Furan and thiophene

Furan and thiophene are the oxygen and sulfur analogues respectively of pyrrole. Oxygen and sulfur contribute two electrons to the aromatic sextet, but still retain lone pair electrons. There is one significant difference, however, in that oxygen uses electrons from a 2p orbital, whereas the electrons that sulfur contributes originate from a 3p orbital. In the case 

Note that the dipoles of furan and thiophene are opposite in direction to that in pyrrole. In furan and thiophene, there is a greater inductive effect opposing the resonance effect, whereas in pyrrole the resonance 

---

The oxidative coupling of thiophene, furan[338] and pyrrole[339,340] is also possible. The following order of reactivity was observed in the coupling of substituted furans[338] R = H > Me > CHO > CO Me > CH(OAc)i > CO2H. The cross-coupling of furans and thiophenes with arene is possible, and 4-phenylfurfural (397) is the main product of the cross-coupling of furfural and benzene[341]. 

Benzoic acid and naphthoic acid are formed by the oxidative carbonylation by use of Pd(OAc)2 in AcOH. t-Bu02H and allyl chloride are used as reoxidants. Addition of phenanthroline gives a favorable effect[360], Furan and thiophene are also carbonylated selectively at the 2-position[361,362]. fndole-3-carboxylic acid is prepared by the carboxylation of 1-acetylindole using Pd(OAc)2 and peroxodisulfate (Na2S208)[362aj. Benzoic acid derivatives are obtained by the reaction of benzene derivatives with sodium palladium mal-onate in refluxing AcOH[363]. 

Cyclic compounds that contain at least one atom other than carbon within their ring are called heterocyclic compounds, and those that possess aromatic stability are called het erocyclic aromatic compounds Some representative heterocyclic aromatic compounds are pyridine pyrrole furan and thiophene The structures and the lUPAC numbering system used m naming their derivatives are shown In their stability and chemical behav lor all these compounds resemble benzene more than they resemble alkenes... 

Section 12 18 Heterocyclic aromatic compounds may be more reactive or less reactive than benzene Pyridine is much less reactive than benzene but pyrrole furan and thiophene are more reactive... 

Pyrrole has a planar, pentagonal (C2 ) stmcture and is aromatic in that it has a sextet of electrons. It is isoelectronic with the cyclopentadienyl anion. The TT-electrons are delocalized throughout the ring system, thus pyrrole is best characterized as a resonance hybrid, with contributing stmctures (1 5). These stmctures explain its lack of basicity (which is less than that of pyridine), its unexpectedly high acidity, and its pronounced aromatic character. The resonance energy which has been estimated at about 100 kj/mol (23.9 kcal/mol) is intermediate between that of furan and thiophene, or about two-thirds that of benzene (5). 

One of the more useful predicative applications of the relatively crude Hiickel method has been to illustrate quantitatively the effect of benzenoid annelation on the resonance energies of furan and thiophene. The results are summarized in Figure 1. As expected, thiophenes are more stable than the corresponding furans and 3,4-fusion results in less stable compounds than 2,3-fusion (77CR(C)(285)42l). 

Although the same theoretical studies indicate very small energy differences between the syn and anti conformers of the 3-carbaldehydes of furan, thiophene and pyrrole with a slight preference for the syn conformer, in chloroform solution the furan- and thiophene-3-carbaldehydes adopt the anti conformers to the extent of 100 and 80% respectively (82X3245). However, A-substituted 3-(trifluoroacetyl)pyrroles exist in solution as mixtures of rotational isomers (80JCR(S)42). 

Only the potentially 2,4-dihydroxy derivatives of furan and thiophene are known and these exist in the solid state and in polar solvents as the monoenols (82) (71T3839). However, in non-polar solvents the furan derivatives exist predominantly in the dioxo form (83). The 2,5-dioxo structure (84) is well established for X=0, NR, S and Se (71BSF3547) and there is no evidence for intervention of any enolic species. The formal tautomer (85) of succinimide has been prepared and is reasonably stable (62CI(L)1576). 

Examples of the remaining potential 3,4-dihydroxy heterocycles are presently restricted to furan and thiophene. Although the parent 3,4-dihydroxyfuran apparently exists as the dioxo tautomer (86), derivatives bearing 2-alkyl or 2,5-dialkyl substituents prefer the keto-enol structure (87) (71T3839, 73HCA1882). The thiophene analogues also prefer the tautomeric structure (87), except in the case of the 2,5-diethoxycarbonyl derivative which has the fully aromatic structure (88) (71T3839). 

The classical structures of pyrrole, furan and thiophene (31) suggest that these compounds might show chemical reactions similar to those of amines, ethers and thioethers (32) respectively. On this basis, the initial attack of the electrophile would be expected to take place at the heteroatom and lead to products such as quaternary ammonium and oxonium salts, sulfoxides and sulfones. Products of this type from the heteroaromatic compounds under consideration are relatively rare. 

