Synthesis and dienophilic behavior of enantiomerically pure (E)-2-p-tolylsulfinylacrylonitrile derivatives

Article abstract of DOI:10.1016/S0957-4166(02)00540-2

The synthesis of (E)-3-formyl 2-sulfinylacrylonitrile 2 and its diethylacetal derivative 3, as well as their behavior as dienophiles in reactions with cyclopentadiene are reported. The acetal 3 evolved with high π-facial selectivity under Eu(fod)₃

Full text of DOI:10.1016/S0957-4166(02)00540-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2003–2010
Synthesis and dienophilic behavior of enantiomerically pure
(E)-2-p-tolylsulfinylacrylonitrile derivatives†
Jose´ L. Garc´ıa Ruano,* Lorena Gonza´lez Gutie´rrez, Ana M. Mart´ın Castro and Francisco Yuste*,‡
Departamento de Qu´ımica Orga´nica (C-I), Facultad de Ciencias, Universidad Auto´noma de Madrid, Cantoblanco ,
28049 Madrid, Spain
Received 10 July 2002; accepted 4 September 2002
Abstract—The synthesis of (E)-3-formyl 2-sulfinylacrylonitrile 2 and its diethylacetal derivative 3, as well as their behavior as
dienophiles in reactions with cyclopentadiene are reported. The acetal 3 evolved with high p-facial selectivity under Eu(fod)3
catalysis. The p-facial selectivity became almost complete after extended reaction times, which evidences that a retro Diels–Alder
reaction occurs. The endo/exo selectivity (ca. 80:20) was only moderate. The reactivity of the aldehyde 2 was higher but its
evolution was less stereoselective than that of 3, the endo/exo product ratio observed being close to 1. © 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
endo-selectivity was very high and in some cases almost
complete. The strong dipolar repulsion between the
cyano and sulfinyl groups, which restricts the confor-
mational equilibrium around the CꢀS bond, accounts
for these results. The excellent features of these acryl-
onitriles with the SOTol and CN groups in a cis
arrangement, led us to study the dienophilic behavior
of a new family of compounds, 2-p-tolylsulfinyl acryl-
onitriles, bearing both functional groups at the same
olefinic carbon, since the presumably strong dipolar
interactions between both geminal groups suggested
their highly stereoselective evolution in asymmetric
Diels–Alder reactions. Herein, we report a synthetic
sequence which affords the (E)-3-formyl and 3-
diethoxymethyl substituted 2-sulfinylacrylonitriles (2
and 3, respectively), and the behavior of these com-
pounds as dienophiles in their reaction with
cyclopentadiene.
The sulfinyl group has been shown to be an interesting
chiral inductor in asymmetric Diels–Alder reactions due
to its ability to differentiate between diastereotopic
faces of neighboring double bonds.1 Nevertheless, vinyl
sulfoxides only exhibit good features as chiral
dienophiles when additional activating groups are
attached to the double bond in order to increase its
dienophilic reactivity and simultaneously restrict the
conformational mobility about the CꢀS bond, which
also improves the stereoselectivity. In this sense, many
electron-withdrawing groups have been inserted into
vinyl sulfoxides, the alkoxycarbonyl ones (in both cis
and geminal positions) being the most widely used.1
However, in the last few years, the cyano group has
been described as an even more interesting group
regarding its effect in increasing the reactivity of vinyl
sulfoxides and the stereoselectivity of their reactions.
Therefore, (Z)-3-p-tolylsulfinylacrylonitriles have been
reported by our research group as the best monoacti-
vated vinyl sulfoxides in asymmetric Diels–Alder reac-
tions.2,3 They were found to react with cyclic and
acyclic dienes, and with furan with complete regioselec-
tivity and p-facial diastereoselectivity. Additionally, the
2. Results and discussion
Initially we focused our interest on the study of the
simplest members of this family, 3-alkyl substituted
2-p-tolylsulfinylacrylonitriles. However, despite many
attempts made to synthesize these compounds via
Knoevenagel4 or Peterson5 reaction, the yields were
rather low. Moreover, the preliminary Diels–Alder
reactions performed with the so obtained acrylonitriles
proved to be disappointing leading to sluggish complex
mixtures, maybe due to their ready tendency to poly-
merize. These results drew our attention to the synthesis
* Corresponding authors. E-mail: joseluis.garcia.ruano@uam.es
† Dedicated to the memory of Professor J. H. Rodr´ıguez Ramos, a
close friend and an outstanding chemist.
‡ Current address: Professor F. Yuste, Instituto de Qu´ımica, Universi-
dad Nacional Auto´noma de Me´xico, Circuito Exterior, Cd. Univer-
sitaria, Coyoaca´n 04510, Me´xico D.F.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00540-2

2004
J. L. Garc´ıa Ruano et al. / Tetrahedron: Asymmetry 13 (2002) 2003–2010
Scheme 1.
of 2-p-tolylsulfinylacrylonitriles bearing additional
groups at C-3 capable of stabilizing the dienophile
structure, such as the formyl group, which would also
increase the dienophilic reactivity, and its correspond-
ing diethylacetal which is presumably more stable.
