1,3-Dipolar cycloaddition of diazoalkanes to (S)-(+)-3-[(4-methylphenyl) sulfinyl]-5,6-dihydropyran-2-one. Synthesis of optically pure cyclopropanes by denitrogenation of sulfinyl and sulfonyl pyrazolines

Article abstract of DOI:10.1021/jo900525s

(Chemical Equation Presented) The addition of diazomethane and diazoethane to enantiopure (S)-(+)-3-[(4-methylphenyl)sulfinyl]-5,6-dihydropyran-2-one (3) afforded the corresponding pyrazolines 4 and 6-exo in good yields and with almost complete π-facial s

Full text of DOI:10.1021/jo900525s

1,3-Dipolar Cycloaddition of Diazoalkanes to
(S)-(+)-3-[(4-Methylphenyl)sulfinyl]-5,6-dihydropyran-2-one.
Synthesis of Optically Pure Cyclopropanes by Denitrogenation of
Sulfinyl and Sulfonyl Pyrazolines
David Cruz Cruz,† Francisco Yuste,*,† M. Rosario Mart´ın,‡ Amelia Tito,‡ and
Jose´ L. Garc´ıa Ruano*,‡
Instituto de Qu´ımica, UniVersidad Nacional Auto´noma de Me´xico, Circuito Exterior, Cd. UniVersitaria,
Coyoaca´n 04510, Me´xico D.F., Me´xico, and Departamento de Qu´ımica Orga´nica (C-I), Facultad de
Ciencias, UniVersidad Auto´noma de Madrid, Cantoblanco, 28049-Madrid, Spain
yustef@serVidor.unam.mx; joseluis.garcia.ruano@uam.es.
ReceiVed March 11, 2009
The addition of diazomethane and diazoethane to enantiopure (S)-(+)-3-[(4-methylphenyl)sulfinyl]-5,6-
dihydropyran-2-one (3) afforded the corresponding pyrazolines 4 and 6-exo in good yields and with
almost complete π-facial selectivity. When the reaction is effected in the presence of Yb(OTf)3, the
facial selectivity is inverted to give the pyrazolines 5 and 7-exo. The denitrogenation of optically pure
sulfinyl pyrazolines 4-7-exo into the corresponding cyclopropanes with Yb(OTf)3 occurred with complete
retention of configuration but moderate chemoselectivity and yields. These results were significantly
improved starting from sulfonyl pyrazolines, which afforded optically pure 3-oxabicyclo[4.1.0]heptan-
2-ones with yields ranging between 65% (17 and ent-17) and g95% (16 and ent-16).
Introduction
synthesis of such compounds.4 3-Oxabicyclo[4.1.0]heptan-2-
ones are interesting intermediates in the synthesis of pyre-
throids,5 mitoxanes,6 and conformationally constrained ana-
logues of glutamate.7 Despite this interest, only two strategies
(starting from enantiomerically pure cyclopropane7,8 or homoal-
lylic diazoacetates and chiral catalysts9) have been used for the
preparation of these skeletons in optically pure form, which
justifies the search for new methods of preparing them.
Cyclopropanes are extremely versatile building blocks in
organic synthesis owing to their ready accessibility and good
reactivity.1,2 This smallest cycloalkane class is found as a basic
structural element in a wide range of naturally occurring and
synthetic compounds with important biological and pharma-
ceutical applications.3 As a consequence, many recent studies
have been devoted to the development of enantioselective
(4) (a) Reissig, H. U. In StereoselectiVe Synthesis of Organic Compounds;
Methods of Organic Chemistry (Houben-Weyl); Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; p 3179. (b) Doyle,
M. P. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim,
Germany, 1993; p 63. (c) Charette, A. B.; Marcoux, J. F. Synlett 1995, 1197.
(d) Reissig, H. U. Angew. Chem., Int. Ed. Engl. 1996, 35, 971. (e) Salaun, J.
Chem. ReV. 1989, 89, 1247. (f) Launtens, M.; Klute, W.; Tam, W. Chem. ReV.
1996, 96, 49. (g) Donaldson, W. A. Tetrahedron 2001, 57, 8589.
(5) Demoute, J. P.; Hoemberger, G.; Pazenok, S.; Babin, D. PCT
WO2001034592, 2001, CA: 134:366801.
(6) Danishefsky, S.; Regan, J.; Doehner, R. J. Org. Chem. 1981, 46, 5255.
(7) (a) Gonza´lez, R.; Collado, I.; Lo´pez, B.; Marcos, A.; Mart´ın-Cabrejas,
L. M.; Pedregal, C.; Blano-Urgoiti, J.; Pe´rez-Castells, J.; Ferna´ndez, M. A.; Andis,
S. L.; Johnson, B. G.; Wright, R. A.; Schoepp, D. D.; Monn, J. A. Bioorg. Med.
Chem. 2005, 13, 6556. (b) Frick, J. A.; Klassen, J. B.; Rapoport, H. Synthesis
2005, 1751.
* To whom correspondence should be addressed. Phone: +55-525-622-4406.
Fax: +55-525-616-2203 (F.Y.). Phone: +34-91-497-4701. Fax: +34-91-497-
3966 (J.L.G.R.).
† Universidad Nacional Auto´noma de Me´xico.
‡ Universidad Auto´noma de Madrid.
(1) (a) Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603. (b) Reissig, H. U.;
Zimmer, R. Chem. ReV. 2003, 103, 1151. (c) Lebel, H.; Marcoux, J. F.; Molinaro,
C.; Charette, A. B. Chem. ReV. 2003, 103, 977. (d) Reichelt, A.; Martin, S. F.
