Isothioureas halides

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. 

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. 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

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... 

Studies by Johnson and Sprague619,620 have shown that the action of chlorine or bromine on aqueous solutions of alkylthiouronium salts affords sulfonyl chlorides or bromides, respectively, and this process is particularly useful because isothiourea derivatives are very easily accessible from alkyl halides and thiourea (see page 692). 

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