3- Methylthiophene, lithiation

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). 

Regioselective side-chain lithiation could also be carried out on 2-methylthiophene-3-carboxylic acid. By contrast, the isomeric 3-methylthiophene-2-carboxylic acid gives a 35 65 mixture of side-chain and nuclear (at position 5) lithiation (80JOC4528). Dilithiation of 2-methylthiophene-3-carboxylic acid with 2 equivalents LDA in THF at - 30°C gave only the dilithium derivative (392) (80%), which could be reacted with electrophiles at the methylene carbon (89BCJ2725). 

Figure 16. Monobromination of 3-methylthiophene with NBS. Preparation and Reactions of Lithiated Thiophenes.

The preparation of 3-methvl-2-f3 7Ur-trimethvldodecvrithiophene. This compound, which has a carbon skeleton resembling that of phytane, is often a major component of certain immature sediments Q). Previous syntheses of this compound have used the acylation method whereby 3-methylthiophene is acylated with 3,7,11-trimethyldodecanoic acid (1, 8). Reference to Figure 5 indicates that the required compound will be accompanied by the 2,4-isomer and this is indeed the case. The pure compound can, however, be prepared using a lithiated alkylthiophene and an aldehyde (Figure 23). 

Thus, 3-methylthiophene is brominated with NBS to give 2-bromo-3-methyl-thiophene (cf Figure 16) which is then metallated with n-butyllithium. The lithiated thiophene is activated with TMEDA and then coupled with 3,7,11-trimethyldodecanal. The coupled product contains a secondary alcohol which is... 

Scheme 9.12 shows the synthetic route. [4-Methyl-2,5-bis(trimethylsilylethy-nyl)-3-thienyl]heptafluorocyclopentene (31) was prepared from 3-bromo-4-methylthiophene (28) in three steps. 2 -methoxy derivative 33 was synthesized by the coupling of 31 with lithiated 32. After desilylation with KOH, Sonogashira coupling with bromoformyl compounds gave bisformylated diarylethenes 34. Formyl derivative 34 was converted into nitroxide radical 27a. 

Lithiation of 3-methylthiophene with lithium 2,2,6,6-tetramethylpiperidide is reported to be highly selective, giving the 5-lithio derivative <2007JOC1031>. 

Although the metallation of thiophene with butyllithium in a THF-hexane mixture proceeds much more easily, ethyllithium in Et20 (prepared from ethyl bromide and lithium) is chosen as the lithiation reagent for the following reasons. 2-Methylthiophene has a boiling point of 112.5 °C, and a distillative separation from the THF and hexane (b.p. between 65 and 70°) would therefore be more difficult and lengthy. Moreover, traces of butanol could be present in the... 

The lithiation of several methylthiophene carboxylic acids has been referred to in CHEC-I. As a further example in this series, the lithiation of 2-methylthiophene-3-carboxylic acid by means of... 

Lithiation of 3-methylthiophene and subsequent addition of an electrophile, in this case methyl iodide, produces a mixture of products at the C2 or C5 positions, with the 2,4-disubstituted thiophene predominating. However, a strong electron-withdrawing or sterically hindered C5-substituent will direct the formation of the C5 methylated thiophene to the more sterieally favorable position. ... 

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