Pyrrole, acylation oxidation

To test the generality of this reaction, the indole systems 70a,b were prepared from hexahydro-8-oxopyrrolo[ 1,2-a]indole 67 and tetrahydro-4-oxindole 68 (Scheme 11). These compounds in turn were readily obtained from cyclohexane-1,3-one and the appropriate amino acid salt according to Franck s pyrrole acylation protocol.53 Attempts to directly oxidize 67 or 68 to the hydroxyindole oxidation state using DDQ met with failure despite numerous attempts involving variation in solvent and reaction temperature. To circumvent this limitation, it was reasoned that... 

The a-hydioxypyiioles, which exist piimadly in the tautomeric pyiiolin-2-one form, can be synthesized either by oxidation of pyrroles that ate unsubstituted in the a-position or by ting synthesis. P-Hydtoxypyttoles also exist primarily in the keto form but do not display the ordinary reactions of ketones because of the contributions of the polar form (25). They can be teaddy O-alkylated and -acylated (41). 

Imidazolium halides pyrolysis, 5, 449 Imidazolium ions acylation, 5, 402 H NMR, 5, 352 hydrogen exchange, 5, 417 nucleophilic attack, 5, 375 reactivity, 5, 375 ring opening, S, 375 Imidazolium oxides in pyrrole synthesis, 4, 344 Imidazolium perchlorate, 1,3-diphenyl-acylation, 5, 402 Imidazolium salts 1-acetyl-... 

Oxidation of the 3-(hydroxyalkyl)pyrrole derivative gives a pure 3-acylpyrrole derivative which is difficult to obtain by direct substitution in the pyrrole ring. Acylation of pyrrole yields 1- and/or 2-acetyl pyrrole, whereas acylation of 1-methyl pyrrole forms both 2- and 3-acetyl-1-methyl-... 

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. 

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. 

The free bases are much less stable than aniline, particularly 2-amino-pyrroles and -furans which are very easily oxidized or hydrolyzed. 2-Aminofurans substituted with electron-withdrawing groups (e.g. N02) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Aminothiophene can be diazotized and the resulting diazonium salt coupled with (3-naphthol. 2,3-Diaminothiophene has been prepared and isolated as the hydrobromide. The free base is not stable (85JCR(S)296). 

The oxidation of indoles and pyrroles by Fe(III) ions is less predictable than other chemical oxidations. 2-Methyl- and 3-methyl-indoles, respectively, yield (187) and (188), and whilst pyrroles may form pyrrole black , the rate of oxidation of pyrrole and of 1-methylpyrrole appears to be relatively slow. C-Alkyl and electron-donating substituents enhance the formation of oligimers, e.g. (189) -> (190) and (191) -> (192), and although electron-withdrawing substituents reduce the susceptibility of the pyrrole ring to oxidation, acyl- and alkoxycarbonyl-pyrroles of the type (193) are readily oxidized to the thermochromic dimer (194), which is in equilibrium with the dimer (195) via the monomeric pyrrolyl radical (72BCJ3584). 

The apparent fickleness of the acyl-pyrroles and -indoles in their reaction with carbanions to form new C—C bonds arises from the contribution made by the zwitterionic structure, e.g. (410b), to the resonance hybrid and the choice of the reaction conditions is critical for a successful nucleophilic reaction. Thus, formyl-pyrroles and -indoles do not normally undergo the Cannizzaro reaction nor do they form stable cyanohydrins or undergo benzoin-type reactions. However, surprisingly, 2-formylpyrrole reacts with arylaldehydes in the presence of potassium cyanide to yield (428), which is easily oxidized to (429) (B-77MI30505). It is noteworthy that the presence of an ester substituent adjacent to the formyl group modifies the mesomeric interaction to such an extent to allow the formation of (430) in low yield, as a result of an initial benzoin-type self-condensation (Scheme 76) (68BSF637). 

The lithium derivatives of 1-substituted pyrroles and indoles provide another general route of access to 2-acyl pyrroles and indoles. The ketones can be obtained directly by reaction with aryl nitriles or acid halides but, at least for 1-benzenesulfonylindole, a two-step procedure involving reaction with an aldehyde followed by oxidation of the carbinol to the ketone is frequently more convenient (equation 179) (73JOC3324, 75JOC2613). This method is probably the most general route to 2-acylindoles, although many have also been prepared by direct Fischer cyclization (see Section 3.06.3.4.2). 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

---