1.3- Dithiols, oxidative cyclization

Examples of reactions involving replacement and cyclization are the long-known preparation of thiophenes (89) from 1,4-diketones, and the formation of l,2-dithiole-3-thione (90) from the salicylate ester analog (91).120 In the latter instance, oxidative cyclization with formation of an S—S bond has occurred this is a common feature of these reactions, particularly if such a link is needed to complete a five-membered ring. Another example of this aspect is afforded by the reaction of the propane-1,3-dione derivatives (92) which yield 3,5-diaryl-1,2-dithiolylium salts (93) when heated with phosphorus pentasulfide in carbon disulfide, followed by perchloric acid.121... 

Dithiolanes are efficiently synthesized by the oxidative cyclization of 1,3-dithiols , as illustrated by the preparation of 1,2-dithiolane 77 in quantitative yield from 1,3-propanethiol 76 by oxidation with iodine in the presence of 2-methyl-2-butene (Scheme 44) <20000L369> and a similar synthesis of the l,2-dithiol-3-one 78 (Scheme 45) <2004TL4307, 2006JME5626>. 

Treatment of Br(CH2) Br with NaaS under heterogeneous conditions yields the appropriate thiacycloalkane. Similarly, the oxidative cyclization of the dithiol HS(CH2) X(CH2) SH (X = O, CH2, or S) with iodine yields the corresponding medium-ring disulphide. A general synthesis of mediumring and macrocyclic disulphides and a variety of dithia-crown ethers has been devised, using caesium dithiolates as starting materials [reaction (1)]. ... 

H-l,2-Dithiole-3-thiones The treatment of )3-oxodithioic acids with H2S and bromine leads to the heterocyclic compounds. Bromine serves as an agent for the oxidative cyclization. 

Thiazepinone (58) was obtained by oxidative cyclization of the corresponding dithiol derivative (56), by the reaction with diethyl bromomalonate in the presence of base, followed by treatment of the resulting cyclic disulfide (57) with trisdiethylaminophosphine (Scheme 20) <93CPB1066>. 

The reduction of ribonucleoside triphosphates by various dithiols which are capable of intramolecular cyclization on oxidation (dihydrolipoate, dithioerythritol, dithiothreitol) yields 2 -deoxyribonucleoside triphosphates. These reactions also require 5-deoxyadenosylcorrinoids. 

There are few examples of the preparations of heterocyclic compounds containing two or more heteroatoms which involve cyclization with formation of a bond between two heteroatoms. The best known instances of this type of reaction, all of which are [6 + 0] reactions, are the preparations of benzocinnolines as outlined in equations (l)-(4). A similar type of approach to that outlined in equation (4) has been used for the direct preparation of the di-N-oxide (2) from the dioxime (1 equation 5). The naphthotriazine betaine (4) is obtained as one of the products of the thermal decomposition of the azidoazo compound (3 equation 6). 1,2-Dithiins and their dibenzo derivatives have been prepared by oxidation of appropriate dithiols and related starting materials as outlined in equation (7). All of these reactions are, however, somewhat specialized and there has been essentially no systematic study of the preparation of six-membered heterocycles via formation of a bond between two heteroatoms. 

Upon oxidation these dithiols cyclize to form stable disulfides, driving the reaction to completion. These same compounds are also widely used to protect SH groups in enzymes against accidental oxidation by oxygen and to dissolve highly crosslinked insoluble proteins. Mercaptoethanol, HS-CH2-CH2-OH, may be used for the same purposes but requires higher concentrations and has a disagreeable odor. 

The amine 196 upon reaction with hydrogen sulfide in dimethylsulfoxide (DMSO) in the presence of base at 25-50 °C afforded the thiazine 197, allyl(2-mercaptopropyl)amine 198, and 3,7-dimethylperhydro[l,2,5]dithiazepine 199 in 10-17%, 2-31%, and 1-50% yields, respectively (Scheme 43) <2000RJC1243>. The formation of 199 is assumed via thiol 198, which reacted with a second hydrogen sulfide molecule to give dithiol 200. Subsequent oxidation of200 resulted in 199. In an alternative mechanistic pathway, the amine 196 can form the intermediate 201, which could cyclize to give 199. 

Ether linkages in open-chain bolaamphiphiles were obtained in a 20% isolated yield from a,o)-dibromoeicosane with an alcohol in THF containing sodium hydride (Scheme 2.8). The synthesis of macrocyclic tetraethers was unsuccessful. Attempts to reduce macrocyclic lactones with four ester groups via a variety of methods failed. The production of macrocyclic thioacetals from benzaldehyde derivatives and a,to-dithiols was unproblematic and produced quantitative yields (Scheme 2.8). The cyclization of 2,2-thiodiethanol with a,(o-diols in the melt and in the presence of /7-toluenesulfonic acid is an intermediate case. Apolar macrocycles were obtained in 50% yield. 5-(2-hydroxyethyl)thiiranium ions are presumably formed as reactive intermediates during the ether formation steps. The sulphur atom was oxidized to the... 

Dithiole-2-one (60), which can be readily transformed into its thio- or seleno-carbonyl derivatives, is a key intermediate for the synthesis of tetrathiafulvalene (Scheme 13)[31]. We first anticipated that compound 57, a Michael addition product of xanthate 54 to vinyl sulfoxide, might be an ideal intermediate for the synthesis of 60 via cyclization under Pummerer rearrangement conditions. However, although Michael addition of dithiocarbamate 53 to vinyl sulfoxide proceeded smoothly to yield compound 55, the addition reaction with xanthate 54 failed. We then turned to the alkylation approach. Xanthate 54 was alkylated smoothly with 56, which served as the synthetic equivalent of the vinyl sulfoxide, in ethanol under sonication in 90% yield [32]. Cyclization of 57 under Pummerer rearrangement conditions in the presence of trifluoroacetic acid afforded 58 in 79% yield. Sodium metaperiodate oxidation gave the unstable sulfoxide 59 which underwent thermal elimination to yield 60 in refluxing benzene in moderate yield. 

Alternatively, Whittaker et al. utilized the reversible oxidation/reduction of a thiol-terminated linear polymer as a homocoupling reaction to access macrocycles that could be reversibly cyclized and cleaved (Scheme 12.5) [29]. The linear precursors were prepared using reversible addition-fragmentation chain transfer (RAFT) polymerization of styrene from a bifunctional initiator (16). The desired polystyrene with thiol end groups could be isolated in near-quantitative yields by aminolysis of the polymer with terminal dithioester groups (17). The linear dithiols... 

Scheme 12.5 Reversible cyclization and ring opening through oxidization of the linear dithiol or reducing the cyclic disulfide [29].

The seven-membered-ring disulphide (77) has been isolated from a species of Hawaiian alga " and the structure confirmed by the following synthesis the reaction of 2-nonenal with vinyl-lithium followed by oxidation with DDQ gave the undeca-l,4-dien-3-one, which readily added thiolacetic acid to each double bond. The dithiol ester thus produced was hydrolysed to the dithiol with methanol-HCl. Cyclization to (77) was effected with iodine in pyridine. A dimeric fourteen-membered-ring tetrasulphide was obtained as by-product. 

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