Synthesis of Some Novel Class of Bis(isoxazoline) and Bis(aziridine) Derivatives

Article abstract of DOI:10.1002/jhet.2657

Synthesis of some new bis(isoxazoline) derivatives has been described from terepthaldehyde derived bis(nitrones) using microwave irradiation via 1,3-dipolar cycloaddition reaction. Bis(isoxazoline) derivatives in turn successfully converted into new bis(a

Full text of DOI:10.1002/jhet.2657

Month 2016
Synthesis of Some Novel Class of Bis(isoxazoline) and
Bis(aziridine) Derivatives
*
Bhaskar Chakraborty, Manjit Singh Chettri, and Govinda Prasad Luitel
Organic Chemistry Laboratory, Sikkim Government College, Gangtok, Sikkim 737 102, India
*
E-mail: bhaskargtk@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received September 3, 2015
DOI 10.1002/jhet.2657
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of some new bis(isoxazoline) derivatives has been described from terepthaldehyde derived bis
(nitrones) using microwave irradiation via 1,3-dipolar cycloaddition reaction. Bis(isoxazoline) derivatives in
turn successfully converted into new bis(aziridine) derivatives via Baldwin rearrangement. Simple reaction
methodology, non involvement of catalysts, and good to excellent yields are the important features noticed
in this synthesis.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
newly reported bis(isoxazoline) derivatives are obtained
as single pure compound when a mixture of bis(nitrone)
1 (1 equivalent) and alkynes (2 equivalents) is exposed
to microwave irradiation for 5–10min at 115 – 130°C.
1,3-Dipolar cycloaddition reactions are an integral and
weighty part of organic chemistry in pedagogy and re-
search as well. The wealthy literature on cycloaddition
reactions of nitrones for the synthesis of isoxazolidine
and isoxazoline derivatives and their further applications
have been widely illustrated [1–3] while synthesis of bis
(isoxazolidine) and bis(isoxazoline) derivatives is chal-
lenging and needs to be explored [4–7] especially because
conversions of these derivatives to aziridines via Baldwin
rearrangement are found to have vast synthetic potential
in this chemistry [8–10]. The chemistry of three-membered
ring heterocycles, especially aziridines, has attracted the
attention of synthetic chemists for more than a century
because of its ability of acting as versatile species in or-
ganic synthesis [11–15]. Baldwin et al. have shown that
1,3-dipolar cycloaddition reactions of nitrones to alkynes
lead to 4-isoxazolines which rearrange easily under ther-
mal conditions to acylaziridine[16–18]. As a part of our
ongoing research programme to develop new meth-
odologies in organic synthesis [19–22], herein, we report
synthesis of some new bis(isoxazoline) derivatives (2)
from terepthaldehyde in good to excellent yields under
microwave irradiation (Scheme 1, Table 1). Furthermore,
these bis(isoxazoline) derivatives are found to have vast
synthetic potential as they could be converted into synthet-
ically more important new bis(aziridines) (3) [23–28]. The
RESULTS AND DISCUSSION
To execute proposed study, terepthalaldehyde and var-
ious N-substituted hydroxylamines (N-Methyl/Phenyl/
Benzyl) were employed for the synthesis of bis(nitrones)
(1) following conventional methodology. This was followed
by 1,3-dipolar cycloaddition reactions of bis(nitrone) 1 with
different alkynes (electron deficient and electron rich) for
the synthesis of a variety of bis(isoxazoline) derivatives (2)
under microwave irradiation by employing reported
protocol [19,29,30]. The electron deficient alkynes used in
this study were acetylene dicarboxylic acid, methyl
phenylpropiolate, and dimethyl acetylene dicarboxylate
while electron rich alkynes were bis-(trimethylsilyl) acety-
lene (BTMSA) and N,N-dimethylaminoprop-1-yne respec-
tively. Bis(isoxazoline) derivatives thus obtained were
exposed to microwave irradiation (maintaining certain time
period and temperature) to obtain a variety of new N-
substituted bis(aziridines) (Scheme 1, Table 1).
In conventional methodology, high reaction temperature
and long reaction time are generally required to obtain
good conversions and yields in these cycloaddition
© 2016 Wiley Periodicals, Inc.

B. Chakraborty, M. Singh Chettri, and G. Prasad Luitel
Vol 000
Scheme 1. Synthesis of bis(isoxazoline) and bis(aziridine) derivatives.
reactions but prolonged heating time results in a drastic
drop of the yield of cycloadducts because of decomposi-
tion. A study of the reaction conditions under microwave
irradiation was thus undertaken as this condition is gener-
ally faster, cleaner, and greener [20,31–33]. The results
are summarized in Table 1. We also examined the effect
of solvent on these reactions and also in the rearrangement
2 to 3. Among the various polar solvents tested, water and
DMSO showed a good level of conversion (90 and 68%,
respectively) but, unfortunately, also induce the formation
of extensive amounts of degradation products (63 and
49% transformation, respectively). As compared to the
other solvents used, CH3CN finally offers the better com-
promise in terms of efficiency (conversion, transformation,
Table 1
Synthesis of bis(isoxazoline) and bis(aziridine) derivatives.
