Factors affecting the competitive reduction of 8,8-dimethylnaphthalene-1,4, 5(8H)-trione in a Diels-Alder cycloaddition with hydroxysulfinyldienes

Article abstract of DOI:10.1007/s13738-013-0370-x

Competing reduction and cycloaddition products were formed in the reaction of 8,8-dimethylnaphthalene-1,4,5(8H)-trione with a hydroxysulfinyldiene. The ratio of reduction to cycloaddition products depended on the stereochemistry of the diene and on the so

Full text of DOI:10.1007/s13738-013-0370-x

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0370-x
ORIGINAL PAPER
Factors affecting the competitive reduction
of 8,8-dimethylnaphthalene-1,4,5(8H)-trione
in a Diels–Alder cycloaddition with hydroxysulfinyldienes
•
Iriux Almodovar Wilson Cardona
•
•
Tomas Delgado-Castro Gerald Zapata-Torres
•
´
Marcos Caroli Rezende Ramiro Araya-Maturana
•
Received: 6 May 2013 / Accepted: 23 October 2013
Ó Iranian Chemical Society 2013
Abstract Competing reduction and cycloaddition pro-
ducts were formed in the reaction of 8,8-dimethylnaph-
thalene-1,4,5(8H)-trione with a hydroxysulfinyldiene. The
ratio of reduction to cycloaddition products depended on
the stereochemistry of the diene and on the solvent
employed, being higher in ethanol than in benzene. The
ratio was also affected by the addition of Lewis acids,
decreasing in the order BF3 = Al2O3 [ MgCl2 [ ZnCl2.
The results help to explain and predict the occurrence of
these competing processes in Diels–Alder cycloadditions
involving quinonedienophiles.
Introduction
Quinones are ubiquitous in nature, playing an important
role in biological systems, where they act as electron-
transfer agents in redox reactions [1–4]. They are found in
most living organisms, in the oxidized (quinone) or
reduced (hydroquinone) states.
Quinone derivatives have found a wide variety of
applications as antineoplastics [5–9], antitumor agents [10–
13], and antibiotics [14, 15], and are also effective against
Alzheimer’s disease [16–21]. They have also been
employed in agriculture as antifungal agents [22–25].
Polycyclic quinones, such as naphthoquinones, are also
important as environmental pollutants, with noxious effects
on human health [26–28].
Keywords Diels–Alder Á Cycloaddition Á Reduction
Á Quinone Á Sulfinyldienes
Quinones are important building blocks in organic
synthesis [29–35]. As good electron-deficient dienophiles,
they have been frequently used in Diels–Alder (D–A)
cycloadditions [36–46]. Their electron deficiency also
makes them good substrates for redox processes that may
compete with the cycloaddition reaction. Fukuzumi et al.
[47, 48] have reported the competing reduction of quinone
dienophiles when performing D–A cycloadditions to these
substrates.
I. Almodovar (&) Á M. C. Rezende
´
Departamento de Ciencias del Ambiente, Facultad de Quımica y
Biologıa, Universidad de Santiago de Chile, Avenida B.
´
´
O’Higgins 3363, Estacion Central, CP 9160000 Santiago, Chile
e-mail: iriux.almodovar@usach.cl
W. Cardona
Departamento de Ciencias Quımicas, Universidad Andres Bello,
´
Autopista Concepcion-Talcahuano 7100, Concepcion, Chile
´
´
´
Because these undesired reduction processes compete
with D–A reactions, thereby diminishing the yields of the
cycloaddition products, a good understanding of the factors
that govern them is important when attempting to exploit
D–A reactions with quinones.
