Diels-Alder reactions with 2-(arylsulfinyl)-1,4-benzoquinones: Effect of aryl substitution on reactivity, chemoselectivity, and π-facial diastereoselectivity

Article abstract of DOI:10.1021/jo9913107

Diels-Alder reactions of (SS)-2-(2'-methoxynaphthylsulfinyl)-1,4- benzoquinone (1b), 2-(p-methoxyphenylsulfinyl)-1,4-benzoquinone (1c), and 2- (p-nitrophenylsulfinyl)-1,4-benzoquinone (1d) with cyclopentadiene are reported. These cycloadditions allowed the highly chemo- and stereoselective formation of both diastereoisomeric endo-adducts resulting from reaction on the unsubstituted double bond C₅-C₆ of quinones working under thermal and Eu(fod)₃- or BF₃ · OEt₂-catalyzed conditions. The synthesis of endo- adduct [4aS*,5S*,8R*,8aR*,SS*]-9d resulting from cycloaddition on the substituted C₂-C₃ double bond was achieved in a chemo- and diastereoselective way from quinone 1d in the presence of ZnBr₂. The reactivity and selectivity of the process proved to be dependent on the electron density of the arylsulfinyl group.

Full text of DOI:10.1021/jo9913107

J . Org. Chem. 2000, 65, 453-458
453
Diels-Ald er Rea ction s w ith 2-(Ar ylsu lfin yl)-1,4-ben zoqu in on es:
Effect of Ar yl Su bstitu tion on Rea ctivity, Ch em oselectivity, a n d
π-F a cia l Dia ster eoselectivity
M. Carmen Carren˜o,* J ose´ L. Garc´ıa Ruano,* Antonio Urbano, Cynthia Z. Remor,† and
Yolanda Arroyo‡
Departamento de Quı´mica Orga´nica (C-I), Universidad Auto´noma, Cantoblanco, 28049-Madrid, Spain
Received August 17, 1999
Diels-Alder reactions of (SS)-2-(2′-methoxynaphthylsulfinyl)-1,4-benzoquinone (1b), 2-(p-methoxy-
phenylsulfinyl)-1,4-benzoquinone (1c), and 2-(p-nitrophenylsulfinyl)-1,4-benzoquinone (1d ) with
cyclopentadiene are reported. These cycloadditions allowed the highly chemo- and stereoselective
formation of both diastereoisomeric endo-adducts resulting from reaction on the unsubstituted
double bond C5-C6 of quinones working under thermal and Eu(fod)3- or BF3‚OEt2-catalyzed
conditions. The synthesis of endo-adduct [4aS*,5S*,8R*,8aR*,SS*]-9d resulting from cycloaddition
on the substituted C2-C3 double bond was achieved in a chemo- and diastereoselective way from
quinone 1d in the presence of ZnBr2. The reactivity and selectivity of the process proved to be
dependent on the electron density of the arylsulfinyl group.
In tr od u ction
benzoquinone (1a ) (Figure 1), a system bearing two
dienophilic double bonds, reacted with cyclic dienes on
the unsubstituted double bond C5-C6 in a highly endo
and π-facial diastereoselective manner (up to 78% de).3a,5a
When the benzoquinone bears a substituent at C5 and/
or C6, cycloaddition occurs on the sulfinyl-substituted
double bond with both cyclic and acyclic dienes.8 (SS)-2-
(p-Tolylsulfinyl)naphthazarin (2),9 another ambident di-
enophile due to the tautomeric equilibrium shown in
Figure 1, has a reactivity profile similar to that of 1a ,
giving rise mainly to the corresponding adducts resulting
from cyclopentadiene cycloadditions on the unsubstituted
C2-C3 double bond of tautomer A (up to 40% de). A
satisfactory and consistent rationale had not yet been
found to explain the stereoselectivity of these cycloaddi-
tions, steric factors being excluded as responsible for the
diastereoselection achieved, due to the distance between
the sulfinyl substituent and the reacting unsubstituted
double bond. Up to date, reaction of cyclic dienes on the
sulfinyl-substituted dienophilic double bond of these
ambident dienophiles had not been achieved.
Although quinones are among the best dienophiles
traditionally used in Diels-Alder reactions, few examples
of chiral derivatives1 for their use in asymmetric syn-
thesis2 are known, despite their potential to construct
structurally complex molecules in enantiomerically pure
form. Some years ago, we reported the short and efficient
synthesis of enantiomerically pure (SS)-2-(p-tolylsulfi-
nyl)-1,4-quinones3 and started the study of their behavior
as dienophiles.4 Reactions with acyclic dienes took place
through a sequential Diels-Alder cycloaddition/pyrolytic
sulfoxide elimination, giving rise to enantiomerically
enriched polycyclic dihydroquinones.5 This process, coupled
with the kinetic resolution of a chiral racemic vinylcy-
clohexene which occurred simultaneously,6 was further
applied to the enantioselective synthesis of several an-
gucyclinones.7 The simplest (SS)-2-(p-tolylsulfinyl)-1,4-
† On leave from the Instituto de Qu´ımica/UFRGS, Porto Alegre (RS),
Brazil.
‡ On leave from the Departamento de Qu´ımica Orga´nica, E.T.S.I.I.,
Valladolid, Spain.
We report herein a series of experimental results which
show that the introduction of electron-donating or electron-
withdrawing substituents in the aryl sulfoxide and the
appropriate choice of the Lewis acid catalyst allows the
reactivity, chemoselectivity, and π-facial diastereoselec-
tion to be controlled and modified in reactions between
2-(arylsulfinyl)-1,4-benzoquinones and cyclopentadiene.
The influence of the arylsulfinyl substitution on the
diastereoselectivity of several processes10 such as â-ad-
ditions of nucleophiles10b and free radicals10c to vinylar-
ylsulfoxides had been already pointed out by other
(1) (a) Beagley, B.; Curtis, A. D. M.; Pritchard, R. G.; Stoodley, R.
