Efficient synthesis of enantiomerically pure α-alkyl cyclopropanecarbonitrile derivatives from pyrazolines

Article abstract of DOI:10.1021/ol047937f

(Chemical Equation Presented) Thermolysis of enantiopure sulfonyl pyrazolines 4 and 5, easily obtained from (Z)-3-p-tolylsulfinylacrylonitriles (1), afforded sulfonyl cyclopropanes (6, 7) in a completely stereoselective manner in almost quantitative yield

Full text of DOI:10.1021/ol047937f

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4945-4948
Efficient Synthesis of Enantiomerically
Pure
r-Alkyl Cyclopropanecarbonitrile
Derivatives from Pyrazolines†
Jose´ L. Garc´ıa Ruano,* Sergio A. Alonso de Diego, M. Rosario Mart´ın,
Esther Torrente, and Ana M. Mart´ın Castro*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain
joseluis.garcia.ruano@uam.es
Received October 7, 2004
ABSTRACT
Thermolysis of enantiopure sulfonyl pyrazolines 4 and 5, easily obtained from (Z)-3-p-tolylsulfinylacrylonitriles (1), afforded sulfonyl cyclopropanes
(6, 7) in a completely stereoselective manner in almost quantitative yields. Both cyclopropanes and alkylidenecyclopropanes, containing one
or two chiral carbon atoms, one of them being quaternary, were obtained by hydrogenolysis of the C−S bonding and under the conditions
reported by Julia, respectively. The highly stereoselective extrusion of nitrogen suggests a concerted mechanism.
The wide occurrence of cyclopropane rings in naturally
occurring and biologically active compounds has stimulated
the development of many methods and strategies for cyclo-
propanation.1 One of the most powerful and efficient methods
for obtaining cyclopropanes involves the enantioselective
cycloaddition of different metal carbenes, generated by
catalytic decomposition of diazocompounds, to alkenes.2
However, its use in an enantioselective manner is restricted
to electron-rich olefins and its efficiency sharply decreases
when the steric hindrance becomes larger. The Michael
addition-ring closure of special nucleophiles, like sulfur
ylides, to electron-deficient alkenes appears as a comple-
mentary cyclopropanation procedure, but the reported ste-
reoselectivities are usually moderate.3
Decomposition of pyrazolines has proved to be an excel-
lent method for the preparation of cyclopropanes.4 Photo-
chemically induced processes are usually more important for
this purpose, in comparison with the thermal ones, because
of their higher stereoselectivity and usually larger proportion
of cyclopropanes.5 Although the thermal extrusion of nitrogen
† This paper is dedicated to the memory of Professor Jesu´s H. Rodr´ıguez
Ramos.
(3) (a) Garc´ıa Ruano, J. L.; Fajardo C.; Mart´ın, R.; Midura, W. H.;
Mikolajczyk, M. Tetrahedron: Asymmetry 2004, 15, 2475. (b) Midura, W.
H.; Krysiak, J. A.; Mikolajczyk, M. Tetrahedron: Asymmetry 2003, 14,
1245. (c) Takagi, R.; Nakamura, M.; Kojima, S.; Ohkata, K. Tetrahedron
Lett. 2001, 42, 5891.
(4) (a) Engel, P. S. Chem. ReV. 1980, 80, 99 and references therein. (b)
Mart´ın-Vila`, M.; Hanafi, N.; Jime´nez, J. M.; AÄ lvarez-Larena, A.; Piniella,
J. F.; Branchadell, V.; Oliva, A.; Ortun˜o, R. M. J. Org. Chem. 1998, 63,
3581.
(1) (a) Small Ring Compounds in Organic Synthesis VI; de Meijere, A.,
Ed.; Springer: Berlin, 2000. (b) Houben-Weyl: Methods of Organic
Chemistry; de Meijere, A., Schaumann, A., Eds.; Thieme Verlag: Stuttgart,
1997; Vol. E17. (c) Lebel, H.; Marcoux, J.; Molinaro, C.; Charette, A. B.
Chem. ReV. 2003, 103, 977. (d) Donaldson, W. A. Tetrahedron 2001, 57,
8589.
(2) (a) See Pfaltz, A.; Lydon, K. M.; McKervey, M. A. In ComprehensiVe
Asymmetric Catalysis II; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999. (b) Doyle, M. P.; Hu, W.; Weathers, T. M., Jr.
