Furans and Thiophenes

Competitive metallation experiments with IV-methylpyrrole and thiophene and with IV-methylindole and benzo[6]thiophene indicate that the sulfur-containing heterocycles react more rapidly with H-butyllithium in ether. The comparative reactivity of thiophene and furan with butyllithium depends on the metallation conditions. In hexane, furan reacts more rapidly than thiophene but in ether, in the presence of tetramethylethylenediamine (TMEDA), the order of reactivity is reversed (77JCS(P1)887). Competitive metallation experiments have established that dibenzofuran is more easily lithiated than dibenzothiophene, which in turn is more easily lithiated than A-ethylcarbazole. These compounds lose the proton bound to carbon 4 in dibenzofuran and dibenzothiophene and the equivalent proton (bound to carbon 1) in the carbazole (64JOM(2)304). 

There are examples of preferential arylation of Af-substituted pyrroles, thiophenes and furans in the 2-position. A preparatively useful reaction of this type is the o-nitrophenylation of thiophene (Scheme 40). A phase transfer catalytic technique has been recommended for this reaction (77TL1871). 

Perfluoroalkanoyl chlorides and anhydrides are also acylating agents Tri-fluoroacetic anhydride acylates a number of pyrroles, thiophenes, and furans without a catalyst [37, 38, 39] AzuUne can be diacylated without a catalyst in 12 h [40] (equation 26). 

Using these assumptions and conventions, Imoto and co-workers have correlated a number of series of reactions of thiophenes and furans. The reactions studied are the acid-base equilibria pK values) and the acid catalyzed methylations (thiophenes only) of thiophene-and furan-carboxylic acids and the alkaline hydrolyses of their ethyl esters the side-chain bromination of the a-acetylthiophenes, and the a-mercuration of thiophenes and the polarographic half-wave potentials of the methyl esters of thiophene- and furan-carboxylic acids and of nitrothiophenes. The pK values were determined and the ester hydrolyses studied for all three substitution orientations in the thiophene series. For the 4-R-2-Y and 5-R-2-Y series, the p-values do not appear significantly different and the data could probably be combined into a single series unfortunately, however, no limits of accuracy are reported for the p-values, and some of the raw data are not readily available so recalculation is not easily possible. For the 5-R-3-Y series the p-values deviate considerably from the other values however, whereas they are higher for the pK values, they are lower for the ester hydrolyses, and it is possible that the differences are neither systematic nor significant. 

Activation of pyrrole, thiophene, and furan molecules with pentaammineos-mium(n) 97CRV1953. 

The fourth chapter of this volume comprises the second part of an ongoing series by Professor A. P. Sadimenko (Fort Hare University, South Africa) dealing with organometallic compounds of pyrrole, indole, carbazole, phospholes, siloles, and boroles. This follows the review in Volume 78 of Advances covering organometallic compounds of thiophene and furan. The enormous recent advances in this area are summarized and classified according to the nature of the heterocycle and of the metals. 

Heterocyclic compounds carrying hydroxyl groups may be compared with phenols. Thomson has reviewed the tautomeric behavior of phenols often both tautomeric forms of polycyclic compounds such as naphthols can be isolated. Early work on hydroxy-thiophenes and -furans was also reviewed by Thomsond but until recently their chemistry has been in a somewhat confused state. A pattern is now beginning to emerge, at least for the a-substituted compounds, which appear to exist as A -oxo derivatives and to attain equilibrium slowly with the corresponding A -oxo forms. For the a-hydroxy compounds, the equilibrium generally favors the A -oxo form. 

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

Rotational equilibria of 2-carbonyl substituted thiophene and furan derivatives were calculated and show that the 2-substituent favors the anti-isomer in thiophene <96MI199>. NMR shifts of 35 alkyl 3-hydroxythiophene-2-carboxylates and 3-alkylamino-l-(3-thienyloxy)-2-propanols have been compiled and analyzed <96HC17>. 

Reactions of tc-excessive heteroaromatic compounds such as pyrroles, thiophenes and furans with carbenoids have been known for several years 6-10>u>. Recent activities were directed towards further synthetic applications of already known reactions, evaluation of the efficacy of novel catalysts and towards mechanistic insights. 

Goncales CEP, Araldi D, Panatieri R B, Rocha J B T, Zeni G and Nogueira C W (2005), Antinociceptive properties of acetylenic thiophene and furan derivatives Evidence for the mechanism of action , Life Sciences, 76, 2221-2234. 

Modelli and coworkers126 studied by PES and ETS (electron transmission spectroscopy) some silicon and tin derivatives of thiophene and furan, with the aim of following the energy gap between the HOMO and the LUMO as a function of the substituents. In particular they investigated the following tin derivatives ... 