The low stability of the resulting adducts prevented
their chromatographic separation as well as their stereo-
chemical assignment. Nevertheless, they could be iden-
tified by chemical correlation with the adducts derived
from compound 3 (vide infra).
The synthesis of the starting enantiomerically pure (S)-
3-formyl and 3-diethoxymethyl 2-sulfinylacrylonitriles 2
and 3 was achieved following the sequence depicted in
Scheme 1. It consisted initially of Knoevenagel conden-
sation of 2,2-diethoxy ethanal (prepared by mono-
acetalization of glyoxal6) with (R)-cyanomethyl p-tolyl
sulfoxide 17 in the presence of a catalytic amount of
piperidine in acetonitrile to give chiral vinyl sulfoxide 3
in 46% yield, which was almost quantitatively
hydrolyzed into the corresponding formyl derivative 2
in the presence of an excess of formic acid. The enan-
tiomeric purity (e.e. >98%) of 3 was determined by
NMR by using enantiopure 2,2,2-trifluoro-1-
(anthryl)ethanol8 as the chiral solvating agent.
The results obtained in reactions of cyclopentadiene
(excess) with the diethylacetal 3 in CH2Cl2 under ther-
mal and catalytic conditions are collected in Table 2.
All four possible adducts were formed under thermal
1
conditions and their ratio was established from the H
NMR spectra of the reaction crudes (entry 1). The
reaction evolved with good p-facial selectivity but mod-
erate endo-selectivity. The addition of ZnBr2 scarcely
modified both the reactivity and the stereoselectivity
(entries 2–4), whereas the use of BF3 as the catalyst
caused the decomposition of the starting material and/
or the resulting adducts to afford a complex mixture
(entry 5). The best results were obtained when the
reactions were conducted in the presence of Eu(fod)3
(entries 6–21). The number of equivalents of the cata-
lyst had a small influence (entries 6–9), with a slight
decrease in the endo/exo ratio at lower catalyst load-
ings. However, the p-facial selectivity, which was higher
than that observed under thermal conditions, remained
practically unaltered. Unexpectedly, both selectivities
slightly decreased at 0°C (entry 10), but significantly
increased at −20°C (entry 11), mainly the p-facial selec-
tivity, which was almost complete under these condi-
tions. A similar facial selectivity was observed under
conditions of entry 12,9 but the endo selectivity was
slightly lower presumably as a consequence of the
smaller number of equivalents of the catalyst.
The results of the Diels–Alder reaction of dienophile 2
at different temperatures are collected in Table 1. Ini-
tially, all attempts to perform the cycloaddition reac-
tion of 2 with cyclopentadiene at room temperature
were unsuccessful because they afforded complex crude
mixtures due to decomposition of the reactants. When
we realized that this was the reason for the poor results
(once we had observed that reaction conditions for 3
were milder), the reactions of 2 were performed at
lower temperatures with the results indicated in Table 1
(entries 2 and 3). Complete transformation of the start-
ing dienophile was detected after short reaction times.
The observed p-facial selectivity was good but the
endo–exo selectivity was scarce, neither of them experi-
encing any improvement on lowering the temperature
(vide infra). These results could not be modified by acid
catalysis, since 2 rapidly decomposed in the presence of
Lewis acids.
As the reaction times described in entries 11 and 12
were significantly longer than those in other cases stud-
ied, we decided to investigate the influence of this
parameter on the composition of the crude reaction
products. In the absence of any catalyst, the reactions
Table 1. Reaction of 2 with cyclopentadiene at different temperatures
Entry
T (°C)
t (h)
4/5/6
p-facial selectivity
endo–exo selectivity
1
2
3
20
−20
−78
0.5
0.5
1
Complex mixture
44/13/43
42/13/45
87/13
87/13
57/43
55/45

J. L. Garc´ıa Ruano et al. / Tetrahedron: Asymmetry 13 (2002) 2003–2010
2005
Table 2. Reaction of 3 with cyclopentadiene under thermal and catalytic conditions
Entry
Lewis acid (equiv.)
