Solvent-free one-pot 1,3-dipolar cycloaddition reactions of dihydropyran derived nitrone

Article abstract of DOI:10.1007/s12039-011-0207-z

Microwave-induced 1,3-dipolar cycloaddition reactions of dihydropyran derived nitrone with various activated alkenes have been studied in situ and found to afford new isoxazolidine derivatives with moderate selectivity. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0207-z

c
J. Chem. Sci. Vol. 124, No. 3, May 2012, pp. 679–685. ꢀ Indian Academy of Sciences.
Solvent-free one-pot 1,3-dipolar cycloaddition reactions of dihydropyran
derived nitrone
BHASKAR CHAKRABORTY∗, PRAWIN KUMAR SHARMA, NEELAM RAI
and CHIRAN DEVI SHARMA
Organic Chemistry Laboratory, Sikkim Government College, Gangtok 737 102, India
e-mail: bhaskargtk@yahoo.com
MS received 4 May 2011; revised 19 October 2011; accepted 31 October 2011
Abstract. Microwave-induced 1,3-dipolar cycloaddition reactions of dihydropyran derived nitrone with vari-
ous activated alkenes have been studied in situ and found to afford new isoxazolidine derivatives with moderate
selectivity.
Keywords. Solid phase; cycloaddition reaction; isoxazolidines and amino alcohols.
1. Introduction
Literature survey reveals that this is quite a new ap-
proach of synthesis of nitrone from dihydropyran using
microwave irradiations.24–26
The synthetic utility of microwave irradiation in organic
synthesis has increased considerably in recent years.1–5
This non-conventional energy source is able to reduce
chemical reaction time and to increase yield and in some
cases leads to better result than those obtained with
conventional heating methods. Microwave reactions are
quite often cleaner, faster, and higher-yielding than
conventional ones. This methodology can be regarded
as environmental friendly, mainly because solvent-free
reactions are especially suited to microwave condi-
tions.6,7 Microwave technology has been successfully
used to perform difficult cycloadditions and to obtain
temperature sensitive compounds.8–13 Particularly inter-
esting part is 1,3-dipolar cycloaddition, which repre-
sents one of the most versatile tools for the construction
of five-membered heterocycles. Owing to the labile na-
ture of the N–O bond under mild reducing conditions,
isoxazolidines provide easy access to a variety of fasci-
nating 1,3-difunctional amino alcohols.14 In continua-
tion of our green methodological synthesis of spiro
isoxazolidine, isoxazolidine, isoxazoline, aldehyde, ke-
tone synthesis using α-chloro and α-amino nitrones in
solid phase and in hydrated media,15–23 we report here
microwave-assisted 1,3-dipolar cycloaddition reactions
of dihydropyran derived nitrone leading to the green
synthesis of new isoxazolidine derivatives with mode-
rate selectivity and excellent yield (scheme 1, table 1).
Synthetic potential of the new isoxazolidine deriva-
tives (2–6) are tremendous as they could be converted
into acyclic chiral 1,3 difunctional amino alcohols
(scheme 2, table 2) by the reductive cleavage of the
N–O bond by treatment with zinc powder in dil acetic
acid under microwave irradiation.27–29
2. Experimental
2.1 General procedures
Melting points were determined in open capillary
tubes and are uncorrected. 1H NMR spectra were
recorded with a Bruker Avance DRX-300 spectrometer
(300 MHz, FT NMR) using TMS as internal standard.
13C NMR spectra were recorded on the same instrument
at 75 MHz. The coupling constants (J) are given in
Hz. IR spectra were obtained with a Perkin–Elmer RX
1-881 machine as KBr pellets for all the products.
MS spectra were recorded with a Jeol SX-102 (FAB)
instrument. Elemental analyses (CHN) were performed
with a Perkin–Elmer 2400 series CHN analyzer. TLC’s
were run on Fluka silica gel pre-coated TLC plates. All
other reagents and solvents were purified after receiving
from commercial suppliers. N-phenylhydroxylamine
was prepared following standard methods available
in literature. Microwave irradiations were carried out
using domestic microwave oven KENSTER (19LKH,
19SSLM, 800 W-2450 MHz).
∗For correspondence
679

680
Bhaskar Chakraborty et al.
NHOH
(i)
O-
OH
+
O
N
OH
N
O
1
C6H5
C6H5
C6H5
C6H5
N
R1
R3
R3
N
2
2
O-
O
3
O
1
3
1
H
R2
H
+
N+
5
4
5
4
OH
(ii)
H
H
H
H
1
C6H5
R1
R2
R1
R2
2b−4b
2a−4a ; 5−6
(i) MWI, 5 min; (ii) MWI, 7 - 9 min
2 : R1, R2 = -CONMeCO-
3 : R1, R2 = -CONPhCO-
4 : R1, R2 = -CONCyCO-
5 : R1 = -COOCH2CH3 ; R2 = H
6 : R1 = C6H5 ; R2 = H
R3 = -(CH2)4-OH
Scheme 1. Synthesis of novel isoxazolidine derivatives.
