1,3-Dipolar cycloadditions of diazoalkanes to activated sulfoxides: Influence of Lewis acids

Article abstract of DOI:10.1021/jo051574v

The reactions of diazomethane and diazoethane with (S)-3-p- tolylsulfinylfuran-2(5H)-one (3) and its 4-methyl derivative (4) have been studied. The sulfinyl group was able to completely control the π-facial selectivity of all these reactions, which decrea

Full text of DOI:10.1021/jo051574v

1,3-Dipolar Cycloadditions of Diazoalkanes to Activated
Sulfoxides: Influence of Lewis Acids
Jose´ L. Garc´ıa Ruano,* M. Teresa Peromingo, Marina Alonso, Alberto Fraile,
M. Rosario Mart´ın,* and Amelia Tito*
Departamento de Quı´mica Orga´nica, Universidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain
joseluis.garcia.ruano@uam.es
Received July 28, 2005
The reactions of diazomethane and diazoethane with (S)-3-p-tolylsulfinylfuran-2(5H)-one (3) and
its 4-methyl derivative (4) have been studied. The sulfinyl group was able to completely control
the π-facial selectivity of all these reactions, which decreased when the polarity of the solvent
increased and could be inverted in the presence of Lewis acids, Yb(OTf)3 being the most efficient
catalyst. This behavior made possible the stereodivergent synthesis of diastereoisomeric pyrazolines
in almost quantitative yields and de’s higher than 98%. The endo/exo selectivity was also complete
in reactions of 3 with diazoethane, whereas 4 afforded an easily separable 1:1 mixture of
diastereoisomers. Steric factors accounts for the endo/exo selectivity, whereas electrostatic
interactions must also be considered to explain the facial selectivity.
SCHEME 1
Introduction
The 1,3-dipolar cicloadditions of electron deficient
olefins with diazoalkanes is one of the best known
methods for preparing pyrazolines.1 The asymmetric
version of this reaction usually involves the use of
electron-deficient olefins bearing different chiral auxil-
iaries,2 which evolve with good or excellent stereoselec-
tivities. However, the use of vinyl sulfoxides in asym-
metric 1,3-dipolar reactions has been scarcely explored.3
Several years ago we initiated a program to explore the
applicability of vinyl sulfoxides in asymmetric 1,3-dipolar
reactions. In this context we have investigated the
reactions with nitrile oxides,4 azomethine ylides,5 ni-
trones,6 and diazoalkanes.7-9 In the last field we have
reported excellent results from the two epimers at C-5
of 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones7 (1 in Scheme
1), which evolved into adducts 2 in a highly stereoselec
(1) Regitz, M.; Heydt, H. In 1,3-Dipolar Cycloadditions Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; Vol. I, Chapter 4, p 393.
(2) (a) Gothelf, K. V.; Jørgersen, K. A. Chem. Rev. 1998, 98, 863. (b)
Karlsson, S.; Ho¨gberg, H. Org. Prep. Proc. Int. 2001, 33 (2), 103-172.
(c) Muray, E.; Alvarez-Larena, A.; Piniella, J. F.; Branchadell, V.;
Ortun˜o, R. M. J. Org. Chem. 2000, 65, 388. (d) Mish, M. R.; Guerra,
F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379.
(3) (a) Cid, M. B.; Garc´ıa Ruano, J. L. In Topics in Curent Chemistry.
Organosulfur Chemistry; Page, P. C. B., Ed.; Springer: Berlin, 1999;
Vol 204, pp 1-126. (b) Louis, C.; Hootele´, C. Tetrahedron: Asymmetry
1997, 8, 109 and references therein. (c) Aggarwal, V. K.; Roseblade,
S.; Barrell, J. K.; Alexander, K. Org. Lett. 2002, 4, 1227.
(4) (a) Garc´ıa Ruano, J. L.; Fraile, A.; Mart´ın M. R. Tetrahedron
1999, 55, 14491. (b) Garc´ıa Ruano, J. L.; Bercial, F.; Fraile, A.; Mart´ın
M. R. Synlett 2002, 73.
(6) (a) Garc´ıa Ruano, J. L.; Gil, I. A.; Fraile, A.; Mart´ın Castro, A.
M.; Mart´ın, M. R. Tetrahedron 2004, 45, 4653. (b) Garc´ıa Ruano, J.
L.; Fraile, A.; Mart´ın Castro, A. M.; Mart´ın, M. R. J. Org. Chem. 2005,
70, 8825.
(7) (a) Garcia Ruano, J. L.; Fraile A.; Mart´ın, M. R. Tetrahedron:
Asymmetry 1996, 7, 1943. (b) Garc´ıa, J. L.; Fraile, A.; Gonza´lez, G.;
Mart´ın, M. R.; Clemente, F. R.; Gordillo, R. J. Org. Chem. 2003, 68,
6522.
(8) (a) Garcia Ruano, J. L.; Alonso de Diego, S. A.; Blanco, D.; Mart´ın
Castro, A. M.; Mart´ın M. R.; Rodr´ıguez, J. H. Org. Lett. 2001, 3, 3173.
(b) Garc´ıa Ruano, J. L.; Alonso de Diego, S. A.; Mart´ın, M. R.; Torrente,
E.; Mart´ın Castro, A. M. Org. Lett. 2004, 6, 4945.
(5) (a) Garc´ıa Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem.
