Ortho-alkynylanilines

The N-tert-butyl imine cyclization strategy can also be applied to the synthesis of isoquinolines via non-oxidative addition/reductive ehmination processes. For example, it has been found that the ortho-alkynyl substituted imine 28 can undergo palladium-catalyzed cyclization in an analogous fashion to the ortho-alkynylanilines noted in Section 6.2.1. In this case, the extra carbon unit provides a synthesis of 2-substituted isoquinolines (Scheme 6.52) [71]. This cyclization can be coupled with the formation of 28 from imines and either TMS-substituted or terminal alkynes, providing access to a diverse range of substituted products with perfect regiocontrol. 

Castro first documented cydoisomerization of ortho-alkynylanilines 96 to give the 2-phenyl indole 97 in the presence of substoidiiometric amounts of Cu(I) catalyst in excellent yield (Scheme 9.35) [77, 111]. Mechanistically, it is believed that 5-exo-dig cydization follows the generally accepted mechanism proposed for an intramolecular addition of various nucleophilic entities to transition metal-activated carbon-carbon multiple bonds. 

Following the original report by Castro vide supra), many other research groups utilized ortho-alkynylanilines as versatile substrates in transition metal-catalyzed... 

A formal [3 + 2] cydoaddition route leading to the preparation of di- and tri-substituted indoles 264 from ortho-haloanilines 261 and copper(I) acetylides 262 was introduced by Castro (Scheme 9.92) [75, 76, 111], simultaneously with the mentioned earlier coupling-cyclization reaction en route to benzofurans 57 (Scheme 9.21). It is believed that this stoichiometric in copper cascade reaction proceeded with the generation of an intermediary ortho-alkynylaniline 263 [77]. Attempts to turn this reaction into a more practical catalytic process, using basic conditions to generate Cu(I)-acetylide from a terminal alkyne in the presence of Cul, provided poor yields of the respective indoles 264. 

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