Benzothiophenes lithiation

TT-acceptor function of the C2C3 double bond. Lithiated benzothiophene can be quenched by [Pt(dppe)Cl2] to give 279 [97JCS(D)2955]. 

A clever synthesis of benzofurans, benzothiophenes and indoles starts with the trifluoroethyl ethers 425 and uses a 5-endo-dig cyclisation. Four equivalents of rc-BuLi perform two eliminations, one substitution, and one lithiation to generate aryllithium 426, which undergoes 5-endo-dig cyclisation. 3-Butylbenzofuran is generated in 40% yield.186... 

In contrast to the 5-endo-trig anionic cyclization reactions, rarely observed, there are several examples in which 5-endo-dig processes are involved. Hence 2,3-disubstituted benzofurans, benzothiophenes and indoles 374 have been synthesized starting from triflu-oroethyl ethers, thioethers and anilines 373, respectively, and alkyllithium compounds. A 5-endo-dig carbolithiation reaction on 375, generated by two successive eliminations, one substitution and one ortho-lithiation reactions, is proposed to account for the formation of the corresponding 2-lithiated heterocycles. Further reaction of these intermediates with electrophiles affords compounds 374 (Scheme 98)159. In the case of thioether 373 (X = S) a bromine substituent must be present at the ortho position. 

A series of Ti complexes of 7r-coordinated thiophene derivatives have been reported. Some of these compounds are shown in Scheme 716. 7r-Coordinated carbonylchromium complexes of thiophene and benzothiophene are readily lithiated with LiBu11 and react with Cp2TiCl2 to afford heterobinuclear Ti-Cr complexes.1796... 

Lithiation of the methyl of (methylthio)benzene followed by acylation with an acyl chloride and acidification to pH 4-5 yields benzothiophene in good yields, but when aroyl chlorides are used, the mixture has to be heated in benzene. An attempted dehydration of the secondary alcohol (87.4) with hydrobromic acid led to S-demethylation and cyclization. Similar treatment of the isomeric 2-(2-methy thio-4-nitrophenyl)-l-phenylethanol gave a high yield of 6-nitro-2-phenyl-2,3-dihydrobenzo[fi]thiophene [2653]. 

Lithio-benzothiophenes can be generated, and reacted with electrophiles, if the temperature is kept low. ° Direct deprotonation of benzothiophenes follows the usual pattern for flve-membered heterocycles and takes place adjacent to the heteroatom,"" and in concord with this pattern, metal-halogen exchange processes favour a 2- over a 3-halogen the sequence below shows how this can be utilised to develop substituted benzothiophenes. 2-Lithiated reagents react with electrophiles for example with p-toluenesulfonyl cyanide, 2-cyano derivatives are produced and similarly, 2-trimethylstannylbenzofuran and -benzothiophene and benzofuran-2- and benzothiophene-2-boronic acids can be prepared. 

Lithiation of commercially available bromoarenes (281) followed by treatment with zirconocene (methyl) chloride affords zirconocene complexes of substituted benzynes (283), which react with symmetric alkynes and l-(trimethylsilyl)propyne to give single regioisomeric zirconacycles, (284) and (285), respectively (Scheme 66). Both (284) and (285) react with disulfur dichloride to produce benzothiophenes (286) and (287), respectively, in 60-80% isolated yields in a one-pot procedure <89JOC2793>. Protodesilylation of (287) can be accomplished in >90% yield to give the corresponding 2-unsubstituted benzothiophenes by treatment with tetrabutylammonium fluoride in tetrahydrofuran. Application of the procedure to the preparation of 2,3-dihydrobenzo[6]thiophenes was also reported <9iOM537>. 

In short, the sequence enantioselective lithiation-electrophilic trapping-reductive elimination represents an enantioselective demethylation of 4 to produce optically pure 9. As seen through this book, secondary phosphine boranes are versatile synthons in P-stereogenic chemistry. In this case, they were alkylated with 2-(chloromethyl)benzothiophene providing phosphine boranes 10 in good yields, which were used in HPLC analysis to evaluate the optical purity of 9. 

TIPS groups have been used in different ways to prevent undesired C-2 lithiation of indoles and benzothiophenes. The introduction of a TIPS group onto 4-bromo-l/f-pyrrolo[2,3b]pyridine permitted metalation to occur exclusively at C-4, affording the 4-fluoro product (eq 16). The TIPS group was removed with TEAR Without TIPS, transmetalation at C-2 was observed. 

Methods for the synthesis of fluorobenzothiophenes are rare. A lithiation-fluorination sequence by treatment of benzothiophenes 57 with n-BuLi followed by fluorination with perchloryl fluoride [35], N2F2 [36], or N-fluorodibenzenesulfonimide afforded 2-fluorobenzo[h]thiophenes 58 in good yields [37]. 

An improved route to 3-(p-D-ribofuranosyl)pyrazole has been described, starting from 2,3-O-isopropylidene-D-ribofuranose and involving acetylenic intermediates. A stereocontrolled route to 4(5)-(P-D-ribofuranosyl)imidazole (115) has also been developed the epimeric mixture 114 was obtained via addition of a lithiated imidazole to 2,3,5-tri-O-benzyl-D-ribofuranose, and cyclization of this under modified Mitsunobu conditions gave selectively the P-product. A mechanistic rationale was presented, and the 2 -deoxycompound was similarly made. Various other 2 -deoxy-C-nucleosides of type 116 have been prepared in a non-stereoselective way by reaction of lithiated heterocycles with 3,5-(9-Tips-2-deoxyribose, followed by acid-catalysed cyclization compoimds made included the 2-furyl, 2-indolyl, 2-pyridyl and benzothiophen-2-yl analogues. ... 

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