777

Reactions of p-Benzoquinone with S-Nucleophiles

Alan R. Katritzky,*,1 Dmytro Fedoseyenko1, Prabhu P. Mohapatra1 and Peter J. Steel2
1

Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA.
Chemistry Department, University of Canterbury, Christchurch, New Zealand.

Fax: +1(352)3929199
E-mail: katritzky@chem.ufl.edu
Abstract: The orientations of reaction of p-benzoquinone with
nucleophiles are discussed. Reaction of p-benzoquinone with alkyl
mercaptans gave 2-, 2,6- and 2,5- conjugate addition products in
one-pot. Novel 2,6- and 2,5- dialkylthio-, 2,3,5-trialkylthio- and
2,3,5,6-tetraalkylthio-p-benzoquinones and their corresponding
hydroquinones were obtained in good yields by sequential
addition/in situ oxidation protocol for testing as polymerization
inhibitors in rubber and petroleum products. Structure of five 2,5and 2,6-isomers were established by X-ray crystallography.

Nitrogen nucleophiles: Conjugate additions of

heterocyclic nitrogen nucleophiles including pyridines,12
imidazole and benzimidazole13 to p-benzoquinones give
2-monosubstituted, 2,3- and 2,5-disubstituted and 2,3,5trisubstituted hydroquinones (Scheme 1). However,
conjugate additions of secondary amines to pbenzoquinone are reported to produce only 2,5disubstituted hydroquinones (Scheme 1).14

Key words: p-benzoquinone, mercaptans, conjugate addition,

hydroquinones, polymerization inhibitors

Derivatives of benzoquinone and hydroquinone are

widely studied in organic synthesis as reagents1 and
electron-accepting components for the synthesis of
charge-transfer complexes and radical-ion salts.2
Naturally occurring quinones and hydroquinones are
subunits in many biological compounds3 and possesses a
variety of biological properties including antitumoral,4
HIV transcriptase inhibition,5 and immunomodulation.6
Sulfur-substituted quinones and hydroquinones are
effective oxidation inhibitors and are widely used for
2,5stabilization
of
petroleum
products.7
Bis(methylthio)-p-benzoquinone has been used to
prepare sulfur-quinone polyurethane coatings for protect
against iron surfaces.8 Metal carbonyl derivatives of
sulfur-containing quinones and hydroquinones have been
synthesized for studying their electrochemical
properties.9 2-Thio-5-amino substituted benzoquinones
and hydroquinones are used as additives in rubber to
prevent degradation and in gasoline and lubricating oil to
inhibit polymerization.10 2-Sulfinyl quinones are used as
cocatalysts in palladium-catalyzed reactions to improve
their stereoselectivity.11
Survey of the orientation of addition of nucleophiles
to monosubstituted p-benzoquinones
Conjugate addition of nitrogen, sulfur, oxygen and
carbon nucleophiles to p-benzoquinone give initially 2substituted mono-adducts. Depending on the character of
the nucleophile, the oxidation potential of the monoadduct, and possible reversible formation of a chargetransfer complex, the initially formed mono adduct may
undergo further nucleophilic addition to give 2,3-, 2,5and/or 2,6-disubstituted bis-adducts. These bis-adducts
can in turn react with a third nucleophile molecule to
afford the 2,3,5-trisubstituted adduct. Finally the trisadduct may react with yet one more equivalent of
nucleophile to give a 2,3,5,6-tetrasubstituted pbenzoquinone.

OH
N

N+

OH

O85%

OH
N

N
H

OH

N
N

OH

N
N
R R
N
N

+
R
OH

OH
R=H
R = Me

R
N
N

OH

OH
R=H
R = Me

R
28%
85%

31%
10%

N
H

OH
R
41%
5%

OH

+
N
OH

48%

N
N

OH

R R
N
N

traces

OH

OH

OH

OH

N
N

OH

N
N

N
N

OH
+

14%

OH

OH

29%
79%

R
R

N
H

N
N

OH

57%
21%

N
O

N
OH

32%

20%

OH

H
N

N
N

46%
OH

Scheme 1.

Reactions
of
pyrazole,
4-nitropyrazole,
3,5dimethylpyrazole, 4-chloro-3,5-dimethylpyrazole and 3(2-pyridyl)pyrazole with p-benzoquinone gave monoand 2,3-bis-adducts; only in the case of pyrazole was
2,5-bis(pyrazol-1-yl)-1,4-dihydroxybenzene
also
formed.12b,c Reactions of imidazole, 2-methylimidazole,
and benzimidazole with p-benzoquinone in dioxane gave
mono-, 2,3- and 2,5-bis-adducts.13 As in the case of
pyrazoles,18,19 preferential formation of 2,3-bis
derivatives vs. 2,5-bis derivatives occurs with hindered
imidazoles.13
Sulfur nucleophiles: Conjugate addition of one molecule
of various sulfur nucleophiles to p-benzoquinones are
well known (Scheme 2).15 However, double conjugate

778

additions of sulfur nucleophiles to p-benzoquinones are

rare and we found only one such example in the
literature:16 thiophenol and p-benzoquinone gave both
2,5- and 2,6-bis(phenylthio)benzoquinone and their
structures were established by X-ray crystallography
(Scheme 2).16

NH

OH

N
H
OH

HN
O

+
Pd(OAc)2

41%

12%

OH

O
SO2Ph

Me

Me
S

6%
O

Me

Me

Me
O

Me
OH

NH3Cl
S

OH

CO2R HS
NH3Cl

OH

CO2R

N
O

AcHN
SH
OAc
OAc

AcHN

CO2Et

OH

S
R

O
O

OH

Cl

Cl
O

2%

O
O
OH

R''

Scheme 2.

