The role of the sulfinyl group on the course of the reactions of 3-p-tolylsulfinylfuran-2(5H)-ones with nitrones. Synthetic uses of cycloreversion processes

Article abstract of DOI:10.1021/jo0513111

The reaction of enantiopure 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) with cyclic (4) and acyclic (6) nitrones afforded furoisoxazolidines (5 and 7) in high yields under mild conditions. The reactivity of the dipolarophile was dramatically enhanced by

Full text of DOI:10.1021/jo0513111

The Role of the Sulfinyl Group on the Course of the Reactions of
3-p-Tolylsulfinylfuran-2(5H)-ones with Nitrones. Synthetic Uses of
Cycloreversion Processes
Jose´ L. Garc´ıa Ruano,* Alberto Fraile, Ana M. Mart´ın Castro, and M. Rosario Mart´ın*
Departamento de Quı´mica Orga´nica, Universidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain
joseluis.garcia.ruano@uam.es
Received June 27, 2005
The reaction of enantiopure 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) with cyclic (4) and acyclic
(6) nitrones afforded furoisoxazolidines (5 and 7) in high yields under mild conditions. The reactivity
of the dipolarophile was dramatically enhanced by the sulfinyl group, which modulated the π-facial
selectivity (it was complete for reactions from 2b, yielding only the anti adducts) and was the main
controller of the endo/exo selectivity. Cycloreversion processes from the resulting sulfinyl furoisox-
azolidines proceeded readily and were to be considered to account for an improvement in the
selectivity (facial and endo/exo) and even for an inversion of it when the composition of the reaction
mixtures obtained under kinetic and thermodynamic conditions were quite different.
Introduction
years ago, we initiated a program to explore the useful-
ness of vinyl sulfoxides in asymmetric 1,3-dipolar reac-
tions. The behavior of arylsulfinylfuran-2(5H)-ones in
their reactions with diazoalkanes,5 and nitrile oxides6
demonstrated the strong influence of the sulfinyl group
in the course of these reactions, as it dramatically
enhanced the features of butenolides as chiral dipolaro-
philes. Similar good results were observed in reactions
of vinyl sulfoxides with azomethine ylides,7 where the
final elimination of the sulfinyl group from the adducts
was used for synthesizing interesting dihydropyrroles.
More recently, we reported the synthesis of pyrrolo-
azepines from the isoxazoloazepines2b obtained by reac-
The asymmetric 1,3-dipolar cycloaddition of nitrones
to homochiral olefins is one of the most efficient methods
for obtaining isoxazolidines.1 In this context, the use of
furan-2(5H)-ones (butenolides) and their 5-alkoxy deriva-
tives as dipolarophiles has been widely investigated due
to the interest in the resulting furoisoxazolidines.2 Vinyl
sulfoxides have been only occasionally used as dipolaro-
philes in these reactions,3 despite the good results
obtained from them in Diels-Alder reactions.4 Several
(1) (a) Tufariello, J. J. in Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; John Wiley and Sons: New York, 1984; Vol. 2, Chapter 9, pp
83-168. (b) Frederickson, M. Tetrahedron 1997, 53, 403-425.
(2) (a) Tufarello, J. J.; Tette, J. P. J. Org. Chem. 1975, 40, 3866-
3869. (b) Garc´ıa Ruano, J. L.; Andres, J. I.; Fraile, A.; Mart´ın Castro,
A. M.; Mart´ın, M. R. Tetrahedron Lett. 2004, 45, 4653-4656. (c)
Venkatesan, A. M.; Levin, J. I. U.S. Patent No 5294611 A, 1994; Chem.
Abstr. 1994, 121, 300910.
(3) With nitrones: (a) Louis, C.; Hootele´, C. Tetrahedron: Asym-
metry 1997, 8, 109-131 and references therein. (b) Aggarwal, V. K.;
Roseblade, S.; Barrell, J. K.; Alexander, K. Org. Lett. 2002, 4, 1227-
1229. With nitrile oxides: (c) Bravo, P.; Bruche´, L.; Crucianelli, M.;
Farina, A.; Meille, S. V.; Merli, A.; Seresini, P. J. Chem. Res., Synop.
1996, 348-349; J. Chem. Res., Miniprint 1996, 1901-1923. (d) Garc´ıa
Ruano, J. L.; Fajardo, C.; Mart´ın, M. R. Tetrahedron 2005, 61, 4363-
4371.
(4) Cid, B.; Garc´ıa Ruano, J. L. In Topics in Current Chemistry; Page,
P. C. B., Ed.; Springer: Weinheim, 1999; pp 1-126.
(5) (a) Garc´ıa Ruano, J. L.; Fraile, A.; Mart´ın, M. R. Tetrahedron:
Asymmetry 1996, 7, 1943-1950. (b) Garc´ıa Ruano, J. L.; Fraile, A.;
Gonza´lez, G.; Mart´ın, M. R.; Clemente, F. R.; Gordillo, R. J. Org. Chem.
2003, 68, 6522-6534. (c) Garc´ıa Ruano, J. L.; Bercial, F.; Gonza´lez,
G.; Mart´ın Castro, A. M.; Mart´ın, M. R. Tetrahedron: Asymmetry 2002,
13, 1993-2002.
(6) (a) Garc´ıa Ruano, J. L.; Fraile, A.; Mart´ın, M. R. Tetrahedron
1999, 55, 14491-14500. (b) Garc´ıa Ruano, J. L.; Bercial, F.; Fraile,
A.; Mart´ın, M. R. Synlett 2002, 73-76.
(7) (a) Garc´ıa Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem.
2003, 68, 10013-10019. (b) Garc´ıa Ruano, J. L.; Tito, A.; Peromingo,
M. T. J. Org. Chem. 2002, 67, 981-987.
10.1021/jo0513111 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/27/2005
J. Org. Chem. 2005, 70, 8825-8834
8825

Garc´ıa Ruano et al.