2002, 67, 981. (b) Garc´ıa Ruano, J. L.; Tito, A.; Peromingo, M. T. J.
Org. Chem. 2003, 68, 10013.
10.1021/jo051574v CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/05/2005
8942
J. Org. Chem. 2005, 70, 8942-8947

1,3-Dipolar Cycloadditions of Diazoalkanes to Activated Sulfoxides
TABLE 1. Reactions of Compound 3 with
tive way and very good yields. Similar results were
obtained in reactions of diazoalkanes with 3-sulfinylacry-
lonitriles8 and 5-menthyloxy-4-phenylsulfinylfuran-2(5H)-
one.9 From all these results we concluded that the sulfinyl
group exerted a strong influence of the course of these
reactions, substantially improving the features of the
furan-2(5H)-ones and acrylonitriles as chiral dipolaro-
philes. Otherwise, the use of Lewis acids as the catalysts
of cycloaddition processes is widely spread,2a,b,10 because
they improve both the reactivity and the stereoselectiv-
ity.10a,b In some cases they are able to invert the facial
selectivity, thus providing stereodivergent routes for two
diastereoisomers from the same substrate. To evaluate
the role of the Lewis acids on the course of the reactions
of vinyl sulfoxides with diazoalkanes, we initially chose
compounds 1 as the dipolarophiles. However, the addition
of the Lewis acids caused the epimerisation at C-5 of
furanones 1, yielding complex mixtures. Consequently,
we decided to use furanones 3 and 4 (Scheme 1), with no
epimerizable C-5 as the dipolarophiles.
Additionally, the obtained results from 3 and 4 would
clarify the actual role of the sulfinyl group on the course
of these reactions because those observed from 1 were
explained as a result of the mutual influence of the two
chiral centers (sulfur and C-5). In this paper we describe
the behavior of compounds 3 and 4 in their reactions with
diazomethane and diazoethane under different condi-
tions. The influence of different Lewis acid as the
catalysts is also considered. This study has furnished one
of the most efficient methods for the stereodivergent
synthesis of enantiopure bicyclic pyrazolines derived from
butenolides.
Diazomethane under Different Conditions
Lewis Acid
(equiv)
5:6 ratioa
(isolated yield)
Entry Solvent
T
t
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
MeOH -40°C
MeCN -40°C
PhCH3 -40°C
30 min 75 (71): 25 (21)
30 min 78 (76): 22 (19)
45 min 87 (85): 13 (10)
30 min 100 (98): 0
20 min 94 (92): 6 (3)
10 min 88 (85): 12 (9)
5 min
2.5 h
1 h
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
-40 °C
-20°C
0°C
rt
85 (81): 15 (11)
100 (97): 0
79 (76): 21 (17)
-78 °C
-78°C ZnBr2 (1.2)
-78°C BF3.OEt2 (1.2) 55 min 92 (86): 8
-78°C Eu(fod)3 (1.2)
-78°C Eu(OTf)3 (1.2) 45 min 30:70 (67)
-78°C Yb(OTf)3 (1.2) 50 min 20 (16): 80 (75)
-40°C ZnBr2 (1.2)
-40°C Yb(OTf)3 (1.2) 35 min 18 (14): 82 (79)
-20°C ZnBr2 (1.2) 15 min 85 (81): 15 (12)
-20°C Yb(OTf)3 (1.2) 10 min 21 (18): 79 (75)
-78°C Yb(OTf)3 (0.5) 50 min 30:70
-78 °C Yb(OTf)3 (1.0) 30 min 13:87 (83)
-78°C Yb(OTf)3 (1.5) 20 min 20:80
35 min Complex Mixture
40 min 92 (88): 8 (4)
a Determined by 1H NMR.
were also performed in the presence of different Lewis
acids at -78 °C (entries 9-13). The use of ZnBr2 or BF3‚
OEt2 slightly increased the rate of the cycloaddition but
decreased the stereoselectivity (compare entries 9 and
10 with 8), whereas the use of Eu(fod)3 afforded complex
mixtures (entry 11). More interesting were the results
obtained under Eu(OTf)3 or Yb(OTf)3 catalysis. The use
of these catalysts also decreased the reaction times, but
which is more important, it also inverted the sense of
the stereoselectivity, determining the predominance of
the isomer 6 in the reaction mixtures (entries 12 and 13).
The influence of the catalysts was also evident at higher
temperatures (entries 14-17). Once the best catalyst was
determined, Yb(OTf)3, we checked the influence of the
amount of catalyst (entries 18-20), the best results
having been obtained with ca. 1 equiv of the Lewis acid
(entry 19), whereas with smaller (entry 18) or larger
(entry 20) amounts of catalyst the observed de’s became
lower. As the yield of all of these reactions was almost
quantitative and the separation of diastereoisomers was
readily achieved, compound 6 could be isolated in 83%
yield despite the fact that the reaction evolved with 74%
de (entry 19).
