Synthesis of biologically active heterocyclic compounds via transition metal-catalyzed carbon-heteroatom bond formation

Abstract

Part 1. Synthesis of Heterocyclic-Fused Benzopyrans via the Pd(II)-Catalyzed C-H Alkenylation/C-O Cyclization of Flavones and Coumarins An efficient and practical method for effecting a tandem C-H alkenylation/C-O cyclization has been achieved via the C-H functionalization of flavone derivatives. The synthetic utility of the one-pot sequence was demonstrated by obtaining convenient access to coumarin-annelated benzopyrans. The reaction scope for the transformation was found to be fairly broad, affording good yields of a wide range of flavone- or coumarin-fused benzopyran motifs, which are privileged structures in many biologically active compounds.

Part 2. Rh(III)-catalyzed 7-Azaindole Synthesis via C-H Activation/Annulative Coupling of Aminopyridines with Alkynes An efficient Rh(III)-catalyzed 7-azaindole synthesis was developed via C-H activation/annulative coupling of aminopyridines with alkynes. The reaction was highly regioselective and tolerated various functional groups, permitting the construction of various 7-azaindoles.

Part 3. Stereoselective Construction of Oxaspirocycles via Chiral Bidentate Directing Group-Mediated C($sp^3$)-O Bond Formation Systematic investigation of chiral bidentate auxiliaries has resulted in the discovery of a chiral 2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine-derived directing group that enables the formation of a stereoselective palladium(II)-catalyzed intramolecular C($sp^3$)-O bond. This new chiral directing group exhibited high reactivity in the activation of methylene C($sp^3$)-H bonds with excellent levels of asymmetric induction (diastereomeric ratio of up to 39:1), which allowed the construction of a wide range of oxaspirocycles. Mechanistic investigations were also conducted to elucidate the reaction mechanism and understand the origin of the diastereoselectivity. DFT-calculations suggest that only modest levels of diastereoselectivity is accomplished at the rate-determining C-H metalation-deprotonation step and the d.r. is further enriched at the reductive elimination step.