Synthesis of CF 3 -Indene-1-ol Fused Pyridones Possessing Potent Anticancer Activities through C-H Activation-Initiated Cascade Annulation Under Redox-Neutral Conditions

Abstract

Presented herein is a novel synthesis of CF3-indene-1-ol fused pyridones through the cascade reaction of N-methoxy acrylamides with CF3-ynones. The formation of product involves an initial vinyl C-H activation of acrylamide, followed by alkynyl insertion and reductive elimination to furnish a substituted pyridone as a key intermediate. Under the reaction conditions, it undergoes an intramolecular aldol type reaction to give CF3-indene-1-ol fused pyridone. Interestingly, this transformation proceeds through concurrent construction of both pyridone and CF3-indene-1-ol skeletons via C-H/N-O bond cleavage along with sequential C-C/C-N/C-C bond formation and functional group introduction. In general, this novel synthetic protocol features redox-neutral reaction conditions, free of external oxidant, good compatibility with labile functional groups, excellent step-/atom-economy, ready scalability and diverse structural elaboration. Moreover, most of the products possess anticancer activities comparable with those of the positive control 5-FU.It is well known that indene, pyridine and their derivatives are valuable structural motifs prevalent in pharmaceuticals and organic functional molecules. 1,2 Consequently, many compounds consisting Figure 1. Some Important Indenopyridi(o)ne Derivatives