Inexpensive ionic liquid mediated green synthetic approach of multi-functionalized regioselective β-lactam fused isoxazolidine heterocyclic hybrids

Article abstract of DOI:10.1016/j.tet.2016.12.004

A novel efficient eco-friendly on “ionic liquid” method has been developed for the synthesis of multi-functionalized isoxazolidines through a nitrone 1,3-dipolar cycloaddition reaction. The low cost and eco-benign room temperature ionic liquid, acetylchol

Full text of DOI:10.1016/j.tet.2016.12.004

Accepted Manuscript
Inexpensive ionic liquid mediated green synthetic approach of multi-functionalized
regioselective β-lactam fused isoxazolidine heterocyclic hybrids
Govindasami Periyasami, Natarajan Arumugam, Ali Aldalbahi
PII:
S0040-4020(16)31272-8
10.1016/j.tet.2016.12.004
TET 28296
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 August 2016
Revised Date: 20 November 2016
Accepted Date: 6 December 2016
Please cite this article as: Periyasami G, Arumugam N, Aldalbahi A, Inexpensive ionic liquid mediated
green synthetic approach of multi-functionalized regioselective β-lactam fused isoxazolidine heterocyclic
hybrids, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.004.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Inexpensive ionic liquid mediated green synthetic approach of multi-
functionalized regioselective
hybrids
β-lactam fused isoxazolidine heterocyclic
Govindasami Periyasami*, Natarajan Arumugam, Ali Aldalbahi*
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455,
Riyadh 11451, Saudi Arabia.
Abstract: A novel efficient eco-friendly on “ionic liquid” method has been developed
for the synthesis of multi-functionalized isoxazolidines through a nitrone 1,3-dipolar
cycloaddition reaction. The low cost and eco-benign room temperature ionic liquid,
acetylcholine iodide-ethylene glycol (ACI/EG) accelerates the formation of the desired
regioselective mono-/di isoxazolidine analogues and reduced the reaction time with high
level of chemical yield. Furthermore, the recyclability of ACI/EG has also been
investigated.
Key words: Nitrone Cycloaddition, Isoxazolidines, β-Lactam, Regioselectivity, Ionic
liquid.
* Corresponding authors: Tel: +351 218419684/756; E-mail address:
pkandhan@ksu.edu.sa (G. Periyasami); aaldalbahi@ksu.edu.sa (Ali Aldalbahi)
1. Introduction
Beyond their well-known biological properties, oxazolidine derivatives and various
β-lactam antibiotics have also been used as building blocks in the stereo controlled
synthesis of complex organic compounds.1 Isoxazolidine functional group play key
roles in several transformations,2 and their analogues are interesting intermediates for
the synthesis of β-amino alcohol and alkaloids. In particular, one of the highly
biological active Gelsemium alkaloids and their building blocks can be synthesized from
isoxazolidine analogues by ring contraction.2d Modified spiro isoxazolidines have also
been proved to efficiently inhibit in vitro and in vivo viral infections caused by sexual
transmission.3 In addition, functionalized isoxazolidine derivatives are known to
possess antifungal, anti-inflammatory, antiviral, and herbicidal properties.4 Azetidine-2-
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one is an another important heterocyclic scaffold as it is prevalent in many antibiotics
such as penicillins, cephalosporins, carbapenems, nocardicins and monobactams.5
Based on the precedents outlined above, we reasoned the combination of the
isoxazolidine and azetidine-2-one motifs in a single molecule would be of interest in the
context of antimicrobial drug discovery.6 Accordingly, research in exploring strategies
for the preparation of functionalized novel isoxazolidine analogues were fascinating for
many decades and it can be effectively synthesized from 1,3-dipolar cycloaddition
reaction between nitrones and electron deficient dipolarophiles. Certainly, 1,3-dipolar
cycloaddition reaction is one of the best known methods to afford, particularly 5-
membered heterocyclic derivatives due to its direct, regio-specific, and stereo-controlled
approach.7 Particularly, nitrone cycloaddition is a quite useful method for the
construction of nitrogen-containing carbon frameworks i.e., carbon-carbon bonds (C=C)
and carbon-oxygen bonds (C=O) in a one- pot reaction.
Considering the growing environmental impacts of organic volatile solvents,
organic reactions conceded on ‘green solvents’ like ionic liquids (ILs) have become one
of the most absorbing area in environmentally benign chemistry. Despite their green
credentials,8 many of the IL reactions require high temperature, prolonged reaction time
and complicated purification processes. The choice of room temperature ionic liquids
(RTILs) in organic synthesis overcome those limitations besides their easy obtainability.
Particularly, imidazolium ionic liquids possess excellent ionic conducting nature and
low volatilities, and are thus encouraging to be utilized as an alternative to the
commonly used organic solvents for eco-friendly reactions.9 In 2008, considering their
cost effect and drastic conditions, Jhong et al.,10 made attempt to prepare quaternary
ammonium salts based RTILs. Recently, S-Y Lu et al.11 synthesized low price
quaternary ammonium salts based RTILs called acetylcholine iodide-ethylene glycol
(ACI/EG) and utilized as low volatile electrolyte for dye sensitized solar cells. ACI/EG
RTILs can be easily prepared by simply mixing and heating quaternary ammonium salt
acetylcholine iodide (ACI) with hydrogen bond donor ethylene glycol (EG). RTILs
gains importance due to their simple preparation and unexplored solvent medium in
nitrone cycloaddition reactions.
2. Results and Discussion
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We chose novel β-lactam fused bicyclic nitrone and hydroxy allylic ketone
derivatives prepared from vinyl β-lactam aldehyde and vinyl ester / nitrile, respectively.
