Benzo thiophenes, alkyl reactions

Both 2- and 3-alkoxybenzo(7>]thiophenes may be obtained by alkylation of the appropriate hydroxy derivative, but there are competing side reactions (70AHC(11)177). 2-Methoxy-benzo[7>] thiophene can be prepared by heating 2-bromobenzo[6]thiophene with sodium methoxide, and 3-methoxybenzo[6]thiophene is obtained by similar treatment of 3-bromobenzo[7>]thiophene. Alkylation of 3-hydroxybenzo[6]thiophene-2-carboxylic ester is more efficient, giving the 3-alkoxy derivative in good yield, and this in turn can be hydrolyzed and decarboxylated in adequate yields (equation 81). 

Reaction at Sulphur.— The kinetics of the oxidation of benzo[/>]thiophen and its 3-substituted derivatives by perbenzoic acid in dichloromethane at 30 °C have been studied. The rate constants obtained for the first step, the oxidation to the sulphoxide, have been correlated with values, whereas the rate constants for the second step, of oxidation to the sulphone, have been correlated with values. A number of benzo[ft]thiophen and dibenzothiophen derivatives and their sulphoxides have been S- and O-alkylated, respectively, with silver perchlorate and alkyl halides. 5-Methoxydibenzothiophenium perchlorate reacted with amines to give 5-aminosulphonium salts, and with certain carbanions to give zwitterionic compounds such as (394). 

Benzo[6]thiophene, 2-acetyl-3-hydroxy-synthesis, 4, 892 Benzo[6]thiophene, 2-acyl-synthesis, 4, 918 Benzo[6]thiophene, 3-acyl-synthesis, 4, 918- 19 Benzo[6]thiophene, acylamino-synthesis, 4, 815 Benzo[6]thiophene, alkenyl-synthesis, 4, 917 Benzo[6]thiophene, 2-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 3-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 4-alkoxy-synthesis, 4, 930 Benzo[6]thiophene, 2-alkyl-synthesis, 4, 877-878 Benzo[6]thiophene, 2-alkylthio-synthesis, 4, 931 Benzo[6]thiophene, 2-amino-diazotization, 4, 810 reactivity, 4, 797 stability, 4, 810 synthesis, 4, 869, 924-925 tautomerism, 4, 38 Benzo[6]thiophene, 3-amino-cycloaddition reactions, 4, 68 synthesis, 4, 109, 881, 925 Benzo[6]thiophene, 4-amino-synthesis, 4, 925 Benzo[6]thiophene, 5-amino-synthesis, 4, 925 Benzo[6]thiophene, 7-amino-synthesis, 4, 925 Benzo[6]thiophene, 3-t-amyl-synthesis, 4, 915 Benzo[6]thiophene, 2-aryl-synthesis, 4, 881... 

Methyl- or 2-ethyl-benzo[Z> ]thiophenes are conveniently prepared by treatment of 2-benzo[6]thienyllithium with the appropriate alkyl sulfate <70AHC(11)177). Clemmensen or Wolff-Kishner reductions of the 2-acylbenzo[Z>]thiophenes are useful, but since acylation produces a mixture of the 2- and 3-acyl isomers (Section 3.14.2.4), these must be separated. Cyclization of phenyl phenacyl sulfide with hydrofluoric acid leads exclusively to 2-phenyl-benzo[6]thiophene, and 3-phenylbenzo[6]thiophene can be rearranged to the 2-isomer in hydrofluoric acid (Section 3.15.2.3.2). Aromatization of 2-cycIohexenylbenzo[6]thiophene, obtained by condensation of the 2-lithio reagent with cyclohexanone, gives 2-phenyl-benzo[6]thiophene, and the reaction is adaptable to the 2-(l-naphthyl) derivative also. 

The use of modern physical methods (NMR, UV, and IR spectroscopy, mass spectrometry, and gas-liquid (GLC) and thin-layer (TLC) chromatography is becoming increasingly noticeable. By 19522 few systematic studies of the preparation of derivatives of benzo [6]thiophene had been undertaken, no attempt had been made to alkylate benzo[6]thiophene by means of the Friedel-Crafts reaction, and Friedel-Crafts acylation had been little studied. Halogenation of benzo[6]thiophene had only been superficially investigated and... 

In 1949, Werner187 announced the synthesis of several 3-alkyl- and 2,3-dialkylbenzo[6]thiophenes by the cyclodehydration of (arylthio)-acetones with phosphorus pentoxide or zinc chloride [Eq. (5)]. The reaction has since been widely used to synthesize alkyl- and aryl-substituted benzo[6]thiophenes (Table IV). Cyclodehydration proceeds most conveniently with PPA,297 298 but concentrated sulfuric acid,299,300 hydrofluoric acid, 299 aluminum chloride in benzene301 or chlorobenzene,302 zinc chloride and hydrochloric acid,303 a melt of aluminum and sodium chlorides,304 and phosphorus pentoxide in boiling o-dichlorobenzene 305 have been less widely used. 

Friedel-Crafts alkylation of benzo[6]thiophene has received little attention. The published results, which deserve reexamination, indicate that exclusive 3-substitution occurs in some cases, whereas in others, 2-substitution predominates. Benzo[6]thiophene is alkylated with isopropyl chloride, isopropanol, or propene in the presence of various acid catalysts under a variety of reaction conditions to give a mixture of 2- and 3-isopropylbenzo[6]thiophene in which the 2-isomer predominates (78-92%).358 410 In contrast, alkylation with isobutene in the presence of either 80% sulfuric acid415 or 100% phosphoric acid416 is said to afford exclusively 3-/er<-butylbenzo[6]thiophene in yields of 100 and 75%, respectively. In neither case was the structure of the product rigorously confirmed. Likewise, 3-Jeri-amylbenzo [63-thiophene is the exclusive product of alkylation with tert-amyl alcohol in the presence of stannic chloride414 alkylation with pent-l-ene, hex-l-ene, and a Ci8 propylene polymer is also claimed to give... 

Nucleophilic displacement of bromine in the readily available benzo[Z>]thiophene-l,l-dioxide 44 with phenols proceeds often in very good yields, as demonstrated by preparation of the molecule 45 <07TL2349>. It has also been found that 4-alkyl-2-nitrothiophenes participate in nucleophilic substitution reactions with secondary aliphatic amines in the presence of silver nitrate, rendering the corresponding 3-alkyl-2-amino-5-nitrothiophenes. In contrast, 2-nitrothiophene itself is ring-opened under such conditions <07JOC5771>. 

Elaboration of the thiophene ring can be achieved by standard electrophilic substitution reactions, which are normally favored at the a-carbons for thiophene and at the 3-position for benzo[fc]thiophene. Reductive alkylation of aminocarbamate 72 with butyraldehyde in the presence of selenophenol gave thiophene 73 . Treatment of 3-methylthiophene with chlorosulfonic acid followed by tcrt-butylamine led to selective sulfonamidation producing 74 . Similarly, selective 2-iodination of 3-alkylthiophenes was ob.served upon treatment with iodine in the presence of mercuric oxide . Exhaustive bromination of thieno[3,2-7i]thiophene 27 gave 2,3,5,6-tetrabromothieno[3,2-ii]thiophene which was... 

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