Maleimide cycloadditions by sulfinyldienes: Is the sulfur configuration the only controller of the diastereofacial selectivity?

Article abstract of DOI:10.1016/j.tet.2005.05.089

Cyclohexylsulfinyl-3-methyl-1,3-butadienes 5, 6, and 1-[1- (cyclohexylsulfinyl)ethenyl]cyclohexene (7), easily prepared from cyclohexanethiol (1) via transient cyclohexanesulfenic acid (4), were reacted with N-phenylmaleimide under different conditions, at normal and high pressure. The stereochemical outcome of these cycloadditions contributes a better understanding of the relationships among different factors controlling facial diastereoselection.

Full text of DOI:10.1016/j.tet.2005.05.089

Tetrahedron 61 (2005) 7719–7726
Maleimide cycloadditions by sulfinyldienes: is the sulfur
configuration the only controller of the diastereofacial selectivity?
b
c
Maria C. Aversa,a Anna Barattucci,a Paola Bonaccorsi,a, Cristina Faggi, Eszter Gacs-Baitz,
*
Assunta Marrocchi,d Lucio Minutid, and Aldo Taticchi
d
*
a
`
Dipartimento di Chimica organica e biologica, Universita degli Studi di Messina, Salita Sperone 31 (vill. S. Agata), 98166 Messina, Italy
b
`
Centro interdipartimentale di Cristallografia, Polo Scientifico, Universita degli Studi di Firenze, via della Lastruccia 13,
50019 Sesto Fiorentino, Firenze, Italy
cCentral Institute for Chemistry, Hungarian Academy of Sciences, PO Box 17, H-1525 Budapest, Hungary
d
`
Dipartimento di Chimica, Universita degli Studi di Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy
Received 24 March 2005; revised 16 May 2005; accepted 26 May 2005
Available online 22 June 2005
Abstract—Cyclohexylsulfinyl-3-methyl-1,3-butadienes 5, 6, and 1-[1-(cyclohexylsulfinyl)ethenyl]cyclohexene (7), easily prepared from
cyclohexanethiol (1) via transient cyclohexanesulfenic acid (4), were reacted with N-phenylmaleimide under different conditions, at normal
and high pressure. The stereochemical outcome of these cycloadditions contributes a better understanding of the relationships among
different factors controlling facial diastereoselection.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In the last 20 years a number of articles have dealt with the
synthetic scope and limitations of the sulfinyl group acting
as stereodifferentiating element in Diels–Alder (DA)
cycloadditions.1 The electronic and structural features of
the chiral sulfur atom, bearing the strongly electron-
withdrawing sulfinyl oxygen, the sterically undemanding
lone pair, and the alkyl or aryl group, assure, in almost all
cases, very good stereoselection results. In particular, the
stereochemical behaviour of sulfinyl dienes, in which the
sulfoxide sulfur is directly linked to the diene skeleton,
depends upon the position of the sulfoxide moiety within the
diene, the electronic and steric nature of dienophile, and
eventually the involvement of a catalyst in the cyclo-
addition. It has been frequently observed that dienophiles
such as maleimides approach 2-sulfinyl dienes from their
less hindered and more nucleophilic face (the one bearing
the electronic lone pair) with the sulfinyl group adopting a
conformation along the C(diene)–S bond in which the
electrostatic repulsions between the sulfinyl oxygen and the
heteroatoms of the dienophile are minimised (A in Fig. 1).2
Figure 1. Favoured endo-approaches of maleimides in Diels–Alder
reactions with sulfinyl dienes.
The presence of a catalyst, able to link the basic centres of
the two reagents, changes the conformational preference
of the diene to allow this association (B in Fig. 1). In the
less reactive 1-sulfinyl dienes the favoured approach of
maleimide takes place again from the less hindered face
of the diene that adopts a conformation exhibiting the
greatest distance between the oxygen atoms of diene and
dienophile (C in Fig. 1).3
Table 1 illustrates the preferred diene face for dienophile
endo-approach in uncatalyzed cycloadditions of several
2-sulfinyl dienes with maleimides. We have chosen to
tabulate all the literature data corroborated by X-ray
analysis of the major (or unique) cycloadduct. In order to
facilitate the reading of the paper, the sulfur CIP descriptors
have been converted into sulfur pseudo-descriptors (pR or
pS, column 6 in Table 1) obtained by assigning arbitrarily
Keywords: Cyclohexylsulfinyl dienes; Diastereofacial selectivity; Diels–
Alder cycloadditions; N-Phenylmaleimide.
*
Corresponding authors. Tel.: C39 090 6765187; fax: C39 090 393895
(P.B.); tel.: C39 075 5855545; fax: C39 075 5855560 (L.M.);
e-mail addresses: paolab@isengard.unime.it; lucio@unipg.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.089

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M. C. Aversa et al. / Tetrahedron 61 (2005) 7719–7726
Table 1. Literature data concerning Diels–Alder endo-diastereoselective cycloadditions of maleimides with
Entry
1
R
R1
H
R3/R4
H/Me
Diene config.
Sulfur pseudo-
config.
Dienophile
Maleimide
Preferred diene face for
dienophile endo-approach
Ref.