Entry
Bis(nitrone)(1a–1c)
Bis(isoxazoline)a,c (2a–2h)
Time (min)
Bis(aziridine)b,c (3a–3h)
Time (min)
1
5
5
Yield = 78% 3a
Yield = 92% (69%) 2a
R1 = COOCH3; R2 = COOCH3
1a (R = CH3)
R1 = COOCH3; R2 = COOCH3
2
6
6
Yield = 75% 3b
Yield = 88% (67%) 2b
1b (R = C6H5)
R1 = COOH; R2 = COOH
R1 = COOH; R2 = COOH
(Continued)
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Synthesis of Bis(isoxazoline) Derivatives
Table 1
(Continued)
Entry
Bis(nitrone)(1a–1c)
Bis(isoxazoline)a,c (2a–2h)
Time (min)
Bis(aziridine)b,c (3a–3h)
Time (min)
3
6
6
Yield = 88% (67%) 2c
R1 = Ph; R2 = COOCH3
1c (R = C6H5CH2)
Yield = 74% 3c
R1 = Ph; R2 = COOCH3
4
7
7
Yield = 73% 3d
R1 = TMS; R2 = TMS
Yield = 87% (65%) 2d
R1 = TMS; R2 = TMS
1c (R = C6H5CH2)
5
7
7
1a (R = CH3)
Yield = 70% 3e
Yield = 86% (66%) 2e
R1 = Me; R2 = NMe2
R1 = Me; R2 = NMe2
6
9
9
1b (R = C6H5)
Yield = 71% 3f
Yield = 86% (64%) 2f
R1 = COOCH3; R2 = COOCH3
R1 = COOCH3; R2 = COOCH3
7
10
10
1a (R = CH3)
Yield = 72% 3 g
Yield = 85% (60%) 2 g
R1 = COOH; R2 = COOH
R1 = COOH; R2 = COOH
(Continued)
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B. Chakraborty, M. Singh Chettri, and G. Prasad Luitel
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Table 1
(Continued)
Entry
Bis(nitrone)(1a–1c)
Bis(isoxazoline)a,c (2a–2h)
Time (min)
Bis(aziridine)b,c (3a–3h)
Time (min)
8
10
10
Yield = 71% 3 h
Yield = 84% (56%) 2 h
R1 = TMS; R2 = TMS
1b (R = C6H5)
R1 = TMS; R2 = TMS
aReaction conditions: Bisnitrone (1 mmol), alkyne (2 equivalent), MWI, MeCN, 5–10 min, 115 – 130°C
bIsoxazoline (1 mmol), MWI, MeCN, 5–10 min, 130°C
cIsolated yield after purification.
Figures in the parentheses of yield indicate products obtained in conventional methodology.
and yield) and of practical convenience. Indeed, at the end
of the reaction, the solvent is removed in vacuo and the res-
idue is directly loaded on silica gel for purification, which
avoids an aqueous workup. We have also observed that re-
arrangement of bis(isoxazoline) derivatives to bis
(aziridines) conducted in the absence of solvent resulted
in the complete degradation of the starting material. We
thus next evaluated the influence of solvent (H2O and
DMSO) for this conversion but because of the formation
of extensive amounts of degradation products (nearly 55–
60%), this methodology was discarded. For the rearrange-
ment of 2 to 3, the best results were obtained when the
reaction was carried out in acetonitrile.
obtained as single signal. Exact stereochemistry of the
bis(isoxazoline) and bis(aziridine) derivatives could not
be assigned because of the absence of adjacent proton
with respect to isoxazoline and aziridine ring proton.
CONCLUSION
In conclusion, we have reported a green chemistry pro-
tocol of the synthesis of bis(isoxazoline) derivatives and
also Baldwin rearrangement of these derivatives to various
new bis(aziridine) derivatives using microwave irradiation
at selected temperature without involvement of any cata-
lysts. The salient feature and the point of attraction in the
present methodology are the entire syntheses that involve
atom efficient green chemistry methodology which should
attract synthetic chemists.
We have obtained expected fragmentation peaks in the
mass spectral studies and majority of these peaks are due
to the development of aziridine derivatives. Base peaks
were obtained because of loss of COOCH3 for dimethyl
acetylene dicarboxylate, methyl phenyl propiolate while
COOH, TMS, and N,N-dimethylaminoprop-1-yne (NMe2)
for acetylene dicarboxylic acid, bis-(trimethylsilyl)acety-
lene (BTMSA), and N,N-dimethylaminoprop-1-yne respec-
tively. For all the cases, development of bis(nitrone), bis
(isoxazolines) and conversions to bis(aziridine) deriva-
tives were monitored by TLC (Rf values of bis(aziridine)
derivatives were found to have lower than bis
(isoxazoline) derivatives). Important signals of R, R1,
and R2 of the bis(isoxazoline) and bis(aziridine) deriva-
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 Shimadzu FT-IR
8400 machine using KBr pellets for all the products. MS
spectra were recorded with a Jeol SX-102/DA-600 (FAB)
instrument, and elemental analysis was carried out using
Heraus C,H and N rapid analyzer. 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.
