Sulfuric alkylation

It is known that on treatment of alkyl aryl sulfoxide 1 with alkylmetal (alkyl-lithium or Grignard reagent) sulfur-aryl (path a) or sulfur-alkyl (path b) bond cleavage occurs to give arylmetal 2 or alkylmetal 3 (Scheme 3.9). This reaction is commonly called the hgand exchange reaction of sulfoxides. Although the predominant path of this reaction depends on the structure of the sulfoxide 1, this dependence remains somewhat obscure at present. 

Treatment of 127 with cysteinate-iron in the presence of excess of methyl cysteinate led to formation of a sulfur-alkylated methyl cysteinate derivative 153 in 33% yield (Scheme 20), suggesting a possible mechanism for antimalarial action by tetroxanes <2003CHJ875>. 

M. Wecker, D. Smith, L. Gold, In vitro selection of a novel catalytic RNA characterization of a sulfur alkylation reaction and interaction with a small peptide, RNA, 1996, 2, 982-994. 

The potential advantages of LPG concern essentially the environmental aspects. LPG s are simple mixtures of 3- and 4-carbon-atom hydrocarbons with few contaminants (very low sulfur content). LPG s contain no noxious additives such as lead and their exhaust emissions have little or no toxicity because aromatics are absent. This type of fuel also benefits often enough from a lower taxation. In spite of that, the use of LPG motor fuel remains static in France, if not on a slightly downward trend. There are several reasons for this situation little interest from automobile manufacturers, reluctance on the part of automobile customers, competition in the refining industry for other uses of and fractions, (alkylation, etherification, direct addition into the gasoline pool). However, in 1993 this subject seems to have received more interest (Hublin et al., 1993). 

Alkylation of 2-methylaminothiazole (204) with ROH in 85% sulfuric acid gives 2-methylimino-3-alkyl-4-thiazoIine (54). 2-Amino-4-rnethyl-thiazoie alkylated with an excess of isopropanol, however, gives 95% of 2-isopropylamino-4-methyl-5-isopropylthiazole (56). The same result is obtained with cyclohexanol (242). These results and those reported in Sections III.l.C and IV.l.E offer interesting new synthetic possibilities in thiazole chemistry. The reactive species in these alkylations is the conjugate acid of 2-aminothiazole. and the diversity of the products obtained suggests that three nucleophilic centers may be operative in this species. 

The general pattern of alkylation of 2-acylaininothiazoles parallels that of 2-aminothia2ole itself (see Section III.l). In neutral medium attack occurs on the ring nitrogen, and in alkaline medium a mixture of N-ring and N-amino alkylation takes place (40, 43, 161. 163). In acidic medium unusual behavior has been reported (477) 2-acetamido-4-substituted thiazoles react with acetic anhydride in the presence of sulfuric acid to yield 2-acetylimino-3-acetyl-4-phenyl-4-thiazolines (255) when R = Ph. but when R4 = Me or H no acetylation occurs (Scheme 151). The explanation rests perhaps in an acid-catalyzed heterocyclization with an acetylation on the open-chain compound (253), this compound being stabilized... 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

Nucleophilic reactivity of exocyclic sulfur appears in acidic medium. 2-AryI thiazolyl sulfones are obtained from the corresponding sulfides by oxidation with HjO- in HOAc at 100°C (272). The same oxidation takes place with alkyl sulfides (203. 214, 273-275) and dithiazolylsulfides (129). However, the same reaction with 2-benzylthio derivatives gives benzylal-cohol and the related A-4-thiazoline-2-thione (169). 

Alkylation of 5-mercaptothiazole in alkaline medium takes place on sulfur (348, 362). 

A-2-Thiazoline-4-ones are usually obtained by the heterocydization method (38b-388). 2 Alkylthio-4(5)-thiazolones (162) are obtained by alkylation at sulfur of rhodanine (160) in nonpolar solvent (Scheme 85). 

The 2-benzamido 4-aryl(alkyl)selenazoles (96) form the corresponding 5-nitro derivatives under mild conditions using the nitrate-sulfuric acid method (Scheme 31). The nitro compounds are well-defined, ciy s-talline compounds. They may be most favorably obtained by dissolving the 2-benzamidoselenazoles in acetone and adding concentrated nitric... 

Alkyl selenazoles have been sulfonated. Thus 2,4-dimethylselenazole with fuming sulfuric acid (5% SO3) at 100°C gives 2.4-dimethy -5-sulfonylselenazole [m.p. 238 C (decomp.) (26)], which is relatively unstable. decomposing to give metallic selenium. 

Some 5-substituted 2-aminothiazoles with alkyl (15, 173, 175, 224, 366, 396), ester (173, 184, 220), aryl (115, 265, 396, 414), a-naphthyl (463), sulfur and sulfones derivatives (329, 373), isonitrosomethyl (772), and chloro groups were synthetized from the corresponding a-haloaldehyde and thiourea in lower yield (Table 11-14). 

The yields with the lower alkyls rarely exceed 50%. For example, with R, =R2 = Me, the yield is 20% in an aqueous acidic solution (219) or 40% in an acetic solution acidified with sulfuric acid (369). 

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