Regio-and stereoselective synthesis of pyrrolo or azepine-fused cyclopenta[ d ]isoxazolines from 2- p -tolylsulfinylcyclopent-2-en-1-one

Article abstract of DOI:10.1080/17415993.2012.705286

Reactions of enantiopure 2-p-tolylsulfinylcyclopent-2-en-1-one with cyclic nitrones afforded pyrrolo or azepine-fused cyclopenta[d]isoxazolidines in high yields under mild conditions. Comparison of these results with those obtained with cyclopent-2-en-1-one as the dipolarophile shows that the sulfinyl group increases the reactivity of the enonic system and efficiently controls the π-facial and endo/exo selectivities of the cycloadditions, which are also dependent on the easy cycloreversion of the resulting compounds. Results obtained in reactions with other dipoles (benzonitrile oxides and those resulting from allenoate and PPh3) are also reported. 2013 Copyright Taylor and Francis Group, LLC.

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Regio- and stereoselective synthesis
of pyrrolo or azepine-fused
cyclopenta[d]isoxazolines from 2-p-
tolylsulfinylcyclopent-2-en-1-one
José L. García Ruano a , José F. Soriano a , Alberto Fraile a , M.
Rosario Martín a & Alberto Núñez a
a Departamento de Química Orgánica , Universidad Autónoma de
Madrid , Cantoblanco, 28049 , Madrid , Spain
Published online: 10 Aug 2012.
To cite this article: José L. García Ruano , José F. Soriano , Alberto Fraile , M. Rosario Martín
& Alberto Núñez (2013) Regio- and stereoselective synthesis of pyrrolo or azepine-fused
cyclopenta[d]isoxazolines from 2-p-tolylsulfinylcyclopent-2-en-1-one, Journal of Sulfur Chemistry,
34:1-2, 17-32, DOI: 10.1080/17415993.2012.705286
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Journal of Sulfur Chemistry, 2013
Vol. 34, Nos. 1–2, 17–32, http://dx.doi.org/10.1080/17415993.2012.705286
Regio- and stereoselective synthesis of pyrrolo
or azepine-fused cyclopenta[d]isoxazolines from
2-p-tolylsulfinylcyclopent-2-en-1-one
José L. García Ruano*, José F. Soriano, Alberto Fraile, M. Rosario Martín and Alberto Núñez
DepartamentodeQuímicaOrgánica, UniversidadAutónomadeMadrid, Cantoblanco, 28049-Madrid, Spain
(Received 18 May 2012; final version received 19 June 2012)
Reactions of enantiopure 2-p-tolylsulfinylcyclopent-2-en-1-one with cyclic nitrones afforded pyrrolo or
azepine-fused cyclopenta[d]isoxazolidines in high yields under mild conditions. Comparison of these
results with those obtained with cyclopent-2-en-1-one as the dipolarophile shows that the sulfinyl group
increases the reactivity of the enonic system and efficiently controls the π-facial and endo/exo selectivities
of the cycloadditions, which are also dependent on the easy cycloreversion of the resulting compounds.
Results obtained in reactions with other dipoles (benzonitrile oxides and those resulting from allenoate
and PPh3) are also reported.
Keywords: 1,3-dipolar cycloadditions; cycloreversion; nitrones; benzonitrile oxide; vinyl sulfoxides;
cyclopenta[d]isoxazolidines
1. Introduction
The [3 + 2] cycloaddition reaction is a useful method for obtaining heterocyclic (1) and car-
bocyclic (2) compounds. Several years ago, we initiated a program aimed at exploring the
usefulness of vinyl sulfoxides in asymmetric 1,3-dipolar reactions (3–9). In all the reported
studies, the most surveyed sulfinyldipolarophile was one of the epimers at C-5 of the 5-ethoxy-3-p-
tolylsulfinylfuran-2(5H)-one. The results obtained in its reactions with diazoalkanes (3a), nitrile
oxides (4), nitrones (5), azomethyne ylide (6), carbonyl ylide (7), and the dipoles generated from
allenoates (8) or allenyl sulfones (9) in the presence of Ph3P clearly demonstrated the beneficial
*Corresponding author. Email: joseluis.garcia.ruano@uam.es
Dedicated to Professor Eric Block on the occasion of his 70th birthday.
© 2013 Taylor & Francis

18 J.L. García Ruano et al.
Scheme 1. Compounds obtained by asymmetric [3+2] cycloadditions to 5-ethoxy-3-p-tolyl-
sulfinylfuran-2(5H)-one.
Figure 1. Dipolarophiles and dipoles used in this paper.
influence of the sulfinyl group in the reactivity and stereoselectivity of the butenolide reactive
system, allowing the preparation of enantiomerically pure adducts which are interesting interme-
diates in the synthesis of different types of heterocycles or carbocycles (5, 8–10). The structures
of some compounds prepared from the 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one are depicted
in Scheme 1.
Saturated cyclopenta-fused heterocycles and pentalenes are interesting substrates with a large
synthetic potential, which are present in the structure of many natural products (11) and biologi-
cally active compounds (11b,c, 12). These compounds would be available by reactions similar to
those indicated at Scheme 1, by the use of 2-p-tolylsulfinylcyclopent-2-enone (1) as dipolarophile.
However, surprisingly, only its reactions with diazoalkanes (13) and azomethine ylides (14) have
been reported to date. In order to expand the scope of applicability of the cyclopentenone skele-
ton as dipolarophile, in this paper we describe the results obtained from the reactions of the
cyclopentenone 1 with cyclic nitrones (3 and 4), nitrile oxide (5), and allenes 6 in the presence of
nucleophiles such as Ph3P (Figure 1). With comparative purposes, reactions with cyclopentenone
21 have also been studied in those cases where they had not been reported previously (15).
2. Results and discussion
2.1. Addition of cyclic nitrones to (SS)-2-p-tolylsulfinylcyclopent-2-enone (1) and
cyclopent-2-enone (2)
Sulfinylcyclopentenone 1 (16), as well as nitrones 3 (17) and 4 (18), was prepared according to
previously reported procedures. We first studied the reaction of 3,4-dihydro-2H-pyrrol 1-oxide (3)

Journal of Sulfur Chemistry 19
Table 1. Cycloaddition of nitrone 3 to sulfinylcyclopentenone 1.
Entry
T (◦C)
Time (h)
Products (%)
Yields
1
2
3
25
25
60
15
20
15
7a (86):7b (11):7c (3)
7a (79):7b (16):7c (5)
7a (49):7b (39):7c (12)
91%
92%
90%
with sulfinylcyclopentenone 12 in CHCl3 under different conditions (Table 1). Mixtures of three
adducts (7a–7c), the ratio of which was dependent on the reaction conditions, were obtained in all
cases. Adducts 7a and 7b were isolated diastereoisomerically pure by column chromatography.
The highest selectivity was observed at room temperature (15 h, Entry 1), but it decreased at
longer reaction times (Entry 2) or higher temperatures (Entry 3).
The regioselectivity of all the reactions was complete, exclusively yielding compounds with the
oxygen atom of the nitrone bonded to C3 in the cyclopentenone. The π-facial selectivity (defined
as 7a+7b:7c) was higher than 95:5 at room temperature (Entries 1 and 2) but it decreased when
working at 60◦C (Entry 3). Changes in the proportion of adducts could be explained assuming
that cycloreversion is possible under reaction conditions. It was supported by the evolution with
the time of a chloroformic solution of pure 7a heated at 60◦C (Scheme 2), which is transformed
into a mixture of 7a, 7b, and 7c along with traces of sulfinylcyclopentenone 1 and nitrone 3. As
we can see in Scheme 2, the composition of the reaction mixture after 14 h at 60◦C is very similar
to that indicated in Entry 3 in Table 1, where the reaction time and the temperature are almost
identical.
Scheme 2. Evolution with the time of a pure sample of 7a in CHCl3 at 60◦C.
The structural and stereochemical assignment of the adducts 7 was performed taking into
account: (a) their NMR parameters (Table 2) as well as those of desulfinylated compounds
8,3 obtained by the reaction of 7 with aluminum amalgam in THF/H2O (Scheme 3); (b) the
stereochemical proposal indicated in Scheme 3 for explaining the obtained results.
The regiochemistry of all adducts 7 (wherein the oxygen atom is bonded to C3) was inferred
from the high δ-H3a value (>4.6 ppm) observed in all compounds 7 and 8 (Scheme 3). The relative
stereochemistry of the protons H8a and H8b in compounds 8a and 8b was deduced from their J8a,8b