SCHEME 1
TABLE 1. Results Obtained in Reactions of 2a with 4
anti
endo/exo
syn
endo/exo
entry
solvent
T (°C)
time (h)
A/B/C/D
anti/syn
1
2
CHCl3
-40
0
336
14
23:39:38:0
28:39:32:1
24:46:29:1
29:40:27:4
35:42:19:4
31:40:28:1
33:36:30:1
36:38:24:2
43:46:7:4
62:38
67:33
70:30
69:31
77:23
71:29
69:31
74:26
89:11
90:10
86:14
86:14
87:13
63:37
58:42
66:34
58:42
55:45
56:44
52:48
51:49
52:48
44:56
52:48
52:48
49:51
100:0
97:3
CHCl3
3a
4
CHCl3
rt
1
97:3
CHCl3
rt
rt
60
0
rt
rt
110
0
24
96
0.3
2
87:13
83:17
97:3
97:3
92:8
64:36
50:50
100:0
100:0
85:15
5
CHCl3
6
CHCl3
7
Toluene
Toluene
Toluene
Toluene
CH3CN
CH3CN
CH3CN
8
0.25
648
0.1
15.5
24
9
10
11
12
13
50:40:5:5
41:45:14:0
41:45:14:0
44:43:11:2
rt
80
0.25
a 86% combined yield.
tion of morphantridine N-oxide 1 with the two epimers
at C5 of 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one (2). The
stereoselectivity of these reactions suggested that the
sulfinyl group played a significant role, but their most
intriguing point was related to the readiness of the
cycloreversion, which determined their use with synthetic
purposes. Thus, reaction of 1 with 2a yielded a mixture
of three adducts (Scheme 1), the major one, anti-3a-endo,
having been obtained with low diastereomeric ratio in
the reactions at rt. However, its relative proportion
increased significantly when the reaction was conducted
at 100 °C and finally it was obtained in 76% isolated yield
after crystallization from the reaction crude.
Initially, we thought that this interesting behavior
associated to the cycloreversion should be related to the
stability of the nitrone 1, but the publication of another
paper on the easy cycloreversion of isoxazolines derived
from alkylidene malonates8 suggested us the possibility
that the easy cycloreversion could be a general property
of isoxazolidines derived from olefines bearing two elec-
tron-withdrawing groups in the gem-position. If this was
the case, sulfinylbutenolides 2a and 2b would exhibit a
higher potential as chiral dipolarophiles because the
stereoselectivity could be substantially modified with the
reaction conditions (kinetic versus thermodynamic con-
trol). To clarify this point, we have studied the reactions
of 2a and 2b with other cyclic and acyclic nitrones (4 and
6), with the aim of better understanding the role of
sulfinyl group on the stereoselectivity of these cycload-
ditions. These results would also provide further evi-
dences to rationalize the cycloreversion involving ni-
trones, which to our knowledge had not been so far
systematically considered in the literature.
Sulfinylfuranones 2a and 2b were prepared according
to previously reported procedures.9 Reaction of furanone
2a with 3,4-dihydro-2H-pyrrole 1-oxide (4) in chloroform
at rt for 1 h (entry 3, Table 1) afforded a mixture of four
stereoisomeric adducts 5a (Table 1).10 All of them, except
the minor one, syn-5a-exo, were isolated as pure com-
pounds by column chromatography. The high stability
of the adducts in the solid state (they remain unaltered
for several months without special precautions) contrasts
with the instability of some of them in polar solvents,
since they evolved in solution at rt into a mixture of
adducts and the starting furanone. This was the first
evidence proving that cycloreversion was very easy from
(8) The easy cycloreversion of isoxazolidines derived from alkylidene
malonates was reported during the preparation of this manuscript
(Huang, Z.-Z., Kang, Y.-B., Zhou, J.; Ye, M.-C.; Tang, Y. Org. Lett. 2004,
6, 1677).
(9) Carretero, J. C.; Garc´ıa Ruano, J. L.; Lorente, A.; Yuste, F.
Tetrahedron: Asymmetry 1993, 4, 177-180.
8826 J. Org. Chem., Vol. 70, No. 22, 2005

Synthetic Uses of Cycloreversion Processes
TABLE 2. Reactions of 2b with Nitrone 4
these adducts. The same conclusion could be reached
from the reaction crudes obtained when the reactions of
2a and 4 were performed at different times or under
different conditions (see Table 1). The reaction was
completely regioselective in all conditions, exclusively
yielding compounds with the oxygen at the nitrone
bonded to C4 at the furanone. The π-facial selectivity
(anti/syn ratio) was moderate in toluene or CHCl3 at low
temperatures (presumably kinetic control conditions),
ranging between ∼2:1 and ∼3:1 (entries 1-4, 7, and 8).
It increased when the reaction times were longer (entries
5 and 9) or when the temperature raised (entries 6 and
10), which presumably are thermodynamic control condi-
tions. The best stereoselectivity was observed in refluxing
toluene (anti/syn ) 90:10, entry 10). The use of acetoni-
trile as the solvent increased significantly the anti/syn
ratio, which was almost identical at 0 °C (86:14, entry
11) and 80 °C (87:13, entry 13) and similar to that of
entry 10 (presumably thermodynamic control conditions).
Concerning the endo/exo selectivity, the anti approach
was moderately endo selective, whereas the syn approach
was almost completely endo selective when the reactions
were conducted under kinetic control conditions. By
contrast, under thermodynamic control conditions, the
anti approach afforded almost equimolecular mixtures
of endo and exo adducts regardless the solvent, whereas
the syn approach gave mixtures where the endo/exo ratio
was very small in toluene (entry 10) but it remained
significant in more polar solvents (entries 5 and 12).
An additional result demonstrating that cycloreversion
was very easy was the formation of a 60:40 mixture of
anti-5a-endo and anti-5a-exo by refluxing in toluene
diastereomerically pure samples of anti-5a-endo or anti-
5-exo.
isolated
yield (%)
entry
solvent
T (°C)
time
48 h
10 min
4 days
48 h
endo/exo
endo
exo
1
2
CH3CN
CH3CN
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
-40
rt
rt
80:20
72:28
59:41
80:20
75:25
69:31
67:33
62:38
54:46
68:32
58:42
59:41
53:47
47:53
18:82
13:87
65
71
58
15
18
29
3
4
-40
-22
0
5
4 h
1 h
6
7
rt
10 min
1 day
4 days
22 h
10 min
5 min
1 day
4 days
5 min
1 h
8
rt
9
rt
10
11
12
13
14
15
16
-40
0
rt
rt
rt
110
110
11
71
TABLE 3. Cycloadditions of N-Methyl-r-phenylnitrone
(6) to Sulfinylfuranone 2a
Reactions of 2b with 4 were faster than those of 2a
and afforded only anti adducts (Table 2), which were
easily separated by chromathography. Under kinetic
control conditions (low temperature and short reaction
time), compound anti-5b-endo was obtained as the major
one. However, under thermodynamic control conditions
(longer reaction times and mainly higher temperatures),
the anti-5b-exo adduct became the major one.