2.1a General procedure for cycloaddition reaction 0.38). Dipolarophiles were added (1 equivalent) at this
(conventional): N-phenylhydroxylamine (250 mg, stage and the reaction mixture was further refluxed for
2.29 mmol) was added to a solution of 2,3-dihydro-4H- 13–15 h. The solvent was evaporated off and the cy-
pyran (192 mg, 1 equivalent) in dry benzene (20 mL) cloadducts (2–6; table 1) were isolated by column chro-
under N2 atmosphere and the reaction mixture was re- matography using benzene-pet ether as eluent. But this
fluxed for 24 h while the progress of the reaction was methodology was discarded because of lengthy reaction
monitored by TLC (hexane:ethyl acetate = 5:1; Rf = process, poor yield and use of benzene as solvent.
Table 1. Physicochemical data of synthesized compounds (2a–4a; 5–6 and 2b–4b).
Entry
Nitrone
Dipolarophilea
Time (min)
Cycloadduct and m.p (◦c)
2a–4a: cis; 2b–4b: trans
Cis/trans
ratio (%)
Yieldb (%)
1
2
3
4
5
N-phenyl-5-
hydroxy nitrone
N-phenyl-5-
hydroxy nitrone
N-phenyl-5-
hydroxy nitrone
N-phenyl-5-
hydroxy nitrone
N-phenyl-5-
hydroxy nitrone
N-methyl
maleimide
N-phenyl
maleimide
N-cyclohexyl
maleimide
Ethyl acrylate
7 (13 h)
9 (14 h)
9 (14 h)
9 (15 h)
9 (15 h)
2a: White crystal, 95
2b: White crystal, 82
3a: Pale yellow solid, 108
3b: White solid, 103
4a: Yellow crystal, 80
4b: Yellow crystal, 88
5: Colourless thick liquid
2a: 64
2b: 32
3a: 68
3b: 25
4a: 62
4b: 31
96 (54)
93 (52)
93 (47)
92 (56)
91 (50)
Styrene
6: Colourless thick liquid
aReaction condition: DHP (1 mmol), N-phenylhydroxylamine (1 equivalent), dipolarophile (1 equivalent), MWI.
bIsolated yields after purification.
Figures in parentheses indicate reactions performed in conventional method

N-O bond cleavage of isoxazolidine derivatives under MWI
681
H
H
R2
R2
OH
O
H
Zn/ CH3CO OH
C6H5
N
N
C6H5
(i)
R3
R3
R1
H
H
R1
H
H
2a - 4a
2c - 4c
(i) MWI, 9 - 10 min
2 : R2, R3 = -CONMeCO-
3 : R2, R3 = -CONPhCO-
4 : R2, R3 = -CONCyCO-
R 1 = - (CH 2)4-OH
Scheme 2. Synthesis of 1,3 amino alcohols.
2.1b General procedure for cycloaddition for diaste- acetate, 5:1); IR (KBr): υmax 3640–3530 (br), 2915 (m),
reomers (MWI): A mixture of N-phenylhydroxylamine 2832 (m), 1774 (s), 1680 (s), 1440 (m), 1380 (m),
1
(250 mg, 2.29 mmol), 2,3-dihydro-4H-pyran (192 mg, 772 (s) cm−1; H NMR (CDCl3, 300 MHz): δ 6.88–
1 equivalent) was taken in a 25 mL Erlenmeyer flask, 6.73 (m, 5H, C6H5), 4.83 (br, s, 1H, OH, exchanged in
mixed well and subjected to microwave irradiation at D2O), 4.64 (d, 1H, J = 6.30 Hz, C5H), 4.23 (dd, 1H,
250 W for 5 min. The formation of nitrone was moni- J = 6.06, 6.04 Hz, C4H), 3.30 (s, 3H, CH3 protons),
tored by TLC (hexane:ethyl acetate = 5:1; Rf = 0.38). 2.78 (dt, 1H, J = 6.40, 6.54 Hz, C3H), 2.36 (dt∼m,
N-methyl maleimide (254 mg, 1 equivalent) was added 2H, CH2 protons of –CH2-(CH2)3OH), 1.80–1.43 (m,
at this stage and the reaction mixture was further irra- 6H, CH2 protons); 13C NMR (CDCl3): δ 176.22, 176.10
diated at 250 W for an appropriate time (table 1). (carbonyl carbons), 130.62, 130.16, 128.88, 128.15
After completion of the reaction, as indicated by TLC (aromatic carbons), 87.15 (C5), 76.42 (C3), 66.23
(hexane:ethyl acetate = 5:1; Rf = 0.44, 0.50), the reac- (CH2OH), 55.50 (C4), 38.00 (CH3), 25.76, 22.31, 20.27
tion mixture was cooled to room temperature (RT) and (3 CH2 carbons); FAB-MS: m/z 304 (M+), 289, 231,
washed with diethyl ether (3 × 10 mL). The combined 227, 212, 154 (B.P), 77, 73; Anal. Found: C, 63.02; H,
ether extract was concentrated in vacuo and the result- 6.35; N, 9.17. C16H20O4N2 requires C, 63.13; H, 6.61;
ing products were directly charged on silica gel column N, 9.21%.