20 J.L. García Ruano et al.
Table 2. Representative 1H NMR data of adducts 7 and 8.
δ (ppm)
J (Hz)
J8a−8b
Compounds
H3a
H8a
H8b
J3a−8b
7a
7b
7c
8a
8b
5.19
4.95
4.63
4.85
4.72
3.84
4.18
3.92
3.80
3.97
–
–
–
2.76
3.08
–
–
–
5.7
5.5
–
–
–
0.0
10.0
Scheme 3. Stereochemical course of the reaction of sulfinylcyclopentenone 1 with nitrone 3 and
desulfinylation of adducts 7.
values, which is close to zero for the trans arrangement in 8a (5b, 19), whereas for the cis one
it is higher than 9 Hz (5b, 19b). Taking into account that desulfinylation (Scheme 3) should not
produce epimerization at C8b, the spatial arrangement of the sulfinyl group in 7a and 7b must
be identical to that of H8b in 8a and 8b, respectively. Finally, the relative stereochemistry of H3a
and H8b could not be unequivocally established in 8a and 8b from the J3a,8b values. However, the
concerted character of these cycloadditions suggests that the sulfinyl group and H3a must adopt
the cis arrangement in 7a and 7b, and the same will be true for H8b and H3a in 8a and 8b.
The absolute configuration of the major compounds 7a and 7b was assigned as indicated in
Scheme 3, byassumingthatthefacialselectivityofthereactionwillbecontrolledbytheorientation
ofthetolylgroupatthestartingcyclopentenone(S)-1, whichmustadopttheconformationdepicted
in Scheme 3 in order to minimize the electrostatic repulsion of the sulfinyl and carbonyl oxygen
atom. The favored exo-A4 and endo-A nitrone approaches will take place to the less hindered
si–si face (A) of the cyclopentenone (S)-1, yielding 7a and 7b, respectively. The smaller steric
interactions of the exo-A approach justify the formation of 7a as the major isomer. The steric
interactions between the sulfinyl group and the pyrrolidine ring in 7a would justify the higher
stability of 7b and, therefore, its higher proportion under conditions favoring cycloreversion.
Finally, the configuration of the minor adduct 7c was tentatively assigned as indicated in Scheme 3
on the assumption that it must derive from the endo-B approach of the nitrone to the most hindered
face (the exo-B approach must be sterically much more unstable).
We have also studied reactions of the cyclic nitrone 4 with sulfinylcyclopentenone 1 under
different conditions. The obtained results, collected in Table 3, indicated the formation of three
adducts (9a–9c). As it happened in the case of the cyclic nitrone 3 (Table 1), the diastereomeric
ratio depends on the reaction time and the temperature, and the relative proportion of the major 9a
adduct decreases at longer times reaction and higher temperatures (Table 3), which evidences once

Journal of Sulfur Chemistry 21
Table 3. Cycloaddition reactions of nitrone 4 to cyclopentenone 1.
T (◦C) Time (h)
Cycloadducts (%)a
Yield (%)b
25
25
60
2.5
20
2.5
9a (62):9b (30):9c (8)
9a (57):9b (32):9c (11)
9a (53):9b (33):9c (14)
ndc
76%
93%
Notes: aMeasured by 1H-NMR.
bOverall yield.
c60% conversion.
Table 4. Representative NMR data of adducts 9 and 10.
δ (ppm)
Compounds
H14a
H3a
H3b
J3a−3b (Hz)
9a
9b
10a
10b
5.28
5.21
5.10
5.17
–
–
3.40
3.47
4.52
4.95
4.28
4.53
–
–
6.6
6.5
more that cycloreversion is taking place. Nevertheless, the comparison of the results collected
in Tables 1 and 3 reveals that, under similar conditions, reactions from 4 are less stereoselective
(compare entries 2 in both tables) and present less marked variations of the diastereomeric ratios
with the time or the temperature.
From the mixtures showed in Table 3, only the major 9a isomer could be isolated as a diastere-
omerically pure compound by precipitation. Contrarily, 9b could not be separated from their
isomers and its NMR signals were obtained from a mixture where it was predominant. The minor
isomer 9c could not be completely characterized, and only some of its NMR signals could be
assigned.
Scheme 4. Desulfinylation reaction of compounds 9.
We could not unequivocally assign the structure and absolute configuration of 9a–9c, despite
they were submitted to studies similar to those used for establishing the structures of 7a–7c.
Thus, desulfinylation of 9a with aluminum amalgam yielded compound 10a, whereas a mixture
of 9a–9c (enriched in 9b) afforded a mixture of two inseparable diastereoisomers (10a and 10b)
(Scheme 4) where the signals of both compounds were clearly assigned. The δ values of H14a

22 J.L. García Ruano et al.
(higher than 5.10 ppm) and the multiplicity of H3a (singlet) for all adducts 9 (Table 4) allowed us
unequivocally establish their regiochemistry, with the oxygen atom of the nitrone bonded to the
β-carbon of the cycloalkenone (C14a in the adduct). However, the endo or exo character of the
cycloadducts 10a and 10b could not be unequivocally established from the J3a−3b values (Table 4),
which are about 6.5 Hz in both compounds and, therefore, intermediate between the values that
unequivocally allow their assignment as endo or exo (5b, 19). Thus, taking into account the similar
behavior observed in reactions from nitrones 3 (Table 1) and 4 (Table 3), we have assigned the
structure and absolute configuration of compounds 9 and 10 by assuming the same sterochemical
course for both nitrones, which means that the major adduct 9a will display the sulfinyl group in
a cis arrangement with respect to the H3b at the azepine ring (Scheme 4) as the result of the exo
approach of the nitrone 4 to the less hindered face of 2-sulfinylcyclopentenone (see Scheme 3).5
We have also studied the reaction of 4 with cyclopent-2-enone 2, which resulted completely
stereoselective, only yielding compound ( )-10a in 72% yield after 18 h at room temperature. The
comparison of this result with that obtained under similar conditions with the sulfinyl derivative
1 (Entry 1, Table 3) indicates that the presence of the sulfinyl group increases the dipolarophilic
reactivity of the double bond, but it has a negative influence on the exo/endo selectivity.
Scheme 5. Reactions of ( )-10a.
Taking into account the presumably high stereoselectivity of the reactions of different nucle-
ophiles with the carbonyl group of compounds 9 and 10, we assumed that they could be
interesting scaffolds for the preparation of dibenzo[c, f ]cyclopenta[4,5]isoxazolo[2,3-a]azepines
or 2-(dibezo[b,e]azepin-6-yl)-cyclopentane derivatives. We confirmed this assumption by study-
ing the chemoselective reduction of 10a with NaBH4 or LiAlH4, which afforded the azepine
derivative 11 as the only diastereoisomer in almost quantitative yield (Scheme 5). A similar
behavior was observed in the reaction of 10a with 4-phenylpiperazine and NaBH(OAc)3 (20),
which afforded, after 15 h, a mixture of the starting product 10a, alcohol ( )-11 (resulting from
the direct reduction of the carbonyl group) and the amine ( )-12 (as the only diastereoisomer),
which were separated by column chromatography. The formation of the amine 12 involves the
reduction of the iminium intermediate following a similar stereochemical course to that proposed
for the carbonyl reduction.
Other interesting transformations concerned the hydrogenolysis of the N–O bonds. Pd(C)-
catalyzed hydrogenation of ( )-10a gave, after 20 h and column chromatography purification,
cyclopentenone ( )-13 (57% yield) by spontaneous elimination of water of the β-hydroxyketone
resulting from the cleavage of the N–O bond in the isoxazolidine. However, catalytic hydrogena-
tion of hydroxyl compound 11 led to diol 14 in good yield (Scheme 5).

