Reaction Outcome Critically Dependent on the Method of Workup: An Example from the Synthesis of 1-Isoquinolones

A striking dependence on the method of workup has been found for annulation of benzonitriles ArC≡N to N-methyl 2-toluamide (1), facilitated by n-BuLi (2 equiv): quenching the reaction by a slow addition of water produced the expected 1-isoquinolones 2; by contrast, slow pouring of the reaction mixture into water afforded the cyclic aminals 5 (retaining the NMe group of the original toluamide). The mechanism of the two processes is discussed in terms of the actual H⁺ concentration in the workup. Both 2 and 5 were then converted into the corresponding 1-chloroisoquinolines 3, coupling of which, mediated by (Ph₃P)₂NiCl₂/Zn, afforded bis-isoquinolines 4.