Highly Stereoselective Synthesis of New Aziridines via Baldwin Rearrangement and Their Potential Biological Activities

Article abstract of DOI:10.1002/jhet.2548

An atom-economical conversion of N-substituted isoxazoline derivatives to new N-substituted aziridines has been described using microwave irradiation through Baldwin rearrangement. N-substituted isoxazoline derivatives have been synthesized using a variet

Full text of DOI:10.1002/jhet.2548

Month 2015
Highly Stereoselective Synthesis of New Aziridines via Baldwin
Rearrangement and Their Potential Biological Activities
*
Bhaskar Chakraborty, Manjit Singh Chhetri, and Esmita Chhetri
Organic Chemistry Laboratory, Sikkim Government College, Gangtok, Sikkim 737102, India
*
E-mail: bhaskargtk@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received June 14, 2015
DOI 10.1002/jhet.2548
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
An atom-economical conversion of N-substituted isoxazoline derivatives to new N-substituted aziridines
has been described using microwave irradiation through Baldwin rearrangement. N-substituted isoxazoline
derivatives have been synthesized using a variety of nitrones and alkynes via 1,3-dipolar cycloaddition reac-
tions in ionic liquid. Simple react\ion methodology, greener approaches, non involvent of catalysts, good to
excellent yields, and cis diastereoselectivities are the important features noticed in this synthesis. Potential
biological activity of the new aziridine derivatives made this protocol more attractive.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
RESULTS AND DISCUSSION
The chemistry of three-membered ring heterocycles, espe-
cially epoxides and aziridines, has attracted the attention of
synthetic chemists for more than a century. This is primarily
because of the essentially high reactivity of these small-ring
heterocycles, which makes them versatile species in organic
synthesis [1–5]. Baldwin et al. have shown that 1,3-dipolar
cycloaddition reactions of nitrones to alkynes lead to 4-
isoxazolines which rearrange easily under thermal condi-
tions to acylaziridines [6–8]. The wealthy literature on cyclo-
addition reactions of nitrones for the synthesis of
isoxazolidine, isoxazoline derivatives, and their further ap-
plications have been widely illustrated [9–11] while conver-
sions of isoxazoline derivatives to aziridines are of
tremendous interest in this chemistry [12–14]. As a part of
our ongoing research program to develop new methodolo-
gies in organic synthesis [15–18], herein, we report
stereoselective synthesis of new N-substituted aziridine de-
rivatives from isoxazolines via Baldwin rearrangement and
their biological activities (Scheme 1; Table 1). The newly re-
ported N-substituted aziridine derivatives are obtained as sin-
gle diastereoisomer when the isoxazoline derivatives are
exposed to microwave irradiation for 5–8min at 90–130°C.
Moreover, potential biological activity of the newly synthe-
sized aziridines has made this protocol more attractive.
To execute proposed study, various isoxazoline derivatives
were synthesized from a variety of nitrones (N-Methyl/
Phenyl/Benzyl nitrones) and alkynes (mainly electron
deficient alkynes were used along with few electron rich
alkynes as well) in ionic liquid by employing reported
protocol [15,19–21]. The electron deficient alkynes used in
this study were propiolic acid, methyl propiolate, and ethyl
propiolate respectively while electron rich alkynes were
trimethylsilylacetylene and tert-butylacetylene (3,3-dimethyl-
1-butyne). Trimethylsilyl or alkyl groups make alkynes
more reactive towards 1,3-DCR. We have also studied the
course of the reported reaction with active disubstituted
acetylenes (diethyl acetylenedicarboxylate, dimethyl
acetylenedicarboxylate etc), but results are not incorporated
because of lack of stereoselectivity. Usually, the reaction con-
ditions are harsh (high temperature or long reaction time), and
the selectivities are poor, and hence we have adopted greener
methodologies in this synthesis and obtained good to excellent
results. Isoxazoline derivatives thus obtained were exposed to
microwave irradiation (maintaining certain time period and
temperature) to obtain a variety of new N-substituted aziridine
derivatives (Scheme 1; Table 1). This is in accordance with
well known Baldwin Rearrangement [6]. Moreover, this
transformation could lead to functionalized N-substituted
© 2015 HeteroCorporation

B. Chakraborty, M. S. Chhetri, and E. Chhetri
Vol 000
Scheme 1. Rearrangement of 2 into cis-3 and trans-3 (aziridine derivatives).
Table 1
Synthesis of aziridines from isoxazoline derivatives.
Entry
1
Nitronea (1)
Isoxazolineb (2)
Aziridine (3)
Time (min) Cis 3/Trans 3c Yieldd(%)
5
97/3
88 (76)
2
5
95/5
85 (71)
3
6
92/8
84 (72)
4
6
85/15
84 (70)
(Continued)
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Month 2015
Stereoselective Synthesis of New Aziridines
Table 1
(Continued)
Entry
5
Nitronea (1)
Isoxazolineb (2)
Aziridine (3)
Time (min) Cis 3/Trans 3c Yieldd(%)
6 90/10 82 (71)
6
7
92/8
82 (69)
7
6
93/7
82 (72)
8
6
92/8
81 (70)
9
7
90/10
80 (64)
10
8
86/14
80 (63)
(Continued)
Journal of Heterocyclic Chemistry
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B. Chakraborty, M. S. Chhetri, and E. Chhetri
Vol 000
Table 1
(Continued)
Entry
Nitronea (1)
Isoxazolineb (2)
Aziridine (3)
Time (min) Cis 3/Trans 3c Yieldd(%)
11
8
92/8
80 (70)
aReaction conditions: Nitrone (1 mmol), alkyne (1 equivalent), [bmim]BF4 (10 mL).
