Amines methyl, from isothiocyanates

A comparatively large selection of thioureas can be formed from the reaction of amines with isothiocyanates, hence they are attractive starting materials for formation of guanidines. A common solution-phase approach to this reaction involves abstraction of the sulfur via a thiophillic metal salt, like mercuric chloride.10 For solid-phase syntheses, however, formation of insoluble heavy-metal sulfides can have undesirable effects on resin properties and on biological assays that may be performed on the product. A more relevant strategy, with respect to this chapter, is S-alkylation of thioureas and then reaction of the methyl carbamimidothioates formed (e.g., 5, Scheme 6) with amines. This type of process has been used extensively in solution-phase syntheses.1 Ul4 Two examples are shown in Scheme 6 11 the second is an intramolecular variant, which involves concomitant detrity-lation.15... 

This is a general method for the preparation of alkyl thioureas. Ethylthiourea, m.p. 103-106°, has been prepared from ethyl isothiocyanate in the same manner. Di- and tri-alkyl thioureas may be prepared from alkyl isothiocyanates in a similar manner by substituting an equivalent amount of an amine solution in place of the ammonium hydroxide. Thus, sym -dimethylthiourea is prepared from methyl isothiocyanate and methylamine solution. A solution of dimethylamine and methyl isothiocyanate gives trimethylthiourea. 

GLC is an important adjunct to protein sequence determination. Automatic "sequenators" based upon the approach developed by Edman are available and have been described in detail by Niall (60). The Edman degradation, summarized in Equation 9.5, makes use of methyl or phenylisothiocyanate which reacts with the N-terminus of a peptide. Exposure of the isothiocyanate derivative of the protein to acid results in cleavage of the terminal amino acid as a thiaxolinones and exposure of the next amine group on the peptide. Thus, the process can be repetitively carried out, each amino acid removed from the peptide, in a sequential manner. Thiazolinones rearrange in acid medium to form thiohydantoin derivatives of amino acids, some of which may be directly gas chromatographed others must be derivatized typically as trimethylsilyl derivatives. 

In the sequential degradation according to the Edman procedure methyl or phenyl-isothiocyanate is used as the reagent and the reaction starts from the amine end of the... 

Condensation reaction between active methyl and methylene compounds and S-alkylated thioureas provides another useful synthetic pathway to the 1,1-enediamines. Rajappa and coworkers20 reported that nitromethane condensed with S-methylated thioureas 72, prepared from the reaction of amines and methyl isothiocyanate followed by S-methylation, to form asymmetric nitro 1,1-enediamines 73 (Scheme 5). 

Dielectrophilic species are 1,4-diketones, certain 1,3-dienes, a,B-unsaturated isocyanates, isothiocyanates, cyanates, and thiocyanates bearing electron-withdrawing (e.g., polyfluorinated and perfluorinated) substituents the most frequently used 1,1-dinucleophiles are water, potassium sulfide, primary amines, and ammonia. From this repertoire of building blocks many combinations are possible. Tetrakis(trifluoro-methyl)furans, thiophenes, and pyrroles have been synthesized from per-fluoro-3,4-dimethylhexa-2,4-diene on addition of water, potassium sulfide, or aniline (90CC1127) (Scheme 39). 

Lithiation of propargyl amine 12 and treatment with methyl isothiocyanate afford the thiolate 13, which cyclizes in the presence of KOBu and is methylated by iodomethane to produce 2,5-bis(iV,iV-dimethylamino)thiophene 14 (Scheme 4) <1997TL7241>. Similar reactions of 15 and 17 give the corresponding thiophenes 16 <1998EJ0253> and 18 <1998TL2433>, respectively. 2-Aminothiophenes 20 are derived from the intermediate 19 <2001TL4687>. 

In situ formation of a-aminoketones has been achieved from the reaction of a-hydroxy- or a-haloketones with amines. l,3-Dihydroxypropan-2-one has been used as a starting material in the Marckwald synthesis <1997JME3297>. Also, reaction of 4-chloro-Wmethyl-3-oxobutanamide 1274 with amines leads to cyclic (E)-N-methyl-5-(methylimino)-2,5-dihydrofuran-3-amines 1275, which behave as latent a-aminoketones. Treatment of 1275 with isothiocyanates in refluxing EtOH affords imidazole-2-thiones 1276 (Scheme 323) <2005JC0826>. 

Diethyl acetals of jV,iV-dimethylaminoformaldehyde react with 5-methyl-l,2-dithiole-3-thione180 giving enamine 8 (R = H). Analogous condensation products could be obtained from thioformyl amines. Condensation of phenyl isothiocyanate with 126a gave 6-aza-l,6a/4-dithiapentalenes (130),181 after methylation. 

Nitenpyram, from Takeda Chemical Industries, is accessible by starting from l,l-bis-(methylsrdfanyl)-2-nitroethene via sequential aminolysis with methyl-amine and 2-chloro-5-(ethylaminomethyl)pyridine, in either order (a). [150, 151] Alternatively, 2-chloro-5- (ethylaminomethyl)pyridine may also be reacted with methyl isothiocyanate, to give the corresponding thiourea this then gives the active agent by S-methylation and reaction with nitromethane (b). 

Thiourea derivatives (11) are available from 2-amino-2-deoxy-l,3,4,6-tetra-Q-acetyl-a-D-glucopyranose (9) or from the corresponding 2-isothiocyanate (10) by treatment with methyl isothiotyanate or a primary amine, respectively (Scheme 4). On exposure to hydrobromic acid they cyclise to give glucopyrano[2,l-d]-2-thiazolinium bromides (12). ... 

Various Side-chain Reactions.—2-(2-Thienyl)ethyl isocyanate has been prepared from the corresponding primary amine, carbonyi suiphide, and. S-ethyl chloro-thioformate. Cyclization of 2-(2-thienyl)ethyl isothiocyanate with methyl fluorosulphonate or triethyloxonium tetrafluoroborate gave (178a) and (178b), respectively. The 3-thienyl isomer reacted in the same way. Monoesters of aliphatic dicarboxylic acids and 2-(2-thienyl)ethanol have been prepared in con-... 

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