Benzofuran and Benzothiophene

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

We studied the effect of replacing the indole nucleus by other non-basic ring systems and prepared the benzofuran and benzothiophen derivatives by the standard route from the appropriate ketone. It may be seen from Table 7.5 that both derivatives were less active than ondansetron. 

In this paper, the selectivity of the ECH method for the reduction of nitro compounds to the corresponding amines on RCu electrodes will be compared with that of reduction by RCu alloy powder in alkaline aqueous ethanol. In the latter method (termed chemical catalytic hydrogenation (CCH)), chemisorbed hydrogen is generated in situ but by reduction of water by aluminium (by leaching of the alloy) (equation [12]). The reductions by in situ leaching must be carried out in a basic medium in order to ensure the conversion of insoluble Al(OH)3 into soluble aluminate (equation [12]). The selectivity and efficiency of the electrochemical reduction of 5-nitro-indoles, -benzofurane, and -benzothiophene at RCu electrodes in neutral and alkaline aqueous ethanol will also be compared with that of the classical reduction with zinc in acidic medium. 

Treatment of benzofuran and benzothiophene with 2 equiv of (NSClfs under these conditions resulted in no reaction. Indole, however, gave the expected 4//-[l,2,5]thiadiazolo[3,4- ] indole in 23% yield. It is suggested that benzofuran and benzothiophene are not sufficiently nucleophilic to undergo reaction with (NSClfs. 

Although not fitting exactly into the scope of this book, the iridium catalyzed borylation of five membered heterocycles through C-H bond activation also deserves mentioning. A recent report by Miyaura disclosed the reaction of bis(pinacolato)diboron with heteroaromatic systems, where thiophene, fiirane and pyrrole were converted to their 2-boryl derivatives with good selectivity (6.86.), The yields presented refer to the diboron compound since the heterocycles were used in excess in all cases. Indole, benzofurane and benzothiophene were monoborylated with similar efficiency.116... 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

While the simultaneous presence of benzofuran and benzothiophene is established in some fractions from coal pyrogenation and from the distillation of some petroleums, benzothiophene is entirely absent in heterocyclic compounds extracted from natural substances of vegetable origin. However, numerous benzofuran or hydrobenzofuran derivatives of biogenetic or metabolic origin have been isolated. 

Our aromaticity-determining reactions for the three heterocycles are endothermic by 70, 40, and 48 kJ mol-1, to be compared with the exothermicity for the corresponding carbocycle, indene, of nearly 9 kJ mol-1. Indole, benzofuran, and benzothiophene are truly aromatic species in terms of thermochemical stabilization. 

Recently, more accurate determinations of isomer distributions and a /3 reactivity ratios in electrophilic substitutions of benzofuran and benzothiophene have been determined using the gas chromatographic technique.77 The data are summarized in Table XVI which also includes a /3 reactivity ratios referring to electrophilic displacement reactions such as protodesilylation and to side-chain reactions related to electrophilic substitution, such as the solvolysis of 1-arylethyl-acetates239 and 1-arylethyl- -nitrobenzoates.240... 

Effect of Temperature on Isomer Distribution of Tin Tetrachloride -Catalyzed Acetylation of Benzofuran and Benzothiophene in... 

Recently the overall reactivities relative to the monocyclic rings have been determined for a number of reactions77 by kinetic or competitive procedures. The data, reported in Table XVIII, show that fusion with a benzene ring produces an overall decrease in reactivity in both systems. The decrease is much more pronounced for furan than for thiophene ring. As a consequence of this, the overall reactivities of benzofuran and benzothiophene are nearly equal in all the substitutions for which quantitative data are available (column 3 of Table XVIII for a useful comparison the relative reactivities of the monocyclic rings in the same reactions are also reported in column 4). 

Electrophilic Substitutions and Related Reactions of Furan, Thiophene, Benzofuran, and Benzothiophene. 

Although obtained only in low yields upon troublesome chromatography of product mixtures that contained much polymeric material, the tricyclic benzofuran and benzothiophene lactones (61) were shown to be isolable products from attempted Diels-Alder reactions on the allene ester precursors shown in Equation (32) <85JCS(Pl)747>. Although it was noted in the case of the two thiophenes that the tricyclics appeared to be forming from a precursor (presumably a dihydro form) on the chromatographic column, it was not possible to convert the crude suspected cycloaddition adducts directly into the aromatics by dehydrogenation with DDQ. Complex mixtures were obtained instead. It is possible that the actual dienophiles in these Diels-Alder reactions are alkynes. In a related study, the bis-lactone (62) was also obtained (Equation (33)) <86H(24)88l>. 

Equilibrium and rate constants for the keto-enol tautomerization of hydroxy heterocycles are summarized in Table 38 <1986TL3275>. The pyrroles ketonize (i.e., 226 — 230) substantially faster (103-104 times) than their sulfur or oxygen analogues, and still faster than the benzo-fused systems (indole, benzofuran, and benzothiophene). 

Benzofurans and benzothiophenes are sometimes obtained by condensation of active methylene and aldehyde groups in ortho substituents on the benzene ring. " The starting materials in the furan series are conveniently prepared in situ torn phenolic aldehydes and a-halo ketones or CL-halo esters. 

If the heteroatom contributes two electrons to the tr-electronic structure of the molecule (e.g., nitrogen in pyrrole or indole, oxygen in furan, sulfur in thiophene), it essentially represents a charge-transfer donor-type substituent. Its effect on the electronic structure and spectra will be dominated by its ability to donate electrons and to a lesser extent by considerations of electronegativity. Thus, the interactions of nitrogen, oxygen, and sulfur in, say, indole, benzofuran, and benzothiophene, with their aromatic systems, are similar to the interactions of amino, hydroxy, and mercapto exocyclic groups with their aromatic systems. 

Hydrodesulfnrisation of benzothiophenes is conveniently achieved using Raney nickel. Reduction of the hetero-rings of both benzofuran and benzothiophene giving 2,3-dihydro derivatives, notably with retention of the snlfur in the latter case, can be achieved using triethylsilane in acidic solution, or with hydrogen over colloidal rhodium. Reductive cleavage of benzofuran to 2-hydroxystyrene is caused by lithium with 4,4 -di-f-butylbiphenyl (DTBB). ... 

Dihydroxylation of benzofuran and benzothiophene giving d5 -2,3-dihydro-2,3-dihydroxy derivatives can be achieved nsing Pseudomonas putida. Benzofurans can be epoxidised at the hetero-ring double bond with dimethyl dioxirane, or alternatively converted into dioxetanes by reaction of that double bond with singlet oxygen. Both oxidised species are unstable and undergo a variety of complex further processes. ... 

Intramolecular aldol/Perkin type condensation of orf/to-formylaryloxyacetic acids and arylthioacetic esters produces benzofuran- and benzothiophene-2-esters respectively, as illustrated below. The synthesis can be performed in one pot, thus ortfto-hydroxyaryl-aldehydes or -ketones, are 0-alkylated with a-halo-ketones, then intramolecular aldol condensation in situ produces 2-acyl or 2-aroyl-benzofurans. ° For benzothiophenes, the ring-closure substrates can also be obtained via methyl thioacetate displacement of fluoride from orf/to-fluoro-araldehydes. ... 

Under conditions of irreversible deprotonation (BuLi in THF or Et20), the 2-position of the hetero ring is metallated [1, 2, 9]. The pK values of benzofuran and benzothiophene [124] are slightly lower than those of the non-condensed heterocycles, so that complete metallation in the 2-position presumably can be effected with LDA in THF. However, the difference in acidity between the 2- and 3-protons is probably less than that in furan and thiophene. Ring opening therefore seems relatively easy under suitable basic reaction conditions (compare [141]), e.g.) ... 

The ASE values correlate with magnetic susceptibility for the five-membered heteroaromatic compounds. Magnetic and polarizability criteria put the order of aromaticity as thiophene > pyrrole > furan. The other criteria of aromaticity discussed in Section 8.2 are also applicable to heterocyclic compounds. HOMO-LUMO gaps and Fukui functions (see Topic 1.5) have been calculated for compounds such as indole, benzofuran, and benzothiophene and are in accord with the known reactivity patterns of these heterocycles. 

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