Synthesis of novel isoxazolidines and medium-ring heterocycles oxazocines and oxazonines

Article abstract of DOI:10.2174/157017811796064502

A number of novel oxa-bridged and methylene oxa-bridged bicyclic isoxazolidines have been synthesized using intramolecular nitrone cycloaddition. The reductive cleavage of N-O bonds of the isoxazolidines to provide novel medium-ring heterocycles oxazocines and oxazonines is also described.

Full text of DOI:10.2174/157017811796064502

Letters in Organic Chemistry, 2011, 8, 391-400
391
Synthesis of Novel Isoxazolidines and Medium-Ring Heterocycles
Oxazocines and Oxazonines
Brindaban Roy*, Rajendra N. De and Somjit Hazra
Department of Chemistry, University of Kalyani, Kalyani, 741235, W.B. India
Received December 16, 2010: Revised March 31, 2011: Accepted March 31, 2011
Abstract: A number of novel oxa-bridged and methylene oxa-bridged bicyclic isoxazolidines have been synthesized
using intramolecular nitrone cycloaddition. The reductive cleavage of N-O bonds of the isoxazolidines to provide novel
medium-ring heterocycles oxazocines and oxazonines is also described.
Keywords: Isoxazolidines, oxazocines, oxazonines, amino alcohols, medium-ring heterocycles.
INTRODUCTION
isoxazolidines and reductive cleavage of N-O bond of
isoxazolidines leading to the synthesis of medium-ring
oxazocines and oxazonines. Different nitrones 4, starting
materials for our study, were prepared by refluxing an
ethanolic solution of 2-allyloxy benzaldehydes 1,
hydroxylamine hydrochloride and pyridine to afford oximes
The nitrone cycloaddition, especially an intramolecular
cycloaddition, finds applications in many organic synthesis
due to the production of isoxazolidines with labile N-O
bonds which can easily be converted into various functional
groups, such as 1,3-aminoalcohols [1], nitroalcohols [2],
ꢀ-enaminocarbonyl compounds [3] etc. Isoxazolidines are
intermediates in the synthesis of various natural products like
alkaloids [4]. Optically pure 1, 3-aminoalcohols have wide
application as chiral auxiliaries [5] and chiral ligands [6] in
asymmetric synthesis. These are structural units of many
synthetic [7] and natural products [8] possessing potent
biological activities. Cyclic 1, 3-aminoalcohols e.g., 3-
hydroxy benzoxazocine were found to possess significant ꢀ-
blocking properties [9]. Medium-ring heterocycles, the
structural basic units found in the framework of a variety of
natural products [10], are regarded as an important class of
compounds. Principally, eight and nine membered
heterocycles, constituent of a number of compounds, are of
increased pharmacological properties [9, 11]. Many medium-
ring compounds with oxygen and/or nitrogen(s) are
medicinally interesting compounds which ensures that they
are important synthetic targets for organic chemists.
Recently, Ivachtchenko et al. synthesized oxazonine
derivatives, which have pharmaceutical importance [12]. As
a part of our research interest in the synthesis of potentially
bioactive heterocyclic compounds [13], we report the
synthesis of some novel benzofused medium-ring
heterocycles, oxazocines and oxazonines which are cyclic 1,
3-aminoalcohols.
2
in 90-95% yields, and subsequent reduction with
Na(CN)BH3 in methanol at pH 3-4 to gave the corresponding
hydroxylamine. Finally condensation with appropriate
aldehydes 3 in presence of anhydrous MgSO4 at room
temperature gave 4a-f in 65-80% yields (Scheme 1).
The substrate 4a was refluxed in xylene (140oC) and the
reaction was monitored by TLC. Reaction was complete in
nine hours and two isoxazolidine compounds 5a and 6a
(Scheme 2) were isolated from the reaction mixture in 52
and 21 % yields respectively together with small amount of
uncharacterizable products.
The structures and stereochemistry of these compounds
were established from their NMR studies involving 2D-
NMR experiments. The NMR data of 5a showed two
methylene carbon resonances, at ꢀC 58.66 and 71.25 and a
high field methylene carbon resonance, at ꢀC 36.93 together
with two proton resonances, at ꢀH 2.45 (dd, J = 8.8, 12.8 Hz)
and ꢀH 3.15 (td, J = 7.6, 12.8 Hz) indicating the presence of
oxabridged isoxazolidine. While the NMR data of 6a
showed three methylene carbon resonances, at ꢀC 53.66,
60.06 and 74.68 together with one proton resonance at ꢀH
4.84 as singlet, indicating the presence of methylene
oxabridged isoxazolidine. The relative stereochemistry of
compounds 5a and 6a were established from 2D-NOESY
interactions (Fig. 1).
RESULTS AND DISCUSSION
To make the reaction faster, the reaction mixture was
refluxed in 1, 2-dichlorobenzene (180oC). The desired
isoxazolidines 5a and 6a were obtained in very poor yields
together with several unwanted and uncharacterizable
products. Actually at this temperature Claisen rearrangement
of the allylphenyl ether moiety of nitrones, polymerization,
or charing etc. were possible, leading to poor yields of the
isoxazolidines. Other nitrones 4b-4f were refluxed in xylene
for 9-12 hours and isoxazolidines 5b-5f and 6b-6f were
obtained in 48-55% and 19-23% yields respectively (Scheme
Palma et.al. synthesized seven membered cyclic 1,3-
aminoalcohols, hydroxyl benzazepines [14]. We have
synthesized eight and nine membered cyclic 1,3-
aminoalcohols
by
sequential
nitrone
preparation,
intramolecular 1, 3-dipolar nitrone cycloaddition to provide
*Address correspondence to this author at the Department of Chemistry,
University of Kalyani, Kalyani, 741235, W.B. India; Tel: +91 033
25827521; Fax: +91 033 2582 8282; E-mail: broybs@rediffmail.com
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

392 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Roy et al.
O
O
O
i
ii
H
N
N
OH
R1
CHO
R1
R1
OH
1a-d
2a-d
CHO
Compound R1 R2
Yields(%)
iii
4a
4b
4c
4d
4e
4f
CH3
H
Cl
H
H
H
H
77
80
78
73
R2
3
O
OCH3
H
CH3 OCH3 65
O-
N+
OCH3 68
R1
4a-f
R2
Scheme 1. Reagents and conditions: i) NH2OH.HCl (1.2 eqv.), Py (3 eqv.) EtOH, reflux, 3hrs. ii) Na(CN)BH3 (1 eqv.), MeOH, pH 3-4, rt,
stir, 3 hrs. iii) CH2Cl2, anh. MgSO4, rt, stir, 5-10 hrs.
O
H
O
O
H
O-
Xylene, reflux
9-12 hrs
N+
H
O
+
H
O
R1
R1
4a-f
N
N
6a-f
R1
5a-f
R2
R2
R2
R2
R1
Yields(%)
Compound
5
6
a
b
c
d
e
f
CH3
H
Cl
OCH3
H
H
H
H
H
OCH3
52
21
53
55
55
50
48
23
21
19
21
20
CH3 OCH3
Scheme 2.
H
H
H
H
H
H
O
H
H
O
H
O
H
H
H
H
H
H
H
H
H
H
O
H
N
H3C
H3C
H
N
H
H
H
H
H
H
H
H
H
H
H
5a
6a
Fig. (1). NOESY interactions of compounds 5a and 6a.
2). Formation of the bridged isoxazolidines may be
rationalized to arise from intramolecular nitrone
cycloaddition via the bridged-ring transition states of Z/E
nitrones. Since Z and E-nitrone transition states are known to
interconvert under our reaction conditions [15], we may
assume that the regioselectivity depends only on the
respective transition states energies (Fig. 2). The formation
of the oxabridged isoxazolidines 5 selectively led to a
conclusion that the Z-nitrone transition-state was
energetically more favourable, although, it is well known
that the E-nitrone is more reactive than the Z-form [4b, c].