T. Delgado-Castro
Departamento de Ciencias Quımicas, Universidad Andres Bello,
´
Republica 237, Santiago, Chile
´
´
G. Zapata-Torres
Departamento de Quımica Inorganica y Analıtica, Universidad
In a recent report of a D–A cycloaddition of (2S, SR)-1-
(p-tolylsulfinyl)-3,5-heptadien-2-ol (1) and of (2R, SR)-1-
(p-tolylsulfinyl)-3,5-heptadien-2-ol (2) with quinone 3 we
obtained high yields of adducts with good regio- and ste-
reoselectivities [46]. A careful analysis of the reaction
mixtures revealed the formation of hydroquinone 4
´
de Chile, Casilla 233, Santiago 1, Chile
´
´
R. Araya-Maturana
´
´
´
´
Departamento de Quımica Organica y Fısico-Quımica,
Universidad de Chile, Casilla 233, Santiago 1, Chile
e-mail: raraya@ciq.uchile.cl
123

J IRAN CHEM SOC
Scheme 1 Reaction of
hydroxysulfinyldienes 1 or 2
with quinone 3
pSOTol
pSOTol
∗
HO
+
HO
∗
O
O
O
O
O
OH O
O
O
O
*
*
*
solvent
+
+
*
∗
O
OH
HO
pSOTol
5a
5b
3
4
6a
6b
1: (2S;SR)
2: (2R;SR)
D-A cyclization products
(cm-1): 3,431, 2,925, 1,598, 1,423. H NMR d (CDCl3,
300.13 MHz): 1.35 (d, 3H, J = 7.0 Hz), 1.58 (s, 3H), 1.64
(s, 3H), 2.42 (s, 3H), 2.86 (dd, 1H, J = 2.0 Hz,
J = 13.0 Hz), 3.18 (dd, 1H, J = 10.0 Hz, J = 13.0 Hz),
3.42 (m, 2H), 3.82 (m, 1H), 4.52 (m, 1H), 4.61 (m, 1H),
5.94 (dd, 1H, J = 5.0 Hz, J = 10.0 Hz), 6.12 (dd, 1H,
J = 5.0 Hz, J = 10.0 Hz), 6.23 (d, 1H, J = 10.0 Hz), 6.82
(d, 1H, J = 10.0 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.51 (d,
2H, J = 8.0 Hz), 13.25 (s, 1H). 13C NMR d (CDCl3,
75 MHz): 21.56, 25.06, 25.27. 30.45, 38.18, 40.56, 60.45,
68.36, 113.07, 121.60, 123.21, 123.94, 124.15, 129.97,
130.00, 132.95, 133.17, 137.69, 141.50, 142.80, 154.7,
161.14, 191.13. Anal. calcd. for C26H28O5S: C, 69.00; H,
6.24; S, 7.08. Found C, 68.25; H, 6.41; S, 6.39.
1
together with the cycloadducts (Scheme 1). The formation
of product 4 depended on the diene employed.
In the present paper, we describe the formation of 4
under various conditions. By analyzing in detail its
dependence on the solvent and on the addition of Lewis
acids, we have clarified some factors that govern this
competing pathway.
Experimental
1H NMR spectra were obtained in CDCl3 with a Bruker
Advance DRX-300 instrument. All chemical shifts are
reported as ppm downfield from TMS; residual CHCl3 (d
7.26) was used as an internal reference.
9,10-dihydroxy-5-{(1S)-1-hydroxy-2-[(4-methylphenyl)-R-
sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-1(4H)-anth-
racenone (5b) Mp: 198–201 °C. IR (KBr) (cm-1): 3,418,
2,924, 1,651, 1,601. 1H NMR d (CDCl3, 300.13 MHz):
0.74 (d, 3H, J = 7.0 Hz), 1.58 (s, 3H), 1.65 (s, 3H), 2.40 (s,
1H), 2.80 (d, 1H, J = 14.0 Hz), 3.53 (d, 1H, J = 14.0 Hz),
3.65 (m, 1H), 3.87 (m, 2H), 5.70 (dd, 1H, J = 5.0,
J = 10.0 Hz), 6.04 (dd, 1H, J = 5.0, J = 10.0 Hz), 6.15
(s, 1H), 6.23 (dd, 1H, J = 1.0, J = 10.0 Hz), 6.84 (dd, 1H,
J = 1.0, J = 10.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.40 (d,
2H, J = 8.0 Hz), 7.99 (s, 1H), 13.15 (s, 1H). 13C NMR d
(CDCl3, 75 MHz): 21.35, 21.43, 25.02, 25.45, 29.45,
38.44, 41.65, 55.06, 76.36, 113.53, 122.62, 124.01, 130.26,
134.36, 134.84, 136.20, 136.78, 142.04, 144.95, 153.98,
161.72, 191.57. Anal. calcd. for C26H28O5S: C, 69.00; H,
6.24; S, 7.08. Found: C, 68.14; H, 6.61; S, 6.53.