bIsoxazoline (1 mmol), MWI, MeCN, 5–8 min, 90–130°C.
cDetermined by 1H NMR of the crude product.
dIsolated yield after purification. Figure in the parenthesis indicates yield of cis isomer.
aziridines, which are valuable intermediates in organic
synthesis [22–29].
of the coupling constant (J) value (7.9Hz) [30]. The
4.2-Hz J constant value of the minor compound indicates
a trans relationship between the C substituents. The reaction
is slow, and the diastereomeric ratio increases with time.
The polarity of the solvent has a moderate influence on the
conversion (compare entries 1 and 6; Table 2) but has a sig-
nificant effect on the dr. In more polar solvent, higher selec-
tivities are observed (compare entries 1 and 6; Table 2).
High reaction temperatures are generally required to obtain
In this communication, we disclose our results on the ap-
plication of Baldwin rearrangement of isoxazolines (2) con-
sidering the influence of three parameters (solvent,
temperature, time; Tables 2 and 3). The rearrangement gave
predominantly one diastereomer, in 83/17 to >95/5 diaste-
reomeric ratio (dr). The cis relative stereochemistry of the
major compound has been assigned from the comparison
Table 2
Microwave assisted rearrangement of 2 (entry 1, Table 1): solvent study.
Entrya
Solvent
Cis3/Trans3b
Conversionc (%)
Transformationb (%)
1
2
3
4
5
6
7
CH3CN
Toluene
Water
DMF
DMSO
EtOH
97/3
85/15
>97/3
94/6
>97/3
97/3
40
22
90
38
68
39
34
20
63
36
49
30
Neat
Degradation
aReaction conditions: 1 mmole, 5 min.
b,cDetermined by 1H NMR of crude product.
bIsolated yield (degradation product).
Table 3
Microwave assisted rearrangement of 2 (entry 1, Table 1) in CH3CN: time and temperature study.
Entry
Time (min)
T (°C)
Cis3/Trans3a
Conversionb (%)
Transformationc (%)
1
2
3
4
5
6
7
5
5
5
5
5
90
100
110
120
130
90
97/3
95/5
97/3
94/6
97/3
97/3
8
18
40
75
97
16
14
15
61
68
60
73
10
15
110
a,bDetermined by 1H NMR of crude product.
cProduct percentage determined by 1H NMR of crude product.
Journal of Heterocyclic Chemistry
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Month 2015
Stereoselective Synthesis of New Aziridines
good conversions (entry 3, 4, and 5; Table 3), but prolonged
heating time result in a drastic drop of the yield because of
decomposition. These results are not that surprising in light
of previous reported examples where strong donating nitro-
gen substituents appear to favor the rearrangement [6]. A
study of the reaction conditions under microwave irradia-
tion was undertaken as this condition is generally faster,
cleaner, greener, and very often more selective [16,31–33].
The results are summarized in Table 1. We first examined
the effect of solvent on the rearrangement of 2 in the follow-
ing conditions: 0.125M, 5-min reaction, 110°C (Table 2).
We have observed that in thermal reactions, apolar solvents
give lower cis/trans selectivities (see entries 2 and 6;
Table 2).
yield (entry 1, Table 1). At 90°C, a slow conversion is observed
(entry 1, Table 3), whereas from 120 to 130°C, product decom-
position is detrimental to the transformation (entries 4 and 5).
We have obtained expected fragmentation peaks in the
mass spectral studies and are because of the development
of aziridine derivatives. Base peaks were obtained because
of loss of COOCH3 for methyl propiolate and
COOCH2CH3 for ethyl propiolate while COOH for
propiolic acid respectively. For all the cases, the initial
progress of the conversions to aziridine derivatives were
monitored by TLC (Rf values were found to have lower
values than isoxazoline derivatives). Important signals of
R, R1, R2, and R3 groups of the aziridine derivatives were
1
obtained in the H NMR spectrum, while prominent car-
Among the various polar solvents tested, water, and
DMSO allow a good level of conversion (90 and 68%, re-
spectively) but, unfortunately, also induce the formation of
extensive amounts of degradation products (63 and 49%
transformation, respectively, see entries 3 and 5; Table 2).
As compared to the other solvents used, CH3CN finally of-
fers the better compromise in terms of efficiency (selectivity,
conversion, and transformation) and of practical conve-
nience. Indeed, at the end of the reaction, the solvent is re-
moved in vacuo, and the residue is directly loaded on silica
gel for purification, which avoids an aqueous workup. The
reaction conducted in the absence of solvent resulted in the
complete degradation of the starting material. We thus next
evaluated the influence of reaction conditions (time and tem-
perature) using CH3CN as solvent (Table 3).
bonyl absorptions were found in IR spectrum as well.
