Cobalt‐Catalyzed ortho‐C−H Functionalization/Alkyne Annulation of Benzylamine Derivatives: Access to Dihydroisoquinolines

Abstract

A practical picolinamide-directed C-H functionalization/alkyne annulation of benzylamine derivatives enabling access to the previously elusive 1,4-dihydroisoquinoline skeleton was developed using molecular O as the sole oxidant and Co(OAc) as precatalyst. The method is compatible with both internal and terminal alkynes and shows high versatility and functional-group tolerance. Furthermore, full preservation of enantiopurity is observed when using non-racemic α-substituted benzylamine derivatives. Kinetic analysis of the reagents and catalyst, labeling experiments, and the isolation and identification of catalytically competent Co-complexes revealed important insights about the mechanism.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Since the pioneering work of Daugulis, 344 the use of this N , N -bidentate DG has been extensively investigated in various transformations. 556 – 558 The cleavage of this DG was conducted under acidic, 559 , 560 basic 561 – 566 and reductive acidic 562 conditions as well as after a treatment with PCl 5 /2,4-lutidine then MeOH and an aqueous work-up. 567 …”

“…Two years later, the same group reported a protocol for the synthesis of 1,4-dihydroisoquinoline compounds (56–96% yield) from benzylamines taking advantage of Co catalysis and using molecular O 2 as oxidant ( Scheme 94C ). 562 An interesting feature is that, in contrast to Rh catalysis, dialkyl alkynes were more efficient in that case as compared to diaryl ones. Additionally, terminal alkynes were suitable coupling partners as well.…”

Cobalt(II)‐Catalyzed [4+2] Annulation of Picolinamides with Alkynes via C−H Bond Activation

“…Later, in 2016, Balaraman reported a highly efficient silver carbonate‐promoted bis‐alkynylation that exhibited good results (40–80 % yields) in the synthesis of bis‐alkynylation products . In 2017, Rodríguez reported a practical picolinamide‐directed C−H functionalization annulation of benzylamine, which accessed to dihydroisoquinolines, under oxygen atmosphere (1 atm) . Thus it can be seen that the picolinamide is a useful synthon whose C(sp 2 )−H bond is also well‐known to be activated by cobalt, rhodium, copper and other metals.…”

Reaching Green: Heterocycle Synthesis by Transition Metal‐Catalyzed C−H Functionalization in Sustainable Medium

“…As oximes 38,p rimary amines 43 a-c can also undergo annulation reactions with alkynes 11 to synthesize isoquinolines as shown in Scheme17. [46] These reactions proceed through amine-directed CÀHm etalation, alkynei nsertion, and reductive eliminationt og ive dihydroisoquinolines, which are then converted to isoquinolines by oxidation. Inexpensive first-row cobalt catalyst was also utilized fort he preparation of isoquinolinesf rom picolinamides 43 c and alkynes as demonstrated by Cui and Carretero's research groups.…”