Asymmetric 1,3-dipolar cycloaddition reactions of nitrones with (S)-(-)-4-benzyl-N-methacryloyl-2-oxazolidinone

Article abstract of DOI:10.1055/s-2005-869992

The [3+2]-nitrone-mediated cycloaddition reaction of (S)-(-)-4-benzyl-N- methacryloyl-2-oxazolidinone has been applied to the synthesis of highly substituted isoxazolidines with controlled stereochemistry. The absolute configuration of the major diastereo

Full text of DOI:10.1055/s-2005-869992

PAPER
2393
Asymmetric 1,3-Dipolar Cycloaddition Reactions of Nitrones with
(
S)-(–)-4-Benzyl-N-methacryloyl-2-oxazolidinone
a
a
a
b
Reactions of
E
Nil
w
i
ith Be
z
nzyl-
N
-me
a
thacryloyl-2
b
-oxazolidin
e
a
School of Pharmacy, Kingston University, Penrhyn Road, Kingston, Surrey, KT1 2EE, UK
E-mail: e.tyrrell@kingston.ac.uk
b
School of Chemistry, University of Poitiers, Poitiers, France
Received 11 March 2005
Abstract: The [3+2]-nitrone-mediated cycloaddition reaction of
(
S)-(–)-4-benzyl-N-methacryloyl-2-oxazolidinone has been applied
to the synthesis of highly substituted isoxazolidines with controlled
stereochemistry. The absolute configuration of the major diastereo-
isomer derived from the reaction between N-(p-nitroben-
zylidene)methylamine
N-oxide
and
(S)-(–)-4-benzyl-N-
methacryloyl-2-oxazolidinone has been deduced from the corre-
sponding X-ray structure.
Key words: chiral auxiliary, nitrones, dipolar cycloaddition reac-
tion, isoxazolidine, isoxazolidinone
Scheme 2
Asymmetric 1,3-dipolar cycloaddition reactions between
nitrones and chiral acrylamide derived dipolarophiles mediated cycloaddition reaction using a methacryloyl-
1
have attracted considerable interest in recent times. This based amide dipolarophile such as 3.
is part due to the enhanced p-diastereoselectivity associat-
The corresponding lactam 5 might then be produced di-
2
ed with chiral auxiliary based dipolarophiles coupled
rectly in one step from isoxazolidine 4 using TiCl or by a
3
with the ease with which the chemistry may then be trans-
two-step process involving an initial hydrolysis of the
3
ferred onto a solid support media by immobilising either
auxiliary followed by an N–O bond cleavage reaction
the dipole or the dipolarophile onto a polymer-derived
(
Scheme 2).
support. Some recent examples of immobilisation have
4
5
From our survey of the chemical literature we found rela-
been revealed using a chiral sultam, a sugar or a chiral
oxazolidinone.
8
6
tively few examples of methacryloyl-based amides as
partners in nitrone cycloaddition reactions. However 3-
hydroxy-b-lactams and related compounds have been
In conjunction with clinical collaborators we were keen to
establish methods for accessing g-lactams for biological
evaluation, in particular, a range of examples containing a
C-3 tertiary hydroxyl group.
synthesised via nitrone cycloaddition reactions with 3-
methylene b-lactams.9
As a general observation the regioselectivity of reactions
involving nitrones and 1,1-disubstituted dipolarophiles,
such as 3, are completely unambiguous in affording the
corresponding 5,5-disubstituted isoxazolidine. It is an
outcome which is largely influenced by the substituent ef-
7
Previous studies from our laboratories revealed that lac-
tams such as 2 may be readily accessed via a TiCl -medi-
3
ated cleavage of the comparatively weak N–O of an
isoxazolidine such as 1 (Scheme 1).
That being the case we reasoned that suitable candidates fects of the dipolarophile rather than electronic influ-
for screening would be readily available from a nitrone- ences.10
Our preliminary investigation focussed upon a compara-
tively simple model that involved the cyclisation reaction
between the dipolarophile 7 and the dipoles 6a,b
(
Scheme 3).
Scheme 1
SYNTHESIS 2005, No. 14, pp 2393–2399
x
x.
x
x
.
2
0
0
5
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-869992; Art ID: P03805SS
Georg Thieme Verlag Stuttgart · New York
Scheme 3
©

2
394
E. Tyrrell et al.
PAPER
In both cycloaddition reactions the 5-disubstituted isox- obtained from single X-ray crystallography or by the
azolidines 8a,b prevailed using the procedure described transformation of 11 into a known compound. Chromato-
1
1
by Fornefeld. This involved the in situ formation of the graphic separation of the major diastereoisomer provided
nitrone in the presence of the dipolarophile 7 and provided a semi-solid, which despite careful recrystallisation
the isoxazolidines 8a,b as clear oils. Inspection of the cor- proved unsuitable for X-ray purposes. In order to achieve
1
responding H NMR spectra however revealed that the a satisfactory sample for this purpose we synthesised a
methylene protons appeared as broadened signals thus range of derivatives 14a–c (Scheme 6).
providing us with limited information. A similar result
emerged when the cyclisation reaction were conducted
with N-methylnitrone 6a and the dipolarophile 3 to afford
the corresponding isoxazolidine 9 (Scheme 4).
Scheme 4
Signal broadening in isoxazolidines has been reported
previously and the cause attributed to pyramidal inversion
Scheme 6
of the ring nitrogen. We observed a significant reduction
1
in this effect when we ran the H NMR spectra at an ele-
vated temperature. However the resolution of the resulting The synthesis of the dipoles (13a–c) were efficiently ac-
spectra were still poor.
complished by a condensation reaction between the rele-
14
vant aldehyde and N-alkylhydroxylamine. The nitrones
were then heated, with the dipolarophile 3, in boiling tol-
uene to afford the cycloadducts in excellent yields. The
distribution of diastereoisomers was similar in all cases
consisting of a major and two minor diastereoisomers.
