The synthesis of symmetrical (2-indolyl)ethynes and reduced congeners via palladium-catalyzed couplings of 2-bromoindole precursors

Starting from a series of 2-bromo-1-methylindole precursors (1b-e) activated in the 3-position with aldehyde, ester, or amide functionality, two approaches have been developed toward the synthesis of 2,2′-bis(indolyl)ethynes and reduced congeners via palladium(0)- or palladium(II)-catalyzed couplings. The first approach utilized Sonogashira coupling of (trimethylsilyl)acetylene to introduce the two-carbon linker followed by desilylation and further coupling with starting 2-bromoindole. A second shorter and more efficient route engaged the starting 2-bromoindole in a double Stille coupling with bis(tributylstannyl) acetylene or (E)-1,2-bis(tributylstannyl)ethylene to provide desired homodimers in one step. Subsequent transformations of dimeric intermediates led to target acids 7a-c and derived amides 8a-c and 9. When tested against a panel of tyrosine kinases, each target compound was found to be inactive.