Studies on chemo- And diastereo-selectivity of the Diels-Alder reactions of sulfinyltoluquinones with cyclopentadiene

Article abstract of DOI:10.1139/V09-070

Sulfinyltoluquinones (2a-2c) were submitted to thermal or catalyzed [4+2] cycloaddition reactions with cyclopentadiene. Forp-tolylsulfin.yltoluqu.inon.es (2b) and (2c), almost complete C2-C3-chemo- and wnZiAc- diastereoselectivity was achieved by catalysi

Full text of DOI:10.1139/V09-070

1135
Studies on chemo- and diastereo-selectivity of the
Diels–Alder reactions of sulfinyltoluquinones with
cyclopentadiene
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Andrea L. F. de Sousa, Jose E. P. Cardoso Filho, Blanka Wladislaw,
Liliana Marzorati, and Claudio Di Vitta
Abstract: Sulfinyltoluquinones (2a–2c) were submitted to thermal or catalyzed [4+2] cycloaddition reactions with cyclo-
pentadiene. For p-tolylsulfinyltoluquinones (2b) and (2c), almost complete C2–C3-chemo- and unlike-diastereoselectivity
was achieved by catalysis with ZnBr2, yielding adducts 6. Under thermal conditions, Diels–Alder reaction took place at
the C5–C6 double bonds of quinones 2a–2c, generating mixtures of diastereoisomeric like- and unlike-adducts 4.
Key words: Diels–Alder reaction, sulfinyltoluquinones, sulfinyl group, stereochemical control, p-facial selectivity.
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Resume : On a soumis les sulfinyltoluquinones (2a–2c) a des reactions de cycloaddition thermiques ou catalysees avec le
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cyclopentadiene. Avec le ZnBr2 comme catalyseur, les p-tolylsulfinyltoluquinones (2b) et (2c) conduisent a la formation
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des adduits 6 et la diastereoselectivite chimique et dissemblable au niveau de la liaison C2–C3 est pratiquement complete.
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Dans des conditions thermiques, la reaction de Diels–Alder se produit au niveau des doubles liaisons C5–C6 des quinones
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2a–2c qui conduit a la formation d’adduits 4 sous la forme de melanges diastereomeres semblables et dissemblables.
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Mots-cles : reaction de Diels–Alder, sulfinyltoluquinones, groupe sulfinyle, controle stereochimique, selectivite de la face p.
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[Traduit par la Redaction]
Considering the ability of the sulfinyl group to control the
chemo- and p-facial diastereoselectivity in DA reactions,11
especially in the case of benzoquinones acting as dienophiles,
the synthesis of adducts (+)- or (–)-1 by p-facial discrimina-
tion of enantiopure sulfinyltoluquinones (2a–2c) (Fig. 2)
seemed quite feasible to us.
Introduction
The Diels–Alder (DA) reaction remains as one of the most
powerful methods for the construction of cyclic systems with
potential for stereochemical control of up to four stereogenic
centers in only one step.1,2 Many natural products like ste-
roids,3 alkaloids,4 and terpenoids,5 among others,6 were syn-
thesized by using quinones as dienophiles. However, due to
the lack of p-facial selectivity, during the cycloaddition step,
many of the above-mentioned syntheses proceeded in a race-
mic way. Only by the intervention of chiral enantiopure di-
enes7 or quinones,8 or by employing chiral Lewis acids or
catalysts,9,10 it was possible to conduct asymmetric DA reac-
tions leading to enantiopure or enantioenriched adducts.
Although resolution steps after the DA reaction may also be
applied, the loss of material, intrinsically associated to the
resolution process, limits its synthetic usefulness.
Only two reports were found in the literature for the DA
reactions of sulfinylbenzoquinones (3), bearing a group dif-
ferent from hydrogen at C3.12,13 Carren˜o and Ruano12 re-
ported a complete chemoselectivity but a moderate p-facial
diastereoselectivity (40%–60% de under catalytic conditions
vs. 0% de under thermal conditions) for the DA reaction of
cyclopentadiene with benzoquinones (+)-(SS)-3 (X = Cl) and
(+)-(SS)-3 (X = Et) with exclusive formation of cycload-
ducts by reaction at the C5–C6 double bond. Better results
were obtained when 2,3-dimethyl-1,3-butadiene was em-
ployed (40%–72% de under catalytic conditions vs. 20%–
34% de under thermal conditions). Similar p-facial diaster-
eoselectivity but complete reversal of chemoselectivity was
observed for the thermal DA reaction of (+)-(SS)-3 (X =
CN)13 (at C2–C3; 0% de for cyclopentadiene and 58%–84%
de for 1-methoxy-1,3-butadiene).
Recently, we became interested in an alternative synthesis
of the enantiomerically pure adducts 1 (Fig. 1). It should be
mentioned that (+)-1a was prepared by Corey et al.10 to be
used as precursors of natural products like (+)-hirsutene,
(–)-corioline, pleurotellol, and pleurotellic acid via the pho-
tothermal olefinic metathesis methodology (PTOM).5b,5d,5h
Results and discussion
Received 12 November 2008. Accepted 15 April 2009.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 27 July 2009.
To evaluate the chemo- and diastereo-selectivity of tolu-
quinones, ( )-2b and ( )-2c (R = pTol, iPr, and iBu) were
prepared by addition of the corresponding thiols to the 2,6-
and 2,5-dimethylbenzoquinones,14 respectively, followed by
subsequent oxidation at sulfur with H2O2/SeO2,15 and of the
aromatic ring with CAN.12 As for the synthesis of quinone
2a, although the analogous compound (+)-3 (X = Et) could
be obtained by the reaction12 of (+)-3 (X = H) with Zn(Et)2,
A.L.F. de Sousa, J.E.P. Cardoso Filho, B. Wladislaw,
1
´
L. Marzorati, and C. Di Vitta. Instituto de Quımica da
Universidade de Sa˜o Paulo, Av. Prof. Lineu Prestes 748, Cidade
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Universitaria, Sa˜o Paulo SP 05508 900, Brazil.
1Corresponding author (e-mail: cldvitta@iq.usp.br).
Can. J. Chem. 87: 1135–1143 (2009)
doi:10.1139/V09-070
Published by NRC Research Press

1136
Can. J. Chem. Vol. 87, 2009
Fig. 1. Diels–Alder adducts between toluquinones and cyclic
dienes.