The hydroxy allylic Baylis-Hillman (BH) adduct would be of great interest as alkenes
have proven to be useful precursors for the synthesis of multifunctional heterocycles
and biologically active molecules.12 Besides that the hydroxy allylic BH adduct was
efficient dipolarophile due to the presence of electron withdrawing group. The synthetic
strategy used for construction of highly regioselective isoxazolidines is shown in Figure
1.
Se
H
H
O
O
N
O
O
1
5
OH
4
2
3
N
O
H
H
O
MeO
Intramolecular
hydrogen bonding
OMe
Intramolecular hydrogen
bondingstabilized by six
member ring
C
O bond formation
NOH
N
H
O
O
O
O
O
Se
H
H
O
O
O
N
H
O
O
O
CHO
N
COOEt
N
Intermolecular
1,3-dipolar
O
cycloaddition
C
C bond
MeO
OMe
formation
Figure 1. Synthetic strategy of β-lactam fused polycyclic isoxazolidine moieties.
β-Lactam bicyclic nitrones were prepared,13, 6a as regioisomeric mixture in good
yield, by the reaction of vinyl
β
-lactam aldehyde 1 with hydroxylamine hydrochloride
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in the presence of Et3N. Initially β–lactam oxime 2 was obtained, which was then
treated with phenylselenyl bromide in dry CH2Cl2 at room temperature followed by the
addition of Et3N to furnish the bicyclic nitrones 3a and 3b (67:33), which were easily
separated by flash column chromatography (Scheme 1).
Scheme 1. Synthesis of β-lactam fused phenylselenylbicyclic nitrone 3a and 3b
The various required substituted hydroxy allylic BH adducts were prepared (Scheme
2) by the reaction of corresponding di/tri ketone with acrylates in the presence of 1,4-
diazabicyclo[2.2.2]octane (DABCO) as base.14
Scheme 2. Synthesis of hydroxy allylic BH adducts
The synthesized dipolarophiles (5a-c to 8a-c) are highly stable, possibly due to the
presence of intramolecular hydrogen bonding between electron withdrawing groups and
oxygen atom in OH group. An IR absorption band confirms our observation and the OH
group exhibit a lower frequency broad band at 3250 cm-1 due to intramolecular
hydrogen bonding between allylic OH and ester carbonyl oxygen / nitrile nitrogen
group.15a In the case of nitrile substitution (eg. 5c), the CN absorption band is at 2123
cm-1, which is in good agreement with Buckingham formula describing the frequency
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shift.15b-d Also the C=O stretching absorption peak appeared at the range of 1690 cm-1 to
1706 cm-1. From the above observations, it is clear that the availability of favored
alkene position for cycloaddition is stabilized by weak O─HꢀꢀꢀO=C / O─HꢀꢀꢀN≡C
intramolecular hydrogen bonds and the O-allylic alkene bond formation is stabilized by
stable six member ring (Figure 2).
H
H
O
O
H
O
N
O
O
O
O
O
R
R
HN
O
R
O
O
H
O
H
N
N
O
H
H
O
O
R
Figure 2. Intramolecular hydrogen bonding between electronegative atoms of BH
adducts
After extensive experimentation in various solvents (organic solvents and ionic
liquids) and reaction conditions like various temperature with various time interval, we
established that the cycloadducts were obtained in high yields by using ACI/EG RTIL
as a suitable medium at room temperature condition. This optimized reaction conditions
were investigated (Table 1) by the reaction of an equimolar quantity of hydroxy allylic
BH adduct 5a derived from ninhydrin and methylacrylate 4a, with isolated 1,3-dipolar,
β
-lactam fused phenylselenylbicyclic nitrone 3a furnished indanedione substituted β-
lactam fused polycyclic novel isoxazolidines 9a in ACI/EG RTIL medium at room
temperature. The cycloadducts 9a was obtained around ~15% to 20% yield in organic
solvents. The same reactant undergoing cycloaddition in ILs gives better chemical yield
from 43% to 55% even though it requires temperature for activation. But, the ACI/EG
RTIL medium afforded excellent yield 92% with high selectivity and also in shorter
reaction time at room temperature. The used ACI/EG was recovered by vacuum
distillation and dried under vacuum at 40 °C overnight and then recycled. The utility of
recovered RTIL was presented in Table 2.
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Table 1. Solvent condition and reaction time optimization of cycloaddition
Entry
Solvent system
Time Yield
(h)
48
48
48
24
48
24
6
6
6
8
8
(%)
20
20
trace
20
-
15
43
52
48
46
44
55
92
90
1
2
3
4
5
6
7
8
Ethanol
Methanol
Acetonitrile
Dry MeCN
Dry dioxane
Dioxane/MeCN (1:1)
[Bmim][Cl]
[Bmim][Br]
[Bmim][Tfa]
9
10
11
12
13
14
[Bmim][PF6]
[Bmim][BF4]/CuI (10 mol%)
[Bmim][BF4]/Cu(OTf) (10 mol%)
ACE/EG, rt
6
1
2
ACE/EG, 60 °C
General conditions: Optimized reaction conditions are in bold (entry 13, 14)
Ionic liquids were subjected to high vacuum before use (entry 7-14)
Table 2. Reusability in various cycles of recovered ACE/EG in the synthesis of 5a at
room temperature
Yield percentage of isoxazolidine 5a in experiments
Medium
First
90
Second
Third
Fourth
Fifth
85
Recovered
ACE/EG
90
87
87
The synthesis of indanedione substituted β-lactam fused polycyclic novel
isoxazolidines (9a-c) was achieved by the addition of an equimolar quantity of hydroxy
allylic BH adduct (5a-c) derived from ninhydrin, with isolated 1,3-dipolar, β-lactam
fused phenylselenylbicyclic nitrone 3a, in ACI/EG RTIL medium at room temperature
(Scheme 3).
