Alkyl halides with thiourea

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. 

The analysis of isothiouronium salts, which are conveniently formed by reacting alkyl halides with thiourea, provide a way to study alkyl halides . The H NMR spectrum of s-butylisothiouronium chloride and bromide exhibited enantiomeric discrimination in the presence of [Eu(tfc)3(fod)] The enantiomeric purity of several alkyl methyl phenyl sulfonium ions (73) under conditions of slow inversion was determined using either [Eu(tfc)3(fod)] or [Eu(tfc)4] It was possible to study the inversion barrier by variable-temperature studies in the presence of the shift reagent. 

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 preparation of thiols involves nucleophilic substitution of the Sn2 type on alkyl halides and uses the reagent thiourea as the source of sulfur. Reaction of the alkyl halide with thiourea gives a compound known as an isothiouronium salt in the first step. Hydrolysis of the isothiouronium salt in base gives the desired thiol (along with urea) ... 

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. 

From the alkyl halide with thiourea in 95% ethanol, followed by additton of picric acid in ethanol For directions and examples see Lmstead, pp 82 3, Shriner, p 245, Vogel, pp 291 2, Wild, p 43, E L Brown and N Campbell, 7 Chem Soc, 1699 (1937), W J Levy and N Campbell, 7 Chem 5oc, 1442 (1939) From the alkyl halide with thiourea in ethylene glycol, followed by addition of picric acid in ethanol See Cheronis, p 550, H M Crosby and J B Entnkin, 7 Chem Ed, 41, 360 (1964)... 

Reaction of primary and secondary alkyl halides with thiourea is usually carried out in the following manner thiourea (2 mmole) is boiled with the corresponding alkyl halide (1 mmole) in ethanol (3 ml) or acetone. Reaction times vary appreciably with the nature of the halide. Primary alkyl bromides may be heated only 20—30 min, and the reaction of primary alkyl iodides requires 10—20 min for primary alkyl chlorides the reaction time has to be prolonged to 120—180 min while adding potassium iodide (0.1 g of KI is first dissolved in a few drops of water). 8econdary alkyl bromides require practically the same time for their reaction as primary alkyl chlorides. 8econdary alkyl chlorides require 3 —10 hr of boiling. 

Reactions of tertiary alkyl halides with thiourea are carried out in 50 — 90% aqueous alcohol (10—15 ml) (6) 5 to 6 mmole of halide and 0.5 g of thiourea are boiled for 2—5 hr until the layer of halide disappears. 

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. 

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 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. 

In the known preparation of thiols from alkyl halides and thiourea, the intermediate thiopseudourea (77) is cleaved by aqueous alkali when an activated thiourea is used, heating with ethanol s ces to produce the thiol directly (Scheme 158). The conversion of thiols into alkyl halides is cited above. ... 

Thiourea, unlike urea, readily reacts in the tautomeric form (I) in the presence of suitable reagents, particularly alkyl halides thus benzyl chloride reacts with... 

Place a mixture of 0-5 g. of finely powdered thiourea, 0-5 g. of the alkyl halide and 5 ml. of alcohol in a test-tube or small flask equipped with a reflux condenser. Reflux the mixture for a j)eriod depending upon the nature of the halide primary alkyl bromides and iodides, 10-20 minutes (according to the molecular weight) secondary alkyl bromides or iodides, 2-3 hours alkyl chlorides, 3-5 hours polymethy lene dibromides or di-iodides, 20-50 minutes. Then add 0 5 g. of picric acid, boil until a clear solution is obtained, and cool. If no precipitate is obtained, add a few drops of water. RecrystaUise the resulting S-alkyl-iso-thiuronium picrate from alcohol. 

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. 

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

An acylated glycosyl halide, such as a 2,3,4,6-tetra-O-acetyl derivative, is treated with thiourea. The resulting pseudothiouronium salt is hydrolyzed with aqueous potassium carbonate to give the 2,3,4,6-tetra-0-acetyl-l-thio-(3-D-glucopyranose,48 which then is alkylated. 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

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 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. - ... 

A special case of SNAr is shown in Fig. 20. It actually involves a tandem 8 2-SNAr process on an Ugi adduct containing both an alkyl and an aryl halide. In 99, the acid-derived alkyl halide behaves therefore as a masked nucleophile. Treatment with thiourea (Sn2) forms an intermediate thiouronium salt which, upon basic hydrolysis, releases the required thiolate that undergoes the SnAt process. A library of benzothiazepinones 100 was produced in this way [92]. 

Polymeric pseudothioureas are made by reacting linear polythioureas with alkylating agents [56], Thioureas may also be alkylated by alkyl sulfates, halo-hydrins [57, 58], sulfonates [59], alkyl halide derivatives [60-64], and certain unsaturated acids and their esters [65]. 

Although thiourea readily reacts with alkyl halides or a mixture of hydrogen halides and alcohols to give pseudothiourea salts, urea fails to react under similar conditions [8, 9] (Eq. 4). 

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 thiols are the sulphur analogues of the alcohols and were formerly called the mercaptans. Although they may be prepared by the interaction of an alkyl halide and sodium hydrosulphide in ethanolic solution, a better method involves the interaction of an alkyl bromide and thiourea to form an S-alkylisothiouronium salt, followed by hydrolysis of the latter with sodium hydroxide solution. 

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