G. J . Chem. Soc., Perkin Trans. 1 1992, 1981. (b) Brimble, M. A.;
McEwan, J . F.; Turner, P. Tetrahedron: Asymmetry 1998, 9, 1239. (c)
Brimble, M. A.; Duncalf, L. J .; Reid, D. C. W.; Roberts, T. R.
Tetrahedron 1998, 54, 5363.
(2) For general reviews on asymmetric Diels-Alder reactions, see:
(a) Oppolzer, W. In Comprehensive Organic Syntheses; Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford 1991, Vol. 5, pp
315-399. (b) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876.
(c) Taschner, M. J . In Asymmetric Diels-Alder Reactions; Taschner,
M. J ., Ed.; J AI Press Inc.: Greenwich, 1989; Vol. 1, pp 1-101.
(3) (a) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A. Tetrahedron
Lett. 1989, 30, 4003. (b) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano,
A. Tetrahedron 1991, 47, 605. (c) Carren˜o, M. C.; Garc´ıa Ruano, J . L.;
Urbano, A. Synthesis 1992, 651.
(4) For an overview of our work, see: (a) Carren˜o, M. C. Chem. Rev.
1995, 95, 1717. (b) Garc´ıa Ruano, J . L.; Carren˜o, M. C.; Carretero, J .
C.; Mart´ın Cabrejas, L. M. Urbano, A. Pure Appl. Chem. 1996, 68, 925.
For more recent references, see: (c) Carren˜o, M. C.; Herna´ndez-
Sa´nchez, R.; Mahugo, J .; Urbano, A. J . Org. Chem. 1999, 64, 1387 and
references therein.
(5) (a) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Toledo, M. A.; Urbano,
A.; Remor, C. Z.; Stefani, V.; Fischer, J . J . Org. Chem. 1996, 61, 503.
(b) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Remor, C. Z.; Urbano, A.
Tetrahedron Lett. 1997, 38, 9077. (c) Carren˜o, M. C.; Garc´ıa-Cerrada,
S.; Urbano, A.; Di Vitta, C. Tetrahedron: Asymmetry 1998, 9, 2965.
(6) (a) Carren˜o, M. C.; Urbano, A.; Fischer, J . Angew. Chem., Int.
Ed. Engl. 1997, 36, 1621. (b) Carren˜o, M. C.; Urbano, A.; Di Vitta, C.
J . Org. Chem. 1998, 63, 8320.
(7) (a) Carren˜o, M. C.; Urbano, A.; Di Vitta, C. Chem. Commun.
1999, 817. (b) Carren˜o, M. C.; Urbano, A.; Di Vitta, C. Chem. Eur. J .,
in press.
(8) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Lafuente, C.; Toledo, M. A.
Tetrahedron: Asymmetry 1999, 10, 1119.
(9) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A. Tetrahedron Lett.
1994, 35, 3789.
10.1021/jo9913107 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/02/2000

454 J . Org. Chem., Vol. 65, No. 2, 2000
Carren˜o et al.
Sch em e 2
F igu r e 1.
benzoquinone (4c) and 2-(p-nitrophenylthio)-1,4-benzo-
quinone (4d ). These compounds were prepared in 88%
and 65% isolated yields, according to an old reported
procedure14 based on the reaction between 2 equiv of 1,4-
benzoquinone and 4-methoxy- and 4-nitrothiophenols, 3c
and 3d , respectively. Direct controlled oxidation of thio-
ether 4d (1 equiv of m-CPBA, CHCl3) gave a 75% yield
of (()-2-(p-nitrophenylsulfinyl)-1,4-benzoquinone (1d ).
Nevertheless, the same oxidation on p-methoxyphenyl
thiosubstituted quinone 4c by using either m-CPBA or
NaIO4 afforded mixtures of unreacted thioether and
variable amounts of the sulfoxide and the sulfone, in a
process lacking synthetic usefulness. Racemic sulfi-
nylquinone 1c could then be prepared in a more versatile
four-step sequence (Scheme 1), starting from reduction
of the quinone ring of thioether 4c with Na2S2O4, followed
by methylation (Me2S2O4/K2CO3) of the resulting hydro-
quinone, to give derivative 5c in quantitative yield.
Controlled oxidation of thioether 5c with 1 equiv of NaIO4
afforded in 91% yield aromatic sulfoxide (()-6c which,
after final oxidative demethylation with CAN, gave
sulfinylbenzoquinone (()-1c in 76% yield.
Sch em e 1a
a
Conditions: (a) EtOH, rt, 0.5 h for 4c and 15 h for 4d , 88%
for 5c and 65% for 5d . (b) m-CPBA, CH2Cl2, rt, 18 h, 75%. (c) (i)
Na2S2O4, Et2O/H2O, rt; (ii) Me2SO4, K2CO3, acetone/H2O, reflux,
14 h, 100%. (d) NaIO4, EtOH/H2O, reflux, 2 h, 91%. (e) CAN,
CH3CN/H2O, rt, 1 h, 76%.
With the desired differently substituted arylsulfinyl-
benzoquinones 1b-d in hand, we began the study of their
Diels-Alder reactions with cyclopentadiene under ther-
mal conditions and in the presence of different Lewis
acids such as BF3‚OEt2, Eu(fod)3, and ZnBr2. The results
obtained are collected in Scheme 2 and Table 1. We have
included data5a for cycloadditions with p-tolyl derivative
(+)-1a for comparison purposes. All cycloadditions were
performed in CH2Cl2 as solvent and took place with good
to excellent yields (60-98%). Diastereoisomeric ratios
were determined from integration of well-separated
signals in the 1H NMR spectra of the crude reaction
mixtures.
authors. The importance of such substitution on the
chemoselectivity of a Diels-Alder reaction is studied here
for the first time.
Resu lts
Enantiomerically pure (SS)-2-(2′-methoxynaphthyl-
sulfinyl)-1,4-benzoquinone (1b)11 was prepared following
the two-step general procedure previously described by
us,3c based on the Andersen’s synthesis,12 using (-)-(SS)-
menthyl-2-methoxynaphthalenesulfinate13 as sulfinylat-
ing agent.
