Schiff bases isoquinoline synthesis

Pomeranz-Fntsch Synthesis, Isoquinolines aie available fiom the cycUzation of benzalamiaoacetals undei acidic conditions (165). The cyclization is preceded by the formation of the Schiff base (33). Although the yields ate modest, polyphosphoric acid produces product in all cases, and is especially useful for 8-substituted isoquinolines (166). 

A variation involves the reaction of benzylamines with glyoxal hemiacetal (168). Cyclization of the intermediate (35) with sulfuric acid produces the same isoquinoline as that obtained from the Schiff base derived from an aromatic aldehyde and aminoacetal. This method has proved especially useful for the synthesis of 1-substituted isoquinolines. 

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 classical approach is the Pictet-Spengler isoquinoline synthesis. 66c x is variation generates an iminium salt from an amine and an aldehyde (a Schiff base), which cyclizes with an aromatic ring to complete the reaction. A synthetic example is taken from Liang s synthesis of chrysotricine.1 2 xhg reaction of amine 279 with aldehyde 280, in the presence of trifluoroacetic acid, initially gave an iminium salt (281). Subsequent Friedel-Crafts cyclization of the iminium salt gave the isoquinoline product (282 in 70% yield). The amino groups of amino acid derivatives also serve as excellent partners in this reaction.1 3... 

Doring et al. developed a CUCI2 -catalyzed synthesis of imidazo[l,5- ]pyridines, imidazo[l,5- ]imidazoles, and imidazo[5,l- ]isoquinolines starting from Schiff base which could be prepared readily from the appropriate aldehydes and primary amines [97] (Scheme 8.56). 

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