As an unequivocal proof that cycloreversion was also
very easy in these reactions, compound anti-5b-endo
evolved into a 90:10 mixture of anti-5b-exo and anti-5b-
endo by refluxing in toluene for 1 h.
isolated
yield (%)
entry
solvent
T (°C)
time (h)
anti/syn
anti
syn
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CHCl3
CHCl3
CHCl3
toluene
toluene
toluene
toluene
0
48
8a
93:7
92:8
90
90
68
6
7
27
rt
rt
18
96
2.5
7.5
24
96
3.5
70:30a
74:26
71:29
82:18
81:19
84:16
89:11
rt
60
rt
rt
rt
110
73
9
a The same results were obtained after 24 h.
The results of the reactions of N-methyl-R-phenylni-
trone 6 with sulfinylfuranones 2a and 2b are shown in
Tables 3 and 4, respectively. The reactivity of the acyclic
nitrone 6 was lower than that of the cyclic one 4, as it
can be deduced from the reaction times required to reach
completion (compare Tables 1 and 3 or 2 and 4). The
π-facial selectivity was very high for 2a and became
complete for 2b (the anti adducts were always favored)
under both kinetic and thermodynamic control condi-
tions. The best de’s were those obtained in acetonitrile
at low temperatures (entries 1 and 2 in Table 3 and entry
1 in Table 4). It indicates that the anti adducts are both
the most easily formed as well as the most stable ones.
However, the observed endo selectivity was complete for
2a and high, but not complete, for 2b. Under conditions
of entries 3, 13, and 14 (Table 4), the endo selectivity was
very high. Therefore, the differences in the behavior of
2b and 2a when they reacted with 6 were similar to those
observed in their reactions with 4. However, both the
π-facial (with 2a) and the endo selectivity substantially
improved for acyclic nitrone 6 as compared with the cyclic
one 4.
(10) The syn or anti character of the adducts, which indicates the
cis or trans relationship between H3 and H3a (Table 1), is related to
the face of the dipolarophile attacked by the dipole, using as a reference
the spatial arrangement of the ethoxy group. Thus, the syn adducts
result from the approach of the dipole to the face bearing the OEt
group, whereas the anti adducts are obtained by the approach to the
opposite face. The endo or exo terms indicate, respectively, the cis or
trans arrangement adopted by the furanone and pyrrolidine (or phenyl)
moieties at the isoxazolidine ring formed in the reactions from nitrone
4 (or 6). They are related to the endo and exo addition modes of the
dipole, using the ester group at the furanone ring as a reference.
J. Org. Chem, Vol. 70, No. 22, 2005 8827

Garc´ıa Ruano et al.
FIGURE 1. Evolution of a 91:9 mixture of syn-5a-endo and anti-5a in acetonitrile at rt.
TABLE 4. Cycloadditions of N-Methyl-r-phenylnitrone
Several experiences have been performed in order to
get a more direct information about the cycloreversion
processes. Thus, starting from a 91:9 (6 + 3) mixture of
syn-5a-endo and anti-5a (exo + endo) solved in acetoni-
trile at rt, when recording the 1H NMR spectra at
different times, we obtained the results depicted in
Figure 1. As we see, the original mixture evolved into a
mixture of three compounds with a similar composition
to that indicated in entry 12 of Table 1, which clearly
evidences that both equilibria (endo/exo and syn/anti)
were taking place.
Clearer results were obtained in cases where only one
of the above-mentioned equilibria were reached. Thus,
reaction of 2b with the cyclic nitrone 4 allowed us to
follow the endo/exo equilibration in acetonitrile or toluene
at 60 °C (Figure 2). We can see that it was slower in
toluene but the proportion of the major adduct was the
highest.
(6) to Sulfinylfuranone 2b
isolated
yield (%)
entry
solvent
T (°C)
time
72 h
2.5 h
24 h
10 h
2.5 h
1 day
4 days
15 min
5.5 h
1 h
1 day
4 days
5 min
1 h
endo/exo
endo
exo
1
2
CH3CN
CH3CN
CH3CN
CHCl3
-20
rt
86:14
84:16
72
13
3
rt
>98:<2
90:10
4
0
5
CHCl3
rt
80:20
67
19
29
6
CHCl3
rt
89:11
7
CHCl3
rt
89:11
8
CHCl3
60
0
79:21
Finally, a similar study was performed with the
reaction of 2a with the acyclic nitrone 6 in order to obtain
evidence about the syn/anti equilibration. The obtained
results were almost identical, the equilibration being
slower in toluene, which was also the solvent where the
observed de’s were the highest.
9
toluene
toluene
toluene
toluene
toluene
toluene
82:18
10
11
12
13
14
rt
67:33
59
rt
70:30
rt
76:24
110
110
>98:<2
>98:<2
86
82
The elucidation of the structures of all the obtained
adducts (5 and 7) was performed from their NMR
parameters and those of their corresponding desulfini-
lated compound (5′ and 7′) shown in Scheme 2.11 All of
the obtained adducts exhibit the same regiochemistry,
which was inferred from the ∆δ values (δC3a - δC6a)
observed for different compounds, all smaller than 6
ppm.12 The syn or anti stereochemistry was easily
deduced from the value of the vicinal coupling constant
J3,3a. It was lower than 2.2 Hz for protons in a trans
relationship (anti adducts) but higher than 4.3 Hz for
protons in a cis arrangement (syn adducts).5b,13 As an
additional confirmation, all of the anti adducts exhibited
higher chemical shifts for the acetalic proton than those
of their corresponding syn adducts, presumably due to
One interesting point deduced from the results col-
lected in Tables 3 and 4 is the fact that they indicate
that cycloreversion also took place from adducts 7, and
it affected the endo/exo and the anti/syn equilibria. As
compounds anti-7a-endo and anti-7b-endo are favored
under both kinetic and thermodynamic conditions, they
were the major isomers obtained under all conditions.