As can be seen (Scheme 2, Table 1, entries 1-4), all
thermal reactions were carried out at -20 °C, giving rise
to mixtures of only two adducts, 7a -d and 8a -d , out of
the eight possible isomers, in excellent yields. Both
adducts resulted from the endo approach of cyclopenta-
diene on the two diastereotropic faces of the unsubtituted
C5-C6 double bond of sulfinylquinones 1a -d and could
be separated diastereoisomerically pure after flash chro-
matography. The configurations shown in Scheme 2 for
all 7 and 8 were established by comparison with the
Sulfinylbenzoquinones 1c and 1d were prepared in
racemic form as outlined in Scheme 1, starting from the
corresponding thioethers 2-(p-methoxyphenylthio)-1,4-
(10) (a) Lee, A. W. M.; Chan, W. H.; Tao, Y.; Lee, Y. K. J . Chem.
Soc., Perkin Trans. 1 1994, 477. (b) Posner, G. H.; Frye, L. L.; Hulce,
M. Tetrahedron 1984, 40, 1401. (c) Mase, N.; Watanabe, Y.; Ueno, Y.;
Toru, T. J . Chem. Soc., Pertkin Trans. 1 1998, 1613.
(11) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A.; Remor, C. Z.;
Arroyo, Y. Tetrahedron: Asymmetry 1999, 10, 4357.
(12) Andersen, K. K.; Gafield, W.; Papanicolaou, N. E.; Foley, J . W.;
Perkins, R. I. J . Am. Chem. Soc. 1964, 86, 5637.
(13) Pyne, S. G.; Hajipour, A. R.; Prabakaran, K. Tetrahedron Lett.
1994, 35, 645.
(14) Snell, J . M.; Weissberger, A. J . Am. Chem. Soc. 1939, 61, 450.

Diels-Alder Reactions with 1,4-Benzoquinones
J . Org. Chem., Vol. 65, No. 2, 2000 455
Ta ble 1. Diels-Ald er Rea ction s of 2-(Ar ylsu lfin yl)-1,4-ben zoqu in on es 1a -d w ith Cyclop en ta d ien e in CH2Cl2
entry
sulfinyl quinone
aryl substitution
Lewis acid (equiv)
T (°C)
time (h)
7:8 (% de)
9 (% de)
yield (%)b
1a
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
p-tolyl
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-78
rt
16
16
15
2
0.5
3
1.25
0.4
0.5
0.75
0.3
0.05
0.05
0.3
0.5
0.05
71:29 (42)
63:37 (26)
68:32 (36)
66:34 (32)
80:10 (78)
82:18 (64)
78: 8 (82)
58:19 (50)
10:90 (80)
5:95 (90)
5:95 (90)
19:81 (62)
20:20 (0)
42:58 (16)
32:32 (0)
6:4 (20)
95
98
98
95
80
90
87
87
90
92
92
65
83
60
75
70
2-methoxynaphthyl
p-methoxyphenyl
p-nitrophenyl
p-tolyl
2-methoxynaphthyl
p-methoxyphenyl
p-nitrophenyl
p-tolyl
2-methoxynaphthyl
p-methoxyphenyl
p-nitrophenyl
p-tolyl
2-methoxynaphthyl
p-methoxyphenyl
p-nitrophenyl
Eu(fod)3 (2)
Eu(fod)3 (2)
Eu(fod)3 (2)
Eu(fod)3 (2)
BF3‚OEt2 (5)
BF3‚OEt2 (5)
BF3‚OEt2 (5)
BF3‚OEt2 (5)
ZnBr2 (2)
10 (100)
14 (100)
23 (100)
9a
10
11
12
13a
14
15
16
60 (100)
ZnBr2 (2)
ZnBr2 (2)
ZnBr2 (2)
rt
rt
rt
36 (100)
90 (100)
a
b
Data taken from ref 5a . Mixture of adducts.
analogue derivatives 7a and 8a resulting from cycload-
ditions of 2-(p-tolylsulfinyl)-1,4-benzoquinone (1a ) with
cyclopentadiene.15 Diastereoisomers 7b-d proceeding
from the attack of the diene on the bottom face of the
quinone moiety were the major isomers in all cases, the
diastereoisomeric excesses (de) being in the range 26-
42%. When we used Eu(fod)3 as Lewis acid (Table 1,
entries 5-8), increases of reactivity and π-facial diaste-
reoselectivity for cycloadditions on C5-C6 were observed.
The chemoselectivity of the process was dependent on the
nature of the substituent of the arylsulfinyl group.
Starting from sulfinylbenzoquinone 1b only compounds
7b and 8b were formed (entry 6) whereas in reactions
with 1a , 1c, and 1d a small amount of derivatives 9a
(10%, entry 5), 9c (14%, entry 7), and 9d (23%, entry 8),
resulting from reaction on the C2-C3 sulfinyl-substituted
double bond, was obtained together with the correspond-
ing derivatives 7 and 8. The formation of only one
diastereoisomer in the cycloadditions on C2-C3 revealed
the efficient control exerted by the sulfinyl group on the
π-facial selectivity when it is situated on the reactive
double bond.
A study of the influence of BF3‚OEt2 on these cycload-
ditions was also carried out (Table 1, entries 9-12).
