(Z)-3-p-Tolylsulfinylacrylonitrile as a chiral dienophile: Diels-Alder reactions with furan and acyclic dienes

Article abstract of DOI:10.1021/jo000963g

The behavior of (Z)-3-p-tolylsulfinylacrylonitrile (1) as a chiral dienophile has been evaluated from its reactions with furan and acyclic dienes. Electrostatic interactions of the cyano group with the sulfinyl one restrict the conformational mobility around the C-S bond, thus controlling the π-facial selectivity, which is almost complete in all cases, the approach of the diene from the less-hindered face of the dienophile (that bearing the lone electron pair) in the predominant rotamer being the favored one. The regioselectivity is also completely controlled by the cyano group. Additionally, the reactivity of compound 1 as well as its endo-selectivity are both higher than those observed for the corresponding (Z)-3-sulfinylacrylates, thus proving the potential of sulfinylnitriles as chiral dienophiles.

Full text of DOI:10.1021/jo000963g

7938
J . Org. Chem. 2000, 65, 7938-7943
(Z)-3-p-Tolylsu lfin yla cr ylon itr ile a s a Ch ir a l Dien op h ile:
Diels-Ald er Rea ction s w ith F u r a n a n d Acyclic Dien es
J ose´ L. Garc´ıa Ruano,*,† Carlos Alemparte,† Ana M. Mart´ın Castro,† Harry Adams,‡ and
J esu´s H. Rodr´ıguez Ramos*,†
Departamento de Quı´mica Orga´nica (C-I), Universidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain, and Department of Chemistry, University of Sheffield,
Sheffield S3 7HF, United Kingdom
jesus.rodriguez@uam.es
Received J une 26, 2000
The behavior of (Z)-3-p-tolylsulfinylacrylonitrile (1) as a chiral dienophile has been evaluated from
its reactions with furan and acyclic dienes. Electrostatic interactions of the cyano group with the
sulfinyl one restrict the conformational mobility around the C-S bond, thus controlling the π-facial
selectivity, which is almost complete in all cases, the approach of the diene from the less-hindered
face of the dienophile (that bearing the lone electron pair) in the predominant rotamer being the
favored one. The regioselectivity is also completely controlled by the cyano group. Additionally,
the reactivity of compound 1 as well as its endo-selectivity are both higher than those observed for
the corresponding (Z)-3-sulfinylacrylates, thus proving the potential of sulfinylnitriles as chiral
dienophiles.
In tr od u ction
nes3 were prepared from the adducts resulting from the
reaction of the p-tolylsulfinylacrylates with cyclopenta-
diene. Nevertheless, the results obtained in the Diels-
Alder reaction showed the rather low reactivitysthey
were unable to react with furan even under forced
conditionssand moderate endo-selectivity of these sul-
foxides as dienophiles.2 Therefore the search of more
reactive sulfinyl derivatives was undertaken. In this
context, pyridylsulfinyl derivatives exhibited a higher
reactivity toward cyclopentadiene,4 and their endo-ad-
ducts were transformed into precursors of the Ohno’s
lactone.5 They were able to react with furan6 and
substituted furans7 yielding mixtures of the four possible
adducts (Scheme 1) with low endo/ exo selectivity in the
presence of Et2AlCl (<2:1). It became higher (ca. 4:1) in
the absence of any catalyst, but the π-facial selectivity
for the endo approach was clearly poorer (55:45, see
Scheme 1).
The sulfinyl group has become one of the most inter-
esting chiral inductors in asymmetric Diels-Alder reac-
tions due to its ability to differentiate between diaste-
reotopic faces of neighboring double bonds. It drew the
attention of many researchers, whose contributions have
been collected in many excellent reviews.1 The poor
results obtained from vinyl sulfoxidessa rather low
reactivity and only a moderate stereoselectivity2swere
substantially improved by incorporating further activat-
ing groups to the double bond, which increases the
reactivity and simultaneously restricts the conforma-
tional mobility around the C-S bond, hence improving
the stereoselectivity of the dienophile. In this sense, many
electron-withdrawing groups have been incorporated to
vinyl sulfoxides, alkoxycarbonyl ones being the most
widely used. The interest of (Z)-3-sulfinylacrylates, clearly
the most frequently used sulfinyl dienophiles, derives
from the fact that the adducts resulting from their
cycloadditions with cyclopentadiene and furan can be
used as chiral building blocks in the synthesis of a
number of natural products. Thus, bicyclic sesquiterpe-
Despite their moderate stereoselectivity, the interest
of these reactions derives from the use of these furan
adducts as building blocks in the synthesis of a number
of natural products such as C-nucleosides,8 methyl epish-
ikimate,9 pseudosugars,10 and glyoxalase I inhibitors.11
(3) (a) Arai, Y.; Yamamoto, M.; Koizumi, T. Chem. Lett. 1986, 1225.
(b) Arai, Y.; Yamamoto, M.; Koizumi, T. Bull. Chem. Soc. J pn. 1988,
61, 467.
(4) Arai, Y.; Hayashi, Y.; Matatoshi, Y.; Takayama, H.; Koizumi, T.
Chem. Lett. 1987, 185.
* Corresponding author. FAX 341 397 3966. E-mail for J . L. Garc´ıa
Ruano: joseluis.garcia.ruano@uam.es.
† Universidad Auto´noma de Madrid.
‡ University of Sheffield.