2a
pMeC6H4
(RS,E)
(pS)
(pR)
(Re)
(Si)
2
3
4
5
H
H
H
H
H/H
(RS)
(RS,E)
(SS,E)
(RS)
NPM
NPM
NPM
NPM
2b
2c
2d
2e
H/OMe
H/OMe
–(CH2)4–
(pR)
(pS)
(pR)
(Si)
(Re)
(Si)
6
7
H
(SS)
(pS)
(pS)
NPM
NPM
(Si)
4
C6H5
Me
H/H
(RS,Z)
(Re)
2f
the priority to the sulfinyl oxygen, followed by the diene
system, and finally by alkyl or aryl substituent at sulfur
atom. Furthermore, the face descriptor is assigned by
referring to the diene carbon directly linked to the sulfur
atom (column 8 in Table 1). Apart from the example shown
in entry 6, the reported cases are consistent with sulfur
configuration controlling the diastereofacial selectivity:
maleimides prefer the approach to (pS)-2-sulfinyl dienes
from their less hindered (Re) face (entries 1, 4, and 7), and
vice-versa the (Si) face of approach is chosen by dienophile
when (pR) is the configuration at the sulfinyl sulfur of the
diene (entries 2, 3, and 5).
selection. NPM cycloadded to the diene from a face
opposite to the one normally observed for analogous
sulfinyl dienes (Table 1, entries 1–5, and 7) and this
unexpected result was explained by proposing a preferred
diene D conformation (Fig. 2) in which the electrostatic
repulsion between the sulfinyl oxygen and the p-system of
the fused benzene ring is avoided in the transition state of
the cycloaddition. In other occasions, we could observe how
the diene steric requirements dramatically affected the
stereochemical results of DA cycloadditions involving
2-sulfinyl dienes,5 and we wondered if the sulfur configu-
ration could be regarded as the only controller of the
diastereofacial selectivity.
In the addition of N-phenylmaleimide (NPM) to the
enantiopure 2-sulfinyldiene reported in entry 6 of Table 1,
low endo/exo-diastereoselectivity and complete but
reversed diastereofacial selectivity in the endo-approach
were observed. A tentative rationalisation of these results
was based on the high steric requirements of both diene and
dienophile,4 such that the less sterically congested exo-
approaches occurred in high percentage but without
significant facial discrimination, while the more sterically
demanding endo-approach happened with complete facial
For a deeper understanding of this matter, we accomplished
the synthesis of 1- and 2-sulfinyl dienes with a cyclohexyl
moiety directly linked to the sulfinyl sulfur atom, and
substituents in 3 or 3,4-positions of the diene skeleton. In
Figure 2. Preferred conformation D of (SS)-4-{1-[(1S)-exo-2-bornylsulfi-
nyl]ethenyl}-1,2-dihydro-7-methoxynaphthalene in its Diels–Alder endo-
approach with NPM (entry 6 in Table 1).
Scheme 1.

M. C. Aversa et al. / Tetrahedron 61 (2005) 7719–7726
7721
Table 2. Reaction conditions of the Diels–Alder cycloadditions of dienes 5–7 with N-phenylmaleimide (NPM)
Entry
Reactants (equiv ratio)a
Solvent
Conditions
Products (ratio)
Yieldb (%)
1
2
3
4
5
6
7
8
9
5/NPM (1:5)
5/NPM (1:5)
5/NPM (1:5)
5/NPM (1:5)
7/NPM (1:6)
7/NPM (1:5.7)
7/NPM (1:5.4)
6/NPM (1:5)
6/NPM (1:5)
CH2Cl2/CHCl3 (3:1)
CH2Cl2/CHCl3 (3:1)
PhMe
40 8C, 60 h, 1 bar
25 8C, 20 h, 8 kbar
70 8C, 20 h, 1 bar
50 8C, 18 h, 8 kbar
70 8C, 21 h, 1 bar
25 8C, 24 h, 8 kbar
50 8C, 19 h, 8 kbar
70 8C, 24 h, 1 bar
25 8C, 24 h, 8 kbar
8
8
8
55
53
48
46
47
69
45
—
60
CH2Cl2
PhMe
CH2Cl2
CH2Cl2
PhMe
CH2Cl2
8
9/10 (5.3:1)
9
9
—
11/12 (3.6:1)
a Diene concentration 0.1 M.
b The yields refer to isolated cycloadducts.
this paper, we report the results of the DA reactions of these
dienes with NPM under thermal conditions, at normal and
high pressure. It is well known that high pressure can
accelerate DA reactions, therefore allowing cycloadditions
of poorly reactive and/or heat sensitive substrates to be
carried out under mild conditions.6 We have chosen NPM as
dienophile mainly for its intrinsic ability to produce
crystalline cycloadducts that could be subjected to X-ray
analysis and give us unassailable stereochemical responses.
gave cyclohexyl sulfoxide 3, that constitutes suitable
precursor of transient sulfenic acid 4.8 Acid 4, thermally
generated in the presence of the enyne acceptor, syn-added
to the triple bond of 2-methyl-1-buten-3-yne leading to the
formation of dienes 5 and 6 in 7:1 ratio and 50% overall
yield. Cyclohexylsulfinyl dienes 5 and 6 were easily
separated by column chromatography and fully charac-
terised. 1-[1-(Cyclohexylsulfinyl)ethenyl]cyclohexene (7)
was obtained in useful yield (50%) as the product of the
completely regioselective addition of sulfenic acid 4 to the
triple bond of 1-ethynylcyclohexene.
2. Results and discussion
Diene 5 cycloadded to NPM under different reaction
conditions, as reported in Table 2, at atmospheric and
high pressure (Scheme 2). The reaction occurred with
complete facial diastereoselection leading to the unique
cycloadduct 8. Results listed in Table 2 show that the
increased pressure accelerates DA process (compare entries
1 and 2) but does not affect either stereochemical results or
yields. Crystallisation from ethyl acetate of compound 8
afforded crystals suitable for X-ray analysis whose result,
shown in Figure 3, confirmed the structural determination
conducted by extensive NMR investigation. Since the
Cyclohexanethiol (1) was reacted with acrylonitrile in the
presence of trimethylbenzylammonium hydroxide (Triton
B) to give the thioether 2 in 90% yield (Scheme 1).7
Oxidation of 2 with 3-chloroperbenzoic acid (m-CPBA)
1
chemical shifts of H2-4 and H2-7 were very close in H
spectra, distinction between them was made by the observed
NOE involving the methyl protons and nearest H-7.
