Synthesis of substituted imidazolines via [3+2]-cycloaddition of aziridines with nitriles

Article abstract of DOI:10.1016/j.tetlet.2003.12.015

An efficient synthesis of 2,4-disubstituted 1H-imidazolines from aziridines and nitriles in the presence of BF₃-Et₂O or triethyloxonium tetrafluoroborate has been described. The reaction proceeds via a [3+2]-cycloaddition reaction. Most of the nitriles successfully underwent cycloaddition reactions with aziridines even at room temperature in a very short time.

Full text of DOI:10.1016/j.tetlet.2003.12.015

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1137–1141
Synthesis of substituted imidazolines via [3+2]-cycloaddition of
aziridines with nitriles
B. A. Bhanu Prasad, Ghanshyam Pandey and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 10 September 2003; revised 22 November 2003; accepted 5 December 2003
3 2
Abstract—An efficient synthesis of 2,4-disubstituted 1H-imidazolines from aziridines and nitriles in the presence of BF –Et O or
triethyloxonium tetrafluoroborate has been described. The reaction proceeds via a [3+2]-cycloaddition reaction. Most of the nitriles
successfully underwent cycloaddition reactions with aziridines even at room temperature in a very short time.
Ó 2003 Elsevier Ltd. All rights reserved.
The synthesis of low molecular weight heterocyclic
compounds with potential pharmacological properties
has attracted considerable attention due to the need to
identify active compounds by high-throughput screening
of large combinatorial libraries. As a part of our pro-
gram to develop small molecule libraries containing
anti-inflammatory activity, we developed an efficient
one-step synthesis of substituted imidazolines through
the [3+2]-cycloaddition of aziridines with nitriles.
have also been found to exhibit anti-inflammatory, anti-
nociceptive, immunomodulating, anti-oxodant, anti-
11
tumor, and anti-cancer activity. We have studied the
synthesis of substituted imidazolines in the presence of
Lewis acids via [3+2]-cycloaddition reactions of azir-
idines with nitriles. Among the Lewis acids investigated,
BF –Et O and triethyloxonium tetrafluoroborate were
3
2
found to be the most efficient affording the substituted
imidazolines in good yields (Scheme 1).
[
3+2]-Cycloaddition of aziridines with dipolarophiles is
a useful method for the synthesis of nitrogen-containing
In the literature, most nitriles are known to be poor
dipolarophiles for intermolecular [3+2]-cycloaddition
1
–8
12
five-membered cyclic moieties. Alkenes and alkynes
have been used as dipolarophiles for the [3+2]-cyclo-
addition of aziridines. Surprisingly, the utilization of
nitriles as dipolarophiles for [3+2]-cycloaddition with
aziridines has not resulted in an efficient entry to imi-
dazolines, which are known to exhibit a wide range of
pharmacological activities. Imidazoline derivatives such
as midaglizole, deriglidole and efaroxan are highly
reactions. However, we observed that in the presence
of 1 equiv of BF –Et O or Et OBF , most of the nitriles
3
2
3
4
2–8
successfully underwent [3+2]-cyclization with aziridines
even at ambient temperature in less than 5 min. When
10 mol % of the Lewis acid was used, the reactions were
incomplete even after two days. Although the reaction
was complete with the use of 20–50 mol % of the cata-
lyst, the yields were poor. Thus, it became necessary to
use stoichiometric amounts of BF –Et O or Et OBF to
9
10
active anti-hyperglycemic agents. Some derivatives
3
2
3
4
R
N
NTs
BF3-Et2O
CH2Cl2, rt, 5 min
46-76%
NTs
or
+
R-CN
+
Et3OBF4
(± ±-1
Scheme 1. [3+2]-Cycloaddition of 1-tosyl-2-phenylaziridine with nitriles in the presence of BF
3
–Et
2
O or Et
3
4
OBF .
Keywords: Aziridine; BF
3
2
–Et O; Triethyloxonium tetrafluoroborate; [3+2]-Cycloaddition; Imidazolines.
*
Corresponding author. Tel.: +91-512-2597291; fax: +91-512-2597436; e-mail: vinodks@iitk.ac.in
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.015