(1) (a) Garc´ıa 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 Organosulphur Chemistry Synthetic Aspects; Page, P. C. B.,
Ed.; Academic Press: New York, 1995; Chapt. 1, pp 1-47. (d) J urczak,
J .; Bauer, T.; Chaouis, C. In Methods of Organic Chemistry (Houben-
Weyl); Helmchem, G.; Hoffmann, R. W.; Mulzer, J .; Schaumann, E.,
Eds.; Georg Thieme: Stuttgart, New York, 1995; Vol. E21b, Sect. 1.6.1,
pp 2735-2987. (e) Aversa, M. C.; Barattucci, A.; Bonaccorse, P.;
Gianneto, P. Tetrahedron: Asymmetry 1997, 8, 1339.
(2) (a) Koizumi, T.; Hakamada, I.; Yoshi, E. Tetrahedron Lett. 1984,
25, 87. (b) Maignan, C.; Guessous, A.; Rouessac, F. Tetrahedron Lett.
1984, 25, 1727. (c) Brimble, M. A.; Davis, B. R. Tetrahedron 1985, 41,
4965.
(5) Arai, Y.; Hayashi, Y.; Matatoshi, Y.; Takayama, H.; Koizumi, T.
J . Chem. Soc., Perkin Trans. 1 1988, 3133.
(6) (a) Takayama, H.; Iyobe, A.; Koizumi, T. J . Chem. Soc., Chem.
Commun. 1986, 771. (b) Arai, Y.; Hayashi, Y.; Matatoshi, Y.; Takaya-
ma, H.; Koizumi, T. Chem. Lett. 1987, 185. (c) Takayama, H.; Hayashi,
K.; Takeuchi, Y.; Koizumi, T. Heterocycles 1986, 24, 2137.
(7) Takahashi, T.; Namiki, T.; Takeuchi, Y.; Koizumi, Y. Chem.
Pharm. Bull. 1988, 36, 3213.
(8) Takayama, H.; Iyobe, A.; Koizumi, T. Chem. Pharm. Bull. 1987,
35, 433.
(9) Takahashi, T.; Iyobe, A.; Arai, Y.; Koizumi, T. Synthesis 1989,
189.
(10) Takahashi, T.; Katsubo, H.; Iyobe, A.; Namiki, T.; Koizumi, T.
J . Chem. Soc., Perkin Trans. 1 1990, 3065.
10.1021/jo000963g CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/26/2000

(Z)-3-p-Tolylsulfinylacrylonitrile
J . Org. Chem., Vol. 65, No. 23, 2000 7939
Sch em e 1
the solvent substantially improved the yields (although
the reaction was never complete) affording en d o-2A and
exo-2A adducts, which could be isolated and character-
ized. Traces of compound en d o-2B could also be detected
(1H NMR) in the crude mixture. Under these conditions
(entry 1) the endo/ exo ratio was 84/16 and the π-facial
selectivity for the endo-approach was estimated as higher
than 33 (A/B ratio).
As expected, the use of Lewis acids as catalysts
shortened the reaction times, but it had no significant
influence on both endo/ exo and π-facial selectivities
(entries 2-5), which were also slightly modified by a
decrease in the reaction temperature.14 In the case of the
The use of high pressures makes the reactions easier with
furan derivatives12 but the endo/ exo selectivity remains
moderate (ca. 42-68% de’s), thus indicating that high
presssures do not have a significant influence in the
stereoselectivity.
Diels-Alder reactions of 1 with cyclopentadiene13
a
complete reversion of the π-facial selectivity was observed
by using BF3 as the catalyst. Nevertheless, all attempts
performed in order to extend this methodology at atmo-
spheric pressure to the use of furan as the diene failed
since they gave rise to the undesired hydrolysis of the
cyano group of the starting dienophile into a carboxamido
group as the major transformation.
Finally, the use of high pressures also increased the
rate of reactions conducted in furan as the solvent, but
the facial diastereoselectivity is slightly modified (entry
6), mainly if reactions are catalyzed by ZnBr2 (entry 7).
At 4 kbar no starting material was detected by NMR
analysis of the crude material. Nevertheless, a small
amount of 1 was isolated by flash chromatography,
presumably due to a retro-Diels-Alder reaction during
the purification stage.
All these results evidenced that the high synthetic
interest of the adducts obtained from furan and (Z)-3-
sulfinylacrylates was basically restricted by the low
reactivity of these dienophiles and the moderate endo/
exo selectivity of their Diels-Alder reactions. The non-
trivial procedure required to prepare optically pure
pyridyl sulfoxides is another disadvantage to the use of
these dienophiles. The search for new, more readily
prepared dienophiles, synthetically equivalent to (Z)-3-
sulfinylacrylates but possessing higher reactivity and
stereoselectivity, became an interesting challenge. Re-
cently we have reported the synthesis of (Z)-3-p-tolyl-
sulfinylacrylonitrile (1) and its dienophilic behavior with
cyclopentadiene.13 The results suggested that this easily
obtained vinyl sulfoxide fulfilled all the expected require-
ments (higher reactivity and more stereoselectivity than
the corresponding ester). In this paper we describe the
reactions of 1 with dienes less reactive than cyclopenta-
diene, such as furan and acyclic dienes, which confirms
the interesting dienophilic features of this vinyl sulfoxide.
The endo or exo character of the isolated adducts was
1
established by H NMR. The absolute configuration of
compound en d o-2A obtained as the major one in these
reactions was unequivocally assigned by X-ray analysis.