Diels-Alder reactions were performed in the presence
of 5 equiv of the Lewis acid at -20 °C, except for
sulfinylquinone 1d whose cycloaddition was conducted
at -78 °C (entry 12). In all cases, we observed a
chemoselective evolution through the unsubstituted C5-
C6 double bond of sulfinylquinones 1a -d with an inver-
sion of the π-facial diastereoselectivity in comparison
with thermal and Eu(fod)3-catalyzed conditions. Diaste-
reoisomers 8a -d , proceeding from the attack of the diene
on the upper face of the quinone moiety were, under these
conditions, the major products. The π-facial diastereose-
lectivity of the process increased significantly when the
electron density of the aromatic sulfinyl substituent
became higher, ranging from 62% for 4-nitrophenyl-
substituted quinone 1d (entry 12) to 90% for meth-
oxyaryl-substituted quinones 1b and 1c (entries 10 and
11).
substituted derivative 1b led again to the exclusive
formation of 7b and 8b in a 42:58 ratio (entry 14). Under
these conditions, the chemoselectivity of cycloadditions
of quinones 1a , 1c, and 1d is strongly influenced by the
nature of the aryl substituent. Thus, 2-(p-methoxyphen-
ylsulfinyl)-1,4-benzoquinone (1c) gave a 36% yield of
derivative 9c (entry 15), p-tolylsulfinyl derivative 1a gave
a 60% yield of 9a (entry 13), and 2-(p-nitrophenylsulfi-
nyl)-1,4-benzoquinone (1d ) afforded a 90% yield of com-
pound 9d (entry 16), all of them resulting from the highly
diastereoselective cycloaddition of cyclopentadiene on
C2-C3. In all cases, the π-facial diastereoselection of
reaction on the C5-C6 double bond was low, ranging from
0 to 20%.
Discu ssion
A significant feature of these results was the higher
reactivity of p-nitrophenyl-substituted quinone 1d (2 h,
entry 4) if compared with that of quinones 1a -c (15-16
h, entries 1-3) in all experimental conditions. A serious
increase of the dienophile reactivity with the strong
electron-withdrawing character of the arylsulfinyl sub-
stituent is evident. This effect was noticed even when
cycloadditions took place on the unsubstituted C5-C6
double bond, suggesting that it was efficiently transmit-
ted through the entire conjugate quinonic system.
To rationalize the results achieved in Diels-Alder
reactions with 2-(arylsulfinyl)-1,4-benzoquinones 1a -d ,
we must differentiate the chemoselectivity and the
π-facial diastereoselectivity. Under thermal and BF3‚
OEt2-catalyzed conditions, highly chemoselective cycload-
ditions occurred from the unsubstituted C5-C6 double
bond, regardless of the sulfinyl substituent. This result
has already been explained5a on the basis of steric
interactions destabilizing the endo transitions states
resulting from the attack on C2-C3.16
When cycloadditions were carried out in the presence
of Eu(fod)3, a dependence of chemoselectivity with the
arylsulfinyl substitution was observed. A reactive associ-
ated species, A (Figure 2), would explain the slight
increase of C2-C3 double bond reactivity observed for 1a
(10% of 9a ), 1b (14% of 9c), and 1d (23% of 9c). In the
When Diels-Alder reactions were performed in the
presence of ZnBr2, sulfinylquinones 1a , 1c, and 1d
afforded variable mixtures of cycloadducts 7, 8, and 9
(entries 13, 15, and 16), whereas 2-methoxynaphthyl-
(16) The high ratios of exo adducts obtained in Diels-Alder reactions
between 2-substituted cyclohexenones and cyclic dienes have been
justified on the basis of similar destabilizing interactions in the endo
transition states. See: Angell, E. C.; Fringuelli, F.; Guo, M.; Minuti,
L.; Taticchi, A.; Wenkert, E. J . Org. Chem. 1988, 53, 4325.
(15) For a detailed discussion of a similar configurational assign-
ment, see ref 5a.

456 J . Org. Chem., Vol. 65, No. 2, 2000
Carren˜o et al.
F igu r e 3.
only occur when such an orbital is oriented parallel to
the π-orbital system (Figure 2). A distortion of the
π-orbital quinonic lobes must increase the electron
density of the face opposite the sulfur electron pair. The
result may be more accurately described as a donation
to the LUMO of the quinone. In accordance with the
reactive s-trans conformation (A in Figure 2), present
under Eu(fod)3-catalyzed conditions, the approach of an
electron-rich diene such as cyclopentadiene to the C5-
C6 quinonic double bond must occur from the bottom face
with the lower electron density (Figure 2). A similar
distortion of the quinone π-cloud in the reactive confor-
mation s-cis when BF3‚OEt2 is present would favor the
diene attack on the top face of C5-C6, explaining the
major formation of diastereoisomers 8.
F igu r e 2.
case of 2-methoxynaphthylsulfinylquinone 1b, the proxi-
mal disposition between the methoxy group and the
sulfinylic oxygen suggests a possible competition for the
association with Eu(fod)3 (B in Figure 2), which would
decrease C2-C3 reactivity.
The participation of A in the conformational equilib-
rium as well as the reactivity of the sulfinyl substituted
C2-C3 double bond must be increased in the presence of
ZnBr2. Under these conditions, chemoselectivity is clearly
related to the electron density of the aromatic sulfinyl
moiety (90% for 1d > 60% for 1a > 36% for 1c).
The diastereoselectivity observed when cycloadditions
occurred on the C5-C6 unsubstituted double bond is
noteworthy considering the remote position of the sul-
foxide with respect to the reacting double bond. This
remoteness as well as the low π-facial diastereoselectivity
observed when quinone 1b, with the bulkiest 2-methoxy-
naphthylsulfinyl substituent, reacted under thermal
conditions (Table 1, entry 2) suggested ruling out steric
effects as responsible for the observed results. The
[4aR,5S,8R,8aS,SS] relative configuration of the major
adducts 7 formed in the presence of Eu(fod)3 (Table 1,
entries 5-8) must be a consequence of the attack of
cyclopentadiene from the bottom face of the reactive
s-trans conformation A.
When BF3‚OEt2 was the catalyst, the π-facial diaste-
reoselectivity of cycloadditions at C5-C6 was inverted
with respect to that resulting with Eu(fod)3. In this case,
the reactive conformation must be s-cis (C in Figure 2).
The endo approach of cyclopentadiene from the upper
face of C would give adducts 8 with the [4aS,5R,8S,
8aR,SS] relative configuration. Under these conditions,
higher diasteroselection was observed for dienophiles
with electron-rich aromatic groups: 90% de for 1b and
1c, 80% for 1a , and 62% for 1d .
The availability of the lone electron pair at sulfur is
dependent on the electron density of the arylsulfinyl
group. As a consequence, the strong electron-withdrawing
ability of the p-nitrophenyl substituent of 1d may de-
crease the diastereoselectivity of the process under all
experimental conditions.