Results and Discussion
The synthesis of the starting sulfinylfuranones 3 and
4 had been previously reported.11 Initially, we studied
the reactions of compound 3 with diazomethane under
different conditions (Table 1). All of these reactions
(except for the reactions in THF at -40 or -78 °C, entries
4 and 8) evolved into mixtures of two compounds, 5 and
6, which could be separated and identified as the two
isomers resulting from the approach of the dipole to a
different face of the dipolarophile. The yield was almost
quantitative in all cases. The influence of different factors
on the facial selectivity was investigated. It decreased
when the polarity of the solvent increased (entries 1-4),
the best results having been obtained in THF. By
lowering the temperature it was possible to improve the
stereoselectivity (entries 4-8), which was complete (de
> 98%) at -40 °C in THF, affording compound 5 as the
only product in 98% isolated yield (entry 4). The reactions
Next we studied reactions of 3 with diazoethane (Table
2). In these reactions, only two, 7-exo and 8-exo, out of
the four possible diastereoisomers were formed in practi-
cally quantitative yield and could be readily separated
by chromatography. The comparison between Tables 1
(diazomethane) and 2 (diazoethane) reveals that both
reactivity and facial selectivity were lower for diazo-
methane than for diazoethane. Hence, diazoethane re-
acted instantaneously with 3 even at -78 °C (entry 4,
Table 2), whereas diazomethane required 2.5 h under
similar conditions (entry 8, Table 1). The facial selectivity
of the reactions with diazoethane at rt (entry 1, Table 2)
(9) Garc´ıa, J. L.; Bercial, F.; Gonza´lez, G.; Mart´ın Castro A. M.;
Mart´ın, M. R. Tetrahedron: Asymmetry 2002, 13, 1993.
(10) For diazoalkanes: Kanemasa, S.; Kanai, T. J. Am. Chem. Soc.
2000, 122, 10710. For nitrones: (a) Sanchez-Blanco, A. I.; Gothelf, K.
V.; Jørgersen, K. A. Tetrahedron Lett. 1997, 38, 7923. (b) Kobayashi,
S.; Kawamura, M. J. Am. Chem. Soc. 1998, 120, 5840. (c) Sibi, M. P.;
Ma, Z.; Craig, P. J. J. Am. Chem. Soc. 2004, 126, 718. (d) Dugovic, B.;
Fisera, L.; Hametner, C. Synlett 2004, 1569-1572. For carbonyl
ylide: (e) Suga, H.; Kakehi, A.; Ito, S.; Inoue, K.; Ishida, H.; Ibata, T.
Bull. Chem. Soc. Jpn. 2001, 74, 1115.
(11) (a) For synthesis of 3: Carretero, J. C.; Garc´ıa Ruano, J. L.;
Mart´ın Cabrejas, L. M. Tetrahedron 1997, 53, 14115 and references
therein. (b) For synthesis of 4: Holton, R. A.; Kim, H. B. Tetrahedron
Lett. 1986, 27, 2191.
J. Org. Chem, Vol. 70, No. 22, 2005 8943

Garc´ıa Ruano et al.
TABLE 2. Reactions of Compound 3 with Diazoethane
under Different Conditions
TABLE 3. Reactions of Compound 4 with
Diazomethane under Different Conditions
9:10 ratioa
(isolated yield)
Lewis Acid
(equiv)
7-exo:8-exo ratioa
(isolated yield)
Lewis Acid
(equiv)
Entry
T
t
Entry
T
t (min)
1
2
3
4
6
7
8
rt
5 min
5 min
5 min
5 min
5 min
92 (87): 8 (4)
94 (89): 6 (3)
95(91): 5 (3)
100 (95): 0
21:79
<2: >98 (94)
10:90
1
2
3
4
5
6
7
8
rt
45
55
65
55
50
60
80
75
97 (91): 3
98 (94): 2
100 (97): 0
28:72 (66)
25:75 (69)
12:88 (80)
10:90 (83)
7:93 (89)
-20°C
-40°C
-78 °C
-78°C
0 °C
-10 °C
0 °C
0 °C
-10 °C
-20 °C
-40 °C
Eu(OTf)3 (1.2)
Yb(OTf)3 (1.2)
Yb(OTf)3 (1.2)
Yb(OTf)3 (1.2)
Yb(OTf)3 (1.0)
Yb(OTf)3 (0.5)
-78 °C Yb(OTf)3 (1.0) 5 min
-78°C
Yb(OTf)3 (1.5)
5 min
a Determined by 1H NMR.
a Determined by 1H NMR.
was larger than that observed with diazomethane (entry
7, Table 1). As expected, the facial selectivity of the
reactions with diazoethane also increased when the
temperature became lower (entries 1-4, Table 2), which
allowed the formation of 7-exo as the only adduct at -78
°C (95% isolated yield, entry 4). The most remarkable
feature of the reactions with diazoethane was the exclu-
sive formation of adducts designated as exo,12 which
means that the endo/exo selectivity was completely
controlled. When the reactions were conducted under Yb-
(OTf)3 catalysis, the facial selectivity was inverted (en-
tries 5-8) but the exo adducts were also exclusively
formed. As in the previous case, the best results were
obtained by using 1 equiv of Lewis acid at -78 °C (entry
7). Under these conditions, compound 8-exo could be
obtained in 94% isolated yield in its optically pure form.
We also studied the reactions of the 4-methyl-substi-
tuted furanone 4 with diazoalkanes. Although the syn-
thesis of 4 had been previously reported,11b we prepared
it in a more convenient way by extrusion of nitrogen from
any mixture of compounds 5 + 6 resulting from reactions
in Table 1. These denitrogenation reactions occurred in
quantitative yields when pyrazolines 5 and/or 6 were
refluxed in toluene. The results obtained in reactions of
4 with diazomethane are collected in Table 3. Compound
4 was less reactive than 3 (compare data of reactions
conducted under similar conditions in Tables 1 and 3).