Biological activity. Significant information is obtained in
the studies on antibacterial activities of the new aziridines
using viable cell count experiments [34]. Selected newly
synthesized aziridine derivatives were employed for the
biological study and were treated as drugs. For example,
aziridine 3 in entries 1–5, Table 1 as drug 1–5 and aziridine
3 in entries 7,8, Table 1 as drug 6,7. Scanning electron
microscopy (SEM) has been performed to study the mode of
action of newly synthesized aziridines as test drugs related to
morphological studies on the newly synthesized aziridines
(3). The new drugs have shown potential biological activities,
and detail studies are in progress using TEM. Altogether 15
bacterial strains of both gram positive and gram negative
varieties were used using method recommended by National
Committee for Clinical Laboratory Standards (NCCLS).
These include, Escherichia coli 25938, Salmonella typhi 62,
Vibrio cholerae 20, Klebsiella pneumoniae 10031, Shigella
dysenteriae 1, Pseudomonas AMRI 100, Salmonella
typhimurium NTCC 74, Staphylococcus aureus 29737,
The reaction is highly sensitive to temperature, as shown in
Table 3, entries 1ꢀ5. For the rearrangement of 2, the best re-
sults are obtained when the reaction is carried out above the
solvent boiling point, at 110°C (entry 3, Table 3). Under this
condition, cis-3 is isolated as a single diastereoisomer in 76%
Table 4
Minimum inhibitory concentration (MIC) of synthetic compounds against different bacteria.
Aziridines (drugs in μg/mL)
Organism
Control
1
2
3
4
5
6
7
Amoxicillin
Escherichia coli 25938
Salmonella typhi 62
Vibrio cholerae 20
Klebsiella pneumoniae 1003
Shigella dysenteriae 1
Pseudomonas AMRI 108
Salmonella typhimurium NTCC 74
Staphylococcus aureus 29737
Bacillus cereus 11778
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
600
600
600
600
800
600
600
600
600
600
600
600
600
600
600
600
400
600
600
600
600
600
600
400
600
400
600
600
600
600
400
+
200
+
400
+
600
400
600
+
600
600
600
600
600
600
400
600
600
600
600
400
+
600
600
600
600
400
600
600
+
+
1000
+
1000
+
+
1000
1000
1000
1000
600
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
600
600
+
+
+
+
+
+
+
25
15
25
25
1
50
25
5
25
50
5
Bacillus subtilis 6633
Streptococcus epidermidis 12228
Micrococcus luteus 10240
Pseudomonas aeruginosa 25619
Bacillus pumilus 14884
+
+
+
+
1
100
50
50
1000
+
Bordetella bronchiseptica 4617
+
“+” represents growth of organism.
Journal of Heterocyclic Chemistry
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B. Chakraborty, M. S. Chhetri, and E. Chhetri
Vol 000
Bacillus cereus 11778, Bacillus subtilis 6633, Streptococcus
epidermidis 12228, Micrococcus luteus 10240,
reduce the bacterial growth, i.e. these drugs have potential
bacteriostatic effect (Table 5). SEM micrographs of few
aziridines (entries 1 and 2, Table 1) have been found to
have potential antimicrobial effects on B. cereus 11778
and M. luteus 10240 respectively. It was clear that both
the aziridine derivatives cleaved the cell surface leading
to lyses of cell components into several fragments and thus
facilitate rapid killing of cells [35,36].
From SEM microscopy it is expected that these drugs
may act as potential antimicrobial agents. Drug 1 (aziridine
3; entry 1, Table 1) kills bacteria by cleaving cell mem-
brane at different junction and leads to cell death. Drug 2
(aziridine 3; entry 2, Table 1) changes the cell permeability
of bacteria. Because of this change fluids are accumulated
within cells and eventually leads to death.
Pseudomonas aeruginosa 25619, Bacillus pumilus 14884,
and Bordetella bronchiseptica 4617 respectively.
Amoxicillin was used as standard drug (Table 4). MIC of
test drugs was determined by agar dilution method. Two sets
of tubes were prepared (control and test), and 2× 106 cfu/mL
of bacterial suspension was added to these tubes. After 24h of
incubation cells were harvested, washed with nutrient broth,
and fixed with 4% glutaraldehyde in phosphate buffer.
Obtained cells were dehydrated in series of alcohol
mounted on slide. The gold coated samples were examined
in JEOL-JSM 6360 Scanning Electron Microscope.
From the experiment it is clear that the tested drugs did
not kill the microorganisms completely but significantly
Effect of drug (Aziridines) on bacterial growth rate
Time dependent in vitro growth curve of B. cereus 11778 at their MIC values against aziridine 3 (entry 1, Table 1).
Time dependent in vitro growth curve of Bacillus polymyxa 4747 at their MIC values against aziridine 3 (entry 2, Table 1).
Journal of Heterocyclic Chemistry
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Month 2015
Stereoselective Synthesis of New Aziridines
Time dependent in vitro growth curve of Klebsiella pneumoniae ATCC 10031 at their MIC values against aziridine 3
(entry 4, Table 1).