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Scheme 3. Synthesis of β-lactam fused polycyclic isoxazolidines 9a-c
The systematic structure analysis for the synthesized cycloadducts to arrive at the
proposed regiochemistry was carried out using one and two-dimensional NMR
spectroscopic techniques. For instance, the IR spectrum of cycloadduct 9b showed three
characteristic peaks at 1755 cm-1, 1740 cm-1 and 1703 cm-1 due to
β-lactam and
ninhydrin carbonyl carbons. The regiochemistry of the cycloadduct 9b was initially
1
determined by its H NMR spectrum, which showed two multiplets in the range δ =
2.43–2.50 ppm and δ = 2.74–2.80 ppm corresponding to isoxazolidine ring methylene.
The presence of two multiplets instead of two doublets for isoxazolidine ring
diastereotopic methylene protons strongly ruled out the formation of other regioisomer
10b. That the Hd proton shows multiplet between δ = 2.43-2.80 ppm supports formation
of regioisomer 9b. The 13C NMR spectrum of 9b exhibited a peak at δ = 164.5 ppm and
δ = 168.9 ppm due to β-lactam and ester carbonyl carbons, respectively. The peaks at δ
= 194.4 ppm and δ = 197.6 ppm corresponded to two carbonyl carbons of the ninhydrin
moiety. The quaternary carbon showed a peak at δ = 85.8 ppm. The off-resonance
decoupled 13C NMR spectrum of 9b showed a triplet at δ = 29.8, δ = 34.5 and δ = 63.4
due to three methylene carbons in the cycloadduct which is also confirmed by DEPT-
1
135 NMR spectrum. H–1H COSY studies indeed showed that cross-peaks were
observed among Ha–He, Ha–Hb; Hb–Hc, Hb–Ha; He–Hd1 and He–Hd2 resonances, whereas
1
the H–13C COSY spectra showed connectivity between the methylene carbons with
corresponding methylene protons; thus, δC = 60.8 (J = 3.67–3.72); δC = 34.5 with Hd
protons and δC = 29.9. Furthermore, the presence of the molecular ion peak at m/z
661.56 (M+) in the mass spectrum of 9b supported the formation of the cycloadduct and
the compound gave satisfactory elemental analysis.
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With the background of theoretical studies, the regioselectivity and endo/exo ratio of
nitrone type dipolar cycloaddition reaction depends on the nature of the dipolarophile,
related to the size of reactants and several environmental factors of the reaction
including solvent systems.16 As we used RTILs as highly polar solvent medium and the
highly rigid dipolar and dipolarophile support the formation of cycloadduct through less
hindered facial selectivity. The assignments of all the hydrogens and carbons of
cycloadduct 9b will be essential for stereochemistry and regiochemistry determination,
particularly the multiplicity between Hc and Hd protons confirms the regiochemistry of
the cycloadduct. Also, the absence of interaction between OH proton with Hd protons
for methylene protons of isoxazolidine ring shows that the intramolecular hydrogen
bond between OH and COOEt is undisturbed during the formation of cycloadducts. In
addition, the intramolecular hydrogen bonding in BH dipolarophile causes the lowering
of LUMOalkene energy level and reduction of the HOMOalkene/LUMOnitrone energy gap.17
Such an interaction also influenced the regioselectivity of adducts during the formation
for transition state in addition reaction. As it can be seen from the above discussion, the
formation of regioisomer 9b is highly favorable and the unfavorable environment for
the formation of regioisomer 10b. Similar results were observed when the reaction was
carried out with isatin dipolarophiles (6a-c) giving cycloadducts (11a-c) in Scheme 4
and acenaphthoquinone dipolarophiles (7a-c) giving cycloadducts (13a-c) in Scheme 5
respectively. The NMR spectra details were discussed in the experimental section and
spectra were presented in supporting information.†
Scheme 4. Synthesis of β-lactam fused polycyclic isoxazolidines 11a-c
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O
O
N
Hc
Ph
HO
Se
Hb
Hc
R
O
Se
Hb
O
Ha
N
N
Hc
O
OH
(i)
O
(i)
N
Hd1
Hd2
3a
Se
H
e R
He
O
Ha
O
N
OMe
Ha
OH
Hb
O
R
N
7a-c
MeO
OMe
14a-c
13a-c
R = a) COOMe; b) COOEt; c) CN
Reagents and conditions: (i) ACI/EG RTIL; Stirring at room temperature, 1h
Scheme 5. Synthesis of β-lactam fused polycyclic isoxazolidines 13a-c
Motivated by the aforementioned results, we sought to extend the scope of the
cycloaddition methodology using methyl 1,4-bis-(3-hydroxy-2-methylenebutanoatonyl)
benzenes (8a-c), as an bis-dipolarophile with bicyclic nitrone 3a. Synthesis of aryl-
bridged bis-isoxazolidines (15a-c) was accomplished by reacting 2.2 equivalent of
bicyclic nitrone 3a with one equivalent of bis-hydroxy allylic BH adducts (8a-c) in
ACI/EG RTIL medium at room temperature. As per our expectation, on extension of
this methodology to these reactions, the regiochemistry of the product remained
unchanged, as observed in the previous schemes (Scheme 6).
Scheme 6. Synthesis of β-lactam fused polycyclic isoxazolidines 15a-c
9

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The structure of regioisomers was elucidated using standard spectroscopic studies.
