The Preparation of 3,4-Dihydroisoquinolines and Related Compounds by the Bischler-Napieralski Reaction

Whaley, Wilson M. and Tutucorin R. Govindachari


The frequent occurrence of the isoquinoline nucleus in alkaloids has led to considerable interest in the synthesis of isoquinolone derivatives. Many methods have been developed, but only three have enjoyed popularity. One of them, the Bischler-Napieralski reaction is discussed in this chapter. The reaction consists in the cyclodehydration of beta-phenethylamides to 3,4-dihydroisoquinolines by heating to high temperatures with phosphorus pentoxide or anhydrous zinc chloride. Yields were not given for the original reaction, but later studies proved that the yields were low. Modifications using lower temperatures and milder condensing agents improved the reaction. The most important variation was introduced by Picet and Gams, which eliminates the dehydrogenation step. The classical synthesis of papaverine by Pictet and Gams is discussed.