The low diastereoselectivity achieved in reactions
through C5-C6 in the presence of ZnBr2 (entries 13-16,
de 0-20%) is more difficult to explain. Although an
associated species such as A (Figure 2) must react when
Eu(fod)3 or ZnBr2 is present in the reaction medium, a
detailed analysis of the interactions existent in each
bicyclic species revealed significant differences. A half-
chair such as A1 (Figure 3), with the bulky aryl substitu-
ent of the sulfoxide in a pseudoequatorial disposition,
must be the reactive species in the presence of Eu(fod)3.
In the similar chelate formed with ZnBr2 (A2 in Figure
3), the shorter Zn-O bond distance could produce a
destabilizing repulsion between the proximal sulfur lone
electron pair and those of the axial bromine, shifting the
conformational equilibrium to a boatlike conformation
such as A3. The inverted half-chair A4 shows a strongly
destabilizing (Br/Ar)-1,3-parallel interaction. Thus, in A1
the pseudoaxial lone electron pair at sulfur is prone to
desymmetrize the π-orbital system of the quinone, jus-
tifying the high diastereoselectivities observed with Eu-
(fod)3. In the case of reactive rotamer A3, the pseudoequa-
torial nonbonding sulfur orbital is not appropriately
situated to overlap with the π-cloud of the dienophile.
This must be the origin of the low π-facial diastereose-
lection achieved in cycloadditions on the unsubstituted
double bond C5-C6 in the presence of ZnBr2. When
cyclopentadiene reacts through the substituted C2-C3
double bond, the attack on both A1 and A3 conformations
is favored by steric and stereoelectronic factors from the
Such strong influence of the arylsulfinyl group on the
reaction rate and diastereoselectivity of C5-C6 cycload-
ditions could be explained invoking an extended desym-
metrization of the π-cloud due to the interaction with the
sulfur lone electron pair orbital. An efficient overlap17 can
(17) Liotta, C. L. Tetrahedron Lett. 1975, 519.

Diels-Alder Reactions with 1,4-Benzoquinones
J . Org. Chem., Vol. 65, No. 2, 2000 457
The mixture was stirred for 18 h at room temperature and
washed with saturated aqueous solution of NaHCO3. After
workup and crystallization (CH2Cl2/hexane), compound 1d was
obtained as an orange solid in 75% yield: mp 168-170 °C; 1H
NMR δ 8.34 and 8.02 (AA′BB′ system, 4H), 7.44 (d, 1H, J )
2.0 Hz), 6.84 (dd, 1H, J ) 2.0 and 10.1 Hz), 6.78 (d, 1H, J )
10.1 Hz); 13C NMR δ 183.4 (2C), 154.4, 150.0, 148.6, 137.8,
136.3, 132.6), 126.7 (2C), 124.6 (2C). IR νmax 1660, 1345, 1090;
EI-MS m/z (rel intens) 277 (M+, 100), 261 (34), 245 (12), 216
(19), 187 (16), 139 (16), 107 (46), 79 (86); HRMS (EI) calcd for
bottom face of the quinone, giving rise to the exclusive
formation of adducts [4aS,5S,8R,8aR,SS]-9.
Con clu d in g Rem a r k s
We have demonstrated that the reactivity, chemose-
lectivity, and π-facial diasteroselectivity of Diels-Alder
reactions of 2-(arylsulfinyl)-1,4-benzoquinones 1a -d and
cyclopentadiene are related to the electron-donating or
electron-withdrawing character of the substituent at the
aromatic sulfoxide as well as the Lewis acid employed.
In the presence of BF3‚OEt2, cycloadditions occurred
exclusively on the unsubstituted double bond C5-C6,
affording diastereoisomers 8 as major isomers (up to 90%
de for quinones 1b and 1c), whereas Eu(fod)3 directed
the attack mainly on C5-C6 with the opposite π-facial
diastereoselection, affording predominantly diastereo-
isomers 7 (up to 82% de for quinone 1c). The opposite
chemoselection (90% of the cycloaddition from the sulfi-
nyl-substituted double bond C2-C3) was achieved from
quinone 1d in the presence of ZnBr2, yielding exclusively
diastereoisomer 9d (100% de).
C
12H7NO5S 277.004 49, found 277.004 83.
1,4-Dim eth oxy-2-(p-m eth oxyp h en ylth io)ben zen e (5c).
A solution of 4c (2.14 g, 8.7 mmol) in Et2O (90 mL) was shaken
in a separatory funnel with Na2S2O4 (1.5 g, 8.7 mmol) in H2O
(90 mL) until the organic layer became colorless. After workup,
the residue containing the corresponding hydroquinone was
dissolved in acetone (10 mL) and added to a suspension of K2-
CO3 (2.37 g, 17.2 mmol) in acetone (25 mL), together with Me2-
SO4 (0.54 mL, 5.7 mmol). The mixture was refluxed for 14 h,
hydrolyzed with NH4OH (25%, 5.08 mL), and neutralized with
10% HCl. After workup and crystallization (MeOH), compound
5c was obtained pure as a yellow solid in quantitative yield:
mp 132-133 °C; 1H NMR δ 7.44 and 6.92 (AA′BB′ system, 4H),
6.77 (d, 1H, J ) 8.6 Hz), 6.61 (dd, 1H, J ) 2.7 and 8.6 Hz),
6.31 (d, 1H, J ) 2.7 Hz), 3.86, 3.83 and 3.63 (3s, 9H); 13C NMR
δ 160.1, 154.0, 149.9, 136.4 (2C), 129.0, 122.1, 115.1 (2C),
114.1, 111.2, 110.2, 56.4, 55.5, 55.29; IR νmax 1590, 1480, 1240,
1130. Anal. Calcd for C15H16O3S: C, 65.19; H, 5.84; S, 11.60.
Found: C, 64.99; H, 5.93; S, 11.95.
