Exploiting microwave-assisted neat procedures: synthesis of N-aryl and N-alkylnitrones and their cycloaddition en route for isoxazolidines

Article abstract of DOI:10.1016/j.tet.2008.08.101

Microwave irradiation allows increasing the speed of several reactions and also offers the possibility of eliminating poisoning organic solvents. In this work we report the microwave-assisted neat synthesis of α-phenyl-tert-butylnitrone (PBN) and other alkyl and aryl nitrones and also the rapid synthesis of isoxazolidines resulting from 1,3-dipolar cycloaddition of nitrones to ethyl trans-crotonate.

Full text of DOI:10.1016/j.tet.2008.08.101

Tetrahedron 64 (2008) 10521–10530
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploiting microwave-assisted neat procedures: synthesis of N-aryl and
N-alkylnitrones and their cycloaddition en route for isoxazolidines
*
*
Marta M. Andrade , Maria Teresa Barros , Rui C. Pinto
REQUIMTE, CQFB, Departamento de Qu´ımica, Faculdade de Cieˆncias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2008
Received in revised form 16 August 2008
Accepted 29 August 2008
Available online 10 September 2008
Microwave irradiation allows increasing the speed of several reactions and also offers the possibility of
eliminating poisoning organic solvents. In this work we report the microwave-assisted neat synthesis of
a
-phenyl-tert-butylnitrone (PBN) and other alkyl and aryl nitrones and also the rapid synthesis of iso-
xazolidines resulting from 1,3-dipolar cycloaddition of nitrones to ethyl trans-crotonate.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Microwave
Neat reactions
Nitrone
1,3-Dipolar cycloaddition
PBN
1. Introduction
situ reduction with Zn/NH4Cl followed by acidification18,19 or in
a two-step procedure, in which the hydroxylamine obtained by
reduction of the nitro-compound is isolated and later reacts with
the aldehyde.20,21
Due to the instability of most hydroxylamines, the first pro-
cedure is usually preferred. However, as N-methylhydroxylamine
and N-tert-butylhydroxylamine are stable as their hydrochloride
salts, the second procedure can be applied for these compounds
and we have developed a novel methodology for the synthesis of
the corresponding nitrones under microwave irradiation in neat
conditions.
Among the plethora of dipoles used in 1,3-dipolar cycloaddi-
tion (1,3-DC), nitrones are certainly the most popular ones. 1,3-DC
reactions play a prominent role in for the production of hetero-
atom-containing cycloadducts with a maximum atomic econ-
omy.22–25 The application of MW irradiation in 1,3-DC is also very
Microwave (MW) radiation has gained the attention of chemists
during the last decades due to its unique advantages, such as
shorter reaction times, cleaner reactions, higher yields and better
selectivities, being a valuable alternative to accomplish more effi-
cient syntheses.1–4 MW technology has attained an importance,
especially when combined with neat procedures. Avoiding organic
solvents during reactions in organic synthesis5 leads to a clean,
efficient and economical technology; safety is largely increased,
work-up is considerably simplified, cost is reduced and the re-
activities and sometimes selectivities are enhanced.6 In other
words, the absence of solvents coupled with the high yields and
short reaction times often associated with MW reactions make
these procedures very attractive. Although there are several studies
on MW-assisted neat reactions,7–10 we have noticed that relatively
little attention has been given to neat reactions in the absence of
a catalyst or a solid support.11–14
Nitrones were recognized in the late 60s as spin trapping agents
and the most studied one is undoubtedly a-phenyl-N-tert-butyl-
nitrone (PBN, Fig. 1) (and its derivatives), due to recognized neu-
roprotective properties.15–17 Nitrones can be synthesized directly
from the corresponding nitro compound and an aldehyde, via in
* Corresponding authors. Tel.: þ351 212948300; fax: þ351 212948550 (M.M.A.);
tel.: þ351 212948361; fax: þ351 212948550 (M.T.B.).
E-mail addresses: marta.andrade@dq.fct.unl.pt (M.M. Andrade), mtbarros@
dq.fct.unl.pt (M.T. Barros).
Figure 1. PBN and examples of PBN-like nitrones.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.101

10522
M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
useful to overcome the low reactivities of some dienophiles or
dipoles.26–28
(Scheme 1 and Table 1). However, for N-alkylnitrones, a novel mi-
crowave-assisted solventless methodology was developed (Scheme
2 and Table 2). N-Methyl or N-tert-butylhydroxylamine (hydro-
chloride salts) was mixed with sodium acetate, the aldehyde
(whether solid or liquid) was added and the homogeneous or
heterogeneous mixture submitted to MW irradiation for the times
indicated in Table 2. With this procedure, these reactions were very
fast, with no need to use a 2 equiv excess of the expensive
hydroxylamines17,33 and/or several days refluxing to obtain good
yields.17 As we have described in previous work34 it is essential to
mention that the melting in this neat reactions between two solid
reactants occurs well below the melting point of the starting ma-
terials, most probably due to the formation of eutectic mixtures or,
as stated by Scott et al.,35 the reaction actually occurs in a liquid
melt. As shown in Table 2, in most cases better yields were obtained
when starting from the more bulky N-tert-butylhydroxylamine,
probably due to its high melting point (183–184 ꢀC) when com-
pared to N-methylhydroxylamine (84–86 ꢀC), which favours the
occurrence of the eutectic mixture. In entry 3, Table 2, the complete
melt of both reagents (hydroxylamine and aldehyde) was not ob-
served and only a sticky paste was obtained. Nevertheless, the
overall results in terms of costs are improved, due to a lesser waste
of costly hydroxylamines.
The addition of nitrones to olefinic dipolarophiles leads to iso-
xazolidines,29,30 which are versatile intermediates in the synthesis
of a multitude of natural compounds, such as alkaloids, amino acids
and amino sugars.22,23 Consequently, numerous methods have
been reported for the construction of isoxazolidines by inter- and
intramolecular nitrone cycloaddition.29,31,32 However, many of
these procedures require high temperatures and long reaction
times, with poor regioselectivity and with the occurrence of other
side reactions.
2. Results and discussion
Our approach is based upon 1,3-DC of open chain nitrones with
unsaturated esters as dipolarophiles. With the view of analyzing
the effect of different substituents on the dipole moieties for these
reactions, several nitrones were synthesized and the results
obtained are shown in Tables 1 and 2. By varying the type of the
substituent at the nitrogen atom (tolyl, phenyl, tert-butyl or
Table 1
Banerji et al.33 also reported the synthesis of C-aryl-N-methyl-
nitrones under MW irradiation; however, their strategy makes use
of a chlorinated solvent and also an excess of hydroxylamine. In this
sense, the method developed in our group brings an important
improvement by eliminating the use of solvents. As far as we know,
synthesis of PBN and PBN-like nitrones has not been described
under MW-assisted neat technology. Nevertheless, most of the
nitrones described here were already synthesized by distinct
methodologies and they are spread in the literature over the years.
With the purpose of creating an efficient library of nitrones, we
have compiled their most relevant data in Section 4.
In general, our approach shows clear advantages over the
techniques described so far15–17 and should become a method of
choice for this type of syntheses. The emerging area of green
chemistry demands the use of alternative energy sources and al-
ternative reaction media, in an attempt to protect human health
and environment.
Nitrones obtained from nitrobenzene and nitrotoluene
Entry
Nitro compound
Aldehyde or R2
Product
Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
2
2
2
2
2
2
H
Cl
5a
5b
5c
5d
5e
5f
5g
5h
5i
81
81
89
58
84
61
49
48
92
58
85
67
NO2
OMe
Furyl
Pyridyl
H
Cl
9
NO2
OMe
Furyl
Pyridyl
10
11
12
5j
5k
5l
methyl), we have studied the stereoselectivity of the reaction. In
order to study the possibility of electronic effects and, conse-
quently, different regioselectivities, we have also introduced elec-
tron withdrawing and electron donating groups at the aromatic
moiety.
2.2. Neat MW-assisted 1,3-dipolar cycloaddition to nitrones
Having synthesized a library of C-aryl-N-alkyl and C,N-diary-
lnitrones, subsequently we have focused our studies on their 1,3-DC
to ethyl trans-crotonate (Scheme 3). MW irradiation and the ab-
sence of solvents were again the main concern. All cycloaddition
reactions were performed in a laboratory multimodal microwave
apparatus, in the absence of solvents and/or catalysts. For N-Me and
N-aryl nitrones, reactions were complete in 10 min, denoting an
enhancement when compared to several hours in refluxing tolu-
ene36 or dichloromethane17 formerly reported for such reactions
(Table 3).
2.1. Neat MW-assisted synthesis of nitrones
A synthesis of N-tolyl and N-phenyl nitrones was accomplished
by applying the direct one-step procedure mentioned before
Table 2
Nitrones synthesized from N-methyl and N-tert-butylhydroxylamine under MW
irradiation
Entry Hydroxylamine Aldehyde or R2 Power Time Tfinal Product Yield
The structures of the isoxazolidines obtained were determined
by NOESY experiments (Fig. 2) and also by comparison with similar
compounds described in the literature.36
(W)
(min) (ꢀC)
(%)
1
2
3
4
5
6
7
8
6
6
6
6
6
6
7
7
7
7
7
7
H
Cl
200
80
2
6
2
3.5
2.5
4
2
2
5
3
1.5
4
161
123
69a
159
128
130
137
143
121
137
115
140
8a
8b
8c
8d
8e
8f
8g
8h
8i
90
92
86
72
86
83
86
85
92
91
96
97
A fast analysis of the results shows that, as expected,36 the
same regioisomer is obtained, independent of the substitution
pattern at the dipole moiety. C,N-Diaryl-nitrones (5a–l) exist
mainly as their Z-isomers due to the presence of the bulky aro-
matic groups and in their cycloaddition to ethyl trans-crotonate
(entries 1–12) we always obtained a marked predominance of the
isoxazolidines resulting from endo37 approach of the nitrone
(9 and its enantiomer). In contrast, with N-methylnitrones the
proportion of isomeric isoxazolidines 9 and 10 is more similar
(entries 13–18) due to the possibility of E–Z interconversion of
NO2
OMe
Furyl
Pyridyl
H
100
100
100
100
150
200
150
100
100
100
Cl
9
NO2
OMe
Furyl
Pyridyl
10
11
12
8j
8k
8l
a
There is no complete melting in this case and a sticky paste is obtained.