Furthermore, H-3a and H-7a were assigned by selective
decoupling of H2-4 and H2-7, and by 1H–13C hetero-
correlated experiments. Finally, the 9.0 Hz value of J3a,7a
confirmed the cis-arrangement of H-3a and H-7a, while the
extended boat conformation of the cyclohexene ring,
observed also in the solid state (Fig. 3), followed from the
coupling constant values J3a,4 (7.1, 2.4 Hz) and J7,7a (6.0,
2.9 Hz). X-ray analysis of adduct 8 allowed the
Scheme 2.
Figure 3. Perspective view of the structure of 8 with probability displacements ellipsoids representing all non-H atoms. The atom-numbering scheme is
consistent with the systematic nomenclature numbering.

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M. C. Aversa et al. / Tetrahedron 61 (2005) 7719–7726
Figure 4. Perspective view of the structure of 9 with probability displacements ellipsoids representing all non-H atoms. The atom-numbering scheme is
consistent with the systematic nomenclature numbering.
unambiguous assignment of the configuration to the newly
formed stereocentres 3a and 7a, in relation to the con-
figuration of the sulfinyl sulfur atom, as (3aS*,7aR*,RS*).
This stereochemical outcome is consistent with NPM endo-
approach to the (Re) face of diene (RS)-5 (analogously to
entry 6 in Table 1).
confirms the cis-arrangement (pseudo-axial/equatorial) of
H-9a and H-9b in 9, and thus a trans stereochemical
relationship (pseudo-diaxial) of the same protons in 10.
Further support to this stereochemical assignment is given
by the NOE observed between H-9a and H-9b: while for
cycloadduct 9 a large NOE was observed between these
protons, also NOE between them, although very small, was
observed in the case of adduct 10, coming from the exo-
approach of NPM to the (Re) face of (RS)-7.
Entries 5–7 in Table 2 concern the results of DA reaction of
NPM with inner-outer diene 7. When cycloaddition was
performed in toluene, at 70 8C, a complete p-facial
selectivity was observed and two cycloadducts 9 (endo)
and 10 (exo) were obtained in 5:1 ratio, 47% total yield
(Scheme 2). High pressure (entries 6 and 7 in Table 2) led to
complete endo/exo-diastereoselectivity, and endo-cyclo-
adduct 9 was isolated as unique and crystalline product of
reaction. The best yield (69%, entry 6 in Table 2) was
obtained when cycloaddition was performed under the
pressure of 8 kbar, at 25 8C in dichloromethane. Cyclo-
adduct 9 was recrystallised from ethyl acetate and its X-ray
structure is shown in Figure 4. The cis-arrangement of H-3a,
H-9a, and H-9b is a consequence of the endo-approach of
NPM that occurs on the (Re) face of (RS)-sulfinyldiene 7, as
demonstrated by the (3aS*,9aS*,9bR*,RS*) configuration of
9. An extensive NMR investigation was performed on both
cycloadducts 9 and 10, the structure determination of the
latest being based on these measurements. All the
experiments were performed in CDCl3/C6D6 mixtures of
different ratios to allow a significant scattering of proton
signals that overlap in neat CDCl3.
Noteworthy, in both cycloadditions of NPM to
2-cyclohexylsulfinyl dienes 5 and 7 the diene face of
dienophile approach was opposite to the one normally
observed in the literature but in accordance with the result
reported in entry 6 of Table 1. The experimental data can be
rationalised by suggesting that, when a tertiary carbon is
directly linked to the sulfinyl group of the diene, the
dienophile approaches the diene face opposite to the one
including the sterically demanding alkyl substituent that
arranges itself at about 908 with respect to the diene reactive
plane. If the diene skeleton is unsubstituted at C(3) (R3ZH
in Fig. 5), E conformation is a reliable alternative to A (Figs.
1 and 5), maintaining transoid sulfur oxygen to C(1)–C(2)
double bond, and directing NPM onto the same (Si) face of
the (pRS)-2-sulfinyl diene. However, if a substituent is
The separation of the cyclohexyl protons H2-20–H2-60 from
1
all the other methylene protons and the consequent H and
13C assignments were performed by TOCSY experiments.
The rather different chemical shifts of the cyclohexyl
protons in the two adducts 9 and 10 is an interesting
consequence of the different configuration of the moiety
C(3a)–C(9b)–C(9a), and then of the different anisotropy
effect of C(5)–C(5a) double bond. The cis-arrangement of
H-3a and H-9b in both cycloadducts 9 and 10 follows from
the NOE observed between them, together with J3a,9b values
(8.7, 9.4 Hz for 9 and 10, respectively). Comparison of J9a,9b
of 9 (5.9 Hz) with the corresponding coupling in 10 (7.3 Hz)
Figure 5. Conformational preferences in Diels–Alder transition states of
(pRS)-2-sulfinyl dienes.

M. C. Aversa et al. / Tetrahedron 61 (2005) 7719–7726
7723
diagnostic in the attribution of stereochemistry to dia-
stereoisomers 11 and 12. H-4 resonates at lower field in 12
(4.00 ppm) with respect to 11 (3.71 ppm) since in 12 H-4
falls into the deshielding cone of NPM carbonyl function.
Furthermore, in both cycloadducts 11 and 12, H-3a
resonates at lower field (3.52 and 3.59 ppm in 11 and 12,
respectively), with respect to H-7a (3.36 and 3.38 ppm in 11
and 12, respectively), this suggests that the sulfinyl group
adopts a rigid disposition with the H-3a in the deshielding
zone of the sulfinyl oxygen atom.3c When cycloadduct 11
was left standing for 15 days at room temperature in
chloroform solution, it evolved into compound 13 as a
consequence of the well-known sulfoxide–sulfenate
rearrangement of allyl sulfoxides. Spontaneous dehydration
of 13 led to known N-phenyl-4-methyl-1,2-dihydrophthali-
mide (14) (Scheme 3).10 The occurrence of these
conversions is supported by mass spectrometry and NMR
experiments.†
Scheme 3.