Isolation of the major isomer obtained from the reaction
between nitrone 12c and 3 was obtained as a crystalline
solid suitable for X-ray analysis. These data were thus
able to provide us with confirmation of the stereochemis-
try of the asymmetric centres formed in the cycloaddition
reaction (Figure 1). This series of cycloaddition reactions
appear to proceed with good regioselectivity in affording
the C-5 disubstituted isoxazolidine with the nitrone ap-
proaching the dipolarophile from the face opposite to the
benzyl group of 3. This observation was based not only
Attempts to suppress nitrogen inversion in cyclisations
such as these have been attempted by targeting the N-sub-
stituent. For instance the use of both an N-benzotriazole
1
2
13
moiety and an N-methoxy group have been reported to
successfully prevent signal broadening. In light of our re-
sult using nitrone 6b, however, the precise mechanism by
which this may be achieved in terms of steric/electronic
factors appears unclear. As well as the effect of the N-sub-
stituent on nitrogen inversion the substitution patterns of
the isoxazolidine ring are thought to be significant. Thus
when the cyclisation reaction was conducted between N-
(
benzylidene)methylamine N-oxide 10 and the oxazolidi-
none 3 the corresponding isoxazolidine 11 was formed in
1
a very high yield. H NMR analysis of the crude reaction
mixture showed the presence of two new compounds that
were related as diastereoisomers in a ratio of 4:1. Impor-
tantly a complete absence of signal broadening was ob-
served in the corresponding NMR spectra (Scheme 5).
1
upon the H NMR chemical shift for the quaternary meth-
yl group for the major diastereoisomer of compounds 11,
1
1
4a–c which fluctuated within the narrow range of d =
.67–1.69 ppm but also upon the observed stereodiffer-
15
entiation between the major and minor isomers. In general
the major diastereoisomer appearing to be deshielded
compared to the minor. This non-equivalence in chemical
shifts between functional groups in diastereoisomers have
16
been described and conformational models provided in
order to rationalise this phenomena.17
The formation of the major diastereoisomer during these
cycloaddition reactions may be rationalised in terms of an
aryl-endo and aryl-exo approach of the dipole to the dipo-
Scheme 5
Although we anticipated that information with regard to larophile 3 (Scheme 7).
the newly formed asymmetric centres in isoxazolidine 11
Having accomplished our aim of establishing a reproduc-
may not be obtained directly via extensive NMR studies
we did envisage that the absolute configuration may be
ible procedure for the efficient and controlled synthesis of
18
C-5 disubstituted isoxazolidines we looked at the cleav-
Synthesis 2005, No. 14, 2393–2399 © Thieme Stuttgart · New York

PAPER
Reactions of Nitrones with Benzyl-N-methacryloyl-2-oxazolidinone
2395
exposure to silica. We speculate that this compound arises
from an initial decarboxylation reaction accompanied by
the subsequent cleavage of the comparatively weak N–O
bond of the isoxazolidine. The synthesis of 1621 was an
unexpected outcome and at the present time our investiga-
tions are continuing and remain focussed not only on the
cleavage reaction itself but also on the generality and syn-
thetic applications of the silica promoted decarboxylation
step.
In summary this paper describes a series of [3+2]-nitrone-
mediated cycloaddition reactions using a methacryloyl-
based amide dipolarophile. Although the low reactivity of
N-methylnitrones in these cycloaddition reactions led to
long reaction times the yields were excellent. In all cases
the cyclisation was regioselective in favour of the C-5 di-
substituted isoxazolidine. The major diastereoisomer has
been isolated and characterised and for one example, the
synthesis of 14c the absolute stereochemistry has been ob-
tained from X-ray analysis. Cleavage of the chiral auxilia-
ry was accomplished in high yield. However the
isoxazolidine was found to undergo spontaneous decar-
boxylation and ring opening upon exposure to silica. This
may provide a general method for the asymmetric synthe-
sis of amino-ketones based upon 16 with a high enantio-
meric excess.
Figure 1 X-ray crystal analysis of 14c
Melting points were recorded on a Buchi 512 capillary tube appara-
tus and are uncorrected. IR spectra were recorded on a Perkin-Elmer
1
600 series FTIR spectrophotometer and were calibrated using a
standard polystyrene film. The spectra were recorded either as thin
films or between NaCl discs for liquids or as a Nujol mull for solids.
–
1 1
Scheme 7
All IR data are quoted in cm . H NMR spectra were recorded at
00 MHz using a Bruker AMX400 FT NMR spectrometer, or at 300
4
MHz on a Bruker AC-300 FTNMR spectrometer. Peak positions
are quoted using the d scale relative to TMS (d = 0) as an internal
age reaction of the chiral auxiliary. Evans described a gen-
1
3
standard. C NMR spectra were recorded at 75.45 MHz on a Bru-
ker AC-300 FTNMR spectrometer using CDCl as an internal stan-
eral method for the selective exo-cyclic hydrolysis of
1
9
3
sterically hindered carboximides using LiOH–H O2
2
dard. Low resolution mass spectra were recorded on a VG TRIO-2
mass spectrometer under EI conditions at an ionising potential of 70
(
Scheme 8).