Exp er im en ta l Section
Melting points were obtained in open capillary tubes and
are uncorrected. 1H NMR and 13C NMR spectra were recorded
in CDCl3 at 300 and 75 MHz, respectively. IR spectra were
obtained as CHCl3 solutions and are given in cm-1. Diastere-
oisomeric adduct ratios were established by integration of well-
separated signals in the crude reaction mixtures and are listed
in Table 1. All reactions were monitored by thin-layer chro-
matography that was performed on precoated sheets of silica
gel 60, and flash column chromatography was done with silica
gel 60 (230-400 mesh) of Macherey-Nagel. Eluting solvents
are indicated in the text. Apparatuses for inert atmophere
experiments were dried by flaming in a stream of dry argon.
Cyclopentadiene was used freshly distilled. Dry THF was
distilled from sodium/benzophenone ketyl. CH2Cl2 was dried
over P2O5. BF3‚OEt2 was distilled from CaCl2. ZnBr2 was
flamed in the reaction flask, in a stream of dry argon before
use. For routine workup, hydrolysis was carried out with
water, extractions with CH2Cl2, and solvent dryness with Na2-
SO4.
2-(p-Meth oxyph en ylth io)-1,4-ben zoqu in on e (4c). 4-Meth-
oxybenzenethiol (3c) (1.26 mL, 10.28 mmol) was added to a
suspension of 1,4-benzoquinone (2.22 g, 20.56 mmol) in EtOH
(30 mL) at rt. After the suspension was stirred for 0.5 h, the
solid was filtered and purified by crystallization (ethyl ether)
to afford pure 4c as a red solid, in 88% yield: mp 94-95 °C;
1H NMR δ 7.40 and 6.99 (AA′BB′ system, 4H), 6.80 (d, 1H, J
) 10.1 Hz), 6.66 (dd, 1H, J ) 2.3 and 10.1 Hz), 5.86 (d, 1H, J
) 2.3 Hz), 3.85 (s, 3H); 13C NMR δ 184.3, 183.9, 161.3, 155.0,
137.2, 136.9 (2C), 135.7, 125.6, 116.8, 115.9 (2C), 55.3; IR νmax
1655, 1635, 1245, 1130. Anal. Calcd for C13H10O3S: C, 63.40;
H, 4.09; S, 13.02. Found: C, 63.37; H, 3.96; S, 12.95.
2-(p -Nit r op h en ylt h io)-1,4-b en zoq u in on e (4d ). 4-Ni-
trobenzenethiol (3d ) (472 mg, 3.04 mmol) in EtOH (3 mL) was
added to a suspension of 1,4-benzoquinone (657 mg, 6.08 mmol)
in EtOH (10 mL) at room temperature. After 15 h, the solid
was filtered and purified by flash chromatography (eluent
hexane/CH2Cl2, 50:50), to afford compound 4d as a yellow solid
in 65% yield: mp 185-186 °C (CH2Cl2/hexane); 1H NMR δ 8.34
and 7.72 (AA′BB′ system, 4H), 6.87 (d, 1H, J ) 10.2 Hz), 6.73
(dd, 1H, J ) 2.2 and 10.2 Hz), 5.94 (d, 1H, J ) 2.2 Hz); 13C
NMR δ 184.0, 183.2, 152.2, 149.0, 137.5, 136.3 (2C), 135.8 (2C),
135.7, 126.6, 125.1; IR νmax 1660, 1640, 1345, 1130. Anal. Calcd
for C12H7O4NS: C, 55.17; H, 2.70; N, 5.36; S, 12.27. Found:
C, 55.31; H, 2.40; N, 5.18; S, 12.48.
(()-1,4-Dim et h oxy-2-(p -m et h oxyp h en ylsu lfin yl)b en -
zen e (6c). To a solution of 5c (350 mg, 1.27 mmol) in EtOH
(9.6 mL) was added NaIO4 (407 mg, 1.9 mmol) dissolved in
H2O (9.6 mL). The mixture was refluxed for 2 h, filtered, and
extracted with CH2Cl2. After workup and flash chromatogra-
phy (eluent hexane/AcOEt, 50:50), compound 6c was obtained
1
as a yellow solid in 91% yield: mp 110-112 °C (MeOH); H
NMR δ 7.60 and 6.90 (AA′BB′ system, 4H), 7.49 (d, 1H, J )
2.4 Hz), 6.90 (dd, 1H, J ) 2.4 and 10.1 Hz), 6.69 (d, 1H, J )
10.1 Hz), 3.78, 3.77 and 3.65 (3s, 9H); 13C NMR δ 161.6, 154.4,
149.3, 136.3, 133.8, 127.2 (2C), 117.6, 114.2 (2C), 112.4, 108.5,
56.0, 55.8, 55.2. Anal. Calcd for C15H16O4S: C, 61.63; H, 5.52;
S, 10.96. Found: C, 61.78; H, 5.43; S, 11.15.
(()-2-(p-Meth oxyph en ylsu lfin yl)-1,4-ben zoqu in on e (1c).
To a solution of 6c (260 mg, 0.89 mmol) in CH3CN (3 mL) was
added CAN (1.46 g, 2.67 mmol) dissolved in H2O (3 mL) at
room temperature. The mixture was stirred for 1 h, and after
workup and flash chromatography (eluent hexane/AcOEt, 65:
35), compound 1c was obtained as an orange solid in 76%
yield: mp 147-148 °C (MeOH); 1H NMR δ 7.67 and 6.96
(AA′BB′ system, 4H), 7.39 (d, 1H, J ) 2.8 Hz), 6.78 (dd, 1H, J
) 2.8 and 10.1 Hz), 6.69 (d, 1H, J ) 10.1 Hz), 3.82 (s, 3H); 13
C
NMR δ 185.1, 183.5, 162.7, 154.9, 137.3, 136.3, 127.8 (2C),
131.3, 114.9 (2C), 114.8, 55.46; IR νmax 1655, 1585, 1250, 1130.
Anal. Calcd for C13H10O4S: C, 59.54; H, 3.85; S, 12.20. Found:
C, 59.62; H, 4.02; S, 11.99.
