The Bischler–Napieralski Reaction refers to an intramolecular electrophilic substitution reaction in which β-aryl ethylamides undergo cyclization in the presence of chlorinating reagents to form 1,2-dihydroisoquinoline derivatives. This reaction was first discovered in 1893 by German chemist August Bischler and Swiss chemist Bernard Napieralski during their research on alkaloids. It is commonly used to synthesize 1,2-dihydroisoquinolines, which can then be oxidized to isoquinolines.

Reagents: Dehydrating agents (e.g., POCl₃, P₂O₅, PPA, TFAA, or Tf₂O)
Reactants: β-Aryl ethylamides
Products: 1,2-Dihydroisoquinolines
Reaction Type: Electrophilic substitution

Experimental Tips:

• The cyclization proceeds via an electrophilic aromatic substitution mechanism. The presence of activating groups on the aromatic ring facilitates the reaction.

• If an electron-donating group is located at the meta-position, cyclization is more likely to occur at the para-position relative to the substituent.

• For substrates lacking electron-donating groups on the aromatic ring, refluxing in POCl₃ with P₂O₅ is most effective.

• One major side reaction is the formation of styrene via a retro-Ritter reaction. To minimize this, nitriles can be used as solvents, or oxalyl chloride can be employed to generate N-acyliminium intermediates, thereby avoiding the elimination of the amide group in nitrile media.

Reaction Mechanism

Original Reference:
August Bischler, Bernard Napieralski. Berichte der Deutschen Chemischen Gesellschaft, 1893, 26 (2): 1903–1908.

Popular Citations:

• Strategies and Synthetic Methods Directed Toward the Preparation of Libraries of Substituted Isoquinolines. J. Org. Chem, 2010, 75(16), 5627–5634.

• Synthesis of Novel Tricyclic Pyrimido[4,5-b][1,4]benzothiazepines via Bischler−Napieralski-Type Reactions. J. Org. Chem, 2005, 70(26), 10810–10816.

• Anomalous Substituent Effects in the Bischler−Napieralski Reaction of 2-Aryl Aromatic Formamides. J. Org. Chem, 2000, 65(26), 9143–9151.