Thioureas reaction with alkyl halides

Thiophene, aromaticity of, 530 Thiourea, reaction with alkyl halides, 667... 

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. 

Silicon tetraisothiocyanate, reaction with 2,6-dimethylaniline to yield 2,6-diraethylphenyl thiourea, 46, 70 Silver cyanide, reaction with alkyl halides in synthesis of isocyanides, 46, 77... 

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... 

The sulfur atom of thiourea is a better source of a sulfur nucleophile in a reaction that will convert a alkyl halide to a thiol. Thiourea reacts with alkyl halides to give an isothiouronium salt. Subsequent hydrolysis of this salt in the same reaction vessel yields a thiol. 

Before the synthesis of the pseudoureas was published, Bernthsen and Klinger [6] reported a pseudothiourea synthesis involving the reaction of thioureas with alkyl halides. This reaction was briefly reviewed by Dains [16] and Stieglitz [49, 50], and it found many commercial applications [51-53]. The preparation of isothiouronium salts by the direct action of thiourea and halogen acids on alcohols (primary, secondary, and tertiary) was reported by Stevens [8] and further developed by Johnson and Sprague [54, 55] (Eq. 25). 

The reaction of disodium telluride with alkyl halides is the oldest known method for the preparation of dialkyl telluriums. The required solutions of disodium telluride can be prepared from tellurium and sodium formaldehyde sulfoxylate (Rongalite C) in aqueous sodium hydroxide (Vol. IX, p. 1048), from tellurium and sodium in liquid ammonia " dimethylformamide or tetrahydrofuran in the presence of naphthalene , from tellurium and hydrazine hydrate/sodium hydroxide in water or dimethylformamide °, from tellurium and thiourea dioxide in aqueous tetrahydrofuranor from tellurium and sodium borohydride in methanol, ethanol, tetrahydrofuran, or aqueous sodium hydroxide ... 

Thioureas generally react with alkyl halides to give S-alkylisothiuronium salts. On the other hand, by reaction with acyl halides, either the N-or S-acylthioureas may be formed. The nature of the product appears especially dependent on the reaction temperature. S-Acylthioureas (108) on heating rearrange to the N-acyl derivatives (109) (Scheme 59). 

Section 15.13 Thiols, compounds of the type RSH, are prepared by the reaction of alkyl halides with thiourea. An intermediate isothiouronium salt is formed, which is then subjected to basic hydrolysis. 

The general knowledge of the mechanism and of the kinetics of nucleophilic reactions has served very well for the reaction of thiourea with alkyl halides. 

In less-polar solvents the reaction rate of thiourea with alkyl halides drops sharply in the following order primary > secondary > tertiary tertiary alkyl halides practically no longer react with thiourea in alcoholic solution (reaction 8 2) however, as soon as the polarity of the medium is increased by the addition of water, tertiary alkyl halides become reactive. The increased polarity of the medium facilitates the 8 1 reaction mechanism. 

Two Other methods which have found general applicability in the laboratory are the reaction of alkyl halides with thiourea with subsequent alkaline hydrolysis, and the reaction of free sulfur with aryl lithium or Grignard reagents as shown below. 

Alkylation. Theoretical treatment by the CNDO method, and the analysis of orbital interactions, show a frontier orbital control for the S -methylation of MeNHC(S)NHMe. Kinetic measurements of the alkylation of thioureas with alkyl halides or tosylates have shown that this reaction is first-order in thiourea and alkylating agent, implying an 5 n2 mechanism, with direct attack by the sulphur atom. 

A variation of the use of thiourea for converting alkyl halides into thiols uses N-acetylthiourea although reaction with an alkyl halide in refluxing EtOH is slow, a separate hydrolysis step is not required and the method may prove useful for the synthesis of water- or alkali-sensitive thiols. Other methods based upon thiocarbonyl derivatives are exemplified by the addition of allylic Grignard reagents to thioketones, giving 7-unsaturated... 

Thiols, the sulfur analogs of alcohols, are usually prepared by Sjv 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide gives back the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an Sk2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are much more nucleophilic than ethers and can be oxidized to sulfoxides and to sulfones. Sulfides can also be alkylated by reaction with a primary alkyl halide to yield sulfonium ions. 

Disulfides can be prepared by treatment of alkyl halides with disulfide ions and also indirectly by the reaction of Bunte salts (see 10-41) with acid solutions of iodide, thiocyanate ion, or thiourea, or by pyrolysis or treatment with hydrogen peroxide. Alkyl halides also give disulfides when refluxed with sulfur and NaOH, and with piperidinium tetrathiotungstate or piperidinium tetrathiomolybdate. ... 

The use of sodium dithionite (Na2S204) and thiourea dioxide (TUDO HN=C(NH2)S(0)0H) has been introduced later as a reducing agent for the preparation of sodium telluride in an aqueous medium, followed by reaction with n-alkyl halides to give dialkyl teUiirides. - ... 

Oxetanes are much less susceptible to cleavage by nucleophiles than oxiranes, except in the presence of acids. Several types of acid-catalyzed nucleophilic reactions are described in the previous section, such as reaction of hydrogen halides to give 3-halogeno-1-propanols and various acid-catalyzed solvolysis reactions. Another example of this type is the reaction of thiourea with 2-alkyloxetanes in the presence of hydrochloric or perchloric acid to give excellent yields of 3-alkyl-3-hydroxybutylisothiouronium salts (equation 39) <67CR(C)(264)1309>. 

Thiols may be prepared from the corresponding alkyl halide by reaction with thiourea followed by treatment of the isothiouronium salt with base. 

The formation of an alkanethiol by reaction of an alkyl halide or alkyl /Moluenesulfonatc with thiourea occurs with inversion of configuration in the step in which the carbon-sulfur bond is formed. Thus, the formation of (R)-2-butanethiol requires (.S Kvcc-butyl /Moluenesulfonatc, which then reacts with thiourea by an SN2 pathway. The /Moluenesulfonatc is formed from the corresponding alcohol by a reaction that does not involve any of the bonds to the stereogenic center. Therefore, begin with (.S )-2-bulanol. 

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