By contrast, the facial selectivity was much higher for 4,
which evolved with 94% de at rt (entry 1, Table 3),
whereas a 70% de was attained for 3 under similar
conditions (entry 7, Table 1). The complete control of the
facial selectivity was achieved at -10 °C for 4 (entry 3,
Table 3), but it required that the temperature be lowered
to -40 °C for 3 (entry 4 Table 1). This behavior allowed
the synthesis of enantiomerically pure 9 in 97% yield
under the conditions of entry 3 (Table 3). As observed in
reactions from 3 (Tables 1 and 2), the facial selectivity
of compound 4 could be inverted in the presence of Eu-
(OTf)3 or Yb(OTf)3 (entries 4 and 5, Table 3). The best
results were obtained at -40 °C under Yb(OTf)3 catalysis
(entry 8, 86% de), yielding 10 in 89% isolated yield.
TABLE 4. Reactions of Compound 4 with Diazoethane
11-exo: 11-endo:
Catalyst
(equiv)
13 ratioa
Entry
T
t (min)
(isolated yields)
1
2
3
4
5
6
rt
55
72
100
50
60
55
50 (45): 50 (47):0
50 (44): 50 (48): 0
50 (46): 50 (47): 0
15:15:70 (65)
0 °C
-10 °C
Yb(OTf)3 (1.2) 0 °C
Yb(OTf)3 (1.2) -10 °C
Yb(OTf)3 (1.0) -20 °C
13:13:74 (68)
10:10:80 (73)
a Determined by 1H NMR
Finally we have studied the reactions of 4 with diazo-
ethane (Table 4). As was the case with diazomethane,
the dipolarophile 4 exhibited a lower reactivity and a
better facial selectivity than 3. Thus, the de observed in
reaction of 4 at rt was 94%, whereas it was only 84% for
3 (compare entries 1 in Tables 2 and 4). On the contrary,
the endo/exo selectivity, which was complete for 3, was
almost inexistent for 4, which evolved into equimolecular
mixtures of 11-exo and 11-endo adducts under all of the
assayed conditions (entries 1-3, Table 4). The addition
of Yb(OTf)3 inverted the facial selectivity and the isomers
11 were now the minor ones, but the expected major
compounds, 12-exo and 12-endo, could not be detected.
Instead of them, the olefin 13 was obtained as the major
component of the mixtures (entries 4-6, Table 4). It
suggests that 13 resulted from the fast evolution of 12-
exo and 12-endo under the reaction conditions. Selectivity
was higher when the temperature decreased. However,
under -10 °C the reactions were not clean and the yields
were lower. The reaction rates of diazomethane and
diazoethane with 4 were not significantly increased in
the presence the Lewis acid (see Tables 3 and 4).
(12) The endo or exo terms, indicative of the cis or trans arrangement
of the methyl group of the diazoethane with respect to the furanone
moiety at the pyrazoline ring, are related to the endo and exo addition
modes of the dipole to the dipolarophile using as the reference the
carbonyl group at the later.
8944 J. Org. Chem., Vol. 70, No. 22, 2005

1,3-Dipolar Cycloadditions of Diazoalkanes to Activated Sulfoxides
SCHEME 2
FIGURE 1. Rationalization of the facial selectivity observed
were conducted under Yb(OTf)3 catalysis, the formation
of the quelated species W changed the spatial arrange-
ment of the tolyl group, thus inverting the facial selectiv-
ity of the reaction. Other catalysts must be less efficient
to furnish W or prefer the formation of other species
involving the association of the metal to only one of the
oxygens at the dipolarophiles, where the spatial arrange-
ment of the tolyl group is similar to that of A rotamers.
The changes observed in the stereoselectivity for reac-
tions conducted with different amounts of Yb(OTf)3 can
be explained by assuming that in the presence of 0.5
equiv of catalyst species W and A were present, and they
evolved into different diastereoisomers. W must be the
only species present when 1 equiv of the catalyst was
used. The presence of an excess of the catalyst would
favor the formation of species such as A but doubly
associated, thus explaining the observed decrease in the
stereoselectivity. A similar behavior of compound 3 had
been observed in its Diels-Alder reactions catalyzed by
Lewis acids.11a The same stereochemical model accounts
for the facial selectivity observed in reactions of 3 and 4
with diazoethane.
The fact that the facial selectivity observed in reactions
from 4 (R ) Me in Figure 1) was even higher than that
observed from 3 (R ) H) is not easily rationalized. It could
be explained by assuming that conformation C did not
participate in these reactions, and the stereoselectivity
would be only dependent on the relative population of A
and B. The strong steric interaction (Tol/Me)1,3-parallel
would account for the lower population of the B rotamer
at compound 4 and, therefore, its higher facial selectivity.
The scarce role of the conformers C in determining the
stereoselectivity of the reactions of 3 (R ) H) and 4 (R )
Me) would be reasonable on steric and electrostatic
grounds. Only the assumption that the reactivity of the
C conformation was very low could explain its scarce
influence on the stereoselectivity control. It is usually
admitted that the strong steric hindrance of the bulky
tolyl group inhibits the approach of the dipole to the face
exhibiting such a group. By contrast, the size of the
oxygen is not large enough to preclude the approach of
the linear diazoalkane, unless the electrostatic repulsion
of the sulfinyl oxygen toward the negatively charged
nitrogen at the dipole also contribute to make it difficult.
