Efficient approach to the unknown isoxazolo[3,4-d]thieno[2,3-b]pyridine system by regioselective intramolecular nitrone cycloadditions

Article abstract of DOI:10.1016/j.tet.2005.01.121

An effective approach to the new isoxazolo[3,4-d]thieno[2,3-b]pyridine system was provided by way of an intramolecular nitrone cycloaddition. The required nitrones were built in good yields starting from thiophene-2-carboxylic acids. The same skeleton was achieved in optically active form employing chiral nitrones derived from N-α-methylbenzyl- and the N-α- hydroxymethylbenzyl-hydroxylamines. The absolute configuration of the products was assigned by X-ray analysis.

Full text of DOI:10.1016/j.tet.2005.01.121

Tetrahedron 61 (2005) 3525–3531
Efficient approach to the unknown
isoxazolo[3,4-d]thieno[2,3-b]pyridine system by regioselective
intramolecular nitrone cycloadditions
Gianluigi Broggini,a Katja Chiesa,a Ivan De Marchi,a Michela Martinelli,a Tullio Pilatib and
Gaetano Zecchia,
*
a
`
Dipartimento di Scienze Chimiche e Ambientali, Universita dell’Insubria, via Valleggio 11, 22100 Como, Italy
bConsiglio Nazionale delle Ricerche - Istituto di Scienze e Tecnologie Molecolari, via Golgi 19, 20133 Milano, Italy
Received 5 November 2004; revised 14 January 2005; accepted 28 January 2005
Abstract—An effective approach to the new isoxazolo[3,4-d]thieno[2,3-b]pyridine system was provided by way of an intramolecular
nitrone cycloaddition. The required nitrones were built in good yields starting from thiophene-2-carboxylic acids. The same skeleton was
achieved in optically active form employing chiral nitrones derived from N-a-methylbenzyl- and the N-a-hydroxymethylbenzyl-
hydroxylamines. The absolute configuration of the products was assigned by X-ray analysis.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In this paper, we report the results on the intramolecular 1,3-
dipolar cycloadditions of thienyl-tethered nitrones derived
from the aldehydes 5, which seemed potentially able to
furnish interesting thieno-piperidine derivatives. The latter
may well be of interest in view of the pharmacological
properties of some thieno-fused azaheterocycles.7
1,3-Dipolar cycloadditions furnish an extensively studied
and widely used method for the synthesis of five-membered
heterocycles.1 Among them, those involving nitrones
constitute an efficient and versatile entry to isoxazolidines,
which in turn represent valuable intermediates in organic
synthesis.2 In particular, the intramolecular nitrone cycload-
dition leads directly to isoxazolidines annulated with
another ring in a fused or bridged mode. Furthermore,
they often benefit from highly regio- and stereoselective
outcomes.3
2. Results and discussion
Aldehydes 5 were synthesized starting from carboxylic
acids of formula 1 by the synthetic sequence depicted in
Scheme 1. The first step was the conversion to the acyl
azides 28 via the corresponding acyl chlorides. Azides 2
were submitted to Curtius degradation in EtOH, in the
absence of water, with the aim to produce directly the
carbamates 3, which were then N-allylated by a standard
procedure. Finally, a Vilsmeier formylation permitted an
entry to the desired aldehydes 5. It must be noted that this
formylation took place exclusively at the C-3 ring carbon in
both cases, reasonably because of the o,p-directing effect of
the aminosubstituent which predominates over that of the
methyl group of 4a.
Dealing with our interest to the synthesis of nitrogenated
heteropolycylic compounds in enantiopure form, we studied
the intramolecular cycloadditions of nitrones already
containing a heterocyclic unit, namely pyrrole,4 indole5
and imidazole,6 bearing an allylic pendant at the nitrogen
atom. At this point, we decided to extend such a synthetic
approach by using nitrones having a non-nitrogenated
heterocycle skeleton, but endowed with an allylic pendant
linked to a ring carbon through a protected amine
functionality.
The generation of the suitable nitrones was performed
employing the commercially available N-benzylhydroxyl-
amine. However, addition of the aldehydes 5 to a suspension
containing the N-benzylhydroxylamine hydrochloride,
NaHCO3 and MgSO4 in diethyl ether at room temperature
Keywords: Nitrones; Intramolecular cycloadditions; Regioselectivity;
Fused-ring thiophenes.
* Corresponding author. Tel.: C39 31 2386441; fax: C39 31 2386449;
e-mail: gaetano.zecchi@uninsubria.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.121

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G. Broggini et al. / Tetrahedron 61 (2005) 3525–3531
Scheme 1. Preparation of 2-(N-allyl-N-carbethoxy-amino)-thiophene-3-
carbaldehydes.
showed somehow different results (Scheme 2). The nitrone
6a was isolated and characterized and successively cyclized
on heating in refluxing toluene. Conversely, the nitrone 6b
directly underwent cyclization at room temperature. This
fact does not find a clear explanation, but confirms the subtle
interplay of steric and electronic factors in dictating
intramolecular nitrone cycloadditions.9 In every case, a
single cycloadduct was obtained in excellent yield.
Comprehensive 2D NMR studies have indicated a spatial
relationship between the methynic hydrogens, thus estab-
lishing a fused-type tricyclic structure with a cis ring
junction. This means that the cycloaddition proceeded with
total regioselectivity and diastereoselectivity.
Scheme 3. Reaction of aldehydes 5a,b with enantiopure hydroxylamines 8
and 9.
The absolute stereochemistry of the cycloadducts 14/18, 16/
20 and 17/21 was unequivocally inferred by X-ray
diffractometric analysis carried out on the minor products
of each pair (Figs. 1–3).12 In all instances, the relative
configuration of the new stereocentres was cis, in particular
R,R in the case of the (R)-a-methylbenzyl pendant and S,S in
the case of the (R)-a-(hydroxymethyl)benzyl one. Unfortu-
nately, neither 15 nor 19 gave crystals suitable for the
diffractometric analysis; hence, by analogy with the above
evidence, we tentatively assigned the R,R absolute con-
figuration to 19 as being the minor product with the (R)-a-
methylbenzyl pendant.
In the light of the satisfactory trend of the cycloaddition in
terms of both selectivity and yields, we directed our
attention to the preparation of the related structures in
optically active form. The devised way to achieve this goal
was to generate nitrones by enantiopure chiral benzyl-type
hydroxylamines. In particular, we envisaged the (R)-a-
methylbenzylhydroxylamine (8) and the (R)-a-(hydroxy-
methyl)benzylhydroxylamine (9), whose preparations have
been described in the literature.10,11
From the point of view of the stereochemistry, it must be
noted that a modest asymmetric induction was operative in
the case of the N-a-methylbenzyl-substituted nitrones 10
and 11, in line with previous results obtained in intramo-
lecular reactions of nitrones bearing the same chiral
The aldehydes 5 showed the same behaviour toward 8 and 9
already noticed with the benzylhydroxylamine, that is only
the nitrones derived from 5a were isolated and fully
characterized. However, all the nitrones 10–13 underwent
a totally regioselective cycloaddition in agreement to the
behaviour of the achiral compounds 6, but each giving two
diastereoisomeric products. Analytical and spectral data of
the cycloadduct pairs were in accordance for diastereoiso-
meric cis ring-fused structures (Scheme 3).
Figure 1. ORTEP plot of 18 at 90 K. Atomic displacement parameters at
50% probability level. H atoms not to scale.
Scheme 2. Reaction of aldehydes 5a,b with N-benzylhydroxylamine.

G. Broggini et al. / Tetrahedron 61 (2005) 3525–3531
3527
Figure 4. Proposed transition state for the compound 20.
In conclusion, we have developed a strategy for the
synthesis of the new isoxazolo[3,4-d]thieno[2,3-b]pyridine
skeleton starting from thiophene-2-carboxylic acids. The
three fused-ring system was assembled directly from a
nitrone intramolecular cycloaddition.
Figure 2. ORTEP plot of 16 at 90 K. Atomic displacement parameters at
50% probability level. H atoms not to scale.
3. Experimental
3.1. General
auxiliary.13 However, the diastereoselectivity increased
when the nitrones having the a-(hydroxymethyl)benzyl-
pendant were used; in the crude product mixture arising
from 12 and 13 the diastereoisomeric ratio was determined
to be 75:25 by 1H NMR spectroscopy. The better
effectiveness of hydroxylated chiral residue may be
reasonably ascribed to the formation of a hydrogen bond
with the nitrone oxygen, so making the substrate less
flexible and consequently increasing the diastereofacial
discrimination of the dipole. Therefore, the allylic moiety
approaches the dipole from the face opposite to the phenyl
group and the latter is forced to move outside during the
rehybridization of the reaction centers, as depicted in Figure
4 representing the suggested transition state for the
formation of the major diastereoisomer 20 from 12.
Melting points were determined on a Bu¨chi B-540 heating
apparatus and are uncorrected. Optical rotations were
measured on a Jasco P-1010 polarimeter. 1H NMR and
13C NMR spectra were obtained on an AVANCE Bruker
400. Chemical shifts are given in ppm downfield from
SiMe4. 13C NMR spectra are 1H-decoupled and the
determination of the multiplicities was achieved by the
APT pulse sequence. IR spectra were recorded on a Jasco
FT/IR 5300 spectrophotometer. Mass spectra were deter-
mined on a WG-70EQ instrument.
3.2. Preparation of acyl azides 2a and 2b
With the aim to improve the degree of diastereoselectivity
and taking into account the known chelating ability14 of the
(R)-a-(hydroxymethylbenzyl)hydroxylamine, we carried
out the cycloaddition of the nitrone 12 in the presence of
metal cations. The reaction was tested with a wide range of
Lewis acid [Zn(OTf)2, Sc(OTf)2, MgBr2, TiCl4, Co(OAc)2,
AgOAc] and TEA, in different solvents (i.e. CH2Cl2 and
toluene) and temperatures. Unfortunately, all the experi-
ments gave no improvement of diastereoselectivity or even
no reaction, probably because of an excessively strong
nitrone oxygen chelation.
The compounds were prepared as described in the
literature.8a,b
3.3. General procedure for the preparation of
2-(N-carbethoxy-amino)-thiophenes (3a,b)
A solution of 2 (11.7 mmol) in EtOH (20 ml) and toluene
(30 ml) was heated to reflux for 24 h. The solvent was
evaporated under reduced pressure to give directly 3a,b.
3.3.1. 2-(N-Carbethoxy-amino)-5-methyl-thiophene (3a).
Yield: 76%. Mp 72–73 8C (cream crystals from diisopropyl
1
ether). IR (nujol): 3246, 1684 cmK1; H NMR (400 MHz,
CDCl3) d: 1.30 (3H, t, JZ7.1 Hz), 2.40 (3H, s), 4.24 (2H, q,
JZ7.1 Hz), 6.41 (1H, d, JZ3.6 Hz), 6.46 (1H, d, JZ
3.6 Hz), 7.03 (1H, br s, missing after deuteriation). 13C
NMR (100 MHz, CDCl3) d: 14.8 (q), 15.3 (q), 62.0 (t),
113.3 (d), 122.7 (d), 131.9 (s), 137.9 (s), 154.7 (s). Anal.
calcd for C8H11NO2S: C, 51.87; H, 5.99; N, 7.56. Found C,
52.01; H, 5.78; N, 7.62.
3.3.2. 2-(N-Carbethoxy-amino)-benzothiophene (3b).
Yield: 87%. Mp 154–155 8C (white crystals from diisoprop-
yl ether). IR (nujol): 3300, 1691 cmK1. 1H NMR (400 MHz,
CDCl3) d: 1.36 (3H, t, JZ7.1 Hz), 4.32 (2H, q, JZ7.1 Hz),
6.83 (1H, s), 7.24 (1H, dd, JZ7.3, 7.8 Hz), 7.32 (1H, dd,
JZ7.3, 7.9 Hz), 7.55 (1H, s), 7.60 (1H, d, JZ7.9 Hz), 7.73
(1H, d, JZ7.8 Hz); 13C NMR (100 MHz, CDCl3) d: 14.9
Figure 3. ORTEP plot of 17 at 90 K. Atomic displacement parameters at
50% probability level. H atoms not to scale.

3528
G. Broggini et al. / Tetrahedron 61 (2005) 3525–3531
(q), 62.7 (t), 107.0 (d), 122.2 (d), 122.4 (d), 123.4 (d), 125.0
(d), 135.3 (s), 138.3 (s), 140.4 (s), 153.6 (s). Anal. calcd for
C11H11NO2S: C, 59.71; H, 5.01; N, 6.33. Found C, 59.79; H,
4.88; N, 6.12.