R'

R'
O

R''

-2H2O

COR''

R''

Oxygen nucleophiles: Conjugate addition of oxygen

nucleophiles such as ethanol and phenol with pbenzoquinone or activated quinones gave only 2,5disubstituted products in addition to the 2monosubstituted adducts (Scheme 4).20
Herein, we report the synthesis of some novel 2,5dialkylthio-,
2,6-dialkylthio-substituted,
2,3,5trisubstituted
and
2,3,4,5-tetrasubstituted
pbenzoquinones and their corresponding hydroquinones
in good yields by sequential addition and in situ
oxidation.

3%

R'

Carbon nucleophiles: Conjugate addition of carbon

nucleophiles
to
p-benzoquinones
gave
2monosubstituted, 2,5- and 2,6-disubstituted products
similar to thiols (Scheme 3).17 Reaction of pbenzoquinone with indole in the presence of either 2
mol% bismuth triflate or 5 mol% indium(III) bromide in
acetonitrile
at
rt
gave
2,5-bis(3-indolyl)-phydroquinone.17a,b Reaction of p-benzoquinone with
palladium acetate in acetic acid containing arenes such
as benzene, p-xylene, and p-dichlorobenzene at reflux
temperature gave the corresponding 2-aryl-, 2,5-diaryland 2,6-diaryl-1,4-benzoquinones.17e Reaction of pbenzoquinone with 4-hydroxycoumarin in aqueous
acetic
acid
gave
3-(1,4-benzoquinonyl)-4hydroxycoumarin which reacted further with pyridine to
give a unique 2,3-disubstituted zwitterionic adduct
(Scheme 3).17c,18 Similarly reaction of 3-(1,4benzoquinonyl)-4-hydroxycoumarin
with
4hydroxycoumarin gave selectively a 2,3-disubstituted
quinone product.19

Cl

OH
OH
O

Cl

SPy

Cl
O

8%

50%

Me
O

Cl

Cl

CO2Et

OAc

O OAc
O

Me

13%

Cl

SH

HS
OAc
OAc

OH

Cl

Me

Cl
S

Pd(OAc)2

S
+

25%

SH

OH

PhSO2H

SH

OH

Me
Pd(OAc)2

O
+
O

R''OC
R'

OH

O
R'

CN

OH
NCCH2COR

O
O

R
CN OH

Scheme 3.
O

OH
R

Me
OH
O

O
O

R = CO2Me
R

Me

R=H

O
O
O

EtOH

O
O

Me

+
Me

O
O

R=H
O
O

Scheme 4.

Results and Discussion

During our ongoing research in the area of rubber
additives,10a,10b,15l we found that reaction of 1,4benzoquinone 1 with cyclohexanethiol 2a in ethanol at
room temperature for 12 h gave seven products including
2-cyclohexylsulfanylbenzene-1,4-diol
3a,10a
211b
cyclohexylsulfanyl-[1,4]benzoquinone 4a,
benzene1,4-diol 5, 2,6-bis(cyclohexylsulfanyl)benzene-1,4-diol
6a, 2,6-bis(cyclohexylsulfanyl)[1,4]-benzoquinone 7a,
2,5-bis(cyclohexyl-sulfanyl)benzene-1,4-diol 8a, 2,5bis(cyclohexylsulfanyl)[1,4]- benzoquinone 9a in 4.5%1,
2.4%, 36.4%, 0.6%, 11.9%, 0.9% and 18.5% yields
respectively (Scheme 5). Products 3a9a were purified
1

All presented yields are calculated for isolated

compounds.

779

by repeated silica gel column chromatography using a

mixture of dichloromethane and hexanes as eluent (1:1)
followed by recrystallization techniques. The
monosubstituted quinone 4a was separated from the
disubstituted quinones 7a and 9a by recrystallization
from methanol. The isomeric disubstituted quinones 7a
and 9a have the same Rf value in TLC and were purified
by successive recrystallization from a mixture of
methanol and chloroform. Mixture of disubstituted
hydroquinones 6a and 8a along with a small amount of
trisubstituted hydroquinone 11a were very difficult to
separate, so they were obtained in pure form by
alternative methods for characterization purposes. The
novel products 6a9a were fully characterized by 1H and
13
C NMR as well as CHN elemental analysis. Structure
of the 2,5-disubstituted quinone 9a was proved by X-ray
crystallography (Figure 1).

phenylsulfanyl]propionic acid methyl ester 6b, 3-[5-(2methoxycarbonylethylsulfanyl)3,6-dioxocyclohexa-1,4dienyl-sulfanyl]propionic acid methyl ester 7b, 3-[2,5dihydroxy-4-(2-methoxycarbonylethylsulfanyl)phenylsulfanyl]propionic acid methyl ester 8b, 3-[4-(2methoxycarbonylethylsulfanyl)3,6-dioxocyclohexa-1,4dienylsulfanyl]propionic acid methyl ester 9b in 5.1%,
3.0%, 37.0%, 1.0%, 12.5%, 2.4% and 15.6% yields
respectively (Scheme 6). The novel products 6b9b
were fully characterized by 1H and 13C NMR as well as
CHN elemental analysis. The structures of 2,6disubstituted quinone 7b and 2,5-disubstituted quinone
9b
were
unambiguously
proved
by
X-ray
crystallography (Figure 2 and 3).

Scheme 6.

Scheme 5.

Figure 2. X-ray structure of 7b. The conformation of one methyl

group is disordered.
Figure 1. X-ray structure of 9a.