Thus removal of the chiral auxiliary using lithium hydro- eV and/or with a Hewlett Packard GC–MS HP5890 (GC) with cap-
2
0
illary column and HP 5971 (MS). Accurate mass analyses were per-
formed and reported on a VG-ZAB-E under EI conditions by the
EPSRC National Mass Spectrometry Service Centre (Swansea)
peroxide provided isoxazolidine 15 in very high yield.
However our attempts to purify this compound by chro-
matography on silica led to the formation of the amino-ke-
tone 16 in variable yields depending upon the duration of
+
using the EI Peak Match on M method.
(
S)-(–)-4-Benzyl-N-methacryloyl-2-oxazolidinone (3)22
n-BuLi (4.52 mL, 11.29 mmol, 2.5 M) was added to (S)-(–)-4-ben-
zyl-2-oxazolidinone (2.00 g, 11.29 mmol) dissolved in THF (20
mL) at –78 °C. The mixture was stirred for 15 min whereupon fresh-
ly distilled methacryloyl chloride (1.21 mL, 12.42 mmol) was add-
ed dropwise over 10 min. The mixture was stirred for a further 30
min and then allowed to reach an ambient temperature whereupon
a sat. solution of NH Cl (30 mL) was added and the organic solvent
4
was removed in vacuo. The aqueous solution was extracted with
Et O (2 × 30 mL) and the organic layer then extracted sequentially
2
with sat. NaHCO (3 × 30 mL) followed by a sat. NaCl solution (30
3
mL). The organic layer was dried over anhyd MgSO , filtered and
4
the solvent removed in vacuo to afford a white amorphous powder.
Recrystallisation from hexane gave the title compound as a white
2
0
crystalline solid (2.66 g, 96%); mp 81–82 °C; [a]D +70.10 (c =
.97, CHCl3).
0
–
1
IR: 3026.4, 1787.4, 1681.9, 1639.6, 1352.2, 1217.0 cm .
Scheme 8
Synthesis 2005, No. 14, 2393–2399 © Thieme Stuttgart · New York

2
396
E. Tyrrell et al.
PAPER
1
MS: m/z [M + H]+ calcd for C H NO : 236.1292; found:
H NMR (300 MHz, CDCl ): d = 1.97 (s, 3 H, CH ), 2.82–2.86 (dd,
3
3
13 18
3
J = 13.5, 9 Hz, 1 H, CH ), 3.31–3.34 (dd, J = 13.5, 3.5 Hz, 1 H,
236.1287.
2
CH ), 4.17–4.18 (dd, J = 9.0,5.0 Hz, 1 H, OCH ), 4.19–4.25 (appar-
2
2
UV–Vis (MeOH): lmax = 237 nm.
ent t, J = 8.5 Hz, 1 H, OCH ), 4.68–4.70 (m, 1 H, CH), 5.401–5.406
2
(
1
d, J = 1.7 Hz, 2 H, =CH ), 7.24–7.49 (m, 5 H, CH).
2
(
S)-(–)-4-Benzyl-N-(5-carbonyl-N,5-dimethylisoxazolidine)-2-
3
C NMR (75.5 MHz, CDCl ): d = 19.1, 37.5, 55.2, 66.5, 120.7,
oxazolidinone (9)
3
1
27.4, 128.9, 129.5, 135.0, 139.6, 152.9, 171.1.
This compound was prepared according to the following procedure
1
1
+
for the in situ synthesis of nitrones. NaOAc (0.13 g, 1.63 mmol)
was added to a stirred solution of N-methylhydroxylamine hydro-
chloride (0.16 g, 1.63 mmol) in EtOH–water (10:1, 5 mL) at an am-
bient temperature. After 30 min the mixture was filtered and added
dropwise, via syringe pump (over 2.5 h), to a solution of formalde-
hyde (37% solution in water, 0.17 mL, 2.12.mmol). The mixture
was stirred for 1 h whereupon (S)-(–)-4-benzyl-N-methacryloyl-2-
oxazolidinone (3) (0.20 g, 0.82 mmol) was added and left to stir for
about 40 h. After this period water (10 mL) was added and the or-
ganics removed in vacuo. The resulting aq solution was extracted
MS (EI): m/z (rel. int., %) = 245 (17) [M ], 69 (100).
Anal. Calcd for C H NO : C, 68.49; H, 6.12; N, 5.71. Found: C,
6
14
15
3
8.56; H, 6.16; N, 5.71.
UV–Vis (CHCl ): l = 205 nm.
3
max
N,5-Dimethyl-5-(methylformyl)isoxazolidine (8a)
This compound was prepared according to the following procedure
1
1
for the in situ synthesis of nitrones. NaOAc (0.75 g, 9.08 mmol)
was added to a stirred solution of N-methylhydroxylamine hydro-
chloride (0.76 g, 9.08 mmol) in EtOH–water (10:1, 10 mL) at an
ambient temperature. After 30 min the solution was filtered and
added dropwise, via syringe pump (over 2.5 h), to a solution of
formaldehyde (37% solution in water, 0.98 mL, 12.12 mmol). The
mixture was stirred for 1 h whereupon methyl methacrylate (1.07
mL, 0.99 mmol) was added and left to stir for about 3 h. After this
period water (10 mL) was added and the organics were removed in
with Et O (3 × 10 mL). The organic layers were recombined, dried
2
over anhyd MgSO , filtered and the solvent was removed in vacuo
4
to afford a mixture of two diastereoisomers in a ratio of 3:1 (0.11 g,
4
2%). Purification and separation of the major isomer by chroma-
tography on silica (EtOAc–hexane, 4:1) provided a clear oil for fur-
ther characterisation.
