Electrophilic substitutions, furan

Quantitative data are available on the effect on electrophilic substitution reactions of the fusion of a benzene ring to the b face of a furan or thiophene ring. The overall effect is to decrease reactivity this decrease is much more pronounced in the case of fusion to a furan than to a thiophene ring. As a consequence the overall reactivities of benzo[Z)]furan and benzo[Z)]thiophene are approximately equal 71AHC(13)235). 

In view of the overall increased reactivity of furan compared with thiophene it would be anticipated that furan would be less regioselective in its reactions with electrophiles than thiophene. Possible reasons for the high regioselectivity of furan in electrophilic substitution reactions include complex formation between substrates and reagents and the ability of heteroatoms to assist in the stabilization of cationic intermediates (80CHE1195). 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the... 

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

Benzo[c]furan, 1,3-dihydro-1,3-diphenyl-mass spectrometry, 4, 585 Benzo[c]furan, 1,3-dfmethyl-synthesis, 4, 699, 701 Benzo[c]furan, 1,3-diphenyl-cycloaddition reactions, 4, 67 electrophilic substitution, 4, 604 history, 4, 533... 

The wide variation in the entropy factors for both the substituted phenyl and heterocyclic compounds and in particular for the methoxyphenyl and furan derivatives was considered to be strong evidence for solvent effects being predominant in determining the activation entropy. Consequently, discussion of the substituent effects in terms of electronic factors alone requires caution in this reaction. Caution is also needed since rates for the substituted phenyl compounds were only determined over a 20 °C range. The significance of entropy factors has also been indicated by the poor correlation of the data of the electrophilic reactivities of the heterocyclic compounds, as derived from protodemercuration, with the data for other electrophilic substitutions and related reactions572. 

The thiophene ring can be elaborated using standard electrophilic, nucleophilic, and organometallic chemistry. A variety of methods have been developed to exploit the tendency for the thiophene ring (analogous to that of furan and pyrrole) to favor electrophilic substitution and metallation at its a-carbons. Substitution at the p-carbons is more challenging, but this problem can also be solved by utilizing relative reactivity differences. 

Furfuryl alcohol in an acid medium gives rise to reactions of polycondensation reactions of successive electrophilic substitutions involving furan molecules. This reaction is identical to the reaction described for benzyl alcohol on p.256 and represents the same dangers. It is carried out under the same conditions, ie in a sulphuric medium. The electrophilic species that comes into play is very similar to the benzyl cation. 

Electrophilic substitution in furan, thiophene, selenophene and pyrrole has, up to 1970, been comprehensively reviewed by Marino.66 Italian workers have determined the relative reactivities of selenophene and thiophene as well67 relative rates are given in Table I. Including furan, the order of reactivity is furan > selenophene > thiophene. 

Furans are even reactive enough to be substituted by some diazonium salts or diazopyrazoles, though other reactions are usual (Section V,A),135 and catalysts are used in response to difficulty in producing an electrophilic species not because the furan ring is unreactive. Scheme 27 shows the synthesis of an interesting a-amino acid derivative136 by electrophilic substitution. 

Modes of cycloaddition of alkylideneallyl cation are also controlled by the reaction conditions. [4 + 3] Cycloaddition occurs in the reaction with furan. The [4 + 3] cycloaddition with furan was observed for the siloxy-substituted allyl cation 5S, but not for the methoxy-substituted allyl cation 5M. The lower electrophilicity of 5S may prefer the concerted pathway of [4 + 3] cycloaddition in competition with the stepwise pathway to yield a [3 + 2] cycloadduct and an electrophilic substitution product. 

On the other hand, we also planned alternative completely new approach (Route B) to Nakadomarin A, which involves the spirolactam followed by coupling reaction with furan derivative and subsequent intramolecular electrophilic substitution reaction of an iminium cation generated from an aminal to give highly functionalized tetracyclic core system (Scheme 10.3). 

The total synthesis of the furo[3,2-a]carbazole alkaloid furostifoline is achieved in a highly convergent manner by successive formation of the car-bazole nucleus and annulation of the furan ring (Scheme 15). Electrophilic substitution of the arylamine 30 using the complex salt 6a provides complex 31. In this case, iodine in pyridine was the superior reagent for the oxidative cyclization to the carbazole 32. Finally, annulation of the furan ring by an Amberlyst 15-catalyzed cyclization affords furostifoline 33 [97]. 

Thus, 2-furfuryl vinyl ether 6a is extremely sensitive to cationic activation (16) because of its very pronounced nucleophilic character, but the polymerization is accompanied by some gel formation due to abundant alkylation of the furan rings pendant to the macromolecules. This structural anomaly is not encountered with the 5-methylated monomer 6b (16) precisely because electrophilic substitutions take place predominantly at C5 and are therefore impossible with this monomer. A similar difference of phenomenolo was observed with the 2-fiiryl oxiranes 4a and 4b (17). 

The propensity of the C5 site towards electrophilic substitution has been exploited to prepare functionalized oligomers by cationic polymerization. Thus monomers like isobutene, s ene, the vinyl ethers, etc. polymerize in the presence of simple furan derivatives such as 2-methyl furan to give essentially short chains (DP between 2 and 100 depending on the specific experimental conditions) with a terminal furan ring as a result of predominant transfer onto the C5 position of the added furan compound (20). 

An example of the first type of study is the cationic pol erization of alkenes and heterocyclic monomers in the presence of 2-alWlfurans. As discussed above, electrophilic substitution at C5 is quite facile with these compounds and one can therefore prepare monofunctional oligomers bearing a furanic end-group. By a judicious choice of experimental conditions this transfer reaction will predominate over all other chain-breaking events and virtually all the chains will have the same terminal structure, i.e. a 5-oligomer-2-al lfuran. Structure 32 illustrates this principle with isobutyl vinyl ether oligomers capped by 2-methylfuran ... 

Nevertheless, we can interpret the reactions of furan and thiophene by logical consideration as we did for pyrrole. In electrophilic substitutions, there is again a preference for 2- rather than 3-substitution, and typical electrophilic reactions carried out under acidic conditions are difficult to control. However, because of lower reactivity compared with pyrrole, it is possible to exploit Friedel-Crafts acylations, though using less-reactive anhydrides rather than... 

The 1,3-diazoles are much less susceptible to electrophilic substitution than pyrrole, furan, and... 

An example of electrophilic substitution on position C2 of the fused furan has been reported for 8H-furo[3,4-d]dibenz[ 7,/]azepine, which reacts with f-butyl hypochlorite to afford a mono chlorinated furan ring product (1995H431). 

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