Thiophenes directed lithiation

Although a limited range of Grignard reagents is available, the most widely used group is undoubtedly the lithio group introduced by direct lithiation (see Section 3.3.1.6.2). The ready formation of the lithio derivatives of pyrroles, furans and thiophenes and their benzo-fused derivatives has had a most important impact on the chemistry of these heterocyclic systems. Reaction of the... 

Lithiation of benzo[6]thiophene occurs exclusively at position 2, leading to good yields of 2-substituted products. 2-Methoxybenzo[6]thiophene is reported to be lithiated at position 3 this is the only known direct lithiation at the /3-position (70AHC(11)177). Competitive metallation of benzo[6]thiophene and N-methylindole affords only 2-benzo[6]thienyl-lithium. 

Thiophene is sufficiently acidic to be directly metallated upon treatment with n-BuLi (see Figure 4.1). This direct lithiation can also be realized with polystyrene-bound 3-(alkoxymethyl)thiophene [96]. The resulting organolithium compounds react as expected with several electrophiles, such as amides (to yield ketones), alkyl halides, aldehydes, and Me3SiCl [96]. 

The thiophene analogues have been prepared through a lithiation reaction, using N,N-dimethylaminomethyl group for directing lithiation... 

We might expect that the sulfonamide group in 155 would direct lithiation of the thiophene ring to its adjacent site in an ortho -lithiation. It doesn t. An a-lithiation to give 156 occurs instead... 

The directed metalation reaction—lithiation with n-butyl-lithium of a position ortho to a substituent on an aromatic ring—is described. Aromatic systems in which the reaction has been studied are benzene, thiophene, naphthalene, and ferrocene. A systematic listing of the bond types that can be formed at the site of metalation is provided. Also of interest is the assessment of the relative directing abilities of directing substituents and comments and observations on the mechanism of the reaction. Utility of the reaction is indicated by the results from asymmetric-directed lithiation and the synthesis of heterocycles. 

Proton abstraction and electrophilic quench provides a method for the function-alizahon of heteroaromahc compounds. The hve-membered heterocycles fiaran and thiophen are deprotonated easily with n-butyhithium at the 2-position. The resulhng 2-hthiofuran or 2-lithiothiophen react with electrophiles such as carbonyl compounds or primary alkyl halides. For example, furan and thiophen have been converted to the 2-substituted derivatives 131 and 132 using such directed lithiation chemistry (1.122). 

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... 

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. 

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). 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

When considering the synthesis of phospholes, one has to forget most of the classical and powerful methods employed for the preparation of thiophenes and pyrroles. For example, Paal-Knorr condensation, direct ortho-lithiation, halogenation with NBS or I2/Hg2+ and Vilsmeier-Haack formylation are not operative in phosphole chemistry. Likewise, no chemical or electrochemical oxidative polymerization... 

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