T (°C)
t (h)
7/8/9/10 ratioa
p-Facial selectivity
endo–exo Ratio
1
2
3
4
5
6
7
8
20
20
20
0
20
20
20
20
20
5
5
5
24
1
1
1
1
1
5
48
24
1.5
17
24
42
66
17
24
42
66
3.5
45
68
60/10/24/6
61/12/20/7
61/9/23/7
62/9/25/4
Complex mixture
74/3/17/6
73/3/18/6
70/4/21/5
68/4/24/4
64/6/24/6
76/4/20/–
70/0/28/2
66/4/24/6
62/8/26/4
71/traces/23/6
72/traces/22/6
72/–/22/–
84/16
81/19
84/16
87/13
70/30
73/27
70/30
71/29
ZnBr2 (3.0)
ZnBr2 (4.0)
ZnBr2 (3.0)
BF3 (1.2)
Eu(fod)3 (6.0)
Eu(fod)3 (4.0)
Eu(fod)3 (2.5)
Eu(fod)3 (1.5)
Eu(fod)3 (4.0)
Eu(fod)3 (4.0)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
Eu(fod)3 (1.5)
91/9
91/9
91/9
92/8
88/12
96/4
98/2
90/10
88/12
94/6
77/23
76/24
74/26
72/28
70/30
80/20
70/30
70/30
70/30
71/29
72/28
72/28
76/24
73/27
76/24
74/26
72/28
70/30
67/33
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0
−20
−20
rt
rt
rt
rt
rt
94/6
100/0
94/6
−20
−20
−20
−20
40
73/3/21/3
73/traces/23/4
76/traces/24/traces
74/–/26/–
59/13/22/6
62/8/23/7
98/2
\98/B2
100/0
81/19
85/15
86/14
40
40
61/6/25/8
a Determined by integration of well-separated signals on the 1H NMR spectra of the reaction crudes.
conducted in refluxing CH2Cl2 (entries 22–24) did not
show any clear variation in their results, with the
reaction time exerting a small influence in the reaction
course. However, in the presence of Eu(fod)3 the
adducts 8 and 10 completely disappeared from the
reaction mixture as the reaction time was longer, which
increased the p-facial selectivity. It became almost com-
plete after 3 days and the adducts resulting from the
endo and exo approaches of the cyclopentadiene to the
same face of the dienophile were the sole products
obtained under these conditions. This result suggested a
thermodynamic equilibrium between the adducts as a
consequence of a retro Diels–Alder process. The endo/
exo ratio was moderate, increasing slightly as the tem-
perature was lowered.
NMR spectrum,11 which indicated that both com-
pounds are enantiomers (7 and 8 have the same
configuration at the sulfinyl sulfur). This allowed us to
unequivocally establish the stereochemistry of the
adduct 8 as endo (Scheme 2). Sulfones 12, resulting
from the oxidation of 9 and 10, showed different NMR
parameters to those of 11, which pointed to the fact
that 9 and 10 were exo adducts. Finally, the stereo-
chemistry of the major exo adduct 9 was tentatively
assigned assuming that it resulted from attack of the
diene to the same face resulting in the formation of the
major endo adduct 7. These stereochemical predictions
1
were confirmed by H NMR analysis, mainly by the
NOE values observed12 for the three isolated adducts
7–9 and the chemical shifts of the proton at C-3, which
appear at higher field for compounds 8 and 10 than
their respective isomers 8 and 10 (see Section 3), which
may be due to the anisotropic effect of the aromatic
ring (see Fig. 2).
Only the adducts 7, 8 and 9 could be isolated by flash
column chromatography and were fully characterized.
1
The H NMR data of the fourth minor adduct 10 were
deduced from the spectra of mixtures containing it. The
absolute configuration and the endo structure of the
major adduct 7 were unequivocally determined by X-
ray diffraction analysis (Fig. 1).10
The configurational assignment of the adducts 4–6 was
established by independent hydrolysis of the isolated
adducts 7–9 (previously characterized) with formic acid,
to give the corresponding aldehydes (Scheme 3).
In order to assign the configuration of compound 8 it
was transformed into the sulfone 11 by treatment with
m-CPBA. When 7 was oxidized under similar condi-
tions, the resulting sulfone exhibited an identical 1H
The stereochemical results observed in reactions of the
acetal 3 can be explained by assuming the endo and exo
approaches of cyclopentadiene to the less hindered

2006
J. L. Garc´ıa Ruano et al. / Tetrahedron: Asymmetry 13 (2002) 2003–2010
Figure 1. X-Ray structure for adduct endo-7.
Scheme 2.
adducts (Fig. 2) supports the preference of the depicted
rotamers with the sulfinyl oxygen deshielding such
protons.
lower face of the dienophile adopting the s-trans
arrangement are favored (Fig. 2), yielding endo-7 and
exo-9 adducts as the major products. A strong NOE
(6.72) between the olefinic proton and the ortho protons
of the p-tolyl group for compound 3 supports the
preference of the conformation depicted in Fig. 2. In
the absence of catalyst, it can be explained by assuming
the stabilizing electrostatic interaction of the negatively
charged sulfinyl oxygen and the positively charged
nitrile carbon. The association of Eu(fod)3 to the sulfi-
nyl oxygen, strongly increasing its relative size, rein-
force this preference from a steric point of view.
Moreover, the higher stability of compounds endo-7
and exo-9, which may be responsible for the complete
p-facial selectivity observed under the conditions favor-
ing a thermodynamic control, could be due to the
interactions between the sulfinyl oxygen with the pro-
ton at C-3 destabilizing the adducts endo-8 and exo-10
(see Fig. 2) in conformations exhibiting the bulkier tolyl
group in the sterically most favored arrangement. The
higher l shift of the protons at C-3 in the minor
Figure 2. Favored approaches of the cyclopentadiene to the
most stable rotamer of compound 3.

