Pd-Catalyzed Enantioselective Tandem C–C Bond Activation/Cacchi Reaction between Cyclobutanones and o-Ethynylanilines

Abstract

A palladium-catalyzed asymmetric tandem C–C bond activation/Cacchi reaction between cyclobutanones and o-ethynylanilines was reported. The transient chiral σ-alkylpalladium species generated via enantioselective C­(sp3)–C­(sp2) bond activation of cyclobutanones promotes cyclization of o-ethynylanilines, leading to one-carbon-tethered chiral indanone-substituted indoles. Two C–C bonds and one C–N bond are created with concomitant formation of an all-carbon quaternary stereocenter. Furthermore, a chiral C2-aryl axis can be created in 2,3-disubstituted indole moiety, leading to indanone-substituted indoles with both central and axial stereogenic elements.

Sequential Pd0‐ and PdII‐Catalyzed Cyclizations: Enantioselective Heck and Nucleopalladation Reactions

“…We speculated that this strategy could be applied toward a much broader set of nucleophiles and aryl halides to fully realize the potential of cooperative domino‐Heck/nucleopalladation cascades. Furthermore, the construction of enantioenriched bis‐heterocyclic frameworks could be enabled using an asymmetric carbopalladation which has not been realized in tandem with nucleopalladation [18] …”

“… [26] An alkene‐tethered urea reacted under similar conditions to furnish product 5 in 62 % yield and 92 % ee , however poor dr was observed. We envisioned that a halogenated indole could be a suitable precursor for an intramolecular C(sp 2 )‐H arylation reaction [18] . The resulting class of indole‐fused polycyclic scaffolds [27] is commonly observed in natural products [17a] .…”

“…Furthermore, the construction of enantioenriched bis-heterocyclic frameworks could be enabled using an asymmetric carbopalladation which has not been realized in tandem with nucleopalladation. [18] We utilized the commonly employed dihydrobenzofuran precursor 1 a, and indole precursor 2 a as a starting point. Our initial success was realized under conditions based on Zhangs report of enantioselective carboiodination.…”

Nickel‐Catalyzed Ring Expansion of Cyclobutanones towards Indanones

“…Indanone, a unique structure in medicinal chemistry and organic synthesis, exists extensively in a variety of synthetic precursors [17–20] and pharmacologically active substances, [21–24] showing principal biological activities in anti‐ Alzheimer ’s disease, anti‐cancer and anti‐virus [25] . Ring opening/cross‐coupling sequence of halogen‐tethered aryl cyclobutanones has shown its efficacy in recent years for the construction of functionalized indanones [26–31] . Xu and coworkers [32] investigated the classical Pd/Cu co‐catalyzed C−C σ‐bond activation/ Sonogashira ‐type cross‐coupling reaction of o ‐iodoarylcyclobutanones with terminal alkynes, leading to 3‐alkynyl indanones as the final products ( Scheme 1 ,A ).…”

“…Alkyl bromides were also successfully involved as electrophilic coupling partners under nickel catalyst as presented by Wang and coworkers ( Scheme 1 ,C ) [34] . Involvement of a second coupling moiety enables the product diversity, and also facilitates the regeneration of the catalytic species through reductive elimination steps [28,32–34] . Based on our interests in nickel catalysts [35,36] and selective C−C bond activation of small rings [37–39] including cyclobutanone derivatives, [40,41] we postulate that addition of proper additives such as boron agents and H 2 O might enable single‐component reaction of halogen‐tethered cyclobutanones using low‐cost nickel catalysts, providing an alternative strategy for the preparation of 3‐methyl indanones.…”