Scheme 2. Diels–Alder adducts formed by attack of cyclopenta-
diene to both sides of C5–C6 double bond of (+)-(SS)-2a.
Fig. 3. Representation of the s-cis conformation between the S–O
and C2–C3 bonds for adducts (+)-5.
Fig. 2. Sulfinyltoluquinones prepared by our group (2) and by Car-
ren˜o and Ruano12,13 (3; X = Cl, Et, and CN).
Scheme 3. Diels–Alder adducts formed by attack of cyclopenta-
diene to both sides of C5–C6 double bonds of racemic toluquinones
2b and 2c, considering only the (SS) isomers.
Scheme 1. Synthesis of toluquinone (+)-(SS)-2a.
the same precursor proved to be unreactive toward Zn(Me)2.
In a search for an alternative methodology, we tried the
reaction of 2-bromo-1,4-dimethoxy-3-methylbenzene16 with
nBuLi, followed by the quenching of the lithiated aromatic
compound with methyl p-toluenesulfinate. However, better
yields (37%) of sulfinylated product were obtained by using
(SS)-menthyl p-toluenesulfinate as sulfinylating agent. After
subsequent oxidation of the obtained aromatic compound
with CAN, quinone (+)-2a was isolated in 79% yield
(Scheme 1).
using (+)-(SS)-3 (X = H). In that case, the H6/H7 lower field
signals (6.13 vs 5.85/4.82 ppm) corresponded to the less
abundant isomer. According to the authors, for the major
isomer ((+)-like-5; Fig. 3) the S–O and the C2–C3 bonds
would lie in an s-cis-favored conformation, in which the p-
tolyl ring would shield the H6/H7 protons. Such effect
would be absent in the other isomer ((+)-unlike-518), which
would be formed by cycloaddition to the C5–C6 top (re)
face of the (+)-(SS)-3 (X = H).
When ( )-2b was treated with cyclopentadiene, under the
Due to the deactivating effect of the methyl group on the
C2–C3 double bond of (+)-2a, its chemoselective DA reac-
tion with cyclopentadiene yielded an inseparable mixture of
adducts like-4a17 and unlike-4a, resulting from the approach
of the diene to each side of the C5–C6 double bond
(Scheme 2).
same conditions (Scheme 3), a mixture of two adducts was
obtained, as evidenced by the H NMR spectra of the crude
1
mixture, which presented only two pairs of signals in the
olefinic region. Additionally, two doublets, at 2.77 and
2.92 ppm (J = 3.9 Hz), attributed to H8a of the ( )-like-4b
and ( )-unlike-4b adducts (Scheme 3), respectively, were
also observed, indicating that endo-cycloadditions took
place chemoselectively at both sides of the C5–C6 double
bond. For this mixture, a 1:1 ratio for the isomeric ( )-4b
adducts could be determined by integration of the absorp-
tions, at 6.06/6.02 and at 5.96/5.56 ppm. However, for
toluquinone ( )-2c (R = pTol) (Scheme 3), a 4:1 mixture of
adducts was obtained. Accordingly, in this case, signals at
lower field (6.14/6.01 ppm) were attributed to H6/H7 of the
most abundant ( )-like-4c (R = pTol), and those at 5.82/
5.67 ppm were attributed to the ( )-unlike-4c (R = pTol)
isomer.
Evidence for the formation of such isomeric adducts was
1
provided by the inspection of the H NMR spectrum of the
reaction crude mixture, which revealed, for the absorptions
of the norbornenyl hydrogens, only two clusters: one, at
6.07, and the other, centered at 5.71 ppm (composed by two
separated multiplets at 5.89 and 5.53 ppm), suggesting the
absence of adducts arising from the cycloaddition at the C2–
C3 double bond of the quinone. A 1.3:1 integral ratio was ob-
tained for the olefinic clusters in favor of signals at 6.07 ppm.
It should be mentioned that a different result was reported
by Carren˜o et al.18 for the analogous DA reaction performed
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de Sousa et al.
1137
Fig. 4. Representation of the s-trans conformation between the S–O
and C2–C3 bonds for adducts unlike-4.
~1.5 Hz) in the case of ( )-2c (R = pTol) indicated that
the DA reactions took place at the C2–C3 double bond for
both quinones. Thus, assuming the sterically favoured
unlike-endo approach of the diene to the bottom face of
the chelates formed between ZnBr2 and toluquinones ( )-2b
or ( )-2c (R = pTol), products ( )-unlike-6b and ( )-unlike-
6c could be advanced (Scheme 4).
The catalytic DA reactions of cyclopentadiene with tolu-
quinones 2c (R = iPr or iBu; see Table 1) showed similar
results and, in some cases, it became possible to separate
and isolate pure adducts by flash chromatography.
Having in hands the diastereomerically pure adducts 4c,
and due to the unambiguous structure assignment for com-
pounds unlike-6c (R = pTol or iBu), we envisaged that the
stereochemical outcome of the DA reactions of (+)-2b and
( )-2c could be determined by comparison of the [a]D
values of the enantiomerically pure desulfurized compounds
arising from like- or unlike-4c and unlike-6. Therefore, if the
initially proposed structures for compounds ( )-like-4c and
( )-unlike-4c were correct, the same enantiomer would
result from desulfurization of the (SS)-like-4c and the (SS)-
unlike-6c compounds. On the other hand, enantiomeric
products would result from desulfurization of adducts (SS)-
unlike-4c and the (SS)-unlike-6c. Furthermore, these desul-
furized compounds would correspond to the desired enantio-
merically pure forms of adduct 1a.
To establish the best experimental conditions for the re-
moval of the sulfinyl group, racemic unlike-6c and like-4c
and unlike-4c were submitted to the reactions with three dif-
ferent desulfurizing agents. Thus, reaction of ( )-unlike-6c
(R = pTol) with aluminum amalgam19 yielded, after 3 h at
0 8C, an equimolar mixture of adduct ( )-1a and its corre-
sponding ( )-C2–C3-dihydro derivative 720 (Scheme 5).