The sense of the high π-facial selectivity for the endo
approach is the expected one from the results obtained
with cyclopentadiene13 and it can be attributed to the
strong conformational polarization around the C-S bond
induced by the cyano group. It determines that the
sulfinyl oxygen adopts almost exclusively the conforma-
tion s-transsin order to minimize the dipolar repulsion
with nitrile15sarranging the p-tolyl group toward the
upper B face (Scheme 2). This becomes so sterically
congested that the diene approach is only possible from
the less-hindered A face containing the lone electron pair.
According to this proposal, which satisfactorily explains
the stereochemistry of the major adduct, the exo approach
of furan will also take place from the same face A, which
allows us to assign compound exo-2A the structure
shown in Table 1.
Resu lts a n d Discu ssion
The synthesis of the starting (Z)-3-sulfinylacrylonitrile
(1) was easily performed by stereoselective conjugated
addition of Et2AlCN to alkinyl sulfoxides.13 The results
obtained in the Diels-Alder reactions of 1 with furan
under different conditions are collected in Table 1.
Treatment of 1 with 8 equiv of furan in refluxing CH2-
Cl2 for several days afforded the unaltered starting
material. The addition of ZnBr2 or Me2AlCl as catalyst
at room temperature allowed the formation of small
amounts of the expected adducts. No improvement in the
results was observed on increasing either the reaction
time or the temperature. However, the use of furan as
Important advantages can be inferred from the com-
parison of the results obtained from compound 1 with
those from the corresponding sulfinyl esters. First, the
reactivity of the p-tolylsulfinylnitrile is higher than that
of pyridylsulfinylacrylates,4,6,7 which, in turn, were more
reactive than p-tolylsulfinylacrylates and unreactive in
the presence of furan, as deduced from the reaction times
required under similar conditions (compare Table 1 and
(11) Takayama, H.; Hayashi, K.; Koizumi, T. Tetrahedron Lett 1986,
27, 5509.
(12) Yamakoshi, Y. N.; Ge, W.-Y.; Sugita, J .; Okayama, K.; Taka-
hashi, T.; Koizumi, T. Heterocycles 1996, 42, 129.
(13) 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.
(14) The scarce influence of the catalyst and the temperature in the
endo/ exo ratio suggested that it was the result of a thermodynamic
control process through a retro-Diels-Alder reaction, which is a quite
common feature of furan adducts. To verify this point, the reaction
time was increased in several days in the reactions carried out without
catalyst. Under these conditions, the endo/ exo ratio decreased down
to 2: 1. Additionally a diastereomerically pure sample of the major
adduct en d o-2A was maintained in furan for 2 days and the formation
of a small amount of exo-2A (<10%) could be observed. This proves
that retro-Diels Alder takes place but it is slower than the normal
reaction. Therefore, we can conclude that the endo/ exo selectivity must
be slighly higher than that indicated in Table 1, but the existing exo-
2A adduct is not exclusively derived from the retro-Diels-Alder but
also from the direct formation through a Diels-Alder process.
(15) The assumption of this repulsion minimizing the conformational
energy is supported by the relative arrangement of cyano and sulfinyl
groups observed in the X-ray structure for adduct en d o-2A. In the
latter case, both groups adopt an eclipsed conformation such as in
dienophile 1.
(16) (a) Dane, E.; Schmitt, J . Liebigs Ann. Chem. 1938, 536, 196.
(b) Ibid. 1939, 537, 246. (c) Robins, D. A.; Walker, J . J . Chem. Soc.
1956, 3249.

7940 J . Org. Chem., Vol. 65, No. 23, 2000
Ta ble 1. Diels-Ald er Rea ction s of 1 a n d F u r a n
Garc´ıa Ruano et al.
entry
catalyst
conditions
pressure
en d o-2A×bb
exo-2Aa
en d o-2Ba
endo/exob
A/Bb
1
2
3
4
5
6
7
s
rt, 2 d
rt, 1 d
0 °C, 7 d
-20 °C, 3 d
rt, 1 d
1 bar
1 bar
1 bar
1 bar
1 bar
4 kbar
4 kbar
51
42
sc
sc
53
61
55
11
13
sc
sc
10
12
16
traces
traces
sc
84/16
86/14
85/15
87/13
87/13
84/16
78/22
>33
>33
>33
>33
>33
∼25
10
ZnBr2
ZnBr2
ZnBr2
Me2AlCl
s
sc
traces
4
6
rt, 1 d
rt, 13 h
ZnBr2
a
b
Isolated yield (%). From integration of well-separated signals of the 1H NMR spectrum of the crude mixture. c Not determined.
Sch em e 2
complete (governed by the cyano group) with both dienes.
The combined influence of high pressure and Lewis acid
catalysis determines, as in the case of furan, a substantial
decrease in the facial diastereoselectivity (entries 3 and
5). The endo/ exo selectivity of the reactions with diene
3 was similar to the observed from furan, whereas it was
clearly higher with diene 4, even in the presence of ZnBr2.
In the presence of a boron catalyst no transformation was
achieved, partially due to the fast polymerization of the
diene under the reaction conditions.
Configurational assignment of compound en d o-5A was
unequivocally established by X-ray diffraction studies
(Supporting Information). Results obtained in these
reactions can also be easily rationalized by assuming the
model proposed in Scheme 2, the approach of acyclic
dienes from the less-hindered face of sulfinylnitrile 1 (in
its electrostatically preferred conformation) being fa-
vored. Finally, we must remark that, as expected, the
regioselectivity is controlled by the cyano group and is
not affected by addition of the Lewis acid, which evi-
dences that the relative magnitude of the coeficients at
the dienophilic double bond must remain identical under
both reaction conditions.