1
Considering an example of nitrile substituted adduct 15c, in the H NMR spectrum, it
showed a singlet at δ = 5.10 ppm due to the benzylic proton. As observed in the earlier
case, isoxazolidine ring methylene protons resonate as two multiplets in the range δ =
2.51-2.57 ppm and δ = 2.87-2.95 ppm which confirm the regiochemistry of the
cycloadduct. The presence of these two multiplets and the absence of two doublets for
isoxazolidine diastereotopic methylene protons strongly ruled out the formation of other
regioisomer 16c. The 13C NMR spectrum of 15c exhibited a peak at δ = 163.8 ppm due
to β-lactam carbonyl carbon. The peak corresponding to CN attached quaternary carbon
appeared at δ = 80.9 ppm and, DEPT-135 studies confirmed that two methylene carbons
are present in the cycloadduct at δ = 30.5 and δ = 35.8 ppm. The mass spectrum of
compound 15c exhibited molecular ion peak at MALDI-TOF m/z 1042.88 (M+), which
confirmed the formation of cycloadduct and the compound gave satisfactory elemental
analysis. Similar results were observed for the cycloadducts 15a and 15b. NOE
irradiation of OH proton in 15c at δ = 2.17 did not cause any enhancement of the signal
for Hd1 and Hd2 protons of isoxazolidinyl ring. All the NMR mass spectra details were
presented in supplementary information.† The yield and results of the synthesized β-
lactam fused polycyclicisoxazolidines were summarized in Table 3.
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Table 3: Synthesis of β-lactam fused polycyclic isoxazolidine derivatives in ACI/EG
RTIL medium through intermolecular 1,3-dipolar cycloaddition methodology
BH
dipolarophile
β-lactam
nitrone
β-lactam fused
polycyclicisoxazolidinesa,b
Entry
Yield (%)c
1.
92
88
90
93
95
92
91
90
92
88
90
88
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
2.
3.
9c
4.
11a
11b
11c
13a
13b
13c
15a
15b
15c
5.
6.
7.
8.
9.
10.
11.
12.
a
Reaction conditions: Stirring at rt in ACI/EG RTIL medium.
b Completion of the reaction monitored by TLC.
c Yield of the isolated product after flash column chromatography.
3. Conclusion
In conclusion, highly regioselective polyfunctionalized β-lactam fused isoxazolidine
heterocyclic hybrids were synthesized by 1,3-dipolar nitrone cycloaddition of β-lactam
fused bicyclic nitrone with hydroxy allylic alkene derived from BH reaction and were
economically achieved in RTIL medium. Comparing the yield and reactivity in organic
solvents medium, it is clear that the high regioselectivity with shorter reaction time in
11

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eco-friendly RTIL ACI/EG medium in room temperature plays a role. ACI/EG RTIL
medium has never been used previously for cycloaddition reactions and it is reported for
first time, showing remarkable reaction rate and selectivity even in hydroxy allylic
dipolarophile. This ionic liquid medium offers high synthetic scope for the synthesis of
highly regioselective novel class of bifunctional fused heterocycles. Also, recycling of
ACI/EG has proved the ionic liquid’s activity and selectivity.
4. Experimental
4.1. General information
All melting points are uncorrected. IR spectra were recorded on a SHIMADZU FT-IR
1
13
8300 instrument. H and C NMR spectra were recorded in CDCl3 using TMS as an
internal standard on BRUKER 300 MHz, mass spectra were recorded on JEOL- DX303
HF mass spectrometer and BRUKER DALTONICS FLEX Analysis spectrometer.
Elemental analyses were carried out on a Perkin-Elmer 2400B instrument. Column
chromatography was performed on silica gel (ACME, 100-200 mesh). Routine
monitoring of the reactions was made using thin layer chromatography developed on
glass plates coated with silica gel-G (ACME) of 25 mm thickness and visualized with
1
13
iodine. After purification, all compounds were characterized by FTIR, H-NMR, C-
NMR, 2D-NMR (1H-1H COSY, 1H-13C COSY, DEPT-135).
4.2. General Procedure for the Synthesis of 2-azetidinone-tethered oximes, 2
Hydroxylamine hydrochloride (2.00 mmol) and triethylamine (2.00 mmol) were
sequentially added at room temperature to a well stirred solution of the corresponding 4-
oxoazetidine-2-carbaldehyde 1 (1.00 mmol) in benzene (10 mL). After the resulting
suspension was stirred at room temperature overnight, the solvent was removed under
reduced pressure. Then, the mixture was diluted with dichloromethane and washed with
saturated aqueous NaHCO3 and then water. The combined organic extract was dried
with anhydrous Na2SO4 and concentrated under reduced pressure. Chromatography of
the residue eluting with ethyl acetate gave analytically pure compound 2.
4.3. General Procedure for the Synthesis of Bicyclic Nitrones, 3a
Phenylselenyl bromide (1.00 mmol) was added at room temperature to a well
stirred solution of the β–lactam oxime 2 (1.00 mmol) in dichloromethane (20 mL).
12

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After the resulting suspension was stirred at room temperature for 3 h, triethylamine
(1.00 mmol) was added and the mixture was stirred for an additional 1 h. The solvent
was removed under reduced pressure. Then, the mixture was diluted with
dichloromethane and washed with brine and water. The organic extract was dried with
anhydrous Na2SO4 and concentrated under reduced pressure. Chromatography of the
residue eluting with ethyl acetate/hexanes (1:3) mixture gave analytically pure
compounds bicyclic nitrones 3a.
