Intramolecular Houben-Hoesch reaction

In a study involving an intramolecular Houben-Hoesch reaction (eq. 19),... 

In the laboratory of D.W. Cameron the total synthesis of the azaanthraquinone natural product bosttycoidin was undertaken using the Minisci reaction and the intramolecular Houben-Hoesch reaction as the key steps. It is worth noting that the synthesis of specific di- and trihydroxyazaanthraquinones by the Friedel-Crafts acylation is very limited due to the lack of orientational specificity and the lack of reactivity of pyridine derivatives in acylation reactions. 

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. 

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 attack of a nitrilium ion is a key step in the Meerwein quinazoline synthesis. A recent example of this reaction can be seen in the synthesis of 4-(A -dimethylamino)-2-arylquinazolines, as demonstrated below. Treatment of imidoyl chloride 39 with NJ -dimethylcyanamide (40) followed by TiCU results in the formation of intermediate 41. Mechanistically, after the production of the likely intermediate nitrilium ion 41, the Houben-Hoesch reaction occurs to give quinazoline 42. A related procedure has been utilized for the synthesis of... 

Various intramolecular reactions are widely used to prepare this type of heterocycle. Intramolecular acylation has been used frequently (84AHC(37)i). Houben-Hoesch cyclization of I -(3-cyanoethylpyrrole (4a) gives l-oxo-2,3-dihydropyrrolizine (5a). The methyl group in (4b) selectively activates C-2 so that only the isomer (5b) is formed (66JA1305). 

Intramolecular acylation has been used frequently. Houben-Hoesch cyclization of 1 -/ -cyanoethylpyrrole (2a) gives l-oxo-2,3-dihydropyrrolizine (3a).9-17 Difficulties occur because polymerization of the nitrile (2a) can be a side reaction. Addition of boron trifluoride [3a (33%)]11 or its ethyl ether complex [3a (60-80%)]15 has been recommended. Treatment of nitrile 2a with a molten aluminum chloride-potassium chloride-sodium chloride mixture yields 70% of ketone 3a but the experimental conditions are highly critical.13 A reproducible procedure that is based mainly on Clemo s specification9,10 gave 22% of ketone 3a.17 Purification of 3a should be carried out in an efficient fume hood because it appears to induce analgesia.1 ... 

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