M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
10523
Scheme 1. One-pot synthesis of nitrones derived from nitrobenzene (1) and nitrotoluene (2). (i) Zn, NH4Cl, H2O, 2 h; (ii) AcOH, 40 min.
N-Me-nitrones.24 The presence of an electron withdrawing group
(nitro or chloro) in the para position of the C-aromatic system
leads to an increase in selectivity for the endo product, with
a more well-defined effect for the nitro group (entries 3, 9 and
15). By 1H NMR, traces (<0.5%) of other diastereoisomeric iso-
xazolidines were detected, but we never identified the presence
of regioisomeric products and concluded that the cycloaddition
proceeded with full regioselectivity.
toluene) we have obtained, after 42 h refluxing, 66% of product and
recovered 25% of starting nitrone. Under MW irradiation, these
reactions were harder to accomplish than the previous, since they
required long irradiation times. We have tested different powers
and reaction times in order to maximize the yield of the products
and the results obtained are listed in Table 4. Several other ad-
justments in time/power were tested but only those conducing to
interesting results are depicted in the table.
It is interesting to notice that in the cycloaddition to tert-
butylnitrones only the enantiomeric products showing 3,4-trans-
4,5-trans configuration were obtained, corresponding to endo ap-
proach, independent of the irradiation time. The exo approach is
less probable with tBu-nitrones due to the steric hindrance be-
tween the two methyl groups (one in the dipole and the other in
the dipolarophile).
According to Banerji et al.,36 separation of cycloadducts 9 and 10
can be achieved by column chromatography over deactivated
alumina.
To the best of our knowledge, there are no reports in the lit-
erature about cycloaddition reactions to olefins with the more
bulky N-tert-butylnitrone. Although all the nitrones studied have
a planar geometry, the presence of a tert-butyl group makes the
faces of the corresponding nitrones more hindered, due to the two
methyl groups positioned under and above the plane of the di-
pole; in consequence, the approach of the dipolarophile is more
difficult.
Another result is worthy of note in Table 4. The duration of
time for which the power is applied seems to play greater in-
fluence in the yield of products than the final temperature. For
example, when comparing entries 2 and 9, the final tempera-
tures are similar but the results are completely different: a fast
In an attempt to carry out the reaction under ‘traditional’ con-
ditions (0.1 g/0.56 mmol PBN, 0.2 mL ethyl trans-crotonate, 5 mL
irradiation at 300 W provides better results than
a long
Scheme 2. Microwave synthesis of nitrones starting from N-methyl- (6) or N-tert-butylhydroxylamine (7). (i) NaOAc, 100–200 W, 2–5 min.

10524
M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
Scheme 3. MW-neat synthesis of isoxazolidines (compounds 9 and 10 are racemic and only one enantiomer is depicted).
irradiation at 200 W. In general, the best results were always
Table 3
obtained with an irradiation time of 60 min (entries 6, 7, 11, 15,
18 and 20), corresponding to different final temperatures.
Results obtained by MW-neat 1,3-DC with N-aryl and N-Me nitrones
Entry Nitrone Power (W) Time (min) Tfinal (ꢀC) Products (ratioa) Yield (%)b
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
8a
8b
8c
8d
8e
8f
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
142
156
157
146
134
145
151
150
146
144
136
145
132
137
151
139
142
134
9aþ10a (89:11) 91
93
9bþ10b (91:9)
9cþ10c (94:6) 82
9dþ10d (84:16) 86
9eþ10e (78:22) 79
9fþ10f (87:13) 98
9gþ10g (87:13) 95
9hþ10h (91:9)
89
9
9iþ10i (94:6) 81
9jþ10j (83:17) 86
9kþ10k (76:24) 86
9lþ10l (90:10) 81
9mþ10m (56:44) 89
9nþ10n (60:40) 89
9oþ10o (76:34) 90
9pþ10p (55:45) 91
9qþ10q (60:40) 75
9rþ10r (66:34) 97
10
11
12
13
14
15
16
17
18
Ratio determined by 1H NMR.
Isolated yields for both isomers.
a
b
Figure 2. Selective NOESY correlations of 5c.

M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
10525
Table 4
4.2.1.1. C-Phenyl-N-phenyl-nitrone (5a). Yield 1.30 g, 81%, colour-
less needles, mp 110 ꢀC. 1H NMR (400 MHz, CDCl3):
7.48–7.52 (m,
6H, Ph–H), 7.79 (dd, J¼1.7, J¼7.7 Hz, 2H, Ph–H), 7.93 (s, 1H, CH),
8.39–8.42 (m, 2H, Ph–H). 13C NMR (100 MHz, CDCl3):
121.8, 128.7,
Results obtained by MW-neat 1,3-DC with N-tBu nitrones
d
Entry Nitrone Power (W) Time (min) Tfinal (ꢀC) Product Yield product/nitrone
recovered (%)
d
1
2
3
4
5
6
7
8
9
8g
400
300
30
10
20
30
45
60
60
75
90
161
144
149
149
151
148
129
132
132
9s
40/-
129.1, 129.2, 130.0, 130.7, 131.0 (11C–Ph), 134.6 (C–H), 149.2 (C–Ph).
26/59
65/16
75/9
40/-
4.2.1.2. C-p-Chlorophenyl-N-phenyl-nitrone (5b). Yield 1.52 g, 81%,
colourless needles, mp 152–153 ꢀC. 1H NMR (400 MHz, CDCl3):
d
7.44–7.52 (m, 6H, Ph–H), 7.75–7.78 (m, 2H, Ph–H), 7.91 (s, 1H, CH),
250
200
78/-
8.37 (d, J¼8.4 Hz, 2H, Ph–H). 13C NMR (100 MHz, CDCl3):
d 121.4,
77/6
59/5
19/-
128.7, 129.0, 129.9, 130.0 (10C–Ph), 133.2 (C–H), 136.1, 148.6 (2C–
Ph).
10
11
8h
8i
300
300
30
60
158
160
9t
63/17
92/-
4.2.1.3. C-p-Nitrophenyl-N-phenyl-nitrone (5c). Yield 1.75 g, 89%,
yellow needles, mp 183–184 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.52–
12
13
14
15
30
45
60
60
152
162
163
123
9u
25/13
37/-
40/-
87/-
7.54 (m, 3H, Ph–H), 7.78–7.80 (m, 2H, Ph–H), 8.01 (s, 1H, CH), 8.32
(d, 2H, J¼8.8 Hz, Ph–H), 8.56 (d, 2H, J¼8.8 Hz, Ph–H). 13C NMR
200
300
(100 MHz, CDCl3):
d 121.7, 123.9, 129.2, 129.4, 130.7 (9C–Ph), 132.3
16
17
8j
30
60
150
151
9v
9w
9x
39/39
78/-
(C–H), 136.2, 148.0, 148.9 (3C–Ph).
18
19
8k
8l
300
200
60
60
148
126
76/-
8/56
4.2.1.4. C-p-Methoxyphenyl-N-phenyl-nitrone (5d). Yield 1.07 g,
58%, colourless needles, mp 115–116 ꢀC. 1H NMR (400 MHz, CDCl3):
20
300
60
151
74/-
d
3.88 (s, 3H, CH3), 7.00 (d, J¼9.2 Hz, 2H, Ph–H), 7.44–7.50 (m, 3H,
Ph–H), 7.78 (dd, J¼8.1, 1.5 Hz, 2H, Ph–H), 7.86 (s, 1H, CH), 8.41 (d,
J¼8.8 Hz, 2H, Ph–H). 13C NMR (100 MHz, CDCl3):
d 55.4 (OCH3),
114.0, 121.7, 123.8, 129.1, 129.6, 131.2 (10C–Ph), 134.2 (C–H), 148.9,
161.5 (2C–Ph).
3. Conclusion
In summary, we have successfully applied microwave radiation
combined with neat methodologies in the synthesis of important
nitrones, such as a-phenyl-N-tert-butylnitrone (PBN), and also for
4.2.1.5. C-2-Furyl-N-phenyl-nitrone (5e). Yield 1.27 g, 84%, colour-
less needles, mp 86–87 ꢀC. 1H NMR (400 MHz, CDCl3):
d 6.65 (d,
J¼1.5 Hz, 1H, Fur–H), 7.43–7.52 (m, 3H, Ph–H), 7.59 (d, J¼1.0 Hz, 1H,
the formation of new isoxazolidines, in short reaction times.
Ph–H), 7.75–7.84 (m, 2H, C–H, Ph–H), 8.02 (d, J¼3.4 Hz, 1H, Fur-H),
8.2 (s, 1H, Fur–H). 13C NMR (100 MHz, CDCl3):
d 112.5, 116.3 (2C–
Fur), 120.9 (2C–Ph), 124.1 (C–H), 129.0, 129.8 (3C–Ph), 144.5, 147.3
(2C–Fur).
4. Experimental section
4.1. General procedures
4.2.1.6. C-3-Pyridyl-N-phenyl-nitrone (5f). Yield 0.98 g, 61%, col-
ourless crystals, mp 114–115 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.45
All solvents were purified before use. N-Methylhydroxylamine
hydrochloride and N-tert-butylhydroxylamine hydrochloride were
purchased from Fluka. All reactions were monitored by thin layer
chromatography, which was performed on aluminium-backed sil-
ica gel Merck 60 F254 plates, and compounds were detected by ul-
traviolet light or by staining with 10% solution of phosphomolybdic
acid in ethanol, followed by heating. Flash chromatography was
carried out using silica gel from Macherey-Nagel (Kieselgel 60 M).
Preparative layer chromatography was performed on glass plates
coated with 1 mm of silica gel (Mackerey-Nagel, Kieselgel DGF254).
Melting points were determined with a capillary apparatus and are
uncorrected. Elemental analyses were performed on Thermo Fin-
nigan-CE Flash EA 1112 CHNS series analyzer. NMR spectra were
recorded on a Bruker AMX-400 MHz apparatus in CDCl3, using TMS
(dd, J¼8.0, 4.9 Hz, 1H, Pyr–H), 7.48–7.54 (m, 3H, Ph–H), 7.79 (dd,
J¼6.7, 2.7 Hz, 2H, Ph–H), 8.01 (s, 1H, C–H), 8.65 (d, J¼3.4 Hz, 1H,
Pyr–H), 9.12 (s, 1H, Pyr–H), 9.22 (d, J¼8.1 Hz, 1H, Pyr–H). 13C NMR
(100 MHz, CDCl3):
d 121.6 (2C–Ph), 123.7, 127.3 (2C–Pyr), 129.3,
130.4 (3C–Ph), 131.4 (C–H), 134.9 (C–Pyr), 148.7 (C–Ph), 150.2, 150.8
(2C–Pyr).