4.4. General procedure for the synthesis of dipolarophiles, 5a-c to 8a-c
To a stirred solution of diketone / triketone (1.0 mmol) and corresponding
acrylate (2.0 mL) was added DABCO (0.1 mmol) and stirred 50-60 °C for 60 min – 180
min. After completing the reaction evidenced by TLC, reaction mixture was diluted
with dichloromethane and water. The organic extract was dried with anhydrous Na2SO4
and concentrated under reduced pressure. The crude was purified by flash column
chromatography (hexane/ethyl acetate, 1:1), we could obtain the desired dipolarophiles
5a-c to 8a-c in good yield.
4.5. General procedure for the synthesis of cycloadducts, 9a–c
The bicyclic nitrone (3a) (500 mg, 1.25 mmol) and BH adduct, 2,3-dihydro-2-
hydroxy-1,3-dioxo-1H-inden-2-yl)acrylates (5a–c) (306 mg, 1.25 mmol) was added in
ACI/EG (10 mL) RTIL medium at room temperature and then stirred another 1 h. After
completion of the reaction, evident by TLC, ionic liquid was distilled off under reduced
pressure. 10 – 20 mL of chloroform was added in the residue and stirred for another
10–15 min. The organic layer was washed with brine (2 × 10 mL), dried over anhydrous
Na2SO4 and the solvent removed under reduced pressure and then crude cycloadducts
were purified by flash column chromatography using hexane/ethyl acetate mixture
(8:2). The purified isoxazolidines (9a-c) were subjected to spectroscopy analysis for
structure determination.
4.5.1. 6-(1-Hydroxyindane-2,3-dione-1-yl)-6-methoxycarbonyl-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 9a.
(92%); Colorless solid, mp 118-120 °C; FTIR (KBr) 3245, 1753, 1742, 1726, 1705
1
cm-1; H (300 MHz, CDCl3) δ 2.15 (s, 1H), 2.40-2.48 (m, 1H, Hd1), 2.70-2.79 (m, 1H,
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Hd2), 3.69 (s, 3H), 3.76 (s, 3H, OMe), 3.70-3.75 (m, 2H, PhSeCH2), 3.77-3.83 (m, 1H,
Ha), 3.86-3.89 (m, 1H, Hc), 3.92-3.96 (m, 1H, He), 4.60-4.64 (m, 1H, Hb), 6.88-8.06 (m,
13
13H, ArH); C (75 MHz, CDCl3) 29.8, 34.5, 55.4, 59.1, 60.8, 63.4, 64.1, 66.8, 85.8,
114.4, 117.3, 123.5, 127.5, 129.4, 131.1, 132.8, 135.4, 135.9, 140.8, 143.1, 156.1,
164.5, 169.2, 194.4, 197.7 ppm; EI-MS m/z 647.53 (M+). Anal. Calcd for
C32H28N2O8Se: C, 59.35; H, 4.36; N, 4.33 %. Found: C, 59.48; H, 4.48; N, 4.25 %.
4.5.2. 6-(1-Hydroxyindane-2,3-dione-1-yl)-6-ethoxycarbonyl-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 9b.
(88%); Colorless solid, mp 126-128 °C; FT-IR (KBr) 3250, 1755, 1740, 1726, 1703
1
cm-1; H (300 MHz, CDCl3) δ 0.91 (t, 3H, J 7.2, 7.5 Hz, COOCH2CH3), 2.17 (s, 1H),
2.43-2.50 (m, 1H, Hd1), 2.74-2.80 (m, 1H, Hd2), 3.67-3.72 (m, 2H, PhSeCH2), 3.77 (s,
3H, OMe), 3.78-3.86 (m, 1H, Ha), 3.89-3.91 (m, 1H, Hc), 3.92-3.94 (m, 1H, He), 4.12
(q, 2H, J 6.9, 6.9 Hz, COOCH2CH3), 4.59-4.62 (m, 1H, Hb), 6.81-7.98 (m, 13H, ArH);
13C (75 MHz, CDCl3) 13.6, 29.9, 34.5, 55.4, 59.1, 60.8, 63.4, 64.1, 66.8, 85.8, 114.4,
117.3, 123.5, 127.5, 129.4, 131.1, 132.9, 135.3, 135.9, 140.9, 143.0, 156.1, 164.5,
168.9, 194.4, 197.6 ppm; EI-MS m/z 661.56 (M+). Anal. Calcd for C33H30N2O8Se: C,
59.91; H, 4.57; N, 4.23 %. Found: C, 60.02; H, 4.66; N, 4.11 %.
4.5.3.
6-(1-Hydroxyindane-2,3-dione-1-yl)-6-cyano-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 9c.
(90%); Colorless solid, mp 122-124 °C; FTIR (KBr) 3242, 2223, 1754, 1739, 1706
1
cm-1; H (300 MHz, CDCl3) δ 2.19 (s, 1H), 2.46-2.53 (m, 1H, Hd1), 2.77-2.84 (m, 1H,
Hd2), 3.66-3.70 (m, 2H, PhSeCH2), 3.79 (s, 3H, OMe), 3.80-3.88 (m, 1H, Ha), 3.90-3.92
(m, 1H, Hc), 3.91-3.94 (m, 1H, He), 4.58-4.62 (m, 1H, Hb), 6.86-8.14 (m, 13H, ArH);
13C (75 MHz, CDCl3) 29.9, 34.5, 55.5, 59.2, 63.4, 64.1, 66.9, 85.9, 114.6, 117.4, 120.1,
123.5, 127.5, 129.6, 131.1, 132.8, 135.4, 135.4, 140.9, 143.2, 156.1, 164.4, 194.4,197.6
ppm; EI-MS m/z 614.51 (M+). Anal. Calcd for C31H25N3O6Se: C, 60.59; H, 4.10; N,
6.84 %. Found: C, 60.68; H, 4.01; N, 6.98 %.
