Benzothiophenes 3-aryl-substituted

The electronic effects ofmeta- and para-substituents located in the phenyl ring have been studied for aryl-substituted benzothiophenes (Scheme 36(a)). 

Benzothiophenes are biologically important molecules that exhibit anti allergenic, and ocular hypotensive properties, and prevent osteoporosis. Kim and coworkers have shown that BE3 OEt2 is efficient in mediating the Eriedel-Craft type cyclization of 2-arylthio-ketones (43) at ambient temperature to give the 3-aryl-substituted benzothiophenes (44) in good yields (Equation 29) [31]. 

Phenyl vinyl sulfides cyclize to substituted benzothiophenes on photolysis. They also rearrange during photolysis to give rearranged benzothiophenes (46). The rearrangement reaction and the elimination of hydrogen (presumably to give the benzothiophene molecule ion) are both prominent processes in the mass spectra of the aryl vinyl sulfides.88)... 

This methodology was also applied to 2-aryl-3-substituted benzothiophenes 271 and 273 bearing either a nitrogen at the 3-position or a phenolic oxygen to give benzothiophenes 272 and 274 in good yields [178d]. 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

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... 

Intramolecular solvomercuration of aryl alkynes (if. 11, 320). The triple bond of alkynylbenzenes substituted at the oz/Zio-position with suitable groups undergoes intramolecular acetoxymercuration with Hg(OAc), in HOAc to afford aromatic heterocycles such as benzofuranes, benzothiophenes, and chmmones. 

Comparable acid- (or Lewis acid) -catalysed ring closures of 2-arylthio- and 2-aryloxy- -ketones, and -2-arylthio- and 2-aryloxyacetyl- chlorides lead to 3-substituted heterocycles and 3-oxygenated heterocycles, respectively. It is possible to combine the preparation of the arylthio-ketone and the ring closure steps utilising two solid-supported reagents in a one-pot procedure, as illustrated. Formation of 3-aryl-benzothiophenes by this route can be complicated by partial or complete isomerisation to the 2-aryl-heterocycle,however using boron trifluoride as the Lewis acid produces only the 3-aryl-isomer. 3-Tosylamino-benzofurans can be prepared from aryl glyoxal hydrates. ... 

A variety of 2- or 3-substituted thiophenes, as well as benzothiophenes, have been subjected to the catalytic direct arylation [3, 9, 10]. As expected, 2,2 -bithio-phene can be diarylated at the 5,5 -positions (Equation 10.47) [72], although the use of a bulky phosphine is of key importance for this reaction. 2,2 -Bithiophene protected by benzophenone at the 5-position reacts with aryl bromides, initially with liberation of the ketone (see Scheme 10.6, to give 5-aryl-2,2 -bithiophene, which is then arylated at the 5 -position (Equation 10.48) [72]. 5-Bromo-2,2 -bithio-phenes undergo oxidative homocoupling in the presence of a palladium complex and a silver salt (Equation 10.49) [73]. 

The synthesis of substituted quinolones [141], benzothiophenes [142] and ben-zylthiazoUdine-2,4-diones [143] has also been achieved using the Meerwein reaction. Ti(III)chloride has been shown to be suitable for the generation of aryl radicals from diazonium salts [144]. Interestingly, a metal-free version of the Meerwein arylation has recently been applied to the synthesis of a-aryhnethyl... 

The further modification of the benzothiophene photochromes can proceed involving both the thiophene and benzene rings. For example, Scheme 24 shows the oxidation products of the sulfur atoms (59) in dihetarylethenes and the iodination products (60), as well the Suzuki reaction leading to a set of compounds 61, where R are substituted aryls or thienyls [69]. The oxidation of the sulfur atoms in dihetarylethenes was also desCTibed in works [70-73]. 

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