N-Methylhydroxylamine, N-benzylhydroxylamine, dime-
thyl acetylenedicarboxylate, methyl phenylpropiolate,
1
tives were obtained in the H NMR spectrum [34] while
prominent carbonyl absorptions were found in IR spec-
trum as well. 1H NMR spectrum of the all the synthesized
bis(isoxazoline) and aziridine derivatives showed that the
four (4) hydrogen atoms of the phenyl ring (1,4 and 3,5
protons) linked with isoxazoline and aziridine rings are
merged and obtained as single singlet signal. 13C NMR
spectrum of the phenyl ring carbons at ortho, meta, and
para positions have been found to be merged and
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Synthesis of Bis(isoxazoline) Derivatives
acetylenedicarboxylic acid, bis-(trimethylsilyl) acetylene
(BTMSA), and N,N-dimethylaminoprop-1-yne etc were
obtained commercially from Aldrich, Lancaster, Fluka
and from Sigma-Aldrich, Switzerland and were used as
received. N-Phenylhydroxylamine and N-cyclohexylhy
droxylamine were prepared following standard methods avail-
able in the literature. Microwave studies were carried out in
Discover Bench Mate system (Make: CEM-USA) producing
continuous irradiation at 2445MHz and infrared control sys-
tem. Microwave experiments were carried out in sealed ves-
sels with an effective magnetic stirring and reflux (which
avoids all problems of non homogeneity in temperature).
Representative experimental procedure for the synthesis of bis
(nitrone) 1a (entry 1,Table 1; R = CH3). Terephthalaldehyde
NMR (CDCl3): δ 6.60 (s, 4H, Ar―H), 5.20 (s, 2H, 2×3-H),
3.80 (s, 12H, 4 ×―COOCH3), 2.52 (s, 6H, 2 ×N―CH3);
13C NMR (CDCl3): δ 172.54 (2 ×COOCH3), 171.13
(2×COOCH3), 134.28, 133.87 (1,4 Ar―C; phenyl ring
carbons linked with isoxazoline rings), 131.13, 130.45 (2,6
and 3,5 Ar―C; phenyl ring carbons linked with isoxazoline
rings), 88.62 (2 × 5-C), 77.43 (2× 3-C), 59.79 (2× 4-C), 52.20
(2×CH3), 38.58 (2 ×―COOCH3), 36.62 (2× ―COOCH3);
FAB–MS (m/z): 476 (M+), 460, 400, 386, 276, 185 (B.P), 75,
59; Anal. Calcd. for C22H24O10N2: C, 55.44; H, 5.07; N,
5.88. Found: C, 55.39; H, 5.02; N, 5.74%.
General experimental procedure for the synthesis of bis
(aziridine) derivatives (3a–3h) under microwave irradiation
(entry 1, Table 1).
Bis(isoxazoline) 2a (0.25mmol,
(1.34g, 10mmol) was added to
a
solution of
120mg) was dissolved in acetonitrile (10mL) and was
heated in a sealed vessel at 130°C during 5min under
microwave irradiation (400W, temperature-controlled
mode). The progress of the reaction was monitored by
TLC (Rf =0.52). The resulting reaction mixture was
concentrated under vacuum, and the crude material was
directly purified by column chromatography on silica gel
(ethyl acetate/hexane) to afford pure bis(aziridine) 3a
(Table 1, entry 1, 78%) as a pale yellow gummy mass.
Same methodology was adopted for the synthesis of other
bis(aziridine) derivatives 3b–3h (Scheme 1, Table 1, entry
2–8).
N-methylhydroxylamine hydrochloride (2.09g, 25mmol)
in CH2Cl2 (20mL) in a 50-mL R.B flask. NaHCO3 (2.52g,
30mmol) was added and the mixture heated at reflux for
18h. The solution was filtered in hot condition and the
inorganic solid washed with warm CHCl3. The bis(nitrone)
crystallized from the filtrate as a white solid and was
collected at the vacuum pump (1.42g, 74%, m.p>250°C).
Spectroscopic data for bis(nitrone) 1a: N-methyl(4-{[methyl
(oxido)iminio]methyl{phenyl)methylideneamine N-oxide.
Rf = 0.50; FT-IR (KBr): υmax 3130 (s), 3010 (m), 2970
(m), 2246 (m), 1690 (s), 1630 (s), 1610 (s), 1515 (s),
1310 (m), 1176 (s), 1150 (s), 782 (s) cmꢀ1; H NMR
1
Spectroscopic data for bis(aziridine) 3a (Table 1, entry 1):
(CDCl3): 8.24 (s, 4H, Ar―H), 7.40 (s, 2H, 2 × CH¼N+),
3.89 (s, 6H, 2 × CH3); 13C NMR (CDCl3): δ 134.66
(2 × CH¼N+), 131.81, 130.54 (1,4 Ar―C), 128.29,
127.52 (2,6 and 3,5 Ar―C), 54.58 (2 × CH3); FAB-MS
(m/z): 192 (M+), 176 (M-O), 134 (M-CHNOCH3); Anal.
Calcd. for C10H12O2N2: C, 62.47; H, 6.30; N, 14.58.
Found: C, 62.33; H, 6.24; N, 14.35%.
dimethyl 3,3′-(1,4-phenylene)bis(2-(2-methoxy-2-oxoacetyl)-1-
methylaziridine-2-carboxylate.