4.6. General procedure for the synthesis of cycloadducts, 11a-c
The bicyclic nitrone (3a) (500 mg, 1.25 mmol) and BH adduct, 2-(3-hydroxy-2-
oxoindolin-3-yl)acrylates (6a-c) (290 mg, 1.25 mmol) was added in ACI/EG (10 mL)
14

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RTIL medium at room temperature and then stirred another 1h. After completion of the
reaction, evident by TLC, ionic liquid was distilled off under reduced pressure. 10 – 20
mL of chloroform was added in the residue and stirred for another 10–15 min. The
organic layer was washed with brine (2 × 10 mL), dried over anhydrous Na2SO4 and the
solvent removed under reduced pressure and then crude cycloadducts were purified by
flash column chromatography using hexane/ethyl acetate mixture (8:2). The purified
isoxazolidines (11a-c) were subjected to spectroscopy analysis for structure
determination.
4.6.1.
6-(3-Hydroxyindolin-2-on-3-yl)-6-methoxycarbonyl-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 11a.
1
(93%); Colorless solid, mp 162-164 °C; FTIR (KBr) 3392, 1756, 1726, 1695 cm-1; H
(300 MHz, CDCl3) δ 2.13 (s, 1H), 2.45-2.51 (m, 1H, Hd1), 2.75-2.81 (m, 1H, Hd2), 3.67
(s, 3H), 3.68-3.72 (m, 2H, PhSeCH2), 3.74 (s, 3H, OMe), 3.75-3.76 (m, 1H, Ha), 3.90-
3.93 (m, 1H, Hc), 3.95-3.97 (m, 1H, He), 4.60-4.62 (m, 1H, Hb), 6.81-7.97 (m, 13H,
13
ArH), 9.11 (s, 1H, NH); C (75 MHz, CDCl3) 30.1, 33.5, 54.4, 59.1, 60.8, 63.4, 64.1,
67.4, 86.9, 108.6, 113.4, 118.4, 122.6, 128.6, 130.5, 131.6, 137.7, 139.2, 139.9, 143.1,
156.2, 164.5, 169.5, 178.1 ppm; EI-MS m/z 634.54 (M+). Anal. Calcd for
C31H29N3O7Se: C, 58.68; H, 4.61; N, 6.62 %. Found: C, 58.80; H, 4.70; N, 6.68 %.
4.6.2.
6-(3-Hydroxyindolin-2-on-3-yl)-6-ethoxycarbonyl-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 11b.
1
(95%); Colorless solid, mp 186-188 °C; FTIR (KBr) 3384, 1752, 1728, 1691 cm-1; H
(300 MHz, CDCl3) δ 0.85 (t, 3H, J 7.5, 7.5 Hz, COOCH2CH3), 2.15 (s, 1H), 2.39-2.43
(m, 1H, Hd1), 2.69-2.75 (m, 1H, Hd2), 3.68-3.75 (m, 2H, PhSeCH2), 3.81 (s, 3H, OMe),
3.83-3.87 (m, 1H, Ha), 3.91-3.95 (m, 1H, Hc), 3.96-3.98 (m, 1H, He), 4.12 (q, 2H, J 7.2,
6.9 Hz, COOCH2CH3), 4.53-4.58 (m, 1H, Hb), 6.73-7.86 (m, 13H, ArH), 9.16 (s, 1H,
13
NH); C (75 MHz, CDCl3) 12.9, 30.6, 33.3, 54.9, 59.1, 60.9, 63.4, 64.5, 66.8, 86.6,
109.0, 113.9, 117.3, 123.6, 127.9, 129.4, 131.4, 135.3, 137.9, 140.5, 143.2, 156.2,
164.4, 169.7, 178.2 ppm; EI-MS m/z 648.56 (M+). Anal. Calcd for C32H31N3O7Se: C,
59.26; H, 4.82; N, 6.48 %. Found: C, 59.38; H, 4.91; N, 6.59 %.
15

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4.6.3.
6-(3-Hydroxyindolin-2-on-3-yl)-6-cyano-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 11c.
1
(92%); Colorless solid, mp 132-134 °C; FTIR (KBr) 3384, 2223, 1753, 1693 cm-1; H
(300 MHz, CDCl3) δ 2.18 (s, 1H), 2.43-2.51 (m, 1H, Hd1), 2.76-2.82 (m, 1H, Hd2), 3.65-
3.72 (m, 2H, PhSeCH2), 3.76 (s, 3H, OMe), 3.78-3.81 (m, 1H, Ha), 3.86-3.89 (m, 1H,
Hc), 3.90-3.93 (m, 1H, He), 4.55-4.58 (m, 1H, Hb), 6.79-7.98 (m, 13H, ArH), 9.16 (s,
13
1H, NH); C (75 MHz, CDCl3) 28.7, 33.5, 55.5, 59.1, 63.4, 64.2, 66.8, 85.9, 109.9,
114.6, 117.3, 120.1, 123.5, 127.5, 129.6, 131.1, 132.8, 135.3, 135.4, 140.9, 143.2,
156.1, 164.5, 178.2 ppm; EI-MS m/z 601.51 (M+). Anal. Calcd for C30H26N4O5Se: C,
59.90; H, 4.36; N, 9.31 %. Found: C, 59.81; H, 4.48; N, 9.39 %.