Formation of the products 3a9a in one-pot can be

explained as follows: single conjugate addition of the
thiol 2a with quinone 1 leads to the formation of
hydroquinone 3a which then undergoes in situ oxidation
by the quinone 1 to give the monosubstituted quinone 4a
and the reduced byproduct 5. The monosubstituted
quinone 4a then becomes the substrate for the second
conjugate addition of the thiol 2a to give a mixture of
isomeric disubstituted hydroquinones 6a and 8a each of
which then undergoes in situ oxidation to give a mixture
of isomeric disubstituted quinones 7a and 9a.
Similarly, the reaction of 1,4-benzoquinone 1 with 3mercapto-propionic acid methyl ester 2b in ethanol at
room temperature for 12 h gave seven products
identified as 3-(2,5-dihydroxyphenylsulfanyl)propionic
acid methyl ester 3b,10a 3-(3,6-dioxocyclohexa-1,4dienylsulfanyl)propionic acid methyl ester 4b,10a 5, 3[2,5-dihydroxy-3-(2-methoxycarbonylethylsulfanyl)-

Figure 3. X-ray structure of 9b.

Yields of the quinones 4ab, 7ab and 9ab were

significantly improved by simply changing the solvent
from ethanol to methanol. Reaction of 1 with 2a in
methanol at rt for 0.5 hours gave 4a in 50% yield.
Similarly, reaction of 1 with 2b in methanol at rt for 0.5
h gave 4b in 70% yield. Reaction of 4a with 2a in
methanol at 60 oC for 0.5 h gave a mixture of the
isomeric disubstituted quinones 7a and 9a, 80% total
yield. Similarly, reaction of 4b with 2b in methanol at 60
o
C for 0.5 h gave the mixed isomeric disubstituted
quinones 7b and 9b in 71% yield. Hydroquinones 3ab,
6ab and 8ab were found to be unstable to air
oxidation; however, they could be obtained in higher

780

yields and pure form as white microcrystals by reduction

of the corresponding quinones with zinc dust in
methanol. Reduction of 4b with zinc in methanol gave
3b in 55% yield. Similarly, reduction of 7a with zinc in
methanol gave 6a in 60% yield.
Encouraged by the above results we tried to obtain
unsymmetrical 2,5-thio and 2,6-thiosubstituted 1,4benzoquinones and their corresponding hydroquinones
by sequential addition of two different thiols. Thus,
reaction of 4a with 2b in methanol at 60 oC for 5 min
gave us two novel asymmetrically substituted products,
namely 3-(5-cyclohexylsulfanyl-3,6-dioxo-cyclohexa1,4-dienyl-sulfanyl)propionic acid methyl ester 10a and
3-(4-cyclohexyl-sulfanyl-3,6-dioxo-cyclohexa-1,4dienylsulfanyl)propionic acid methyl ester 10b each in
13% yield (Scheme 7). The structures of the 2,6disubstituted quinone 10a and 2,5-disubstituted quinone
10b were proved by X-ray crystallography (Figure 4 and
5).
O

O
S
O

O
4a

SH MeOH

60 oC O
5 min

O
S

O
+
S

2b

O
10a (13%)

O
10b (13%)

Scheme 7.

with p-benzoquinone may also have played a role in the

above oxidation of hydroquinones.
O

OH

O
S
S

S
O

OH

S
O

13a (65%)

11a (7.3%)

9a

+
SH
O

OH
S

2a

S
O

OH
14a (80%)

12a (5%)

Scheme 8.

Similarly, reaction of 9b and 2b in methanol at 65 oC for

0.2 h gave 3-[3,6-dihydroxy-2,4-bis-(2-methoxycarbonylethylsulfanyl)phenylsulfanyl]propionic acid methyl
ester
11b
and
3-[2,5-dihydroxy-3,4,6-tris-(2methoxycarbonylethylsulfanyl)phenylsulfanyl]propionic
acid methyl ester 12b each in 17% yield (Scheme 9).
Reaction of 11b with p-benzoquinone in methanol at
reflux for 10 min gave 3-[2,4-bis-(2-methoxycarbonylethylsulfanyl)-3,6-dioxocyclohexa-1,4-dienylsulfanyl]propionic acid methyl ester 13b in 72% yield (Scheme
9). Similarly reaction of 12b with p-benzoquinone in
methanol at rt for 4 h gave 3-[2,4,5-tris-(2methoxycarbonyl-ethylsulfanyl)-3,6-dioxocyclohexa1,4-dienylsulfanyl]propionic acid methyl ester 14b in
96% yield (Scheme 9).

Figure 4. X-ray structure of 10a.

OH

O
O

OH

O
S

Figure 5. X-ray structure of 10b.

O
O

O
O

O
O

O
O
O

After obtaining the disubstituted quinones we utilized

them to prepare the 2,3,5-tri- and 2,3,5,6-tetrasubstituted derivatives (Scheme 8 and 9). We found that
the 2,5-disubstituted quinones are more convenient for
the synthesis of 2,3,5-trisubstituted hydroquinones,
probably due to their less solubility and more stability
towards oxidation than the 2,6-isomer. Thus, reaction of
9a and 2a in methanol at reflux for 2 h gave 2,3,5-triscyclohexylsulfanyl-benzene-1,4-diol 11a and 2,3,5,6tetrakis-cyclohexylsulfanyl-benzene-1,4-diol 12a in 73%
and 5% yield respectively (Scheme 8). Reaction of 11a
with p-benzoquinone in methanol at rt for 1 h gave
2,3,5-tris-cyclohexylsulfanyl-1,4-benzoquinone 13a in
65% yield (Scheme 8). Similarly reaction of 12a with pbenzoquinone in methanol at rt for 4 h gave 2,3,5,6tetrakis-cyclohexylsulfanyl-[1,4]benzoquinone 14a in
80% yield (Scheme 8). We believe atmospheric air along

OH
HS

OH
O

13b (72%)

9b

11b (17%)
S

12b (17%)

O
O

14b (96%)

2b

Scheme 9.