This last compound was also obtained when aluminum
amalgam was used for reduction of ( )-like- or unlike-4c (R
= iBu). The use of Ni2B21 resulted in the formation of the
( )-C6–C7-dihydro derivative ( )-8, starting from ( )-un-
like-6c (R = pTol) but converted ( )-unlike-4c (R = iPr)
into ( )-1a in low yield (12%) (Scheme 5). On the other
hand, employing Raney–Ni22 for desulfurizing ( )-unlike-
6c (R = pTol), an equimolar mixture of ( )-7 and ( )-8 was
obtained. However, by using deactivated Raney–Ni,23 we
were able to obtain pure ( )-1a, although in a moderate
yield (50%) (Scheme 5).
Having established the conditions for the successful syn-
thesis of adduct ( )-1a by desulfurization of ( )-unlike-6c
(R = pTol) and unlike-4c (R = iPr), we prepared the
optically active quinones (SS)-2c (R = pTol) and (SR)-2c
(R = iPr) to compare the [a]D values of their desulfurized
cyclopentadiene DA adducts. Thus, by treating 3-bromo-
1,4-dimethoxy-2,5-dimethylbenzene24 with nBuLi, followed
by quenching with the adequate sulfinylating agent, toluqui-
nones (+)-(SS)-2c (R = pTol) and the (–)-(SR)-2c (R = iPr)
were isolated25 after oxidation with CAN. Next, cyclo-
pentadiene was used for the reactions with (+)-2c (R =
pTol) chelated with ZnBr2, and with (–)-2c (R = iPr) com-
plexed with BF3ÁEt2O. After desulfurization of the corre-
sponding obtained adducts (Scheme 6), the observed [a]D
value for the resulting adducts 1a,10a was +7.6 in both cases,
thus confirming the initially proposed relative configurations
for adducts 4.
Thermal DA reactions of cyclopentadiene with sulfinylto-
luquinones 2c (R = iPr) and 2c (R = iBu) yielded mixtures
of adducts for which the most abundant isomers (ratios: 2.3
to 1, for R = iPr; 4 to 1, for R = iBu) presented H6/H7 ab-
sorptions at 6.04/6.21 ppm for R = iPr and at 6.04/6.23 ppm
for R = iBu. For the minor isomers, the corresponding H6/
H7 signals were observed at 6.04/6.13 ppm (R = iPr) and at
6.04/6.15 ppm (R = iBu).
Considering that, in the case of adducts arising from ben-
1
zoquinone (+)-(SS)-3, the major isomer presents H6/H7 H
NMR absorptions at higher field in comparison with the
minor isomer, and that the opposite was observed starting
from toluquinones (+)-2a and ( )-2c (for R = pTol), and as-
suming the same p-facial diastereoselectivity for the DA re-
action of all three quinones, the observed lower-field
absorptions for H6/H7 of the unlike-4 adducts can only be
explained if, in these compounds, an s-trans conformation
(instead of an s–cis conformation) between the S–O and
C2–C3 bonds is assumed (Fig. 4). Accordingly, for the like-
4c and unlike-4c (R = iPr and iBu) adducts, for which no p-
tolyl shielding effects are expected, similar chemical shifts
values were observed for H6/H7.
However, a reversed p-facial diastereoselectivity for the
DA reactions of quinones (+)-2a and ( )-2c, as compared
with that for (+)-(SS)-3 (X = H), with preferential unlike ap-
proach of the diene to the top (re) face of (+)-2a and ( )-2c,
considering the SS configuration, giving rise to the unlike-4a
and ( )-unlike-4c (R = pTol) adducts, could not be dis-
carded. Thus, aiming to elucidate the stereochemistry of ad-
ducts 4, and to obtain diastereoisomerically pure
compounds, required for the synthesis of enantiomerically
pure 1, we decided to essay some catalytic conditions for
the DA reactions with toluquinones 2.
When quinone (+)-2a was submitted to the ZnBr2-
catalyzed DA reaction with cyclopentadiene, the same
chemo- and diastereo-selectivities were observed as com-
pared with the thermal process. However, a completely re-
versed p-facial diastereoselection was observed for ( )-2c
(R = pTol) under BF3ÁEt2O catalysis (see Table 1), as the
most abundant adduct is the one with the H6/H7 signals at
higher field. Furthermore, when ( )-2b and ( )-2c (R =
pTol) were treated with ZnBr2, only one product was
1
formed in each case. The H NMR spectra of these last ad-
ducts showed no doublets for the ring-junction hydrogens,
but the presence of a broad singlet at 5.88 ppm (in the
case of ( )-2b) and of a quartet at 6.13 ppm (J is
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Can. J. Chem. Vol. 87, 2009
Table 1. Diels–Alder catalytic reactions of cyclopentadiene with ( )-2c.
Entry
R
Condition
BF3ÁEt2O
ZnBr2
Time (days)a like-4cb
unlike-4cb
2.3
—
2
1
1
unlike-6cb
—
1
—
2.5
1
2
3
4
5
pTolc
pTolc
iBu
iBu
iPrd
14
3
8
1
—
1
BF3ÁEt2O
ZnBr2
5
4
—
—
BF3ÁEt2O
—
aAt –20 8C.
bIn this Table, like-4c and unlike-4c adducts were named according to the chemical shifts of H6 and
H7: like for highest and unlike for lowest chemical shifts, respectively.
cAlso prepared in an enantiomericaly pure SS form.
dPrepared in racemic and in enantiomerically pure SR form.
Scheme 4. Modes of approaching of cyclopentadiene to both faces of C2–C3 double bonds of racemic chelates formed between ZnBr2 and
toluquinones 2b and 2c, considering only the (SS) isomers.
recorded on the same instruments at 50 or 75 MHz, and are
referenced against the central line of the solvent signal
(CDCl3 triplet at 77.0 ppm). The coupling constants (J) are
Conclusion
The above results indicate that the same stereochemical
outcome is observed for the DA reactions of cyclopenta-
given in Hz. IR spectra were obtained with a BOMEN in-
diene with sulfinylbenzo- and sulfinyl-toluquinones, despite
strument (KBr pellets for all compounds). TLC was carried
the presence of an extra methyl group attached to the C5–
out on Merck silica-gel TLC-cards. All reagents and sol-
C6 double bond of such toluquinones. However, in the case
vents were used as received from commercial suppliers.
of adducts 4, the C2 methyl group sterically interacts with
the sulfinyl group, thus imposing an s-trans conformation
between the S–O and the C2–C3 bonds, causing, in the case
of pTol derivatives, a shielding effect on the olefinic hydro-
gens (H6/H7) only for the unlike adducts.