4.7. General procedure for the synthesis of cycloadducts, 13a-c
The bicyclic nitrone (3a) (500 mg, 1.25 mmol) and BH adduct, 2-(1,2-dihydro-
1-hydroxy-2-oxoacenaphthylen-1-yl) acrylates (7a-c) (335 mg, 1.25 mol) was added in
ACI/EG (10 mL) RTIL medium at room temperature and then stirred another 1h. After
completion of the reaction, evident by TLC, ionic liquid was distilled off under reduced
pressure. 10 – 20 mL of chloroform was added in the residue and stirred for another
10–15 min. The organic layer was washed with brine (2 × 10 mL), dried over anhydrous
Na2SO4 and the solvent removed under reduced pressure and then crude cycloadducts
were purified by flash column chromatography using hexane/ethyl acetate mixture
(8:2). The purified isoxazolidines (13a-c) were subjected to spectroscopy analysis for
structure determination.
4.7.1. 6-(2-Hydroxyacenaphthen-1-on-2-yl)-6-methoxycarbonyl-1-(4-methoxyphenyl)-
3-(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 13a.
1
(91%); Colorless solid, mp 242-244 °C; FTIR (KBr), 1756, 1695 cm-1; H (300 MHz,
CDCl3) δ 2.12 (s, 1H), 2.41-2.52 (m, 1H, Hd1), 2.71-2.79 (m, 1H, Hd2), 3.62 (s, 3H),
3.67-3.73 (m, 2H, PhSeCH2), 3.74-3.77 (m, 1H, Ha), 3.78 (s, 3H, OMe), 3.90-3.94 (m,
13
1H, Hc), 3.95-3.98 (m, 1H, He), 4.58-4.61 (m, 1H, Hb), 6.83-8.15 (m, 15H, ArH); C
(75 MHz, CDCl3) 28.6, 31.3, 55.5, 59.2, 63.4, 64.0, 66.6, 88.6, 105.3, 114.5, 120.6,
121.1, 122.9, 123.5, 124.6, 126.7, 127.7, 128.3, 128.5, 129.6, 130.9, 131.1, 134.2,
135.3, 137.2, 141.6, 156.2, 164.5, 201.5 ppm; EI-MS m/z 669.58 (M+). Anal. Calcd. for
C35H30N2O7Se: C, 62.78; H, 4.52; N, 4.18 %. Found: C, 62.89; H, 4.61; N, 4.26 %.
16

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4.7.2. 6-(2-Hydroxyacenaphthen-1-on-2-yl)-6-ethoxycarbonyl-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 13b.
1
(90%); Colorless solid, mp 226-228 °C; FTIR (KBr), 1752, 1691 cm-1; H (300 MHz,
CDCl3) δ 0.87 (t, 3H, J 7.2, 7.5 Hz, COOCH2CH3), 2.13 (s, 1H), 2.38-2.43 (m, 1H,
Hd1), 2.67-2.73 (m, 1H, Hd2), 3.68-3.72 (m, 2H, PhSeCH2), 3.80 (s, 3H, OMe), 3.77-
3.82 (m, 1H, Ha), 3.90-3.93 (m, 1H, Hc), 3.96-3.99 (m, 1H, He), 4.01 (q, 2H, J 7.2, 7.2
13
Hz, COOCH2CH3), 4.57-4.64 (m, 1H, Hb), 6.86-8.19 (m, 15H, ArH); C (75 MHz,
CDCl3) 12.6, 28.5, 31.3, 55.5, 59.2, 63.4, 64.0, 66.6, 88.6, 105.3, 114.5, 120.6, 121.0,
123.3, 124.5, 126.7, 127.8, 128.3, 128.6, 129.6, 130.9, 131.1, 134.2, 135.3, 137.2,
141.6, 156.2, 164.5, 201.6 ppm; EI-MS m/z 683.61 (M+). Anal. Calcd. for
C36H32N2O7Se: C, 63.25; H, 4.72; N, 4.10 %. Found: C, 63.33; H, 4.61; N, 4.18 %.
4.7.3.
6-(2-Hydroxyacenaphthen-1-on-2-yl)-6-cyano-1-(4-methoxyphenyl)-3-
(phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 13c.
1
(92%); Colorless solid, mp 210-112 °C; FTIR (KBr) 2118, 1751, 1706 cm-1; H (300
MHz, CDCl3) δ 2.15 (s, 1H), 2.39-2.45 (m, 1H, Hd1), 2.73-2.81 (m, 1H, Hd2), 3.68-3.75
(m, 2H, PhSeCH2), 3.76-3.79 (m, 1H, Ha), 3.80 (s, 3H, OMe), 3.91-3.95 (m, 1H, Hc),
13
3.96-3.99 (m, 1H, He), 4.59-4.65 (m, 1H, Hb), 6.88-8.16 (m, 15H, ArH); C (75 MHz,
CDCl3) 29.6, 30.3, 55.5, 59.2, 63.4, 64.0, 66.6, 88.6, 105.3, 114.5, 120.6, 121.0, 122.9,
123.5, 124.6, 126.7, 127.8, 128.3, 128.5, 129.6, 130.9, 131.1, 134.2, 135.3, 137.2,
141.6, 156.2, 164.5, 201.5 ppm; EI-MS m/z 636.56 (M+). Anal. Calcd for
C34H27N3O5Se: C, 64.15; H, 4.28; N, 6.60 %. Found: C, 64.27; H, 4.37; N, 6.51 %.
