(Z)-3-p-tolylsulfinylacrylonitriles as chiral dipolarophiles: Reactions with diazoalkanes

Article abstract of DOI:10.1021/ol016481o

(figure presented) The dipolarophilic reactivity of enantiopure (Z)-3-p-tolylsulfinylacrylonitriles (1) has been evaluated with diazoalkanes. 3-Cyanopyrazoles are obtained when R = H, but with R = alkyl (Bn, n-Bu, and t-Bu) only one cycloadduct (4 or 5) is formed in high yield under mild conditions, therefore evidencing a complete control of the regioselectivity and the endolexo and π-facial selectivities. These reactions are a new straightforward entry to the synthesis of pyrazolines and related structures and reveal the excellent dipolarophilic features of (Z)-sulfinylacrylonitriles.

Full text of DOI:10.1021/ol016481o

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3173-3176
(Z)-3-p-Tolylsulfinylacrylonitriles as
Chiral Dipolarophiles: Reactions with
Diazoalkanes
Jose´ L. Garc´ıa Ruano,* Sergio A. Alonso de Diego, Daniel Blanco,
Ana M. Mart´ın Castro, M. Rosario Mart´ın,* and Jesu´s H. Rodr´ıguez Ramos*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049-Madrid, Spain
joseluis.garcia.ruano@uam.es
Received July 24, 2001
ABSTRACT
The dipolarophilic reactivity of enantiopure (Z)-3-p-tolylsulfinylacrylonitriles (1) has been evaluated with diazoalkanes. 3-Cyanopyrazoles are
obtained when R ) H, but with R ) alkyl (Bn, n-Bu, and t-Bu) only one cycloadduct (4 or 5) is formed in high yield under mild conditions,
therefore evidencing a complete control of the regioselectivity and the endo/exo and π-facial selectivities. These reactions are a new
straightforward entry to the synthesis of pyrazolines and related structures and reveal the excellent dipolarophilic features of (Z)-
sulfinylacrylonitriles.
In the course of our studies on the behavior of differently
substituted vinyl sulfoxides in asymmetric cycloaddition
reactions, searching for the ideal sulfinyl dienophile, we
recently reported the results obtained from Diels-Alder
reactions of optically pure (Z)-sulfinylacrylonitriles with a
range of dienes, such as cyclopentadiene,1 and less reactive
dienes such as furan and acyclic dienes.2 The main feature
of these reactions is their complete π-facial selectivity, and
in the case of the (Z)-3-p-tolylsulfinylacrylonitrile, both the
reactivity and the endo-selectivity are also remarkable, which
determines that this compound can be considered as one of
the best monosubstituted vinyl sulfoxides reported thus far.
On the other hand, its 2-alkyl-substituted derivatives exhibit
a poor endo-selectivity and a clearly lower reactivity, which
makes their reactions with cyclopentadiene the only ones to
take place. These results prompted us to study the dipolaro-
philic behavior of optically pure sulfinylacrylonitriles.
In contrast to the wide scope of uses of chiral vinyl
sulfoxides in asymmetric Diels-Alder reactions,3 their use
in dipolar reactions is much less extended,3a,4 maybe due to
the easy desulfinylation of the resulting cycloadducts. Since
this problem was minimized with dipolarophiles lacking a
hydrogen atom at a cis-arrangement with respect to the
sulfinyl group, the structure of the easily obtained (Z)-3-p-
tolylsulfinylacrylonitriles suggested their potential efficiency
as chiral dipolarophiles. Taking into account that the sulfinyl
group was shown to be very efficient in increasing the
reactivity of some dipolarophilic moieties with diazoalkanes,5
we decided to begin our study with these 1,3-dipoles, to
(3) Some reviews: (a) Garcia Ruano, J. L.; Cid, B. In Topics in Current
Chemistry; Page, P. C. B., Ed.; Springer: Berlin, 1999; Vol. 204, pp 1-126.
(b) Carren˜o, M. C. Chem ReV. 1995, 95, 1717. (c) Solladie´, G.; Carren˜o
M. C. In Organosulfur Chemistry: Synthetic Aspects; Page, P. C. B., Ed.;
Academic Press: New York, 1995; pp 1-47.
(4) (a) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863. (b)
Midura, W. H.; Krysiak, J. A.; Mikolajczyk, M. Tetrahedron 1999, 55,
14791. (c) Garc´ıa Ruano, J. L.; Fraile, A.; Mart´ın, M. R. Tetrahedron 1999,
55, 14491. (d) Bruche, L.; Arnone, A.; Bravo, P.; Panzeri, W.; Pesenti, C.;
Viani, F. Eur. J. Org. Chem. 1999, 1665.
(1) 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.
(2) Garc´ıa Ruano, J. L.; Alemparte, C.; Mart´ın Castro, A. M.; Adams,
H.; Rodr´ıguez Ramos, J. H. J. Org. Chem. 2000, 65, 7938.
(5) Garc´ıa Ruano, J. L.; Fraile, A.; Martin, M. R. Tetrahedron:
Asymmetry 1996, 7, 1943.
10.1021/ol016481o CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/13/2001