Formation of quinones vs. hydroquinones in the

nucleophilic addition to p-benzoquinone:
It is well established that the formation of quinones vs.
hydroquinones for different nucleophiles can be
explained through a mechanism in which both addition
and oxidation processes are involved.12c Addition of one
mole of nucleophile to p-benzoquinone first produces the
mono-substituted hydroquinone which can then undergo
oxidation with an excess quinone to finally afford the
mono-substituted p-benzoquinone as the product
(Scheme 10). Therefore, the oxidation potential of the

781

intermediate hydroquinone as compared to the oxidant

will determine the nature of the final product.
O

OH
+ NuH

O
O

Nu

addition

OH

Nu

oxidation

Scheme 10.

In case of N-nucleophiles, the hydroquinone formed by

addition has a higher oxidation potential than that of pbenzoquinone and is therefore not oxidized by excess pbenzoquinone.12c Thus addition of N-nucleophiles to pbenzoquinone gave only the hydroquinones (Scheme 1).
In the present case reaction of different alkyl thiols with
p-benzoquinone formed both the quinones and the
corresponding hydroquinones in varying yields probably
due to their comparable oxidation potentials (Scheme 5
and 6).
Orientation
of
nucleophilic
addition
to
monosubstituted p-benzoquinone:
Frontier Molecular Orbital (FMO) theory and resonance
theory have been employed to explain and predict
substituent effects on orientations of nucleophilic
additions and cycloadditions to p-benzoquinones.21 The
proposed order of reactivity for the second conjugate
addition with donor substituents at the 2-position of the
p-benzoquinone is C-5 > C-6 >> C-3 whereas for
acceptor substituents at the 2-position of the pbenzoquinone the order is C-3 >> C-6 > C-5 (Figure
6).21
O
2

O
D

6 2
5 3
3

A
6 2
5 3
1

Figure 4. Sites of nucleophilic attack on substituted benzoquinones: D

= donor; A = acceptor substituent. Position 1 is the most reactive;
position 2 is the next, etc.

Reaction of p-benzoquinone with cyclohexanethiol gave

the corresponding disubstituted quinones; 2,5-isomer 9a
and 2,6-isomer 7a, in a ratio of 1.52 (Scheme 5).
However, reaction of p-benzoquinone with 3mercaptopropionic acid methyl ester gave the
corresponding disubstituted quinones; 2,5-isomer 9b and
2,6-isomer 7b, in a lower ratio of 1.25 (Scheme 6).
Evidently cyclohexanethiol has more donor properties as
compared to 3-mercaptopropionic acid methyl ester.
Thus this slight difference in reactivity of these two
thiols is in accordance with FMO and resonance theory.
Conclusion
p-Benzoquinone in reactions with alkyl mercaptans gave
2-, 2,6- and 2,5- conjugate addition products in one-pot.
Novel 2,6- and 2,5- dialkylthio-, 2,3,5-trialkylthio- and
2,3,5,6-tetraalkylthio-p-benzoquinones
and
their

corresponding hydroquinones were obtained in good

yields by sequential addition and oxidation protocol.
1
H NMR (300 MHz) and 13C NMR (75 MHz) were
recorded in CDCl3 with TMS (0.00 ppm) for 1H NMR
and chloroform-d for 13C NMR (77.0 ppm) as the
internal reference.
General Procedure for the synthesis of 3a9a. To a
solution of p-benzoquinone (16.2 g, 149.8 mmol) in
ethanol was added cyclohexylmercaptan (17.4 mL, 149.8
mmol) and stirred 12 h at rt. Red crystals formed were
filtered, washed with hexanes and successively
recrystallized from methanol followed by a mixture of
chloroform and methanol to give the quinones 4a, 7a
and 9a. The filtrate was concentrated and the residue was
purified by column chromatography (silica gel; eluent,
hexanes to dichloromethane / hexanes 1:1) followed by
recrystallization from a mixture of hexanes and
dichloromethane to give the hydroquinones 3a, 6a and
8a.
General Procedure for reduction of quinones to
hydroquinones. To a solution of the corresponding
quinone (1 g) in 20 mL methanol was added zinc dust (1
g) and stirred vigorously at reflux. Saturated ammonium
chloride solution was added dropwise until the color
disappeared (10 min.). Then the reaction mixture was
cooled, filtered, washed with methanol and the combined
solution was evaporated, extracted with chloroform and
evaporated to get the corresponding hydroquinone.
2-Cyclohexylsulfanylbenzene-1,4-diol (3a)
Compound 3a was purified by column chromatography
(silica gel; eluent, dichloromethane / hexanes 1:1)
followed by recrystallization from a mixture of hexanes
and dichloromethane.
Yield 1.76 g (4.5%); white crystal; mp = 7678 oC (lit.10a
m. p. 2527 oC).
1

H NMR (300 MHz, CDCl3): = 6.79 (d, J = 2.8 Hz,

1H), 6.87 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 8.6 Hz, 2.8
Hz, 1H), 6.49 (bs, 1H), 5.00 (bs, 1H), 2.862.77 (m,
1H), 1.931.89 (m, 2H), 1.761.72 (m, 2H), 1.601.56
(m, 1H), 1.381.15 (m, 5H).
13

C NMR (75 MHz, CDCl3): = 151.6, 148.8, 122.8,

118.6, 118.2, 115.1, 49.0, 33.7, 26.3, 25.7.
Alternately 3a was prepared by the reduction of 4a (1g).
Yield (0.5 g, 50%).
2-Cyclohexylsulfanyl-[1,4]benzoquinone (4a)
Compound 4a was purified by recrystallization from
methanol. Yield 0.8 g (2.4%); orange crystal; mp = 114
116 oC (lit.11b m. p. 114116 oC).
1

H NMR (300 MHz, CDCl3): = 6.81 (d, J =9.9, 1H),

6.72 (dd, J = 9.9, 2.4, 1H), 6.42 (d, J = 2.4, 1H), 3.17
3.06 (m, 1H), 2.072.02 (m, 2H), 1.82-1.80 (m, 2H),
1.671.65 (m, 1H), 1.531.37 (m, 5H).
13

C NMR (75 MHz, CDCl3): = 184.0, 184.0, 152.0,

137.2, 136.2, 124.7, 42.5, 31.8, 25.6, 25.4.

