Synthesis of some novel bisisoxazolidine derivatives from glyoxal-derived bisnitrones via simultaneous double cycloaddition reactions in water

Article abstract of DOI:10.1002/jhet.2181

Simultaneous double 1,3-dipolar cycloaddition reactions of glyoxal-derived bisnitrones have been described in water. Significant rate acceleration and improved yields of exclusively diastereoselective and regioselective bisisoxazolidines in water have bee

Full text of DOI:10.1002/jhet.2181

Month 2014
Synthesis of Some Novel Bisisoxazolidine Derivatives from Glyoxal-de-
rived Bisnitrones via Simultaneous Double Cycloaddition Reactions in
Water
*
Bhaskar Chakraborty and Govinda Prasad Luitel
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 at the publisher’s website.
Received October 3, 2013
DOI 10.1002/jhet.2181
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Simultaneous double 1,3-dipolar cycloaddition reactions of glyoxal-derived bisnitrones have been described
in water. Significant rate acceleration and improved yields of exclusively diastereoselective and regioselective
bisisoxazolidines in water have been observed at room temperature in a short reaction time compared with
conventional solvents.
J. Heterocyclic Chem., 00, 00 (2014).
pyrrolidines. This rate of acceleration of organic reactions in
aqueous media was ascribed to one or a combination of the
following factors and phenomena [3], the high cohesive en-
ergy density of water, the high internal pressure within the
medium, the hydrogen-bonding ability, the hydrophobic
packing of diene and dienophile in cycloaddition reactions,
the hydrophobic versus antihydrophobic effects, the micellar
catalysis, the solvophobicity, and the solvent polarity. To-
day’s status, the insolubility of organic reactants in water,
once considered a drawback, turns out to be advantageously
a leading factor for the success of organic reactions in pure
water. In 2005, Sharpless coined these heterogeneous reac-
tions as “on-water” reactions [4,5]. The “on water” method
consists simply of stirring the reactant(s) with water to gener-
ate an aqueous suspension, and it has been observed that both
kinetics and yields are extremely enhanced in most cases,
compared with those in organic solvents.
INTRODUCTION
1,3-Dipolar cycloaddition reactions are an integral and
weighty part of organic chemistry in pedagogy and research
as well. The wealthy literature on cycloaddition reactions
from their birth up to now, unequivocally witnesses to their
leading chemistry. The so-called “conventional solvents”
are organic solvents that have undoubtedly promoted their
success. Yet, the toxicity aspect of these solvents impedes
their use freely and with no fear. Not only is the operating
chemist uncomfortable while experimenting, but also the en-
vironment is equally threatened. Working out the cycloaddi-
tion reactions and other organic ones in aqueous system
would certainly bring some relief to the chemist and to the
environment as well. Unusual outcomes in terms of yield,
reactivity, and selectivity compared with those performed in
organic solvents were commonly observed and have
overwhelmed the chemists with surprise indeed [1,2]. The
1,3-dipolar cycloaddition methodology applied to aqueous
media has brought forth a number of heterocyclic com-
pounds, usually with a regio and stereoselectivity pecularity.
These heterocycles include isoxazoles, isoxazolidines, and
In continuation of our efforts to establish green method-
ologies in nitrone cycloaddition reactions [6–9], herein, we
wish to report a new route to the synthesis and 1,3-dipolar
cycloaddition reaction of glyoxal-derived bisnitrones (having
vast synthetic potentials) with a variety of alkenes to produce
© 2014 HeteroCorporation

B. Chakraborty and G. Prasad Luitel
Vol 000
novel bisisoxazolidine derivatives (2–6) in water (Scheme 1) .
