Synthesis of bicyclo[3.1.0]hexanones via 1,3-dipolar cycloaddition of diazoalkanes to homochiral α-sulfinyl-2-cyclopentenones

Article abstract of DOI:10.1016/j.tet.2008.08.088

The reactions of diazomethane, diazoethane, and (trimethylsilyl)diazomethane with (S)-2-p-tolylsulfinylcyclopent-2-en-1-one have been studied. The sulfinyl group increases the reactivity and controls the π-facial and endo/exo selectivities. The π-facial s

Full text of DOI:10.1016/j.tet.2008.08.088

Tetrahedron 64 (2008) 10546–10551
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Synthesis of bicyclo[3.1.0]hexanones via 1,3-dipolar cycloaddition
of diazoalkanes to homochiral a-sulfinyl-2-cyclopentenones
a
,
a
b
a
a,
*
*
´
´
´
Jose Luis Garcıa Ruano , Marina Alonso , David Cruz , Alberto Fraile , M. Rosario Martın
,
M. Teresa Peromingo a, Amelia Tito a , Francisco Yuste
,
b
*
a
´
´
´
Facultad de Ciencias, Departamento de Quımica Organica, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Circuito Exterior, Cd. Universitaria, Coyoacan, 04510 Mexico DF, Mexico
b
´
´
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2008
Received in revised form 26 August 2008
Accepted 27 August 2008
Available online 4 September 2008
The reactions of diazomethane, diazoethane, and (trimethylsilyl)diazomethane with (S)-2-p-tolylsulfi-
nylcyclopent-2-en-1-one have been studied. The sulfinyl group increases the reactivity and controls the
p
-facial and endo/exo selectivities. The p-facial selectivity can be inverted in the presence of Yb(OTf)3,
which makes possible the stereodivergent synthesis of both diastereoisomeric pyrazolines. Completely
stereoselective denitrogenation of optically pure pyrazolines into cyclopropanes was achieved under
substoichiometric Yb(OTf)3 catalysis.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
In the course of our studies on the influence of the sulfinyl group
on the asymmetric 1,3-dipolar cycloadditions with diazoalkanes11
Bicyclo[3.1.0]hexanones are relevant structural moieties be-
cause of the biomedical properties associated to such a skeleton,1 as
well as their use in the flavor and fragrance industry,2 or as syn-
thetic intermediates.3 This interest is reflected in the numerous
methods for their asymmetric synthesis reported in the last years.
Many of them are based on the intramolecular cyclopropanation of
diazoderivatives. Thus Lahuerta et al. reported the preparation of
bicyclo[3.1.0]hexanones from diazoketones bearing a double bond
we have recently reported that reactions of these dipoles with (S)-
3-p-tolylsulfinylfuran-2(5H)-ones proceed with high yields and
excellent stereoselectivity.12 Moreover, the stereoselective extru-
sion of nitrogen from the resulting 1D-pyrazolines under Yb(OTf)3
catalysis provides an excellent method for the synthesis of
enantiomerically pure 3-oxabicyclo[3.1.0]hexanones.13 Taking into
account that bicyclo[3.1.0]hexanones could be obtained from
cycloalkenones following a similar sequence, we decided to study
the behavior of sulfinyl derivative 1 (it had previously shown to be
efficient as a chiral dienophile14 and dipolarophile15) in their re-
actions with diazoalkanes. The results obtained in this study as well
as those observed in denitrogenation of the resulting 1D-pyrazo-
lines are reported in this paper.
at the
d
position employing chiral dirhodium(II) complexes,4
whereas Nakada et al. used the reaction of a-diazo-b-ketosulfones
with CuOTf and chiral ligands.5 Optically active metallo-Salen
complexes have shown to be efficient catalysts for the cyclization of
phenyl alkenyl a
-diazoketones,6 and chincona alkaloids were used
in the first enantioselective organocatalytic cyclopropanation.7 On
the other hand, Marquez et al. have used the enzymatic resolution
of the racemic bicycle obtained by cyclopropanation of the in-
2. Results and discussion
expensive a-diazo b
-ketoesters.8 Other methodology widely used
We first studied the reaction of
a
-sulfinylcyclopentenone 116
in the construction of the enantiomerically enriched bicy-
clo[3.1.0]hexanones is based on the reaction of cyclopentenones
with ylides, with the chiral auxiliary supported by any of the re-
agents.9 The stereoselective epoxidation of suitable substituted
cyclopentenes, followed by an intramolecular epoxide ring
opening, has also been used in the synthesis of some fluorinated
derivatives containing the desired skeleton.10
with diazomethane under different conditions (Table 1). The ad-
dition of an ethereal solution of diazomethane over sulfinylcyclo-
pentenone 1 dissolved in Et2O produced, almost instantaneously,
a mixture of only two 1
D-pyrazolines, 2A (major) and 2B, in almost
quantitative combined yield. As expected, the facial selectivity in-
creased and the reaction times were longer when the temperature
became lower (Table 1, entries 1–3). The use of THF as the solvent
provided similar results (Table 1, entries 4–6). Chromatographic
separation of both isomers afforded major 2A (>95% de) in 83%
yield (entry 6).