IR (nujol): 1714, 1682 cmK1 1H NMR (400 MHz, CDCl3)
d: 1.22 (3H, t, JZ6.9 Hz), 2.44 (3H, s), 4.20 (2H, q, JZ
6.9 Hz), 4.28 (2H, d, JZ6.4 Hz), 5.20 (1H, dd, JZ17.0 Hz),
5.23 (1H, dd, JZ10.3 Hz), 5.91 (1H, tdd, JZ6.4, 10.3,
17.0 Hz), 6.96 (1H, s), 9.71 (1H, s). 13C NMR (100 MHz,
CDCl3) d: 14.6 (q), 15.7 (q), 55.1 (t), 62.9 (t), 119.6 (t),
121.8 (d), 132.5 (d), 136.3 (s), 137.7 (s), 151.8 (s), 155.0 (s),
183.8 (d). Anal. calcd for C12H15NO3S: C, 56.90; H, 5.97;
N, 5.53. Found C, 56.98; H, 6.11; N, 5.42.
3.4. General procedure for the preparation of 2-(N-allyl-
N-carbethoxy-amino)-thiophenes (4a,b)
A solution of 3 (2.4 mmol) in THF (5 ml) was added
dropwise to a suspension of 60% NaH (150 mg, 3.6 mmol)
in dry THF (33 ml), under nitrogen atmosphere. Allyl
bromide (0.42 ml, 4.8 mmol) was added at K5 8C, then the
mixture was heated to reflux for 24 h. After cooling to room
temperature, H2O (30 ml) was added. The mixture was
extracted with CH2Cl2 (2!60 ml) and the organic layer was
dried over Na2SO4. The solvent was evaporated under
reduced pressure to give 4.
3.5.2. 2-(N-Allyl-N-carbethoxy-amino)-benzothiophene-
3-carbaldehyde (5b). Yield: 78%. Pale yellow oil. IR
1
(nujol): 1719, 1676 cmK1. H NMR (400 MHz, CDCl3) d:
1.20 (3H, t, JZ7.0 Hz), 4.21 (2H, q, JZ7.0 Hz), 4.38 (2H,
d, JZ6.4 Hz), 5.10–5.28 (2H, overlapping), 5.94 (1H, tdd,
JZ6.4, 10.5, 17.1 Hz), 7.38 (1H, dd, JZ7.3, 8.1 Hz), 7.46
(1H, dd, JZ7.3, 7.8 Hz), 7.74 (1H, d, JZ7.8 Hz), 8.61 (1H,
d, JZ8.1 Hz), 10.05 (1H, s). 13C NMR (100 MHz, CDCl3)
d: 14.8 (q), 55.4 (t), 63.6 (t), 120.6 (t), 122.4 (d), 125.3 (d),
126.5 (d), 126.6 (d), 129.4 (s), 132.1 (d), 134.8 (s), 136.3 (s),
155.0 (s), 158.5 (s), 184.9 (d). Anal. calcd for C15H15NO3S:
C, 62.26; H, 5.23; N, 4.84. Found C, 62.45; H, 5.07; N, 5.02.
3.4.1. 2-(N-Allyl-N-carbethoxy-amino)-5-methyl-thio-
phene (4a). Yield: 74%. Colourless oil. IR (nujol):
1
1711 cmK1. H NMR (400 MHz, CDCl3) d: 1.28 (3H, t,
JZ6.9 Hz), 2.41 (3H, s), 4.20–4.28 (4H, overlapping), 5.18
(1H, dd, JZ1.5, 17.0 Hz), 5.21 (1H, dd, JZ1.5, 10.3 Hz),
5.90 (1H, tdd, JZ5.6, 10.3, 17.0 Hz), 6.49 (2H, s). 13C
NMR (100 MHz, CDCl3) d: 14.8 (q), 15.6 (q), 54.7 (t), 62.3
(t), 117.5 (t), 122.8 (d), 126.7 (d), 133.9 (d), 142.0 (s), 146.3
(s), 154.0 (s). Anal. calcd for C11H15NO2S: C, 58.64; H,
6.71; N, 6.22. Found C, 58.61; H, 6.87; N, 6.09.
3.6. General procedure for the reactions between 5a,b
and benzylhydroxylamine
A suspension of benzylhydroxylamine hydrochloride
(90 mg, 0.56 mmol), NaHCO3 (138 mg, 1.65 mmol) and
MgSO4 (1.13 g, 4.46 mmol) in Et2O (30 ml) was stirred for
15 min. A solution of 5 (0.44 mmol) in Et2O (2 ml) was
added and the mixture was stirred at r.t. for 24 h. After
filtration, the evaporation of the solvent under reduced
pressure followed by recrystallization gave 6a or 7b.
3.4.2. 2-(N-Allyl-N-carbethoxy-amino)-benzothiophene
(4b). Yield: 69%. Colourless oil. IR (nujol): 1696 cmK1
.
1H NMR (400 MHz, CDCl3) d: 1.36 (3H, t, JZ7.1 Hz), 4.33
(2H, q, JZ7.1 Hz), 4.48 (2H, d, JZ4.8 Hz), 5.26 (1H, d,
JZ10.2 Hz), 5.29 (1H, d, JZ16.4 Hz), 5.97 (1H, tdd, JZ
4.8, 10.2, 16.4 Hz), 6.85 (1H, s), 7.26 (1H, dd, JZ7.3,
7.9 Hz), 7.33 (1H, dd, JZ7.3, 7.8 Hz), 7.65 (1H, d, JZ
7.8 Hz), 7.74 (1H, d, JZ7.9 Hz). 1H NMR (400 MHz,
CD3OD) d: 1.32 (3H, t, JZ7.1 Hz), 4.27 (2H, q, JZ7.1 Hz),
4.49 (2H, br s), 5.22 (1H, dd, JZ1.1, 10.3 Hz), 5.25 (1H, dd,
JZ1.1, 17.1 Hz), 5.96 (1H, tdd, JZ5.3, 10.3, 17.1 Hz), 6.94
(1H, s), 7.24 (1H, dd, JZ7.1, 7.6 Hz), 7.30 (1H, dd, JZ7.1,
7.8 Hz), 7.64 (1H, d, JZ7.6 Hz), 7.71 (1H, d, JZ7.8 Hz).
13C NMR (100 MHz, CDCl3) d: 14.9 (q), 60.8 (t), 63.3 (t),
117.8 (t), 122.1 (d), 122.9 (d), 123.8 (d), 124.5 (d), 124.8
(d), 132.8 (d), 137.2 (s), 138.1 (s), 144.8 (s), 154.6 (s). Anal.
calcd for C14H15NO2S: C, 64.34; H, 5.79; N, 5.36. Found C,
64.18; H, 5.75; N, 5.22.