achieve a new entry to enantiomerically pure ∆1-cyano-
pyrazolines, whose structures are much less frequently
reported in the literature6 than those of their corresponding
∆2-analogues.7 The asymmetric synthesis of pyrazolines has
been studied mainly from cyclic5,8 and much less from
acyclic alkenes.4b,8c,9
detected in the NMR spectra of the crude reactions, and it
was isolated in almost quantitative yields (Table 1). Reactions
Table 1
The synthesis of the starting (Z)-3-sulfinylacrylonitriles 1
[Scheme 1: R ) H (1a), n-Bu (1b), t-Bu (1c), and Bn (1d)]
producta
Scheme 1
substrate
R
R′
T (°C)
time
1b
1c
1d
1b
1c
1d
n-Bu
t-Bu
Bn
n-Bu
t-Bu
Bn
H
H
H
Me
Me
Me
-10
0
-10
-10
0
1.5 h
1.5 h
45 min
2 min
5 min
10 min
4b
4c
4d
5b
5c
5d
-10
a Isolated yield >93%.
can be performed easily in just two steps from terminal
alkynes according to a previously reported method1 involving
sulfinylation with optically pure menthylsulfinate followed
by a completely stereoselective conjugated addition of
Et2AlCN to the resulting alkynyl sulfoxides.
The reactions of 1a with diazomethane and diazoethane
take place instantaneously, even at -10 °C, yielding the
corresponding cyanopyrazoles 2a10,11 and 3a.11
This reaction results from the easy desulfinylation of the
obtained cycloadducts into the aromatic compounds, once
the ∆2 rearrangement of the initially formed pyrazolines,7
favored by the conjugation of the CdN bond with the cyano
group, has taken place (Scheme 2).
with diazoethane were even faster, yielding the pyrazolines
5b-d in less than 10 min under the same reaction conditions,
also in quantitative yields (Table 1). Since compounds 4 and
5 bear a cyano group on a quaternary carbon (R ) alkyl),
thus preventing the formation of a conjugated double bond
by ∆1 f D2 pyrazoline rearrangement, desulfinylation is not
so favored (the formation of the aromatic heterocycle is not
possible), making them stable enough to be isolated and
purified.
Since the reactivity of diazoalkanes with acrylonitriles13
is lower than that of compound 1a (see above), we must
conclude that the sulfinyl group increases the dipolarophilic
reactivity with these 1,3-dipoles. The same conclusion had
also been reached from the results obtained for 3-p-
tolylsulfinyl-5-alkoxyfuranones with diazoalkanes.5 Other-
wise, the reactivity of compounds 1 as dipolarophiles is
clearly higher than their dienophilic reactivity. 1b and 1d
react with cyclopentadiene1 after 1 day at room temperature
in the presence of 2 equiv of ZnBr2, whereas they do not
Scheme 2
IzV. Akad. Nauk, Ser. Khim. 1992, 452. Hassaneen, H. M.; Ead, H. A.;
Elwan, N. M.; Shawali, A. S. Heterocycles 1988, 27, 2857. Ezmirly, S. T.;
Shawali, A. S. J. Heterocycl. Chem. 1988, 25, 257. 1,3-Dipolar Cycload-
dition Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York, 1984,
and references cited.
(8) (a) Diaz, M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1995, 6, 1845.
(b) Rispens, M. T.; Keller, E.; de Lange, B.; Zijlstra, W. J.; Feringa, B. L.
Tetrahedron: Asymmetry 1994, 5, 607. (c) Martin-Vila`, M.; Hanafi, N.;
Jimenez, J. M.; Alvarez-Larena, A.; Piniella, J. F.; Branchadell, V.; Oliva,
A.; Ortun˜o, R. M. J. Org. Chem. 1998, 63, 3581.
(9) Mancera, M.; Rodriguez, E.; Roffe´, I.; Galbis, J. J. Org. Chem. 1988,
53, 5648. Jime´nez, J. M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1996, 7,
537. Misch, M. R.; Guerra, f. M.; Carreira, E. M. J. Am. Chem. Soc. 1997,
119, 8379. Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710.
(10) Lancelot, J.-C.; Maume, D.; Robba, M. J. Heterocycl. Chem. 1981,
18, 1319. Cabildo, P.; Claramunt, R. M. Org. Magn. Reson. 1984, 22, 603.
(11) Tsuchiya, T.; Arai, H.; Igeta, H. J. Chem. Soc., Chem. Commun.
1972, 1059.
(12) General procedure: To a solution of (Z)-3-p-tolylsulfinylacrylo-
nitrile (1) (1 mmol) in anhydrous Et2O (substrates 1a-c) or MeOH (substrate
1d) (2 mL), cooled at the indicated temperature (see Table 1), was added
a 0.95 M solution of diazoalkane in Et2O (10 equiv). The resulting mixture
was stirred under the conditions shown in Table 1 and evaporated.
(13) In our hands, reaction of acrylonitrile with diazomethane was
complete in ca. 15 min at -5 °C.
The reactions of 1b-d with diazomethane take place under
very mild conditions (T < 0 °C) and moderated reaction
times (<90 min).12 Only one cycloadduct (4b-d) was
(6) Franck-Neumann, M.; Miesch, M. Bull. Soc. Chim. Fr. 1984, 362.
Gulbrandsen, T.; Kolsaker, P. Acta Chem. Scand., Ser. B 1983, B37 (3),
219.
(7) Molteni, G.; Orlandi, M.; Broggini, G. J. Chem. Soc., Perkin Trans.
1 2000, 3742. Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M.; Coles, S. J.;
Hursthouse, M. B. J. Chem. Soc., Perkin Trans. 1 2000, 2930. Chen, D.-
W.; Chen, Z.-Ch. Synth. Commun. 1995, 25, 1617. Bach, K. K.; El-Seedi,
H. R.; Jensen, H. M.; Nielsen, H. B.; Thomsen, I.; Torssell, K. B. G.
Tetrahedron 1994, 50, 7543, Linev, V. V.; Kolomiets, A. F.; Fokin, A. F.
3174
Org. Lett., Vol. 3, No. 20, 2001