FT-IR (KBr): υmax 3028
(s), 2985 (m), 1766 (s), 1720 (s), 1660 (s), 1590 (m),
1
1520 (s), 786 (s) cmꢀ1; H NMR (CDCl3): δ 6.53 (s, 4H,
Ar―H), 4.86 (s, 2H, 2× aziridine protons), 3.92 (s, 6H,
2 × ―COOCH3, linked with aziridine rings), 3.70 (s, 6H,
2 × ―COOCH3, linked with keto group), 2.68 (s, 6H,
2 × N―CH3); 13C NMR (CDCl3): δ 174.10 (2× C¼O),
170.74 (2× ―COOCH3, linked with aziridine rings),
169.20 (2 × ―COOCH3, linked with keto group), 130.80,
130.23 (1,4 Ar―C; phenyl ring carbons linked with
aziridine rings), 128.15, 127.30 (2,6 and 3,5 Ar―C;
phenyl ring carbons linked with aziridine rings), 60.24
(2 × aziridine ring carbons), 54.24 (2 × aziridine ring
carbons), 48.60 (2 × CH3), 35.06 (2× ―COOCH3, linked
with aziridine rings), 33.18 (2× ―COOCH3, linked with
keto group); FAB–MS (m/z): 476 (M+), 461, 417, 400, 386,
276, 200, 76, 75, 59; Anal. Calcd. for C22H24O10N2: C,
55.44; H, 5.07; N, 5.88. Found: C, 55.26; H, 4.92; N, 5.61%.
General experimental procedure for the synthesis of bis
(isoxazoline) derivatives (2a–2h) under microwave
irradiation (entry 1, Table 1; R = CH3).
Bis(nitrone) 1a
(0.41 mmol, 80 mg) and dimethyl acetylene dicarboxylate
(0.82 mmole, 116 mg) were dissolved in acetonitrile (10 mL)
and were heated in a sealed vessel at 115°C during 5 min
under microwave irradiation (400W, temperature-controlled
mode). The progress of the reaction was monitored by TLC
(Rf =0.58).The resulting reaction mixture was concentrated
under vacuum, and the crude material was directly purified
by column chromatography on silica gel (ethyl
acetate/hexane) to afford pure bis(isoxazoline) 2a (Table 1,
entry 1, 92%) as a colourless gummy mass. Same
methodology was adopted for the synthesis of other bis
(isoxazoline) derivatives 2b–2h (Scheme 1, Table 1, entry 2–8).
Spectroscopic data for bis(isoxazoline) 2a (Table 1, entry 1):
(3R,3′R)-tetramethyl 3,3′-(1,4-phenylene)bis(2-methyl-2,3-dihy
droisoxazole-4,5-dicarboxylate. FT-IR (KBr): υmax 3036 (s),
2255 (m), 1760 (s), 1710 (s), 1600 (s), 1520 (s), 1440 (s),
Spectroscopic data of bis(isoxazoline) and bis(aziridine)
derivatives. Spectroscopic data for bis(isoxazoline) 2b (Table 1,
entry 2): (3R,3′R)-3,3′-(1,4-phenylene)bis(2-phenyl-2,3-dihydro
isoxazole-4,5-dicarboxylic acid. Gray gummy liquid (88%),
FT-IR (KBr): υmax 3285 (s), 3080 (s), 2250 (m), 1760 (s),
1685 (s), 1585 (s), 1545 (s), 1360 (m), 1285 (m), 1015 (m),
;
880 (s) cmꢀ1 1H NMR (CDCl3): δ 10.13 (s, 2H,
1
1324 (m), 1314 (s), 1260 (m), 1170 (s), 780 (s) cmꢀ1; H
2×―COOH), 10.06 (s, 2H, 2 × ―COOH), 7.05 (s, 4H,
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B. Chakraborty, M. Singh Chettri, and G. Prasad Luitel
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Ar―H), 6.84–6.68 (m, 10H, 2×Ar―H), 5.42 (s, 2H,
2×3-H); 13C NMR (CDCl3): δ 174.27 (2 ×COOH), 173.45
(2×COOH), 136.54, 135.42 (1,4 Ar―C; phenyl ring
carbons linked with isoxazoline rings), 133.25, 132.72 (2,6
and 3,5 Ar―C; phenyl ring carbons linked with isoxazoline
rings), 129.44, 128.70 (2×1,4 Ar―C; N-phenyl carbons),
128.12, 127.83 (2 ×2,6 and 3,5 Ar―C; N-phenyl carbons),
85.71 (2× 5-C), 78.32 (2 ×3-C), 57.14 (2×4-C); FAB–MS
(m/z): 544 (M+), 467, 466, 310, 234, 77; Anal. Calcd. for
C28H20O10N2: C, 61.75; H, 3.70; N, 5.14. Found: C, 61.63;
H, 3.57; N, 5.03%.
Spectroscopic data for bis(aziridine) 3c (Table 1, entry 3):
dimethyl 3,3′-(1,4-phenylene)bis(2-benzoyl-1-benzylaziridine-2-
carboxylate. Gray gummy liquid. Yield 74%; FT-IR (KBr):
υmax 3070 (s), 1744 (s), 1714 (s), 1622 (s), 1590 (s), 1484
(m), 1475 (m), 1358 (m), 1282 (m), 1016(m), 850 (s)
cmꢀ1; 1H NMR (CDCl3): δ 7.23 (s, 4H, Ar―H), 7.06–6.90
(m, 20H, 4× Ar―H), 4.82 (s, 2H, 2 ×aziridine protons),
3.82 (s, 4H, 2× CH2C6H5), 3.34 (s, 6H, 2 ×–COOCH3);
13C NMR (CDCl3):
δ
174.68 (2 ×C¼O), 172.80
(2× COOCH3), 133.00, 132.74 (1,4 Ar―C; phenyl ring
carbons linked with aziridine rings), 132.06, 131.90 (2,6
and 3,5 Ar―C; phenyl ring carbons linked with aziridine
rings), 130.68, 130.52 (2× 1,4 Ar―C; phenyl carbons
linked with C5 and C5′ carbons), 129.24, 129.10 (2 ×2,6
and 3,5 Ar―C; phenyl carbons linked with C5 and C5′
carbons), 128.61, 128.30 (2× 1,4 Ar―C; phenyl carbons
linked with benzyl carbons), 127.83, 127.29 (2× 2,6 and 3,5
Ar―C; phenyl carbons linked with benzyl carbons), 60.46
(2× aziridine ring carbons), 57.54 (2× aziridine ring
carbons); 37.70 (2 × CH2C6H5), 27.94 (2× ―COOCH3);
