3- Bromothiophene, reaction with metals

Halogen-metal interconversion between bromothiophenes and n -butyllithium occurs almost instantaneously and in very high yield. The reaction with 3-bromothiophene is usually carried out at -70 °C to avoid any (rans-lithiation. When bromine-lithium exchange takes place, steric crowding in the molecule decreases. As a consequence the percentage of 2-lithio derivative in relation to the 5-lithio isomer formed from 3-alkyl-2,5-... 

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). 

The reaction of 3-thienyl-lithium, prepared by halogen-metal exchange of 3-bromothiophens, has been used for the synthesis of many geminal 3,3-dithienyl derivatives of pharmacological interest. Thus the reactions with ethyl 3-bromopropionate, ethyl cyclopropylcarboxylate, and (90) were used for the synthesis of (91), (92), and (93), respectively. The reaction of 3-thienyl-lithium with quinoxaline has been used for the preparation of... 

Remarkably, one year later Leadbeater described that biaryls can be synthesized via a Suzuki-type coupling under transition-metal free conditions [51, 52]. The reaction conditions were almost identical to those reported for the ligand-free process, with the difference being that a larger amoimt of Na2C03 and arylboronic acid were used. Only one successful example of a heteroaryl haUde substrate is shown namely, the coupling of 2-bromopyridine with phenylboronic acid (Scheme 32). 3-Bromothiophene did not couple under the same reaction conditions. Unfortimately, attempts to use heteroarylboronic acids such as 3-pyridinylboronic acid, 3-thienylboronic acid, and lH-indol-5-ylboronic acid on 4-bromoacetophenone completely failed. 

Syntheses of unsubstituted thieno[3,2-A]thiophene (2) and 3-methyl-thieno[3,2-6]thiophene were carried out in a similar way metalation of 3-bromothiophene with n-butyllithium at —70° and subsequent treatment with sulfur and methyl monochloroacetate gave methyl (3-thienyl-thio)acetate (60). Further reactions along the lines indicated above led to the thienothiophenes 2 and 27. 

The formation of arylzinc reagents can also be accomplished by using electrochemical methods. With a sacrificial zinc anode and in the presence of nickel 2,2-bipyridyl, polyfunctional zinc reagents of type 36 can be prepared in excellent yields (Scheme 14) . An electrochemical conversion of aryl halides to arylzinc compounds can also be achieved by a cobalt catalysis in DMF/pyridine mixture . The mechanism of this reaction has been carefully studied . This method can also be applied to heterocyclic compounds such as 2- or 3-chloropyridine and 2- or 3-bromothiophenes . Zinc can also be elec-trochemically activated and a mixture of zinc metal and small amounts of zinc formed by electroreduction of zinc halides are very reactive toward a-bromoesters and allylic or benzylic bromides . ... 

A facile transition metal-catalyzed formation of C-N bonds has been reported <2005T2931>. 3-Bromothiophene can be coupled with 2-pyridone to form the A -(3-thienyl) derivative in a Cul-catalyzed reaction. The catalyst consists of Cul in the presence of T,Ar -dimethylcyclohexane-l,2-diamine and KOAc or K2CO3 (Equation 39). 

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