A new entry to enantiopure polysubstituted cyclopropanes: Stereoselective denitrogenation of sulfinylpyrazolines under Yb(OTf)3 catalysis

Article abstract of DOI:10.1021/ol061168d

Chemoselective and completely stereoselective denitrogenation of optically pure pyrazolines, derived from 3-sulfinylfuran-2(5H)-ones, into cyclopropanes can be achieved under substoichiometric Yb(OTf)₃ catalysis. Reactions evolve in almost quan

Full text of DOI:10.1021/ol061168d

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3295-3298
A New Entry to Enantiopure
Polysubstituted Cyclopropanes:
Stereoselective Denitrogenation of
Sulfinylpyrazolines under Yb(OTf)3
Catalysis
Jose´ L. Garc´ıa Ruano,* M. Teresa Peromingo, M. Rosario Mart´ın,* and
Amelia Tito*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049-Madrid, Spain
joseluis.garcia.ruano@uam.es
Received May 12, 2006
ABSTRACT
Chemoselective and completely stereoselective denitrogenation of optically pure pyrazolines, derived from 3-sulfinylfuran-2(5H)-ones, into
cyclopropanes can be achieved under substoichiometric Yb(OTf)3 catalysis. Reactions evolve in almost quantitative yields with complete
retention of the configuration at both carbons flanking the nitrogen atoms. The resulting enantiomerically pure polysubstituted cyclopropanes,
containing up to five substituens, can be desulfinylated with Ra−Ni providing polysubstituted cyclopropanecarboxylic acid derivatives.
Polysubstituted cyclopropanes are basic structural moieties
in a wide range of natural and biologically active compounds,
as well as important intermediates in organic synthesis.1a,b
As a consequence, many strategies have been developed for
their preparation in their optically pure form.1c-e In this
context, reactions of ylides with electron-deficient alkenes,2
halomethylmetals (modified Simmons-Smith reagents) with
electron-rich alkenes,3 and olefins with metal carbenes
generated by metal-catalyzed decomposition of diazoalkanes4
have been applied to build the polysubstituted cyclopropanic
skeletons. However, very few of these methods are efficient
for preparing enantiomerically pure cyclopropanes with three
chiral carbons. Thus, Doyle’s procedure has been used with
only moderate success to prepare 1,2,3-trisubstituted rings,5
and only some very recent articles describe the efficient
synthesis of these systems. Those from Taylor6 and Hoppe7
(1) (a) Small Ring Compounds in Organic Synthesis; de Mejiere, A.,
Ed.; Springer: Berlin, Germany, 2000; Vol. VI. (b) Houben-Weyl: Methods
of Organic Chemistry; de Mejiere, A.; Ed.; Thieme Verlag: Stuttgart, 1997;
Vol. E17. (c) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
ReV. 2003, 103, 977. (d) Donalson, W. A. Tetrahedron 2001, 57, 8589. (e)
Maas, G. Chem. Soc. ReV. 2004, 33, 183.
(2) (a) Liao, W.-W.; Li, K.; Tang, Y. J. Am. Chem. Soc. 2003, 125,
13030 and references therein. (b) Kunz, R. K.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2005, 127, 3240. (c) Aggarwal, V. K.; Grange, E. Chem.
Eur. J. 2006, 568. (d) Garc´ıa, J. L.; Fajardo, C.; Mart´ın, M. R.; Midura,
W.; Mikolajczyk, M. Tetrahedron: Asymmetry 2004, 15, 2475.
(3) (a) Lacasse, M.-C.; Poulard, C.; Charette, A. B. J. Am. Chem. Soc.
2005, 127, 12440. (b) Fournier, J.-F.; Mathieu, S.; Charette, A. B. J. Am.
Chem. Soc. 2005, 127, 13140 and references therein.
(4) Doyle, P.; Hu, W.; Weathers, T. M. Chirality 2003, 15, 369 and
references therein.
(5) Collado, I.; Pedregal, C.; Bueno, A. B.; Marcos, A.; Gonza´lez, R.;
Blanco-Urgoiti, J.; Pe´rez-Castells, J.; Schoepp, D. D.; Wright, R. A.; Jonson,
B. G.; Kingston, A. E.; Moher, E. D.; Hoard, D. W.; Griffey, K. I.; Tizzano,
J. P. J. Med. Chem. 2004, 47, 456.
(6) Risatti, C. A.; Taylor, R. E. Angew. Chem., Int. Ed. 2004, 43, 6671.
10.1021/ol061168d CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/29/2006

are based on the completely stereoselective cyclization of
enantiomerically enriched homoaldol adducts, with the
structure and optical purity of the precursors as the main
limitation. Donaldson reported8 the synthesis of optically
active 2-(2′-carboxycyclopropyl)glycines in moderate yield
by using an organoiron methodology. Organocatalysis also
has been applied to the synthesis of cyclopropanes. Aggarwal
provided the first example in this field when he described
the catalytic asymmetric cyclopropanation of electron-
deficient alkenes, which evolved in moderate yields and
diastereoselectivities but with good enantioselectivity.9 The
results reported by Gaunt,10 concerning the intramolecular
cyclopropanation yielding synthetically versatile [3.1.0]-
bicycloalkenes, describe only one example of optically active
substrate, which is formed in moderate yield and with good
ee. MacMillan2b has recently published a more general
catalytic method for synthesizing enantiomerically pure
polysubstituted cyclopropane carbaldehydes. Finally, one
method has been published from the R,â-unsaturated Fischer
carbene complex for the synthesis of tetrasubstituted cyclo-
propanes with three chiral centers, therefore containing a
quaternary carbon.11
The synthesis of cyclopropanes by extrusion of nitrogen
from pyrazolines12 is a well-known reaction whose efficiency
is restricted by the easy ∆1 f ∆2 rearrangement of the
substrates, as well as by the competitive formation of olefins,
which are usually the major products under thermal condi-
tions. The addition of Bro¨nsted or Lewis acids significantly
increases the proportion of cyclopropanes13 and lowers the
temperature required for denitrogenation. Very few papers
have been reported on the use of pyrazolines as starting
materials in the asymmetric synthesis of cyclopropanes. It
could be due to the low configurational stability of the
diradical or zwitterionic species usually postulated as inter-
mediates for these reactions.14 Photochemical extrusion of
nitrogen has been efficiently used for synthesizing optically
pure cyclopropanes15 but, to our knowledge, only two reports
concerning thermal denitrogenation in a totally stereoselective
way have been so far published.16,17 As they proceed at high
temperatures, which are scarcely compatible with the con-
figurational stability of zwitterionic intermediates, concerted
mechanisms have been postulated to account for their
stereoselective evolution.
We have recently reported a highly stereoselective and
efficient method for synthesizing pyrazolines by reaction of
diazoalkanes with optically pure (S)-3-p-tolylsulfinylfuran-
2(5H)-ones, 1 and 2 (Scheme 1).18
Scheme 1. Synthesis of Pyrazolines
The formation of small amounts of cyclopropanes in a
totally stereoselective way when some sulfinyl furopyrazo-
lines were oxidized into their corresponding sulfones with
m-CPBA19 drew our attention onto the so far never reported
role of acids in the stereochemical course of the denitroge-
nation processes. We report herein the conditions allowing
totally stereoseletive denitrogenation of the pyrazolines
depicted in Scheme 1, which provide a new access to
optically pure cyclopropanes containing up to five substit-
uents and their three chiral carbons.
Initially, we investigated the extrusion of nitrogen from
pyrazolines 3 under different conditions (Table 1). When 3A
(R ) H) was heated in refluxing toluene for 2 h, olefin 11
was obtained in almost quantitative yield20 (entry 1). The
addition of Lewis acids (ZnBr2, Eu(fod)3, Eu(OTf)3, BF3.OEt2,
Yb(OTf)3) substantially lowered the reaction temperature and
led to the formation of cyclopropane 8A. Olefin 11 was
quantitatively obtained in the presence of Eu(fod)3 at room
temperature (entry 2), whereas Yb(OTf)3 provided the highest
chemoselectivity favoring cyclopropane 8A,21 which was
dependent on the amount of the catalyst. Olefins were
exclusively obtained in the presence of 3 equiv of Yb(OTf)3
(entry 3). Mixtures of cyclopropanes and olefins were formed
by decreasing the amount of the catalyst (see entries 3 and
4), the highest proportion of cyclopropanes being observed
when 0.5 equiv of Yb(OTf)3 was used. Under these condi-
tions, cyclopropane 8A was obtained in 97% isolated yield
after 5 h at room temperature (entry 5).
(7) Kalkofen, R.; Brandau, S.; Wibbeling, B.; Hoppe, D. Angew. Chem.,
Int. Ed. 2004, 43, 6667.
(8) (a) Lukesh, J. M.; Donaldson, W. A. Chem. Commun. 2005, 110.
(b) Yun, Y. K.; Godula, K.; Cao, Y.; Donaldson, W. A. J. Org. Chem.
2003, 68, 901.
(9) Aggarwal, V, K.; Alonso, E.; Fang, G.; Ferrara, G. H.; Porcelloni,
M. Angew. Chem., Int. Ed. 2001, 40, 1433.
(10) Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2004, 43, 2681.
(11) Capriati, V.; Florio, S.; Renzo, L.; Perna, F. M.; Barluenga, J.;
Rodr´ıguez, F.; Fan˜anas, F. J. J. Org Chem. 2005, 70, 5852.
(12) (a) McGreer, 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.
(13) (a) Nomine, G.; Bertin, D. Bull. Soc. Chim. Fr. 1960, 550. (b) Doyle,
M. P.; Buhro, W. E.; Dellaria, J. F. Tetrahedron Lett. 1979, 4429. (c) Padwa,
A.; Filipkowski, M. A.; Kline, D. N.; Murpheree, S. S.; Yeskes, P. E. J.
Org. Chem. 1993, 58, 2061.
(14) Engel, P. S. Chem. ReV. 1980, 80, 99 and references therein.
(15) Muray, E.; Illa, O.; Castillo, J. A.; Alvarez-Larena, A.; Bourdelande,
J. L.; Branchadell, V.; Ortun˜o, R. M. J. Org. Chem. 2003, 68, 4906 and
references therein.
(17) 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.
(18) Garc´ıa Ruano, J. L.; Peromingo, M. T.; Alonso, M.; Fraile, A.;
Mart´ın, M. R.; Tito, A. J. Org. Chem. 2005, 70, 8942.
(19) Garc´ıa Ruano, J. L.; Fraile, A.; Fajardo, C.; Mart´ın, M. R. J. Org.
Chem. 2005, 70, 4300.
(20) A similar result had been obtained from other pyrazolines. See:
Garc´ıa Ruano, J. L.; Fraile, A.; Gonza´lez, G.; Mart´ın, M. R.; Clemente, F.
R.; Gordillo, R. J. Org. Chem. 2003, 68, 6522.
(16) Hamaguchi, M.; Nakaishi, M.; Nagai, T.; Tamura, H. J. Org. Chem.
2003, 68, 9711.
(21) ZnBr2, Eu(OTf)3, and BF3 also give cyclopropanes in substantial
amounts, but the observed chemoselectivity is lower than with Yb(OTf)3.
3296
Org. Lett., Vol. 8, No. 15, 2006

9B only. These reactions required slightly shorter times than
those from 3A and 3B and exhibited a lower tendency to
form cyclopropanes. At room temperature 4A yielded a 65:
35 mixture of 11:9A (entry 13). However, the chemoselec-
tivity favoring cyclopropanes increased when the temperature
was lower, and thus at -40 °C the reaction only yielded 9A
(87% isolated yield, >98% de, entry 14). 4B also afforded
olefin 11 under the conditions of entries 15 and 16, and
exhibited an even smaller tendency than 4A to evolve into
cyclopropane 9B, which could not be obtained in a com-
pletely chemoselective manner. Thus, at -40 °C it gave a
52:48 mixture of 9B:11 (entry 17), and under the best
conditions (-78 °C), optically pure 9B was isolated in 68%
yield (entry 18).
Table 1. Denitrogenation of Pyrazolines 3, 4, and 5 under
Different Conditions
It is noteworthy that the configuration of 9A and 9B at
all their chiral centers is identical with that of their respective
precursors 4A and 4B, which indicates that denitrogenation
takes place with retention of configuration.
The cyclopropane formation under Yb(OTf)3 catalysis can
be explained as depicted in Figure 1. Initially, the metal forms
products
(ratio)e
isolated
a
b
catalc (d) T, °C t, h
yield, %d
1
3A
3A
3A
3A
3A
3B
3B
3B
3B
110f
25
25
2
3.5
3.5
2
2
2
98
97
91
2
3
4
5
6
7
8
9
A (1)
B (3)
B (1.3)
B (0.5)
25
25
110f
25
25
25
25
110f
25
4.5 8A (53)/2 (47)
5
1
2
2
2
3
1
8A
2
2
2
97
99
97
A (1)
B (3)
B (1.3)
B (0.5)
8B (45)/2 (55)
10 3B
11 4A
12 4A
13 4A
14 4A
15 4B
16 4B
17 4B
18 4B
19 5A
20 5A
21 5B
22 5B
8B
11
91
98
95
A (1)
0.7 11
B (0.5)
B (0.5)
25
3
19
1
45
10
14
1
9A (65)/11 (35)
-40
110f
25
-40
-78
25
9A
11
11
87
98
96
A (1)
B (0.5)
B (0.5)
A (1)
9B (52)/11 (48)
9B (70)/11 (30)
11
68 (9B)
96
95
97
91
B (0.5)
A (0.5)
B (0.5)
25
25
0
1
10A
0.6 11
1
11
a Entry. b Starting material. c A: Eu(fod)3. B: Yb(OTf)3). d Number of
1
equivalents. e Determined by H NMR. f Toluene.
A similar behavior was observed for diastereomeric
pyrazoline 3B but its denitrogenation was slightly easier than
that of 3A and hence required shorter reaction times (compare
entries 1-5 with 6-10). Additionally 3B exhibited a lower
tendency than 3A to evolve into their corresponding cyclo-
propane with Yb(OTf)3 (compare entries 4 and 9). Neverthe-
less, 3B can also be completely transformed into 8B at room
temperature by using 0.5 equiv of this catalyst (entry 10).
The behavior of 4A and 4B under different conditions was
similar to that observed for 3A and 3B. They afforded olefin
11 by heating in refluxing toluene (entries 11 and 15) or
treating with Eu(fod)3 (entries 12 and 16) at room temper-
ature. Much more interesting were the reactions of 4A and
4B with 0.5 equiv of Yb(OTf)3 because they afforded
trisubstituted cyclopropanes. To our delight, these reactions
were completely stereoselective yielding compounds 9A and
Figure 1. Stereochemical course of denitrogenation.