Sulfinyl 1,4-benzoquinones ( )-2b and ( )-2c (R = pTol,
iBu, and iPr)
( )-2b and ( )-2c (R = pTol, iBu, and iPr) were prepared
by the following three-step procedure.
It should be also mentioned that we could establish the
adequate conditions for the synthesis of (+)-1a, a valuable
precursor for synthesis of (+)-hirsutene, (–)-corioline, pleu-
Step 1: addition of thiol to quinone14
To a solution of quinone (2.2 mmol) in ethanol (10 mL)
was added dropwise a solution of the thiol (2.2 mmol) in
ethanol (10 mL), under stirring and at room temperature.
After 2 h, the solvent was removed under vacuum, and the
residue was submitted to flash chromatography.
rotellol, and pleurotellic acid.
Experimental
General
Melting points were determined on a Koffler micro hot
stage and are uncorrected. H NMR spectra were recorded
3-(Isobutylthio)-2,5-dimethylbenzene-1,4-diol was ob-
tained as a colorless oil, in 96% yield, using hexane/ethyl
acetate (6:1) as eluting solvent. dH (300 MHz, CDCl3): 1.02
(d, 6H, J = 6.6), 1.76 (m, 1H), 2.21 (s, 3H), 2.41 (s, 3H),
1
with a Bruker AC 200 or a Varian INOVA 300 spectrometer
using TMS as an internal standard. 13C NMR spectra were
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de Sousa et al.
1139
Scheme 5. Products arising from reactions of adducts ( )-unlike-6c and ( )-unlike 4c with desulfurizing agents.
Scheme 6. Product resulting from desulfurization of the Diels–Alder adducts between cyclopentadiene and toluquinones (+)-(SS)-2c and (–)-
(SR)-2c.
2.48 (d, 2H, J = 6.9), 4.30 (s, 1H), 6.62 (s, 1H), 6.83 (s,
1H). dC (75 MHz, CDCl3): 14.5, 16.7, 22.4, 29.2, 45.5,
119.2, 120.2, 121.9, 125.6, 146.9, 149.9. Elemental analysis
(%) (C12H18O2S): C 63.7, H 8.0 (calcd.); C 63.2, H 7.8
(found).
3-(Isopropylthio)-2,5-dimethylbenzene-1,4-diol was ob-
tained as a white solid, in 82% yield, using hexane/ethyl ace-
tate (6:1) as eluting solvent. Mp 71–74 8C. dH (300 MHz,
CDCl3): 1.23 (d, 6H, J = 6.6), 2.22 (s, 3H), 2.40 (s, 3H),
3.05 (m, 1H, J = 6.4), 4.32 (s, 1H), 6.64 (s, 1H), 6.84 (s,
1H). Elemental analysis (%) (C11H16O2S): C 62.2, H 7.6
(calcd.); C 61.8, H 7.8 (found).
ylthio)benzene-1,4-diol.14 Mp 163–165 8C. IR (KBr, cm–1):
1428, 1471, 2915, 3133, 3314. dH (300 MHz, CDCl3): 2.20
(s, 3H), 2.22 (s, 3H), 2.38 (s, 3H), 4.63 (bs, 1H), 6.57 (s,
1H), 7.27 (d, 2H, J = 7.8), 7.56 (d, 2H, J = 8.1), 10.49 (s,
1H). dC (75 MHz, CDCl3): 12.6, 16.9, 21.8, 119.2, 119.6,
122.1, 126.2, 130.1, 130.7, 140.5, 142.7, 145.4, 154.3. Ele-
mental analysis (%) (C15H16SO3): C 65.2, H 5.8 (calcd.); C
64.9, H 5.8 (found).
( )-3-(Isobutylsulfinyl)-2,5-dimethylbenzene-1,4-diol
was obtained, as a colorless oil, in 87% yield, starting from
3-(isobutylthio)-2,5-dimethylbenzene-1,4-diol. dH (300 MHz,
CDCl3): 1.12 (d, 3H, J = 6.6), 1.16 (d, 3H, J = 6.6), 2.14 (s,
3H), 2.16 (s, 3H), 2.25 (m, 1H), 2.63 (dd, 1H, vic J = 9.3
and gem J = 13.2), 3.36 (dd, 1H, vic J = 4.8 and gem J =
12.9), 4.62 (bs, 1H), 6.70 (s, 1H), 10.51 (s, 1H). dC
(75 MHz, CDCl3): 11.4, 15.3, 21.6, 22.9, 24.4, 62.6, 118.6,
121.0, 121.3, 126.8, 146.0, 152.9.
( )-3-(Isopropylsulfinyl)-2,5-dimethylbenzene-1,4-diol
was obtained, in 79% yield, starting from 3-(isopropylthio)-
2,5-dimethylbenzene-1,4-diol. Mp 129–132 8C. dH (300 MHz,
CDCl3): 1.24 (d, 3H, J = 6.8), 1.45 (d, 3H, J = 6.8), 2.14 (s,
3H), 2.16 (s, 3H), 3.39 (h, 1H, J = 6.5), 6.73 (s, 1H). dC
(75 MHz, CDCl3): 12.4, 15.6, 16.0, 17.1, 54.0, 119.3,
120.4, 121.8, 126.7, 146.3, 153.2.
Step 2: oxidation at the sulfur atom15
To a water cooled solution of the sulfanylbenzene-1,4-diol
(1.1 mmol) in methanol (3 mL) was slowly added a solution
of H2O2 30% (0.11 mL; 1.1 mmol) and SeO2 (0.12 g;
1.1 mmol) in water (1 mL). After 1 h, water (5 mL) was
added, and the mixture was extracted with CHCl3. After
drying (Na2SO4) and concentration, the solid sulfinyl deriva-
tive was isolated.
( )-2,5-Dimethyl-3-(p-tolylsulfinyl)benzene-1,4-diol was
obtained, in 74% yield, starting from 2,5-dimethyl-3-(p-tol-
ylthio)benzene-1,4-diol,14 and was used without purification.
Mp 171–174 8C. dH (300 MHz, CDCl3): 2.13 (s, 3H), 2.22
(s, 3H), 2.38 (s, 3H), 4.80 (bs, 1H), 6.70 (s, 1H), 7.28 (d,
2H, J = 7.5), 7.56 (d, 2H, J = 7.5), 10.61 (bs, 1H). dC
(75 MHz, CDCl3): 11.6, 15.2, 21.4, 119.2, 121.3, 125.8,
126.7, 130.3, 139.8, 142.3, 145.7, 152.4.
