777

Reactions of p-Benzoquinone with S-Nucleophiles Alan R. Katritzky,*,1 Dmytro Fedoseyenko1, Prabhu P. Mohapatra1 and Peter J. Steel2

1Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA. 2 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 2,5- and 2,6-isomers were established by X-ray crystallography. 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 stabilization of petroleum products.7 2,5-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 2-substituted mono-adducts. Depending on the character of the nucleophile, the oxidation potential of the mono-adduct, and possible reversible formation of a charge-transfer complex, the initially formed mono adduct may undergo further nucleophilic addition to give 2,3-, 2,5- and/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 tris-adduct may react with yet one more equivalent of nucleophile to give a 2,3,5,6-tetrasubstituted p-benzoquinone.

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 2,3,5-trisubstituted hydroquinones (Scheme 1). However, conjugate additions of secondary amines to p-benzoquinone are reported to produce only 2,5-disubstituted hydroquinones (Scheme 1).14

O

O

NH

N

R

NH

N

OH

OH

N

NROH

OH

N

NR

N

NR

OH

OH

N

NR

N

N R

OH

OH

N

N OH

OH

N N

N N

OH

OH

N N

NN

NH

N R OH

OH

NN

R

R

OH

OH

NN

NN

R

RR

R

OH

OH

NN

NN

R

RR

R

OH

OH

NN

NN

R

RR

R

NN

R

R

HN

OH

OH

N

N

N OHOH

OH

N+

O-

+ +

R = H 31% 28% 41%R = Me 10% 85% 5%

+ +

48% 32% 20%

+ + +

R = H 57% 29% 14% tracesR = Me 21% 79%

46%

85%

Scheme 1.

Reactions of pyrazole, 4-nitropyrazole, 3,5-dimethylpyrazole, 4-chloro-3,5-dimethylpyrazole and 3-(2-pyridyl)pyrazole with p-benzoquinone gave mono- and 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

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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

O

O

N SO

O

R O

O

SPy

R

OAcOAc

OAcAcHN

SHOAc

OAc

OAcAcHN

SO

O

OH

OH

SO2Ph

SHSH

OH

OH

S

S

O

O

SS

O

O

NH3Cl CO2R

HS

OH

OH

SCO2R

NH3Cl

CO2Et

HS

OH

OH

SCO2Et

+

PhSO2H

SH

O

O

S

S

+O

O

SS

Scheme 2.

Carbon nucleophiles: Conjugate addition of carbon nucleophiles to p-benzoquinones gave 2-monosubstituted, 2,5- and 2,6-disubstituted products similar to thiols (Scheme 3).17 Reaction of p-benzoquinone 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)-p-hydroquinone.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-diaryl- and 2,6-diaryl-1,4-benzoquinones.17e Reaction of p-benzoquinone with 4-hydroxycoumarin in aqueous acetic acid gave 3-(1,4-benzoquinonyl)-4-hydroxycoumarin which reacted further with pyridine to give a unique 2,3-disubstituted zwitterionic adduct (Scheme 3).17c,18 Similarly reaction of 3-(1,4-benzoquinonyl)-4-hydroxycoumarin with 4-hydroxycoumarin gave selectively a 2,3-disubstituted quinone product.19 Oxygen nucleophiles: Conjugate addition of oxygen nucleophiles such as ethanol and phenol with p-benzoquinone or activated quinones gave only 2,5-disubstituted products in addition to the 2-monosubstituted adducts (Scheme 4).20 Herein, we report the synthesis of some novel 2,5-dialkylthio-, 2,6-dialkylthio-substituted, 2,3,5-trisubstituted and 2,3,4,5-tetrasubstituted p-benzoquinones and their corresponding hydroquinones in good yields by sequential addition and in situ oxidation.

O

O

O

O O

OH

O

O

OH

O

OH

OH

NH

HN

NH

O

O

O

O

+ +

O

O

O

O

O

O

+ +

O

O

O

O

O

O

+ +

O

O

Me

Me

Me

Me

Me

Me Me

Me

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Me

Cl

Me

Cl

41% 12% 6%

25% 13% 8%

50% 3% 2%

R'O

O

R'' OH

OH

R'O

O

R''

R' O

O

R''

-2H2OO

O

R'

COR''

R''OC

R'

NCCH2COROH

OH

CN

O

R

CN

O

R

O

OH

O

Scheme 3.