3. Conclusions
present at C(3), as occurs in dienes 5 and 7, the steric
hindrance between sulfinyl oxygen and unsaturated moiety
including R3 affords the dienophile approach from the
opposite (Re) face, (pRS)-sulfinyl diene adopting in the
transition state the F conformation (Fig. 5) that corresponds
to D in Figure 2.
The stereochemical results observed in uncatalyzed
cycloadditions of NPM with chiral 2-cyclohexylsulfinyl-
1,3-dienes 5 and 7 allowed a deeper insight into the
comprehension of the factors that affect the facial
diastereoselection in these DA reactions. We have demon-
strated the exiguousness of the generally accepted assump-
tion that the sulfur configuration is the only controller of the
diastereofacial selectivity in DA reactions involving
2-sulfinyl dienes, since (i) the feature of the non-diene
group linked to the sulfoxide sulfur, (ii) the steric
requirements of the dienophile, (iii) the presence of a
3-substituent on the 2-sulfinyl-1,3-diene skeleton all
contribute to the identification of the preferred face of
approach by the dienophile. All these factors, together with
sulfur configuration, have to be taken into consideration
for an accurate foresight of the facial discrimination.
In particular, the relevance of the structural characteristics
of the non-diene group linked to the sulfoxide sulfur become
evident if we compare the reactivity of diene 7 and the one
quoted in Table 1, entry 5: these dienes differ only for
cyclohexyl or isoborneol substituent at sulfur, and this
difference alone exchanges the preferred face of NPM
approach. The use of high pressure improved the
stereochemical outcome of NPM cycloaddition by 1-[1-
(cyclohexylsulfinyl)ethenyl]cyclohexene (7), and allowed
DA reaction of the poorly reactive (E)-1-cyclohexylsulfinyl-
3-methyl-1,3-butadiene (6).
It has been demonstrated that 1-sulfinyl dienes are much less
reactive than 2-sulfinyl dienes, and the reactivity depen-
dence on the position of the sulfinyl group in the diene
skeleton has been explained on the basis of the electronic
characteristics of the sulfoxide moiety.9 It was not a surprise
when (E)-1-cyclohexylsulfinyl-3-methyl-1,3-butadiene (6)
did not give any significant result in its reaction with NPM
at atmospheric pressure: complex mixtures, but no
cycloadducts, were detected (Table 2, entry 8). When
NPM reacted with 6 under high pressure (entry 9) a 3.6:1
mixture of cycloadducts 11 and 12 was obtained in 60%
yield (Scheme 3). The major product of the reaction comes
from the endo-approach of NPM to the (Re) face of
(RS)-sulfinyl diene 6 (C in Fig. 1) as commonly accepted,3
while the minor cycloadduct was obtained by the exo-
approach of dienophile to the same face of (RS)-sulfinyl
diene 6. The 1H NMR data are in good agreement with these
structure assignments if we consider conformational
preferences of the cyclohexene ring as half-boat G in the
endo-cycloadduct 11 and half-chair H in the exo-
cycloadduct 12 (Fig. 6). On this basis the chemical shift
difference of H-4, geminal to the sulfinyl group, appears
† (3aR*,5S*,7aS*)-3a,4,5,7a-Tetrahydro-5-hydroxy-5-methyl-2-phenyl-
1H-isoindole-1,3(2H)-dione (13). 1H NMR (400 MHz) d 7.5–7.2 (m, 5H,
H-200,300,400,500,600), 6.00 (m, 2H, H-6,7), 3.61 (m, 1H, H-7a), 3.08 (m, 1H,
H-3a), 2.40 (m, 1H, HA-4), 1.86 (m, 1H, HB-4), 1.37 (s, 3H, Me). 13C
NMR (100 MHz) d 179.0 and 175.8 (C-1,3), 137.1 and 123.7 (C-6,7),
132.1 (C-100), 129.1 (C-300,500), 128.6 (C-400), 126.5 (C-200,600), 67.0 (C-5),
40.6 (C-7a), 37.1 (C-3a), 36.2 (C-4), 29.4 (Me); MS m/z (rel. intensity)
257 (MC, 23), 242 (6), 214 (3), 138 (21), 93 (base), 77 (14). N-Phenyl-4-
Figure 6. Partial stereostructures of (4S*,RS*)-4-cyclohexylsulfinyl-
3a,4,7,7a-tetrahydro-6-methyl-2-phenyl-1H-isoindole-1,3(2H)-diones 11
and 12.
methyl-1,2-dihydrophthalimide (14): MS m/z (rel. intensity) 239 (MC
,
24), 193 (3), 120 (41), 105 (base), 91 (40), 77 (1).

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M. C. Aversa et al. / Tetrahedron 61 (2005) 7719–7726
4. Experimental
water (80 mL) was added. The crude product was extracted
with Et2O (4!80 mL). The combined organic layers were
washed with saturated NaCl solution (3!50 mL) and dried
(Na2SO4). Evaporation of the solvent gave an oily residue
that was purified by column chromatography eluting with
petrol/EtOAc 4:1. Sulfide 2 (1.52 g, 9.0 mmol, 90% yield)
4.1. General
Solvents were purified according to standard procedures.