Finally, reactions with 3,4-dihydro-6-methoxy-1-vinyl-
naphthalene (7) (Dane’s diene)16 were also studied (Table
3). The interest of this diene, one of the most frequently
used in the construction of the steroidal systems,17 is
related to the regioselectivity of their reactions, mainly
to the role of the Lewis acid catalysts, which are able to
invert it in many cases.18
Scheme 1). Second, the π-facial selectivity of compound
1 is almost complete, regardless the presence of a catalyst
(Table 1), whereas it was poorer starting from pyridyl-
acrylate, mainly in the absence of Lewis acids (Scheme
1). Finally, the endo/ exo selectivity of the reaction was
also higher for sulfinyldienophiles containing a cyano
group than for those with an ester moiety.13 Additionally,
the synthesis of 1 is much easier than that of sulfinyl
esters.
The lower endo-selectivity of the sulfinylacrylate with
respect to its corresponding acrylonitrile 1 can be under-
stood by assuming that steric interactions between the
ester and sulfinyl groups distort the planarity of the
former one. Such a distortion can also be responsible for
the lower reactivity of the acrylate.
These good results prompted us to investigate the
behavior of 1 with acyclic dienes, which had never been
studied with 3-sulfinylacrylates, maybe due to their low
reactivity. The results obtained in reactions with (E)-1-
methoxy-1,3-butadiene (3) and piperylene (4) are col-
lected in Table 2. When 1 reacted with an excess of
1-methoxy derivative 3 in the absence of a cosolvent, a
complete transformation of the starting material was
achieved after 4 days at room temperature (entry 1). By
contrast, all attempts to perform the reaction of 1 with
piperylene (4) at atmospheric pressure were unsuccessful
even in the presence of different catalysts and working
at high temperatures for long reaction times. The lower
reactivity of 4 and the scarce solubility of 1 in this diene,
which precludes its use as a solvent (the reactions were
performed with 8 equiv of 4 in CH2Cl2 as the solvent)
can account for this unsuccessful result. At a pressure
of 4 kbar, 1-methoxy derivative 3 required shorter
reaction times (entry 2) and piperylene evolved into the
corresponding cycloadducts after 10 days at room tem-
perature (entry 4). The π-facial selectivity for the endo-
approach (A/B ratio) is very high and the regioselectivity
In the absence of a catalyst, 1 reacted with 4 equiv of
Dane’s diene 7 in CH2Cl2-benzene, but the formation of
(17) (a) Cole, J . E.; J ohnson, W. S.; Robin, P. A. J . Chem. Soc. 1962,
244. (b) Dickinson, R. A.; Kubela, R.; MacAlpine, G. A.; Stojanac, Z.;
Valenta, Z. Can. J . Chem. 1972, 50, 2377. (c) Quinkert, G.; Stark, H.
Angew. Chem., Int. Ed. Engl. 1983, 22, 637. (d) Takano, S.; Moriya,
M.; Ogasawara, K. Tetrahedron Lett. 1992, 33, 1909. (e) Quinkert, G.;
Grosso, M.; Bucher, A.; Bauch, M.; Doring, W.; Bats, J . W.; Durner,
G. Tetrahedron Lett. 1992, 33, 3617. (f) Alonso, I.; Carretero, J . C.;
Garc´ıa Ruano, J . L.; Mart´ın Cabrejas, L. M.; Lo´pez-Solera, I.; Raithby,
R. Tetrahedron Lett. 1994, 35, 9461. (g) Quinkert, G.; Grosso, M.;
Do¨ring, A.; Do¨ring, W.; Schenkel, R. I.; Bauch, M.; Dambacher, G. T.;
Bats, J . W.; Zimmermann, G.; Du¨rner, G. Helv. Chim. Acta 1995, 78,
1345. (h) Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1996, 37,
7403. (i) Schuster, T.; Kurz, M.; Go¨bel, M. W. J . Org. Chem. 2000, 65,
1697.
(18) (a) Tou, J . S.; Reusch, W. J . Org. Chem. 1980, 45, 5012. (b)
Arseniyadis, S.; Rodr´ıguez, R.; Spanevello, R.; Ca´mara, J .; Thompson,
A.; Guittet, E.; Ourisson, G. Tetrahedron 1992, 48, 1255. (c) Arseniya-
dis, S.; Rodr´ıguez, R.; Yashunsky, D. V.; Ca´mara, J .; Ourisson, G.
Tetrahedron Lett. 1994, 35, 4843, and ref 17b and 17e.
(19) Garc´ıa Ruano, J . L.; Mart´ın Castro, A. M.; Rodr´ıguez, J . H.
Tetrahedron Lett. 1996, 37, 4569.

(Z)-3-p-Tolylsulfinylacrylonitrile
J . Org. Chem., Vol. 65, No. 23, 2000 7941
Ta ble 2. Diels-Ald er Rea ction s of 1 w ith Acyclic Dien es 3 a n d 4
entry
diene
catalyst
pressure
time (d)
product
en d o-Aa
exo-Aa
en d o-Ba
1
2
3
4
5
3
3
3
4
4
s
s
ZnBr2
s
ZnBr2
1 bar
4
3
3
10
7
5
5
5
6
6
70
70
63
70
57
12
9
13
5
traces
5
16
traces
13
4 kbar
4 kbar
4 kbar
4 kbar
4
a
Isolated yield (%).
Ta ble 3. Diels-Ald er Rea ction s of 1 a n d Da n e’s Dien e 7
double bond is not altered by the Lewis acid (see before),
the results indicated in Table 3 suggest that it is also
the case for Dane’s diene. This does not agree with those
explanations attributing changes in regioselectivity only
to the association of the methoxy group to the catalyst,20
but it suggests that alterations of the dienophile must
be mainly responsible for the changes in the regioselec-
tivity.