Step 3: oxidation with CAN
To a solution of the sulfinyl derivative (1.0 mmol) in
MeCN (10 mL) was added 5 mL of an aqueous solution of
CAN (3.0 mmol), and the resulting mixture was stirred for
1 h at room temperature. After removal of half volume of
the solvent, the quinone was extracted with CH2Cl2. The ex-
( )-3,5-Dimethyl-2-(p-tolylsulfinyl)benzene-1,4-diol was
obtained, in 90% yield, starting from 3,5-dimethyl-2-(p-tol-
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Can. J. Chem. Vol. 87, 2009
tract was dried (Na2SO4) and concentrated under vacuum,
resulting in a red solid.
and the extracts were dried (MgSO4) and concentrated. The
resulting sulfoxide was isolated by column chromatography.
(–)-(S,S)-1,4-Dimethoxy-2-methyl-3-(p-tolylsulfinyl)ben-
zene was obtained, in 37% yield, from 2-bromo-1,4-
dimethoxy-3-methylbenzene16 and (S,S)-menthyl p-toluene-
sulfinate. [a]D –115 (c 1.8, CH2Cl2). dH (300 MHz,
CDCl3): 2.36 (s, 3H), 2.41 (s, 3H), 3.71 (s, 3H), 3.77 (s,
3H), 6.74 (d, 2H, J = 9.0), 6.90 (d, 1H, J = 9.0), 7.21 (d,
2H, J = 8.4), 7.43 (d, 2H, J = 8.4). dC (75 MHz, CDCl3):
11.3, 21.2, 56.3, 56.6, 110.1, 114.5, 124.3, 129.2, 130.2,
132.1, 139.5, 141.5, 152.4, 152.7. Elemental analysis (%)
(C16H18SO3Á1/2H2O): C 64.2, H 6.4 (calcd.); C 64.2, H 6.0
(found).
(–)-(S,S)-1,4-Dimethoxy-2,5-dimethyl-3-(p-tolylsulfinyl)-
benzene was obtained, in 37% yield, from 3-bromo-1,4-
dimethoxy-2,5-dimethylbenzene24 and (S,S)-menthyl p-tol-
uenesulfinate. Mp 132–135 8C. [a]D –123.7 (c 1, CHCl3).
dH (300 MHz, CDCl3): 2.28 (s, 3H), 2.29 (s, 3H), 2.36
(s, 3H), 3.70 (s, 3H), 3.81 (s, 3H), 6.77 (s, 1H), 7.23 (m,
2H), 7.44 (m, 2H). dC (75 MHz, CDCl3): 10.4, 16.0, 21.2,
56.0, 62.1, 116.6, 124.3, 124.8, 127.0, 129.4, 129.9, 136.8,
139.7, 141.6, 151.0, 154.4. Elemental analysis (%)
(C17H20SO3): C 67.1, H 6.6 (calcd.); C 66.8, H 6.7
(found).
( )-2,5-Dimethyl-3-(p-tolylsulfinyl)cyclohexa-2,5-diene-
1,4-dione, ( )-2c (R = pTol), was obtained from ( )-2,5-di-
methyl-3-(p-tolylsulfinyl)benzene-1,4-diol in 82% yield.
Mp 138–139 8C. dH (300 MHz, CDCl3): 2.02 (s, 3H), 2.40
(s, 3H), 2.49 (s, 3H), 6.64 (s, 1H), 7.31 (m, 2H), 7.64 (m,
2H). dC (75 MHz, CDCl3): 9.9, 16.0, 22.0, 125.3, 130.5,
134.1, 140.0, 142.0, 146.1, 146.5, 147.5, 185.2, 186.2.
Elemental analysis (%) (C15H14SO3): C 65.7, H 5.1 (calcd.);
C 65.3, H 5.5 (found).
( )-3,5-Dimethyl-2-(p-tolylsulfinyl)cyclohexa-2,5-diene-
1,4-dione, ( )-2b, was obtained from ( )-3,5-dimethyl-2-(p-
tolylsulfinyl)benzene-1,4-diol in 90% yield. Mp 100–102 8C.
IR (KBr, cm–1): 1630, 1647, 1665, 3044. dH (300 MHz,
CDCl3): 2.04 (d, 3H, J = 1.8), 2.39 (s, 3H), 2.49 (s, 3H),
6.54 (q, 1H, J = 1.5), 7.30 (d, 2H, J = 7.8), 7.63 (d, 2H, J =
8.1). dC (75 MHz, CDCl3): 9.6, 16.5, 21.7, 125.2, 130.4,
133.2, 140.0, 141.9, 146.1, 147.0, 147.2, 184.8, 187.1. Ele-
mental analysis (%) (C15H14SO3): C 65.7, H 5.1 (calcd.); C
65.2, H 5.0 (found).
( )-2,5-Dimethyl-3-(isobutylsulfinyl)cyclohexa-2,5-di-
ene-1,4-dione, ( )-2c (R = iBu), was obtained from ( )-3-
(isobutylsulfinyl)-2,5-dimethylbenzene-1,4-diol
in
87%
(+)-(S,R)-3-(Isopropylsulfinyl)-1,4-dimethoxy-2,5-dime-
thylbenzene was obtained, in 45% yield as a colorless oil,
from 3-bromo-1,4-dimethoxy-2,5-dimethylbenzene24 and
yield. Mp 75–78 8C. IR (KBr, cm–1): 1650, 1603, 1466,
1438, 1042. dH (300 MHz, CDCl3): 1.12 (d, 3H, J = 6.6),
1.19 (d, 3H, J = 6.9), 2.05 (d, 3H, J = 1.5), 2.25 (m, 1H),
2.45 (s, 3H), 3.22 (dd, 1H, J = 4.8 and 12.9), 3.26 (dd, 1H,
vic J = 4.5 and 12.3), 6.69 (q, 1H, J = 1.8). dC (75 MHz,
CDCl3): 9.4, 15.7, 21.6, 23.2, 24.9, 63.4, 134.3, 145.9,
146.3, 148.4, 185.5, 185.8. Elemental analysis (%)
(C12H16SO3): C 60.0, H 6.7 (calcd.); C 59.2, H 6.5 (found).