This is quite a new approach of the synthesis of nitrone from
glyoxal. The present study has been carried out with three
different maleimides (N-methyl/phenyl/cyclohexyl) and
ethyl acrylate, styrene respectively in water. Simultaneously,
the reactions have been also studied in organic solvent
(CH2Cl2) as well.
higher than the cycloaddition reactions performed in solvents
like THF, CH2Cl2 (Table 1). We suggest an explanation for
these results in terms of the frontier molecular orbital
(FMO) theory, which has been used extensively to explain
regioselectivity and to predict the yield, rate in 1,3-dipolar
cycloadditions [12,13]. This theory states that the Gibbs en-
ergy of activation is related to the energy gap between the
interacting highest occupied molecular orbital and lowest
unoccupied molecular orbital. The dipolarophiles such as
styrene are weak hydrogen bond acceptor, which means
that their FMO’s are only slightly affected by hydrogen
bond interactions and leads to a reduction of the energy
gap between the interacting FMO’s (in this case, the highest
occupied molecular orbital of the dipolarophile and lowest
unoccupied molecular orbital of the 1,3-dipole). Conse-
quently, the Gibbs energy of activation of the reaction is
reduced, and the reaction is accelerated in water with
good yield. Bisnitrones (1) reacted with N-substituted
maleimides giving bisisoxazolidines. Diastereoselective
reactions of the dipole 1 furnished diastereoselective
cycloadducts (2–4) and are classified as trans biscycloadducts
as the 3-H and 4-H protons on each isoxazolidine ring are
RESULTS AND DISCUSSION
We classified dipolarophiles into water-super and water-
normal on the basis of the magnitude of their rate response
to water. A ketone (C═O) conjugated to an alkene or
alkyne is a water-super dipolarophile. Esters, ethers, and
aryl rings conjugated to an alkene are water-normal
dipolarophiles. Almost all the reactions in water are very
fast (3–4 h in case of maleimides, ethyl acrylate and 5 h
for styrene) compared with the normal cycloaddition reac-
tions in organic solvents, which are reported to take longer
periods (26–48 h) [10,11].
It is possible that water promotes the reaction through
hydrogen bond formation with the carbonyl oxygen atom
of the α,β-unsaturated carbonyl compounds and thereby in-
creasing the eletrophilic character at the β-carbon, which is
attacked by nucleophilic oxygen atom of the nitrone. Thus,
water activates maleimide and ethyl acrylate and thereby
greatly facilitates the reaction. The reaction rate is compar-
atively slower in styrene because of very lesser possibility
of the formation of hydrogen bonding between water and
alkenes but still the rate of the reaction and the yield is
1
trans orientated as evidenced from H-NMR spectroscopy
[14,15]. On the other hand, bisnitrones 1 reacted with ethyl
acrylate and styrene giving exclusively regioselective
bisisoxazolidines (5–6). All the novel biscycloadducts (2–6)
are obtained as diastereoselective and regioselective iso-
meric forms and stereochemical information portrayed in
the drawing implies relative and not absolute relations [16].
The structures of the diastereoselective and regioselective
Scheme 1. Synthesis of bisnitrone and bisisoxazolidine derivatives from glyoxal.
Journal of Heterocyclic Chemistry
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Synthesis of Some Novel Bisisoxazolidine Derivatives from Glyoxal-derived
Bisnitrones via Simultaneous Double Cycloaddition Reactions in Water
Table 1
1,3-Dipolar cycloaddition reaction of glyoxal-derived bisnitrones with alkenes in water.
Entry
1
Bisnitronea (1)
Alkene
Bisisoxazolidineb (2–6)
Time (h)
3 (26)
Yieldc (%)
94 (62)
2
3 (27)
91 (59)
3
4
5
4 (28)
4 (30)
5 (35)
91 (60)
88 (60)
83 (57)
aReaction conditions: bisnitrone (1 mmol), alkenes (2 equivalent), water (15 mL), and N2 atmosphere.
bAll products were characterized by IR,1H-NMR, 13C-NMR, and MS spectral data.
cIsolated yield after purification. Figures in parentheses indicate reactions performed in conventional solvents (CH2Cl2).
