No. 053115) are gratefully acknowledged.

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279
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