Halides, aryl, arylation metal mediated coupling

As in the case of quinolines, isoquinolines can be prepared by metal-mediated annotation processes. Reaction of t-butylimines of iodo-benzaldehydes with acetylenes in the presence of palladium catalyst affords 3,4-disubstituted isoquinolines. The power of this reaction relies on its ability to introduce different type of substituents on 4-position of the heterocycle by using the formed intermediate palladium complex in the cross-coupling reaction with aryl and alkyl halides or alkenes. This methodology was successfully applied to the total synthesis of decumbenine... 

Based on these precedents for C—X bond formation between C=N and alkene intermediates (derived from alkynes), the Larock group developed the first transition-metal-mediated pyridine ring formation by direct reaction between C=N and alkynes. Using terminal alkynes 11, rcrt-butylimines 10 were subjected to Sonogashira coupling followed by Cu(I)-catalyzed annulation to afford isoquinolines or pyridines 12 in moderate to good yields (46 to 95%, Scheme 19.5) [5]. A variety of terminal alkynes and aryl/alkenyl halides can be used in the reaction. The stepwise reaction also worked well to form the same products. Similarly, p- and y -carbolines were synthesized effectively, as shown in Scheme 19.6 [6]. 

Abstract Although requiring the use of stoichiometric amounts of metal and harsh conditions, the copper-mediated coupling reactions of aryl halides with amines and phenols (Ullmann craidensatiOTis), amides and carbamates (Ullmann-Goldberg condensations), or activated methylene compounds (Ullmann-Hurtley condensations) have been for a long time useful methods for the formation of C(aryl)-N, C(aryl)-0, and C(aryl)-C bonds. In 2001, a renaissance of the Ullmann reaction has been initiated with the discovery of versatile new copper catalytic systems for C-C, C-N, or C-O coupling under mild temperature ccmditions. 

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