In turn, the minor components, syn-7a-endo and anti-
7b-exo, can only be obtained in low yields under specific
conditions (entry 3, Table 3, and entry 10, Table 4). The
completely stereoselective conversion of 2b into anti-7b-
endo under thermodynamic conditions (entries 3, 13, and
14 in Table 4) was also remarkable. From Tables 3 and
4, it seems that thermodynamic equilibria were reached
more quickly as the solvent polarity increased, the
shorter times having been observed in acetonitrile. The
same conclusion could be reached from the results
collected in Tables 1 and 2. Finally, the composition of
the reaction mixtures obtained under thermodynamic
conditions was dependent on the relative stability of the
species in equilibrium, which in turn were related to the
solvent polarity.
(11) To simplify the discussion of structural elucidation of adducts,
all adducts are numbered as indicated in Scheme 2, despite the fact
that it is not correct for compounds 7.
(12) The regioisomer with a sulfur and an oxygen bonded to the
same carbon would display a higher ∆δ value because of the additive
influence of the two electronegative atoms.
(13) Rispens, M. T.; Keller, E.; de Lange, B.; Zijlstra, W. J.; Feringa,
B. L. Tetrahedron: Asymmetry 1994, 5, 607-624.
8828 J. Org. Chem., Vol. 70, No. 22, 2005

Synthetic Uses of Cycloreversion Processes
FIGURE 2. Evolution of adducts anti-5b at 60 °C in acetonitrile or toluene.
SCHEME 211
were transformed into (-)-9 by following the sequence
indicated in Scheme 3. This correlation confirms that 8
and anti-5b′-exo exhibit the same absolute configurations
at C6, C6a, and C3a.
To determine the role of the sulfinyl group on the
course of the 1,3-dipolar cycloadditions, it was necessary
to compare the results of Tables 1-4 with those obtained
in reactions of 4 and 6 with 5-alkoxyfuran-2(5H)-ones
bearing no sulfinyl group. These reactions were studied
by Feringa from 5-methoxy- and (5R)-menthyloxyfuran-
2(5H)-ones13,16 and by Hegedus from 5-alkyl-5-alkoxyfu-
ran-2(5H)-ones and cyclic nitrones.17 The reactions of
5-monosubstituted furanones with 4 and 6 required 16
and 12 h, respectively (in refluxing toluene), and gave
only the anti-exo and anti-endo adducts (exo/endo ) 88:
12 from 4 and 69:31 from 6 and menthyloxyfuranone).
Reactions of 5-disubstituted furanones with 4 (in reflux-
ing toluene for 3-4 h at rt) afforded anti-exo as the only
adduct. Steric13,16 and electrostatic repulsions between
the oxygen at nitrone and the 5-alkoxy moiety17 were
invoked to account for the complete control of the π-facial
selectivity. Comparison of these results with those col-
lected in Tables 1-4 allowed us to reach some conclu-
sions. Concerning the reactivity, the influence of the
sulfinyl group seemed very high, mainly in the case of
the epimer 2b (which was more reactive than 2a, vide
infra), whose reactions in refluxing toluene were complete
in 5 min with both nitrones (Tables 2 and 4). This
dramatic enhancement of the dipolarophilic reactivity
toward nitrones induced by the sulfinyl group at C3 of
furan-2(5H)-ones had also been found in their reactions
with diazoalkanes5 but significantly contrasts with the
rather moderate influence the sulfinyl group on the
dienophilic reactivity of the furanones.18 This different
behavior suggests an important role of the electrostatic
interactions in the stability of the transition states of 1,3-
dipolar cycloadditions, which is not significant in Diels-
the shielding effect of the p-tolyl group in the latter ones.
The relative configuration of C6 and C6a, indicative of the
endo or exo character of the adducts, could not be
unequivocally established from the NMR parameters of
compounds 5-7. This problem was solved by desulfin-
ylation of these adducts with aluminum amalgam in
THF/H2O (9:1), which afforded compounds 5′-7′ with a
hydrogen atom at the position initially occupied by the
sulfur function. The rigid cyclic structure of the adducts
precludes epimerization at C6a, and therefore, H6a and
H
3a are in a cis relationship. The endo or exo stereochem-
istry of compounds 5′-7′ was unequivocally deduced from
their J6,6a values, which were higher than 7 Hz for
compounds exhibiting a cis relationship between the
involved protons and lower than 4.5 Hz for those with a
trans relationship.2b,13,14
The structures and absolute configurations for com-
pounds syn-5a-endo and anti-5b-endo were unequivocally
established by X-ray diffraction studies.15 In Figure 3,
the relative position of the p-tolyl group with respect to
H3 in adduct syn-5a-endo can be seen, which would
explain the shielding observed for such a proton in
compounds of identical stereochemistry.
We have also confirmed the absolute configuration of
compound anti-5b-exo by chemical correlation with the
adduct 8, obtained by Feringa in the reaction of 5-men-
thyloxyfuran-2(5H)-one with nitrone 4.13 Both compounds
(14) Alonso-Perarnau, D.; de March, P.; Figueredo, M.; Font, J.;
Soria, A. Tetrahedron 1993, 49, 4267-4274.
(16) Keller, E.; de Lange, B.; Rispens, M. T.; Feringa, B. L.
Tetrahedron 1993, 49, 8899-8910.
(15) Crystallographic data (excluding structure factors) for syn-5a-
endo and anti-5b-endo have been deposited with the Cambridge
Crystallographic Data Centre as suplementary publication number
CCDC 274908 and 274907, respectively. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, U.K. [fax: +44(0)-1223-366033 or e-mail:
deposit@ccdc.cam.ac.uk].
(17) Reed, A. D.; Hegedus, L. S. J. Org. Chem. 1995, 60, 3787-3794.