Petrol refers to light petroleum, bp 30–40 8C. All reactions
were monitored by TLC on commercially available pre-
coated plates (Aldrich silica gel 60 F 254) and the products
were visualised with vanillin [1 g dissolved in MeOH
(60 mL) and conc. H2SO4 (0.6 mL)] and/or I2. Column
chromatographies were performed on Aldrich 60 and/or
1
was isolated as an oil. H NMR (300 MHz) d 2.81 (split t,
2H, JvicZ7.3 Hz, H2-3), 2.73 (m, 1H, H-10), 2.62 (split t,
2H, H2-2), 2.0–1.2 (m, 10H, H2-20,30,40,50,60). Anal. Calcd
for C9H15NS: C, 63.85; H, 8.93. Found: C, 63.93; H, 9.06.
¨
Riedel de Haen silica gel (32–63 mm; 230–400 mesh
4.1.2. 3-Cyclohexylsulfinylpropanenitrile (3). m-CPBA
(3.82 g 80%, 17.7 mmol) was dissolved in CH2Cl2 (50 mL)
freshly distilled and added dropwise to a solution of sulfide
2 (3.00 g, 17.7 mmol) in CH2Cl2 (50 mL) at K40 8C. When
the reaction appeared complete by TLC (30 min) a 10%
solution of Na2S2O3 was added (50 mL) and the organic
layer was extracted and washed with a saturated solution of
NaHCO3 (3!60 mL, until the neutrality was reached) and
water (2!80 mL). Evaporation of the solvent under
reduced pressure gave sulfoxide 3 as an oil not needing of
purification (quantitative yield). 1H NMR (300 MHz) d 3.0–
2.8 (m, 4H, H2-2,3), 2.67 (tt, 1H, JvicZ11.2, 3.5 Hz, H-10),
2.2–1.2 (m, 10H, H2-20,30,40,50,60). Anal. Calcd for
C9H15NOS: C, 58.34; H, 8.16. Found: C, 58.22; H, 8.40.
ASTM). Melting points were determined on a Bu¨chi
microscopic apparatus and are uncorrected. IR spectra
were recorded in CHCl3 solution on a Perkin-Elmer Paragon
500 FT-IR. 1H and 13C NMR spectra were recorded in
CDCl3 solutions (unless otherwise stated) with SiMe4 as
internal standard on Varian Mercury 300 and VXR-400
spectrometers. The NMR attributions are supported by APT,
homodecoupling, COSY, H–{1H} NOE, HETCOR, and
1
TOCSY experiments. Quaternary carbons were assigned by
2D long-range hetero-correlated experiments. Proton and
carbon nuclei, marked with (0), pertain to the cyclohexyl
moiety, while (00) marks vinyl protons in compound 7 and
phenyl nuclei in compounds 8–13. Mass spectra were
measured by a Hewlett Packard 5970 GC–MS instrument.
All chiral compounds are racemic mixtures. Cycloadditions
under pressure were realised using an UNIPRESS-
EQUIPMENT liquid piston vessel LV 30/16.
4.1.3. Cyclohexylsulfinyl-3-methyl-1,3-butadienes 5 and
6. A solution of sulfoxide 3 (3.00 g, 16.2 mmol) and
2-methyl-1-buten-3-yne (15.4 mL, 162.0 mmol) in toluene
(25 mL) was maintained at 95 8C. When the reaction
appeared complete by TLC (7 h) the solvent was removed
under reduced pressure. Column chromatography (petrol/
EtOAc 9:1) of the crude product mixture afforded
2-cyclohexylsulfinyl-3-methyl-1,3-butadiene (5) as first
eluted oil (1.41 g, 7.1 mmol, 44% yield). 1H NMR
(300 MHz) d 5.88 (s, 1H, HA-1), 5.87 (s, 1H, HB-1), 5.16
(s, 1H, HA-4), 5.14 (s, 1H, HB-4), 2.56 (tt, 1H, JvicZ12.0,
3.7 Hz, H-10), 2.00 (s, 3H, Me), 1.9–1.1 (m, 10H,
H2-20,30,40,50,60). Anal. Calcd for C11H18OS: C, 66.62; H,
9.15. Found: C, 66.61; H, 9.18. Then the minor product
X-ray crystallography. All measurements were carried out
with a Goniometer Oxford Diffraction KM4 Xcalibur2 at
room temperature. Graphite-monochromated Cu Ka radia-
tion (40 mA/K40 kV) and a KM4 CCD/SAPPHIRE
detector were used for cell parameter determination and
data collection. The integrated intensities, measured using
the u scan mode, were corrected for Lorentz and
polarisation effects.11 The substantial redundancy in data
allows empirical absorption corrections (SADABS12) to be
applied using multiple measurements of symmetry-equiv-
alent reflections. The structures were solved by direct
methods of SIR9713 and refined using the full-matrix least
squares on F2 provided by SHELXL97.14 The non-
hydrogen atoms were refined anisotropically, whereas
hydrogen atoms were refined as isotropic. Aromatic and
cyclohexyl hydrogens were assigned in calculated positions,
the others were found in the Fourier difference synthesis.
(E)-1-cyclohexylsulfinyl-3-methyl-1,3-butadiene
(6)
(0.20 g, 1.0 mmol, 6% yield) was eluted as an oil. 1H
NMR (300 MHz) d 6.92 (AB d, 1H, J1,2Z15.4 Hz, H-2),
6.27 (AB d, 1H, H-1), 5.28 (br s, 2H, H2-4), 2.64 (tt,
1H, JvicZ11.4, 3.5 Hz, H-10), 2.2–1.1 (m, 10H,
H2-20,30,40,50,60), 1.92 (s, 3H, Me). Anal. Calcd for
C11H18OS: C, 66.62; H, 9.15. Found: C, 66.50; H, 8.99.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 264418 (adduct 8) and 264419
(adduct 9). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ UK (fax: C44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
4.1.4. 1-[1-(Cyclohexylsulfinyl)ethenyl]cyclohexene (7).