Chirality 2003, 15, 369 and references therein.
(5) (a) Otto, A.; Ziemer, B.; Liebscher, J. Synthesis 1999, 965. (b) Bartels,
A.; Jones, P. G.; Liebscher, J. Synthesis 1998, 1645. (c) De Lange, B.;
Feringa, B. L. Tetrahedron Lett. 1988, 29, 5317.
10.1021/ol047937f CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/02/2004

from pyrazolines mainly gives olefins, there are also known
examples yielding cyclopropanes as the main products.6 The
use of these processes in asymmetric synthesis has been only
occasionally exploited because of their usually low stereo-
selectivity. Additionally, the low number of general and
efficient methods for preparing optically pure ∆1-pyrazo-
lines7,8 could be another important reason accounting for this
absence.
to complex reaction mixtures. To avoid pyrolytic desulfi-
nylation, able to promote decomposition of these compounds,
we decided to oxidize the sulfinyl group into a sulfonyl group
prior to treatment of pyrazolines under conditions of thermal
decomposition. Sulfonyl pyrazolines 4 and 5 were readily
obtained in quantitative yields by oxidation with m-CPBA
(Scheme 2).
Recent efforts in our laboratory have focused on the use
of vinyl sulfoxides as chiral dipolarophiles in reactions with
different dipoles.9 They have been shown to be excellent
precursors for the synthesis of pyrazolines.9a Namely, reac-
tions of optically pure (Z)-3-p-tolylsylfinylacrylonitriles with
diazoalkanes afforded differently substituted ∆1-pyrazolines
(2 and 3) in high yields and with a complete control of the
regioselectivity and the endo/exo and π-facial selectivities10
(Scheme 1). The easy availability of the starting sulfinyl
Scheme 2
Scheme 1
Compounds 4a-c and 5a-c proved to be excellent
starting materials for the synthesis of the sulfonyl cyclopro-
panenitriles 6a-c and 7a-c. Thus, after stirring for 7-9 h
in refluxing toluene, cyclopropanes were obtained in almost
quantitative yields (>96%) in all cases. This is one of the
most efficient reactions reported to date affording cyclopro-
panes by thermal decomposition of pyrazolines. The forma-
tion of the corresponding olefins was not detected in any
experience. However, even more interesting is the exclusive
formation of one cyclopropane, 6 or 7, exhibiting a cis
arrangement between the alkyl groups R and R′, even in the
case of the t-butyl derivative. This result demonstrates that
these reactions take place in a completely stereoselective way
(de > 98%), as it was determined by integration of well-
nitriles 111 (two steps from commercial alkynes) conferred
this procedure a wide scope in the synthesis of optically pure
sulfinyl pyrazolines. Consequently, we decided to evaluate
the efficiency of these compounds as the starting materials
for the preparation of optically pure cyclopropanes. The
results obtained in this study are reported herein.
Compounds 2a-c and 3a-c (Scheme 1) were prepared
according to the previously reported procedure10 and sub-
sequently used as starting materials. Initially, we studied the
behavior of these substrates under thermal conditions (re-
fluxing toluene). However, all attempts failed, giving rise
1
separated signals of the H NMR of their crude mixtures.
The absolute configuration at the stereogenic center of
cyclopropanes 6 and 7 bearing the sulfonyl group was
assigned as S by assuming that it was maintained unaltered
in the extrusion step (it had been unequivocally assigned for
the starting sulfinyl pyrazolines 2 and 310). The cis relation-
ship existing between the R groups and the proton at
sulfonylated carbon in compounds 6 and 7 as well as between
R and Me groups in compounds 7 could be deduced from
(6) (a) Vasquez, P. C.; Bennett, D. C.; Tows, K. K.; Kennedy, G. D.;
Baumstark, A. L. Heteroatom Chem. 2000, 11, 299. (b) Begley, M. J. Chem.
Commun. 1978, 461.
(7) See, for example: Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000,
122, 10710.
(8) There are several efficient methods for preparing optically pure ∆2-
pyrazolines (see: (a) Barluenga, J.; Fernandez-Marti, F.; Aguilar E.; Viado,
A. L.; Olano, B.; Garc´ıa Granda, S.; Moya-Rubiera, C. Chem. Eur. J. 1999,
5, 883 and references therein. (b) Mish, M. R.; Guerra, F. M.; Carreira, E.
