[Advances in Heterocyclic Chemistry] Volume 109 || Recent Progress in 1,2-Dithiole-3-thione Chemistry

Advances in Heterocyclic Chemistry, Volume 109 ISSN 0065-2725, http://dx.doi.org/10.1016/B978-0-12-407777-5.00001-4 1

© 2013 Elsevier Inc.All rights reserved.

CHAPTER ONE

Recent Progress in 1,2-Dithiole- 3-thione Chemistry*Gunther FischerGeibelstraße, D-04129 Leipzig, Germany

*Respectfully dedicated to Professor Carl Th. Pedersen — the Master of 1,2-dithiole-3-thione chemistry.

Contents

1. Introduction� 32. Occurrence�and�Synthesis� 4

2.1. Natural�and�Environmental�Occurrence� 42.2. Synthesis�of�Alkyl-�and�Aryl-1,2-dithiole-3-thiones�from�

Nonheterocyclic�Precursors� 42.2.1. From Hydrocarbon Moieties 42.2.2. From Ketones and Ketone Equivalents 42.2.3. From 1,3-Dicarbonyl Compounds and Equivalents 82.2.4. From Sulfides 11

2.3. Synthesis�of�Functionalized�1,2-Dithiole-3-thiones�from�Nonheterocyclic�Precursors� 112.3.1. Amino Derivatives 112.3.2. Sulfur-Containing Derivatives 122.3.3. Carboxylic Acid, Acyl, and Alkoxy Derivatives 142.3.4. Fluoro Derivatives 14

2.4. Synthesis�of�1,2-Dithiole-3-thiones�by�Transformation�of�Other�Heterocyclic�Compounds� 142.4.1. From 1,2-Dithiole Derivatives 142.4.2. From 1,3-Dithiole Derivatives 18

2.5. Synthesis�of�Benzo-1,2-dithiole-3-thiones� 193. Structure� 19

3.1. Theoretical�Methods� 193.2. X-ray�Diffraction� 203.3. Molecular�Spectra� 22

3.3.1. 1H-NMR Spectra 223.3.2. 13C-NMR Spectra 223.3.3. Electronic Spectra 223.3.4. IR Spectra 263.3.5. Mass Spectra 26

3.4. Physicochemical�and�Structural�Properties� 303.4.1. Electrochemical Properties 303.4.2. Optical Properties 31

Gunther�Fischer2

Abstract

This� chapter� deals� with� the� remarkable� group� of� pseudoaromatic� 1,2-dithiole-3-thiones�(DTTs)�and�covers�relevant�literature�published�from�about�1992�through�2012.�

3.4.3. pKa Values 323.4.4. Solubility and Partition 323.4.5. Aromaticity and Polarity 34

4. Reactivity� 344.1. Complexes� 344.2. Ring-Preserving�Reactions�of�the�Thiocarbonyl�Group� 36

4.2.1. 1,2-Dithiolium Salts by Oxidation or S-alkylation 364.2.2. 1,2-Dithiole-3-ones by Oxidation 374.2.3. 3-Imino and 3-Methylene Derivatives 394.2.4. Spiro Compounds 404.2.5. Reactions of Fluorine Derivatives 40

4.3. Ring�Cleavage� 414.3.1. Thermolysis 414.3.2. Electrolysis and Reduction 424.3.3. Reactions with Amines 444.3.4. Reactions with Phosphorus Compounds 45

4.4. Ring�Transformation� 464.4.1. Formation of 1,3-Dithioles 464.4.2. Formation of 1,3-Dithietanes 504.4.3. Formation of Thiopyrans and Other Sulfur-Containing Heterocycles 524.4.4. Formation of Nitrogen-Containing Heterocycles 564.4.5. Formation of Metal Complexes 59

4.5. Nucleophilic�Substitution�of�Functional�Nuclear�Substituents� 604.6. Transformation�of�Individual�Substituents�at�the�1,2-Dithiole-3-thione�Ring� 60

4.6.1. 4-Thio or 5-Thio Substitution 604.6.2. Open-chain 4,5-bis-thio Substitution 614.6.3. Fused-Ring 4,5-bis-thio Substitution 634.6.4. Amino Groups 654.6.5. Carboxylic Acid Derivatives 66

4.7. Reactivity�of�Side�Chains�and�Aromatic�Rings� 664.7.1. Side Chains 664.7.2. Linked Phenyl Groups 684.7.3. Linked Heterocyclyl Groups 73

5. Applications� 745.1. Pharmaceutical�Uses� 74

5.1.1. Classical Drugs 745.1.2. Novel Drugs 77

5.2. Photographic�Uses� 805.3. Technical�Uses� 80

List�of�Abbreviations� 81References 82

Recent�Progress�in�1,2-Dithiole-3-thione�Chemistry 3

The�synthetic�section�describes�the�formation�of�DTTs�and�their�benzo�derivatives�both�by� cyclization� of� nonheterocyclic� precursors� and� by� transformation� of� other� hetero-cyclic�compounds.� In�a�structure-related�section,�outstanding�properties�such�as� the�spectroscopic� and� electrochemical� behavior� are� especially� stressed.�The� reactivity� of�DTTs�is�predominantly�characterized�by�ring-preserving�reactions�at�the�thiocarbonyl�group,� ring� cleavage,� and� ring� transformation.� Finally,� the� important� pharmaceutical�action�and�other�uses�of�DTTs�are�reviewed.

KEYWORDS1,2-Dithiole-3-thiones; Heterocycles; Organic chemistry; Organic sulfur compounds; Pharmaceutical use; Thiocarbonyl compounds

1. INTRODUCTION

The remarkable pseudoaromatic structure of 1,2-dithiole-3- thione (DTT, formerly named trithione) has attracted much interest because of its properties and applications. Thus, it serves as a precursor of other sulfur- containing or of nitrogen-containing heterocyclic rings, and several derivatives have proven to exhibit marked pharmaceutical activity.

After a number of reviews published between 1951 and 1980 (listed in 65CRV237 and 82AHC(31)63), new results have been summarized by Pedersen (82AHC(31)63, 95SR(16)173) and Lozac’h (89SR(9)153) and, in a wider context, in Katritzky’s Comprehensive Heterocyclic Chemistry (84CHEC(6)783, 96CHEC2(3)569, 08CHEC3(4)893).

This chapter is based on Pedersen’s 1995 review cited above and covers relevant literature published through 2011 together with some work printed in 2012. Patents are included, provided they reveal essential aspects of syn-thesis or application. Coverage is restricted to derivatives of the monocyclic DTT (1, Scheme 1) and benzo-fused analogs (e.g. 2).

For consistency, the DTT moiety is, in this chapter, generally drawn and numbered as shown in Formula 1.

SS

S

SS

S

1

24

5

4

7

21

Scheme 1

Gunther�Fischer4

2. OCCURRENCE AND SYNTHESIS

2.1. Natural and Environmental OccurrenceThe occurrence of DTT in cruciferous plants has repeatedly been men-tioned (e.g. 97MI1). Moreover, the parent substance (1) was found in the sediment of the Eastern Gulf of Finland (04EJS737).

2.2. Synthesis of Alkyl- and Aryl-1,2-dithiole-3-thiones from Nonheterocyclic Precursors

2.2.1. From Hydrocarbon MoietiesRecently published examples of the synthesis of 4-phenyl DTTs from cumols and sulfur include those of derivatives 3a–d1 (Scheme 2) (95BSF624, 98J(P2)2227, 09WOA37556). Similar cyclizations start from aromatic isopro-penyl compounds to give, for example, derivatives of DTT 3a (06WOA89861), 4,5-diphenyl compound 5a formed from stilbene 4 (09BMC558), and 4-ferrocenyl DTT 6a (09JOM36). Propenylbenzene derivatives afford con-sequently 5-phenyl DTTs (e.g. 6b) (07USA197479). Finally, sulfuration of 1-tert-butylpropyne yields 18% 5-tert-butyl DTT (93BCJ623).

2.2.2. From Ketones and Ketone Equivalents2.2.2.1. Via Dithiocarboxylic Acid or KetenedithiolateCurphey et al. (93TL7231, 00TL6977) have described improved methods of the known ketone/CS2/sulfuration reaction using hexamethyldisilathi-ane as a sulfur source and N-chlorosuccinimide (NCS) or hexachloroeth-ane as oxidizing agents to give substituted DTTs (e.g. 7a–c, Scheme 3, Paths A and B). Path B, passing through the dianion, enables a one-pot reaction in optimum yield.

Examples of similar cyclizations are listed in Table 1 (cf. Scheme 3). Biphe-nylyl derivative 15 (Scheme 4) forms directly from the ketoketene dithiol or through 1,2,4-trithiole 14 (disaurine) (93PS(84)191).

2.2.2.2. Via KetenemercaptalThe reaction of ketones with base (usually sodium tert-butylate or tert-amylate) and carbon disulfide, subsequent methylation of the dithiolate, and sulfuration (P4S10) was used to prepare derivatives of 4-phenyl DTT

1 In the captions beneath the formulas, substituents (R) in parentheses refer, in the order given, to substructures a, b, c, etc. of the respective formula or all formulas of the reaction.


(94PS(88)195), of 4-benzyl DTT (95EPA641792), and of 5-phenyl DTT (95BSF624, 98J(P2)2227) as well as 5-ferrocenyl DTT (16, Scheme 5) (09JOM36) and bicyclo[5.3.0]deceno DTT 17 (63UP1). Ethylene bromide serves likewise in mercaptalizing a dithiolate to yield, for instance, agent 18 (06WOA89861).

2.2.2.3. Via EnamineThe enamine route leads to cyclopenteno DTT 19a (Scheme 6) (10JME4761), whereas the intermediacy of enamines 20 in the reactions

OH

SS

S

Fe

R

MeO

OMe

S

S

Fe

BBr3

SS

SRO

RO

SS

SR

Fe

SS

S

NH2

200-240 °C

3a-d (R = H, OH, NH2, COOMe)

220 °C

5a (R = Me)

5b (R = H)

4

120 °C S (6 equ)

6a

1. S, 150 °C

2. HCl

6b

tBuOOC-NH

Scheme 2

Gunther�Fischer6

R O

A

R O

CSSH

SS

S

MeOCH2O

SS

SR

Ph

SS

S

SS

MeSO2

RS

R O

SS

B

S

SS

R

SS

S

X

SS

S

1. tBuOK, CS22. H+

2 KHCS2, DMPU

(Me3Si)2S, NCSimidazole

(Me3Si)2S, C2Cl6 7a-c

(R = Me,Ph, tBu)

8 9a, b (R = Me, Ph) 10a, b (X = O, S)

11a, b (R = H, Me) 12 13

Scheme 3

Table 1 DTTs from ketones through dithiocarboxylic acidsSubstitution or fusion type

Example Conditions* References

5-Aryl 8 as with 7, Path B 10AJC9469a 1. tBuOK, DMPU; 2. CS2,

(Me3Si)2S07MI2

10a,b 1. tBuOK, CS2, 0 °C; 2. H2SO4//; 3. P4S10, 80 °C

07PS(182)2205

4,5-Diaryl 11a,b S, LR, 220 °C 09BMC5584,5-Cycloalkeno 12† 1. (Me3Si)2NLi, CS2; 2. H2SO4 00HAC120

13 1. tBuOK, CS2; 2. (Me3Si)2S; 3. C2Cl6

07MI2

* //means: intermediate was isolated.† By-product.


Ph

OO

Ph

S S

S

P4S10 P4S10

Ph

C(SH)2

O

SS

S

Ph

80 °C

C°08C°041

14

15

2

Scheme 4

O

C(SMe)2

OS

S

S

Fe

O

NO S

S

O

O

NO

O

FeP4S10

SS

S

O

NO

SS

S

Fe120 °C

1. tC5H11ONaCS2

2. MeI16

1. tC5H11ONa 2. (CH2Br)2CS2

17

18

Scheme 5

Gunther�Fischer8

of acetophenone and sulfur dioxide-secondary amine adducts to give small amounts of 5-phenyl DTT (7b) could be proven (93PS(84)223).

2.2.3. From 1,3-Dicarbonyl Compounds and Equivalents2.2.3.1. From β-ketoestersTo begin with important molecules, the one-step synthesis of active agent oltipraz (20, Scheme 7), obtained by sulfuration in boiling toluene (Method A1),

N

N

COOMe

O

COOEt

O

MeO (Me3Si)2O

B

P4S10, S

SS

S

N

N

SS

S

MeO

SS

S

N

N

14CH3

SS

S

EtO

P4S10toluene (rfl.)

P4S10toluene/xylene (rfl.)

A1

A2

20 21

22 23

Scheme 7

OPh

HOOCO

HOOCN

R2NH SO2

NR2Ph

EtOHH2SO4

SS

S

ROOC

piperidine CS2, S19a (R = H)

19b (R = Et)

.

20a, b (R2N = Me2N, piperidino)

CS2, S7b

Scheme 6


(01WOA9118) was optimized by using a mixed toluene/xylene solvent (Method A2). This enables higher reaction temperatures and, therefore, reduced reaction times and better yields (04WOA48369). Labeled [Me14C] oltipraz (21) (95ABB(324)143) and desmethyl oltipraz (07MI2) were similarly prepared.

On the other hand, drug sulfarlem (anethole dithiolethione (ADT), 22) is prefer-entially formed by sulfuration in the presence of hexamethyldisiloxane (HMDO, Method B) (09MIP1). A careful evaluation of this method (02JOC6461) allows to conclude that yields are generally superior to those obtained with phospho-rus pentasulfide or even with Lawesson’s reagent (LR), and by-products may much easily be removed. The optimum molar ratio of ester:P4S10:S:HMDO may be 1:0.65:1:3. The yield of oltipraz, however, is nevertheless small, presum-ably because of the presence of basic nitrogen in the ketoester.

Other examples may be found in Table 2. Remarkably, the thionation of ketoesters 24 (Scheme 8) is accompanied by the deprotection of the phenolic hydroxyl (10AJC946), and keto-dicarboxylic ester 26 yields a 1:1 mixture of desired product 27a and thionoester 27b (03SUL(26)195).

2.2.3.2. From β-ketoester DerivativesKetoamides 28 (Scheme 9) give with LR the corresponding thioamides together with DTTs 7a and b (98HCA1207). Additional sulfur, being inef-fective with precursor 28b, shifts the result, in the case of acetyl derivative 28a, to exclusively DTT 7a in 51% yield. Thionation of enaminoni-triles 29a and b was also used to obtain DTTs 7b and 9a, respectively (96SUL(19)235).

Table 2 DTTs from β-ketoestersSubstitution or fusion of DTTs Formula Method* References

5-Pr A 94PS(88)1954-Bu, 4-C5H11, 4-Me-5-Pr A 95JPS11075-Alk, 5-Ar, 5-Het; 4,5-di-Alk;

4,5-cycloalkeno7a, b, 12, 13,

16, 20, etc.B 02JOC6461

4-(C6H4OEt-p)-5-(C6H4SO2Me-p) A1 05WOA519414-(1-Naphthyl)-5-(C6H4OMe-p) A1 09WOA268374,5-Cyclopenteno 12 A2 07MI24-Benzyl-5-Alk(Ar); 4,5-benzocy-

cloalkadieno23, etc. † 95EPA641792

* See Scheme 7.† P4S10 in boiling pyridine.

Gunther�Fischer10

COOMeR

MeOCH2O

EtOOC-CH2CH2 COOEt

O

EtOXC-CH2CH2P4S10

SS

S

HO

R

SS

S

tBu

tBu

tBu

tBu

P4S10, S

(Me3Si)2O

b,a52b,a42 (R = H, Me)

140 °C+ 27b

(X = S)27a (X = O)26

Scheme 8

R

O

NHPh

O R

S

NHPh

O SS

S

R

R CN

NH2Ph SS

S

Ph

R

S

MeOOCCOOMe

S

SS

S

S

MeOOCCOOMe

S

SS

Snn

LR (+ S)

110 °C+

b,a7b,a82 (R = Me, Ph)

S

LR or P4S10

29a, b (R = H, Me) 7b, 9a (R = H, Me)

FeCl3

LR, S

LR, S

a13a03

b13b03

Scheme 9


2.2.3.3. From Dicarbonyl and Dicarboxylic DerivativesParent DTT (1) was prepared from malonic acetal (95BSF624). Thienyl malonic ester 30a and the corresponding polymer (30b) could be cyclized to give thienyl DTT 31a and DTT-substituted polythiophene 31b, respectively (04CL1482).

2.2.4. From SulfidesSimple DTTs may be formed by thermolyzing aliphatic di- and polysul-fides (Scheme 10); examples are parent DTT (1) and 4-methyl DTT (33) in maximum yields of 52 and 72%, respectively (04RJC1754, 03RJO752, resp.) or 5-methyl DTT (7a) (92JOU1995). Another route leads from poly-sulfide dendrimer 34 to DTT 1 in a maximum yield of 37% (04RJC1754).

Molybdenum dithiopropiolato complexes (such as 35) react with trimethylamine N-oxide under mild thermolysis, directly or through oxo complexes (e.g. 36), to form 5-phenyl DTT (7b) (04JOM1325).

2.3. Synthesis of Functionalized 1,2-Dithiole-3-thiones from Nonheterocyclic Precursors

2.3.1. Amino DerivativesDifferent from all thionating reagents mentioned before, disulfur dichloride (cf. 08AHC(96)175) is the agent that mildly transforms Hünig’s base (37) or other diisopropylamines to DTTs (Schemes 11 and 122). Thus, depend-ing on the molar ratio of base 37 and disulfur dichloride, DTTs 38 and 39 and thiazines 40 and 41 may be isolated, one or two isopropyl groups being cyclized, respectively (01MC165). For instance, ratios of 2:1 and of 1:1 lead exclusively to mixtures of the monocyclic DTTs 38 and 39 or of the tricyclic compounds 40 and 41, respectively.

Similar diisopropylamines give likewise with disulfur dichloride in the ratio 2.2:1 corresponding mercapto DTTs (e.g. 42a and b) as major pro-drugs (06RCB147). Other reactions of base 37 unexpectedly resulted in the formation of bis(dithiolyl)amines 44 (01J(P1)2409) and 45a and b together with amino DTT 46 (98JOC2189) in low yields.

The interaction of phthalimidoethyl derivatives (e.g. 47, Scheme 12) and disulfur dichloride yields atropisomeric, remarkably stable 4-amino- 5-chloro DTT derivatives (e.g. 48) (03OL929). The stability may be due to dipole–dipole interactions between the electron-rich DTT ring and the electron-poor phthalimido group.

2 Instead of excessive subdividing reaction sequences reported in the papers, subsequent reactions of cyclized products will sometimes be included in the synthetic formula schemes of Section 2; they will later in due course be described in Section 4.

Gunther�Fischer12

2.3.2. Sulfur-Containing Derivatives2.3.2.1. From Hydrocarbons, Halides, and Sulfides4-Mercapto and 4-methylthio DTTs (52a–c and 53a–c, respectively, Scheme 13) are easily formed by deprotonation of terminal alkynes fol-lowed by sequential treatment with carbon disulfide, sulfur, and, in the last step, acid or methyl iodide, respectively (04TL7671).

5-Mercapto derivatives (e.g. 55), on the other hand, may be synthe-sized from β-bromocumol and sulfur (06WOA89861), whereas one-pot

R

(CH3-CH-CH2)2Sn

(CH3-CCl=CH-CH2S)2

CH2Cl-CHCl-CH2Cl

Me3NO 2 H2O, 25 °Cor h , air, 0 °C

PhC CS

SMo

3 Na2Sn

cpCO

CO

R

SS

S

SS

S

---SnCH2-CH-CH2Sn---

Sn

S

S S

CCPh

Mo

cp

O

Me3NO 2 H2O65 °C S

S

S

Ph

1

200 °C

5 Torr

x

34 (n = 2 or 3)

500 °C

N2+

7a (27 %) (18 %)

ca. 400 °C

N2

32a, b (R = H, Me)(n = 3-4)

1, 33 (R = H, Me)

35

.

36

7b

.

Scheme 10


reactions of diisopropylsulfide and disulfur dichloride lead to derivatives56 and 57 of 4,5-dimercapto DTT (99JOC4376).