SEM micrographs of the application of aziridine (3) as test drugs (entry 1, 2; Table 1)
Before treatment with aziridine 3 (entry 1, Table 1)
After treatment with aziridine 3 (entry 1, Table 1)
Before treatment with aziridine 3 (entry 2, Table 1)
After treatment with aziridine 3 (entry 2, Table 1)
Journal of Heterocyclic Chemistry
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B. Chakraborty, M. S. Chhetri, and E. Chhetri
Vol 000
CONCLUSION
Chemical Company and were used as received. N-phenyl-
hydroxylamine and N-cyclohexylhydroxylamine were pre-
pared following standard methods available in the
literature and have been used for the synthesis of various
new isoxazoline derivatives using ionic liquid as recyclable
solvent. Microwave studies were carried out in Discover
Bench Mate system (Make: CEM-USA) producing contin-
uous irradiation at 2445MHz and infrared control system.
Microwave experiments were carried out in sealed vessels
with an effective magnetic stirring and reflux (which
avoids all problems of non homogeneity in temperature).
All other reagents and solvents were purified after receiv-
ing from commercial suppliers. Methyl propiolate, ethyl
propiolate, propiolic acid, trimethyl acetylene, dimethyl
acetylene dicarboxylate etc were obtained commercially
from Aldrich, Lancaster, Fluka, and from Sigma-Aldrich,
Switzerland and were used without purification, unless oth-
erwise indicated. Characterization of the novel aziridines
has been confirmed on the basis of spectral data. The mi-
croorganisms used in this experiment include 15 bacterial
strains of both gram positive and gram negative varieties.
These were obtained from Division of Microbiology, Dept
of Pharmaceutical Technology, Jadavpur University,
Kolkata, India.
In conclusion, we have reported a protocol of Baldwin
rearrangement for the conversion of isoxazoline deriva-
tives to various new aziridine derivatives with good to ex-
cellent selectivity using microwave irradiation at selected
temperature without involvement of any catalysts. The sa-
lient feature and the point of attraction in the present meth-
odology in entire syntheses involve atom efficient green
chemistry methodology (synthesis of isoxazolines using
ionic liquids as recyclable solvent and aziridine synthesis
using microwave irradiation) which should attract syn-
thetic chemists. Interestingly, majority of these aziridine
derivatives are found to have potential biological activities
and thereby warrant further work in these syntheses as
well.
EXPERIMENTAL
1H NMR spectra were recorded with a Bruker DRX 300
spectrometer (300 MHz, FT NMR) using TMS as internal
standard. 13C NMR spectra were recorded on the same in-
strument at 75MHz. The coupling constants (J) are given
in Hz. IR spectra were obtained with a Perkin-Elmer RX
1-881 machine as film or as KBr pellets for all the prod-
ucts. MS spectra were recorded with a Jeol SX-102
(FAB) instrument. All the reactions were monitored by
TLC using 0.25-mm silica gel plates (Merck 60F254 UV
indicator) while column chromatography was performed
with silica gel (E.Merck India) 60–200mesh. All other re-
agents and solvents were purified after receiving from
commercial suppliers. N-Methylhydroxylamine and N-
benzylhydroxylamine were purchased from Aldrich
General procedure for isoxazoline synthesis [15] using ionic
liquid (Table 1; entry 1).
2,6-Difluoro benzaldehyde
(1 mmol) and N-benzylhydroxylamine (1 equivalent) were
added to [bmim]BF4 (2 mL) in a 10-mL conical flask,
mixed thoroughly, and stirred at r.t. for 2 h. The
formation of nitrone was monitored by TLC (Rf = 0.40).
The nitrone was isolated as white crystalline solid (m.p.
42°C, uncorrected) following the methodology as adopted
in the following cycloaddition reactions. As the nitrone
decomposes on keeping at room temperature, in situ
Table 5
Diameter of zone of inhibition at MIC.
Diameter of zone of inhibition (mm) at MIC
Organism
Drug-1
Drug-2
Drug-3
Drug-4
Drug-5
Drug-7
Escherichia coli 25938
Salmonella typhi 62
Vibrio cholerae 20
Klebsiella pneumoniae 1003
Shigella dysenteriae 1
Pseudomonas AMRI 108
Salmonella typhimurium NTCC 74
Staphylococcus aureus 29737
Bacillus cereus 11778
14 0.3
15 0.1
14 0.1
14 0.2
20 0.2
17 0.1
19 0.2
15 0.1
16 0.2
14 0.1
16 0.1
25 0.2
21 0.2
38 0.2
36 0.6
24 0.1
20 0.2
27 0.3
13 0.1
25 0.2
14 0.1
28 0.3
18 0.2
26 0.2
33 0.1
15 0.1
15 0.2
12 0.1
22 0.1
27 0.1
20 0.2
19 0.2
18 0.2
17 0.1
23 0.4
13 0.2
20 0.2
29 0.2
28 0.2
26 0.2
23 0.1
17 0.3
12 0.1
25 0.1
26 0.8
14 0.1
13 0.1
33 0.2
27 0.2
17 0.2
42 0.4
44 0.3
22 0.2
35 0.3
37 0.3
20 0.3
37 0.1
—
—
—
18 0.2
—
26 0.2
—
—
25 0.2
25 0.2
25 0.2
14 0.2
26 0.3
—
—
30 0.2
26 0.2
—
—
—
—
—
—
—
Bacillus subtilis 6633
Streptococcus epidermidis 12228
Micrococcus luteus 10240
Pseudomonas aeruginosa 25618
Bacillus pumilus 14884
—
—
—
—
42 0.2
36 0.3
11 0.1
—
Bordetella bronchiseptica 4617
—
“—” shows no measurable zone of inhibition.
