Thioethers, from displacement reaction

Salts of hydrogen cyanide have also been found to be capable of nucleophilic cleavage of the disulfide bond in keratin fibers [72]. In addition, nearly quantitative conversion of cystinyl residues to lanthionyl residues can be achieved in this reaction [73]. The most plausible mechanism is given in Equations G and H [65]. This mechanism consists of two nucleophilic displacement reactions the first by cyanide on sulfur and the second by mercaptide ion on carbon. The following mechanism is consistent with the observed formation of thioether from the reaction of N-(mercaptomethyl)polyhexamethyleneadipamide disulfide (XV) with cyanide, but not with alkali [65]. 

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]. 

Reactions between the sulfur-containing amino acids cysteine and methionine (Fig. 2.18) and rufhenium(II) arene anticancer complexes are of much interest in view of the strong influence of sulfur amino acids on the intracellular chemistry of platinum drugs, their involvement in detoxification and resistance mechanisms [100]. We found [101] that [(ri -biphenyl)Ru(en)Cl][PF 5] reacts slowly with the thiol amino add L-cysteine in aqueous solution at 310 K, pH 2-5, and only to about 50% completion at a 1 2 mM ratio. Reactions appeared to involve aquation as the first step followed by initial formation of 1 1 adducts via substitution of water by S-bound or O-bound cysteine. Two dinuclear complexes were also detected as products from the reaction. In these reactions half or all of the chelated ethylene-diamine had been displaced and one or two bridging cysteines were present The unusual cluster species (biphenyl) Ru g was also formed espedaUy at higher cysteine concentrations. The reaction was suppressed in 50 mM triethylammo-nium acetate solution at pH > 5 or in 100 mM NaCl suggesting that thiols may not readily inactivate Ru(II)-en arene complexes in blood plasma or in cells. Similarly, reactions with the thioether sulfur of methionine appeared to be relatively weak. Only 27% of [(r -biphenyl)Ru(en)Cl][PF5] reacted with L-methionine (L-MetH) at an initial pH of 5.7 after 48 h at 310 K, and gave rise to only one adduct [(ri -biphenyl) Ru(en) (i-MetH -S)]. ... 

Trifluoromethyl thioethers are produced in a fluoride-catalysed one-pot reaction of alkyl or aryl thiocyanates with trifluoromethyl silanes [37]. The reaction is initiated by fluoride ion displacement of the trifluoromethyl anion from the silane the thioether is formed from the thiocyanate by displacement by the trifluoromethyl anion of the cyanide ion, which then perpetuates the reaction. Trifluoromethyl selenoethers are obtained by an analogous route. In a similar manner, disulphides can be converted into trifluoromethyl thio- or selenoethers [38],... 

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). 

Several replacement reactions at C-4 in sydnones may be carried out but aqueous bases must be avoided. Butyllithium can be used to displace bromine from a 3-phenylsydnone the resulting organolithium salt can be carbonylated, will add to ketones, and forms a silyl derivative (80CB1830). A sydnone Grignard derivative can also be made and will add ketones in the normal way (80JCS(Pl)20). Sodium borohydride will reduce a sydnone sulfone, formed by oxidation of a thioether (Table 5) with hydrogen peroxide, back to the unsubstituted sydnone (74T409). 

Many donor solvents displace 14S4 from Ni(II). Accordingly Rosen and Busch developed new synthetic methods that have since been widely used for preparation of thioether complexes [49,51]. Reaction of [Ni(HOAc)g] with 14S4 in MeN02 yields the red low-spin [Ni(14S4)] " cation [3]. X-ray diffraction reveals a square-planar NiS coordination sphere (Table 1) with anti stereochemistry... 

The relative ease of the cyclization step from A to C may also be linked to the nucleophilic or coordinative ability of the heteroatom bound to the metal. The reaction of 7 with diphenylacetylene (Ph2C2) leads to the seven-membered derivatives 68 and 69 after prior isolation of the monoinsertion product 24, treatment with a silver salt, followed by the usual thermolytic conditions. This is another rare example of an intramolecular formation of a C-S bond within the coordination sphere of a transition metal and a novel, albeit limited to one alkyne, route to the rare family of dibenzo[bd] thiepins. With the closely related 8, which differs from 7 only by the tertiary amine unit in the metallacyclic framework instead of a thioether function, a carbocyclic product 71 is obtained (see under carbocycle reactions, next section). The formation of the seven-membered S-heterocycles is attributed to the good coordinative ability of the thioether group in 7. The S-atom remains close to the vinylic carbon function before the cyclization. With the poorly coordinating, readily displaced amine function in 8, the N-atom is detached from the metal and ultimately affords a spirocyclic product (see Scheme 18). 

In the presence of visible light irradiation provided by a 120 W lamp and with 1 atm of O2, the Ru(II) complex in solution promoted the oxidation of dibutyl sulfide to the corresponding dibutyl sulfoxide obtained in 32% yield. Under identical experimental conditions but in the presence of the capsule, the reaction did not occur as a consequence of the encapsulation of the Ru(ll) photocatalyst. The catalytic activity was restored when repeating the same experiment with [Ru(bpy)3] in the presence of both capsule and tetraethylam-monium competitive guest, due to the displacement of the metal catalyst from the cavity of the capsule. Similar results were observed with other thioethers showing conversions to the corresponding sulfoxides that were dependent on the electron density on the sulfur atom in all cases, no conversion was observed with the encapsulated Ru(ll) catalyst. Since it was danonstrated that the absorption properties of the Ru(ll) metal center were substantially not influenced by the capsule, it is likely that the inactivation provided by the capsule could be due to interrupted energy transfer from the Ru(ll) center to O2. 

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