Gen er a l P r oced u r e for Th er m a l Diels-Ald er Rea c-
tion s. Meth od A. To a solution of the corresponding sulfi-
nylquinone 1b-d (0.4 mmol) in dry CH2Cl2 (10 mL) was added
cyclopentadiene under argon (see Table 1 for reaction condi-
tions). After the consumption of all the quinone and evapora-
tion of the solvent, the resulting material was purified by flash
chromatography (CH2Cl2/acetone, 30:1, for cycloadditions with
1b and 1c and hexane/EtOAc, 2:1, for cycloadditions with 1d ).
Yields and diastereoisomeric ratios of the adducts are detailed
in Table 1.
Gen er a l P r oced u r e for Lew is Acid Diels-Ald er Rea c-
tion s. Meth od B. A solution of the corresponding sulfi-
nylquinone 1b-d (0.4 mmol) in dry CH2Cl2 (10 mL) was added
to the appropiate Lewis acid under argon (see Table 1 for
reaction conditions). The mixture was stirred for 1 h at room
temperature, and then cyclopentadiene (0.4 mmol) was added
at the desired temperature. After the time required in each
case and workup, the resulting material was purified by
crystallization (CH2Cl2/hexane). Yields and diastereoisomeric
ratios of the adducts are detailed in Table 1.
(()-2-(p-Nitr op h en ylsu lfin yl)-1,4-ben zoqu in on e (1d ).
To a solution of 4d (450 mg, 1.72 mmol) in CH2Cl2 (10 mL)
was added m-CPBA (523 mg, 1.72 mmol) in CH2Cl2 (10 mL).

458 J . Org. Chem., Vol. 65, No. 2, 2000
Carren˜o et al.
en do-[4aR,5S,8R,8aS,(S)S]-5,8-Meth an o-2-(2(′)-m eth oxy-
n a p h th ylsu lfin yl)-4a ,5,8,8a -tetr a h yd r o-1,4-n a p h th oqu in -
on e (7b). 7b was obtained from (+)-(SS)-1b following method
A or B [Eu(fod)3] as a yellow solid: mp 120-121 °C (CH2Cl2/
hexane); [R]20D ) +286 (c 1.6, CHCl3); 1H NMR δ 8.46 (dd, 1H,
J ) 1.0 and 8.4 Hz), 8.00 (d, 1H, J ) 9.1 Hz), 7.91 (dd, 1H, J
) 1.0 and 8.4 Hz), 7.60 (dt, 1H, J ) 1.0 and 8.4 Hz), 7.45 (dt,
1H, J ) 1.0 and 8.1 Hz), 7.41 (s, 1H,), 7.26 (d, 1H, J ) 9.1
Hz), 5.83 (dd, 1H, J ) 2.8 and 5.3 Hz), 4.77 (m, 1H), 4.00 (s,
3H), 3.51 (m, 1H), 3.26 and 3.19 (2dd, 2H, J ) 4.0 and 8.1
Hz), 3.12 (m, 1H), 1.40 and 1.30 (2m, 2H); 13C NMR δ 196.8,
195.8, 159.0, 158.4, 139.9, 135.6, 135.5, 135.4, 135.1, 132.3,
129.0, 128.6, 128.5, 124.7, 122.9, 113.7, 56.9, 50.1, 49.4, 48.7,
48.4, 48.3; EI-MS m/z (rel intens) 378 (M+, 10), 205 (16), 173
(42), 158 (100), 115 (24), 66 (18); HRMS (EI) calcd for
C22H18O4S 378.092 58, found 378.09232.
en do-[4aS*,5S*,8R*,8aR*,(S)S*]-5,8-Meth an o-4a-(p-m eth -
oxyp h e n ylsu lfin yl)-4a ,5,8,8a -t e t r a h yd r o-1,4-n a p h t h o-
qu in on e (9c). 9c was obtained from (()-1c following method
B (ZnBr2) as an unseparable 36:32:32 mixture with 7c and
8c: 1H NMR (from the mixture) δ 7.63 and 6.96 (AA′BB′
system, 4H), 6.15 (t, 2H, J ) 1.8 Hz), 6.10 and 6.06 (AB system,
2H, J ) 10.3 Hz), 3.94 (m, 1H), 3.81 (s, 3H), 3.64 (m, 1H),
3.25 (d, 1H, J ) 2.8 Hz), 2.05 (m, 1H), 1.67 (dt, 1H, J ) 9.7
and 1.7 Hz).
en d o-[4a R*,5S*,8R*,8a S*,(S)S*]-5,8-Met h a n o-2-(p -n i-
tr oph en ylsu lfin yl)-4a,5,8,8a-tetr ah ydr o-1,4-n aph th oqu in o-
n e (7d ). 7d was obtained from (()-1d following method A or
B [Eu(fod)3] as a brown solid: mp 114-115 °C; 1H NMR δ 8.35
and 7.98 (AA′BB′ system, 4H), 7.31 (s, 1H), 5.85 (dd, 1H, J )
3.0 and 5.8 Hz), 4.90 (dd, 1H, J ) 2.0 and 5.8 Hz), 3.52 (m,
1H), 3.4-3.2 (m, 3H), 1.46 and 1.40 (2dt, 2H, J ) 9.1 and 1.4
Hz); 13C NMR δ 196.8, 195.9, 158.5, 139.9, 135.6, 134.5, 128.7,
128.6, 124.7 (2C), 113.6 (2C), 56.9, 50.1, 49.5, 48.8, 48.5; EI-
MS m/z (rel intens) 343 (M+, 14), 277 (63), 145 (19), 117 (24),
107 (56), 79 (74), 66 (100); HRMS (EI) calcd for C17H13NO5S
343.051 44, found 343.051 22.
