Reactions of C-metallated Thiophenes

Monolithiation of thiophene takes place at C-2 two mol equivalents of lithiat-ing agent easily produces 2,5-dilithiothiophene.  

Lithiation at a thiophene p-position, in the presence of a free a-position, has been achieved with the assistance of an ortho-dircciing substituent at C-2. A surprising degree of functionality can be tolerated in some lithiations.  

Thiophene-2-carboxylic acid lithiates at C-3, via ortho assistance, using butyllithium, but at C-5 using lithium diisopropylamide. The lithiation of 2-chloro-5-methoxythiophene at C-4 and C-3, in a ratio of 2 1, is instructive. 2-and 3-Bromothiophenes undergo lithium-halogen exchange with w-butyllithium, but a-deprotonation with LDA.  

2- Bromo- and -iodothiophenes readily form thienyl Grignard reagents, as do 

There are two complications which can arise in the formation and the use of lithiated thiophenes the occurence of a base-catalysed halogen dance ,and the 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 final 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. 

2 Palladium-catalysed reactions (also nickel- and copper-catalysed reactions) 

There are by now many examples involving palladium(0)-catalysed couplings using halothiophenes, thiophene boronic acids, thienylstannanes, and thienylzinc 

---

Reactions with bases reactions of C-metallated benzo[b]thiophenes and benzo[b]furans... 

REACTIONS WITH BASES REACTIONS OF C-METALLATED BENZO[ ]THIOPHENES AND BENZO[Z ]FURANS... 

The reaction of heterocyclic lithium derivatives with organic halides to form a C-C bond has been discussed in Section 3.3.3.8.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp2 carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable heterocyclic metal derivative. The metal is usually zinc, magnesium, boron or tin occasionally lithium, mercury, copper, and silicon derivatives of thiophene have also found application in such reactions. In addition to this type, the Pd-catalyzed reaction of halogenated heterocycles with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. 

In some cases, the reaction of silicon and methanol has been optimized for formation of (MeO)4Si. As discussed above, thiophene addition favored formation of (MeO SiH. Both thiophene and propyl chloride poison copper copper poisoning seems to favor formation of the trialkoxysilane. High-temperature pretreatment disfavors trialkoxysilane formation copper is formed on the surface of the silicon during pretreatment at 450 °C98. Metallic Cu catalyzes dehydrogenation of alcohols and favors formation of (RO)4Si. Workers from Tonen Corporation reported 50% conversion of silicon to make (MeO Si with 92% selectivity if silicon, methanol and Cu(OMe)2 were pretreated (lower conversion and selectivity without pretreatment) and then reacted at 180 °C and 1 atmosphere99. 

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). 

Discovered over a century ago, electrophilic mercuration is probably the oldest known C-H bond-activation reaction with a metal compound. The earliest examples of aromatic mercuration were reported by Volhard (mercuration of thiophene) [1], Pesci (mercuration of aromatic amines) [2], and Dimroth [3], who was the first to mercurate benzene and toluene, generalize the reaction, and assign the correct structures to the products originally observed by Pesci. Since the work of Dimroth electrophilic aromatic metalation reactions with compounds of other metals, for example Tl(III), Pb(IV), Sn(IV), Pt(IV), Au(III), Rh(III), and Pd(II), have been discovered [4], In this chapter, we will focus on intermolecular SEAr reactions involving main-group metal electrophiles and resulting in the formation of isolable metal aryls which find numerous important applications in synthesis [5], Well-known electrophilic cyclometalation reactions, for example cyclopalla-dation can be found in other chapters of this book and will not be reviewed here. 

---