Thiophenes 2- -, selective lithiations

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). 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

This and other older methods, which have been reviewed previously (21, 22), have been largely superceded in the laboratory by more controlled, selective reactions, starting from suitable thiophene precursors. We shall discuss two major reactions which can be used for the preparation of alkylthiophenes electrophilic substitution of thiophenes and the formation and reactions of lithiated thiophenes. For further details and other aspects of thiophene chemistry the reader is referred to previous reviews (21, 22) and references cited therein. Accounts of yearly developments in thiophene chemistry can also be found in the relevant Royal Society of Chemistry publications. 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

The (thiophene)Cr(CO)3 complex (62) is unusual in undergoing highly efficient double deprotonation at the positions adjacent to the sulfur (to give 63, Eq. 39) [134]. The first and second deprotonation steps appear to proceed with comparable rates, making selective formation of the mono-lithiation product difficult. When both a-positions are occupied, lithiation occurs in the p posi-tion [54]. 

The selection of the lithiation reagent also has a strong influence over the regioselectivity of the electrophilic substitution the bulkier the base, the more favorable the reaction at the C5 position. For example, lithium 2,2,6,6-tetramethylpiperidine (LiTMP) directs the formation of the C5-substituted product at a 79 1 ratio to the C2-substituted thiophene. A variety of electrophiles can be substituted after lithiation by LiTMP. ... 

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