Journal of Sulfur Chemistry 23
2.2. Other cycloadditions of sulfinylcyclopentenone 1
Reactions of cyclopent-2-enone 2 with benzonitrile oxide had been previously reported (15c). In
order to know the influence of the sulfinyl group on the course of this reaction, we studied the
reactions of this dipole with sulfinylcyclopentenone 1. When we treated 1 with an excess amount
of benzonitrile oxide (5), in ethyl ether at room temperature, we obtained, after 30 min, a 95:5
mixture of two regioisomeric isoxazoles 15 and 16 (Scheme 6). The major one (15) was isolated
pure by column chromatography in 66% yield. The observed regioselectivity was not improved
by lowering the temperature. The isoxazoline precursors of these isoxazoles were not detected,
even at low temperatures, which is not surprising due to the easy desulfinylation of the adducts
into the aromatic isoxazoles.
Scheme 6. Cycloaddition of benzonitrile oxide (5) to 1.
The structure of the major regioisomer was assigned on the basis of the NOE effect observed
between the phenyl and methylene groups, such as it is indicated in Scheme 6 (this NOE effect was
not observed in 16) and the comparison of the 13C NMR data [ꢀδ (C4–C5)] of heterocyclic carbons
of 15 with those of other isoxazoles (4a, 21) or pyrazoles (3a) previously reported.The comparison
of the results obtained from compound 1 (Scheme 6) and those reported for 2, which required 12 h
at room temperature to react with 5 (15c), suggests that the sulfinyl group substantially improves
the reactivity, which is in agreement with the results that we observed in reactions with other
sulfinyl dipolarophiles and other dipoles. The regioselectivity is also affected, being higher for 1
(95:5) and opposite to that reported for cyclopentenone 2, which yielded a 25:75 regioisomeric
mixture (15c). This inversion of the regioselectivity produced by the sulfinyl group had also been
observed in reactions of 5-alkoxyfuran-2(5H)-furanones and their 3-sulfinyl derivatives (4a).
Other significant difference is the stability of primary adducts, high for those obtained from 2,
but very low for those derived from 1; these adducts cannot be isolated not even detected due to
the easier and spontaneous sulfinyl elimination (4a). This uncontrolled evolution precluded us to
obtain any information about the influence of the sulfinyl group on the stereoselectivity of the
reaction.
Finally, and taking into account our recent contributions to the asymmetric use of Lu’s reaction
(8), we have also studied the reactions of allenoates with sulfinylcyclopentenone 1, because
the resulting adducts would be promising starting materials for the regio- and stereoselective
synthesis of polyfunctionalized pentalenes. However, reactions of dipolarophile 1 with ethyl 2,3-
butadienoate in the presence of PPh3 did not afford the expected adduct, but the hydroxyketone
17 (40%) and the tricyclic compound 18 (Scheme 7). Slightly better yields (45% and 13%,
respectively) were obtained in the presence of 2,2,6,6-tetramethylpiperidine (10%) and phosphine
(15%). The formation of 17 can be explained as the result of the migration of the double bond of
1 (favored by the base) to form the allylic sulfoxide 19 (Scheme 7) evolving through a sulfoxide–
sulfenate rearrangement (22) to the sulfenate intermediate 19ꢀ easily transformed into the carbinol
17 by cleavage of the S–O bond. The conjugate addition of alcohol 17 to sulfinylcyclopentenone

24 J.L. García Ruano et al.
Scheme 7. Transformation of 1 under Lu’s reaction conditions.
Scheme 8. Reactions of 2-p-tolylsulfonylallene with different cyclopent-2-enones.
1 (oxa-Michael) followed by intramolecular reaction of the intermediate (exo-trig cyclization) led
to tricyclic compound 18.
We also studied reactions of the sulfinylcyclopentenone 1 with p-tolylsulfonylallene, under the
best conditions recently reported for reactions with sulfinyl furanones (9) (Scheme 8). Results
were unsuccessful and only a complex mixture was obtained. It is interesting that reactions of
the sulfonylallene with 2-cyclopentenone 2 and its 2-p-tolylsulfonyl derivative gave the expected
adducts in low and moderate yields. It supports that the course indicated in Scheme 7 must be
responsible for the results obtained with the sulfinyl derivative 1.
In summary, we report herein the results of the reactions of 2-p-tolylsulfinylcyclopent-2-en-
1-one (1) with different dipoles. They have provided a simple methodology for achieving new
polyfunctionalized cyclopentaheterocyclic derivatives in a regio- and stereoselective manner, by
using the [3+2] cycloadition as the key step. The positive influence of the sulfinyl group on
the dipolarophilic reactivity of the 2-cyclopentenone, as well as on the regioselectivity of its
reactions with some dipoles, can be inferred from the obtained results, which are not so good as
those obtained from 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one.
3. Experimental
3.1. General
All melting points were determined in open capillary tubes and are uncorrected. IR spectra were
determined as indicated for each compound with a Bruker FTIR-Vector 22 spectrophotometer.
The NMR spectra were determined using TMS as an internal reference on a Bruker AC-300

