A new and efficient procedure for Bi(OTf)3-promoted [3+2] cycloaddition of N-tosylaziridines to yield imidazolines

Article abstract of DOI:10.1002/ejoc.201100270

[3+2] Cycloaddition of a series of substituted N-tosylaziridines with various nitriles promoted by Bi(OTf)₃ is described for the synthesis of substituted imidazolines under mild reaction conditions. The procedure works well over a range of substrates to give the corresponding products in good to excellent yields (up to 99 %). Copyright

Full text of DOI:10.1002/ejoc.201100270

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100270
A New and Efficient Procedure for Bi(OTf)3-Promoted [3+2] Cycloaddition of
N-Tosylaziridines to Yield Imidazolines
Xing Li,[a] Xueqi Yang,[a] Honghong Chang,*[a] Yanwei Li,[a] Bin Ni,[a] and Wenlong Wei*[a]
Keywords: Heterocycles / Cycloaddition / N-Tosylaziridines / Imidazolines / Bismuth
[3+2] Cycloaddition of a series of substituted N-tosylazirid-
ines with various nitriles promoted by Bi(OTf)3 is described
for the synthesis of substituted imidazolines under mild reac-
tion conditions. The procedure works well over a range of
substrates to give the corresponding products in good to ex-
cellent yields (up to 99%).
Bi(OTf)3 as Lewis acid catalyst, which promotes the [3+2]
cycloaddition reaction of N-tosylaziridines with nitriles to
afford excellent yields (up to 99%) under mild conditions.
Introduction
Imidazolines are useful intermediates for the preparation
of drugs, natural products, and relevant compounds, such
as midaglizole, deriglidole, and efaroxan, which have been
found to exhibit anti-inflammatory, antinociceptive, immu-
nomodulating, antioxidative, antitumor, and anticancer ac-
tivity.[1] Because of their synthetic value and pharmacologi-
cal properties,[2] interest and considerable effort have fo-
cused on the construction of imidazolines and their deriva-
tives. In recent years, some attractive methods for their syn-
thesis have been developed.[3] Among these methods, the
[3+2] cycloaddition of N-tosylaziridines with nitriles, as a
more efficient method, provides direct access to them and
tremendous efforts have been devoted to devising catalytic
versions of this transformation. Several Lewis acids includ-
ing BF3·Et2O,[4,7] Cu(OTf)2,[5] ZnX2 (X = Cl, Br, I),[6]
Results and Discussion
Optimization of the Reaction Conditions
Initially, with N-tosyl-2-phenylaziridine (1a) and acetoni-
trile (2a) as the model reaction, our aim was to identify the
best catalyst for this reaction. Consequently, a series of
Lewis acids were screened under an atmosphere of air at
room temperature. As summarized in Table 1, the signifi-
cant effect of the central metal on the yield was observed.
When Ti(OiPr)4 was tried, the reaction did not take place
(Table 1, entry 1). Other Lewis acids such as ZnCl2, FeCl3,
ZrCl4, Sm(OTf)3, La(OTf)3, In(OTf)3, and BF3·Et2O af-
forded weaker effects (Table 1, entries 2–8). To our delight,
this initial attempt revealed that Bi(OTf)3 possessed the best
activity and afforded the highest yield (38%) (Table 1, entry
9).
Having identified Bi(OTf)3 as a viable activator, an opti-
mization of other reaction conditions was undertaken to
lead to further improvements in the reaction, and the re-
sults are presented in Table 2. Solvent screening revealed
that no products could be obtained with toluene and THF.
CH2Cl2 provided the product in 34% yield (Table 2, entry
3). However, CH3CN showed the best potential, and a 38%
yield was achieved (Table 2, entry 4). The reaction tempera-
ture evidently affected the yield (Table 2, entries 4–8). There
was a tendency for higher temperature to result in higher
yields. The yield of the reaction reached the highest value
(67%) at 65 °C (Table 2, entry 8). Subsequently, the reaction
time was investigated. Interestingly, the product was ob-
tained with 75% yield in 1 h (Table 2, entry 10). Either re-
ducing or prolonging the reaction time failed to increase
the yield (Table 2, entries 8, 9, 11). The amount of CH3CN
had little or no effect on the reaction (Table 2, entries 10,
[8]
Zn(OTf)2,[7] and Sc(OTf)3 have been employed as cata-
lysts and identified for this transformation. Despite these
creative efforts and significant progress, the design of new
catalysts that are cheaper and more efficient and the devel-
opment of new methods that are more effective remain a
considerable challenge and are a long-standing problem.