Acc. Chem. Res. 2006, 39, 433. (e) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005,
61, 321. (f) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C. Chem. ReV.
1989, 89, 165.
(2) For recent results, see: (a) Ogoshi, S.; Nagata, M.; Kurosawa, H. J. Am.
Chem. Soc. 2006, 128, 5350. (b) Liu, L.; Montgomery, J. J. Am. Chem. Soc.
2006, 128, 5348. (c) Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 183.
(3) Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2251.
3820 J. Org. Chem. 2009, 74, 3820–3826
10.1021/jo900525s CCC: $40.75 2009 American Chemical Society
Published on Web 04/17/2009

1,3-Dipolar Cycloaddition of Diazoalkanes
TABLE 1. Reactions of (+)-3 with Diazomethane
SCHEME 1. Sulfinyllactones Used As Dipolarophiles
entry
solvent
T, °C
t, min
4:5 ratioa
4 (%)b
1
2
3
4
5
6
7
8
Et2O/MeOH
Et2O/MeOH
Et2O/MeOH
CH3CN
0
-40
-78
-40
-78
-78
-78
-40
10
15
20
15
15
30
30
30
95:5
>95:5
>98:2
95:5
>98:2
20:80
∼40:60
50:50
92
95
97
92
97
The synthesis of cyclopropanes by extrusion of nitrogen from
pyrazolines is a well-known reaction.10 Recently, we reported
a highly stereoselective and efficient method to transform
sulfinyl furopyrazolines into sulfinyl cyclopropanes, which can
be easily desulfinylated.11 We had previously reported efficient
and highly stereoselective syntheses of the sulfinyl furopyra-
zolines by reaction of diazoalkanes with optically pure 3-[(4-
methylphenyl)sulfinyl]furan-2(5H)-ones12 1 and with both C-5
epimers of 5-ethoxy-3-[(4-methylphenyl)sulfinyl]furan-2(5H)-
ones13 2 (Scheme 1). Our success in this area suggested to us
that a new method for synthesizing 3-oxabicyclo[4.1.0]heptan-
2-ones could be achieved by addition of the diazoalkanes to
(S)-(+)-3-[(4-methylphenyl)sulfinyl]-5,6-dihydropyran-2-one 3
and subsequent nitrogen extrusion from the product(s) obtained
thereby. In this paper, we report the results obtained in this study
as well as some mechanistic aspects related to the conversion
of pyrazolines into cyclopropanes by extrusion of nitrogen.
THF
THFc
Et2O/MeOHc
CH3CNc
a Determined by 1H NMR. b Isolated yield. c In the presence of 1
equiv of Yb(OTf)3.
TABLE 2. Reactions of (+)-3 with Diazoethane
ratioa
entry
solvent
T, °C
6-exo
7-exo
other
yield %
1
2
3
4
5
6
b
b
0
-78
0
-78
-78
-78
95
>98
95
>98
<10
∼60
5
<2
5
95
97
95
97
>80
95
Results and Discussion
THF
THF
THFc
d
<2
This study was initiated by examining the reaction of the
recently described14 (+)-sulfinylpyranone 3 with diazomethane
under various conditions (Table 1). In all cases, a separable
mixture of the two isomeric bicyclic pyrazolines 4 and 5 was
obtained. The ratio of 4:5 varied somewhat with the solvent
used and the reaction temperature, but isomer 4 was always
the strongly predominant product (de >96%; entries 3 and 5).
When the cycloaddition reaction was effected in the presence
of an equivalent of Yb(OTf)3, compound 5 became the
predominant product with the best de being observed in THF
at -78 °C (entry 6). Under these conditions, the solvent was
partially converted into a polymeric material which could not
be separated from compound 5, and thus this product was not
characterized spectroscopically. The impurity could, however,
be removed in the next step of the synthetic sequence.
>90
∼40
a Determined by 1H NMR. b Et2O/MeOH. c With 1 equiv of Yb(OTf)3.
d Et2O/MeOH and 1 equiv of Yb(OTf)3.
in each case. When the addition reaction was conducted in the
presence of 1 equiv of Yb(OTf)3 at -78 °C in THF, the 7-exo
compound predominated over the 6-exo isomer with a de >80%
(entry 5).
With the pyrazolines in hand, the susceptibility thereof to
thermal and Lewis acid induced nitrogen elimination was studied
(Table 3). When solutions of 4, 5, 6-exo, or 7-exo in toluene
were briefly heated at 100 °C, aromatization to the pyrazoles
14 (from 4 or 5, entries 1 and 2) or 15 (from 6-exo or 7-exo,
entries 11 and 12) occurred nearly quantitatively, instead of
nitrogen loss, which indicates that desulfinylation is strongly
favored under these conditions. The pyrazole 15 was also
produced in high yield at room temperature in a THF solution
of 6-exo containing an equivalent of Eu(fod)3 (entry 20). In
contrast, in THF solution containing Yb(OTf)3, the pyrazolines
4 or 5 were converted into mixtures of the desired cyclopropanes
8 or 9 and the olefin 12. The cyclopropane/olefin ratio was
independent of the number of equivalents of Yb(OTf)3 used but
increased from 70:30 at room temperature (entries 3 and 4, and
7-10) to 80:20 at -40 °C (entries 5 and 6) with the isolated
cyclopropane yields ranging from 65 to 73%. No reaction
occurred at -78 °C. Under similar conditions, the 6-exo or 7-exo
pyrazolines were converted into the cyclopropanes 10 or 11,
each of which was admixed with the olefin 13, which was now
the major product (entries 13 and 14, and 16-19). Lowering
the reaction temperature did not improve the cyclopropane
content of the mixture (entry 15), and a small amount of the
pyrazole 15 was also obtained. It is remarkable that the tendency
The reaction of 3 with diazoethane gave results which closely
resembled those obtained with diazomethane, in that the
formation 6-exo was very strongly favored in the absence of a
Lewis acid (Table 2). Compound 7-exo was not observed under
these conditions, but a minor unidentified substance was formed
(8) Chang, H. S.; Bergmeier, S. C.; Frick, J. A.; Bathe, A.; Rapoport, H. J.