Synthesis of Novel Isoxazolidines
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
393
H
H
O
O
H
H
O
O
O-
N+
R1
H
R1
R1
N
O
E-nitrone
N
5
H
T. S. II
R2
R2
R2
H
O
O
H
O
O
H
O-
N+
Z-nitrone
R1
H
R2
H
R1
R2
N
O
R1
N
T. S. I
6
R2
H
Fig. (2).
The synthetic routes for the construction of medium-ring
heterocycles involving direct ring closure are often slow and
inhibited by an unfavorable entropy, enthalpy and also
transannular interaction [16]. Hence, we cleaved reductively
[17] the labile N-O bonds of isoxazolidines to afford the
eight and nine membered cyclic 1, 3-aminoalcohols. We
performed the reductive cleavage (Scheme 3) of the
substrates 5a and 6a with zinc dust in acetic acid, water and
tetrahydrofuran mixture (2:1:1) at 60oC for 2 hours. To our
delight, we obtained the 1, 3-aminoalcohols oxazonine
derivative 7a from 5a and oxazocine derivative 8a from 6a
in very good yields with retention of their configuration [3a].
In summary, we have synthesized a number of novel
bridged isoxazolidines. The reductive cleavages of nitrogen-
oxygen bond of these bridged isoxazolidines were performed
efficiently to provide eight and nine membered cyclic 1, 3-
aminoalcohols, oxazocine and oxazonine derivatives, in very
good yields with retained configuration. To the best of our
knowledge these medium-ring cyclic 1, 3-aminoalcohols,
specifically novel derivatives of oxazocine and oxazonine,
are not reported earlier.
EXPERIMENTAL SECTION
Melting points were determined in open capillaries and
are uncorrected. Boiling points were not determined. IR
spectra were recorded on KBr discs and NMR spectra were
determined for solutions in CDCl3 with TMS as internal
standard (ꢀ in ppm) in Bruker Ultrashield 400 MHz and
Bruker DPX 300 MHz. Elemental analyses were done from
the University of Kalyani, in Perkin Elmer CHN analyzer
2400 series II and mass spectra were done on Jeol JMS600
instrument from Indian Institute of Chemical Biology,
Kolkata and IICT Hyderabad, India. NOESY experiments
were done in Bruker DPX 500 MHz instrument from Bose
Institute, Kolkata. Silica gel (60-120 mesh) was used for
chromatographic separation. Silica gel-G[Spectrochem
(India)] was used for TLC. Petroleum-ether refers to the
fraction between 60 and 80oC. In NMR spectral analysis td,
qd and dt refer to triplet of doublet, quartet of doublet and
doublet of triplet respectively.
O
H
OH
O
H
O
iv
H
R1
H
N
R1
5a-f
N
H
7a-f
R2
N
R2
H
O
H
O
OH
iv
R1
H
H
O
N
R1
H
8a-f
6a-f
R2
R2
Scheme 3. Reagents and conditions: iv) Zn dust, AcOH, THF-H2O,
60oC, stir, 2 hrs.
Preparation of Nitrone 4
Procedure
The structures were determined from their spectral data
and elemental analyses. Similar results were obtained from
substrates 5b-5f and 6b-6f. The results are summarized in
Tables 1 and 2.
To a stirred solution of 1.00 g (5.235 mmol) of oxime 2a
and 0.33 g (5.235 mmol) of Na(BH3)CN in 15 mL methanol

394 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Roy et al.
Table 1. Synthesis of Nine Membered Cyclic 1, 3-Aminoalcohols 7 from Substrate 5
Yieldsa (%)
Substrate
Product
Entry
O
O
H
OH
H
O
H
H
H3C
1
N
86
H3C
5a
7a
N
H
O
O
H
OH
H
O
H
H
2
3
4
N
88
81
83
5b
N
7b
H
O
O
H
OH
O
H
H
Cl
H
N
Cl
5c
7c
N
H
O
O
H
OH
O
H
H
H3CO
H
N
H3CO
5d
7d
N
H
O
H
OH
H
O
O
H
H
N
5e
5
78
N
7e
H
OCH3
OCH3
O
H
OH
H
O
H
O
H
H3C
N
5f
H3C
6
75
7f
N
H
OCH3
OCH3
aIsolated yield.
at room temperature 2N hydrochloric acid solution was
added dropwise to maintain at pH 3-4. The mixture was
stirred for 3 hours maintaining the pH 3-4. The pH was
lowered to 1 and methanol was removed by rotary
evaporator. 10 mL water was added to the residue and pH
was adjusted to 8 with 20% K2CO3 solution. It was then
and filtered. To this hydroxylamine solution, 0.555 g (5.235
mmol) of benzaldehyde 3a and 1.88 g (15.7 mmol) of
anhydrous MgSO4 were added and stirred for 7 hours at
room temperature. The reaction mixture was filtered and
concentrated. After purification by column chromatography
nitrone 4a was obtained as a solid in 77% yield. Similarly,
compounds 4b-4f were synthesized.
extracted with (25 mL
x 3) dichloromethane. The
dichloromethane extract was dried over anhydrous Na2SO4

Synthesis of Novel Isoxazolidines
Table 2
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
395
Synthesis of Eight Membered Cyclic 1, 3-aminoalcohols 8 from Subatrates 6
Yieldsa (%)
Product
Substrate
Entry
O
O
H
H
H
OH
O
H
1
84
80
87
77
H3C
H3C
N
NH
8a
6a
O
O
H
H
H
OH
O
H
2
3
4
N
N
8b
6b
H
O
O
H
H
OH
H
O
H
Cl
Cl
N
N
6c
8c
H
O
O
H
H
OH
H
O
H
H3CO
H3CO
N
N
6d
8d
H
O
O
H
H
H
OH
O
H
N
N
6e
8e
5
75
H
OCH3
OCH3
O
O
H
H
OH
H
O
H
H3C
H3C
N
N
6f
6
8f
81
H
OCH3
OCH3
aIsolated yield.
Compound 4a
C, 76.84; H, 6.81; N, 4.98%. Found: C, 76.73; H, 6.85; N,
5.21%. Recrystallized from chloroform-petroleum ether
(1:1) 3 mL/100 mg
Yield 77 %, white solid, m.p. 70 oC; IR (KBr):
=
3058, 2918, 1578, 1504 cm-1. 1H NMR (400 MHz, CDCl3): ꢀ
= 2.29 (s, 3H, -CH3), 4.53 (td, 2H, J = 1.2, 4.0 Hz, -OCH2),
5.07 (s, 2H, -NCH2), 5.26 (qd, 1H, J = 1.2, 10.0 Hz, =CH2),
5.38 (qd, 1H, J = 1.2, 18.0 Hz, =CH2), 5.96-6.06 (m, 1H, -
CH=), 6.79 (d, 1H, J = 8.4 Hz, ArH), 7.11 (d, 1H, J = 8.4
Hz, ArH), 7.28 (s broad, ArH), 7.36-7.38 (m, 3H, ArH),
7.45 (s, 1H, =CH-Ph), 8.18-8.21 (m, 2H, ArH). 13C NMR
(100 MHz, CDCl3): ꢀ = 20.5, 66.2, 69.0, 111.9, 117.8, 121.5,
128.4, 128.7, 130.2, 130.4, 130.7, 130.8, 132.6, 133.0, 134.4,
154.6. MS (m/z) =282(M++H), Anal. Calcd for C18H19NO2:
Compound 4b
Yield 80 %, white solid, m.p. 44 oC; IR (KBr):
=
1
3064, 2923, 2856, 1603, 1493 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 4.55 (d, 2H, J = 4.8 Hz, -OCH2), 5.10 (s, 2H, -
NCH2), 5.27 (d, 1H, J = 10.4 Hz , =CH2), 5.38 (d, 1H, J =
17.6 Hz, =CH2), 5.96-6.06 (m, 1H, -CH=), 6.89 (d, 1H, J =
8.4 Hz, ArH), 6.98 (t, 1H, J = 7.2 Hz, ArH), 7.30-7.37 (m,
4H, ArH), 7.44 (s, 1H, =CH-Ph), 7.47 (d, 1H, J = 7.2 Hz,
ArH), 8.19 (t, 2H, J = 4.0 Hz, ArH). 13C NMR (100 MHz,

396 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Roy et al.