J. L. Garc´ıa Ruano et al. / Tetrahedron: Asymmetry 13 (2002) 2003–2010
2007
Scheme 3.
Finally, the low endo/exo selectivity observed in the
reactions of compound 2 was completely unforeseen.
Taking into account that the acetal 3 preferentially
evolved into the endo adduct, we expected that chang-
ing the CH(OEt)2 group to an aldehyde, with stronger
endo orientating character, would increase the endo/exo
ratio. The observed opposite result is not easy to
explain, mainly after having looked unsuccessfully for
evidence proving that a retro Diels–Alder process was
also taking place in these reactions.13
adducts. The endo/exo selectivity is moderate and simi-
lar to that observed from acrylates. The synthesis of
other sulfinylacrylonitriles in order to improve the
dienophilic features of the vinyl sulfoxides is currently
in progress.
It is interesting to compare these results with those
obtained in the reactions of 2-p-tolylsulfinylacrylates.14
The reactivity of the sulfinyl ester lacking alkyl sub-
stituents is similar to that of compound 3. Bearing in
mind the negative influence of the diethoxymethyl
group on the reactivity (mainly due to its steric interac-
tions with the diene), we can conclude that sulfinyl
nitriles are more reactive than their alkoxycarbonyl
counterparts. This conclusion is supported by the
results obtained with 3-p-tolylsulfinyl butenolides15 and
their 5-alkoxy derivatives,16 exhibiting a structure of
2-sulfinylacrylate with alkyl substituents at the double
bond. These compounds were clearly less reactive than
3 and required several days or the use of high pressure
for their reactions to reach completion. With respect to
the stereoselectivity, nitriles and acrylates exhibit the
opposite facial stereoselection in the absence of cata-
lysts. As a consequence, the 2-p-tolylsulfinylacrylates
evolve mainly through the electrostatically most stable
conformations, with the sulfinyl oxygen in the s-cis
arrangement,14 whereas the corresponding nitriles
evolve through the s-trans conformations shown in Fig.
2. In the case of acrylates and lactones, the use of ZnX2
as catalysts led to inversion of the facial selectivity and
strongly increased the reactivity as a consequence of the
formation of a chelated species, whereas these effects
are less significant in nitriles because chelated species
can not form due to the linear structure of the cyano
group (Scheme 4).
Scheme 4.
3. Experimental
3.1. General methods
All reactions were carried out in flame dried glassware
under argon atmosphere. Flash chromatography was
performed with silica gel 60 (230–400 mesh ASTM) and
silica gel F254 plates were used for preparative TLC.
Melting points were determined in a Gallenkamp
apparatus in open capillary tubes and are uncorrected.
The optical rotations were measured at room tempera-
ture (20–23°C) using a Perkin–Elmer 241 MC polarime-
ter (concentration in g/100 mL). NMR spectra were
determined in CDCl3 solutions unless otherwise indi-
1
cated at 200 (or 300) and 50.3 (or 75.5) MHz for H
and 13C NMR, respectively. J values are given in hertz.
All described compounds were over 97% pure by NMR
analysis.
3.2. (2E,SS)-4,4-Diethoxy-2-[(4-methylphenyl)sulfinyl]-
but-2-enenitrile, 3
In summary, we have described the synthesis and Diels–
Alder reactions of cyclopentadiene of the first hitherto
reported enantiomerically pure 2-p-tolylsulfinyl acryl-
onitriles 2 and 3. The reactivity of these compounds is
clearly higher than that observed for the corresponding
acrylates, and the p-facial selectivity is high and can
become complete by increasing the reaction times, due
to the occurrence of a retro Diels–Alder process, which
leads to formation of the thermodynamically favored
To a solution of 17 (238 mg, 1.33 mmol, 1 equiv.) in
anhydrous CH3CN (10 mL) under argon, were sequen-
,
tially added 4 A molecular sieves (0.5 g), 2,2-diethoxy
ethanal6 (473 mg, 3.58 mmol, 2.7 equiv.) and piperidine
(28 mg, 33 mL, 0.33 mmol, 0.25 equiv.). The resulting
mixture was stirred for 22 h at room temperature. The
mixture was filtered through a Celite pad and treated
with 1% HCl (10 mL). The aqueous layer was extracted

2008
J. L. Garc´ıa Ruano et al. / Tetrahedron: Asymmetry 13 (2002) 2003–2010
with CH2Cl2 (2×30 mL). The organic layers were com-
bined, dried (Na2SO4) and evaporated, then purified by
flash chromatography (ethyl acetate–hexane 15:85),
(yield 46%, orange oil); [h]D +189.9 (c 1.0, chloroform);
lH 7.58 and 7.36 (AA%BB% system, 4H), 7.16 (d, 1H, J
5.2), 5.31 (d, 1H, J 5.2), 3.73–3.51 (m, 4H), 2.42 (s, 3H),
1.23 (t, 3H, J 7.0), 1.22 (t, 3H, J 7.0); lC 144.9 (2C),
143.6, 137.4, 130.4 (2C), 126.2, 125.2, 111.1, 98.1, 62.3,
62.2, 21.5, 14.9 (2C); IR: 2979, 2930, 2219, 1596, 1493,
1445, 1373, 1337, 1064, 811; MS (EI) 293 (10) M+, 276
(12), 248 (10), 219 (30), 200 (62), 172 (16), 139 (89), 103
(100), 91 (44), 75 (86); HRMS (EI): C15H19NO3S
requires 293.1086. Found: 293.1079.
was extracted with CH2Cl2 (3×4 mL). The organic layer
was dried (Na2SO4) and concentrated.