The use of Lewis acids in organic synthesis, especially in
catalysis, has been one of the most rapidly developing fields
in synthetic organic chemistry. Among these Lewis acids,
bismuth(III) trifluoromethanesulfonate, [Bi(OTf)3], has at-
tracted much attention and has also been used in numerous
reactions[9] in the last decade due to its strong activity and
low cost relative to those of most other known catalysts,
easy removal by filtration, versatility, and water-stability.[10]
Herein, we will describe another new application of
[a] Department of Chemistry and Chemical Engineering, Taiyuan
University of Technology,
79 West Yingze Street, Taiyuan 030024, P. R. China
Fax: +86-351-6111165
E-mail: weiwenlong@tyut.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100270.
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[3+2] Cycloaddition of N-Tosylaziridines to Imidazolines
Table 1. The [3+2] cycloaddition reaction of N-tosyl-2-phenylazir- to obtain better yields (Table 2, entries 17–19). In summary,
idine with acetonitrile promoted by various Lewis acids.[a]
extensive screening showed that the optimized reaction con-
ditions were 0.2 mmol N-tosyl-2-phenylaziridine and
40 mol-% Bi(OTf)3 in 0.5 mL CH3CN in air at room tem-
perature and a reaction time of 4 h (Table 2, entry 19).
Yield [%][b]
Substrate Generality
Entry
Lewis acid
1
2
3
4
5
6
7
8
9
Ti(OiPr)4
ZnCl2
FeCl3
ND[c]
14
11
18
22
7
17
10
38
The [3+2] cyclization reaction was then extended to a
variety of N-tosylaziridines derived from various substi-
tuted styrenes with acetonitrile (2a) (aliphatic nitrile) and
benzonitrile (2b) (aromatic nitrile). The reaction worked
with either acetonitrile or benzonitrile equally well, and the
corresponding products were obtained in good to excellent
yields (Table 3). With regard to acetonitrile, the electronic
properties of the substituents on the aromatic ring of N-
tosylaziridines had an obvious influence on the yield. Azir-
idines bearing electron-withdrawing groups supplied better
results than those with electron-donating groups (Table 3,
entries 2–5 vs. 6–10). It was noteworthy that steric hin-
drance had no evident effect on the yield, and the ortho-,
meta-, and para-substituted aziridines afforded equable
yields (Table 3, entries 3–10). In addition, aromatic azirid-
ines with condensed rings were also found to be suitable
substrates (Table 3, entries 11–12). As for benzonitrile,
equally good results were attained (up to 95% yield). Both
electronic and steric properties of the substituents on the
phenyl rings of the aziridines played an important role on
the yield. Somewhat lower yield was obtained with azirid-
ines possessing electron-donating groups (Table 3, entry 8
vs. 5), and 2- and 4-chlorostyrene-derived aziridines gave
higher yields than 3-chlorostyrene-derived aziridine
(Table 3, entries 3, 5 vs. 4). Because of the effect of steric
hindrance, 4-chlorostyrene-directed aziridine afforded bet-
ter yield than 2-chlorostyrene-directed aziridine (Table 3,
entry 5 vs. 3).
ZrCl4
Sm(OTf)3
La(OTf)3
In(OTf)3
BF3·Et2O
Bi(OTf)3
[a] All reactions were performed with N-tosyl-2-phenylaziridine
(0.2 mmol) and Lewis acid (10 mol-%) in acetonitrile (1.0 mL) at
25 °C for 4 h. [b] Isolated yield. [c] Not detected.