2.3.2.2. From Carboxylic and Thiocarboxylic EstersThe one-pot thionation of unsubstituted or substituted malonate esters of primary alcohols produces 5-alkylthio DTTs (e.g. 58 and 59, respectively, Scheme 14) as major products in moderate yields, sometimes accompanied by a corresponding disulfide (60) (00S1749). The suggested mechanism (thionation of malonic ester, thione–thiol rearrangement, thionation, and cyclization) is corroborated by the convenient synthesis of, for instance, thioethers 61a–c from thiolesters in good yields (02TL1947). That means,

CH2RN

N

N

SS

S

iPr

Et

HS

N

SS

S

iPr

Et

N

SS

SEt

SS

S

PhN NHPh

S2Cl2

N

SS

S

iPr

CH2R

HS

N

SS

XEt

SS

S

DABCO

S2Cl2

SS

ON

SS

S

S Et

SS

SN

SS

S

S Et

N

SS

O

iPr

CH2R

Cl

EtNH

SS

S

40

41

37

1. S2Cl2, 0 °C2. HCOOH, 60 °C

+ +

S2Cl2, Et3N

S2Cl2, Et3N38 39

+

1. S2Cl2, 0 °C

2. HCOOH, 60 °C

42a, b (R = Ph, CH2COOEt) 43a, b

+

37

1. S2Cl2, DABCO2. PhNH2, 60 °C

44 45a and b (X = O, S) 46H

Scheme 11

Gunther�Fischer14

this method is also suitable for malonic esters of secondary and tertiary alcohols and of phenols. (Other DTT thioethers (e.g. 62) are obtained from dithioesters and carbon disulfide with subsequent oxidation (94AP813).)

2.3.3. Carboxylic Acid, Acyl, and Alkoxy DerivativesCarboxylic ester 63 (Scheme 15) is formed in a common reaction (98J(P2)387), but aminonitrile 65 is the result of an unexpected one-pot process (08JST(888)354). Acetyl DTT 66a and methoxy DTT 66b were synthesized by sulfuration of diacetylacetic ester (00PS(166)27) or reaction of methoxyacetone using the mercaptal method (94PS(88)195), respectively.

2.3.4. Fluoro DerivativesTypical examples (Scheme 16) involve the efficient synthesis of 4- fluoro-5-fluoroalkyl DTTs 67 from polyfluoroketene dithioacetals, directly or through dithiocrotonic esters (02TL5809), and of DTT 68 from a β-iminosulfone (06MI4).

2.4. Synthesis of 1,2-Dithiole-3-thiones by Transformation of Other Heterocyclic Compounds

2.4.1. From 1,2-Dithiole DerivativesThe standard procedure of thionating 1,2-dithiole-3-ones (e.g. 69, Scheme 17) is that of boiling in pyridine in the presence of phosphorus pentasulfide to get,

NPhthN

iPrNPhthN

SS

Cl

S DMAD

iPrNPhthN

SS

N

S

iPrNPhthN

CSCl

S

S

COOMe

COOMe

iPrNN

SS

N

S

O

O

N

47

1. S2Cl2, DABCO2. Et3N

9484

pyrrolidine(2 equ)pyrrolidine

50 51

H

Scheme 12


for instance, 5-phenyl DTT (7b) (95BSF624, 00JOC3690, 00SUL(23)169). Compound 70 forms similarly in boiling xylene (06PS(181)2307). Dithiole disulfides (e.g. 269, see below, Scheme 62) are reduced to DTTs (e.g. 270) by the action of sodium sulfide (94PS(88)195).

The optimum synthesis of 4,5-dichloro DTT (72) proceeds by the action of thioacetamide on 1,2-dithiolium salt 71 (Boberg’s salt) (11PS(186)1201). Moreover, analogous salt 73 on reductive ring open-ing and subsequent oxidation yields DTT 74a and, as by-product (5%), dimer 74b or its isomer (95JCM312). Finally, fluoro DTT 67b results from the dehalogenation of dithiolium sulfenylchloride 121 or, in small amounts, from the disproportionation of S-oxide 124 (see below, Scheme 29) (06RJO124).

R

CH2Br

Ph

SS

S

R

MeS

SS

S

R

SS

S

iPrSS

iPrSS2Cl2

DABCO

SS

S

S

Ph

SS

S

R

HS

SS

SS S

PhS

S

S

Ph

Me2NH2+

SS

S

SS

S

S S

SiPr iPrS

1. BuLi2. CS2

3. S

1. S

2. H+52a-c (R = tBu,

Ph, mesityl)

1. S2. MeI

(52b) air

53a-c 54

_

S, DMF

150 °C

55

+

56 (33 %) 57 (19 %)1. S2Cl2, DABCO, 25 °C2. (iPrS)2, 130 °C(yield: 48 % 56)

iPr2S

Scheme 13

Gunther�Fischer16

(K+)2

COOEt

OEtOOC

CN

NCS

S NbCl5

Et4N+ I-

SS

S

EtOOC

SS

S

NH2

NC

Na2S

SS

SR

SS

S

HOOC

_

_

P4S10

140 °C

63 64

65 66a, b

(R = Ac, OMe)

Scheme 15

COOEt

COOEtR

COSR

COSR

COOR

COOR

SS

S

EtS

R

SS

S

RS

SS

S

MeS

Et

CSSMe

SS

S

RS

SS

S

EtSS

R

P4S10, S, 140 °C

MBT, ZnO

58a-c (R = Me, Et, Bu)

P4S10, S, 140 °C

MBT, ZnO+

59a, b (R = Ph, OMe) 60a, b

P4S10, S, MBT, ZnO, 140 °C

or LR, S, MBT, ZnO, 100 °C

61a-c (R = tBu, Ph,cyclopentyl)

1. NaH, CS2

2. I2 62

Scheme 14


CHF2CF2CF2

CRF2-CF=C(SEt)2

MgBr2

C CH2TsNtBu

Br

R CSSEt

F

S

SS

SF

R

SS

STs

CHF2CF2CF2

MgBr2, S

210 °C

67a, b (R = CF3, CF2CHF2)

180 °C 210 °C

1. CS2, KOH, 40 °C

2. HCl68

Scheme 16

SS

O

Ph

SS

SMe

MeS

MeS

l

MeS

MeS CSSNa

SNa

NaBH4NaOH

SS

Cl

Cl

Cl

SS

S

MeS

MeS

SS

S

Ph

Cl

MeS

MeS

SSS

SS

S

SMe

SMe

SS

S

NO

SS

S

Cl

Cl

_+_+

P4S10, pyridine

07b796

CH3CSNH2

- CH3CN - HCl

271737

I2 or O2 +

74a 74b

115 °C

Scheme 17

Gunther�Fischer18

2.4.2. From 1,3-Dithiole DerivativesThe Steimecke rearrangement of 4,5-dimercapto-1,3-dithiole-2-thione (salt 75a of dmit, Scheme 18) gives isomeric 4,5- dimercapto-1,2- dithiole-3-thione (dmt, 75c) through salt 75b, complex 76, and derivative 77 (which may serve for purification and storage) (77DDP124044, 92CCR(117)99, 92T8143). The method was used to prepare 13C-enriched product 75c (enrichment of 15%) (05NJC465). DTT 78b forms as by-product of the alkylation of 1,3-dithiole zinc complex 78a, together with the 1,3-dithiole isomer in the ratio of 1:9 (07AXE4056).

Alkyne cyclopentadiene complex 79 (Scheme 19) reacts with 1,3-dithiole-2-thione 80 to produce complex 81, which is rapidly sulfurated to give dithiolene complex 83 and DTT 82, a substance otherwise not accessible (98CC389). This process reforms the thione unit, which had been cleaved during the formation of complex 81.

CS2

(Bu4N+)2

SS

S

HS

HS

H+

EtONa

S

S

S

SZn S

(Na+)2

SS

S

PhCOS

PhCOS

S

S

S

SS

2 BrCH2CH2CN

PhCOCl(R4N+)2

ZnCl2R4N+ Br-

(Na+)2

SS

S

NCCH2CH2S

NCCH2CH2S

SS

S

S

SZn

SS

S

S

SNa, DMF

ca. 50 °C

120–140 °C

75a 75b

2

2

_

75b

(pure)

77 76a, b (R = Et, Bu)

75c

2

2

_

78a 78b (+ isomer)

45 °C

Scheme 18


2.5. Synthesis of Benzo-1,2-dithiole-3-thionesBenzo DTT (2, Scheme 20) is found among the products of the flash vacuum thermolysis of 1,3-benzothiazine-4-thione 84a (06HCA991) or, more selectively, of 1,3-benzodithiin-4-thione (84b) (09PS(184)1269). Just recently, it was detected to be formed by the heterocyclization of benzal-dehyde derivatives 85 (11PS(186)2341). Thionation of the appropriate pre-cursor yields tris(1,2-dithiole-3-thione) 86 (01JPA139731).

3. STRUCTURE

3.1. Theoretical MethodsQuantum-chemical calculations on DTTs serve in predicting structural data, assisting studies, and corroborating results with several fields that may be exemplified as follows:

SMo

MeOOC COOMe

cp

COOMeMeOOC

cpS

SS

S

MeOOC

MeOOC

S

S

MeOOC

MeOOCSMo2 (MeOOC-C=C-COOMe) (CO)4 (cp)2_ +

0897

81

MoS

MoScp

S S

S COOMe

COOMecp

+

S 110 °C

3828

Mo

S

Scheme 19

Gunther�Fischer20

• molecular structure and vibrational spectrum of parent DTT (1), the aromatic delocalization being calculated to be low (98VSP(16)77), and of DTT 65 (08JST(888)354),

• geometric and electronic structure by the MINDO-PM3 method, espe-cially bond length values of DTTs 1, 3a, 7b, 22, and 33, charge distribu-tion of DTTs 1, 7a, 12, 13, 33, and 87 (cf. Scheme 21), dipole moments of nine DTTs just mentioned together with 2, 9a, 88, 89a and b etc. (including some abnormal cases), and heat of formation of DTT 88 (00PS(166)27),

• electronic structure of 4-amino DTT (90) because of its unexpectedly very low pKa value (06PS(181)2307),

• intramolecular charge transfer in parent substance 1, derivatives 7b and 22, oltipraz (20), and vinylogous oltipraz 91 as nonlinear optics chromo-phores (93TCA175),

• nucleophilicity of DTTs 1, 2, 7b, 10b, and 87 (92CPC1667, 95JOC2330).

3.2. X-ray DiffractionX-ray diffraction of DTTs (Table 3, cf. Scheme 21) serves in determining molecular structures and stereochemistry in spite of the difficulty of gaining suitable crystals (cf. 10ICA(363)4074).

S

S

S

CHO

X

CH2BrCl

CH2BrCl

BrCH2

Cl SS

SS

S SS

S

S

SS

S

S

NH

S850 °C

1,5 10-3 Torr. 1,5 10-3 Torr.

1000 °C

b48a48

2

K2S, air 120 °C

85 (X = halogen, NO2)

S, MeONa

65 °C, 120 h

86

Scheme 20


Table 3 X-ray diffraction of DTTsSubstitution or fusion Formula Reference*

1,2-Dithiole-3-thiones

4-CN-5-NH2 65 08JST(888)3544-C6H4Cl(p)-5-NH2 92a 05POL29444-SMe-5-Ph 53b 04TL76715-SMe 58a 98AXC19025-SEt 58b4-CH2Ph-5-SEt 92b 97AXC11254,5-di-SMe 74a 95JCM312, 10ZK124,5-di-SCH2CH2CN 78b 07AXE40564-SCOPh-5-SMe 229a 10ZK124-SCOPh-5-SCH2Ph 229b4,5-di-SCH2SnPh3 231a 08JOM7634-SSnPh3-5-SCH2SnPh3 231b4,5-Cyclopenteno 12 00HAC120

Bis(3-thioxo-1,2-dithiol-4-yl)disulfides

5,5′-di-Ph 54 04TL76715,5′-di-SH 240† 10ICA(363)40745,5′-di-SMe 241 07CYR84

* Immediately successive identical references are not repeated (in following tables, too).† Dicaesium salt.

SS

SCl

SS

SNH2

SS

S

N

N

SS

SHOOC

RSS

S

SS

S

Ac

SS

SS

SSS

SPhCH2

EtS SS

SS

S

87 88 89a, b (R = H, Me)

a291909

b39a39b29

Scheme 21

Gunther�Fischer22

Table 4 1H-NMR chemical shifts of the DTT moiety

Substitution of DTTs Formula

δ (ppm) in positions

Solvent Reference4 5

4-Me 33 – 8.10 03RJO7525-C6H4NO2 (o) 306a 7.56 – CDCl3 98EAC2015-C6H4NO2 (m) 306b 7.56 –5-C6H4NH2 (o) 307a 7.42 –5-C6H4NH2 (m) 307b 7.40 –5-C6H4NH2 (p) 307c 7.38 –4-Ferrocenyl 6a – 8.39 CDCl3 09JOM365-Ferrocenyl 16 7.20 –(Parent substance) 1 7.15 8.30 96CHEC2(3)569, p 573

3.3. Molecular Spectra3.3.1. 1H-NMR Spectra1H-NMR data of some monosubstituted DTTs having hydrogen atoms attached to carbon ring atoms C-4 and C-5 may be found in Table 4 and compared with those reported of parent substance 1.

3.3.2. 13C-NMR Spectra13C-NMR chemical shifts of the ring atoms of selected DTTs are shown in Table 5. Moreover, dynamic NMR reveals that phthalimidoethylamino derivative 48 constitutes a rare example of chirality, due to restricted rota-tion of the DTT group, which gives rise to atropisomers at room tempera-ture (03OL929).

With respect to the E/Z isomerism of oximes 270 (see below, Scheme 62), the assignment of structures has been based on the homonuclear Over-hauser effect (94PS(88)195, 94SUL(17)231). With ferrocenyl derivatives 6a and 16, there is a good linear correlation between the substituent constants of the DTT groups and the 13C chemical shifts of the cyclopentadienyl groups (09JOM36).

3.3.3. Electronic SpectraUV–vis spectral data of some DTTs are compiled in Table 6. The n → π* transitions in parent DTT (1) and benzo DTT (2) have been calcu-lated with an ab initio procedure (06JPC(A)9145). Linear dependency between color characteristics and ionization potentials of DTTs 12, 13, its cyclohepta homolog, and 87 has been confirmed (09MI4, 11MI2). The

Recent�Progress�in�1,2-Dithiole-3-thione�Chem

istry23

Table 5 13C-NMR chemical shifts of DTT heterorings

Substitution Formula


Solvent* Reference3 4 5

1,2-Dithiole-3-thiones

5-COEt 271b 217.1 140.2 166.7 C 94PS(88)1954-Et-5-CHO 272a 217.2 155.1 159.6 03PS(178)17214-Et-5-COEt 272b 218.2 151.6 163.64-CH2CH2COOH-5-Me 275 213.9 144.3 171.0 S 03SUL(26)1954-CH2CH2COOEt-5-Me 27a 215.1 144.4 168.3 C4-CH2CH2COOH-5-CHO 274 219.4 151.5 164.1 A4-CH2CH2COOH-5-CH]NOH 273 217.2 146.6 162.1 A4-Me-5-CH(CH2-morpholine)2 267c 215.3 142.4 172.7 C 93JHC5454-Morpholino-5-Me 99 211.7 151.8 168.4 C 06PS(181)23074-COOEt-5-NHCOPh 251b 208.1 119.0 175.3 C 03CCC12434-CN-5-NHCOPh 251a 203.0 107.9 181.8 S4-CONH2-5-NHCOPh 251c 206.7 119.6 166.6 S4-COOEt-5-N]CHNMe2 253b 203.5 130.3 181.1 S4-NEtiPr-5-SH 38 198.7 133.8 193.7 C 01MC1654-Et-5-SMe 62 210.4 145.0 170.3 C 94AP8134-S−Na+-5-SMe 207.2 151.5 166.5 M 98JPR4504-SC12H25-5-SMe 233c 209.4 134.2 181.0 C4,5-di-SiPr 170 210.0 134.8 179.4 C 99JOC43764-SiPr-5-SSiPr 56 212.4 133.4 185.0 C4-F-5-CF3 67a 198.2 156.2 136.9 C 02TL58094-Ph 3a 214.7 149.9 154.5 C 95BSF6245-C6H4Br(p) 108 215.4 136.0 171.2 C

Continued

Gunther�Fischer

24

5-Ph 7b 215.6 135.9 172.9 C 00SUL(23)1695-C6H4NH2(m) 307b 215.6 135.8 173.5 C 98EAC2015-C6H4OH(m) 216.9 136.5 174.3 A 98J(P2)22274-C6H4OH(m) 215.1 149.4 157.9 A4-C6H4Me(p)-5-morpholino 70 207.5 138.3 178.9 C 06PS(181)23075[C6H2OH(4)-di-tBu(3,5)] 25a 215.2 123.5 175.1 C 10AJC9464,5(CH2-CHCOOEt-CH2) 19b 208.0 152.9 171.9 C 10JME47614-Ferrocenyl 6a 212.6 146.8 151.4 C 09JOM365-Ferrocenyl 16 213.8 113.6 176.9 C

Bis(3-thioxo-1,2-dithiol-5-yl)disulfide

4,4′-di-SiPr 57 211.5 135.6 176.3 C 99JOC4376

* Solvents: A, acetone-d6; C, CDCl3; M, CH3OD; S, DMSO-d6.

Table 5 13C-NMR chemical shifts of DTT heterorings—cont’d

Substitution Formula


Solvent* Reference3 4 5


istry25

Table 6 UV–vis maxima of DTTsSubstitution or fusion Formula λmax in nm (log ε) Color Solvent* Reference

5-SEt 58b 422 (3.86) 319 (4.11) 255 (3.92) 243 sh D 00S17494-Ph-5-SEt 59a 430 (4.07) 327 (4.32) 256 sh O4-Ph-5-SSEt 60a 426 (3.97) 322 (4.15) 265 (4.05) 202 (4.41) O4,5-dithia[18]crown-6 244c 423 (4.05) 335 (4.02) Orange C 98JPR4505-C6H4-

(CH2)6CONHOH(p)428 (4.06) 348 (4.31) 265 sh 236 (4.10) E 10BMC4187

di-Me-bicyclo[5.3.0]deceno 17 420 (3.93) 325 (3.83) 279 (3.87) 252 (3.93) Yellow CH 63UP1232 (4.02)

* Solvents: C, chloroform; CH, cyclohexane; E, ethanol; O, isooctane.

Gunther�Fischer26

solvatochromism of 5-butylthio DTT (58c) and 5-methyl DTT complex 101c (see below, Scheme 24) was measured and correlated with calculated parameters; the influence of micelle-forming surfactants was investigated (08JPO1007).

The luminescence spectrum of 5-phenyl DTT (7b) has been repro-duced (95MI1), and correlations between photoelectron spectra and mea-sured nucleophilicity of DTTs 1, 2, 7b, 10b, and 87 have been obtained (95JOC2330).

3.3.4. IR SpectraRelevant IR bands of some DTTs are listed in Table 7, including parent compound 1 (98VSP(16)77) and derivative 65 (08JST(888)354), the exper-imental vibrational frequencies of which had been assigned on the basis of calculated results.

3.3.5. Mass SpectraToday, mass spectrometry is an important tool in DTT chemistry. Table 8 pre-sents, in a condensed form, a compilation of selected data taken from an early study by Giese (76TH1). Some conclusions may be added: the base peak is nor-mally the peak of the molecular ion. The [M–H] process seems to be preferred with C-4 substituents having a cleavable hydrogen atom in a sterically favored position near the thiocarbonyl sulfur (e.g. phenyl in 3a and 9b). By contrast, [M–S2H] is the main fragmentation of DTTs unsubstituted in 4-position. Frag-mentation [M–SH] and key fragment C3SH are typical of DTTs. In the case of monosubstituted DTTs (e.g. 7a and b), the relative intensity of the substituent-containing fragment often equals that of the respective [M–X] fragment.

Newer results are listed in Table 9. As regards alkyl, aryl, and heterocyclyl DTTs, there are only a few new data. Thus, the mass spectra of nor-methyl anethole dithiolethione (desmethyl anethole dithiolethione (ADTOH), 98, see below, Scheme 23) (11JPB(54)551) and of oltipraz (20) and its ethyl homolog (11JPB(56)623) have been reproduced. The fragmentation of phe-nyl derivatives 3a and 7b (95BSF624) and fused DTT 12 (00HAC120), already described in Table 8, was discussed.

By contrast, a wide variety of thio derivatives have been fragmented. Here, the molecular peak is not always the base peak (see Table 9, formu-las 56, 233c, 233d). The electron impact (EI) ionization mass spectra of DTT bis-thioethers 74a, 93a, and 93b (cf. Table 9) together with those of the 1,3-dithiole isomers thereof enable an unambiguous isomer differentia-tion (94OMS321). The fragmentation pattern is supported by metastable


istry27

Table 7 IR bands of DTTs

Substitution or fusion Formula

Bands

In ReferenceCH C]C C]S C–S S–S

(Parent substance) 1 3090, 3070 1495 1330, 1172 777, 659, 580

499 * 98VSP(16)77

4-CN-5-NH2 65 1505 1006 892, 552 501 KBr 08JST(888)3544,5-Cyclopenteno 12 1508 1141 KBr 00HAC1205,5′-di-SH-4,4′-disulfide,

di-Cs salt240 1294 1047 911, 804,

719429 CsI 10ICA(363)4074

4,5-di-S-, polymer 154 1429 1292, 1063 480 KBr 93IC5467

* In CCl4 or CS2.

