Thioether Formation

The phase transfer method did not succeed well when applied to the 

Diphenyl thioether and (meso-tetraphenylporphyrinato)iron(lll) chloride supported on silica, by treatment with 1 mole of iodosobenzene at ambient temperature, gave with stirring during 3 hours under nitrogen, diphenylsulphoxide in 74% yield with 7% of the corresponding sulphone, formation of which was suppresed by adsorption of the main product on the silica (ref. 123). 

The method of ref.122 was also effective for phenols and would undoubtedly be favourable for the preparation of ethers of long-chain phenols which react only moderately well under phase transfer conditions. 

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For a method of avoiding thioether formation, see Vasil tsov, A.M. Trofimov, B.A. ... 

Thioamide formation benzodiazepinone, 505 heteiodiazepinone, 621 phosphorus pentasulf ide, 323, 600 Thioazole formation, nitrile addition, 301 Thiocarbamate formation, 588 phenol, 95 rearrangement, 517 Thioenol ether formation, 185, 517 addition-elimination, 554 Thioester formation, mixed anhydride, 184 Thioether formation, 241, 300, 413, 416 alkylation, 586, 588 aromatic displacement, 416 Thiohydantoin formation, 293 Thiol interchange, benzothiazole formation, 422... 

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-... 

Thiomorpholinones have been prepared on cross-linked polystyrene by intramolecular thioether formation and by the lactamization of suitable amino acids (Entries 8 and 9, Table 15.34). l,3,5-Thiadiazine-2-thiones (Entry 11, Table 15.34) are not stable towards TFA/DCM (1 1) and have therefore been prepared on Sasrin cleavage from the support could be achieved using 3% TFA in DCM [411],... 

Numerous researchers have employed thiols as weak bases in the thioalkylation reaction to ligate unprotected peptides with a haloacetyl group to form thioethers at pH 7 8.5[90 91 131-133 or thioesters at acidic to basic conditions. 108"110 Of these two reactions, thioether formation is often the choice because thioesters suffer from instability in aqueous basic conditions. Haloacetyl derivatives, either as carboxylic acids or active esters, can be attached to either the N-terminal or side-chain amines during the stepwise solid-phase synthesis of either the peptide or the core and are stable to either HF or TFA cleavage conditions. Capping an amino group with a chloroacetyl group is compatible with Fmoc chemistry when used at a terminal step. 

Thioacetamide as Starting Material in Crown Thioether Formation 788... 

The glutathione 5-transferases catalyze numerous reactions in which the glutathione thiolate anion (GS ) serves as a nucleophile (A20, G11, J2). Thus the fundamental catalytic action of GST is to facilitate the formation or stabilization of GS , which can, in turn, attack electrophilic carbon, nitrogen, sulfur, or oxygen atoms contained in any xenobiotic. Literally hundreds of different compounds exist that contain a carbon atom sufficiently electrophilic to be able to react with GS" and form thioether conjugates. Thioether formation has been widely studied since the earliest convenient spectrophotmetric assays represented this type of reaction for example, the conjugation of GSH with l-chloro-2,4-dinitrobenzene, 1,2-dichloro-... 

Fio. 9. GST substrates that represent components of oxidized lipid and DNA. Cholesterol-5,6-oxide (a) and 4-hydroxynon-2-enal (b) are detoxified by GST through thioether formation, whereas 9-hydroperoxy-linoleic acid (c) and 5-hydroperoxymethyl-uracil (d) are reduced by GST peroxidase activity. 

Ligands with free amino groups can be immobilized on Afli-Gel 201 and 202 by the EDAC method. Ligands can be attached to Afii-Gel 401 by disulfide, thioester, or thioether formation. Affi-Gel 5C has a high capacity for selectively purifying SH-containing proteins. 

