Thiophene lithiation

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). 

This and other older methods, which have been reviewed previously (21, 22), have been largely superceded in the laboratory by more controlled, selective reactions, starting from suitable thiophene precursors.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. 

Another method for the preparation of synthetically useful thiophene-carboxaldehydes will be outlined in the section dealing with lithiated thiophenes. 

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

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). 

Figure 18. Formation of lithiated thiophenes from brominated thiophenes.

Figure 21. Examples of the reactions of lithiated thiophenes with alkylhalides, aldehydes and dialkylsulfates.

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... 

When the stereo genic centre is further away from the site of attack, the stereoselectivity may not be so good. Zeneca have announced the manufacture of a drug by the addition of a lithiated thiophene to another heterocyclic ketone, which initially gave a mixture of dia stereo isomers. 

The use of lithiated thiophenes for the introduction of substituents on the ring through C-C bond formation is now a standard tool in organic synthesis. This has been covered exhaustively in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Further elaboration of this topic is therefore not necessary. 

There are two complications that can arise in the formation and the use of lithiated thiophenes the occurence of a Base Catalysed Halogen Dance ,and the isomerisation or ring opening of 3-lithiated thiophenes. As an example of the first of these, and one in which the phenomenon is put to good use, consider the transformation of 2-bromothiophene into 3-bromothiophene by reaction with sodamide in ammonia. The final result is governed, in a set of equilibrations, by the stability of the hnal anion the system settles to an anion in which the charge is both adjacent to halogen and at an a-position. 

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

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