The isoquinoline ring system is a very commonly occurring structural unit in natural products. A large number of isoquinoline alkaloids have been found which possess useful physiologicel activity, including activity as antibiotics, antitumor agents, drugs for treating mental health disorders, narcotic antagonists, analgesics, and antihypertensive agents.l Several methods have been developed for the synthesis of iaoquinolinea, the most commonly used methods being the Bischler-Napierslski and the Pictet-Spengler reactions.ly2
A method which is related to our work is the reaction of 2-phenethyl halides with nitrilea in the presence of a Lewis acid such as stennic chloride.3 Because these methods involve electrophilic aromatic substitution in the key ring-forming steps, a limitation of these methods is that they often afford the beat results only when the aromatic ring bears electrondonating substituents. We wish to report a new method for the synthesis of the isoquinoline ring system which promises to be of more general utility. Rather than being based upon carbonium ion intermediates, our approach employs nucleophilic carbanionic species.
Recently, Parhem reported the selective bromine-lithium exchange reaction of 2-(2'-bromophenyl)ethyl bromide (&) with q-butyllithium in a mixture of tetrahydrofuran (TRF) and hexane to give the aryllithium (a which undergoes reactions with various electrophiles including cyclohexanone.4 We have found that the exchange reaction is not limited to &but may readily be performed with a number of additional dihalides of this type (Ib-c). The resulting aryllithiums (&,&) react with benzonitrile to afford 1-phenyl-3,k-dihydroiaoquinolines (3a-d) in high yields (equation 1). The results are summarized in the Table.