and eluted with a mixture of ethyl acetate:hexane to
afford pure isoxazolidine derivatives 2a and 2b (entry
2.1d Dihydro-3-(4-hydroxybutyl)-5-methyl-2-phenyl-
1, table 1). This procedure was followed for other
2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6a-H)-dione (2b):
substrates listed in table 1.
White crystal. Yield 32%; Rf = 0.50 (hexane-ethyl
acetate, 5:1); IR (KBr): υmax 3645–3550 (br), 2910 (m),
2.1c Dihydro-3-(4-hydroxybutyl)-5-methyl-2-phenyl-
2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6a-H)-dione (2a):
White crystal. Yield 64%; Rf = 0.44 (hexane-ethyl
2830 (m), 1776 (s), 1676 (s), 1440 (m), 1385 (m),
1
775 (s) cm−1; H NMR (CDCl3, 300 MHz): δ 6.76–
6.63 (m, 5H, C6H5), 5.04 (br, s, 1H, OH, exchanged in
Table 2. Physicochemical data of synthesized 1,3 amino alcohols (2c–4c).
Entry
Isoxazolidine
Reagenta
Time (min)
1,3 amino alcohol (2c–4c)
Yieldb (%)
1
2
3
2a
3a
4a
Zn and dil acetic acid
Zn and dil acetic acid
Zn and dil acetic acid
9
10
10
2c: Yellowish white thick liquid
3c: White thick liquid
4c: Dark gray thick liquid
84
81
80
aReaction condition: Isoxazolidine (100 mg), Zn (5 mg), glacial acetic acid (3 mL), MWI.
bIsolated yields after purification

682
Bhaskar Chakraborty et al.
D2O), 4.80 (d, 1H, J = 3.76 Hz, C5H), 4.15 (dd, 1H, 2.1g 5-cycohexyl-dihydro-3-(4-hydroxybutyl)-2-phenyl-
J = 2.18, 2.64 Hz, C4H), 3.34 (s, 3H, CH3 protons), 2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6 a-H)-dione (4a):
2.70 (dt, 1H, J = 3.10, 2.80 Hz, C3H), 2.08 (dt∼m, Yellow crystal. Yield 62%, Rf = 0.50 (hexane-ethyl
2H, CH2 protons of –CH2-(CH2)3OH), 1.76–1.30 (m, acetate, 5:1); IR (KBr): υmax 3638–3515 (br), 2865 (s),
6H, CH2 protons); 13C NMR (CDCl3): δ 170.90, 170.17 1785 (s), 1680 (s), 1446 (m), 1380 (m), 1265 (m), 780
(carbonyl carbons), 129.12, 128.75, 128.53, 127.33 (s) cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.40–7.17 (m,
(aromatic carbons), 85.56 (C5), 73.21 (C3), 63.08 5H, C6H5), 5.94 (d, 1H, J = 6.64 Hz, C5H), 4.40 (br, s,
(CH2OH), 54.22 (C4), 34.44 (CH3), 23.63, 22.70, 1H, OH, exchanged in D2O), 3.44 (dd, 1H, J = 6.26,
22.12 (3 CH2 carbons); FAB-MS: m/z 304 (M+), 289, 6.08 Hz, C4H), 2.23 (dt, 1H, J = 6.60, 6.14 Hz, C3H),
231, 230, 227, 212, 154 (B.P), 77, 73; Anal. Found: C, 1.69 (dt∼m, 2H, CH2 protons of –CH2-(CH2)3OH),
62.98; H, 6.40; N, 9.09. C16H20O4N2 requires C, 63.13; 1.45–1.17 (m, 17H, cyclohexyl and CH2 protons); 13C
H, 6.61; N, 9.21%.
NMR (CDCl3): δ 173.16, 171.37 (carbonyl carbons),
136.04, 135.52, 134.07, 133.93 (aromatic carbons),
86.80 (C5), 77.08 (C3), 62.50 (CH2OH), 55.62 (C4),
38.51, 36.07, 34.40, 31.10, 29.52, 27.70, 26.30, 25.00,
23.28 (cyclohexyl and CH2 carbons); FAB-MS: m/z
372 (M+), 313, 299, 222 (B.P), 216, 83, 77, 73, 59;
Anal. Found: C, 67.62; H, 7.43; N, 7.35. C21H28O4N2
requires C, 67.71; H, 7.56; N, 7.52%.