Major Isomer
vacuo. The resulting aqueous solution was extracted with Et O (3 ×
1
2
2
0
[
a]D +43.14 [c = 1.40, (CH ) CO].
0 mL). The organic layers were recombined, dried over anhyd
3 2
MgSO , filtered and the solvent removed in vacuo to afford the title
compound as a clear oil (0.96 g, 67%).
IR: 2998.1, 2957.4, 1785.9, 1702.5, 1216.4 cm–1.
4
1
H NMR (300 MHz, CDCl ): d = 1.63 (s, 3 H, CH ), 2.38 (br m, 2
3
3
–
1
IR: 2998.1, 2957.4, 1735.6 cm .
H, CH ), 2.65 (br m, 2 H, CH ), 2.72 (s, 3 H, NCH ), 3.14 (br m, 1
2
2
3
1
H, CH ), 3.19 (dd, J = 13.5, 3.0 Hz, 1 H, CH), 4.11–4.19 (m, 2 H,
H NMR (300 MHz, CDCl ): d = 1.35 (s, 3 H, CH ), 1.97 (br m, 1
2
3
3
OCH ), 4.64–4.72 (m, 1 H, CH), 7.13–7.28 (m, 5 H, ArH).
H, CH ), 2.34 (br m, 1 H, CH ), 2.58 (s, 3 H, NCH ), 2.68 (br m, 1
2
2
2
3
H, CH ), 3.12 (br m, 1 H, CH ), 3.60 (s, 3 H, OCH ).
13
2
2
3
C NMR (75.5 MHz, CDCl ): d = 22.3, 37.6, 40.4, 44.9, 56.5, 57.6,
3
1
3
66.2, 84.0, 127.4, 128.9, 129.5, 135.3, 152.2, 174.1.
C NMR (75.5 MHz, CDCl ): d = 23.9, 39.2, 45.3, 52.4, 57.1, 81.9,
3
1
75.1.
+
MS (EI): m/z (rel. int., %) = 304 [M ] (18), 55 (100).
+
MS (EI): m/z (rel. int., %) = 159 [M ] (92), 59 (100).
UV–Vis (MeOH): lmax = 206 nm.
+
MS: m/z [M + H] calcd for C H NO : 160.0966; found: 160.0974.
7
14
3
N-(Benzylidene)methylamine N-Oxide (10)
UV–Vis (MeOH): lmax = 201 nm.
This compound was prepared according to the following procedure
2
3
for the synthesis of nitrones. Benzaldehyde (1.16 mL, 11.44
mmol) was added to a stirred solution of N-methylhydroxylamine
hydrochloride (1.00 g, 11.97 mmol) in aq NaOH [0.48 g, 12.00
mmol dissolved in deionised water (20 mL)] at an ambient temper-
N-Benzyl-5-methyl-5-(methylformyl)isoxazolidine (8b)
This compound was prepared according to the following procedure
1
1
for the in situ synthesis of nitrones using the following quantities.
NaOAc (0.75 g, 9.08 mmol) was added to a stirred solution of N-
benzylhydroxylamine hydrochloride (1.45 g, 9.08 mmol) in EtOH–
water (10:1, 10 mL) at an ambient temperature. After 30 min the so-
lution was filtered and added dropwise, via syringe pump (over 2.5
h), to a solution of formaldehyde (37% solution in water, 0.98 mL,
ature. After 30 min the solution was extracted with CHCl (3 × 10
3
mL). The combined organic layers were dried over anhyd MgSO4,
filtered and the solvent removed in vacuo to afford the title com-
pound as a white solid (1.53 g, 99%). Recrystallisation from
EtOAc–hexane provided white crystalline plates; mp 86–87 °C (lit.
1
2.12 mmol). The mixture was stirred for 1 h whereupon methyl
24
8
5 °C).
methacrylate (1.07 mL, 0.99 mmol) was added and left to stir for
about 3 h. After this period water (10 mL) was added and the organ-
ics were removed in vacuo. The resulting aqueous solution was ex-
IR: 3057.6, 2957.4, 1595.0, 1445.1, 1420.8, 1406.9, 1301.9, 1166.0
–
1
cm .
tracted with Et O (3 × 10 mL). The organic layers were recombined,
1
2
H NMR (300 MHz, CDCl ): d = 3.83 (s, 3 H, NCH ), 7.28 (s, 1 H,
3
3
dried over anhyd MgSO , filtered and the solvent removed in vacuo
4
CH), 7.30–7.35 (m, 3 H, ArH), 8.12–8.15 (m, 2 H, ArH).
to afford the title compound as a clear oil (1.70 g, 80%).
1
3
C NMR (75.5 MHz, CDCl ): d = 54.3, 128.37, 128.41, 130.4,
3
–
1
IR: 2997.5, 2959.4, 1732.9 cm .
1
30.5, 135.2.
1
H NMR (300 MHz, CDCl ): d = 1.42 (s, 3 H, CH ), 2.06–2.15 (br
+
3
3
MS (EI): m/z (rel. int., %) = 135 [M ], 134 (100), 118, 107, 77, 65.
UV–Vis (MeOH): lmax 289 nm.
m, 1 H, CH ), 2.68–2.78 (br m, 1 H, CH ), 2.88–2.96 (br s, 1 H,
2
2
CH ), 3.01–3.08 (br m, 1 H, CH ), 3.67 (s, 3 H, OCH ), 3.68 (d, J =
2
2
3
6
.0 Hz, 1 H, ArCH ), 3.94 (d, J = 6.0 Hz, 1 H, ArCH ), 6.98–7.18
2
2
(
S)-(–)-4-Benzyl-N-(5-carbonyl-N,5-dimethyl-phenylisoxazoli-
(m, 5 H, ArH).
dine)-2-oxazolidinone (11); General Cycloaddition Procedure
To a solution of (S)-(–)-4-benzyl-N-methacryloyl-2-oxazolidinone
(
zylidene)methylamine N-oxide (10) (0.22 g, 1.63 mmol). The mix-
ture was stirred at a reflux temperature until 3 was consumed (about
1
3
C NMR (75.5 MHz, CDCl ): d = 24.1, 38.9, 52.4, 54.4, 62.2, 82.4,
3
1
27.3, 128.3, 128.8, 136.9, 175.8.