Journal of Sulfur Chemistry 25
1
FT NMR spectrometer operating at 300 and 75 MHz for H and 13C NMR, respectively. High-
resolution mass spectrometra were obtained using a Waters, VG AutoSpec, spectrometer by FAB
technique. The optical rotations were measured at room temperature in the solvent and concen-
tration (g/100 ml) indicated in each case. Silica gel 60 (230–400 mesh ASTM) and DC-Alufolien
60 F254 were used for flash column chromatography and analytical TLC, respectively. Micro-
analyses were carried out on a LECO CHNS-932 in Laboratory of Elemental Analyses of SIDI
of Universidad Autónoma de Madrid and were in good agreement with the calculated values.
3.2. Cycloaddition reactions of 3,4-dihydro-2H-pyrrol-1-oxide (3) to cyclopentenone 1
To a stirred solution of 1 (300 mg, 1.4 mmol) in chloroform (5 ml), under argon atmosphere and
at room the temperature, a solution of nitrone 3 (178 mg, 2.10 mmol) in 15 ml of chloroform
was added. The reaction mixture was kept at room temperature or 60◦C for 15 h. The reaction
was monitored by TLC and 1H NMR. The solvent was removed under reduced pressure and the
residue was purified by column chromatography (hexane/ethyl acetate 4:1), to afford compounds
7a, 7b, and 7c in decreasing order of Rf . Combined yield was 91% or 90%.
3.2.1. 8b-(p-Tolysulfinyl)octahydro-1H-cyclopenta[d]pyrrolo[1,2-b]isoxazol-1-ones (7).
◦
=
(3aS,8aS,8bR,SS)-isomer (7a): W◦hite solid, mp: 75–76 C. IR (KBr): 1731 (C O), 1598, 1494,
20
1
1083, 1062, 815 cm−1. [α]D :−34.8 (c 0.5, acetone). H NMR (CDCl3)δ 1.46–1.67 (m, 2H),
=
1.74–1.88 (m, 1H), 1.94–2.20 (m, 3H), 2.40 (s, 3H), 2.28–2.58 (m, 2H), 2.93–3.ꢀ03 (m, 1H), 3.20–
ꢀ
=
=
3.29 (m, 1H), 3.84 (t, 1H, J 7.8 Hz), 5.19 (d, 1H, J 5.0 Hz), 7.46 and 7.30 (AA BB system, 4H).
13C NMR (CDCl3)δ 21.4 (CH3), 24.1 (CH2), 25.1 (CH2), 27.0 (CH2), 37.8 (CH2), 55.0 (CH2),
73.0 (CH), 77.3 (CH), 86.0 (C), 125.5 (CH), 129.9 (CH), 136.0 (C), 142.9 (C), 212.7 (C).
(3aS,8aR,8bR,SS)-isomer (7b): Recrystallized from ethyl acetate-diethyl ether, white solid,
◦
20
=
=
mp: 113–114 C. [α]D : +258.2 (c 0.5, acetone). IR (KBr): 1728 (C O), 1593, 1492, 1082,
1061, 815 cm−1. 1H NMR (CDCl3)δ 0.93–1.19 (m, 1H), 1.67–2.10 (m, 6H), 2.32–2.52 (m, 1H),
=
2.42 (s, 3H), 2.82–3.02 (m, 1H), 3.23–3.41 (m, 1H), 4.14–4.28 (m, 1H), 4.95 (d, 1H, J 5.1 Hz),
7.48, and 7.31 (AAꢀBBꢀ system, 4H). 13C NMR (CDCl3)δ 21.6 (CH3), 22.9 (CH2), 24.8 (CH2),
26.8 (CH2), 38.6 (CH2), 56.4 (CH2), 72.9 (CH), 81.6 (CH), 83.7 (C), 125.3 (CH), 129.9 (CH),
136.0 (C), 142.9 (C), 212.4 (C).Anal. Calcd. for C16H19NO3S: C, 62.93; H, 6.27; N, 4.9; S, 10.50.
Found: C, 62.84; H, 6.62; N, 4.60; S, 10.96.
(3aR,8aS,8bS,SS)-isomer (7c): It was not isolated pure. The signals were assigned from the
NMR spectrum of a mixture of 7c and starting dipolarophile 1. 1H NMR (CDCl3)δ 2.42 (s, 3H),
=
=
=
3.04 (dt, 1H, J 8.3 and 14.2 Hz), 3.34 (ddd, 1H, J 4.2, 7.8, and 14.2 Hz), 3.92 (t, 1H, J 8.2 Hz),
4.61–4.65 (m, 1H), 7.48 and 7.31 (AAꢀBBꢀ system, 4H). The remaining signals were not included
because they overlap with the signals of compound 1. 13C NMR (CDCl3) δ 21.5 (CH3), 24.3
(CH2), 25.7 (CH2), 26.8 (CH2), 38.1 (CH2), 56.0 (CH2), 73.6 (CH), 79.0 (CH), 82.7 (C), 125.4
(CH), 130.2 (CH), 135.9 (C), 143.4 (C), 210.3 (C).
3.3. Transformation of adduct 7a by reflux in toluene
A solution of 20 mg of diastereomerically pure sample of adduct 7a in 5 ml of chloroform was
heated at 60◦C for 3, 6, or 14 h. After removal of the solvent, the residues, analyzed by 1H NMR,
were mixtures 74:19:7, 62:29:9, or 53:37:10 of 7a:7b:7c, respectively.

26 J.L. García Ruano et al.
3.4. Desulfinylation of sufinyl adducts with aluminum amalgam
Aluminum amalgam was prepared by immersing strips of aluminum foil in 10% hydrochloric
acid. After rinsing with water, the strips were immersed in a 5% aqueous solution of mercuric
chloride for 15–30 s, and the solution was decanted; the strips were rinsed with absolute ethanol,
then with ether, and cut into pieces of ca. 1 cm2.
To a stirred solution of sulfinyl adduct (0.23 mmol) in a 10:1 mixture of THF-H2O (3 ml) at
room temperature, an excess amount of aluminum amalgam was added. The reaction mixture was
stirred at room temperature for 4 h and then filtered. The solid was washed with THF (50 ml), and
the solution was evaporated at reduced pressure to dryness.
3.4.1. Octahydro-1H-cyclopenta[d]pyrrolo[1,2-b]isoxazol-1-ones (8).
(3aS,8aS,8bS)-isomer (8a): It was obtained after 1 h from adduct 7a. It cannot be isolated pure
by column chromatography (hexane/ethyl acetate 1:1). 1H NMR (CDCl3)δ 0.80–2.70 (m, 8H),
=
2.76 (d, 1H, J 5.7 Hz), 3.08–3.16 (m, 1H), 3.77–3.83 (m, 1H), 4.82–4.87 (m, 1H).
(3aS,8aR,8bS)-isomer (8b): It was obtained after 2.5 h from adduct 7b. It cannot be isolated
pure by column chromatography (hexane/ethyl acetate 2:1). 1H NMR (CDCl3) δ 1.60–2.63 (m,
=
8H), 2.79–2.93 (m, 1H), 3.08 (dd, 1H, J 5.5 and 10.0 Hz), 3.28–3.42 (m, 1H), 3.90–4.02 (m,
=
1H), 4.72 (t, 1H, J 4.8 Hz).
3.5. Cycloadditions of 11H-dibenzo[b,e]azepine 5-oxide (4) to cyclopentenones 1 and 2
To a solution of (S)-2-p-tolylsulfinyl-2-cyclopentenone (1) (1.4 mmol) in 10 ml of CHCl3, under
argon atmosphere and at the temperature indicated inTable 2, was added 11H-dibenzo[b,e]azepine
5-oxide (1.7 equiv.). The reaction was monitored by TLC. After the indicated time, the solvent
was removed under reduced pressure and the residue analyzed by 1H NMR. Yields and ratio of
adducts are indicated in Table 2 for each case.
3.5.1. 3a-((S)-p-Tolylsulfinyl)-3a,3b,8,14a-tetrahydro-1H-dibenzo[c,f]cyclopenta[4,5]
isoxazolo[2,3-a]azepin-3(2H)-ones (9).
(3aR,3bS,14aS)-isomer (9a): It was obtained from sulfinylcyclopentenone 1 and nitrone 4 as
the major stereoisomer. It was isolated as a pure diastereoisomer by precipitation with acetone
from the crude reaction mixture.Additional amount of 9a was isolated by column chromatography
(hexane/ethyl acetate 9:1) of the residue resulting from concentrating the filtrate. White solid,
◦
20
=
=
mp: 135–137 C. (with decomposition). [α]D : +181.4 (c 0.5, CHCl3. IR (KBr): 1734 (C O),
1597, 1485, 1249, 1150 cm−1. 1H NMR (CDCl3)δ 0.67–0.84 (m, 1H), 1.92–2.13 (m, 2H), 2.38
=
=
(s, 3H), 2.65–2.81 (m, 1H), 3.50 (d, 1H, J 13.9 Hz), 4.52 (s, 1H), 4.89 (d, 1H, J 13.9 Hz), 5.28
ꢀ
ꢀ
=
(d, 1H, J 6.1 Hz), 6.99–7.04 (m, 1H), 7.20 and 7.49 (AA BB system, 4H), 7.22–7.36 (m, 6H),
7.94 (d, 1H, J 7.9 Hz). 13C NMR (CDCl3)δ 21.3 (CH3), 23.2 (CH2), 37.5 (CH2), 39.4 (CH2),
=
75.3 (CH), 78.9 (CH), 86.2 (C), 115.3 (CH), 124.5 (CH), 125.1 (CH), 126.2 (CH), 127.2 (CH),
127.4 (CH), 128.1 (CH), 130.0 (CH), 130,0 (CH), 130.2 (CH), 130.6 (C), 132.8 (C), 135.8 (C),
137.9 (C), 142.3 (C), 145.3 (C), 212.5 (C). Anal. Calcd. for C26H23NO3S: C, 72.70; H, 5.40; N,
3.26; S, 7.46. Found: C, 72.44; H, 5.50; N, 3.35; S, 7.71.
(3aR,3bR,14aS)-isomer (9b): It was obtained from sulfinylcyclopentenone 1 and nitrone 4. It
was not isolated as a pure compound by column chromatography (hexane/ethyl acetate 9:1). Data