3.6.1. N-Benzyl-C-[2-(N-carbethoxy-allylamino)-5-
methyl-thien-3-yl]nitrone (6a). Yield: 89%. Mp 116–
117 8C (cream crystals from diisopropyl ether). IR (nujol):
1711, cmK1 1H NMR (400 MHz, CDCl3) d: 1.15 (3H, t, JZ
6.7 Hz), 2.43 (3H, s), 4.09–4.14 (4H, overlapping), 4.98
(2H, s), 5.10 (1H, d, JZ16.5 Hz), 5.14 (1H, d, JZ10.3 Hz),
5.72 (1H, tdd, JZ6.3, 10.3, 16.5 Hz), 7.13 (1H, s), 7.37–
7.45 (5H, overlapping), 8.00 (1H, s), 13C NMR (100 MHz,
CDCl3) d: 14.6 (q), 16.1 (q), 55.1 (t), 62.9 (t), 70.7 (t), 119.6
(t), 124.2 (d), 127.8 (d), 128.3 (d), 128.7 (d), 129.2 (d),
129.5 (d), 129.6 (d), 132.5 (d), 133.7 (s), 137.1 (s), 137.7 (s),
142.9 (s), 155.5 (s). Anal. calcd for C19H22N2O3S: C, 63.66;
H, 6.19; N, 7.81. Found C, 63.57; H, 6.04; N, 7.62.
3.5. General procedure for the preparation of 2-(N-allyl-
N-carbethoxy-amino)-thiophene-3-carbaldehydes (5a,b)
3.6.2. (3aR*,10cR*)-1-Benzyl-5-carbethoxy-1,3,3a,4,
5,10c-hexahydro-benzothieno[2,3-b]isoxazolo[3,4-d]pyr-
idine (7b). Yield: 72%. Mp 139–140 8C (white crystals
1
from diisopropyl ether). IR (nujol): 1712 cmK1; H NMR
To a solution of POCl3 (0.82 ml, 8.8 mmol) and DMF
(0.90 ml, 12.0 mmol) in CCl4 (40 ml), cooled at 0 8C, 4
(5.8 mmol) was added. The mixture was heated at reflux for
24 h, then the solvent was removed under reduced pressure.
The residue was treated with aqueous NaHCO3 and extracted
with CH2Cl2 (50 ml!3). The organic layer was dried over
Na2SO4 and the solvent evaporated under reduced pressure.
The crude product was purified through a silica gel column
with light petroleum/AcOEt (10:1) as eluent to afford 5.
(400 MHz, CDCl3) d: 1.42 (3H, br s), 3.25 (1H, br s), 3.88
(1H, br s), 4.12 (4H, br s), 4.32–4.70 (4H, overlapping),
7.19–7.55 (8H, overlapping), 7.73 (1H, br s). 1H NMR
(400 MHz, CDCl3, 50 8C) d: 1.43 (3H, t, JZ7.1 Hz), 3.25
(1H, br s), 3.87 (1H, dd, JZ4.9, 8.2 Hz), 3.98–4.25 (4H,
overlapping), 4.33–4.52 (4H, overlapping), 7.23 (1H, ddd,
JZ1.3, 7.2, 7.2 Hz), 7.27–7.32 (2H, overlapping), 7.35 (2H,
dd, JZ7.2, 7.5 Hz), 7.42 (2H, d, JZ7.0 Hz), 7.46 (1H, d,
JZ7.2 Hz), 7.71 (1H, d, JZ7.0 Hz). 13C NMR (100 MHz,
CDCl3) d: 14.8 (q), 40.6 (d), 46.2 (t), 60.1 (d), 60.2 (t), 63.5
(t), 68.6 (t), 121.2 (d), 122.0 (d), 123.6 (d), 124.6 (d), 127.8
3.5.1. 2-(N-Allyl-N-carbethoxy-amino)-5-methyl-thio-
phene-3-carbaldehyde (5a). Yield: 62%. Pale yellow oil.

G. Broggini et al. / Tetrahedron 61 (2005) 3525–3531
3529
(d), 128.7 (d), 129.5 (d), 135.9 (s), 137.4 (s), 138.0 (s), 140.9
(s), 153.8 (s), 155.4 (s). Anal. calcd for C22H22N2O3S: C,
66.98; H, 5.62; N, 7.10. Found C, 67.01; H, 5.47; N, 7.22.
(2H, d, JZ7.4 Hz), 7.61 (1H, d, JZ7.9 Hz). 13C NMR
(100 MHz, CDCl3) d: 14.8 (q), 20.5 (q), 41.2 (d), 46.2 (t),
59.3 (d), 63.4 (t), 63.6 (d), 68.0 (t), 121.6 (d), 122.0 (d),
123.5 (d), 124.0 (d), 128.6 (d), 129.0 (d), 129.2 (d), 135.9
(s), 137.1 (s), 140.8 (s), 142.8 (s), 143.3 (s), 154.1 (s). Anal.
calcd for C23H24N2O3S: C, 67.62; H, 5.92; N, 6.86. Found
C, 67.49; H, 5.88; N, 6.98.
3.6.3. Cycloaddition reaction of nitrone 6a. A solution of 6a
(568 mg, 1.6 mmol) in toluene (8 ml) was heated to reflux for
24 h. The solvent was evaporated under reduced pressure to
give (3aR*,8bR*)-1-benzyl-5-carbethoxy-1,3,3a,4,5,10c-
hexahydro-7-methyl-isoxazolo[3,4-d]thieno[2,3-b]pyridine
(7a) as a pure colourless oil. Yield: 94%. Oil. IR (nujol):
3.7.3. (aR,3aR,10cR)-5-Carbethoxy-1-(a-methylbenzyl)-
1,3,3a,4,5,10c-hexahydro-benzothieno[2,3-b]isoxazolo
[3,4-d]pyridine (19). Yield: 14%. Mp 151–152 8C (white
crystals from diisopropyl ether). [a]2D3ZK65.5 (cZ0.09,
1
1697, cmK1; H NMR (400 MHz, CDCl3, 50 8C) d: 1.38
(3H, t, JZ7.1 Hz), 2.38 (3H, s), 3.00 (1H, br s), 3.70 (1H,
dd, JZ4.4, 8.2 Hz), 3.73–3.82 (2H, overlapping), 4.00 (1H,
d, JZ13.4 Hz), 4.11 (1H, dd, JZ4.6, 12.8 Hz), 4.24–4.31
(2H, overlapping), 4.33 (2H, q, JZ7.1 Hz), 6.40 (1H, s),
7.30–7.38 (3H, overlapping), 7.42 (2H, d, JZ7.3 Hz).1H
NMR (400 MHz, DMSO, 100 8C) d: 1.31 (3H, t, JZ
7.1 Hz), 2.32 (3H, s), 3.11–3.16 (1H, m), 3.57 (1H, dd, JZ
4.5, 8.1 Hz), 3.69 (1H, dd, JZ8.1, 12.9 Hz), 3.90–4.02 (2H,
overlapping), 3.97, 4.14 (2H, sistema AB, JZ13.8 Hz), 4.21
(1H, dd, JZ8.0, 8.1 Hz), 4.25 (2H, q, JZ7.1 Hz), 6.46 (1H,
s), 7.30–7.43 (5H, overlapping). 13C NMR (100 MHz,
CDCl3) d: 14.9 (q), 15.2 (q), 40.3 (d), 45.2 (t), 61.0 (t), 62.2
(d), 63.0 (t), 68.8 (t), 118.1 (s), 123.2 (d), 127.8 (d), 128.8
(d), 129.3 (d), 131.7 (s), 136.4 (s), 137.9 (s), 153.4 (s). Anal.
calcd for C19H22N2O3S: C, 63.66; H, 6.19; N, 7.81. Found
C, 63.82; H, 6.01; N, 7.98.
CHCl3). IR (nujol): 1721 cmK1 1H NMR (400 MHz,
.
CDCl3, 50 8C) d: 1.39 (3H, t, JZ7.2 Hz), 1.68 (3H, d, JZ
6.6 Hz), 3.15–3.24 (1H, m), 3.55–3.62 (1H, m), 3.68 (1H,
dd, JZ7.3, 7.5 Hz), 4.05–4.15 (2H, overlapping), 4.27–4.42
(2H, overlapping), 4.43–4.50 (1H, m), 4.88 (1H, d, JZ
7.5 Hz), 7.22–7.31 (2H, overlapping), 7.32 (2H, dd, JZ6.9,
7.6 Hz), 7.37 (1H, dd, JZ7.1, 8.1 Hz), 7.43–7.52 (2H,
overlapping), 7.71 (1H, d, JZ7.9 Hz), 7.84 (1H, d, JZ
8.1 Hz). 13C NMR (100 MHz, CDCl3) d: 14.9 (q), 22.9 (q),
40.9 (d), 44.8 (t), 58.8 (d), 63.4 (t), 63.6 (d), 67.9 (t), 121.8
(d), 122.0 (d), 123.6 (d), 124.5 (d), 127.8 (d), 128.7 (d),
129.2 (d), 137.1 (s), 140.8 (s), 142.6 (s), 143.3 (s), 143.5 (s),
154.0 (s). Anal. calcd for C23H24N2O3S: C, 67.62; H, 5.92;
N, 6.86. Found C, 67.55; H, 6.05; N, 6.93.
3.8. Cycloaddition reaction of nitrone 10
3.7. General procedure for the reactions between 5a,b
and 8
A solution of 10 (350 mg, 0.9 mmol) in toluene (8 ml) was
heated to reflux for 24 h. The solvent was removed under
reduced pressure and the residue was chromatographed on a
silica gel column with hexane/AcOEt (10:1) as eluent to
give 18 and 14.
A solution of 5 (1.58 mmol), 8 (195 mg, 1.42 mmol), and
MgSO4 (1.90 g, 15.8 mmol) in Et2O (15 ml) was stirred at
rt for 72 h. After filtration and evaporation of the solvent
under reduced pressure, the residue was chromatographed
on a silica gel column with hexane/AcOEt (10:1) as eluent
to afford 10 or 15 and 19.
3.8.1.
(aR,3aR,8bR)-5-Carbethoxy-7-methyl-1-(a-
methylbenzyl)-1,3,3a,4,5,8b-hexahydro-isoxazolo[3,4-
d]thieno[2,3-b]pyridine (18). Yield: 38%. Mp 132–133 8C
(white crystals from diisopropyl ether). [a]2D3ZC52.2 (cZ
0.23, CHCl3). IR (nujol): 1691 cmK1. 1H NMR (400 MHz,
CDCl3, 50 8C) d: 1.36 (3H, t, JZ7.1 Hz), 1.57 (3H, d, JZ
6.7 Hz), 2.41 (3H, s), 2.86 (1H, br s), 3.63 (1H, dd, JZ4.7,
8.1 Hz), 3.80–3.86 (1H, m), 3.93 (1H, dd, JZ4.7, 12.9 Hz),
4.03 (1H, dd, JZ7.7, 7.8 Hz), 4.05–4.12 (2H, overlapping),
4.30 (2H, q, JZ7.1 Hz), 6.55 (1H, s), 7.29 (1H, d, JZ
8.2 Hz), 7.37 (2H, dd, JZ8.2, 8.2 Hz), 7.48 (2H, d, JZ
8.2 Hz). 1H NMR (400 MHz, DMSO, 80 8C) d: 1.28 (3H, t,
JZ7.1 Hz), 1.41 (3H, d, JZ6.6 Hz), 2.35 (3H, s), 3.08–3.18
(1H, m), 3.42 (1H, dd, JZ5.2, 8.0 Hz), 3.76–3.84 (2H,
overlapping), 3.97 (1H, dd, JZ8.0, 8.1 Hz), 4.05 (1H, q, JZ
6.6 Hz), 4.17–4.28 (3H, overlapping), 6.56 (1H, s), 7.24
(1H, d, JZ8.2 Hz), 7.32 (2H, dd, JZ8.2, 8.2 Hz), 7.39 (2H,
d, JZ8.2 Hz). 13C NMR (100 MHz, CDCl3) d: 14.9 (q),
15.2 (q), 22.3 (q), 41.3 (d), 44.9 (t), 58.7 (d), 62.9 (t), 63.8
(d), 68.2 (t), 120.7 (s), 123.4 (d), 127.7 (d), 128.7 (d), 131.9
(s), 136.2 (s), 142.3 (s), 153.6 (s). Anal. calcd for
C20H24N2O3S: C, 64.49; H, 6.49; N, 7.52. Found C,
64.54; H, 6.40; N, 7.63.
3.7.1. (R)-N-(a-Methylbenzyl)-C-[5-methyl-2-(N-carb-
ethoxy-allylamino)-thien-3-yl] nitrone (10). Yield: 81%.
Pale yellow oil. [a]2D3ZC39.2 (cZ1.00, EtOH). IR (nujol):
1714 cmK1. 1H NMR (400 MHz, CDCl3) d: 1.12 (3H, br s),
1.84 (3H, d, JZ6.9 Hz), 2.41 (3H, s), 4.05–4.12 (4H,
overlapping), 5.04–5.14 (3H, overlapping), 5.75 (1H, tdd,
JZ6.6, 11.2, 17.2 Hz), 7.20 (1H, s), 7.33–7.40 (3H,
overlapping), 7.47 (2H, d, JZ7.6 Hz), 8.00 (1H, s). 13C
NMR (100 MHz, CDCl3) d: 14.8 (q), 16.1 (q), 19.2 (q), 55.1
(t), 62.8 (t), 74.9 (d), 119.7 (t), 124.4 (d), 126.8 (d), 127.6
(d), 128.8 (s), 129.1 (d), 129.2 (d), 132.6 (d), 137.1 (s),
138.9 (s), 142.5 (s), 155.7 (s). Anal. calcd for C20H24N2O3S:
C, 64.49; H, 6.49; N, 7.52. Found C, 64.65; H, 6.36; N, 7.34.
3.7.2. (aR,3aS,10cS)-5-Carbethoxy-1-(a-methylbenzyl)-
1,3,3a,4,5,10c-hexahydro-benzothieno[2,3-b]isoxazolo
[3,4-d]pyridine (15). Yield: 34%. Mp 194–195 8C (white
crystals from diisopropyl ether). [a]2D3ZC148.5 (cZ0.13,
CHCl3). IR (nujol): 1723 cmK1 1H NMR (400 MHz,
.
CDCl3, 50 8C) d: 1.42 (3H, t, JZ7.1 Hz), 1.56 (3H, d, JZ
6.4 Hz), 3.25–3.61 (2H, overlapping), 3.93 (1H, dd, JZ5.7,
5.8 Hz), 3.99 (1H, q, JZ6.4 Hz), 4.29–4.47 (3H, overlap-
ping), 4.49–4.67 (2H, overlapping), 6.89 (1H, br s), 7.09
(1H, dd, JZ7.3, 7.7 Hz), 7.16 (1H, dd, JZ7.2, 7.8 Hz), 7.42
(1H, dd, JZ7.2, 7.3 Hz), 7.47 (2H, dd, JZ7.1, 7.5 Hz), 7.53
3.8.2.
(aR,3aS,8bS)-5-Carbethoxy-7-methyl-1-(a-
methylbenzyl)-1,3,3a,4,5,8b-hexahydro-isoxazolo[3,4-
d]thieno[2,3-b]pyridine (14). Yield: 51%. Mp 164–165 8C
(white crystals from diisopropyl ether). [a]2D3ZC27.7 (cZ

3530
G. Broggini et al. / Tetrahedron 61 (2005) 3525–3531
1
1.00, CHCl3).IR (nujol): 1700 cmK1. H NMR (400 MHz,
CDCl3, 50 8C) d: 1.36 (3H, t, JZ7.1 Hz), 1.52 (3H, d, JZ
6.4 Hz), 2.31 (3H, s), 3.18–3.24 (1H, m), 3.59 (1H, br d, JZ
14.6 Hz), 3.80 (1H, dd, JZ5.9, 8.1 Hz), 3.92 (1H, q, JZ
6.4 Hz), 4.09 (1H, d, JZ7.4 Hz), 4.20 (1H, br s), 4.26–4.34
(3H, overlapping), 6.13 (1H, s), 7.32 (1H, d, JZ8.2 Hz),
overlapping), 7.48–7.54 (2H, overlapping), 7.73 (1H, d, JZ
7.4 Hz), 7.75 (1H, d, JZ7.4 Hz). 13C NMR (100 MHz,
CDCl3) d: 14.8 (q), 40.8 (d), 44.1 (t), 60.1 (d), 63.5 (t), 64.3
(t), 72.5 (d), 68.0 (t), 121.4 (d), 122.2 (d), 123.7 (d), 124.8
(d), 129.0 (d), 129.2 (d), 129.7 (d), 135.9 (s), 137.4 (s),
137.6 (s), 137.7 (s), 139.6 (s), 153.9 (s). Anal. calcd for
C23H24N2O4S: C, 65.07; H, 5.70; N, 6.60. Found C, 64.90;
H, 5.58; N, 6.78.
1
7.38 (2H, dd, JZ8.2, 8.2 Hz), 7.45 (2H, d, JZ8.2 Hz). H
NMR (400 MHz, DMSO, 80 8C) d: 1.28 (3H, t, JZ7.1 Hz),
1.37 (3H, d, JZ6.4 Hz), 2.26 (3H, s), 3.22–3.36 (1H, m),
3.57 (1H, dd, JZ5.9, 8.1 Hz), 3.61 (1H, dd, JZ3.5,
13.2 Hz), 3.94–4.08 (3H, overlapping), 4.18–4.28 (3H,
overlapping), 6.08 (1H, s), 7.36 (1H, d, JZ8.2 Hz), 7.39
(2H, dd, JZ8.2, 8.2 Hz), 7.43 (2H, d, JZ8.2 Hz). 13C NMR
(100 MHz, CDCl3) d: 14.9 (q), 15.2 (q), 21.9 (q), 40.3 (d),
45.0 (t), 60.1 (d), 63.0 (t), 64.1 (d), 68.1 (t), 122.2 (s), 123.1
(d), 128.2 (d), 129.2 (d), 131.7 (s), 136.1 (s), 143.6 (s), 153.8
(s). Anal. calcd for C20H24N2O3S: C, 64.49; H, 6.49; N,
7.52. Found C, 64.41; H, 6.68; N, 7.34.
3.9.3.
(aR,3aR,10cR)-5-Carbethoxy-1-(a-hydroxy-
methylbenzyl)-1,3,3a,4,5,10c-hexahydro-benzothieno[2,3-
b]isoxazolo[3,4-d]pyridine (21). Yield: 54%. Mp 170–
171 8C (white crystals from diisopropyl ether).
[a]2D3ZK392.0 (cZ0.05, CHCl3). IR (nujol): 3429,
1
1742 cmK1. H NMR (400 MHz, CDCl3) d: 1.49 (3H, br
s), 2.91 (1H, br s, missing after deuteriation), 3.51 (1H, br s),
3.61 (1H, br s), 3.84–3.90 (1H, m), 3.97 (1H, dd, JZ6.9,
7.4 Hz), 4.07 (1H, dd, JZ3.6, 6.8 Hz), 4.27–4.40 (3H,
overlapping), 4.51–4.62 (3H, overlapping), 6.99–7.22 (3H,
overlapping), 7.42–7.58 (5H, overlapping), 7.65 (1H, br s).
1H NMR (400 MHz, CDCl3, 50 8C) d: 1.42 (3H, t, JZ
7.1 Hz), 2.72 (1H, br s, missing after deuteriation), 3.51
(1H, br d, JZ13.0 Hz), 3.53–3.59 (1H, m), 3.89 (1H, br d,
JZ10.2 Hz), 3.96 (1H, dd, JZ6.4, 7.8 Hz), 4.06 (1H, dd,
JZ4.0, 6.4 Hz), 4.26 (1H, dd, JZ6.5, 11.7 Hz), 4.32–4.45
(2H, overlapping), 4.48–4.67 (3H, overlapping), 7.10 (1H,
br s), 7.16 (1H, ddd, JZ1.1, 7.1, 7.1 Hz), 7.20 (1H, ddd, JZ
1.6, 7.1, 7.1 Hz), 7.41–7.59 (5H, overlapping), 7.64 (1H, dd,
JZ1.6, 6.9 Hz). 13C NMR (100 MHz, CDCl3) d: 14.9 (q),
40.6 (d), 45.2 (t), 60.1 (d), 63.6 (t), 67.7 (t), 68.2 (t), 69.5 (d),
121.9 (d), 122.4 (d), 123.7 (d), 124.2 (d), 129.1 (d), 129.5
(d), 129.6 (d), 135.5 (s), 136.7 (s), 138.0 (s), 138.1 (s), 141.0
(s), 154.0 (s). Anal. calcd for C23H24N2O4S: C, 65.07; H,
5.70; N, 6.60. Found C, 65.06; H, 5.81; N, 6.38.
3.9. General procedure for the reactions between 5a,b
and 9
A solution of 5 (1.65 mmol), 9 (315 mg, 2.06 mmol) and
MgSO4 (2.00 g, 16.5 mmol) in Et2O (20 ml) was stirred at
r.t. for 72 h. After filtration and evaporation of the solvent
under reduced pressure, the residue was chromatographed
on a silica gel column with hexane/AcOEt (10:1) as eluent
to afford 12 or 17 and 21.
3.9.1. (R)-N-(a-Hydroxymethylbenzyl)-C-[5-methyl-2-
(N-carbethoxy-allylamino)-thien-3-yl] nitrone (12).
Yield: 74%. Pale yellow oil. [a]2D3ZK64.3 (cZ1.00,
CHCl3). IR (nujol): 3414, 1726 cmK1 1H NMR
(400 MHz, CDCl3) d: 1.10 (3H, br s), 2.46 (3H, s), 3.80
(1H, br s, missing after deuteriation), 3.92 (1H, dd, JZ3.4,
12.2 Hz), 4.01–4.15 (4H, overlapping), 4.53 (1H, dd, JZ
8.9, 12.2 Hz), 5.01–5.08 (2H, overlapping), 5.10 (1H, d, JZ
10.2 Hz), 5.73 (1H, tdd, JZ6.5, 10.2, 16.8 Hz), 7.18 (1H, s),
7.37–7.42 (3H, overlapping), 7.44–7.48 (2H, overlapping),
7.99 (1H, s). 13C NMR (100 MHz, CDCl3) d: 14.7 (q), 16.1
(q), 55.1 (t), 62.9 (t), 63.9 (t), 79.9 (d), 119.8 (t), 124.2 (d),
127.9 (d), 128.2 (s), 129.2 (d), 129.3 (d), 129.4 (d), 130.0
(d), 132.4 (d), 135.5 (s), 137.3 (s), 143.7 (s), 155.6 (s). Anal.
calcd for C20H24N2O4S: C, 61.84; H, 6.23; N, 7.21. Found
C, 61.91; H, 6.39; N, 7.11.
3.10. Cycloaddition reaction of nitrone 12
A solution of 12 (250 mg, 0.6 mmol) in toluene (8 ml) was
refluxed for 24 h. The solvent was removed under reduced
pressure and the residue was chromatographed on a silica
gel column with hexane/AcOEt (5:1) as eluent to give 16
and 20.
3.10.1.
(aR,3aS,8bS)-5-Carbethoxy-1-(a-hydroxy-
methylbenzyl)-1,3,3a,4,5,8b-hexahydro-7-methyl-isoxa-
zolo[3,4-d]thieno[2,3-b]pyridine (16). Yield: 22%. Mp
131–132 8C (white crystals from diisopropyl ether).
[a]2D3ZK72.4 (cZ0.25, CHCl3). IR (nujol): 3447,
3.9.2. (aR,3aS,10cS)-5-Carbethoxy-1-(a-hydroxymethyl-
benzyl)-1,3,3a,4,5,10c-hexahydro-benzothieno[2,3-b]iso-
xazolo[3,4-d]pyridine (17). Yield: 25%. Mp 197–198 8C
(white crystals from diisopropyl ether). [a]2D3ZC76.8 (cZ
1
1697 cmK1. H NMR (400 MHz, CDCl3, 50 8C) d: 1.37
(3H, t, JZ7.1 Hz), 1.56 (1H, br s, missing after deuteria-
tion), 2.43 (3H, s), 2.61 (1H, br s), 3.64 (1H, dd, JZ4.3,
7.8 Hz), 3.67 (1H, dd, JZ9.5, 12.7 Hz), 3.70–3.79 (1H, m),
3.90–3.98 (2H, overlapping), 4.04 (1H, br dd, JZ4.3,
12.9 Hz), 4.09–4.18 (2H, overlapping), 4.31 (2H, q, JZ
7.1 Hz), 6.57 (1H, s), 7.36–7.43 (3H, overlapping), 7.49–
7.54 (2H, overlapping). 1H NMR (400 MHz, DMSO,
100 8C) d: 1.29 (3H, t, JZ7.1 Hz), 2.37 (3H, s), 2.97–3.09
(1H, m), 3.44 (1H, dd, JZ3.6, 7.3 Hz), 3.63–3.73 (1H, m),
3.78–3.88 (3H, overlapping), 3.91 (1H, dd, JZ8.0, 8.0 Hz),
4.00 (1H, dd, JZ5.1, 7.3 Hz), 4.23 (2H, q, JZ7.1 Hz), 4.46
(1H, d, JZ7.2 Hz), 6.63 (1H, s), 7.28–7.34 (3H, overlap-
ping), 7.39–7.44 (2H, overlapping). 13C NMR (100 MHz,
CDCl3) d: 14.9 (q), 15.2 (q), 40.4 (d), 44.7 (t), 57.7 (d), 63.0
0.04, CHCl3). IR (nujol): 3432, 1735 cmK1 1H NMR
.
(400 MHz, CDCl3) d: 1.36 (3H, br s), 2.47 (1H, br s), 2.83
(1H, br s, missing after deuteriation), 3.45 (1H, br s), 3.65
(1H, dd, JZ7.6, 7.6 Hz), 3.77 (1H, dd, JZ3.6, 10.2 Hz),
3.94 (1H, dd, JZ8.0, 8.2 Hz), 4.12–4.44 (5H, overlapping),
4.83 (1H, br s), 7.29 (1H, dd, JZ7.6, 7.7 Hz), 7.38–7.44
(4H, overlapping), 7.48–7.54 (2H, overlapping), 7.74 (2H,
1
d, JZ7.4 Hz). H NMR (400 MHz, CDCl3, 50 8C) d: 1.38
(3H, t, JZ7.1 Hz), 2.58 (2H, br s, missing after deuteria-
tion), 3.53 (1H, dd, JZ3.5, 9.2 Hz), 3.66 (1H, dd, JZ7.6,
7.6 Hz), 3.78 (1H, dd, JZ3.6, 10.2 Hz), 3.94 (1H, dd, JZ
8.0, 8.2 Hz), 4.12–4.44 (5H, overlapping), 4.83 (1H, d, JZ
7.6 Hz), 7.27 (1H, dd, JZ7.6, 7.7 Hz), 7.38–7.44 (4H,

G. Broggini et al. / Tetrahedron 61 (2005) 3525–3531
3531
Zecchi, G. J. Org. Chem. 1998, 63, 9279–9284. (b) Broggini,
G.; La Rosa, C.; Pilati, T.; Terraneo, A.; Zecchi, G.
Tetrahedron 2001, 57, 8323–8332.
(t), 64.4 (t), 69.0 (t), 69.4 (d), 122.9 (d), 128.7 (d), 128.8 (d),
129.2 (s), 130.6 (d), 131.8 (s), 136.3 (s), 136.9 (s), 153.3 (s).
Anal. calcd for C20H24N2O4S: C, 61.84; H, 6.23; N, 7.21.
Found C, 61.84; H, 6.08; N, 7.37.
5. Beccalli, E. M.; Broggini, G.; La Rosa, C.; Passarella, D.;
Pilati, T.; Terraneo, A.; Zecchi, G. J. Org. Chem. 2000, 65,
8924–8932.
3.10.2.
(aR,3aR,8bR)-5-Carbethoxy-1-(a-hydroxy-
methylbenzyl)-1,3,3a,4,5,8b-hexahydro-7-methyl-isoxa-
zolo[3,4-d]thieno[2,3-b]pyridine (20). Yield: 68%. Mp
117–118 8C (white crystals from diisopropyl ether).
[a]2D3ZK31.1 (cZ0.24, CHCl3). IR (nujol): 3455,
6. (a) Basso, D.; Broggini, G.; Passarella, D.; Pilati, T.; Terraneo,
A.; Zecchi, G. Tetrahedron 2002, 58, 4445–4450. (b) Beccalli,
E. M.; Broggini, G.; Contini, A.; De Marchi, I.; Zecchi, G.;
Zoni, C. Tetrahedron: Asymmetry 2004, 15, 3181–3187.
7. (a) Lisowski, V.; Fabis, F.; Pierre, A.; Caignard, D.-H.;
Renard, P.; Rault, S. J. Enzym. Inhib. Med. Chem. 2002, 17,
403–407. (b) Baba, A.; Mori, A.; Yasuma, T.; Unno, S.;
Makino, H.; Sohda, T. Chem. Pharm. Bull. 1999, 47, 993–999.
(c) Albright, J. D.; Reich, M. F.; Sum, F.-W.; Delos, S.; Efren,
G. Eur. Pat. Appl. Patent No. EP 636625, 1995; Chem. Abstr.
1995, 123, 228,225. (d) Rault, S.; Boulouard, M.; Robba, M.;
Guardiola, B.; Devissaguet, M. Eur. Pat. Appl. Patent No. EP
449728, 1991; Chem. Abstr. 1992, 116, 59411.
1
1706 cmK1. H NMR (400 MHz, CDCl3, 50 8C) d: 1.37
(3H, t, JZ7.1 Hz), 2.33 (3H, s), 2.91–2.96 (1H, m), 3.24–
3.32 (1H, m), 3.51–3.57 (1H, m), 3.77 (1H, ddd, JZ3.3, 8.6,
11.9 Hz), 3.87 (1H, dd, JZ6.8, 7.7 Hz), 3.99 (1H, dd, JZ
3.4, 6.8 Hz), 4.12–4.20 (2H, overlapping), 4.25–4.37 (3H,
overlapping), 4.44 (1H, dd, JZ7.9, 9.3 Hz), 6.20 (1H, s),
7.35–7.47 (5H, overlapping). 13C NMR (100 MHz, CDCl3)
d: 14.9 (q), 15.2 (q), 40.1 (d), 44.5 (t), 61.0 (d), 63.2 (t), 68.4
(t), 68.9 (t), 69.9 (d), 121.3 (s), 122.7 (d), 128.6 (d), 128.9
(d), 129.5 (d), 132.2 (s), 135.3 (s), 138.6 (s), 153.8 (s). Anal.
calcd for C20H24N2O4S: C, 61.84; H, 6.23; N, 7.21. Found
C, 61.69; H, 6.32; N, 7.07.
8. (a) Binder, D.; Habison, G.; Noe, C. R. Synthesis 1977,
255–256. (b) Galvez, C.; Garcia, F.; Veiga, M.; Viladoms, P.
Synthesis 1983, 932–933.
9. (a) Werner, K. M.; De los Santos, J. M.; Weinreb, S. M. J. Org.
Chem. 1999, 64, 4865–4873. (b) Hems, W. P.; Tan, C.-H.;
Stork, T.; Feeder, N.; Holmes, A. B. Tetrahedron Lett. 1999,
40, 1393–1396.
Acknowledgements
We are grateful to MURST and CNR for financial support.
10. Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41,
3455–3462.
11. Tamura, O.; Gotanda, K.; Yoshino, J.; Morita, Y.; Terashima,
R.; Kikuchi, M.; Miyawaki, T.; Mita, N.; Yamashita, M.;
Ishibashi, H.; Sakamoto, M. J. Org. Chem. 2000, 65,
8544–8551.
References and notes
1. (a) Padwa, A. In 3-Dipolar Cycloaddition Chemistry, Vols. I
and II; Wiley: New York, 1984. (b) Padwa, A.; Pearson, W. H.
Synthetic Applications of 1,3-Dipolar Cycloaddition Chem-
istry Toward Heterocycles and Natural Products; Wiley: New
York, 2003. (c) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev.
12. CCDC 251812 contain the supplementary crystallographic
data (excluding structure factors) for compound (C)-18.
CCDC 251813 contain the supplementary crystallographic
data (excluding structure factors) for compound (K)-16.
CCDC 251814 contain the supplementary crystallographic
data (excluding structure factors) for compound (C)-17.
These data can be obtained free of charge via www.ccdc.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
C44-1223-336-033; or deposit@ccdc.cam.ac.uk).
¨
1998, 98, 863–909. (d) Karlsson, S.; Hogberg, H. Org. Prep.
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