4.2.1.7. C-Phenyl-N-tolyl-nitrone (5g). Yield 0.75 g, 49%, colourless
needles, mp 125–127 ꢀC. 1H NMR (400 MHz, CDCl3):
d 2.41 (s, 3H,
CH3), 7.26 (d, J¼8.1 Hz, 2H, Ar–H), 7.46 (dd, J¼5.2, 1.9 Hz, 3H, Ar–H),
7.66 (d, J¼8.4 Hz, 2H, Ar–H), 7.90 (s, 1H, C–H), 8.39 (dd, J¼7.1, 2.3 Hz,
2H, Ar–H). 13C NMR (100 MHz, CDCl3):
d 20.9 (CH3), 121.3 (2C–Tol),
128.4, 128.8 (5C–Ph), 129.4 (2C–Tol), 130.6 (C–Ph), 133.9 (C–H),
140.0, 146.6 (2C–Tol).
as internal standard, with chemical shift values (d) in parts per
million. Structural assignment of all new compounds was made by
bi-dimensional NMR techniques (COSY-45, HMQC, NOESY, TOCSY).
Microwave experiments were conducted in a Milestone Micro-
SYNTH apparatus. Internal temperatures were measured with ATC-
FO fibre-optic sensor in conjunction with Milestone immersion
well.
4.2.1.8. C-p-Chlorophenyl-N-tolyl-nitrone (5h). Yield 0.86 g, 48%,
colourless needles, mp 163–164 ꢀC. 1H NMR (400 MHz, CDCl3):
d
2.41 (s, 3H, CH3), 7.26 (d, J¼8.2 Hz, 2H, Ar–H), 7.43 (d, J¼8.7 Hz, 2H,
Ar–H), 7.65 (d, J¼8.4 Hz, 2H, Ar–H), 7.88 (s, 1H, C–H), 8.35 (d,
J¼8.7 Hz, 2H, Ar–H). 13C NMR (100 MHz, CDCl3):
d 21.2 (CH3), 121.4
(2C–Tol), 128.9, 129.3 (3C–Ph), 129.7 (2C–Tol), 130.1 (2C–Ph), 132.9
(C–H), 136.2 (C–Ph), 140.4, 146.6 (2C–Tol).
4.2. Synthesis of nitrones38
4.2.1.9. C-p-Nitrophenyl-N-tolyl-nitrone (5i). Yield 1.72 g, 92%, yel-
4.2.1. General method for C-aryl-N-aryl nitrones
Nitrones 5a–l were synthesized following to the procedure de-
scribed in the literature,19 starting from 1 g of the corresponding
nitro compound.
low crystals, mp 119–121 ꢀC. 1H NMR (400 MHz, CDCl3):
d 2.44 (s,
3H, CH3), 7.31 (d, J¼8.3 Hz, 2H, Ar–H), 7.68 (d, J¼8.5 Hz, 2H, Ar–H),
8.05 (s, 1H, C–H), 8.31 (d, J¼9.0 Hz, 2H, Ar–H), 8.55 (d, J¼9.0 Hz, 2H,
Ar–H). 13C NMR (100 MHz, CDCl3):
d 20.8 (CH3), 121.1 (2C–Tol),

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M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
123.5 (2C–Ph), 128.8, 129.5 (2C–Ph), 130.1 (2C–Tol), 131.4 (C–H),
136.0 (C–Ph), 140.8, 146.2 (2C–Tol), 147.5 (C–Ph).
13C NMR (100 MHz, CDCl3):
d 53.9 (OCH3), 55.3 (N–CH3), 113.8,
123.5, 130.3 (5C–Ph), 134.8 (C–H), 161.0 (C–Ph).
4.2.1.10. C-p-Methoxyphenyl-N-tolyl-nitrone (5j). Yield 1.02 g, 58%,
4.2.2.5. C-2-Furyl-N-methyl-nitrone (8e). Eluent:AcOEt/MeOH19:1.
colourless needles, mp 118–120 ꢀC. 1H NMR (400 MHz, CDCl3):
Yield 644.2 mg, 86%, colourless needles, mp 90 ꢀC. 1H NMR
d
2.40 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.98 (d, J¼9.0 Hz, 2H, Ar–H),
(400 MHz, CDCl3):
7.48 (br s, 1H, Fur–H), 7.55 (s, 1H, C–H), 7.76 (d, J¼3.3 Hz, 1H, Fur–H).
13C NMR (100 MHz, CDCl3):
52.6 (N–CH3), 112.1, 115.1 (2C–Fur),
d
3.84 (s, 3H, CH3), 6.56 (d, J¼1.3 Hz, 1H, Fur–H),
7.25 (d, J¼8.2 Hz, 2H, Ar–H), 7.66 (d, J¼8.4 Hz, 2H, Ar–H), 7.83 (s, 1H,
C–H), 8.39 (d, J¼8.9 Hz, 2H, Ar–H). 13C NMR (100 MHz, CDCl3):
d
21.1
d
(CH3), 55.4 (OCH3), 114.0, 121.4, 123.8 (5C–Ph), 129.6, 131.2 (4C–Tol),
133.9 (C–H), 139.8, 146.6 (2C–Tol), 161.5 (C–Ph).
126.1 (C–H), 143.5, 146.5 (2C–Fur).
4.2.2.6. C-3-Pyridyl-N-methyl-nitrone (8f). Eluent: AcOEt/MeOH
4.2.1.11. C-2-Furyl-N-tolyl-nitrone (5k). Yield 1.25 g, 85%, colourless
19:1. Yield 676.5 mg, 83%, colourless crystals, mp 75–77 ꢀC. 1H NMR
needles, mp 132 ꢀC. 1H NMR (400 MHz, CDCl3):
d
2.41 (s, 3H, CH3),
(400 MHz, CDCl3):
d
3.93 (s, 3H, CH3), 7.38 (dd, J¼7.9, 4.9 Hz,1H, Pyr–
6.64 (d, J¼1.6 Hz, 1H, Fur–H), 7.27 (d, J¼8.1 Hz, 2H, Ph–H), 7.58 (s,
H), 7.46 (s,1H, C–H), 8.60 (d, J¼3.5 Hz,1H, Pyr–H), 8.97 (s,1H, Pyr–H),
1H, C–H), 7.69 (d, J¼8.4 Hz, 2H, Ph–H), 8.00 (d, J¼3.4 Hz, 1H, Fur–H),
9.01 (d, J¼8.09 Hz,1H, Pyr–H).13C NMR (100 MHz, CDCl3):
d 54.6 (N–
8.14 (s, 1H, Fur–H). 13C NMR (100 MHz, CDCl3):
d
21.1 (CH3), 112.6,
CH3),123.6,127.0 (2C–Pyr),132.3 (C–H),134.6,149.5,150.5 (3C–Pyr).
116.2 (2C–Fur), 120.7 (2C–Tol), 123.8 (C–H), 129.6 (2C–Tol), 140.2,
144.4 (2C–Tol), 144.9, 147.5 (2C–Fur).
4.2.2.7. C-Phenyl-N-tert-butyl-nitrone (8g). Eluent: ether/hexane
2:1. Yield 606.8 mg, 86%, colourless needles, mp 72–73 ꢀC. 1H NMR
t
4.2.1.12. C-3-Pyridyl-N-tolyl-nitrone (5l). Yield 1.04 g, 67%, colour-
(400 MHz, CDCl3):
d
1.62 (s, 9H, Bu–H), 7.35–7.47 (m, 3H, Ph–H),
less crystals, mp 131–133 ꢀC. 1H NMR (400 MHz, CDCl3):
d
2.43 (s,
7.55 (s, 1H, C–H), 8.29 (dd, J¼7.6, 2.1 Hz, 2H, Ph–H). 13C NMR
3H, CH3), 7.29 (d, J¼8.2 Hz, 2H, Ph–H), 7.45 (dd, J¼8.0, 4.9 Hz, 1H,
Pyr–H), 7.68 (d, J¼8.4 Hz, 2H, Ph–H), 7.99 (s, 1H, C–H), 8.64 (d,
J¼3.5 Hz, 1H, Pyr–H), 9.12 (s, 1H, Pyr–H), 9.22 (d, J¼8.1 Hz, 1H, Pyr–
(100 MHz, CDCl3): d 28.3 (C(CH3)3), 70.8 (C(CH3)3), 128.4,128.8 (4C–
Ph), 129.9 (C–H), 130.1, 131.0 (2C–Ph).
H). 13C NMR (100 MHz, CDCl3):
d
21.0 (CH3), 121.1 (2C–Tol), 123.4,
4.2.2.8. C-p-Chlorophenyl-N-tert-butyl-nitrone (8h). Eluent: ether/
127.2 (2C–Pyr), 129.5 (2C–Tol), 130.7 (C–H), 134.6 (C–Pyr), 140.5,
146.2 (2C–Tol), 149.9, 150.4 (2C–Pyr).
hexane 1:1. Yield 716.3 mg, 85%, colourless crystals, mp 69–71 ꢀC.
t
1H NMR (400 MHz, CDCl3):
d
1.61 (s, 9H, Bu–H), 7.38 (d, J¼8.6 Hz,
2H, Ph–H), 7.53 (s, 1H, C–H), 8.25 (d, J¼8.6 Hz, 2H, Ph–H). 13C NMR
4.2.2. General method for C-aryl-N-alkyl nitrones
(100 MHz, CDCl3): d 28.3 (C(CH3)3), 71.1 (C(CH3)3), 128.6, 128.7,
In an open flask, 0.5 g (1 equiv) of methyl or tert-butylhydroxyl-
amine hydrochloride and 1.2 equiv of NaOAc were mixed for a few
seconds using a spatula, followed by addition of 1.2 equiv of the al-
dehyde(solidorliquid);astirringbarwasalsoplaced inside theflask.
The flask containing the homogeneous or heterogeneous mixture
was positioned in the centre of the microwave cavity, over a Weflon-
made support provided by the manufacturer, and irradiated for the
time and power indicated in Table 2. Reactions were monitored by
TLC. After completion, dichloromethane was added and the solid salt
was filtered off. In some cases, the nitrone crystallized directly from
dichloromethane, in other cases it was purified by column chroma-
tography, as indicated for each nitrone.
129.5, 129.9 (6C–Ph), 135.4 (C–H).