3) (0.20 g, 0.815 mmol) in toluene (15 mL) was added N-(ben-
+
MS (EI): m/z (rel. int., %) = 235 [M ] (16), 91 (100).
Synthesis 2005, No. 14, 2393–2399 © Thieme Stuttgart · New York

PAPER
Reactions of Nitrones with Benzyl-N-methacryloyl-2-oxazolidinone
2397
–
1
7
2 h). The solvent was removed in vacuo to afford a separable mix-
IR: 3022.6, 2957.4, 1699.8, 1598.3, 1511.7, 1478.5, 1428.5 cm .
ture of two diastereoisomers (4:1, 0.33 g, 94%). The major diaste-
1
H NMR (300 MHz, CDCl ): d = 3.819 (s, 3 H, CH ), 3.824 (s, 3 H,
3
3
reoisomer was isolated by chromatography on silica [Et O–light
2
CH ), 6.89–6.93 (d, J = 6.8 Hz, 2 H, ArH) 7.26 (s, 1 H, CH), 8.16–
8
3
petroleum (40:60), 1:1] to afford a white semi-solid.
.21 (d, J = 6.8 Hz, 2 H, ArH).
1
3
C NMR (75.5 MHz, CDCl ): d = 54.05, 55.43, 113.93, 123.47,
Major Isomer
3
20
130.36, 134.94, 142.16.
[
a]D +150.54 (c = 1.38, CHCl3).
–
1
UV–Vis (MeOH): lmax = 253 nm
IR: 1785.8, 1705.3, 1216.7 cm .
1
Anal. Calcd for C H NO : C, 65.39; H, 6.65; N, 8.44. Found: C,
H NMR (300 MHz, CDCl ): d = 1.67 (s, 3 H, CH ), 2.56 (s, 3 H,
9
11
2
3
3
6
5.45; H, 6.67; N, 8.48.
NCH ), 2.61 (dd, J = 9.5, 3.5 Hz, 1 H, CH ), 2.71–2.84 (m, 2 H,
3
2
CH ), 3.23 (dd, J = 13.5, 3.5 Hz, 1 H, CH ), 3.48 (t, J = 8.5 Hz, 1 H,
2
2
(
S)-(–)-4-Benzyl-N-[3-(p-bromophenyl)-5-carbonyl-N,5-di-
CH), 4.07–4.19 (m, 2 H, OCH ), 4.69–4.77 (m, 1 H, NCH), 7.15–
2
methylisoxazolidine]-2-oxazolidinone (14a)
Using the procedure described for the synthesis of 11 the title com-
pound was obtained as a mixture of three diastereoisomers
7
.27 (m, 10 H, ArH).
1
3
C NMR (75.5 MHz, CDCl ): d = 22.6, 37.7, 42.8, 50.5, 56.5, 66.6,
3
7
1
3.4, 83.2, 127.4, 127.7, 128.1, 128.8, 129.0, 129.5, 135.3, 137.9,
52.2, 174.2.
(
6.3:1:0.3) in a yield of 99%. Separation of the major isomer was
undertaken using chromatography on silica (hexane–EtOAc, 2:1) to
afford a white semi-solid; [a]D +170.28 (c = 1.57 in CHCl3).
MS: m/z [M + H]+ calcd for C H N O : 381.1819; found:
20
2
2
25
2
4
3
81.1814.
IR: 1785.8, 1707.3, 1216.1 cm–1.
UV–Vis (MeOH): lmax = 207 nm.
1
H NMR (300 MHz, CDCl ): d = 1.66 (s, 3 H, CH ), 2.46 (dd, J =
3
3
1
3.5, 9.5 Hz, 1 H, CH ), 2.48 (s, 3 H, NCH ), 2.64–2.76 (m, 2 H,
2
3
N-(p-Bromobenzylidene)methylamine N-Oxide (13a)
The title compound was obtained as white crystalline plates (yield:
CH ), 3.16 (dd, J = 13.5, 3.0 Hz, 1 H, ArCH ), 3.36 (t, J = 8.5 Hz, 1
H, CH), 4.04–4.14 (m, 2 H, OCH ), 4.62–4.70 (m, 1 H, CH), 7.03
2
2
2
9
0%); mp 128.3–129.4 °C.
(
d, J = 8.5 Hz, 2 H, ArH), 7.08–7.21 (m, 5 H, ArH), 7.28 (d, J = 8.5
–
1
IR: 3018.5, 2957.4, 1601.0, 1443.1, 1420.8, 1406.9, 1215.9 cm .
Hz, 2 H, ArH).
1
13
H NMR (300 MHz, CDCl ): d = 3.76 (s, 3 H, NCH ), 7.26 (s, 1 H,
C NMR (75.5 MHz, CDCl ): d = 22.6, 37.7, 42.8, 50.5, 56.5, 66.6,
3
3
3
CH), 7.44 (dm, J = 8.5 Hz and others, 2 H, ArH), 8.01 (dm, J = 8.5
Hz and others, 2 H, ArH).