(5-substituted) novel bisisoxazolidine derivatives are con-
are expected to be symmetrical in nature and that 3-H and
4-H are cis orientated on both rings while vicinal coupling
constant has been found to be J3,4 ~ 6.80Hz [17]. Compared
with conventional conditions, the cycloaddition reactions
1
firmed on the basis of H-NMR spectroscopy [14,15]. It is
also evident from the 1H-NMR spectrum of the
diastereoselective bisisoxazolidines (2–4) that the structures
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B. Chakraborty and G. Prasad Luitel
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performed in water are much faster and selective [18]. As an
example, the reaction between nitrone 1 and alkenes,
afforded bisisoxazolidine (2) at room temperature (RT) af-
ter 34 h in 57% yield in CH2Cl2 and after 3 h in 93% yield
in water (entry 1), respectively. The reaction of nitrone 1
with various alkenes follow the general mechanistic pattern
of 1,3-dipolar cycloaddition reactions as found in literature
[10,11]. Initial study reports on the biological activity of the
synthesized bisisoxazolidine derivatives are also very en-
couraging. All the novel bisisoxazolidine derivatives (2–
6) have been found to be very effective against both
gram-positive and gram-negative organisms, which gives
an opportunity to develop new broad spectrum antimicro-
bial agents. Screening study (SEM and TEM) on these
novel bisisoxazolidines are going on at present.
could not be calculated. High selectivity is observed in
these simultaneous double cycloaddition reactions and
best selectivity (diastereomeric excess) was observed in
the cycloaddition reactions of N-phenylbisnitrone with
N-phenyl maleimide (de% 96, entry 2, Table 1). Enhanced
reaction rates, excellent yields, and high selectivity are
the features observed in these double cycloaddition reactions.
1
All the products are characterized by H-NMR, 13C-NMR,
IR and mass spectrometry (MS) spectroscopic data.
CONCLUSION
In conclusion, we have reported a new methodology of
the synthesis of bisisoxazolidines from one pot double
cycloaddition reactions on bifunctional nitrones with
maleimides and other activated alkenes. N-methyl dipoles
are more reactive, but less selective than their N-phenyl
analogs. Biscycloadducts with N-methyl/N-phenyl substit-
uents on the isoxazolidine ring are cis disposed with
respect to 3-H and 4-H protons. Finally, we have also
shown that these cycloaddition reactions may be conve-
niently carried out in water with the obtainment of corre-
sponding novel bisisoxazolidines in good conversions
and yields with high synthetic potentials, selectivities.
Furthermore, these novel biscycloadducts (2–6) are
found to have vast synthetic potential as they could be
converted into 1,3 difunctional amino alcohols (Scheme 2).
Studies are in progress.
To explore the potentiality of this procedure, we are now
extending the protocol, to N-substituted bisnitrones (with
hydroxyl derivatives in phenyl ring also) for the synthesis
of novel bisisoxazolidine derivatives. Synthesis of various
bisisoxazolidine derivatives from terepthaldehyde-derived
bisnitrones are also in progress at present. All the
biscycloadducts are found to be stable and have prominent
molecular ion peak and base peaks in the mass spectrum as
expected. It has been observed that the N-methyl dipole re-
acts less selectively but furnishes higher yields than its
electron poor N-phenyl analog. A plausible stereochemistry
of the bisisoxazolidines obtained from maleimides (2–4)
has been assigned on the basis of 3-H and 4-H proton sig-
nals of both the isoxazolidine rings appeared as double
doublet and doublets, respectively [19,20].
In addition, these bisisoxazolidine derivatives could be
easily recovered on work-up. Because the products are
fairly soluble in water, they could be easily extracted with
ether. Important signals of C3H, C4H, and C5H protons of
both the isoxazolidine rings (cis, cis) of the novel
bisisoxazolidine derivatives have been found to be merged
and obtained as a single signal. Double doublet signal
of C4H protons appeared as broad signal in majority of
the novel biscycloadducts and coupling constant values
EXPERIMENTAL
1H-NMR spectra were recorded with a Bruker DRX 300 (SAIF-
CDRI, Lucknow, Uttar Pradesh, India) spectrometer (300 MHz,
FT-NMR) using tetramethylslane as internal standard. 13C-NMR
spectra were recorded on the same instrument at 75 MHz. The cou-
pling constants (J) are given in hertz. IR spectra were obtained
with a Perkin-Elmer RX 1-881 (SAIF-CDRI, Lucknow, Uttar
Pradesh, India) machine as film or as KBr pellets for all the
products. MS spectra were recorded with a Jeol SX-102 (FAB)
(SAIF-CDRI, Lucknow, Uttar Pradesh, India) instrument. All the
reactions were monitored by TLC using 0.25 mm silica gel plates
(Merck 60 F254 UV indicator) while column chromatography was
performed with silica gel (E. Merck India) 60–200 mesh. All
other reagents and solvents were purified after receiving
from commercial suppliers. N-Benzylhydroxylamine, N-Phenyl
maleimide, N-Methyl maleimide, starting materials, and reagents
used in the reactions were obtained commercially from Aldrich,
Lancaster, Fluka and were used without purification, unless other-
wise indicated. Characterization of the novel biscycloadducts has
been confirmed on the basis of spectral data.