Synthesis of the reacting compounds and characteriza-
tion of all the products have been reported before [46, 49–
52].
Toluene was dried over Na under N2, using benzophe-
none as an indicator. CH2Cl2 was dried over P2O5 under
N2.
Reaction of sulfinyldienol 1 or 2 with dienophile 3
In the absence of Lewis acids
The sulfinyldienol 1 or 2 (0.128 mmol) and dienophile 3
(0.128 mmol) were dissolved in the appropriate solvent
(benzene or EtOH, 5 mL). The solution was allowed to
react at room temperature, in the absence of light, for
1 week. When EtOH was used as solvent it was evaporated
and the residue redissolved in benzene. Silicagel (60 mg)
was added, and the mixture was stirred overnight. The
suspension was then filtered, and silicagel was washed
repeatedly with a mixture of AcOEt:MeOH (1:1 v/v). The
filtrates were concentrated to give a mixture of anthrace-
(5R, 8S)-9,10-dihydroxy-8-{(1R)-1-hydroxy-2-[(4-methyl-
phenyl)-R-sulfinyl]
ethyl}-4,4,5-trimethyl-5,8-dihydro-
1(4H)-anthracenone (6a) Mp: 144–147 °C. IR (KBr)
(cm-1) 3,416, 3,020, 2,959, 2,937, 1,651, 1,597, 1,029,
809. 1H NMR d (CDCl3, 300.13 MHz): 1.43 (d, 3H,
J = 7.0 Hz), 1.58 (s, 3H), 1.63 (s, 3H), 2.42 (s, 3H),
2.98(dd, 1H, J = 12.9, J = 2.1 Hz), 3.17 (dd, 1H,
J = 12.9, J = 10.4 Hz), 3.45(m, 1H), 3.56 (d, 1H,
J = 4.1 Hz), 3.82 (m, 1H), 4.59 (m, 1H), 4.73 (s, 1H), 5.81
(dd, 1H, J = 9.9, J = 5.0 Hz), 6.10 (dd, 1H, J = 10.1,
1
nones which was analyzed by H NMR. Characterization
of products 5a, 5b, 6a, and 6b are given below.
(5S,8R)-9,10-dihydroxy-8-{(1S)-1-hydroxy-2-[(4-methyl-
phenyl)-R-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-
1(4H)-anthracenone (5a) Mp: 234–236 °C. IR (KBr)
123

J IRAN CHEM SOC
J = 5 Hz), 6.23 (d, 1H, J = 10.0 Hz), 6.82 (d, 1H,
J = 10.1 Hz), 7.33 (d, 2H, J = 8.2 Hz), 7.56 (d, 2H,
J = 8.3 Hz), 13.39 (s, 1H). 13C NMR d (CDCl3, 75 MHz):
21.45, 21.51, 25.03, 25.28, 30.44, 38.19, 40.95, 62.00,
69.75, 113.08, 121.94, 122.92, 123.85, 124.26, 130.09,
133.35, 133.40, 137.10, 140.32, 140.02, 142.98, 154.14,
161.27, 191.22. HRMS (ESI–MS): Anal. clacd. for
C26H29O5S (M?H)? 453.1711 found 453.1711.