12–13). Considering its operational stability and conve-
nience, CH3CN (0.5 mL) was chosen. On the contrary, the
catalyst loading had an effect on the reactivity of the reac-
tion. With increased catalyst loading, the reactivity was im-
proved gradually and the yield rose steadily (Table 2, entries
13–16). Up to 99% yield was obtained when 30 mol-% Bi-
(OTf)3 was used (Table 2, entry 16). In order to achieve
milder reaction conditions, the reaction temperature was re-
duced and the catalyst loading was accordingly increased
Table 2. Effects of other conditions on the reaction.[a]
Furthermore, we explored the [3+2] cycloaddition of N-
tosyl-2-phenylaziridine with other nitriles for a better un-
derstanding of the generality of this method in the presence
of Bi(OTf)3 under the optimum reaction conditions
(Table 4). With substituted benzonitriles, the electronic
properties of the substituents on the aromatic ring of the
aziridines played an important role on the yield. Accord-
ingly, the electron-richness of the substituent showed a posi-
tive effect on the yield (Table 4, entry 1 vs. 2). Aliphatic
nitriles such as phenylacetonitrile could also afford 77%
yield, which was lower than that with acetonitrile; this
might be attributed to the steric effect (Table 4, entry 3).
Entry Solvent
T
[°C]
t
[h]
Solvent
dosage
[mL]
Catalyst Yield
loading [%][b]
[mol-%]
1
2
toluene
THF
25
25
25
25
0
4
4
4
4
4
4
4
4
0.5
1
2
1
1
1
1
1
1
1
4
1
1
1
1
1
1
1
1
10
10
10
10
10
10
10
10
10
10
10
10
10
5
ND[c]
ND
34
38
32
50
61
67
56
75
68
73
75
53
87
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
45
55
65
65
65
65
65
65
65
65
65
25
25
25
1
1
1
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Mechanistic Considerations
20
30
30
40
40
99
94
According to these experimental results and previous
studies, we assume that Bi(OTf)3 would be the active species
that activated aziridine 1, and a possible catalytic cycle that
would explain the origin of the reactivity is proposed
(Scheme 1). At the first stage, aziridinium salt 8 is formed
through a combination of the N-atom of aziridines and the
98
Ͼ99
[a] Unless otherwise indicated, all the reactions were carried out
with the specified conditions according to the given procedure (see
the Experimental Section). [b] Isolated yield. [c] Not detected.
Eur. J. Org. Chem. 2011, 3122–3125
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X. Li, X. Yang, H. Chang, Y. Li, B. Ni, W. Wei
SHORT COMMUNICATION
Table 3. Substrate scope for the Bi(OTf)3 promoted [3+2] cycload-
dition of N-tosylaziridine 1 with nitrile 2.
Table 4. [3+2] Cycloaddition of N-tosyl-2-phenylaziridine with a
variety of nitriles (RCN) in the presence of Bi(OTf)3.[a]
[a] These reactions were performed with N-tosyl-2-phenylaziridine
(1a) (0.2 mmol) and Bi(OTf)3 (30 mol-%) in nitrile (0.5 mL) at
65 °C in air for 1 h. [b] Isolated yield. [c] In this case, CH2Cl2 served
as the solvent, and 10 equiv. of nitrile was used.
Bi center of Bi(OTf)3, which enhances the electrophilicity
of the C-atom of the aziridines. At the second stage, the
nitrile attacks the substituted C-atom of the nitrogen-con-
taining heterocycle of salt 8 activated to form key interme-
diate 9. At the third stage, the C-atom of the nitrile is at-
tacked by the activated N-atom to generate the product,
which is more stable in view of stereostructure, and Bi-
(OTf)3 is regenerated.
Scheme 1. The proposed catalytic cycle.
Conclusions
[a] Isolated yield. Satisfactory spectroscopic data were obtained for
these compounds (see Supporting Information). [b] These reactions
were performed with aziridine 1 (0.2 mmol) and Bi(OTf)3 (40 mol-
%) in acetonitrile (0.5 mL) at 25 °C under an atmosphere of air for
4 h. [c] These reactions were performed with aziridine 1 (0.2 mmol)
and Bi(OTf)3 (30 mol-%) in benzonitrile (0.5 mL) at 65 °C in air
for 1 h.
We have described Bi(OTf)3 as a novel and efficient cata-
lyst in the [3+2] cycloaddition of aziridines with nitriles and
developed a new and direct strategy for the synthesis of
imidazolines under mild reaction conditions. More import-
antly, good to excellent yields have been obtained for a wide
variety of substrates. The attractive advantages of this pres-
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[3+2] Cycloaddition of N-Tosylaziridines to Imidazolines
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Received: February 26, 2011
Published Online: May 5, 2011
Eur. J. Org. Chem. 2011, 3122–3125
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