Preparation of Thioethers

Support-bound thiols can be alkylated under mild reaction conditions with alkyl halides, a, 3-unsaturated carbonyl compounds, or reactive aryl halides (Table 8.4). These reactions should be conducted under an inert atmosphere or in the presence of a reducing additive to prevent disulfide formation. PEG-bound thiophenol has been S-alkylated under conditions similar to those used in solution (DMF, Cs2C03, 20 °C, 15 h [52-54]). 

Because thioether formation is a rapid, irreversible reaction, it has been widely used for the macrocyclization of peptides or peptoids on supports (Entries 1-4, Table 8.5 [62]). For this purpose, either S-protected cysteine or S-protected co-aminomercap-tans are linked to a support and then elongated by standard solid-phase peptide/pep-toid chemistry. When a suitable length has been reached, the terminal amine is acy- 

Thioethers have also been prepared on cross-linked polystyrene by radical addition of thiols to support-bound alkenes and by reaction of support-bound carbon radicals (generated by addition of carbon radicals to resin-bound acrylates) with esters of l-hydroxy-l,2-dihydro-2-pyridinethione ( Barton esters Entry 6, Table 8.5). Additional methods include the reaction of metallated supports with symmetric disulfides (Entries 7-9, Table 8.5) and the alkylation of polystyrene-bound, a-lithiated thioani-sole [65], 

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In two patents,the preparation of thioether-substituted selena-zoles of the general formula (6) have been described. These are stated to be formed by reaction of halogenoketothioethers with selenoamide components selenoacetamide, selenobenzamide, and A -ethylseleno-urea are given as examples. The resulting selenazoles were not further characterized. They are stated to be starting materials for the preparation of cyanine dyestuffs which are useful photographically. 

Scheme 9. Preparation of thioether appended porphyrazines. [Adapted from (2).]...

Following the synthetic route for the preparation of thioether appended por-phyrazines developed by Schramm and Hoffman (2), a series M[pz(S-Et)g] M = Mn, Co, Fe, were prepared by Ricciardi and co-workers (113-116). Their goal was to study the effect of the central metal and the immediate electronic environment, that is, oxidation state and axial ligand, on the physicochemical properties of the pz (Scheme 10). 

Table 4.15. Preparation of thioethers by S-alkylation of thiols with electrophilic carbene complexes.

Table 8.3. Preparation of thioethers from support-bound electrophiles.

Note that these reactions are reversible, and indeed one of the best methods for the preparation of thioether complexes is by alkylation of a co-ordinated thiolate. In general, the dealkylation reactions require forcing conditions, but in some cases they proceed in an... 

One of the simplest and widely used methods of forming C-S bonds involves nucleophilic attack of a thiolate on a suitable C-centred electrophile such as an alkyl halide (Fig. 5-74). Co-ordinated thiolate ligands behave as nucleophiles in exactly the same manner, and the method has been extensively used for the preparation of thioethers and their metal complexes. The method has been particularly commonly utilised in the formation of macrocyclic ligands in templated syntheses (see Chapter 6). 

Other methods such as disulfide contraction [43] or photochemical addition of alkenes [44] or alkynes [45] have also been used for the preparation of thioether-linked... 

A similar reaction has been described for the preparation of thioethers with aryl-and alkylthiotrimethyl silanes.Ring-closure occurs with co-bromo-1,2-epoxyalkanes on the action of magnesium and lithium in the presence of Cul. By this means, cyclobutanol, cyclopentanol, and cyclohexanol can be prepared. (e.g. Eq. 294). 

Many donor solvents displace 14S4 from Ni(II). Accordingly Rosen and Busch developed new synthetic methods that have since been widely used for preparation of thioether complexes [49,51]. Reaction of [Ni(HOAc)g] with 14S4 in MeN02 yields the red low-spin [Ni(14S4)] " cation [3]. X-ray diffraction reveals a square-planar NiS coordination sphere (Table 1) with anti stereochemistry... 

Considerable use has been made of the copper(i) benzenethiolate and butanethiolate in the preparation of thioethers. A large series of compounds of general formula (RS)nX, n>l, R = Ph or Bu, and X is an aryl group, have been prepared from the copper(i) thiolates and aryl halides (aryl bromides only reacted with the butanethiolate) . ... 