Gunther�Fischer

28

Table 8 MS fragmentation* of selected DTTs (Irel in %)† (76TH1)

Substitution or fusion Formula

Fragments of the (M–X)+type Key fragmentsFragments‡ containing the substituentM–H M–SH M–CS M–S2H M–CS2 M–CS3

§ C3SH C3S2H CS3

– 1 6 5 94 24 11 94 64-Me 33 7 42 6 10 5 25 MeC2 (20), MeC2S (20),

MeC3S (6)4-Ph 3a 100 27 9 13 10 24 20 PhC2S (14), PhC3S (13),

PhC2S2 (16)5-Me 7a 68 4 7 MeC2 (15), MeCS (13),

MeC3S (68)5-Ph 7b 8 5 95 8 27 12 5 PhC2S (8), PhC3S (95),

PhC3S2 (5)4,5-di-Me 87 23 24 7 Me2C2 (10), MeC3S

(24), Me2C3S2 (23)4,5-di-Ph 9b 100 11 18 12 Ph2C2 (12), Ph2C3S (18)Cyclopenteno 12 51 44 16 4 21 5 C3H5 (6), (CH2)3C2S

(20), (CH2)3C3S (16)Benzo 2 24 4 8 10 23 8 C6H4C3S (52),

C6H4C2S2 (24)

* For the sake of simplicity, the plus signs have been omitted (in Table 9, too).† Irel < 4% has been neglected.‡ Empirical formulas (the structures may be changed by rearrangement).§ In two steps splitting off CS2 + S or CS + S2.


istry29

Table 9 MS fragmentation of DTTs (Part 2)Substitution or fusion Formula Selected assigned fragments (Irel in %) Reference

4-F-5-CF3 67a M–CS2, M–C2S3 02TL58094-F-5-CF2CHF2 67b M–CHF2, M–CS24-SH-5-Ph 52b M–SH 04TL76714-SH-5-mesityl 52c M–Me5-SEt 58b M–Et, M–SH, M–S2, M–S2H 96TL21375-SBu 58c M–C3H5, M–C4H8, M–Bu, M–S2H5-SPh 61b M–S2H, M–PhS, M–C7H5S, M–C6H3S 02TL19475-S-cyclopentyl 61c M–C5H8, M–C5H9S4,5-di-SMe 74a M–Me (59), M–S2-Me (22), M–CS2-Me (4), M–S2-SMe (8),

M–CS2-SMe (13), M–S2-SMe2 (53)94OMS321

4,5(SCH2CH2S) 93b M–C2H4 (88), M–S2(7), M–S2-C2H4 (41), M–CS2-C2H4 (20), M–S2-SC2H4 (44)

4-Ph-5-SSEt 60a M–S, M–EtS, M–EtS2, M–EtS3, M-C3H5S3 04FA2454-SiPr-5-SSiPr 56 M–iPrS (100) 99JOC43764-SC12H25-5-SMe 233c M–Me (3), M–S (11), M–MeS (8), M–C12H25 (100) 98JPR4504,5-di-SC12H25 233d M–C12H25 (79), M–C12H25S (62), M–C24H48 (100)4,5-di-SCHMePh 232 M–PhCHMeS, M–PhCHMeS-PhCH]CH2 09MIP2

Gunther�Fischer30

ion analysis and collision-induced dissociation spectra. Whereas bis-methyl thioether 74a and its 1,3-isomer do not show EI-induced isomerization to each other at all, cyclic thioether 93a and its 1,3-isomer under the same conditions readily isomerize and cyclic homolog 93b and its isomer partially isomerize.

Dissociative ionization of thioether 74a, as studied in a tandem mass spectrometer, has also allowed to detect carbon disulfide radical cations (SCnS

.+, n = 1–3) and their S-methyl forms (MeSCnS+) in the gas phase of the spectrometer (95JPC16849).

3.4. Physicochemical and Structural Properties3.4.1. Electrochemical PropertiesPolarograms of 5(nitrophenyl) DTTs (306a–c, see below, Scheme 69) show successive cathodic waves corresponding to the reduction of the nitro group and the DTT ring, respectively (98EAC201); the comparison with polarograms of the respective 5(aminophenyl) DTTs (307a–c) and cyclic voltammetry of the nitro compounds 306a–c confirm the results. The standard reduction potential of isomer 306c enters into a linear correlation allowing the electronic effect of the DTT-5-yl group to be determined (02EAC107).

The redox potential of m- and p-substituted 5-phenyl DTTs (e.g. 7b and 22), when investigated in a DMF electrolyte at a platinum electrode, follows a linear correlation with the respective Hammett substituent para-meters (02JEC(537)145). The same compounds (7b, 22) and similar 4-phe-nyl DTTs (e.g. 3a) show an analogy with the electrochemical behavior of the corresponding 3-methylthio-1,2-dithiolium salts (e.g. 107, see below, Scheme 25) (05EAC2219). The investigation of ADT (22) just mentioned by cyclic voltammetry revealed that it acts as a scavenger for the superoxide anion radical (02MI1).

The study of the redox behavior of DTT-substituted polythiophene 31b (by cyclic voltammetry) and its electronic states (by UV–vis spectroelec-trochemistry) enabled observation of a DTT radical cation (formed by the oxidation of the DTT ring directly conjugated to polythiophene) and the subsequent oxidation of the thiophene ring (04CL1482).

The electrochemical oxidation of 4-(6a) and 5-ferrocenyl DTT (16) was recently studied by cyclic voltammetry (09JOM36). Both compounds exhibit a one-electron reversible oxidation leading to the respective fer-rocenium cation (e.g. 94, Scheme 22). The particular behavior of isomer 16 at low scan (showing two irreversible oxidation peaks) is attributed to a


subsequent electron transfer (to give 95) and a dimerization to yield dica-tion 96. A linear correlation between reversible oxidation potentials and electronic effects allowed the Hammett constant of the DTT-5-yl group (σp = 0.55) to be obtained; that means, an inductive electron withdrawing effect comparable to that of a formyl group.

3.4.2. Optical PropertiesSeveral studies deal with DTTs acting as nonlinear optics chromophores, such as parent substance 1, 5-phenyl derivatives 7b and 22, oltipraz (20), and vinylogous oltipraz 91 (93TCA175) as well as bis(benzylthioether) 97 (Scheme 23) (99PCA6930).

SS

S

HO

SS

SPhCH2S

PhCH2S SS

SN

O

SSNHO S

SSN

S

OH SSN

S

O SSN

S

O

97

98 99

100a (E)

_

_

100a (Z) 100b 100c

- H+

Scheme 23

SS

S

SS

S

SS

S

Fe+ eFeF

+. +

2

16

- e

695949

-

Scheme 22

Gunther�Fischer32

3.4.3. pKa ValuesTable 10 lists pKa values of several DTTs bearing acidic or basic groups. DTT 5-carboxylic acids (e.g. 64) are rather strong acids, comparable to dichloroacetic acid (98J(P2)387); in the case of the less-acidic 4-carboxylic acid (89a), an alkyl group in the 5-position unexpectedly lowers the pKa value by about 0.60 unit, presumably for thermodynamic reasons. Com-parison of 5- and 4(hydroxyphenyl) DTTs (e.g. 98 and 3b) shows similarly the lower acidity of the latter (98J(P2)2227), obviously because of a weaker withdrawing effect of the DTT-4-yl group.

The strong withdrawing action of the DTT-5-yl moiety explains also the low pKa value of oxime 100a in the E form (03JHC155). The anomalous value obtained with isomer 100a(Z) is in accordance with a resonance-conjugated base involving oximate 100b and thiolate 100c.

Relatively low pKa values have also been found with 4-amino DTT derivatives (e.g. 90 and 99), and even lower values have been obtained with 5-amino compounds (e.g. 70) (06PS(181)2307).

3.4.4. Solubility and PartitionSolubility and dissolution rate of DTTs 1, 7b, 22, and 87 may be improved by complexation with β-cyclodextrin and its derivatives (99JPS889).

Owing to the great importance of the water/n-octanol partition coef-ficient (log P or log Poct) in pharmacochemistry, this parameter was deter-mined with numerous alkyl, aryl, dialkyl, diaryl, alkylaryl, cycloalkeno, and benzo DTTs (e.g. 22) by reversed-phase high-performance liquid chromatography (RP-HPLC) measurement of the concentration of the solute in aqueous solution after equilibrium (95JPS1107). These data were used to establish correlations between log P and RP-HPLC capacity factors of DTTs; these correlations allowed to calculate, by extrapolation, log P values of very lipo-philic DTTs, that is, certain alkylaryl, diaryl, and cycloalkeno derivatives (e.g. 9b) having log P values between 3.7 and 7.2 (96JPS990).

A comparison between experimental values and the results of several cal-culative methods included similar nonfunctionalized DTTs and, additionally, 5-acyl derivatives (e.g. 88 and 271a) (05MI1). The thermometric titration of 5-formyl derivative 274 (see below, Scheme 62) allows to infer that the far too high log P values of 5-acyl DTTs may be explained by the hypothesis that these substances are more solvated in water than expected (04THE(424)143).

Finally, the log P value was used as molecular parameter in biomedici-nal quantitative structure–activity relationship (QSAR) studies with several structural “families” of DTTs including, for instance, active agents oltipraz (20) and ADT (22) (05BML1249).


istry33

Table 10 pKa values of DTTsSubstitution Formula pKa Method* Solvent† Reference

4-COOH 89a 2.81 P‡ W 98J(P2)3874-COOH-5-Me 89b 2.09 P‡ W4-COOH-5-Et 2.03 P‡ W5-COOH 64 1.19 P‡ W4-Me-5-COOH 1.6 P‡ W4-CH2COOH-5-Me 4.14 00ABB(382)1894-C6H4OH (m) 9.58 S M/W 2% 98J(P2)22274-C6H4OH (p) 3b 9.28 S M/W 2%5-C6H4OH (m) 8.96 S M/W 2%5-C6H4OH (p) 98 7.86 S M/W 2%4-Me-5-CH]NOH (E) 100a (E) 8.28 W 03JHC1554-Me-5-CH]NOH (Z) 100a (Z) 5.13 W4-OH-5-Ph 6.93 S E/W 5% 06PS(181)23074-NH2 90 1.06 S M/W 2%4-Morpholino-5-Me 99 −0.06 S M/W 2%5-NEt2 −2.16 S M/W 2%4-COOEt-5-NH2 −2.47 S M/W 1%4-p-tolyl-5-morpholino 70 −2.32 S M/W 2%4,5-di-SH 75c 2.09; 11.82 P D/W 75% 95SUL(19)1194-SH-5-SMe 6.41 P D/W 75%4-OH-5-SMe 9.03 P D/W 75%

* P, potentiometry; S, spectrophotometry.† D, dioxane; E, ethanol; M, methanol; W, water.‡ Values obtained by thermometric titrimetry are nearly identical, those got by spectrophotometry are systematically lower (by about 2–20 %).

Gunther�Fischer34

3.4.5. Aromaticity and PolarityBenzo-DTT (2) has been included in a study of thermochemistry and aroma-ticity of nitrogen, oxygen, and sulfur containing analogs of indane (09THC1).

In order to validate the PM3 semiempirical calculation method for the study of DTT structures, the experimental and calculated dipole moments of numerous compounds (e.g. 1, 2, 3a, 7a and b, 9, 12, 22, 33, 87, 88, 89a and b) were compared, the results being satisfactory (00PS(166)27, 06MI2).

4. REACTIVITY

4.1. ComplexesMetal complexes of DTTs have been summarized in Table 11 (cf. Scheme 24). With respect to chromium carbonyl complex 101b, rate

Table 11 DTT complexesLigand L

Metal M

Complex

ReferenceSubstitution or fusion Formula

M:L relation Formula

Parent compound, 4-Ph

1, 3a Cu 1:2 90TRH9

Benzo 2 Hg 1:1 09AXE1080, 10CCE41

Sn 1:2 11CCE8185-SBu, 5-SC12H25,

5-MeCr 1:1 101a–c 06JOC808,

06JPO823, 08JPO1007

4-SH-5-Ph, -5-mesityl

52b,c Ru 1:1 102b,c 10ICA(363)173

Mo 1:24,5-di-SH 75c Zn 1:2 76a 03PIC(52)1

Sn 1:1 09AXE1592, 11ZK(226)535

Ti 1:1 157 93IC5467Cu 1:1 96IC793Cu, Au, Ni,

Pd, Pt1:2 03IJA2344

Se, Te 1:2 e.g. 103 93POL28494,5-di-SH,

4-SH-5-SMe, 4-OH-5-SMe

Sn, Mn, Ni, Ag, Zn, Cd

1:2 95SUL(19)119


and activation parameters of ligand exchange (decomplexation) in sol-vent acetonitrile have been reported (06JPO823). In complexes 102, the heterocycle is bound as a bidentate uninegative ligand through the two exocyclic sulfur atoms; the formation of precursors 52b and c from alkynes (Scheme 13), deprotonation, and reaction with the ruthenium reagent constitute an effective one-pot synthesis of complexes 102b and c (10ICA(363)173).

The majority of DTT complexes are those of 4,5-dimercapto com-pound 75c (dmt). Thus, titanium complex 157 (see below, Scheme 39) was prepared by the chelate transfer reaction of zinc complex 76a (93IC5467). The reaction of salt 75b with sodium telluropentathionate in the presence of appropriate cations yielded complexes 103 (93POL2849). Moreover, the synthesis of a mixed dmt–dmit crown ether complexBu4N+ [K(18-crown-6)] [Cd4 dmt3 dmit2]− has been described (03MI1).

Inclusion complexes between DTTs (1, 7b, 22, 87) and β-cyclodextrin or derivatives thereof were prepared by spray-drying and characterized

SS

S

R

(CO)5CrS

S

S

R

S

SS

SSS

S S

SS

S

[RuH(Cl)(CO)(PPh3)3]

SS

S

S

STe

SS

R

S

RuOC

HPPh3

Ph3P S

2

2

_

101a-c (R = SBu, SC12H25, Me)

52b, c (anions) 102b, c (R = Ph, mesityl)

2 75b

1. Na2Te(S2O3)2 2 H2O

2. Ph3P=N+=PPh3 Cl-

.

103

+ polymer C3Sx

105 (x = 5.5)104

I2 or TCNQ

(Ph3P=N+=PPh3)2

Scheme 24

Gunther�Fischer36

(99JPS889, 09MI2). Stability constants obtained were the highest for the more lipophilic drugs (7b, 22).

4.2. Ring-Preserving Reactions of the Thiocarbonyl Group4.2.1. 1,2-Dithiolium Salts by Oxidation or S-alkylationThe known synthesis of 1,2-dithiolium salts (cf. 02SOS(11)107), for instance, of parent compound 106 (Scheme 25), by oxidation has been improved (96RCM1519).

Selected examples of the alkylation at the exocyclic sulfur atom are listed in Table 12. Thus, ADT (22) gives salt 107 (05EAC2219). Related reactions of 5-amino- (250b) and 5-acetamido-4-ethoxycarbonyl DTT (255) to afford salts 256, 257, and 259 will be depicted in the context of Section 4.6.4 (Schemes 59 and 60) (03CCC1243, 06CCC650).

The rate constants of the reactions of several DTTs (1, 2, 7b, 10b, 87) with methyl iodide or tosylate were determined among those of about 40 thiocarbonyl compounds (92CPC1667, 95JOC2330). With most of these compounds, a satisfactory correlation of the calculated total charge on the sulfur atom with the measured nucleophilicity of the thiocarbonyl group is observed; the nucleophilicity of the five DTTs mentioned above, however, is significantly higher than the charge one would suggest. Annulation of a ben-zene ring (with 2) decreases the reactivity by about one order of magnitude.

SS

S

Br

SS

SS

SMe

MeO

Br

MeOSO3

S SNO

SMe

S SNOH

S

+ +

_

_

1

1. H2O2,AcOH, 15 °C

2. HBr

22

(MeO)2SO2, 35 °C

801701601

MeI

NaOH

901a001

Scheme 25


The S-methylation of DTT oximes having E or Z configuration (e.g. 100a) in alkaline solution affords exclusively nonionic nitroso derivatives 109 (03JHC155), which may be named heteropentalenes because of a weak interaction between oxygen and sulfur atom S-1.

4.2.2. 1,2-Dithiole-3-ones by OxidationSeveral recent examples of oxidizing the thiocarbonyl group are displayed in Table 13. The presence of thioether sulfur atoms (e.g. in 58c) limits the use of oxidants (07ARK(is4)279). The action of aromatic nitrile oxides, pos-sibly generated in situ from aldehyde oxime chlorides and triethylamine, is worth mentioning.

The course of the dethionation of DTT 110 (Scheme 26) by DMSO in a buffered solution (pH 7.4) at 120 °C to give product 111 was monitored by HPLC (10AJC946). 5-Mercapto DTTs, such as 42, unexpectedly suf-fered a twofold desulfuration to yield chlorodithiolones 43 (06RCB147). It should be noted that benzo DTT (2) when mildly oxidized is attacked at ring atom S-1 to form sulfoxide 112 (03FA995).

Table 12 Alkylation of the DTT thione groupDTT

Reagent Condition ReferenceSubstitution Formula

5-Me 7a (MeO)2SO2 125 °C 99JOC69374-CH2tBu-5-tBu PhCH2Br, allylBr 65 °C 95USP54567674-CN-5-NH2 65 MeI, PhCH2I 25 °C 03CCC12434-COOEt-

5-NH2

250b MeI, PhCH2I 25 °C

4-COOEt-5-NHAc

255 MeI, PhCH2I 25 °C

4-COOEt-5-NH2

250b p-MeC6H4CO-CH2Br

25 °C 06CCC650

5-SMe 58a Me3O+ BF4− 25 °C 94AP813

5-Aryl e.g. 7b MeI 25 °C 00JOC36905-C6H4NO2(p) 306c MeI 02EAC1074-Aryl e.g. 3a,3d MeI 80 °C 95BSF6245-Aryl e.g. 108 MeI 80 °C4-Aryl e.g. 3a (MeO)2SO2 35 °C 05EAC22195-Aryl e.g. 7b, 22 (MeO)2SO2 35 °C4-Ferrocenyl 6a MeI 55 °C 09JOM365-Ferrocenyl 16 MeI or

(MeO)2SO2

Gunther�Fischer38

Table 13 1,2-Dithiole-3-ones by oxidation of DTTsDTT

Reagent Condition* ReferenceSubstitution or fusion Formula

4-Et-5-CHO 272a (AcO)2Hg A, 120 °C 03PS(178)17214-Et-5-COEt 272b (AcO)2Hg A, 120 °C5-[C6H2OMe(4)-di-

tBu(3,5)]110 (AcO)2Hg A, 120 °C

4-Ph-5-C6H4SO2Me(p)

11a KMnO4 C, 25 °C 09BMC558

4,5-di[C6H4OMe(p)] 5a KMnO4 C, 25 °C4-Cl-5-morpholino ClC6H4CNO(p)† 11PS(186)12014-Cl-5-SPh 168 ClC6H4CNO(p)†

5-SBu 58c (AcO)2Hg A, 50 °C 07ARK(is4)2795-SPh 61b (AcO)2Hg A, 50 °C5-S-cyclopentyl 51c (AcO)2Hg A, 50 °C4,5-di-SMe 74a (AcO)2Hg A, 25 °C 94RCM4554,5(SCH2S) 93a (AcO)2Hg A, 25 °C4,5(SCH2CH2S) 93b (AcO)2Hg A, 25 °C4-Ferrocenyl 6a PhCCl]NOH,

Et3NE, 20 °C 09JOM36

5-Ferrocenyl 16 PhCCl]NOH, Et3N

E, 20 °C

* A, acetic acid; C, acetone; E, ether.† Or other aromatic nitrile oxides.

SS

S

MeO

tBu

tBu

SS

O

MeO

tBu

tBu

SS

S

O

H2O2

AcOH

(AcO)2Hg, AcOHor DMSO, pH 7.4

120 °C

111011

2112

SS

S

Scheme 26


4.2.3. 3-Imino and 3-Methylene DerivativesThe substitution of the thiocarbonyl sulfur atom in many DTTs under the influence of nucleophiles to form, for example, oxime 113 (Scheme 27) (00SUL(23)169) is well known.

