9.

1 Bischler-Napieralski Reaction
9.1.1 Description The Bischler-Napieralski' reaction involves the cyclization of phene ...y I amides 1 in the presence of dehydrating agents such as P205 or POC13 to afford 3,4-dihydroisoquinoline products 2.2-5T his reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products6 The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2).

9.1.3 Mechanism Despite the synthetic utility of this transformation, nearly eighty years elapsed between the discovery of the Bischler-Napieralski reaction and the first detailed studies of its rnechani~m.~E-a~rl y mechanistic proposals regarding the Bischler-Napieralski reaction involved protonation of the amide oxygen by traces of acid present in P2O5 or POCL followed by electrophilic aromatic substitution to provide intermediate 5, which upon dehydration would afford the observed product 2. However, this proposed mechanism fails to account for the formation of several side products that are observed under these conditions (vide infra), and is no longer favored.

Detailed mechanistic studies by Fodor demonstrated the intermediacy of both imidoyl chlorides (6) and nitrilium salts (7) in Bischler-Napieralski reactions promoted by a variety of reagents such as PC15, Poc13, and SOC~Z)F. ~or- ~ex ample, amide 1 reacts with POC13 to afford imidoyl chloride 6. Upon heating, intermediate 6 is converted to nitrilium salt 7, which undergoes intramolecular electrophilic aromatic substitution to

afford the dihydroisoquinoline 2. Fodor's studies showed that the imidoyl chloride and nitrilium salt intermediates could be generated under mild conditions and characterized spectros~opicallyF.~o~do~r also found that the cyclization of the imidoyl chlorides is accelerated by the addition of Lewis acids (SnC14, ZnC12), which provides further evidence to support the intermediacy of nitrilium salt^.^-^

Side reactions consistent with decomposition of intermediate nitrilium salt 7 have also been observed, including retro-Ritter reactions that afford alkenes (8), and VonBraun reactions that provide alkyl chlorides (9).7-9
I

In some instances the attack of the arene on the nitrilium salt occurs at the ips0 carbon rather than the ortho carbon." For example, the Bischler-Napieralski cyclization of phenethyl amide 10 affords a 2:l mixture of regioisomeric products 11 and 12. The formation of 12 presumably results from attack of the ips0 aromatic carbon on the nitrilium salt 13 followed by rearrangement of the spirocyclic carbocation 14 to afford 15, which upon loss of a uroton yields uroduct 12.''