Journal of Heterocyclic Chemistry
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Month 2015
Stereoselective Synthesis of New Aziridines
reactions were performed with alkynes. Methyl propiolate
(1 mmol) was added at the time of development of
nitrone, and the reaction mixture was further stirred at
room temperature for an appropriate time (26 min). After
completion of reaction, as indicated by TLC (Rf = 0.58;
ethyl acetate:hexane =1:10), the reaction mixture was
washed with diethyl ether (3× 10 mL). The combined
ether extracts were concentrated in vacuo, and the
resulting product was directly charged on silica gel
column and eluted with a mixture of ethyl acetate:n-
hexane (1:8) to afford pure isoxazoline 2 (Table 1, entry
1, 93%). The rest of the viscous ionic liquid was further
washed with ether and dried at 80°C under reduced
pressure to retain its activity in subsequent runs.
δ
173.52 (―C¼O), 168.52 (―COOCH3), 137.20,
137.04, 136.87, 136.66 (aromatic carbons), 132.77,
132.35, 132.08, 131.78, 130.80, 129.90 (2,6 difluoro
phenyl carbons), 36.80 (benzylic carbon), 31.54, 30.44
(aziridine ring carbons), 18.42 (―COOCH3); FAB–MS
(m/z): 331 (M+), 330, 272, 244 (B.P), 218, 113, 87, 59.
Anal. Calcd. for C18H15O3F2N: C, 65.26; H, 4.56; N,
4.22. Found: C, 65.13; H, 4.41; N, 4.15%.
Aziridine 3: methyl 2-((2R,3S)-1-benzyl-3-(2,6-difluoro-
phenyl)aziridin-2-yl)-2-oxoacetate (Table 1, entry 1: Trans
isomer).
Yellow oil. Yield 12%; Rf = 0.60; IR (KBr):
υmax 3014 (m), 2976 (m), 2240 (m), 1744 (s), 1710 (s),
1685 (s), 1470 (s), 1440 (m), 1320 (m), 1172 (s), 780 (s)
cmꢀ1; H NMR (CDCl3): δ 7.80–7.72 (m, 3H, C6H3F2),
1
Spectroscopic data for isoxazoline 2 (Table 1, entry 1).
(S)-methyl 2-benzyl-3-(2,6-difluorophenyl)-2,3-dihydroi-
soxazole-5-carboxylate; yellow gummy mass. Yield
93%; Rf = 0.58; IR (KBr): υmax 3010 (m), 2970 (m), 2246
(m), 1740 (s), 1710 (s), 1690 (s), 1474 (s), 1440 (m),
7.60–7.43 (m, 5H, C6H5), 4.15 (d, J= 4.20 Hz, 1H), 4.06
(d, J = 4.20Hz, 1H), 3.30 (s, 3H, ―COOCH3), 2.70
(s,2H, C6H5CH2); 13C NMR (CDCl3):
δ 174.28
(―C¼O), 170.40 (―COOCH3), 135.73, 135.60, 135.46,
135.54 (aromatic carbons), 133.69, 133.26, 132.78,
132.45, 132.23, 131.93 (2,6 difluoro phenyl carbons),
34.55 (benzylic carbon), 32.27, 31.17 (aziridine ring
carbons), 18.24 (―COOCH3); FAB–MS (m/z): 331 (M+),
330, 272, 244 (B.P), 218, 217, 113, 87, 59. Anal. Calcd.
for C18H15O3F2N: C, 65.26; H, 4.56; N, 4.22. Found: C,
65.07; H, 4.36; N, 4.08%.
1
1324 (m), 1176 (s), 782 (s) cmꢀ1; H NMR (CDCl3): δ
7.87–7.80 (m, 3H, C6H3F2), 7.68–7.31 (m, 5H, C6H5),
4.24 (d, J = 7.90 Hz, 1H), 4.12 (d, J = 7.90 Hz, 1H), 3.38
(s, 3H, ―COOCH3), 2.68 (s,2H, C6H5CH2); 13C NMR
(CDCl3): δ 173.52 (―C¼O), 168.52 (―COOCH3),
137.20, 137.04, 136.87, 136.66 (aromatic carbons),
132.77, 132.35, 132.08, 131.78, 130.80, 129.90 (2,6
difluoro phenyl carbons), 36.80 (benzylic carbon), 31.54,
30.44 (aziridine ring carbons), 19.26 (―COOCH3);
FAB–MS (m/z): 331 (M+), 330, 272, 244 (B.P), 218,
113, 87, 59. Anal. Calcd. for C18H15O3F2N: C, 65.26; H,
4.56; N, 4.22. Found: C, 65.13; H, 4.41; N, 4.15%.
General procedure for the synthesis of aziridine derivatives
under microwave irradiation (entry 1, Table 1). Isoxazoline
2 (1.5 mmol, 535 mg) was dissolved in acetonitrile (12 mL)
and was heated in a sealed vessel at 110°C during 5min
under microwave irradiation (400 W, temperature-
controlled mode). The resulting reaction mixture was
concentrated under vacuum, and the crude material was
directly purified by column chromatography (separation
of diastereomers) on silica gel (ethyl acetate/hexane) to
give the N-substituted aziridine 3 (Cis isomer; 359.7 mg,
76%) as a yellow gummy mass. Same methodology was
adopted for the synthesis of other aziridine derivatives 3
(Scheme 1, Table 1).