1138
B. A. B. Prasad et al. / Tetrahedron Letters 45 (2004) 1137–1141
Ph
C
N
NTs
N
BF3-Et2O
NTs
Ph
NTs
± ±-3
CH2Cl2
BF3.Et2O
R-(−±-1
(
2
Scheme 2. Proposed mechanism for the [3+2]-cycloaddition of N-tosyl-(2R)-phenylaziridine with benzonitrile.
H
N
CH3
F
Et3OBF4
NTs
+
CH CN
O
+
3
CH2Cl2, RT
n
n
n
NHTs
NHTs
4
5
n = 1
n = 2
4a
5a
32%
33%
4b
5b
30%
30%
Scheme 3. Formation of the hydrolyzed a-acetamido b-sulphonamide products in the presence of Et
3
4
OBF .
3 2 3 4
Table 1. [3+2]-Cycloaddition of 1-tosyl-2-phenylaziridine (±)-1 with a variety of nitriles (R–CN) in the presence of BF –Et O or Et OBF
Entry
R–CN
Product
Yield (%)
3 4
Et OBF
BF
3
–Et
2
O
N
Ph
Ph
1
2
CH
3
CN
CN
CN
75
74
72
NTs
N
72
NTs
N
Ph
Ph
3
4
5
76
67
63
74
65
59
NTs
N
Ph
PhCN
NTs
N
Ph
Ph
Ph
Ph
CN
NTs
N
CN
6
7
8
9
65
49
55
60
65
50
49
56
NTs
N
CN
Ph
Ph
NTs
N
CN
NTs
MeO
N
OMe
Ph
Ph
CN
NTs
N
CN
1
0
51
50
NTs
F
F

B. A. B. Prasad et al. / Tetrahedron Letters 45 (2004) 1137–1141
1139
Table 1 (continued)
Entry
R–CN
Product
Yield (%)
3 4
Et OBF
BF
3
–Et
2
O
N
Ph
CN
CF3
11
49
47
NTs
F3C
F3C
N
CF3
Ph
Ph
CN
1
1
2
3
46
53
48
49
NTs
N
O
O
O
O
CN
NTs
N
Ph
CN
1
4
48
47
NTs
Cl
Cl
Cl
Cl
Cl
N
Ph
Ph
Cl
Br
1
1
5
6
CN
48
47
49
46
NTs
N
Br
CN
NTs
a
Table 2. [3+2]-Cycloaddition of nitriles with a variety of aziridines
Entry
Aziridine
Product
Yield (%)
R ¼ Me
R ¼ Ph
NTs
NTs
Cl
1
N
52
59
R
R
Cl
Br
NTs
Br
N
2
3
54
52
60
55
NTs
Br
NTs
N
R
Br
NTs
NTs
Me
N
R
4
5
5
1
54
56
NTs
Me
NTs
H
N
H
R
54
NTs
a
3 2
For all the reactions 1 equiv of BF –Et O was used, all reactions were complete in less than 5 min.
achieve good yields. It is proposed that the reaction
involves a highly stabilized zwitterionic intermediate
derived from the aziridine that undergoes cyclization
with nitriles leading to the formation of an imidazoline.
In order to substantiate this, a chiral aziridine R-())-1
was prepared, which on reaction with benzonitrile
13