Scheme 2. Synthesis of bis 1,3-amino alcohols.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Some Novel Bisisoxazolidine Derivatives from Glyoxal-derived
Bisnitrones via Simultaneous Double Cycloaddition Reactions in Water
General procedure for the synthesis of nitrone 1.
To a
66.47 (C3, C3′), 55.80 (C4, C4′). FAB-MS (m/z): 586 (M+), 293,
solution of glyoxal (309mg, 5.3127 mM) in diethyl ether (20 mL),
N-methylhydroxylamine (500 mg, 2 equivalent), and anhydrous
MgSO4 (2 g) was added. The reaction mixture was kept at RT
with constant stirring with a magnetic stirrer under N2 atmosphere
for 8 h. The formation of bisnitrone was monitored by TLC
(Rf = 0.36). Usual workup followed by concentrated in vacuo
furnished N-methyl bisnitrone as white crystals (86%; mp: 78°C).
Same methodology was followed for the synthesis of other
bisnitrones (R = C6H5; CH2C6H5). All the bisnitrones were found
to be stable and were reacted with various activated alkenes in
1,3-dipolar cycloaddition reaction in water at RT.
292, 216, 77. Calcd for C34H26O6N4: C, 69.60; H, 4.46; N,
9.55%. Found: C, 69.50; H, 4.38; N, 9.49%.
(3R, 3aR, 6aS)-2-Benzyl-3-((3′S, 3′aS, 6aR)-2′-benzyl-
hexahydro-5-methyl-4,6-dioxo-2H-pyrrolo[3,4-d]isoxazol-3-yl)-
dihydro-5-methyl-2H-pyrrolo[3,4-d]isoxazole-4,6(5H, 6aH)dione
4. 4 (entry 3, Table 1): White crystals, Yield 91%; Rf = 0.62;
FTIR (KBr): υmax 3010 (m), 2900 (m), 1760 (s), 1660 (s), 1482
(m), 1340 (m), 780 (s) cmÀ1. 1H-NMR (CDCl3): δ 7.46–7.26 (m,
10H, 2×CH2C6H5), 4.37 (d, 2H, J = 7.16Hz, 2×C5H), 3.24 (d,
2H, J = 7.14Hz, 2×C3H), 2.89 (dd, br, 2H, 2×C4H), 2.60 (s, 6H,
2×N–CH3 protons), 2.15 (s, 4H, 2×CH2C6H5). 13C-NMR
(CDCl3): δ 177.18, 177.04 (carbonyl carbons), 133.22, 133.12,
132.90, 132.70 (aromatic carbons), 73.67 (C5, C5′), 64.80 (C3,
C3′), 53.77 (C4, C4′), 32.05, 31.94 (benzyl carbons), 28.70, 28.58
(N–Me carbons). FAB-MS (m/z): 490 (M+), 245, 244, 154, 77.
Calcd for C26H26O6N4: C, 63.64; H, 5.34; N, 11.42%. Found: C,
Spectroscopic data for nitrone 1 (R = CH3): UV λmax 233 nm.
1
IR (KBr): υmax 1635 (m), 1610 (s) cmÀ1. H-NMR (300 MHz,
CDCl3): δ 6.45 (d, 1H, J = 3.22 Hz, –CH = N+), 6.23 (d,
J = 3.22 Hz, –CH═N+), 3.84 (s, 6H, 2×CH3, N+–CH3). 13C-NMR
(75 MHz, CDCl3): δ 141.60 (CH═N+), 140.94 (CH═N+), 24.74,
63.57; H, 5.26; N, 11.35%.