react either with furan or acyclic dienes, even at high
The stereochemical result of these reactions can be
rationalized as follows. The dipolar repulsion between the
S-O and C-N bonds, which unstabilizes the conformation
with the sulfinyl oxygen in an s-cis arrangement, must be
strong enough to shift the conformational equilibrium around
the C-S bond completely toward the s-trans rotamer. A more
detailed discussion of the conformational preference of
compounds 1 can be found in ref 1.
pressures.2 1c does not react with any dienes.
The most outstanding result concerning these 1,3-dipolar
cycloadditions is the complete control of the stereoselectivity.
Only one adduct is isolated in practically quantitative yield,
even in the case of reactions with diazoethane, where four
adducts could have been formed. This result indicates that
the sulfinyl group is able to control the π-facial diastereo-
selectivity at both the starting sulfinylacrylonitrile and the
dipole.
As shown in Scheme 3, the p-tolyl group sterically hinders
The cis relationship between the R and methyl groups in
cycloadducts derived from diazoethane was established from
the 1H NMR parameters (values of NOE’s) observed for 5b
(see Figure 1).14
Scheme 3. Stereochemical Course of the Reactions of 1b-d
with Diazomethane
Figure 1. NOE values for 5b.
the dipole approach to the lower face of the favored s-trans
conformation, thus determining exclusive attack to the less
hindered upper face of the dipolarophile, which is the one
supporting the lone electron pair. This assumption, which is
able to explain the configuration at C-3 and C-4 of the
adducts 4 and 5, was also used to explain the behavior of
compound 1a as dienophile.1, 2
The absolute configuration of the cycloadduct 4b was
unequivocally determined by X-ray crystallography. To get
good crystals, the N-N double bond in compound 4b was
reduced by treatment with Al(Hg) in THF-H2O (9:1) to
afford compound 6b in 90% yield, whose X-ray structure is
represented in Figure 2.15
To explain the control of the π-facial selectivity on the
dipole fragment, we assume that the interaction of Me and
SOTol groups, which unstabilizes the approach of the
dipolarophiles (from the less hindered face in their most
stable s-trans conformation) to the pro-S face of the dipole
(Scheme 4), must be strong enough to justify the exclusive
evolution of the reagents through the most stable endo-like
Scheme 4. Stereochemical Course of the Reactions of 1b-d
with Diazoethane
Figure 2. X-ray structure of compound 6b.
Org. Lett., Vol. 3, No. 20, 2001
3175

TS resulting from the approach of the dipolarophile to the
pro-R face of the diazoethane, where such an interaction is
absent.
fragments. These reactions are one of the most straightfor-
ward and efficient entries to the asymmetric synthesis of
enantiomerically pure ∆1-pyrazolines.
In conclusion, we have shown that 2-alkyl-substituted (Z)-
3-p-tolylsulfinylacrylonitriles exhibit very good properties
as chiral dipolarophiles in their reaction with diazoalkanes.
Their reactivity is very high and they are able to control the
stereoselectivity of both the dipole and the dipolarophile
Acknowledgment. We thank CAICYT (Grants BQU2000-
0246 and PB98-0102) for financial support.
Supporting Information Available: Experimental sec-
tion containing characterization of compounds 4, 5, and 6b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Double Pulsed Field Gradient Echo-DPFGS (Bruker DRX-500).
(15) The authors have deposited atomic coordinates for 6b with the
Cambridge Crystallographic Data Centre (deposition number CCDC
167473). The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK.
OL016481O
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Org. Lett., Vol. 3, No. 20, 2001