CDCl3): ꢀ = 66.2, 68.9, 111.9, 118.0, 121.1, 121.2, 128.4,
128.7, 130.3, 130.5, 130.7, 132.0, 132.9, 134.5, 156.7. MS
(m/z) =290(M++Na), Anal. Calcd for C17H17NO2: C, 76.38;
H, 6.41; N, 5.24%. Found: C, 76.29; H, 6.50; N, 5.11%.
Recrystallized from chloroform-petroleum ether (1:1) 3
mL/100 mg.
Hz, =CH2), 5.99-6.08 (m ,1H, -CH=), 6.82 (d, 1H, J = 8.4
Hz, ArH), 6.93 (d, 2H, J = 8.8 Hz, ArH), 7.13-7.15 (m, 1H,
ArH), 7.31 (s, 1H, ArH), 7.40 (s, 1H, =CH-Ph), 8.21 (d, 2H,
J = 8.8 Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 20.4,
55.3, 66.1, 68.9, 111.7, 112.90, 117.7, 120.2, 128.4, 128.8,
130.4, 130.7, 130.9, 132.8, 134.4, 155.7, 160.9. MS (m/z)
=334(M++Na), Anal. Calcd for C19H21NO3: C, 73.29; H,
6.80; N, 4.50%. Found: C, 73.14; H, 6.89; N, 4.56%.
Recrystallized from chloroform-petroleum ether (1:1) 3
mL/100 mg.
Compound 4c
o
Yield 78 %, white solid, m.p.110 C; IR (KBr):
=
1
3026, 2927, 2870, 1584, 1491 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 4.48-4.49 (m, 2H, -OCH2), 5.00 (s, 2H, -NCH2),
5.23 (dd, 1H, J = 1.2, 10.4 Hz, =CH2), 5.29-5.34 (m, 1H,
=CH2), 5.89-5.97 (m, 1H, -CH=), 6.76 (d, 1H, J = 8.8 Hz,
ArH), 7.21 (dd, 1H, J = 2.44, 9.0 Hz, ArH), 7.31-7.34 (m,
3H, ArH, =CH-Ph), 7.41-7.45 (m, 2H, ArH), 8.11-8.14 (m,
2H, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 65.6, 63.3,
113.1, 118.4, 123.4, 125.9, 128.4, 128.7, 130.1, 130.4, 130.5,
131.6, 132.5, 135.1, 155.3. MS (m/z) =302(M++H),
304(M++H+2) Anal. Calcd for C17H16ClNO2: C, 67.66; H,
5.34; N, 4.64%. Found: C, 67.54; H, 5.43; N, 4.59%.
Recrystallized from chloroform-petroleum ether (1:1) 3
mL/100 mg.
Synthesis of Compound 5a and 6a from Compound
4a:Procedure
0.4 g (1.423 mmol) of nitrone 4a was dissolved in 20 mL
of distilled xylene and it was refluxed for 10 hours. It was,
then purified by flash column chromatography using 3%
ethyl acetate-petroleum ether to afford two isoxazolidines 5a
and 6a in 52% and 21% yields respectively. Isoxazolidines
5b-5f and 6b-6f were prepared similarly from nitrones 4b-4f.
Compound 5a
o
Yield 52 %, white solid, m.p. 122 C; IR (KBr):
=
1
3028, 2940, 2918, 1496, 1467 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 2.33 (s, 3H, -CH3), 2.45 (dd, 1H, J = 8.8, 12.8
Hz, PhCHCH2) 3.15 (td, 1H, J = 7.6, 12.8 Hz, PhCHCH2),
4.07-4.15 (m, 3H, -OCH2, -NCH2), 4.17 (d, 1H, J = 10.8 Hz,
-NCH2), 4.34-4.38 (m, 1H, -NOCH), 4.55 (d, 1H, J = 7.6 Hz
PhCH), 6.98 (d, 1H, J = 7.6 Hz, ArH), 7.10-7.12 (m, 2H,
ArH), 7.19-7.32 (m, 2H, ArH), 7.30 (t, 2H, J = 7.6 Hz,
ArH), 7.40 (d, 1H, J = 7.2 Hz, ArH). 13C NMR (100 MHz,
CDCl3): ꢀ = 20.9, 36.9, 58.7, 71.2, 73.8, 80.3, 121.0, 126.4,
126.9, 128.5, 129.8, 130.4, 131.4, 134.2, 142.5, 159.2. MS
(m/z) =282(M+H), Anal. Calcd for C18H19NO2: C, 76.84; H,
6.81; N, 4.98%. Found: C, 76.77; H, 6.69; N, 5.04%.
Recrystallized from ethanol, 3 mL/100 mg.
Compound 4d
o
Yield 73 %, white solid, m.p. 64 C; IR (KBr):
=
3060, 2935, 2832, 1579, 1502 cm-1. H NMR (300 MHz,
CDCl3): ꢀ = 3.78 (s, 3H, -OCH3), 4.53 (td, 2H, J = 1.5, 5.1
Hz, -OCH2), 5.09 (s, 2H, -NCH2), 5.27 (td, 1H, J = 1.5, 10.5
Hz, =CH2), 5.38 (td, 1H, J = 1.5, 16.5 Hz, =CH2), 5.95-6.08
(m, 1H, -CH=), 6.84-6.87 (m, 2H, ArH), 7.07 (d, 1H, J = 2.4
Hz, ArH), 7.37-7.40 (m, 2H, ArH), 7.46 (s, 1H, =CH-Ph),
8.18-8.21 (m, 3H, ArH). 13C NMR (100 MHz, CDCl3): ꢀ =
55.78, 66.2, 69.6, 113.2, 115.5, 117.3, 117.8, 122.7, 128.4,
128.7, 130.3, 130.6, 133.1, 134.6, 150.8, 153.8. MS (m/z)
=320(M++Na), Anal. Calcd for C18H19NO3: C, 72.71; H,
6.44; N, 4.71%. Found: C, 72.61; H, 6.36; N, 4.47%.
Recrystallized from chloroform-petroleum ether (1:1) 3
mL/100 mg.
1
Compound 5b
o
Yield 53 %, white solid, m.p. 112 C; IR (KBr):
=
3031, 2927, 2882, 1486, 1453 cm-1. 1H NMR (400 MHz,
CDCl3): ꢀ = 2.40 (dd, 1H, J = 8.8, 12.8 Hz, PhCHCH2), 3.08
(td, 1H, J = 7.6, 12.8 Hz, PhCHCH2), 4.07-4.09 (m, 2H, -
OCH2), 4.11 (d, 1H, J = 10.8 Hz, -NCH2), 4.15 (d, 1H, J =
10.8 Hz, -NCH2), 4.32 (dt, 1H, J = 2.0, 8.0 Hz, -OCH2CH),
4.49 (d, 1H, J = 7.6 Hz, PhCH), 7.01-7.05 (m, 1H, ArH),
7.08 (dd, 1H, J = 1.2, 7.4 Hz, ArH), 7.13-7.17 (m, 1H ,
ArH), 7.21-7.27 (m, 4H, ArH), 7.33 (d,2H, J = 7.6 Hz,
ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 36.9, 58.7, 71.3,
73.8, 80.4, 121.4, 124.7, 126.4, 126.9, 128.5, 130.0, 130.3,
130.8, 142.5, 161.44. MS (m/z) =268(M++H), Anal. Calcd
for C17H17NO2: C, 76.38; H, 6.41; N, 5.24%. Found: C,
76.31; H, 6.25; N, 5.23%. Recrystallized from ethanol, 3
mL/100 mg.
