Electron-rich heteroaromatic

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. 

Few examples of preparatively useful intermolecular C-H insertions of electrophilic carbene complexes have been reported. Because of the high reactivity of complexes capable of inserting into C-H bonds, the intermolecular reaction is limited to simple substrates (Table 4.9). From the results reported to date it seems that cycloalkanes and electron-rich heteroaromatics are suitable substrates for intermolecular alkylation by carbene complexes [1165]. The examples in Table 4.9 show that intermolecular C-H insertion enables highly convergent syntheses. Elaborate structures can be constructed in a single step from readily available starting materials. Enantioselective, intermolecular C-H insertions with simple cycloalkenes can be realized with up to 93% ee by use of enantiomerically pure rhodium(II) carboxylates [1093]. 

As a furllier example of the addition of electron rich heteroaromatics to electron deficient alkenes, MacMillan has shown that y-butenolides can be prepared in one-step by the addition of silyloxyfurans (45) to a,p-unsaturated aldehydes (Scheme 19) [88]. Reactions were tolerant to substitution at the 4- and 5-positions of the furan... 

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. 

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] ... 

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). 

Subsequently, Corma and coworkers [49] reported the acylation of anisole with phenacetyl chloride over H-Beta and H-Y. The FC acylation of electron-rich heteroaromatics, such as thiophene and fur an, with acetic anhydride over modified ZSM-5 catalysts (Fig. 2.17) in the gas phase [50] or liquid phase [51] was also reported. 

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). 

Ruthenium-based catalysts display some utility for electrophilic amination of heteroaromatic substrates. Che and coworkers have found that [Ru(TTP)(CO)J in combination with PhI=NTs will oxidize arenes such as furan, indole, and pyrrole (Fig. 13) [68]. Reactions occur optimally under the action of ultrasound, a rather unusual addendum to the standard protocol for C-H amination. More intriguingly still, iV,A-ditosylated products are isolated in most instances, a finding that is not easily resolved mechanistically. As the substrate profile for this amination process involves only electron-rich heteroaromatics, aziridination of the arene nucleus would seem a likely step along the reaction coordinate. Interestingly, no amination product is observed when stoichiometric [Ru(TMP)(NTs)2] (TMP = tetra(2,4,-6-trimethylphenyl)porphyrin) is mixed with either furan or /V-phenylpyrrole. though a reduction of the starting Ru(VI) complex to a Ru(IV) species is noted... 

Fig. 13 Electrophilic animation of electron-rich heteroaromatic substrates...

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]. 

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