4.2.2.9. C-p-Nitrophenyl-N-tert-butyl-nitrone (8i). Crystallizes di-
rectly from dichloromethane. Yield 813.9 mg, 92%, yellow needles,
mp 146–147 ꢀC. 1H NMR (400 MHz, CDCl3):
d
1.64 (s, 9H, Bu–H),
t
7.71 (s, 1H, C–H), 8.25 (d, J¼9.1 Hz, 2H, Ph–H), 8.45 (d, J¼9.0 Hz, 2H,
Ph–H). 13C NMR (100 MHz, CDCl3):
d
28.3 (C(CH3)3), 72.4 (C(CH3)3),
123.7 (2C–Ph), 127.9 (C–H), 128.9, 136.7, 147.6 (4C–Ph).
4.2.2.10. C-p-Methoxyphenyl-N-tert-butyl-nitrone (8j). Eluent: eth-
er/hexane 1:1. Yield 750.9 mg, 91%, colourless needles, mp 94–95 ꢀC.
1H NMR (400 MHz, CDCl3): 1.61 (s, 9H, tBu–H), 3.85 (s, 3H, OCH3),
d
6.85–7.01 (m, 2H, Ph–H), 7.48 (s, 1H, C–H), 8.29 (d, J¼8.9 Hz, 2H, Ph–
4.2.2.1. C-Phenyl-N-methyl-nitrone (8a). Eluent: AcOEt. Yield
H). 13C NMR (100 MHz, CDCl3):
d
28.3 (C(CH3)3), 55.3 (OCH3), 70.1
728.2 mg, 90%, colourless needles, mp 83–84 ꢀC. 1H NMR (400 MHz,
(C(CH3)3), 113.7, 124.0 (3C–Ph), 129.6 (C–H), 130.8, 160.8 (3C–Ph).
CDCl3):
d
3.88 (s, 3H, N–CH3), 7.37 (s, 1H, C–H), 7.42 (d, J¼2.4 Hz, 2H,
Ph–H), 7.43 (d, J¼0.9 Hz, 1H, Ph–H), 8.22 (dd, J¼3.0, 6.6 Hz, 2H, Ph–
4.2.2.11. C-2-Furyl-N-tert-butyl-nitrone (8k). Eluent: ether/hexane
H). 13C NMR (100 MHz, CDCl3):
(6C–Ph), 135.2 (C–H).
d
54.4 (N–CH3), 128.4, 128.5, 130.4
1:1. Yield 639.0 mg, 96%, colourless needles, mp 68–69 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
1.59 (s, 9H, tBu–H), 6.56 (br d, J¼1.1 Hz,1H, Fur–
H), 7.73 (s, 1H, C–H), 7.79 (d, J¼3.3 Hz, 1H, Fur–H). 13C NMR
4.2.2.2. C-p-Chlorophenyl-N-methyl-nitrone (8b). Eluent: AcOEt.
(100 MHz, CDCl3): d 28.1 (C(CH3)3), 69.7 (C(CH3)3), 112.2, 114.8 (2C–
Yield 934.2 mg, 92%, colourless needles, mp 126–127 ꢀC. 1H NMR
Fur), 121.4 (C–H), 143.5, 147.6 (2C–Fur).
(400 MHz, CDCl3):
d 3.88 (s, 3H, NCH3), 7.36 (s, 1H, C–H), 8.27 (d,
J¼8.8 Hz, 2H, Ph–H), 8.38 (d, J¼8.8 Hz, 2H, Ph–H). 13C NMR
4.2.2.12. C-3-Pyridyl-N-tert-butyl-nitrone (8l). This nitrone was
washed with ethyl acetate instead of dichloromethane. Eluent:
AcOEt. Yield 688.2 mg, 97%, colourless crystals, mp 88–90 ꢀC. 1H
(100 MHz, CDCl3): d 54.4 (N–CH3), 128.7, 128.9, 129.5 (5C–Ph), 134.0
(C–H), 135.8 (C–Ph).
NMR (400 MHz, CDCl3):
d
1.63 (s, 9H, tBu–H), 7.36 (dd, J¼7.6, 4.9 Hz,
4.2.2.3. C-p-Nitrophenyl-N-methyl-nitrone (8c). Crystallizes imme-
1H, Py–H), 7.62 (s, 1H, C–H), 8.58 (d, J¼3.0 Hz, 1H, Py–H), 8.99 (s, 1H,
diately. Yield 927.5 mg, 86%, yellow needles, mp 210–212 ꢀC. 1H NMR
Py–H), 9.02–9.26 (m, 1H, Py–H). 13C NMR (100 MHz, CDCl3):
d 28.1
(400 MHz, CDCl3):
d
3.96 (s, 3H, NCH3), 7.39 (d, J¼8.8 Hz, 2H, Ph–H),
(C(CH3)3), 71.3 (C(CH3)3), 123.2 (C–Pyr), 126.7 (C–H), 127.4 (C–Pyr),
134.5 (C–Pyr), 149.8 (C–Pyr), 149.9 (C–Pyr).
7.53 (s, 1H, CH), 8.18(d, J¼8.8 Hz, 2H, Ph–H).13CNMR(100 MHz, CDCl3):
d
55.2 (N–CH3), 123.8, 128.7 (4C–Ph), 133.1 (C–H), 136.0, 147.8 (2C–Ph).
4.3. Synthesis of isoxazolidines
4.2.2.4. C-p-Methoxyphenyl-N-methyl-nitrone (8d). Eluent: AcOEt/
MeOH 19:1. Yield 712 mg, 72%, colourless crystals, mp 72–73 ꢀC.
4.3.1. General method
A mixture containing 0.1 g of nitrone and 0.2 mL of ethyl trans-
crotonate was placed in a quartz tube, a weflon magnetic stirrer
1H NMR (400 MHz, CDCl3):
d
3.85 (s, 6H, OCH3, NCH3), 6.94 (d,
J¼8.8 Hz, 2H, Ph–H), 7.29 (s, 1H, CH), 8.21 (d, J¼8.8 Hz, 2H, Ph–H).

M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
10527
was added, the tube was sealed and equipped with fibre-optic
temperature probe and placed in the MW cavity. It was then irra-
diated for the time and power indicated in Tables 3 and 4. Products
were purified by preparative layer chromatography with the eluent
indicated for each case. Characterization of compounds 9, 10a–d is
according to the literature.36 Compounds 9, 10f39 and 9, 10m40 are
described in the literature with no data. For all minor stereoisomers
of 10, only relevant peaks are depicted in their NMR analysis.
4.3.1.4. 3RS-(3R
*
,4S
*
,5R
*
)-2-Tolyl-3-(p-chlorophenyl)-4-carbethoxy-5-
methyl-isoxazolidine (9h) and 3RS-(3R
*
,4R
*
,5S )-2-tolyl-3-(p-chl-
*
orophenyl)-4-carbethoxy-5-methyl-isoxazolidine (10h). Eluent: eth-
er/hexane 1:2. Yield 130.6 mg, 89%, colourless oil. Ratio 9h/
10h¼91:9. Anal. Calcd for C20H22ClNO3: C, 66.75; H, 6.16; N, 3.89.
Found: C, 66.31; H, 6.27; N, 3.88. IR (cmꢁ1, NaCl) nmax 3027, 2980,
2934, 2872, 1731, 1611, 1507, 1188, 1090, 815. Compound 9h: 1H NMR
(400 MHz, CDCl3):
d
1.22 (t, J¼7.1 Hz, 3H, CH3CH2), 1.49 (d, J¼6.0 Hz,
3H, CH3), 2.26 (s, 3H, CH3–Ph), 3.09 (dd, J¼8.9, 7.0 Hz, 1H, H-4), 4.15
(q, J¼7.1 Hz, 2H, CH3CH2), 4.42 (qd, J¼9.0, 6.0 Hz, 1H, H-5), 5.07 (d,
J¼7.0 Hz, 1H, H-3), 6.86 (d, J¼8.5 Hz, 2H, Ar–H), 7.04 (d, J¼8.3 Hz, 2H,
4.3.1.1. 3RS-(3R
*
,4S
*
,5R
*
)-2-Phenyl-3-(2-furyl)-4-carbethoxy-5-met-
,4R ,5S )-2-phenyl-3-(2-furyl)-4-
hyl-isoxazolidine (9e) and 3RS-(3R
*
*
*
carbethoxy-5-methyl-isoxazolidine (10e). Eluent: ether/hexane 1:2.
Yield 127.7 mg, 79%, colourless oil. Ratio 9e/10e¼78:22. Anal. Calcd
for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.70; H, 6.53; N,
4.64. IR (cmꢁ1, NaCl) nmax 3063, 2981, 2935, 2904, 1735, 1598, 1488,
1191, 1031, 756, 695. Compound 9e: 1H NMR (400 MHz, CDCl3):
Ar–H), 7.33 (d, J¼8.5 Hz, 2H, Ar–H), 7.47 (d, J¼8.4 Hz, 2H, Ar–H). 13
C
NMR (100 MHz, CDCl3):
d 13.5 (CH3CH2), 17.0 (CH3), 19.9 (CH3–Ph),
60.8 (CH3CH2), 64.9 (C-4), 72.4 (C-3), 76.8 (C-5), 113.6, 127.2, 128.3,
128.9, 130.6, 132.7, 139.8, 148.4 (C–Ph), 169.6 (C]O). Compound 10h:
Detected in the isomeric mixture by 1H NMR analysis. 1H NMR
d
1.19 (t, J¼7.1 Hz, 3H, CH3CH2), 1.54 (d, J¼5.9 Hz, 3H, CH3), 3.40 (dd,
(400 MHz, CDCl3):
H-4), 4.73 (d, J¼10.1 Hz, 1H, H-3), 4.77 (m, 1H, H-5).
d
1.44 (d, J¼6.1 Hz, 3H, CH3), 3.31 (t, J¼9.8 Hz, 1H,
J¼8.4, 6.3 Hz, 1H, H-4), 4.12 (dd, J¼14.1, 7.0 Hz, 2H, CH3CH2), 4.32–
4.46 (m,1H, H-5), 5.25 (d, J¼6.0 Hz,1H, H-3), 6.27–6.46 (m, 2H, Fur–
H), 6.94 (br t, J¼7.0 Hz, 1H, Ph–H), 7.08 (br d, J¼8.0 Hz, 2H, Ph–H),
7.18–7.33 (m, 2H, Ph–H), 7.42 (s, 1H, Fur–H). 13C NMR (100 MHz,
4.3.1.5. 3RS-(3R ,4S ,5R )-2-Tolyl-3-(p-nitrophenyl)-4-carbethoxy-5-
*
*
*
methyl-isoxazolidine (9i) and 3RS-(3R ,4R ,5S )-2-tolyl-3-(p-nitro-
*
*
*
CDCl3):
d
14.1 (CH3CH2), 17.6 (CH3), 61.1 (C-4), 61.4 (CH3CH2), 67.5
phenyl)-4-carbethoxy-5-methyl-isoxazolidine (10i). Eluent: ether/
hexane 1:2. Yield 113.1 mg, 81%, yellow oil. Ratio 9i/10i¼94:6. Anal.
Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.83; H,
6.19; N, 7.56. IR (cmꢁ1, NaCl) nmax 2981, 2935, 1732, 1605, 1521, 1347,
(C-3), 77.6 (C-5), 107.1, 110.4 (C–Fur), 114.5, 121.9, 128.6, 128.9 (C–
Ph), 142.7, 151.0 (C–Fur), 170.1 (C]O). Compound 10e: Detected in
the isomeric mixture by 1H NMR analysis. 1H NMR (400 MHz,
CDCl3):
d
1.48 (d, J¼6.0 Hz, 3H, CH3), 3.26 (t, J¼9.4 Hz, 1H, H-4), 4.83
1189, 856. Compound 9i: 1H NMR (400 MHz, CDCl3):
d 1.24 (t,
(dt, J¼12.0, 6.1 Hz, 1H, H-5), 4.98 (d, J¼9.2 Hz, 1H, H-3).
J¼7.1 Hz, 3H, CH3CH2), 1.51 (d, J¼6.0 Hz, 3H, CH3), 2.28 (s, 3H, CH3–
Ph), 3.09 (dd, J¼8.9, 6.7 Hz, 1H, H-4), 4.18 (q, J¼7.1 Hz, 2H, CH3CH2),
4.45 (qd, J¼8.9, 6.0 Hz, 1H, H-5), 5.24 (d, J¼6.7 Hz, 1H, H-3), 6.86 (d,
J¼8.5 Hz, 2H, Ar–H), 7.07 (d, J¼8.3 Hz, 2H, Ar–H), 7.73 (d, J¼8.6 Hz,
2H, Ar–H), 8.23 (d, J¼8.8 Hz, 2H, Ar–H). 13C NMR (100 MHz, CDCl3):
4.3.1.2. 3RS-(3R ,4S ,5R )-2-Phenyl-3-(3-pyridyl)-4-carbethoxy-5-
methyl-isoxazolidine (9f) and 3RS-(3R ,4R ,5S )-2-phenyl-3-(3-pyri-
*
*
*
*
*
*
dyl)-4-carbethoxy-5-methyl-isoxazolidine (10f). Eluent: ether/hex-
ane 4:1. Yield 154 mg, 98%, colourless oil. Ratio 9f/10f¼87:13. Anal.
Calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.44; H,
6.65; N, 9.02. IR (cmꢁ1, NaCl) nmax 3059, 3034, 2981, 2935, 2904,
1730, 1597, 1488, 1194, 1029, 758, 696. Compound 9f: 1H NMR
d
14.0 (CH3CH2O), 17.5 (CH3), 20.4 (CH3–Ph), 61.6 (CH3CH2O), 65.2
(C4), 72.5 (C3), 77.5 (C5),114.0, 124.0, 127.2, 129.5,131.4, 147.4, 148.4,
149.3 (Ph–C), 169.8 (CO2Et). Compound 10i: Detected in the iso-
meric mixture by 1H NMR analysis. 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
d
1.23 (t, J¼7.1 Hz, 3H, CH3CH2), 1.52 (d, J¼6.0 Hz,
d
1.47 (d, J¼6.1 Hz, 3H, CH3), 3.39 (t, J¼9.7 Hz, 1H, H-4), 4.77 (qd,
3H, CH3), 3.13 (dd, J¼8.9, 6.8 Hz, 1H, H-4), 4.16 (q, J¼7.1 Hz, 2H,
CH3CH2), 4.45 (qd, J¼9.1, 6.0 Hz, 1H, H-5), 5.21 (d, J¼6.7 Hz, 1H, H-
3), 6.96 (m, 3H, Ph-H), 7.16–7.31 (m, 3H, Ph–H, Pyr–H), 7.91 (br d,
J¼9.8, 6.0 Hz, 1H, H-5), 4.87 (d, J¼10.1 Hz, 1H, H-3).
4.3.1.6. 3RS-(3R ,4S ,5R )-2-Tolyl-3-(p-methoxyphenyl)-4-carbethoxy-
5-methyl-isoxazolidine (9j) and 3RS-(3R ,4R ,5S )-2-tolyl-3-(p-metho-
*
*
*
J¼7.8 Hz, 1H, Pyr–H), 8.56 (m, 1H, Pyr–H), 8.75 (br s, 1H, Pyr–H). 13
C
*
*
*
NMR (100 MHz, CDCl3):
d
14.1 (CH3CH2), 17.5 (CH3), 61.6 (CH3CH2),
xyphenyl)-4-carbethoxy-5-methyl-isoxazolidine (10j). Eluent: ether/
hexane 1:2. Yield 126 mg, 86%, colourless oil. Ratio 9j/10j¼83:17.
Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94. Found: C,
70.75; H, 7.31; N, 3.93. IR (cmꢁ1, NaCl) nmax 2979, 2934, 2837, 1731,
1612, 1513, 1249, 1035, 816. Compound 9j: 1H NMR (400 MHz,
65.3 (C-4), 71.3 (C-3), 77.7 (C-5), 114.0, 121.9 (C–Ph), 123.8 (C–Pyr),
129.1, 130.9, 134.2 (C–Ph), 148.3, 149.2, 151.2 (C–Pyr), 169.9 (C]O).
Compound 10f: Detected in the isomeric mixture by 1H NMR
analysis. 1H NMR (400 MHz, CDCl3):
d
1.48 (d, J¼6.1 Hz, 3H, CH3),
3.38 (t, J¼9.7 Hz, 1H, H-4), 4.80 (qd, J¼12.1, 6.0 Hz, 1H, H-5), 4.89 (d,
J¼10.0 Hz, 1H, H-3).
CDCl3):
d
1.21 (t, J¼7.1 Hz, 3H, CH3CH2), 1.49 (d, J¼6.0 Hz, 3H, CH3),
2.26 (s, 3H, CH3–Ph), 3.12 (dd, J¼8.9, 7.3 Hz, 1H, H-4), 3.81 (s, 3H,
OCH3), 4.14 (q, J¼7.1 Hz, 2H, CH3CH2), 4.42 (qd, J¼9.0, 6.0 Hz, 1H, H-
5), 5.02 (d, J¼7.2 Hz, 1H, H-3), 6.82–6.93 (m, 4H, Ar–H), 7.03 (d,
J¼8.3 Hz, 2H, Ar–H), 7.43 (d, J¼8.6 Hz, 2H, Ar–H). 13C NMR
4.3.1.3. 3RS-(3R
*
,4S
*
,5R
*
)-2-Tolyl-3-phenyl-4-carbethoxy-5-methyl-
,4R ,5S )-2-tolyl-3-phenyl-4-carbet-
isoxazolidine (9g) and 3RS-(3R
*
*
*
hoxy-5-methyl-isoxazolidine (10g). Eluent: ether/hexane 1:2. Yield
146.9 mg, 95%, colourless oil. Ratio 9g/10g¼87:13. Anal. Calcd for
(100 MHz, CDCl3): d 14.0 (CH3CH2), 17.6 (CH3), 20.5 (CH3-Ph), 55.2
(OCH3), 61.1 (CH3CH2), 65.6 (C-4), 73.4 (C-3), 77.3 (C-5), 114.1, 114.4,
127.6, 129.3, 130.8, 133.7, 149.3, 158.9 (C–Ph), 170.3 (C]O). Com-
pound 10j: Detected in the isomeric mixture by 1H NMR analysis.
C
20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 77.65; H, 7.31; N,
4.34. IR (cmꢁ1, NaCl) nmax 3029, 2980, 2934, 1733, 1612, 1507, 1187,
814. Compound 9g: 1H NMR (400 MHz, CDCl3):
d
1.22 (t, J¼7.1 Hz,
1H NMR (400 MHz, CDCl3):
d
1.44 (d, J¼6.1 Hz, 3H, CH3), 3.28 (t,
3H, CH3CH2), 1.50 (d, J¼6.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3–Ph), 3.15
(dd, J¼8.9, 7.1 Hz, 1H, H-4), 4.14 (q, J¼7.1 Hz, 2H, CH3CH2), 4.43 (qd,
J¼9.0, 6.0 Hz, 1H, H-5), 5.10 (d, J¼7.0 Hz, 1H, H-3), 6.89 (d, J¼8.5 Hz,
2H, Ar–H), 7.04 (d, J¼8.3 Hz, 2H, Ar–H), 7.26–7.33 (m, 1H, Ar–H),
7.37 (t, J¼7.5 Hz, 2H, Ar–H), 7.52 (d, J¼7.4 Hz, 2H, Ar–H). 13C NMR
J¼9.8 Hz, 1H, H-4), 4.71 (d, J¼10.2 Hz, 1H, H-3), 4.80 (qd, J¼9.5,
6.0 Hz, 1H, H-5).
4.3.1.7. 3RS-(3R
isoxazolidine (9k) and 3RS-(3R
* * *
,4S ,5R )-2-Tolyl-3-(2-furyl)-4-carbethoxy-5-methyl-
*
,4R ,5S )-2-tolyl-3-(2-furyl)-4-car-
*
*
(100 MHz, CDCl3):
d
13.6 (CH3CH2), 17.1 (CH3), 20.1 (CH3–Ph), 60.8
bethoxy-5-methyl-isoxazolidine (10k). Eluent: ether/hexane 1:2.