A solution of sulfoxide 3 (2.00 g, 10.8 mmol) in neat
1-ethynylcyclohexene (8 mL, 67.4 mmol) was maintained
at 130 8C. When the reaction appeared complete by TLC
(30 min) the crude mixture was purified by column
chromatography eluting with petrol/EtOAc 9:1. Diene 7
1
4.1.1. 3-Cyclohexylthiopropanenitrile (2).7 Acrylonitrile
(0.79 mL, 12.0 mmol) was added slowly to a solution
(anhydrous THF, 45 mL) of cyclohexanethiol (1.22 mL,
10.0 mmol) and Triton B (0.54 mL, 40 wt% solution in
MeOH, 1.2 mmol) at K78 8C. The reaction mixture was
allowed to reach spontaneously the room temperature, and
was isolated as an oil (1.29 g, 5.4 mmol, 50% yield). H
NMR (300 MHz) d 5.95 (br t, 1H, J2,3Z4.0 Hz, H-2), 5.73
(s, 1H, HA-200), 5.72 (s, 1H, HB-200), 2.51 (tt, 1H, JvicZ12.0,
3.7 Hz, H-10), 2.4–1.1 (m, 18H, H2-20,3,30,4,40,5,50,6,60).
Anal. Calcd for C14H22OS: C, 70.54; H, 9.30. Found: C,
70.69; H, 9.47.

M. C. Aversa et al. / Tetrahedron 61 (2005) 7719–7726
7725
4.2. General procedure for the Diels–Alder reactions of
sulfinyl dienes 5–7 with NPM
1H, HA-20), 1.85 (m, 1H, HA-50), 1.84 (m, 1H, HA-7), 1.83
(m, 1H, HB-9), 1.70 (m, 1H, HA-30), 1.62 (m, 1H, HA-40),
1.60 (m, 1H, HA-8), 1.51 (m, 1H, HA-60), 1.46 (m, 1H,
HB-7), 1.45 (m, 1H, HB-20), 1.29 (m, 1H, HB-8), 1.23 (m,
1H, HB-40), 1.21 (m, 1H, HB-50), 1.19 (m, 1H, HB-30), 1.17
(m, 1H, HB-60). 13C NMR (100 MHz, CDCl3/C6D6 1:1) d
177.0 (C-3), 176.6 (C-1), 150.9 (C-5a), 132.0 (C-100), 130.8
(C-5), 128.9 (C-300,500), 128.5 (C-400), 126.0 (C-200,600), 58.7
(C-10), 43.3 (C-9b), 39.8 (C-3a), 39.2 (C-9a),0 27.2 (C-6),
26.5 (C-20), 26.0, 25.7, 25.4, and 25.1 (C-30,4 ,50,60), 25.2
(C-9), 22.6 (C-8), 22.2 (C-7), 20.0 (C-4). Anal. Calcd for
C24H29NO3S: C, 70.04; H, 7.10. Found: C, 70.12; H, 6.98.
As reported in Table 2, the cycloadditions were accom-
plished at atmospheric pressure (entries 1, 3, 5, and 8) and
under high pressure conditions (entries 2, 4, 6, 7, and 9). For
the experiments performed at atmospheric pressure, a
solution of the diene (1.5 mmol) in the quoted solvent
(5 mL) was added to NPM dissolved in the same solvent
(10 mL). The resulting solution was maintained at the
indicated temperature, then cooled and the solvent
evaporated under vacuum. For the experiments performed
at high pressure, a solution of diene (1.5 mmol) and
dienophile in the quoted solvent (12 mL) was placed into
a 15 mL Teflon vial and solvent was added until the vial was
completely filled. The vial was closed and kept at 8 kbar at
the indicated temperature. After depressurising, the solvent
was removed in vacuo. Each crude mixture obtained (all
entries in Table 2) was purified by column chromatography
on silica gel eluting with EtOAc/hexane 4:1.
X-ray structural analysis of 9: formula C24H29NO3S, MZ
˚
411.54, orthorhombic, space group P cab, aZ12.427(1) A,
3
˚
˚
˚
bZ16.259(1) A, cZ21.454(1) A, VZ4334.8(5) A , ZZ8,
DcZ1.261, mZ1.519 mmK1, F(000)Z1760. 10429 reflec-
tions were collected in a 4.93!q!59.05 range with a
completeness to q 95.8%; 2985 were independent, the
parameters were 274, and the final R index was 0.0505 for
reflections having IO2sI, and 0.0632 for all data.
4.2.1. (3aS*,7aR*,RS*)-5-Cyclohexylsulfinyl-3a,4,7,7a-
tetrahydro-6-methyl-2-phenyl-1H-isoindole-1,3(2H)-
dione (8). Pale yellow crystals, mp 162–163 8C (EtOAc), IR
4.2.3.
(3aR*,9aS*,9bS*,RS*)-5-Cyclohexylsulfinyl-
3a,4,6,7,8,9,9a,9b-octahydro-2-phenyl-1H-benz[e]iso-
indole-1,3(2H)-dione (10). Pale yellow crystals, mp 182–
1
nmax 1713 (C]O) cmK1. H NMR (400 MHz) d 7.42 (m,
2H, H-300,500), 7.34 (m, 1H, H-400), 7.28 (m, 2H, H-200,600),
183 8C (EtOAc), IR nmax 1712 (C]O) cmK1 1H NMR
.
