Thiophene reaction with butyllithium

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). 

Thiophene, bromotetrahydromethyl-pyrolysis, 3, 902 Thiophene, 5-t-butyl-2-methyl-dealkylation, 4, 800 Thiophene, chloro-polymerization, 4, 758 reaction with n-butyllithium, 4, 831 synthesis, 4, 835, 882, 933 Thiophene, 2-chloromercurio-reactions... 

All the above examples refer to thiophenes containing functional groups indifferent to the presence of butyllithium. In reactions with reagents in an equimolar ratio, it is highly probable that only one of the fluorine atoms at the double bond of cyclene will be replaced. For example, the target product 26 (Scheme 8) was prepared by either a one-pot reaction in the presence of a twofold excess of lithium derivative 24 with respect to per-fluorocyclopentene or in two steps including the isolation of monofluoride 25 (99IZV10n). 

Reaction of thiophene or of 2-alkylthiophenes with butyllithium in the presence of HMPT is suggested to lead to the generation of dilithio intermediates (12), which are then cleaved in the usual way (entry 2 in Table I) the use of HMPT is critical in bringing about ring cleavage. 3,4-Dilithio species (13) give conjugated diacetylenes as products (see entries 17 and 26). 

Butylpotassium and butylcesium deprotonate furan at the 2-position (75BSF1302), but butyllithium is the reagent of choice. When furan is treated with butyllithium the reactions in Scheme 114 occur (77JCS(P1)887>. The conditions, however, may be controlled to yield predominantly the mono- or the di-lithio derivative. By carbonation and esterification of the reaction mixture obtained by treatment of furan with butyllithium and TMEDA (1 1 1) in ether at 25 °C for 30 min, a 98% yield of methyl furan-2-carboxylate is obtained. Similarly, a butyllithium TMEDA furan ratio of 2.5 2.5 1 in boiling hexane for 30 min results in 91% of dimethyl furan-2,5-dicarboxylate and 9% of the monoester. Competition experiments indicate that furan reacts with butyllithium faster than thiophene under non-ionizing conditions but that the order is reversed in ether or in the presence of TMEDA. 

Metallated thiophenes can also be readily prepared by halogen-metal exchange. Thus, 2-bromothiophene is rapidly metallated with n-butyllithium at low temperatures (e.g. -78°C) to give 2-lithiothiophene (Figure 18). This method has been shown to be applicable to the preparation of polylithiothiophenes. Thus, di-, tri- and tetra-brominated thiophenes afford the corresponding di-, tri- and tetra-lithiated thiophenes upon reaction with n-butyllithium (30 e.g. Figure 18). 

Treatment of thiophene-3-carboxamides with butyllithium gave 2-lithio derivatives, which cross-coupled to form the benzo[ 1,2-6 4,5-6 ]di thiophene (Scheme 4) <76JOC3668>. Lithium exchange of l,l,l-tris-3-(2-bromo-5-methylthienyl)ethane (78) and reaction with diethyl carbonate gave the... 

Analogous reaction with the adduct 11 of thiophene 1,1-dioxide gave only a very poor yield of the substituted cycloheptatriene 12. The latter could be converted to l//-cyclopropabenzene (13) in 11% yield by reaction with titanium(III) chloride and lithium aluminum hydride in tetrahydrofuran, or in 50% yield by reaction with butyllithium in hexane. 

Benzo[Z ]thiophene is somewhat less reactive in electrophilic substitutions than thiophene, and also less reactive than benzo[Z ]furan. Moreover, regioselectivity is poor, giving rise to mixtures. Frequently, the 3-position is attacked preferentially over the 2-position, e.g. in halogenation, nitration and acylation. Only the reaction with n-butyllithium is regioselective, giving 2-lithiated benzo[6]-thiophene. 

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