Aziridine 3: ethyl 2-((2R,3R)-1-benzyl-3-(2,6-difluorophenyl)
aziridin-2-yl)-2-oxoacetate (Table 1, entry 2; Cis isomer).
Colorless gummy mass. Yield 71%; Rf =0.74; IR (KBr):
υmax 3016 (m), 2978 (m), 2350 (m), 1744 (s), 1710 (s),
1685 (s), 1470 (s), 1440 (m), 1330 (m), 1220 (s), 780 (s)
1
cmꢀ1; H NMR (CDCl3): δ 7.54–7.42 (m, 3H, C6H3F2),
7.22–7.08 (m, 5H, C6H5), 4.52 (d, J=6.96Hz, 1H), 4.46
(d, J=6.96Hz, 1H), 2.68 (s,2H, C6H5CH2), 2.20 (dd, 2H,
J=4.22Hz, J=4.26Hz, ―COOCH2CH3), 1.84 (t, 3H,
J=3.80Hz, ―COOCH2CH3); 13C NMR (CDCl3): δ 172.28
(―C¼O), 169.80 (―COOCH2CH3), 135.60, 135.44,
135.25, 135.06 (aromatic carbons), 129.46, 129.37, 129.22,
129.07, 128.85, 128.60 (2,6 difluoro phenyl carbons), 35.20
(benzylic carbon), 32.76, 31.90 (aziridine ring carbons),
19.56, 18.74 (―COOCH2CH3); FAB–MS (m/z): 345 (M+),
300, 272, 244, 232 (B.P), 113, 101, 73, 45. Anal.
Calcd. for C19H17O3F2N: C, 66.08; H, 4.95; N, 4.05.
Found: C, 66.02; H, 4.83; N, 3.95%.
Aziridine 3: ethyl 2-((2R,3S)-1-benzyl-3-(2,6-difluorophenyl)
aziridin-2-yl)-2-oxoacetate (Table 1, entry 2; Trans isomer).
Colorless liquid. Yield 14%; Rf = 0.70; IR (KBr): υmax
3026 (m), 2986 (m), 2280 (m), 1748 (s), 1710 (s), 1680
(s), 1480 (s), 1440 (m), 1336 (m), 1235 (s), 788 (s)
Spectroscopic data of some new aziridine derivatives.
Aziridine 3: methyl 2-((2R,3R)-1-benzyl-3-(2,6-difluoro-
phenyl)aziridin-2-yl)-2-oxoacetate (Table 1, entry 1: Cis
isomer). Yellow gummy mass. Yield 76%; Rf = 0.66; IR
(KBr): υmax 3010 (m), 2970 (m), 2246 (m), 1740 (s),
1710 (s), 1690 (s), 1474 (s), 1440 (m), 1324 (m), 1176
1
cmꢀ1; H NMR (CDCl3): δ 7.50–7.37 (m, 3H, C6H3F2),
7.16–7.03 (m, 5H, C6H5), 4.46 (d, J = 4.16 Hz, 1H), 4.35
(d, J = 4.16 Hz, 1H), 2.54 (s, 2H, C6H5CH2), 2.34 (dd,
2H, J = 3.90 Hz, J = 3.96 Hz, ―COOCH2CH3), 1.70 (t,
3H, J = 3.28 Hz, ―COOCH2CH3); 13C NMR (CDCl3): δ
170.80 (―C¼O), 168.14 (―COOCH2CH3), 134.46,
1
(s), 782 (s) cmꢀ1; H NMR (CDCl3): δ 7.87–7.80 (m,
3H, C6H3F2), 7.68–7.31 (m, 5H, C6H5), 4.24 (d,
J =7.90 Hz, 1H), 4.12 (d, J= 7.90 Hz, 1H), 3.38 (s, 3H,
―COOCH3), 2.68 (s,2H, C6H5CH2); 13C NMR (CDCl3):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. Chakraborty, M. S. Chhetri, and E. Chhetri
Vol 000
1
134.28, 134.20, 134.12 (aromatic carbons), 130.42,
130.26, 130.12, 130.04, 129.55, 129.47 (2,6 difluoro
phenyl carbons), 33.66 (benzylic carbon), 30.40, 29.63
(aziridine ring carbons), 19.52, 18.90 (―COOCH2CH3);
FAB–MS (m/z): 345 (M+), 300, 272, 244, 232 (B.P),
231, 113, 101, 73, 45. Anal. Calcd. for C19H17O3F2N:
C, 66.08; H, 4.95; N, 4.05. Found: C, 65.93; H, 4.78; N,
3.88%.
(s), 786 (s) cmꢀ1; H NMR (CDCl3): δ 7.06–6.92 (m, 5H,
C6H5), 4.06 (d, J=4.24 Hz, 1H), 3.94 (d, J=4.22Hz, 1H),
1.72 (s, 3H, CH3), 1.20 (s, 9H); 13C NMR (CDCl3): δ
172.82 (―C¼O), 131.60, 131.39, 131.14, 130.95 (aromatic
carbons), 32.70, 31.49 (aziridine ring carbons), 18.14
(―CH3), 16.20 (t-butyl carbon), 13.68, 13.50, 13.33
(methyl carbons attached with t-butyl carbon); FAB–MS
(m/z): 217 (M+), 202, 160, 139, 132, 131 (B.P), 85, 77, 57.
