Thioethers, from nucleophilic substitution

In a one-pot synthesis of thioethers, starting from potassium 0-alkyl dithiocarbonate [36], the base hydrolyses of the intermediate dialkyl ester, and subsequent nucleophilic substitution reaction by the released thiolate anion upon the unhydrolysed 0,5-dialkyl ester produces the symmetrical thioether. Yields from the O-methyl ester tend to be poor, but are improved if cyclohexane is used as the solvent in the hydrolysis step (Table 4.13). In the alternative route from the 5,5-dialkyl dithiocarbonates, hydrolysis of the ester in the presence of an alkylating agent leads to the unsymmetrical thioether [39] (Table 4.14). The slow release of the thiolate anions in both reactions makes the procedure socially more acceptable and obviates losses by oxidation. 

In the unconventional synthesis of thioethers (Scheme 4.11), cyanide ion is displaced from thiocyanates by carbanions [52, 53], which have been generated under phase-transfer catalytic conditions (cf. 4.1.12). Thiocyanates are readily obtained by a standard catalysed nucleophilic substitution reaction [4, 54-58] (see Table 4.19). Aryl thiocyanates are obtained from activated aryl halides [4, 57] (see Chapter 2). 

Alternatively, a-(dialkylsulfonium)alkyl iron complexes can be prepared from a-haloalkyl iron complexes by silver- or thallium-promoted nucleophilic substitution with thioethers [474],... 

Sodium/alcohol Nucleophilic substitution with strong nucleophiles Thioethers from halides... 

As already noted above, thiols, produced by nucelophiUc substitution or from organometallic reagents, can be converted to thioethers by a second nucleophilic substitution reaction.These sulfides, on alkylation,produce sulfonium salts (Equation 8.65), which can be used or further alkylation reactions (e.g., see SAM Figure 8.24). 

The nucleophilic substitution approach was also used by several research groups for syntheses of polysulfides with broad variation of the chemical structure and of the reaction conditions [343-352]. For instance, a poly(thioether-ketone) was prepared from DFBP and dry Na2S with variation of the reaction medium [337]. N-Cyclohexylpyrrolidone was found to yield the highest molecular weights. In another publication random copoly(ketone sulfone sulfide)s were prepared by copolycondensation of 4,4 -dichloro-benzophenone and 4,4 -dichlorodiphenylsulfone with NaSH (222) [344]. The crystallinity was found to depend on the molar fraction of benzophenone moieties. 

Cupric chloride Nucleophilic substitution of 2-thiopyridme oxide groups Ethers from thioethers... 

The cleavage of heteroaryl sulfones from polymeric supports can be achieved by reaction with azide ions. Suckling el al. applied this strategy to the synthesis of pteridines. In fact, the starting pyrimidine was linked to polystyrene via a thioether 214. After con-stmction of the pteridine ring system, the activation of the sulfur linker by oxidation to the sulfone with dimethyldioxirane followed by nucleophilic substitution with sodium azide affords the target molecule 218 in 41% overall yield (Scheme 3.30). 

A suspension of cuprous oxide promotes nucleophilic substitution in aprotic polar solvents at e. g. 150-200°. Effective nucleophiles are the anions ArO , AlkO , ArS , AlkS , CN", I, Br , and Gl phenols and thiols may be used in place of their salts.—E Thioethers from halides. 1-Bromonaphthalene and Na-thio-phenoxide heated 24 hrs. at 153° in dimethylformamide containing CugO -> 1-phenylthionaphthalene. Y 99%. F. e. s. R. G. R. Bacon and H. A. O. Hill, Soc. 1964, 1108. 

An alternate and more controlled approach to the synthesis of phenothiazines involves sequential aromatic nucleophilic displacement reactions. This alternate scheme avoids the formation of the isomeric products that are sometimes observed to form from the sulfuration reaction when using substituted aryl rings. The first step in this sequence consists of the displacement of the activated chlorine in nitrobenzene (30-1) by the salt from orf/io-bromothiophenol (30-2) to give the thioether (30-3). The nitro group is then reduced to form aniline (30-4). Heating that compound in a solvent such as DMF leads to the internal displacement of bromine by amino nitrogen and the formation of the chlorophenothiazine (30-4). Alkylation of the anion from that intermediate with 3-chloro-l-dimethylaminopropane affords chlorpromazine (30-5) [31]. 

Tables IV through IX summarize the data that are currently available on the rates of bimolecular substitution and dehydrohalogenation reactions between sulfur nucleophiles and halogenated aliphatic substrates in aqueous solution (i.e., either measured in water or extrapolated to water from a non-aqueous or partially aqueous solvent). The sulfrir nucleophiles considered in these tables are HS-, S2-, S42-, S52- (Table IV), S2032 (Tables V and VIII), SO32-, HSO3 (Table VI), thiolate anions (Tables VII, VIII, and IX), thiols, thioethers, and thioadds (Table VII).

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

The photochemical step Is initiation of radical anion formation by electron transfer from the nucleophile to the aryl halide, one of the two being In the excited state. Thus amino acid substituted diaryl thioethers have been prepared In high... 

Oxidation of the thioether function to a sulfoxide function (Equation (22)) is also completely stereoselective (154). Ligands (157)-(160) are obtained in enantiopure form from the enantiopure functionalized oxirane shown in Equation (23). The starting material shown in Equation (24) is obtained from ortho-CeE FCE NE and is easily transformed into ligand (166). The starting material shown in Equation (25) is prepared from ortho-C6H4ECI IO in a multistep procedure. The fluorine function may be substituted by a phosphorus nucleophile to yield (167) and (168). 

Villalgordo et al. [22, 23] as well as Gayo and Suto [25] developed a strategy to cleave pyrimidines from the solid support. After oxidation of the thioether-linkage 17, aromatic substitution of the sulfonyl unit was performed with different N-nucleophiles as amines and azides to give free amino- or azido-pyrimidines 19 (Scheme 16.5). To demonstrate the stability of the linker, the resin-bound derivatives were subjected to different reactions such as saponification, ester reduction, acid chloride formation or Mitsunobu alkylation. A similar approach was presented later on by Hwang and Gong in the SPOS of 2-aminobenzoxazoles [26]. 

---