782

Alternately 4a was prepared from p-benzoquinone (21.6

g, 0.2 mol) as per a literature procedure.11b Yield 10.7 g
(50%).
2,6-Bis(cyclohexylsulfanyl)benzene-1,4-diol (6a)
Compound 6a was purified by column chromatography
(first fraction eluted with hexanes). Yield 0.4 g (0.6%);
colorless oil.
1

H NMR (300 MHz, CDCl3): = 6.85 (s, 3H), 4.99 (s,

1H), 3.102.90 (m, 2H), 2.001.20 (m, 20H).
13
C NMR (75 MHz, CDCl3): = 150.7, 148.0, 121.2,
119.5, 48.8, 46.8, 33.5, 33.3, 26.0, 25.6, 25.4.
Anal.: Calcd for C18H26O2S2: C, 63.86. H, 7.74; found:
C, 63.96. H, 7.99.
Alternately 6a was prepared by reduction of 7a (0.06 g).
Yield 0.04 g (70%).
2,6-Bis(cyclohexylsulfanyl)[1,4]benzoquinone (7a)
Compound 7a was purified by recrystallization from a
mixture of chloroform and methanol. Yield 6 g (11.9%);
red crystal; mp = 145.0146.0 oC.
1

H NMR (300 MHz, CDCl3): = 6.34 (s, 2H), 3.133.05

(m, 2H), 2.062.02 (m, 4H), 1.821.80 (m, 4H), 1.68
1.63 (m, 2H), 1.561.31 (m, 10H).

13

C NMR (75 MHz, CDCl3): = 182.0, 151.4, 125.7,

43.0, 32.2, 25.9, 25.7.
Anal.: Calcd for C18H24O2S2: C, 64.25. H, 7.19; found:
C, 63.86. H, 7.37.
Alternatively 7a was prepared from 4a (2.22 g, 0.01
mol) and 2a (0.58 g, 0.005 mol) in methanol (50 mL) at
reflux for 5 min. Yield 0.22 g (13%). 9a was also
obtained in the above reaction. Yield 0.45 g (20%). Ratio
of the 2,5- and 2,6- isomers was found to be 1.52 by
NMR spectroscopy.
2,5-Bis(cyclohexylsulfanyl)benzene-1,4-diol (8a)
Compound 8a was purified by column chromatography
(first fraction eluted with hexanes). Yield 0.4 g (0.6%);
white crystal; mp = 9596 oC.
1

H NMR (300 MHz, CDCl3): = 7.09 (s, 1H), 6.37 (s,

1H), 2.902.82 (m, 2H), 1.951.91 (m, 4H), 1.771.73
(m, 4H), 1.621.56 (m, 2H), 1.411.17 (m, 10H).
13
C NMR (75 MHz, CDCl3): = 150.4, 121.0, 120.5,
48.9, 33.5, 26.1, 25.5.
Anal.: Calcd for C18H26O2S2: C, 63.86. H, 7.74; found:
C, 63.38. H, 7.89.
2,5-Bis(cyclohexylsulfanyl)[1,4]benzoquinone (9a)
Compound 9a was purified by recrystallization from a
mixture of chloroform and methanol. Yield 6 g (11.9%);
red crystal; mp = 203.0 205.0 oC.
1
H NMR (300 MHz, CDCl3): = 6.42 (s, 2H), 3.133.05
(m, 2H), 2.062.02 (m, 4H), 1.821.80 (m, 4H), 1.66
1.63 (m, 2H), 1.571.31 (10H).
13

C NMR (75 MHz, CDCl3): = 180.9, 154.0, 124.2,

42.9, 32.1, 25.9, 25.7.

Anal.: Calcd for C18H24O2S2: C, 64.25. H, 7.19; found:

C, 63.86. H, 7.37.
Alternatively 9a was prepared from 4a (2.22 g, 0.01
mol) and 2a (0.58 g, 0.005 mol) in methanol (50 mL) at
reflux for 5 min. Yield 0.45 g (20%).
General Procedure for the synthesis of 3b9b. To a
solution of p-benzoquinone (16.2 g, 149.8 mmol) in
ethanol was added 3-mercaptopropionic acid methyl
ester (18.0 g, 149.8 mmol) and stirred 12 h at rt. The red
crystals formed were filtered, washed with hexanes and
successively recrystallized from methanol followed by a
mixture of chloroform and methanol to give the
quinones 4b, 7b and 9b. The filtrate was concentrated,
the residue was purified by column chromatography
(silica gel; eluent, hexanes to dichloromethane/ hexanes
1:1) followed by recrystallization from a mixture of
hexane/dichloromethane to give the hydroquinones 3b,
6b and 8b.
3-(2,5-Dihydroxyphenylsulfanyl)propionic
acid
methyl ester (3b)
Compound 3b was purified by column chromatography
(silica gel; eluent, dichloromethane/ hexanes 1:1)
followed by recrystallization from a mixture of hexanes
and dichloromethane. Yield 1.99 g (5.1%); white
microcrystals; mp = 4850 oC (lit.10a m. p. 2125 oC).
1
H NMR (300 MHz, CDCl3): = 6.97 (d, J = 2.9 Hz,
1H), 6.86 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.6 Hz, 2.7
Hz, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 3.70 (s, 3H), 2.95 (t,
J = 7.0 Hz, 2H), 2.57 (t, J = 7.0 Hz, 2H).
13
C NMR (75 MHz, CDCl3): = 172.8, 150.9, 149.1,
121.7, 118.7, 117.9, 115.7, 52.1, 34.0, 30.9.
Alternately 3b was prepared by reduction of 4b (1 g).
Yield 0.55 g (55%).
3-(3,6-Dioxocyclohexa-1,4-dienylsulfanyl)propionic
acid methyl ester (4b)
Compound 4b was purified by recrystallization from
methanol. Yield 1.0 g (3.0%); red crystal; mp = 8789
o
C (lit.10a m. p. 9194 oC).
1
H NMR (300 MHz, CDCl3): = 6.82 (d, J = 10.0 Hz,
1H), 6.74 (dd, J = 10.0 Hz, 2.2 Hz, 1H), 6.43 (d, J = 2.3
Hz, 1H), 3.73 (s, 3H), 3.07 (t, J = 7.3 Hz, 2H), 2.74 (t, J
= 7.3 Hz, 2H).
13
C NMR (75 MHz, CDCl3): = 183.8, 183.6, 171.1,
151.9, 137.4, 136.1, 124.9, 52.2, 31.9, 25.0.
Alternately 4b was prepared from p-benzoquinone (21.6
g, 0.2 mol) and 2b (11.06 g, 0.1 mol) in methanol at rt
for 1 h. Yield 15.1 g (70%).
3-[2,5-Dihydroxy-3-(2-methoxycarbonylethylsulfanyl)phenylsulfanyl]propionic acid methyl ester (6b)
Compound 6b was purified by column chromatography
(first fraction eluted with hexanes). 6b quickly oxidized
and became a red color when exposed to air. Yield 0.66 g
(1.0%); colorless oil.