24.70 (N+–CH3).
General procedure of synthesis of regioselective
General procedure of synthesis of diastereoselective
bisisoxazolidine derivatives in water (Table 1; entry 4).
Methyl acrylate (2 equivalent) was added to a solution of
bisnitrone (1 equivalent; R = C6H5) in water (15 mL), and the
reaction mixture was stirred at RT for an appropriate time
(Table 1). After completion of reaction, as indicated by TLC
(Rf = 0.76), the reaction mixture was extracted with diethyl
ether (3 × 10 mL), the organic layer was washed with
saturated brine (2 × 15 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. The resulting crude product was
directly charged on silica gel column and eluted with a
mixture of ethyl acetate:n-hexane (1:6) to afford pure
bisisoxazolidine 5 (Table 1, entry 4, 88%) as colorless liquid.
Same methodology was followed for other substrate depicted
bisisoxazolidine derivatives in water (Table 1; entry 1). N-
methylmaleimide (2 equivalent) was added to a solution of
bisnitrone (1 equivalent; R = CH3) in water (15 mL), and the
reaction mixture was stirred at RT for an appropriate time
(Table 1). After completion of reaction, as indicated by TLC
(Rf = 0.68, 0.62), the reaction mixture was extracted with
diethyl ether (3 × 10 mL), the organic layer was washed with
saturated brine (2 × 15 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The resulting crude products were directly
charged on silica gel column and eluted with a mixture of
ethyl acetate:n-hexane (1:6) to afford pure bisisoxazolidines 2
(Table 1, entry 1, 94% and 6%, respectively) as yellowish white
crystals. Same methodology was followed for other substrates
depicted in Table 1.
in Table 1.
Spectral data of regioselective bisisoxazolidine derivatives
Both the major and minor bis diastereomers gave satisfactory
1H-NMR, 13C-NMR, MS, IR, and elemental analyses data.
Spectral data of the major bis diastereomers are represented as
(5–6)
(3S,5S)-Methyl-3-(((5′R)-5-(methoxycarbonyl)-2-phenylisoxa
zolidine-3-yl)methyl)-2′-phenyl isoxazolidine-5′-carboxylate 5.
5 (entry 4, Table 1): Colorless gummy liquid, Yield 88%; Rf = 0.58;
FTIR (KBr): υmax 3026 (m), 2890 (m), 1760 (s), 1664 (s), 1485 (m),
783 (s) cmÀ1. 1H-NMR (CDCl3): δ 8.07–8.02 (m, 5H, C6H5), 7.52–
7.45 (m, 5H, C6H5), 3.72 (dd, 2×1H, J= 5.44, 5.40 Hz, C4H, endo),
3.43 (s, 2×3H, –COOCH3), 2.96 (d, 2H, J= 6.32 Hz, 2×C5H), 2.59
(d, 2H, J= 6.30 Hz, 2×C3H), 1.24 (dd, 2×1H, J= 2.80, 2.82 Hz, C4H).
13C-NMR (CDCl3): δ 170.24, 170.15 (carbonyl carbons), 129.47,
129.38, 129.25, 129.17 (aromatic carbons), 70.46(C5, C5′),
60.54 (C3, C3′), 52.49 (C4, C4′), 17.22, 17.07 (ester methyl
carbons). FAB-MS (m/z): 412 (M+), 206, 205, 147, 129, 77,
59. Calcd for C22H24O6N2: C, 64.05; H, 5.86; N, 6.79%.
follows.
Spectral data of diastereomeric bisisoxazolidine derivatives
(2–4)
(3R, 3aR, 6aS)-Dihydro-3-((3′S, 3′aS, 6aR)-hexahydro-2,5-
dimethyl-4,6-dioxo-2H-pyrrolo[3,4-d]isoxazol-3-yl)-2′, 5′-dimethyl-2
H-pyrrolo[3,4-d]isoxazole-4,6(5H, 6aH) dione 2.