Org. Chem. 1994, 59, 5336.
(9) (a) Doyle, M. P.; Proptopopova, M. N. Tetrahedron 1998, 54, 7946. (b)
Doyle, M. P.; Phillips, I. M. Tetrahedron Lett. 2001, 42, 3155.
(10) (a) Mc Greer, D. E.; McKinley, J. W. Can. J. Chem. 1971, 49, 2740.
(b) Clarke, T. C.; Wendinling, L. A.; Bergman, R. G. J. Am. Chem. Soc. 1977,
99, 2740. (c) Farin˜a, F.; Mart´ın, M. V.; Paredes, M. C.; Tito, A. Heterocycles
1988, 27, 365.
(11) Garc´ıa Ruano, J. L.; Peromingo, M. T.; Mart´ın, M. R.; Tito, A. Org.
Lett. 2006, 8, 3295.
(12) Garc´ıa Ruano, J. L.; Peromingo, M. T.; Alonso, M.; Fraile, A.; Mart´ın,
M. R.; Tito, A. J. Org. Chem. 2005, 70, 8942.
(13) (a) Garc´ıa Ruano, J. L.; Fraile, A.; Mart´ın, M. R. Tetrahedron:
Asymmetry 1996, 7, 1943. (b) Garc´ıa Ruano, J. L.; Fraile, A.; Gonza´lez Gutie´rrez,
L.; Mart´ın, M. R.; Clemente, F. R.; Gordillo, R. J. Org. Chem. 2003, 68, 6522.
(14) Cruz Cruz, D.; Herna´ndez Linares, A.; Yuste, F.; Mart´ın, M. R.; Garc´ıa
Ruano, J. L. Synthesis 2009, 1095.
J. Org. Chem. Vol. 74, No. 10, 2009 3821

Cruz et al.
TABLE 3. Decomposition of Pyrazolines 4-7-exo under Different Conditions
entry
pyrazoline
solvent
Lewis acid (equiv)
T, °C
t
products (ratio)a
isolated yield, %
1
2
3
4
5
6
7
8
4
5
4
5
4
5
4
5
toluene
toluene
THF
THF
THF
THF
THF
THF
THF
100
100
25
30 min
30 min
10 min
10 min
24 h
14
14
97
97
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.5)
Yb(OTf)3 (1)
Yb(OTf)3 (1)
Yb(OTf)3 (3)
Yb(OTf)3 (3)
8 (70) 12 (30)
9 (70) 12 (30)
8 (80) 12 (20)
9 (80) 12 (20)
8 (70) 12 (30)
9 (70) 12 (30)
8 (70) 12 (30)
9 (70) 12 (30)
15
66b
65b
73b
70b
66b
65b
66b
65b
97
25
-40
-40
25
25
25
24 h
10 min
10 min
10 min
10 min
30 min
30 min
1 h
9
4
5
10
11
12
13
14
15
16
17
18
19
20
THF
25
6-exo
7-exo
6-exo
7-exo
7-exo
6-exo
7-exo
6-exo
7-exo
6-exo
toluene
toluene
THF
THF
THF
THF
THF
THF
THF
100
100
25
25
-20
25
25
25
25
25
15
97
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.5)
Yb(OTf)3 (1)
Yb(OTf)3 (1)
Yb(OTf)3 (3)
Yb(OTf)3 (3)
Eu(fod)3 (1)
10 (45) 13 (55)
11 (45) 13 (55)
11 (40) 13 (50) 15 (10)
10 (45) 13 (55)
11 (45) 13 (55)
10 (45) 13 (55)
11 (45) 13 (55)
15
37b
35b
3 h
48 h
30 min
30 min
30 min
30 min
3 days
37b
35b
37b
35b
97
THF
a
Determined by H NMR. b Yield of cyclopropane.
1
SCHEME 2. Chemical Correlation of Cyclopropanes 8 and
10 with 9 and 11
to form cyclopropanes by the denitrogenation of these (6 + 5)
bicyclic pyrazolines 4-7-exo is lower than that observed for
the corresponding (5 + 5) bicyclic pyrazolines.11 In Table 3, it
can be seen that olefins 12 or 13 are always obtained as a
significant or even the major product. By contrast, cyclopropanes
were obtained as exclusive products in most of the reactions
described in ref 11.
The absolute configurations of (SS)-1-[(4-methylphenyl)sulfi-
nyl]-3-oxabicyclo[4.1.0]heptan-2-one (8)15 and of (SS)-7-methyl-
1-[(4-methylphenyl)sulfinyl]-3-oxabicyclo[4.1.0]heptan-2-one
(10)15 were unequivocally established by X-ray diffraction
analysis as (1R,6R) and (1R,6R,7R), respectively. The configu-
rational assignment of their stereoisomers 9 and 11 as (1S,6S)
and (1S,6S,7S) was determined by chemical correlation with 8
and 10 through the corresponding sulfones (Scheme 2).