3.37 (ddd, 1H, J3a,4AZ2.4 Hz, J3a,4BZ7.1 Hz, J3a,7a
9.0 Hz, H-3a), 3.34 (ddd, 1H, J7a,7AZ2.9 Hz, J7a,7B
Z
Z
(400 MHz, CDCl3/C6D6 1:1) d 7.35 (m, 2H, H-300,500), 7.24
(m, 1H, H-400), 7.22 (m, 2H, H-200,600), 3.22 (dd, 1H, J3a,4A
1.9 Hz, J4A,4BZ16.4 Hz, H-4), 3.07 (ddd, 1H, J3a,4B
Z
Z
6.0 Hz, H-7a), 3.26 (dd, 1H, J4A,4BZ15.2 Hz, HA-4) 2.82
(dd, 1H, J7A,7BZ15.2 Hz, HA-7), 2.61 (tt, 1H, JvicZ10.8,
3.8 Hz, H-10), 2.47 (dd, HB-7), 2.36 (dd, 1H, HB-4), 2.16 (m,
1H, HA-60), 2.04 (br s, 3H, Me), 1.89 (m, 1H, HA-30), 1.79
(m, 1H, HA-20), 1.68 (m, 1H, HA-50), 1.57 (m, 1H, HA-40),
1.47 (m, 1H, HB-60), 1.28 (m, 2H, HB-20,40), 1.25 (m, 1H,
HB-30), 1.22 (m, 1H, HB-50). 13C NMR (100 MHz) d 177.9
and 177.3 (C-1,3), 145.2 (C-6), 133.7 (C-5), 132.0 (C-1000),
129.3 (C-300,500), 128.8 (C-400), 126.7 (C-200,600), 59.1 (C-1 ),
39.90 (C-7a), 39.8 (C-3a), 31.9 (0C-7), 26.6 (C-60), 26.2
(C-2 ), 25.8, 25.5, and 25.2 (C-3 ,40,50), 20.8 (Me), 20.5
(C-4). Anal. Calcd for C21H25NO3S: C, 67.89; H, 6.78.
Found: C, 67.80; H, 6.81.
7.3 Hz, J3a,9bZ9.4 Hz, H-3a), 2.92 (dd, 1H, J9a,9bZ7.3 Hz,
H-9b), 2.63 (tt, 1H, JvicZ10.8, 3.6 Hz, H-10), 2.58 (ddd, 1H,
J6A,6BZ15.4 Hz, J6A,7Z4.4, 3.5 Hz, HA-6), 2.32 (ddd, 1H,
J9,9aZ13.4, 4.6 Hz, H-9a), 2.30 (dd, 1H, HB-4), 2.20 (m,
1H, HA-20), 2.14 (m, 1H, HB-6), 2.02 (m, 1H, HA-9), 1.80
(m, 1H, HB-9), 1.78 (m, 1H, HA-8), 1.74 (m, 1H, HA-30),
1.6–1.5 (m, 2H, H2-7), 1.38 (m, 1H, HA-40), 1.34 (m, 1H,
HB-20), 1.30 (m, 1H, HB-8), 1.20 (m, 1H, HB-30), 1.17
(m, 1H, HA-50), 1.03 (m, 2H, HB-40, HA-60), 0.88 (m, 1H,
HB-60), 0.77 (m, 1H, HB-50). 13C NMR (100 MHz, CDCl3/
C6D6 1:1) d 177.5 (C-3), 175.9 (C-1), 150.4 (C-5a), 132.1
(C-100), 00131.9 (C-5), 128.9 (C-300,500), 128.2 (C-400), 126.0
(C-200,6 ), 57.3 (C-10), 43.1 (C-9b), 39.8 (C-3a), 390.5
(C-9a), 26.7 (C-20), 26.3 (C-6), 25.9 (C-60), 25.5 (C-4 ),
24.8 (C-30), 24.5 (C-50,9), 21.7 (C-8), 21.2 (C-7), 20.5 (C-4).
Anal. Calcd for C24H29NO3S: C, 70.04; H, 7.10. Found: C,
69.98; H, 7.15.
X-ray structural analysis of 8: formula C21H25NO3S, MZ
˚
371.48, monoclinic, space group P21/c, aZ11.399(7) A,
˚
˚
bZ10.761(8) A, cZ16.815(10) A, bZ107.43(5)8, VZ
1968(2) A , ZZ4, DcZ1.254, mZ1.618 mmK1, F(000)Z
3
˚
792. 5223 Reflections were collected in a 13.28!q!58.93
range with a completeness to q 92.7%; 2616 were
independent, the parameters were 264, and the final R
index was 0.0506 for reflections having IO2sI, and 0.0549
for all data.
4.2.4.
(3aS*,4S*,7aR*,RS*)-4-Cyclohexylsulfinyl-
3a,4,7,7a-tetrahydro-6-methyl-2-phenyl-1H-isoindole-
1,3(2H)-dione (11). Low melting solid, IR nmax 1712
(C]O) cmK1
.
010 H NMR (400 MHz) d 7.5–7.3 (m, 5H,
4.2.2.
(3aS*,9aS*,9bR*,RS*)-5-Cyclohexylsulfinyl-
H-200,300,400,500,6 ), 5.69 (m, 1H, H-5), 3.71 (dd, 1H, J3a,4
Z
3a,4,6,7,8,9,9a,9b-octahydro-2-phenyl-1H-benz[e]iso-
indole-1,3(2H)-dione (9). Pale yellow crystals, mp 202–
7.0 Hz, J4,5Z6.4 Hz, H-4), 3.52 (dd, 1H, J3a,7aZ9.6 Hz,
H-3a), 3.36 (dt, 1H, J3a,7aZJ7a,7BZ9.6 Hz, J7a,7AZ5.7 Hz,
203 8C (EtOAc), IR nmax 1713 (C]O) cmK1
.