en do-[4aS,5R,8S,8aR,(S)S]-5,8-Meth an o-2-(2(′)-m eth oxy-
n a p h th ylsu lfin yl)-4a ,5,8,8a -tetr a h yd r o-1,4-n a p h th oqu in -
on e (8b). 8b was obtained from (+)-(SS)-1b following method
B (BF3‚OEt2) as a yellow solid: mp 118-119 °C; [R]20D ) +336
1
(c 0.1, CHCl3); H NMR δ 8.48 (dd, 1H, J ) 1.0 and 8.4 Hz),
7.99 (d, 1H, J ) 9.1 Hz), 7.80 (dd, 1H, J ) 1.0 and 8.1 Hz),
7.62 (dt, 1H, J ) 1.0 and 8.4 Hz), 7.44 (dt, 1H, J ) 1.0 and 8.4
Hz), 7.41 (s, 1H), 7.26 (d, 1H, J ) 9.1 Hz), 6.14 (t, 2H, J ) 1.7
Hz), 3.99 (s, 3H), 3.56 and 3.46 (2m, 2H), 3.26 and 3.07 (2dd,
2H, J ) 4.0 and 8.5 Hz), 1.54 and 1.36 (2dt, 1H, J ) 1.6 and
8.9 Hz); 13C NMR δ 196.7, 195.9, 158.3 (2C), 139.9, 135.6,
135.4, 135.0, 134.0, 132.4, 128.9, 128.6, 128.4, 124.7, 123.2,
113.0, 56.6, 49.9 49.6, 49.5 (2C), 49.2; EI-MS m/z (rel intens)
378 (M+, 5), 346 (10), 173 (25), 158 (100), 115 (27), 66 (22);
HRMS (EI) calcd for C22H18O4S 378.092 58, found 378.092 68.
en d o-[4a S*,5R*,8S*,8a R*,(S)S*]-5,8-Met h a n o-2-(p -n i-
tr oph en ylsu lfin yl)-4a,5,8,8a-tetr ah ydr o-1,4-n aph th oqu in o-
n e (8d ). 8d was obtained from (()-1d following method B
(BF3‚OEt2) as a brown solid: mp 144-145 °C; 1H NMR δ 8.32
and 7.97 (AA′BB′ system, 4H), 7.22 (s, 1H), 6.15 (m, 2H), 3.58
(m, 2H), 3.24 and 3.16 (2dd, 2H, J ) 3.8 and 8.3 Hz), 1.58 and
1.42 (2m, 2H); 13C NMR δ 196.5, 196.0, 157.2, 138.2, 135.8,
135.2, 126.6, 126.6, 124.4 (2C), 112.1 (2C), 56.1, 50.4, 49.5, 49.1,
49.0; EI-MS m/z (rel intens) 343 (M+, 20), 145 (33), 117 (48),
79 (26), 66 (100); HRMS (EI) calcd for C17H13NO5S 343.051 44,
found 343.051 53.
en do-[4a R*,5S*,8R*,8a S*,(S)S*]-5,8-Meth an o-2-(p-m eth -
oxyp h e n ylsu lfin yl)-4a ,5,8,8a -t e t r a h yd r o-1,4-n a p h t h o-
qu in on e (7c). 7c was obtained from (()-1c following method
A or B [Eu(fod)3] as a yellow solid: mp 125-126 °C; 1H NMR
δ 7.57 and 6.98 (AA′BB′ system, 4H), 7.15 (s, 1H), 5.88 (dd,
1H, J ) 2.7 and 5.4 Hz), 4.94 (dd, 1H, J ) 2.2 and 5.4 Hz),
3.82 (s, 3H), 3.50 (m, 1H), 3.25 (m, 3H), 1.40 (m, 2H); 13C NMR
δ 196.9, 196.7, 162.6, 136.5, 135.3, 134.2, 128.1 (2C), 114.7
(2C), 55.6, 50.1, 49.7, 49.6, 49.5, 49.3. Anal. Calcd for
C18H16O4S: C, 65.84; H, 4.91; S, 9.76. Found: C, 66.02; H, 5.13;
S, 9.71.
en d o-[4a S*,5S*,8R*,8a R*,(S)S*]-5,8-Meth a n o-4a -(p-n i-
tr oph en ylsu lfin yl)-4a,5,8,8a-tetr ah ydr o-1,4-n aph th oqu in o-
n e (9d ). 9d was obtained from (()-1d following method B
(ZnBr2) as a yellow solid which decomposes on standing: mp
91-93 °C (ethyl ether); 1H NMR δ 8.32 and 7.78 (AA′BB′
system, 4H), 6.23 and 6.13 (2dd, 2H, J ) 2.8 and 5.6 Hz), 6.22
and 6.15 (AB system, 2H, J ) 10.0 Hz), 3.91 (m, 1H), 3.73 (m,
1H), 3.33 (d, 1H, J ) 3.8 Hz), 2.07 and 1.69 (2dt, 2H, J ) 9.7
and 1.7 Hz).
en do-[4aS*,5R*,8S*,8aR*,(S)S*]-5,8-Meth a n o-2-(p-m eth -
oxyp h e n ylsu lfin yl)-4a ,5,8,8a -t e t r a h yd r o-1,4-n a p h t h o-
qu in on e (8c). 8c was obtained from (()-1c following method
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (Grants PB95-0174
and PB96-0035) for financial support.
1
B (BF3‚OEt2) as a yellow solid: mp 160-161 °C; H NMR δ
7.63 and 6.96 (AA′BB′ system, 4H), 7.21 (s, 1H), 6.12 (t, 2H, J
) 2.0 Hz), 3.83 (s, 3H), 3.55 (m, 2H), 3.23 and 3.12 (2dd, 2H,
J ) 4.0 and 8.5 Hz), 1.56 and 1.49 (2dt, 2H, J ) 8.9 and 1.6
Hz); 13C NMR δ 196.9, 196.0, 162.7, 160.7, 137.0, 135.7, 135.3,
132.2, 127.8 (2C), 114.9 (2C), 55.6, 55.5, 50.3, 49.5, 48.9, 48.7.
Anal. Calcd for C18H16O4S: C, 65.84; H, 4.91; S, 9.76. Found:
C, 65.68; H, 4.81; S, 10.03.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for compounds 1d , 7b, 8b, 7d , 8d , and 9d . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O9913107