Heteroaromatic oxidation pyrrole

Triazine 4-oxides 26 react with aromatic (phenols, anilines) and heteroaromatic (indoles, pyrroles) C-nucleo-philes in the presence of benzoyl chloride to form the corresponding products 121 by means of autoaromatization with elimination of benzoic acid (Scheme 64) <2000RJ01050, 2002AHC(82)261, 2005RCB2187, 2006TL869>. 

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). 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

Anodic oxidations of heteroaromatic cycles (furans, pyrroles, benzofurans) in the presence of methanol have been extensively studied [148-165]. The electromethoxyla-tion of differently substituted furans gives 2,5-dimethoxy-2,5-dihydrofurans in moderate to good yields (Scheme 96) [148-159, 166-170]. 

A novel tandem carbonyiation/cyclization radical process has been developed for the intramolecular acylation of l-(2-iodoethyl)indoles and pyrroles <99TL7153>. In this process, an acyl radical is formed when CO is trapped by an alkyl radical formed from the AIBN-induced radical reaction of l-(2-iodoethyl)indoles 104 with BusSnH. Intramolecular addition of the acyl radical to the C-2 position of the heteroaromatic system presumably affords a benzylic radical which undergoes in situ oxidative rearomatization to the bicycloketones 105. 

Yttrium-catalyzed cyclization/hydrosilylation was also applied to the synthesis of silylated heteroaromatic bicyclic compounds. Reaction of l-allyl-2-vinyl pyrrole (32, n = R = H) with phenylsilane catalyzed by [(Gp )2YMe]2 at room temperature for 6 h followed by oxidation gave the corresponding heterobicycle amine 33 in 90% yield as a 98 2 mixture of isomers (Equation (23)). It was noteworthy that selective conversion of 32 to 33 required initial... 

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. 

Oxazole chemistry, advances in, 17, 99 Oxazolone chemistry new developments in, 21, 175 recent advances in, 4, 75 Oxidation of monocyclic pyrroles, 15, 67 Oxidative transformations of heteroaromatic iminium salts, 41, 275 3-Oxo-2,3-dihydrobenz[d]isothiazole 1,1-dioxide (saccharin) and derivatives, IS, 233... 

A tandem carbonylation-cyclization radical process in heteroaromatic systems bearing electron-attracting substituents such as l-(2-iodoethyl)indoles and pyrroles 970 result in the formation of 2,3-dihydto-l//-pyrrolo[l,2- ]indol-1-ones and 2,3-dihydro-l//-pyrrolizin-l-ones 974 (Scheme 188). The AIBN-induced radical reaction of compounds 970 with Bu3SnH under pressure of CO suggests that the acyl radical 972, derived from radical 971 and CO, would undergo intramolecular addition to C-2 of heteroaromatic system, and the benzylic radical 973 so obtained, upon in situ oxidation would produce final product 974 <1999TL7153>. 

They found that combination of the Ir(T) catalyzed C-H borylation and Suzuki coupling sequence led to a two-step, one-pot C-H Suzuki arylation that enabled direct transformation of the N-Boc pyrrole to the C3 arylated intermediate in 78% yield. Following installation of the required acyl group, an application of their oxidative Pd-catalyzed C-H alkenylation reaction enabled formation of the key structural architecture of the natural deliver the natural product. The orthogonal selectivity characteristics displayed by these C-H functionalization processes makes possible iterative functionalization of the heteroaromatic pyrrole core. Utilization of the highly versatile C-H borylation - Suzuki coupling to install the aromatic functionality opens up possibilities of facile analogue synthesis via this route. 

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... 

In our view, the explanation for this high reactivity is not to be ascribed to a lack of aromaticity these compounds have resonance energies in excess of that of benzene (Section IV,A). Rather, the reactivity is thought to be due to the ease with which this rc-excessive heteroaromatic system can undergo one-electron oxidation or 1,3-addition to generate another aromatic (benzenoid) system, as shown at structures 67 and 68, respectively. In terms of more familiar systems, the reactivity of the 1,3-positions of isoindole may be thought of as a compounding of the reactivity at the a-positions of pyrrole with that at the meso positions of anthracene. 

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