Thioethers reaction 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. 

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

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. 

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. ... 

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. 

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 ... 

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 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]. 

Thioethers (sulfides) can be prepared by treatment of alkyl halides with salts of thiols (thiolate ions).7S2 R may be alkyl or aryl. As in 0-35, RX cannot be a tertiary halide, and sulfuric and sulfonic esters can be used instead of halides. As in the Williamson reaction (0-12), yields are improved by phase-transfer catalysis.753 Instead of RS ions, thiols themselves can be used, if the reaction is run in benzene in the presence of DBU (p. 1023).754 Neopentyl bromide was converted to Me3CCH2SPh in good yield by treatment with PhS in liquid NH3 at -33°C under the influence of light.755 This probably takes place by an SrnI mechanism (see p. 648). Vinylic sulfides can be prepared by treating vinylic bromides with PhS in the presence of a nickel complex,756 and with R3SnPh in the presence of Pd(PPh3)4.757 R can be tertiary if an alcohol is the substrate, e.g,758... 

Symmetrical thioethers can also be prepared by treatment of an alkyl halide with sodium sulfide,769 in a reaction similar to 0-30. 

Sulfonium salts of thiepanes are readily formed by electrophilic attack of alkyl halides on the cyclic thioether. Thus, thiepane (35) was found to yield a sulfonium iodide (123), which at elevated temperatures and in the presence of excess methyl iodide underwent ring cleavage to yield 1,6-diiodohexane (isolated as the 1,6-diphenoxy derivative Scheme 24) (53M1206). The alkoxysulfonium salt (124) formed by reaction of (35) with t-butyl hypochlorite (equation 23) was characterized as a stable hexachloroantimonate (67JOC2014). Reduction of thiepane 1-oxide (115) to thiepane has been achieved using an aqueous solution of NaHSC>3 (72JOC919). A hydroxysulfonium salt intermediate (125) has been proposed in the latter reduction reaction which provides a general method for sulfoxide reductions under mild conditions (equation 24). 

Sulfoxides and sulfones can be prepared on cross-linked polystyrene by oxidation of thioethers. The most commonly used reagent for this purpose is MCPBA in DCM [8,12,32,57,80-82] or dioxane [50,83] (Table 8.6), but other oxidants such as H2O2 in acetic acid [34], oxone (Entry 7, Table 8.6), or oxaziridines [84] have also been used. PEG-bound thioethers have been converted into sulfones by oxidation with MCPBA in DCM [52,54] or with Os04/NMO [85], The oxidation of thioethers to sulfoxides requires careful control of the reaction conditions to prevent the formation of sulfones. Sulfones have also been prepared by S-alkylation of polystyrene-bound sulfi-nates (Entries 8 and 9, Table 8.6), by a-alkylation of sulfones (BuLi, THF, alkyl halide [86]), and by addition of sulfinyl radicals to resin-bound alkenes or alkynes (Entry 11, Table 8.6). 

Homofamesyl iodide 7 was prepared by the reaction sequence shown in the margin. Of interest here is the two-step transformation of an alkyl halide into a Crextended alkyl halide.9 Compound 30 is first subjected to a nucleophilic substitution by an urganolithium species with formation of a homoallylic phenyl thioether This is then methylated in a second step to an intermediate sulfonium salt. The final SN2 reaction with an iodide ion releases thioanisol as a stable leaving group to give compound 7. 

Arylmethyl(homobenzyl)ethylsulfonium salts are appropriate substrates for Suzuki-type coupling reactions. In this reaction, performed on a polymer-bound sulfonium tetrafluoroborate, the benzyl fragment on the sulfur atom was transferred to the boronic acid residue. The sulfonium salt was prepared from an al-kylthiol resin by alkylation with a substituted benzyl halide to give thioether 98 and subsequent alkylation with triethyloxonium tetrafluoroborate. Reaction with a boronic acid derivative yielded diaryl methanes 99 [94] (Scheme 6.1.22). 

Thiols can be prepared by the action of alkyl halides with an excess of KOH and hydrogen sulphide. It is an SN2 reaction and involves the generation of a hydrogen sulphide anion (HS ) as nucleophile. In this reaction, there is the possibility of the product being ionised and reacting with a second molecule of alkyl halide to produce a thioether (RSR) as a by-product. An excess of hydrogen sulphide is normally used to avoid this problem. 

Thioethers (or sulphides) can be prepared by the SN2 reaction of primary or secondary alkyl halides with a thiolate anion (RS ). The reaction is similar to the Williamson ether synthesis. 

Symmetrical thioethers can be prepared by treating an alkyl halide with KOH and an equivalent of hydrogen sulphide. The reaction produces a thiol which is ionised again by KOH and reacts with another molecule of alkyl halide. 

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