(18) The reactivity at room temperature of the sulfinylfuranone 2
with cyclopentadiene (see ref 9) was less than 20 times higher than
that of the desulfinylated furanone (Garc´ıa Ruano, J. L.; Bercial, F.;
Fraile, A.; Mart´ın Castro, A. M.; Mart´ın, M. R. Tetrahedron: Asym-
metry 2000, 11, 4737-4752).
J. Org. Chem, Vol. 70, No. 22, 2005 8829

Garc´ıa Ruano et al.
FIGURE 3. X-ray structures for syn-5a-endo and anti-5b-endo.
SCHEME 3
Alder reactions. In this sense, the reactions of 2 and
nitrones are faster in toluene, the less polar solvent out
of all those used.
The regioselectivity of the reactions of 2a and 2b with
4 and 6 was complete, only affording isoxazolidines with
the nitrone oxygen bonded to C4 at furanone. As this is
the same regioisomer that it was obtained in reactions
of these nitrones with 5-alkoxyfuran-2-(5H)-one, we can
conclude that the regioselectivity was not modified by the
sulfinyl group.
The π-facial selectivity observed in reactions from 2b
was identical to that of desulfinylated furanones, with
the exclusive formation of the anti adducts (Tables 2 and
4). It can be easily explained by assuming that the anti
approach was strongly favored by the 5-alkoxy group due
to its steric and electrostatic repulsions with the oxygen
at the nitrone,17 as well as the steric grounds of the
sulfoxide adopting the s-cis arrangement of its sulfinyl
oxygen (Figure 4) to minimize repulsions with the car-
bonyl oxygen. Therefore, the anti approach to 2b must
be favored by both 5-alkoxy and 3-p-tolylsulfinyl groups
(Figure 4). In the case of the epimer 2a, the preferred
conformation around the C-S bond arranges the p-tolyl
group at the opposite face to that bearing the ethoxy
group, which would explain the incomplete π-facial
selectivity observed in these reactions (Tables 1 and 3)
as a consequence of the competence between both direct-
ing groups (Figure 4). As the anti adducts also were
predominant in reactions from 2a (Tables 1 and 3), a
conformational equilibrium between A and B rotamers
(Figure 4) can be assumed and the anti adducts were
obtained by anti approach to B conformer. We can
conclude that the orientating character of the alkoxy
group was rather higher than that of the sulfinyl one.
The same model would allow us to explain the lower
reactivity exhibited by the epimer 2a.
The presence of the sulfinyl group sharply increased
the proportion of the endo isomers in all the cases (with
cyclic or acyclic nitrone, anti or syn approach). The
cycloadditions reported in this paper, under kinetic
control conditions, were almost completely endo selective
(Tables 1-4), except for the addition of nitrone 4 to 2a
in the anti approach (see Table 1), where the endo/exo
ratios ranged between 63/37 and 52/48. The sulfinyl
group must be the main responsible for this behavior as
it can be inferred from the comparison of our results with
those obtained in reactions of 5-alkoxyfuran-2(5H)-ones
FIGURE 4. π-Facial selectivity of additions of nitrones to 3-sulfinylfuranones 2.
8830 J. Org. Chem., Vol. 70, No. 22, 2005

Synthetic Uses of Cycloreversion Processes
FIGURE 5. Transition states for the syn-approach of nitrone 4 to furanone 2a.
FIGURE 6. Stereochemical course of the reactions of 5-alkoxyfuranones with nitrone 4.
with 4 and 6, which afforded the exo isomers as the only
or major product.
explained by evolution via the E-isomer, which is usually
much more reactive, despite the fact that it exists as the
minor isomer in the equilibrium.20 The fact that the same
product was obtained through an anti-endo approach of
the Z-nitrone or an anti-exo approach of the E-isomer,
as it is illustrated in Figure 7 for the formation of anti-
7a,b-endo and anti-7a,b-exo, makes difficult any expla-
nation. However, in Figure 7 it can be seen that the
approaches I and II to yield anti-7a,b-endo are more
stabilized than III and IV, which afford their correspond-
ing exo isomers, due to the steric interaction Ph/SOTol
in the later ones. This interactions must be more desta-
bilizing for 2a than for 2b (compare the approaches
III,IV-a with III,IV-b). This justifies the low or none
proportion of the anti-7b-exo and anti-7a-exo in their
respective reactions.
The last point to be discussed concerns the cyclorever-
sion processes, which determined significant changes in
the composition of the reaction mixtures depending on
the reaction conditions and can be used for synthetic
purposes. Under thermodynamic control conditions (high
temperatures and long reaction times) the formation of
the presumably more stable anti adducts was always
favored (see Tables 1 and 3) but the endo/exo ratio was
markedly dependent on the stereochemistry of the sul-
finylfuranone and the structure of the nitrone. The
predominance of the endo adducts was very high or even
exclusive in reactions from the acyclic nitrone 6 (Tables
3 and 4), but it was almost inexistent or even the exo
adduct was predominant in reactions from cyclic nitrone
4 (Tables 1 and 2). The different polarity of the adducts
must be responsible for the different composition of the
equilibria in the studied solvent.
In Figure 5 are depicted the TSs for the endo-syn and
exo-syn approaches of nitrone 4 to 2a. The endo-orienting
character of the ester group and the electrostatic attrac-
tion between the negative charge at the acetalic oxygen
and the positive charge at the nitrogen could account for
the almost exclusive formation of the endo-5a-syn adduct
under kinetic control conditions.19
In the case of the anti approaches, where the above-
mentioned electrostatic attraction was not significant,
steric interactions must be predominant. TS-I and TS-
II (Figure 6) are the two possible transition states for
the reactions of 4 with 5-alkoxyfuran-2(5H)-ones. The
formation of the anti-exo adduct as the major13,16 or only17
product can be explained by assuming that steric interac-
tions at TS-I are larger than at TS-II. The introduction
of the sulfinyl group at C3 of dipolarophile increases the
proportion of the endo isomers under kinetic control
conditions (Tables 1 and 2) and scarcely modifies the
stability of the transition state corresponding to the endo-
anti approach (TS-III and TS-I only differ in the H/SOTol
interaction) whereas strongly destabilizes the exo-anti
approach (TS-IV much less stable than TS-II due to the
ring/SOTol interactions), which could become the least
stable one for reactions of sulfinylbutenolides with 4.