O

O

OH O

OO

O

R R = H

OH

Me

O

OO

O

RR = CO2Me

+

Me

Me

O

O

O

R Me

R = H

O

OO

O

EtOH

Scheme 4.

Results and Discussion During our ongoing research in the area of rubber additives,10a,10b,15l we found that reaction of 1,4-benzoquinone 1 with cyclohexanethiol 2a in ethanol at room temperature for 12 h gave seven products including 2-cyclohexylsulfanylbenzene-1,4-diol 3a,10a 2-cyclohexylsulfanyl-[1,4]benzoquinone 4a,11b benzene-1,4-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, 2,5-bis(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 3a−9a were purified

1 All presented yields are calculated for isolated compounds.

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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 6a−9a were fully characterized by 1H and 13C NMR as well as CHN elemental analysis. Structure of the 2,5-disubstituted quinone 9a was proved by X-ray crystallography (Figure 1).

Scheme 5.

Figure 1. X-ray structure of 9a.

Formation of the products 3a−9a 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 3-mercapto-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-1,4-dienylsulfanyl)propionic acid methyl ester 4b,10a 5, 3-[2,5-dihydroxy-3-(2-methoxycarbonylethylsulfanyl)-

phenylsulfanyl]propionic acid methyl ester 6b, 3-[5-(2-methoxycarbonylethylsulfanyl)3,6-dioxocyclohexa-1,4-dienyl-sulfanyl]propionic acid methyl ester 7b, 3-[2,5-dihydroxy-4-(2-methoxycarbonylethylsulfanyl)-phenylsulfanyl]propionic acid methyl ester 8b, 3-[4-(2-methoxycarbonylethylsulfanyl)3,6-dioxocyclohexa-1,4-dienylsulfanyl]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 6b−9b were fully characterized by 1H and 13C NMR as well as CHN elemental analysis. The structures of 2,6-disubstituted quinone 7b and 2,5-disubstituted quinone 9b were unambiguously proved by X-ray crystallography (Figure 2 and 3).

Scheme 6.

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

Figure 3. X-ray structure of 9b.

Yields of the quinones 4a−b, 7a−b and 9a−b 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 oC for 0.5 h gave the mixed isomeric disubstituted quinones 7b and 9b in 71% yield. Hydroquinones 3a−b, 6a−b and 8a−b 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 1,4-benzoquinones 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-cyclohexa-1,4-dienyl-sulfanyl)propionic acid methyl ester 10a and 3-(4-cyclohexyl-sulfanyl-3,6-dioxo-cyclohexa-1,4-dienylsulfanyl)propionic acid methyl ester 10b each in 13% yield (Scheme 7). The structures of the 2,6-disubstituted quinone 10a and 2,5-disubstituted quinone 10b were proved by X-ray crystallography (Figure 4 and 5).

O

O

S S

O

O

S

O

O

O

SH

O

S

O

OS

O

O +

10a (13%) 10b (13%)

+

4a 2b

60 oC5 min

MeOH

Scheme 7.

Figure 4. X-ray structure of 10a.

Figure 5. X-ray structure of 10b.

After obtaining the disubstituted quinones we utilized them to prepare the 2,3,5-tri- and 2,3,5,6-tetra-substituted 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-tris-cyclohexylsulfanyl-benzene-1,4-diol 11a and 2,3,5,6-tetrakis-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 p-benzoquinone in methanol at rt for 4 h gave 2,3,5,6-tetrakis-cyclohexylsulfanyl-[1,4]benzoquinone 14a in 80% yield (Scheme 8). We believe atmospheric air along

with p-benzoquinone may also have played a role in the above oxidation of hydroquinones.

