Decarboxylative Addition of Propiolic Acids with Indoles to Synthesize Bis(indolyl)methane Derivatives with a Pd(II)/LA Catalyst

Exploring new protocols for efficient organic synthesis is crucial for pharmaceutical developments. The present work introduces a Pd(II)/LA-catalyzed (LA: Lewis acid) decarboxylative addition reaction for the synthesis of bis(indolyl)-methane derivatives. The presence of Lewis acid such as Sc(OTf)(3) triggered Pd(II)-catalyzed decarboxylative addition of propiolic acids with indoles to offer the bis(indolyl)methane derivatives in moderate to good yields, whereas neither Pd(II) nor Lewis acid alone was active for this synthesis. The catalytic efficiency of Pd(OAc)(2) was highly dependent on the Lewis acidity of the added Lewis acid, that is, a stronger Lewis acid provided a higher yield of the bis(indolyl)methane derivatives. Meanwhile, this Pd(II)/LA-catalyzed decarboxylative addition reaction showed good tolerance toward versatile electron-rich or -deficient substituents on the indole skeleton and on the benzyl ring of propiolic acids. The studies on the in situ H-1 NMR kinetics of this Pd(II)/Sc(III) catalysis disclosed the formation of a transient vinyl-Pd(II)/Sc(III) intermediate generated by the pyrrole addition to the alkynyl-Pd(II)/ Sc(III) species after decarboxylation, which was scarcely observed before.

Automated summary

Effective organic synthesis protocols are crucial for pharmaceutical developments. A Pd(II)/LA-catalyzed decarboxylative addition reaction was introduced for the synthesis of bis(indolyl)-methane derivatives with moderate to good yields. The catalytic efficiency was highly dependent on the Lewis acidity, showing good tolerance towards different substituents on the indole skeleton and benzyl ring of propiolic acids.