3.4.4.
methylphenyl)sulfinyl]bicyclo[2.2.1]hept-5-ene-2-carboni-
trile, endo-7. Prepared by reaction of with
(1S,2S,3R,4R,SS)-3-(Diethoxymethyl)-2-[(4-
3
cyclopentadiene following method B. It was purified by
flash chromatography (ethyl acetate–hexane, 1:4) and
crystallized from ethyl acetate–hexane (yield 59%), mp
82–83°C (white solid); [h]D +35.1 (c 1.12, chloroform);
lH 7.69 and 7.34 (AA%BB% system, 4H), 6.47 (dd, 1H, J
3.0 and 5.7), 6.30 (dd, 1H, J 3.2 and 5.7), 3.96 (d, 1H,
J 9.1), 3.62–3.45 (m, 4H), 3.25–3.15 (m, 1H), 3.11–3.06
(m, 1H), 2.73 (dd, 1H, J 3.2 and 9.1), 2.41 (s, 3H) 2.08
(dt, 1H, J 1.4 and 9.5), 1.56 (dt, 1H, J 1.6 and 9.5), 1.20
(t, 3H, J 7.1), 0.75 (t, 3H, J 7.1); lC 143.1, 140.6, 135.7,
135.1, 129.6 (2C), 126.3 (2C), 116.4, 103.8, 66.9, 64.5,
60.8, 50.1 (2C), 45.3, 45.2, 21.5, 15.5, 14.5; IR 3027,
2906, 2230, 1659, 1598, 1494, 1454, 1373, 1334, 1260,
1059, 814, 735; MS (EI) 359 (3) M+, 220 (23), 174 (30),
139 (68), 118 (49), 91 (100), 66 (58); HRMS (EI):
C20H25NO3S requires 359.1555. Found: 359.1547.
3.3. (2E,(SS)-2-[(4-Methylphenyl)sulfinyl]-4-oxobut-2-
enenitrile, 2
To 3 (260 mg, 0.89 mmol, 1 equiv.) under argon was
added formic acid (98%, 1.96 g, 1.6 mL, 42.66 mmol, 50
equiv.) and the resulting mixture was stirred for 1 h at
room temperature. The mixture was treated with H2O
(20 mL). The aqueous layer was extracted with CH2Cl2
(2×40 mL) and the organic layer was treated with
aqueous NaHCO3 (10 mL), dried (Na2SO4) and evapo-
rated (yield 98%, brown oil); [h]D +510 (c 0.12, chloro-
form); lH 7.04 (d, 1H, J 7.0), 7.62 and 7.41 (AA%BB%
system, 4H), 7.38 (d, 1H, J 6.7), 2.45 (s, 3H); lC 185.7,
144.7, 142.0, 138.2, 135.7, 130.9 (2C), 125.4 (2C), 110.2,
21.6. IR: 3041, 2924, 2221, 1696, 1595, 1085, 811; MS
(EI) 219 (3) M+, 203 (3), 139 (100), 124 (26), 91 (73), 77
(22); HRMS (EI): C11H9NO2S requires 219.0354.
Found: 219.0347.
3.4.5.
methylphenyl)sulfinyl]bicyclo[2.2.1]hept-5-ene-2-carboni-
trile, endo-8. Prepared by reaction of with
(1R,2R,3S,4S,SS)-3-(Diethoxymethyl)-2-[(4-
3
cyclopentadiene following method B. It was purified by
flash chromatography (ethyl acetate–hexane, 1:4) (yield
5%, oil); [h]D +96.2 (c 0.5, chloroform); lH 7.64 and
7.32 (AA%BB% system, 4H), 6.52 (dd, 1H, J 2.8 and 5.7),
6.34 (dd, 1H, J 3.0 and 5.7), 3.92 (d, 1H, J 8.5),
3.63–3.49 (m, 2H), 3.48–3.40 (m, 1H), 3.35–3.38 (m,
1H), 3.21–3.11 (m, 1H), 3.08–3.04 (m, 2H), 2.41 (s, 3H),
2.15 (dt, 1H, J 1.4 and 9.3), 1.48 (dt, 1H, J 1.6 and 9.3),
1.19 (t, 3H, J 7.1), 0.76 (t, 3H, J 7.1); lC 143.0, 141.4,
136.8, 134.9, 129.3 (2C), 126.5 (2C), 117.0, 103.3, 65.6,
64.2, 59.8, 53.3, 47.2, 45.1, 44.7, 21.5, 15.4, 14.5; IR
3064, 2978, 2928, 2228, 1676, 1597, 1454, 1374, 1152,
1060, 810; MS (EI) 359 (3) M+, 220 (12), 174 (14), 139
(39), 118 (29), 91 (100), 66 (75); HRMS (EI):
C20H25NO3S requires 359.1555. Found: 359.1549.