The absolute configuration of compounds 8 and 10 at C-1
and C-6 is that which is expected based on the observed
stereochemical course of the cycloaddition of diazoalkanes to
the sulfinylfuranones 1a and 1b (Scheme 1) and the denitro-
genation of the pyrazolines so obtained.11,12 The configurations
assigned to pyrazolines 4-7-exo can be rationalized on steric
grounds, whereby the diazoalkanes approach the less hindered
face of the presumably most stable s-cis A conformation
(electrostatic repulsion between the sulfinyl and carbonyl oxygen
atoms is minimized) of compound 3, yielding adducts 4 and
6-exo (Scheme 3). When the cycloadditions are effected in the
presence of Yb(OTf)3, the s-trans conformation is likely to be
preferred due to the formation of the chelated species W. The
change in the spatial arrangement of the p-tolyl group is
responsible for the inversion of the facial selectivity in these
cases, giving rise to 5 and 7-exo.
The complete exo selectivity of the reactions with diazoethane
(compounds 6-exo and 7-exo are exclusively formed) was
previously also observed with sulfinylbutenolides,12 and there-
fore, it can be explained on the basis of the different steric
repulsions affecting the endo and exo approaches (Scheme 4).
A more detailed explanation can be found in ref 12.
A comparison of the results observed for compounds 4-7-
exo (Table 3) with those previously reported for the pyrazolines
derived from sulfinylbutenolides12 shows that the product spectra
are significantly different. These results stem from the structural
differences between the two bicyclic systems. The 7a-(p-
(15) Crystallographic data (excluding structure factors) for 8 and 10 have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC- 718417 (8) and CCDC- 718418 (10). Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
3822 J. Org. Chem. Vol. 74, No. 10, 2009

1,3-Dipolar Cycloaddition of Diazoalkanes
SCHEME 3. Stereochemical Course of the Reactions of
(+)-3 with Diazoalkanes
SCHEME 6. Yb(OTf)3-Induced Decomposition of
7a-(p-Tolylsulfinyl)tetrahydropyrano[3,4-c]pyrazol-7(7aH)-ones
explain the low tendency of these compounds to undergo
pyrolytic desulfinylation to pyrazoles.
SCHEME 4. Rationalization of the endo/exo Selectivity
The effect of the Yb(OTf)3 on the reaction course of the 7a-
(p-tolylsulfinyl)tetrahydropyrano[3,4-c]pyrazol-7-ones (5 + 6
bicyclic system) can be rationalized (Scheme 6) by means of a
model similar to that used to explain the completely stereose-
lective transformation of 6a-(p-tolylsulfinyl)furo[3,4-c]pyrazol-
6-one (5 + 5 bicyclic pyrazoline) into cyclopropanes.11 The
chelation of the catalyst to the sulfinyl and carbonyl oxygens
(species I) decreases the electron density at C-7a, provoking
the concerted migration of C-3 with extrusion of nitrogen. This
migration would be more difficult when R ) Me for steric
reasons, thus explaining the larger proportion of 13 from 6-exo
(Table 3). In contrast, the association of the metal to the less
hindered nitrogen (species II) would explain the formation of
the 3-sulfinyl-5,6-dihydropyran-2-ones. This association de-
creases the electron density at C-3, facilitating the breaking of
the N(2)-C(3) bond, forming secondary (from 6-exo) or primary
(from 4) carbocations which are transformed into the most stable
tertiary carbocations by hydrogen migration. These species easily
extrude nitrogen forming sulfinyl pentenolides 12 and 13.17 The
different orientation of the carbonyl oxygen in (5 + 5) and (6
+ 5) bicyclic pyrazolines (see Scheme 5) explains their differing
behavior under denitrogenation conditions. Chelation of
Yb(OTf)3 with the (6 + 5) systems brings the sulfinyl and
carbonyl oxygens into closer proximity, consequently inducing
conformational changes which are less favorable to cyclopropane
formation.
SCHEME 5. Thermolysis of Sulfinyl Pyrano[3,4-c]pyrazol-
7-ones and Furo[3,4-c]pyrazol-6-ones
The Yb(OTf)3-provoked increase in the electron-withdrawing
character of the substituents on the pyrazoline ring of the sulfinyl
pyrazolines is clearly an important factor in the conversion
thereof into cyclopropanes. On this basis, as well as on literature
precedent,18 we predicted that oxidation of the sulfinyl group
to the sulfone would favor cyclopropane formation. Indeed,
reaction of the sulfinyl pyrazoline 4 with excess m-CPBA (2
equiv, at 0 °C for 30 h) gave the sulfonyl cyclopropane 16 as
the only product (77% yield, Table 4, entry 1). When the
reaction was stopped after 24 h, a 70:30 mixture of the
intermediate sulfonyl pyrazoline 18 and the cyclopropane 16
tolylsulfinyl)tetrahydropyrano[3,4-c]pyrazol-7-ones (5 + 6 bi-
cyclic system) undergo desulfinylation and are transformed
exclusively into the pyrazoles 14 and 15 on thermolysis (entries
1, 2, 11, and 12, Table 3) or on treatment with Eu(fod)3 (entry
20). In contrast, the 6a-(p-tolylsulfinyl)furo[3,4-c]pyrazol-6-
ones12 (5 + 5 bicyclic system) are converted into 3-sulfinyl-
4-alkylfuran-2(5H)-ones by extrusion of nitrogen. The facile
desulfinylation of compounds 4-7-exo implies that these
bicyclic systems adopt the conformation shown in Scheme 5,
wherein the sulfinyl group and H-3 are nearly eclipsed. Thus,
the transition state for the cycloelimination of p-tolylsulfenic
acid would be readily accessible in this conformation.16 The
analogous transition state for the furo[3,4-c]pyrazolines would
be strongly destabilized by an unfavorable interaction of the
p-tolyl group with the carbonyl oxygen atom, which would
(16) Analogous situation is produced when the reaction is conducted under
Eu(fod)3 catalysis (entry 20, Table 3) because Eu will be joined to the nitrogen
(see ref 11).