M. J. Am. Chem. Soc. 1997, 119, 8379. (c) Guerra, F. M.; Mish, M. R.;
Carreira, E. M. Org. Lett. 2000, 2, 4265. (d) Sasaki, H.; Carreira, E. M.
Synthesis 2000, 135), but they are not the most convenient substrates for
the preparation of cyclopropanes.
1
the H NMR parameters (values of NOEs). In Figure 1 are
indicated the most significant values observed for 7b.12 This
assignment indicates that the extrusion of nitrogen has taken
place with retention of the configuration at the three chiral
(9) (a) Diazoalkanes: Garc´ıa Ruano, J. L.; Fraile, A.; Gonzalez, G.;
Mart´ın, M. R.; Clemente, F. R.; Gordillo, R. J. Org. Chem. 2003, 68, 6522
and references therein. (b) Nitrile oxides: Garc´ıa Ruano, J. L.; Bercial, F.;
Fraile, A.; Mart´ın, M. R. Synlett 2002, 73 and references therein. (c)
Nitrones: Garc´ıa Ruano, J. L.; Andre´s Gil, J. I.; Fraile, A.; Mart´ın Castro,
A. M.; Mart´ın, M. R. Tetrahedron Lett. 2004, 45, 4653. (d) Azomethine
ylides: Garc´ıa Ruano, J. L.; Peromingo, M. Tito, A. J. Org. Chem, 2003,
68, 10013 and references therein.
(10) Garc´ıa Ruano, J. L.; Alonso de Diego, S. A.; Blanco, D.; Mart´ın
Castro, A. M.; Mart´ın, M. R.; Rodr´ıguez Ramos, J. H. Org. Lett. 2001, 3,
3173.
(11) Garc´ıa Ruano, J. L.; Esteban Gamboa, A.; Mart´ın Castro, A. M.;
Rodr´ıguez, J. H.; Lo´pez-Solera, M. I. J. Org. Chem. 1998, 63, 3324.
Figure 1. NOE values for 7b.
4946
Org. Lett., Vol. 6, No. 26, 2004

centers of the starting pyrazoline. To our knowledge, this is
one of the few examples of extrusion of nitrogen from
pyrazolines under thermal conditions giving rise to optically
pure cyclopropanes with complete control of the stereose-
lectivity.
of the pyrazoline ring, supporting an electron-withdrawing
group able to stabilize the negative charge.18
Due to the potential interest of the availability of a
cyclopropane moiety in organic structures, as a consequence
of its presence in building blocks of naturally occurring
compounds19 or to its effectiveness in restricting the con-
formational mobility of biologically active compounds,20 we
embarked on the task of transforming our previously
synthesized enantiopure sulfonyl cyanocyclopropanes (6 and
7) into other cyclopropane derivatives.21
Reductive desulfonylation of compounds 7a (R ) n-Bu)
and 7b (R ) t-Bu) proved to be a difficult task in the
synthesis of other sulfinyl cyclopropanes.3 In our case, we
used different systems to get the hydrogenolysis of the C-S
bond such as Li+Naft-,22 [Al(Hg)],23 [Na(Hg)],24 Ni(Raney),
Li/EtNH2,25 but the results obtained were not satisfactory in
any case. Finally, it was accomplished by treatment of 7a
and 7b with magnesium in methanol following previously
reported procedures,20a,26 which were slightly modified.27
After 1-3 days at room temperature, we obtained the
expected compounds (Scheme 3) in ca. 80% yield of the
crude reaction (chemically pure by NMR). Distillation of
the crude mixture afforded 8a and 8b in 60 and 56% yields,
respectively.28 The four-step procedure described herein for
preparing enantiomerically pure cyclopropanes containing
two chiral centers (one of them quaternary) from sulfinyl
Whereas a diradical mechanistic pathway has been pro-
posed by several groups13 to explain the highly stereoselec-
tive evolution of pyrazolines under photolytic conditions, the
course of the thermal decomposition of pyrazolines into
cyclopropanes still remains controversial. Indeed, the hitherto
reported stereochemical results from thermal decomposition
of 1-pyrazolines are quite divergent and strongly dependent
on the nature of the substituents at the ring. Ionic14 or
diradical15 mechanisms have been postulated to explain the
most usual pyrolytic processes proceeding without stereo-
selectivity, although there is a report that assumes a diradical
mechanism to explain some stereoselective transformations.16
Many years ago,17 a concerted mechanism was invoked
to account for the retention of configuration observed in some
cyclopropanes resulting from extrusion of nitrogen of pyra-
zolines. Bearing in mind the electron-withdrawing groups
existing at the pyrazoline rings reported herein, our stereo-
chemical results are consistent with the concerted thermal
decomposition proposed by McGreer17a,b of a series of 4-
and 5-alkyl-substituted 3-methyl-3-methoxycarbonyl-∆1-
pyrazolines, which afford cyclopropanes by extrusion of
nitrogen through a polar transition state, where the degree
of bond breaking of the C(3)-N bond is advanced over the
bond breaking of the C(5)-N bond (Figure 2). The common
(18) Stereoselective formation of alkylidenecyclopropanes by thermal
nitrogen extrusion from alkylidenepyrazolines has been recently published
(Hamaguchi, M.; Nakaishi, M.; Nagai, T.; Tamura, H. J. Org. Chem. 2003,
68, 9711). The mechanistic model proposed in that paper by the authors is
not significantly different from that proposed by McGreer in refs 16a and
16b. Alkylidenepyrazolines described therein also contain electron-
withdrawing groups (apparently very important in the course of the reaction)
and quaternary centers.