To verify the assumption that the approach of diazo-
alkanes to any face occupied by the sulfinyl oxygen or
the tolyl group would be strongly hindered, we have
prepared the sulfones 14 and 15 (Scheme 2), any of whose
possible conformations exhibits a tolyl group or a sulfonyl
oxygen oriented toward the face of approach of the dipole.
in reactions with diazomethane.
Configurational Assignment. The structure of 6a-
[(4-methylphenyl)sulfinyl]-3,3a,4,6a-tetrahydro-6H-furo-
[3,4-c]pyrazol-6-one was established for all of the adducts
from their spectral data. The most relevant and general
data for the assignment of the regiochemistry of the
adducts were the δ values of the carbons common to
pyrazoline and furanone rings. The existence of a qua-
ternary carbon at 110-122 ppm, corresponding to C-6a,
and the high ∆δ (δC-3a-δC-6a) was only compatible with
the regioisomer bearing the two electronegative atoms
(sulfur and nitrogen) joined to the same carbon. The
relative configuration at C-3 and C-3a of the adducts 7
and 8 could be unequivocally established from their J3,3a
values (4 Hz), which showed a trans relationship between
the involved protons. The configuration of C-3a and C-6a
was assigned taking into account the effect of the
p-tolylsulfinyl group on the π-facial selectivity for the
addition of diazoalkanes to both epimers at C-5 of
furanones 1, which had been previously reported by us.7
The higher chemical shift of C-6a in the [3aS,6aR,(S)S]-
6H-furo[3,4-c]pyrazol-6-ones (5, 7, 9) than that in the
corresponding 3aR,6aS,(S)S (6, 8, 10) stereoisomers
agrees with the values observed for other 6H-furo[3,4-c]-
pyrazol-6-ones. Additionally, the fact that in the presence
of a Lewis acid the diazoalkane attacks the dipolarophile
from the opposite face (vide infra) was also in agreement
with the assigned stereochemistry for the adducts.
Stereochemical Proposals. The facial selectivity for
reactions of diazomethane with compounds 3 and 4 can
be rationalized from their conformational behavior and
the different reactivity of the involved rotamers. The
presumably most stable conformations of these dipolaro-
philes around the C-S bond are depicted in Figure 1.
Electrostatic repulsion of the sulfinyl and carbonyl oxy-
gens must destabilize B and C rotamers and favor the
s-cis A conformations. The favored approach of the
diazomethane to this rotamer will be that avoiding the
steric interactions with the tolyl group, thus yielding
adducts 5 or 9. The negative influence of the solvent
polarity on the facial selectivity of the reactions from 3
(it was lower in MeCN or MeOH than in THF or toluene,
see Table 1) can be explained by assuming that the
population of the rotamer B or C (Figure 1) must be
higher in these solvents where the role of the electrostatic
interactions is minimized. The population of the rotamer
C must be low for compound 3 (R ) H), because of the
electrostatic and steric interactions of the substituents
at sulfur with the carbonyl oxygen. When the reactions
J. Org. Chem, Vol. 70, No. 22, 2005 8945

Garc´ıa Ruano et al.
FIGURE 2. Rationalization of the endo/exo selectivity in reactions with diazoethane.
indicated in Table 1, cooled at the temperature indicated in
Tables 1-4, was added an excess of an ethereal solution of
diazomethane (0.95 M) (Tables 1 and 3) or diazoethane (0.95
M) (Table 2 or 4). The reaction was kept at the same
temperature for the time indicated in Tables 1-4. The solvent
Their reactions with diazomethane were much slower
than those of their corresponding sulfoxides. Compound
14 required 2 days to be transformed into 16 (43% yield
and less than 50% of conversion), and 15 remained
unaltered after 5 days at rt in the presence of diazo-
methane (17 was not detected, Scheme 2). These results
support the assumption on the scarce reactivity of
conformations C of the sulfoxides 3 and 4 (Figure 1), since
the electronic effect of the sulfonyl group should increase
the dipolarophilic reactivity more that of the sulfinyl
group.
Concerning the complete exo selectivity observed in
reactions with diazoethane, steric interactions should
account for the observed results. In Figure 2 are depicted
the two possible approaches (endo and exo) of diazoethane
to the favored face of compounds 3 and 4. The most
important interactions to be considered are those of the
methyl group at the dipole with the substituents at C-4
of both furanones. These interactions are quite different
in the case of compound 3 (Me/CH2 for the endo approach
and the much smaller Me/H for the exo one), thus
determining its completely exo-selective evolution. By
contrast, they are almost identical for compound 4 (Me/
CH2 for the endo approach and Me/Me for the exo one),
thus explaining the complete absence of endo/exo selec-
tivity observed in its reactions.
In summary, we have described the behavior of the
sulfinyl furanones 3 and 4 with diazomethane and
diazoethane under different conditions. The sulfinyl
group was able to completely control the π-facial selectiv-
ity. The use of some Lewis acids as the catalysts, such
as Yb(OTf)3, substantially inverted the selectivity making
possible the stereodivergent synthesis of pyrazolines. The
endo/exo selectivity was controlled by steric effects and
it was also complete in reactions starting from 3. The
excellent yields and the almost complete stereoselectivity
indicated that these reactions were a satisfactory and
efficient method for preparing enantiomerically pure
pyrazolines derived from butenolides.
1
was removed, and the residue was analyzed by H NMR and
purified as indicated in each case.