(17) In ref 12, it was proposed that migration of H at C-3a is concerted with
the extrusion of nitrogen. As both alternatives are reliable, we are currently
performing studies on isotopically marked substrates to clarify this point.
(18) Garc´ıa Ruano, J. L.; Alonso, S. A.; Mart´ın, M. R.; Torrente, E.; Mart´ın,
A. M. Org. Lett. 2004, 6, 4945.
J. Org. Chem. Vol. 74, No. 10, 2009 3823

Cruz et al.
TABLE 4. Reaction of Pyrazolines 4-7-exo with m-CPBA and Yb(OTf)3
entry
pyrazoline
T, °C
t
products (ratio)a
A
product (isolated yield %)
1
2
3
4
5
6
7
4
4
5
0
0
0
0
0
30 h
24 h
24 h
7 days
7 days
19 h
16
16 (77)
b
b
18 (70) 16 (30)
ent-18 (70) ent-16 (30)
17 (78) 15 (22)
ent-17 (78) 15 (22)
17 (78) 15 (22)
ent-17 (78) 15 (22)
Yb(OTf)3
Yb(OTf)3
16 (100)
ent-16 (95)
17 (65)
ent-17 (65)
17 (65)
6-exo
7-exo
6-exo
7-exo
25
25
19 h
ent-17 (65)
a
Determined by H NMR. b Conditions: 0.5 equiv of Yb(OTf)3 in THF, rt, 5 min.
1
saturated potassium sodium tartrate and extracted with CH2Cl2 (3
was obtained. Addition of Yb(OTf)3 (0.5 equiv) to a room
temperature THF solution of this mixture produced cyclopropane
16 quantitatively in 5 min (entry 2). The sulfinyl pyrazoline 5,
when subjected to the same reaction sequence, gave the sulfonyl
cyclopropane ent-16 (95%, entry 3). No 3-sulfonyl-5,6-dihy-
dropyran-2-one was detected in these reaction mixtures. The
6-exo and 7-exo sulfinyl pyrazolines gave, respectively, cyclo-
propanes 17 and ent-17, accompanied by significant amounts
of the pyrazole 15 (cyclopropane/pyrazole ratios of 78:22; entries
4 and 5).
Under these conditions, sulfonyl pyrazolines 19-exo or ent-
19-exo could not be detected in the reaction mixtures. When
the reaction was carried out at room temperature, the reaction
time was reduced (entries 6 and 7), but the composition of the
reaction mixtures was unaltered. The cyclopropanes 17 or ent-
17 were easily purified by flash chromatography.
× 10 mL). The extracts were washed with brine, dried and
1
concentrated. The residue was analyzed by H NMR and purified
as indicated in each case.
(3aR,7aR,SS)-7a-[(4-Methylphenyl)sulfinyl]-3,3a,4,5-tetrahy-
dropyrano[3,4-c]pyrazol-7(7aH)-one (4). Compound 4 was ob-
tained from 3 and diazomethane by method A (entry 5 in Table 1)
and purified by crystallization from Et2O: white solid (97% yield),
mp 86-87 °C; [R]D +93.1 (c 0.45, acetone); IR (KBr) νmax 1722,
1
1084 cm-1; H NMR (CDCl3, 300 MHz) δ 1.35-1.48 (m, 1H),
1.75-1.84 (m, 1H), 2.46 (s, 3H), 2.73-2.83 (m, 1H), 2.98 (dt,
1H, J ) 2.4 and 11.4 Hz), 3.87 (td, 1H, J ) 4.2 and 11.4 Hz), 4.62
(dd, 1H, J ) 2.7 and 18.6 Hz), 4.90 (dd, 1H, J ) 8.4 and 18.6
Hz), 7.41 and 7.65 (AA′BB′ system, 4H); 13C NMR (CDCl3, 75
MHz) δ 21.5, 25.4, 27.3, 66.4, 86.8, 116.6, 125.5, 130.4, 134.1,
143.8, 160.6; EIMS m/z 278 (5%, M+), 246 (22), 214 (13), 139
(100), 138 (55), 108 (75), 53 (50); HRMS (EI) m/z calcd for
C13H14O3N2S [M+] 278.0725, found 278.0736.
The absolute configuration of the sulfonyl cyclopropanes
obtained from sulfinyl pyrazolines was determined by compari-
son of the [R] values and spectroscopic data with those of the
sulfonyl cyclopropanes obtained by oxidation of corresponding
sulfinyl cyclopropanes.
(3aS,7aS,SS)-7a-[(4-Methylphenyl)sulfinyl]-3,3a,4,5-tetrahy-
dropyrano[3,4-c]pyrazol-7(7aH)-one (5). Compound 5 was ob-
tained from 3 and diazomethane by method B (entry 6 in Table 1).
In this reaction, decomposition of THF was observed giving a
nonidentified polymeric product. Therefore, the spectroscopic data
of 5 were not possible to obtain.