O

O

S

S

SH

OH

OH

S

S S

+

OH

OH

S

S S

S

11a (7.3%)

12a (5%)

9a

O

O

S

S S

O

O

S

S S

S

13a (65%)

14a (80%)

2a

+

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-methoxycarbony-lethylsulfanyl)phenylsulfanyl]propionic acid methyl ester 11b and 3-[2,5-dihydroxy-3,4,6-tris-(2-methoxycarbonylethylsulfanyl)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-methoxycarbonyl-ethylsulfanyl)-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-(2-methoxycarbonyl-ethylsulfanyl)-3,6-dioxocyclohexa-1,4-dienylsulfanyl]propionic acid methyl ester 14b in 96% yield (Scheme 9).

11b (17%)

12b (17%)

9b

OHS O

OS

O

OS

O

O

OHO

S

SO

HS O

O

OHS O

OS

O

OSOH

O O

SO

O

+13b (72%)

14b (96%)

OS O

OS

O

OS

O

O

O

OS O

OS

O

OSO

O O

SO

O

+

+

O O

O O

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

O

+ NuH

O

OOH

OH

NuO

O

Nuaddition

oxidation Scheme 10.

In case of N-nucleophiles, the hydroquinone formed by addition has a higher oxidation potential than that of p-benzoquinone and is therefore not oxidized by excess p-benzoquinone.12c Thus addition of N-nucleophiles to p-benzoquinone 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 p-benzoquinone the order is C-3 >> C-6 > C-5 (Figure 6).21

O

O

D235

6

3

2

1

O

O

A235

6

3

2

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 3-mercaptopropionic 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. 1H 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 3a−9a. 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 = 76–78 oC (lit.10a

m. p. 25–27 oC). 1H NMR (300 MHz, CDCl3): δ = 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), 2.86–2.77 (m, 1H), 1.93–1.89 (m, 2H), 1.76–1.72 (m, 2H), 1.60–1.56 (m, 1H), 1.38–1.15 (m, 5H). 13C NMR (75 MHz, CDCl3): δ = 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. 114–116 oC). 1H NMR (300 MHz, CDCl3): δ = 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), 2.07–2.02 (m, 2H), 1.82-1.80 (m, 2H), 1.67–1.65 (m, 1H), 1.53–1.37 (m, 5H). 13C NMR (75 MHz, CDCl3): δ = 184.0, 184.0, 152.0, 137.2, 136.2, 124.7, 42.5, 31.8, 25.6, 25.4.

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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. 1H NMR (300 MHz, CDCl3): δ = 6.85 (s, 3H), 4.99 (s, 1H), 3.10–2.90 (m, 2H), 2.00–1.20 (m, 20H). 13C NMR (75 MHz, CDCl3): δ = 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 = 145.0–146.0 oC. 1H NMR (300 MHz, CDCl3): δ = 6.34 (s, 2H), 3.13–3.05 (m, 2H), 2.06–2.02 (m, 4H), 1.82–1.80 (m, 4H), 1.68–1.63 (m, 2H), 1.56–1.31 (m, 10H). 13C NMR (75 MHz, CDCl3): δ = 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 = 95–96 oC. 1H NMR (300 MHz, CDCl3): δ = 7.09 (s, 1H), 6.37 (s, 1H), 2.90–2.82 (m, 2H), 1.95–1.91 (m, 4H), 1.77–1.73 (m, 4H), 1.62–1.56 (m, 2H), 1.41–1.17 (m, 10H). 13C NMR (75 MHz, CDCl3): δ = 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. 1H NMR (300 MHz, CDCl3): δ = 6.42 (s, 2H), 3.13–3.05 (m, 2H), 2.06–2.02 (m, 4H), 1.82–1.80 (m, 4H), 1.66–1.63 (m, 2H), 1.57–1.31 (10H). 13C NMR (75 MHz, CDCl3): δ = 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 3b−9b. 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 = 48–50 oC (lit.10a m. p. 21–25 oC). 1H NMR (300 MHz, CDCl3): δ = 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). 13C NMR (75 MHz, CDCl3): δ = 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 = 87–89 oC (lit.10a m. p. 91–94 oC). 1H NMR (300 MHz, CDCl3): δ = 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). 13C NMR (75 MHz, CDCl3): δ = 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.