Initial progress was swift and the two subunits required for the CIO-C16 dithiane fragment, sulfone 12 and aldehyde 10, were easily prepared. Ester 13 was first converted to the mono-protected diol 18 by silylation followed by ester reduction (Scheme 4). The phenyl sulfone auxiliary was next installed in two steps by a Mitsunobu-like thioether formation with diphenyl disulfide and tributylphosphine followed by oxidation with Oxone . The resulting sulfone 19 was desilylated and the liberated hydroxyl group converted to an aldehyde with Swem s procedure. Subunit 12 was completed by formation of the dithiane from aldehyde 20 under standard conditions. 

Michael reaction, 150 Michael-type addition, 20 Mitsunobu-like thioether formation, 180... 

As with C-N couplings, C-0, C-S, and C-P bond formations also require a Cu(I) or Cu(II) source, a base, and solvent, with reaction temperatures ranging from 45 to 195°C. Typically the couplings see CoupUn are performed with aryl/vinyl boronic acids and aryl iodides (Scheme 3). Use of microwave technology allows for aryl thioether formation between aryl bromides and thiophenols. Inclusion of external ligands is not required for coupling, although several have... 

Buchwald reported a more cost-effective, high-yielding method for aryl thioether formation, including substrates for which the Palomo conditions were ineffective (2). Notably, this process employs a relatively low loading of an air-stable catalyst (Cul) and K2CO3 as the base. The simplicity of the reported conditions, the high degree of chemoselectivity and the broad substrate scope render this process an attractive choice for C-S bond formation [35]. 

In 2000, Guy reported the stoichiometric coupling of alkane thiols and arylboronic acids, which was initially thought to be mediated by Cu(ll) [71]. Liebeskind proposed that the reaction was more likely catalyzed by Cu(l), generated by oxidation of the alkane thiols into dialkyl disulfides. Based on this hypothesis, Liebeskind predicted that disulfides and disulfide equivalents should be effective reagents for thioether formation [34]. This process would constitute a modification of the Chan-Evans-Lam, which involves the coupling of arylboronic acids and amines or alcohols in the presence of tertiary amine bases, generating aryl amines and ethers, respectively. Indeed, the coupling of diphenyl disulfide with phenyl boronic acid would yield diphenyl sulfide. 

Earland and Raven [65] have examined the reaction of A-(mercap-tomethyl) polyhexamethyleneadipamide disulfide (XV) with alkali. Under alkaline conditions that produce lanthionyl residues in wool, no thioether is formed from this polymeric disulfide however, cyanide readily produces thioether from either (XV) or wool fiber. Therefore, the mechanism for thioether formation must be different in these two reactions. Because this polymeric disulfide (XV) contains no beta-hydrogen atoms (beta to the disulfide group), a likely mechanism for formation of lanthionyl residues in keratins, under alkaline conditions, is the beta-elimination scheme [64] (the reaction depicted by Equation F). Other mechanisms that have been suggested for this reaction have been summarized by Danehy and Kreuz [66]. 

Meyer C, Beirbaum G, Heidrich C, Reis M, Suling J, Iglesias-Wind MI, Kempter C, Molitor E, Sahl HG (1995) Nucleotide sequence of the lantibiotic Pep 5 biosynthetic gene cluster and functional analysis of PepP and PepC. Evidence for a role in PepC in thioether formation. Eur J Biochem 232 478-489... 

Commercially available, air-stable Pd phosphinous acid complex is an active catalyst for the thioether formation by the reaction of 1-cyclopentenyl chloride (49) with thiophenol (50) and hexylmercaptan (52) to give the thioethers 51 and 53 [15]. 1-Cyclopentenyl phenyl thioether (55) was obtained by the reaction of 1-cyclopentenyl triflate (54) with lithium phenyl sulfide [16]. 

Aryl-substituted dithiazole thioethers 16 are prepared from aryl methyl ketones 15 with thiourea in the presence of iodine (14T5544).The iodine-promoted reactions presumably proceed through a sequence of iodination of methyl ketone, Hantzsch cyclization, iodination, thio formation, and thioether formation. 

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