Electron-rich heteroaromatic compounds

Anodic addition to an electron-rich heteroaromatic compound is used to transform furan to 2,5-dimethoxy-2,5-dihydrofuran, a valuable synthetic intermediate. Again, an indirect electrochemical process occurs. The bromide ion as redox catalyst is electrochemically oxidized to give bromine, which then acts as chemical oxidant for furan [7] ... 

This route is especially valuable for the transformation of electron-rich heteroaromatic compounds into their fluorinated analogues, which are not suitable for the nucleophilic exchange route. The method has been extended by addition of fluorinated olefins. The fluoroolefins add in a radical process to the 2-position of tetrahydrofuran, followed by perfluori-nation to give the perfluorinated 2-alkyl-substituted tetrahydrofurans in excellent yields [84JFC(25)523 85JFC(29)323] (Scheme 3). 

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. 

The Pd(II)-mediated reaction of benzene with alkenes affords styrene derivatives 164. The reaction can be vmderstood by palladation, insertion of olefin to give 163, and y3-H elimination [67,68]. In addition to benzene and naphthalene derivatives, electron-rich heteroaromatic compounds such as ferrocene, furan and thiophene react with alkenes to give vinyl heterocycles. The effect of substituents in this reaction is similar to that observed in the electrophilic aromatic substitution [69]. 

Of all the heterocycles featured in nature and in man-made compounds, indole is the most abundant This electron-rich heteroaromatic compound reacts with a range of electrophiles, predominantly at the C3 position via an electrophilic aromatic substi-tntion pathway. The C2 position of indole is the most reactive site for metalation however C—activation reactions can proceed at either the C2 or C3 positions therefore, the control of site-selectivity is the major challenge. 

Miscellaneous Transformations. The hypervalent iodine(III) reagent phenyliodine bis(trifluoroacetate) (PIFA) mediates the selective cyanation reaction of a wide range of electron-rich heteroaromatic compounds such as pyrroles, thiophenes, and indoles under mild conditions (eq 42). Nonactivated arylalkenes are effectively converted to tertiary benzylic nitriles in the presence of triflic acid and cyanotrimethylsilane (eq 43). ... 

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). 

Apart from the A-methyl group, three double-bond equivalents and three multiplets remain in the chemical shift range appropriate for electron rich heteroaromatics, Sh = 6.2 to 6.9. A-Methyl-pyrrole is such a compound. Since in the multiplets at Sh = 6.25 and 6.80 the Jhh coupling of 4.0 Hz is appropriate for pyrrole protons in the 3- and 4-positions, the pyrrole ring is deduced to be substituted in the 2-position. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

In contrast to H shifts, l3C 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 13C and the ]H NMR spectra. By analogy with their proton resonances, the 13C chemical shifts of n electron-deficient heteroaromatics (pyridine type) are larger than those of n electron-rich heteroaromatic rings (pyrrole type). 

Oxidation Reaction. An efficient and regioselective method for iodination of electron-rich aromatic compounds has been reported by using NCS and sodium iodide in AcOH. This method is also applicable to nonbenzenoid aromatic or heteroaromatic compounds. NCS reacts with Nal to form the key intermediate ICl (eq 50). ... 

Besides heteroaromatic compounds also electron-rich aromatic compounds like aniline or naphthol derivatives have been employed in organocatalytic Friedel-Crafts reactions (267, 268). Kim et al. demonstrated this in the synthesis of (+)-curcuphenol (294) (267), a bioactive sesquiterpene phenol isolated from the marine... 

---