Preparation of 2 4-dinitrophenyl-sulphides. Dissolve about 0-5 g. (or 0 005 mol) of the mercaptan in 10-15 ml, of rectified spirit (or in the minimum volume necessary for solution warming is permissible) and add 2 ml. of 10 per cent, sodium hydroxide solution. Mix the resulting sodium mercaptide solution with a solution of 1 g. of 2 4-dinitrochlorobenzene in 5 ml. of rectified spirit. Reaction may occur immediately with precipitation of the thioether. In any case reflux the mixture for 10 minutes on a water bath in order to ensure the completeness of the reaction. Filter the hot solution rapidly allow the solution to cool when the sulphide will crystaUise out. RecrystaUise from alcohol. 

The nucleophUic reactivity in neutral medium has been used extensively to prepare various thioethers of thiazole (122). In acidic medium, alkylation may be performed with alcohols (123, 124). An unexpected reaction encountered was the decarboxylation of 2-mercapto-4-methyl-5-thiazolecarboxyhc acid (60) when treated with butyl alcohol under acidic conditions (Scheme 27) (123). Reaction between A-4-thiazoline-2-thione... 

Since the exocyclic sulfur is more reactive in the ambident anion than in A-4-thiazoIine-2-thione. greater nucleophilic reactivity is to be expected. Thus a large variety of thioethers were prepared in good yields starting from alkylhalides (e.g.. Scheme 38 (54, 91, 111, 166-179). lactones (54, 160), aryl halides (54, 152. 180, 181), acyl chlorides (54. 149, 182-184). halothiazoles (54, 185-190), a-haloesters (149. 152. 177. 191-194), cyanuric chloride (151). fV.N-dimethylthiocarbamoyl chloride (151, 152. 195. 196), /3-chloroethyl ester of acrylic acid (197), (3-dimethylaminoethyl chloride (152). l,4-dichloro-2-butyne (152), 1,4-dichloro-2-butene (152), and 2-chloro-propionitrile (152). A general... 

The preparation of substituted selenazole thioethers (Scheme 22) has already been described (35. 36). These compounds are obtained by the action of a haloketothioether on. for example, selenoacetamide. selenobenzamide, and A -ethylselenourea. These selenazoles have not been characterized, but they have been used as intermediates in the preparation of cyanine dyes. 

The most widely applied method to prepare sulfones is the oxidation of thioethers. In the course of these oxidations sulfoxides must occur as intermediates. However, since oxidation mechanisms for thioethers and sulfoxides are partly different, these oxidations will be discussed separately. A recently published method337,338 allows oxidation of a... 

Substituted selenazole thioethers, intermediates in preparation of cyanine dyes, 236... 

The preparation of novel triazole-containing 20-22 membered macrocyclic azacrown ether-thioethers was reported <96JCR(S)182> and the first selective synthetic method fra the synthesis of dicyanotriazolehemiporhyrazines was published <96JOC6446>. 1,2,4-Triazole-containing polyimide beads were prepared and employed as Mo(VI) epoxidation catalyst supports, liie 1,2,4-nitronyl nitroxide 29 was also synthesized and found to have remarkable magnetic properties <96AM60>. 

Since carbohydrates constitute an inexpensive and highly modular chiral source for preparing chiral ligands," Claver et al. have reported the use of a series of thioether-phosphite" and thioether-phosphinite furanoside ligands" in the test palladium-catalysed allylic substitution reaction. In the first type of ligand, a systematic variation of the donor group attached to the carbon atom C5 indicated that the presence of a bulky phosphite functionality had a positive effect on the enantioselectivity. Indeed, the enantioselectivity was controlled mainly by the phosphite moiety. This was confirmed by the use of a ligand... 

However, since SMCC forms nonreversible thioether linkages with sulfhydryl groups, it only can be used in the preparation of immunotoxins if intact A-B toxins are employed in the conjugate. In such conjugates, the A chain still have the potential for reductive release from the B-chain subunit after cellular docking and internalization. Immunotoxins prepared with A-chain or single-subunit toxins will not display cytotoxicity if crosslinked with SMCC, since the crosslinker does not create cleavable disulfide bonds upon conjugation. 

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