Method B. To a stirred solution of Yb(OTf)3 (amounts
indicated in Tables 1-4) in THF (0.1 M) at room temperature
was added a solution of furanones 3 or 4 (0.5 mmol) in THF
(5 mL). The mixture was stirred for 1 h and cooled at the
corresponding temperature.Then was added an ethereal solu-
tion of diazomethane or diazoethane (0.95 M). The reaction
was kept at the same temperature for the time indicated in
Tables 1-4. The reaction was quenched with aqueous potas-
sium sodium tartrate at the indicated temperature and
extracted with AcOEt (3 × 8 mL). The organic extracts were
washed with brine (7 mL) and dried (MgSO4). The solvent was
removed under vacuum. The resulting residue was analyzed
1
by H NMR and purified as indicated in each case.
(3aS,6aR,(S)S)-6a-[(4-Methylphenyl)sulfinyl]-3,3a,4,6a-
tetrahydro-6H-furo[3,4-c]pyrazol-6-one (5). Compound 5
was obtained from 3 and diazomethane (Table 1) and purified
by flash chromatography (AcOEt-hexane, 1:1) and crystallized
from AcOEt-hexane: mp 100-102 °C (white solid, 98% yield);
1
[R]D +65 (c 0.5, CHCl3); IR (film) 1712, 1498, 1432; H NMR
(300 MHz) δ 7.64 and 7.39 (AA′BB′ system, 4H), 5.15 (dd, 1H,
J ) 19.0 and 9.4 Hz), 4.66 (dd, 1H, J ) 19.0 and 4.0 Hz), 3.83
(dd, 1H, J ) 9.9 and 3.5 Hz), 3.65 (dd, 1H, J ) 9.9 and 8.3
Hz), 3.28-3.16 (m, 1H), 2.45 (s, 3H); 13C NMR (75 MHz) δ
164.3, 143.6, 133.9, 130.5, 124.8, 120.9, 87.7, 72.3, 29.7, 21.4.
Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60; S,
12.13. Found: C, 54.59; H, 4.62; N, 10.72; S, 12.31.
(3aR,6aS,(S)S)-6a-[(4-Methylphenyl)sulfinyl]-3,3a,4,6a-
tetrahydro-6H-furo[3,4-c]pyrazol-6-one (6). Compound 6
was obtained from 3 and diazomethane (Table 1), purified by
flash chromatography (AcOEt-hexane, 1:1), and crystallized
from AcOEt-hexane: mp 90-94 °C (white solid, 83% yield);
[R]D +228 (c 0.5, CHCl3); IR (film) 1721, 1485, 1428; 1H NMR
(300 MHz) δ 7.41 and 7.30 (AA′BB′ system, 4H), 4.57 (m, 2H),
3.81 (m, 2H), 3.33 (m, 1H), 2.41 (s, 3H); 13C NMR (75 MHz) δ
165.7, 143.8, 133.5, 129.7, 125.3, 118.6, 86.3, 72.6, 30.6, 21.4.
Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60; S,
12.13. Found: C, 54.71; H, 4.53; N, 10.82; S, 12.29.
(3R,3aS,6aR,(S)S)-3-Methyl-6a-[(4-methylphenyl)sulfi-
nyl]-3,3a,4,6a-tetrahydro-6H-furo[3,4-c]pyrazol-6-one (7-
exo). Compound 7-exo was obtained from 3 and diazoethane
(Table 2), purified by flash chromatography (AcOEt-hexane,
1:1), and crystallized from AcOEt-hexane: mp 97-98 °C
(white solid, 95% yield); [R]D +59 (c 0.5, CHCl3); IR (film)
Experimental Section
1,3-Dipolar Cycloadditons. Method A. To a solution of
1 mmol of (SS)-3-[(4-methylphenyl)sulfinyl]-2(5H)-one (3), or
its corresponding 4-methyl derivative (4), in the solvent (2 mL)
8946 J. Org. Chem., Vol. 70, No. 22, 2005

1,3-Dipolar Cycloadditions of Diazoalkanes to Activated Sulfoxides
1758, 1471, 1456; 1H NMR (200 MHz) δ 7.61 and 7.38
(AA′BB′ system, 4H), 4.77 (qd, 1H, J ) 7.3 and 4.0 Hz), 3.92
(dd, 1H, J ) 9.7 and 3.0 Hz), 3.54 (dd, 1H, J ) 9.7 and
8.3 Hz), 2.67 (ddd, 1H, J ) 8.3, 4.0, and 3.0 Hz), 2.43 (s, 3H),
1.62 (d, 3H, J ) 7.3); 13C NMR (50 MHz) δ 164.3, 143.7, 133.9,
130.4, 124.6, 121.3, 96.3, 71.8, 37.0, 21.4, 18.1. Anal. Calcd
for C13H14N2O3S: C, 56.10; H, 5.07; N, 10.06; S, 11.52. Found:
C, 56.10; H, 5.11; N, 9.99; S, 11.81.
