Bischler-Napieralski isoquinoline synthesis

What is Bischler-Napieralski isoquinoline synthesis?

The Bischler-Napieralski isoquinoline synthesis, also referred as the Bischler-Napieralski cyclization or Bischler-Napieralski reaction, is a well-known two-step reaction that involves the cyclization of N-acyl phenylethylamines with various dehydrating agents to produce 1-alkyl or 1-aryl 3,4-dihydroisoquinolines. This is followed by dehydrogenation or oxidation to yield isoquinolines.

Bischler-Napieralski isoquinoline synthesis - general reaction scheme - Bischler-Napieralski reaction -  Bischler-Napieralski cyclization
Bischler-Napieralski isoquinoline synthesis

The Bischler-Napieralski cyclization has been widely used to synthesize many naturally occurring alkaloids such as laudanosine, laudanine, and papaverine, cotarnine, and hydrastinine, among others.

The dehydrating agents used in this reaction include phosphoric acid H3PO4, sulfonic acid derivatives, phosphorus oxychloride POCl3, phosphorus pentoxide P2O5, zinc chloride ZnCl2, aluminium chloride AlCl3, and ferric chloride FeCl3. The reaction is typically carried out in boiling toluene or xylene, although it can also be performed in low boiling point solvents such as acetonitrile H3C−C≡N or dichloromethane CH2Cl2. Additionally, this reaction can be employed to synthesize thiophene derivatives.

References

Bischler, A. and Napieralski, B. (1893), Zur Kenntniss einer neuen Isochinolinsynthese. [On the knowledge of a new isoquinoline synthesis.] Ber. Dtsch. Chem. Ges., 26: 1903-1908. https://doi.org/10.1002/cber.189302602143

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