Alkyl halide reaction with thiols

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 often works poorly unless an excess of the nucleophile is used because the product thiol can undergo a second S 2 reaction with alkyl halide to give a sulfide as a by-product. To circumvent this problem, thiourea, (NH2J2C=S, is often used as the nucleophile in the preparation of a thiol from an alkyl halide. The reaction occurs by displacement of the halide ion to yield an intermediate alkyl isothiourea salt, which is hydrolyzed by subsequent reaction with aqueous base. 

Sodium hydrogen sulfide can be used for the preparation of thiols (19) by reaction with alkyl halides. A large excess of sodium hydrogen sulfide must be employed to avoid formation of the dialkyl sulfide (Scheme 17) (see Chapter 4, p. 41). 

In the presence of sodium hydroxide, thiols react with alkyl halides to form the sulfides (20) the reaction occurs via the sodium thiolate and is analogous to the well-known Williamson synthesis of ethers and can also be applied to obtain unsymmetrical sulfides (Scheme 18). Symmetrical sulfides may be prepared directly by condensation of sodium sulfide with alkyl halides (Scheme 18). These reactions are of the SN2 type, and consequently the optimum yields of sulfides are realised using primary alkyl halides. 

The value of thiourea for the preparation of thiols is that on reaction with alkyl halides,271 mixtures of hydrogen bromide and alcohols,272 or suitable aromatic273 or heterocyclic halides274 it readily yields S-alkyl- or S-aryl-thiouronium salts, from which the thiols are usually obtained in good yield by alkaline hydrolysis or by aminolysis with high-boiling, strongly nucleophilic... 

Support-bound thiols can be alkylated under mild reaction conditions with alkyl halides, a, 3-unsaturated carbonyl compounds, or reactive aryl halides (Table 8.4). These reactions should be conducted under an inert atmosphere or in the presence of a reducing additive to prevent disulfide formation. PEG-bound thiophenol has been S-alkylated under conditions similar to those used in solution (DMF, Cs2C03, 20 °C, 15 h [52-54]). 

A kinetic study of the alkylation of coordinated thiol in NH2CH2-CH2SH and related ligands revealed that the reaction proceeded without the breaking of the metal-sulfur bond (11). The nucleophilicity of the coordinated sulfur was found to depend on the central metal involved but was greater than that of the sulfur in a thiol. It was found that sulfur in such ligands did not react with alkyl halides when it occupied a bridging position between two metal atoms in a polynuclear complex. 

Sodium sulfhydride (NaSH) is a much better reagent for the formation of thiols (mercaptans) from alkyl halides than H2S and is used much more often. It is easily prepared by bubbling H2S into an alkaline solution, but hydrosulfide on a supported polymer resin has also been used. " The reaction is most useful for primary halides. Secondary substrates give much lower yields, and the reaction fails completely for tertiary halides because elimination predominates. Sulfuric and sulfonic esters can be used instead of halides. Thioethers (RSR) are often side products. The conversion can also be accomplished under neutral conditions by treatment of a primary halide with F and a tin sulfide, such as PhsSnSSnPhs. An indirect method for the preparation of a thiol is the reaction of an alkyl halide with thiourea to give an isothiuronium salt (119), and subsequent treatment with alkali or a... 

The open-chained thioacetamide, on the other hand, yields iminium salts (34) on acylation. Reaction of (34) with alkyl halides and subsequent hydrolysis results in the formation of thiocarboxylic esters (1). This reaction is actually performed in one step under phase transfer catalysis (equation 21). No unpleasant smelling thiols or thiocarboxylic acids are required as educts, the yields are high and a large variety of substituents R and R are possible. ... 

Hydrogen sulfide also reacts by nucleophilic substitution with alkyl halides and alcohols under appropriate conditions to form thiols (Scheme 10) (see Chapter 4, p. 42). The reaction with an alkyl halide is generally facilitated by using sodium hydrogen sulfide (NaSH) rather than hydrogen sulfide since NaSH is a much better nucleophile. Hydrogen sulfide also adds to ketones to give gem-dithiols (13) (Scheme 11). 

Symmetrical disulfides (73) may be prepared by reaction of alkyl halides with disodium disulfide (Scheme 43). The product is contaminated with triand polysulfides owing to the presence of impurities in the disodium disulfide however, lower members of the series of dialkyl disulfides may be purified by fractional distillation. Disulfides can also be obtained from thiols by mild oxidation, e.g. by treatment with iodine or dimethyl sulfoxide (DMSO) (Scheme 44). In the reaction with iodine, the hydriodic acid formed must be removed, otherwise the disulfide is largely reduced back to the thiol by hydriodic acid which is a powerful reducing agent. Pure unsymmetrical disulfides are more difficult to prepare owing to their tendency to undergo disproportionation they can, however, be synthesised from thiols by treatment with imides (see p. 59) or sulfenyl halides (51) (Scheme 45). 

---