As a conclusion we can state that the readily obtained
(Z)-3-p-tolylsulfinylacrylonitrile (1) is a very efficient
chiral sulfinyldienophile exhibiting some important ad-
vantages with respect to its corresponding sulfinylacryl-
ate. The higher reactivity of the nitrile 1, allowing its
reactions with furan and acyclic dienes, as well as its
higher endo-selectivity could be a consequence of the
linear structure of the nitrile, which avoids the steric
interactions between CO2R and SOTol groups that distort
the planarity in the case of the ester. The higher π-facial
selectivity exhibited by 1 must be a consequence of the
strong repulsion between the CtN and SsO dipoles.
These features make compound 1 an advantageous
synthetic equivalent of sulfinylacrylate as a chiral di-
enophile.
entry diene equiv catalyst pressure time (d) en d o-8Aa
9
1
2
3
4
2.5
2
ZnBr2
s
ZnBr2
1 bar
4 kbar
4 kbar
7
7
3
50
60
84
12
s
4
a
Isolated yield (%).
the adducts is extremely slow, the degree of transforma-
tion being very low even after long reaction times (27
days at room temperature). However, addition of ZnBr2
led to a complete transformation of 1 after 7 days (Table
3, entry 1) yielding compound en d o-8A as the only
adduct, along with â-sulfenylacrylamide 9, presumably
resulting from the hydrolysis of cyano group of the
dienophile with concomitant anchimeric assistance of the
sulfinyl oxygen.19 The configuration of this adduct was
also determined by X-ray analysis (Supporting Informa-
tion).
The use of high pressure makes the reaction easier by
reducing the reaction times and the number of diene
equivalents (entries 2 and 3), but the exclusive formation
of the adduct en d o-8A (no other adduct could be detected
by 1H NMR from the reaction crudes) was observed under
all conditions. These results demonstrate that reactions
of (Z)-3-p-tolylsulfinylacrylonitrile (1) with Dane’s diene
(7) are completely regio endo and π-facial selective, thus
confirming that compound 1 is one of the best chiral
dienophiles to be used with Dane’s diene to build steroi-
dal skeletons. Concerning the regioselectivity, which
remains unaltered under all conditions, it seems to be
controlled by the cyano group at the dienophile and the
substituent at C-1 at the diene. Taking into account that
the relative magnitude of the coeficients at dienophilic
Exp er im en ta l Section
Gen er a l Meth od s. Dienes, except Dane’s diene (7), and
Lewis acids are commercially available and were used without
further purification. ZnBr2 was flame-dried in the reaction
flask before use. Flash chromatography was performed with
silica gel 60 (230-400 mesh ASTM), and silica gel F 254 plates
were used for preparative TLC. NMR spectra were determined
in CDCl3 solutions at 200 (or 300) and 50.3 (or 75) MHz for
1H and 13C NMR, respectively. J values are given in hertz.
Yields are shown in Tables 1-3. Compound 1 was synthesized
and purified according to procedure described in ref 13. To
verify the optical purity of 1 to be used as the substrate in
further reactions, it is necessary to check it by NMR using
Yb(hfc)3 as the LSR (substrate-LSR molar ratio 1:0.3). Reac-
tions with piperylene were carried out with racemic 1. High-
pressure reactions were performed in 1.5 mL polyethylene
sample vials in a Unipressequipment 101 LV 30/16 apparatus.
Diels-Ald er Cycloa d d ition s of 1 w ith F u r a n . Meth od
i: Th er m a l Con d ition s. A solution of 1 (0.75 mmol) in an
excess of furan (2 mL) was stirred at room temperature. When
the reaction was completed (2 days at atmospheric pressure
or 1 day at 4 kbar), the crude mixture was concentrated, and
the residue was purified by flash chromatography (2:3 hex-
anes-ethyl acetate).
Meth od ii: In th e P r esen ce of Zn Br 2. To a solution of
ZnBr2 (337.8 mg, 1.5 mmol) in THF (0.4 mL), under argon at
room temperature, was added a solution of 1 (143.5 mg, 0.75
(20) Carretero, J . C.; Garc´ıa Ruano, J . L.; Mart´ın Cabrejas, L. M.
Tetrahedron: Asymmetry 1997, 8, 2215.

7942 J . Org. Chem., Vol. 65, No. 23, 2000
Garc´ıa Ruano et al.
mmol) in furan (3 mL). When the reaction was completed (see
Table 1), water (4 mL) was added, and the mixture was
extracted with CH2Cl2 (3 × 4 mL). The organic layer was dried
(Na2SO4) and concentrated.
Meth od iii: In th e P r esen ce of Me2AlCl. To a solution
of 1 (0.75 mmol) in furan (3 mL), under argon at room
temperature, was added a 1.0 M solution of Me2AlCl (900 µL,
0.9 mmol) in hexanes. The reaction mixture was stirred for 1
day at room temperature, poured into saturated aqueous
sodium potassium tartrate (4 mL), and extracted with CH2-
Cl2 (3 × 4 mL). The organic layer was dried (Na2SO4) and
concentrated.
7.62 and 7.39 (AA′BB′ system, 4H), 5.94 (ddt, 1H, J ) 4.2,
10.3 and 2.1), 5.72 (m, 1H), 3.86 (m, 1H), 3.37 (s, 3H), 3.13
(dd, 1H, J ) 2.8 and 5.6), 2.88 (ddd, 1H, J ) 2.8, 6.1 and 10.5),
2.77-2.53 (m, 2H), 2.44 (s, 3H); 13C NMR δ 143.2, 137.3, 130.3,
127.0, 126.3, 125.1, 115.1, 75.6, 59.5, 56.7, 30.5, 23.5, 21.5.
Anal. Calcd for C15H17NO2S: C, 65.43; H, 6.22; N, 5.09; S,
11.64. Found: C, 65.64; H, 6.05; N, 4.95; S,11.81.
(1R,2S,6S)-2-Met h oxy-6-[(R)-p -t olylsu lfin yl]-3-cyclo-
h exen e-1-ca r bon itr ile (exo-5A). It was obtained (partially
unpurified with ca. 3% of en d o-5A) as a colorless oil from
reaction of 1 with (E)-1-methoxybutadiene (3) and further
chromatographic purification (4:5 hexanes-ethyl acetate).
[R]20D ) +82.5 (c 0.9, CHCl3); 1H NMR δ 7.58 and 7.37 (AA′BB′
system, 4H), 6.09 (ddd, 1H, J ) 2.4, 4.9 and 9.9), 5.87 (m, 1H),
3.92 (m, 1H), 3.21 (s, 3H), 3.11 (ddd, 1H, J ) 3.2, 5.7 and 11.1),
2.97 (t, 1H, J ) 3.0), 2.64 (dddt, 1H, J ) 1.2, 10.9, 18.4 and
2.4), 2.58 (ddt, 1H, J ) 2.0, 18.6 and 5.2), 2.43 (s, 3H); 13C
NMR δ 142.9, 137.5, 130.6, 130.2, 125.0, 123.3, 116.2, 74.2,
56.8, 56.2, 29.8, 22.3, 21.5; HRMS (FAB) 276.1055 [M + H]+
(C15H18NO2S requires 276.1058).
(1S,2R,3R,4R)-3-[(R)-p-Tolylsu lfin yl]-7-oxabicyclo[2.2.1]-
h ep t-5-en e-2-ca r bon itr ile (en d o-2A). It was crystallized
from hexanes-ethyl acetate (white solid): mp 105-107 °C;
[R]20 ) +24.6 (c 1, CHCl3); 1H NMR δ 7.79 and 7.36 (AA′BB′
D
system, 4H), 7.03 (dd, 1H, J ) 1.7 and 5.9), 6.80 (dd, 1H, J )
1.7 and 5.9), 5.45 (ddd, 1H, J ) 1.1, 1.6 and 4.2), 5.35 (ddd,
1H, J ) 1.0, 1.7 and 4.3), 3.76 (dd, 1H, J ) 4.2 and 9.0), 3.03
(dd, 1H, J ) 4.3 and 9.0), 2.43 (s, 3H); 13C NMR δ 143.1, 139.0,
136.0, 135.9, 130.2, 125.7, 116.3, 81.1, 80.6, 66.0, 29.2, 21.4.
Anal. Calcd for C14H13NO2S: C, 64.84; H, 5.05; N, 5.40; S, 12,
36. Found: C, 64.69; H, 4.96; N, 5.04; S 11.84.
(1S,2S,6R)-2-Met h oxy-6-[(R)-p -t olylsu lfin yl]-3-cyclo-
h exen e-1-ca r bon itr ile (en d o-5B). It was obtained from
reaction of 1 with (E)-1-methoxybutadiene (3) and further
chromatographic purification (4:5 hexanes-ethyl acetate). It
was crystallized from 1:1 hexanes-ethyl acetate (white
(1R,2R,3R,4S)-3-[(R)-p-Tolylsu lfin yl]-7-oxabicyclo[2.2.1]-
h ep t-5-en e-2-ca r bon itr ile (exo-2A). It was crystallized from
hexanes-ethyl acetate (white solid): mp 117-118 °C; [R]20
solid): mp 169-170 °C; [R]20 ) +107.0 (c 0.25, CHCl3); 1H
D
D
) -91.2 (c 0.27, CHCl3); 1H NMR δ 7.80 and 7.34 (AA′BB′
system, 4H), 6.55 (dd, 1H, J ) 1.6 and 5.9), 6.43 (dd, 1H, J )
1.6 and 5.9), 5.74 (t, 1H, J ) 1.3), 5.40 (t, 1H, J ) 1.3), 3.04
(d, 1H, J ) 7.8), 2.54 (d, 1H, J ) 7.8), 2.41 (s, 3H); 13C NMR
δ 143.1, 139.6, 137.0, 135.4, 130.2, 126.1, 117.9, 83.4, 79.1, 65.9,
31.0, 21.5; HRMS (FAB) 260.0755 [M + H]+ (C14H14NO2S
requires 260.0745). Anal. Calcd for C14H13NO2S: C, 64.84; H,
5.05; N, 5.40; S, 12.36. Found: C, 64.41; H, 4.86; N, 5.17; S
12.44.
NMR δ 7.58 and 7.36 (AA′BB′ system, 4H), 5.69 (br s, 2H),
4.16 (dd, 1H, J ) 3.1 and 6.0), 4.00 (m, 1H), 3.49 (s, 3H), 2.86
(ddd, 1H, J ) 3.0, 5.6 and 11.6), 2.42 (s, 3H), 2.29 (ddd, 1H, J
) 3.2, 11.6 and 17.8), 1.54 (m, 1H); 13C NMR δ 143.3, 137.6,
130.3, 127.8, 125.9, 125.3, 115.4, 75.5, 61.3, 57.0, 30.7, 22.6,
21.5; HRMS (FAB) 276.1052 [M + H]+ (C15H18NO2S requires
276.1058). Anal. Calcd for C15H17NO2S: C, 65.43; H, 6.22; N,
5.09; S, 11.64. Found: C, 64.55; H, 6.16; N, 4.88; S 11.63.
