Furans electrophilic aromatic substitution

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

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>. 

Pyrrole, furan, and thiophene, on the other hand, have electron-rich aromatic rings and are extremely reactive toward electrophilic aromatic substitution— rnore like phenol and aniline than benzene. Like benzene they have six tt electrons, but these tt electrons are delocalized over five atoms, not six, and ar e not held as strongly as those of benzene. Even when the ring atom is as electronegative as oxygen, substitution takes place readily. 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

Hence the positional selectivity is different from that of the furan additions to 417 (Scheme 6.90). Assuming diradical intermediates for these reactions [9], the different types of products are not caused by the nature of the allene double bonds of 417 and 450 but by the properties of the allyl radical subunits in the six-membered rings of the intermediates. Also N-tert-butoxycarbonylpyrrole intercepted 450 in a [4 + 2]-cycloaddition and brought about 455 in 29% yield. Pyrrole itself and N-methylpyr-role furnished their substituted derivatives of type 456 in 69 and 79% yield [155, 171b]. Possibly, these processes are electrophilic aromatic substitutions with 450 acting as electrophile, as has been suggested for the conversion of 417 into 442 by pyrrole (Scheme 6.90). 

Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron... 

As described in the previous sections, a variety of nucleophiles attack the Cy atom of ruthenium-allenylidene intermediates. Aromatic compounds should also be suitable candidates and this was found to be the case [30]. Thus, reactions of propargylic alcohols with heteroaromatic compounds such as furans, thiophenes, pyrroles, and indoles in the presence of a diruthenium catalyst such as la proceeded smoothly to afford the corresponding propargylated heteroaromatic compounds in high yields with complete regioselectivity (Scheme 7.25). The reaction is considered to be an electrophilic aromatic substitution if viewed from the side of aromatic compounds. 

The text states that electrophilic aromatic substitution in furan, thiophene, and pyrrole occurs at C-2. The sulfonation of thiophene gives thiophene-2-sulfonic acid. 

Predict the product expected from electrophilic aromatic substitution reactions of pyrrole, furan, and thiophene. 

For benzo[b]furan and indole no such precise data are available, but it is possible to adduce some information from the various reactions described below. The positional reactivity orders for these molecules and also for benzo[b]thiophene, which have been calculated by various methods, are given in Table 8.1. In principle the ab initio calculations should be the more reliable, but neither the tt nor the (a + it) order is correct for benzo[6]thiophene, suggesting that these are incorrect for the other molecules also. The calculations using the STO-3G basis set certainly wrongly predict the site of most rapid protonation. Notably, only the Hiickel calculations give the correct order for benzo[b]thiophene and indeed they are usually the most reliable indicators for electrophilic aromatic substitution. 

Furan undergoes electrophilic aromatic substitution more readily than benzene mild reagents and conditions are sufficient. For example, furan reacts with bromine to give 2-bromofuran. 

The other simple five-membered heterocycles are furan, with an oxygen atom instead of nitro- pyrrole gen, and thiophene with a sulfur atom. They also undergo electrophilic aromatic substitution very Ft ft readily, though not so readily as pyrrole. Nitrogen is the most powerful electron donor of the three, 1 J> oxygen the next, and sulfur the least. Thiophene is very similar to benzene in reactivity. N... 

With 2-substituted benzo[7]furans, the regioselective electrophilic aromatic substitutions of formyl and nitro groups to C-3 of 2-aryl-7-methoxy-2-phenylbenzo[ ]furans were achieved (Equation 62). Further synthetic transformations of the resulting formyl group into methyl, hydroxymethyl, 1-hydroxyethyl, and cyano groups were also reported <1992JOC7248>. 

Heterocycles also undergo electrophilic aromatic substitution. Explain why furan undergoes substitution with electrophiles mainly at the 2-position. 

A similar electrophilic aromatic substitution was observed between l-bromo-1-(methyl-sulfanyl)cyclopropane (43) and furan in 2,2,2-trifluoroethanol. 

Side-chain reactions in which a deiocalizable positive charge is developed in the transition state are frequently considered together with electrophilic aromatic substitutions 60 the analogy between these two classes of reactions has been confirmed also in heteroaromatic chemistry.61 However, a comparison of the solvolysis data with those referring to electrophilic substitutions (Tables XVII-XIX) indicates that tellurophene behaves in a different way in the two types of reactions. As concerns the reactivity, tellurophene is less reactive than furan in electrophilic substitution but more reactive than furan in the solvolysis of 1 (2-aryl)ethyl acetates as concerns the k,tJkH reactivity ratios, tellurophene appears to be more sensitive to substituent effects than selenophene in electrophilic substitutions and less sensitive in side-chain reactions. 

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