Benzothiophene analogs

In 06MI2, aminothiazole 259 was synthesized. Recently, Japanese researchers have used this method for the synthesis of benzothiophene analogs 260 and 261 (09NJC1368). 

Lilly also disclosed two series of conformationally restricted benzanthracene derivatives [185]. These tetracyclic compounds showed high ERa affinity, but subtype selectivity was modest. Thus, benzothiophene analog 149 expressed 5-fold preference for ERa and similar ERa selectivity was noted for benzanthracene analog 150. The latter compound showed high MCF-7 antagonistic activity, whereas analog 149 was 20-fold less active. 

Analogous compounds derived by fusion of a benzene ring to a pyrrole furan or thio phene nucleus are called indole benzofuran and benzothiophene... 

Dimethylene-2,3-dihydrothiophene (37, Figure 2.3) is the thiophene analog [38] of o-quinodimethanes and has been used to develop a Diels-Alder-based synthetic approach to benzothiophene derivatives. Generated in situ by treating the trimethylsylyl ammonium derivatives 38 or 39 with Bu4N F , it... 

By analogy with anthracene, dioxygenation of dibenzothiophene produces 2-hydroxyben-zothiophene-3-carboxaldehyde, and this may be transformed into a number of products including benzothiophene-2,3-dione and further into disulfides and thioindigo (Bressler and Fedorak 2001a,b). 

Figure 15. Relative removal of dibenzothiophenes and benzothiophenes from the middle-distillate cut of OB oil in the presence (left frame) and absence (right frame) of sulfate. Compounds are ranked in order of their relative depletion. Bars with solid and hatched lines represent the sum of the results for alkylated compounds with n pendant carbons, with CO indicating the unalkylated parent open bars in the left frame represent individual dibenzothiophenes. In the right frame, the bars represent sum of alkylated analogs for each carbon number. Figure reproduced from Ref. [86],...

Pinney et al. reported the synthesis of benzothiophene CA4 analogs and an example synthesis is given in Scheme 38 [83]. Benzothiophene (145) was produced by reacting aromatic thiol 146 with a-bromoacetophenone 147 to generate the sulfide 148. Compound 148 was then cyclized to the benzothiophene 149 using polyphosphoric acid and heat. Formation of 145 was achieved by Friedel-Crafts aroylation of 149 with the methoxybenzoyl chloride 144. 

Replacement of one or more of the C or N atoms of the indole nucleus by atoms of N, C, O or S will result in dialkyltryptamine analogs some of which are very likely to be psychedelic. Among the indole analogs are isoindole, indene, indazole, diazindoles, benzo-furan, benzothiophene and benzimidazole. The syntheses of several such compounds follows. 

Benzothiophenes retain the sulphur atom during anodic oxidation and give 2,3-dihydro-2,3-dimethoxy products [199] analogous to the oxidation ofbenzofuran. 

Examples of the formation of sulphur containing heterocycles by similar transformations are quite rare. The palladium catalysed ring closure of S-propargyl-2-iodophenylmercaptane in the presence of formic acid and an amine-base, analogously to phenols and anilines, led to the formation of the partially reduced benzothiophene skeleton, bearing a 3-methylydene function (3.32.),40... 

Unlike in the case of the preparation of indoles and benzofuranes, the synthesis of benzothiophenes from o-ethynyl-thiophenols is not known. A close analogy was reported by Larock, where phenylacetylene was coupled with 2-iodothioanisole. Ring closure of the formed o-ethynyl-sulfide was initiated by the addition of different electrophiles. The reaction led to the formation of the benzothiophene core bearing the electrophile in the... 

The coupling can also be extended to condensed systems. Indole, benzofurane or benzothiophene were all coupled with chloropyrazine derivatives with varying success. For example indole and the 3,6-diisobutyl-pyrazine derivative gave the desired product in moderate yield (7.58.), The coupling of the diethyl-pyrazine derivative with benzofuran led to 54% isolated yield, while the analogous process using benzothiophene afforded the 2-pyrazyl-benzothiophene in 81%.77... 

Both these examples deal with annulations to heterocyclic rings, but analogous transformations can lead to benzothiophenes and indoles, respectively. Conversely, annulations to heterocyclic rings can also utilize the methods enumerated in the previous sections. 

Furo[3,2-fa]benzothiophenes (37) were synthesized in an analogous way (91JHC269) by smooth cyclization of the cyanomethyl ether 36 in the presence of K2C03/DMF. The starting 2-cyano-3-hydroxybenzothiophene 35 was obtained from methyl 2-thiohydroxybenzoate and chloroacetonitrile. Under Vilsmeier conditions (POCl3/DMF), the 2-cyano-3-cyanomethoxy-... 

The 1-benzoselenophenes are relatively stable and easy to manipulate. Their synthesis has been extensively studied since some of them are analogs of naturally occurring biologically active 1-benzofurans, 1-benzothiophenes, and indoles [1,14, 118, 120],... 

Fusion of a benzene ring onto the C2/C3 positions of pyrrole formally produces the corresponding benzopyrrole 7.1 known as indole. An analogous theoretical transformation can be envisaged to form benzofuran 7.2 and benzothiophene 7.3. This chapter will concentrate exclusively on indole, by far the most important member of this series. 

In the case of fused aromatic nuclei (e.g., p-naphthols, 5- and 6-hydroxyindoles or -hydroxy benzothiophenes, 6- and 7-hydroxycoumarins and analogous derivatives - ), however, the ortho/ot position (77) is still predominantly aminomethylated, even when it is appreciably hindered. - In this connection, it has been discov-ered- - - that the ortho/p position of 5- and 6-hydroxyindoles 78 is not active at all. 

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