(1S*,2R*,6S*)-2-Meth yl-6-[(R)-p-tolylsu lfin yl]-3-cyclo-
h exen e-1-ca r bon itr ile (en d o-6A). It was obtained from
reaction of 1 with piperylene and further chromatographic
purification (1:2 hexanes-ethyl acetate). It was crystallized
from hexanes-ethyl acetate (white solid): mp 154-155 °C;
1H NMR δ 7.58 and 7.35 (AA′BB′ system, 4H), 5.80 (ddt, 1H,
J ) 5.3, 10.1 and 2.8), 5.41 (m, 1H), 2.90 (ddd, 1H, J ) 2.9,
7.0 and 10.1), 2.66 (dd, 1H, J ) 2.8 and 5.3), 2.64-2.56 (m,
(1R,2S,3S,4S)-3-[(R)-p-Tolylsu lfin yl]-7-oxa bicyclo[2.2.1]-
h ep t-5-en e-2-ca r bon itr ile (en d o-2B). It was crystallized
from hexanes-ethyl acetate (white solid): mp 131-132 °C;
[R]20 ) +122.4 (c 0.17, CHCl3); 1H NMR δ 7.69 and 7.42
D
(AA′BB′ system, 4H), 6.80 (dd, 1H, J ) 1.6 and 5.8), 6.52 (dd,
1H, J ) 1.6 and 5.8), 5.37 (ddd, 1H, J ) 1.1, 1.9 and 4.2), 4.30
(dt, 1H, J ) 1.3 and 4.2), 3.69 (dd, 1H, J ) 4.2 and 8.7), 3.55
(dd, 1H, J ) 4.2 and 8.6), 2.47 (s, 3H); 13C NMR δ 143.6, 138.9,
136.7, 134.2, 130.6, 125.2, 116.2, 80.8, 79.5, 69.7, 31.5, 21.5;
HRMS (FAB) 260.0751 [M + H]+ (C14H14NO2S requires
260.0745). Anal. Calcd for C14H13NO2S: C, 64.84; H, 5.05; N,
5.40; S, 12,36. Found: C, 64.07; H, 5.33; N, 5.14; S 12.35.
Diels-Ald er Cycloa d d ition s of 1 w ith Acyclic Dien es.
Meth od i: Th er m a l Con d ition s. The reactions were carried
out at room temperature and at 4 kbar from a solution of 1
(0.5 mmol) and an excess of diene (4 mmol) in CH2Cl2 (1 mL)
or at atmospheric pressure from a mixture of 1 in 1.03 mL of
(E)-1-methoxybutadiene (3) (5 mmol). When the reaction was
completed (see Table 2), the crude mixture was concentrated,
and the residue was purified by flash chromatography (4:5
hexanes-ethyl acetate).
2H), 2.48-2.36 (m, 1H), 2.42 (s, 3H), 1.13 (d, 3H, J ) 7.3); 13
C
NMR δ 143.1, 137.9, 130.4, 129.5, 125.2, 124.9, 116.3, 62.0,
33.4, 32.3, 23.2, 21.6, 18.3; HRMS (FAB) 260.1101 [M + H]+
(C15H18NOS requires 260.1109). Anal. Calcd for C15H17NOS:
C, 69.46; H, 6.61; N, 5.40; S, 12.36. Found: C, 69.07; H, 6.21;
N, 5.18; S 12.63.
(1S*,2S*,6S*)-2-Met h yl-6-[(R)-p -t olylsu lfin yl]-3-cyclo-
h exen e-1-ca r bon itr ile (exo-6A). It was obtained from reac-
tion of 1 with piperylene (4). Flash chromatography of the
crude reaction (1:2 hexanes-ethyl acetate) afforded impure
exo-6A, which could not be furtherly purified. 1H NMR δ 7.61
and 7.37 (AA′BB′ system, 4H), 5.81 (dddd, 1H, J ) 1.6, 2.8,
4.6, and 9.1), 5.63 (m, 1H), 2.97 (ddd, 1H, J ) 3.2, 6.1 and
9.1), 2.78-2.53 (m, 3H), 2.49 (t, 1H, J ) 3.6), 2.44 (s, 3H), 1.00
(d, 3H, J ) 7.1).
Meth od ii: In th e P r esen ce of Zn Br 2. To a solution of
ZnBr2 (337.8 mg, 1.5 mmol) in THF (0.4 mL), under argon at
room temperature, was added a solution of 1 (143.5 mg, 0.75
mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred for
1 h at room temperature. Then the corresponding diene [6
mmol of piperylene (4) or 3 mmol of (E)-1-methoxybutadiene
(3)] was added, and the mixture was kept at 4 kbar at room
temperature. When the reaction was completed, the crude
mixture was poured into water (4 mL) and extracted with CH2-
Cl2 (3 × 5 mL). The organic layer was dried (Na2SO4) and
concentrated.
