Thioethers with alkyl halides

Pyrrolethiols, readily obtained from the corresponding thiocyanates by reduction or treatment with alkali, rapidly oxidize to the corresponding disulfides. They are converted into thioethers by reaction with alkyl halides in the presence of base. Both furan- and thiophene-thiols exist predominantly as such rather than in tautomeric thione forms. 

The reaction of hydrogen sulfide with two equivalents of ethylmagnesium bromide in ether gives a reagent as a viscous mass , which is soluble in THF and reacts with alkyl halides in that solvent to give thioethers [16] ... 

The sulfur analogs of ethers are called sulfides or thioethers. Sulfur is an excellent nucleophile because its electron cloud is polarizable (Section 10.3). Sulfides, therefore, react readily with alkyl halides to form sulfonium salts—a reaction that an ether cannot undergo because oxygen is not as nucleophilic and cannot accommodate a charge as easily. 

Thiols are sulfur analogs of alcohols. They are stronger acids and have lower boiling points than alcohols. Thiolate ions are weaker bases and better nucleophiles in protic solvents than alkoxide ions. Sulfur analogs of ethers are called sulfides or thioethers. Sulfides react with alkyl halides to form sulfonium salts. 

The reactions of lithiophosphide reagents with alkyl halides or sulphonate esters have continued to find wide application in the synthesis of new phosphines. A series of phosphino-ethers, e.g., (22), has been prepared from the reactions of chloromethyl-substituted ethers with lithium diphenylphosphide. " A one-step synthesis of macrocyclic phosphino-ethers and -thioethers (23) is afforded by the reactions of dilithio-organophosphides with bis(j8-chloroethyl)-ethers and -thioethers derived from ethane-1,2-diol and ethane-1,2-dithiol, respectively. " A new family of water soluble phosphonio-phosphine ligands (24) has been prepared by the reaction of a,o)-dihaloalkanes with one mole of lithium diphenylphosphide, followed by quatemisation of the intermediate w-haloalkylphosphine with trimethylphosphine. The new ligand system (25) has been prepared by the reaction of chloromethylbenzene-chromium tricarbonyl with... 

The thiolactams can be alkylated on sulfur by treatment with alkyl halides and base under aqueous or nonaqueous conditions, for example, (99 X = S) is converted into (100) (Scheme 16) <82CPBil4l>. The thioether (100) can be obtained directly from the lactam (99, X = O) on reaction with dimethylaminoethane thiol in the presence of either titanium tetracUoride or silicon tetrachloride other Lewis acids were ineffective <82CPB1473>. 

Alkyl thiocyanates have also been prepared from thioethers with cyanogen bromide and via the reaction of polymer-based quaternary ammonium salts with alkyl halides. Enethiocyanates have been prepared by Markovnikov addition of in situ generated thiocyanic acid to alk-l-ynes, and via the reaction of epoxy-ketones with Ph3P(SCN)2. ... 

Thioethers react with alkyl halides to form sulfonium salts, which have excellent leaving groups, so they undergo substitution reactions with ease. 

If the substrate is an alcohol, some dialkyl ethers can be synthesized in a two-phase version of the Williamson synthesis, and thioethers or dithioacetals result from alkylation of thiols, with alkyl halides or CH2CI2 respectively, under similar conditions. The related reaction of equation (2) has been used to make an evaluation of several catalysts, and it has been found that the larger, more symmetrical, quaternary ions are the most efficient. 

In contrast to the hydroxpyridines, pyridine-2-thiol reacts with alkyl halides , methyl sulphate ", alkyl halides and alkali " or with diazo-methane to give thioethers or their salts. Pyridine-3-thiol in alkali also reacts at the sulphur atom, as do pyridine-4-thiols with alkyl halides . 

Only when the sulphur atom is already substituted, as in 3-pyridyl thioben-zoate , or pyridyl thioethers, does reaction occur at the nitrogen atom i . In contrast to l-alkylpyrid-2-ones, l-alkylpyrid-2-thiones react readily with alkyl halides , and sequences such as those of the diagram are characteristic ... 

Urea forms addition compounds with paraffinic and olefinic hydrocarbons, with alcohols, ethers, carbonyl compounds, mono-and dicarbo-xylic acids and their esters, with alkyl halides, thioethers, amines, diamines. 

Alkyl iodides afford mixtures of radical- and ion-derived photoproducts in solution, with the latter usually predominating. Indeed, this is a powerful method for generating carbocations, including many that cannot be readily prepared by other methods. Alkyl bromides display similar photobehavior, but with a lower proportion of ionic products. Analogous behavior has also been observed for phenyl thioethers and selenoethers, as well as some organosilicon iodides. In a process related to the formation of ionic intermediates, irradiation of dihalomethanes in the presence of alkenes results in cyclopropanation, a synthetically useful procedure that complements traditional methods. This chapter, which is concerned with alkyl halides, is a major expansion of an earlier review. The solution-phase photobehavior of aryl, benzylic, and homobenzylic hahdes has been reviewed, along with that of alkyl systems." The photobehavior of alkyl halides in the gas phase has also been reviewed. ... 

The alkyl sulphides or thioethers, the sulphur analogues of the ethers, are conveniently obtained by boiling alkyl halides with anhydrous sodium sulphide in alcoholic solution, for example ... 

The same diamine, when treated with carbon disulfide in alkaline medium, yielded 2-mercapto- l//-imidazo[4,5-/]quinoline (88PS267,88SC973,86IJC264), which, on treatment with alkyl, aralkyl, and acid halides, gave the corresponding thioethers and thioesters 111, respectively (88PS267, 86IJC264). 

Thioethers (sulfides) can be prepared by treatment of alkyl halides with salts of thiols (thiolate ions). The R group may be alkyl or aryl and organolithium bases can be used to deprotonate the thiol. As in 10-37, RX cannot be a tertiary halide, and sulfuric and sulfonic esters can be used instead of halides. As in the Williamson... 

Symmetrical thioethers can also be prepared by treatment of an alkyl halide with sodium sulfide, or with S(MgBr)2 with allylic halides. ... 

Alkyl halides, treated with thioethers, give sulfonium salts. Other leaving groups have also been used for this purpose. ... 

Further, a large number of examples with simple alkyl substituents [168, 171, 176-184], cyclic alkanes [185], aryl substituents [177, 186-192], olefmic substituents [78, 177, 193-196], deuterated compounds [172], thioether groups [171], ester groups [197], orthoesters [198, 199], acetals [168, 182, 200-204], silyl-protected alcohols [198, 205-211], aldehydes [212], different heterocycles [213-217], alkyl halides [218, 219] and aryl halides [192, 220-223] have been reported. A representative example is the reaction of 92, possessing a free hydroxyl group, an acetal and a propargylic ether, to 93 [224] (Scheme 1.40). 

The most promising tools developed for this sort of analysis are active-site-directed irreversible inhibitors of DUBs. These inhibitors are ubiquitin or ubiquitin-like proteins chemically modified at the C-terminus by an electrophilic moiety such as a Michael acceptor or alkyl halide. The modified ubiquitin can be incubated with a purified DUB or a cell lysate containing DUB activity. Ubiquitin vinyl sul-fone (UbVS) is one such irreversible inhibitor because the vinyl sulfone moiety reacts with the active-site cysteine of the DUB, forming a thioether linkage. The covalent adduct is stable and can be detected in a variety of ways. Labeling of DUBs is specific, as only a DUB active-site cysteine will efficiently react with the vinyl sulfone moiety. 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

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