Bischler-Napieralski reaction
| Bischler-Napieralski reaction | |
|---|---|
| Named after |
August Bischler Bernard Napieralski |
| Reaction type | Ring forming reaction |
| Identifiers | |
| Organic Chemistry Portal | bischler-napieralski-reaction |
| RSC ontology ID | RXNO:0000053 |
The Bischler–Napieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by August Bischler and Bernard Napieralski, in affiliation with Basle Chemical Works and the University of Zurich. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently oxidized to isoquinolines.
Two types of mechanisms have appeared in the literature for the Bischler–Napieralski reaction. Mechanism I involves a dichlorophosphoryl imine-ester intermediate, while Mechanism II involves a nitrilium ion intermediate (both shown in brackets). This mechanistic variance stems from the ambiguity over the timing for the elimination of the carbonyl oxygen in the starting amide. In Mechanism I, the elimination occurs with imine formation after cyclization; while in Mechanism II, the elimination yields the nitrilium intermediate prior to cyclization. Currently, it is believed that different reaction conditions affect the prevalence of one mechanism over the other (see reaction conditions).
In certain literature, Mechanism II is augmented with the formation of an imidoyl chloride intermediate produced by the substitution of chloride for the Lewis acid group just prior to the nitrilium ion.
Because the dihydroisoquinoline nitrogen is basic, neutralization is necessary to obtain the deprotonated product.
The Bischler–Napieralski reaction is carried out in refluxing acidic conditions and requires a dehydrating agent. Phosphoryl chloride (POCl3) is widely used and cited for this purpose. Additionally, SnCl4 and BF3 etherate have been used with phenethylamides, while Tf2O and polyphosphoric acid (PPA) have been used with phenethylcarbamates. For reactants lacking electron-donating groups on the benzene ring, phosphorus pentoxide (P2O5) in refluxing POCl3 is most effective. Depending on the dehydrating reagent used, the reaction temperature varies from room temperature to 100 °C.
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