783
1

H NMR (300 MHz, CDCl3): = 7.00 (s, 2H), 6.35 (s,

1H), 3.81 (s, 6H), 3.18 (t, J = 6.9 Hz, 4H), 2.73 (t, J =
6.9 Hz, 4H).
13
C NMR (75 MHz, CDCl3): = 172.5, 149.6, 149.0,
120.6, 120.2, 119.9, 53.4, 52.0, 34.0, 33.8, 30.8, 29.2.
Anal.: Calcd for C14H18O6S2: C, 48.54. H, 5.24; found:
C, 48.82. H, 5.37.
Alternately 6b was prepared by reduction of 7b (0.52 g,
1.5 mmol). Yield 0.42 g (80%).
3-[5-(2-Methoxycarbonylethylsulfanyl)3,6-dioxocyclohexa-1,4-dienylsulfanyl]propionic acid methyl ester
(7b)
Compound 7b was purified by recrystallization from a
mixture of chloroform and methanol. Yield 6.3 g
(12.5%); red crystal; mp = 95.096.0 oC.
1

H NMR (300 MHz, CDCl3): = 6.37 (s, 2H), 3.73 (s,

6H), 3.07 (t, J = 7.3 Hz, 4H), 2.73 (t, J = 7.3 Hz, 4H).
13
C NMR (75 MHz, CDCl3): = 181.2, 171.3, 151.2,
125.8, 52.4, 32.1, 25.4.
Anal.: Calcd for C14H16O6S2: C, 48.82. H, 4.68; found:
C, 48.60. H, 4.57.
Alternatively 7b was prepared from 4b (6.03 g, 0.027
mol) and 2b (1.6 g, 0.013 mol) in methanol at reflux for
0.5 h. Yield 0.8 g (17%).
3-[2,5-Dihydroxy-4-(2-methoxycarbonylethylsulfanyl)phenylsulfanyl]propionic acid methyl ester (8b)
Compound 8b was purified by column chromatography
(first fraction eluted with hexanes). Yield 1.6 g (2.4%);
white crystal; mp = 118.0120.0 oC.
1
H NMR (300 MHz, CDCl3): = 7.04 (s, 2H), 6.35 (s,
2H), 3.64 (s, 6H), 2.92 (t, J = 7.0 Hz, 4H), 2.51 (t, J =
7.0 Hz, 4H).
13

C NMR (75 MHz, CDCl3): = 219.8, 172.1, 150.4,

120.9, 52.0, 33.9, 31.1.

Anal.: Calcd for C14H18O6S2: C, 48.54. H, 5.24; found:

C, 48.36. H, 5.20.
Alternately 8b was prepared by reduction of 9b (0.52 g,
1.5 mmol). Yield 0.39 g (75%).
3-[4-(2-Methoxycarbonylethylsulfanyl)3,6-dioxocyclohexa-1,4-dienylsulfanyl]propionic acid methyl ester
(9b)
Compound 9b was purified by recrystallization from a
mixture of chloroform and methanol. Yield 9.7 g
(19.2%); yellow crystal; mp = 164.0166.0 oC.
1

H NMR (300 MHz, CDCl3): = 6.43 (s, 2H), 3.73 (s,

6H), 3.06 (t, J = 7.3 Hz, 4H), 2.73 (t, J = 7.3 Hz, 4H).
13
C NMR (75 MHz, CDCl3): = 180.2, 171.3, 154.1,
124.2, 52.4, 32.1, 25.4.
Anal.: Calcd for C14H16O6S2: C, 48.82. H, 4.68; found:
C, 48.60. H, 4.57.
Alternatively 9b was prepared from 4b (6.03 g, 0.027
mol) and 2b (1.6 g, 0.013 mol) in methanol at reflux for
0.5 h. Yield 0.5 g (11%).