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1H NMR (300 MHz, CDCl3): δ = 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). 13C NMR (75 MHz, CDCl3): δ = 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-dioxocycl-ohexa-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 = 95.0–96.0 oC. 1H NMR (300 MHz, CDCl3): δ = 6.37 (s, 2H), 3.73 (s, 6H), 3.07 (t, J = 7.3 Hz, 4H), 2.73 (t, J = 7.3 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ = 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 = 118.0–120.0 oC. 1H NMR (300 MHz, CDCl3): δ = 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). 13C NMR (75 MHz, CDCl3): δ = 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-dioxocycl-ohexa-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 = 164.0–166.0 oC. 1H NMR (300 MHz, CDCl3): δ = 6.43 (s, 2H), 3.73 (s, 6H), 3.06 (t, J = 7.3 Hz, 4H), 2.73 (t, J = 7.3 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ = 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-dien-ylsulfanyl)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 2,5- and 2,6- isomers (2.4 g, 71%). Further fractional crystallization gave 10a. Yield 0.45 g (13%); red crystal; mp = 96.0–98.0 oC. 1H NMR (300 MHz, CDCl3): δ = 6.35 (dd, J = 4.7 Hz, 2.2 Hz, 2H), 3.73 (s, 3H), 3.13–3.04 (m, 3H), 2.73 (t, J = 7.3 Hz, 2H), 2.06–2.02 (m, 2H), 1.82–1.79 (m, 2H), 1.68–1.31 (m, 6H). 13C NMR (75 MHz, CDCl3): δ = 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-1,4-dien-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 = 136.0–137.0 oC. 1H NMR (300 MHz, CDCl3): δ = 6.42 (d, J = 2.3 Hz, 2H), 3.73 (s, 3H), 3.13–3.04 (m, 3H), 2.73 (t, J = 7.3 Hz, 2H), 2.06–2.02 (m, 2H), 1.82–1.74 (m, 2H), 1.68–1.28 (m, 6H). 13C NMR (75 MHz, CDCl3): δ = 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 n-pentane to give 11a. Yield 0.1 g (73%); green crystal; mp = 88.0–90.0 oC. 1H NMR (300 MHz, CDCl3): δ = 7.06 (s, 1H), 6.98 (s, 1H), 6.71 (s, 1H), 3.25–2.98 (m, 3H), 2.03–1.59 (m, 15H), 1.48–1.21 (m, 15H). 13C NMR (75 MHz, CDCl3): δ = 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. 1H NMR (300 MHz, CDCl3): 7.40 (s, 2H), 3.36–3.29 (m, 4H), 1.86–1.85 (m, 8H), 1.76–1.73 (m, 8H), 1.61–1.60 (m, 4H), 1.39–1.22 (m, 20H). 13C NMR (75 MHz, CDCl3): δ = 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 p-benzoquinone (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 = 71.0–73.0 oC. 1H NMR (300 MHz, CDCl3): δ = 6.37 (s, 1H), 3.98–3.89 (m, 1H), 3.77–3.67 (m, 1H), 3.08–3.00 (m, 1H), 2.04–1.15 (m, 30H). 13C NMR (75 MHz, CDCl3): δ = 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 = 155.0–156.0 oC. 1H NMR (300 MHz, CDCl3): δ = 3.74–3.65 (m, 4H), 1.92–1.57 (m, 20H), 1.47–1.21 (m, 20H). 13C NMR (75 MHz, CDCl3): δ = 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-methoxycarbonylethylsu-lfanyl)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. 1H NMR (300 MHz, CDCl3): δ = 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). 13C NMR (75 MHz, CDCl3): δ = 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-methoxycarbonylethyl-sulfanyl)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 = 58.0–59.0 oC. 1H NMR (300 MHz, CDCl3): δ = 7.43 (s, 2H), 3.68 (s, 12H), 3.17 (t, J = 7.1 Hz, 8H), 2.57 (t, J = 7.0 Hz, 8H). 13C NMR (75 MHz, CDCl3): δ = 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 p-benzoquinone (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)-3,6-diox-ocyclohexa-1,4-dienylsulfanyl]propionic acid methyl ester (13b) A mixture of 11b (0.5 g, 1.07 mmol) and p-benzoquinone (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. 1H NMR (300 MHz, CDCl3): δ = 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), 2.69-2.59 (m, 6H). 13C NMR (75 MHz, CDCl3): δ = 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)-3,6-dioxocyclohexa-1,4-dienylsulfanyl]propionic acid methyl ester (14b) A mixture of 3-[2,5-dihydroxy-3,4,6-tris-(2-methoxy-carbonylethylsulfanyl)-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. 1H NMR (300 MHz, CDCl3): δ = 2.43 (s, 12H), 2.08 (t, J = 7.0 Hz, 8H), 1.45 (t, J = 7.0 Hz, 8H). 13C NMR (75 MHz, CDCl3): δ = 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.

References (1) (a) Batenko, N. G.; Karlivans, G.; Valters, R. Chem. Het.

Comp. 2005, 41, 691. (b) Lenaz, G.; Genova, M. L. Encyclopedia Biol. Chem. 2004, 3, 621. (c) Aguilar-Martinez, M.; Macias-Ruvalcaba, N. A.; Bautista-Martinez, J. A.; Gomez, M.; Gonzalez, F. J.; Gonzalez, I. Curr. Org. Chem. 2004, 8, 1721.

(2) (a) Vazquez, C.; Calabrese, J. C.; Dixon, D. A.; Miller, J. S. J. Org. Chem. 1993, 58, 65. (b) Neilands, O. Fizikas un Tehnisko Zinatnu Serija 1981, 63.

(3) Miyashita, K.; Imanishi, T. Chem. Rev. 2005, 105, 4515. (4) Barrero, A. F.; Alvarez-Manzaneda, E. J.; MarHerrador,

M.; Chahboun, R.; Galera, P. Bioorg. Med. Chem. Lett. 1999, 9, 2325.

(5) Loya, S.; Tal, R.; Kashman, R. Y.; Hizi, A. Antimicrob. Agents Chemother. 1990, 34, 2009.

(6) Bourguet-Kondraki, M. L.; Longeon, A.; Morel, E.; Guyot, M. Int. J. Immunopharmac. 1991, 13, 393.

(7) Farzaliev, V. M.; Allakhverdiev, M. A.; Shamkhalova, S. A.; Rzaeva. I. A Russian J. Appl. Chem. 2004, 77, 783.

(8) Parvez, M.; Mesher, S. T.; Clark, P. D. Acta. Cryst. 2000, C56, 574.

(9) Adams, R. D.; Miao, S. Inorg. Chem. 2004, 43, 8414. (10) (a) Katritzky, A. R.; Odens H. H.; Voronkov, M. V.; Rostek,

C. J.; Maender, O. W. (2001) Rubber Chem. Tech. 2001, 74, 915. (b) Maender, O. W.; Rostek, C. J.; Katritzky, A. R.; Odens, H. H.; Voronkov, M. V. WO 2002046149, Chem. Abstr. 137, 21378.

(11) (a) Carreno, M. C.; Garcia R. J. L.; Toledo, M. A. Chem. Eur. J. 2000, 6, 288. (b) Grennberg, H.; Gogoll, A.; Backvall, J.-E. J. Org. Chem. 1991, 56, 5808.

(12) (a) Schmidt, A.; Mordhorst, T. ARKIVOC 2003, xiv, 233. (b) Catalan, J.; Fabero, F.; Guijarro, M. S.; Claramunt, R. M.; Maria, M. D. S.; Foces-Foces, M. de la C.; Cano, F. H.; Elguero, J.; Sastre, R. J. Am. Chem. Soc. 1990, 112, 747. (c) Ballesteros, P.; Claramunt, R. M.; Escolastico, C.; Maria, M. D. S. J. Org. Chem. 1992, 57, 1873.

(13) Escolastico, C.; Maria, M. D. S.; Claramunt, R. M.; Jimeno, M. L.; Alkorta, I.; Foces-Foces, C.; Cano, F. H.; Elguero, J. Tetrahedron 1994, 50, 12489.