Yield 134.1 mg, 86%, colourless oil. Ratio 9k/10k¼76:24. Anal. Calcd
for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.43; H 6.75; N
4.42. IR (cmꢁ1, NaCl) nmax 2981, 2934, 1735, 1612, 1507, 1191, 817,
(CH3CH2), 65.1 (C-4), 73.2 (C-3), 77.0 (C-5), 113.8, 126.0, 127.1, 128.3,
128.9, 130.4, 141.4, 148.9 (C–Ar), 169.9 (C]O). Compound 10g:
Detected in the isomeric mixture by 1H NMR analysis. 1H NMR
(400 MHz, CDCl3):
H-4), 4.75 (d, J¼10.2 Hz, 1H, H-3), 4.81 (qd, J¼9.6, 6.1 Hz, 1H, H-5).
d
1.45 (d, J¼6.1 Hz, 3H, CH3), 3.31 (t, J¼9.8 Hz,1H,
740. Compound 9k: 1H NMR (400 MHz, CDCl3):
d
1.20 (t, J¼7.1 Hz,
3H, CH3CH2), 1.54 (d, J¼6.0 Hz, 3H, CH3), 2.27 (s, 3H, CH3–Ph), 3.39

10528
M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
(dd, J¼8.5, 6.3 Hz, 1H, H-4), 4.12 (q, J¼7.1 Hz, 2H, CH3CH2), 4.40 (qd,
J¼12.0, 6.0 Hz, 1H, H-5), 5.21 (d, J¼6.2 Hz, 1H, H-3), 6.35 (td, J¼4.7,
3.4 Hz 2H, Fur–H), 6.98 (d, J¼8.4 Hz, 2H, Ph–H), 7.07 (d, J¼8.4 Hz,
170.9 (C]O). Compound 10n: 1H NMR (400 MHz, CDCl3):
d 0.82 (t,
J¼7.1 Hz, 3H, CH3CH2), 1.36 (d, J¼6.1 Hz, 3H, CH3), 2.60 (s, 3H, N–
CH3), 3.18 (t, J¼8.5 Hz, 1H, H-4), 3.55–3.79 (m, 2H, CH3CH2), 3.85 (d,
J¼10.3 Hz, 1H, H-3), 4.67 (qd, J¼12.3, 6.1 Hz, 1H, H-5), 7.27–7.37 (m,
2H, Ph–H), 7.41 (s, 1H, Fur–H). 13C NMR (100 MHz, CDCl3):
d 14.1
(CH3CH2), 17.7 (CH3), 20.6 (CH3–Ph), 60.9 (C-4), 61.4 (CH3CH2), 67.6
(C-3), 77.4 (C-5), 107.1 (C–Fur), 110.4, 114.8, 116.3, 129.4 (C–Ph),
142.6, 148.6 (C–Fur), 170.2 (C]O). Compound 10k: Detected in the
isomeric mixture by 1H NMR analysis. 1H NMR (400 MHz, CDCl3):
4H, Ph–H). 13C NMR (100 MHz, CDCl3):
d 13.6 (CH3CH2), 18.4 (CH3),
43.3 (CH3–N), 60.6 (CH3CH2), 60.9 (C-4), 75.2 (C-3), 75.6 (C-5),
128.9, 129.8, 133.9, 135.1 (6C–Ph), 170.1 (C]O).
d
1.48 (d, J¼6.1 Hz, 3H, CH3), 3.25 (t, J¼9.3 Hz, 1H, H-4), 4.81 (qd,
4.3.1.11. 3RS-(3R
*
,4S
*
,5R
*
)-2-Methyl-3-(p-nitrophenyl)-4-carbethoxy-
J¼11.9, 6.0 Hz, 1H, H-5), 4.92 (d, J¼9.3 Hz, 1H, H-3).
5-methyl-isoxazolidine (9o) and 3RS-(3R
*
,4R ,5S )-2-methyl-3-
*
*
(p-nitrophenyl)-4-carbethoxy-5-methyl-isoxazolidine (10o). Eluent:
ether/hexane 1:2. Yield 147.2 mg, 90%, yellow oil. Ratio 9o/
10o¼76:34. Anal. Calcd for C14H18N2O5: C, 57.13; H, 6.16; N, 9.52.
Found: C, 56.99; H, 6.17; N, 9.49. IR (cmꢁ1, NaCl) nmax 2981, 2934,
2874, 1732, 1524, 1349, 1187, 856. Compound 9o: 1H NMR
4.3.1.8. 3RS-(3R ,4S ,5R )-2-Tolyl-3-(3-pyridyl)-4-carbethoxy-5-met-
hyl-isoxazolidine (9l) and 3RS-(3R ,4R ,5S )-2-tolyl-3-(3-pyridyl)-4-
*
*
*
*
*
*
carbethoxy-5-methyl-isoxazolidine (10l). Eluent: ether/hexane 4:1.
Yield 167.5 mg, 81%, colourless oil. Ratio 9l/10l¼90:10. Anal. Calcd
for C19H22N2O3: C, 69.92; H, 6.79; N, 8.58. Found: C, 69.71; H, 6.77;
N, 8.57. IR (cmꢁ1, NaCl) nmax 3029, 2980, 2934, 1731, 1612, 1508,
1193, 1026, 814, 715. Compound 9l: 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
d
1.27 (t, J¼7.1 Hz, 3H, CH3CH2), 1.48 (d, J¼6.1 Hz,
3H, CH3), 2.70 (s, 3H, N–CH3), 2.99 (dd, 1H, J¼7.6, 6.8 Hz, 1H, H-4),
4.20 (m, 3H, H-3, CH3CH2), 4.53–4.61 (m, 1H, H-5), 7.62 (d, J¼8.7 Hz,
2H, Ph–H), 8.21 (d, J¼8.9 Hz, 2H, Ph–H). 13C NMR (100 MHz, CDCl3):
d
1.23 (t, J¼7.1 Hz, 3H, CH3CH2), 1.51 (d, J¼6.0 Hz, 3H, CH3), 2.27 (s,
3H, CH3–Ph), 3.12 (dd, J¼8.8, 6.8 Hz, 1H, H-4), 4.16 (q, J¼7.1 Hz, 2H,
CH3CH2), 4.46 (qd, J¼8.8, 6.0 Hz, 1H, H-5), 5.17 (d, J¼6.7 Hz, 1H, H-
3), 6.88 (d, J¼8.4 Hz, 2H, Ph–H), 7.06 (d, J¼8.2 Hz, 2H, Ph–H), 7.32
(dd, J¼7.7, 4.9 Hz, 1H, Pyr–H), 7.92 (d, J¼7.9 Hz, 1H, Pyr–H), 8.56 (d,
J¼3.7 Hz, 1H, Pyr–H), 8.74 (s, 1H, Pyr–H). 13C NMR (100 MHz,
d 14.2 (CH3CH2), 20.5 (CH3), 43.8 (CH3–N), 61.5 (CH3CH2), 64.7 (C-4),
74.8 (C-3), 76.1 (C-5), 123.9, 128.3, 147.1, 147.6 (6C–Ph), 170.9 (C]O).
Compound 10o: 1H NMR (400 MHz, CDCl3):
d
0.82 (t, J¼7.2 Hz, 3H,
CH3CH2), 1.39 (d, J¼6.1 Hz, 3H, CH3), 2.64 (s, 3H, N–CH3), 3.27 (dd,
J¼10.4, 8.2 Hz, 1H, H-4), 3.55–3.78 (m, 2H, CH3CH2), 4.01 (d,
J¼10.5 Hz, 1H, H-3), 4.67 (m, 1H, H-5), 7.57 (d, J¼8.7 Hz, 2H, Ph–H),
CDCl3):
d 13.5 (CH3CH2), 17.1 (CH3), 20.0 (CH3–Ph), 61.0 (CH3CH2),
64.7 (C-4), 70.8 (C-3), 77.0 (C-5), 113.8 (C–Ph), 123.2 (C–Pyr), 129.0,
130.9 (C–Ph), 133.8, 137.1, 147.6, 148.2, 148.4 (C–Pyr), 169.4 (C]O).
8.18 (d, J¼9.0 Hz, 2H, Ph–H). 13C NMR (100 MHz, CDCl3):
d 13.7
(CH3CH2), 18.3 (CH3), 43.5 (CH3–N), 60.8 (CH3CH2), 60.9 (C-4), 74.8
(C-3), 75.9 (C-5), 123.3, 129.5, 144.3, 147.7 (6C–Ph), 169.7 (C]O).
Compound 10l: Detected in the isomeric mixture by 1H NMR
1
analysis. H NMR (400 MHz, CDCl3):
d
1.47 (d, J¼6.1 Hz, 3H, CH3),
3.37 (t, J¼9.7 Hz, 1H, H-4), 4.73–4.81 (m, 1H, H-5), 4.82 (d,
J¼10.1 Hz, 1H, H-3).
4.3.1.12. 3RS-(3R
*
,4S
*
,5R
*
)-2-Methyl-3-(p-methoxyphenyl)-4-carbeth-
oxy-5-methyl-isoxazolidine (9p) and 3RS-(3R
*
,4R ,5S )-2-methyl-3-(p-
*
*
methoxyphenyl)-4-carbethoxy-5-methyl-isoxazolidine (10p). Eluent:
ether/hexane 1:2. Yield 153.2 mg, 91%, colourless oil. Ratio 9p/
10p¼55:45. Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01.
Found: C, 64.71; H, 7.57; N, 4.97. IR (cmꢁ1, NaCl) nmax 2978, 2934,
2839, 1732, 1612, 1514, 1377, 1250, 1182, 1036, 834. Compound 9p:
4.3.1.9. 3RS-(3R
isoxazolidine (9m) and 3RS-(3R
* * *
,4S ,5R )-2-Methyl-3-phenyl-4-carbethoxy-5-methyl-
*
,4R ,5S )-2-methyl-3-phenyl-4-
*
*
carbethoxy-5-methyl-isoxazolidine (10m). Eluent: ether/hexane
1:2. Yield 163.4 mg, 89%, colourless oil. Ratio 9m/10m¼56:44. Anal.
Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.71; H,
7.73; N, 5.57. IR (cmꢁ1, NaCl) nmax 3063, 3032, 2980, 2932, 2872,
1734, 1455, 1377, 1279, 1184, 1044, 756, 701. Compound 9m: 1H
1H NMR (400 MHz, CDCl3):
d
1.21 (t, J¼7.1 Hz, 3H, CH3CH2), 1.48 (d,
J¼6.2 Hz, 3H, CH3), 2.60 (s, 3H, CH3–N), 3.04 (dd, J¼8.6, 6.5 Hz, 1H,
H-4), 3.80 (s, 3H, OCH3), 3.78–3.93 (m, H-3), 4.14 (q, J¼7.1 Hz, 2H,
CH3CH2), 4.48 (p, J¼6.1 Hz, 1H, H-5), 6.88 (d, J¼8.7 Hz, 2H, Ph–H),
NMR (400 MHz, CDCl3):
d
1.20 (t, J¼7.1 Hz, 3H, CH3CH2), 1.47 (d,
J¼6.2 Hz, 3H, CH3), 2.62 (s, 3H, N–CH3), 3.05 (dd, J¼8.4, 6.5 Hz, 1H,
H-4), 3.95 (d, J¼5.8 Hz, 1H, H-3), 4.13 (q, J¼7.1 Hz, 2H, CH3CH2), 4.49
(p, J¼6.2 Hz, 1H, H-5), 7.29 (m, 5H, Ph–H). 13C NMR (100 MHz,
7.31 (d, J¼8.7 Hz, 2H, Ph–H). 13C NMR (100 MHz, CDCl3):
d 14.2
(CH3CH2), 21.1 (CH3), 43.3 (CH3–N), 55.2 (OCH3), 61.0 (CH3CH2), 64.4
(C-4), 75.5 (C-3), 76.0 (C-5), 114.1, 129.6, 132.0, 159.4 (6C–Ph), 171.4
CDCl3):
d
14.1 (CH3CH2), 21.0 (CH3), 43.3 (CH3–N), 61.0 (CH3CH2),
(C]O). Compound 10p: 1H NMR (400 MHz, CDCl3):
d 0.81 (t,
64.6 (C-4), 76.1 (C-5), 76.3 (C-3), 128.0, 128.2, 128.7, 138.5 (6C–Ph),
J¼7.2 Hz, 3H, CH3CH2), 1.36 (d, J¼6.1 Hz, 3H, CH3), 2.60 (s, 3H, CH3–
N), 3.14 (dd, J¼10.1, 8.1 Hz, 1H, H-4), 3.57–3.76 (m, 2H, CH3CH2),
3.78 (s, 3H, OCH3), 3.78–3.93 (m, H-3), 4.68 (qd, J¼12.3, 6.1 Hz, 1H,
171.4 (C]O). Compound 10m: 1H NMR (400 MHz, CDCl3):
d
0.74 (t,
J¼7.0 Hz, 3H, CH3CH2), 1.35 (d, J¼6.1 Hz, 3H, CH3), 2.64 (s, 3H, N–
CH3), 3.16 (dd, J¼10.3, 7.9 Hz, 1H, H-4), 3.49–3.75 (m, 2H, CH3CH2),
3.86 (d, J¼10.3 Hz, 1H, H-3), 4.69 (qd, J¼12.3, 6.2 Hz, 1H, H-5), 7.29
H-5), 6.84 (d, J¼8.7 Hz, 2H, Ph–H), 7.26 (d, J¼8.7 Hz, 2H, Ph–H). 13
C
NMR (100 MHz, CDCl3):
d 13.7 (CH3CH2), 18.4 (CH3), 43.3 (CH3–N),
(m, 5H, Ph–H). 13C NMR (100 MHz, CDCl3):
d
13.5 (CH3CH2), 18.4
55.2 (OCH3), 60.4 (CH3CH2), 61.0 (C-4), 75.5 (C-3, C-5), 113.6, 128.8,
130.0, 159.4 (6C–Ph), 170.5 (C]O).
(CH3), 43.4 (CH3–N), 60.4 (CH3CH2), 61.1 (C-4), 75.5 (C-5), 76.1 (C-3),
127.6, 128.1, 128.4, 136.4 (6C–Ph), 170.4 (C]O).
4.3.1.13. 3RS-(3R
*
,4S
*
,5R
*
)-2-Methyl-3-(2-furyl)-4-carbethoxy-5-methyl-
4.3.1.10. 3RS-(3R
*
,4S
*
,5R
*
)-2-Methyl-3-(p-chlorophenyl)-4-carbethoxy-
isoxazolidine (9q) and 3RS-(3R
*
,4R ,5S )-2-methyl-3-(2-furyl)-4-carbe-
*
*
5-methyl-isoxazolidine (9n) and 3RS-(3R
*
,4R ,5S )-2-methyl-3-(p-chlor-
*
*
thoxy-5-methyl-isoxazolidine (10q). Eluent: ether/hexane 1:2. Yield
142.4 mg, 75%, colourless oil. Ratio 9q/10q¼60:40. Anal. Calcd for
ophenyl)-4-carbethoxy-5-methyl-isoxazolidine (10n). Eluent: ether/
hexane 1:2. Yield 148.8 mg, 89%, colourless oil. Ratio 9n/
10n¼60:40. Anal. Calcd for C14H18ClNO3: C, 59.26; H, 6.34; N, 4.94.
Found: C, 59.29; H, 6.37; N, 5.01. IR (cmꢁ1, NaCl) nmax 2980, 2932,
2873, 1733, 1492, 1376, 1184, 1091, 1044, 819. Compound 9n: 1H
C
12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.24; H, 7.22; N,
5.92. IR (cmꢁ1, NaCl) nmax 2979, 2933, 2874, 1736, 1376, 1187, 1044,
742. Compound 9q: 1H NMR (400 MHz, CDCl3):
d
1.01 (t, J¼7.1 Hz,
3H, CH3CH2), 1.36 (d, J¼6.1 Hz, 3H, CH3), 2.65 (s, 3H, CH3–N), 3.16 (br
s, 1H, H-4), 3.84–3.97 (m, 2H, CH3CH2), 4.02 (br s, 1H, H-3), 4.59–
4.76 (m, 1H, H-5), 6.32 (dd, J¼8.8, 2.5 Hz, 2H, Fur–H), 7.36 (s, 1H,
NMR (400 MHz, CDCl3):
d
1.23 (t, J¼7.1 Hz, 3H, CH3CH2), 1.47 (d,
J¼6.1 Hz, 3H, CH3), 2.63 (s, 3H, N–CH3), 2.99 (dd, J¼8.1, 6.6 Hz, 1H,
H-4), 3.96 (d, J¼6.6 Hz, 1H, H-3), 4.16 (q, J¼7.1 Hz, 2H, CH3CH2), 4.50
(p, J¼6.1 Hz, 1H, H-5), 7.27–7.37 (m, 4H, Ph–H). 13C NMR (100 MHz,
Fur–H). 13C NMR (100 MHz, CDCl3):
d 13.7 (CH3CH2),18.3 (CH3), 43.5
(CH3–N), 58.8 (C-4), 60.6 (CH3CH2), 69.1 (C-3), 75.3 (C-5), 110.2,
CDCl3):
d 14.2 (CH3CH2), 20.9 (CH3), 43.4 (CH3–N), 61.2 (CH3CH2),
110.3, 142.3, 149.7 (4C–Fur), 169.9 (C]O). Compound 10q: 1H NMR
64.5 (C-4), 75.4 (C-3), 76.1 (C-5), 128.4, 128.9, 133.5, 136.8 (6C–Ph),
(400 MHz, CDCl3):
d
1.25 (t, J¼7.1 Hz, 3H, CH3CH2), 1.49 (d, J¼6.0 Hz,

M.M. Andrade et al. / Tetrahedron 64 (2008) 10521–10530
10529
3H, CH3), 2.65 (s, 3H, CH3–N), 3.33 (br s, 1H, H-4), 4.14 (d, J¼10.3 Hz,
1H, H-3), 4.18 (dd, J¼14.2, 7.1 Hz, 2H, CH3CH2), 4.48 (br s, 1H, H-5),
6.32 (dd, J¼8.8, 2.5 Hz, 2H, Fur–H), 7.41 (s, 1H, Fur–H). 13C NMR
(100 MHz, CDCl3):
d
13.6 (CH3CH2), 17.4 (CH3), 25.5 (3C, (CH3)3C–N),
60.1 ((CH3)3C–N), 60.8 (CH3CH2), 65.1 (C-4), 65.4 (C-3), 77.3 (C-5),
123.2, 127.2, 146.7, 149.9 (C–Ph), 169.1 (C]O). IR (cmꢁ1, NaCl) nmax
2977, 2937, 2908, 2874, 1732, 1599, 1523, 1348, 1186, 855, 836. Anal.
Calcd for C17H24N2O5: C, 60.70; H, 7.19; N, 8.33. Found: C, 60.53; H,
7.23; N, 8.36.
(100 MHz, CDCl3):
d 14.0 (CH3CH2), 18.3 (CH3), 43.6 (CH3–N), 60.0
(C-4), 61.1 (CH3CH2), 69.1 (C-3), 76.1 (C-5), 108.4, 108.7, 142.7, 149.7
(4C–Fur), 171.2 (C]O).
4.3.1.14. 3RS-(3R
*
,4S
*
,5R
*
)-2-Methyl-3-(3-pyridyl)-4-carbethoxy-5-
,4R ,5S )-2-methyl-3-(3-
4.3.1.18. 3RS-(3R
*
,4S
*
,5R )-2-tert-Butyl-3-(p-methoxyphenyl)-4-car-
*
methyl-isoxazolidine (9r) and 3RS-(3R
*
*
*
bethoxy-5-methyl-isoxazolidine (9v). Eluent: ether/hexane 1:2.
pyridyl)-4-carbethoxy-5-methyl-isoxazolidine (10r). Eluent: ether/
hexane 4:1. Yield 178.5 mg, 97%, colourless oil. Ratio 9r/10r¼66:34.
Anal. Calcd for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C,
62.26; H, 7.44; N, 11.12. IR (cmꢁ1, NaCl) nmax 2980, 2933, 2874, 1731,
1577, 1429, 1188, 1038, 715. Compound 9r: 1H NMR (400 MHz,
Yield 121 mg, 78%, colourless oil. 1H NMR (400 MHz, CDCl3):
d
1.07
t
(s, 9H, Bu–H), 1.20 (t, J¼7.1 Hz, 3H, CH3CH2), 1.34 (d, J¼5.9 Hz, 3H,
CH3), 2.93 (t, J¼9.5 Hz, 1H, H-4), 3.78 (s, 3H, OCH3), 4.07–4.18 (m,
2H, CH3CH2), 4.32 (qd, J¼11.8, 5.9 Hz,1H, H-5), 4.62 (d, J¼9.6 Hz,1H,
H-3), 6.82 (d, J¼8.7 Hz, 2H, Ph–H), 7.37 (d, J¼8.6 Hz, 2H, Ph–H). 13
C
CDCl3):
d
1.24 (t, J¼7.1 Hz, 3H, CH3CH2), 1.49 (d, J¼6.1 Hz, 3H, CH3),
NMR (100 MHz, CDCl3): d 13.8 (CH3CH2), 17.6 (CH3), 25.8 (3C,
2.66 (s, 3H, CH3–N), 2.98–3.08 (m, 1H, H-4), 4.04 (d, J¼7.2 Hz,1H, H-
3), 4.17 (q, J¼7.1 Hz, 2H, CH3CH2), 4.48–4.61 (m, 1H, H-5), 7.30 (dd,
J¼7.8, 4.9 Hz, 1H, Pyr–H), 7.78 (d, J¼7.8 Hz, 1H, Pyr–H), 8.55 (d,
J¼2.5 Hz, 1H, Pyr–H), 8.62 (s, 1H, Pyr–H). 13C NMR (100 MHz,
(CH3)3C–N), 54.8 (OCH3), 60.1 ((CH3)3C–N), 60.5 (CH3CH2O–), 65.6
(C-4), 66.2 (C-3), 76.9 (C-5), 113.3, 127.6, 134.0, 158.4 (C–Ph), 169.9
(C]O). IR (cmꢁ1, NaCl) nmax 2979, 2934, 1732, 1612, 1511, 1248, 1182,
1034, 815. Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N, 4.36.