Journal of Sulfur Chemistry 27
1
=
were measured from the mixture of 9b+9c+9a. H NMR (CDCl3)δ 3.38 (d, 1H, J 14.8 Hz),
=
=
4.48 (d, 1H, J 14.8 Hz), 4.95 (s, 1H), 5.21 (d, 1H, J 6.7 Hz).
(3aS,3bS,14aR)-isomer (9c): It was obtained as minor stereoisomer from 1 and nitrone 4. It
was not isolated as a pure compound by column chromatography (hexane/ethyl acetate 9:1). Data
1
=
were measured from the mixture of 9b+9c+9a. H NMR (CDCl3)δ 3.14 (d, 1H, J 14.5 Hz), 4.40
=
=
(d, 1H, J 14.5 Hz), 4.44 (s, 1H), 5.51 (d, 1H, J 4.4 Hz).
3.5.2. ( )-(3aS,3bR,14aS)-3a,3b,8,14a-Tetrahydro-1H-dibenzo[c,f]cyclopenta[4,5]
isoxazolo[2,3-a]azepin-3(2H)-one [( )-10a].
It was obtained diastereoisomerically pure from cyclopentenone 2 and nitrone 4 following the
general procedure. It was isolated in 72% yield by column chromatography (hexane/ethyl acetate
◦
=
9:1) of the crude reaction. White solid, mp: 158–159 C. IR (KBr): 1739 (C O), 1591, 1488, 1150,
757, 725 cm−1. 1H NMR (CDCl3)δ 2.04–2.32 (m, 1H), 2.37–2.60 (m, 2H), 2.73–2.98 (m, 1H),
=
=
=
=
3.40 (t, 1H, J 6.6 Hz), 3.69 (d, 1H, J 14.7 Hz), 4.28 (d, 1H, J 6.6 Hz), 4.60 (d, 1H, J 14.7 Hz),
=
5.07–5.13 (m, 1H), 6.98–7.06 (m, 1H), 7.15–7.33 (m, 5H), 7.42 (d, 1H, J 7.8 Hz), 7.63 (d, 1H,
J 7.0 Hz). 13C NMR (CDCl3)δ 24.3 (CH2), 35.9 (CH2), 39.8 (CH2), 63.4 (CH), 72.7 (CH), 80.4
(CH), 115.1 (CH), 124.2 (CH), 126.9 (CH), 127.3 (CH), 127.6 (CH), 128.1 (CH), 129.4 (CH),
130.4 (C), 132.8 (CH), 135.8 (C), 135.9 (C), 147.5 (C), 212.7 (C). Anal. Calcd. for C19H17NO2:
C, 78.33; H, 5.88; N, 4.81. Found: C, 78.10; H, 5.97; N, 4.73.
=
3.6. Transformations of adducts 9a and 10a
3.6.1. 3a,3b,8,14a-Tetrahydro-1H-dibenzo[c,f]cyclopenta[4,5]isoxazolo[2,3-a]azepin-3(2H)-
ones (10).
(3aS,3bR,14aS)-isomer (+)-10a. It was obtained by desulfinylation of 9a with aluminum amal-
gam, following the above-indicated general procedure. The product was isolated by column
20
chromatography (hexane/ethyl acetate 9:1) in 81% yield. White solid, mp: 158–159◦C. [α]D :
=
+95.7 (c 0.5, acetone).
(3aS,3bS,14aS)-isomer (−)-10b: It was obtained along with (+)-10a by desulfinylation of
a 41:59 mixture 9a and 9b with aluminium amalgam, following the above-indicated general
procedure. The product was◦isolated by column chromatography (hexane/ethyl acetate 9:1) as
20
=
=
a white solid, mp: 165–167 C. [α]D : −31.2 (c 0.18, CHCl3). IR (KBr): 1739 (C O), 1590,
1488, 757 and 725 cm−1. 1H NMR (CDCl3) δ 2.10–2.33 (m, 2H), 2.39–2.53 (m, 1H), 2.75–2.89
=
=
=
(m, 1H), 3.42 (d, 1H, J 13.8 Hz), 3.47 (td, 1H, J 1.1 and 6.5 Hz), 4.53 (d, 1H, J 6.5 Hz), 4.56
=
=
(d, 1H, J 13.8 Hz), 5.13–5.20 (m, 1H), 7.03 (td, 1H, J 1.3 and 7.4 Hz), 7.15–7.32 (m, 6H), 7.46
(dd, 1H, J 1.2 and 7.8 Hz). 13C NMR (CDCl3)δ 30.4 (CH2), 39.1 (CH2), 39.3 (CH2), 59.1 (CH),
73.5 (CH), 77.8 (CH), 115.4 (CH), 124.2 (CH), 126.1 (CH), 127.4 (CH), 127.5 (CH), 129.8 (CH),
129.9 (CH), 131.0 (C), 131.8 (C), 136.0 (C), 146.7 (C), 215.2 (CO).
=
3.6.2. ( )- and (+)-(3S,3aR,3bR,14aS)-2,3,3a,3b, 8,14a-Hexahydro-1H-dibenzo
[c,f]cyclopenta[4,5]isoxazolo[2,3-a]azepine-3-ol (11).
To a solution of enantiopure or racemic compound 10a (0.23 mmol) in anhydrous THF (5 ml), vig-
orously stirred at room temperature, was added LiAlH4 (0.35 mmol) or NaBH4 (0.81 mmol). The
reaction mixture was stirred for 5 min (LiAlH4) or 4 h (NaBH4) and then ethyl acetate (10 ml)

