Thiophene metal-halogen exchange

Benzothiophene, like thiophene, is a n-electron rich heterocycle. Unlike thiophene, electrophilic attack occurs selectively at the P-position (or 3-position) [10a, Ila] however, substitution at the a-center (2-position) can also be achieved [11b]. The order of positional reactivity, based on nitration, is 3 > 2 > 6 > 5 > 4 > 7 [1 la, 12a]. Also, halogenation under acidic conditions affords the 3-halobenzothiophene [11c, 13a]. In terms of metalation chemistiy, deprotonation occurs preferentially at the 2-position (a) [lid, 13b] metal-halogen exchange is also favored at the a-center over the P-center [12b]. 

To summarize, electrophilic substitutions and metalations of thiophenes take place preferably at the a-positions due to the electronegativity of the sulfur atom. This is the consequence of the more effective incorporation of lone pair electrons on the sulfur into the aromatic system. In contrast, electrophilic substitution of benzo[fe]thiophenes occurs at the P-position however, the preference is not strong and substitution can result in other positions. Like thiophene, metalation and metal-halogen exchange are favored at the a-position. Also, oxidative couplings of thiophenes and benzothiophenes are not very... 

Benzene-ring-lithiated intermediates can be prepared by metal-halogen exchange, even, in the case of indoles, without protection of the NH, i.e. it is possible to produce an N,C-dimetallated species (20.5.2). The 1,3-azoles lithiate very readily, at C-2. One may understand this in terms of a combination of the acidifying effects seen at an a-position of pyridine (both inductive and mesomeric electron withdrawal) with that at the a-positions of thiophene, furan and pyrrole (inductive only). 2-Substituted-l,3-azoles generally lithiate at C-5 °... 

Hexachlorobenzo[h]thiophene undergoes metal-halogen exchange first in the 2-position, then in the 6-position.342 When benzo[b]thiophene is lithiated in the presence of Al,N,M, M -tetramethylethylenediamine, under conditions which lead to 2,5-dilithiation in thiophene, some 2,7-dimetallated derivative (12%) is formed.580... 

Halogenated thiophenes are undoubtedly the most often used thiophene derivatives. They can be further converted into various substituted thiophenes through metal-halogen exchange reactions, electrophilic or nucleophilic substitutions or any of several types of palladium(0)-catalysed chemistry [21, 22, 74-76]. 

Much effort has been devoted to studies of thiophene oligomers and polymers, in particular in connection with development of new organic materials for electronic applications. Many of the synthetic approaches towards oligothiophenes rely on well-established methodology, such as metalations, halogen-metal exchange reactions, and transition metal catalyzed couplings. 

Preparation of both a- and p-substituted thiophenes can be achieved by halogen-metal exchange. The synthesis of 3,4-bis(isopropylthio)thiophene is achieved in 60-70% yield from... 

A copper-mediated cyclization of metallated thiophenes has been utilized to prepare polycyclic thiophenes and thiophene cyclophanes. Treatment of dibromide 106 in succession with M-butyllithium (halogen-metal exchange), zinc chloride (transmetallation), and copper chloride gave 7//-cyclopcnta[ 1,2-fc 4,3-6 dithiophene (107) <00H(52)761>. This conversion has also been achieved using a palladium-mediated cyclization performed in the presence of hexamethylditin . Copper-mediated cyclizations have also been applied to the syntheses of cyclopenta[2,l-6 3,4-A ]dithiophen-4-one (108) (three steps from 73) <00S1253> and cyclophane 109 <00CC2329>. 

Reaction of 5-bromobenzo[6]thiophene with one mole of n -butyllithium leads to 5-bromo-2-benzo[6]thienyllithium with two moles of n-butyllithium, the 2,5-dilithio derivative is formed (70AHC( 11)177). Monolithio derivatives of dibenzothiophene have been prepared by halogen-metal exchange from the 1-, 2- and 3-bromo compounds. Dilithio-dibenzothiophenes have also been prepared by the same procedure (74AHC(i6)l8i). 

Halogen-metal exchange can also be conveniently used to prepare lithium derivatives of benzo[7 ]thiophene. Some examples are shown in Scheme 168 <70AHC(ll)l77. ... 

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