1140
B. A. B. Prasad et al. / Tetrahedron Letters 45 (2004) 1137–1141
oxazolidin-2-ones without undergoing any [3+2]-cyclo-
addition reaction with nitriles.
16
In conclusion, we have demonstrated an efficient one-
step synthesis of substituted imidazolines in the presence
of a Lewis acid via facile [3+2]-cycloaddition reactions
of aziridines with nitriles in less than 5 min. We have
also shown that most of the nitriles are good dipolaro-
philes undergoing [3+2]-cycloaddition with aziridines
even under routine conditions. These imidazolines will
find scope in the synthesis of various N-substituted
compounds after the cleavage of sulphonamide and
18;19
alkylation.
General procedure: A solution of N-tosyl aziridine
1 mmol) in anhydrous dichloromethane (3 mL) and
nitrile (1 mmol) was treated with freshly distilled
BF ÆEt O (1 mmol) or Et OBF (1 mmol, 1 M in DCM).
After 5 min, saturated aqueous NaHCO3 solution
2 mL) was added. The organic layer was separated and
(
3
2
3
4
Figure 1. X-ray structure of tricyclic imidazoline (Table 2, entry 5,
R ¼ Ph).
17
(
the aqueous layer was extracted with dichloromethane.
The combined organic layers were washed with water,
brine, dried over anhydrous Na SO , then concentrated
to give the crude product, which was purified over silica
gel (30% EtOAc in petroleum ether) to give the substi-
tuted imidazoline.
gave a racemic product 3 due to the formation of the
benzyl carbocation 2. This proved the participation of a
zwitter ion as proposed in Scheme 2. Because of the
stability of the benzyl carbocation, the cyclization is
highly regioselective.
2
4
3 2
Both the Lewis acids BF –Et O and triethyloxonium
tetrafluoroborate show similar reactivity in the [3+2]-
cycloaddition reactions of aziridines with nitriles. In the
Acknowledgements
3 4
presence of Et OBF , cyclopentene and cyclohexene
V.K.S. thanks the Department of Science and Tech-
nology, New Delhi for the research grant and B.A.B.P.
thanks CSIR, New Delhi for a Senior Research Fel-
lowship. We also thank V. Krishnan for solving the
crystal structure.
aziridines underwent the [3+2]-cycloaddition reaction
with acetonitrile but gave the hydrolyzed a-acetamido
b-sulphonamide products after workup along with the
fluorine-opened products (Scheme 3). BF
complex mixture for the same reaction. However, in the
presence of BF –Et O and Et OBF , aryl substituted
3 2
–Et O gave a
3
2
3
4
N-tosyl aziridines underwent the [3+2]-cycloaddition
reaction with nitriles efficiently and gave imidazolines in
References and notes
14
moderate to good yields (Table 1). High yields were
obtained with aliphatic nitriles (Table 1, entries 1–3)
whereas aryl nitriles gave only moderate yields of imi-
dazolines. Ortho-substituted aryl nitriles were found to
be more reactive than the meta-substituted nitriles
1
2
3
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(
(
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such as TMSCN, benzoyl cyanides, and hydroxy cya-
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4
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aziridines with acetonitrile and benzonitrile (Table 2). In
case of the aziridine derived from 1,2-dihydronaphthal-
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5
6
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8
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15
crystal study (Fig. 1). The imidazolines derived from
acetonitrile slowly hydrolyzed to the corresponding
a-acetamido b-sulphonamide on standing. In the pres-
9
. Only a few reports are known where harsh conditions and
higher amounts of nitrile were used and the examples are
limited to only acetonitrile and benzonitrile. (a) Hiyama,
3 2
ence of BF –Et O, N-Boc aziridines gave rearranged

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1141
T.; Koide, H.; Fujita, S.; Nozaki, H. Tetrahedron 1973, 29,
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3
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2.04 (m, 1H); C NMR (CDCl , 100 MHz) d 158.4, 144.5,
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1
þ
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1
1
1
9
455.
4. All the compounds were fully characterized by H,
1
13
C
NMR and mass spectrometry, and elemental analysis.
1
5. H NMR (CDCl
7
3
, 400 MHz) d 7.75 (d, J ¼ 8:3 Hz, 2H),
.55 (d, J ¼ 8:3 Hz, 2H), 7.45 (m, 2H), 7.38 (m, 2H), 7.29