72.6, 83.2, 121.8, 127.4, 129.0, 129.3, 129.5, 131.8, 135.2, 137.1,
152.1, 174.1.
1
3
MS: m/z [M + H]+81Br calcd for C H N O Br: 461.0899; found:
C NMR (75.5 MHz, CDCl ): d = 54.4, 124.2, 129.3, 129.7, 131.7,
3
22 24
2
4
1
34.2.
461.0881.
+
MS (EI): m/z (rel. int., %) = 212 [M ] (99), 214 (100).
UV–Vis (MeOH): lmax = 297 nm.
UV–Vis (MeOH): lmax = 241 nm.
(
S)-(–)-4-Benzyl-N-[3-(p-chlorophenyl)-5-carbonyl-N,5-di-
methylisoxazolidine]-2-oxazolidinone (14b)
Using the procedure described for the synthesis of 11 the title com-
pound was obtained as a mixture of three diastereoisomers
N-(p-Chlorobenzylidene)methylamine N-Oxide (13b)
The title compound was obtained as a white crystalline solid (yield:
8
2%); mp 127.2–129 °C.
(
4.8:0.9:0.4) in a yield of 97%. Separation of the major isomer was
–
1
IR: 3019.6, 2957.4, 1604.0, 1443.1, 1420.8, 1406.9, 1215.4 cm .
undertaken using chromatography on silica (hexane–EtOAc, 2:1) to
2
0
1
afford a white foam; [a]D +199.09 (c = 0.66 in CHCl3).
H NMR (300 MHz, CDCl ): d = 3.78 (s, 3 H, NCH ), 7.27 (s, 1 H,
3
3
CH), 7.28 (d, J = 8.5 Hz, 2 H, ArH), 8.08 (d, J = 8.5 Hz, 2 H, ArH).
IR: 1785.7, 1703.2, 1216.8 cm–1.
1
3
C NMR (75.5 MHz, CDCl ): d = 54.4, 128.7, 128.9, 129.6, 134.2,
1
3
H NMR (300 MHz, CDCl ): d = 1.68 (s, 3 H, CH ), 2.54 (dd, J =
3
3
1
35.8.
1
3.5, 9.5 Hz, 1 H, CH ), 2.56 (s, 3 H, NCH ), 2.71–2.85 (m, 2 H,
2
3
CH ), 3.24 (dd, J = 13.5, 2.5 Hz, 1 H, ArCH ), 3.45 (t, J = 8.5 Hz, 1
MS (EI): m/z (rel. int., %) = 168 (100).
UV–Vis (MeOH): lmax = 296 nm.
2
2
H, CH), 4.14 (dd, J = 9.0, 3.5 Hz, 1 H, OCH ), 4.16–4.22 (m, 1 H
2
OCH ), 4.71–4.77 (m, 1 H, CH), 7.15–7.26 (m, 9 H, ArH).
2
1
3
C NMR (75.5 MHz, CDCl ): d = 22.4, 37.8, 42.8, 50.5, 55.9, 66.6,
N-(p-Nitrobenzylidene)methylamine N-Oxide (13c)
3
7
2.6, 83.2, 121.8, 127.4, 128.9, 129.4, 129.5, 133.7, 135.2, 136.6,
The title compound was obtained as a white crystalline solid (yield:
2
5
152.1, 174.7.
9
8%); mp 215–217 °C (lit. 217–218.2 °C).
MS: m/z [M + H]+35Cl calcd for C H N O Cl: 415.1425; found:
415.1429.
IR: 3019.6, 2957.4, 1598.3, 1577.8, 1510.7, 1468.5, 1419.5, 1341.0,
22 24
2
4
–
1
1
110.4 cm .
1
UV–Vis (CHCl ): l = 204 nm.
H NMR (300 MHz, CDCl ): d = 3.94 (s, 3 H, NCH ), 7.51 (s, 1 H,
3
max
3
3
CH), 8.257–8.262 (d, J = 9.0 Hz, 2 H, ArH), 8.357–8.379 (d, J = 9.0
Hz, 2 H, ArH).
(
S)-(–)-4-Benzyl-N-[3-(p-nitrophenyl)-5-carbonyl-N,5-dimeth-
ylisoxazolidine]-2-oxazolidinone (14c)
1
3
C NMR (75.5 MHz, CDCl ): d = 55.13, 123.79, 128.62, 130.42,
3
Using the procedure described for the synthesis of 11 the title com-
pound was obtained as a 3:1 mixture of diastereoisomers (5.6:1:0.5)
in a yield of 98%. Separation of the major isomer was undertaken
using chromatography on silica (hexane–EtOAc, 2:1) to afford a
1
33.07, 147.80.
+
MS (EI): m/z (rel. int., %) = 180 [M] , (70), 179 (100), 163 (98),
1
33, 117, 105, 77, 63.
yellow powder. Recrystallisation from Et O–light petroleum (bp
2
UV–Vis (MeOH): lmax = 296 nm.
4
0–60 °C) provided spindle shaped crystals; mp 148.4–149.8 °C;
2
0
[
a]D +280.90 (c = 0.71 in CHCl3).
N-(p-Methoxybenzylidene)methylamine N-Oxide (13d)
The title compound was obtained as a white crystalline solid (79%);
mp 82.4 °C.
–
1
IR: 1784.6, 1703.4, 1523.0, 1349.1, 1216.2 cm .