The results obtained in reactions of the acyclic nitrone
6 are much more difficult to be explained because of the
configurational instability of the nitrone. At low temper-
ature, this compound adopts the Z configuration but the
Z-E equilibration is very easy, and on many occasions
the formation of the resulting cycloadducts has been
(19) One of the reviewers has suggested that the endo/exo selectivity
in polar cycloadditions could be explained by favorable coulombic
interactions between the nitrone, positively charged, and the furanone,
negatively charged, at the corresponding endo zwitterionic TS.
(20) Cristina, D.; De Micheli, C.; Gandolfi, R. J. Chem. Soc., Perkin
Trans. 1 1979, 2891-2895 and references therein.
J. Org. Chem, Vol. 70, No. 22, 2005 8831

Garc´ıa Ruano et al.
FIGURE 7. Stereochemical course of the reactions of sulfinylfuranones 2 with nitrone 6.
SCHEME 4
SCHEME 5
Cycloreversion could take place either according to
concerted or by step mechanisms (route 1 and route 2,
respectively, Scheme 4). The influence of the solvent
polarity on the cycloreversion rate (it was faster in the
most polar solvent, see Figures 1 and 2) does not allow
differentiation because the ring-opening products are
more polar in any case. However, from the available data
it seemed that the endo/exo equilibration required shorter
reaction times than the syn/anti equilibration (see Tables
1-4). It supports route 2 (Scheme 4) involving the
cleavage of the C-C in the first step because the resulting
intermediates I are able to give the endo/exo conversion
but not the syn/anti conversion, which would require the
cleavage of the O-C bond.
banion generated in the first step. Then, the cyclorever-
sion would be faster from sulfonylisoxazolidines than
from the corresponding sulfinyl derivatives, whereas it
would be slower from isoxazolidines bearing only one
electron-withdrawing group. Thus, cycloreversion from
sulfonylisoxazolidines 11, obtained by reaction of 5-ethoxy-
3-p-tolylsulfonylfuran-2(5H)-one (10)21 with nitrone 4
(Scheme 5), was faster than that from the corresponding
sulfinyl derivatives 5. In turn, when starting from (+)-
anti-5′-endo, with no sulfur function, the cycloreversion
was scarcely detected (after 16 h in refluxing toluene only
15% of the presumably most stable (-)-anti-5′-exo was
obtained). It suggests that the ready cycloreversion took
If route 2 was operative, the readiness of the cyclo-
reversion would depend on the stabilization of the car-
(21) Garc´ıa Ruano, J. L.; Fajardo, C.; Fraile, A.; Mart´ın, M. R. J.
Org. Chem. 2005, 70, 4300-4306.
8832 J. Org. Chem., Vol. 70, No. 22, 2005

Synthetic Uses of Cycloreversion Processes
(CH3). Anal. Calcd for C17H21NO5S: C, 58.10; H, 6.02; N, 3.99;
S, 9.12. Found: C, 58.13; H, 5.91; N, 4.15; S, 9.43.
place only when two electron-withdrawing groups were
bonded to C8b.
(R3,SS)-3-Ethoxy-8b-[(4-methylphenyl)sulfinyl-
3a,6,7,8,8a,8b-hexahydrofuro[3,4-d]pyrrolo[1,2-b]isoxazol-
1(3H)-ones (5b). Compound 5b was obtained as a mixture of
anti-5b-exo and anti-5b-endo from (R5,SS)-5-ethoxy-3-[(4-methyl-
phenyl)sulfinylfuran-2(5H)-one (2b) and 4. The experimental
conditions, the stereoisomer ratio, and the obtained yields are
shown in Table 2. The products were separated by column
chromatography (hexane/ethyl acetate, 3:1).
Conclusion
We have studied the reactions of sulfinyl furanones 2a
and 2b with cyclic and acyclic nitrones (4 and 6). The
sulfinyl group significantly enhances the dipolarophilic
reactivity of the furanones, it is the main responsible for
the endo/exo selectivity, and modulates the facial selec-
tivity imposed by the 5-alkoxy substituent. The adducts
suffer an easy cycloreversion, which determines signifi-
cant changes in the composition of the equilibria depend-
ing on the experimental conditions. As these changes
increase or invert the stereoselectivity, they can be used
with synthetic purposes. Finally, we have established
that cycloreversion must be expected for those isoxazo-
lidines bearing two electron withdrawing groups at C4.
(R3,S3a,S8a,R8b,SS)-anti-5b-exo. Colorless oil. [R]20D ) -52.8
1
(c 1.4, CHCl3). IR (CHCl3): 1765, 1597, 1352, 1083, 1057. H
NMR (200 MHz) δ: 7.58 and 7.28 (AA′BB′ system, 4H), 5.35
(s, 1H), 4.83 (s, 1H), 4.06 (dd, 1H, J ) 8.1 and 8.9), 3.40 (m,
3H), 3.02 (m, 1H), 2.58 (m, 1H); 2.40 (s, 3H), 2.22 (m, 1H),
2.06 (m, 1H), 1.89 (m, 1H), 0.99 (t, 3H, J ) 7.0). 13C NMR (50.3
MHz) δ: 171.2 (C), 143.0 (C), 135.4 (C), 129.4 (CH), 126.4 (CH),
108.1 (CH), 83.0 (C), 78.3 (CH), 74.2 (CH), 65.6 (CH2), 55.0
(CH2), 24.7 (CH2), 24.1 (CH2), 21.4 (CH3), 14.5 (CH3). Anal.
Calcd for C17H21NO5S: C, 58.10; H, 6.02; N, 3.99; S, 9.12.
Found: C, 57.45; H, 6.12; N, 4.13; S, 8.65.
