Lithiation thiophenes

A few other thiophene lithiations of interest have been reported. 2-Iodo-5-lithiothiophene has been prepared in good yield and reacted with several electrophiles <90SL755>. The key to success was the use of LDA in THF at — 40°C. 2,5-Dilithiation of thiophene with -BuLi and TMEDA in hexane <77JCS(P1)887> followed by reaction with DMF gives thiophene-2,5-dicarbaldehyde <88S316>. 

Competitive metallation experiments with IV-methylpyrrole and thiophene and with IV-methylindole and benzo[6]thiophene indicate that the sulfur-containing heterocycles react more rapidly with H-butyllithium in ether. The comparative reactivity of thiophene and furan with butyllithium depends on the metallation conditions. In hexane, furan reacts more rapidly than thiophene but in ether, in the presence of tetramethylethylenediamine (TMEDA), the order of reactivity is reversed (77JCS(P1)887). Competitive metallation experiments have established that dibenzofuran is more easily lithiated than dibenzothiophene, which in turn is more easily lithiated than A-ethylcarbazole. These compounds lose the proton bound to carbon 4 in dibenzofuran and dibenzothiophene and the equivalent proton (bound to carbon 1) in the carbazole (64JOM(2)304). 

Directive effects on lithiation have also been studied. The regiospecific /3-metallation of A-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect of the oxazolino group (82JCs(Pl)1343). 2-Substituted furans and thiophenes are metallated in the 5-position. The formation of 2-lithio-3-bromofuran on treatment of... 

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). 

Benzo[b]thiophene, 3-mercapto-2-methyl-synthesis, 4, 931 Benzo[6]thiophene, 2-methoxy-lithiation, 4, 773 synthesis, 4, 929 Benzo[6]thiophene, 3-methoxy-alkylation, 4, 765 synthesis, 4, 929 Benzo[6]thiophene, 4-methoxy-anodic oxidation, 4, 798 Benzo[6]thiophene, 5-methoxy-synthesis, 4, 929 Benzo[6]thiophene, 6-methoxy-synthesis, 4, 929 Benzo[6]thiophene, 7-methoxy-synthesis, 4, 929-930... 

The lithiated Cr(CO)3 derivatives of thiophene may react with organometal-lic species. Their interaction with hexacarbonyls of chromium and tungsten... 

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

An improved synthesis of dithieno[3,2-A2, 3 -<7]thiophene 15a has been achieved from 2,3-dibromothiophene 304 (Scheme 57). Lithiation of 2,3-dibromothiophene 304 using -butyllithium followed by oxidative coupling with cupric chloride provided 3,3 -dibromo-2,2 -bithiophene 305 in 79% yield. Treatment of 305 with 2 equiv of -butyllithium in ether at —78 °C under nitrogen for 40 min and then adding benzenesulfonic acid thioanhydride and leaving the reaction mixture to reach room temperature afforded dithieno[3,2-A2, 3 -<7]thiophene 15a in 70% yield <2002TL1553>. 

The synthesis of dithieno[3,2-3 2, 3 -<7]thiophene 15a has also been accomplished using a combination of the methods described by De Jong et al. and Brandsma . In this approach, 3-bromothiophene 298 was lithiated and the 3-lithiothiophene 308 species reacted with sulfur dichloride to give di(3-thienyl)sulfide 309. Ring closure of 309 was effected using -butyllithium followed by addition of cupric chloride to yield dithieno[3,2-3 2, 3 -. 

Lithiation of furan and thiophene, followed by the reaction with 1,2-dichlorotetramethyldisilane, gave linear compounds 26 and 27 (Scheme 6). The second lithiation and reaction with 1,2-dichlorotetra-methyldisilane under the conditions of high dilution afforded the desired furanophane (28) and thiophenophane (29) (32). 

Lithiothiophene, arising from lithiation of thiophene with n-BuLi, was treated with iodine to give 2-iodothiophene, which was allowed to react with sodium malononitrile in the presence of catalytic PdCl2(Ph3P)2 to afford thienylmalononitrile 18. Interestingly, a-metalation of ethyl 3-... 

Scheme 24 shows the synthesis of a quinone by a second lithiation a to the sulphur of a thiophene . 

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... 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

Regioselactive g-metallation of ir-excessive five ring heterocycles is not a novel reaction. Oxazoline and pyridine as well as carboxylate- and carboxamide -substituted heterocycles have been lithiated. From the point of synthetic utility thiophenes have been shown to be useful substrates after careful optimization of reaction conditions furans have been of less utility. 

Litvinov et prepared selenophenothiophenes 14 and 15 according to Schemes 13 and 14 by inserting two functional groups into the thiophene ring, using lithiation methods, followed by intramolecular condensation of an acetic ester residue. The intermediates from the first three steps need not be isolated. 

It is also possible to produce covalently bonded alkyl MLs on Si(l 11) surfaces using a variety of chemical reactions with passivated H-terminated Si(l 11), but the preparation methods are more complex than the immersion strategy in part due to the higher reactivity of silicon. This is a major achievement because it allows direct coupling between organic and bio-organic materials and silicon-based semiconductors. Both pyrolysis of diacyl peroxides (Linford Chidsey, 1993) and Lewis acid-catalyzed hydrosilylation of alkenes and direct reaction of alkylmagnesium bromide (Boukherroub et al, 1999) on freshly prepared Si(lll)-H produce surfaces with similar characterishcs. These surfaces are chemically stable and can be stored for several weeks without measurable deterioration. Thienyl MLs covalently bonded to Si(l 11) surfaces have also been obtained, in which a Si(l 11)-H surface becomes brominated, Si(lll)-Br, and is further reacted with lithiated thiophenes (He etal, 1998). 

Butyllithium effects C-2 lithiation, and the lithium derivative can then be reacted with electrophiles (this is a good way to synthesize a wide variety of 2-substituted thiophenes) (Scheme 6.36). 

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