Palladium‐Catalyzed Regiodivergent Synthesis of 1,3‐Dienyl and Allyl Esters from Propargyl Esters

Abstract

Catalyst-controlled regiodivergent catalysis is a vital chemical tool that allows efficient access to large collections of structurally diverse molecules from a common precursor but remains a challenge. We report a catalyst-controlled, tunable, and predictable regiodivergency in transforming the internal aliphatic propargyl esters into diverse libraries of highly substituted 1,3dienyl and allyl products by Pd-catalysis. Depending on the ligand employed, the palladium catalyst can involve two typical approaches: electrophilic palladium catalysis and a sequential oxidative addition-reductive elimination pathway. This regiodivergent protocol endows facile access to four regioisomers with high regio-and stereoselectivity from the common propargyl esters. In terms of synthetic utility, a notable feature of this protocol is amenable to structural diversification of bioactive relevant molecules, enabling rapid assembly of many useful structural analogs of pharmaceutical candidates.

Regiodivergent and Stereoselective Synthesis of Highly Substituted 1,3-Dienes via Arylative Acyloxy Migration of Propargyl Esters

“…As a result of these efforts, readily available propargyl esters have been well-established as an appealing class of synthetic intermediates for accessing functionalized conjugated dienes via transition-metal catalysis. − Notably, electrophilic metals (e.g., Au, Pd, or Ru) catalyzing the rearrangement of propargyl esters through two classic 1,2 vs. 1,3-acyloxy migration routes constitute a powerful and useful tool for this event. − However, this strategy is strictly limited to furnishing mono-, di-, or trisubstituted conjugated dienes with key protonation as the terminal step (Figure c, type I). To date, the rearrangement of propargyl esters involving C–C bond formation as carbofunctionalization of the propargyl moiety with an external carbon-based reagent in delivering highly substituted 1,3-dienes is still undiscovered (Figure c, type II).…”

“…Additionally, attempts to develop a regiodivergent approach that allows the synthesis of structurally diverse conjugated dienes from the same propargyl esters remain scarce and represent a formidable challenge . Recently, we have reported a palladium-catalyzed regiodivergent synthesis of trisubstituted 1,3-dienes from internal propargyl esters . To the best of our knowledge, the stereoselective construction of tetra- or more highly substituted 1,3-dienes by this method remains a formidable challenge, and additionally, no regiodivergent example has been reported yet.…”

“…To the best of our knowledge, the stereoselective construction of tetra- or more highly substituted 1,3-dienes by this method remains a formidable challenge, and additionally, no regiodivergent example has been reported yet. As a continuation of our interest in this area, we questioned whether we could create a general method to produce challenging but synthetically useful 1,2,3,4-tetrasubstituted conjugated dienes by incorporating a carbon subunit into the diene core. If accomplished, this chemistry not only offers a new tactic for highly functionalized 1,3-diene synthesis but also broadens the existing migration types of propargyl esters.…”