Tetrahydroisoquinolines, alkynylation

The asymmetric alkynylation of isoquinoline iminium ion was reported in the presence of CuBr/QUINAP system (Scheme 5.7). ° Various alkynyl tetrahydroiso-quinolines were obtained in excellent yields and enantiomeric excesses. A natural product, homolaudanosine, was synthesized by the reduction of the obtained propargyl tetrahydroisoquinoline. 

Scheme 16 Asymmetric alkynylation of tetrahydroisoquinolines with terminal alkynes...

A catalytic enantioselective alkynylation of tetrahydroisoquinoline 104 was carried out using CuOTf (Scheme 46). The relatively high enantioselectivity observed for tetrahydroisoquinoline 105 is attributed to a combination of steric effects and possible coordination of the oxygen of the methoxy substituent to copper <04OL4997>. 

The recyclable Cu-MOF catalyst, Cu2(BPDC)2(BPY), was utiftzed in the A reaction of tetrahydroisoquinoHne, aldehydes, and alkynes to generate the C-1 alkynylated tetrahydroisoquinolines (2015JMC162). This catalyst exhibited higher catalytic activity than other Cu-, Ni-, Mn-, Co-, and Zn-MOFs tested and was found to be most effective in coupftng 1,2,3,4-tetrahydroisoquinoline (250), benzaldehyde (251), and phenylace-tylene (252). 

Li and Li have reported Cu(I)-catalyzed enantioselective alkynylation of prochiral sp C-H bonds adjacent to a nitrogen atom [58]. In this approach, a combination of CuOTf and pybox (197) in the presence of t-BuOOH results in coupling of N-aryl tetrahydroisoquinolines (209) with terminal alkynes (Scheme 17.42). The desired coupling products (211) were generally isolated in moderate to good yields with moderate enantioselectivities. Although it is not clear if the catalytically active Cu(I) species acts as a Lewis acid in this protocol, the chemistry is, nonetheless, worthy of mention. 

Recently, Singh and co-workers reported an unprecedented Cu(I)/pybox-diPh-catalyzed highly enantioselective cascade alkynylation-lactamization reaction of readily available o-formyl methyl benzoates, aromatic amines, and terminal alkynes (Scheme 41) [66]. This protocol provides a straightforward and efficient approach to a wide range of enantiomerically enriched isoindolinones in good yield with an exceptionally high level of enantioselectivity. The methodology was further extended to the synthesis of synthetically important tetrahydroisoquinoline scaffolds in a two-step sequence with remarkable selectivity. 

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