Synthesis 2005, No. 14, 2393–2399 © Thieme Stuttgart · New York

2
398
E. Tyrrell et al.
PAPER
1
H NMR (300 MHz, CDCl ): d = 1.69 (s, 3 H, CH ), 2.57 (dd, J = Acknowledgment
3
3
1
3.5, 9.5 Hz, 1 H, CH ), 2.58 (s, 3 H, NCH ), 2.77 (dd, J = 13.5, 9.5
2 3
The authors wish to thank the EPSRC National Mass Spectrometry
Service Centre, University of Swansea for High Resolution Mass
Spectra and Dr John Fawcett at the University of Leicester for ge-
nerously conducting the single crystal X-ray analysis. Special
thanks to the Department of Chemistry at the University of Poitiers
and Mr Jean-Rene DeFaye for providing me with an excellent
Maitrise student (RB).
Hz, 1 H, ArCH ), 2.86 (dd, J = 13.5, 8.0 Hz, 1 H, CH ), 3.23 (dd,
2
2
J = 13.5, 3.0 Hz, 1 H, ArCH ), 3.60 (t, J = 8.5 Hz, 1 H, CH), 4.15
2
(
dd, J = 9.0, 3.5 Hz, 1 H, OCH ), 4.18–4.24 (m, 1 H, OCH ), 4.71–
2
2
4
.79 (m, 1 H, CH), 7.16–7.29 (m, 5 H, ArH), 7.41 (dd, J = 9.0, 2.0
Hz, 2 H, ArH), 8.07 (dd, J = 9.0, 2.0 Hz, 2 H, ArH).
1
3
C NMR (75.5 MHz, CDCl ): d = 22.5, 37.6, 42.9, 50.6, 56.4, 66.4,
3
7
1
2.4, 83.4, 123.9, 127.5, 128.4, 129.0, 129.5, 135.1, 145.9, 147.6,
52.2, 173.7.
References
UV–Vis (CHCl ): l = 240 nm.
3
max
+
MS: m/z [M + Na] calcd for C H N O Na: 448.1495; found:
(1) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513.
2
2
23
3
4
4
48.1494.
(
(
2) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
3) (a) Allin, S. M.; Shuttleworth, S. J. Tetrahedron Lett. 1996,
Anal. Calcd for C H N O : C, 62.11; H, 5.45; N, 9.88. Found: C,
2
2
23
3
6
6
1.99; H, 5.15; N, 9.83.
3
7, 8023. (b) Green, R.; Taylor, P. J. M.; Bull, S. D.; James,
T. D.; Mahon, M. F.; Merritt, A. T. Tetrahedron: Asymmetry
003, 14, 2619. (c) For a review of chiral auxiliaries in
N,5-(S)-Dimethyl-3-(R)-(p-nitrophenyl)isoxazolidine-5-carbox-
ylic Acid (15)
To a 0 °C solution of (S)-(–)-4-benzyl-N-[3-(p-nitrophenyl)-5-car-
bonyl-N,5-dimethylisoxazolidine]-2-oxazolidinone (14c) (0.20 g,
2
polymer-supported organic synthesis: Chung, C. W. Y.;
Toy, P. H. Tetrahedron: Asymmetry 2004, 15, 387.
4) Gefflaut, T.; Bauer, U.; Airola, K.; Koskinen Ari, M. P.
Tetrahedron: Asymmetry 1996, 7, 3099.
(
(
(
0
.47 mmol) dissolved in a THF–water mixture (3:1, 9 mL) were
added H O (30%) (0.32 mL, 2.82 mmol) and LiOH·H O (0.04 g,
2
2
2
5) Tamura, O.; Mita, N.; Kusaka, N.; Suzuki, H.; Sakamoto, M.
Tetrahedron Lett. 1997, 38, 429.
0
.95 mmol). The mixture was stirred for 2 h and then allowed to
warm to an ambient temperature over a period of 2 h. Aqueous so-
dium sulfite (0.98 g in 10.00 mL of water) was added and the organ-
ic solvent was removed in vacuo. The residue was extracted with
6) (a) Faita, G.; Paio, A.; Quadrelli, P.; Rancati, F.; Seneci, P.
Tetrahedron Lett. 2000, 41, 1265. (b) Desmoni, G.; Faita,
G.; Galbiati, A.; Pasini, D.; Paio, A.; Rancati, F.
CHCl (3 × 10 mL) and the combined organic layers dried over an-
3
Tetrahedron: Asymmetry 2002, 13, 333. (c) Faita, G.; Paio,
A.; Quadrelli, P.; Rancati, F.; Seneci, P. Tetrahedron 2001,
hyd MgSO , filtered and the solvent removed in vacuo to afford the
4
chiral auxiliary (0.08 g, 99%).
5
7, 8313.
7) Tyrrell, E. PhD Thesis; University of Southampton: UK,
989.
Acidification of the aqueous phase, using 2.0 M HCl to a pH 2–3,
followed by extraction with EtOAc (3 × 10 mL), drying over anhyd
(
1
MgSO followed by filtration and solvent removal gave the title
4
(8) (a) For an example of 5,5-disubstituted isoxazolidines see:
Bouillon, J.-P.; Janousek, Z.; Viehe, H. G.; Tinnant, B.;
Declerq, J.-P. J. Chem. Soc., Perkin Trans. 1 1996, 1853.
(b) Strauss, A.; Otto, H.-H. Helv. Chim. Acta 1997, 80, 1823.
compound (0.12 g, 97%). This was purified by chromatography on
20
s
i
l
i
c
a
;
[
a
]
+
8
8
.
9
0
(
c
=
0
.
9
5
i
n
C
H
C
l
)
.
D
3
–
1
IR: 3313.2, 1720.5, 1524.3, 1348.2, 1216.7 cm .
(
9) (a) Basak, A.; Bdour, H. M. M.; Bhattacharya, G.
Tetrahedron Lett. 1997, 38, 2535. (b) Anklam, S.;
Liebscher, J. Tetrahedron 1998, 54, 6369.
1
H NMR (300 MHz, CDCl ): d = 1.56 (s, 3 H, CH ), 2.62 (s, 3 H,
3
3
NCH ), 2.63–2.68 (m, 2 H, CH ), 3.72 (t, J = 8.5 Hz, 1 H, CH), 7.45
3
2
(
d, J = 8.5 Hz, 2 H, ArH), 7.6 (br s, 1 H, OH disappears on D O
2
(
(
10) Dopp, D.; Henseleit, M. Chem. Ber. 1982, 115, 798.
11) (a) Fornefeld, E. J.; Pike, A. J. J. Org. Chem. 1979, 44, 835.
(b) For a discussion on regiochemistry: Ali, S. A.; Senaratne,
P. A.; Illig, C. R.; Meckler, M.; Tufariello, J. J. Tetrahedron
Lett. 1979, 20, 4167.
shake), 8.16 (dm, J = 8.5 Hz, 2 H, ArH).
1
3
C NMR (75.5 MHz, CDCl ): d = 21.9, 42.4, 49.2, 72.2, 81.7,
3
1
24.3, 128.7, 144.1, 175.9, 189.1.
+
MS (EI): m/z (rel. int., %) = 266 (5) [M] , 191 (33), 176 (100).
UV–Vis (CHCl ): l = 270 nm.
(
12) Katritzky, A. R.; Gregory, J. H.; Xiaohong, Z. J. Chem. Soc.,
3
max
Perkin Trans. 1 1990, 2371.
Anal. Calcd for C H N O : C, 54.13; H, 5.26; N, 10.53. Found: C,
(13) Muller, P.; Eschenmoser, A. Helv. Chim. Acta 1969, 52,
1
2
14
2
5
5
3.98; H, 5.27; N, 10.48.
1823.
(
14) (a) Exner, O. Collect. Czech. Chem. Commun. 1951, 16,
258. (b) An alternative procedure: Robl, J. A.; Hwu, J. R. J.
Org. Chem. 1985, 50, 5913.
Amino Ketone 17
Found in the second fraction; [a]D +2.30 (c = 1.3, MeOH).
2
0
(
15) The use of NMR studies to establish stereochemistry of
comparable molecules is not without precedent see:
(a) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Halls, T. D. G.;
Wenkert, E. J. Org. Chem. 1982, 47, 5056. (b) Snider, B.
A.; Kirk, T. C. J. Am. Chem. Soc. 1983, 105, 2364.
(c) Smith, A. B. III; Toder, B. H.; Branca, S. J.; Dieter, K. R.
J. Am. Chem. Soc. 1981, 103, 1996. (d) Schnizer, D.; Ringe,
K. Synlett 1994, 463. (e) Whitesell, J. K.; Matthews, S. S. J.
Org. Chem. 1977, 42, 3878.
–
1
IR: 3643.6, 3583.9, 1706.8, 1527.8, 1348.2, 1215.8 cm .
1
H NMR (300 MHz, CDCl ): d = 2.20 (s, 3 H, CH ), 2.61 (s, 3 H,
3
3
NCH ), 2.63 (m, 2 H, CH ), 2.82 (br, 1 H, NH disappears on D O
3
2
2
shake), 3.80 (m, 1 H, CH), 7.44 (d, J = 8.5 Hz, 2 H, ArH), 8.16 (dm,
J = 8.5 Hz, 2 H, ArH).
1
3
C NMR (75.5 MHz, CDCl ): d = 21.7, 29.7, 42.4, 72.1, 101.3,
3
1
23.7, 131.3, 174.6, 172.1.
+
MS (EI): m/z (rel. int., %) = 221 (23) [M – H], 205 (100), 176
(
16) (a) Kakisawa, H.; Kashman, Y.; Kusumi, T.; Ohtani, I. J.
Am. Chem. Soc. 1991, 113, 4092. (b) Heumann, A. J. Chem.
Soc., Chem. Commun. 1993, 113. (c) Riguera, R.; Quinoa,
E.; Seco, J. M.; Latypov, S. K. J. Org. Chem. 1995, 60, 1538.
(100).
UV–Vis (CHCl ): l = 264 nm.
3
max
Anal. Calcd for C H N O : C, 59.46; H, 6.31; N, 12.61. Found: C,
1
1
14
2
3
5
8.96; H, 6.28; N, 12.61.
Synthesis 2005, No. 14, 2393–2399 © Thieme Stuttgart · New York

PAPER
Reactions of Nitrones with Benzyl-N-methacryloyl-2-oxazolidinone
2399
(
17) (a) Dale, J. A.; Dull, D.; Mosher, H. S. J. Org. Chem. 1969,
(21) The enantiomeric excess (92%) was determined by chiral
GC using a Supercot a-dex 225 column.
34, 2543. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1
973, 95, 512.
(22) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238.
(23) Hamer, J.; Macaluso, A. Chem. Rev. 1964, 64, 473.
(24) Abou-Gharbia, M.; Joulke, M. M. Synthesis 1977, 318.
(25) Bjorgo, J.; Boyd, D. R.; Neill, D. C.; Jennings, W. B. J.
Chem. Soc., Perkin Trans. 1 1976, 254.
(
(
(
18) All compounds provided satisfactory spectral data that were
consistent with the assigned structures.
19) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett.
1987, 28, 6141.
1
20) Only one isomer was detectable by H NMR studies on the
crude isolate.
Synthesis 2005, No. 14, 2393–2399 © Thieme Stuttgart · New York