Synthesis of 3-substituted benzo[g]isoquinoline-5,10-diones: a convenient one-pot Sonogashira coupling/iminoannulation procedure

A series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines were prepared by coupling of terminal alkynes with the tert-butylimine of 3-bromo-1,4-dimethoxy-2-naphthaldehyde in the presence of a Pd-catalyst and subsequent Cu-catalyzed cyclization of the intermediate 3-alkynyl-2-naphthylcarbaldehyde. A CAN-mediated oxidative demethylation yielded the corresponding 2-azaanthraquinones in excellent yields. Since this methodology proved to be limited to alkynes bearing aromatic groups, an alternative and more general Pd-catalyzed coupling procedure was developed, starting from 3-bromo-1,4-dimethoxy-2-naphthaldehyde. For more acidic terminal alkynes, like phenylacetylene, a combination of Pd(OAc)2/P(t-Bu)3/CuI (2/6/1) with potassium carbonate in DMF gave a complete conversion within 24 h. For less acidic acetylenes, 2 equiv of alkyne and caesium carbonate as a base were required in order to obtain complete conversion of the starting material within 24 h. These altered Sonogashira conditions also allowed the isolation of a benzo[f]indenone as an interesting side product in case Bu4NCl was added to the reaction mixture. The 3-alkynyl-1,4-dimethoxy-2-naphthaldehyde acquired after completion of the Pd-catalyzed coupling could be cyclized by adding a solution of ethanolic ammonia and an extra equivalent of potassium carbonate to the reaction mixture. As such, this consecutive one-pot coupling/iminoannulation procedure was a convenient alternative to the Larock isoquinoline procedure, enabling the isolation of a series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines.