Houben-Hoesch pyrrole acylation

For a complete description of the synthetic utility of the Houben-Hoesch reaction as it applies to other aromatic systems, as well as some mechanistic discussions, the reader is directed to two reviews on the subject. Due to the diminished electrophilic reactivity of nitriles compared to other carboxylic acid derivatives as well as the broad number of Friedel-Crafts substrates, most Houben-Hoesch pyrrole acylation reactions are conducted intramolecularly. However, an impressive intermolecular example was delineated by Chang and co-workers in efforts directed toward the synthesis of novel 2-[5-aroylpyrrolo]alkanoic acids, for evaluation of their potential analgesic and anti-inflammatory activities. Treatment of substituted pyrrole 4 and 3-cyanopyridine (5) with acid in dry chloroform resulted in the preparation of 6 in good yield. 

Friedel-Crafts acylation with nitriles and HC1 is called the Hoesch or the Houben-Hoesch reaction,354 In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds, e.g., pyrrole, but it can be extended to aromatic amines by the use of BCly.355 Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones354 but are attacked at the oxygen to produce imino esters. 

Pyrroles and furans also undergo the Gattermann aldehyde synthesis with HC1 and HCN, furan gives furfuraldehyde and 2-methylindole gives 2-methylindole-3-carboxaldehyde. The Houben-Hoesch ketone synthesis is also applicable to the preparation of acyl derivatives of furans and pyrroles, e.g. ethyl 2,4-dimethylpyrrole-3-carboxylate with MeCN and HC1 yields (81). 

Alkylation of pyrroles proves to be problematic because the usual Lewis acid catalysts initiate polymerization. The Vilsmeier-Haack formylation, however, leads to the formation of pyrrole-2-carbaldehyde in good yield. The Houben-Hoesch acylation (reaction with nitriles in the presence of hydrogen chloride) provides 2-acylpyrroles ... 

As is the case with pyrroles, C-alkylation of indoles results in mixtures of products. Formylation and acylation, however, occur more readily. The Vilsmeier-Haack reaction furnishes indole-3-carbaldehyde heating with acetic anhydride produces 3-acetylindole. In the Houben-Hoesch acylation, substitution takes place in the 3-position. 

The Houben-Hoesch acylation of pyrroles describes the electrophilic substitution of an activated nitrile onto an electron-rich pyrrole ring. Typically requiring either a Lewis acid or protic acid, the resulting imine is immediately hydrolyzed to yield the corresponding ketone. 

The first intramolecular Houben-Hoesch acylation of pyrrole was reported by Clemo and Ramage, and later used by Adams and co-workers in their efforts to prepare 1-hydroxypyrrolizidine and related compounds. Treatment of cyanopyrrole 7 under standard conditions provided 8, albeit with inconsistent yields presumably due to a nonproductive polymerization reaction that accompanies product formation. A short time later. Gabel provided a modified procedure, using BF3-OEt2 as the solvent." Formation of a somewhat stable BF3-pyrrole complex is suggested to prevent polymerization, while still allowing for cyclization. 

The intramolecular Houben-Hoesch acylation of pyrroles has been used for the synthesis of a number of compounds with interesting properties. An intramolecular acylation was reported by the Meinwald group to synthesize the hairpencil secretion of the butterfly Lycorea ceres... 

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