1,2:5,6-di-O-isopropylidene-a-D-glucofuranosyl
(+)-(R)-2-
propanesulfinate.25 [a]D + 91 (c 0.45, CHCl3). dH (300 MHz,
CDCl3): 1.05 (d, 3H, J = 6.9), 1.44 (d, 3H, J = 6.9), 2.28
(s, 3H), 2.45 (s, 3H), 3.64 (m, 1H), 3.80 (s, 3H), 3.81 (s, 3H),
6.75 (s, 1H). dC (75 MHz, CDCl3): 10.9, 15.8, 16.6, 16.7,
52.0, 55.9, 61.7, 115.8, 127.1, 129.4, 133.9, 150.7, 154.1
( )-2,5-Dimethyl-3-(isopropylsulfinyl)cyclohexa-2,5-di-
ene-1,4-dione, ( )-2c (R = iPr), was obtained from ( )-3-
(isopropylsulfinyl)-2,5-dimethylbenzene-1,4-diol in 78%
yield. Mp 83–84 8C. IR (KBr, cm–1): 1665, 1650, 1595,
1465, 1432, 1059. dH (300 MHz, CDCl3): 1.35 (d, 3H, J =
6.9), 1.40 (d, 3H, J = 7.2), 2.05 (d, 3H, J = 1.8), 2.44 (s,
3H), 3.43 (h, 1H, J = 7.9), 6.70 (q, 1H, J = 1.8). dC
(75 MHz, CDCl3): 9.7, 15.2, 15.8, 17.7, 53.4, 134.4, 144.2,
146.3, 149.9, 185.7, 185.8. Elemental analysis (%)
(C11H14SO3): C 58.4, H 6.2 (calcd.); C 58.7, H 6.0 (found).
Step 2
To a solution of the sulfoxide (1.0 mmol) in MeCN
(5 mL) was added 5 mL of an aqueous solution of CAN
(2.5 mmol), and the resulting mixture was stirred 1 h at
room temperature. After removal of half volume of the sol-
vent, the quinone was extracted with CH2Cl2 (two portions
of 20 mL). The extract was dried (Na2SO4) and concentrated
under vacuum, yielding a solid.
(+)-(S,S)-2-Methyl-3-(p-tolylsulfinyl)cyclohexa-2,5-di-
ene-1,4-dione, (+)-2a, was obtained, in 79% yield, from 1,4-
dimethoxy-2-methyl-3-(p-tolylsulfinyl)benzene. Mp 107–
109 8C. [a]D +898 (c 0.50, CH2Cl2). dH (300 MHz, CDCl3):
2.40 (s, 3H), 2.50 (s, 3H), 6.70 (d, 1H, J = 9.9), 6.80 (d, 1H,
J = 9.9), 7.31 (d, 2H, J = 8.7), 7.63 (d, 2H, J = 8.7). dC
(75 MHz, CDCl3): 9.2, 21.3, 124.8, 130.1, 136.0, 136.8,
139.2, 141.7, 146.0, 146.8, 184.3, 185.9. Elemental analysis
(%) (C14H12SO3Á1/2H2O): C 62.4, H 4.9 (calcd.); C 62.9, H
4.7 (found).
Sulfinyltoluquinones (+)-2a, (+)-2c (R = pTol), and (–)-2c
(R = iPr)
(+)-2a, (+)-2c (R = pTol) and (–)-2c (R = iPr) were
prepared by a two-step procedure, as described below, by
employing the adequate combination of bromo-1,4-
dimethoxyarene and the sulfinylating agent.
Step 1
(+)-(S,S)-2,5-Dimethyl-3-(p-tolylsulfinyl)cyclohexa-2,5-
diene-1,4-dione, (+)-2c (R = pTol), was obtained as a red
solid, in 71% yield, from (–)-(S,S)-1,4-dimethoxy-2,5-
dimethyl-3-(p-tolylsulfinyl)benzene. Mp 136–139 8C.
[a]D +440 (c 0.40, CHCl3). Spectroscopic data are identical
to those described for ( )-2c (R = pTol).
(–)-(S,R)-3-(Isopropylsulfinyl)-2,5-dimethylcyclohexa-
2,5-diene-1,4-dione, (–)-2c (R = iPr), was obtained as a red
solid, in 79% yield, from (+)-(S,R)-3-(isopropylsulfinyl)-1,4-
To a cooled solution (–20 8C) of nBuLi (3.0 mmol) in
ethyl ether (5 mL) was added a solution of the bromo-1,4-
dimethoxy-arene (2.7 mmol) in ethyl ether (5 mL). After
1 h at –20 8C, a solution of the sulfinylating agent
(3.3 mmol) in ethyl ether (5.0 mL) was slowly added. The
mixture was stirred for 2 h at –20 8C and for 1 h at RT.
Cold aqueous saturated ammonium chloride (50 mL) was
added to the mixture, and the organic layer was separated.
The aqueous phase was extracted with ethyl ether (25 mL),
Published by NRC Research Press

de Sousa et al.
1141
dimethoxy-2,5-dimethylbenzene. Mp 82–84 8C. [a]D –806
(c 0.2, CHCl3). Spectroscopic data are identical to those re-
ported for ( )-2c (R = iPr).
vent. dH (300 MHz, CDCl3): 1.10 (d, 3H, J = 6.6), 1.16 (d,
3H, J = 6.6), 1.49 (s, 3H), 1.65 (m, 2H), 2.30 (m, 1H), 2.40
(s, 3H), 2.70 (dd, 1H, J = 4.2 and 12.6), 2.92 (d, 1H, J =
4.2), 3.15 (m, 2H), 3.44 (m, 1H), 6.04 (m, 1H), 6.15 (m, 1H).
( )-Like-4c (R = iPr) was isolated as a yellow oil, in
25% yield, using hexane/ethyl acetate (3:1). dH (300 MHz,
CDCl3): 1.29 (d, 3H, J = 6.6), 1.35 (d, 3H, J = 6.6), 1.49
(s, 3H), 1.59 (m, 2H), 2.31 (s, 3H), 2.91 (d, 1H, J = 3.9),
3.09 (bs, 1H), 3.45 (m, 1H), 3.48 (m, 1H), 6.04 (m, 1H),
6.21 (m, 1H).