The experimental results indicated that the filled and empty 71 MOs of thiophene and furan are perturbed in opposite directions by the MR3 substituents, causing a reduction of their energy gap. Furthermore, the empty orbitals of the substituents do not stabilize significantly the filled ring tt orbitals, whilst mixing significantly with the unoccupied 71 orbitals. 

NMR studies on 28 and 29 indicate that both the thiophene and furan rings rotate freely at room temperature (vide infra) and therefore, anomalies in the UV spectra of 28 and 29 should be attributed to the through-bond interaction between the Si-Si cr bonds and aromatic 77 bonds. This was further confirmed by photoelectron spectral studies. As shown in Table II, the lift of HOMO for 12 relative to the model compound was 0.4 eV, but those for 28 and 29 were 0.7 and 0.6 eV, respectively. Apparently, more effective through-bond interaction occurs for 28 and 29 (21). 

Falck has recently reported dehydrogenative silylation of heteroarenes with triethylsilane (18) [97]. Coupling with the Si-H bond of triethylsilane, rather than the disilane Si-Si bond, in conjunction with the use of norbomene that presumably acts as a hydrogen acceptor, gives good yields with indoles, thiophenes, and furans, under relatively mild condition (80°C). Unlike the reaction shown in Scheme 7, silylation of indole did not require protection of the N-H group. 

The aromatic silylation of five-membered heteroarenes under the same conditions (catalyst, temperature, solvent) also proceeded in regioselective fashion. Both, thiophene and furane derivatives are exclusively silylated at the a-position, but 1-triisopropylsily 1-pyrrole and -indole each produce selectively ]3-silyl products (Equations 14.9 and 14.10). 

Di-2-thienyl and di-2-furyl ditelluride are prepared from thiophene and furan by lithia-tion with n-buthyllithium, tellurium insertion and oxidative work-up. 

Thiophene is present in the benzene fraction from the distillation of coal tar. As with pyrrole and furan, the same type of resonance forms contribute to its overall molecular constitution, and the compound is aromatic in character. There is a difference between thiophene and furan, however, because sulfur is less electronegative than oxygen. Thus, the chemistry of thiophene tends to be closer to that of pyrrole than to that of furan. For example, thiophene does not enter easily into [4 + 2] cycloaddition reactions and quite severe conditions, high pressure (15 bar) and a temperature of 100 C, are necessary in order to force a cycloaddition between it and maleic anhydride. 

The results of the polymerization experiments are shown in Table 1.6. Besides the facts discussed, it can be seen that triphenyl phosphite, propylamine, and tributylphosphine effectively inhibit the polymerization reaction. In contrast, benzonitrile, triphenyl-arsine, anhydrous acetonitrile, thiophene, and furan accelerate the reaction (25). 

Reduced thiophenes and furans are named systematically as 2,3-dihydro (12), 2,5-dihydro (13) and 2,3,4,5-tetrahydro compounds (14). Alternatively, delta (A) can be used to indicate the position of the remaining double bond. Thus, (12) and (13) are named as A2- and A3-dihydro compounds, respectively tetrahydrothiophene is also called thiophane. 

The data shown in Table 2 illustrate the general paucity of comparative toxicity data within an isosteric series of chemicals. In this Table a variety of toxic end-points observed for benzene and naphthalene have been compared with those of their simple heterocyclic analogues, and it is clear that it is almost impossible to derive chemical structure-biological activity relationships from the published literature for even such a simple series of compounds. Even basic estimates of mammalian toxicity such as LD50 values cannot be accurately compared due either to the absence of relevant data or the noncomparability of those available. Thus in a field where there are little comparative data on the relative toxicity to mammals of pyrrole, thiophene and furan for example, it is difficult to relate chemical structure to biological activity in historical heterocyclic poisons such as strychnine (3) and hemlock [active agent coniine (4)]. 

Table 1 Relative Yields of Thiophenes and Furans from H2S Treatment of (179) (68CB1540)...

Raney nickel reduction of 2-benzyl-5-ethylselenophene (71) yields 1-phenylheptane (72), a conversion analogous to the much used reductive desulfurization of thiophenes (73JGU871). The electrochemical reduction of selenophene-2-carboxylic acid gives a mixture of dimeric products the major product is compound (73). This is in contrast to the 2,5-dihydro derivatives obtained by electrochemical reduction of thiophene and furan carboxylic acids (82CS( 19)95). Wolff-Kishner reduction of 2-selenienyl 2 -thienyl ketone gives, in addition to the expected methylene derivative, 2-(pentenyl)thiophene (72ZOB1780). 

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