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

Alkylation of furan and thiophene has been effected with alkenes and catalysts such as phosphoric acid and boron trifluoride. In general, Friedel-Crafts alkylation of furans or thiophenes is not preparatively useful, partly because of polymerization by the catalyst and partly because of polyalkylation. 

Pyrroles, furans and thiophenes undergo photoinduced alkylation with diarylalkenes provided that the alkene and the heteroaromatic compound have similar oxidation potentials, indicating that alkylation can occur by a non-ionic mechanism (Scheme 20) (81JA5570). 

Mercury(II) acetate tends to mercurate all the free nuclear positions in pyrrole, furan and thiophene to give derivatives of type (74). The acetoxymercuration of thiophene has been estimated to proceed ca. 10 times faster than that of benzene. Mercuration of rings with deactivating substituents such as ethoxycarbonyl and nitro is still possible with this reagent, as shown by the formation of compounds (75) and (76). Mercury(II) chloride is a milder mercurating agent, as illustrated by the chloromercuration of thiophene to give either the 2- or 2,5-disubstituted product (Scheme 25). 

The first proton to be removed from iV-methylpyrrole by w-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. The formation of a 2,4-dilithio derivative is noteworthy since in the case of both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(P1)887). iV-Methylindole, benzo[6]furan and benzo[6]thiophene are also deprotonated at C-2. Selenophene and benzo[6]selenophene and tellurophene and benzo[6]tellurophene similarly yield 2-lithio derivatives (77AHC(21)119). 

Directive effects on lithiation have also been studied. The regiospecific /3-metallation of A-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect of the oxazolino group (82JCs(Pl)1343). 2-Substituted furans and thiophenes are metallated in the 5-position. The formation of 2-lithio-3-bromofuran on treatment of... 

It is estimated that thiophene reacts with phenyl radicals approximately three times as fast as benzene. Intramolecular radical attack on furan and thiophene rings occurs when oxime derivatives of type (112) are treated with persulfate (8UCS(Pt)984). It has been found that intramolecular homolytic alkylation occurs with equal facility at the 2- and 3-positions of the thiophene nucleus whereas intermolecular homolytic substitution occurs mainly at position 2. 

Furan and thiophene undergo addition reactions with carbenes. Thus cyclopropane derivatives are obtained from these heterocycles on copper(I) bromide-catalyzed reaction with diazomethane and light-promoted reaction with diazoacetic acid ester (Scheme 41). The copper-catalyzed reaction of pyrrole with diazoacetic acid ester, however, gives a 2-substituted product (Scheme 42). 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of iV-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive... 

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. 

Pyrrolethiols, readily obtained from the corresponding thiocyanates by reduction or treatment with alkali, rapidly oxidize to the corresponding disulfides. They are converted into thioethers by reaction with alkyl halides in the presence of base. Both furan- and thiophene-thiols exist predominantly as such rather than in tautomeric thione forms. 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

Intramolecular attack of the carbenes shown in Scheme 30a provides benzo[6]cyclo-hepta[(5 ]-furans and -thiophenes, but the nitrogen analogue (X = NH) yields 9,10-dihydro-acridine 81AJC1037). Photolysis of 2-biphenyl isocyanide (Scheme 30b) (72JOC3571) and thermolysis of 2-biphenylsulfonyl diazomethane (Scheme 30c) (72CC893) also result in ring expansion. 

The replacement of two CH groups in benzene by a neutral NR, O or S introduces into the new ring an electron-donating heteroatom. This electron-donor character is accentuated in the pyrrole anion where N is introduced. Thus the five-membered rings with one heteroatom are electron rich (rr-excessive), and the chemistry of pyrrole, furan and thiophene is dominated by this effect and is again considered together as a whole in Part 3. 

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. 

The second chapter concerns the tautomerism of five-membered ring systems with a single heteroatom concentrating mainly on pyrroles, furans, and thiophenes. It is authored by Professor W. Friedrichsen and Dr. T. Traulsen (University of Kiel, Germany) together with Drs. J. Elguero and A. R. Katritzky. 

In agreement with the previously reported theoretical study, the results of semi-empirical calculations showed that the formation of the Dewar isomer is favored [99H(50)1115]. Probably, the observed formation of the azirine derives from a thermal isomerization of the first photoproduct, in line with that described in the case of furan and thiophene derivatives (Fig. 11). 

This chapter is a continuation of the one on organometallic chemistry of furans and thiophenes [01AHC(78)1]. It starts with the trends of coordination of... 

Regiospecific synthesis of 3,4-disubstituted furans and thiophenes 97LA459. 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

---