(R3,S3a,R8a,R8b,SS)-anti-5b-endo. White solid. Mp: 103-
104 °C. [R]20 ) +81.2 (c 1.0, CHCl3). IR (KBr): 1765, 1595,
Experimental Section
D
1361, 1086, 1063. 1H NMR (200 MHz) δ: 7.55 and 7.31 (AA′BB′
system, 4H), 5.21 (s, 1H), 4.66 (s, 1H), 4.31 (m, 1H), 3.37-
3.06 (m, 4H), 2.41 (s, 3H), 2.22-1.79 (m, 4H), 0.84 (t, 3H, J )
7.0). 13C NMR (50.3 MHz) δ: 170.3 (C), 142.8 (C), 135.1 (C),
129.7 (CH), 125.6 (CH), 105.1 (CH), 83.7 (C), 82.3 (CH), 72.6
(CH), 65.6 (CH2), 55.6 (CH2), 26.1 (CH2), 23.6 (CH2), 21.4 (CH3),
14.2 (CH3). Anal. Calcd for C17H21NO5S: C, 58.10; H, 6.02; N,
3.99; S, 9.12. Found: C, 58.15; H, 5.70; N, 3.74; S, 8.86.
(S6,SS)-6-Ethoxy-2-methyl-3a-[(4-methylphenyl)sulfinyl]-
3-phenyl-3,3a,6,6a-tetrahydrofuro[3,4-d]isoxazol-4(2H)-
ones (7a). Compound 7a was obtained as a mixture of anti-
7a-endo and syn-7a-endo from (S5,SS)-5-ethoxy-3-[(4-methyl-
phenyl)sulfinyl]furan-2(5H)-one (2a) and nitrone 6, following
the general procedure. The stereoisomer ratio and the obtained
yields are indicated in Table 3. The products were isolated by
column chromatography (hexane/ethyl acetate, 3:1).
Cycloadditions of Nitrones. General Procedure. A
solution of furanone 2a or 2b (1.21 mmol) and nitrone 4 (1.82
mmol in 15 mL) or 6 (4.84 mmol in 16 mL) in the solvent
indicated in Tables 1-4 was stirred under argon at the
temperature and for the time indicated in Tables 1-4. The
1
reaction was monitored by TLC and H NMR. After comple-
tion, the solvent was removed at reduced pressure. The
adducts were isolated by column chromatography with the
eluent indicated in each case.
(S3,SS)-3-Ethoxy-8b-[(4-methylphenyl)sulfinyl]-
3a,6,7,8,8a,8b-hexahydrofuro[3,4-d]pyrrolo[1,2-b]isoxazol-
1(3H)-ones (5a). Compound 5a was obtained from (S5,SS)-5-
ethoxy-3-[(4-methylphenyl)sulfinyl]furan-2(5H)-one (2a) and
nitrone 4 (see Table 1) after 1 h of reaction time in chloroform
at room temperature in 86% combined yield. The stereoisomers
were separated by column chromatography (hexane/ethyl
acetate, 3:2).
(S3,S3a,S6,R6a,SS)-anti-7a-endo. White solid. Mp: 56-58
°C. [R]20D ) +188.0 (c 0.5, CHCl3). IR (KBr): 1778, 1595, 1083,
1
(S3,R3a,R8a,S8b,SS)-anti-5a-exo. White solid. Mp: 86-87 °C.
1051. H NMR (300 MHz) δ: 7.75 and 7.34 (AA′BB′ system,
[R]20 ) +219.7 (c 1.0, CHCl3). IR (Nujol): 1770, 1595, 1460,
4H), 7.22 (m, 3H), 6.89 (m, 2H), 5.64 (d, 1H, J ) 2.2), 4.98 (d,
1H, J ) 2.2), 3.88 (m, 1H), 3.73 (s, 1H), 3.70 (m, 1H), 2.47 (s,
3H), 2.45 (s, 3H), 1.25 (t, 3H, J ) 7.1). 13C NMR (75.5 MHz) δ:
168.2 (C), 143.2 (C), 135.2 (C), 132.1 (C), 129.7 (CH), 129.0
(CH), 128.3 (CH), 126.5 (CH), 106.5 (CH), 83.2 (CH), 81.3 (C),
76.8 (CH), 66.3 (CH2), 42.1 (CH3), 21.4 (CH3), 14.7 (CH3). Anal.
Calcd for C21H23NO5S: C, 62.82; H, 5.77; N, 3.49; S, 7.99.
Found: C, 62.90; H, 5.78; N, 3.44; S, 8.33.
D
1090, 1070. 1H NMR (200 MHz) δ: 7.60 and 7.25 (AA′BB′
system, 4H), 5.18 (s, 1H), 4.25 (s, 1H), 3.84 (dd, 1H, J ) 7.6
and 9.1), 3.34 (m, 1H), 3.31 (q, 2H, J ) 7.1), 2.95 (m, 1H), 2.40-
2.07 (m, 3H), 2.34 (s, 3H), 1.95-1.83 (m, 1H), 0.88 (t, 3H, J )
7.1). 13C NMR (50.3 MHz) δ: 170.0 (C), 143.2 (C), 135.4 (C),
129.7 (CH), 126.2 (CH), 106.5 (CH), 81.2 (CH), 79.6 (C), 73.9
(CH), 65.4 (CH2), 55.2 (CH2), 24.8 (CH2), 24.3 (CH2), 21.4 (CH3),
14.4 (CH3). Anal. Calcd for C17H21NO5S: C, 58.10; H, 6.02; N,
3.99; S, 9.12. Found: C, 57.78; H, 5.66; N, 4.01; S, 8.82.
(R3,R3a,S6,S6a,SS)-syn-7a-endo. White solid. Mp: 122-124
°C. [R]20D ) -41.6 (c 0.25, CHCl3). IR (KBr): 1773, 1595, 1495,
1073, 1053. 1H NMR (300 MHz) δ: 7.50 and 7.34 (AA′BB′
system, 4H), 7.46 (m, 5H), 4.87 (d, 1H, J ) 5.1), 4.28 (s, 1H),
4.25 (d, 1H, J ) 5.1), 3.82 (m, 1H), 3.57 (m, 1H), 2.69 (s, 3H),
2.42 (s, 3H), 1.23 (t, 3H, J ) 7.1). 13C NMR (75.5 MHz) δ: 166.9
(C), 143.4 (C), 134.9 (C), 131.4 (C), 130.3 (CH), 129.2 (CH),
128.6 (CH), 128.5 (CH), 124.6 (CH), 103.1 (CH), 84.4 (C), 76.5
(CH), 74.0 (CH), 67.3 (CH2), 43.1 (CH3), 21.4 (CH3), 14.6 (CH3).
Anal. Calcd for C21H23NO5S: C, 62.82; H, 5.77; N, 3.49; S, 7.99.
Found: C, 62.60; H, 5.42; N, 3.48; S, 7.60.
(R6,SS)-6-Ethoxy-2-methyl-3a-[(4-methylphenyl)sulfinyl]-
3-phenyl-3,3a,6,6a-tetrahydrofuro[3,4-d]isoxazol-4(2H)-
ones (7b). Compound 7b was obtained following the general
procedure from (R5,SS)-5-ethoxy-3-[(4-methylphenyl)sulfinyl]-
furan-2(5H)-one (2b) and 6 as mixtures of anti-7b-endo and
anti-7b-exo in the ratio and yields indicated in Table 4. The
adducts were purified by column chromatography (hexane/
ethyl acetate, 7:1).
(S3,R3a,S8a,S8b,SS)-anti-5a-endo. White solid. Mp: 74-75
°C. [R]20D ) +56.8 (c 1.0, CHCl3). IR (Nujol): 1775, 1595, 1460,
1082, 1057. 1H NMR (200 MHz) δ: 7.64 and 7.36 (AA′BB′
system, 4H), 5.36 (s, 1H), 4.72 (s, 1H), 4.27 (m, 1H), 3.74 (m,
1H), 3.61 (m, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.45 (s, 3H),
1.90-1.65 (m, 4H), 1.17 (t, 3H, J ) 7.0). 13C NMR (50.3 MHz)
δ: 169.1 (C), 143.1 (C), 135.0 (C), 129.4 (CH), 126.0 (CH), 102.6
(CH), 84.4 (CH), 78.9 (C), 68.4 (CH), 65.6 (CH2), 55.9 (CH2),
25.6 (CH2), 23.6 (CH2), 21.4 (CH3), 14.4 (CH3). Anal. Calcd for
C17H21NO5S: C, 58.10; H, 6.02; N, 3.99; S, 9.12. Found: C,
58.08; H, 5.71; N, 3.80; S, 9.56.
(S3,S3a,R8a,R8b,SS)-syn-5a-endo. White solid. Mp: 89-90
°C. [R]20D ) +256.6 (c 1.0, CHCl3). IR (Nujol): 1760, 1595, 1460,
1080, 1055. 1H NMR (200 MHz) δ: 7.55 and 7.35 (AA′BB′
system, 4H), 5.00 (d, 1H, J ) 4.3), 4.68 (d, 1H, J ) 4.3), 4.09
(m, 1H), 3.78 (m, 1H), 3.59 (m, 1H), 3.32 (m, 1H), 3.05 (m,
1H), 2.43 (s, 3H), 2.11-1.68 (m, 4H), 1.19 (t, 3H, J ) 7.1). 13
C
NMR (50.3 MHz) δ: 167.5 (C), 143.6 (C), 135.0 (C), 130.0 (CH),
125.1 (CH), 101.9 (CH), 83.6 (C), 80.1 (CH), 71.1 (CH), 67.9
(CH2), 55.6 (CH2), 25.2 (CH2), 23.6 (CH2), 21.5 (CH3), 14.6
(R3,R3a,R6,S6a,SS)-anti-7b-endo. White solid. Mp: 142-143
°C. [R]20D ) -144.0 (c 0.5, CHCl3). IR (KBr): 1773, 1594, 1493,
1082, 1051. 1H NMR (300 MHz) δ: 7.49 and 7.29 (AA′BB′
J. Org. Chem, Vol. 70, No. 22, 2005 8833

Garc´ıa Ruano et al.
system, 4H), 7.42 (s, 5H), 5.38 (d, 1H, J ) 1.4), 4.65 (d, 1H, J
) 1.4), 4.31 (s, 1H), 3.38 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H),
0.87 (t, 3H, J ) 7.1). 13C NMR (75.5 MHz) δ: 168.5 (C), 142.8
(C), 135.0 (C), 131.6 (C), 129.9 (CH), 129.3 (CH), 128.8 (CH),
128.4 (CH), 125.5 (CH), 107.5 (CH), 84.4 (C), 80.0 (CH), 76.9
(CH), 65.3 (CH2), 42.6 (CH3), 21.4 (CH3), 14.5 (CH3). Anal.
Calcd for C21H23NO5S: C, 62.82; H, 5.77; N, 3.49; S, 7.99.
Found: C, 62.98; H, 5.71; N, 3.49; S, 8.35.
(S3,R3a,R6,S6a,SS)-anti-7b-exo. White solid. Mp: 100-102
°C. [R]20D ) +62.8 (c 0.25, CHCl3). IR (KBr): 1771, 1494, 1374,
1085, 1062, 1032. 1H NMR (55 °C, 300 MHz) δ: 7.65 (m, 2H),
7.46 (m, 5H), 7.22 (d, 2H, J ) 7.9), 5.32 (s, 1H), 4.99 (s, 1H),
4.16 (broad s, 1H), 3.36 (m, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 0.94
(t, 3H, J ) 7.1). 13C NMR (55 °C, 75.5 MHz) δ: 170.8 (C), 142.4
(C), 134.9 (C), 131.2 (C), 129.8 (CH), 129.4 (CH), 129.4 (CH),
128.6 (CH), 126.4 (CH), 105.1 (CH), 84.1 (C), 80.3 (CH), 79.5
(CH), 65.7 (CH2), 43.0 (CH3), 21.4 (CH3), 14.4 (CH3). Anal.
Calcd for C21H23NO5S: C, 62.82; H, 5.77; N, 3.49; S, 7.99.
Found: C, 62.78; H, 5.82; N, 3.44; S, 8.00.
Acknowledgment. We thank the Spanish Govern-
ment (Grant BQU2003-04012) for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of compounds [(+)-anti-5′a-
exo], [(-)-anti-5′a-endo], [(-)-anti-5′b-exo], [(+)-anti-5′b-endo],
[(+)-anti-7′a-endo], [(-)-syn-7′a-endo], [(-)-anti-7′b-endo], [(-)-
anti-7′b-exo], [(-)-9], and adducts 11, as well as the crystal-
lographic data for compounds syn-5a-endo and anti-5b-endo
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0513111
8834 J. Org. Chem., Vol. 70, No. 22, 2005