Dihydroisoquinolines cyclodehydration

The scheme used to prepare the direct 8-aza-analogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence. Acylation of the phenethylamine 9 with acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17. 

Bischler-Napieralski Reaction. This synthetic method involves (he cyclodehydration of 4/-acyl derivatives of /t-phenethylamines to 3,4-dihyriroisoi uiiiolmrs. such as 1-methyl-3.4-dihydroisoquinoline. 

Reagent for cyclodehydration. A Japanese groups prepared PPE as above and used the chloroform solution as such and found it to be an excellent reagent for the Bischler-Napieralski reaction. Thus phenylethylamides (I) are cyclized smoothly to dihydroisoquinolines (2) by refluxing with PPE in chloroform. Phenylpropylamides (3) similarly yield 3.4-dihydro-5H-2-benzopines (4). The same workers report that... 

Cyclodehydration. Cava1 used PPE for cyclization of the amide (1) to the dihydroisoquinoline (2) in 79% yield. This reaction had been conducted previously in unspecified yield with phosphorus pentachloride.3... 

The first step of this cyclodehydration brought about by POCI3 is akin to the Vilsmeier reaction. It proceeds via chloroimines 49 (or their conjugate acids) and the electrophilic nitrilium ions 50, which are isolable as hexachloroantimonates. The 3,4-dihydroisoquinolines can be transformed to isoquinolines 48 by conventional methods, e.g. catalytic dehydrogenation. 

Cyclodehydration of p-phenethylamides to 3,4-dihydroisoquinoline derivatives by means of condensing agents such as phosphorous pentoxide or zinc chloride ... 

---