28 J.L. García Ruano et al.
and water (2 ml) were added. The layers were separated and the aqueous phase was extracted
with ethyl acetate (3 × 20 ml). The organic phase was dried over Na2SO4 and evaporated at
reduced pressure. Compound 11 was isolated by column chromatography (hexane/ethyl acetate
5:1) with 98% or 91% yield. White solid, mp: 145–147◦C. IR (KBr): 3419, 1600, 1486, and
1
1070 cm−1. H NMR (CDCl3)δ 1.72–1.86 (m, 1H), 1.93–1.99 (m, 1H), 2.00–2.14 (m, 3H),
=
=
=
3.34 (dt, 1H, J 6.7 and 7.9 Hz), 3.85 (d, 1H, J 14.7 Hz), 4.45 (d, 1H, J 14.7 Hz), 4.42–
=
=
4.53 (m, 1H), 4.66 (d, 1H, J 6.7 Hz), 4.76–4.81 (m, 1H), 6.98 (td, 1H, J 1.3 and 7.5 Hz),
7.14–7.25 (m, 5H); 7.41 (dd, 1H, J 1.2 and 7.9 Hz), 7.44–7.48 (m, 1H). 13C NMR (CDCl3)δ
27.1 (CH2), 33.7 (CH2), 40.2 (CH2), 58.6 (CH), 68.2 (CH), 76.6 (CH), 82.4 (CH), 116.5
=
(CH), 123.7 (CH), 126.6 (CH), 127.0 (CH), 127.5 (CH), 128.1 (CH), 129.1 (CH), 129.3 (CH),
20
=
130.3 (C), 136.9 (C), 137.1 (C), 148.1 (C). Enantiopure compound: [α]D : +116.7 (c 0.3,
acetone).
3.6.3. (3S,3aS,3bR,14aS)-3-(4-Phenylpiperazin-1-yl)-2,3,3a,3b,8,14a-hexahydro-1H-
dibenzo[c,f] cyclopenta[4,5]isoxazolo[2,3-a]azepine[( )-12].
A mixture of ( )-10a (100 mg, 0.34 mmol), 4-phenylpiperazine (55 mg, 0.34 mmol), acetic acid
(20 mg, 0.34 mmol)andNaBH(OAc)3 (120 mg, 0.56 mmol)in1,2-dichloroetane(5 ml)wasstirred
under argon at room temperature for 15 h. Then the reaction mixture was washed with a saturated
aqueous solution of NaHCO3. The layers were separated and the aqueous phase was extracted
with CH2Cl2 (3 × 20 ml). The organic phase was dried over MgSO4 and evaporated at reduced
pressure. The residue analyzed by 1H NMR was a mixture of the starting material ( )-10a, alcohol
( )-11, and amine ( )-12. Column chromatography (hexane/ethyl acetate 2:1) afforded ( )-12
(20% or 36% based on the recovered starting material), 10a (20 mg, 0.07 mmol), and ( )-11
(15 mg, 0.05 mmol, 9%).
1
Compound [( )-12]: White amorphous solid. H NMR (CDCl3)δ 1.66–2.15 (m, 4H), 2.46–
=
2.65 (m, 4H), 2.70–2.80 (m, 1H), 2.87–3.04 (m, 4H), 3.72 (d, 1H, J 15.2 Hz), 3.71–3.79
=
=
(m, 1H), 4.65 (d, 1H, J 15.2 Hz), 4.76–4.83 (m, 1H), 5.58 (d, 1H, J 5.3 Hz), 6.78–6.88 (m,
4H), 7.04–7.28 (m, 8H), 7.54 (broad d, 1H, J 6.9 Hz). 13C NMR (CDCl3) δ 28.0 (CH2), 30.5
=
(CH2), 40.3 (CH2), 48.9 (CH2), 52.1 (CH), 52.6 (CH2), 62.7 (CH), 68.9 (CH, C14b), 81.8 (CH,
C3a), 115.7 (CH), 119.5 (CH), 122.6 (CH), 122.8 (CH), 126.4 (CH), 126.8 (C), 126.9 (CH),
127.4 (CH), 127.9 (CH), 128.2 (CH), 129.0 (CH), 129.7 (CH), 134.7 (C), 141.1 (C), 146.5 (C),
151.2 (C).
3.6.4. 2-(6,11-Dihydro-5H-dibenzo[b,e]azepin-6-yl)cyclopent-2-en-1-one [( )-13].
A solution of ( )-10a (0.23 mmol) and Pd(C) 10% (5 mg) in ethanol (5 ml) was stirred under
positive pressure of hydrogen at room temperature.After 20 h, the suspension was filtered through
celite, the solid residue was washed with ethyl acetate, and the solvent was removed in vacuo.
The residue was purified by column chro◦matography (hexane/ethyl acetate 3:2) to afford 13 in
57% yield as a yellow solid, mp: 136–138 C. IR (KBr): 1696 (C O), 1626, 1603, 1240 cm−1.1H
=
=
=
NMR (CDCl3)δ: 2.37–2.57 (m, 4H), 3.97 (d, 1H, J 15.0 Hz), 4.29 (d, 1H, J 15.0 Hz), 4.47
=
=
(broad s, 1H), 5.52 (s, 1H), 6.61 (d, 1H, J 7.7 Hz), 6.79 (td, 1H, J 1.1 and 7.3 Hz), 6.94–7.04
(m, 3H), 7.09–7.27 (m, 4H). 13C NRM (CDCl3)δ: 26.4 (CH2, C4); 35.0 (CH2, C5); 40.0 (CH2,
ꢀ ꢀ
C11 ), 55.3 (CH, C6 ), 119.9 (CH), 120.7 (CH), 126.4 (CH), 127.2 (CH), 127.5 (CH), 128.7 (CH),
129.0 (C), 129.2 (CH), 129.3 (CH), 136.5 (C), 138.1 (C), 145.3 (C), 148.2 (C), 160.2 (CH),
208.6 (CO).

Journal of Sulfur Chemistry 29
3.6.5. ( )-(1S,3S)-2-((R)-6,11-Dihydro-5H-dibenzo[b,e]azepin-6-yl)cyclopentane-1,3-
diol (14).
A solution of ( )-11 (0.23 mmol) and Pd(C) 10% (5 mg) in ethanol (5 ml) was stirred under
positive pressure of hydrogen at room temperature. After 1 h, the suspension was filtered through
celite, the solid residue was washed with ethyl acetate, and the solvent was removed in vacuo.
1
=
Yield 78%. H NMR (CDCl3)δ 1.87–2.08 (m, 4H), 2.20–2.40 (m, 1H), 3.82 (d, 1H, J 14.4 Hz),
=
=
4.05–4.15 (m, 1H), 4.41 (d, 1H, J 14.4 Hz), 4.54–4.68 (m, 1H), 5.09 (d, 1H, J 7.2 Hz), 6.70–
6.80 (m, 2H), 6.90–7.25 (m, 6H) 13C NMR (CDCl3)δ 32.8 (CH2), 33.9 (CH2), 40.0 (CH2),
55.5 (CH), 56.5 (CH), 74.0 (CH), 74.6 (CH), 119.4 (CH), 120.3 (CH), 126.8 (CH), 127.4
(CH), 127.6 (CH), 128.0 (C), 128.4 (CH), 128.9 (CH), 129.4 (CH), 137.3 (C), 139.0 (C),
143.9 (C).
3.7. Reaction of 1 with benzonitrile oxide (5)
To a stirred mixture of sodium hydroxide solution 10% (4.5 ml) and ether (4.5 ml), benzaldehyde
chloroxime (7.5 mmol) was portionwise added during 10 min at 0◦C. The ethereal layer was
separated, quickly dried over MgSO4, and added to a solution of the sulfinylcyclopentenone
(1.4 mmol) in ether (10 ml).After stirring at room temperature for 30 min, the solvent was removed
under reduced pressure and the residue analyzed by 1H NMR was a 95:5 mixture of 15:16. The
major regioisomer 15 was isolated pure in a 66% yield by column chromatography (hexane/ethyl
acetate 4:1).
3.7.1. 3-Phenyl-4,5-dihydro-6H-cyclopenta[d]isoxazol-6-one (15).
Recrystallized from ethyl acetate–hexane, white solid, mp: 162–163◦C. IR (KBr) 1715
−1
.
1H NMR (CDCl3)δ 3.08–3.13 (m, 2H), 3.21–3.26 (m, 2H,),
=
(C O), 1607, 1593 cm
7.46–7.57 (m, 3H), 7.78–7.88 (m, 2H). 13C NMR (CDCl3)δ 18.3 (CH2), 43.3 (CH2),
127.0 (CH), 127.7 (C), 129.3 (CH), 130.8 (CH), 146.0 (C), 159.0 (C), 171.5 (C), 186.5
=
(C O). Anal. Calcd. for C12H9NO2: C, 72.35; H, 4.55; N, 7.0. Found: C, 72.14; H, 4.55;
N, 6.80.
3.7.2. 3-Phenyl-5,6-dihydro-4H-cyclopenta[d]isoxazol-4-one (16).
It was not isolated as a pure compound. 1H NMR (CDCl3) δ 3.11–3.17 (m, 2H), 3.27–3.33 (m,
2H), 7.46–7.57 (m, 3H), 8.18–8.25 (m, 2H).
3.8. Reaction of ethyl 2,3-butadienoate with sulfinylcyclopentenone 1 catalyzed by
triphenylphosphine
To a stirred solution 0.2 M of sulfinylcyclopentenone 1 (84 mg, 0.38 mmol), in benzene, under
positive pressure of argon, commercial ethyl 2,3-butadienoate (64 mg, 0.29 mmol) was added
at room temperature, and finally (32 mg, 0.12 mmol) of triphenylphosphine (solution 0.6 M) in
benzene. The reaction was monitored by TLC. The solvent was removed in vacuo and the crude
reaction, analyzed by 1H NMR, was a complex mixture, which afforded compounds 17 and 18
by column chromatography.

