Isoquinoline ring closure involving

The Pomeranz-Fritsch synthesis [Eqs. (1) and (2)]1 is the only isoquinoline synthesis involving a simple two-step sequence from common starting materials. Furthermore, it is one of the few methods which can be used to prepare isoquinolines substituted in the 7- and 8-positions. The first step, Schiff base formation [Eq. (1)], takes place readily, but the ring closure [Eq. (2)] is difficult. The yields vary markedly with the concentration of H2S04 and are generally low. Frequently the reaction fails completely. Most of the work described in this chapter was undertaken to circumvent these problems and to realize the potential promise of the synthesis. 

Another synthesis of isoquinolines in which two ring bonds are formed involves the reaction of benzyl halides (74) with the sodium salt of N-(tosylamino)acetaldehyde dimethyl acetal. Treatment of the intermediate (75) with hydrochloric acid results both in ring-closure and aromatization (Scheme 48). ... 

In the course of studies on the incorporation of 0-[m /- C]methylnorbelladine [as 6.181) into haemanthamine 6.187) it was demonstrated [128], for the first time, that a methylene-dioxy-group [as in 6.187) arises by oxidative ring closure of an o-methoxyphenol [as in 6.181) Subsequent results on the biosynthesis of other alkaloids have confirmed the generality of this observation. The mechanism may be one involving radicals or cationic species (Scheme 6.36). A related oxidative cyclization is found in the conversion of an isoquinoline into a protoberberine (Section 6.3.6) where an A -methyl group closes on to an aromatic ring. 

One of the new methods studied for the building of the isoquinoline structure made use of the condensation of nitrilium salts with j3-chloro-ethylbenzene 181). It has been used for the preparation of many 3,4-dihydroisoquinolines, which can be easily dehydrogenated to the corresponding isoquinolines. 3,4-Dihydropapaverine was obtained as picrate, in 21% yield, by condensing a-chloro-j8-(3,4-dimethoxyphenyl)-ethane (CIX) with homoveratronitrile-stannic chloride (CX), a reaction which involves the ring closure of the mesomeric ion CXI (182). 

Besselievre and Husson have published full details of their syntheses of ellipticine, olivacine, and guatambuine.86 A new approach to the synthesis of ellipticine87 involves construction of an appropriately substituted anilino-isoquinoline, e.g. (166) closure of the five-membered ring then constitutes the last stage (Scheme 24). Other synthetic work in this area includes syntheses of 16-desmethyl-16-methoxyellipticine88 and 11-hydroxy- and 11-methoxy-ellipticines.89... 

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