3.4. Diels–Alder cycloadditions
3.4.1. Method A: Thermal conditions. To a solution of 2
or 3 (1 mmol) in CH2Cl2 (3 mL) was added cyclopenta-
diene (714 mL, 8 mmol). Reaction times and tempera-
tures are indicated in Tables 1 and 2, respectively.
When the reaction was complete, the crude mixture was
concentrated, and the residue was purified by flash
chromatography (ethyl acetate–hexane, 1:4).
3.4.2. Method B: In the presence of Eu(fod)3. A solution
of 3 (293 mg, 1 mmol) and Eu(fod)3 (1.56 g, 1.5 mmol)
in CH2Cl2 (4 mL), under argon, was stirred at room
temperature for 1 h. Then cyclopentadiene (714 mL, 8
mmol) was added and the mixture was stirred at the
temperature described in Table 2 for the time indicated
in each case. Water (4 mL) was added, and the mixture
was extracted with CH2Cl2 (3×4 mL). The organic layer
was washed with 10% HCl (10 mL), dried (Na2SO4),
and concentrated.
3.4.6.
methylphenyl)sulfinyl]bicyclo[2.2.1]hept-5-ene-2-carboni-
trile, exo-9. Prepared by reaction of with
(1R,2S,3R,4S,SS)-3-(Diethoxymethyl)-2-[(4-
3
cyclopentadiene following method B. It was purified by
flash chromatography (ethyl acetate–hexane, 1:4) (yield
20%, oil); [h]D +139.8 (c 1.07, chloroform); lH 7.65 and
7.32 (AA%BB% system, 4H), 6.52–6.49 (m, 2H), 4.06 (d,
1H, J 6.9) 3.68–3.65 (m, 1H), 3.64–3.42 (m, 2H), 3.42–
3.34 (m, 1H), 3.21–3.13 (m, 1H), 3.14–3.12 (m, 1H),
2.41 (s, 3H), 1.97 (dt, 1H, J 2.0 and 10.1), 1.80 (dd, 1H,
J 2.0 and 6.9), 1.75 (dc, 1H, J 2.0 and 9.7), 1.82 (t, 3H,
J 7.0), 0.71 (t, 3H, J 7.0); lC 143.2, 140.5, 136.7, 134.0,
129.5 (2C), 126.4 (2C), 116.9, 103.3, 70.0, 64.8, 62.6,
53.1, 48.0, 46.3, 44.7, 21.5, 15.3, 14.6; IR 2977, 2229,
1644, 1455, 1059, 811, 746. MS (EI) 359 (2) M+, 220
(10), 174 (21), 154 (100) 139 (36), 126 (23), 91 (65), 75
(49); HRMS (EI): C20H25NO3S requires 359.1555.
Found: 359.1547.
3.4.3. Method C: In the presence of ZnBr2. To a solution
of 3 (293 mg, 1 mmol) in CH2Cl2 (4 mL) was added
ZnBr2 (675 mg, 3.0 mmol) in THF (0.5 mL) under
argon, and the mixture was stirred at room temperature
for 1 h. Then cyclopentadiene (714 mL, 8 mmol) was
added and the reaction mixture was stirred at the
temperature described in Table 2 for the time indicated
in each case. Water (4 mL) was added, and the mixture

J. L. Garc´ıa Ruano et al. / Tetrahedron: Asymmetry 13 (2002) 2003–2010
2009
3.4.7.
methylphenyl)sulfinyl]bicyclo[2.2.1]hept-5-ene-2-carboni-
trile, exo-10. Prepared by reaction of with
(1S,2R,3S,4R,SS)-3-(Diethoxymethyl)-2-[(4-
115.3, 69.3, 54.2, 53.4, 52.6, 47.5, 44.4, 21.5; IR 2924,
2230, 1728, 1083, 1062, 812. MS (EI) 285 (1) M+, 214
(1), 149 (2), 139 (57), 126(2), 116 (35), 91 (100), 77 (25),
66 (89). C16H15NO2S requires 285.0823. Found:
285.0827.
3
cyclopentadiene following method B. It was obtained
along with endo-7 by flash chromatography (ethyl acet-
ate–hexane, 1:4). Data deduced from an endo-7/exo-10
mixture: lH 7.66 and 7.37 (AA%BB% system, 4H), 6.53
(dd, 1H, J 3.2 and 5.6), 6.21 (dd, 1H, J 2.8 and 5.6),
4.58 (d, 1H, J 4.1), 3.86–3.45 (m, 5H), 2.89–2.87 (m,
1H), 2.46 (dd, 1H, J 2.0 and 4.2), 2.43 (s, 3H), 2.14–
2.12 (m, 1H), 1.59 (dq, 1H, J 2.0 and 9.7), 1.21 (t, 3H,
J 7.0), 1.20 (t, 3H, J 7.0); lC 143.1, 141.5, 135.7, 132.3,
129.5 (2C), 125.4 (2C), 116.4, 103.5, 69.6, 63.7 (2C),
51.9, 47.8 (2C), 43.8, 21.5, 15.2, 14.9.