3-(5-Cyclohexylsulfanyl-3,6-dioxocyclohexa-1,4-dienylsulfanyl)propionic acid methyl ester (10a)

To the solution of 4a (4.44 g, 0.02 mol) in methanol (100
mL) at reflux under stirring, 2b (1.2 g, 0.01 mol) was
added during 5 min. After cooling to rt over 1 h the
reaction mixture was filtered to give a mixture of 2,5and 2,6- isomers (2.4 g, 71%). Further fractional
crystallization gave 10a. Yield 0.45 g (13%); red crystal;
mp = 96.098.0 oC.
1

H NMR (300 MHz, CDCl3): = 6.35 (dd, J = 4.7 Hz,

2.2 Hz, 2H), 3.73 (s, 3H), 3.133.04 (m, 3H), 2.73 (t, J =
7.3 Hz, 2H), 2.062.02 (m, 2H), 1.821.79 (m, 2H),
1.681.31 (m, 6H).
13

C NMR (75 MHz, CDCl3): = 181.6, 181.2, 151.4,

151.2, 125.7, 125.7, 124.3, 124.1, 52.4, 43.1, 42.9, 32.1,
25.9, 25.7, 25.4, 25.3.
Anal.: Calcd for C16H20O4S2: C, 56.45. H, 5.92; found:
C, 56.52. H, 6.02.
3-(4-Cyclohexylsulfanyl-3,6-dioxo-cyclohexa-1,4dien-ylsulfanyl)propionic acid methyl ester (10b)
Compound 10b was isolated along with 10a and purified
by fractional crystallization from methanol. Yield 0.45 g
(13%); red crystal; mp = 136.0137.0 oC.
1

H NMR (300 MHz, CDCl3): = 6.42 (d, J = 2.3 Hz,

2H), 3.73 (s, 3H), 3.133.04 (m, 3H), 2.73 (t, J = 7.3 Hz,
2H), 2.062.02 (m, 2H), 1.821.74 (m, 2H), 1.681.28
(m, 6H).

13

C NMR (75 MHz, CDCl3): = 180.6, 180.3, 171.3,

154.2, 153.8, 124.3, 124.0, 52.4, 42.9, 32.1, 25.8, 25.7,
25.3.
Anal.: Calcd for C16H20O4S2: C, 56.45. H, 5.92; found:
C, 56.10. H, 5.93.
2,3,5-Triscyclohexylsulfanylbenzene-1,4-diol (11a)
To a solution of 9a (0.1 g, 0.3 mmol) in methanol (10
mL) was added to 2a (0.035 g, 0.3 mmol) and stirred at
rt until all the red crystals of the quinone were dissolved
(48 h) and the solution became colorless. The volatiles
were removed and the residue was crystallized from npentane to give 11a. Yield 0.1 g (73%); green crystal; mp
= 88.090.0 oC.
1
H NMR (300 MHz, CDCl3): = 7.06 (s, 1H), 6.98 (s,
1H), 6.71 (s, 1H), 3.252.98 (m, 3H), 2.031.59 (m,
15H), 1.481.21 (m, 15H).
13
C NMR (75 MHz, CDCl3): = 151.7, 150.4, 124.4,
123.4, 121.0, 117.0, 49.5, 49.1, 44.9, 33.7, 33.3, 26.3,
26.2, 25.9, 25.8.
Anal.: Calcd for C24H36O2S3: C, 63.67. H, 8.40; found:
C, 63.92. H, 8.40.
2,3,5,6-Tetrakiscyclohexylsulfanylbenzene-1,4-diol
(12a)
A solution of 9a (0.65 g, 0.002 mol) in dichloromethane
(5 mL) was added to a solution of 2a (0.23 g, 0.002 mol)
in methanol (50 mL) during 2 h under reflux and then
allowed to stand overnight at rt. The reaction mixture
was filtered to give red crystals of 9a. The filtrate was

784

evaporated and the residue was separated by silica gel

column chromatography with hexanes followed by
hexanes/dichloromethane (2:1 to 1:1 ratio) to give 12a.
Yield 0.05 g (5%); pale orange crystal; mp = 185.0
186.0 oC.
1

H NMR (300 MHz, CDCl3): 7.40 (s, 2H), 3.363.29 (m,

4H), 1.861.85 (m, 8H), 1.761.73 (m, 8H), 1.611.60
(m, 4H), 1.391.22 (m, 20H).

13

C NMR (75 MHz, CDCl3): = 152.6, 124.9, 47.8,

33.3, 16.0, 25.7.
Anal.: Calcd for C30H46O2S4: C, 63.55. H, 8.18; found:
C, 63.20. H, 8.41.
2,3,5-triscyclohexylsulfanyl-1,4-benzoquinone (13a)
A mixture of 11a (0.23 g, 0.5 mmol) and pbenzoquinone (0.05 g, 0.5 mmol) in methanol (20 mL)
was stirred at rt for 1 h. Methanol was removed and the
residue was extracted with chloroform, washed with
water, dried over sodium sulfate to give a brown oil
which was recrystallized from hexanes to give 13a. Yield
0.15 g (65%); red crystal; mp = 71.073.0 oC.
1

H NMR (300 MHz, CDCl3): = 6.37 (s, 1H), 3.983.89

(m, 1H), 3.773.67 (m, 1H), 3.083.00 (m, 1H), 2.04
1.15 (m, 30H).

13

C NMR (75 MHz, CDCl3): = 178.2, 177.8, 153.0,

148.9, 143.7, 125.5, 47.0, 46.8, 46.4, 42.9, 34.0, 33.8,
32.0, 25.9, 25.8, 25.7, 25.5, 25.4.
Anal.: Calcd for C24H34O2S3: C, 63.95. H, 7.60; found:
C, 63.83. H, 7.93.
2,3,5,6-Tetrakiscyclohexylsulfanyl[1,4]benzoquinone
(14a)
A mixture of 12a (50 mg, 0.09 mol) and p-benzoquinone
(10 mg, 0.09 mol) in methanol (20 mL) were stirred at rt
for 4 h. Then methanol was removed and the residue was
extracted with dichloromethane, washed with water,
dried over sodium sulfate to give 14a after
recrystallization from a mixture of n-pentane and
diethylether. Yield 0.04 g (80%); red crystal; mp =
155.0156.0 oC.
1

