Thiourea isothiouronium salts

The sulfur atom of the thiocarbonyl group is a good nucleophile, and reaction between benzyl bromide and l-(2-thiazolyl)thiourea yields the isothiouronium salt (496). The sulfur atom may also be engaged in a chelate, as exemplified by the Cu chelate of 2-thioureido-4-methylthiazole (491). These chelates with metal ions were thoroughly studied in acidic, neutral, and alkaline media for 66 metal ions in order to define their analytical use. They are formed in the molar ratio of 1 2 for metal II compounds (498). 

Thiourea derivative of Hercosett (isothiouronium salt) Scheme 10.63 Build-up good for dichlorotriazine dyes. Dyes of other types gave good results up to about 2% applied depths... 

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). 

Aminopropanols, when reacted with cyanogen bromide, also afford 2-amino-(or imino)-dihydro-1,3-oxazines (Scheme 90) (64ZOB3427), and related thiazines are formed when allylic isothiouronium salts (207) are cyclized with trifluoroacetic acid and stannic chloride. The necessary starting materials are synthesized from aldehydes or ketones by the action of vinylmagnesium chloride and subsequent treatment of the product allyl alcohols (206) first with hydrogen chloride and then with a thiourea (Scheme 91) (77JHC717). 

Some strategies used for the preparation of support-bound thiols are listed in Table 8.1. Oxidative thiolation of lithiated polystyrene has been used to prepare polymeric thiophenol (Entry 1, Table 8.1). Polystyrene functionalized with 2-mercaptoethyl groups has been prepared by radical addition of thioacetic acid to cross-linked vinyl-polystyrene followed by hydrolysis of the intermediate thiol ester (Entry 2, Table 8.1). A more controllable introduction of thiol groups, suitable also for the selective transformation of support-bound substrates, is based on nucleophilic substitution with thiourea or potassium thioacetate. The resulting isothiouronium salts and thiol acetates can be saponified, preferably under reductive conditions, to yield thiols (Table 8.1). Thiol acetates have been saponified on insoluble supports with mercaptoethanol [1], propylamine [2], lithium aluminum hydride [3], sodium or lithium borohydride, alcoholates, or hydrochloric acid (Table 8.1). 

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

The conversion of halogenopyrazines into pyrazinethiones is usually done either with sodium hydrogen sulfide solution or by initial treatment with thiourea and subsequent hydrolysis of the intermediate isothiouronium salt (frequently unisolated). A third method, involving treatment of the halogeno substrate with thiosulfate, has proven promising in some heterocyclic series but not so far in the pyrazines 2-chloropyrazine did so give 2(1 //)-pyrazinethionc but only in 20% yield.1358... 

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. 

Cyanomethyl isothiouronium salt, as acyclic intermediate in reaction of thiourea with o-halonitrile, 297 Cyanothiazoles, from dehydration of amides, 530, 531... 

The preparation of thiols involves nncleophilic snbstitntion of the Sn2 type on alkyl halides and nses the reagent thiourea as the sonrce of snlfnr. Reaction of the alkyl halide with thionrea gives a compound known as an isothiouronium salt in the hrst step. Hydrolysis of the isothiouronium salt in base gives the desired thiol (along with urea) ... 

Thiourea Alkyl halide Isothiouronium salt Urea Thiol... 

The enol form of compound 32 can be transformed into 4-chloro derivative 33 by phosphorus oxychloride. Thiourea with the latter produced a 6-mercapto derivative through the respective isothiouronium salt and mild hydrolysis. The last three compounds revealed antitumor and antiviral activities against Herpes simplex type 1 and influenza virus, respectively (92KFZ(9-10)63) (Scheme 7). 4-Chloro derivative... 

The mercapto group can also be formed via the isothiouronium salt (Andriska et al., 1962b Kniisli et al., 1962). With thiourea 2-chloro-4,6-bis(alkylamino)-5-triazines give isothiouronium salt in a practically quantitative yield this is then decomposed by alkali to the corresponding mercapto compound and dicyano diamide. From this, the 2-mercapto-4,6-bis(alkylamino)-s-triazinc derivative is obtained with a methylating agent. The reaction scheme is as follows ... 