Acknowledgements
Financial support from Direccio´n de Investigacio´n
Cient´ıfica y Te´cnica CAICYT (BQU2000-0246) is
gratefully acknowledged. L.G.G. thanks Consejo
Nacional de Ciencia y Tecnolog´ıa (CONACYT-Me´x-
ico) for a fellowship. F.Y. thanks Direccio´n General de
Universidades del Ministerio de Educacio´n, Cultura y
Deporte from Spain for a grant (SAB1999-0161).
3.5. Hydrolysis of diethoxymethyl cycloadducts into
formyl cycloadducts; general procedure
A solution of adduct (1 mmol) and an excess of formic
acid (2 mL) was stirred under argon at room tempera-
ture for 1.5 h. Water (2 mL) was added and the mixture
was extracted with CH2Cl2 (3×4 mL). The organic
layers were combined and treated with aqueous
NaHCO3 (10 mL). The organic layer was dried
(Na2SO4) and evaporated.
References
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, 1717–1760; (c) Solladie, G.; Carren˜o, M. C. In
Organosulphur Chemistry Synthetic Aspects; Page, P. C.
B., Ed.; Academic Press: New York, 1995; Chapter 1, pp.
1–47; (d) Jurczak, 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, 1339–1367.
2. Garc´ıa Ruano, J. L.; Esteban Gamboa, A.; Mart´ın
Castro, A. M.; Rodr´ıguez Ramos, J. H.; Lo´pez-Solera,
M. I. J. Org. Chem. 1998, 63, 3324–3332.
3. Garc´ıa Ruano, J. L.; Alemparte, C.; Mart´ın Castro, A.
M.; Adams, H.; Rodr´ıguez Ramos, J. H. J. Org. Chem.
2000, 65, 7938–7943.
3.5.1. (1S,2S,3R,4R,SS)-3-Formyl-2-[(4-methylphenyl)-
sulfinyl]bicyclo[2.2.1]hept-5-ene-2-carbonitrile,
endo-4.
Obtained by reaction of endo-7 with formic acid (yield
98%), mp 126–127°C (white solid); [h]D +136.4 (c 0.26,
chloroform); lH 8.93 (d, 1H, J 2.0), 7.73 and 7.40
(AA%BB% system, 4H), 6.54 (dd, 1H, J 2.9 and 5.6), 6.39
(dd, 1H, J 3.2 and 5.6), 3.75 (d, 1H, J 1.5), 3.41–3.38
(m, 1H), 2.95 (t, 1H, J 2.3), 2.44 (s, 3H), 2.05 (d, 1H, J
10.0), 1.75 (d, 1H, J 10.3); lC 197.9, 144.3, 139.8, 135.5,
135.1, 130.2 (2C), 125.7, 125.1, 114.8, 67.5, 56.6, 49.8,
46.0, 45.3, 21.6; IR 2989, 2232, 1729, 1453, 1336, 1088,
1065, 818. MS (EI) 285 (3) M+, 246 (1), 214 (2), 149 (2),
139 (46), 126(2), 116 (49), 91 (100), 77 (23), 66 (58).
HRMS (EI): C16H15NO2S requires 285.0823 Found:.
285.0836.
4. Hiroi, K.; Umemura, M. Tetrahedron 1993, 49, 1831–
1840.
3.5.2. (1R,2R,3S,4S,SS)-3-Formyl-2-[(4-methylphenyl)-
5. Han, D. I.; Oh, D. Y. Synth. Commun. 1988, 18, 2111–
2116.
6. Sangsari, F. H.; Chastrette, F.; Chastrette, M. Synth.
Commun. 1988, 18, 1343–1348.
7. Numata, T.; Itoh, O.; Yoshimura, T.; Oae, S. Bull. Chem.
Soc. Jpn. 1983, 56, 257–265.
sulfinyl]bicyclo[2.2.1]hept-5-ene-2-carbonitrile,
endo-5.
Obtained by reaction of endo-8 with formic acid (yield
80%, oil). It partially decomposed on purification. lH
8.99 (t, 1H, J 1.0), 7.68 and 7.39 (AA%BB% system, 4H),
6.59 (dd, 1H, J 2.8 and 5.4), 6.34 (dd, 1H J 3.2 and
5.4), 3.57 (t, 1H, J 5.6), 3.45 (dd, 2H, J 1.4 and 3.2),
3.39–3.34 (m, 1H), 2.44 (s, 3H), 2.40 (d, 1H, J 11.5),
2.16 (dt, 1H, J 1.6 and 9.5); lC 198.4, 144.1, 141.3,
136.0, 135.6, 129.9 (2C), 125.6 (2C), 115.9, 65.7, 54.9,
51.9, 45.1, 44.3, 21.6.