2.1e Dihydro-3-(4-hydroxybutyl)-2,5-diphenyl-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6a-H)-dione
(3a):
Pale yellow solid. Yield 68%; Rf = 0.56 (hexane-ethyl
acetate, 5:1); IR (KBr): υmax 3585–3453 (br), 2920 (m),
2835 (m), 1780 (s), 1684 (s), 1600 (s), 1480 (m),
1346 (m), 770 (s) cm−1; H NMR (CDCl3, 300 MHz):
1
δ 7.49–7.26 (m, 2X5H, C6H5), 6.84 (br, s, 1H, OH,
exchanged in D2O), 4.95 (d, 1H, J = 6.52 Hz, C5H),
3.91 (dt, 1H, J = 6.04, 6.16 Hz, C3H), 3.55 (dd, 1H,
J = 6.18, 6.22 Hz, C4H), 1.90 (dt∼m, 2H, CH2 protons
of –CH2-(CH2)3OH), 1.63–1.18 (m, 6H, 3 CH2 pro-
tons); 13C NMR (CDCl3): δ 172.12, 171.86 (carbonyl
carbons), 133.77, 133.14, 132.22, 131.78, 129.80,
129.61, 128.15, 127.72 (aromatic carbons), 87.80 (C5),
75.18 (C3), 65.27 (CH2OH), 56.37 (C4), 34.55, 26.40,
25.00 (3 CH2 carbons); FAB-MS: m/z 366 (M+), 306,
293, 289, 216 (B.P), 77, 73, 59; Anal. Found: C, 68.67;
H, 5.83; N, 7.52. C21H22O4N2 requires C, 68.82; H,
6.04; N, 7.65%.
2.1h 5-cyclohexyl-dihydro-3-(4-hydroxybutyl)-2-phenyl-
2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6 a-H)-dione (4b):
Yellow crystal. Yield 31%, Rf = 0.44 (hexane-ethyl
acetate, 5:1); IR (KBr): υmax 3623–3534 (br), 2880 (s),
1782 (s), 1680 (s), 1440 (m), 1385 (m), 1260 (m), 774
(s) cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.26–7.08 (m,
5H, C6H5), 4.90 (d, 1H, J = 2.66 Hz, C5H), 4.56 (br, s,
1H, OH, exchanged in D2O), 3.54 (dd, 1H, J = 2.22,
2.50 Hz, C4H), 2.40 (dt, 1H, J = 3.08, 3.04 Hz, C3H),
1.60 (dt∼m, 2H, CH2 protons of –CH2-(CH2)3OH),
1.52–1.20 (m, 17H, cyclohexyl and CH2 protons); 13C
NMR (CDCl3): δ 170.22, 170.04 (carbonyl carbons),
132.68, 132.30, 131.54, 131.38 (aromatic carbons),
85.10 (C5), 76.20 (C3), 63.44 (CH2OH), 56.70 (C4),
37.32, 36.40, 33.69, 31.28, 30.55, 28.12, 26.90, 25.43,
24.20 (cyclohexyl and CH2 carbons); FAB-MS: m/z
372 (M+), 313, 299, 289, 222 (B.P), 216, 83, 77, 73, 59;
Anal. Found: C, 67.57; H, 7.45; N, 7.30. C21H28O4N2
requires C, 67.71; H, 7.56; N, 7.52%.
2.1f Dihydro-3-(4-hydroxybutyl)-2,5-diphenyl-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6a-H)-dione
(3b):
White solid. Yield 25%; Rf = 0.48 (hexane-ethyl ace-
tate, 5:1); IR (KBr): υmax 3590–3476 (br), 2934 (m),
2830 (m), 1780 (s), 1680 (s), 1610 (s), 1476 (m),
1
1340 (m), 776 (s) cm−1; H NMR (CDCl3, 300 MHz):
δ 7.36–7.15 (m, 2X5H, C6H5), 6.25 (br, s, 1H, OH,
exchanged in D2O), 4.48 (d, 1H, J = 2.70 Hz, C5H),
3.54 (dt, 1H, J = 3.04, 2.86 Hz, C3H), 3.12 (dd, 1H,
J = 2.26, 2.18 Hz, C4H), 1.84 (dt∼m, 2H, CH2 protons
of –CH2-(CH2)3OH), 1.50–1.16 (m, 6H, 3 CH2 pro-
tons); 13C NMR (CDCl3): δ 170.63, 170.14 (carbonyl
carbons), 131.62, 131.08, 130.27, 130.14, 129.19,
128.40, 128.05, 127.58 (aromatic carbons), 88.06 (C5),
73.90 (C3), 62.83 (CH2OH), 53.45 (C4), 31.72, 24.44,
23.19 (3 CH2 carbons); FAB-MS: m/z 366 (M+), 306,
293, 289, 216 (B.P), 212, 77, 73, 59; Anal. Found: C,
68.63; H, 5.87; N, 7.60. C21H22O4N2 requires C, 68.82;
H, 6.04; N, 7.65%.