30 J.L. García Ruano et al.
3.8.1. 4-Hydroxycyclopent-2-enone (17) (23).
1
=
It was obtained in 40% yield. H NMR (CDCl3, 300 MHz) δ 2.25 (dd, 1H, J 2.3 and 18.4 Hz),
=
=
=
2.70 (dd, 1H, J 6.0 and 18.4 Hz), 4.08 (d, 2H, J 5.3 Hz), 4.99 (broad s, 1H), 6.14 (dd, 1H, J 1.3
and 5.7 Hz).
3.8.2. 7b-(p-Tolylsulfinyl)hexahydrodicyclopenta[b,d]furan-1,6(2H,7bH)-dione (18).
It was isolated by column chromatography (dichloromethane/diethyl ether 6:1) as yellow oil in
9% yield. 1H NMR (CDCl3, 300 MHz) δ 1.68–1.82 (m, 1H), 1.85–1.98 (m, 1H), 1.98–2.11 (m,
=
=
1H), 2.43 (s, 3H), 2.26–2.63 (m, 4H), 3.02 (dd, 1H, J 9.1 and 18.8 Hz), 3.17 (td, 1H, ꢀJ 4.5 and
ꢀ
9.0 Hz), 4.52 (t, 1H, J 4.4 Hz), 5.29 (d, 1H, J 5.6 Hz), 7.33 and 7.45 (system AA BB , 4H). 13C
NMR (CDCl3, 75 MHz) δ 21.6 (CH3), 27.9 (CH2), 37.6 (CH2), 38.3 (CH2), 43.6 (CH2), 47.3
(CH), 80.9 (CH), 81.1 (CH), 82.6 (C), 125.3 (CH), 130.0 (CH), 143.2 (C), 153.8 (C), 213.2 and
=
=
=
214.0 (C O). EM: 319.0 [M + H] (30%), 179 [M-SOTol] (100%).
3.9. ( )-(3aR,6aR)-5-Tosyl-3,3a,6,6a-tetrahydropentalen-1(2H)-one (20)
To a stirred 0.1 M solution in benzene of cyclopent-2-en-1-one (2) (85 mg, 1.03 mmol) at room
temperature, p-tolyl-1-allenyl sulfone (100 mg, 0.52 mmol), 18-crown-6 ether (55 mg, 0.21 mmol)
and anhydrous p-TolSO2Na (37 mg, 0.21 mmol) were added. The reaction was monitored by TLC,
1
the solvent was removed under vacuum, and the crude reaction was analyzed by H NMR and
purified by flash column chromatography (hexane/ethyl acetate 2:1) to afford 20 as colorless oil
in 24% yield. 1H NMR δ 2.12–2.00 (m, 2H), 2.13–2.27 (m, 1H), 2.28–2.38 (m, 1H), 2.44 (s, 3H),
2.88–2.63 (m, 3H), 3.60–3.74 (m, 1H), 6.61–6.65 (m, 1H), 7.33 and 7.73 (AAꢀBBꢀ system, 4H).
13C NMR: DEPT 135 δ 21.7 (CH3), 24.9 (CH2), 35.1 (CH2), 36.5 (CH2), 47.8 (CH), 49.4 (CH),
128.0 (CH), 130.0 (CH), 143.7 (CH).
3.10. ( )-(3aR,6aR)-5,6a-Ditosyl-3,3a,6,6a-tetrahydropentalen-1(2H)-one (21)
It was obtained following the above procedure starting from 2-p-tolylsulfonylcyclopent-2-en-1-
one (24 mg, 0.10 mmol), p-tolyl 1-allenyl sulfone (29 mg, 0.15 mmol), 18-crown-6 ether (18 mg,
0.07 mmol) and anhydrous p-TolSO2Na (13 mg, 0.07 mmol). It was isolated by flash column
chromatography (hexane/ethyl acetate 2:1) as colorless oil in 63% yield. 1H NMR δ 1.95–2.06
=
(m, 1H), 2.15–2.30 (m, 1H), 2.44 (s, 3H), 2.47 (s, 3H), 2.62–2.76 (m, 2H), 3.06 (dt, 1H, J 2.2
=
=
and 16.4 Hz), 4.36 (dt, 1H, J 2.4 and 8.6 Hz), 6.54 (td, 1H, J 1.4 and 2.3 Hz), 7.30–7.37 (m,
4H), 7.56–7.61 (m, 2H), 7.65–7.71 (m, 2H). 13C NMR δ 21.7, 21.8, 24.0, 37.0, 37.5, 50.5, 79.2,
127.9, 129.8, 130.0, 130.1, 132.6, 135.4, 141.8, 142.9, 145.2, 146.1, 209.7.
Acknowledgements
We thank DGICYT (Grant CTQ-2009-12168) and Comunidad Autónoma de Madrid (AVANCAT CS2009/PPQ-1634)
for financial support.
Notes
1. The cyclopent-2-en-1-one (2) has been less studied as dipolarophile than furan-2(5H)-one. For cycloadditions to
cyclopentenone 2, see (15a, b) for nitrones, (15c) for nitrile oxides. For selected examples of azomethine ylides,
see (15d–f ) and references cited therein. For diazomethane, see (12).