* Corresponding authors. Tel.: þ34 91 497 4701; fax: þ34 91 497 3966.
´
E-mail address: joseluis.garcia.ruano@uam.es (J.L. Garcıa Ruano).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.088

J.L. Garc´ıa Ruano et al. / Tetrahedron 64 (2008) 10546–10551
10547
Table 1
Table 2
Reactions of compound 1 with diazomethane
Reactions of compound 1 with diazoethane
O
O
O
O
TolOS
N
N
TolOS
O
TolOS
O
Tol
O
Tol
O
TolOS
Et
N
N
N
S
S
CH3CHN2
CH2N2
conditions
+
N
H
5A
H
Me
H
1
2A
2B
1
6
T (ꢀC)
Time
Ratio 5A/5B/6
Entry
Solvent
T (ꢀC)
Lewis acid
Time
Ratioa 2A/2B
Yieldb (%)
Entry
Solvent
(equiv)
(yield, %)
1
2
3
4
5
6
7
Et2O
Et2O
Et2O
THF
THF
THF
THF
0
ꢁ40
ꢁ78
0
ꢁ40
ꢁ78
ꢁ78
d
5 min
3 h
12 h
5 min
30 min
9 h
91/9
92/7
95/5
88/12
90/10
96/4
>95 (2)
>95 (2)
>95 (2)
63 (2A)
80 (2A)
83 (2A)
63 (2B)
1
2
3
4
5
THF
THF
THF
THF
Et2O
0
ꢁ20
ꢁ40
ꢁ78
ꢁ40
5 min
5 min
50 min
4 h
68/d/32
75/d/25
83 (55)/d/17
90 (67)/d/10
81/8/11
d
d
d
d
2 h
d
Yb(OTf)3
(0.5)
5 min
21/79
a
Determined by 1H NMR from the reaction crude.
Isolated yield.
reaction time than the reactions with diazomethane and diazo-
ethane. Additionally, trimethylsilylpyrazoline was neither isolated
nor characterized, since spontaneously evolved into 3-(trime-
thylsilyl)cyclopenta[c]pyrazol 7, 3-methylcyclopentanone 3,
and pyrazol 8 (Scheme 2), which were isolated by column
chromatography.20
b
The reaction was then performed in the presence of Yb(OTf)3
(Table 1, entry 7), which inverted the -facial selectivity de-
p
termining the predominance of isomer 2B, which could be obtained
in 63% isolated yield in the conditions of entry 7.17 Taking into ac-
count that the opening of the tetrahydrofuran ring by reaction with
diazoalkane/boron trifluoride etherate had been reported18 and it
also takes place under Yb(OTf)3 catalysis, as we could demonstrate
the formation of the pyrazolines under the conditions used in entry
7 can only be explained as the consequence of the high reactivity of
sulfinylcyclopentenone 1 toward diazomethane.19
We have also studied the reaction of (S)-3-methyl-2-(p-tol-
ylsulfinyl)cyclopent-2-enone (3)16 with diazomethane. As expected,
it proved to be much less reactive than 1, yielding a 69/31 mixture of
4A/4B after 10 h at 0 ꢀC (Scheme 1), which precluded the use of
lower temperatures.
O
TolOS
O
Tol
O
N
Me3SiCHN2
rt
S
N
Si
1
H
N
O
O
H
N
O
Tol
+
S
N
N
+
O
Me
3 (10%)
Si
H
7 (49%)
8 (22%)
Scheme 2. Reaction of sulfinylcyclopentenone 1 with (trimethylsilyl)-diazomethane.
In order to obtain bicyclo[3.1.0]hexan-2-ones, we studied the
reactions of the previously obtained pyrazolines 2A, 2B, 4A, 4B,
and 5A with Yb(OTf)3 in the best conditions (0.5 equiv of the acid
at ꢁ78 ꢀC) that had allowed the formation of cyclopropane
derivatives from the 1D-pyrazoline ring of the furo[3,4-c]pyr-
azolones.13 Pyrazoline 2A only needed 20 min to be quantitatively
transformed into an 88/12 mixture of 9A and 3 (Scheme 3). A
similar behavior was observed for the pyrazoline 4A but, in this
case, cyclopropane 10A was obtained as the only product. By
contrast, the formation of olefin 6 was clearly favored starting
from 5A and only a small amount of cyclopropane 11A could be
detected by NMR.
O
O
TolOS
TolOS
O
Tol
O
N
N
N
S
CH2N2
THF
0 °C
+
N
Me
Me
Me
3
4A
4B
Scheme 1. Reaction of cyclopentenone 3 with diazomethane.
When reaction was conducted in the presence of Yb(OTf)3 the
isolation of pyrazolines is very difficult, because reactions of
diazomethane with THF and with the C]O bond competed with
the slower cycloaddition to the C]C of 3.
We next studied reactions of compound 1 with diazoethane.
Under thermal conditions, they were very fast, and afforded mix-
tures of compounds 5A and 6 (Table 2). Olefin 6 could result from
the extrusion of nitrogen from pyrazolines 5A or 5B. However, as
compound 5A dissolved in THF at 0 ꢀC is stable for hours without
significant decomposition, compound 6 obtained in the absence of
acids (entries 1–4, Table 2) must derive from 5B (not shown), which
must be much less stable than 5A. Therefore, the ratio 5A/6 in-
dicated in Table 2 could be considered as a measure of the facial
selectivity.