2.1i General procedure for cycloaddition for regioi-
somers (MWI): A mixture of N-phenylhydroxylamine
(250 mg, 2.29 mmol), 2,3-dihydro-4H-pyran (192 mg,
1 equivalent) was taken in a 25 mL Erlenmeyer flask,
mixed well and subjected to microwave irradiation at
250 W for 5 min. The formation of nitrone was moni-
tored by TLC (hexane:ethyl acetate = 5:1; Rf = 0.38).
Ethyl acrylate (229 mg, 1 equivalent) was added at this
stage and the reaction mixture was further irradiated
at 250 W for appropriate time (table 1). After comple-
tion of the reaction, as indicated by TLC (hexane:ethyl
acetate = 5:1; Rf = 0.52), the reaction mixture was

N-O bond cleavage of isoxazolidine derivatives under MWI
683
cooled to RT and washed with diethyl ether (3 × was taken in a 25 mL Erlenmeyer flask, mixed well and
10 mL). The combined ether extract was concentrated subjected to microwave irradiation at 250 W for appro-
in vacuo and the resulting product was directly charged priate time (entry 1, table 2). The completion of reac-
on silica gel column and eluted with a mixture of ethyl tion was monitored by TLC ((hexane:ethyl acetate, 5:1;
acetate:hexane to afford pure isoxazolidine derivative 5 Rf = 0.66). The reaction mixture was cooled to RT,
(entry 4, table 1). This procedure was followed for other extracted with diethyl ether and filtered. Excess acetic
substrate listed in table 1.
acid in the filtrate was removed through basic work up
and finally charged on silica gel column and eluted with
a mixture of ethyl acetate:hexane to afford pure 1,3
amino alcohol in 84% yield (entry 1; scheme 2; table 2).
This procedure was followed for other substrates listed
in table 2.
2.2 Ethyl 3-(4-hydroxy butyl)-2-phenyl
isoxazolidine-5-carboxylate (5)
Colourless thick liquid. Yield 92%, Rf = 0.52 (hexane-
ethyl acetate, 5:1); IR (KBr): υmax 3610–3525 (br),
2930 (s), 2842 (m), 1760 (s), 1444 (s), 790 (s) cm−1;
1HNMR (CDCl3, 300 MHz): δ 7.24–7.08 (m, 5H,
C6H5), 4.92–4.80 (br, s, 1H, −OH, exchanged in D2O),
4.20 (q, 2H, J = 6.10, 6.06 Hz, −OCH2CH3), 4.06 (t,
1H, J = 6.68 Hz, C5H), 3.40 (ddd, 1H, J = 6.54,
6.58 Hz, C3H), 3.18 (dd, 2H, J = 6.12, 6.14 Hz,
C4 2H), 1.68 (dt∼m, 2H, CH2 protons of –CH2-
(CH2)3OH), 1.26 (t, 3H, J = 5.40 Hz, −OCH2CH3),
1.18–0.82 (m, 6H, CH2 protons); 13C NMR (CDCl3):
δ 169.77 (carbonyl carbon), 130.72, 130.54, 130.27,
129.88 (aromatic carbons), 84.16 (C5), 79.62 (C3),
66.40 (CH2OH), 61.52 (CH2 carbon of −OCH2CH3),
56.86 (C4), 22.28, 21.68, 20.94 (3 CH2 carbons), 16.40
(CH3 carbon of OCH2CH3); FAB-MS: m/z 293 (M+),
220, 219, 143 (B.P), 111, 77, 73; Anal. Found: C, 65.22;
H, 7.48; N, 4.54. C16H23O4N requires C, 65.49; H, 7.89;
N, 4.77%.