a chelated species with the sulfinyl and carbonyl oxygens (I
and II). It increases the electronic deficiency at C-6a and
provokes the concerted migration of C-3 (from nitrogen to
C-6a) with extrusion of nitrogen. This process affords
cyclopropanes with retention of the configuration at the
migrating carbon. By contrast, the Eu(fod)3 associates with
the nitrogen (III and IV in Figure 1), which increases the
electronic deficiency at C-3 provoking the migration of the
hydrogen at C-3a and the extrusion of nitrogen, giving as
the result the formation of the olefin. This latter migration
must be easier than the former one affording cyclopropanes
and therefore the olefins will be predominant when the
association of the catalyst takes place at both nitrogenated
Org. Lett., Vol. 8, No. 15, 2006
3297

and oxygenated basic centers (as was the case when an excess
of Yb(OTf)3 was used). The selectivity of the catalysts could
be attributed to their differential affinity to the oxygen but
mainly to their different size. This would deal with the
formation of cyclopropanes as the major reaction product
when the catalyst was Eu(OTf)3 instead of Eu(fod)3. The
model at Figure 1 explains that isomers A and compounds
3 evolve into cyclopropanes more readily than isomers B
and compounds 4, respectively. Chelates I derived from A
are more stable than II resulting from B due to the (Ph/
H)1,3-diaxial interaction, which decreases the stability of II.
Moreover, steric effects suggest that the migration of C-3
onto C-6a must be easier when R1 is hydrogen (pyrazolines
3) than when R1 ) Me (pyrazolines 4).
Finally we have studied the behavior of pyrazolines
bearing a methyl group at C-3a. The results obtained from
5A and 5B are collected in Table 1. By refluxing in toluene
or in the presence of Eu(fod)3 they afforded 11 (entries 19
and 21). Under Yb(OTf)3 catalysis, 5A evolved into 10A
(entry 20), whereas 5B was transformed into 11 (entry 22)
even at low temperatures. This behavior is not unexpected
due to the low stability of its chelated species, similar to
species II in Figure 1, with the (Tol/Me)1,3-diaxial interaction
instead of the (Tol/H)1,3-diaxial one. The behavior of pyrazo-
lines 6A and 7A (Scheme 2) is similar to that observed for
Raney-Ni desulfinylation of sulfinyl cyclopropanes yielded
optically pure bicyclic lactones (Scheme 3), which are
Scheme 3. Desulfurization of Sulfinylcyclopropanes
immediate precursors of cyclopropanecarboxylic acids con-
taining up to four substituents at the ring. Compounds
obtained from 8A and 9A are enantiomers of those obtained
from 8B and 9B, respectively.
Despite enantiomers (+)-17, (+)-18, and (+)-19 not being
obtained from (S)-4-methyl-3-p-tolylsulfinylfuran-2(5H)-one
(2), it is noteworthy that all of them can be easily obtained
starting from the enantiomer of compound 2.
In summary, we have proven that optically pure sulfinyl
pyrazolines can be easily transformed into cyclopropanes in
the presence of substoichiometric amounts of Yb(OTf)3 under
very mild conditions in almost quantitative yields. The
extrusion of nitrogen proved to be completely stereoselective,
taking place with complete retention of configuration at the
carbons flanking the nitrogen atoms. The combined use of
this reaction with the cycloaddition of diazoalkanes to (R)-
and (S)-3-p-tolylsulfinylfuran-2(5H)-ones18 provides one of
the most efficient procedures for synthesizing enantiomeri-
cally pure sulfinyl cyclopropanes bearing up to five sub-
stituens at the ring, which can be easily desulfinylated. We
are currently extending the scope of this new method to
obtain polysubstituted cyclopropanes to many other pyra-
zolines 3,3-disubstituted by electron-withdrawing groups.
Scheme 2
Acknowledgment. We thank CAICYT (Grant BQU2003-
04012) for financial support.
the other A stereoisomers that evolved into the olefin 1418
under thermal and Eu(fod)3 catalyzed conditions, but afforded
cyclopropanes 12A and 13A in the presence of Yb(OTf)3.
Configurational assignment of the obtained cyclopropanes
has been made by NMR studies and chemical correlations
with known compounds (see the Supporting Information).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 8-19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061168D
3298
Org. Lett., Vol. 8, No. 15, 2006