H NMR (300 MHz, CDCl3): = 3.743.65 (m, 4H),

1.921.57 (m, 20H), 1.471.21 (m, 20H).
13
C NMR (75 MHz, CDCl3): = 174.7, 147.2, 46.7,
37.6, 34.3, 26.2, 25.7.
Anal.: Calcd for C30H44O2S4: C, 63.78. H, 7.85; found:
C, 63.82. H, 8.00.
3-[3,6-Dihydroxy-2,4-bis-(2-methoxycarbonylethylsulfanyl)phenylsulfanyl]propionic acid methyl ester
(11b)
A mixture of 9b (0.5 g, 1.5 mmol) in methanol (15 mL)
was added to 2b (0.18 g, 1.5 mmol) and refluxed until
the solution became colorless (10 min). The volatiles
were removed and the residue was purified by silica gel
column chromatography using chloroform as an eluent
to give 11b. Yield 0.12 g (17%); brown oil.
1

H NMR (300 MHz, CDCl3): = 7.16 (s, 1H), 6.98 (s,

1H), 6.83 (s, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H),

3.18 (t, J = 7.4 Hz, 2H), 3.06 (dt, J = 17.2, 7.0 Hz, 4H),
2.69 (t, J = 7.4 Hz, 2H), 2.55 (dt, J = 10.6, 3.7 Hz, 4H).
13
C NMR (75 MHz, CDCl3): = 172.3, 172.2, 172.0,
152.1, 150.1, 125.9, 122.6, 120.0, 116.9, 52.1, 52.1,
52.0, 33.9, 33.8, 33.7, 31.6, 31.2, 27.3.
Anal.: Calcd for C18H24O8S3: C, 46.54. H, 5.21; found:
C, 46.47. H, 5.32.
3-[2,5-Dihydroxy-3,4,6-tris-(2-methoxycarbonylethylsulfanyl)phenylsulfanyl]propionic acid methyl ester
(12b)
A mixture of 9b (0.5 g, 1.5 mmol) in methanol (15 mL)
was added to 2b (0.18 g, 1.5 mmol) and refluxed until
the solution became colorless (10 min). The volatiles
were removed and the residue was purified by silica gel
column chromatography using chloroform as an eluent
to give 12b. Yield 0.15 g (17%); brown crystal; mp =
58.059.0 oC.
1
H NMR (300 MHz, CDCl3): = 7.43 (s, 2H), 3.68 (s,
12H), 3.17 (t, J = 7.1 Hz, 8H), 2.57 (t, J = 7.0 Hz, 8H).
13

C NMR (75 MHz, CDCl3): = 152.8, 125.5, 52.1,

34.3, 30.6.
Anal.: Calcd for C22H30O10S4: C, 45.35. H, 5.19; found:
C, 45.35. H, 5.14.
Alternately reaction of 13b (0.3 g, 6.5 mmol) with pbenzoquinone (0.08 g, 6.5 mmol) in methanol (10 mL) at
rt for 2 h and then 0 oC for 6h gave 12b. Yield 0.25 g
(66%).
3-[2,4-Bis-(2-methoxycarbonylethylsulfanyl)-3,6diox-ocyclohexa-1,4-dienylsulfanyl]propionic
acid
methyl ester (13b)
A mixture of 11b (0.5 g, 1.07 mmol) and pbenzoquinone (0.45 g, 1.07 mmol) in methanol (50 mL)
was refluxed for 10 min. Then methanol was evaporated
and the residue was extracted with dichloromethane,
washed twice with water (2 20 mL), dried over sodium
sulfate and evaporated to give 13b. Yield 0.36 g (72%).
Red oil.
1
H NMR (300 MHz, CDCl3): = 6.32 (s, 1H), 3.67 (s,
3H), 3.63 (s, 3H), 3.62 (s, 3H), 3.40 (t, J = 7.1 Hz, 2H),
3.26 (t, J = 7.1 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.692.59 (m, 6H).
13
C NMR (75 MHz, CDCl3): = 180.0, 177.5, 171.8,
171.1, 169.9, 153.0, 125.7, 124.0, 112.3, 103.6, 90.2,
53.9, 52.2, 52.0, 37.4, 35.2, 31.9, 31.9, 29.8, 29.5, 25.3,
25.1.
Anal.: Calcd for C18H22O8S3: C, 46.74. H, 4.79; found:
C, 47.10. H, 4.83.
3-[2,4,5-Tris-(2-methoxycarbonylethylsulfanyl)-3,6dioxocyclohexa-1,4-dienylsulfanyl]propionic
acid
methyl ester (14b)
A mixture of 3-[2,5-dihydroxy-3,4,6-tris-(2-methoxycarbonylethylsulfanyl)-phenylsulfanyl]propionic
acid
methyl ester (0.25 g, 0.43 mmol) and p-benzoquinone
(0.05 g, 0.43 mmol) in methanol (10 mL) was stirred at
rt for 2 h and then refluxed for 20 min. The solvent was

785

evaporated, diluted with chloroform, washed with water

(2 20 mL), dried over sodium sulfate and evaporated to
give 14b. Yield 0.24 g (96%). Red crystal; mp = 58.0
59.0 oC.
1

H NMR (300 MHz, CDCl3): = 2.43 (s, 12H), 2.08 (t, J

= 7.0 Hz, 8H), 1.45 (t, J = 7.0 Hz, 8H).
13
C NMR (75 MHz, CDCl3): = 174.0, 171.7, 145.8,
51.9, 35.1, 29.1.
Anal.: Calcd for C22H28O10S4: C, 45.50. H, 4.86; found:
C, 45.85. H, 4.89.
CCDC-635867-635871 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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786

Graphical Abstract
Short title of the article: Reactions of p-Benzoquinone with S-Nucleophiles
O
R2

R1

S
S

OH

OH

R1 R2

OH

OH

R1

S
R2

S
R3

O
S

R1

OH

R1

S
R2

R1 R2

R4
S

O
S

S
OH R2

S
O

R1
R3

S
R2

R4
S

OH

S
OH R2

R1