2.2c 3-hydroxy-4-(5-hydroxy-1-(phenylamino)pentyl)-
1-methylpyrrolidine-2,5-dione (2c): Yellowish white
thick liquid. Yield 84%, Rf = 0.66 (hexane-ethyl
acetate, 5:1); IR (KBr): υmax 3650–3585 (br), 3510–
3435 (br), 2845 (m), 1782 (s), 1685 (m), 1490 (m),
1
783 (s) cm−1; H NMR (CDCl3, 300 MHz): δ 7.05–
6.88 (m, 5H, C6H5), 5.24 (br, 2H, 2XOH, exchanged in
D2O), 4.52 (d, 1H, J = 6.50 Hz, C1H), 3.80 (dd, 1H,
J = 6.54, 6.30 Hz, C2H), 3.50 (br, 1H, −NHC6H5),
3.36 (s, 3H, CH3 proton), 2.90 (dt, 1H, J = 6.36,
6.28 Hz, C3H), 2.64 (dt∼m, 2H, CH2 protons of –
CH2-(CH2)3OH), 2.12–1.65 (m, 6H, CH2 protons); 13C
NMR (CDCl3): δ 173.70, 172.66 (carbonyl carbons),
129.94, 129.66, 129.14, 128.85 (aromatic carbons),
86.54 (C1), 74.62 (C3), 66.30 (CH2OH), 55.08 (C2),
33.12 (CH3), 26.50, 24.22, 22.77 (3 CH2 carbons);
FAB-MS: m/z 306 (M+), 233, 229, 156, 77, 73; Anal.
Found: C, 62.36; H, 7.06; N, 9.01. C16H22O4N2 requires
C, 62.74; H, 7.23; N, 9.15%.
2.2a 4-(2,5-diphenyl-isoxazolidin-3-yl)butan-1-ol (6):
Colourless thick liquid. Yield 91%, Rf = 0.50 (hexane-
ethyl acetate, 5:1); IR (KBr): υmax 3620–3565 (br),
2925 (s), 2844 (m), 1710 (s), 1440 (m), 1324 (s),
2.2d 3-hydroxy-4-(5-hydroxy-1-(phenylamino)pentyl)-1-
phenyl pyrrolidine-2,5-dione (3c): White thick liquid.
Yield 81%, Rf = 0.68 (hexane-ethyl acetate, 5:1); IR
(KBr): υmax 3670–3590 (br), 3505–3420 (br), 2840 (m),
1
804 (m), 776 (s) cm−1; H NMR (CDCl3, 300 MHz):
δ 6.93–6.56 (m, 2X5H, C6H5 protons), 5.02 (t, 1H,
J = 6.08 Hz, C5H), 4.85–4.76 (br, s, 1H, exchanged in
D2O), 4.28 (ddd, 1H, J = 6.52, 6.50 Hz, C3H), 3.87
(dd, 2H, J = 6.22, 6.20 Hz, C4 2H), 1.96 (dt∼m, 2H,
CH2 protons of –CH2-(CH2)3OH), 1.50–1.24 (m, 6H,
CH2 protons); 13C NMR (CDCl3): δ 136.75, 136.52,
136.17, 135.94, 131.88, 131.54, 131.12, 130.82 (aro-
matic carbons), 85.95 (C5), 77.32 (C3), 60.64 (CH2OH),
56.40 (C4), 21.48, 20.10, 19.63 (3 CH2 carbons); FAB-
MS: m/z 297 (M+), 265, 224, 219, 147 (B.P), 77, 73;
Anal. Found: C, 76.60; H, 7.47; N, 4.63. C19H23O2N
requires C, 76.73; H, 7.78; N, 4.71%.
1
1780 (s), 1680 (m), 1486 (m), 775 (s) cm−1; H NMR
(CDCl3, 300 MHz): δ 7.22–7.08 (m, 2X5H, C6H5),
5.18–5.00 (br, 2H, 2XOH, exchanged in D2O), 4.80
(d, 1H, J = 6.74 Hz, C1H), 3.76 (dd, 1H, J = 6.30,
6.38 Hz, C2H), 3.43 (br, 1H, −NHC6H5), 2.78 (dt, 1H,
J = 6.44, 6.40 Hz, C3H), 2.55 (dt∼m, 2H, CH2 protons
of –CH2-(CH2)3OH), 1.95–1.40 (m, 6H, CH2 protons);
13C NMR (CDCl3): δ 174.08, 172.55 (carbonyl car-
bons), 135.80, 135.47, 133.54, 133.11, 132.12, 130.80,
130.23, 129.90 (aromatic carbons), 85.66 (C1), 75.20
(C3), 63.90 (CH2OH), 55.30 (C2), 27.03, 24.80, 22.13
2.2b General procedure for synthesis of 1,3 amino (3 CH2 carbons); FAB-MS: m/z 368 (M+), 295, 291,
alcohols (MWI): A mixture of isoxazolidine 2a 218, 214, 77, 73; Anal. Found: C, 68.33; H, 6.25; N,
(100 mg) and Zn dust (5 mg) in dil acetic acid (3 mL) 7.28. C21H24O4N2 requires C, 68.47; H, 6.52; N, 7.60%.

684
Bhaskar Chakraborty et al.
