Isothioureas thioureas

Sulfur is reactive ia many forms. Mercaptides are alkylated to thioethers, and thioethers react further to give sulfonium salts, R2S" CH20S0 2-Suitable thiones also alkylate. Thioachdone (34) and thiourea (35) are examples the first gives the alkylmetcaptoacridine and the second gives the isothiourea. 

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. 

Preparation of guanidine from thioureas has been carried out. There are many ways to synthesize guanidines. Converting thioures and isothiourea moieties into guanidine is one of the most popular methods. 

The reactions of the cis thiourea 118 ( = 1, 2 R = H, Me) with methyl iodide and subsequent alkali treatment, similar to the synthesis of 110-117, afforded the unsubstituted oxazine derivatives 119 only the attempted cyclization of the N-methyl analog failed, when the reaction furnished the isothiourea derivatives 120 (n = 1, 2). Compounds 120 could not be... 

In most of these reactions, it is nitrogen of a urea, thiourea, isothiourea, or an amidine which is the nucleophile for the addition to an appropriately situated electrophilic carbon. Conditions which enhance the electrophilic character of the carbon, or the nucleophilicity of the nitrogen, promote cyclization. Most commonly, this cyclization is affected by nitrogen addition to the electrophilic / -carbon of a Michael acceptor, and can be performed under acid or basic conditions. 

Suitable thiones also alkylate. Thioachdone (34) and thiourea (35) are examples the first gives the alkylmetcaptoacridine and the second gives the isothiourea. 

Scheme 14 shows a typical example in a series of reactions in which a supported amino acid reacted with fluorenylmethoxycarbonyl isothiocyanate to give a supported (on Rink s amide)35 thiourea.36 Removal of the protection followed by 5-alkylation gave supported isothioureas. Reaction of these with amines, then cleavage from the resin, afforded substituted guanidines. For 10 examples the purities were between 40 and 92%. An aryl group separates the resin from the guanidine, just as in the sequences shown in Schemes 11 and 12. 

Isothioureas similarly give, in neutral media, the corresponding 3-alkylthio-5-amino-l,2,4-thiadiazoles (65) in yields exceeding 70%.84"86 However, the attempted preparation of the parent 5-amino-3-mercap-to-l,2,4-thiadiazole from thiourea or dithioformamidine by this route yielded only intractable mixtures.85... 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Due to its high potency and selectivity imetit (24) proved to be a valuable tool in pharmacological trials related to H3 receptors, but in spite of that the potential toxicity of its isothiourea moiety emerges to impede further pharmacological development. A similar situation arose with the H3 antagonist thioperamide, the clinical development of which was ceased due to hepatotoxicity which is most probably related to its thiourea functionality. 

Conversion of the diamine of 52 to a guanidine proved very challenging. Reaction of 52 with thiophosgene26 afforded cyclic thiourea 53 in only 40% yield and initial attempts to convert 53 to the guanidine were unsuccessful. Reaction with methyl iodide in MeOH at reflux afforded isothiourea 54, which did not form the desired guanidine on treatment with ammonia in MeOH. 

In order to classify the reactive building blocks, we grouped them into mono-and bidentate nucleophiles (e.g. amines, alcohols, thioureas, isothioureas, amidi-nes, amidrazones), into their mono- and bis-acceptor counter parts (e.g. alkyl halides, a-bromomethyl ketones, a-alkinyl ketones), and into donor-acceptor species (e.g. isocyanates, isothiocyanates, 2-azido benzoic acids215), as depicted in Figure 40. 

Thiourea reacted with a-bromophenylacetonitrile and as a result of this reaction 2-(cyanophenylmethyl)isothiourea was obtained. 

Thioalcohols react with carbodiimides to give isothioureas 540. Ehmination of thiourea can occur if an acidic jS-hydrogen is available. ... 

As mentioned earlier, the other main NCN synthons which are commonly available are ureas, thioureas and isothioureas, which condense with... 

Treatment of 3-amino-6-methoxypyridine or the corresponding thiourea 471 with thiophosgene gives the l,3-thiazetidine-2-thione 472. 1,3-Thiazetidine-2-thiones are possible intermediates in the reaction of carbon disulfide or isothiocyanates with isothioureas,in the reaction of carbon disulfide with imines, " and in the reaction of salts of dithiocarbamic acids with a,/3-unsaturated acid chlorides. 4-Imino-l,3-thiazetidine-2-thione is suggested as an intermediate in reactions of isothiocyanic acid (HNCS). ... 

A problem with the first route is that even with excess of the thiolate, it is difficult to avoid some further reaction leading to formation of the sulfide (R2S). The secondary reaction can be avoided by starting with thiourea (la) and obtaining the thiol via the intermediate S-alkylisothiuronium salt (2) by subsequent hydrolysis (Scheme 2). The formation of the isothiuronium salt (2) depends on the relative instability of the thione ( C=S ) bond in thiourea (la), which therefore exists mainly as the enethiol form isothiourea (lb) which then reacts with the halide. S-Benzylisothiuronium salts are used in organic qualitative analysis for the characterisation of carboxylic acids with which they form nicely crystalline... 

Preparation of mercaptans (thiols). An alkyl halide, for example lauryl bromide, reacts with thiourea to give the isothiourea hydrobromide, which on alkaline hydrolysis affords the mercaptan. In the preparation of lauryl mercaptan the... 

Alkoxy- and alkylthio-substituted aminothienopyrimidines 94 were prepared by cyclization of the corresponding isoureas and isothioureas 95. Isoureas are generated in situ from thiophenes 30 with cyanates in the presence of acids (1984INDP151496). Isothioureas are produced by alkylation of thioureas 33 (1991GEP287503). 

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