Found: C, 67.15; H, 8.51; N, 4.37.
CDCl3):
d 13.5 (CH3CH2), 20.1 (CH3), 42.9 (CH3–N), 60.7 (CH3CH2),
63.8 (C-4), 72.9 (C-3), 75.3 (C-5), 123.0, 134.3, 135.2, 148.8, 149.4
(5C–Pyr), 170.3 (C]O). Compound 10r: 1H NMR (400 MHz, CDCl3):
4.3.1.19. 3RS-(3R
methyl-isoxazolidine (9w). Eluent: ether/hexane 1:2. Yield 128 mg,
76%, colourless oil. 1H NMR (400 MHz, CDCl3): 1.11 (s, 9H, tBu–H),
*
,4S
*
,5R
*
)-2-tert-Butyl-3-(2-furyl)-4-carbethoxy-5-
d
0.79 (t, J¼7.1 Hz, 3H, CH3CH2), 1.38 (d, J¼6.1 Hz, 3H, CH3), 2.63 (s,
3H, CH3–N), 3.24 (dd, J¼10.1, 8.4 Hz, 1H, H-4), 3.57–3.78 (m, 2H,
CH3CH2), 3.93 (d, J¼10.4 Hz, 1H, H-3), 4.68 (qd, J¼12.5, 6.1 Hz, 1H,
H-5), 7.26 (dd, J¼9.0, 6.1 Hz, 1H, Pyr–H), 7.74 (d, J¼7.9 Hz, 1H, Pyr–
H), 8.53 (d, J¼5.0 Hz, 1H, Pyr–H), 8.62 (s, 1H, Pyr–H). 13C NMR
d
1.24 (t, J¼7.1 Hz, 3H, CH3CH2), 1.37 (d, J¼5.9 Hz, 3H, CH3), 3.22 (t,
J¼9.0 Hz, 1H, H-4), 4.17 (m, 2H, CH3CH2), 4.32 (ddd, J¼11.8, 9.0,
5.9 Hz, 1H, H-5), 4.74 (d, J¼8.9 Hz, 1H, H-3), 6.27 (m, 2H, Fur–H),
(100 MHz, CDCl3):
d
13.0 (CH3CH2), 17.6 (CH3), 42.7 (CH3–N), 60.0
7.35 (br s, 1H, Fur–H). 13C NMR (100 MHz, CDCl3):
d 14.2 (CH3CH2),
(CH3CH2), 60.2 (C-4), 72.6 (C-3), 75.1 (C-5), 122.6, 131.8, 134.0, 148.7,
148.9 (5C–Pyr), 169.3 (C]O).
18.4 (CH3), 26.0 (3C, (CH3)3C–N), 60.2 ((CH3)3C–N), 60.7 (C-3), 61.1
(CH3CH2), 62.1 (C-4), 77.5 (C-5), 107.0, 110.2, 141.9, 153.9 (C–Fur),
170.3 (C]O). IR (cmꢁ1, NaCl) nmax 2978, 2934, 2874, 1735, 1364,
1184, 1030, 736. Anal. Calcd for C15H23NO4: C, 64.03; H, 8.24; N,
4.98. Found: C, 64.13; H, 8.23; N, 5.03.
4.3.1.15. 3RS-(3R
isoxazolidine (9s). Eluent: ether/hexane 1:2. Yield 133.3 mg, 77%,
colourless oil. 1H NMR (400 MHz, CDCl3): 1.08 (s, 9H, tBu-H), 1.19
*
,4S
*
,5R
*
)-2-tert-Butyl-3-phenyl-4-carbethoxy-5-methyl-
d
(t, J¼7.1 Hz, 3H, CH3CH2), 1.35 (d, J¼5.9 Hz, 3H, CH3), 2.96 (t,
J¼9.5 Hz, 1H, H-4), 4.06–4.19 (m, 2H, CH3CH2), 4.34 (qd, J¼9.5,
5.9 Hz, 1H, H-5), 4.67 (d, J¼9.5 Hz, 1H, H-3), 7.21 (t, J¼7.3 Hz, 1H,
4.3.1.20. 3RS-(3R
5-methyl-isoxazolidine (9x). Eluent: ether/hexane 4:1. Yield
121 mg, 74%, colourless oil. 1H NMR (400 MHz, CDCl3):
1.08 (s, 9H,
*
,4S
*
,5R
*
)-2-tert-Butyl-3-(3-pyridyl)-4-carbethoxy-
d
Ph–H), 7.28 (t, J¼7.3 Hz, 2H, Ph–H), 7.46 (d, J¼7.2 Hz, 2H, Ph–H). 13
C
tBu–H), 1.22 (t, J¼7.1 Hz, 3H, CH3CH2), 1.37 (d, J¼5.89 Hz, 3H, CH3),
2.94 (t, J¼9.5 Hz, 1H, H-4), 4.03–4.24 (m, 2H, CH3CH2), 4.36 (qd,
J¼11.7, 5.8 Hz, 1H, H-5), 4.70 (d, J¼9.5 Hz, 1H, H-3), 7.25 (br dd,
J¼7.7, 4.8 Hz, 1H, Pyr–H), 7.88 (d, J¼7.8 Hz, 1H, Pyr–H), 8.46–8.52
(m, 1H, Pyr–H), 8.62 (br s, 1H, Pyr–H). 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d 14.2 (CH3CH2), 18.1 (CH3), 26.2 (3C,
(CH3)3C–N), 60.5 ((CH3)3C–N), 61.0 (CH3CH2O), 66.1 (C-4), 67.0 (C-
3), 77.6 (C-5), 127.0, 127.2, 128.4, 142.5 (C–Ph), 170.3 (C]O). IR
(cmꢁ1, NaCl) nmax 3064, 3030, 2977, 2935, 2907, 2874, 1731, 1601,
1454, 1364, 1215, 1183, 1030, 752, 702. Anal. Calcd for C17H25NO3: C,
70.07; H, 8.65; N, 4.81. Found: C, 70.00; H, 8.78; N, 4.74.
d
14.2 (CH3CH2), 18.0 (CH3), 26.2 (3C, (CH3)3C–N), 60.7 ((CH3)3C–N),
61.3 (CH3CH2), 64.6 (C-3), 65.8 (C-4), 77.7 (C-5), 123.5, 134.7, 138.3,
148.8, 148.9 (C–Pyr), 169.8 (C]O). IR (cmꢁ1, NaCl) nmax 2977, 2936,
2910, 2874, 1731, 1589, 1479, 1191, 1026, 767, 716. Anal. Calcd for
4.3.1.16. 3RS-(3R
*
,4S
*
,5R )-2-tert-Butyl-3-(p-chlorophenyl)-4-carbe-
*
thoxy-5-methyl-isoxazolidine (9t). Eluent: ether/hexane 1:2. Yield
C16H24N2O3: C, 65.73; H, 8.27; N, 9.58. Found: C, 65.65; H, 8.45; N,
9.47.
141.1 mg, 92%, colourless crystals, mp 51–53 ꢀC. 1H NMR (400 MHz,
CDCl3):
d
1.06 (s, 9H, tBu–H), 1.21 (t, J¼7.1 Hz, 3H, CH3CH2), 1.34 (d,
J¼5.9 Hz, 3H, CH3), 2.90 (t, J¼9.5 Hz, 1H, H-4), 4.09–4.19 (m, 2H,
CH3CH2), 4.32 (qd, J¼11.8, 5.9 Hz, 1H, H-5), 4.65 (d, J¼9.5 Hz, 1H, H-
3), 7.26 (d, J¼8.4 Hz, 2H, Ph–H), 7.41 (d, J¼8.3 Hz, 2H, Ph–H). 13C
References and notes
NMR (100 MHz, CDCl3):
d 13.8 (CH3CH2), 17.6 (CH3), 25.7 (3C,
1. Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–
9283.
(CH3)3C–N), 60.2 ((CH3)3C–N), 60.7 (CH3CH2), 65.5 (C-4), 65.8 (C-3),
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2312.
77.2 (C-5), 127.9, 128.2, 132.5, 140.7 (C–Ph), 169.6 (C]O). IR (cmꢁ1
,
NaCl) nmax 2977, 2936, 2907, 2873,1732, 1490, 1363, 1184, 1090, 832.
Anal. Calcd for C17H24ClNO3: C, 62.67; H, 7.42; N, 4.30. Found: C,
62.76; H, 7.70; N, 4.29.
4.3.1.17. 3RS-(3R
*
,4S
*
,5R )-2-tert-Butyl-3-(p-nitrophenyl)-4-carbethoxy-
*
5-methyl-isoxazolidine (9u). Eluent: ether/hexane 1:2. Yield 132 mg,
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87%, yellow crystals, mp 60–62 ꢀC. 1H NMR (400 MHz, CDCl3):
d
1.06 (s, 9H, tBu–H), 1.22 (t, J¼7.1 Hz, 3H, CH3CH2), 1.35 (d, J¼5.8 Hz,
ˇ
12. Jeselnik, M.; Varma, R. S.; Polanc, S.; Kocevar, M. Chem. Commun. 2001, 1716–
3H, CH3), 2.90 (t, J¼9.4 Hz, 1H, H-4), 4.06–4.24 (m, 2H, CH3CH2),
4.35 (qd, J¼11.7, 5.8 Hz, 1H, H-5), 4.78 (d, J¼9.4 Hz, 1H, H-3), 7.66 (d,
J¼8.7 Hz, 2H, Ph–H), 8.16 (d, J¼8.7 Hz, 2H, Ph–H). 13C NMR
1717.
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