(1R*,2S*,6R*)-2-Meth yl-6-[(R)-p-tolylsu lfin yl]-3-cyclo-
h exen e-1-ca r bon itr ile (en d o-6B). It was obtained from
reaction of 1 with piperylene (4). Chromatographic purification
(1:2 hexanes-ethyl acetate) and crystallization from hexanes-
ethyl acetate afforded en d o-6B as a white solid (partially
unpurified with ca. 4% of both en d o-6B and exo-6A): mp 155-
1
156 °C; H NMR δ 7.59 and 7.35 (AA′BB′ system, 4H), 5.61
(ddt, 1H, J ) 5.1, 9.9 and 2.6), 5.46 (m, 1H), 3.72 (dd, 1H, J )
3.0 and 5.1), 2.91 (ddd, 1H, J ) 3.0, 5.7 and 11.9), 2.56 (m,
1H), 2.43 (s, 3H), 2.26 (m, 1H), 1.58 (m, 1H), 1.29 (d, 3H, J )
7.3); 13C NMR δ 143.0, 137.9, 130.3, 130.2, 125.3, 123.9, 116.7,
63.3, 32.9, 32.6, 22.2, 21.5, 18.7; HRMS (FAB) 260.1109 [M +
(1R,2R,6S)-2-Met h oxy-6-[(R)-p -t olylsu lfin yl]-3-cyclo-
h exen e-1-ca r bon itr ile (en d o-5A). It was obtained from
reaction of 1 with (E)-1-methoxybutadiene (3). The residue was
treated with 1:2 hexane-acetone, en d o-5A remaining in-
soluble as a white solid [the yield can be increased by
chromatographic purification of mother liquors (4:5 hexanes-
ethyl acetate)]. It was crystallized from hexane-CH2Cl2 (white
H]+ (C15H18NOS requires 260.1109). Anal. Calcd for C15H17
-
NOS: C, 69.46; H, 6.61; N, 5.40; S, 12.36. Found: C, 68.84;
H, 6.73; N, 5.13; S, 12.42.
Diels-Ald er Cycloa d d ition s of 1 w ith Da n e’s Dien e 7.
Meth od i: Th er m a l Con d ition s. A mixture of 48 mg (0.25
mmol) of 1 and 625 µL of 1 M benzene solution of 716 (0.63
solid): mp 126-127 °C; [R]20 ) +7.1 (c 1, CHCl3); 1H NMR δ
D

(Z)-3-p-Tolylsulfinylacrylonitrile
J . Org. Chem., Vol. 65, No. 23, 2000 7943
mmol) in CH2Cl2 was kept at 4 kbar for 7 days at room
temperature. When the reaction was completed, the crude
mixture was concentrated, and the residue was treated with
1:2 hexane-acetone, en d o-8A remaining insoluble as a white
solid. The mother liquors were evaporated and chromatogra-
phied (1:1 hexanes-ethyl acetate) to yield en d o-8A and
3-sulfenylacrilamide (9).
2.8 and 8.9), 6.57 (d, 1H, J ) 2.8), 6.32 (m, 1H), 3.77 (s, 3H),
3.01-2.77 (m, 6H), 2.51 (m, 1H), 2.45 (s, 3H), 1.96-1.83 (m,
2H); 13C NMR δ 159.0, 143.0, 138.0, 137.1, 132.1, 130.4, 125.2,
125.1, 125.0, 116.5, 115.1, 113.2, 113.1, 61.5, 55.2, 38.7, 32.5,
29.6, 27.6, 24.3, 21.5. Anal. Calcd for C23H23NO2S: C, 73.18;
H, 6.14; N, 3.71; S, 8.49. Found: C, 73.03; H, 6.12; N, 3.61; S,
8.44.
Meth od ii: In th e P r esen ce of Zn Br 2. To a solution of
ZnBr2 (337.8 mg, 1.5 mmol) in THF (0.4 mL), under argon at
room temperature, was added a solution of 1 (143.5 mg, 0.75
mmol) in CH2Cl2 (1 mL). The mixture was stirred for 1 h at
room temperature, and then a 1 M solution of Dane’s diene
(7)16 in benzene (1.5 mL, 1.5 mmol) was added. The reaction
mixture was kept at 4 kbar for 3 days or stirred at atmospheric
pressure for 7 days at room temperature. When the reaction
was completed, it was poured into water (10 mL), and the
aqueous layer was extracted with CH2Cl2 (3 × 8 mL). The
combined organic layers were dried (Na2SO4) and concen-
trated. The residue was treated as described above.
Ack n ow led gm en t. We thank Direccio´n General
Cient´ıfica y Te´cnica (Grants PB98-0078 and PB98-0102)
for financial support. One of us C.A. wishes to thank
Ministerio de Educacio´n y Ciencia for a grant.
Su p p or tin g In for m a tion Ava ila ble: IR and MS data and
copies of 1H NMR spectra of adducts en d o-2B, exo-5A, en d o-
5B, and en d o-6B; X-ray diagrams for compounds en d o-2A,
en d o-5A, and en d o-8A; crystal data and structure refinement
for compounds en d o-2A, en d o-5A, and en d o-8A including
atomic coordinates, isotropic and anisotropic displacement
parameters, and a listing of bond angles and bond lengths.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(1S,2S,10aS)-1,2,3,9,10,10a-Hexah ydr o-7-m eth oxy-2-[(R)-
p-tolylsu lfin yl]p h en a n th r en e-1-ca r bon itr ile (en d o-8A). It
was obtained from reaction of 1 with Dane’s diene. It was
crystallized from hexane-CH2Cl2 (white solid): mp 176-177
°C; [R]20 ) +138.4 (c 1, CHCl3); 1H NMR δ 7.64 and 7.39
D
(AA′BB′ system, 4H), 7.53 (d, 1H, J ) 8.9), 6.73 (dd, 1H, J )
J O000963G