(19) See, for example, Hirohara, H.; Mitsuda, S.; Audo, E.; Komaki, R.
In Biocatalysts in Organic Synthesis; Tramper, J., Van der Plas, H. C., Linko,
P., Eds.; Elsevier: Amsterdam, 1985; p 119. See also Johnson, C. R.;
Barbachyn, M. J. Am. Chem. Soc. 1982, 104, 4290. Greuter, H.; Dingwall,
J.; Martin, P.; Bellus, D. HelV. Chim. Acta 1981, 64, 2812. Kim, G.; Chu-
Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993,
115, 30. Salau¨n, J. Top. Curr. Chem. 2000, 207, 1. Pietruszka, J. Chem.
ReV. 2003, 103, 1051. Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem.
ReV. 2003, 103, 1625.
Figure 2. Proposed transition states for the concerted nitrogen
extrusion under thermal conditions.
(20) (a) Kazuta, Y.; Matsuda, A.; Shuto, S. J. Org. Chem. 2002, 67,
1669. (b) D´ıaz, M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1996, 7, 3465.
(21) The low stability of the benzyl derivatives 2c and 3c - they
decomposed upon standing at room temperature for several hours - justified
that their use in further transformations was discarded.
(22) (a) Ager, D. J. J. Chem. Soc., Chem. Commun. 1984, 486. (b) Ager,
D. J. J. Org. Chem. 1984, 49, 168.
feature of compounds 4 and 5 with those studied by
McGreer17a,b is the existence of a quaternary carbon at C-3
(12) Double Pulsed Field Gradient Echo-DPFGS (Bruker DRX-500).
(13) (a) 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. (b) Karatsu, T.; Itoh, H.; Kikunaga, T.;
Ebashi, Y.; Hotta, H.; Kitamura, A. J. Org. Chem. 1995, 60, 8270. (c) White,
D. H.; Condit, P. B.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 1348.
(14) (a) Tabushi, I.; Takagi, K.; Okano, M.; Oda, R. Tetrahedron 1967,
23, 2621. (b) Van Auken, T. V.; Rinehart, K. L., Jr. J. Am. Chem. Soc.
1962, 84, 3736.
(15) (a) Padwa, A.; Meske, M.; Rodr´ıguez, A. Heterocycles 1995, 40,
191. (b) Reedich, D. E.; Sheridan, R. S. J. Am. Chem. Soc. 1988, 110,
3697. (c) Crawford, R. J.; Erickson, G. L. J. Am. Chem. Soc. 1967, 89,
3907. (d) Crawford, R. J.; Ali, L. H. J. Am. Chem. Soc. 1967, 89, 3908.
(16) Nakano, Y.; Hamaguchi, M.; Nagai, T. J. Org. Chem. 1989, 54,
1135.
(23) De Lucchi, O.; Lucchini, V.; Marchioro, C.; Valle, G.; Modena, G.
J. Org. Chem. 1986, 51, 1457.
(24) Trost, B. M.; Seoane, P.; Mignani, S.; Acemoglu, M. J. Am. Chem.
Soc. 1989, 111, 7487.