The evidence available suggests that, in a general way, steric factors affect the course of the reaction. Increase in the size of substituents at positions 5 or 7 or in the size of the nucleophile appears to favor protode-bromination over nucleophilic substitution, Furthermore it appears that 6-iododihydrodiazepines undergo protodeiodination rather than nucleophilic substitution irrespective of the size of the nucleophile or of 5(7)-substituents, whereas 6-chlorodihydrodiazepines are less susceptible to protodchalogenation.64 Thus with thiourea 6-bromodihydrodiazepines undergo protodebromination, whereas 6-chlorodihydrodiazepines form 6-isothiouronium salts, in contrast to the normally more ready formation of isothiouronium salts from bromo compounds than from chloro compounds. It is not unreasonable that protodehalogenation should be favored for more bulky dihydrodiazepines or nucleophiles since this reaction has less steric demands than nucleophilic substitution. Similarly, both for... 

Quinoxaline-2-thione (2) is prepared from 2-chloroquinoxaline by treatment with thiourea in methanol, followed by hydrolysis of the resulting isothiouronium salt (1) with 2.5 M sodium hydroxide. A number of other quinoxaline-2-thiones have been prepared by this method, in most cases without the isolation of the intermediate isothiouronium salt. 3-Hydrazinoquinoxaline-2-thiones are obtained from the corresponding 2-chloro-3-hydrazinoquinoxalines by treatment with an aqueous solution of alkali sulfide or alkali hydrogen sulphide.3-Amino-quinoxaline-2-thione has been prepared similarly by treating 2-amino-3-chloroquinoxaline with methanolic potassium hydrogen sulfide in an... 

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. 

A soln. of phenothiazine, thiourea, and K-acetate in methanol treated with a soln. of anhydrous FeClg in the same solvent -> isothiouronium salt (Y 60%) refluxed with Og-free 6 N NaOH under N, product (Y 80%). F. e. s. J. Daneke et al., Tetrah. Let. 1970, 1271. 

Ethyl bromide refluxed 6 hrs. with thiourea and ethanol, the resulting soln. coned, in vacuo on a water bath, water and aq. NaOH or KOH added during 10 min. to the resulting isothiouronium salt, refluxed 1 hr., cooled, ethyl bromide added dropwise during 0.5 hr., and gently refluxed for 5 hrs. diethyl sulfide. Y 65%. F. e. s. G. Drefahl and H. Schick, Z. Chem. 4, 347 (1964). 

The benzylsulfonamide (XIII) used in the preparation of bensulfuron is obtained via the free radical chlorination of methyl i toluate to the a-chlorotoluate (Z). This compound reacts with thiourea to form the isothiouronium salt which is chlorinated in the presence of water to the sulfonyl chloride followed by amination to the sulfonamide as shown in Equation 10. 

Aminopyrimidine. Early representative examples of a sulfone traceless linker were demonstrated by Villalgordo et al. and Gayo and Suto in the synthesis of 2-aminopyrimidines. The sulfur linkage was obtained by treating Merrifield resin with thiourea to provide the isothiouronium salts 1 (Scheme 12.5). Condensation of 1 with acetylenic ketones 2 or malononitrile derivatives 3 yielded the pyrimidine skeleton 4. Oxidation of the alkylthio linkage with mCPBA provided the corresponding sulfone derivatives that underwent nucleophilic substitution with various amines to form 2-aminopyrimidines 5. 

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. 

The reaction of a-halocarbonyl compounds or their equivalents with [ C]thiourea leads to [ C]isothiouronium salts that spontaneously cyclize to 2-auiiuo[2- C]thiazoles (route B). The simplest member of the class, was au iutermediate iu the preparation of [ C]-niridazole ( 611. This reaction has been widely exploited for the preparation of more complex 2-amino[2- C]thiazole derivatives as building blocks for the preparation of compounds such as the cephalosporin [ " C]E1101 (62) and [ " C]cefepime and the /3-lactam antibiotic [ C]AMA-1080... 

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