Methylthiophenes

Dry distillation of sodium laevulinate (I) with phosphorus sulphide gives 2-methylthiophene (II) as the main product ... 

Table 1 indicates the significant physical properties of thiophene and 2- and 3-methylthiophene Table 2, the toxicological and ecotoxicological properties. 

Table 2. Toxicological and Ecotoxicological Properties of Thiophene and Methylthiophenes ...

Table 3. Physical, Toxicological, and Ecotoxicological Properties of 2-Bromothiophene, 3-Bromothiophene, and 2-Bronio-3-Methylthiophene...

Property 2-Bromo-thiophe ne 3-Bromo-thioph ene 2-Bromo-3-methylthiophene... 

Side-Chain Derivatization. Reaction of thiophene with aqueous formaldehyde solution in concentrated hydrochloric acid gives 2-chloromethylthiophene [765-50-4]. This relatively unstable, lachrymatory material has been used as a commercial source of further derivatives such as 2-thiopheneacetonitrile [20893-30-5] and 2-thiopheneacetic acid [1918-77-0] (24). Similar derivatives can be obtained by peroxide, or light-catalyzed (25) halogenation of methylthiophenes, eg, Ai-bromosuccinimide/benzoylperoxide on 2-, and 3-methylthiophenes gives the corresponding bromomethylthiophenes. 

Sales of thiophene in the 1990s amount to hundreds of metric tons per year. SuppHes are available worldwide from Synthetic Chemicals Ltd. (SCL) in the United Kingdom and Elf-Atochem SA in France. There is currendy no U.S. producer of thiophene or the principal thiophene derivatives. At these levels of demand, material is shipped in 200-hter dmms and in bulk quantities. Market price is dependent on the level of off-take. 3-Methylthiophene is also available from SCL, but demand is low and even lower in the case of 2-methylthiophene lower production and lower market demand have led to higher prices for these derivatives. 

Thiophene and 3-methylthiophene are Hsted on the TSCA chemical substances inventory. Thiophene is regulated as a hazardous material under OSHA and also regulated under the Clean Air Act, Section 110, 40 CFR 60.489, but there are no exposure limits or controls set for 3-methylthiophene. Both materials are regulated under sections 311/312 of the Superfund Amendments and Reauthorization Act, 1986 (SARA), as materials with an acute health and fire hazard, and under the Resource Conservation and Recovery Act, as ignitable hazardous wastes (DOOl). 

Bromothiophenes are toxic materials by aU routes. Inhalation toxicity of 2-bromothiophene is significant. Ecotoxicity is also noted for these materials, particularly for 2-bromo-3-methylthiophene. 2-Thiophenecarboxaldehyde and the 3-methyl derivative can cause minor irritation to the skin and eyes of rabbits. The former is a sensitizer to guinea pig skin, the latter is not. 2-Acetylthiophene is toxic in aU modes of contact. Severe exposure causes serious inflammation of the lung, damage to many organs, and depression of the central nervous system. 

TicarcHHn [34787-01-4] (SB) (52) is a significant penicillin antibiotic that incorporates the thiophene ring system. A number of routes to the required intermediate, 3-thiophenemalonic acid [21080-92-2] have been used over the years. Those from thiophene-based starting materials have involved 3-methylthiophene and 3-bromothiophene. 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Bromomethyl-5-methylthiophene gives normal displacement products with amines but it is isomerized on attempted reaction with copper(I) cyanide (Scheme 59) 48MI30200. Whereas 2-hydroxymethylthiophene reacts normally with hydrogen halides to give 2-halomethylthiophenes, reaction of 2-hydroxymethylfuran (2-furfuryl alcohol) with hydrochloric acid results in formation of laevulinic acid (151). 2-Furfuryl alcohol derivatives are... 

A novel method for preparing amino heterocycles is illustrated by the preparation of 2-amino-5-methylthiophene (159). In this approach vinyl azides act as NH2 equivalents in reaction with aromatic or heteroaromatic lithium derivatives (82TL699). A further variant for the preparation of amino heterocycles is by azide reduction the latter compounds are obtained by reaction of lithio derivatives with p- toluenesulfonyl azide and decomposition of the resulting lithium salt with tetrasodium pyrophosphate (Scheme 66) (82JOC3177). 

In 1885, Paal reported the synthesis of 2-phenyl-5-methylthiophene 2 from 1. ... 

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