(25) Solladie`, G.; Demailly, G.; Greck, C. J. Org. Chem. 1985, 50, 1552.
(26) Benedetti, F.; Berti, F.; Risaliti, A. Tetrahedron Lett. 1993, 34, 6443.
Brown, A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749.
(27) Reported procedure did not yield the expected cyclopropanes.
Therefore, it was modified as follows: To a flask containing 15 mL of
anhydrous methanol were added Mg turnings (10 equiv), and the mixture
was heated (55 °C) under argon. A solution of sulfonyl cyclopropane (1
equiv) in 3 mL of anhydrous methanol was cannulated under positive argon
pressure, and the resulting mixture was vigorously stirred at room
temperature. Two additional portions of Mg (2 × 10 equiv) were added at
regular intervals (every 2 h). Upon completion, the reaction was quenched
by dilution with CH2Cl2 (10 mL) and further addition of Na2SO4‚10H2O
(200 mg). The mixture was stirred overnight, filtered through a Celite pad,
and concentrated under reduced pressure.
(17) (a) McGreer, D. E.; Chiu, W. K.; Vinge, M. G.; Wong, K. C. K.
Can. J. Chem. 1965, 43, 1407. (b) McGreer, D. E.; Masters, I. M. E.; Liu,
M. T. H. J. Chem. Soc., Perkin Trans. 2 1975, 1791. (c) Deleux, J. P.;
Leroy, G.; Weiler, J. Tetrahedron 1973, 29, 1135. (d) Eberhard, P.; Huisgen,
R. J. Am. Chem. Soc. 1972, 94, 1345.
(28) All the tested chromatographic attempts to purify compounds 8a
and 8b were unsuccessful.
Org. Lett., Vol. 6, No. 26, 2004
4947

Scheme 3
Scheme 4
acrylonitriles (six steps from commercial terminal alkynes)
is one of the shortest and most efficient methods so far
reported.
We have also taken advantage of the presence of the SO2-
Tol moiety in the cyclopropanenitriles 6 and 7 to incorporate
other functionality into the molecule during the elimination
step of the sulfonyl group. Thus, we have used them to
prepare optically pure alkylidenecyclopropanes, interesting
substrates in the synthesis of heterocyclic compounds,29 as
well as for the preparation of other cyclopropane derivates.30
In our case, compounds 9a,b and 10a,b were obtained from
6a,b and 7a,b, respectively, under the conditions reported
by Julia31 (Scheme 4). Yields were almost quantitative as
determined by NMR, only small amounts of the unaltered
substrates having been detected in the reaction crudes.
However, optically pure 9a,b and 10a,b could be isolated
only in moderate to high yields by distillation from the
reaction crudes.32
In conclusion, in this paper we describe one of the most
efficient methods for synthesizing optically pure cyclopro-
panes and alkylidenecyclopropanes containing a quaternary
chiral center. It involves six steps from commercial alkynes,
many of them evolving in quantitative yields. The key step
is the thermal extrusion of the nitrogen from chiral pyrazo-
lines, which contain a quaternary carbon (C-3) bearing an
electron-withdrawing group (CN). This extrusion takes place
in very high yields with complete retention of the configu-
ration of all the chiral centers.
Acknowledgment. We thank CAICYT (Grant BQU2003-
04012) for financial support.
Supporting Information Available: Experimental sec-
tion containing characterization of compounds 4-10 and 1H
NMR spectra for compounds 8-10. This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) Brandy, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003,
103, 1213. For recent papers, see: Chowdhury, M. A.; Senboku, H.; Tokuda,
M. Synlett 2004, 11, 1933. Amal, I. S.; Itaru, N.; Yoshinori, Y. J. Org.
Chem. 2004, 69, 3202.
(30) (a) Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. J. Org. Chem.
2004, 69, 5471. (b) Nordvik, T.; Miesusset, J.; Brinker, U. H. Org. Lett.
2004, 6, 715. (c) Satoh, T.; Saito, S. Tetrahedron Lett. 2004, 45, 347.
(31) Lima, C.; Julia, M.; Verpeaux, J.-N. Synlett 1992, 133. In the
originally described conditions, 2.0 equiv of CH2I2 was used. Our best results
were obtained when using 1.8 equiv of CH2I2 in the methylenation step.
OL047937F
(32) Chromatographic purification of these compounds was unsuccessful
in our hands.
4948
Org. Lett., Vol. 6, No. 26, 2004