Compound 4e
o
Yield 68 %, yellow solid, m.p. 90 C; IR (KBr):
=
3064, 2868, 2828, 1602, 1507, 1494 cm-1. H NMR (400
MHz, CDCl3): ꢀ = 3.75 (s, 3H, -OCH3), 4.50 (dt, 2H, J = 1.2,
5.2 Hz, -OCH2), 5.01 (s, 2H, -NCH2), 5.20 (qd, 1H, J = 1.2,
10.4 Hz, =CH2), 5.32 (qd, 1H, J = 1.2, 16.8 Hz, =CH2), 5.93-
6.00 (m, 1H, -CH=), 6.83 (d, 3H, J = 8.8 Hz, ArH), 6.92 (dt,
1H, J = .8, 7.6 Hz, ArH), 7.25 (dt, 1H, J = 1.2, 7.8 Hz, ArH),
7.29 (s, 1H, =CH-Ph), 7.40 (dd, 1H, J = 1.2, 7.4 Hz, ArH),
8.10-8.13 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3): ꢀ =
55.3, 65.6, 68.9, 111.8, 113.8, 117.9, 121.1, 121.9, 123.6,
130.4, 130.7, 131.9, 132.9, 134.2, 156.7, 160.9. MS (m/z)
=320(M+Na), Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44;
N, 4.71%. Found: C, 72.54; H, 6.39; N, 4.62%.
Recrystallized from chloroform-petroleum ether (1:1) 3
mL/100 mg.
1
Compound 5c
o
Yield 55 %, White solid, m.p. 131 C; IR (KBr):
=
3027, 2931, 2907, 1688, 1484 cm-1. 1H NMR (400 MHz,
CDCl3): ꢀ = 2.43 (dd, 1H, J = 8.4, 12.6 Hz, PhCHCH2), 3.09
(td, 1H, J = 7.6, 12.8 Hz, PhCHCH2), 4.0-4.04 (m, 2H,
OCH2), 4.10 (d, 2H, J = 12.4 Hz, -NCH2), 4.32 (dt, 1H, J =
2.4, 8.4 Hz, -OCH2CH), 4.49 (d, 1H, J = 7.2 Hz, PhCH),
6.95 (d, 1H, J = 8.4 Hz, ArH), 7.14-7.17 (m, 2H, ArH), 7.20-
7.24 (m, 3H, ArH), 7.32 (d, 2H, J = 7.6 Hz, ArH). 13C NMR
Compound 4f
o
Yield 65 %, yellow solid, m.p. 91 C; IR (KBr):
=
3060, 2926, 2856, 2832, 1602, 1506 cm-1. H NMR (400
MHz, CDCl3): ꢀ = 2.32 (s, 3H, -CH3), 3.85 (s, 3H, -OCH3),
4.56 (d, 2H, J = 4.0 Hz, -OCH2), 5.07 (s, 2H, -NCH2), 5.29
(dd, 1H, J = 1.2, 10.6 Hz, =CH2), 5.39 (dd, 1H, J = 1.6, 17.2
1

Synthesis of Novel Isoxazolidines
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
397
(100 MHz, CDCl3): ꢀ = 36.8, 58.2, 71.3, 73.9, 80.4, 122.7,
126.3, 127.1, 128.5, 128.7, 129.8, 130.6, 131.9, 142.1, 160.1.
MS (m/z) =324(M++Na), 326(M++Na+2) Anal. Calcd for
C17H16ClNO2: C, 67.66; H, 5.34; N, 4.64%. Found: C, 67.47;
H, 5.31; N, 4.55%. Recrystallized from ethanol, 3 mL/100
mg.
OCH2CH), 3.24 (s broad, 1H, -NOCH2), 3.93 (dd, 1H, J =
8.4, 9.6 Hz, -NOCH2), 4.01 (d, 1H, J = 12.4 Hz, -OCH2),
4.30 (d, 1H, J = 14.0 Hz, -NCH2), 4.42 (d, 1H, J = 14.0 Hz, -
NCH2), 4.50 (dd, 1H, J = 4.0, 12.4 Hz, -OCH2), 4.84 (s, 1H,
PhCH), 7.03 (d, 1H, J = 8.0 Hz, ArH), 7.07 (s, 1H, ArH),
7.13 (d, 1H, J = 8.0 Hz, ArH), 7.21-7.24 (m, 1H, ArH), 7.32
(t, 2H, J = 7.6 Hz, ArH), 7.40 (d, 2H, J = 7.6 Hz, ArH). 13C
NMR (100 MHz, CDCl3): ꢀ = 20.8, 53.7, 60.1, 71.7, 72.9,
74.7, 120.9, 126.0, 126.8, 128.6, 130.8, 131.6, 133.3, 134.4,
144.5, 156.5. MS (m/z) =282(M++H), Anal. Calcd for
C18H19NO2: C, 76.84; H, 6.81; N, 4.98%. Found: C, 76.89;
H, 6.75; N, 5.08%. Recrystallized from ethyl acetate-
petroleum ether (2:1) 3 mL/100 mg.
Compound 5d
o
Yield 55 %, white solid, m.p. 128 C; IR (KBr):
=
3028, 2916, 2885, 2856, 1496, 1463 cm-1. 1H NMR (400
MHz, CDCl3): ꢀ = 2.49 (dd, 1H, J = 8.8, 12.4 Hz,
PhCHCH2), 3.18 (td, 1H, J = 7.6, 12.4 Hz, PhCHCH2), 3.81
(s, 3H, -OCH3), 4.08-4.13 (m, 2H, -OCH2), 4.18 (d, 1H, J =
10.4 Hz, -NCH2), 4.22 (d, 1H, J = 10.4 Hz, -NCH2), 4.40-
4.45 (m, 1H, -OCH2CH), 4.59 (d, 1H, J = 7.6 Hz, PhCH),
6.85 (dd, 1H, J = 2.8, 8.6 Hz, ArH), 6.91 (d, 1H, J = 2.8 Hz,
ArH), 7.04 (d, 1H, J = 8.4 Hz, ArH), 7.23-7.27 (m 1H,
ArH), 7.33 (t, 2H, J = 7.6 Hz, ArH), 7.42 (d, 2H, J = 7.6 Hz,
ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 36.9, 55.6, 58.9,
71.3, 73.8, 80.4, 114.8, 115.8, 121.9, 126.4, 127.0, 128.5,
128.7, 142.4, 154.9, 156.2. MS (m/z) =320(M++Na), Anal.
Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71%. Found:
C, 72.65; H, 6.56; N, 4.59%. Recrystallized from ethanol, 3
mL/100 mg.
Compound 6b
o
Yield 23 %, white solid, m.p. 108 C; IR (KBr):
=
1
3031, 2949, 2923, 1885, 1495 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 2.95-2.99 (m, 1H, -OCH2CH), 3.22 (s broad,
NO-CH2), 3.95 (1H, dd, 1H, J = 8.0, 9.6 Hz, NO-CH2), 4.07
(d, 1H, -OCH2), 4.37 (d, 1H, J = 14.0 Hz, -NCH2), 4.50 (d,
1H, J = 14.0 Hz, -NCH2), 4.56 (dd, 1H, J = 4.0, 12.4 Hz, -
OCH2), 4.88 (s, 1H, PhCH), 7.15 (s broad, 1H, ArH), 7.18
(d, 1H, J = 7.6 Hz, ArH), 7.25 (t, 2H, J = 7.2 Hz, ArH),
7.30-7.33 (m, 1H, ArH), 7.36 (d, 2H, J = 8.0 Hz, ArH), 7.43
(d, 2H, J = 7.2 Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ =
53.7, 60.0, 71.8, 72.8, 74.8, 121.3, 124.9, 126.0, 126.9,
128.6, 130.4, 132.2, 132.8, 144.5, 158.8. MS (m/z)
=320(M++Na), Anal. Calcd for C17H17NO2: C, 76.38; H,
6.41; N, 5.24%. Found: C, 76.26; H, 6.37; N, 5.20%.
Recrystallized from ethyl acetate-petroleum ether (2:1) 3
mL/100 mg.
Compound 5e
o
Yield 50 %, white solid, m.p. 151 C; IR (KBr):
=
3032, 2895, 2924, 1512 cm-1. 1H NMR (400 MHz, CDCl3):
ꢀ = 2.37 (dd, 1H, J = 8.8, 12.4 Hz, PhCHCH2), 3.06 (td, 1H,
J = 7.6, 12.8 Hz, PhCHCH2), 3.71 (s, 3H, -OCH3), 3.94-4.09
(m, 3H, -OCH2, -NCH2), 4.13 (d, 1H, J = 10.4 Hz, -NCH2),
4.30-4.35 (m, 1H, -OCH2CH), 4.46 (d, 1H, J = 7.6 Hz,
PhCH), 6.77 (d, 2H, J = 8.8 Hz, ArH), 7.02 (d, 1H, J = 8.4
Hz, ArH), 7.07 (d, 1H, J = 8.4 Hz, ArH), 7.23-7.26 (m, 4H,
ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 36.9, 55.3, 58.6,
70.9, 73.8, 80.4, 113.8, 121.3, 124.7, 127.1, 127.5, 130.0,
130.8, 141.4, 158.5, 161.4. MS (m/z) =320(M++Na), Anal.
Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71%. Found:
C, 72.63; H, 6.19; N, 4.52%. Recrystallized from ethanol, 3
mL/100 mg.
Compound 6c
o
Yield 21 %, white solid, m.p. 115 C; IR (KBr):
=
3034, 2944, 2888, 1480, 1454 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 2.94-2.98 (m, 1H, -OCH2CH), 3.24 (s, broad,
NO-CH2), 3.95 (t, 1H, J = 8.4 Hz, NO-CH2), 4.01 (d, 1H, J =
12.4 Hz, -OCH2), 4.27 (d, 1H, J = 14.4 Hz, -NCH2), 4.41 (d,
1H, J = 14.0 Hz, -NCH2), 4.54 (dd, 1H, J = 4.4, 12.0 Hz, -
OCH2), 4.84 (s, 1H, Ph-CH), 7.08 (d, 1H, J = 8.4 Hz, ArH),
7.22-7.25 (m, 1H, ArH), 7.27-7.29 (m, 1H, ArH), 7.32 (d,
1H, J = 2.0 Hz, ArH), 7.33 (t, 2H, J = 7.6 Hz, ArH), 7.40 (d,
2H, J = 7.2 Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ =
53.5, 59.7, 71.8, 73.1, 75.1, 122.5, 125.9, 126.9, 128.7,
129.8, 130.1, 132.5, 134.1, 144.2, 157.4. MS (m/z)
1
Compound 5f
o
Yield 48 %, white solid, m.p. 125 C; IR (KBr):
=
1
3015, 2947, 2917, 1514, 1495 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 2.24 (s, 3H, -CH3), 2.35 (dd, 1H, J = 8.8, 12.6
Hz, PhCHCH2), 3.07 (td, 1H, J = 7.6, 12.4 Hz, PhCHCH2),
3.70 (s, 3H, -OCH3), 3.99-4.04 (m, 3H, -OCH2, -NCH2),
4.09 (d, 1H, J = 10.4 Hz, -NCH2), 4.28-4.32 (m, 1H, -
OCH2CH), 4.44 (d, 1H, J = 7.6 Hz, PhCH), 6.74-6.78 (m,
2H, ArH), 6.91 (d, 1H, J = 8.0 Hz, ArH), 7.02 (d, 1H, J =
2.0 Hz, ArH), 7.05 (s broad, 1H, ArH), 7.22-7.25 (m, 2H,
ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 20.8, 36.9, 55.3,
58.6, 70.8, 73.8, 80.4, 113.7, 120.9, 127.6, 129.8, 130.4,
131.4, 134.2, 134.7, 158.5, 159.2. MS (m/z) =312(M++H),
Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50%.
Found: C, 73.09; H, 6.93; N, 4.48%. Recrystallized from
ethanol, 3 mL/100 mg.
=324(M++Na),
326(M++Na+2)
Anal.
Calcd
for
C17H16ClNO2: C, 67.66; H, 5.34; N, 4.64%. Found: C, 67.58;
H, 5.33; N, 4.59%. Recrystallized from ethyl acetate-
petroleum ether (2:1) 3 mL/100 mg.
Compound 6d
o
Yield 19 %, white solid, m.p. 113 C; IR (KBr):
=
3027, 2939, 2885, 1502 cm-1. 1H NMR (400 MHz, CDCl3): ꢀ
= 2.91-2.95 (m, 1H, -OCH2CH), 3.28 (s, broad, 1H, NO-
CH2), 3.80 (s, 3H, -OCH3), 3.94 (t, 1H, J = 8.4 Hz, NO-
CH2), 3.99 (d, 1H, J = 12.4 Hz, -OCH2), 4.31 (d, 1H, J =
14.0 Hz, -NCH2), 4.42 (d, 1H, J = 14.0 Hz, -NCH2), 4.47
(dd, 1H, J = 4.0, 12.2 Hz, -OCH2), 4.84 (s, broad, 1H,
PhCH), 6.81 (d, 1H, J = 3.2 Hz, ArH), 6.86 (dd, 1H, J = 3.2,
8.6 Hz, ArH), 7.06 (d, 1H, J = 8.4 Hz, ArH), 7.21-7.24 (m,
1H, ArH), 7.32 (t, 2H, J = 7.6 Hz, ArH), 7.40 (d, 2H, J = 7.2
Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 54.0, 55.3, 59.1,
Compound 6a
o
Yield 21 %, white solid, m.p. 140 C; IR (KBr):
=
1
3052, 2949, 2920, 2893, 1500 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 2.33 (s, 3H, -CH3), 2.91-2.96 (m, 1H, -

398 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Roy et al.
72.0, 73.5, 122.3, 123.9, 127.7, 128.5, 129.7, 133.1, 133.6,
143.7, 156.1, 157.8. MS (m/z) =320(M++Na), Anal. Calcd
for C18H19NO3: C, 72.71; H, 6.44; N, 4.71%. Found: C,
72.64; H, 6.39; N, 4.66%. Recrystallized from ethyl acetate-
petroleum ether (2:1) 3 mL/100 mg.
52.9, 66.2, 73.1, 78.5, 118.9, 126.1, 127.4, 129.1, 129.3,
130.1, 131.7, 132.9, 146.2, 158.3. MS (m/z) =306(M++Na),
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94%.
Found: C, 76.25 H, 7.31; N, 5.14%. Recrystallized from
ethyl acetate-petroleum ether (1:1) 2 mL/50 mg.
Compound 6e
Compound 7b
o
Yield 21 %, white solid, m.p. 110 C; IR (KBr):
=
Yield 88 %, gummy liquid, IR (KBr):
= 3354, 3032,
3020, 2925, 2883, 1508 cm-1. 1H NMR (400 MHz, CDCl3): ꢀ
= 2.91-2.93 (m, 1H, -OCH2CH), 3.19 (s, broad, 1H, NO-
CH2), 3.79 (s, 3H, -OCH3), 3.93 (t, 1H, J = 8.4 Hz, NO-
CH2), 4.03 (d, 1H, J = 12.4 Hz, -OCH2), 4.32 (d, 1H, J =
14.0 Hz, -NCH2), 4.46 (d, 1H, J = 14.0 Hz, -NCH2), 4.51
(dd, 1H, J = 3.6, 12.2 Hz, -OCH2), 4.80 (s, 1H, PhCH), 6.86
(d, 2H, J = 8.4 Hz, ArH), 7.12-7.15 (m, 2H, ArH), 7.26-7.36
(m, 4H, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 53.6, 55.3,
59.9, 71.3, 72.8, 74.8, 114.0, 121.3, 124.8, 127.1, 130.3,
132.2, 132.8, 136.8, 158.5, 158.9. MS (m/z) =320(M++Na),
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71%.
Found: C, 72.69; H, 6.28; N, 4.84%. Recrystallized from
ethyl acetate-petroleum ether (2:1) 3 mL/100 mg.
2985, 1509 cm-1, H NMR (400 MHz, CDCl3): ꢀ = 1.96 (td,
1H, J = 3.6, 14.8 Hz, PhCHCH2), 2.04 (s, 1H, -NH), 2.37-
2.46 (m ,1H, PhCHCH2), 3.62 (s, broad, 1H, -OH), 3.86 (d,
1H, J = 14.8 Hz, -NCH2), 4.02 (m, 1H, -OCH2CH), 4.11 (d,
1H, J = 14.4 Hz, -NCH2), 4.54 (d, 1H, J = 12.4 Hz, -OCH2),
4.73-4.76 (m 1H, PhCH), 4.81 (dd, 1H, J = 4.4, 12.4 Hz, -
OCH2), 6.94 (t, 1H, J = 7.2 Hz, ArH), 7.0 (d, 1H, J = 7.2 Hz,
ArH), 7.16 (d, 1H, J = 8.4 Hz, ArH), 7.28-7.32 (m, 2H,
ArH), 7.35-7.41 (m, 4H, ArH). 13C NMR (100 MHz,
CDCl3): ꢀ = 40.6, 52.8, 66.1, 72.9, 78.4, 119.1, 122.4, 126.1,
127.4, 128.9, 129.0, 129.5, 133.5, 146.2, 160.6. MS (m/z)
=292(M++Na), Anal. Calcd for C17H19NO2: C, 75.81; H,
7.11; N, 5.20%. Found: C, 75.98; H, 6.93; N, 5.09%.
1
Compound 6f
Compound 7c
o
o
Yield 20%, white solid, m.p. 150 C; IR (KBr):
=
Yield 81 %, white solid, m.p. 109 C; IR (KBr):
=
3020, 2960, 2923, 1514, 1501 cm-1. H NMR (400 MHz,
CDCl3): ꢀ = 2.32 (s, 3H, -CH3), 2.88-2.92 (m, 1H, -
OCH2CH), 3.24 (s, broad, 1H, NO-CH2), 3.78 (s, 3H, -
OCH3), 3.90-3.95 (m, 1H, NO-CH2), 3.99 (d, 1H, J = 12.4
Hz, -OCH2), 4.29 (d, 1H, J = 14.0 Hz, -NCH2), 3.39 (d, 1H,
J = 14.0 Hz, -NCH2), 4.46 (dd, 1H, J = 4.0, 12.0 Hz, -
OCH2), 4.79 (s, broad, PhCH), 6.85 (d, 2H, J = 8.4 Hz,
ArH), 7.02 (d, 1H, J = 8.0 Hz, ArH), 7.07 (s, 1H, ArH), 7.12
3304, 3024, 2932, 2868, 1482, 1445 cm-1. H NMR (400
MHz, CDCl3): ꢀ = 1.90 (s, broad, -NH), 1,95 (td, 1H, J =
4.0, 14.4 Hz, PhCHCH2), 2.38-2.45 (m, 1H, PhCHCH2),
3.78 (d, 1H, J = 14.8 Hz, -NCH2), 4.01 (s, broad, 1H, -
OCH2CH), 4.06 (d, 1H, J = 14.8 Hz, -NCH2), 4.53 (d, 1H, J
= 12.8 Hz, PhCH), 4.69 (d, 1H, J = 12.4 Hz, -OCH2), 4.77
(dd, 1H, J = 4.8, 12.4 Hz, -OCH2), 6.98 (d, 1H, J = 2.4 Hz,
ArH), 7.09 (d, 1H, J = 8.8 Hz, ArH), 7.23 (dd, 1H, J = 2.4,
8.4 Hz, ArH), 7.28-7.41 (m, 5H, ArH). 13C NMR (100 MHz,
CDCl3): ꢀ = 40.4, 52.6, 66.5, 72.9, 78.7, 120.3, 125.9, 126.9,
127.5, 128.6, 129.1, 129.2, 135.0, 145.9, 159.2. MS (m/z)
=304(M++H), 306(M++H+2) Anal. Calcd for C17H18ClNO2:
C, 67.21; H, 5.97; N, 4.61%. Found: C, 67.31; H, 6.00; N,
4.89%. Recrystallized from ethyl acetate-petroleum ether
(1:1) 2 mL/50 mg.
1
1
(d, 1H, J = 7.6 Hz, ArH), 7.30 (d, 2H, J = 8.4 Hz, ArH). 13
C
NMR (100 MHz, CDCl3): ꢀ = 20.8, 53.6, 55.3, 60.0, 71.2,
72.9, 74.6, 113.9, 120.9, 127.2, 130.7, 131.7, 133.3, 134.3,
136.9, 156.5, 158.5. MS (m/z) =334(M++Na), Anal. Calcd
for C19H21NO3: C, 73.29; H, 6.80; N, 4.50%. Found: C,
73.13; H, 6.88; N, 4.41%. Recrystallized from ethyl acetate-
petroleum ether (2:1) 3 mL/100 mg.
Synthesis of Aminoalcohols
Compound 7d
A suspension of 50 mg of isoxazolidine in glacial acetic
acid (1 mL), THF (0.6 mL), Zinc dust 95 mg and water (0.60
mL), was stirred at 60 C for 2 hrs. The reaction was cooled
to room temperature and diluted with 5 mL water; it was
neutralized by Na2CO3 solution and was extracted with
dichloromethane (10 mL x 3) and dried over anhydrous
Na2SO4. The crude product was purified by flash column
chromatography to afford aminoalcohols.
Yield 83 %, gummy liquid, IR (KBr):
= 3349, 3025,
2925, 1496 cm-1. H NMR (400 MHz, CDCl3): ꢀ = 1.95 (td,
1H, J = 3.6, 14.4 Hz, PhCHCH2), 2.29 (s, 1H, -NH), 2.38-
2.46 (m, 1H, PhCHCH2), 3.75 (s, 3H, -OCH3), 3.79 (d, 1H, J
= 14.8 Hz, -NCH2), 4.00 (s, broad, -OCH2CH), 4.06 (d, 1H,
J = 14.8 Hz, -NCH2), 4.48 (d, 1H, J = 12.4 Hz, PhCH), 4.65
(dd, 1H, J = 2.0, 12.4 Hz, -OCH2), 4.78 (dd, 1H, J = 4.0,
12.4 Hz, -OCH2), 6.54 (d, 1H, J = 3.2 Hz, ArH), 6.80 (dd,
1H, J = 3.2, 8.8 Hz, ArH), 7.08 (d, 1H, J = 8.8 Hz, ArH),
7.28-7.31 (m, 1H, ArH), 7.34-7.40 (m, 4H, ArH). 13C NMR
(100 MHz, CDCl3): ꢀ = 40.5, 52.8, 55.6, 65.9, 72.9, 78.6,
113.1, 115.2, 119.8, 126.0, 127.4, 129.1, 134.1, 146.1, 154.3,
154.5. MS (m/z) =322(M++Na), Anal. Calcd for C18H21NO3:
C, 72.22; H, 7.07.; N, 4.68%. Found: C, 72.31; H, 6.89 N,
4.81%.
1
o
Compound 7a
Yield 86 %, white solid, m.p. 89 oC; IR (KBr):
=
3350, 3025, 2923, 1498 cm-1. 1H NMR (400 MHz, CDCl3): ꢀ
= 1.95 (ddd, 1H, J = 3.6, 4.4, 14.4 Hz, PhCHCH2), 2.26 (s,
3H, -CH3), 2.28 (s, 1H, -NH), 2.38-2.46 (m, 1H, PhCHCH2),
3.02 (s broad, -OH), 3.79 (d, 1H, J = 14.8 Hz, -NCH2), 3.98-
4.01(m, 1H, -OCH2CH), 4.07 (d, 1H, J = 14.4 Hz, -NCH2),
4.48 (dd, 1H, J = .8, 12.0 Hz, PhCH), 4.69 (dt, 1H, J = 2.0,
12.4 Hz, -OCH2), 4.80 (dd, 1H, J = 4.4, 12.4 Hz, -OCH2),
6.79 (s broad, ArH), 7.04 (d, 1H, J = 8.0 Hz, ArH), 7.06 (d,
1H, J = 2.0 Hz, ArH), 7.28-7.13 (m, 1H, ArH), 7.34-7.40
(m, 4H, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 20.7, 40.5,
Compound 7e
Yield 78 %, white solid, m.p. 78 oC; IR (KBr):
=
3353, 3030, 2926, 2897, 1514, 1492 cm-1. H NMR (400
MHz, CDCl3): ꢀ = 1.93 (td, 1H, J = 4.0, 14.4 Hz,
PhCHCH2), 1.95 (s, 1H, -NH), 2.41 (dt, 1H, J = 2.0, 12.8
1

Synthesis of Novel Isoxazolidines
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
399
Hz, PhCHCH2), 3.82 (s, 3H, -OCH3), 3.84 (d, 1H, J = 6.4
Hz, -OCH2), 4.0 (s, broad, 1H, -OCH2CH), 4.10 (d, 1H, J =
14.8 Hz, -NCH2), 4.52 (d, 1H, J = 12.4 Hz, PhCH), 4.74 (d,
1H, J = 14.4 Hz, -NCH2), 4.75-4.78 (m, 1H, -OCH2), 6.90-
6.93 (m, 2H, ArH), 6.95 (d, 1H, J = 7.2 Hz, ArH), 6.99 (d,
1H, J = 7.2 Hz, ArH), 7.15 (d, 1H, J = 8.0 Hz, ArH), 7.27-
7.29 (m, 3H, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 40.6,
52.8, 55.4, 65.6, 73.0, 78.5, 114.3, 119.1, 122.4, 127.1,
128.9, 129.4, 133.4, 138.6, 158.8, 160.6. MS (m/z)
=322(M++Na), Anal. Calcd for C18H21NO3: C, 72.22; H,
7.07; N, 4.68%. Found: C, 72.07; H, 6.93; N, 4.81%.
Recrystallized from ethyl acetate-petroleum ether (1:1) 2
mL/50 mg.
Compound 8c
Yield 87%, gummy, IR (KBr):
= 3352, 3015, 2925,
2854, 1482cm-1. 1H NMR (400 MHz, CDCl3): ꢀ = 2.15-2.18
(m, 1H, -OCH2CH), 2.41 (s, broad, 2H, -NH, -OH), 3.64 (d,
2H, J = 5.6 Hz, -CH2OH), 3.89 (d, 1H, J = 15.2 Hz, -NCH2),
4.12 (dd, 1H, J = 4.8, 12.2 Hz, -OCH2), 4.26 (s, broad, 1H,
PhCH), 4.40 (d, 1H, J = 15.2 Hz, -NCH2), 4.61 (dd, 1H, J =
6.8, 12.4 Hz, -OCH2), 7.03 (d, 1H, J = 8.8 Hz, ArH), 7.09 (d,
1H, J = 2.4, ArH), 7.21-7.27 (m, 2H, ArH), 7.32 (t, 2H, J =
7.2 Hz, ArH), 7.87 (d, 2H, J = 7.2 Hz, ArH). 13C NMR (100
MHz, CDCl3): ꢀ = 46.9, 49.6, 60.4, 61.7, 74.2, 123.2, 126.9,
127.4, 128.6, 128.8, 129.1, 130.0, 133.2, 143.6, 157.4. MS
(m/z) =326(M++Na), 328(M++Na+2) Anal. Calcd for
C17H18ClNO2: C, 67.21; H, 5.97; N, 4.61%. Found: C, 67.11;
H, 6.01; N, 4.84%.
Compound 7f
Yield 75 %, gummy liquid, IR (KBr):
= 3351, 3028,
1
2926, 2837, 1497cm-1. H NMR (400 MHz, CDCl3): ꢀ =
1.89-1.93 (m, 1H, PhCHCH2), 1.96 (s, 1H, -NH), 2.63 (s,
3H, -CH3), 2.37-2.43 (m, 1H, PhCHCH2), 3.78 (d, 1H, J =
15.2 Hz, -NCH2), 3.81 (s, 3H, -OCH3), 3.98 (s, broad, -
OCH2CH), 4.06 (d, 1H, J = 14.8 Hz, -NCH2), 4.48 (d, 1H, J
= 12.4 Hz, PhCH), 4.68 (d, 1H, J = 12.4 Hz, -OCH2), 4.75
(dd, 1H, J = 3.2, 12.0 Hz, -OCH2), 6.78 (s, 1H, ArH), 6.91
(d, 2H, J = 8.0 Hz, ArH), 7.02-7.05 (m, 2H, ArH), 7.28 (d,
2H, J = 8.0 Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ =
20.7, 40.5, 52.8, 55.4, 65.6, 73.0, 78.5, 114.3, 118.8, 127.1,
129.3, 130.0, 131.6, 132.8, 138.5, 158.3, 158.8. MS (m/z)
=336(M++Na), Anal. Calcd for C19H21NO3: C, 72.82; H,
7.40; N, 4.47%. Found: C, 72.71; H, 7.54; N, 4.40%.
Compound 8d
Yield 77 %, gummy liquid, IR (KBr):
= 3351, 3028,
2926, 2837, 1497 cm-1. H NMR (400 MHz, CDCl3): ꢀ =
2.22 (s, broad, 3H, -OCH2CH, -OH, -NH), 3.63 (dd, 1H, J =
7.2, 10.8 Hz, -CH2OH), 3.70 (dd, 1H, J = 5.6, 11.2 Hz, -
CH2OH ), 3.92 (d, 1H, J = 15.2 Hz, -NCH2), 4.04 (dd, 1H, J
= 4.8, 12.4 Hz, -OCH2), 4.25 (s, broad, PhCH), 4.35 (d, 1H,
J = 14.8 Hz, -NCH2), 4.47 (dd, 1H, J = 6.0, 12.4 Hz, -
OCH2), 6.65 (d, H, J = 2.8 Hz, ArH), 6.81 (dd, 1H, J = 2.8,
8.8 Hz, ArH), 7.04 (d, 1H, J = 8.8 Hz, ArH), 7.22-24 (m,
1H, ArH), 7.32 (t, 2H, J = 7.2 Hz, ArH), 7.39 (d, 2H, J = 7.6
Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 46.7, 49.7, 55.6,
60.4, 62.3, 74.7, 114.1, 114.3, 122.9, 127.0, 127.2, 128.5,
133.8, 144.0, 152.0, 156.1. MS (m/z) =322(M++Na), Anal.
Calcd for C18H21NO3: C, 72.22; H, 7.07.; N, 4.68%. Found:
C, 72.12; H, 6.83 N, 4.74%.
1
Compound 8a
Yield 84 %, gummy liquid, IR (KBr):
= 3351, 3341,
1
3027, 2922, 1497cm-1. H NMR (400 MHz, CDCl3): ꢀ =
2.07-2.13 (m, 3H, -OH, -NH, -OCH2CH), 2.22 (s, 3H, -
CH3), 3.58-3.60 (m, 2H, -CH2OH), 3.82 (d, 1H, J = 14.8 Hz,
-NCH2), 4.04 (dd, 1H, J = 5.2, 12.6 Hz, -OCH2), 4.21 (d,
1H, J = 2.0 Hz, PhCH), 4.35 (d, 1H, J = 14.8 Hz, -NCH2),
4.52 (dd, 1H, J = 6.0, 12.4 Hz, -OCH2), 6.84 (d, 1H, J = 1.6
Hz, ArH), 6.91 (d, 1H, J = 8.4 Hz, ArH), 6.99 (dd, 1H, J =
2.0, 8.0 Hz, ArH), 7.14-7.16 (m ,1H, ArH), 7.24 (t, 2H, J =
7.6 Hz, ArH), 7.31 (d, 2H, J = 7.2 Hz, ArH). 13C NMR (100
MHz, CDCl3): ꢀ = 20.7, 46.9, 49.7, 60.4, 61.8, 74.1, 121.5,
127.0, 127.2, 128.5, 129.7, 130.6, 131.4, 133.6, 143.9, 156.4.
MS (m/z) =306(M++Na), Anal. Calcd for C18H21NO2: C,
76.29; H, 7.47; N, 4.94%. Found: C, 76.19 H, 7.33; N,
5.01%.
Compound 8e
Yield 75 %, gummy liquid, IR (KBr):
= 3368, 3000,
2928, 1708, 1610 cm-1. H NMR (400 MHz, CDCl3): ꢀ =
2.16-2.19 (m, 1H, -OCH2CH), 2.60 (s, broad, 1H, -OH),
2.74 (s, 1H, -NH), 3.61-3.70 (m, 2H, -CH2OH), 3.78 (s, 3H,
-OCH3), 3.93 (d, 1H, J = 15.2 Hz, -NCH2), 4.13 (dd, 1H, J =
5.2, 12.4 Hz, -OCH2), 4.27 (s, broad, PhCH), 4.52 (d, 1H, J
= 15.2 Hz, -NCH2), 4.64 (dd, 1H, J = 6.8., 12.4 Hz, -OCH2),
6.85 (d, 2H, J = 8.4 Hz, ArH), 7.04-7.12 (m, 3H, ArH), 7.28-
7.30 (m, 1H, ArH), 7.32 (d, 2H, J = 8.8 Hz, ArH). 13C NMR
(100 MHz, CDCl3): ꢀ = 46.8, 49.7, 55.3, 60.4, 61.0, 73.9,
113.8, 121.8, 124.0, 128.1, 129.2, 130.3, 131.5, 135.7, 154.4,
158.6. MS (m/z) =322(M++Na), Anal. Calcd for C18H21NO3:
C, 72.22; H, 7.07; N, 4.68%. Found: C, 72.03; H, 6.97; N,
4.88%.
1
Compound 8b
Yield 80 %, gummy liquid, IR (KBr):
= 3351, 3060,
Compound 8f
2921, 1489cm-1. 1H NMR (400 MHz, CDCl3): ꢀ = 2.13-2.20
(m, 1H, -OCH2CH), 2.45 (s, broad, 2H, -NH, -OH), 3.65-
3.66 (m, 2H, -CH2OH), 3.94 (d, 1H, J = 15.2 Hz, -NCH2),
4.15 (dd, 1H, J = 5.2, 12.4 Hz, -OCH2), 4.30 (s, broad,
PhCH), 4.49 (d, 1H, J = 15.2 Hz, -NCH2), 4.65 (dd, 1H, J =
6.8, 12.4 Hz, -OCH2), 7.04-7.12 (m, 3H, ArH), 7.22-7.28
(m, 2H, ArH), 7.32 (t, 2H, J = 7.6 Hz, ArH), 7.39 (d, 2H, J =
7.6 Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ = 46.9, 49.7,
60.2, 61.7, 74.0, 121.9, 124.2, 127.0, 127.2, 128.5, 129.2,
130.2, 131.8, 143.8, 158.7. MS (m/z) =270(M++H), Anal.
Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20%. Found:
C, 75.95; H, 6.99; N, 5.13%.
Yield 81 %, gummy liquid, IR (KBr):
= 3351, 2998,
2924, 2855, 1511, 1498 cm-1. 1H NMR (400 MHz, CDCl3): ꢀ
= 2.14-2.17 (m, 3H, -OCH2CH, -NH, -OH), 2.29 (s, 3H, -
CH3), 3.67 (d, 2H, J = 5.6 Hz, -CH2OH), 3.79 (s, 3H, -
OCH3), 3.89 (d, 1H, J = 15.2 Hz, -NCH2), 4.09 (dd, 1H, J =
5.2, 12.4 Hz, -OCH2), 4.25 (s, broad, PhCH), 4.44 (d, 1H, J
= 14.8 Hz, -NCH2), 4.57 (dd, 1H, J = 6.8, 12.4 Hz, -OCH2),
6.85 (d, 2H, J = 8.8 Hz, ArH), 6.91 (s, 1H, ArH), 6.97 (d,
1H, J = 8.0 Hz, ArH), 7.07 (d, 1H, J = 8.0 Hz, ArH), 7.32 (d,
2H, J = 8.4 Hz, ArH). 13C NMR (100 MHz, CDCl3): ꢀ =
20.8, 45.1, 49.5, 55.0, 60.6, 61.3, 74.1, 113.8, 120.2, 126.3,
128.9, 130.4, 132.9, 133.3, 137.1, 158.8, 160.0. MS (m/z)

400 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Roy et al.
=336(M++Na), Anal. Calcd for C19H21NO3: C, 72.82; H,
7.40; N, 4.47%. Found: C, 72.68; H, 7.50; N, 4.37%.
hydroxytramadol
and
O-desmethyltramadol”
Tetrahedron
asymmetry, 2000, 11, 917-928. (c) Carlier, P. R.; Lo, K. L.; Lo, M.
M. C.; Williams, I. D. Anti-Selective Aldol Reaction of Benzylic
Nitriles and Synthesis of y-Amino Alcohols. J. Org. Chem., 1995,
60, 7511-7517.
ACKNOWLEDGEMENTS
[8]
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We thank to UGC (New Delhi, India) and University of
Kalyani for financial assistantce. R. N. De is grateful to
UGC (New Delhi, India) and S. Hazra is grateful to CSIR
(New Delhi, India) for their fellowships. We also thank the
DST (New Delhi) for providing Bruker NMR Spectrometer
(400 MHz) and Perkin-Elmer CHN Analyzer under its FIST
program.
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