(3S,3aR,6aS,(S)S)-3-Methyl-6a-[(4-methylphenyl)sulfi-
nyl]-3,3a,4,6a-tetrahydro-6H-furo[3,4-c]pyrazol-6-one (8-
exo). Compound 8-exo was obtained from 3 and diazoethane
(Table 2), purified by flash chromatography (AcOEt-hexane,
1:1), and crystallized from AcOEt-hexane: mp 89-91 °C
(white solid, 82% yield); [R]D +239 (c 0.5, CHCl3); IR (film)
1763, 1467, 1453; 1H NMR (200 MHz) δ 7.46 and 7.33 (AA′BB′
system, 4H), 4.62 (qd, 1H, J ) 7.3 and 4.0 Hz), 4.56 (dd, 1H,
J ) 9.7 and 8.3 Hz), 4.09 (dd, 1H, J ) 9.7 and 2.7 Hz, 1H),
2.63 (ddd, 1H, J ) 8.3, 4.0, and 2.7 Hz), 2.41 (s, 3H), 0.77 (d,
3H, J ) 7.3 Hz); 13C NMR (50 MHz) δ 165.4, 143.3, 133.2,
129.2, 125.4, 119.5, 94.8, 71.6, 37.6, 21.4, 18.3. Anal. Calcd
for C13H14N2O3S: C, 56.10; H, 5.07; N, 10.06; S, 11.52. Found:
C, 56.22; H, 5.18; N, 10.26; S, 11.83.
(3aS,6aR,(S)S)-3a-Methyl-6a-[(4-methylphenyl)sulfinyl]-
3,3a,4,6a-tetrahydro-6H-furo[3,4-c]pyrazol-6-one (9). Com-
pound 9 was obtained from 4 and diazomethane (Table 3),
purified by flash chromatography (AcOEt-hexane, 1:1), and
crystallized from Et2O: mp 125-127 °C (white solid, 97%
yield); [R]D +111 (c 0.5, CHCl3); IR (film) 1769, 1541, 1457; 1H
NMR (200 MHz) δ 7.75 and 7.42 (AA′BB′ system, 4H), 5.13
(d, 1H, J ) 18.3 Hz), 4.46 (d, 1H, J ) 18.3 Hz), 4.19 (AB
system, 2H), 2.47 (s, 3H), 1.63 (s, 3H); 13C NMR (50 MHz) δ
163.1, 143.4, 133.8, 129.5, 126.7, 108.7, 91.8, 74.1, 47.2, 21.6,
18.1. Anal. Calcd for C13H14N2O3S: C, 56.10; H, 5.07; N, 10.06;
S, 11.52. Found: C, 56.48; H, 5.18; N, 10.25; S, 11.30.
(3aR,6aS,(S)S)-3a-Methyl-6a-[(4-methylphenyl)sulfinyl]-
3,3a,4,6a-tetrahydro-6H-furo[3,4-c]pyrazol-6-one (10). Com-
pound 10 was obtained from 4 and diazomethane (Table 3),
purified by flash chromatography (AcOEt-hexane, 1:1), and
crystallized from Et2O-pentane: mp 109-111 °C (white solid,
89% yield); [R]D +289 (c 0.5, CHCl3); IR (film) 1775, 1520, 1446;
1H NMR (200 MHz) δ 7.56 and 7.28 (AA′BB′ system, 4H), 5.34
(d, 1H, J ) 11.6 Hz), 5.02 (d, 1H, J ) 11.6 Hz), 4.62 (d, 1H, J
) 9.9 Hz), 4.11 (d, 1H, J ) 9.9 Hz), 2.45 (s, 3H), 1.42 (s, 3H);
13C NMR (50 MHz) δ 164.8, 143.6, 133.6, 129.2, 127.1, 108.3,
91.5, 74.2, 47.6, 21.4, 17.7; MS (FAB+) m/z 279 (M + 1, 100),
251 (53), 131 (12); HRMS (FAB) calcd for C13H15N2O3S
279.3279 [M + H], found 279.3284.
7.5 Hz); 13C NMR (50 MHz) δ 163.2, 142.8, 134.4, 129.1, 127.3,
110.0, 95.4, 72.6, 47.1, 21.5, 17.7, 16.5; MS (FAB+) m/z 293
(M + 1, 100), 265 (48), 127 (9); HRMS (FAB) calcd for
C14H17N2O3S 293.0882 [M + H], found 293.0888.
[(S)S]-4-Isopropyl-3-[(4-methylphenyl)sulfinyl]furan-
2(5H)-one (13). Compound 13 was obtained from 4 and
diazoethane (entry 6, Table 4). The residue was crystallized
from Et2O-pentane: mp 115-116 °C (yellow solid, 73% yield);
1
[R]D +123 (c 0.5, CHCl3); IR (film) 1748; H NMR (200 MHz)
δ 7.59 and 7.30 (AA′BB′ system, 4H), 4.67 (AB system, 2H),
3.12 (m, 2H), 2.42 (s, 3H), 1.30 (d, 3H, J ) 7.1 Hz), 1.22 (d,
3H, J ) 7.1 Hz); 13C NMR (50 MHz) δ 173.1, 165.2, 142.0,
139.7, 130.1, 129.8, 125.3, 73.6, 26.2, 21.4, 18.9, 16.1. Anal.
Calcd for C14H16O3S: C, 63.61; H, 6.10; S, 12.13. Found: C,
63.59; H, 6.13; S, 12.01.
3-[(4-Methylphenyl)sulfonyl]furan-2(5H)-one (14). To
a solution of (()-3-p-tolylsulfinylfuran-2(5H)-one13 in CH2Cl2
(0.1 M) was added a solution of m-CPBA (1.2 equiv) in CH2-
Cl2 (0.1 M) for 1 h at room temperature. The reaction was
quenched with a NaHSO3 solution (0.1 mmol/1 mL) and then
washed with saturated aqueous sodium bicarbonate (0.1
mmol/1 mL). The organic extracts were dried (MgSO4), and
the solvent was removed under vacuum. It crystallized from
Et2O: mp 164-165 °C dec (white solid, 96% yield); IR (film)
1
1758; H NMR (acetone-d6, 300 MHz) δ 8.63 (t, 1H, J ) 1.5
Hz), 7.97 and 7.52 (AA′BB′ system, 4H), 5.19 (s, 2H), 2.50 (s,
3H); 13C NMR (75 MHz) δ 171.9, 162.1, 146.6, 132.1, 131.5,
130.7, 129.6, 71.3, 21.6. Anal. Calcd for C11H10O4S: C, 55.45;
H, 4.23; S, 13.46. Found: C, 55.33; H, 4.35; S, 12.39.
6a-[(4-Methylphenyl)sulfonyl]-3,3a,4,6a-tetrahydro-
6H-furo[3,4-c]pyrazol-6-one (16). To a solution of 14 (1
mmol) in THF (2 mL) at room temperature was added an
excess of an ethereal solution of diazomethane (0.95 M). The
reaction was stirred at the same temperature for 2 days. The
solvent was removed under vacuum. The residue was crystal-
lized from AcOEt-hexane: mp 107-109 °C (white solid, 43%
1
yield); IR (film) 1721, 1492, 1438; H NMR (300 MHz) δ 7.90
and 7.45 (AA′BB′ system, 4H), 5.23 (dd, 1H, J ) 19.0 and 8.9
Hz), 4.85 (dd, 1H, J ) 19.0 and 3.6 Hz), 4.64 (dd, 1H, J ) 9.7
and 8.5 Hz), 3.96 (dd, 1H, J ) 9.7 and 3.8 Hz), 3.78 (m, 1H),
2.50 (s, 3H); 13C NMR (50 MHz) δ 163.0, 147.1, 131.2, 131.0,
129.8, 115.5, 87.5, 70.9, 34.2, 21.9; MS (FAB+) m/z 281 (M +
1, 100), 252 (65), 99 (5); HRMS calcd for C12H13N2O4S [M +
H] 281.0518, found 281.0517.
4-Methyl-3-[(4-methylphenyl)sulfonyl]furan-2(5H)-
one (15). A solution of 16 (0.5 mmol) in toluene (15 mL) was
refluxed for 3 h. The solvent was evaporated, and the residue
was crystallized from Et2O: mp 176-178 °C (white solid, 90%
(3R,3aS,6aR,(S)S)-3,3a-Dimethyl-6a-[(4-methylphenyl)-
sulfinyl]-3,3a,4,6a-tetrahydro-6H-furo[3,4-c]pyrazol-6-
one (11-exo). Compound 11-exo was obtained from 4 and
diazoethane (Table 4), purified by flash chromatography
(AcOEt-hexane, 1:3), and crystallized from Et2O: mp 135-
137 °C (yellow solid, 46% yield); [R]D +89 (c 0.5, CHCl3); IR
1
yield); IR (film) 1764, 1425, 1398; H NMR (300 MHz) δ 7.97
and 7.35 (AA′BB′ system, 4H), 4.75 (s, 2H), 2.56 (s, 3H), 2.44
(s, 3H); 13C NMR (50 MHz) δ 171.8, 166.3, 145.6, 136.2, 129.8,
128.7, 128.5, 72.5, 21.7, 13.8. Anal. Calcd for C12H12O4S: C,
57.13; H, 4.79; S, 12.71. Found: C, 57.40; H, 4.69; S, 13.03.
1
(film) 1756, 1443, 1431; H NMR (200 MHz) δ 7.75 and 7.41
(AA′BB′ system, 4H), 4.29 (q, 1H, J ) 7.3), 4.13 (s, 2H), 2.46
(s, 3H), 1.72 (d, 3H, J ) 7.3), 1.46 (s, 3H); 13C NMR (50 MHz)
δ 162.7, 142.9, 134.4, 129.1, 127.3, 109.5, 92.5, 74.0, 50.0, 21.5,
17.6, 16.6; MS (FAB+) m/z 293 (M + 1, 100), 265 (31); HRMS
(FAB) calcd for C14H17N2O3S 293.0882 [M + H], found 293.0888.
(3S,3aS,6aR,SS)-3,3a-Dimethyl-6a-[(4-methylphenyl)-
sulfinyl]-3,3a,4,6a-tetrahydro-6H-furo[3,4-c]pyrazol-6-
one (11-endo). Compound 11-endo was obtained from 4 and
diazoethane (Table 4), purified by flash chromatography
(AcOEt-hexane, 1:3): colorless oil; 48% yield; [R]D +256 (c 0.5,
CHCl3); IR (film) 1772, 1515, 1465; 1H NMR (200 MHz) δ 7.76
and 7.41 (AA′BB′ system, 4H), 5.02 (q, 1H, J ) 7.5 Hz), 4.17
(AB system, 2H), 2.46 (s, 3H), 1.47 (s, 3H), 1.33 (d, 3H, J )
Acknowledgment. We thank the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica (DGICYT) for
financial support (Grant No. BQU2003-04012).
1
Supporting Information Available: Copies of H NMR
and 13C NMR spectra of compounds 10, 11-exo, 11-endo, and
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO051574V
(13) Posner, G. H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.;
He, C. H.; Clardy, J. Tetrahedron 1986, 42, 2919.
J. Org. Chem, Vol. 70, No. 22, 2005 8947