(3R,3aR,7aR,SS)-3-Methyl-7a-[(4-methylphenyl)sulfinyl]-
3,3a,4,5-tetrahydropyrano[3,4-c]pyrazol-7(7aH)-one (6-exo). Com-
pound 6-exo was obtained from 3 and diazoethane by method A
(entry 4 in Table 2) and purified by crystallization from Et2O: white
solid (97% yield), mp 71-73 °C; [R]D +284 (c 0.45, acetone); IR
(KBr) νmax 1720, 1273, 1086 cm-1; 1H NMR (CDCl3, 300 MHz) δ
1.40-1.65 (m, 2H), 1.65 (d, 1H, J ) 7.5 Hz), 2.20 (ddd, 1H, J )
4.5 and 7.2 Hz), 2.45 (s, 3H), 3.14 (ddd, 1H, J ) 3.3, 8.1, and
11.4 Hz), 3.82 (ddd, 1H, J ) 3.3, 7.2, and 11.4 Hz), 4.65 (dq, 1H,
J ) 4.5 and 7.2 Hz), 7.38 and 7.63 (AA′BB′ system, 4H); 13C NMR
(CDCl3, 75 MHz) δ 17.6, 21.5, 26.5, 30.9, 65.8, 94.7, 117.0, 125.6,
130.2, 134.2, 143.6, 160.7; EIMS m/z 278 (12%, M+ - 14), 152
(84), 139 (100), 122 (70), 91 (69), 53 (68).
Experimental Section
A. Dipolar Cycloadditions. Method A. To a solution of 0.05 g
(0.21 mmol) of (S)-(+)-3-[(4-methylphenyl)sulfinyl]-5,6-dihydro-
pyran-2-one (3), in the solvent (5 mL) indicated in Tables 1 and 2,
cooled at the temperature indicated in Tables 1 and 2, was added
an excess of an ethereal solution of diazomethane (0.6 M) or
diazoethane (0.6 M). The reaction was kept at the same temperature
for the time indicated in Tables 1 and 2. The solvent was removed
1
under vacuum, and the residue was analyzed by H NMR and
purified as indicated in each case.
Method B. To a solution of Yb(OTf)3 (0.13 g, 0.21 mmol) in
the solvent indicated in Tables 1 and 2 (0.1 M), at room temperature,
was added a solution of (S)-(+)-3-[(4-methylphenyl)sulfinyl]-5,6-
dihydropyran-2-one (3) (0.05 g, 0.21 mmol) in the same solvent
(5 mL). The mixture was stirred for 1 h and cooled at -78 °C.
Then, an excess of an ethereal solution of diazomethane (0.6 M)
or diazoethane (0.6 M) was added. The reaction was kept at the
same temperature for 1 h and then was quenched with aqueous
(3S,3aS,7aS,SS)-3-Methyl-7a-[(4-methylphenyl)sulfinyl]-3,3a,4,5-
tetrahydropyrano[3,4-c]pyrazol-7(7aH)-one (7-exo). Compound
7-exo was obtained from 3 and diazoethane by method B (entry 5
in Table 2) and purified by crystallization from CH2Cl2/hexane:
white solid (80% yield), mp 87-90 °C; [R]D +113.8 (c 0.45,
1
acetone); IR (KBr) νmax 1732, 1268, 1047; H NMR (CDCl3, 300
3824 J. Org. Chem. Vol. 74, No. 10, 2009

1,3-Dipolar Cycloaddition of Diazoalkanes
MHz) δ 0.85 (d, 3H, J ) 7.2 Hz), 1.58-1.70 (m, 1H), 2.24-2.30
(m, 2H), 2.41 (s, 3H), 4.13 (ddd, 1H, J ) 3.3, 5.7, and 11.4 Hz),
4.38 (m, 2H), 7.33 and 7.47 (AA′BB′ system, 4H); 13C NMR
(CDCl3, 75 MHz) δ 16.5, 21.5, 27.8, 33.8, 66.6, 93.5,113.2, 126.6,
129.5, 135.4, 143.7, 162.5; EIMS m/z 278 (7%, M+ - 14), 264
(44), 152 (29), 139 (100), 125 (38), 91 (47), 53 (25).
B. Extrusion of Nitrogen from Pyrazolines 4-7-exo under
Lewis Acid Catalyst. To a solution of Yb(OTf)3 (0.056 g, 0.09
mmol) in THF (2 mL) under argon was added a solution of
pyrazolines 4-7-exo (0.18 mmol) in THF (3 mL). The mixture
was stirred at the temperature and time indicated in Table 3. Then,
the reaction was quenched with aqueous saturated potassium sodium
tartrate at the indicated temperature and extracted with CH2Cl2 (3
× 10 mL). The extracts were washed with brine and dried. The
solvent was removed under vacuum and purified as indicated in
each case.
(1R,6R,SS)-1-[(4-Methylphenyl)sulfinyl]-3-oxabicyclo[4.1.0]-
heptan-2-one (8). Compound 8 was obtained from 4 (entry 3 in
Table 3) and was purified by flash chromatography (ethyl
acetate-hexane 80:20): white crystals (66% yield), mp 140-143
°C; [R]20D +79.8 (c 0.5, acetone); IR (KBr) νmax 1709, 1119, 1041
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.73-1.84 (m, 1H), 1.81 (t,
1H, J ) 6.3 Hz), 1.85 (dd, 1H, J ) 6.3 and 8.7 Hz), 1.97-2.05
(m, 1H), 2.27-2.34 (m, 1H), 4.01-4.16 (m, 2H), 7.28 and 7.61
(AA′BB′ system, 4H); 13C NMR (CDCl3, 75 MHz) δ 13.4, 14.3,
20.5, 21.4, 43.2, 64.3, 125.1, 129.7, 139.3, 142.1, 167.7; EIMS m/z
250 (100%, M+), 234 (3), 222 (9), 139 (72), 111 (16), 92 (34), 53
(15); HRMS (FAB+) m/z calcd for C13H15O3S [M + 1] 251.0742,
found 251.0740.