Acrylic acid 114c is obtained from DTT 15 through isolable ionic inter-mediates 114a and b, which expel hydrogen sulfide (93PS(84)191). Simi-lar products 115 are the result of the Knoevenagel condensation between benzo DTT (2) and active methylene compounds (11PS(186)2341). The treatment of DTT 116 with Wittig–Horner reagents affords phos-phonate 117 (05JHC103) or compounds 192 and (through 193) 194 (see Scheme 46).

Ph

SS

C+R-COOEtHS

SS

S

S

Cl

SS

NC

Ph

SS

COOH

Cl

SS

NC

MeS PO(OEt)2

NOH

SS

Ph

SS

R COOEt

Br

BrCHR-COOEt

RCH2COOEt

Na2CO3

7b

NH2OH HClAcONa

80 °C

.

113

_

15

114a, b (R = H, COOEt) 114c

2 115a, b (R = CN, COOEt)

MeSCH2PO(OEt)2

711611

Scheme 27

Gunther�Fischer40

4.2.4. Spiro Compounds1,3-Dipoles react with DTT 15 by addition to the thiocarbonyl group to form spiro systems 118–120 (Scheme 28) (96PS(108)7). A similar addition of Wittig–Horner reagents to DTT 116 leads to bis-spiro compounds 188 (see below, Scheme 45) (04HCO217).

4.2.5. Reactions of Fluorine DerivativesThe treatment of fluoro DTT 67b with oxidants, several nitrogen and car-bon nucleophiles, and other reagents gives rise to a wide variety of deriva-tives (Schemes 29 and 30).

The chlorination leads, dependent on the conditions, to the formation of 3-chlorosulfonyl chloride 121 rather than the expected 3-chloro deriv-ative, to polychlorinated product 122, or to dithiolone 123, respectively (06RJO124). DTT 67b is readily oxidized to S-oxide 124, whereas the oxi-dative imination with chloramine-T, depending on the temperature, yields sulfimide 125 or imine 126.

Fluoro DTTs, such as 67b, undergo the known condensation with hydroxylamine or hydrazines to give derivatives 127 (Scheme 30) (06RJO261). An improved, more selective procedure for the imination by primary amines proceeds through intermediate 121 to afford imines 128a and b. The same intermediate enables condensation with silylated second-ary amines and active methylene compounds to give iminium salt 129 and acrylonitrile 130, respectively.

PhN3

S

S

N

N

NS

Ph

Ph

S

S

O NS

Ph NO2

S

S

N NS

Ph NO2

Ph

p-NO2C6H4-C+=N-O_

_

15

p-NO2C6H4-C+=N-N-Ph

118

021911

PhNH2

Scheme 28


4.3. Ring Cleavage4.3.1. ThermolysisThe flash vacuum thermolysis of DTTs (e.g. parent substance 1) as already reviewed (95SR(16)173, p 203) has once again been described in detail (94PS(95)485, 03MI2) and applied to mercapto and alkylthio DTTs. The aim was to obtain carbon subsulfide C3S2 (131, Scheme 31), the only sulfur-containing heterocumulene that allows to be isolated at room temperature for a short time at least. For instance, DTT 53b and its 4-phenyl-5- methylthio isomer give, compared to DTT 1, drastically augmented amounts of carbon subsulfide, together with carbon disulfide, presumably via thioacyl thioketenes (96TL4805, 98SUL(21)139). Both these end-products each are identified in an argon matrix at 10 K; they are obviously formed in two competing pathways.

SS

SCl

CHF2CF2

F

SS

SF

CHF2CF2

SS

OF

CHF2CF2

SS

SF

CHF2CF2

NTs

Cl

H2O

Et3N

TsNCl Na+ TsNCl Na+

MCPBA

SS

SF

CHF2CF2

O

SS

ClClFClCl

CHF2CF2

SS

NTsF

CHF2CF2

+

221121 (crude)

SO2Cl2 (excess)

_

67b + 123

(1:4)

Cl2or SO2Cl2 SO2Cl2 (excess)

67b

AcOH Cl2or SO2Cl2

or (AcO)2Hg

421321

48 h67b + 123

(1:9)

67b

-50 °C 25 °C

__

621521

- S

(in solution)

Scheme 29

Gunther�Fischer42

4.3.2. Electrolysis and ReductionAt a mercury electrode, identical intermediates (e.g. 132, Scheme 32) are implicated in the reduction of 1,2-dithiolium cations (e.g. 107) and in the reductive alkylation of the corresponding DTTs (e.g. 22) (05EAC2219). Moreover, cation 107 acts as methylation reagent toward anion 132 and leads to ester 133 and reformed DTT 22. Finally, thiolic ester 134 is accessible from the electrolysis of DTT 3a after successive methylation and benzoylation; this stepwise reaction is possible because the alkylation proceeds with different rates at the nucleophilic sites.

NCCH2COOEtEt3N

SO2Cl2

SS

F

CHF2CF2

NCCOOEt

Et2NSiMe3

SS

NRF

CHF2CF2

SS

N+Et2F

CHF2CF2S

S

NR'F

CHF2CF2

RNH2

80 °C67b 121

127a-c

(R = OH, NH2, NHPh)

a: tBuNHSiMe3 or

b: p-BrC6H4NH2

_Cl

128a, b (R' = tBu,p-BrC6H4)

129 130

Scheme 30

SS

S

Ph

MeS

CSCCSPh

SMeCSCCS

S+Me-PhCSCCS

_ + PhSMe

1000 °C10-5 mbar

53b

131

Scheme 31


A study of radical intermediates formed during the electroreduction of DTTs and the corresponding cations was realized at a platinum or glassy carbon electrode (05PS(180)1419). With compounds unsubstituted in the 5-position (e.g. 3a), the mechanism mainly followed a dimerization route; when the 4-position was free (e.g. with 7b and 22), it was a combination of that route and an ECE mechanism (electron transfer/chemical step/electron transfer).

DTTs (e.g. 22 or 1), when undergoing reductive cleavage by purely chemical means (thiolates or sodium borohydride) and subsequent meth-ylation, afford 3-methylthiodithioacrylic esters (e.g. 133/133a or 133b/c, Scheme 33) (09CRT1427) just as during the electrochemical process

SS

S

SS

S

MeO

MeO

S

CSSMe

MeO

SMe

CSSMe

SS

SMe

MeO

+

_

Ph

SCOPh

CSSMePh

107 (cation)

2 e_

22

MeI

331231

107 cation133 + 22

1. 2 e2. MeI

_

1. 2 e2. MeI (1 equ)

3. PhCOCl

431a3

_

Scheme 32

Gunther�Fischer44

mentioned before. The reversal of the reduction (with sodium borohydride) by exposure to oxygen reforms DTTs 22 or 1.

5-Methylthio DTT (58a), despite of its low reactivity against nucleo-philes, in the presence of organometallics suffers an analogous ring opening leading to dithioacrylates 135 (95SUL(19)141).

Contrary to the expectation, DTTs (such as 1) are not reduced by nico-tinamide coenzyme NADPH in the presence of glutathione reductase, dif-ferent from the behavior of the respective 3-alkylthio-1,2-dithiolium salts (00ABB(382)189).

4.3.3. Reactions with AminesThe nucleophilic ring opening of diphenyl DTT (9b, Scheme 34) by means of cyclohexylamine to give 3-aminoacrylthioamide 136 has been cleared up (97SUL(20)179). Fluoro DTTs 67a and b undergo a similar aminolysis with secondary amines, for instance, morpholine (06MI3): heating both the DTTs with morpholine in excess reveals different regioselectivity of nucleophilic addition and leads to 1,3-addition product 137a or 1,1-addi-tion product 137b, respectively. Amination and concomitant alkylation (with methyl iodide, allyl bromide, p-bromobenzyl bromide) give, for example, α,β-unsaturated thioamides 138a and b.

SS

S

MeO

SMe

CSSMe

MeO

SMe

MeSSC

SS

S

MeSX Li

SMe

CSSMe

X S

CSSMe

SMe

MeSSC

SMe

+22

1. MeS or NaBH4

2. MeI

a331331

_

1. MeS or NaBH4

2. MeI

_

+

133b 133c

1. - 78 °C

2. MeI, 25 °C+ + isomers

58a 135a, b (X = O, S)

1

Scheme 33


4.3.4. Reactions with Phosphorus CompoundsThe treatment of parent DTT (1) with triphenylphosphine gives a black polymer, the composition of which corresponds roughly to (C3H2S)x (139, Scheme 35) (97SUL(20)179). This observation has lead to the application of DTT 1 as a new sulfur transfer agent for trivalent phosphorus compounds (04BKC1692). The reaction smoothly proceeds with trialkyl and triaryl phosphines and with trialkyl phosphites (to yield 140) but not with triaryl

SS

SPh

Ph

SS

SF

R

NH2

Ph

NH

CS-NH

Ph

CCHC

NS

CF3 N

O

O

CCHC

NN

CHF2CF2 S

O O

CCFC

NS

R SMe

O

+135 °C

631b9

morpholine(excess)

80 °Cor

a731b,a76 (from 67a) 137b (from 67b)R = CF3,CF2CHF2)

morpholineMeI

138a, b

Scheme 34

SS

S

+ Ph3P110 °C

(C3H2S)x + Ph3P=S

9311

Me

PPrS

Ph

O

PtBuHS

Ph(AlkO)3P=S

(AlkO)3P

241141041

Scheme 35

Gunther�Fischer46

phosphites. Chiral phosphines and phosphine oxides react stereospecifically and with retention of configuration at phosphorus to afford, for instance, sulfurized derivatives 141 and 142, respectively.

Just recently, a number of 5-amino DTTs, substituted at their amino group and at 4-position, were first evaluated for their efficiency as thion-ating agents for triphenylphosphine in solution (11TL434). Most of them reacted quantitatively in less than five minutes. In a test as sulfurizing agents in oligonucleotide synthesis on solid phase, however, the DTTs studied proved to be inferior by far to some N-substituted 5-amino-1,2,4-dithiazole- 3-thiones.

4.4. Ring Transformation4.4.1. Formation of 1,3-Dithioles4.4.1.1. Dipolarophiles as ReactantsThe dominant reaction with dipolarophiles provides a route to dithiafulvenes, which are precursors as well of other mono- and bicyclic sulfur-containing heterocycles, for instance, of the important tetrathiafulvalenes and analogs (04CRV5151).

Hence, upon [3+2] dipolar cycloaddition of DTT 9a to highly elec-tron-deficient dimethyl acetylenedicarboxylate (DMAD) (Scheme 36), the isolable 1:1 adduct 143 was first produced, but by means of an excess of DMAD, a second cycloaddition finally gave rise to 1:2 adduct 144 (94CHE(30)783). 5-Methyl DTT (7a) yielded an analogous 1:2 adduct (06H(68)2243).

SS

S

Ph

COOMe

COOMe

S

SMeOOC

MeOOC CSPh

DMAD

S

SMeOOC

MeOOCS

Ph

MeOOC COOMe

+

(DMAD) 9a

441341

Scheme 36


4.4.1.2. Reactions of Chloro DTTsChloro DTTs gave by 1:1 addition a novel class of thioacid chlorides, for instance, amino derivative 49 from 5-chloro DTT 48 (see above, Scheme 12) (03OL929). 4,5-Dichloro DTT (72) and DMAD yield under mod-erate conditions α-chlorothioacylchloride 145 (Scheme 37); then, in the presence of bifunctional anilines, the second nucleophilic center cyclizes at the thiocarbonyl group, eliminating hydrogen sulfide rather than displac-ing chlorine, to give benzazolyl derivatives 146 (03MC50). On the other hand, product 145, on heating with additional DMAD, undergoes a new cycloaddition and an unprecedented rearrangement with loss of chlorine to yield thienothiopyranthiones 147a and b (05OL791). Using more drastic

SS

SCl

Cl

S

MeOOC

MeOOCS

COOMeCOOMe

S

S

MeOOC

MeOOC S

S

COOMeCOOMe

HC CPh

S

SPh Cl

CSCl S

S

Ph

Cl

CSCl

DMAD

S

SMeOOC

MeOOC

Cl

CSCl

COOMe

N

X

ClS

S

MeOOC

MeOOC

72

146a-c

(X = O, S, NH)

1. DMAD

2. NH2C6H4XH (o) 100 °C

+

14525 °C

DMAD, 140 °C DMAD, 140 °C

147a 147b

+72

148a 148b

110 °C

Scheme 37

Gunther�Fischer48

conditions from the beginning, both transformations (giving 146 and 147) can be performed as one-pot reactions starting from DTT 72.

The replacement of DMAD in the second step by diethyl acetylenedi-carboxylate or dibenzoylacetylene leads to analogs of isomers 147a and b having mixed substitution. Finally, different from internal alkynes (such as DMAD), terminal alkynes yield already in the first step a pair of isomers (for example, 148a and b) (11PS(186)1201).

4.4.1.3. Reactions of Fluoro DTTsFluoro DTTs 67 react with DMAD to afford, for instance, less stable thio-ketone 149 (Scheme 38) (02TL5809), which can be regarded as a heterodiene. It undergoes with more DMAD, consequently, a [4+2] cycloaddition to yield spiro compound 150 as a 1:1 mixture with rearranged bicyclus 151 (150 being an intermediate toward 151) (03EJO2471). Either product 150 or 151 may be selectively obtained in one-pot processes starting directly from DTT 67a.

SS

SF

CF3

S

COOMeCOOMe

S

S

MeOOC

MeOOC

CF3HO

DMAD

S

SMeOOC

MeOOC

F

CS-CF3

H2O

S

SMeOOC

MeOOCS

F CF3

MeOOC COOMe

149

25 °C

filtration (SiO2)

[150]

DMAD, hν, air

67a

DMADhν, air

crystallization

151 150

air

Scheme 38

4.4.1.4. Reactions of Dimercapto DTT DerivativesSulfur-rich compounds 56 and 57 yield on treatment with one or two equi-valents DMAD, respectively, perthiocarboxylate 152 or dimeric product 153 (Scheme 39) (99JOC4376). Polymeric dimercapto DTT 154, when degraded with DMAD, gives 1:2 adduct 155 and 1:3 adduct 156 (93IC5467), whereas


titanium complex 157, also originating from zinc complex 76a, when add-ing to DMAD forms dithiocarboxylate complex 158. Finally, complex 76a and DMAD give directly a similar (but ionic) zinc complex.

4.4.1.5. Reactions with Other DipolarophilesExamples of other alkynes are those of diacetylacetylene or acetylene dicar-boxylic acid, which produce remarkably stable thials 159 (96TL8861) or thioketene 160 (07PS(182)2205), respectively (Scheme 40). Analogous alkenes, for instance, maleic acid or the anhydride thereof, lead to the

S

SMeOOC

MeOOC

SiPr

CS-SSiPr S

SMeOOC

MeOOC

SiPr

CS-S

S

SMeOOC

MeOOC S

SMeOOC

MeOOC

S

SMeOOC

MeOOC

SS

S S

S

S

SCOOMe

COOMe

S SS

MeOOCCOOMe

MeOOCCOOMe

STi(cp)2S

S

SS S

Ti(cp)2

SS

2

7565

DAMD2DAMD

351251

+

155 156

n

DMAD, Bu3P

SO2Cl276a

154 (cp)2TiCl2

DMAD

851751

Scheme 39

Gunther�Fischer50

corresponding 1,3-dithiolanes (e.g. 161). Acetylene dialdehyde or, prefer-entially, its monoacetal (162, Scheme 41) adds 5-substituted DTTs (e.g. 7b) to yield stable 163-type thioketones (95BSF975). DTTs unsubstituted in the 5-position, however, give 164-type thials, which (possibly in a one-pot reaction) are dimerized with loss of sulfur to trienes 165, that is a kind of vinylogous tetrathiafulvalenes.

The reaction of DTTs (e.g. 7a) with alkynyl Fischer carbene complex 166 affords dithiafulvene complexes (such as 167) and is found to be com-pletely regioselective toward the Z-isomer (08CC483). Calculations are in good agreement with the experimental outcome (11OM466).

Finally, crowned dithiafulvalene 239 (see below, Scheme 55) is a by-product of the phosphite-induced ring transformation of bridged bis-DTT 236b (98CC1653).

4.4.2. Formation of 1,3-DithietanesIsonitriles, for instance, phenylisonitrile, are likewise dipolarophilic reagents. They undergo cycloaddition to DTTs 72 and 168 (Scheme 42) having electron-withdrawing substituents to achieve imino-1,3-dithietanes 169, which are rather stable in the solid state but dissociate into the starting com-ponents upon heating in solution (09RCB430, 11PS(186)1201).

Reductive dimerization of 5-alkylthio DTTs with phosphorus(III) reagents yields 2,4-bis(2-thioxoethylidene)-1,3-dithietane derivatives or thiodesaurines. This way, Z/E isomers 171 are obtained from disulfide 56 either directly by the action of two equivalents triphenylphosphine or in

SS

S

O

S

SHOOC

HOOCS

OS

SHOOC

HOOCS

O

S

SAc

Ac

R

CHS

159a, b

(R = H, p-MeC6H4)10a

HOOC-CH=CH-COOHHOOC-C=C-COOH_

161061

Scheme 40


SS

SCl

R

SS

SiPrS

iPrS

S

SCl

SR

NPh

S

SiPrS

SiPrS SiPr

SSiPr

+ PhNC25 °C

60 °C

b,a961861,27

)hPS,lC=R()hPS,lC=R(

56

S2Cl2 PPh3(1.27 equ) PPh3 (2 equ)

PPh3 (1.36 equ)

171071

Scheme 42

SS

S

Ph

SS

S

SS

SR

S

SOHC

(EtO)2CHS

Ph

S

SPh

S(CO)5Cr

OMe

S

SOHC

(EtO)2CH CHS

R

S

SOHC

(EtO)2CH

R

S

S CHO

CH(OEt)2R

CHO

CH(OEt)2

Ph

(CO)5Cr OMe

+

162 7b 163

1, 3a

(R = H, Ph)

162

140 °C

164a, b 165a, b (R = H, Ph)

+- 40 °C

761a7661

Scheme 41

Gunther�Fischer52

two steps, each of them being released by a little more than one equivalent of the reagent (99JOC4376).

Similar transformations occur with long-chain DTT thioesters 233c and d and oligooxyethylene-bridged compounds 236a and b (see below, Scheme 55) or dithiacrown ethers 244a–c (see Scheme 57) (98CC1653, 98JPR450). In contrast to Z/E isomers 171, products 234 and 245 exclu-sively show E configuration, obviously because of the greater steric demand of the substituents. The length of the bridges in DTTs 236a and b determines the stereochemistry of the thiodesaurines 237 and 238 formed. The bridging chain in DTT 236b is long enough to enable cycli-zation that forms isomer (E)-238, together with dithiafulvene (E)-239 (10–20% each).

4.4.3. Formation of Thiopyrans and Other Sulfur-Containing Heterocycles

4-Phenyl DTT (3a) suffers on treatment with active acrylonitriles or similar compounds in the presence of base extrusion of sulfur or aromatic thio-carbonyl compounds and formation of thiopyranthiones (e.g. 172–175, Scheme 43) (00PS(165)1, 03PS(178)2255, 10JSF255). Moreover, analogous ω-functionalized crotononitriles give bicyclic pyranthiones 177–179 or isothiazolothiazines 180. The formation of thiopyrans results from an initial nucleophilic attack at C-5 of the DTTs and a ring-opening ring-closure sequence.

Fluoro DTT 67b reacts as a dienophile to yield less-stable spirocyclic adduct 181 (Scheme 44) (02TL5809). The reaction of the starting sub-stance with sodium sulfide strongly depends on the quantity of reagent used, resulting in the formation of trithiapentalene 182 or thiopyranthione 183, respectively (06JFC(127)774).

Among alkylthio DTTs, substance 58a with cyclopentadienides affords tricyclic thiopyrans 184 (95SUL(19)141), whereas derivative 74a, when photolyzed, undergoes dimerization and extrusion of sulfur to form trithiolane 185 (99JHC823).

Several reactions of DTT 116 with Wittig–Horner reagents are depicted in Schemes 45 and 46 (04HCO217, 06LOC634). Treatment with three equivalents of phosphonoacetates 186a or b resulted in the formation of a mixture of dispiro products 188 and thienothiophenes 189 (through intermediates 187) together with 1,3-dithiolone 191 (through 190). Simi-lar reagent 186c produced a mixture of Wittig–Horner adduct 192 and (through 193) thiophene 194. By contrast, reagents 186d and e with DTT


SS

SPh

SS

SPh

S

SPh

COOEtNH2

S

SPh

CNNHPh

S

SPh

NH

XN

X

NCH2CN

S

SPh

O

NH2CN

NH

S

SPh

N

NH2CN

NH2

S

SPh

O

RNH

N

S

S

PhR'

NC CN

S

SPh

CNNH2

PhCH=C(CN)COOEt

EtOOCCH2CMe=C(R)CNpiperidine, 80 °C

NCCH2CONHPhEt3N, 80 °C

ArCH=C(CN)CONH2Et3N, 150 °C

- ArCHS

piperidine, 80 °C

- PhCHS

371271

3a

176a, b

Et3N, 80 °C

- S - S

b,a571471 (X = S, NH)

176a, b

3a

EtOOCCH2C(NH2)=C(CN)2Et3N, 80 °C

- S - S

NCCH2C(NH2)=C(CN)2piperidine, 80 °C

b,a871771 (R = CN, COOEt)

1. Br2, 2. CH2R-C(NH2)=C(CN)2(R = CN, COOEt)

- S - S

b,a081971 (R' = NH2, OH)

Scheme 43

Gunther�Fischer54

116 initiated insertion processes to yield 1,3-dithiane-4-thiones 195 and 196, respectively, the latter being produced together with open-chain bisphosphonate 197.

The insertion of carbanions (formed in situ) between two sulfur atoms has also been reported to proceed when DTT 116 is allowed to react with unsaturated and other reactive phosphonium salts (05JHC103). The attack of vinyl or allyl salts (198a or b, respectively, Scheme 47) in an alkaline medium initially gives rise to zwitterions (e.g. 199), which sub-sequently follow two different pathways leading to dithianethiones 200a and b or thienothiopyranones 201a and b, respectively. Alkyl analogs 202a and b give under the same conditions 1,3-dithianes 203 and thio-phenes 204.

SS

S

CHF2CF2

SS

S

MeS

SS

S

MeS

MeS

SS

R

S S

SCHF2CF2

F

S SS

FSH

FS

FSH

F

S

S

SS

R

S S

SSMeMeS

SS

MeS SMe

30 °C

181b76

1. 2 Na2S, 80 °C2. HCl

1. 3 Na2S, 80 °C2. HCl

1. Na2S, 80 °C

2. HCl

381281

_Na+ +- 78 °C

58a 184a, b (R = H, tBu)

2h

581a47

F

Scheme 44


SS

CHCNNC

Ar SS

CNC

Ar

PO(OEt)2CN

NC

Ar S

S

S

PO(OEt)2

NC

Ar S

S

S

PO(OEt)2

PO(OEt)2

S

CHNC

Ar

CNPO(OEt)2

CN

NC

Ar SH

SCH

SPO(OEt)2PO(OEt)2

LiH

EtONa

(Ar = p-ClC6H4)

(186c)

+

+

391291

491591

196 (19 %) 197 (48 %)

116

CH2=CHPO(OEt)2(186d)

NC-CH2PO(OEt)2(186c)

CH2[PO(OEt)2]2(186e)

LiOH, 0 °C

Scheme 46

SS

SNC

Ar

SS

SNC

Ar

CHCOOR

PO(OEt)2

SSNC

Ar

SS

ROOC

COORCH2PO(OEt)2

Na+

SS

Ar

CN

SAr

NCS

SNa

CHCOOR

PO(OEt)2

S

S

O

PO(OEt)2NC

SAr

S

SNH2

ArCOOR

ROOC

_

116

186a, b

(R = Me, Et)

+

(116)

EtONa (186a, b)

187a, b

188a, b

190a, b

189a, b

191(Ar = p-ClC6H4)

Scheme 45

Gunther�Fischer56

4.4.4. Formation of Nitrogen-Containing HeterocyclesThe synthesis of isothiazole-3-thiones (e.g. 205, Scheme 48) by the attack of ethylamine on 5-substituted 4-methyl DTTs could be improved (91J(P2)1763). On the other hand, ADT (22) reacts with primary amines to give tetrahydropyrimidines 208 (93JRM1671). In this case, solvent dichloromethane serves as a C1-unit donor yielding, in the presence of catalytic (extruded) elemental sulfur, in situ Mannich-type compounds 206, which react with enamine intermediates 207. Isolated enamines 207 give with amine and sulfur under identical conditions or with triazanes 206 in chloroform likewise products 208.

S

ArCN

S

SCCH2 P+Ph3

S

ArCN

S

SCHR-P+Ph3

CHR-P+Ph3

S S

ArCN

S

S S

ArCN

S

S

Ar CN

CH2R

S S

CHP+Ph3

Ar CN

S S

ArCN

CHR

S S

OAr

S S

OAr

(Ar = p-ClC6H4)

__

_

_

116

+116

199

200a (43 %) 201a

(21 %)

CH2=CH-P+Ph3 Br(198a),

LiOH

_

CH2=CHCH2P+Ph3 Br_

(198b)

LiOH

200b 201b (18 %)(47 %)

203a, b (52 %)

204a, b (16 %)(R = H, Me)

CH2R-P+Ph3 Br_

(202a, b)LiOH

Scheme 47


Treatment of benzo DTT (2) with ethanolamine or 2- or 3-hydroxy-propylamine yields mixtures of benzoisothiazolethiones and 3-iminobenzo-1,2-dithioles (e.g. 209a and b, respectively), inseparable by preparative liquid chromatography (96EJM919).

When the thiocarbonyl group of 4-chloro DTTs 210 (Scheme 49) reacts as a dipolarophile toward diphenyl nitrile imine, 5-methylene-1,3,4-thiadi-azolines 211 are obtained (05MC55). In reactions of, for instance, 5-phenyl DTT (7b) or benzo DTT (2) with pyrrolopyrazine 212, the imine fragment of the latter is inserted into the 1,2-dithiole ring to give fused 1,3-thiazine-4-thiones 213a and b, respectively (08RCB1790).

SS

S

Ph SN

S

Ph

SS

S

MeO

MeO MeO

SS

S

SS

NCH2CH2OH

SN

S

EtN

N

NR R

R

NHR

RNH-CS

N

N

R

RRNH-CS

CH2CH2OH

206a, b

(R = Et, CH2Ph)

EtNH2

40 °C9a 205

[CH2Cl2]

[S]

22

RNH2, 40 °C

RNH2, CH2Cl2,S, 40 °C

206a or b

40 °C

b,a802b,a702 (70-80 %)

(R = Et, CH2Ph)

NH2CH2CH2OH2

b902a902

Scheme 48

Gunther�Fischer58

Cancer chemopreventive oltipraz (20) is during its human metabolism converted to pyrrolopyrazine 214 (or tautomers thereof) and subsequently to bis-methylated product 215 (Scheme 50). The latter substance as well as bis-disulfide 216 and bis-thiolsulfonate 217 have been synthesized to serve as alternative precursors to major metabolite 214 (02JOC9406).

SS

S

R

Cl

SS

S

Ph

PhNH-N=CCl-PhEt3N

NN

[ PhN-N=C+-Ph ]

NN

S

S

Ph

N

S

NPhPh

Cl

SR

NN

S

S

- S

210a-c (210a = 72) 211a-c

(R = Cl, OPh, SPh)

7b

212

+

- S

213a 213b

_

Scheme 49

SS

S

N

N

NN

SH

SH

NN

SSMe

SSMe

NN

SMe

SMe

NN

SSO2Me

SSO2Me

1. AcONH4, MeSNa

2. MeI

512412

1. MeSNa2. MeSO2SMe 1. MeSNa 2. MeSO2Cl

712612

Scheme 50


4.4.5. Formation of Metal ComplexesThe reaction of 5-phenyl DTT (7b) with rhodium or cobalt penta-methylcyclopentadienyl complexes 218 (Scheme 51) yields 1,2,5-rho-diadithiolene complex 219a or the cobalt compound 219b, respectively (96CL191).

The insertion of Fischer carbene complexes 220 into DTTs 7a or 58c has been found to give, different from an initial structural assignment (02TL8037), dithioorthoesters 221a and b, respectively (06JOC808), the chromium pentacarbonyl group being close to the thiocarbonyl. Complexation of the starting material has little influence on the reac-tion pathway as shown by the formation of complex 222. In this case, however, the C]C double bond is involved in the coordination with the metal.

S

S

S

OMe

Ph

Cr(CO)5

SS

S

BuS

SS

S

Ph

SS

S

SS

S

BuS BuS S

S

S

OMe

Cr(CO)5

OMe

(CO)5CrOMe

Ph

(CO)5Cr (CO)5Cr

OMe

OMe(CO)5Cr

S

S

BuS

S

OMe

Ph

SM

ScpMe5

Ph(CO)2M(cpMe5)+

7b 218a, b 219a, b (M = Rh, Co)

+40 °C

a122a022a7

40 °C+

b122b022c85

40 °C

220a

222a101

Scheme 51

Gunther�Fischer60

4.5. Nucleophilic Substitution of Functional Nuclear Substituents

Examples of the nucleophilic substitution of 5-position chlorine include those affording DTTs 223 (Scheme 52) (05MC20) or 50 and 51 (Scheme 12) (03OL929); the inertness of 4-position halogen has been reported. The 5-methylthio group is also replaced to give, for instance, derivative 224 (06WOA89861).

4.6. Transformation of Individual Substituents at the 1,2-Dithiole-3-thione Ring

4.6.1. 4-Thio or 5-Thio SubstitutionAlkylation of, for instance, 5-mercapto DTT 225 (Scheme 53) or its anion leads to thioether 59a (98SUL(21)139) or precursor 226a of inhibitor 226b (06WOA89861) while influence of air during recrystallization transforms 4-mercapto DTT 52b (Scheme 13) to disulfide 54 (04TL7671).

SS

SCl

Cl

SS

SPh

MeS

SS

SCl

XNH2

SS

SPh

NO

ON

NH2

XH

NO

ONH

+

72 223a-c (X = O, S, NH)

+224

Scheme 52

SS

SPh

EtS

SS

SPh

SS

SPh

HS S

RNHC=C-CH2-N(COOtBu)-CMeCH2CH2I_

EtBr 226a (R = COOtBu)

226b (R = H,hydrochlorid)

HCl225

59a

Scheme 53


SS

SS

S SS

SMeS

MeS

SS

SPhCOS

PhCOS

SS

SPhCOS

RSSS

SPhCOS

S

SS

SPh3SnS

Ph3SnCH2SSS

SPh3SnCH2S

Ph3SnCH2S

SS

SPhCHMe-S

PhCHMe-S

SS

SS

S

MeI

RI

PhCHBrMe

Cs+

(Na+)2PhCH2Cl

Ph3SnCH2I

(Cs+)2

_

_

_

_

_

a47b57MeONa

CsOH (1 equ)

97

228 229a, b

(R = Me, CH2Ph)

77

CsOH (excess)

230

231a 231b

76b

+

Scheme 54

4.6.2. Open-chain 4,5-bis-thio Substitution4,5-Dimercapto DTT (dmt, 75c) has been a main focus of DTT chemistry. In addition to complexes (Section 4.1), numerous S-alkylated derivatives as well as disulfides have been described, the syntheses frequently starting from S-benzoyl derivatives (e.g. 77, Scheme 54) or complexes (e.g. 76b).

This way, precursor 77 gave dibenzoyl derivative 97 (99PCA6930) or dimethyl thioether 74a (10ZK12) in one-pot reactions through dithiolate salt 75b. The regiospecific partial hydrolysis of diester 77 occurs preferen-tially by cesium hydroxide to yield, in another one-pot reaction, monoes-ters 228 and, after alkylation, 229. More cesium hydroxide affords unstable dithiolate salt 230 (sensitive to air) and, after alkylation, a cocrystallized mixture of stannylated compounds 231a and b (08JOM763).

Gunther�Fischer62

SS

SC12H25S

RS

SS

S

MeSSS

SS

SMe

OS

SS

S

MeSSS

SS

SMe

OS

SS

SHS

MeS

S

S

MeS

S

CSSMe

SS

O O O

S

S

MeSSC

S

S

O O

OMeSSC

S

S

MeSSC

S S

CSSMe

O O

S

S

C12H25S

RSSC SC12H25

CSSR

2

3

(EtO)3P

130 °C

229a

1. MeONa2. C12H25Br

75b

233c, d 234c, d (R = Me, C12H25)C12H25Br

(EtO)3P, 100 °C

high dilution

236a 237 (Z)

BrCH2(CH2OCH2)2CH2Br

BrCH2(CH2OCH2)3CH2Br

Cs2CO3, 80 °C

229a

1. MeONa2. HCl

235

+

(EtO)3P, 100 °C, high dil.236b

238 (E) 239 (E)

Scheme 55

An example of the alkylation of coordinated dimercapto DTT is that of forming thioether 232 from complex 76b (09MIP2).

Long-chain DTT thioethers 233 (98JPR450) and oligooxyethylene-bridged bis-DTTs 236a and b (98CC1653) were obtained from mono- and dimercapto DTT anions, likewise prepared by saponification (Scheme 55).


Aerial oxidation of the respective bis-thiolate ions gives bis-DTT disul-fides 240 (10ICA(363)4074) and 241 (07CYR84) (Scheme 56). Oxidation with sulfuryl chloride transforms complex 76a to new polymeric carbon sulfide (C3S5)n (154, Scheme 39) (93IC5467). Finally, disulfide 56 is partially desulfurated by triphenylphosphine (to give bis-thioether 170, Scheme 42) but, surprisingly, partly regenerated by treatment with sulfuryl chloride (99JOC4376).

4.6.3. Fused-Ring 4,5-bis-thio SubstitutionDimercapto DTT (75c), salt 75b or complexes 76 react analogously with bidentate alkylating agents to give dithiolene 242 and dithiin 243 (Scheme 57) (92T8143, 94OMS321) or, with oligoethylene glycol dibromides, stable On/S2-coronands 244a–c (94SUL(17)177, 98JPR450).

Diethylene glycol dichloride, however, yields acyclic ionic compound 246.

The cyclization of dimercaptide 75b with thiophosgene affords almost planar carbon sulfide C4S6 (247, Scheme 58) (06JCD1174), whereas annu-lation of 2,3-dichloronaphthoquinones leads to tetracyclic quinones 248 (96ZNB901). Among dimeric compounds, carbon sulfide C6S8 (249) is obtained by thermal elimination of hydrogen sulfide from dimercapto com-pound 75c (93IC5467) while oxidation of respective complexes (e.g. 103, Scheme 24) affords carbon sulfide C6S10 (104) together with polymeric C3Sx (105) (93POL2849).

SS

S

SS

SS S

SMe MeS

SS

S

SS

SS S

S S

SS

SS

MeS

_ _

_

230

air(Cs+)2

NH4+

air

240

241

Scheme 56

Gunther�Fischer64

SS

SS

S

SS

SHS

HS

SS

SS

S

SS

SO S

O S

S

S

O

S

O

S

O

S

O

SS

S

CH2Br2 (CH2Br)2

SS

S

ClCH2(CH2OCH2)2CH2SS

Cs+ +

n-1

n-1

n-1_

_

76a or b

342242

BrCH2(CH2OCH2)nCH2Br

Cs2CO360-70 °C, high dilution

75c

244a-c (n = 2-4)(11-14 %)

246 (5 %)

(EtO)3P130 °C

245a-c

ClCH2(CH2OCH2)2CH2ClCs2CO3

Scheme 57

SS

SHS

HS SS

SS

S

SS

S

SS

SS

S SS

SS

SS(Na+)2

CSCl2

RR

RR

Cl

ClO

O

RR

RR

O

OS

S

SS

S

_

_

742b57

+ 75b

248a, b (R = H, Cl)

110 °C

N2

942c57

Scheme 58


4.6.4. Amino Groups5-Amino DTT derivatives 250 when treated with aliphatic or aromatic carboxylic chlorides and anhydrides or benzene sulfonyl chloride yield, for instance, acylamides 251 and 255 or sulfonamide 254, respectively (Scheme 59) (03CCC1243, 11TL434). Moreover, they were converted to dimeth-ylaminomethylene-protected derivatives 253 and several dithiolium salts (Section 4.2.1); the formation of salt 252e by treatment with triethyl ortho-formate is a rare reaction. Alkylation of amide 255 with p-methylphenacyl bromide (258) leads to nonionic products 262 (directly or through 261) or 260 (Scheme 60) (06CCC650).

SS

SR

NH2S

S

SR

PhCONH

SS

SR

Me2NCH=NSS

SR'NC

N

O

SS

SEtOOC

AcNHSS

SEtOOC

PhSO2NH

SS

EtOOC

NH2

SR

SS

EtOOC

AcNH

Me2NCH(OMe)2

SR

+ +

_+

250a-c

(250a = 65)

PhCOCl, py or

(PhCO)2O (py)

251a-c

(R = CN, COOEt, CONH2)(250a) HC(OEt)3 orAc2O PhCh2Cl, resp.

250a, b, d

252e, f (R' = Et, CH2Ph) 253a, b, d (R = CN,COOEt, SO2Ph)

250b

PhSO2Cl AcCl, py

or Ac2O (py)

552452

II__

IRIR

253b

251b + 253b

CSCl2DMF PhCOCl

DMFEt3N

256c, d (R = Me, CH2Ph) 257c, d

Scheme 59

Gunther�Fischer66

4.6.5. Carboxylic Acid DerivativesThe saponification of ethyl ester 63 to give carboxylic acid 64 (Scheme 15) proceeds by means of sodium sulfide (98J(P2)387). A route through acid 89a was chosen to prepare amide 264 from ester 263 (Scheme 60) (98CAG1609).

4.7. Reactivity of Side Chains and Aromatic Rings4.7.1. Side ChainsThe condensation of the activated methyl group of 5-methyl DTT (7a) with benzaldehyde or cinnamaldehyde derivatives (Scheme 61) yields styryl compounds 265a (93JPA05301868) and 265b (06WOA89861) or phenylbutadiene 266a (92JPA04117377), respectively. The Mannich

SS

SH2NCO

SS

SEtOOC

AcNH

CH2CO-tol

SS

SHOOC

SS

SEtOOC

AcN

CH2CO-tol

SS

SEtOOC

SS

EtOOC

AcNH

CO-tol

BrCH2CO

BrSS

SEtOOC

NH2

CH2CO-tol

Et3N

AcOH

H2SO4

+ _

+

250b

258

AcCl

or Ac2O255 +

062952

260

258

Et3N (1 equ)258 258

Et3N (4 equ)

262162

258

AcONH4

CMCD

462a98362

Br_

Scheme 60


reaction of DTT 87 with cyclic amines leads to a mixture of, for instance, mono-Mannich base 267a, retro-Mannich base 267b, and bis-Mannich base 267c, the respective yields depending on the excess of reagents used (93JHC545).

The reactivity of 5-alkyl DTTs against nitrosating agents opens path-ways, through oximes, to acyl DTTs (Scheme 62). One of the general reac-tions proceeds by reacting, for example, DTTs 268 with sodium nitrite and subsequent reducing insoluble intermediate disulfides 269 with sodium sulfide to yield oximes 270, which are easily transformed to acyl deriva-tives 271 (94PS(88)195). Other DTTs (e.g. 272) are analogously formed (03PS(178)1721). According to the structure of the starting DTT, E- or Z-oximes or a mixture of both were obtained (e.g. 100a(E) and 100a(Z), Scheme 23) (03JHC155).

SS

S

R

CHO

tBuOOC

SS

S

SS

S

SS

S

RCH2CH2S

S

S

SS

S

CHO

R

SS

S

ROOC

RCH2 RCH2

RCH2

+piperidine

65-80 °C

b,a562a7 (R = OH, NEt2)

7a

(MeO)2Mg

266a (R = tBu)

266b (R = H)H2SO4

+ +

morpholine 80 °C(HCHO)3 72 h

87

267a (R = morpholino) 267b 267c

Scheme 61

Gunther�Fischer68

A second general oxime synthesis involves a one-step reaction of, for instance, DTT 268b with isoamyl nitrite in the presence of base to give oxime 270b (94SUL(17)231) or of DTT 27a to yield oxime 273 and for-myl derivative 274 (03SUL(26)195). Saponification of ester 27a or thionic ester 27b affords carboxylic acid 275.

4.7.2. Linked Phenyl Groups4.7.2.1. Electrophilic SubstitutionExamples of resultant products (Scheme 63) are sulfonate 276 (95EPA641792), azo compound 277 (07USA197479), and Mannich bases 278 and 279 (95JPA07118262). 4(4-Methoxy-3-sulfophenyl)-5-phenyl DTT (another sulfonation product, cf. 65CRV237) has proven to crystallize as a dihydrate (68UP1).

SS

SEtOOC(CH2)2

S SS

RCH2

SS

SHOOC(CH2)2

NHO

SS

SHOOC(CH2)2

SS

SHOOC(CH2)2

OHC

S SS

R

NOH

S SS

RCOEt

S SS

RCO

S SS

R

NO

NaNO2 1. Na2S

HCHO

HCHO

2

b,a072b,a962b,a862

(268b) iC5H11ONO, tC5H11ONa

271a, b (R = H, Et)272a, b (R = H, Et)

1. iC5H11ONO, tC5H11ONa

2. H2O

372a72

27a

or

27b

H2SO4, AcOH

100 °C

472572

H.2HOcA +

(268a = 7a)

Scheme 62


4.7.2.2. Transformation of Hydroxyl GroupsIn recent years, numerous O-substituted derivatives of ADTOH (98) have been synthesized as analogs of ADT (22). Examples of ether-type compounds (Schemes 64 and 65) include enanthic ester 280a and hydroxamic acid 280c (10BMC4187), ammonium salts 281 and 282 (10EJM3005), and ethylene glycol derivatives 283, the latter being

SS

S

HO

PhCH2

SS

S

HO

PhCH2

Et2NCH2

SS

S

HO

N

NCH2Ph

NN

CH2Ph

SS

S

OMe

SS

S

OMeNaO3S

SS

S

OMeClSO2

SS

S

NN

OHHOOCPAS

Et2NH HCHO

ClSO3H 0 °C

1. H2SO4, 100 °C

2. Na2CO3

Na2CO3100 °C

1. NaNO2, HCl2. 7b 277

1-benzylpiperazineHCHO

98

972872

276

Scheme 63

Gunther�Fischer70

SS

S

HO

SS

S

MeO

SS

S

RR'NCH2CH2O

SS

S

ROCH2CH2OSS

S

Et3N+CH2CH2O

SS

S

HONHCO(CH2)6O

SS

S

ROOC(CH2)6O

HCl

Br_

280a (R = Et)

280b (R = H)

1. tBuMe2SiONH2DMAP, EDAC

2. HCl

AcOHH2SO4100 °C

280c

.

281a, b

(RR'N = NMe2, piperidino)

pyridine HCl215 °C

.

22

98

EtOOC(CH2)6BrNaOH, 80 °C

1. ClCH2CH2NRR'(a) Bu4N+ Br ,

NaOH, 25 °C

(b) K2CO3, 60 °C2. HCl gas

1. BrCH2CH2BrK2CO3, 60 °C

2. Et3N, 110 °C

THP-OCH2CH2OHiPrOOC-N=N-COOiPr

PPh3, -15 °C

282

283a (R = THP)

283b (R = H)PPTS, 55 °C

_

Scheme 64


prepared with tetrahydropyranyl-protected glycol under Mitsunobi conditions (11JMC5478). Thiolic carbonate 284 provides an access to carbonates 285 (Scheme 65).

Hydrolysis of ADT derivative 286a and coupling to l-3,4-dihydroxy-phenylalanine (DOPA) methyl ester through an amide linkage gives l-DOPA hybrid 287 (10JBC17318). Deprotection of methoxymethyl ether 8 with trifluoroacetic acid recovers ADTOH (98) (10AJC946).

Among esters of ADTOH (Schemes 66–68), there are, for example, ace-tate 288 (10CCL1427, 10MI3) and derivatives 289–291 (10BMC4187). Isomeric acetate 292 was saponified with sulfuric acid (50%) at 100 °C (98J(P2)2227).

SS

S

NHCOCH2O

MeOCOOMe

OHHO

OAc

COOCH2OCOSEt

SS

S

ROOCCH2O

MeO

SS

S

OAc

COOCH2OCO(OCH2CH2)nO

1. SO2Cl22. 98 or 283b, resp.,

-15 °C, 4-Me-morpholine

285a, b (n = 0, 1)

286a (R = Me)

286b (R = H)hydrolysis

284

L-DOPA methylester HClHOBt, EDAC, Et3N

25 °C

.

287

Scheme 65

Gunther�Fischer72

Similar methods of esterifying ADTOH (Scheme 67) lead, for instance, to salicylates 293a and b (09MI3), aminosalicylate 294 (06JEP(319)447), carbonate 295 (07USA197479), and nitrate 296 (12MI1). Furthermore, known drugs diclofenac (297) and sulindac (299) as well as valproyl chlo-ride (301) were coupled with ADTOH to yield esters 298, 300, and 302, respectively (Scheme 68) (07BJP(151)142). Valproic ester 302 has proven to be quite stable against hydrolysis at pH 8 (08BML1893). Finally, derivative 303 of latanoprost acid is worth mentioning (09BML1639).

On the other hand, 4( p-hydroxyphenyl) DTT (3b) gives trifluoro-sulfonate 304 (95BSF624) and polyethoxy compound 305 (Scheme 69) (95USP5456767). 4,5-Bis(p-hydroxyphenyl) DTT (5b, Scheme 2) is formed by cleavage of dimethyl ether 5a with boron tribromide (09BMC558).

4.7.2.3. Transformation of Nitro and Amino GroupsThe selective reduction of nitro groups in 5(nitrophenyl) DTTs 306a–c was accomplished by phase-transfer indirect electroreduction in the pre-sence of a titanocene complex used as a mediator to yield amino deriva-tives 307a–c (98EAC201). p-Isomer 307c gives azo compound 308 (07USA197479).

SS

S

AcO

SS

S

Ph(CH2)3COO

SS

S

AcO

SS

S

PhNHCO(CH2)6COO

SS

S

HOOC(CH2)6COO98

AcOH, DCCDMAP

288

1. ClCO(CH2)6COCl

2. H2O

Ph(CH2)3COOHDCC, DMAP

PhNHCO(CH2)6COOHEDAC, DMAP

289

290

291

292

Scheme 66


4.7.2.4. Transformation of Carboxyl GroupsReactions of 4(p-carboxyphenyl) DTT (309, Scheme 70) yield carbox-ylic esters 310a and b (95BSF624), l-DOPA amide 311 (10JBC17318) or hydroxamic ester 312 (10BMC4187).

4.7.3. Linked Heterocyclyl GroupsNucleophilic substitution with chloro oltipraz (313, Scheme 71) gives methoxy oltipraz (314) (07MI2).

SS

S

COO

OHOH

COOH

OAc

COCl

OH

COOHNH2

COOH

OCO(CH2)3ONO2

OCOOEt

NH2

COOtBu

OAc SS

S

COO

OH SS

S

COONH2

OCO(CH2)3ONO2

SS

S

COO

NH2

COOH

SS

S

OCOO

98

DCC, DMAP 293a

98

iPr2NEt 293b

1. (tBuOCO)2O, Et3N, 0 °C2. 98, DCC, HOBt, 0 °C

3. CF3COOH294

2. (tBuO)2CO2, Et3N3. 98, DCC, HOBt

4. CF3COOH

1. NaOH

295

98

DCC, DMAP

296

Scheme 67

Gunther�Fischer74

5. APPLICATIONS

5.1. Pharmaceutical Uses5.1.1. Classical DrugsThe physiological activity of DTTs has for a long time been known, espe-cially that of parent substance 1, ADT (22) (cf. 65CRV237), and oltipraz (20) (cf. 95SR(16)173). During the period under review, studies at first centered on cancer prevention and protective effects by inducing phase 2 and antioxidative enzymes with both known and similar new substances (cf. 07ARK(is4)279, 08JST(888)354). Hence, QSAR between electrophile detoxication properties and water/n-octanol log P values of numerous

SS

S

FCH2COO

SOMe

CH2COOH

NHCl Cl

SS

S

CH2COO

NHCl Cl

SS

S

Pr2CHCOO

SS

S

COO

HO

HOCH2Ph

OH

FCH2COOH

SOMe

98

DCC, DMAP

98

DCC, DMAP

297

298

299

300

98

iPr2NEt, 65 °CPr2CHCOCl

301

302

Latanoprost acid

98, N2EDAC, DMAP

303

Scheme 68


DTTs were checked (96IJP(129)295) and the regulation of phase 2 enzyme induction in the cancer protective action was investigated (94CAG177). As regards the oral toxicity of DTT parent substance (1) in the rat, the no-observed-adverse effect dose was 6 mg/kg/day (00MI2).

The properties of ADT (anethole dithiolethione, anethole trithione, 22) have once again been reviewed (95MI4, cf. 05EAC2219). Its role in can-cer prevention is described as that of a free radical scavenger that increases synthesis and enzyme activity of glutathione (02MI2). To make its applica-tion easier by solubilization, it may be included by 2-hydroxypropyl-β-cyclodextrin (the solubility increases by 460 times) (09MI2) or transformed to ammonium salt prodrugs 281a and b or 282 (10EJM3005); compound 281a exhibits best activity, obviously owing to its metabolic conversion to ADT. The bioavailability of ADT has been improved by administering the ADT–phospholipid complex (10MI4). Examples of relevant analytical methods include those of quantifying ADT by HPLC with electrochemical

SS

S

SS

S

SS

SHO

SS

SHO(CH2CH2O)n

SS

SCF3SO2O

SS

S

HOCOOH

NN

NO2 NH2

Im-OSO2CF3

PhONa403b3

305

e

[Ti(cp)2OH]+

_

306a-c (o, m, p-NO2) 307a-c (o, m, p-NH2)(307c = 6b)

307c

1. NaNO2, HCl

2. salicylic acid, KOH 308

Scheme 69

Gunther�Fischer76

detection (99MI2) and of determining metabolite ADTOH (98) in human plasma by HPLC-tandem mass spectrometry (11JPB(54)551).

The pharmacology of oltipraz (20) has repeatedly been reviewed (e.g. 92MI1, 93MI2, 98MI1). It was found in laboratory and clinical tests to be an inhibitor of many kinds of cancer, a radioprotector, a chemoprotective agent (93MI1), and (as well as its metabolite 215) an inhibitor of HIV-1 replication (95MI3, 96BBR(221)548). A reduction metabolism pathway was discussed (92APF183). The maximum tolerated dose was estimated to be about 125 mg/day (95MI2). In toxicity studies, the no-effect dose was considered to be 5 or 10 mg/kg/day (97MI1).

SS

SHOOC

SS

SMe3SiOOC

COOMe

OHHO

SS

SNHCO

SS

SCCl3CH2OOC

SS

SPhNHCO(CH2)6CONHOOC

PhNHCO(CH2)6CONHOH

Me3SiClDBU

TsOH

CCl3CH2OH

L-DOPA methyl ester HClHOBt, EDAC, Et3N

3d

AcOH H2SO4100 °C

25 °C

.

HOBt, EDAC

310a

310b

311

312

309

Scheme 70

SS

S

N

N

SS

S

N

N

Cl MeOMeOH, K2CO3

65 °C

413313

Scheme 71


In more recent years, the investigation on the metabolism of oltipraz (cf. 98MI1) has been continued and possible mechanisms of the interaction with thiols have been discussed because induction of phase 2 enzymes (such as glutathione S-transferase) seems to be a condition for chemoprevention (99CRT113, 00MI1). The kinetics of the thiolysis with thiols (GSH, that is, reduced glutathione) and dithiols were studied (01CRT939, 02DIS5741). Metabolic reactions convert oltipraz to a small amount of dithiolone 315 (Scheme 72) but preferentially to dimethyl product 215 (Scheme 50), which arises from the biological methylation of dimercapto compound 214 (cf. 02JOC9406).

The pharmacological role of these metabolites and numerous deriva-tives, especially disulfide 216 and oxidized species, has extensively been dis-cussed (07MI1, 10MI1, 10MI2). Whereas metabolites 215 and 315 protect cells from chemical-induced carcinogenesis, sulfines 316a and b do not (09DMD1187).

Oltipraz, when reacting with thiols, produces reactive oxygen spe-cies (peroxide radical anion and hydrogen peroxide) that are messengers in phase 2 enzyme induction (09CRT1427). (So does DTT parent sub-stance 1 (08MI2).) On the other hand, oltipraz may directly inactivate pro-tein tyrosine phosphatase by covalent modification of active site residues (10BMC5945).

Numerous studies deal with the quantitative determination of olti-praz, for instance, by liquid chromatography-tandem mass spectrometry (11JPB(56)623).

5.1.2. Novel DrugsGreat effort has been made to identify DTTs with better chemopre-ventive properties and less side effects than ADT and oltipraz have, for instance, in the inhibition of hepatic toxicity and cancer (98CAG1609,

SS

O

N

N

NN

SOMe

R

315 316a, b (R = SMe, SOMe)

Scheme 72

Gunther�Fischer78

03CAG1919), of hepatic insulin resistance (07MI2) or of other diseases (08MI1, 09MPH(75)242). Among other substances, cyclopenteno DTT (12) is a promising cancer preventing agent (09MI1). This finding has been supported by the modeling of biochemical properties by QSAR studies (05BML1249, 06MI1, 10JME4761).

Further examples of specific substances are those of 5-tert-butyl deriv-ative 7c (09CAG480), antifungal thioethers 59b and 61b (04FA245), zinc-chelating and histone-deacetylase inhibiting ADT derivatives 280c (10BMC4187) and 302 (08BML1893), ADT prodrug 288 (10CCL1427, 10MI3) as well as esters of glycyrrhetinic acid and 283b-type hydroxy ethers (11MIP1).

Other compounds have been developed aiming to find nonsteroidal anti-inflammatory drugs (NSAIDs), acting by inhibition of the cyclooxygenase enzymes, for instance, diaryl derivative 11b (09BMC558). Moreover, it has been suggested that the cardioprotective activity of ADTOH and its hybrids may be due to the release of hydrogen sulfide (cf. 10BMC4187). Thus, derivative 293b of aspirin (the most widely used NSAID) maintained the desired activity of its parent substance but seemed to be stomach-sparing (09MI3). Its in vivo metabolism, however, shows rapid deacety-lation (within 10 min) to form intermediate 293a and slower subsequent deesterification to give precursor ADTOH (98), in this way, unfortunately releasing salicylic acid rather than aspirin. Certain linking groups between aspirin and ADTOH moieties serve to change the situation; derivatives 285a and b are rapidly metabolized producing nonhydrolyzed aspirin (11JMC5478).

A number of other ADT analogs were tested as hydrogen sulfide releas-ing agents, for example, ether-type l-DOPA derivative ACS 84 (287) (10JBC17318) and ester-type compounds ATB 429 (294) (06JEP(319)447), S-diclofenac and S-sulindac (298 and 300, respectively) (07EPJ(569)149, 09CLC1964), ACS 67 (303) (09BML1639), ATB 345 (naproxen derivative 317a, Scheme 73) (10BJP(159)1236), corresponding ibuprofen derivative 317b (12MI2), ACS 6 (sildenafil derivative 318a) (11MI1), and oleano-lic acid derivatives (12MIP5). Further examples are those of amide-type l-DOPA derivative 311 (10JBC17318) and 318b-type hydrogen sulfide gas-eous signal molecule donors (12MIP4). NSAIDs 293b, 300, and 317a and b were found to inhibit the growth of human cancer cells (12MI2). Other ADTOH ester-type compounds (e.g. 318c) have been claimed to be effec-tive in treating male infertility diseases (12MIP1, 12MIP2, 12MIP3).


The release of hydrogen sulfide by hydrolysis of DTTs was investigated with product 110 (see Section 4.2.2, Scheme 26); for therapeutic applica-tions, the release should be at a slow but steady state (10AJC946).

In addition, it has been suggested to use nitric oxide-releasing aspirin derivatives having lower gastric toxicity than the parent aspirin (09MI3, 11JMC5478). In this context, the latest achievement is that of developing so-called NOSH aspirins, that is derivatives releasing both nitric oxide and hydrogen sulfide, for instance, nitrate 296 (12MI1).

SS

S

CHMe-COO

iBu

SS

SS S

SS

S

CH2-CHOH-COO

HO

HO

SS

S

CHMe-COO

MeO

SS

S

NN

CH2COO

SO2

NH

N

NN

Me

Pr

O

EtO

SS

S

COO

MeSO2

OMe

317a

318a

317b

318b

913c813

S

Scheme 73

Gunther�Fischer80

5.2. Photographic UsesDTTs had been used to sensitize photographic silver halide emulsions dur-ing digestion, for instance, alkyl and amino derivatives (67DDP54187), benzo DTT (2) (97JPA09138478), and 4-phenyl DTT (3a) (68UP1); by contrast, 5-phenyl DTT (7b) does not exhibit the properties mentioned above. Stabilizing activity has also been claimed (04MI1).

To explain the photographic activity of most DTTs, adsorptive, hydro-lytic, and aminolytic processes may be discussed; the acceleration of the hydrolysis in the presence of gelatin supports an aminolytic mechanism (76TH2).

5.3. Technical UsesAlkyl DTTs (07WOA147857) or DTT bis-thioethers (e.g. 232) (09MIP2) are chain-transfer agents in the controlled free-radical poly-merization. DTTs (e.g. 2 and 7b) and other thiocarbonyl compounds are used, because of good antioxidant properties, as polyethylene modifiers (99MI1).

Alkyl or aryl DTTs are contained in rubber compositions during vul-canization; they provide improved heat resistance (e.g. 3a, 7b, and 319) (94JPA06200082) or are easily degradable (e.g. 86) (01JPA139731).

4-Aryl DTTs (e.g. 3a) (06MI2) and polymeric DTT derivative 305 (95USP5456767) serve to inhibit corrosion on metal surfaces. Aiming at get-ting new sulfur compounds as passivants for gold nanoparticles, just recently, the degree of surface functionalization of such particles with 5-alkylthio DTTs (58b and higher homologs) was analyzed (12JPC(C)6520).

MeO

PS

PS

S S

OMe

N=C=N-CH2CH2N

Me +TsO

_ N NMe Me

O123023

322

Scheme 74


LIST OF ABBREVIATIONS

ADT anethole dithiolethione (22)ADTOH desmethyl anethole dithiolethione (98)Alk alkylAr arylCMCD 1-cyclohexyl-3(2-morpholinoethyl)carbodiimide, methotosylate (320, Scheme 74)cp cyclopentadiene (ligand)DABCO 1,4-diazabicyclo[2,2,2]octaneDBU 1,5-diazabicyclo[5,4,0]undec-5-eneDCC dicyclohexylcarbodiimidedil. dilutionDMAD dimethyl acetylenedicarboxylateDMAP 4-dimethylaminopyridinedmit 4,5-dimercapto-1,3-dithiole-2-thione (dimercaptoisotrithione)DMPU N,N′-dimethyltrimethyleneurea (321)dmt 4,5-dimercapto-1,2-dithiole-3-thione (dimercaptotrithione, 75c)DOPA 3,4-dihydroxyphenylalanineDTT 1,2-dithiole-3-thioneEDAC 1-ethyl-3(3-dimethylaminopropyl)carbodiimide, hydrochlorideEI electron impactequ equivalent(s)h hour(s)Het heterocyclylHMDO hexamethyldisiloxaneHOBt 1-hydroxybenzotriazoleIm imidazole-1-ylLR Lawesson reagent (322)MCPBA m-chloroperoxybenzoic acidNADPH dihydronicotinamide adenine dinucleotide phosphateNCS N-chlorosuccinimideNSAID non-steroidal anti-inflammatory drugp pagePAS p-aminosalicylic acidPhthN phthalimidoPPTS pyridinium tosylatepy pyridineQSAR quantitative structure-activity relationshiprfl. refluxTCNQ 7,7,8,8-tetracyano-p-quinodimethaneTHP tetrahydropyran-2-yltol p-tolylTs p-toluenesulfonyl

Gunther�Fischer82

REFERENCES 63UP1 G. Fischer, unpublished results (1963). 65CRV237 P. Landis, Chem. Rev., 65, 237 (1965). 67DDP54187 L. Bülling, J. Faust, M. Fischer, S. Gahler, J. Jentzsch, and R. Mayer, DDR

Pat. 54,187 (1967) [CA 67 77879(1967)]. 68UP1 G. Fischer, unpublished results (1968–1976). 76TH1 S. Giese, Thesis Technische Universität Dresden (1976). 76TH2 S. Pörschmann, Diploma Thesis Universität Leipzig (1976). 77DDP124044 S. Hoyer, G. Steimecke, Ch. Schröter, G. Fischer, and W. Walther, DDR

Pat. 124,044 (1977) [CA 88 50836(1978)]. 82AHC(31)63 C.Th. Pedersen, Adv. Heterocycl. Chem., 31, 63 (1982). 84CHEC(6)783 D.M. McKinnon, Comp. Heterocycl. Chem., 6, 783 (1984). 89SR(9)153 N. Lozac’h, Sulfur Rep., 9, 153 (1989). 90TRH9 W.O. Foye and K. Ghosh, Trends Heterocycl. Chem., 1, 9 (1990). 91J(P2)1763 Th. Martens and M. Fleury, J. Chem. Soc., Perkin Trans. 2, 1763 (1991). 92APF183 M.B. Fleury, Ann. Pharm. Francaises, 50, 183 (1992). 92CCR(117)99 R. Olk, B. Olk, W. Dietzsch, R. Kirmse, and E. Hoyer, Coord. Chem. Rev.,

117, 99 (1992). 92CPC1667 M. Arbelot and M. Chanon, J. Chim. Phys. Physicochim. Biol., 89, 1667

(1992). 92JOU1995 L.P. Turchaninova, E.N. Sukhomazova, E.P. Levanova, N.A. Korchevin,

E.N. Deryagina, and M.G. Voronkov, J. Org. Chem. USSR (Engl. Transl.), 28, 1995 (1992).

92JPA04117377 I. Yamamoto, A. Matsubara, K. Sakasai, O. Mizuno, H. Tanada, and M. Kumakura, Jpn. Pat. Appl. 04,117,377 (1992) [CA 117 171424(1992)].

92MI1 Th. Kensler, P. Styczynski, J. Groopman, K. Helzlsouer, Th. Curphey, Y. Maxultenko, and B.D. Roebuck, J. Cell. Biochem., Suppl., 16I, 167 (1992).

92T8143 M.R. Bryce, G.R. Davison, A.J. Moore, M.B. Hursthouse, and K.M. Abdul Malik, Tetrahedron, 48, 8143 (1992).

93BCJ623 K.S. Choi, I. Akiyama, M. Hoshino, and J. Nakayama, Bull. Chem. Soc. Jpn., 66, 623 (1993).

93IC5467 D.D. Doxsee, C.P. Galloway, Th. B. Rauchfuss, S.R. Wilson, and X. Yang, Inorg. Chem., 32, 5467 (1993).

93JHC545 C. Vaccher, P. Berthelot, and M. Debaert, J. Heterocycl. Chem., 30, 545 (1993). 93JPA05301868 K. Sakasai, Sh. Mita, N. Oodo, K. Kawai, M. Mori, and K. Watanabe, Jpn.

Pat. Appl. 05,301,868 (1993) [CA 120 217648(1994)]. 93JRM1671 Th. Martens and F. Souquet, J. Chem. Res. (M), 1671 (1993). 93MI1 A.B. Benson, J. Cell. Biochem., Suppl., 17F, 278 (1993). 93MI2 K.J. Helzlsouer and Th. W. Kensler, Prev. Med., 22, 783 (1993). 93POL2849 J.D. Singh and H.B. Singh, Polyhedron, 12, 2849 (1993). 93PS(84)191 S.E. Zayed and I.A. Hussin, Phosphorus Sulfur Silicon, 84, 191 (1993). 93PS(84)223 H. Matschiner, C. Maschmeier, N. Maier, and J. Hansen, Phosphorus

Sulfur Silicon, 84, 223 (1993). 93TCA175 A. Botrel, B. Illien, P. Rajczy, I. Ledoux, and J. Zyss, Theor. Chim. Acta, 87,

175 (1993). 93TL7231 Th. J. Curphey and H.H. Joyner, Tetrahedron Lett., 34, 7231 (1993). 94AP813 X. Popp and K. Hartke, Arch. Pharm. (Weinheim, Ger.), 327, 813 (1994). 94CAG177 P.A. Egner, Th.W. Kensler, T. Prestera, P. Talalay, A.H. Libby, H.H. Joyner,

and Th. J. Curphey, Carcinogenesis, 15, 177 (1994). 94CHE(30)783 V.N. Drozd, I.V. Magedov, D.S. Yufit, and Yu. T. Struchkov, Chem. Hetero-

cycl. Compd. (Engl. Transl.), 30, 783 (1994).


94JPA06200082 K. Hatayama, Jpn. Pat. Appl. 06,200,082 (1994) [CA 122 163249(1995)]. 94OMS321 R. Andreu, I. Gayán, J. Garín, J. Orduna, and M. Savirón, Org. Mass

Spectrom., 29, 321 (1994). 94PS(88)195 M. Abazid, H.O. Bertrand, M. Christen, and J. Burgot, Phosphorus Sulfur

Silicon, 88, 195 (1994). 94PS(95)485 C.Th. Pedersen and C.O. Kappe, Phosphorus Sulfur Silicon, 95–96, 485

(1994). 94RCM455 R. Andreu, I. Gayán, J. Garín, J. Orduna, and M. Savirón, Rapid Commun.

Mass Spectrom., 8, 455 (1994). 94SUL(17)177 A. Spannenberg, D. Abeln, J. Kopf, A. Knöchel, and H. Holdt, Sulfur Lett.,

17, 177 (1994). 94SUL(17)231 H.O. Bertrand, M. Abazid, M. Christen, and J. Burgot, Sulfur Lett., 17,

231 (1994). 95ABB(324)143 S.J. Chavan, W.G. Bornmann, Ch. Flexner, and H.J. Prochaska, Arch.

Biochem. Biophys., 324, 143 (1995). 95BSF624 G. Charbonnel-Jobic, J. Guémas, B. Adelaere, J. Parrain, and J. Quintard,

Bull. Soc. Chim. Fr., 132, 624 (1995). 95BSF975 P. Frère, A. Belyasmine, Y. Gouriou, M. Jubault, A. Gorgues, G. Duguay,

S. Wood, C.D. Reynolds, and M.R. Bryce, Bull. Soc. Chim. Fr., 132, 975 (1995).

95EPA641792 N. Mita, T. Ando, A. Kanematsu, K. Sakai, M. Mori, T. Sugawara, Sh. Yuasa, and K. Kawai, Eur. Pat. Appl. 641,792 (1995) [CA 123 83394(1995)].

95JCM312 J.D. Singh, H.B. Singh, K. Das, and U.C. Sinha, J. Chem. Res. (S), 312 (1995).

95JOC2330 M. Arbelot, A. Allouche, K.F. Purcell, and M. Chanon, J. Org. Chem., 60, 2330 (1995).

95JPA07118262 Sh. Mita, T. Ando, A. Kanematsu, K. Sakasai, M. Mori, T. Sugawara, Sh. Yuasa, and K. Kawai, Jpn. Pat. Appl. 07,118,262 (1995) [CA 123 313969(1995)].

95JPC16849 M.W. Wong, C. Wentrup, and R. Flammang, J. Phys. Chem., 99, 16849 (1995).

95JPS1107 M. Bona, P. Boudeville, O. Zekri, M.O. Christen, and J.L. Burgot, J. Pharm. Sci., 84, 1107 (1995).

95MI1 R.P. Vorob’eva, T.A. Oleinikova, Zh.V. Shmyreva, and L.F. Ponomareva, J. Appl. Spectrosc., 62, 497 (1995).

95MI2 Th. W. Kensler and K.J. Helzlsouer, J. Cell. Biochem. Suppl., 22, 11 (1995). 95MI3 H.J. Prochaska, S.J. Chavan, P. Baron, and B. Polsky, J. Cell. Biochem.

Suppl., 22, 117 (1995). 95MI4 M. Christen, Methods Enzymol., 252, 316 (1995). 95SR(16)173 C.Th. Pedersen, Sulfur Rep., 16, 173 (1995). 95SUL(19)119 S. Schmidt, F. Dietze, A. Jokuszies, S. Zeltner, R. Olk, J. Reinhold, and

E. Hoyer, Sulfur Lett., 19, 119 (1995). 95SUL(19)141 X. Popp and K. Hartke, Sulfur Lett., 19, 141 (1995). 95USP5456767 S.S. Shah, Th.G. Braga, A.B.A. Oude, and J. Mathew, US Pat. 5,456,767

(1995) [CA 124 63741(1996)]. 96BBR(221)548 H.J. Prochaska, Ch. L. Fernandes, R.M. Pantoja, and S.J. Chavan,

Biochem. Biophys. Res. Commun., 221, 548 (1996). 96CHEC2(3)569 D.M. McKinnon, Comp. Heterocycl. Chem., second ed. 3, 569 (1996). 96CL191 Sh. Nozawa, T. Sugiyama, M. Kajitani, T. Akiyama, and A. Sugimori,

Chem. Lett., 191 (1996). 96EJM919 P. Borgna, M.L. Carmellino, M. Natangelo, G. Pagani, F. Pastoni,

M. Pregnolato, and M. Terreni, Eur. J. Med. Chem., 31, 919 (1996).

Gunther�Fischer84

96IC793 A.E. Pullen, J. Piotraschke, Kh. A. Abboud, and J.R. Reynolds, Inorg. Chem., 35, 793 (1996).

96IJP(129)295 G. Burgot, M. Bona, M. Christen, and J. Burgot, Int. J. Pharm., 129, 295 (1996).

96JPS990 Ph. Boudeville, M. Bona, and J. Burgot, J. Pharm. Sci., 85, 990 (1996). 96PS(108)7 S.E. Zayed, Phosphorus Sulfur Silicon, 108, 7 (1996). 96RCM1519 R. Flammang and C.Th. Pedersen, Rapid Commun. Mass Spectrom., 10,

1519 (1996). 96SUL(19)235 A. Corsaro, U. Chiacchio, G. Gumina, and V. Pistarà, Sulfur Lett., 19, 235

(1996). 96TL2137 M.L. Aimar and R.H. Rossi, Tetrahedron Lett., 37, 2137 (1996). 96TL4805 C.Th. Pedersen, Tetrahedron Lett., 37, 4805 (1996). 96TL8861 P. Leriche, A. Belyasmine, M. Sallé, P. Frère, A. Gorgues, A. Riou, M.

Jubault, J. Orduna, and J. Garín, Tetrahedron Lett., 37, 8861 (1996). 96ZNB901 T. Knieß and R. Mayer, Z. Naturforsch., B, 51, 901 (1996). 97AXC1125 R. Baggio, D. Vega, M.L. Aimar, R.H. de Rossi, and J. Ellena, Acta Crys-

tallogr., Sect. C, 53, 1125 (1997). 97JPA09138478 M. Kubodera, T. Ikeda, and Sh. Tanaka, Jpn. Pat. Appl. 09,138,478 (1997)

[CA 127 57960 (1997)]. 97MI1 J.A. Crowell, J.G. Page, L.E. Rodman, J.E. Heath, E.I. Goldenthal, L.B.

Hall, and G.J. Kelloff, Fundam. Appl. Toxicol., 35, 9 (1997). 97SUL(20)179 C.Th. Pedersen, Sulfur Lett., 20, 179 (1997). 98AXC1902 R. Baggio, L.L. Aimar, R.H. de Rossi, and L. Suescun, Acta Crystallogr.,

Sect. C, 54, 1902 (1998). 98CAG1609 Yu. Y. Maxuitenko, A.H. Libby, H.H. Joyner, Th. J. Curphey, D.L.

MacMillan, Th. W. Kensler, and B.D. Roebuck, Carcinogenesis, 19, 1609 (1998).

98CC389 A. Abbott, M.N. Bancroft, M.J. Morris, C. Hogarth, and S.P. Redmond, Chem. Commun., 389 (1998).

98CC1653 S. Rudershausen, H. Holdt, H. Reinke, H. Drexler, M. Michalik, and J. Teller, Chem. Commun., 1653 (1998).

98EAC201 M. Chollet, J. Burgot, and C. Moinet, Electrochim. Acta, 44, 201 (1998). 98HCA1207 T. Nishio, Helv. Chim. Acta, 81, 1207 (1998). 98JOC2189 Ch. W. Rees, A.J.P. White, D.J. Williams, O.A. Rakitin, C.F. Marcos,

C. Polo, and T. Torroba, J. Org. Chem., 63, 2189 (1998). 98J(P2)387 M. Chollet and J. Burgot, J. Chem. Soc., Perkin Trans. 2, 387 (1998). 98J(P2)2227 M. Chollet, B. Legouin, and J. Burgot, J. Chem. Soc., Perkin Trans. 2, 2227

(1998). 98JPR450 S. Rudershausen, H. Drexler, and H. Holdt, J. Prakt. Chem. Chem. Ztg.,

340, 450 (1998). 98MI1 M.L. Clapper, Pharmacol. Ther., 78, 17 (1998). 98SUL(21)139 C.Th. Pedersen, R.H. de Rossi, and M.L. Aimar, Sulfur Lett., 21, 139

(1998). 98VSP(16)77 J. Fabian and K. Herzog, Vib. Spectrosc., 16, 77 (1998). 99CRT113 Th. W. Kensler, J.D. Groopman, Th. R. Sutter, Th. J. Curphey, and B.D.

Roebuck, Chem. Res. Toxicol., 12, 113 (1999). 99JHC823 M.R. Bryce, A.K. Lay, A.S. Batsanov, and J.A.K. Howard, J. Heterocycl.

Chem., 36, 823 (1999). 99JOC4376 Ch. W. Rees, O.A. Rakitin, C.F. Marcos, and T. Torroba, J. Org. Chem., 64,

4376 (1999). 99JOC6937 D.D. Mysyk, I.F. Perepichka, D.F. Perepichka, M.R. Bryce, A.F. Popov,

L.M. Goldenberg, and A.J. Moore, J. Org. Chem., 64, 6937 (1999).


99JPS889 G. Dollo, P. Le Corre, M. Chollet, F. Chevanne, M. Bertault, J. Burgot, and R. Le Verge, J. Pharm. Sci., 88, 889 (1999).

99MI1 V.A. Struk, D.A. Oparin, and A.V. Medved, Dokl. Nats. Akad. Nauk Bela-rusi, 43(3), 119 (1999).

99MI2 K. Traber and L. Packer, Methods Enzymol., 299, 300 (1999). 99PCA6930 J.G. Breitzer, D.D. Dlott, L.K. Iwaki, S.M. Kirkpatrick, and Th. B. Rauch-

fuss, J. Phys. Chem. A, 103, 6930 (1999). 00ABB(382)189 B. Levron, G. Burgot, and J. Burgot, Arch. Biochem. Biophys., 382, 189

(2000). 00HAC120 A. González-Castro, R. Gutiérrez-Pérez, G. Penieres-Carrillo, E. Díaz-

Torres, R.A. Toscano, M. Moya-Cabrera, A. Cabrera-Ortiz, and C. Alvarez-Toledano, Heteroatom Chem., 11, 120 (2000).

00JOC3690 B.S. Kim and K. Kim, J. Org. Chem., 65, 3690 (2000). 00MI1 Th. W. Kensler, Th. J. Curphey, Yu. Maxiutenko, and B.D. Roebuck, Drug

Metab. Drug Interact., 17, 3 (2000). 00MI2 A.P. Brown, R.L. Morrissey, Th. A. Tolhurst, J.A. Crowell, and B.S.

Levine, Int. J. Toxicol., 19, 375 (2000). 00PS(165)1 M.A. Barsy, F.M. Abd El Latif, S.M. Ahmed, and M.A. El-Maghraby,

Phosphorus Sulfur Silicon Relat. Elem., 165, 1 (2000). 00PS(166)27 M. Chollet-Krugler, A. Botrel, J.J. Charbit, J. Barbe, and J. Burgot,

Phosphorus Sulfur Silicon Relat. Elem., 166, 27 (2000). 00S1749 M.L. Aimar and R.H. de Rossi, Synthesis, 1749 (2000). 00SUL(23)169 S.L. Tardif and D.N. Harpp, Sulfur Lett., 23, 169 (2000). 00TL6977 Th. J. Curphey and A.H. Libby, Tetrahedron Lett., 41, 6977 (2000). 01CRT939 K.A. Carey, Th. W. Kensler, and J.C. Fishbein, Chem. Res. Toxicol., 14, 939

(2001). 01J(P1)2409 S.A. Amelichev, S. Barriga, L.S. Konstantinova, T.B. Markova, O.A.

Rakitin, Ch. W. Rees, and T. Torroba, J. Chem. Soc., Perkin Trans. 1, 2409 (2001).

01JPA139731 M. Akiba, Jpn. Pat. Appl. 2001,139,731 [CA 134 368153 (2001)]. 01MC165 L.S. Konstantinova, O.A. Rakitin, and Ch. W. Rees, Mendeleev Commun.,

11, 165 (2001). 01WOA9118 P.T. Prendergast and P. Armstrong, World Pat. Appl. 2001,009,118 [CA

134 157573 (2001)]. 02DIS5741 H. Zang, Diss. Abstr. B, 62, 5741 (2002). 02EAC107 J. Burgot, A. Darchen, and M. Saïdi, Electrochim. Acta, 48, 107 (2002). 02JEC(537)145 M. Abasq, J. Burgot, A. Darchen, and S. Dervout, J. Electroanal. Chem.,

537, 145 (2002a). 02JOC6461 Th. J. Curphey, J. Org. Chem., 67, 6461 (2002). 02JOC9406 M. Navamal, C. McGrath, J. Stewart, P. Blans, F. Villamena, J. Zweier, and

J.C. Fishbein, J. Org. Chem., 67, 9406 (2002). 02MI1 M. Abasq, J. Burgot, M. Christen, A. Darchen, and S. Dervout, Proc. Bienn.

Meet. Soc. Free Radical Res. Int., 11, 575 (2002). [CA 140 417858(2004)]. 02MI2 M. Christen, B. La Roche, and J. Maugard, Proc. Bienn. Meet. Soc. Free

Radical Res. Int., 11, 643 (2002). [CA 141 46556(2004)]. 02SOS(11)107 C.Th. Pedersen, Sci. Synth., 11, 107 (2002). 02TL1947 M.L. Aimar, J. Kreiker, and R.H. de Rossi, Tetrahedron Lett., 43, 1947

(2002). 02TL5809 V.M. Timoshenko, J. Bouillon, Yu. G. Shermolovich, and Ch. Portella,

Tetrahedron Lett., 43, 5809 (2002). 02TL8037 A.M. Granados, J. Kreiker, and R.H. de Rossi, Tetrahedron Lett., 43, 8037

(2002).

Gunther�Fischer86

03CAG1919 B.D. Roebuck, Th. J. Curphey, Y. Li, K.J. Baumgartner, S. Bodreddigari, J. Yan, S.J. Gange, Th. W. Kensler, and Th. R. Sutter, Carcinogenesis, 24, 1919 (2003).

03CCC1243 R. Čmelík, M. Čajan, J. Marek, and P. Pazdera, Collect. Czech. Chem. Commun., 68, 1243 (2003).

03EJO2471 V.M. Timoshenko, J. Bouillon, A.N. Chernega, Yu. I. Shermolovich, and Ch. Portella, Eur. J. Org. Chem., 2471 (2003).

03FA995 R. Salvetti, G. Martinetti, D. Ubiali, M. Pregnolato, and G. Pagani, Farmaco, 58, 995 (2003).

03IJA2344 Kochurani, K. Kandesamy, H.B. Singh, and B. Varghese, Indian J. Chem., Sect. A, 42, 2344 (2003).

03JHC155 M. Chollet-Krugler, E. Finner, M. Christen, and J. Burgot, J. Heterocycl. Chem., 40, 155 (2003).

03MC50 V.A. Ogurtsov, O.A. Rakitin, Ch. W. Rees, and A.A. Smolentsev, Men-deleev Commun., 13, 50 (2003).

03MI1 D. Wang, J. Dou, M. Niu, D. Li, and Y. Liu, Huaxue Xuebao, 61, 551 (2003). [CA 139 190047(2003)].

03MI2 C.Th. Pedersen, Pr. Nauk.-Wyzsza Szk. Pedagog. Czestochova, Chem., 7, 7 (2003). [CA 142 155275(2005)].

03OL929 M. García-Valverde, R. Pascual, and T. Torroba, Org. Lett., 5, 929 (2003). 03PIC(52)1 Th. B. Rauchfuss, Prog. Inorg. Chem., 52, 1 (2003). 03PS(178)1721 S. Gargadennec, B. Legouin, and J. Burgot, Phosphorus Sulfur Silicon Relat.

Elem., 178, 1721 (2003). 03PS(178)2255 M.A. Barsy, Phosphorus Sulfur Silicon Relat. Elem., 178, 2255 (2003). 03RJO752 N.A. Korchevin, E.N. Sukhomazova, and E.N. Deryagina, Russ. J. Org.

Chem. (Engl. Transl.), 39, 752 (2003). 03SUL(26)195 M. Chollet-Krugler and J. Burgot, Sulfur Lett., 26, 195 (2003). 04BKC1692 J. Drabowicz, J. Łuczak, P. Łyżwa, M. Mikołajczyk, and C.Th. Pedersen,

Bull. Korean Chem. Soc., 25, 1692 (2004). 04CL1482 I. Takemura, T. Iwasaki, Sh. Takeoka, and H. Nishide, Chem. Lett., 33,

1482 (2004). 04CRV5151 A. Gorgues, P. Hudhomme, and M. Sallé, Chem. Rev., 104, 5151 (2004). 04EJS737 V.V. Takhistov, L.O. Khoroshko, I.V. Viktorovskii, M. Lahtipera, and J.

Paasivirta, Eur. J. Mass Spectrom., 10, 737 (2004). 04FA245 F.A. Giannini, M.L. Aimar, M. Sortino, R. Gomez, A. Sturniollo, A.

Juarez, S. Zacchino, R.H. de Rossi, and R.D. Enriz, Farmaco, 59, 245 (2004).

04HCO217 W.M. Abdou, M.D. Khidre, and A.A. Kamel, Heterocycl. Commun., 10, 217 (2004).

04JOM1325 P. Mathur, V.D. Avasare, A.K. Ghosh, and Sh. M. Mobin, J. Organomet. Chem., 689, 1325 (2004).

04MI1 G. Fischer, Stabilizers for Photographic Silver Halide Emulsions, Kluwer Academic/Plenum Publishers, New York (2004). pp. 27 and 270.

04RJC1754 N.A. Korchevin, N.V. Russavskaya, G.A. Yakimova, and E.N. Deryagina, Russ. J. Gen. Chem. (Engl. Transl.), 74, 1754 (2004).

04THE(424)143 M. Chollet-Krugler, B. Legouin, S. Gargadennec, G. Burgot, and J. Burgot, Thermochim. Acta, 424, 143 (2004).

04TL7671 H. Adams, L. Chung, M.J. Morris, and P.J. Wright, Tetrahedron Lett., 45, 7671 (2004).

04WOA48369 J. Kim, K. Choi, J. Lim, K. Lee, and S. Lee, World Pat. Appl. 2004,048,369 [CA 141 38632 (2004)].

05BML1249 P. Khadikar, M. Jaiswal, M. Gupta, Dh. Mandloi, and R.S. Sisodia, Bioorg. Med. Chem. Lett., 15, 124 (2005).


05EAC2219 M. Abasq, J. Burgot, A. Darchen, and M. Saidi, Electrochim. Acta, 50, 2219 (2005).

05JHC103 M.D. Khidre, A.A. Kamel, and W.M. Abdou, J. Heterocycl. Chem., 42, 103 (2005).

05MC20 V.A. Ogurtsov, O.A. Rakitin, Ch. W. Rees, A.A. Smolentsev, and K.A. Lyssenko, Mendeleev Commun., 15, 20 (2005).

05MC55 V.A. Ogurtsov, O.A. Rakitin, Ch. W. Rees, and A.A. Smolentsev, Mendeleev Commun., 15, 55 (2005).

05MI1 S. Gargadennec, G. Burgot, J. Burgot, R. Mannhold, and R.F. Rekker, Pharm. Res., 22, 875 (2005).

05NJC465 J. Beck, J. Weber, A.B. Mukhopadhyay, and M. Dolg, New J. Chem., 29, 465 (2005).

05OL791 V.A. Ogurtsov, O.A. Rakitin, Ch. W. Rees, A.A. Smolentsev, P.A. Belyakov, D.G. Golovanov, and K.A. Lyssenko, Org. Lett., 7, 791 (2005).

05POL2944 H.H. Alkam, Kh. M. Kanan, and Ch. C. Hadjikostas, Polyhedron, 24, 2944 (2005).

05PS(180)1419 M. Abasq, J. Burgot, A. Darchen, E. Furet, and M. Saïdi, Phosphorus Sulfur Silicon Relat. Elem., 180, 1419 (2005).

05WOA51941 I. Cho et al., World Pat. Appl. 2005,051,941 [CA 143 43881 (2005)]. 06CCC650 R. Čmelík and P. Pazdera, Collect. Czech. Chem. Commun., 71, 650 (2006). 06H(68)2243 T. Shigetomi, A. Nojima, K. Shioji, K. Okuma, and Y. Yokomori, Hetero-

cycles, 68, 2243 (2006). 06HCA991 T. Drewnowski, S. Leśniak, A. Chrostowska, A. Dargelos, and S. Khayar,

Helv. Chim. Acta, 89, 991 (2006). 06JCD1174 J. Beck, J. Daniels, A. Roloff, and N. Wagner, J. Chem. Soc., Dalton Trans.,

1174 (2006). 06JEP(319)447 E. Distrutti, et al., J. Pharmacol. Exp. Ther., 319, 447 (2006). 06JFC(127)774 I.N. Fesun, A.B. Rozhenko, and V.M. Timoshenko, J. Fluorine Chem.,

127, 774 (2006). 06JOC808 A.M. Granados, J. Kreiker, R.H. de Rossi, P. Fuertes, and T. Torroba,

J. Org. Chem., 71, 808 (2006). 06JPC(A)9145 D. Jacquemin, V. Wathelet, and E.A. Perpète, J. Phys. Chem. (A), 110, 9145

(2006). 06JPO823 A.M. Granados, A.M. Fracaroli, J. Kreiker, and R.H. de Rossi, J. Phys.

Org. Chem., 19, 823 (2006). 06LOC634 W.M. Abdou, M.D. Khidre, and A.A. Sediek, Lett. Org. Chem., 3, 634

(2006). 06MI1 R. Munday, Y. Zhang, Ch. M. Munday, and J. Li, Chem.-Biol. Interact.,

160, 115 (2006). 06MI2 C. Kadiri, S. Mokhtar, D. Benbertal, and K. Ameur, J. Saudi Chem. Soc.,

10, 549 (2006). 06MI3 I.N. Fesun, V.M. Timoshenko, D.V. Poltorak, A.N. Chemega, and Yu. G.

Shermolovich, Zh. Organ. Farmats. Khim. (Charkiv), 4(3), 50 (2006). [CA 147 9825(2007)].

06MI4 I.N. Fesun, V.M. Timoshenko, E.B. Rusanov, and Yu. G. Shermolov-ich, Zh. Organ. Farmats. Khim. (Charkiv), 4(4), 29 (2006). [CA 148 33673(2008)].

06PS(181)2307 M. Chollet-Krugler, B. Legouin, S. Gargadennec, L. Mouret, and J. Burgot, Phosphorus Sulfur Silicon Relat. Elem., 181, 2307 (2006).

06RCB147 L.S. Konstantinova, A.A. Berezin, K.A. Lysov, and O.A. Rakitin, Russ. Chem. Bull., 55, 147 (2006).

Gunther�Fischer88

06RJO124 I.N. Fesun, V.M. Timoshenko, A.N. Chernega, and Yu. G. Shermolovich, Russ. J. Org. Chem. (Engl. Transl.), 42, 124 (2006).

06RJO261 I.N. Fesun, V.M. Timoshenko, and Yu. G. Shermolovich, Russ. J. Org. Chem. (Engl. Transl.), 42, 261 (2006).

06WOA89861 B. Drukarch, A.N.M. Schoffelmeer, R.W. Feenstra, M. Christen, J. Burgot, M. Chollet, W.I. Iwema Bakker, B.J. van Vliet, and M.Th.M. Tulp, World Pat. Appl. 2006,089,861 [CA 145 293072 (2006)].

07ARK(is4)279 A.M. Fracaroli, J. Kreiker, R.H. de Rossi, and A.M. Granados, ARKIVOC, (4), 279 (2007).

07AXE4056 Q. Fang, A.S. Batsanov, and J.A.K. Howard, Acta Crystallogr., Sect. E, 63, o4056 (2007).

07BJP(151)142 J.S. Isenberg, et al., Br. J. Pharmacol., 151, 142 (2007). 07CYR84 S. Rudershausen, H. Drexler, W. Bansse, A. Kelling, U. Schilde, and H.

Holdt, Cryst. Res. Tech., 42, 84 (2007). 07EPJ(569)149 J. Sidhapuriwala, L. Li, A. Sparatore, M. Bhatia, and Ph. K. Moore, Eur. J.

Pharmacol., 569, 149 (2007). 07MI1 M. Velayutham, R.B. Muthukumaran, J.Z. Sostaric, J. McCraken, J.C.

Fishbein, and J.L. Zweier, Free Rad. Biol. Med., 43, 1076 (2007). 07MI2 E.J. Bae, Y.M. Yang, J.W. Kim, and S.G. Kim, Hepatology, 46, 730 (2007). 07PS(182)2205 S.E. Zayed, M.E. Hassan, and R. Ragab, Phosphorus Sulfur Silicon Relat.

Elem., 182, 2205 (2007). 07USA197479 J.L. Wallace, G. Cirino, G. Caliendo, A. Sparatore, V. Santagada, and S.

Fiorucci, USA Pat. Appl. 2007,197,479 [CA 147 300859 (2007)]. 07WOA147857 Sz. Csihony, A. Lange, Y. Dieckmann, and M. Haag, World Pat. Appl.

2007,147,857 [CA 148 79489 (2008)]. 08AHC(96)175 O.A. Rakitin and L.S. Konstantinova, Adv. Heterocycl. Chem., 96, 175

(2008). 08BML1893 E. Perrino, G. Cappelletti, V. Tazzari, E. Giavini, P. del Soldato, and A.

Sparatore, Bioorg. Med. Chem. Lett., 18, 1893 (2008). 08CC483 A.M. Granados, A.M. Fracaroli, R.H. de Rossi, P. Fuertes, and T. Torroba,

Chem. Commun., 483 (2008). 08CHEC3(4)893 R. Marković and A. Rašovic, Comp. Heterocycl. Chem., third ed.,4, 893

(2008). 08JOM763 J. Bordinhão, N.M. Comerlato, L. de Castro Cortás, G.B. Ferreira, R.A.

Howie, and J.L. Wardell, J. Organomet. Chem., 693, 763 (2008). 08JPO1007 A.M. Fracaroli, O.F. Silva, A.M. Granados, and R.H. de Rossi, J. Phys.

Org. Chem., 21, 1007 (2008). 08JST(888)354 Y. Cao, H. Zhang, Y. Lin, Ch. Huang, Y. Chen, F. Zhang, and J. Chen, J.

Mol. Struct., 888, 354 (2008). 08MI1 Y. Zhang and R. Munday, Mol. Cancer Ther., 7, 3470 (2008). 08MI2 Zh. Jia, H. Zhu, M.A. Trush, H.P. Misra, and Y. Li, Mol. Cell Biochem.,

307, 185 (2008). 08RCB1790 V.A. Ogurtsov, Yu. V. Karpychev, and O.A. Rakitin, Russ. Chem. Bull., 57,

1790 (2008). 09AXE1080 El A. Laifa, L. Bendjeddou, N. Boudraa, S. Dahaoui, and C. Lecomte,

Acta Crystallogr., Sect. E, 65, m1080 (2009). 09AXE1592 N.M. Comerlato, E.R.T. Tiekink, J.L. Wardell, and S.M.S.V. Wardell,

Acta Crystallogr., Sect. E, 65, m1592 (2009). 09BMC558 M. Scholz, H.K. Ulbrich, O. Soehnlein, L. Lindborn, A. Mattern, and G.

Dannhardt, Bioorg. Med. Chem., 17, 558 (2009). 09BML1639 E. Perrino, C. Uliva, C. Lanzi, P. del Soldato, E. Masini, and A. Sparatore,

Bioorg. Med. Chem. Lett., 19, 1639 (2009).


09CAG480 Q.T. Tran, et al., Carcinogenesis, 30, 480 (2009). 09CLC1964 S.E. Bass, P. Sienkiewicz, Ch.J. McDonald, R.Y.S. Cheng, A. Sparatore, P.

del Soldato, D.D. Roberts, T.W. Moody, D.A. Wink, and G.Ch. Yeh, Clin. Cancer Res., 15, 1964 (2009).

09CRT1427 R. Holland, M. Navamal, M. Velayutham, J.L. Zweier, Th. W. Kensler, and J.C. Fishbein, Chem. Res. Toxicol., 22, 1427 (2009).

09DMD1187 Y.N. Kwon, S.M. Shin, I.J. Cho, and S.G. Kim, Drug Metab. Dispos., 37, 1187 (2009).

09JOM36 M. Abasq, M. Saïdi, J. Burgot, and A. Darchen, J. Organomet. Chem., 694, 36 (2009).

09MI1 J.D. Paonessa, Ch. M. Munday, P. Mhawech-Fauceglia, R. Munday, and Y. Zhang, Chem.-Biol. Interact., 180, 119 (2009).

09MI2 Y. Ou and H. Huang, Chongqing Yike Daxue Xuebao, 34, 1389 (2009). [CA 155 104778(2011)].

09MI3 A. Sparatore, E. Perrino, V. Tazzari, D. Giustarini, R. Rossi, G. Rossoni, K. Erdman, H. Schröder, and P. del Soldato, Free Radical Biol. Med., 46, 586 (2009).

09MI4 M.Yu. Dolomatov and G.U. Jarmuhametova, Prikl. Fiz., 5, 31 (2009). [CA 154 109029(2011)].

09MIP1 Z. Ma, Sh. Zhu, Y. Wang, J. You, and W. Lu, Chin. Pat. 101,463,030 (2009). [CA 151, 173440(2009)].

09MIP2 E. Martin Arrieta and L. Flores Santos, Mex. Pat. Appl. 2007,010,558 (2009) [CA 153 555691(2010)].

09MPH(75)242 S.M. Shin and S.G. Kim, Mol. Pharmacol., 75, 242 (2009). 09PS(184)1269 T. Drewnowski, S. Leśniak, A. Chrostowska, A. Dargelos, and S. Khayar,

Phosphorus Sulfur Silicon Relat. Elem., 184, 1269 (2009). 09RCB430 V.A. Ogurtsov, Yu. V. Karpychev, P.A. Belyakov, Yu. V. Nelyubina, K.A.

Lyssenko, and O.A. Rakitin, Russ. Chem. Bull., 58, 430 (2009). 09THC1 M.A.R. Matos and J.F. Liebman, Top. Heterocycl. Chem., 19, 1 (2009). 09WOA26837 W. Zhang, G. Lu, L. Wu, R. Zhao, and Y. Wu, World Pat. Appl.

2009,026,837 [CA 150 306658 (2009)]. 09WOA37556 G. Santus, P. del Soldato, and A. Sparatore, World Pat. Appl. 2009,037,556

[CA 150 374509 (2009)]. 10AJC946 Sh. D. Zanatta, B. Jarrott, and S.J. Wiliams, Aust. J. Chem., 63, 946 (2010). 10BJP(159)1236 J.L. Wallace, G. Caliendo, V. Santagada, and G. Cirino, Br. J. Pharmacol.,

159, 1236 (2010). 10BMC4187 V. Tazzari, G. Cappelletti, M. Casagrande, E. Perrino, L. Renzi, P. del

Soldato, and A. Sparatore, Bioorg. Med. Chem., 18, 4187 (2010). 10BMC5945 S. Bhattacharyya, H. Zhou, D.R. Seiner, and K.S. Gates, Bioorg. Med.

Chem., 18, 5945 (2010). 10CCE41 E. Laifa, Kh. Boukebbous, A. Houam, Kh. T. Fatima, and A.M.H.

Kermandji, J. Chem. Chem. Eng., 4, 41 (2010). 10CCL1427 M. Guan, W. Fan, Q. Shan, R.Q. Xiao, and Y. Wu, Chin. Chem. Lett., 21,

1427 (2010). 10EJM3005 P. Chen, Y. Luo, L. Hai, Sh. Qian, and Y. Wu, Eur. J. Med. Chem., 45, 3005

(2010). 10ICA(363)173 H. Adams, A.M. Coffey, and M.J. Morris, Inorg. Chim. Acta, 363, 173

(2010). 10ICA(363)4074 J. Bordinhão, N.M. Comerlato, L.C. Cortas, G.B. Ferreira, and R.A.

Howie, Inorg. Chim. Acta, 363, 4074 (2010). 10JBC17318 M. Lee, V. Tazzari, D. Giustarini, R. Rossi, A. Sparatore, P. del Soldato, E.

McGeer, and P.L. McGeer, J. Biol. Chem., 285, 17318 (2010).

Gunther�Fischer90

10JME4761 R. Munday, Y. Zhang, J.D. Paonessa, Ch.M. Munday, A.L. Wilkins, and J. Babu, J. Med. Chem., 53, 4761 (2010).

10JSF255 M.A. Barsy and E.A. El Rady, J. Sulfur Chem., 31, 255 (2010). 10MI1 S.G. Kim, et al., Clin. Pharmacol. Ther., 88, 360 (2010). 10MI2 S.H. Choi, Y.M. Kim, J.M. Lee, and S.G. Kim, Expert Opin. Drug Metab.

Toxicol., 6, 213 (2010). 10MI3 X. Li, W. Fan, L. Hai, Sh. Qian, Q. Xiao, and M. Guan, Lett. Drug Des.

Discovery, 7, 747 (2010). 10MI4 T. Yao, Y. Gan, S. Han, Ch. Zhu, Sh. Hu, and W. Pan, Shenyang Yaoke

Daxue Xuebao, 27, 168 (2010). [CA 154 495858(2011)]. 10ZK12 J. Bordinhão, N.M. Comerlato, E.A.S. Costa, G.B. Ferreira, R.A. Howie,

L. da S. Junior, B. dos, S. Peixoto, J.F.M. Silva, and J.L. Wardell, Z. Kristal-logr., 225, 12 (2010).

11CCE818 Kh. Boukebbous, E. Laifa, Kh. T. Fatima, and A.M.H. Kermandji, J. Chem. Chem. Engng., 5, 818 (2011).

11JMC5478 L. Lazzarato, K. Chegaev, E. Marini, B. Rolando, E. Borretto, S. Gug-lielmo, S. Joseph, A. di Stilo, R. Fruttero, and A. Gasco, J. Med. Chem., 54, 5478 (2011).

11JPB(54)551 J. He, T. Qin, J. Wen, F. Qin, and F. Li, J. Pharm. Biomed. Anal., 54, 551 (2011). 11JPB(56)623 J. Lee, H. Lim, D. Kim, D. Park, Y. Woo, H. Noh, Q. Jin, K. Lee, G. Lee,

and Ch. Kim, J. Pharm. Biomed. Anal., 56, 623 (2011). 11MI1 X. Tang, R. Chen, Y. Ren, P. del Soldato, A. Sparatore, Y. Zhuang, H.

Fang, and Ch. Wang, Med. Gas Res., 1, 20 (2011). 11MI2 M.Yu. Dolomatov, G.U. Yarmukhametova, and D.O. Shulyakovskaya,

Prikl. Fiz., 1, 20 (2011). [CA 156 44634(2012)]. 11MIP1 G. Ao, Ch. Qiao, B. Hou, Y. Cao, and X. Chu, Chin. Pat. 102,241,726

(2011) [CA 155 683939(2011)]. 11OM466 D.M. Andrada, A.M. Granados, M. Solà, and I. Fernández, Organometallics,

30, 466 (2011). 11PS(186)1201 V.A. Ogurtsov, Yu. V. Karpychev, A.A. Smolentsev, and O.A. Rakitin,

Phosphorus Sulfur Silicon, 186, 1201 (2011). 11PS(186)2341 H. Jin, D. Jiang, J. Gao, G. Qiang, and Y. Gong, Phosphorus Silver Silicon,

186, 2341 (2011). 11TL434 A.P. Guzaev, Tetrahedron Lett., 52, 434 (2011). 11ZK(226)535 R.A. Howie, G.M. de Lima, J.L. Wardell, S.M.S.V. Wardell, and N.M.

Comerlato, Z. Kristallogr., 226, 535 (2011). 12JPC(C)6520 A.E. Lanterna, E.A. Coronado, and A.M. Granados, J. Phys. Chem. C,

116, 6520 (2012). 12MI1 R. Kodela, M. Chattopadhyay, and Kh. Kashfi, ACS Med. Chem. Lett., 3,

257 (2012). 12MI2 M. Chattopadhyay, R. Kodela, N. Nath, Y.M. Dastagirzada, C.A.

Velázquez-Martínez, D. Boring, and Kh. Kashfi, Biochem. Pharmacol., 83, 715 (2012). 12MIP1 J. Bian, Zh. Cai, and H. Wu, Chin. Pat. 102,417,501 (2012) [CA 156

560316(2012)]. 12MIP2 Zh. Cai, J. Bian, and H. Wu, Chin. Pat. 102,417,504 (2012) [CA 156

560312(2012)]. 12MIP3 J. Bian, Zh. Cai, and H. Wu, Chin. Pat. 102,417,529 (2012) [CA 156

552180(2012)]. 12MIP4 G. Xu, J. Sheng, W. Zheng, L. Pan, G. Ao, J. Cheng, T. Qiu, and F. Shi,

Chin. Pat. 102,503,932 (2012) [CA 157 133799(2012)]. 12MIP5 T. Qiu, F. Shi, J. Cheng, G. Xu, J. Sheng, W. Sheng, and G. Ao, Chin. Pat.

102,504,005 (2012) [CA 157 133945(2012)].

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