Anal. Calcd. for C14H19ON: C, 77.37; H, 8.81; N, 6.45.
Found: C, 77.20; H, 8.66; N, 6.30%.
Aziridine 3: 2-((2R,3R)-1-methyl-3-phenylaziridin-2-yl)-2-
oxoacetic acid (Table 1, entry 3; Cis isomer).
Milky
gummy mass. Yield 72%; Rf = 0.64; IR (KBr): υmax 3030
Aziridine 3 ((2R,3R)-1-methyl-3-phenylaziridin-2-yl)(trimethylsilyl)
methanone (Table 1, entry 5; Cis isomer). Pale yellow liquid.
Yield 71%; Rf =0.68; IR (KBr): υmax 3140 (s), 3010 (m),
2840 (m), 1710 (s), 1650 (s), 1445 (s), 1400 (m), 1240 (s),
(s), 2994 (m), 2446 (m), 1740 (s), 1710 (s), 1665 (s),
1
1460 (s), 1430 (m), 1340 (s), 1230 (s), 776 (s) cmꢀ1; H
NMR (CDCl3): δ 9.80 (s, 1H, COOH), 6.90–6.75 (m,
5H, C6H5), 3.96 (d, J= 7.16 Hz, 1H), 3.80 (d, J= 7.16Hz,
1H), 1.70 (s, 3H, CH3); 13C NMR (CDCl3): δ 173.80
(―C¼O), 170.27 (―COOH), 134.00, 133.94, 134.80,
134.68 (aromatic carbons), 36.50, 34.63 (aziridine ring
carbons), 17.69, (―CH3); FAB–MS (m/z): 205 (M+),
190, 188, 160, 131 (B.P), 117, 73, 45. Anal. Calcd. for
C11H11O3N: C, 64.36; H, 5.40; N, 6.82. Found: C, 64.28;
H, 5.36; N, 6.70%.
1
778 (s) cmꢀ1; H NMR (CDCl3): δ 6.62–6.50 (m, 5H,
C6H5), 4.80 (d, J=7.26Hz, 1H), 4.64 (d, J=7.26Hz, 1H),
1.69 (s, 3H, CH3), 0.10 (s, 9H); 13C NMR (CDCl3): δ
170.56 (―C¼O), 129.48, 129.32, 129.20, 129.05
(aromatic carbons), 31.60, 30.32 (aziridine ring carbons),
19.42 (―CH3), 0.10 (trimethyl silyl carbons); FAB–MS
(m/z): 233 (M+), 218, 160, 155, 132, 117 (B.P), 77, 55.
Anal. Calcd. for C13H19SiON: C, 66.91; H, 8.20; N, 6.00.
Found: C, 66.64; H, 8.16; N, 5.83%.
Aziridine 3: 2-((2R,3S)-1-methyl-3-phenylaziridin-2-yl)-2-
oxoacetic acid (Table 1, entry 3; Trans isomer).
liquid. Yield 12%; Rf = 0.60; IR (KBr): υmax 3026 (s),
White
Aziridine 3 ((2R,3S)-1-methyl-3-phenylaziridin-2-yl)(trimethylsilyl)
methanone (Table 1, entry 5; Trans isomer). Yellow liquid.
Yield 11%; Rf = 0.62; IR (KBr): υmax 3152 (s), 3014 (m),
2846 (m), 1710 (s), 1655 (s), 1436 (s), 1410 (m), 1236
(s), 776 (s) cmꢀ1; 1H NMR (CDCl3): δ 6.69–6.50 (m, 5H,
C6H5), 4.73 (d, J= 3.90 Hz, 1H), 4.60 (d, J =3.90 Hz, 1H),
1.64 (s, 3H, CH3), 0.10 (s, 9H); 13C NMR (CDCl3): δ
171.96 (―C¼O), 127.80, 127.75, 127.66, 127.54
(aromatic carbons), 33.58, 31.80 (aziridine ring carbons),
17.63 (―CH3), 0.10 (trimethyl silyl carbons); FAB–MS
(m/z): 233 (M+), 218, 160, 155, 132, 117 (B.P), 77. Anal.
Calcd. for C13H19SiON: C, 66.91; H, 8.20; N, 6.00.
Found: C, 66.61; H, 8.13; N, 5.88%.
2990 (m), 2450 (m), 1744 (s), 1714 (s), 1662 (s), 1460
(s), 1435 (m), 1340 (s), 1240 (s), 774 (s) cmꢀ1; H NMR
1
(CDCl3): δ 9.86 (s, 1H, COOH), 6.86–6.77 (m, 5H,
C6H5), 3.80 (d, J = 4.50Hz, 1H), 3.72 (d, J= 4.50Hz,
1H), 1.78 (s, 3H, CH3); 13C NMR (CDCl3): δ 172.34
(―C¼O), 170.90 (―COOH), 133.00, 132.90, 132.83,
132.77 (aromatic carbons), 35.60, 34.58 (aziridine ring
carbons), 18.82, (―CH3); FAB–MS (m/z): 205 (M+),
190, 188, 160, 131 (B.P), 128, 117, 73, 45. Anal. Calcd.
for C11H11O3N: C, 64.36; H, 5.40; N, 6.82. Found: C,
64.25; H, 5.30; N, 6.73%.
