Alkylation of thioamides

Imidothioesters are easily obtained through 5-alkylation of thioamides, and we have noted (see Section 2.8.3) a general preparation of such compounds from isothiocyanates via addition of an organometallic and 5-alkylation. 

The alkylation of thioamides is currently used for the Eschenmoser reaction which is discussed later in this article. 

In general S-alkylation of thioamides occurs much more readily and selectively than O-alkylation of amides. Thus, N-silylmethylthioamides obtained by the reaction of N-silylmethylamides with Lawesson s reagent (83JOC4773) are treated with methyl triflate to give C-methylthioiminium triflate ylide precursors. Their desilylation with cesium fluoride generates C-hetero-substituted azomethine ylides 35 (83JOC4773 85JOC2170). 

Alkylation of thioamides with Meerwein s reagent (trialkoxonium fluoroborate) proceeds via a thioiminoester and subsequent base hydrolysis with sodium carbonate (equation 32). For the synthesis of 2-pyridones from 2-thiopyridones, chloroacetic acid has been used. ° Mild reaction conditions are provided by nitrosyl species which are derived from a variety of reagents excess NaNOa/HCP in aqueous medium, nitrosonium tetrafluoroborate in dichloromethane, dinitrogen tetroxide in acetonitrile at low temperature and f-butyl thionitrate. ... 

The high nucleophilicity of sulfur facilitates the alkylation of thioamides. The alkylation of thioamides and thiolactams is a long-known synthesis of alkylmercaptomethyleneiminium compounds (107 equation 66), which has been reviewed several times. - Nearly all types of alkylating reagents and amides were used for these reactions (see Table 3). 

Table 6 Starting Compounds for the Synthesis of Thioimidates by Alkylation of Thioamides...

In the latter case the S N allyl group migration is only efficient when Pd catalysis is employed, otherwise, at much higher temperatures, a double bond isomerization occurs first and is then followed by an S C allyl shift by means of a thio-Claisen rearrangement. As the appropriate 5-allyl thioimidates are easily prepared by alkylation of thioamides with allyl halides, the overall process is an 5n substitution of an allylic halide by an amine, a reaction which is difficult to achieve directly. 

Reactions.—Many examples of the normal S -alkylation of thioamides have been reported > > 322-325,353,354 5 c-alkylation of selenobenz-... 

Alkylation of 737 with 738 gave 739 (81USP4252806). Reaction of 2-hydrazinoquinoline with the quaternary salts of N,N-substituted thioamides gave the hydrazones 735 whose cyclization in acetic acid gave triazoloquinolines 736 (80PJC661) (Scheme 127). 

The coupling of thioamides with a variety of oxidizing agents is a widely utilized method for the synthesis of 3,5-diaryl-l,2,4-thiadiazoles (see Section 5.08.9.2). This method is not suitable for alkyl derivatives. 3,5-Dialkyl derivatives can be more effectively prepared from a suitably substituted thioacylamidine (see Equation 22), and this method allows a range of unsymmetrical derivatives to be prepared. 

The thiophene synthesis described herein is related to the synthesis in solution reported by Laliberte, and Medawar4 but differs in some aspects from the procedure in homogeneous phase. Laliberte and Medawar succeeded in obtaining aminothio-phenes in a one-pot reaction from acceptor-substituted acetonitriles, isothiocyanates, a-haloketones, and sodium ethoxide. In contrast to their procedure, solid-phase S-alkylation of the intermediate thioamides under basic conditions led to the formation of product mixtures. We obtained pure aminothio-phenes only when conducting the S-alkylation under neutral or slightly acidic conditions. 

General procedure for alkylation of amidic and thioamidic heterocyclic systems... 

Benzenecarhodithioesters and carbo-thio-S-esters were shown to yield diphenylacetylene by the cathodic reduction in aprotic media. Thus, the formation of diphenylacetylene involves [202] two molecules of a substrate. The cathodic reactivity of thioamides involving a similar alkylation of the C=S group in the presence of primary alkyl halides was reviewed [199-201]. 

As mentioned earlier, the first example of the generation of a thiocarbonyl ylide by deprotonation of a thioxonium salt was reported by Knott (18) and is presented in Scheme 5.1. This method is frequently used since the starting materials 32 are easily available via alkylation of C=S functionalized compounds such as thioke-tones, thioamides, thiourea derivatives, and dithioesters (Scheme 5.11). 

Scheme 28 shows the alkylation of the thioamides to give alkyl sulfides of pyrazolo[3,4-. 

Support-bound C,F I-acidic compounds, such as acetoacetamides, react with isocyanates under basic conditions to yield amides through C-carbamoylation [71]. Similarly, polystyrene-bound aryllithium compounds can be converted into benzamides by treatment with isocyanates [111]. These reactions are closely related to C-thiocarbamoyla-tion, which has been used for the solid-phase synthesis of thioamides (see Section 13.9). Amides have also been prepared by C-alkylation of resin-bound N-acylaminals with allyltrimethylsilane or diethylzinc (Entry 11, Table 13.7). 

Trialkyloxonium ions have been extensively used to carry out O-alkylation of lactams, amides, sulfoxides, oxo-sulfonium ylides, iV-alkylation of iV-heterocycles, 5-alkylation of thioethers, thioacetals, thioamides, and thiolactams.1,90 Although trialkyloxonium ions do not alkylate benzene or toluene directly, alkylations readily occur in combination with highly ionizing superacids such as HS03F-SbF5. This may indicate protosolvation of a nonbonded electron pair on oxygen in the superacid medium. 

Phenylthiosemicarbazones cyclize easily to triazolo derivatives when heated alone or refluxed in high-boiling solvents. Phenylthiosemicarbazones 95 were refluxed in DMF and cyclized into 4,5-dihydro[l,2,4]tria-zolo[3,4-t/][l, 5]benzothiazepine-l(2tf)-thiones (96), which can exist either in the thioamidic or in the iminothiolic form. Infrared spectra showed that the thioamidic form seems to be preferred. By PTC alkylation of 96 with methyl iodide, ethyl chloroformate, or chloroacetic acid, the corresponding -substituted derivatives 97 were obtained (Scheme 28) (91MI1). Many of the compounds were cytotoxic and hence not screened further others were tested as antibacterial, antimycotic, and antiviral agents, but no appreciable activity was observed. 

The use of soft metal ions to direct the course of reactions of sulfur compounds has been utilised in the preparation of nitriles from thioamides. The first step involves the alkylation of the thioamide to give the iminothioester, which is then converted to the nitrile on treatment with mercury(n) salts (Fig. 4-41). 

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