2.2e 1-cyclohexyl-3-hydroxy-4-(5-hydroxy-1-(phenyl- minor conformation, or point inside the envelope, i.e.,
amino)pentyl)pyrrolidine-2,5-dione (4c): Dark gray major conformation. The minor conformer has the N-
thick liquid. Yield 80%, Rf = 0.64 (hexane-ethyl lone pair antiperiplanar and therefore, capable of shield-
acetate, 5:1); IR (KBr): υmax 3665–3580 (br), 3500– ing 3-H proton, so this conformation is assigned to the
3425 (br), 2845 (m), 1778 (s), 1684 (m), 1440 (m), minor conformer (figure 1). The diastereomeric isoxa-
1
1210 (m), 770 (s) cm−1; H NMR (CDCl3, 300 MHz): zolidines 2a–4a and 2b–4b were separated by column
δ 6.83–6.66 (m, 5H, C6H5), 5.22–5.09 (br, 2H, 2XOH, chromatography and obtained in analytically pure form
exchanged in D2O), 4.70 (d, 1H, J = 6.50 Hz, C1H), by recrystalization from heptane-ethyl acetate.
3.90 (dd, 1H, J = 6.88, 6.76 Hz, C2H), 3.33 (br, 1H,
In all the diastereomers, the configurations of H-5
−NHC6H5), 2.60 (dt, 1H, J = 6.70, 6.26 Hz, C3H), and H-4 are cis as evidenced from their coupling con-
2.28 (dt∼m, 2H, CH2 protons of –CH2-(CH2)3OH), stant values. The cycloaddition reactions of N-phenyl-
1.90–0.96 (m, 17H, CH2 protons); 13C NMR (CDCl3): 5-hydroxy nitrone with ethyl acrylate and styrene are
δ 170.20, 170.05 (carbonyl carbons), 128.90, 128.56, found to be regioselective and results 5-substituted
128.05, 127.66 (aromatic carbons), 86.22 (C1), 74.28 isoxazolidine derivatives exclusively. This was rational-
1
(C3), 62.50 (CH2OH), 56.80 (C2), 29.00, 28.45, 28.19, ized by using frontier molecular orbital theory and H
27.06, 25.60, 23.86, 22.32, 20.72, 20.16 (CH2 car- NMR experiments. The results remind us the pioneer-
bons); FAB-MS: m/z 374 (M+), 301, 291, 224, 214, ing works on the study of regioselectivity in cycloaddi-
83, 77, 73; Anal. Found: C, 67.18; H, 7.88; N, 7.26. tion reactions by Houk et al. and Huisgen which state
C21H30O4N2 requires C, 67.37; H, 8.02; N, 7.48%.
that exclusively regioselective cycloadducts are possi-
ble only when LUMO (nitrone)-HOMO (dipolarophile)
interactions completely dominate the reaction and lead
to the formation of only 5-substituted adducts.32–34
3. Results and discussion
1
From the H NMR spectrum of cycloadducts 5–6, it
has been found that clear double–doublet signal for H-4
protons and double triplet (ddd) signal for H-3 protons
are obtained in all the cases due to further coupling from
vicinal hydrogens and hence confirms in favour of 5-
substituted adducts. From the detailed investigations on
the nature of these cycloaddition reactions using TLC
and 1H NMR spectrum studies for the cycloadducts 5–
6, it is also confirmed that no diastereomers are formed.
The relative configurations of H-3, H-4 and H-5 pro-
tons in these adducts are syn and the cycloadducts
In the present study, the formation of nitrone 1 has been
achieved by treating 2,3-dihydro-4H-pyran with N-
phenylhydroxylamine under microwave irradiation and
has been trapped in situ by various activated alkenes in
1,3-dipolar cycloaddition reaction with moderate selec-
tivity and high yield resulting new isoxazolidine deriva-
tives (2–6) (scheme 1; table 1). Dimerization of nitrone
could be controlled under this condition.
Induction of three asymmetric centres at C5, C4
and C3 positions of the newly developed isoxazo-
lidine derivatives have made this one-pot synthesis
highly attractive. The development of diastereomers
can be rationalized by an exo approach of nitrone 1
which has Z configuration for the formation of major
cycloadducts 2a–4a (transition state 1). The minor
cycloadducts 2b–4b are formed by the endo approach
of Z nitrone (transition state 2). The mixture of diastere-
omers are identified by considering the multiplicity of
the proton signals at 3-H and 4-H along with their cou-
pling constant values.30,31 The most significant differ-
H
C
H
C6H5
R3
C
R3
N
O
C6H5
N
O
O
O
R4
R4
N
N
O
O
TS 1
TS 2
R3
..