FAB–MS (m/z): 664 (M+), 559, 514, 468, 370, 294, 105,
91, 77; Anal. Calcd. for C42H36O6N2: C, 75.87; H, 5.45; N,
4.21. Found: C, 75.60; H, 5.27; N, 4.17%.
Spectroscopic data for bis(aziridine) 3b (Table 1, entry 2):
dimethyl 3,3′-(1,4-phenylene)bis(2-(2-methoxy-2-oxoacetyl)-1-
methylaziridine-2-carboxylate. Dark gray gummy mass
(75%), FT-IR (KBr): υmax 3280 (s), 3076 (s), 2250 (m),
1765 (s), 1754 (s), 1682 (s), 1660 (s), 1585 (s), 1540 (s),
1
1364 (m), 1282 (m), 1016 (m), 870 (s) cmꢀ1; H NMR
(CDCl3): δ 10.20 (s, 2H, 2×―COOH), 10.05 (s, 2H,
2×―COOH), 7.14 (s, 4H, Ar―H), 6.77–6.62 (m, 10H,
2×Ar―H), 4.90 (s, 2H, 2×aziridine protons); 13C NMR
(CDCl3): δ 175.50 (2× C¼O), 174.27 (2×COOH), 173.45
(2 × COOH), 135.80, 135.26 (1,4 Ar―C; phenyl ring
carbons linked with aziridine rings), 132.88, 132.51 (2,6
and 3,5 Ar―C; phenyl ring carbons linked with aziridine
rings), 130.12, 129.42 (2×1,4 Ar―C; N-phenyl carbons),
128.30, 127.67 (2×2,6 and 3,5 Ar―C; N-phenyl carbons),
67.20 (2×aziridine ring carbons), 60.43 (2×aziridine ring
carbons); FAB–MS (m/z): 544 (M+), 499, 466, 394, 310,
234, 77, 45; Anal. Calcd. for C28H20O10N2: C, 61.75; H,
3.70; N, 5.14. Found: C, 61.54; H, 3.74; N, 5.10%.
Spectroscopic data for bis(isoxazoline) 2d (Table 1, entry 4):
1,4-bis((R)-2-benzyl-4,5-bis(trimethylsilyl)-2,3-dihydroisoxazol-
3-yl)benzene. Yellow sticky liquid. Yield 87%; FT-IR (KBr):
υ
max 3073 (s), 2255 (m), 1665 (s), 1585 (s), 1500 (m), 1470
(m), 1350 (m), 1282 (m), 1025 (m), 860 (s) cmꢀ1; 1H NMR
(CDCl3): δ 7.16 (s, 4H, Ar―H), 7.05–6.92 (m, 10H,
2×Ar―H), 5.02 (s, 2H, 2 ×3-H), 3.43 (s, 4H,
2×CH2C6H5), 0.82 (s, 36H, 4× SiMe3); 13C NMR (CDCl3):
δ 136.66, 134.80 (1,4 Ar―C; phenyl ring carbons linked
with isoxazoline rings), 132.54, 131.89 (2,6 and 3,5 Ar―C;
phenyl ring carbons linked with isoxazoline rings),129.70,
129.64 (2 ×1,4 Ar―C; phenyl carbons linked with benzyl
carbons), 128.75, 128.43 (2× 2,6 and 3,5 Ar―C; phenyl
carbons linked with benzyl carbons), 80.67 (2× 5-C), 75.90
(2× 3-C), 56.44 (2 ×4-C), 31.75 (2× CH2C6H5), 0.12
(4× SiMe3 carbons); FAB–MS (m/z): 684 (M+), 607, 583,
380, 304, 91, 77; Anal. Calcd. for C38H56Si4O2N2: C, 66.62;
H, 8.23; N, 4.09. Found: C, 66.50; H, 8.12; N, 4.12%.
Spectroscopic data for bis(isoxazoline) 2c (Table 1, entry 3):
(3R,3′R)-dimethyl 3,3′-(1,4-phenylene)bis(2-benzyl-5-phenyl-
2,3-dihydroisoxazole-4-carboxylate. Colourless liquid. Yield
88%; FT-IR (KBr): υmax 3065 (s), 1740 (s), 1660 (s), 1590
(s), 1490 (m), 1480 (m), 1355 (m), 1290 (m), 1020 (m),
1
830 (s) cmꢀ1; H NMR (CDCl3): δ 7.80 (s, 4H, Ar―H),
7.54–7.35 (m, 10H, 2 ×Ar―H, phenyl protons linked with
C5 and C5′ carbons), 7.12–6.94 (m, 10H, 2×CH2C6H5),
5.13 (s, 2H, 2 × 3-H), 3.74 (s, 4H, 2 × CH2C6H5), 3.30
(s, 6H, 2 × –COOCH3); 13C NMR (CDCl3): δ 174.54
(2 × COOCH3), 134.07, 133.85 (1,4 Ar―C; phenyl ring
carbons linked with isoxazoline rings), 133.14, 133.03
(2,6 and 3,5 Ar―C; phenyl ring carbons linked with
isoxazoline rings), 130.92, 130.64 (2× 1,4 Ar―C; phenyl
carbons linked with C5 and C5′ carbons), 129.75, 129.57
(2× 2,6 and 3,5 Ar―C; phenyl carbons linked with C5
and C5′ carbons), 128.77, 128.64 (2 ×1,4 Ar―C; phenyl
carbons linked with benzyl carbons), 128.15, 127.97
(2× 2,6 and 3,5 Ar―C; phenyl carbons linked with
benzyl carbons), 83.80 (2× 5-C), 74.46 (2× 3-C), 59.32
(2× 4-C), 32.16 (2× CH2C6H5), 28.12 (2 ×―COOCH3);
FAB–MS (m/z): 664 (M+), 587, 559, 370, 294, 91, 77;
Anal. Calcd. for C42H36O6N2: C, 75.87; H, 5.45; N, 4.21.
Found: C, 75.79; H, 5.38; N, 4.23%.
Spectroscopic data for bis(aziridine) 3d (Table 1, entry 4):
(3,3′-(1,4-phenylene)bis(1-benzyl-2-(trimethylsilyl)aziridine-3,
2-diyl))bis((trimethylsilyl)methanone. Gray gummy liquid.
Yield 73%; FT-IR (KBr): υmax 3085 (s), 1760 (s), 1710 (s),
1665 (s), 1584 (s), 1500 (m), 1475 (m), 1356 (m), 1285 (m),
1
1014 (m), 865 (s) cmꢀ1; H NMR (CDCl3): δ 7.03 (s, 4H,
Ar―H), 6.87–6.74 (m, 10H, 2× Ar―H), 4.54 (s, 2H,
2 × aziridine protons), 2.65 (s, 4H, 2 × CH2C6H5), 0.80
(s, 36H, 4 × SiMe3); 13C NMR (CDCl3): δ 173.48
(2×C¼O), 135.90, 135.34 (1,4 Ar―C; phenyl ring
carbons linked with aziridine rings), 133.68, 132.72 (2,6
and 3,5 Ar―C; phenyl ring carbons linked with aziridine
rings),130.54, 130.23 (2×1,4 Ar―C; phenyl carbons
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Bis(isoxazoline) Derivatives
linked with benzyl carbons), 128.78, 128.16 (2×2,6 and 3,5
Ar―C; phenyl carbons linked with benzyl carbons), 57.54
(2×aziridine ring carbons), 55.75 (2×aziridine ring
carbons), 34.42 (2×CH2C6H5), 0.15 (4×SiMe3 carbons);
FAB–MS (m/z): 684 (M+), 611, 607, 583, 520, 492, 380,
304, 101, 91, 77; Anal. Calcd. for C38H56Si4O2N2: C,
66.62; H, 8.23; N, 4.09. Found: C, 66.43; H, 8.14; N, 4.10%.
(2×3-C), 61.23 (2×4-C), 39.52 (2×―COOCH3), 37.80
(2×―COOCH3); FAB–MS (m/z): 600 (M+), 523, 482,
446, 338, 262 (B.P), 77, 59; Anal. Calcd. for
C32H28O10N2: C, 63.98; H, 4.69; N, 4.66. Found: C,
63.90; H, 4.57; N, 4.60%.
Spectroscopic data for bis(aziridine) 3f (Table 1, entry 6):
diphenyl 3,3′-(1,4-phenylene)bis(2-(2-methoxy-2-oxoacetyl)-1-
phenylaziridine-2-carboxylate. Yellow liquid. Yield 71%;
FT-IR (KBr): υmax 3035 (s), 2980 (m), 1763 (s), 1726 (s),
Spectroscopic data for bis(isoxazoline) 2e (Table 1, entry 5):
(3R,3′R)-3,3′-(1,4-phenylene)bis(N,N,2,5-tetramethyl-2,3-dihy
droisoxazol-4-amine. Deep yellow liquid. Yield 86%; FT-IR
(KBr): υmax 3035 (s), 2250 (m), 1680 (s), 1580 (s), 1510 (m),
1
1660 (s), 1585 (m), 1535 (s), 780 (s) cmꢀ1; H NMR
(CDCl3): δ 7.42 (m, 2 ×5H), 6.50 (s, 4H, Ar―H), 4.74
(s, 2H, 2×aziridine protons), 3.80 (s, 6H, 2×―COOCH3,
linked with aziridine rings), 3.53 (s, 6H, 2×―COOCH3,
linked with keto group); 13C NMR (CDCl3): δ 173.11
(2×C¼O), 172.06 (2×―COOCH3, linked with aziridine
rings), 170.15 (2×―COOCH3, linked with keto group),
130.80, 130.23 (1,4 Ar―C; phenyl ring carbons linked
with aziridine rings), 129.80, 129.56 (2,6 and 3,5 Ar―C;
phenyl ring carbons linked with aziridine rings), 128.06,
127.90 (2×1,4 Ar―C; N-phenyl carbons), 127.24, 127.03
(2×2,6 and 3,5 Ar―C; N-phenyl carbons), 62.62
(2×aziridine ring carbons), 59.46 (2×aziridine ring
carbons), 37.12 (2×―COOCH3, linked with aziridine
rings), 35.47 (2×―COOCH3, linked with keto group);
FAB–MS (m/z): 600 (M+), 523, 513, 436, 338, 262 (B.P),
87, 77, 59; Anal. Calcd. for C32H28O10N2: C, 63.98; H,
4.69; N, 4.66. Found: C, 63.81; H, 4.54; N, 4.52%.
