Benzo thiophenes, alkyl preparations

Silica gel is an effective catalyst for the t-butylation of thiophene and benzo[/ ]thiophene using t-butyl bromide. 2,5-Di-r-butylthiophene and 3-f-butylbenzo[b]thiophene can be prepared easily by this procedure (84JOC4161). Alkylation of thiophene with f-butyl chloride, isopropyl chloride or ethyl chloride at - 70°C in the presence of A1C13 produced a-complexes under kinetic control. On thermal equilibration, migration of alkyl from position 3 to position 2, as well as disproportionation to dialkyl-and trialkyl thiophenes can occur (86T759). 

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). 

The synthetic utility of o-quinodimethane generated by cheletropic elimination of S02 has been amply demonstrated by Oppolzer and Nicolaou, who have conducted an intramolecular cycloaddition coupled with the alkylation of 1,3-dihydrobenzo[c]thiophene 2,2-dioxide122. When 1,3-dihydro-l-(4-pentenyl)benzo[c]thiophene 2,2-dioxide (201) prepared from 1,3-dihydrobenzo[c]thiophene 2,2-dioxide and 4-pentenyl bromide is heated in di-n-butyl... 

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 3-acylbenzo[6]thiophenes, separated from the mixture obtained on acylation of benzo[6]thiophene (Section 3.14.2.4), are readily reduced to 3-alkylbenzo[6]thiophenes. 3-Benzo[6 ]thienyllithium can be prepared from 3-bromobenzo[6]thiophene at -70 °C (68JCS2733) and this may serve as a source of 3-acylbenzo[Z>]thiophenes. In certain instances, Friedel-Crafts alkylation gives the 3-substituted benzo[6]thiophenes nearly exclusively. For example, 3-t-amylbenzo[6]thiophene was the exclusive product of alkylation of benzo[6 Jthiophene with t-amyl alcohol in the presence of tin(IV) chloride <70AHC(11)177). 

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... 

Dihydrobenzo[6] thiophene is probably most conveniently prepared (in low yield 43°) by reduction of benzo[6]thiophene with sodium and alcohol.430 431 It can also be prepared, as can its alkyl derivatives, by modified Wolff-Kishner281,426 or Clemmensen182 reduction of the corresponding thioindoxyl. 3-Methylbenzo[6]thio-phene is reduced catalytically to its 2,3-dihydro derivative,275 and... 

Hydrodesulfurization of certain hydroxy-437 and methoxy-sub-stituted615 alkybenzo[6]thiophenes is a useful means of preparing some otherwise inaccessible alkyl-substituted phenols [e.g., Eq. (15)].015 Various p-methoxyphenylbenzo[6]thiophenes have been employed similarly to prepare the corresponding hydroxydiphenyl-alkanes.464 Catalytic hydrodesulfurization of a-alkyl-/ -(3-benzo[6]-thienyl)propionic acids affords a convenient method of preparing a,y-disubstituted y-phenylbutyric acids.636 Treatment of / -(3-benzo[6]thienyl)acrylic acid with Raney nickel alloy, sodium meth-oxide, and deuterium oxide affords the deuterated acid (366).667... 

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>. 

Dianions derived from sulfur and oxygen containing polycyclic systems have not been reported until very recently. The weak carbon-sulfur bond could discourage attempts to prepare such dianions. Sulfur removal studies by alkali metals were successful due to the properties of the carbon-sulfur bond 182,183). Reductive alkylation studies on model compounds which are relevant to sulfur containing systems demonstrated the stability of hydrocarbon dianions 182). A spectroscopic study performed under mild conditions afforded the characterization of sulfur and oxygen containing dianions 184 186). Benzo[b]thiophene, (73), 1,3-diphenylbenzo[c]thiophene (74) and l,3-diphenylbenzo[c]furan (75) form the respective dianions at low temperature. 

C2-Arylated 1,3-Azoles In 1998, Miura reported the first example of the catalytic C-H arylation of (benzo)azoles and thiophenes (at their C2 position) with aryl halides [98, 99a]. In the presence of catalytic Pd(OAc)2 and stoichiometric carbonate base at high temperature (140 °C), 1,3-azoles (oxazoles, N-alkylated imidazoles, fhiazoles) were coupled with various aryl bromides selectively at the C2 position. For the reactions of N-alkylated benzimidazoles, benzoxazoles, and benzothiazoles, addition of Cul was necessary to increase the yield of products. Furthermore, when N-methylbenzimidazole was used, Miura discovered that the coupling with aryl bromides proceeds without the palladium catalyst (i.e., by a copper-mediated C-H/C-X coupling of azoles with aryl halides). Thereafter, Miura enhanced the efficiency of the coupling reaction to allow for multiple arylations of azoles both C2 and C5 positions [99b]. In 2000, Rondo [100] prepared polymer-supported aryl iodides, with which the direct coupling reaction with 1,3-azoles (Miura s conditions) was conducted. 

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