C. Reaction of Pyrazolines 4-7-exo with m-CPBA.
Method A. To a solution of pyrazoline 4 or 5 (0.05 g, 0.18 mmol)
in 5 mL of CH2Cl2 at 0 °C was added a solution of m-CPBA (0.062
g 0.36 mmol) in 5 mL of CH2Cl2. The mixture was stirred at 0 °C
for 24 h. Then a 10% solution of Na2CO3 was added, and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The organic
extracts were dried with Na2SO4 and concentrated. The residue was
dissolved in THF (5 mL), and Yb(OTf)3 (0.039 g, 0.063 mmol)
was added. The mixture was stirred at room temperature for 5 min,
quenched with aqueous saturated potassium sodium tartrate, and
extracted with CH2Cl2 (3 × 10 mL). The extracts were dried with
Na2SO4, concentrated, and purified by crystallization from Et2O.
Method B. To a solution of pyrazoline 6-exo (0.037 g, 0.13
mmol) or 7-exo (0.025 g, 0.086 mmol) in 5 mL of CH2Cl2 at room
temperature was added a solution of m-CPBA (2 equiv) in 4 mL
of CH2Cl2. The mixture was stirred at room temperature for 19 h.
Then a 10% solution of Na2CO3 was added, and the mixture was
extracted with CH2Cl2 (3 × 10 mL). The organic extracts were
dried with Na2SO4 and concentrated. The residue was purified by
flash chromatography (ethyl acetate-hexane 60:40).
(1R,6R)-1-[(4-Methylphenyl)sulfonyl]-3-oxabicyclo[4.1.0]heptan-
2-one (16). Compound 16 was obtained from 4 by method A (entry
2 in Table 4): white solid (100% yield), mp 142 °C (d); [R]20
D
-42.8 (c 0.25, acetone); IR (KBr) νmax 2931, 1727, 1302, 1154
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.87 (t, 1H, J ) 6.6 Hz),
2.03-2.11 (m, 2H), 2.24-2.36 (m, 1H), 2.44 (s, 3H), 2.84-2.91
(m, 1H), 4.07 (dt, 1H, J ) 3.6 and 12 Hz), 4.23-4.30 (m, 1H),
7.33 and 7.91 (AA′BB′ system, 4H); 13C NMR (CDCl3, 75 MHz)
δ 16.0, 20.7, 21.6, 22.5, 44.1, 64.9, 129.4, 129.6, 136.1, 144.9,
163.9; EIMS m/z 267 (1%, M+), 202 (24), 187 (37), 157 (61), 143
(27), 91 (100), 65 (46), 53 (45), 41 (48); HRMS (FAB+) m/z calcd
for C13H15O4S [M + 1] 267.0691, found 267.0692.
(1S,6S,SS)-1-[(4-Methylphenyl)sulfinyl]-3-oxabicyclo[4.1.0]-
heptan-2-one (9). Compound 9 was obtained from 5 (entry 4 in
Table 3) and was purified by flash chromatography (ethyl
(1S,6S)-1-[(4-Methylphenyl)sulfonyl]-3-oxabicyclo[4.1.0]heptan-
2-one (ent-16). Compound ent-16 was obtained from 5 by method
acetate-hexane 80:20): opaque oil (65% yield); [R]20 +120 (c
D
A (entry 3 in Table 4): white solid (95% yield); [R]20 +40.4 (c
1
0.5, acetone); IR (film) νmax 1715, 1121, 1015 cm-1; H NMR
D
0.25, acetone). The spectroscopic data were identical to those
compound 16.
(CDCl3, 300 MHz) δ 1.48 (dd, 1H, J ) 6.3 and 9.0 Hz), 1.63 (t,
1H, J ) 6.6 Hz), 2.07-2.13 (m, 1H), 2.27 (ddt, 1H, J ) 3.3, 6.0,
and 14.7 Hz), 2.40 (s, 3H), 2.51 (m, 1H), 4.07 (dt, 1H, J ) 3.3 and
12.0 Hz), 4.29-4.35 (m, 1H), 7.29 and 7.74 (AA′BB′ system, 4H);
13C NMR (CDCl3, 75 MHz) δ 10.0, 20.4, 21.3, 21.4, 43.4, 64.4,
125.3, 129.5, 139.9, 141.7, 168.3; EIMS m/z 250 (100%, M+), 234
(3), 222 (9), 139 (91), 111 (20), 92 (41), 53 (24); HRMS (FAB+)
m/z calcd for C13H15O3S [M + 1] 251.0742, found 251.0737.