O
O
O
Yb(OTf)3
TolOS
N
TolOS
R'
TolOS
(0.5 equiv)
+
N
THF, -78 °C
R'
R
R
R
R'
2A: R' = R = H
4A: R' = H, R =Me 30 min
5A: R' = Me, R = H 15 min
9A: 88 (87%)
10A:100 (78%)
11A: 5
3: 12
----
20 min
6: 95
Scheme 3. Denitrogenation of pyrazolines A under Yb(OTf)3 catalysis.
The proportion of 5A increased when the temperature became
lower (entries 1–4, Table 2) with the best isolated yield (67%)
having been obtained at ꢁ78 ꢀC (entry 4). In the presence of
Yb(OTf)3 compound 6 was exclusively formed, even at ꢁ78 ꢀC.
Cyclopropanes derived from 5A or 5B were not detected in any case.
The low reactivity of trimethylsilyldiazomethane determined
that its reaction with 1 required higher temperature and longer
Pyrazolines 2B and 4B exhibited lower tendency to the forma-
tion of cyclopropane rings than their corresponding 2A and 4A
diastereoisomers. Only a small amount of cyclopropane 9B was
formed from 2B, and olefin 6 was the only product detected in the
reaction crude from 4B (Scheme 4).

10548
J.L. Garc´ıa Ruano et al. / Tetrahedron 64 (2008) 10546–10551
Table 4
O
TolOS
N
Yb(OTf)3
TolOS
R
1H and 13C NMR data of pyrazolines
O
O
TolOS
R
(0.5 equiv)
O
O
TolOS
N 6a
+
N
TolOS
N 6a
THF, -78 °C
R
5
N
N
3a
3
3a
3
4
H
2B: R = H
4B: R = Me
9B: 7 (5 %)
-----
3: 93 (88%)
6:100 (80%)
R'
25 min
38 min
R
en
R
ex
H
H
ex
en
A
B
Scheme 4. Denitrogenation of pyrazolines B under Yb(OTf)3 catalysis.
Pyrazoline
Chemical shifts
Coupling constant
Finally, in order to clarify the effect of the sulfinyl group on the
reactivity of the sulfinylcyclopentenone 1 with diazoalkanes, we
have studied the reactions of diazomethane with cyclopent-2-
enone (12) and its 2-(p-tolylsulfanyl) and 2-(p-tolylsulfonyl)
derivatives 1321 and 14.21 The results are collected in Table 3. The
sulfinyl group strongly increased the reactivity of the double bond
(compare entries 1 and 3). Moreover, the presence of the sulfinyl
group stabilized the adduct (15 completely decomposed after 2
days at ꢁ20 ꢀC whereas 2A can be stored for over two weeks under
similar conditions). Sulfone 14 exhibited a reactivity even larger
than that of sulfoxide 1 (entry 4), whereas thioether 13 did not react
with diazomethane after 2 days at room temperature (entry 2),
which are the expected results according to the electronic effects of
the substituents.
No.
R
R0
H3endo
H3exo H3a
C3a
C6a
J3exo,3a
J3endo,3a
2A
2B
4A
4B
5A
H
H
Me
Me
H
H
H
H
H
4.57
4.37
4.84 3.00
3.23 2.97
30.4
31.0
36.9
37.2
37.5
125.1 8.7
124.6 8.1
3.2
2.1
d
4.51 and 4.81
4.61 and 4.05
d
121.3
118.0
125.3
d
d
d
d
d
Me
4.60
d
2.56
3.6
Tol
R
H
endo
S
O
N
O
N
H
H
H
exo
shielding
2A (R=H)
4A (R=Me)
O
Tol
S
N
2B (R=H)
4B (R=Me)
H
H
N
H
exo
R
B
endo
O
H
A
Yb(OTf)3
Yb(OTf)3
3. Structural and configurational assignments
Tol
H
endo
9B (R=H)
6
S
1
O
Significant NMR parameters of the obtained pyrazolines are
depicted in Table 4. The regiochemistry of compounds 2A, 2B, and
5A could be easily deduced from the value of the coupling constant
between the protons at C-3a and C-3. The structure is also
supported by the dC-6a value observed for these compounds.
Regiochemistry of compounds 4A and 4B (lacking of the protons at
C-3a) must be identical (dC-3a and dC-6a are very similar for both
isomers) and the same applies for pyrazolines 2A and 2B (similar
values of dC-6a and dC-3a).
The different J3,3a values observed for the protons at C-3 allows
to differentiate Hendo and Hexo in compounds 2A and 2B (see Table
4). The J3,3a value (3.6 Hz) in compound 5A suggests that they are in
a trans relationship, which means that the Me group at C-3 occupies
an exo position.
H
Tol
O
exo
H
9A (R=H)
10A (R=Me)
R
exo
1
O
S
H
H
H
6
H
H
endo
O
H
Figure 1. Assignation of the A or B stereoisomer.
because of the quasi 1,3-syndiaxial interaction Tol/R (R¼Me), which
would destabilize the conformation of diastereoisomer B shown in
Figure 1, provoking conformational changes decreasing the
shielding effect of the tolyl group at Hexo. The stereochemical model
proposed to explain the experimental results (see later) also sup-
ports this assignment.22
The stereochemical assignments of cyclopropanes 9A, 9B, and
10A can be easily made taking into account that the extrusion of
the nitrogen from the corresponding pyrazolines does not affect
any bond at C-3a and therefore configuration of C-5 at cyclopro-
pane must be the same than that of C-3a in the pyrazoline
precursor (see Fig. 1).
The absolute configuration of C3a and C6a in compounds 2A and
2B was tentatively assigned from the very different values of
d-H3exo in both compounds. Taking into account the S configuration
of the sulfinyl group in these compounds, the presumably most
stable conformations for the two possible diastereoisomers (A and
B) are depicted in Figure 1. As we can see, Hexo must be shielded by
the tolyl group in B, but not in A. Compound 2A, with the highest
4. Stereochemical model
value of
-H3exo¼3.23 ppm) must be assigned as B. The same criteria should
be valid for the assignment of compounds 4A (larger -H3exo) and
-H3exo). In these cases the Dd values are not so marked
d-H3exo (4.84 ppm) must be assigned as A, whereas 2B
(d
The
p-facial selectivity of these reactions can be explained by
d
assuming that the sulfinyl group at compounds 1 and 3 mainly
adopts conformation I, with the oxygen and C]C in an s-cis ar-
rangement, thus minimizing its electrostatic repulsion with the
carbonyl oxygen. The orientation of the p-tolyl group at this con-
formation determines the favored approach of the dipole (Fig. 2a).
4B (lower
d
Table 3
Reactivity of cyclopentenone and sulfur derivatives with diazomethane
O
O
R
Dipole
Dipole
favored
N
R
CH2N2
THF
N
Tol
O
O
O
O
S
(Me)H
H
(Me)H
S
Yb
Entry
R
Starting
material
T (ꢀC)
Time
Adduct
I
II
Tol
favored
Dipole
Dipole
1
2
3
4
H
12
13
1
0
25
3 days
2 days
9 h
15
d
2A
16
Tol-S
Tol-SO
Tol-SO2
b) 1 or 3 with Yb(OTf)3
a) 1 or 3 without catalyst
Figure 2. Rationalization of the
ꢁ78
14
ꢁ78
0.5 min
p
-facial selectivity of the cycloadditions.

J.L. Garc´ıa Ruano et al. / Tetrahedron 64 (2008) 10546–10551
10549
TolOS
H
The residue was analyzed by 1H NMR and purified as indicated in
each case.
O
TolOS
H
TolOS
H
O
O
TolOS
H
O
H
H
H
H
Method B. To a stirred solution of Lewis acid (amounts indicated
in Table 1) in THF at room temperature was added a solution of
sulfinylcyclopentenone 1 or 3 (0.5 mmol) in THF. The mixture was
stirred for 1 h, cooled at the temperature indicated in Table 1, then
was added the solution of diazoalkane in Et2O. The reaction mix-
ture was stirred for the time indicated in Table 1. The reaction was
quenched at the indicated temperature with a saturated solution of
potassium sodium tartrate and extracted with ethyl acetate
(3ꢂ8 mL). The organic layer was washed with brine (7 mL) and
dried (MgSO4). The solvent was removed under vacuum. The
resulting residue was analyzed by 1H NMR.
N
N
N
H
H
N
H
H
N
H
Me
N
N
H
Me
N
H
Me
H
Me
endo-approach
5A
exo-approach
Figure 3. Rationalization of the endo/exo-selectivity in reactions of
1 with
diazoethane.
As the conformational preference must be less marked for com-
pound 3 because of the (Me/O)1,3-syndiaxial interaction, the facial
selectivity in the absence of catalyst is lower (compare entry 4 in
Table 1 with Scheme 1).
The influence of Yb(OTf)3 can be rationalized by assuming the
formation of a chelated species II involving the two oxygens
(Fig. 2b). It arranges the p-tolyl group in the opposite face to that
occupied in I (compare Fig. 2a and b), thus explaining the inversion
of stereoselectivity produced by this catalyst.
The complete exo-selectivity observed in the reaction of diazo-
ethane with 1 can be explained on the basis of the steric
interactions of the methyl group at the dipole with the substituents
at C-3 of 1. They are stronger for the endo approach (Fig. 3) and
therefore the exo adduct 5A was exclusively formed.
Finally, the formation of the cyclopropyl rings in the reactions of
bicyclic pyrazolines 2A, 4A, and 5A with substoichiometric amounts
of Yb(OTf)3 and the low tendency of pyrazolines 2B and 4B to form
these cycles, thus preferring the formation of the olefins, can be
rationalized on the basis of the same stereochemical model pro-
posed for the synthesis of the 3-oxabicyclo[3.1.0]hexanones.13
6.2.1. (3aR, 6aR, SS)-6a-[(4-Methylphenyl)sulfinyl]-3a,4,5,6a-
tetrahydrocyclopenta[c]pyrazol-6(3H)-one (2A)
It was obtained from (þ)-(S)-2-(p-tolylsulfinyl)cyclopent-2-
enone (1) and diazomethane in ether or THF (see Table 1) following
method A. It was isolated by dissolving the crude reaction in AcOEt
and further precipitation with Et2O/hexane. White solid, mp: 92–
94 ꢀC. [
d
a
]
D þ277.0 (c 1, acetone). IR (KBr) 1700, 1491, 1429. 1H NMR
7.48 and 7.33 (AA0BB0 system, 4H), 4.84 (dd, 1H, J¼8.7 and 18.8),
4.57 (dd, 1H, J¼3.2 and 18.8), 3.00 (m, 1H), 2.40 (s, 3H), 2.01 (m, 1H),
1.65 (m,1H), 1.43 (m,1H), 1.24 (m, 1H). 13C NMR
d 202.3, 143.1, 134.8,
130.2, 125.1, 87.3, 37.6, 30.4, 24.8, 21.4. Anal. Calcd for C13H14N2O2S:
C, 59.52; H, 5.38; N, 10.68; S, 12.22. Found: C, 59.64; H, 5.52; N,
10.76; S, 12.18.
6.2.2. (3aS, 6aS, SS)-6a-[(4-Methylphenyl)sulfinyl]-3a,4,5,6a-
tetrahydrocyclopenta[c]pyrazol-6(3H)-one (2B)
It was obtained from (þ)-(S)-2-(p-tolylsulfinyl)cyclopent-2-
enone (1) and diazomethane inTHFat ꢁ78 ꢀC following method B. It
was isolated by dissolving the crude reaction in AcOEt and further
5. Conclusions
precipitation with hexane. Yellow solid, mp: 68–70 ꢀC. [
a
]
þ68
D
(c 1, CHCl3). IR (film) 1708,1475,1425.1H NMR 7.47 and 7.30 (AA0BB0
d
In summary, we have demonstrated that the sulfinyl group at
cyclopentenones is able to control the
p-facial and endo/exo
system, 4H), 4.37 (dd, 1H, J¼2.1 and 18.8), 3.23 (dd, 1H, J¼8.1 and
selectivities of their 1,3-dipolar reactions with diazoalkanes. The
reaction of some of the obtained pyrazolines with Yb(OTf)3 pro-
vides an efficient procedure for preparing bicyclo[3.1.0]hexanone
derivatives in their optically pure form.
18.8), 2.97 (m,1H), 2.35 (s, 3H),1.98 (m,1H),1.65 (m,1H),1.42 (m,1H),
1.22 (m, 1H). 13C NMR
d 202.3, 142.9, 134.8, 130.2, 125.1, 124.6, 86.1,
37.6, 31.0, 25.5, 21.4. Anal. Calcd for C13H14N2O2S: C, 59.52; H, 5.38; N,
10.68; S, 12.22. Found: C, 59.38; H, 5.45; N, 10.82; S, 12.05.
6. Experimental section
6.1. General methods
6.2.3. (3aR, 6aR, SS)-3a-Methyl-6a-[(4-methylphenyl)sulfinyl]-
3a,4,5,6a-tetrahydrocyclopenta[c]pyrazol-6(3H)-one (4A)
It was obtained from (þ)-(S)-3-methyl-2-(p-tolylsulfinyl)cyclo-
pent-2-enone (3) and diazomethane in THF at 0 ꢀC following
method A. It was isolated by dissolving the crude reaction in AcOEt
and further precipitation with Et2O/hexane. White solid, mp: 85–
THF and diethyl ether were distilled from sodium benzophe-
none under argon. Lewis acids are commercially available and were
used without further purification. Flash chromatography was car-
ried out with silica gel Merck 60 (230–400 mesh ASTM). NMR
spectra were determined in CDCl3 solutions at 300 and 75 MHz for
1H and 13C NMR, respectively; J values are given in hertz. Melting
points were measured using a Gallenkamp apparatus in open
capillary tubes and are uncorrected. The optical rotations were
measured at room temperature (20–23 ꢀC) using a Perkin–Elmer
241MC polarimeter (concentration in g/100 mL). Compounds 1,16
3,16 13,21 and 1421 were synthesized and purified following the
reported procedures.
86 ꢀC. [
d
a
]
þ210.0 (c 1, CHCl3). IR (film) 1718, 1502, 1421. 1H NMR
D
7.62 and 7.35 (AA0BB0 system, 4H), 4.81 and 4.51 (AB system, 2H,
J¼18.3), 2.43 (s, 3H), 2.31–1.81(m, 4H), 1.67 (s, 3H). 13C NMR
d 202.0,
143.5, 134.4, 129.8, 125.0, 121.3, 86.8, 36.9, 31.2, 26.3, 25.4, 21.4.
Anal. Calcd for C14H16N2O2S: C, 60.85; H, 5.84; N, 10.14; S, 11.60.
Found: C, 60.59; H, 6.08; N, 10.24; S, 11.82.
6.2.4. (3aS, 6aS, SS)-3a-Methyl-6a-[(4-methylphenyl)sulfinyl]-
3a,4,5,6a-tetrahydrocyclopenta[c]pyrazol-6(3H)-one (4B)
It was obtained from (þ)-(S)-3-methyl-2-(p-tolylsulfinyl)cyclo-
pent-2-enone (3) and diazomethane in THF at 0 ꢀC following
method A. It was isolated by dissolving the crude reaction in AcOEt
and further precipitation with hexane. Yellow solid, mp: 75–78 ꢀC.
6.2. 1,3-Dipolar cycloadditions of diazomethane or
diazoethane
[
a
]
D þ61.0 (c 1, CHCl3). IR (film) 1704, 1492, 1412. 1H NMR
d 7.61 and
Method A. To a solution of cyclopent-2-enones 1, 3, 12, 13, or 14
(1 mmol) in the appropriate solvent cooled at the indicated
temperature (see Tables 1 or 2 and Schemes 1 or 2), was added
a solution of diazoalkane in Et2O. The resulting mixture was stirred
under the conditions shown in tables and schemes and evaporated.
7.31 (AA0BB0 system, 4H), 4.61 and 4.05 (AB system, 2H, J¼18.3),
2.40 (s, 3H), 2.28–1.80 (m, 4H), 1.49 (s, 3H). 13C NMR
d 202.3, 143.7,
134.4,129.6,125.2,118.0, 85.9, 37.2, 32.0, 26.9, 24.8, 21.3. Anal. Calcd
for C14H16N2O2S: C, 60.85; H, 5.84; N, 10.14; S, 11.60. Found: C,
60.71; H, 5.72; N, 10.34; S, 11.75.

10550
J.L. Garc´ıa Ruano et al. / Tetrahedron 64 (2008) 10546–10551
6.2.5. (3aR, 6aR, 3R, SS)-3-Methyl-6a-[(4-methylphenyl)sulfinyl]-
3a,4,5,6a-tetrahydrocyclopenta [c]pyazol-6(3H)-one (5A)
It was obtained from (þ)-(S)-2-(p-tolylsulfinyl)cyclopent-2-
6.4.1. (1R, 5R, SS)-1-[(4-Methylphenyl)sulfinyl]bicyclo[3.1.0]hexan-
2-one (9A)
It was obtained from 2A and purified by flash chromatography
enone (1) with diazoethane (see Table 2) following method A.
(AcOEt/hexane, 1/5). White solid, mp: 84–86 ꢀC. [
a]
D ꢁ36.2 (c 0.505,
20
White solid, mp: 89–91 ꢀC. [
a
]
þ620.0 (c¼1, CHCl3). IR (KBr)
acetone). IR (KBr) 1722. 1H NMR 7.47 and 7.28 (AA0BB0 system, 4H),
d
D
1737, 1455, 1405. 1H NMR
d
7.34 and 7.53 (AA0BB0 system, 4H), 4.60
2.36 (s, 3H), 2.12 (m, 6H), 1.45 (t, 1H, J¼5.5). 13C NMR
d 204.8, 142.3,
(cd, 1H, J¼3.6 and 7.5), 2.56 (m, 1H), 2.43 (s, 3H), 2.05 (m, 2H), 1.61
139.8, 128.9, 125.4, 54.6, 33.1, 26.3, 21.4, 20.9, 17.9. Anal. Calcd for
(d, 3H, J¼7.5), 1.49 (m, 2H). 13C NMR
d
202.4, 142.9, 134.7, 130.1,
C13H14O2S:C,66.64;H, 6.02;S,13.68.Found:C, 66.58;H, 6.20;S,13.97.
125.3, 124.9, 95.6, 37.5, 37.2, 23.8, 21.3, 18.1. Anal. Calcd for
C
14H16N2O2S: C, 60.85; H, 5.84; N, 10.14; S, 11.60. Found: C, 60.52; H
6.4.2. (1S, 5S, SS)-1-[(4-Methylphenyl)sulfinyl]bicyclo[3.1.0]
hexan-2-one (9B)
5.59; N, 9.97; S, 11.84.
It was obtained from 2B and purified by flash chromatography
6.2.6. (ꢃ)-3a,4,5,6a-Tetrahydrocyclopentapyrazol-6(3H)-one (15)
It was obtained from 2-cyclopenten-1-one (500 mg, 6.09 mmol)
and diazomethane in THF (15 mL) at 0 ꢀC following method A. The
residue was analyzed by 1H NMR (46% conversion) and purified by
flash chromatography (AcOEt/hexane,1/1). Colorless oil (35% yield).
(AcOEt/hexane, 1/5). White solid, mp: 64–61 ꢀC. [
a
]
þ131.1 (c 1.1,
D
acetone).9d IR (film) 1714. 1H NMR
d
7.45 and 7.27 (system AA0BB0,
4H), 2.34 (s, 3H), 2.21–2.03 (m, 6H), 0.82 (t, 1H, J¼5.3). 13C NMR
d
203.4, 142.1, 139.2, 129.4, 125.2, 54.1, 33.0, 25.9, 21.3, 20.7, 18.4.
HRMS (EI): C13H14O2S requires 234.0715. Found: 234.0713.
1H NMR
d 4.92–4.87 (m, 1H), 4.51–4.46 (m, 2H), 2.76–2.64 (m, 1H),
2.15–1.82 (m, 3H), 1.26–1.12 (m, 1H). 13C NMR
36.1, 31.3, 25.8.
d
207.6, 99.0, 85.6,
6.4.3. (1R, 5R, SS)-5-Methyl-1-[(4-methylphenyl)-
sulfinyl]bicyclo[3.1.0]hexan-2-one (10A)
It was obtained from 4A and purified by flash chromatography
6.2.7. (ꢃ)-6a-[(4-Methylphenyl)sulfonyl]-3a,4,5,6a-
tetrahydrocyclopentapyrazol-6(3H)-one (16)
(AcOEt/hexane, 1/2). White solid, mp: 121–123 ꢀC. [
a
]
D ꢁ2.9 (c 0.14,
CHCl3). IR (KBr) 3050, 1723. 1H NMR
d
7.56–7.27 (AA0BB0 system,
It was obtained from 2-(4-methylphenyl)sulfonylcyclopent-2-
4H), 2.37 (s, 3H), 2.14–1.87 (m, 4H), 1.89 and 1.48 (AB system, 2H,
en-1-one (14) (500 mg, 6.09 mmol) and diazomethane in THF at
J¼5.5), 1.41 (s, 3H). 13C NMR
d 207.1, 141.3, 139.2, 129.6, 124.9, 55.7,
33.2, 31.2, 28.2, 24.2, 21.4, 18.1. Anal. Calcd for C14H16O2S: C, 67.71;
H, 6.49; S, 12.91. Found: C, 67.53; H, 6.35; S, 13.12.
0 ꢀC following method A. 1H NMR
d
7.77 and 7.42 (AA0BB0 system,
4H), 4.91 (dd, 1H, J¼7.2 and 18.7), 4.83 (dd, 1H, J¼3.3 and 18.7),
3.54 (m, 1H), 2.65 (m, 1H), 2.50 (s, 3H), 2.38 (m, 2H), 1.26 (m, 1H).
13C NMR
24.9, 21.7.
d
199.4, 146.2, 131.9, 130.7, 129.5, 119.1, 86.9, 38.1, 35.0,
6.4.4. (SS)-3-Ethyl-2-[(4-methylphenyl)sulfinyl]cyclopent-
2-en-1-one (6)
It was obtained from 5A and purified by flash chromatography
6.3. Addition of (trimethylsilyl)diazomethane to (SS)-2-(4-
methylphenyl)sulfinylcyclopent-2-enone (1)
(AcOEt/hexane, 2/1). White solid, mp: 108–110 ꢀC. [
a
]
þ18.0 (c 1,
acetone). IR (KBr) 1693. 1H NMR
d
7.61 and 7.28 (AA0BB0 Dsystem, 4H),
3.08–2.87 (m, 2H), 2.72–2.66 (m, 2H), 2.42–2.37 (m, 2H), 2.39 (s,
To a solution of 252 mg (1.145 mmol) of 1 in Et2O (24 mL) was
added at room temperature 0.356 mL of 2 M TMSCHN2 in hexane
(1.5 equiv, 1.718 mmol). After 30 h the solvent was removed under
reduced pressure and the resulting oil purified by column
chromatography (AcOEt/hexane, 3/1) to afford 108 mg (49% yield)
of 3-trimethylsilylcyclopentan[1,2-c]pyrazol-6-one (7), 14 mg of
the cyclopenta[1,2-c]pyrazol(3)-6-one (8) (22% yield), and 59 mg
(10% yield) of cyclopentenone 3.
3H), 1.20 (t, 3H, J¼7.5). 13C NMR
d 202.6, 186.4, 141.1, 140.7, 139.7,
129.8, 124.4, 34.3, 30.3, 24.0, 21.3, 12.1. Anal. Calcd for C14H16O2S: C,
67.71; H, 6.49; S, 12.91. Found: C, 67.64; H, 6.29; S, 13.24.
Acknowledgements
We thank DGICYT (Grant CTQ2006-06741/BQU) and Comunidad
´
Autonoma de Madrid (CCG07-UAM/PPQ-1709) for financial
support.
6.3.1. 3-(Trimethylsilyl)-4,5-dihydrocyclopenta[c]
pyrazol-6(1H)-one (7)
References and notes
White solid, mp: 128 ꢀC. IR (KBr) 1718. 1H NMR
d 3.03 (m, 4H),
0.36 (s, 9H). 13C NMR
Anal. Calcd for C9H14N2OSi: C, 55.63; H, 7.26; N, 14.42. Found: C,
55.68; H, 7.19; N, 13.99.
d
197.4, 153.4, 148.2, 140.2, 42.8, 18.8, ꢁ1.5.
1. (a) Pedregal, C.; Prowse, W. Bioorg. Med. Chem. 2002, 10, 433; (b) Nakazato, A.;
Kumagai, T.; Sakagami, K.; Yoshikawa, R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi,
T.; Nakanishi, S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893; (c) Wong, A.; Welch,
C. J.; Kuethe, J. T.; Vazquez, E.; Shaimi, M.; Henderson, D.; Davies, I. W.; Hughes,
D. L. Org. Biomol. Chem. 2004, 2, 168.
2. Kiyota, H.; Koike, T.; Higashi, E.; Oritani, T. Flavour Fragrance J. 2002, 17, 267.
3. (a) Aavula, B. R.; Cui, Q.; Mash, E. A. Tetrahedron: Asymmetry 2000, 11, 4681; (b)
6.3.2. 4,5-Dihydrocyclopenta[c]-pyrazol-6(1H)-one (8)
Yellow solid, mp: 134 ꢀC. IR (KBr) 3355, 3106, 1708. 1H NMR
´
˜
´
Abad, A.; Agullo, C.; Cunat, A. C.; Jimenez, D.; Perni, R. H. Tetrahedron 2001, 57,
d
7.58 (s, 1H), 3.0 (m, 4H). 13C NMR
d 195.0, 149.7, 142.5, 130.2,
9727; (c) Jiang, X.; Covey, D. F. J. Org. Chem. 2002, 67, 4893.
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4. (a) Barberis, A.; Perez-Prieto, J.; Stiriba, S.-E.; Lahuerta, P. Org. Lett. 2001, 3, 3317;
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Pe´rez-Prieto, J.; Stiriba, S.-E.; Moreno, E.; Lahuerta, P. Tetrahedron: Asymmetry
2003, 14, 787.
6.4. Nitrogen extrusion reaction
5. Honma, M.; Sawada, T.; Fujisawa, Y.; Utsugi, M.; Watanabe, H.; Umino, A.;
Matsumura, T.; Takano, M.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 2860.
6. Saha, B.; Uchida, T.; Katsuki, T. Tetrahedron: Asymmetry 2003, 14, 823.
7. Bremeyer, N.;Smith,S.C.;Ley, S.V.;Gaunt, M. T. Angew. Chem., Int. Ed.2004, 43, 2681.
8. Yoshimura, Y.; Moon, H. R.; Choi, Y.; Marquez, V. E. J. Org. Chem. 2002, 67, 5938.
9. (a) Domı´nguez, C.; Ezquerra, J.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron:
Asymmetry 1997, 8, 511; (b) Lee, W.; Miller, M. J. J. Org. Chem. 2004, 69, 4516; (c)
Aggarwal, V. K.; Grange, E. Chem.dEur. J. 2006, 12, 568; (d) Miko1ajczyk, M.;
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Acta 2005, 88, 1769.
To a stirred solution of pyrazolines 2, 4 or 5 in THF (0.1 M)
cooled at ꢁ78 ꢀC was added a solution of Yb(OTf)3 (0.5 equiv) in
THF (0.1 M). The mixture was stirred for the time indicated in
Scheme 3 or 4. The reaction was quenched at the indicated tem-
perature with a saturated solution of potassium sodium tartrate
and extracted with ethyl acetate (3ꢂ8 mL). The organic extracts
were washed with brine (7 mL) and dried (MgSO4). The solvent
was removed under vacuum. The resulting residue was analyzed
by 1H NMR.
10. (a) Zhang, F.; Song, Z. J.; Tschaen, D.; Volante, R. P. Org. Lett. 2004, 6, 3775; (b)
Tan, L.; Yasuda, N.; Yoshikawa, N.; Hartner, F. W.; Eng, K. K.; Leonard, W. R.;
Tsay, F.-R.; Volante, R. P.; Tillyer, R. D. J. Org. Chem. 2005, 70, 8027.

J.L. Garc´ıa Ruano et al. / Tetrahedron 64 (2008) 10546–10551
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11. (a) Garcı´a Ruano, J. L.; Fraile, A.; Martı´n, M. R. Tetrahedron: Asymmetry 1996, 7,
17. Higher temperatures than ꢁ78 ꢀC and/or longer reaction times than 5 min lead
to decomposition of pyrazoline.
´
´
´
1943; (b) Garcıa Ruano, J. L.; Fraile, A.; Gonzalez, G.; Martın, M. R.; Clemente, F.
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Diego, S. A.; Blanco, D.; Martın Castro, A. M.; Martın, M. R.; Rodrıguez Ramos, J.
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M. R.; Torrente, E.; Martı´n Castro, A. M. Org. Lett. 2004, 6, 4945.
19. The amount of diazomethane added must be monitored (TLC) to obtain good
yields. As diazomethane is consumed by THF, the addition of small amounts of
this reagent is required. However, when an excess of diazomethane is added,
the signals corresponding to pyrazolines 2 were not observed in the 1H NMR
spectra of the crude reaction, presumably due to the reaction of diazomethane
with the carbonyl group.
20. Pyrazoles 7 and 8 have never been reported. 3-Trimethylsilylpyrazol 7 afforded
8 in 81% isolated yield by treatment with Bu4NF 1 M in THF.
21. Garcı´a Ruano, J. L.; Fajardo, C.; Fraile, A.; Martı´n, M. R. J. Org. Chem. 2005,
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pyrazol-6(6aH)-ones with 3-oxabicyclo[3.1.0]hexan-2-one of known config-
uration (see Ref. 13) validates the stereochemical model used and confirms
the configuration assigned to A and B isomers.
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