1
1465 (m), 1315 (m), 1245 (s), 1005 (m), 858 (s) cmꢀ1; H
NMR (CDCl3): δ 7.48 (s, 4H, Ar―H), 4.93 (s, 2H,
2× 3-H), 2.80 (s, 12H, 2× NMe2), 2.12 (s, 6H, 2× N―CH3),
1.63 (s, 6H, 2×CH3); 13C NMR (CDCl3): δ 134.76, 134.37
(1,4 Ar―C; phenyl ring carbons linked with isoxazoline
rings), 133.50, 133.13 (2,6 and 3,5 Ar―C; phenyl ring
carbons linked with isoxazoline rings), 83.70 (2×5-C), 73.47
(2×3-C), 55.60 (2 ×4-C), 39.52 (2× NMe2), 30.21
(2×N―CH3), 20.43 (2× CH3); FAB–MS (m/z): 358 (M+),
343, 342, 242, 217, 141, 126; Anal. Calcd. for C20H30O2N4:
C, 66.99; H, 8.43; N, 15.63. Found: C, 66.84; H, 8.32; N,
15.53%.
Spectroscopic data for bis(aziridine) 3e (Table 1, entry 5):
1,1′-(3,3′-(1,4-phenylene)bis(2-(dimethylamino)-1-methylaziri
dine-3,2-diyl))diethanone. Brown sticky liquid. Yield 70%;
FT-IR (KBr): υmax 3042 (s), 2244 (m), 1755 (s), 1715 (s),
1660 (s), 1575 (s), 1510 (m), 1460 (m), 1315 (m), 1250 (s),
Spectroscopic data for bis(isoxazoline) 2g (Table 1, entry 7):
(3R,3′R)-3,3′-(1,4-phenylene)bis(2-methyl-2,3-dihydroisoxazole-
4,5-dicarboxylic acid. White liquid. Yield 85%; FT-IR (KBr):
1
1008 (m), 846 (s) cmꢀ1; H NMR (CDCl3): δ 7.40 (s, 4H,
Ar―H), 4.76 (s, 2H, 2×aziridine protons), 2.74 (s, 12H,
2×NMe2), 2.10 (s, 6H, 2×N―CH3), 1.57 (s, 6H,
2× COCH3); 13C NMR (CDCl3): δ 174.06 (2× C¼O),
132.96, 132.57 (1,4 Ar―C; phenyl ring carbons linked
with aziridine rings), 131.34, 131.10 (2,6 and 3,5 Ar―C;
phenyl ring carbons linked with aziridine rings), 54.95
(2×aziridine carbons), 52.64 (2 ×aziridine carbons), 37.78
(2×NMe2), 31.60 (2× N―CH3), 22.43 (2×COCH3);
FAB–MS (m/z): 358 (M+), 343, 342, 300, 289, 272, 242,
217, 141, 126, 43; Anal. Calcd. for C20H30O2N4: C, 66.99;
H, 8.43; N, 15.63. Found: C, 66.90; H, 8.36; N, 15.44%.
υ
max 3280 (s), 3073 (s), 2235 (m), 1755 (s), 1684 (s), 1590
(s), 1540 (s), 1358 (m), 1280 (m), 1018 (m), 805 (s) cmꢀ1
;
1H NMR (CDCl3): δ 10.05 (s, 2H, 2 × ―COOH), 9.96
(s, 2H, 2 × ―COOH), 6.80 (s, 4H, Ar―H), 5.42 (s, 2H,
2 × C3H), 2.08 (s, 6H, 2 × N―CH3); 13C NMR (CDCl3):
δ 173.78 (2 × COOH), 173.20 (2 × COOH), 134.69,
133.80 (1,4 Ar―C; phenyl ring carbons linked with
isoxazoline rings), 131.78, 130.80 (2,6 and 3,5 Ar―C;
phenyl ring carbons linked with isoxazoline rings),
80.64 (2 × 5-C), 77.30 (2 × 3-C), 55.85 (2 × 4-C), 51.30
(2 × N―CH3); FAB–MS (m/z): 420 (M+), 405, 330, 248,
172, 76; Anal. Calcd. for C18H16O10N2: C, 51.41; H,
3.83; N, 6.66. Found: C, 51.33; H, 3.60; N, 6.47%.