(1R,6R,7R,SS)-7-Methyl-1-[(4-methylphenyl)sulfinyl]-3-oxabi-
cyclo[4.1.0]heptan-2-one (10). Compound 10 was obtained from
6-exo (entry 13 in Table 3) and was purified by flash chromatog-
raphy (ethyl acetate-hexane 80:20): white crystals (37% yield),
mp 151-152 °C; [R]20D +142 (c 0.5, acetone); IR (KBr) νmax 1706,
1282, 1042 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.54 (d, 1H, J )
6.3 Hz), 1.89-2.07 (m, 3H), 2.39 (s, 3H), 2.57-2.62 (m, 1H), 7.27
and 7.65 (AA′BB′ system, 4H); 13C NMR (CDCl3, 75 MHz) δ 10.6,
18.5, 21.3, 21.4, 25.6, 47.1, 65.9, 126.1, 129.6, 140.3, 142.4, 166.9;
EIMS m/z 264 (74%, M+), 216 (8), 140 (45), 125 (100), 92 (41),
79 (24), 67(24), 41 (25); HRMS (FAB+) m/z calcd for C14H17O3S
[M + 1] 265.0898, found 265.0895.
(1R,6R,7R)-7-Methyl-1-[(4-methylphenyl)sulfonyl]-3-oxabicy-
clo[4.1.0]heptan-2-one (17). Compound 17 was obtained from
6-exo by method B (entry 4 in Table 4): white solid (65% yield),
mp 137-139 °C; [R]20D -18.4 (c 0.5, CHCl3); IR (KBr) νmax 2930,
1
1733, 1309, 1150 cm-1; H NMR (CDCl3, 300 MHz) δ 1.60 (d,
3H, J ) 6.6 Hz), 1.97 (dq, 1H, J ) 6.3 and 6.6 Hz), 1.93-2.08
(m, 1H), 2.28 (ddd, 1H, J ) 5.1, 9.6, and 19.5 Hz), 2.74-2.79 (m,
1H), 4.14 (ddd, 1H, J ) 4.2, 9.0, and 11.7 Hz), 4.22-4.29 (m,
1H), 7.33 and 7.93 (AA′BB′ system, 4H); 13C (CDCl3, 75 MHz) δ
11.6, 21.6, 21.8, 48.1, 66.6, 129.3, 129.4, 136.9, 144.8, 164.3; EIMS
m/z 281 (1%, M+), 215 (23), 201 (71), 125 (100), 91 (40), 79 (26),
67 (25), 41 (24).
(1S,6S,7S)-7-Methyl-1-[(4-methylphenyl)sulfonyl]-3-oxabicy-
clo[4.1.0]heptan-2-one (ent-17). Compound ent-17 was obtained
from 7-exo by method B (entry 5 in Table 4): white solid (65%
yield); [R]20 +18.2 (c 0.5, CHCl3). The spectroscopic data were
D
identical to those compound 17.
Conclusions
(1S,6S,7S,SS)-7-Methyl-1-[(4-methylphenyl)sulfinyl]-3-oxabi-
cyclo[4.1.0]heptan-2-one (11). Compound 11 was obtained from
7-exo (entry 14 in Table 3) and was purified by flash chromatog-
raphy (ethyl acetate-hexane 80:20): white crystals (35% yield),
mp 184-186 °C; [R]20D +53.8 (c 0.5, acetone); IR (KBr) νmax 1706,
We have provided a new and efficient methodology for
preparing enantiomerically pure 3-oxabicyclo[4.1.0]heptan-2-
ones by almost complete stereoselective reactions of (S)-(+)-
3-[(4-methylphenyl)sulfinyl]-5,6-dihydropyran-2-one (3) with
diazoalkanes and subsequent treatment with Yb(OTf)3. Sulfinyl
pyrazolines afforded mixtures of cyclopropanes and olefins,
whereas from sulfonyl pyrazolines, cyclopropanes are exclu-
sively obtained in better yields. This behavior provides evidence
for the relationship between the magnitude of the electron-
withdrawing character of the substituents on the pyrazoline ring
and the ease of the conversion thereof into cyclopropanes.
1
1277, 1137, 1028 cm-1; H NMR (CDCl3, 300 MHz) δ 1.04 (d,
3H, J ) 6.3 Hz), 2.06-2.14 (m, 2H), 2.17-2.25 (m, 1H), 2.29 (q,
1H, J ) 6.6 Hz), 2.40 (s, 3H), 4.13 (dt, 1H, J ) 3.9 and 12.0 Hz),
4.24-4.31 (m, 1H), 7.28 and 7.78 (AA′BB′ system, 4H); 13C NMR
(CDCl3, 75 MHz) δ 11.3, 20.2, 21.3, 26.2, 46.4, 65.6, 125.4, 129.5,
139.3, 140.7, 167.8; EIMS m/z 264 (70%, M+), 216 (7), 140 (50),
125 (100), 92 (42), 79 (21), 67 (30), 41 (26); HRMS (FAB+) m/z
calcd for C14H17O3S [M + 1] 265.0898, found 265.0899.
J. Org. Chem. Vol. 74, No. 10, 2009 3825

Cruz et al.
Acknowledgment. We thank M.I. Cha´vez, E. Garc´ıa-R´ıos,
E. Huerta, R. Patin˜o. M.A. Pen˜a, F.J. Pe´rez, H. R´ıos, L. Velasco,
and M.N. Zavala for their technical assistance. D.C.C. thanks
Consejo Nacional de Ciencia y Tecnolog´ıa (CONACYT-
Me´xico) for a predoctoral fellowship. Financial support from
Spanish Government (Grant CTQ2006-06741/BQU) is gratefully
acknowledged. We also thank Dr. J.M. Muchowski for critically
reviewing this manuscript.
Supporting Information Available: Experimental proce-
dures and spectral data for compounds 12-15, experimental
procedure for the oxidation of cyclopropanes 8-11, NMR
spectra for all new compounds, and crystallographic data for
compounds 8 and 10 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JO900525S
3826 J. Org. Chem. Vol. 74, No. 10, 2009