Aziridine 3: 2,2-dimethyl-1-((2R,3R)-1-methyl-3-phenylaziridin-
2-yl)propan-1-one (Table 1, entry 4; Cis isomer). Colorless
liquid. Yield 70%; Rf = 0.58; IR (KBr): υmax 3165 (s), 3130
(m), 2450 (m), 1720 (s), 1660 (s), 1465 (s), 1430 (m), 1125
Aziridine 3: methyl 2-((2R,3R)-3-(2,6-difluorophenyl)-1-
methylaziridin-2-yl)-2-oxoacetate (Table 1, entry 6: Cis
isomer).
Colorless liquid. Yield 69%; Rf = 0.60; IR
(KBr): υmax 3020 (m), 2960 (m), 2240 (m), 1740 (s), 1710
1
(s), 788 (s) cmꢀ1; H NMR (CDCl3): δ 6.96–6.74 (m, 5H,
(s), 1680 (s), 1475 (s), 1460 (m), 1320 (m), 1170 (s), 786
C6H5), 4.18 (d, J=6.90Hz, 1H), 4.06 (d, J=6.90Hz, 1H),
1.80 (s, 3H, CH3), 1.22 (s, 9H); 13C NMR (CDCl3): δ
174.10 (―C¼O), 130.73, 130.58, 130.46, 130.32 (aromatic
carbons), 33.70, 32.66 (aziridine ring carbons), 18.54
(―CH3), 15.06 (t-butyl carbon), 12.60, 12.54, 12.50
(methyl carbons attached with t-butyl carbon); FAB–MS
(m/z): 217 (M+), 202, 160, 140, 131 (B.P), 85, 77, 57. Anal.
Calcd. for C14H19ON: C, 77.37; H, 8.81; N, 6.45. Found: C,
77.28; H, 8.62; N, 6.26%.
Aziridine 3: 2,2-dimethyl-1-((2R,3S)-1-methyl-3-phenylaziridin-
2-yl)propan-1-one (Table 1, entry 4; Trans isomer). Colorless
liquid. Yield 14%; Rf =0.54; IR (KBr): υmax 3160 (s), 3134
(m), 2445 (m), 1725 (s), 1660 (s), 1460 (s), 1432 (m), 1120
(s) cmꢀ1 1H NMR (CDCl3): δ 7.30–7.16 (m, 3H,
;
C6H3F2), 4.54 (d, J =6.86 Hz, 1H), 4.47 (d, J= 6.86 Hz,
1H), 3.34 (s, 3H, ―COOCH3), 1.96 (s,3H, N―CH3); 13
C
NMR (CDCl3): δ 175.13 (―C¼O), 170.22 (―COOCH3),
128.80, 128.65, 128.52, 128.27 (aromatic carbons), 33.70,
32.62 (aziridine ring carbons), 17.80 (―COOCH3), 15.84
(N―CH3); FAB–MS (m/z): 255 (M+), 240, 196, 168, 167
(B.P), 142, 113, 87, 59. Anal. Calcd. for C12H11O3F2N:
C, 56.47; H, 4.34; N, 5.48. Found: C, 56.34; H, 4.30; N,
5.29%.
Aziridine 3: methyl 2-((2R,3S)-3-(2,6-difluorophenyl)-1-
methylaziridin-2-yl)-2-oxoacetate (Table 1, entry 6: Trans
isomer).
Colorless liquid. Yield 13%; Rf = 0.56; IR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Stereoselective Synthesis of New Aziridines
[10] Kobayashi, S.; Jørgensen, K. A. Cycloaddition Reactions in
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(KBr): υmax 3016 (m), 2955 (m), 2740 (m), 2440 (m), 1735
(s), 1712 (s), 1685 (s), 1475 (s), 1446 (m), 1330 (m), 1205
(s), 780 (s) cmꢀ1; 1H NMR (CDCl3): δ 7.06–6.87 (m, 3H,
C6H3F2), 4.13 (d, J= 4.15 Hz, 1H), 4.06 (d, J = 4.16Hz,
1H), 3.30 (s, 3H, ―COOCH3), 2.05 (s,3H, N―CH3);
13C NMR (CDCl3):
δ
174.76 (―C¼O), 171.57
(―COOCH3), 127.93, 127.80, 127.68, 127.51 (aromatic
carbons), 35.06, 33.47 (aziridine ring carbons), 19.73
(―COOCH3), 17.42 (N―CH3); FAB–MS (m/z): 255
(M+), 240, 196, 168, 167 (B.P), 142, 141, 113, 87, 59.
Anal. Calcd. for C12H11O3F2N: C, 56.47; H, 4.34; N,
5.48. Found: C, 56.30; H, 4.22; N, 5.31%.
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Acknowledgments. We are pleased to acknowledge the financial
support from the Department of Science and Technology,
Government of India, New Delhi (grant no: SR/S1/OC-34/
2011). We are equally grateful to SAIF (Sophisticated
Analytical Instrumentation Facility), CDRI (Central Drug
Research Institute), Lucknow, India for providing spectral data.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet