Palladium(II)-catalyzed synthesis of isoxazolidines: Using a catalytic copper acetate and molecular oxygen as the cooxidant

Article abstract of DOI:10.1080/00397910500516233

An environmentally friendly process is reported for the palladium(II)-catalyzed cyclofunctionalization of allylic hydroxylamine derivatives using a catalytic amount of copper(II) acetate and molecular oxygen as the cooxidant. Copyright Taylor & Francis Gr

Full text of DOI:10.1080/00397910500516233

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Palladium(II)‐Catalyzed Synthesis of
Isoxazolidines: Using a Catalytic Copper
Acetate and Molecular Oxygen as the
Cooxidant
Boon Ying Tay a , Kai Xiang a , Thies Thiemann b & Krishna Gopal Dongol a
a Institute of Chemical and Engineering Sciences , Jurong Island, Singapore
b Institute of Material Chemistry and Engineering , Kyushu University ,
Kasuga Koh‐en, Kasuga‐shi, Japan
Published online: 24 Feb 2007.
To cite this article: Boon Ying Tay , Kai Xiang , Thies Thiemann & Krishna Gopal Dongol (2006)
Palladium(II)‐Catalyzed Synthesis of Isoxazolidines: Using a Catalytic Copper Acetate and Molecular Oxygen
as the Cooxidant, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:09, 1247-1257
To link to this article: http://dx.doi.org/10.1080/00397910500516233
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Synthetic Communicationsw, 36: 1247–1257, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500516233
Palladium(II)-Catalyzed Synthesis
of Isoxazolidines: Using a Catalytic
Copper Acetate and Molecular Oxygen
as the Cooxidant
Krishna Gopal Dongol, Boon Ying Tay, and Kai Xiang
Institute of Chemical and Engineering Sciences, Jurong Island,
Singapore
Thies Thiemann
Institute of Material Chemistry and Engineering, Kyushu University,
Kasuga Koh-en, Kasuga-shi, Japan
Abstract: An environmentally friendly process is reported for the palladium(II)-
catalyzed cyclofunctionalization of allylic hydroxylamine derivatives using a catalytic
amount of copper(II) acetate and molecular oxygen as the cooxidant.
Keywords: Allyl hydroxylamine, cyclofunctionalization, isoxazolidine, molecular
oxygen, palladium(II) catalysis
1. INTRODUCTION
During recent decades, much effort has been directed toward the development
of environmentally benign catalytic processes for palladium-catalyzed
reactions.[1–3] Most palladium-catalyzed processes involve a reduction of pal-
ladium(II) to give palladium(0),[4] which must be reoxidized to palladium(II)
so as to establish a catalytic cycle. This oxidation is usually achieved with a
cooxidant, typically benzoquinone or alternative metals, which must be
Received in Japan August 11, 2005
Address correspondence to Krishna Gopal Dongol, Institute of Chemical and
Engineering Sciences, 1 Pesek Road, Jurong Island, Singapore 627833. Tel.: þ65
6796 3917; Fax: þ65 6316 6184; E-mail: Krishna_dongol@ices.a-star.edu.sg
1247

1248
K. G. Dongol et al.
used in stoichometric amounts.[5,6] For example, copper(II) salts have been
used widely for palladium(II)-catalyzed aminocarbonylation reactions.[7,8]
Bates and Sa-Ei recently reported the palladium(II)-catalyzed synthesis of iso-
xazolidines via the cyclofunctionalization of hydroxyamines.[9] Three equiva-
lents of copper(II) acetate were required to ensure that palladium(II) chloride
could be used in catalytic amounts (Scheme 1). In general, isoxazolidines
are valuable synthetic intermediates and are particularly valuable synthetic
precursors for b-aminoesters.[10–12]
Because of concern that copper by-products may be detrimental to
the environment, it is desirable to limit the use of copper(II) salts. This also
compromises the usefulness of many existing cyclofunctionalization
reactions involving copper(II) salts in ligand-based asymmetric transform-
ations.[13–16] We aimed to develop a viable process for this important cyclo-
functionalization reaction involving a significant reduction in the amount of
copper(II) salt used.[17,18] A logical approach toward the development of a
reduced copper(II) method would involve the use of an alternative oxidant
or cooxidant. Hayashi et al. successfully utilized molecular oxygen to
achieve the palladium(II)-catalyzed bis-alkoxycarbonylation of olefins in
the presence of carbon monoxide and phosphine sulphide ligands.[19] Sub-
sequently, Yokota et al. reported the use of a palladium(II)/molybdovanado-
phosphate system for the oxidative carboalkoxylation of alkenes in methanol
using carbon monoxide and oxygen in a pressurized system.[20] Herein, report
our efforts directed toward the development of a palladium(II)-catalyzed intra-
molecular oxidative carboamination of alkenes using a catalytic amount of
copper(II) acetate in the presence of molecular oxygen and carbon
monoxide at atmospheric pressure.
2. RESULTS AND DISCUSSION
Copper(I) can be efficiently converted to copper(II) using a range of oxidants.
In the well-known Wacker reaction, oxygen is used to convert cuprous
chloride into cupric chloride.[21] We aimed to develop a process for the cyclo-
functionalization of allyl hydroxyamines whereby molecular oxygen could be
used as a cooxidant to reduce or to eliminate the amount of copper(II) salts
required (Scheme 2).
The conditions employed by Bates et al. for the synthesis of isoxazoli-
dines involve the use of 10 mol% palladium chloride, 3 equivalents of
Scheme 1. Z ¼ t-Boc, CO2Me, Ns, CBZ; R ¼ Ph, i-Pr, TBSOCH2; TMG ¼ 1,1,3,3-
tetramethylguanidine.

Synthesis of Isoxazolidines
1249
Scheme 2. Z ¼ Boc; a, R ¼ Ph; b, R ¼ p-CH3OC6H4; c, R ¼ CH3; d, R ¼ furyl.
copper(II) acetate, and 3 equivalents of 1,1,3,3-tetramethylguanidine (TMG)
in acetonitrile and methanol under a carbon monoxide atmosphere.[9] We
initially examined the reaction of N-Boc-protected homoallyl hydroxylamine
(2a) under identical conditions with the exception that just 10 mol% of
copper(II) acetate was used. A small amount of the desired cyclized product
was detected by GC analysis, and the starting material was recovered as a
major compound. Following an exhaustive examination of the reaction con-
ditions at various temperatures and using different bases, we were unable to
improve on the conversion to the desired product.
When further studies were conducted using analogous conditions in the
presence of molecular oxygen at atmospheric pressure, the cyclization
reaction proceeded in good yield. We were therefore able to access several
isoxazolidines using a catalytic amount of copper(II) acetate (Table 1).
Reiter et al. previously reported the use of sodium hydrogen phosphate as
an additive for the synthesis of 2,3-dihydro-4H-pyran-4-ones from the corre-
sponding b-hydroxyenones by oxidative cyclization.[22] To our delight, the
addition of 10 mol% of Na2HPO4 in the presence of 10 mol% copper(II)
Table 1. Cyclofunctionalization of allylic hydroxyamines under various conditionsa
Additive
(10 mol%)
Yields
(%)b
Entry
Methods
R
Cooxidant
1
2
A
B
C
A
B
C
A
B
C
A
B
C
Phenyl
Phenyl
Phenyl
10% Cu(II)
—
Na2HPO4
—
trace
78
10% Cu(II)/O2
3 eq. Cu(II)
10% Cu(II)
3
79
4
4-Methoxybenzyl
4-Methoxybenzyl
4-Methoxybenzyl
Methyl
—
trace
60
5
10% Cu(II)/O2
3 eq. Cu(II)
10% Cu(II)
Na2HPO4
—
—
6
68
7
trace
55
8
Methyl
Methyl
10% Cu(II)/O2
3eq. Cu(II)
Na2HPO4
—
—
9
60
10
11
12
Furyl
Furyl
Furyl
10% Cu(OAc)2
10% Cu(II)/O2
3eq. Cu(II)
trace
55
Na2HPO4
—
58
aThe reactions were carried out in three different methods (A–C) as outlined in the
Experimental section.
bIsolated yields.

1250
K. G. Dongol et al.
acetate resulted in the formation of the desired isoxazolidine (3a), in compar-
able yield to when 3 equivalents of copper(II) salt was utilized. These con-
ditions were then employed to examine the reaction of other allyl
hydroxyamines (2b–d). In all cases, the yield of cyclized product obtained
was comparable to that obtained when 3 equivalents of copper(II) acetate
were employed (Table 1).
In general, the desired cyclofunctionalized products were obtained in
moderate yields (Table 1) when the reaction was performed with 10 mol%
copper(II) acetate in the presence of molecular oxygen. The use of
analogous reaction conditions, with the addition of 10 mol% Na2HPO4,
resulted in an increase in the yield of the cyclofunctionalized product. An
increase in the amount of Na2HPO4 did not further increase the yield. These
results represent a significant step toward a catalytic, environmentally
benign process for this useful cyclofunctionalization reaction.
Proposed Catalytic Cycle and Mechanism
Although the mechanism of this reaction is not entirely clear, a catalytic cycle
(Figure 1) is proposed based on a similar palladium-catalyzed reaction that
employs copper(II) acetate as the oxidant.[9] In the initial step, the coordi-
nation of palladium(II) to the alkene moiety gives the species 4, which
then undergoes an intramolecular nucleophilic attack of the nitrogen onto
the more electron-deficient nonterminal carbon atom of alkene to give the
pallado complex 5. The insertion of carbon monoxide to Pd(II) of intermediate
complex 5, followed by reaction with methanol, provides the cyclofunctiona-
lized products 3 and the intermediate palladium species HLnPdCl. The
Figure 1. Proposed catalytic cycle.

Synthesis of Isoxazolidines
1251
intermediate HLnPdCl undergo reductive decomposition to palladium(0) and
HCl. The Cu(II) salt present in the reaction system then oxidizes the
palladium(0) to palladium(II), thereby establishing the catalytic cycle.
However, to maintain a functioning catalytic cycle, it is critical to have at
least two equivalents of a copper(II) salt in the absence of oxygen. It is
proposed that the presence of oxygen allows for the conversion of
copper(I), formed by the oxidation of Pd(0) to Pd(II), to copper(II), thereby
generating a second catalytic cycle. A catalytic amount of copper(II) is thus
required and, a significantly more efficient catalytic process is established
(Figure 1).
The role of Na2HPO4 as an additive for this improved process is not
clear, but it is possible that it serves as a proton scavenger, neutralizing the
hydrochloric acid produced from the decomposition of HLnPdCl to LnPd(0)
that facilitated the efficient generation of palladium(0) in the catalytic cycle.
To the best of our knowledge, this is the first report where the use of a
palladium(II) salt, a catalytic amount of copper(II), and a mixture of CO
and O2 has led to efficient cyclofunctionalization.
We were also interested in an investigation into the stereoselectivity of
this reaction. As reported earlier[9] the products are formed exclusively as
the cis-diastereomers. We have examined the stereochemistry of the trans-
formation reported herein using one-dimensional (Nuclear overhauser
effect) NOE and (Nuclear overhauser effect spectroscopy) NOESY and
found that this reaction is highly diastereoselective to give cis-isoxazolidines.
The cis/trans selectivity of cyclic isoxazolidine was established by NOESY
spectra as shown.
Therefore, the reaction was examined using an enantiomerically pure chiral
hydroxylamine derivative. The hydroxylamine (7) was synthesized from com-
mercially available enantiomerically pure (S)-(þ)-4-methylpentenol (S-6) via
the Mitsunobu reaction. Subsequent N-protection of allyl hydroxylamine 7
gave the N-Boc protected allyl hydroxyamide 8 (Scheme 3).
The Boc-protected hydroxylamine 8 was then reacted under the con-
ditions described previously for the cyclofunctionalization, and the cyclic
adduct 9 (Scheme 4) was obtained in 99% ee.

1252
K. G. Dongol et al.
Scheme 3. Synthesis of chiral O-(1-methyl-but-3-enyl)-N-(tert-butyloxycarbonyl)
hydroxylamine.
3. SUMMARY AND CONCLUSION
In conclusion, we have developed an efficient and environmentally benign
process for the cyclofunctionalization of allyl hydroxylamine derivatives
in the presence of a catalytic amount of copper(II) acetate using oxygen
as the cooxidant. These results represent a significant step toward an environ-
mentally benign process for this important reaction. Further exploration of this
reaction is under way in our group.
4. EXPERIMENTAL
4.1. General
Unless otherwise noted, reagents were obtained from commercial sources and
used without further purification. 4-Methyl-, 4-phenyl-, 4-methoxyl, and
4-furyl-substituted homoallylhydroxylamines were prepared by procedures
similar to those described in the literature.[5] THF was distilled from a
sodium-benzophenone ketyl. Acetonitrile was distilled over calcium
hydride. Flash chromatography was performed on Merck silica gel 60 by
gradient elution with ethyl acetate in hexane. 1H NMR and 13C NMR
spectra were recorded in CDCl3 on a Bruker Advance 400-MHz instrument
using the residual CHCl3 as the internal standard. Chemical shifts are given
in ppm. Electron impact mass spectra [m/z, relative intensity (%)] were
determined with a Finnigan Mat SSQ 710 instrument working at 70-eV
Scheme 4. Asymmetric cyclofunctionalization.

Synthesis of Isoxazolidines
1253
ionization energy. IR spectra were recorded on a BIO-RAD Excalibur series
instrument as liquid film or KBr discs. Elemental analysis was performed
on Euro EA 3000.
4.2. General Procedure for the Synthesis of N-Boc Protected
Hydroxyamines
The homoallylhydroxyamine was dissolved in water/dichloromethane
(10 mL, 1:1). Sodium hydroxide (2 mmol, 2eq) was added to the reaction
mixture followed by di-tert-butyldicarbonate (1 mmol, 1eq). The resulting
reaction mixture was stirred at 258C for 24 h. The organic layer was
separated, and the aqueous layer was extracted with dichloromethane
(3 ꢀ 50 mL). The combined organic layers were washed with H2O, dried
over MgSO4, and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude product by column chromatography
by gradient elution first with hexane and then with a mixture of ethyl
acetate and hexane gave the desired N-Boc protected hydroxyamines.
O-(1-Phenyl-but-3-enyl)hydroxylamine (1a) (5 g, 0.03 mol) afforded O-(1-
phenyl-but-3-enyl)-N-(tert-butyloxycarbonyl)hydroxylamine (2a) (6.5 g,
1
90%) as a colorless oil; H NMR (400 MHz, CDCl3): d 7.35 (m, 5H), 6.91
(br, s, 1H), 5.82 (m, 1H), 5.08 (m, 2H), 4.81 (t, 1H, J ¼ 7.2 Hz,
J ¼ 7.2 Hz), 2.79 (m, 1H), 2.51 (m, 1H), 1.49 (s, 9H). 13C NMR
(100.4 MHz, CDCl3) d 156.4, 139.8, 133.8, 128.4, 128.2, 127.2, 117.5, 87.1,
81.6, 39.7, 28.2. IR (neat): n 2980, 1732, 1369, 1318, 1162, 1066, 1000,
910, 847, 733 cm21. MS m/z 263 (Mþ, 4), 238 (5.1), 221 (8.5), 194 (10.3),
167 (38.3), 149 (72.5), 131 (100), 105 (88.6), 77 (86.3), 57 (83.8). EA:
calcd. C, 68.42; H, 8.04; N, 5.32; found C, 69.13; H, 8.08; N, 5.23.
O-f1-(4-Methoxyphenyl)-but-3-enylghydroxylamine (1b) (2 g, 0.01 mol)
afforded O-f1-(4-methoxyphenyl)-but-3-enylg-N-(tert-butyloxycarbonyl)
1
hydroxylamine (2b) (2.6 g, 90%) as a colorless oil; H NMR (400 MHz,
CDCl3): d 7.19 (d, 2H, J ¼ 8.0 Hz), 6.83 (d, 2H, J ¼ 8.4 Hz), 6.76 (br, s,
1H), 5.72 (m, 1H), 5.04 (dd, 2H, J ¼ 15.6 Hz, 7.6 Hz), 4.67 (t, 1H,
J ¼ 6.8 Hz), 3.74 (s, 3H, OCH3), 2.66 (m, 1H), 2.42 (m, 1H), 1.37 (s, 9H).
13C NMR (100.4 MHz, CDCl3) d 159.6, 156.4, 133.9, 131.7, 128.6, 117.4,
113.9, 86.6, 81.5, 55.3, 39.5, 28.2. IR (neat): n 3243, 2982, 1708, 1612,
1515, 1245, 1108, 834 cm21. MS m/z 293 (Mþ, 0.2), 277 (0.2), 259 (0.3),
226 (0.3), 220 (4.76), 196 (14.6), 176 (7.28), 161 (100), 135 (98.6), 121
(63.7), 107 (59.2), 77 (58.2), 59 (54.2). EA: calcd. C, 65.51; H, 7.90; N,
4.77; Found C, 65.83; H, 7.67; N, 4.49.
O-(1-Methyl-but-3-enyl)hydroxylamine (1c) (3 g, 0.03 mol) afforded O-(1-
methyl-but-3-enyl)-N-(tert-butyloxycarbonyl)hydroxylamine (2c) (4.02 g,

1254
K. G. Dongol et al.
80%) as a colorless oil; 1H NMR (400 MHz, CDCl3): d 7.05 (br, s, 1H), 5.82
(m, 1H), 5.12 (m, 2H), 3.95 (dd, 1H, J ¼ 6 Hz, J ¼ 6.4 Hz), 2.42 (m, 1H), 2.25
(m, 1H), 1.49 (s, 9H), 1.20 (d, 3H). 13C NMR (100.4 MHz, CDCl3) d 171.3,
134.4, 117.2, 81.5, 80.9, 39.2, 28.2, 27.7. IR (neat): n 3303, 2979, 1720,
1479, 1456, 1392, 1369, 1250, 1171, 1110, 914, 773 cm21. MS m/z 201
(Mþ, 2), 185 (1.0), 152 (1.4), 131 (27.3), 104 (27.7), 57 (100), 41 (73.9).
O-f1-(4-Furyl)-but-3-enylghydroxylamine (1d) (1 g, 6.5 mmol) afforded
O-f1-(4-furyl)-but-3-enylg-N-(tert-butyloxycarbonyl)hydroxylamine (2d)
1
(1.9 g, 85%) as a colorless oil; H NMR (400 MHz, CDCl3): d 7.35 (s, 1H),
6.89 (s, 1H), 6.29 (m, 2H), 5.73 (m, 1H), 5.09–4.99 (dd, 2H, J ¼ 8.8 Hz,
J ¼ 15.6 Hz), 4.74 (t, 1H, J ¼ 7.2 Hz), 2.71 (m, 1H), 2.61 (m, 1H), 1.39
(s, 9H). 13C NMR (100.4 MHz, CDCl3) d 156.5, 152.2, 142.8, 133.3, 117.7,
110.2, 109.7, 81.7, 80.2, 35.98, 28.2. IR (neat): n 3306, 2981, 2934, 1714,
1479, 1453, 1369, 1249, 1167, 1105, 1012, 922, 741 cm21. MS m/z 253
(Mþ, 0.75), 242 (0.73), 217 (2.3), 191 (2.5), 180 (40.5), 156 (59.1), 138
(25.8), 121 (100), 95 (81.0), 57 (77.5), 55 (88.1). EA: calcd. C, 61.64; H,
7.56; N, 5.53; found C, 61.051; H, 7.29; N, 5.34.
4.3. Palladium(II)-Catalyzed Cyclization Reaction
General Procedure A
A 50 mL Schlenk flask charged with PdCl2 (10 mol%) and Cu(OAc)2
(10 mol%) was evacuated and back-filled with argon. Acetonitrile (5 mL)
was then added. N-Boc hydroxylamine (1.0 mmol) dissolved in methanol
(5 mL) was then added to the reaction mixture. The flask was placed under
a carbon monoxide atmosphere, and 1,1,3,3-tetramethyl guanidine (TMG,
3.0 mmol) was added to the reaction mixture. The resultant mixture was
stirred at room temperature for 20 h. The reaction was monitored by GC.
The resulting mixture was filtered through a pad of silica gel and washed
with ethyl acetate. Evaporation of the solvent provided the crude product,
which was further purified by flash-column chromatography by using
hexane and ethyl acetate.
General Procedure B
A 100 mL three-necked round-bottom flask was charged sequentially with
PdCl2 (10 mol%), Cu(OAc)2 (10 mol%), and Na2HPO4 (10 mol%). The flask
was then evacuated and back-filled with oxygen three times by using a
balloon at ca. 1 atm. Acetonitrile (5 mL) was added to the flask followed by
the addition of a solution of N-Boc hydroxylamine (1.0 mmol) in methanol
(5 mL). Carbon monoxide was then introduced with a balloon at ca. 1 atm.
TMG (3.0 mmol) was then added to the reaction mixture. The reaction

Synthesis of Isoxazolidines
1255
mixture was stirred at room temperature for 20 h. The reaction was monitored
by GC. The resulting reaction mixture was filtered through a pad of silica gel
and washed with ethyl acetate. Evaporation of the solvent provided the crude
product, which was further purified by flash-column chromatography using
hexane and ethyl acetate.
General Procedure C
A 100 mL three-necked round-bottom flask was charged with PdCl2
(10 mol%) and Cu(OAc)2 (3 mmol). The flask was then evacuated and back-
filled with argon prior to the addition of acetonitrile (5 mL). A solution of
N-Boc hydroxylamine (1.0 mmol) in methanol (5 mL) was then added,
followed by TMG (3 mmol). The reaction mixture was stirred for 20 h. The
reaction was monitored by GC. The resultant mixture was filtered through a
pad of silica and washed with ethyl acetate. Evaporation of the solvent
provided the crude product, which was further purified by flash-column
chromatography using hexane and ethyl acetate.
O-(1-Phenyl-but-3-enyl)-N-(tert-butyloxycarbonyl)hydroxylamine
(2a)
(0.2 g, 0.76 mmol) afforded tert-butyl 3f(methoxycarbonyl)methylg-5-
1
phenylisoxazolidine carboxylate (3a) (0.19 g, 78%) as a colorless oil. H
NMR (400 MHz, CDCl3): d 7.35 (m, 5H), 4.90 (dd, 1H, J ¼ 6.4 Hz,
J ¼ 3.6 Hz), 4.70 (m, 1H), 3.69 (s, 3H, OCH3), 2.98 (d, 1H, J ¼ 5.6 Hz),
2.93 (m, 1H), 2.63 (dd, 1H, J ¼ 8.8 Hz, 7.2 Hz), 2.03 (m, 1H), 1.65 (s, 9H).
13C NMR (100.4 MHz, CDCl3) d169.08, 155.3, 134.9, 126.4, 126.1, 124.5,
80.7, 80.1, 55.3, 49.6, 41.1, 38.59, 26.1. IR (neat): n 2980, 1732, 1369,
1318, 1256, 1162, 1066, 1000, 910, 847, 733 cm21. MS m/z 321 (Mþ,1.52),
277 (12.7), 262 (20.7), 244 (0.24), 232 (0.65), 221 (87.3), 204 (53.2), 189
(89.7), 157 (85.8), 148 (81.0), 129 (87.71), 105 (100), 77 (75.9), 57 (97.9).
HRMS C17H23NO5: calcd. 321.1576, found 321.1576.
O-f1-(4-Methoxyphenyl)-but-3-enylg-N-(tert-butyloxycarbonyl)hydro-
xylamine (2b) (0.2 g, 0.68 mmol) afforded tert-butyl 3f(methoxycarbonyl)
methylg-5-(4-methoxyphenyl)isoxazolidine carboxylate (3b) (0.14 g, 60%)
1
as a colorless oil. H NMR (400 MHz, CDCl3): d 7.29 (d, 2H, J ¼ 8.4 Hz),
6.90 (d, 2H, J ¼ 8.4 Hz), 4.84 (dd, 1H, J ¼ 6.4 Hz, J ¼ 3.6 Hz), 4.67
(m, 1H), 3.80 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 2.98 (dd, 1H, J ¼ 5.6 Hz,
J ¼ 10.4 Hz), 2.88 (m, 1H), 2.63 (dd, 1H, J ¼ 8.8 Hz, J ¼ 6.8 Hz), 2.03
(m,1H), 1.49 (s, 9H). 13C NMR (100.4 MHz, CDCl3) d 173.3, 161.9, 159.5,
136.8, 133.0,116.0, 84.8, 84.3, 59.6, 57.4, 53.9, 45.0, 42.8, 30.2. IR (neat):
n 2980, 1736 (CO), 1612, 1516, 1456, 1369, 1300, 1251, 1171, 1066, 1034,
913, 831, 733 cm21. MS (70eV), m/z 351(Mþ, 38.28), 279 (31.8), 251
(22.8), 234 (10.7), 219 (57.7), 201 (3.2), 178 (17.6), 167 (77.0), 149 (100),
132 (8.0), 119 (38.2), 77 (39.0), 57 (78.6). HRMS C18H25NO6: calcd.