(14) Marxer, A. Helv. Chim. Acta 1955, 38, 1473. (15) (a) Ling, T.; Poupon, E.; Rueden, E. J.; Kim, S. H.;

Theodorakis, E. A. J. Am. Chem. Soc. 2002, 124, 12261. (b) Knapp, S.; Myers, D. S. J. Org. Chem. 2002, 67, 2995. (c) Yadav, J. S.; Reddy, B. V. S.; Swamy, T.; Ramireddy, N. Synthesis 2004, 1849. (d) Tandon, V. K.; Yadav, D. B.; Singh, R. V.; Vaish, M.; Chaturvedi, A. K.; Shukla, P. K. Bioorg. Med. Chem. Lett. 2005, 15, 3463. (e) Nishiyama, T.; Sugimoto, T.; Andoh, Y. Poly. Degrad. Stab. 2001, 74,

189. (f) Lowik, D. W. P. M.; Tisi, L. C.; Murray, J. A. H.; Lowe, C. R. Synthesis 2001, 1780. (g) Tolstikov, G. A.; Shul'ts, E. E.; Mukhametyanova, T. Sh.; Spirikhin, L. V. Zhu. Org. Khim. 1991, 27, 273. (h) Crescenzi, O.; Prota, G.; Schultz, T. M.; Wolfram, L. J. Gazz. Chim. Ital. 1990, 120, 21. (i) Hanzlik, R. P.; Weller, P. E.; Desai, J.; Zheng, J.; Hall, L. R.; Slaughter, D. E. J. Org. Chem. 1990, 55, 2736. (j) Rudorf, W. –D., Gunther, E.; Augustin, M. Tetrahedron 1984, 40, 381. (k) Huang, S.-T.; Kuo, H.-S.; Hsiao, C.-L.; Lin, Y.-L. Bioorg. Med. Chem. 2002, 10, 1947. (l) Borokov, V. V.; Evstigneeva, R. P.; Mirakova, E. V.; Rozynov, B. V. Khim. Geterotsikl. Soedin. 1991, 1419.

(16) Becker, J. Y.; Bernstein, J.; Bittner, S.; Harlev, E.; Sarma, J. A. R. P.; Shaik, S. S. New J. Chem. 1988, 12, 875.

(17) (a) Yadav, J. S.; Reddy, B. V. S.; Swamy, T. Tetrahedron Lett. 2003, 44, 9121. (b) Yadav, J. S.; Reddy, B. V. S.; Swamy, T. Synthesis 2004, 106. (c) Jurd, L. Aust. J. Chem. 1980, 33, 1603. (d) Singh, P. K.; Rohtagi, B. K.; Khanna, R. N. Synth. Commun. 1992, 22, 987. (e) Itahara, T. J. Org. Chem. 1985, 50, 5546.

(18) Zhang, S.-L.; Huang, Z.-S.; An, L.-K.; Bu, X.-Z.; Ma, L.; Li, Y.-M.; Chan, A. S. C.; Gu, L.-Q. Org. Lett. 2004, 6, 4853.

(19) Zhang, S.-L.; Huang, Z.-S.; Shen, Y.-D.; Li, Y.-M.; Yao, J.-H.; Huang, M.; Chan, A. S. C.; Gu, L.-Q. Tetrahedron Lett. 2006, 47, 6757.

(20) (a) Musso, H. Angew. Chem. 1963, 75, 965. (b) Mueller, P.; Venakis, T.; Eugster, C. H. Helv. Chim. Acta 1979, 62, 2350. (c) Knoevenagel, E.; Bueckel, C. Chem. Ber. 1901, 34, 3993.

(21) Rozeboom, M. D.; Tegmo-Larsson, I.; Houk, K. N. J. Org. Chem. 1981, 46, 2338.

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Graphical Abstract

Short title of the article: Reactions of p-Benzoquinone with S-Nucleophiles

O

O

S

SR2

R1

O

O

SR1S

R2

O

O

S

SR3

R1

SR2

O

O

S

SR3

R1

SR2

SR4

OH

OH

S

SR2

R1

OH

OH

SR1S

R2

OH

OH

S

SR3

R1

SR2

OH

OH

S

SR3

R1

SR2

SR4