( )-Unlike-4c (R = iPr) was isolated as a yellow oil, in
60% yield, using hexane/ethyl acetate (3:1) as eluting sol-
vent. dH (300 MHz, CDCl3): 1.29 (d, 3H, J = 6.0), 1.37 (d,
3H, J = 6.0), 1.52 (s, 3H), 1.60 (m, 2H), 2.38 (s, 3H), 2.90
(d, 1H, J = 3.3), 3.09 (bs, 1H), 3.37 (m, 1H), 3.50 (bs, 1H),
6.04 (m, 1H), 6.13 (m, 1H). dC (75 MHz, CDCl3): 9.6, 15.3,
18.0, 26.9, 46.8, 49.6, 53.8, 53.9, 57.3, 135.5, 138.7, 149.8,
155.7, 197.8, 200.8.
( )-Unlike-6b (R = pTol) was isolated, in 91% yield, as a
yellow solid by employing hexane/ethyl acetate (3.5:1) as
eluting solvent. dH (200 MHz, CDCl3): 1.66 (m, 1H), 1.75
(d, 3H, J = 1.5), 1.81 (s, 3H), 2.29 (m, 1H), 2.41 (s, 3H),
3.24 (bs, 1H), 4.02 (bs, 1H), 5.88 (q, 1H, J = 1.2), 6.05 (m,
1H), 6.22 (m, 1H), 7.27 (m, 2H), 7.49 (m, 2H). dC (50 MHz,
CDCl3): 16.3, 21.5, 25.0, 43.3, 49.6, 54.3, 57.5, 81.4, 126.2,
129.2, 136.8, 137.4, 139.4, 140.3, 142.6, 149.6, 191.2, 201.4.
( )-Unlike-6c (R = pTol) was isolated, in 95% yield, as a
yellow solid, using hexane/ethyl acetate (3.5:1) as eluting
solvent. Mp 111–114 8C. dH (300 MHz, CDCl3): 1.24 (d,
3H, J = 1.5), 1.68 (m, 1H), 1.85 (s, 3H), 2.23 (m, 1H), 2.40
(s, 3H), 3.25 (bs, 1H), 4.09 (bs, 1H), 6.05 (m, 1H), 6.13 (q,
1H, J = 1.5), 6.23 (m, 1H), 7.28 (m, 2H), 7.48 (m, 2H). dC
(75 MHz, CDCl3): 15.3, 21.3, 25.6, 43.3, 50.2, 54.4, 58.0,
81.3, 126.1, 129.7, 136.4, 136.6, 137.7, 140.4, 142.3, 153.2,
192.0, 200.4. Elemental analysis (%) (C20H20SO3): C 70.6,
H 5.9 (calcd.); C 70.7, H 6.0 (found).
(–)-Unlike-6c (R = pTol) was isolated as a yellow oil, in
36% yield, employing hexane/ethyl acetate (3.5:1) as eluting
solvent. [a]D –134 (c 0.5, CHCl3). Spectroscopic data are
identical to those described for ( )-unlike-6c (R = pTol).
( )-Unlike-6c (R = iBu) was isolated as a yellow oil, in
34% yield, using hexane/ethyl acetate (2:1) as eluting sol-
vent. dH (300 MHz, CDCl3): 1.08 (d, 3H, J = 6.9), 1.10 (d,
3H, J = 6.9), 1.50 (s, 3H), 1.61 (m, 1H), 2.02 (d, 3H, J =
1.5), 2.20 (m, 1H), 2.30 (m, 1H), 2.35 (m, 1H), 2.45 (m,
1H), 2.50 (dd, 1H, J = 3.9 and 4.2), 3.20 (bs, 1H), 3.95 (bs,
1H), 6.10 (dd, 1H, J = 2.7 and 3.0), 6.24 (dd, 1H, J = 2.7
and 3.0), 6.50 (q, 1H, J = 1.5). dC (75 MHz, CDCl3): 15.9,
21.7, 22.8, 23.4, 25.4, 43.2, 50.3, 55.2, 57.6, 60.5, 136.5,
138.4, 140.5, 153.1, 193.1, 200.6.
Diels–Alder reactions
Thermal conditions
A solution of sulfinyl-1,4-benzoquinone (1.0 mmol) and
cyclopentadiene (3.0 mmol) in CH2Cl2 (2 mL) was stirred
at –20 8C. After complete consumption of the quinone, the
solvent was removed under vacuum, and the DA adduct
was isolated by column chromatography.
Catalytic conditions
A solution of sulfinylquinone (1.0 mmol) and the Lewis
acid (see Table 1) in CH2Cl2 (2 mL) was stirred at –20 8C for
1 h, and at room temperature for 1 h. The mixture was cooled
to –20 8C, and cyclopentadiene (3.0 mmol) was added. The
mixture was stirred at –20 8C, and after complete consump-
tion of the quinone, the solvent was removed under vacuum,
and the adduct was isolated by column chromatography.
( )-Like-4b was isolated as a yellow solid, in 40% yield,
using hexane/ethyl acetate (4.5:1) as eluting solvent. Mp 97–
99 8C. IR (KBr, cm–1): 1329, 1659, 1673, 2977. dH
(300 MHz, CDCl3): 1.47 (s, 3H), 1.48 (m, 1H), 1.65 (m,
1H), 2.32 (s, 3H), 2.39 (s, 3H), 2,92 (d, 1H, J = 3.9), 3.04 (s,
1H), 3.35 (s, 1H), 5.56 (m, 1H), 5.96 (m, 1H), 7.29 (m, 2H),
7.55 (m, 2H). dC (75 MHz, CDCl3): 9.9, 21.8, 26.8, 46.8,
49.3, 53.5, 54.2, 58.1, 125.2, 130.4, 135.0, 141.8, 138.6,
139.5, 151.9, 152.8, 196.9, 201.7. Elemental analysis (%)
(C20H20SO3): C 70.6, H 5.9 (calcd.); C 69.9, H 6.2 (found).
( )-Unlike-4b was isolated as a yellow oil, in 30% yield,
using hexane/ethyl acetate (4.5:1) as eluting solvent. dH
(300 MHz, CDCl3): 1.41 (s, 3H), 1.54 (m, 1H), 1.64 (m,
1H), 2.37 (s, 3H), 2.39 (s, 3H), 2.77 (d, 1H, J = 3.9), 3.06
(s, 1H), 3.39 (s, 1H), 6.02 (m, 1H), 6.06 (m, 1H), 7.29 (m,
2H), 7.60 (m, 2H). dC (75 MHz, CDCl3): 10.8, 21.8, 27.0,
47.0, 49.5, 53.6, 54.4, 58.2, 125.4, 130.4, 135.6, 138.4,
140.0, 141.9, 151.7, 153.0, 196.2, 201.5.