1256
K. G. Dongol et al.
351.1682, found 351.1689; EA: calcd. C, 61.52; H, 7.16; N, 3.98; found C,
61.56; H, 7.03; N, 4.05%.
O-(1-Methyl-but-3-enyl)-N-(tert-butyloxycarbonyl)hydroxylamine (2c)
(0.2 g, 1 mmol) afforded tert-butyl 3f(methoxycarbonyl)methylg-5-
methylisoxazolidine carboxylate (3c) (0.14 g, 55%) as a colorless oil.1H
NMR (400 MHz, CDCl3): d 4.47 (m, 1H), 3.94 (m, 1H), 3.62 (s, 3H,
OCH3), 2.88 (dd, 1H, J ¼ 5.6 Hz), 2.58 (m, 1H), 2.46 (dd, 1H, J ¼ 8.8 Hz),
1.56 (m, 1H), 1.43 (s, 9H), 1.28 (d, 3H, J ¼ 6.00 Hz). 13C NMR
(100.4 MHz, CDCl3) d 171.3, 167.2, 81.9, 57.2, 53.4, 42.4, 40.9, 28.6, 19.1,
17.8. IR (neat): n 2980 (m), 1731 (CO), 1439, 1368, 1331, 1257, 1169,
1082, 911, 849, 733 cm21. MS (70 eV), m/z 259 (Mþ,4.5), 231 (3.1), 220
(2), 185 (7.1), 166 (84.9), 148 (100), 112 (49.6), 82 (43.1), 56 (72.7), 43
(51.7). HRMS C12H21NO5: calcd. 259.1420; found 259.1418. EA: calcd. C,
55.58; H, 8.16; N, 5.40; found C, 55.40; H, 7.75; N, 5.38%.
O-f1-(4-Furyl)-but-3-enylg-N-(tert-butyloxycarbonyl)hydroxylamine (2d)
(0.2 g, 0.79 mmol) afforded tert-butyl 3f(methoxycarbonyl)methylg-5-
(furane-2-yl)isoxazolidine carboxylate (3d) (0.14 g, 55%) as a colorless
1
oil. H NMR (400 MHz, CDCl3): d7.36 (d, 1H, J ¼ 1.6 Hz), 6.39 (d, 1H,
J ¼ 3.2 Hz), 6.29 (d, 1H, J ¼ 3.2 Hz), 4.91 (t, 1H, J ¼ 8.4 Hz), 4.66
(m, 1H), 3.64 (s, 3 H), 2.89 (dd, 1 H, J ¼ 6 Hz, J 10.4 Hz), 2.67 (m, 2 H),
2.24 (m, 1H), 1.44 (s, 9H). 13C NMR (100.4 MHz, CDCl3) d 171.4, 157.3,
149.1, 142.8, 110.5, 110.3, 82.4, 75.3, 57.3, 51.8, 40.0, 38.4, 28.2. IR
(neat): n2981, 1740, 1456, 1439, 1369, 1313, 1255, 1162, 1073, 1012, 850,
740 cm21. MS m/z (%) 311 (Mþ,1.70), 279 (0.62), 252 (2.5), 224 (20.6),
211 (66.7), 179 (95.6), 162 (17.1), 138 (58.2), 121 (67.9), 94 (100), 81
(33.2), 57 (97.4), 41 (70.3). EA: calcd. C, 57.87; H, 6.80; N, 4.50; found C,
57.64; H, 6.71; N, 4.29%.
ACKNOWLEDGMENTS
Authors thank the Agency for Science, Technology, and Research (AꢁSTAR)
of Singapore under project code ICES 03-142001 for financial support. The
authors also thank Holger Butenschoen, University of Hannover, Germany,
for giving valuable suggestions and comments for this manuscript. The
authors are very grateful to Felicity Kate Moore for correcting the manuscript.
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