8. Pirkle, W. H.; Beare, S. D. J. Am. Chem. Soc. 1969, 91,
5150–5155.
9. The 1H NMR spectra of the crude product obtained
under these conditions do not reveal the presence of
compound 10, but a small amount of it was isolated by
chromatography—as a mixture of 7 and 10—and there-
fore, it has been included in entry 12 (Table 2).
10. The authors have deposited the atomic coordinates for 7
with the Cambridge Crystallographic Data Centre
(Deposit No. CCDC 188910). The coordinates can be
obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK.
3.5.3. (1R,2S,3R,4S,SS)-3-Formyl-2-[(4-methylphenyl)-
sulfinyl]bicyclo[2.2.1]hept-5-ene-2-carbonitrile,
exo-6.
Obtained by reaction of exo-9 with formic acid; mp
132–133°C (white solid); [h]D +273.4 (c 0.53, chloro-
form); lH 9.00 (s, 1H), 7.67 and 7.37 (AA%BB% system,
4H), 6.56–6.49 (m, 2H), 3.78 (sp, 1H, J 1.6), 3.40 (sp,
1H, J 1.6), 2.42 (s, 3H), 2.22 (t, 1H, J 1.8), 1.88 (dq,
1H, J 1.8 and 10.1), 1.80 (dt, 1H, J 1.6 and 10.1); lC
196.8, 144.2, 139.7, 135.9, 134.2, 130.2, 125.4 (2C),
11. The reaction was carried out in an NMR tube in order to
1
be monitored by H NMR. A solution of 0.57 mmol of

2010
J. L. Garc´ıa Ruano et al. / Tetrahedron: Asymmetry 13 (2002) 2003–2010
m-CPBA in 0.3 mL of CDCl3 was added into a solution
1H), 2.56 (dd, 1H, J 2.2 and 7.5), 2.45 (s, 3H), 1.96 (d,
1H, J 9.7), 1.66 (d, 1H, J 9.7), 1.22 (t, 3H, J 7.1), 0.81 (t,
3H, J 7.1).
of 0.38 mmol of adduct in 0.3 mL of CDCl3 until the
1
signals of the starting material were not observed by H
NMR. No sulfone was isolated. 1H NMR are those
deduced from the spectra of the reaction mixtures.
(1S,2S,3R,4R)- and (1R,2R,3S,4S)-3-(diethoxymethyl)-2-
[(4-methylphenyl) sulfonyl]bicyclo[2.2.1]hept-5-ene-2-car-
bonitrile, 11 were obtained from 7 and 8, respectively: lH
7.87 and 7.35 (AA%BB% system, 4H), 6.53 (dd, 1H, J 2.4
and 5.5), 6.38 (dd, 1H, J 3.2 and 5.5), 3.91 (d, 1H, J 8.9),
3.85–3.83 (m, 1H), 3.65–3.56 (m, 2H), 3.49–3.37 (m, 2H),
3.18–3.05 (m, 2H) 2.44 (s, 3H), 2.41 (d, 1H, J 9.7), 1.55
(d, 1H, J 9.5), 1.22 (t, 3H, J 7.1), 0.62 (t, 3H, J 7.1).
(1R,2S,3R,4S)- and (1S,2R,3S,4R)-3-(Diethoxymethyl)-2-
[(4-methylphenyl) sulfonyl]bicyclo[2.2.1]hept-5-ene-2-car-
bonitrile, 12 were obtained from 9 and 10, respectively:
lH 7.84 and 7.36 (AA%BB% system, 4H), 6.48 (dd, 1H, J
3.4 and 5.7), 6.29 (dd, 1H, J 3.0 and 5.7), 4.44 (d, 1H, J
7.5), 3.73–3.49 (m, 4H), 3.42–3.25 (m, 2H), 3.15–3.10 (m,
12. Double Pulsed Field Gradient Echo-DPFGS (Bruker
DRX-500). NOE values for endo-7: 3.5% [C(3)HꢀC(7)H];
endo-8:
2.7%
[C(3)HꢀC(7)H];
exo-9:
1.8%
[C(3)HꢀC(5)H].
13. All reactions performed for longer reaction times or
those consisting in treating any of the adducts 4–6
under the reaction conditions optimized for the cycload-
dition, did not give any evidence of retro Diels–Alder
reaction.
14. (a) Arai, Y.; Kuwayama, S.; Takeuchi, Y.; Koizumi, T. J.
Tetrahedron Lett. 1985, 26, 6205–6208; (b) Chau, T.-Y.;
Lin, H.-C.; Hu, W. Synth. Commun. 1996, 1867–1874.
15. Carretero, J. C.; Garc´ıa Ruano, J. L.; Mart´ın Cabrejas,
L. Tetrahedron 1997, 53, 14115–14126.
16. Carretero, J. C.; Garc´ıa Ruano, J. L.; Lorente, A.; Yuste,
F. Tetrahedron: Asymmetry 1993, 4, 177–193.