Table 1 Yields of hydroquinone 4 and of regioisomers 5 and 6 from
the reactions of quinone 3 with dienes 1 or 2 in benzene or ethanol
Product
Product yield (%)
Benzene
Ethanol
Diene 1
Diene 2
Diene 1
Diene 2
4
5
6
15
70
15
30
60
10
50
30
20
65
10
25
9,10-dihydroxy-5-{(1R)-1-hydroxy-2-[(4-methylphenyl)-R-
sulfinyl]
ethyl}-4,4,5-trimethyl-5,8-dihydro-1(4H)-anth-
racenone (6b) Mp: 248 °C. IR (KBr) (cm-1): 3,377,
3,020, 2,925, 2,854, 1,655, 1,599, 1,077, 804.1H NMR d
(CDCl3, 300.13 MHz): 1.37 (d, 3H, J = 7 Hz), 1.57 (s,
3H), 1.65 (s, 3H), 2.45 (s, 3H), 3.09 (dd, 1H J = 13.1 Hz,
J = 9.5 Hz), 3.14 (dd, 1H, J = 12.9 Hz, J = 2.0 Hz), 3.80
(m, 2H), 4.32 (ddd, 1H, J = 9.6 Hz, J = 9.6 Hz,
J = 1.9 Hz), 5.67 (dd, 1H, J = 9.7 Hz, J = 5.5 Hz), 6.02
(s, 1H), 6.22 (d, 1H, J = 10.1 Hz), 6.24 (dd, 1H,
J = 9.6 Hz, J = 5.5 Hz), 6.82 (d, 1H, J = 10.0 Hz), 7.39
(d, 2H, J = 8.2 Hz), 7.60 (d, 2H, J = 8.2 Hz), 8.01 (s,
1H), 13.18 (s, 1H). 13C NMR d (CDCl3, 75 MHz): 21.51,
22.37, 25.04, 25.47, 29.82, 38.42, 42.12, 59.14, 78.34,
113.61, 122.62, 123.90, 123.93, 127.68, 130.46, 134.32,
134.42, 136.83, 139.90, 142.81, 145.00, 154.13, 161.61,
191.52. HRMS (ESI–MS): Anal. calcd. for C26H28O5NaS
(M?Na)? 475.1549, found 475.1547.
reduction product 4, determined from the 1H NMR spectra
of the reaction mixtures, showed that the medium played
an important role in this reaction. This led us to compare
the effect of different Lewis acids added to the reaction in
toluene, to gain a more detailed picture of the medium
effects that govern the reduction process.
Effect of the solvent and of the sulfinyldienol
on the reduction of 3
When the reaction of 1 or 2 with quinone 3 was carried out
in benzene, the major products were in both cases D–A
adducts [46]. Besides, non-negligible amounts of hydro-
quinone 4 were also formed, in yields that depended on the
diene. However, the same reaction in ethanol led to a very
different product distribution with a strong preference for
the reduction product over the D–A adducts 5 and 6: qui-
none 3 was reduced in 50–65 % yield when compared with
15–30 % observed when the reaction was run in benzene.
Relevant variations in the ratio of the obtained regioi-
somers in the D–A cycloaddition were also observed in
ethanol.
In the presence of Lewis acids
A mixture of diene 1 or 2 (0.128 mmol) and the appro-
priate Lewis acid (0.128 mmol) dissolved in dry toluene
(3 mL) was stirred under N2 at 0 °C for 30 min. Then, a
solution of 3 (0.128 mmol) in dry toluene (3 mL) was
added. The reaction was allowed to warm up to room
temperature, and course of the reaction was followed by
TLC.
Table 1 summarizes the results described above.
The data of Table 1 show that the formation of hydro-
quinone 4 depends not only on the employed solvent, but
also on the stereochemistry of the dienol (1 or 2).
When the reaction was complete, a saturated aqueous
solution of NH4Cl was added, the mixture was stirred for
15 min, and was then extracted with EtOAc. The combined
organic extracts were dried with Na2SO4 and filtered, the
filtrate was concentrated and the residue redissolved in
benzene. Silicagel (60 mg) was added, and the mixture was
stirred overnight. The suspension was then filtered. Sili-
cagel was washed several times (as described above), and
the filtrates were concentrated to give a mixture of anth-
The drastic differences observed when the reaction
solvent was changed from nonpolar aprotic benzene to
polar protic ethanol most likely reflect the importance of
hydrogen bonds between the solvent and the quinone 3
[53], favoring reduction of the latter. In fact, reports of
catalysis by hydrogen bond donors in the reduction of
quinones are found in the literature [54, 55]. Hydride
transfer to these substrates is assisted by partial protonation
of the carbonyl oxygen; thus, increasing the electrophilicity
of the quinone. The hydride source in these reductions is
doubtless the dienol 1 or 2. Hydride transfer from these
compounds should be made easier by the presence of the
neighboring sulfoxide group, and by the formation of a
conjugated dienone system (Scheme 2).
1
racenones which was analyzed by H NMR.
