Heteroaromatic compounds pyrrole

K. Schofield, Heteroaromatic Compounds—Pyrroles and Pyridines. Butterworth, London, 1967. 

Just as electrophilic substitution is the characteristic reaction of benzene and electron-rich heteroaromatic compounds (pyrrole, furan etc.), so substitution reactions with nucleophiles can be looked on as characteristic of pyridines. 

Schofield, K. (1967). Heteroaromatic Nitrogen Compounds Pyrroles and Pyridines. London Butterworths. 

Indole is a heteroaromatic compound consisting of a fused benzene and pyrrole ring, specifically ben2o[ ]pyrrole. The systematic name, IJT-indole (1) distinguishes it from the less stable tautomer 3JT-indole [271-26-1] (2). Iff-Indole [120-72-9] is also more stable than the isomeric ben2o[ ] pyrrole, which is called isoindole, (2H, (3) and IH (4)). A third isomer ben2o[i ]pyrrole is a stable compound called indoli2idine [274-40-8] (5). 

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. 

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). 

Small shift values for CH or CHr protons may indicate cyclopropane units. Proton shifts distinguish between alkyne CH (generally Sh = 2.5 - 3.2), alkene CH (generally 4, = 4.5-6) and aro-matic/heteroaromatic CH (Sh = 6 - 9.5), and also between rr-electron-rich (pyrrole, fiiran, thiophene, 4/ = d - 7) and Tt-electron-deficient heteroaromatic compounds (pyridine, Sh= 7.5 - 9.5). 

In contrast to H shifts, C shifts cannot in general be used to distinguish between aromatic and heteroaromatic compounds on the one hand and alkenes on the other (Table 2.2). Cyclopropane carbon atoms stand out, however, by showing particularly small shifts in both the C and the H NMR spectra. By analogy with their proton resonances, the C chemical shifts of k electron-deficient heteroaromatics (pyridine type) are larger than those of k electron-rieh heteroaromatic rings (pyrrole type). 

The heteroaromatic compounds can be divided into two broad groups, called n-excessive and n-deficient, depending on whether the heteroatom acts as an electron donor or an electron acceptor. Furan, pyrrole, thiophene, and other heterocyclics incorporating an oxygen, nitrogen, or sulfur atom that contributes two n electrons are in the rr-exeessive group. This classification is suggested by resonance structures and confirmed by various MO methods. ... 

The regioseleciivicy of Fnedel-Crafts-lypc acylations on heteroaromatic compounds has been studied intensively [57 58, 59] In the case of pyrroles, the orientation of the entering acyl group strongly depends on the bulkiness of the group at the nitrogen atom (equation 29)... 

The first group consists of monocyclic heteroaromatic compounds with one heteroatom and without strongly electron-donating substitutents (OH, NH2). Pyrrole, furan, and thiophene are better electron donors than benzene. The order of their reactivities in azo coupling is thiophene > pyrrole > furan > benzene. 

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. 

The heteroaromatic compounds like furans, pyrroles or thiophenes cannot be generally used as dienes in Diels-Alder syntheses, because at the higher temperature required for the addition of less reactive dienophiles, the equilibrium is on the side of the starting materials due to the unfavorable T AS term comparable to the benzenoid aromatic compounds as mentioned. High pressure again shows the two effects already discussed the shift of the equilibrium toward the products and the enhancement of the rate of reaction which allows the temperature of reaction to be lowered. One... 

The reactions of heteroaromatic compounds such as furans, pyrroles, and indoles with alkynoates proceed under very mild conditions (in acetic acid or even in neutral solvents such as CH2C12 at room temperature). For example, the reaction of pyrrole with ethyl phenylpropiolate gives the 2-alkenylated pyrrole (Equation (44)).47c This reaction is applied to the direct synthesis of a /3-alkenylpyrrole, the pyrrole fragment of haemin (Equation (45)).47d The present reaction provides a very convenient method for functionalization of arenes and heteroarenes. 

A -Sulphonylation of pyrroles and indoles, using a liquidtliquid two-phase procedure [3, 48, 50-54], is superior to the traditional methods, which frequently require preformation of the heteroaryl sodium derivative, whereas A-sulphonylation of indole using a sulphonyl chloride in the presence of pyridine leads to the formation of the l,4-dihydro-4-indol-3-ylpyridine [49], The liquid liquid two-phase procedure outlined below is suitable for most A -Sulphonylation reactions with heteroaromatic compounds, but it is sometimes advisable to add a second quantity of the sulphonyl chloride during the course of the reaction [22,47]. 

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. 

Carbon-13 signals of parent heteroaromatic compounds [433-464] (Table 4.67) occur between 105 and 170 ppm. CNDO calculations performed for six-membered heteroaromatic compounds such as pyridine and azines [456, 458, 465] give a linear correlation between carbon-13 shift and total electron density at the individual carbon. The experimental slope, 160 ppm per electron, is the same as that found for monocyclic aromatic compounds (Section 4,11.1). The 13C shift values of pyrrole (107-117 ppm) and pyridine... 

INDOLES. Indole is a heteroaromatic compound consisting of a fused benzene and pyrrole ring, specitieally benzo[fc pyrrole. The indole ring is incorporated into the structure of Ihe amino acid tryptophan and occurs in proteins and in a wide variety of plant and animal metabolites. 

The commonest five-membered heteroaromatic compounds containing one heteroatom are pyrrole (30), furan (31) and thiophene (32). Their substituted derivatives and the substituted derivatives of the corresponding benzo analogues [indole (33), benzofuran (34) and benzothiophene (35)] are widespread naturally-occurring compounds. 

Pyridine (C5H5N), pyrrole (C4H5N), furan (C4H40), and thiophene (C4HtS) are examples of heteroaromatic compounds. 

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