Cobalt-Catalyzed Selective Synthesis of Isoquinolines Using Picolinamide as a Traceless Directing Group

Abstract

Picolinamide has first been employed as a traceless directing group for the cobalt-catalyzed oxidative annulation of benzylamides with alkynes to synthesize isoquinolines through C-H/N-H bonds activation. Oxygen is used as a terminal oxidant. This protocol exhibits good functional group tolerance and excellent regioselectivity. Both terminal and internal alkynes can be efficiently applied to this catalytic system as substrates.

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

“…[9,10] The scarcity of studies involving benzylamine derivatives in Co-catalyzed CÀHf unctionalization [11] may be attributed to their propensity to undergo dehydrogenation att he benzylic positionu nder oxidative conditions, potentially leading to imine-type intermediates and/or aromatization of the final products. [13] In this report, dehydrogenation at the benzylic positionoccurs concomitantly to the annulation process, resulting in the formationo fi soquinolines. During the preparation of this manuscript, Cui reported a Co(OAc) 2 -catalyzed picolinamide-directed annulation of benzylamine derivatives with alkynes using a5 0mol %o fc atalyst loading and O 2 as terminal oxidant.…”

“…During the preparation of this manuscript, Cui reported a Co(OAc) 2 -catalyzed picolinamide-directed annulation of benzylamine derivatives with alkynes using a5 0mol %o fc atalyst loading and O 2 as terminal oxidant. [13] In this report, dehydrogenation at the benzylic positionoccurs concomitantly to the annulation process, resulting in the formationo fi soquinolines. Here, we presenta no perationally simple and structurally flexible procedure for the synthesis of avariety of DHIQ, including chiral, non-racemic derivatives.…”

“…The peak at m/z = 775.1922 was assigned to Co III -complex B (theoretical value: m/z = 775.2050, M + Na + ), which keeps the three units of picolinamidel igand in the coordination sphere of Co, but one of which is now coordinated asamonodentate neutral ligand (rathert han in ab identate monoanionic fashion), with an acetate occupying the vacant site. The relative ease of forming the off-cycle tris-picolinamidec helate Co III complexes of type A,w hich should be less favorable in the case of using the more-hindered 8-quinolinamide substrates, could explain the higher reactivity of the latter substrates over picolinamided erivatives [8] andt he use of high catalyst loadings [8,13] described in previousr eports. Presumably,c omplex C resultsf rom complex A through ligand displacement via complex B.I nterestingly,a Scheme7.Isolationo fap reformedCo-complex and study of its competency.…”

“…Acetate-assisted ortho-CÀHb ond functionalization would lead to the coordinatively unsaturated 16-electron Co III complex D.A lkynyl coordination (E)a nd subsequent 1,2-migratory insertion of the cobalt-carbonb ond across the alkyne would result in the formation of the seven-membered alkenylcobalt intermediate F.S ubsequent reductivee limination step releases the 1,2-DHIQ product, whereas the concomitantly formed Co I species is reoxidized by O 2 to regenerate the Co II and/or Co III species, thus closing the catalytic cycle. The relative ease of forming the off-cycle tris-picolinamidec helate Co III complexes of type A,w hich should be less favorable in the case of using the more-hindered 8-quinolinamide substrates, could explain the higher reactivity of the latter substrates over picolinamided erivatives [8] andt he use of high catalyst loadings [8,13] described in previousr eports. Interestingly,t he excess of acetate ions seems to counteractt he formation of trispicolinamidec helate Co III complexes of type A by promoting ligand displacement to form complexeso ft ype C.…”

Cobalt‐Catalyzed Annulation Reactions via C−H Bond Activation

“…Very recently, Cui used picolinamide 133 as a directing group in Co‐catalyzed C−H bond activation reactions with alkynes to afford isoquinolines 134 under O 2 as a sole oxidant (Scheme ) . This protocol works well with functionalized benzylamines, and high regioselective products were obtained with unsymmetrical and internal alkynes.…”