4.8. General procedure for the synthesis of cycloadducts, 15a-c
The bicyclic nitrone (3a) (500 mg, 1.25 mmol) and bis-BH adduct, 2-(1,2-
dihydro-1-hydroxy-2-oxoacenaphthylen-1-yl) acrylates (8a-c) (180 mg, 0.05 mmol)
was added in ACI/EG (10 mL) RTIL medium at room temperature and then stirred
another 1h. After completion of the reaction, evident by TLC, ionic liquid was distilled
off under reduced pressure. 10 – 20 mL of chloroform was added in the residue and
stirred for another 10–15 min. The organic layer was washed with brine (2 × 10 mL),
dried over anhydrous Na2SO4 and the solvent removed under reduced pressure and then
crude cycloadducts were purified by flash column chromatography using hexane/ethyl
17

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acetate mixture (7:3). The purified isoxazolidines (15a-c) were subjected to
spectroscopy analysis for structure determination.
4.8.1.
6-[1,4-Phenylenebis(hydroxymethyl-1-yl)]-6,6'-bi(methoxycarbonyl)-1-
(4-methoxyphenyl)- 3- (phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]
isoxazol-2-one, 15a. (88%); Colorless solid, mp 222-224 °C; FTIR (KBr) 3200, 2128,
1753 cm-1; 1H (300 MHz, CDCl3) δ 2.17 (s, 2H), 2.49-2.56 (m, 2H, Hd1), 2.72-2.79 (m,
2H, Hd2), 2.97-3.12 (m, 4H, PhSeCH2), 3.30 (s, 6H, COOMe), 3.76 (s, 6H, OMe), 3.79-
3.81 (m, 2H, Ha), 4.08-4.10 (m, 2H, Hc), 4.32-4.35 (m, 2H, He), 4.49-4.51 (m, 2H, Hb),
13
5.03 (s, 2H, benzylicproton), 6.69-7.59 (m, 22H, ArH); C (75 MHz, CDCl3) 30.6,
32.7, 52.5, 55.3, 55.4, 57.0, 59.6, 63.3, 64.6, 90.2, 114.2, 114.4, 117.2, 126.5, 126.6,
126.9, 127.5, 129.3, 131.1, 133.2, 133.3, 137.8, 156.1, 164.4, 170.1 ppm; MALDI-TOF
m/z 1108.97 (M+). Anal. Calcd for C54H54N4O12Se2: C, 58.49; H, 4.91; N, 5.05 %.
Found: C, 58.58; H, 4.80; N, 5.16 %.
4.8.2.
6-[1,4-Phenylenebis(hydroxymethyl-1-yl)]-6,6'-bi(ethoxycarbonyl)-1-
(4-methoxyphenyl)-3- (phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]
isoxazol-2-one, 15b. (90%); Colorless solid, mp 254-256 °C; FTIR (KBr) 3235, 2122,
1
1755 cm-1; H (300 MHz, CDCl3) δ 0.82 (t, 3H, J 7.2, 6.9 Hz, COOCH2CH3), 2.18 (s,
2H), 2.50-2.56 (m, 2H, Hd1), 2.73-2.81 (m, 2H, Hd2 ), 2.98-3.12 (m, 4H, PhSeCH2), 3.79
(s, 6H, OMe), 3.80-3.83 (m, 2H, Ha), 3.96 (dq, 4H, J 6.9, 7.5 Hz, COOCH2CH3), 4.10-
4.13 (m, 2H, Hc), 4.34-4.36 (m, 2H, He), 4.39-4.43 (m, 2H, Hb), 5.11 (s, 2H,
benzylicproton), 6.71-7.82 (m, 22H, ArH); 13C (75 MHz, CDCl3) 13.7, 30.6, 29.8, 33.9,
55.3, 55.8, 57.1, 59.6, 63.3, 64.6, 90.2, 114.2, 114.5, 117.2, 126.5, 126.6, 126.9, 127.5,
129.3, 131.1, 133.3, 133.5, 137.7, 156.1, 164.4, 171.0 ppm; MALDI-TOF m/z 1137.03
(M+). Anal. Calcd for C56H58N4O12Se2: C, 59.16; H, 5.14; N, 4.93 %. Found: C, 59.25;
H, 5.22; N, 5.01 %.
4.8.3. 6-[1,4-Phenylenebis(hydroxymethyl-1-yl)]-6,6'-bi(cyano)-1-(4-methoxyphenyl)-
3- (phenylselenenylmethyl)octahydroazeto[2',3':3,4]pyrrolo[1,2-b]isoxazol-2-one, 15c.
1
(88%); Colorless solid, mp 228-230 °C; FTIR (KBr) 3218, 2123, 1755 cm-1; H (300
MHz, CDCl3) δ 2.17 (s, 2H), 2.51-2.57 (m, 2H, Hd1), 2.87-2.95 (m, 2H, Hd2), 2.98-3.12
(m, 4H, PhSeCH2), 3.74 (s, 6H, OMe), 3.85-3.87 (m, 2H, Ha), 4.10-4.14 (m, 2H, Hc),
18

ACCEPTED MANUSCRIPT
4.24-4.25 (m, 2H, He), 4.68-4.72 (m, 2H, Hb), 5.10 (s, 2H, benzylic proton), 6.82-7.87
13
(m, 22H, ArH); C (75 MHz, CDCl3) 30.5, 30.8, 35.8, 55.4, 57.1, 59.8, 63.6, 65.6,
80.9, 114.6, 117.8, 127.8, 127.9, 129.0, 129.5, 129.6, 130.5, 133.3, 136.7, 142.4, 156.5,
163.8 ppm; MALDI-TOF m/z 1042.88 (M+). Anal. Calcd for C52H48N6O8Se2: C, 59.89;
H, 4.64; N, 8.06 %. Found: C, 59.98; H, 4.72; N, 8.13 %.
Acknowledgement
Authors acknowledge the support by the Deanship of Scientific Research, College
of Science Research Centre at King Saud University.
Supplementary data
† Supplementary data (NMR, MALDI-TOF spectra of representative compounds
are given in supplementary information material).
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