Thioether formation with

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. 

The H- and N-isoforms of Ras support the first (isoprenoid) hydrophobic modification by additional thioester formation with palmitoylic acids [18]. At physiological temperature (37°C) the dissociation of doubly modified lipo-peptides with an isoprenyl thioether and a palmitoyl thioester is very slow and characterized by half-times in the order of 50 h. Here, the relative effect of the carboxymethylation is significantly reduced. Palmitoyl groups with their C16 alkane chain length contribute more efficiently to membrane anchoring than the farnesyl modification. 

The amino and bromo substituents in the 3//-azepine (111 X = Br) are susceptible to nucleophilic displacement and are hydrolyzed surprisingly easily by aqueous methanol or DMF to the azepine-2,7-dione. Sodium thiocyanate in DMF yields the aminothiocyanate (111 R = SCN) (67JOC2367). It has been noted that amidine formation with the lactim thioether (112) is much slower than with isomer (113) (77JHC933). 

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. 

Palladium-catalyzed annulation of the thioether 26 with various alkenes has been demonstrated to furnish the tricyclic systems 27 in modest yields <07JOC775>. Formation of 2,3-dihydrobenzo[Z>]thiophenes has also been observed upon fluoride induced rearrangement of certain aryl 2-(trimethylsilyl)ethyl sulfoxides <07OBC1595>. 

Bromoacetyl groups cannot be used for thioether bond formation with cysteine residue in the presence of free amino groups. Only the chloroacetyl group is suitable for this purpose. 

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-... 

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. 

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... 

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]. 

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. 

A one-pot variation of the thioether generation, applicable to the formation of cyclic sulfones, involves reaction of a dihalide (or halide equivalent) with a divalent sulfide, such as sodium sulfide. This methodology was used in the synthesis of conduritols, whereby sodium sulfide reacted with diepoxy stereoisomers 13 in a one-step thioether formation fScheme 8.5). The resulting thiapane isomers 14 were separated (HPLC) and then individually methylated and oxidized with m-CPBA to a set of isomeric sulfones, 15. 

A similar double substitution in a single pot was employed for thioether formation in the RBR-based synthesis of eremantholide A (see Section 8.6.41. " In this case, the sulfide generated from hexamethyldisilathiane [bis(trimethylsilyl)sulfide] and sodium methoxide reacted with the bromoiodide 16 to form the 10-membered thioether 17 (Scheme 8.6). This was oxidized with Oxone to provide the sulfone 18. 

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