Journal of Sulfur Chemistry 31
2. Lee et al. (15a) report the results obtained in reaction of cyclopent-2-en-1-one (2) with a five-membered cyclic
nitrone. However, to our knowledge, reactions of 2 with nitrone 3, or with any seven-membered cyclic nitrones,
such as 4, have never been reported.
3. Although the desulfinylated compounds 8 could not be isolated pure, the 1H NMR data indicated in Scheme 3 could
be measured.
4. The endo or exo terms indicate, respectively, the cis or trans arrangement adopted by cyclopentanone and pyrrolidine
(for adducts 7) or azepine (for adducts 9 and 10) moieties at the isoxazolidine ring formed in the reactions from
nitrones. They are related to the endo and exo dipole addition modes, using the carbonyl group at cyclopentenone
ring as a reference.
5. The higher δ of H-3b and the smaller ꢀδ (δH8–δH8ꢀ) observed for adduct 9b (endo), when compared with those
corresponding to adduct 9a (exo), support the assigned stereochemistry.
References
(1) (a) In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards Heterocycles and Natural Products;
Padwa, A.; Pearson, W.H., Eds; The Chemistry of Heterocyclic Compounds, Vol. 59; John Wiley & Sons: NJ, 2002;
(b) Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (c) Nair, V.; Suja, T.D. Tetrahedron 2007, 63, 12247–12275; (d)
Kissane, M.; Maguire, A.R. Chem. Soc. Rev. 2010, 39, 845–883. (e) Stanley, L.M.; Sibi, M.P. Chem. Rev. 2008, 108,
2887–2902; (f) Synthesis of Heterocycles via Cycloadditions I; Hassner, A., Ed.; Topics in Heterocyclic Chemistry,
Vol. 12; Springer-Verlag: Berlin, Heidelberg, 2008.
(2) (a) Cowen, B.J.; Miller, S.J. Chem. Soc. Rev. 2009, 38, 3102–3116; (b) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2001, 34, 535–544; (c) Lautens, M.; Klute, W.; Tam. W. Chem. Rev. 1996, 96, 49–92; (d) Takasu, K.; Nagao, S.;
Iharaa, M. Adv. Synth. Catal. 2006, 348, 2376–2380 and references therein.
(3) (a) García Ruano, J.L.; Fraile, A.; González, G.; Martín, M.R.; Clemente, F.R.; Gordillo, R. J. Org. Chem. 2003,
68, 6522–6534; (b) García Ruano, J.L.; Peromingo, M.T.; Alonso, M.; Fraile, A.; Martín, M.R.; Tito, A. J. Org.
Chem. 2005, 70, 8942–8947; (c) García Ruano, J.L.; Bercial, F.; González, G.; Martín Castro, A.M.; Martín, M.R.
Tetrahedron: Asymmet. 2002, 13, 1993–2002; (d) García, J.L.; Alonso, S.A.; Blanco, D.; Martín, A.M.; Martín,
M.R.; Rodríguez, J.H. Org. Lett. 2001, 3, 3173–3176; (e) Cruz, D; Yuste, F.; Martín, M.R.; Tito, A.; García Ruano,
J. L. J. Org. Chem. 2009, 74, 3820–3826.
(4) (a) García Ruano, J.L.; Fraile,A.; Martín, M.R. Tetrahedron 1999, 55, 14491–14500; (b) García Ruano, J.L.; Bercial,
F.; Fraile, A.; Martín, M.R. Synlett 2002, 73–76.
(5) (a) García Ruano, J.L.; Andrés, I.; Fraile A.; Martín Castro, A.M.; Martín, M.R. Tetrahedron Lett. 2004, 45, 4653–
4656; (b) García Ruano, J.L.; Fraile A.; Martín Castro, A.M.; Martín, M.R. J. Org. Chem. 2005, 70, 8825–8834.
(6) (a) García Ruano, J.L.; Fraile A.; Martín, M.R.; González, G.; Fajardo, C. J. Org. Chem. 2008, 73, 8484–8490; (b)
García Ruano, J.L.; Fraile A.; Martín, M.R.; González, G.; Fajardo, C.; Martín Castro, A.M. J. Org. Chem. 2011,
76, 3296–3305.
(7) García Ruano, J.L.; Fraile, A.; Martín, M.R.; Núñez, A. J. Org. Chem. 2006, 71, 6536–6541.
(8) García Ruano, J.L; Núñez, A.; Martín, M.R.; Fraile, A. J. Org. Chem. 2008, 73, 9366–9371.
(9) Núñez, A.; Martín, M.R.; Fraile, A.; García Ruano J.L. Chem. Eur. J. 2010, 16, 5443–5453.
(10) Fraile, A.; García Ruano, J.L.; Martín, M.R.; Tito, A. Tetrahedron 2010, 66, 235–241.
(11) (a) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron Lett. 1992, 33, 2701–2704; (b) Hong, T.W.;
Jímenez, D.R; Molinski, T.F. J. Nat. Prod. 1998, 61, 158–161; (c) Kinel, R.B.; Grhrken, H.-P.; Scheurer, P.J. J. Am.
Chem. Soc. 1993, 115, 3376–3377; (d) Bringmann, G.; Hamm, A.; Kraus, J.; Ochse, M.; Noureldeen, A.; Jumbam,
D.N. Eur. J. Org. Chem. 2001, 1983–1987; (e) Taglialatela-Scafati, O.; Deo-Jangra, U.; Campbell, M.; Roberge, M.;
Andersen, J. Org. Lett. 2002, 4, 4085–4088.
(12) (a) Ratni, H.; Blum-Kaelin, D.; Dehmlow, H.; Hartman, P.; Jablonski, P.; Masciadri, R.; Maugeais, C.; Patiny-Adam,
A.; Panday, N.; Wright, M. Bioorg. Med. Chem. Lett. 2009, 19, 1654–1657; (b) Conti, P.; De Amici, M.; Grazioso,
G.; Roda, G.; Stensbøl, T.B.; Bräuner-Osborne, H.; Madsen, U.; Toma, L.; De Micheli, C. Eur. J. Org. Chem. 2003,
4455–4461; (c) Santora, V.J.; Covel, J.A.; Hayashi, R.; Hofilena, B.J.; Ibarra, J.B.; Pulley, M.D.; Weinhouse, M.I.;
Sengupta, D.; Duffield, J.J.; Semple, G.; Webb, R.R.; Sage, C.; Ren, A.; Pereira, G.; Knudsen, J.; Edwards, J.E.;
Suarez, M.; Frazer, J.; Thomsen, W.; Hauser, E.; Whelan, K.; Grottick, A.J. Bioorg. Med. Chem. Lett. 2008, 18,
1490–1494; (d) Kramp, G.J.; Kim, M.; Gais, H.-J.; Vermeeren C. J. Am. Chem. Soc. 2005, 127, 17910–17920
and references cited therein; (e) Bisht, K.S.; Van Olphen, A.; Khan, P.M.; Bucher, C. PCPT Int. Appl. 2009, WO
2009076397 A2 20090618; (f) Conti, P.; De Amici, M.; Grazioso, G.; Roda, G.; Pinto, A.; Hasen, K.B.; Nielsen, B.;
Madsen, U.; Bräuner-Osborne, H.; Egebjerg, J.; Vestri, V.; Pellegrini-Giampietro, D.E.; Sibille, P.; Acher, F.C.; De
Micheli, C. J. Med. Chem. 2005, 48, 6315–6325; (g) Jones, R.M.; Han, S.; Thoresen, L.; Jung, J.; Strah-Pleynet, S.;
Zhu, X.; Xiong, Y.; Yue, D. PCPT Int. Appl. 2011, WO 2011025541 A1 20110303.
(13) García Ruano, J.L.; Alonso, M.; Cruz, D.; Fraile, A.; Martín, M.R.; Peromingo, M.T.; Tito, A.;Yuste, F. Tetrahedron
2008, 64, 10546–10551.
(14) García Ruano, J.L.; Tito, A.; Peromingo, M.T. J. Org. Chem. 2003, 68, 10013–10019.
(15) (a) Lee, S.-G.; Kim, Y.Y.; Yoo, J.H.; Lee, J.K. Korean J. Med. Chem. 2000, 10, 10–13; (b) Lorello, G.R.; Legault,
M.C.B.; Rakic´, B.; Bisgaard, K.; Pezacki, J. P. Bioorg. Chem. 2008, 36, 91–97. (c) Bianchi, G.; De Micheli, C.;
Gandolfi, R.; Grünanger, P.; Vita Finzi, P.; Vajna de Pava, O. J. Chem. Soc. Perkin I 1973, 1148–1155. (d) Kraus,
G.A.; Nagy, J.O. Tetrahedron 1985, 41, 3537–3545; (e) Chaulagain, M.R.; Aron, Z.D. J. Org. Chem. 2010, 75,
8271–8274; (f) Zhang, C.; Yu, S-B.; Hu, X-P.; Wang, D-Y.; Zheng, Z. Org. Lett. 2010, 12, 5542–5545.

32 J.L. García Ruano et al.
(16) Hulce, M.; Mallamo, J.P.; Frye, L.L.; Kogan, T.P.; Posner, G.H. Org. Synth. 1986, 64, 196–206.
(17) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383–2386.
(18) Andrés, J.I.;Alcázar, J.;Alonso, J.M.; Díaz,A.; Fernández, J.; Gil, P.; Iturrino, L.; Matesanz, E.; Meert, T.F.; Megens,
A.; Sipido, V.K. Bioorg. Med. Chem. Lett. 2002, 12, 243–248.
(19) (a) Reed,A.D.; Hegedus, L.S. J. Org. Chem. 1995, 60, 3787–3794; (b)Alonso-Perarnau, D.; de March, P.; Figueredo,
M.; Font, J.; Soria, A. Tetrahedron 1993, 49, 4267–4274; (c) Keller, E.; de Lange, B.; Rispens, M.T.; Feringa, B.L.
Tetrahedron 1993, 49, 8899–8910.
(20) Abdel-Magid, A.F.; Carson, K.G.; Harris, B.D.; Maryanoff, C.A.; Shah, R.D. J. Org. Chem. 1996, 61, 3849–3862.
(21) (a) Fariña, F.; Fraile, M.T.; Martín, M.R.; Martín, M.V.; Martínez, A. Heterocycles 1995, 40, 285–292; (b) Alguacil,
R.; Fariña, F.; Martín, M.V. Tetrahedron 1996, 52, 3457–3472; (c) García Ruano, J.L.; Fajardo, C. Martín, M.R.
Tetrahedron 2005, 61, 4363–4371.
(22) (a) Evans, D.A.;Andrews, G.C. Acc. Chem. Res. 1974, 7, 147–155; (b) Hoffmann, R.W. Angew. Chem. Int. Ed. 1979,
18, 563–572.
(23) (a) Curran, T.T.; Hay, D.A.; Koegel, C.P.; Evans, J.C. Tetrahedron 1997, 53, 1983–2004; (b) Becker, N.; Carreira,
E.M. Org. Lett. 2007, 9, 3857–3858.