Results and discussion
A comparison of the two dienols also shows that, in both
solvents, reactions with dienol 2 led to higher yields of the
The reaction of sulfinyldienes 1 or 2 with quinone 3 was
carried out in benzene and ethanol. The different yields of
123

J IRAN CHEM SOC
Scheme 2 Hydride transfer
from dienol 1 or 2 to quinone 3
in ethanol
OEt
H
OEt
H
O
S
+
O
O
O
OH
O
O
O
OH
H
:
:
S
:
+
*
+
OH
H
O
S
O
O
O
+
OH
O
O
Table 2 Yields of hydroquinone 4 in the reaction of dienols 1 or 2
with quinone 3 in toluene, in the presence of various Lewis acids
O
pSOTol
H
H
pTol
HO
S
O
O
O
Dienols
Lewis acid
% of 4
*
1
1
2
1
2
1
2
BF3 Et2O
Al2O3
100
100
100
75
89
2
*
O
O
5a
Al2O3
TS-I
MgCl2
MgCl2
ZnBr2
O
O
O
pSOTol
H
ZnBr2
6
pTol
HO
S
O
O
O
H
*
*
transition states. The interaction between diene and die-
nophile is facilitated by their proximity in complex TS-I,
which originates from dienol 1. In the corresponding
complex TS-II for dienol 2, diene and dienophile are
widely separated and it must dissociate for the D–A tran-
sition state to arise. Instead, in this complex, a hydride
transfer from the dienol to the quinone becomes an
important competing process with the D–A cycloaddition,
leading, in all cases, to a greater proportion of the reduced
hydroquinone product 4 (Table 1).
O
O
5b
TS-II
Scheme 3 Possible transition-state geometries for reactions of 1 (TS-
I) or 2 (TS-II) with 3
reduction product 4, and to lower regioselectivities in the
D–A cycloaddition (Table 1). Both effects may be ratio-
nalized by invoking the cyclic complexes depicted below
for these reactions (Scheme 3) [46].
Effect of Lewis acids on the reduction of 3
As discussed previously [46], such postulated com-
plexes should account for the preferential formation of
regioisomers 5a and 5b in the D–A cycloadditions, because
of the role played by the hydroxyl proton of the dienol in
bringing together dienes and quinone 3 in the appropriate
conformations. This role is more important in benzene than
in ethanol, due to competition with the hydroxyl proton of
the latter solvent, which should partly disrupt the inter-
molecular interaction between diene and quinone. The
result of this is the lower regioselectivity observed in eth-
anol in the formation of the D–A adducts 5 and 6 (Table 1).
The different outcome of the reaction with dienols 1 and
2 can also be explained resorting to the postulated
Lewis acids have been extensively used in D–A cycload-
ditions, to increase selectivities or reaction rates [56–58].
The reactions of dienols 1 or 2 with quinone 3 was,
therefore, investigated in toluene, in the presence of vari-
ous Lewis acids. Interestingly, the competing reduction of
3 was strongly dependent on the nature of the acid, as can
be seen from the data of Table 2.
The data of Table 2 allow a distinction to be made
between three types of acid: those which elicited a com-
plete reduction of 3 to the hydroquinone 4 (BF3, Al2O3),
those that strongly favored this process (MgCl2), or that
123

J IRAN CHEM SOC
+
between the quinone C-1 carbonyl and a hydrogen bond
donor solvent-like ethanol, or an added Lewis acid. In the
latter case, the harder the metal cation, the greater the yield
of reduced quinone. Quinones are frequently used in D–A
cycloadditions that are often modified or accelerated by the
addition of Lewis acids. Thus, the present results and
interpretations may prove useful in defining the reaction
conditions or optimizing these reactions in synthesis.
Mn
O
O
O
O
O
O
Mn+
Scheme 4 Activated complex formed by interaction between qui-
none 3 and Lewis acid Mn? in toluene
Acknowledgments This work was supported by USACH-DICYT,
Fondecyt Grant 1110176 and the Deutscher Akademischer Aust-
ausch-Dienst (Grant to IA and to WC).
suppressed it almost completely (ZnBr2). This order may
be related to the hardness of the studied cations. According
to Klopman [59], hardness decreases in the order B?-
= Al?3 [ Mg?2 [ Zn?2, and the same order is followed
3
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