Spectroscopic data for bis(isoxazoline) 2f (Table 1, entry 6):
(3R,3′R)-tetramethyl 3,3′-(1,4-phenylene)bis(2-phenyl-2,3-dihy
droisoxazole-4,5-dicarboxylate. Pale yellow liquid. Yield
86%; FT-IR (KBr): υmax 3018 (s), 2246 (m), 1763 (s),
1710 (s), 1605 (s), 1532 (s), 1436 (s), 1320 (m), 1254 (m),
Spectroscopic data for bis(aziridine) 3g (Table 1, entry 7):
dimethyl 3,3′-(1,4-phenylene)bis(2-(2-methoxy-2-oxoacetyl)-1-
methylaziridine-2-carboxylate. Gray liquid. Yield 72%;
FT-IR (KBr): υmax 3282 (s), 3070 (s), 2255 (m), 1762 (s),
1756 (s), 1680 (s), 1660 (s), 1580 (s), 1540 (s), 1360 (m),
1
1184 (s), 776 (s) cmꢀ1; H NMR (CDCl3): δ 7.85 (m,
2×5H), 6.94 (s, 4H, Ar―H), 5.68 (s, 2H, 2×3-H), 3.37
(s, 12H, 4×―COOCH3); 13C NMR (CDCl3): δ 171.86
(2×COOCH3), 169.35 (2×COOCH3),137.53, 137.59 (1,4
Ar―C; phenyl ring carbons linked with isoxazoline rings),
135.62, 135.71 (2,6 and 3,5 Ar―C; phenyl ring carbons
linked with isoxazoline rings), 132.60, 129.86 (2×1,4
Ar―C; N-phenyl carbons), 127.64, 127.42 (2×2,6 and
3,5 Ar―C; N-phenyl carbons), 86.12 (2×5-C), 75.48
865 (s) cmꢀ1 1H NMR (CDCl3): δ 10.12 (s, 2H,
;
2 × ―COOH), 10.00 (s, 2H, 2× ―COOH), 6.90 (s, 4H,
Ar―H), 5.10 (s, 2H, 2× aziridine protons), 2.08 (s, 6H,
2 × N―CH3); 13C NMR (CDCl3): δ 173.38 (2× C¼O),
172.20 (2 ×COOH), 171.70 (2× COOH),134.62, 134.13
(1,4 Ar―C; phenyl ring carbons linked with aziridine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. Chakraborty, M. Singh Chettri, and G. Prasad Luitel
Vol 000
REFERENCES AND NOTES
rings), 132.21, 132.10 (2,6 and 3,5 Ar―C; phenyl ring
carbons linked with aziridine rings), 65.75 (2 × aziridine
ring carbons), 61.54 (2 × aziridine ring carbons), 50.23
(2 × N―CH3); FAB–MS (m/z): 420 (M+), 405, 360, 347,
332, 73, 45; Anal. Calcd. for C18H16O10N2: C, 51.41; H,
3.83; N, 6.66. Found: C, 51.30; H, 3.63; N, 6.44%.
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Spectroscopic data for bis(isoxazoline) 2h (Table 1, entry 8):
1,4-bis((R)-2-benzyl-4,5-bis(trimethylsilyl)-2,3-dihydroisoxazol-3-
yl)benzene. Yellow gummy liquid. Yield 84%; FT-IR (KBr):
υmax 3078 (s), 2256 (m), 1660 (s), 1583 (s), 1500 (m), 1480
(m), 1354 (m), 1280 (m), 1020 (m), 850 (s) cmꢀ1; 1H NMR
(CDCl3): δ 7.06 (s, 4H, Ar―H), 6.80–6.62 (m, 10H,
2×Ar―H), 4.86 (s, 2H, 2×3-H), 1.13 (s, 36H, 4×SiMe3);
13C NMR (CDCl3): δ 135.34, 135.18 (1,4 Ar―C; phenyl
ring carbons linked with isoxazoline rings), 133.62, 133.40
(2,6 and 3,5 Ar―C; phenyl ring carbons linked with
isoxazoline rings),130.68,130.52 (2×1,4 Ar―C; phenyl
carbons), 128.48, 127.90 (2×2,6 and 3,5 Ar―C; phenyl
carbons), 83.55 (2× 5-C), 76.43 (2×3-C), 55.60 (2×4-C),
1.05 (4× SiMe3 carbons); FAB–MS (m/z): 656 (M+), 583,
579, 510, 367, 289, 77; Anal. Calcd. for C36H52Si4O2N2: C,
65.85; H, 7.92; N, 4.56. Found: C, 65.74; H, 7.82; N, 4.47%.
Spectroscopic data for bis(aziridine) 3h (Table 1, entry 8):
(3,3′-(1,4-phenylene)bis(1-phenyl-2-(trimethylsilyl)aziridine-3,2-
diyl))bis((trimethylsilyl)methanone. Gray liquid. Yield 71%;
FT-IR (KBr): υmax 3080 (s), 1766 (s), 1710 (s), 1664 (s), 1580
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(s), 1475 (m), 1355 (m), 1280 (m), 1010 (m), 860 (s) cmꢀ1
;
1H NMR (CDCl3): δ 6.95 (s, 4H, Ar―H), 6.80–6.63
(m, 10H, 2× Ar―H), 4.65 (s, 2H, 2 ×aziridine protons), 0.96
(s, 36H, 4× SiMe3); 13C NMR (CDCl3): δ 174.35 (2 ×C¼O),
136.23, 136.12 (1,4 Ar―C; phenyl ring carbons linked with
aziridine rings), 133.47, 133.14 (2,6 and 3,5 Ar―C; phenyl
ring carbons linked with aziridine rings),128.80,128.68 (2 ×1,4
Ar―C; phenyl carbons), 127.66, 127.53 (2 × 2,6 and 3,5
Ar―C; phenyl carbons), 55.79 (2× aziridine ring carbons),
53.65 (2× aziridine ring carbons), 0.84 (4 ×SiMe3 carbons);
FAB–MS (m/z): 656 (M+), 579, 506, 478, 101,77, 73; Anal.
Calcd. for C36H52Si4O2N2: C, 65.85; H, 7.92; N, 4.56. Found:
C, 65.74; H, 7.69; N, 4.42%.
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