( )-Like-4c (R = pTol) was isolated as a yellow oil in ad-
mixture with ( )-unlike-4c (R = pTol), using hexane/ethyl
acetate (3.5:1) as eluting solvent. dH (300 MHz, CDCl3):
1.25 (s, 3H), 1.55 (m, 2H), 2.39 (s, 3H), 2.40 (s, 3H), 2.80
(d, 1H, J = 3.9), 3.04 (m, 1H), 3.42 (m, 1H), 6.01 (m, 1H),
6.14 (m, 1H), 7.29 (m, 2H), 7.58 (m, 2H).
( )-Unlike-4c (R = pTol) was isolated as a yellow oil in
admixture with ( )-like-4c (R = pTol) using hexane/ethyl
acetate (3.5:1) as eluting solvent. dH (300 MHz, CDCl3):
1.49 (s, 3H), 1.55 (m, 2H), 2.35 (s, 3H), 2.40 (s, 3H), 2.86
(d, 1H, J = 3.9), 3.04 (m, 1H), 3.40 (m, 1H), 5.67 (dd, 1H,
J = 3.0 and 2.4), 5.82 (dd, 1H, J = 3.0 and 2.4), 7.58 (m,
2H), 7.49 (m, 2H).
(–)-Unlike-4c (R = iPr) was isolated as a yellow oil, in
56% yield, using hexane/ethyl acetate (6:1). [a]D –132 (c 0.5,
CHCl3). Spectroscopic data are identical to those described
for ( )-unlike-4c (R = iPr).
( )-Like-4c (R = iBu) was isolated as a yellow oil, in
22% yield, using hexane/ethyl acetate (2:1) as eluting sol-
vent. dH (300 MHz, CDCl3): 1.10 (d, 3H, J = 6.6), 1.16 (d,
3H, J = 6.6), 1.49 (s, 3H), 1.65 (m, 2H), 2.30 (m, 1H), 2.31
(s, 3H), 2.70 (dd, 1H, J = 4.2 and 12.6), 2.92 (d, 1H, J =
4.2), 3.08 (bs, 1H), 3.20 (dd, 1H, J = 4.5 and 12.6), 3.44
(bs, 1H), 6.04 (m, 1H), 6.23 (m, 1H).
Desulfurization reactions
Using Al–Hg
To a solution of the DA adduct (0.42 mmol) in THF/
water (9:1; 12 mL), pieces of aluminum foil19 (1.0 g; re-
cently immersed into a HgCl2 aqueous solution and washed
( )-Unlike-4c (R = iBu) was isolated as a yellow oil, in
20% yield, using hexane/ethyl acetate (2:1) as eluting sol-
Published by NRC Research Press

1142
Can. J. Chem. Vol. 87, 2009
bela, R.; MacAlpine, G. A.; Stojanac, Z.; Valenta, Z. Can.
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with ethanol and ethyl ether) were added, and the mixture
was stirred at room temperature for 3.5 h. The solids were
filtered off, and the solvent was removed under vacuum. The
residue was submitted to flash chromatography separation.
Using Raney–Ni
A suspension of Raney–Ni (W222 or deactivated;23 ~1 mL
of the decanted solid metal) in ethanol (5 mL) was added to
a solution of the DA adduct (0.45 mmol) in ethanol (10 mL)
under stirring at room temperature. The desulfurization proc-
ess was monitored by the consumption of the DA adduct (by
TLC). The residual metal was removed by filtration, and the
solvent was evaporated under vacuum. The residue was pu-
rified by flash chromatography.
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Using Ni2B21
To a well-stirred mixture of the DA adduct (0.21 mmol)
and NiCl2Á6H2O (0.10 g; 0.42 mmol) in methanol/THF (3:1;
12 mL) at 0 8C, NaBH4 (0.050 g; 1.3 mmol) was added, re-
sulting in a black solid. After 15 min, the mixture was fil-
tered over Celite, and the solvent was removed under
vacuum. The residue was dissolved in CH2Cl2 (20 mL) and
washed with water (20 mL). After drying (Na2SO4) and con-
centration under vacuum, the residue was purified by flash
chromatography.
( )-4a,7-Dimethyl-1,2,3,4,4a,8a-hexahydro-1,4-meth-
ano-naphthalene-5,8-dione, 8, was isolated as a colorless
oil, in 40% yield, using hexane/ethyl acetate (3:1) as eluting
solvent. dH (300 MHz, CDCl3): 1.25 (s, 3H), 1.35 (m, 1H),
1.45 (m, 2H), 1.69 (m, 1H), 1.97 (bs, 2H), 2.02 (d, 3H, J =
1.5), 2.48 (bs, 1H), 2.56 (dd, 1H, J = 1.5 and 1.8), 2.86 (bs,
1H), 6.56 (q, 1H, J = 1.5).
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Supplementary data
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca) or may be purchased
from the Depository of Unpublished Data, Document Deliv-
ery, CISTI, National Research Council Canada, Ottawa, ON
K1A 0R6, Canada. DUD 3978. For more information on ob-
taining material, refer to cisti-icist.nrc–Cnrc.gc.ca/cms/
unpub_e.shtml.
Acknowledgement
`
We acknowledge Fundac¸a˜o de Amparo a Pesquisa do Es-
tado de Sa˜o Paulo (FAPESP), Conselho Nacional de Desen-
2002,
41
(15),
2755–2757.
doi:10.1002/1521-
´
´
Tecnologico (CNPq), and
volvimento Cientıfico
e
3773(20020802)41:15<2755::AID-ANIE2755>3.0.CO;2-A.
PMID:12203475.; (d) Boezio, A. A.; Jarvo, E. R.; Lawrence,
B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 2005,
44 (37), 6046–6050. doi:10.1002/anie.200502178. PMID:
16108082.; (e) Carren˜o, M. C.; Somoza, A.; Ribagorda, M.;
Urbano, A. Chem. Eur. J. 2007, 13 (3), 879–890. doi:10.
1002/chem.200600809.
´
Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nıvel Supe-
rior (CAPES) for financial support.
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