4-Alkenyl substituted isoquinolines

Various cyclizations of alkynylbenzaldimines (e.g., 174) are particularly useful in the synthesis of isoquinolines as summarized in Scheme 101 . The use of electrophiles and base yields 3,4-disubstituted isoquinolines 175 <2002JOC3437> whereas the palladium-catalyzed carbonylation affords 4-aroylquinolines 173 <2002JOC7042>. Cyclization followed by Heck reaction gives rise to 4-alkenyl substituted isoquinolines 176 (Scheme 101) <2002TL3557>. 

A rhodium-catalyzed one-pot synthesis of substituted pyridine derivatives from a,(3-unsaturated ketoximes and alkynes was developed in 2008 by Cheng and coworkers [99], Good yields of the desired pyri-dines can be obtained (Scheme 3.48). The reaction was proposed to proceed via rhodium-catalyzed chelation-assisted activation of the (3—C—H bond of a,(3-unsaturated ketoximes and subsequent reaction with alkynes followed by reductive elimination, intramolecular electro-cyclization, and aromatization to give highly substituted pyridine derivatives finally [100]. Later on, in their further studies, substituted isoquinolines and tetrahydroquinoline derivatives can be prepared by this catalyst system as well [101]. Their reaction mechanism was supported by isolation of the ort/jo-alkenylation products. Here, only asymmetric internal alkynes can be applied. 

Synthesis of substituted isoquinolines via nickel-catalyzed alkenylation of... 

In 2009, Fagnou et al. discovered a Rh(III)-catalyzed synthesis of substituted isoquinolines 45 by oxidative annulation between N-tBu aromatic aldimines and internal alkynes [28a]. The -Bu leaving group was eliminated as isobutene in the reaction process and avoided the generation of a mixture of isoquinolines. However, the substrate scope was limited to aldimines, and a stoichiometric amount of Cu(0Ac)2-H20 was used as an external oxidant. Mechanistic studies omitted the ort/zo-alkenylation/64 -electrocyclization/oxidation pathway, and intermediate H2 was crucial for the C-N reductive elimination to proceed (Eq. (5.44)). At the same time, Satoh and Miura groups also exploited a Rh(III)-catalyzed oxidative cyclization of N-H benzophenone imine and internal alkynes to give isoquinolines [28b]. Both aromatic and aliphatic alkynes were agreeable for this protocol, but a stoichiometric amount of the Cu(II) salt was required. 

Jun et al. demonstrated a Rh(I)-catalyzed cyclization of an N-benzyl aromatic ketimine with diphenylacetylene to provide isoquinoline 44 [27]. The chelation-assisted C-H activation strategy was employed for the first time for isoquinoline synthesis. However, the reaction required a high temperature (150 C) and led to two different isoquinoline derivatives 44 and 44. Based on the experimental results, the authors proposed a plausible reaction mechanism that involved ortho-alkenylation, 6. r-electrocyclization, intermolecular nucleophilic substitution, and dehydrogenative aromatization (Eq. (5.43)). 

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