2 (entry 1,
Table 1): Yellowish white crystals, Yield 94%; Rf =0.68; FTIR
(KBr): υmax 2820 (m), 1760 (s), 1675 (s), 1465 (m), 1230 (m), 1125
1
(s) cmÀ1. H-NMR (CDCl3): δ 3.31 (d, 2H, J=4.06Hz, 2×C5H),
3.10 (s, 6H, 2×ONCH3), 2.99 (s, 6H, 2×(O═C)NCH3), 2.85 (d, 2H,
J= 4.22 Hz, 2×C3H), 2.50 (dd, br, 2H, 2×C4H). 13C-NMR (CDCl3):
δ 174.78, 173.12 (carbonyl carbons), 75.80 (C5, C5′), 69.94 (C3,
C3′), 56.77 (C4, C4′), 26.63, 26.58 (methyl carbons). FAB-MS
(m/z): 338 (M+), 169, 168, 154. Calcd for C14H18O6N4: C, 49.68;
Found: C, 63.97; H, 5.74; N, 6.70%.
(3S, 5S)-2-Methyl-3-(((5′R)-2′-methyl-5-phenylisoxazolidin-
3-yl)methyl)-5′-phenylisoxazolidine 6.
6 (entry 5, Table 1):
Greenish thick liquid, Yield 83%; Rf = 0.52; FTIR (KBr): υmax
H, 5.36; N, 16.56%. Found: C, 49.53; H, 5.25; N, 16.44%.
(3R, 3aR, 6aS)-Dihydro-3-((3′S, 3′aS, 6aR)-hexahydro-4,6-
1
3215 (m), 2905 (m), 2245 (s), 1484 (m), 780 (s) cmÀ1. H-NMR
dioxo-2,5-diphenyl-2H-pyrrolo[3,4-d]isoxazol-3-yl)-2′, 5′-diphenyl-2
(CDCl3): δ 7.88–7.73 (m, 5H, C6H5), 7.50–7.44 (m, 5H, C6H5),
3.60 (dd, 2×1H, J = 6.24, 6.22 Hz, C4H, endo), 2.76 (d, 2H,
J = 6.06 Hz, 2×C5H), 2.62 (d, 2H, J = 6.28 Hz, 2×C3H), 2.30
(s, 2×3H, N–Me protons), 1.70 (dd, 2×1H, J = 3.66, 3.62 Hz,
C4H). 13C-NMR (CDCl3): δ 136.67, 136.58, 136.52, 136.38,
131.80, 131.72, 131.55, 131.23 (aromatic carbons), 73.60
(C5, C5′), 58.45 (C3, C3′), 55.37 (C4, C4′), 36.64, 35.21 (N–Me
carbons). FAB-MS (m/z): 324 (M+), 246, 161, 147, 77. Calcd
for C20H24O2N2: C, 74.03; H, 7.45; N, 8.64%. Found: C,
73.95; H, 7.33; N, 8.59%.
H-pyrrolo[3,4-d]isoxazole-4,6(5H, 6aH)dione 3.
3 (entry 2,
Table 1): White crystals, Yield 91%; Rf = 0.66; FTIR (KBr):
υmax 3025 (m), 2830 (m), 1764 (s), 1660 (s), 1485 (m), 1345
(m), 784 (s) cmÀ1 1H-NMR (CDCl3): δ 7.36–7.26 (m, 10H,
.
2×(O═C)NC6H5), 6.62–6.50 (m, 10H, 2×ONC6H5), 2.11 (dd,
br, 2H, 2×C4H), 1.85 (d, 2H, J = 6.00 Hz, 2×C5H), 1.67 (d, 2H,
J = 6.10 Hz, 2×C3H). 13C-NMR (CDCl3): δ 172.40, 172.26
(carbonyl carbons), 138.83, 138.12, 137.94, 137.71, 129.74,
129.70, 129.33, 129.04 (aromatic carbons), 76.15 (C5, C5′),
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B. Chakraborty and G. Prasad Luitel
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Acknowledgments. We are pleased to acknowledge the financial
support from the Department of Science 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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