Phenethylamines reaction with aldehydes

In 1911, Ame Pictet and Theodor Spengler reported that P-arylethyl amines condensed with aldehydes in the presence of acid to give tetrahydroisoquinolines. Phenethylamine 6 was combined with dimethoxymethane 7 and HCl at elevated temperatures to give tetrahydroisoquinoline 8. Soon after, the Pictet-Spengler reaction became the standard method for the formation of tetrahydroisoquinolines. 

Whereas 5-endo-trig processes are unfavorable, 6-endo-trig cyclizations are allowed. For this reason the reaction conditions used for several well-known preparations of six-membered rings cannot be used to prepare the corresponding five-membered rings. For example, treatment of phenethylamines with aldehydes and acid yields tetrahydroisochinolines (Pictet-Spengler synthesis), but treatment of benzylamines under these conditions does not yield dihydroisoindoles (Scheme 9.6). 

Since its discovery the Pictet-Spengler cyclization has formed the basis of numerous syntheses of alkaloids containing aromatic subunits. This high-yielding reaction involves, in its broadest sense, nucleophilic attack on an iminium ion by the Tr-electrons of a tethered aromatic moiety. In the classical reaction a substituted P-phenethylamine is condensed with an aldehyde under acidic conditions to produce a te-trahydroisoquinoline (Scheme 16). A useful variant of the Pictet-Spengler reaction, which provides tetr ydro-(3-carbolines and their derivatives, involves the condensation of a tryptamine derivative and an aldehyde (Scheme 16). Whether nucleophilic attack on the resulting iminium ion occurs initially at the a- or -indole carbon is a topic of current debate and, indeed, there is evidence to suggest that the mechanistic pathway could be substrate dependent. ... 

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