R3
H5
C6H5
H4
H4
1
N
O
ences in the H NMR data for the diastereomers are
O
C6H5
H5
H3
the position and multiplicity of the 3-H signal. In the
major adducts 2a–4a, coupling constant between 3-H
and 4-H has been measured as J3,4 ∼ 6.26 Hz whilst
for minor adducts 2b–4b, J3,4 is ∼2.54 Hz. These dif-
ferences can be explained by considering the available
isoxazolidine ring conformations. Due to the 4,5-fused
pyrrolidindione, the isoxazolidine ring adopts an enve-
lope conformation and allowing for inversion, its nitro-
gen atom will either extend out from the envelope, i.e.,
H
O
3O
N
..
R4
N
R4
N
O
O
Minor conformation 1
Major conformation 2
R3 = (CH2)4OH; R4 = Ph; Me; Cy
Figure 1. TS for the development of cycloadducts and
their conformations.

N-O bond cleavage of isoxazolidine derivatives under MWI
685
are in favour of exo transition state geometry as evi-
5. Loupy A 2006 Microwaves in organic synthesis
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denced from their coupling constant values (JH4, H5
6.08–6.52 Hz; JH4, H3 = 6.10–6.68 Hz).
=
The newly developed N-phenyl isoxazolidine deriva-
tives (2a–4a) can be easily converted into acyclic chi-
ral 1,3 difunctional amino alcohols (2c–4c) (scheme 2,
table 2) by the reductive cleavage of the N–O bond.
These conversions have been achieved by simply treat-
ing the substrates with zinc powder in dil acetic acid
under microwave irradiation.27–29
5055
11. Chiacchio U, Corsaro A, Iannazzo D, Piperno A, Romeo
G, Romeo R, Saita M G and Rescifina A 2007 Eur. J.
Org. Chem. 4758
The relative configurations of H-1, H-2 and H-3 pro-
tons of the newly developed 1,3 amino alcohols (2c– 12. Mabrour M, Bougrin K, Benhida R, Loupy A and
Saufiaoui M 2007 Tetrahedron Lett. 48 443
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Chhetri M S 2010 J. Chem. Res. 34(3) 147
16. Chakraborty B, Kafley S, Chhetri M S and Samanta A
2010 Indian J. Chem. 49B 209
17. Chakraborty B and Chhetri M S 2010 Indian J. Chem.
49B 102
18. Chakraborty B, Chhetri M S and Samanta A 2010 Indian
J. Chem. 49B 1155
4c) are syn as evidenced from their coupling constant
values (JH1, H2 ∼ 6.70 Hz; JH2, H3 ∼ 6.10 Hz). Expected
broad signals for N–H proton around δ 3.40 and alco-
holic OH groups around δ 5.20 ppm are also obtained.
Synthesis of 1,3 amino alcohols using other isoxazoli-
dine derivatives (2b–4b; 5,6) are in progress. In gene-
ral, all the reactions are very clean and high yield-
ing compared to conventional cycloaddition reactions
of nitrones.24–26 The products have been characterized
from their spectroscopic (IR, 1H NMR, 13C NMR, MS)
data. No catalyst or co-organic solvent is required.
19. Chakraborty B and Sharma P K 2011 Synth. Commmun.
(MS No: LSYC-2010–544833, in production house for
online publication)
20. Chakraborty B, Sharma P K and Chhetri M S 2011
J. Heterocycl. Chem. (Wiley) DOI:10.1002/jhet.971,
releasing online soon
4. Conclusion
21. Chakraborty B and Chhetri M S 2008 Indian J. Chem.
47B 485
This paper represents an extension of our studies deal-
ing with the synthesis of heterocyclic compounds hav-
ing isoxazolidine and isoxazoline cores in their struc-
ture. Further studies will be carried out in the near
future to test their potential biological activities.
22. Chakraborty B, Sharma P K, Kafley S, Chhetri M S and
Ghosh A R 2011 J. Indian Chem. Soc. 88 245
23. Chakraborty B, Sharma P K, Chhetri M S, Kafley S and
Rai N 2010 J. Indian Chem. Soc. 87 1399
24. Pandey G, Banerjee P and Gadre S R 2006 Chem. Rev.
106 4484
25. Molteni G 2006 Heterocycles 68 2177
26. Padwa A and Pearson W H 2003 Synthetic applications
of 1,3-Dipolar cycloaddition chemistry towards hetero-
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27. Hoffman W R, Eichler G and Endesfelder A 1983
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Acknowledgements
We thank Dr. M P Kharel, Principal, Sikkim Gov-
ernment College for providing facilities and constant
encouragement. We acknowledge the financial support
from the University Grants Commission (UGC), New
Delhi (grant no:34–304/2008-SR) and also to the
Central Drug Research Institute (CDRI), Lucknow for
providing spectral data.
30. Deshong P, Li W, Kennington J W Jr, Ammon H L and
Leginus J M 1991 J. Org. Chem. 56 1364
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823
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