Isoquinolone Synthesis Lab Report

Guimond and Fagnou et al disclosed an intermolecular and mechanistically distinct approach for the synthesis of the isoquinolone motif 1.46 via Rh(III)-catalyzed annulation of benzhydroxamic acids 1.45 with alkynes (Scheme 1.13).20 This reaction proceeds in the absence of any external oxidant and N-O bond in the hydroxamic acid is utilized for the C-N bond formation. In the case of meta-substituted benzhydroxamic acids, annulation occur regioselectively at the less hindered side. Both symmetrical and unsymmetrical alkynes successfully coupled with benzhydroxamic acids.

The synthesis of isoquinolones from benzamides and alkynes in the presence of rhodium complex was reported by Rovis et al (Scheme 1.14) also.21 In this reaction, Cu(OAc)2.H2O

Pioneering work by Ackermann et al disclosed that less expensive ruthenium complex also can catalyze the isoquinolone synthesis from benzamides with alkynes.24 The reaction of N-substituted benzamides with internal alkynes in the presence of [RuCl2(p-cymene)]2 with Cu(OAc)2.H2O as an oxidant afforded isoquinolones with good substrate scope (Scheme 1.17). The reaction works well with both symmetrical and unsymmetrical alkynes, and in case of unsymmetrical alkynes highly regioselectivity was achieved. Following this report, the same group discovered a green protocol for the synthesis of isoquinolones from N-methoxybenzamides in water (Scheme 1.18).25 In this reaction, carboxylate salts are used as additives along with the ruthenium complex. The green protocol was viable with free hydroxamic acids also. Li et al also reported the synthesis of isoquinolone motif using N-methoxybenzamides 1.60 under mild reaction conditions in the presence of ruthenium catalyst without using any external oxidant.26 Here C-H bond functionalization occurs at room

Some bidentate directing groups also used for these heterocyclic syntheses. Chatani et al discovered a nickel catalyzed synthesis of isoquinolones from aromatic amides containing 2-pyridylmethylamine moiety 1.72 by oxidative cycloaddition with alkynes (Scheme 1.23).32 The reaction proceeds via coordination of amide 1.72 to the nicker center in a N,N-fashion and forms a cyclometallated complex. Insertion of alkyne into this ortho-metalated complex, followed by reductive elimination afforded the