Bischler–Napieralski reaction

It was first discovered in 1893 by August Bischler and Bernard Napieralski [de], in affiliation with Basel Chemical Works and the University of Zurich.

This mechanistic variance stems from the ambiguity over the timing for the elimination of the carbonyl oxygen in the starting amide.

For reactants lacking electron-donating groups on the benzene ring, phosphorus pentoxide (P2O5) in refluxing POCl3 is most effective.

For example, research done by Doi and colleagues suggests that the presence or absence of electron-donating groups on the aryl portion of β-arylethylamides and the ratio of dehydrating reagents influence the patterns of ring closure via electrophilic aromatic substitution, leading to two possible products (see below).

Other research on the variations on the Bischler-Napieralski Reaction have investigated the effects of nitro and acetal aryl groups on product formation (see references).

A general scheme of the Bischler-Napieralski reaction.
A mechanism for the Bischler-Napieralski reaction involving an imine-ester intermediate .
A mechanism for the Bischler-Napieralski reaction involving a nitrilium intermediate.
An example of mechanistic and product variation in the Bischler-Napieralski reaction. Treatment of N-[2-(4-methoxyphenyl)-ethyl]-4–methoxybenzamide with POCl 3 results in the formation of the normal product, 7-methoxy-1-(4-methoxyphenyl)-3,4-dihydroisoquinoline. Treatment exclusively with P 2 O 5 results in a mixture of the normal product and an unexpected product, 6-methoxy-1-(4-methoxyphenyl)-3,4-dihydroisoquinoline. The formation of the abnormal product is attributed to the cyclization via the ipso carbon on the phenyl ring to yield a spiro intermediate.