1H NMR
H-7a), 2.9–2.8 (m, 2H, H-10, HA-7), 2.38 (dd, 1H, J7A,7B
Z
(400 MHz, CDCl3/C6D6 1:1) d 7.37 (m, 2H, H-300,500), 7.27
16.8 Hz, HB-7), 2.0–1.2 (m, 10H, H2-20,30,40,50,60), 1.96 (s,
3H, Me). 13C NMR (100 MHz) d 177.6 and 175.8 (C-1,3),
144.3 (C-60)0, 131.7 (C-100), 129.1 (C-300,500), 128.5 (C-400),
126.6 (C-2 ,600), 112.6 (C-5), 56.5 (C-10), 52.4 (C-4), 41.4
(C-3a), 38.4 (C-7a), 28.5 (C-7), 26.4, 25.5, 25.2, 25.0, and
24.6 (C-20,30,40,50,60), 24.2 (Me). Anal. Calcd for
C21H25NO3S: C, 67.89; H, 6.78. Found: C, 67.77; H, 6.84.
(m, 1H, H-400), 7.26 (m, 2H, H-200,600), 3.28 (dd, 1H, J3a,4A
2.4 Hz, J4A,4BZ15.8 Hz, HA-4), 3.17 (ddd, 1H, J3a,4B
Z
Z
8.1 Hz, J3a,9bZ8.7 Hz, H-3a), 3.07 (dd, 1H, J9a,9bZ5.9 Hz,
H-9b), 2.54 (tt, 1H, JvicZ10.8, 3.7 Hz, H-10), 2.50 (m, 1H,
HA-6), 2.39 (ddd, 1H, J8,9aZ11.0, 6.2 Hz, H-9a), 2.30 (m,
1H, HB-6), 2.24 (m, 1H, HA-9), 2.18 (dd, HB-4), 2.17 (m,

7726
M. C. Aversa et al. / Tetrahedron 61 (2005) 7719–7726
Policicchio, M. Tetrahedron Lett. 2000, 41, 4441–4445.
(3aR*,4S*,7aS*,RS*)-4-Cyclohexylsulfinyl-
4.2.5.
(f) Chou, S.-S. P.; Liang, P.-W. Tetrahedron Lett. 2002, 43,
4865–4870.
3a,4,7,7a-tetrahydro-6-methyl-2-phenyl-1H-isoindole-
1,3(2H)-dione (12). Low melting solid, IR nmax 1712
(C]O) cmK1
.
010 H NMR (400 MHz) d 7.5–7.4 (m, 5H,
3. (a) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman, L. E.
J. Am. Chem. Soc. 1988, 110, 4625–4633. (b) Fisher, M. J.;
Overman, L. E. J. Org. Chem. 1988, 53, 2630–2634. (c) Arce,
H-200,300,400,500,6 ), 5.53 (m, 1H, H-5), 4.00 (dd, 1H, J3a,4
Z
5.4 Hz, J4,5Z5.5 Hz, H-4), 3.59 (dd, 1H, J3a,7aZ9.5 Hz,
H-3a), 3.38 (ddd, 1H, J7a,7AZ6.2 Hz, J7a,7BZ9.3 Hz,
H-7a), 2.8–2.7 (m, 2H, H-10, HA-7), 2.54 (dd, 1H,
J7A,7BZ16.5 Hz, HB-7), 2.0–1.2 (m, 10H, H2-20,30,40,
50,60), 1.90 (s, 3H, Me). 13C NMR (100 MHz) d 178.8 and
175.8 (C-1,3), 143.4 (C-6), 132.9 (C-100), 129.9 (C-0300,500),
129.3 (C-400), 127.5 (C-200,600), 117.0 (C-5), 58.0 (C-1 ), 55.9
(C-4), 42.4 (C-3a), 39.08 (C-7a), 29.5 (C-7), 28.6, 26.7, 26.3,
26.1, and 23.2 (C-20,3 ,40,50,60), 24.6 (Me). Anal. Calcd for
C21H25NO3S: C, 67.89; H, 6.78. Found: C, 67.95; H, 6.80.
´
E.; Carren˜o, M. C.; Cid, M. B.; Garcıa Ruano, J. L. J. Org.
Chem. 1994, 59, 3421–3426. (d) Carren˜o, M. C.; Cid, M. B.;
´
Garcıa Ruano, J. L. Tetrahedron: Asymmetry 1996, 7,
´
2151–2158. (e) Blasco, S.; Carren˜o, M. C.; Cid, M. B.; Garcıa
´
Ruano, J. L.; Martın, M. R. Tetrahedron: Asymmetry 1999, 10,
3473–3477. (f) Bell, A. S.; Fishwick, C. W. G.; Reed, J. E.
Tetrahedron 1999, 55, 12313–12330.
4. Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bruno, G.;
Caruso, F.; Giannetto, P. Tetrahedron: Asymmetry 2001, 12,
2901–2908.
5. Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bonini, B. F.;
Acknowledgements
`
Giannetto, P.; Nicolo, F. Tetrahedron: Asymmetry 1999, 10,
3919–3929.
This work was carried out under the auspices of the national
projects ‘Stereoselezione in sintesi organica, metodologie
ed applicazioni’ and supported by MIUR (Ministero
6. Aben, R. W. M.; Minuti, L.; Scheeren, H. W;. Taticchi, A.
Tetrahedron Lett. 1991, 32, 6445–6448. Fringuelli, F.; Minuti,
L.; Pizzo, F.; Taticchi, A. Acta Chem. Scand. 1993, 47, 255–
263. Minuti, L.; Taticchi, A. In Seminars in Organic Synthesis;
Trombini, C., Ed. Multiple and High Pressure Diels–Alder
Reactions. Minuti, L.; Taticchi, A.; Costantini, L. Recent Res.
Dev. Org. Chem. 1999, 3, 105–116.
`
dell’Istruzione, dell’Universita e della Ricerca) Rome,
Italy. The work was also supported by the University of
Messina.
7. Choudary, B. M.; Lakshmi Kantam, M.; Kavita, B. Green
Chem. 1999, 1, 289–292.
8. Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.;
Jones, D. N. J. Org. Chem. 1997, 62, 4376–4384.
´
9. Carren˜o, M. C.; Cid, M. B.; Garcıa Ruano, J. L.; Santos, M.
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