2-Aryl benzothiophene derivatives

This methodology was used by researchers at Eli Lilly to generate benzothiophene derivatives of tamoxifen. The cyclization and rearrangement reaction to produce the desired 2-aryl benzothiophene derivatives were promoted by polyphosphoric acid (PPA). These 2-aryl benzothiophene were then subjected to several additional transformations to produce LYl 56758 (raloxifene). 

The sulfur-heterocyclic compounds in the mid-distillate range are primarily the thiacyclane derivatives, benzothiophene derivatives and dibenzothiophene derivatives. with lesser amounts dialkyl-, diaryl- and aryl-alkyl sulfides. Sulfur compounds are significant contributors to the vacuum gas oil fraction (Ma et al., 1997). The major sulfur species are alkyl benzothiophene derivatives, dibenzo-... 

In 2004, Lemaire[73] developed a new mechanism for the synthesis of benzo[h]thiophene through palladium-catalyzed C-H arylation of benzothiophene derivatives with aryl iodides. Mori [74] discovered a new catalytic system for the... 

In the copper catalyzed aromatic nucleophilic substitution of aryl halides bromoindole derivatives were converted to the appropriate cyanoindoles. Both 5-bromoindole and its 7V-tosyl derivative gave excellent yields, when a substoichiometric amount potassium iodide was added to the reaction mixture (6.80.), Pyrazole and benzothiophene showed a similar reactivity. The role of the added iodide is to activate the aromatic system through a bromine-iodine exchange.111... 

The diazonium salt 453, derived from aminoisoquinoline 452, undergoes thermal cyclization to afford 6-thiaellip-ticine 454 and 37/-pyrazolo[3,4-, ]isoquinoline 455. Formation of 454 may involve the cyclization of an aryl radical intermediate (Scheme 74) <1996CC2711>. Isomerically pure 4,6-dimethyldibenzothiophene 457 <1996T3953> and benzothiophene 459 <2005T8711> can be synthesized from the diazonium salts 456 and 458, respectively. 

However, a truly general method for electron-rich heterocycle arylation was not reported until 2007 [38], Electron-rich, bulky butyl-di-l-adamantylphosphine or /er/-buty I dicyclohexyl phosphine in combination with Pd(OAc)2 afforded the best results, and the former was chosen because of cost considerations. Interestingly, electron-rich AMieterocyclic carbene ligands that facilitate oxidative addition of aryl chlorides to low-valent transition metals are inefficient in heterocycle arylation. A number of structurally diverse electron-rich heterocycles are reactive (Scheme 3). Thiophene, benzothiophene, 1,2- and 1,3-oxazole derivatives, benzofuran, thiazoles, benzothiazole, 1-alkylimidazoles, 1-alky 1-1,2,4-triazoles, and caffeine can be arylated. Electron-rich, electron-poor, and heteroaryl chlorides can be used. 

The arene substrates are not limited to simple benzene derivatives. A variety of het-eroarenes can also participate in alkene arylations to generate the desired coupling products. Stoichiometric oxidative coupling of aromatic heterocycles such as furan, thiophene, selenophene, A-methylpyrrole, benzofiiran and benzothiophene with a variety of alkenes, including acrylonitrile, styrene and methyl acrylate, have been extensively studied by Fu-jiwara and coworkers [8]. Furan, thiophene, selenophene and A-methylpyrrole are easily alkenylated with alkenes to give 2-alkenylated and 2,5-dialkenylated heterocycles in relatively low yields (3 6%) [8a], while the reactions of benzofuran and benzothiophene with alkenes produced a mixture of 2- and 3-alkenylated products [8b]. 

A review entitled thiophenes from Viktor Meyer to Poly (thiophene) some reactions and synthesis was published in a special issue of Phosphorus, Sulfur and the related elements (13PS287). Over 80 reaction schemes are presented outlining important discoveries in the chemistry of thiophenes. Another review generalized published data on the reactions of 4-(2-R-aryl)-1,2,3-thia- and selenadiazoles (13RJOC479). Special emphasis on the use of these selenadiazole for the synthesis of 1-benzothiophenes, 1-benzosele-ophenes, and their more complex derivatives was presented. A recent review on recent advances in the use of the Wfllgerodt-Kindler reaction in thiophene syntheses appeared this year (13CSV7870). Extensive reviews on selenium and tellurium chemistry from small molecules to biomolecules and materials (B-13M001) as well as data on the synthesis, reactions, crystal structures, and spectral characteristics of benzo[b]tellurophene, dibenzo[b,d]... 

Synthesis of Fused Heterocycles. Use of chloroacetyl chloride in the reaction with l-[(trimethylsilyl)methyl]benzotriazole opens new possibilities. Thus, the l-(benzotriazol-l-yl)-3-chloroacetone obtained in the first step is further reacted with 2-mercaptobenzothiophene to give l-(benzotriazol-l-yl)-3-[(benzothiophen-2-yl)thio]acetone in a practically quantitative yield (eq 8). Cyclization of the obtained acetone derivative with ZnCl2 readily provides 3-[(benzotriazol-l-yl)methyl][2,3-ft]benzothiophene (eq 9). The structure can be further modified by subshtufion of the benzotriazolyl moiety with other groups. Preparation of several other fused thiophene systems, starting from other aryl mercaptans, is also reported. ... 

---